Longitudinal and regional association between dietary factors and prevalence of Crohn's disease in Japan.

Although a Western diet has been identified as a risk factor for Crohn's disease (CD), there is still controversy surrounding the specific foods that may contribute to the development of the disease. In this study, we examined the association between food intake and the prevalence of CD in Japan, as Japanese patients with CD are known to have limited genetic involvement. We identified changes in food intake associated with an increase in the number of patients with CD by analyzing the per capita consumption of food types from 1981 to 2014. Additionally, we examined the association between CD prevalence and food intake in each prefecture. Finally, the relationship between food intake and estimated age at CD onset was also investigated. Between 1981 and 2014, we observed Increased consumption of meat, eggs, milk and dairy products, oil, and potatoes and decreased consumption of grains, beans, vegetables, fruit, fish, sugar, and seaweed. The annual incidence of CD increased by 1388% over the same period. We found that meat consumption was significantly associated with CD prevalence (ß = 0.503, p = 0.0003), while a significant negative correlation was observed between CD prevalence and fruit and vegetable consumption (fruit, ß = 0.464, p = 0.0012; vegetables, ß = 0.404, p = 0.0023). Furthermore, we estimated that the peak consumption of more meat and less fruit and vegetables and the peak age of CD onset occurred within the age range of 20-24 years. Our study identified a clear correlation between the consumption of meat, fruits, and vegetables and the prevalence of CD in Japan. Additionally, we found an association between meat, fruit, and vegetable consumption and the age at CD onset.

Immunomodulators after the discontinuation of anti-tumor necrosis factor-alpha antibody treatment and relapse in ulcerative colitis: A multicenter cohort study.

BACKGROUND AND AIM: Strategies to reduce relapse using immunomodulators (IMs) after discontinuing anti-tumor necrosis factor-alpha (TNF-α) antibody treatment are controversial in patients with ulcerative colitis (UC). In this study, we assessed the association between IMs after discontinuing anti-TNF-α antibody treatment and relapse in patients with UC. METHODS: This retrospective, multicenter cohort study included 257 patients with UC in clinical remission. These patients discontinued anti-TNF-α antibody treatment between June 2010 and March 2019 and were followed up until March 2020. We evaluated the differences in relapse rates between patients with IMs (IM group) and those without IMs (non-IM group) after discontinuing the treatment. Relapse was defined as further undergoing an induction treatment or colectomy. Cox proportional hazards models adjusted for confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for relapse. Exploratory analyses were performed to identify other factors that could predict relapse. RESULTS: During the median follow-up period of 22 months (interquartile range: 10-41), 114 relapses occurred: 42/100 (42.0%) in the IM group and 72/157 (45.9%) in the non-IM group. In the multivariable analysis, IMs were not associated with relapse (HR, 0.95 [95% CI, 0.64-1.41]). In the exploratory analyses, discontinuation due to side effects (HR, 1.83 [95% CI, 1.18-2.82]) and younger age (HR, 0.99 [95% CI, 0.98-1.00]) predicted relapse. CONCLUSION: Immunomodulators were not associated with relapse after discontinuing anti-TNF-α antibody treatment in patients with UC. Careful patient follow-up is needed when discontinuing due to side effects or when the patient is of a younger age at the time of discontinuation.

Severe Disease Activity May Predispose Patients to Post-colectomy Duodenitis Associated with Ulcerative Colitis.

Objective Diffuse mucosal inflammation in the duodenum, distinct from peptic ulcer disease, has been repeatedly reported in patients with ulcerative colitis (UC). The pathogenesis of this complication remains uncertain; however, colectomy for medically refractory UC appears to trigger duodenitis. Cases in which colectomy was performed for UC were analyzed to characterize UC-related duodenitis after colectomy. Methods A retrospective case-control study of UC-related duodenitis that developed after colectomy in medically refractory UC between January 2011 and June 2020 was conducted. UC-related duodenitis was diagnosed based on typical clinical, endoscopic, and histological findings, and no duodenitis was endoscopically defined by the normal duodenal mucosa. Clinical and laboratory data, disease severity, and medications used were collected and compared between the UC-related and non-duodenitis cases. Results Ten UC-related duodenitis and 35 non-duodenitis cases were identified among 45 patients with UC who underwent esophagogastroduodenoscopy after colectomy. Disease severity, defined by the C-reactive protein level and partial Mayo score prior to colectomy, was significantly higher in duodenitis patients than in non-duodenitis patients. In comparison to non-duodenitis patients, duodenitis patients more frequently received rescue therapies with calcineurin inhibitors or anti-TNF-α agents at the time of colectomy (100% vs. 65.7%). Conclusion Patients with UC with higher disease activity, especially those who require rescue therapies with calcineurin inhibitors and anti-TNF-α agents, may be prone to developing UC-related duodenitis after colectomy.

Tyrosine kinase alterations in colorectal cancer with emphasis on the distinct clinicopathological characteristics.

AIMS: Tyrosine kinase (TK) alterations, such as anaplastic lymphoma kinase (ALK) fusion, neurotrophic tyrosine receptor kinase (NTRK) fusion, c-ros oncogene 1 (ROS1) fusion and mesenchymal-epithelial transition factor (MET) exon 14 skipping, have been reported in colorectal cancers (CRC). We have previously reported CRCs with NTRK fusion among our cohort. However, their clinicopathological features have not been fully elucidated. METHODS AND RESULTS: Tissue microarray (TMA)-based immunohistochemistry (IHC) was performed on 951 CRC lesions from 944 patients. IHC was evaluated as positive or negative for ALK and ROS1 and 0 to 3+ for c-MET. For ALK and ROS1 IHC-positive cases, RNA-based imbalanced gene expression assays, Archer FusionPlex assays and reverse transcription-polymerase chain reaction (RT-PCR) followed by Sanger sequencing were performed. For c-MET IHC 3+ cases, RT-PCR followed by Sanger sequencing were performed. ALK IHC was positive in three cases (0.2%) and all showed imbalanced ALK gene expression. The following ALK fusions were confirmed: EML4 (exon 21)::ALK (exon 20), EML4 (exon 6)::ALK (exon 19) and HMBOX1 (exon 6)::ALK (exon 20). Two showed microsatellite instability-high/mismatch repair (MMR)-deficient, and all were located in the right colon. ROS1 IHC was positive in one case; however, imbalanced expression and ROS1 fusion was negative. Forty-two cases (4.4%) showed c-MET IHC3+. MET exon 14 skipping was confirmed in nine cases. All cases were microsatellite stable/MMR-proficient, and eight were located in the left colon and rectum. CONCLUSIONS: CRCs with these TK alterations had distinct clinicopathological features. Together with our previous study, 15 cases (1.6%) harboured targetable TK alterations (three NTRK fusion, three ALK fusion, nine MET exon 14 skipping).

Gastric Juvenile Polyposis with Intramucosal Cancer Diagnosed by Magnifying Endoscopy with Narrow-band Imaging.

Although gastric juvenile polyposis (GJP) often coexists with gastric cancer, a preoperative accurate diagnosis is still difficult to obtain. A 70-year-old woman was referred for epigastralgia and anemia. Esophagogastroduodenoscopy with a conventional endoscope showed numerous gastric polyps with no cancerous findings. Magnifying endoscopy with narrow-band imaging (M-NBI) showed cancerous findings, and a target biopsy revealed adenocarcinoma. Histopathological findings after endoscopic resection confirmed a diagnosis of juvenile polyposis with intramucosal adenocarcinoma. Genetic analyses revealed a germline pathogenic variant of SMAD4. A target biopsy using M-NBI and endoscopic resection proved useful for confirming the preoperative diagnosis of coexisting cancerous lesions in GJP.

Enterocolic Lymphocytic Phlebitis Treated Preoperatively with Biologics and Immunosuppressive Agents.

Enterocolic lymphocytic phlebitis is phlebitis of unknown etiology in which lymphocytes affect veins without arteries and shows evidence of systemic vasculitis in the intestinal wall and mesentery, mainly in the small intestine and colon. Although patients present with a variety of gastrointestinal symptoms and findings like those of inflammatory bowel disease or ischemic bowel disease, there are no specific findings for enterocolic lymphocytic phlebitis. As a result, a diagnosis tends to be made after surgery. There are few case reports of enterocolic lymphocytic phlebitis, and the impact of chronic courses and immunosuppressive drugs on enterocolic lymphocytic phlebitis is not well known. A 47-year-old man was treated with infliximab and steroids for unexplained ulceration and narrowing of the ileocecal area, which was suspected to be inflammatory bowel disease with atypical findings. Lymphocytic phlebitis was noted in the surgical specimen, and enterocolic lymphocytic phlebitis was diagnosed. No recurrence of enterocolic lymphocytic phlebitis was observed postoperatively. This disease should also be considered among patients with inflammatory bowel disease-like lesions that do not respond to infliximab or steroids.

Safety Prediction of Infants Born to Mothers with Crohn's Disease Treated with Biological Agents in the Late Gestation Period.

OBJECTIVES: Knowledge gaps exist in the use of biologics for pregnant patients with Crohn's disease (CD), especially the usage of ustekinumab (UST) and infliximab (IFX) infusion during the late gestation period. In this case series, we investigated perinatal and neonatal outcomes and pharmacokinetics of these biologics in pregnant CD patients. METHODS: Pregnant CD patients under treatment with IFX or UST during January 2017 to December 2019 were monitored. Growth and development of their babies were followed up to six months. Drug concentrations were measured in maternal peripheral and cord blood at delivery and infants' blood at six months of age. RESULTS: Four cases were kept IFX treatment until late gestation (median last dose: 31.2 weeks). One case received UST until 23 weeks of gestation. All cases were in clinical remission but moderately undernourished. Babies were delivered by cesarean section at full term without any complications or congenital abnormalities. No growth or developmental defects and no susceptibility to infections were observed by six months. However, two babies whose mothers received IFX after 30 weeks of gestation were detected IFX in their blood at six months of age (0.94 and 0.24 pg/ml). Concentrations of UST in maternal and cord blood were 267.7 and 756.5 ng/ml, respectively. UST was not detected in the infant at six months of age. CONCLUSIONS: Administration of UST or IFX to pregnant patients with CD is safe, particularly IFX to be given in the late gestation period. Understanding of the pharmacokinetics of biologics in maternal-infant interactions may improve the management of pregnant CD patients.

Epithelioid Cell Granulomas in Crohn's Disease Are Differentially Associated With Blood Vessels and Lymphatic Vessels: A Sequential Double Immunostaining Study.

Crohn's disease (CD) is a gastrointestinal disorder of unknown etiology. CD-specific longitudinal ulcers show an association between disease pathogenesis and vasculature dysfunction. Granulomatous lymphangitis may also contribute to CD pathogenesis; meanwhile, vasculitis is the primary CD lesion. We investigated the association between granulomas and lymphatic and blood vessels to assess the role of vasculature in CD pathogenesis. Two small and large intestine specimens were obtained from four CD patients. From each specimen, 160 sequential sections were obtained and double immunohistochemical stained to label lymphatic and blood vessels in association with granulomas. We found that 289 of 342 granulomas (85%) were associated with a lymphatic vessel and 313 of 364 granulomas (86%) were associated with a blood vessel. Although intrablood vessel granulomas were not detected, intralymphatic vessel granulomas were. In the internal region of the granuloma, we found more blood vessels than lymphatic vessels. Hence, these results cumulatively demonstrate that CD epithelioid cell granulomas are differentially associated with lymphatic and blood vessels, suggesting both as essential for the formation and maintenance of these granulomas. Moreover, both lymphatic and blood vessels may participate in granulomatous inflammation in the primary CD lesions; however, additional studies with larger numbers of participants are required to validate our findings.

A case of refractory chronic pouchitis successfully treated with tofacitinib.

We describe a case of refractory pouchitis successfully treated with tofacitinib. The patient was a 20-year-old woman diagnosed with ulcerative colitis at the age of 14 years. She underwent surgery at the age of 18 years for chronic active inflammation, despite an optimal medication regimen. Ten months after surgery, she was diagnosed with pouchitis. She did not respond to conventional conservative treatment; thus, the case was considered as that of refractory chronic pouchitis. Anti-tumor necrosis factor-α (TNF-α) therapy was administered, which led to some improvement; however, pouchitis recurred. Systemic steroid and vedolizumab were also administered, but the response was unsatisfactory. Therefore, surgery was considered; however, the patient refused to undergo surgery. As identical therapies are recommended for ulcerative colitis and pouchitis, they are considered to have a common etiology. Therefore, we considered tofacitinib therapy in this case. After obtaining the patient's informed consent, tofacitinib treatment was initiated. The therapy led to improvement in her symptoms as well as in the appearance of the pouch when observed on endoscopy, and surgery was avoided. Thus, tofacitinib may be considered a therapy option for refractory chronic pouchitis.

[Three cases of severe and fulminating ulcerative colitis with megacolon treated with continuous intravenous infusion of cyclosporine].

Dilatation of the colon in severe and fulminating ulcerative colitis is a sign of toxic megacolon and emergency surgery is usually the favored treatment option. Here we describe our experience with three cases of ulcerative colitis with megacolon in which surgery was avoided by treating the patients with a continuous intravenous infusion of cyclosporine, with full cooperation of the surgeons. We recommend that continuous intravenous infusion of cyclosporine be considered as an effective option for the conservative management of severe, fulminating ulcerative colitis with megacolon.