M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is ...initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor-associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.
Endoscopic resection is effective in treating nonampullary duodenal adenomas but has a high incidence of complications. Cold polypectomy, including cold forceps polypectomy (CFP) and cold snare ...polypectomy (CSP), is safe and effective in treating colorectal polyps. However, its utility in sporadic nonampullary duodenal adenomas has not been investigated. The purpose of this prospective study was to examine the safety and efficacy of cold polypectomy for sporadic nonampullary duodenal adenomas.
Between March 2015 and June 2016, patients who were endoscopically diagnosed with sporadic nonampullary duodenal adenomas up to 6 mm underwent cold polypectomy. Patients with pathologically confirmed adenomas underwent endoscopic biopsy 3 months after resection. The main outcomes of interest were incomplete resection and complications.
Overall, 39 lesions in 30 patients were removed via cold polypectomy (CFP, 9 lesions in 8 patients; CSP, 30 lesions in 22 patients). Seven of 9 (77.8 %) and 29 of 30 (96.7 %) lesions were removed en bloc via CFP and CSP, respectively. Pathologically, 34 of the 39 lesions (87.2 %) were confirmed as adenomas, and their mean size was 3.9 ± 1.2 mm (range 2 - 6 mm). Of the 34 adenomas, 20 (58.8 %) were R0 resection lesions, of which 3 of 9 (33.3 %) and 17 of 25 (68.0 %) had undergone CFP and CSP, respectively. No delayed bleeding or intraprocedural/delayed perforation was observed. All 30 patients with the 34 pathologically confirmed adenomas underwent upper gastrointestinal endoscopy 3 months after cold polypectomy, and no morphological or pathological recurrence was identified.
In this small study, cold polypectomy appeared to be safe and effective in treating diminutive and small sporadic nonampullary duodenal adenomas.(Clinical trial registration number: UMIN000016829).
Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The ...mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Aim
Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is ...not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post‐gastric ESD relative to PPI.
Methods
Thirty‐five patients who underwent gastric ESD between April and November 2015 were treated with vonoprazan 20 mg/day for 4 weeks and subsequently underwent endoscopy for evaluation of ulcer size (V group). Ulcer contraction rate was determined by the following formula: (ESD specimen size – ulcer size at 4 weeks after ESD)/(ESD specimen size) × 100%. We compared the results with those of a historical control group treated with esomeprazole 20 mg/day for 4 weeks after gastric ESD and subsequently measured their ulcer size (33 patients, E group) by propensity score‐matching methods.
Results
Sixty‐two subjects were enrolled after propensity score‐matching. Ulcer contraction rate at 4 weeks after ESD in the V group was significantly higher than that of the E group (97.7 ± 3.2% vs 94.5 ± 6.7%, respectively, P = 0.025). Number of subjects with a scar‐stage ulcer (100% contraction rate) tended to be higher in the V group relative to the E group (32% 10 of 31 vs 13% 4 of 31, respectively, P = 0.070, McNemar's chi‐squared test).
Conclusion
Vonoprazan has a faster post‐gastric ESD artificial ulcer contraction rate than esomeprazole. Vonoprazan may supersede PPI in treating post‐ESD artificial ulcers of the stomach.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
In Western countries, most patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). The number of patients with UC in East Asia has increased markedly over the past ...two decades. However, current clinical features of PSC and of PSC associated with UC (PSC-UC) have not yet been clarified in East Asia, particularly in Japan. We aimed to reveal the clinical courses and associations with UC in Japanese patients with PSC from the mutual viewpoint of PSC and UC.
We retrospectively retrieved medical records of patients with PSC (69) and UC (1242) who were diagnosed at Chiba University Hospital between June 1991 and August 2017.
In the present cohort, 37 patients had PSC-UC; the cumulative risks of PSC in patients with UC and of UC in patients with PSC were 3.0% and 53.6%, respectively. We confirmed similar distinctive results by a Japanese nationwide survey, noting that younger patients with PSC had a notably high possibility of association with UC. From the viewpoint of the UC cohort, the occurrence of right-sided disease was significantly higher in patients with PSC-UC than in those with UC (16.2% vs. 4.2%, P = 0.003). Pancolitis was more commonly observed in PSC-UC, and proctits/left-sided colitis was less commonly found in patients with UC. The number of patients with young-onset PSC-UC may be increasing similar to an increase in patients with UC in Japan.
In our cohort, the comorbidity rate of PSC-UC was higher than that obtained in previous reports. The incidence of PSC-UC and UC may increase in the future in East Asia, particularly in Japan.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To gain a better understanding of the effects of biologics, we evaluated clinical outcomes in patients with moderate to severe exacerbations of ulcerative colitis (UC). This retrospective, ...multicenter study retrieved the entire clinical courses of UC patients who began treatments between 2004 and 2018. All exacerbations and clinical parameters, including treatment details for exacerbations and both remission and re-exacerbation dates, were identified during the observation period. Two different endpoints, the cumulative incidence rates of surgical resection and re-exacerbation, were evaluated separately in moderate to severe exacerbation events. Among 1401 patients, 1626 exacerbation events were determined according to a partial Mayo score (remission: < 2, mild: 2-4, moderate: 5-7, and severe: > 7). During the observation period, as administration rates of biologics increased, both surgical resection and hospitalization rates decreased, for 959 moderate to severe exacerbation events. We confirmed that biologics significantly reduced the cumulative re-exacerbation rate in moderate to severe exacerbation events during the study period compared with suboptimal therapies (a 0.507-fold decreased risk according to COX regression analysis, P < 0.001). However, they had not enough impact in reducing the cumulative incidence rate of surgical resection in moderate to severe exacerbation events that were corticosteroid-refractory or dependent (a 0.878-fold decreased risk according to COX regression analysis, P = 0.606). Biologics may improve remission duration, but these agents had no significant impact in reducing the risk of surgical resection in moderate to severe active UC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Irsogladine maleate (2,4-diamino-6-2,5-dichlorophenyl-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the ...effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10−/−) mice. Five-week-old IL-10−/− mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10−/− mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-α) (−2.5-fold), IL-1β (−5.4), interferon-gamma (IFN-γ) (−4.5), IL-17 (−113.0), IL-12p35 (−21.0), IL-12p40 (−3.4), and IL-23p19 (−4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10−/− mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells.
Introduction. Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is well accepted. However, its adaptation for elderly patients is unclear. This study aimed to investigate the ...prognosis and long-term outcomes of ESD for EGC in elderly patients aged ≥80 years by comparing their findings to the findings of patients aged <80 years. Materials and Methods. The study included 533 patients (632 lesions). The patients were divided into an elderly group (age, ≥80 years; 108 patients; 128 lesions; mean age, 83.4 ± 2.7 years) and a nonelderly group (age, <80 years; 425 patients; 504 lesions; mean age, 69.6 ± 7.9 years). We compared patient and lesion characteristics, overall survival (OS), and disease-specific survival (DSS) between the 2 groups retrospectively. Multivariate analysis was performed to clarify the risk factors of death after ESD. Results. The rate of curative resection and adverse events was not significantly different between the groups. The mean survival time periods with regard to OS/DSS in the elderly and nonelderly groups were 75.8 ± 5.9 and 122.8 ± 2.6 months (P<0.05)/120.0 ± 3.0 and 136.4 ± 0.6 months (not significant), respectively. In the elderly group, eGFR <30 ml/min/1.73 m2 was an independent risk factor of death (hazard ratio = 5.32; 95% confidence interval = 1.39–20.5; P=0.015). Conclusion. ESD for EGC can be performed safely and can achieve high curability with good prognosis in elderly patients aged ≥80 years. After ESD, close attention should be paid to elderly patients with severe chronic kidney disease.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Aim
Evidence regarding safety and efficacy of heparin‐bridging therapy for colonoscopic polypectomy remains scarce. The aim of the present study was to evaluate the risk of ...post‐polypectomy bleeding (PPB) in patients receiving heparin‐bridging therapy.
Methods
We retrospectively reviewed the database of patients who underwent colonoscopic polypectomy with prophylactic clip closure between January 2007 and December 2014 at our institution. We evaluated patients receiving heparin‐bridging therapy (HB group) compared with those who did not receive antithrombotic therapy (No‐HB group).
Results
A total of 1421 polypectomies were carried out on 773 patients; 45 patients were in the HB group and 728 patients were in the No‐HB group. The incidence of PPB per patient was significantly higher in the HB group (22.2% vs 1.9%, P < 0.0001), and multivariate analysis showed that heparin‐bridging therapy was an independent risk factor for PPB (OR 9.80, 95% CI 4.23–22.3, P < 0.0001). In the HB group, the polyp size was not a risk factor for PPB (OR 0.67, 95% CI 0.19–2.26, P = 0.55); the incidence of PPB in lesions of <10 mm and ≥10 mm in size was 14.6% and 10.2% respectively. In contrast, that was a significant risk factor in the No‐HB group (OR 4.71, 95% CI 1.41–21.3, P = 0.011). Activated partial thromboplastin time and international normalized ratio were in or under the therapeutic range in the HB group when PPB occurred.
Conclusions
Heparin‐bridging therapy is associated with a high risk of PPB regardless of polyp size.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background & Aims Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular ...mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B–mediated protein sorting in the maintenance of gastrointestinal immune homeostasis. Methods The role of AP-1B in intestinal immunity was examined in AP-1B–deficient mice ( Ap1m2−/− ) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B–mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2−/− mice. Results Ap1m2−/− mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A–producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. Conclusions AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B–mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.
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