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Background: Several studies have suggested an association between inflammatory bowel disease (IBD) and the risk of prostate cancer development. However, these findings are inconsistent, and studies based on Asian populations are limited., Objectives: We compared the risk of prostate cancer according to IBD status using the Korean National Health Insurance Service database., Design: A population-based retrospective cohort of age-matched 59,044 non-IBD patients and 14,761 IBD patients between January 2009 and December 2011 was analyzed up to December 2017., Methods: The risk of prostate cancer was compared between patients with IBD and controls using the Cox proportional hazards regression model and Kaplan-Meier survival analysis., Results: During a median follow-up of 6 years, the incidence rate of prostate cancer was 264 per 100,000 person-years in non-IBD patients and 242 per 100,000 person-years in patients with IBD. IBD status was not associated with the risk of prostate cancer compared to non-IBD [adjusted hazard ratio (aHR) 0.93, 95% confidence interval (CI): 0.80-1.08, p  = 0.32). The cumulative incidence of prostate cancer did not differ by IBD status (non-IBD patients versus IBD patients: log-rank p  = 0.27; non-IBD patients versus ulcerative colitis versus Crohn's disease: log-rank p  = 0.42). In multivariate analysis, age was an independent risk factor for the development of prostate cancer (HR 1.03, 95% CI: 1.02-1.03, p  < 0.001)., Conclusion: In our population-based study, IBD status was not associated with the risk of prostate cancer., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Therapeutic drug monitoring (TDM) is effective in optimizing the efficacy of infliximab in patients with inflammatory bowel disease (IBD). An affordable way of monitoring is in high demand. This study evaluated the analytical and clinical performances of the newly available Remsima monitor kits and compared them with the established enzyme-linked immunosorbent assay kits. The trough level of infliximab in patients with IBD treated with an infliximab originator (Remicade) or biosimilar compounds (Remsima and Remaloce) was measured using a Remsima® Monitor Drug Level (Remsima) kit at the Samsung Medical Center, Seoul, Korea. Twenty-six plasma samples were collected immediately before the infusion of infliximab from 18 patients with IBD (Remicade, n = 8; Remsima, n = 6; and Remaloce, n = 4). The intra-assay intraclass correlation coefficient (ICC) of the RIDA and Remsima kits was 0.951 (95% CI = 0.908-0.976) and 0.990 (95% CI = 0.981-0.995). The inter-assay ICC of infliximab trough level between the RIDA and Remsima kits was very high (R = 0.971; 95% CI = 0.935-0.987), and the mean difference between the kits was 1.458 (95% limits of agreement = -3.302 to 6.219). The intra- and inter-assay reliabilities of all types of infliximab did not show significant differences. Qualitative stratification revealed substantial similarities between the kits (weighted kappa = 0.798). This study indicated that the Remsima kit was reproducible and highly correlated with the RIDA kit., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Endoscopic submucosal dissection (ESD) can provide a high en bloc resection rate and has been widely applied as curative treatment for early colorectal cancer (ECC). However, surgical treatment is occasionally required, and reports on the long-term prognosis of ESD are insufficient. This study aimed to investigate the long-term outcomes of ECC removal by ESD, including local recurrence and metastasis., Methods: This multicenter study was conducted retrospectively on 450 consecutive patients with ECC who were treated with ESD between November 2003 and December 2013. Clinical, pathological, and endoscopic data were collected to determine tumor depth, resection margin, lymphovascular invasion, and recurrence., Results: The median follow-up period was 53.8 (12-138 months). The en bloc resection rate was 85.3% (384) and in intramucosal cancer being 84.1% and in superficial submucosal invasion (SM1) cancer being 89.8% (p = 0.158). The curative resection rate was 76.0% (n = 342), and there was no statistical difference between the two groups (77.3% vs. 71.4%, p = 0.231). The overall recurrence free survival rate (RFS) was 98.7% (444/450). In patients with curative resection, there was no statistically significant difference in RFS according to invasion depth (intramucosal: 99.3% vs. SM1: 97.1%, p = 0.248)., Conclusions: Patients with curatively resected ECC treated with ESD showed favorable long-term outcomes. Curatively resected SM1 cancer has a RFS similar to that of intramucosal cancer., (© 2022. The Author(s).)

Background: When endoscopically resected specimens of early colorectal cancer (CRC) show high-risk features, surgery should be performed based on current guidelines because of the high-risk of lymph node metastasis (LNM). The aim of this study was to determine the utility of an artificial intelligence (AI) with deep learning (DL) of hematoxylin and eosin (H&E)-stained endoscopic resection specimens without manual-pixel-level annotation for predicting LNM in T1 CRC. In addition, we assessed AI performance for patients with only submucosal (SM) invasion depth of 1000 to 2000 μm known to be difficult to predict LNM in clinical practice., Methods: H&E-stained whole slide images (WSIs) were scanned for endoscopic resection specimens of 400 patients who underwent endoscopic treatment for newly diagnosed T1 CRC with additional surgery. The area under the curve (AUC) of the receiver operating characteristic curve was used to determine the accuracy of AI for predicting LNM with a fivefold cross-validation in the training set and in a held-out test set., Results: We developed an AI model using a two-step attention-based DL approach without clinical features (AUC, 0.764). Incorporating clinical features into the model did not improve its prediction accuracy for LNM. Our model reduced unnecessary additional surgery by 15.1% more than using the current guidelines (67.4% vs. 82.5%). In patients with SM invasion depth of 1000 to 2000 μm, the AI avoided 16.1% of unnecessary additional surgery than using the JSCCR guidelines., Conclusions: Our study is the first to show that AI trained with DL of H&E-stained WSIs has the potential to predict LNM in T1 CRC using only endoscopically resected specimens with conventional histologic risk factors., (© 2022. Japanese Society of Gastroenterology.)

Background and Aims: Currently there is no Food and Drug Administration-approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut-liver axis in their pathogenesis, we investigated the therapeutic effect of a long-acting dual agonist of glucagon-like peptide (GLP)-1 and GLP-2 receptors in mice with NAFLD/NASH., Approach and Results: C57BL/6J mice were fed a choline-deficient high-fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1-Fc, GLP2-Fc, or GLP1/2-Fc fusion (GLP1/2-Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well-developed NASH phenotypes. GLP1/2-Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2-Fc were found in in vitro cell systems. GLP1/2-Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2-Fc-mediated protection. We confirmed that FMT exerted an additive effect on GLP1-Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis., Conclusions: A long-acting dual agonist of GLP-1 and GLP-2 receptors is a promising therapeutic strategy to treat NAFLD/NASH., (© 2021 American Association for the Study of Liver Diseases.)

A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum β-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1β (IL-1β) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. In ex-vivo experiments with macrophages, both FGF21 and BHB further reduced IL-1β secretion compared to either BHB or FGF21 alone. The inhibitory effect of FGF21 on IL-1β secretion was blunted with bafilomycin treatment, which blocked autophagy flux. In conclusion, isocaloric KD for 3 days is a promising approach to improve metabolic and inflammatory status., Clinical Trial Registration: clinicaltrials.gov (NCT02964572)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Kim, Cho, Lee, Kim, Kim, Choi, Kim, Yu, Lee, Kang, Cha, Lee, Cho, Jeon and Lee.)

Background and Aims: Clinical decision support tools (CDST) were developed to predict drug response to various biological treatments for Crohn's disease (CD). This study investigated whether CDSTs for vedolizumab (V-CDST) and ustekinumab (U-CDST) can be used as prognostic or drug-specific markers to predict response., Methods: A hypothetical scenario involving 872 patients with CD who were exposed to the first biological therapy at Samsung Medical Center between 1995 and 2020 is presented. V-CDST & U-CDST were calculated based on clinical and laboratory data immediately before the first biologic was initiated. The Cumulative Link Mixed Model (CLMM) test, weighted Kappa and plot, and Spearman's correlation was used to determine the degree of agreement and difference between the two tools., Results: 25% of all patients diagnosed with biologically naïve CD were categorized into different probability groups using V-CDST and U-CDST. The difference between the two tools was significantly based on a two-sample paired ordinal test with Cumulative Link Mixed Model (CLMM) ( p -value < .001). Concordance between the two tools with a total of 654 subjects (75% of all patients) showed a similar probability (weighted Kappa: 0.47, 95% CI: 0.41-0.52)., Conclusions: V-CDST and U-CDST are useful in selecting vedolizumab or ustekinumab in 25% of biologically naïve CD patients in our hypothetical scenario.

Background and Aims: Although recent studies have reported that inflammatory bowel disease [IBD] is associated with the development of neurodegenerative diseases via chronic intestinal inflammation and the gut-brain axis, there is insufficient evidence supporting this notion. The aim of this study was to determine the risk of neurodegenerative diseases including Parkinson's disease [PD] and Alzheimer's disease [AD] in patients with IBD., Methods: Using the National Health Insurance Service data for the entire Korean population, we identified patients with IBD and controls from 2009 to 2011 and followed them up until 2017. We selected the controls in a 1:4 ratio based on age and sex for comparison with cases., Results: Of 24 830 IBD patients and 99 320 non-IBD controls, 98 IBD patients and 256 controls developed PD, and 644 IBD patients and 2303 controls developed AD. The overall neurodegenerative disease risk was higher in IBD patients (PD: adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.24-1.97; AD: adjusted HR, 1.14; 95% CI, 1.05-1.25). Younger IBD patients aged 40-65 years had a higher risk of PD compared with controls [adjusted HR, 2.34; 1.63-3.35]. In contrast, patients aged ≥65 years had an increased risk of AD compared with controls [adjusted HR, 1.14; 1.04-1.25]. In a nested case-control study of the IBD cohort, patients aged ≥65 years and the female sex were risk factors for AD, whereas living in an urban area was protective against AD., Conclusions: The risk of neurodegenerative diseases was higher in IBD patients than in the non-IBD population., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Little is known about the ability for epithelial regeneration and wound healing in patients with inflammatory bowel diseases. We evaluated the epithelial proliferation and wound healing ability of patients with Crohn's disease (CD) using patient-derived intestinal organoids. Human intestinal organoids were constructed in a three-dimensional intestinal crypt culture of enteroscopic biopsy samples from controls and CD patients. The organoid-forming efficiency of ileal crypts derived from CD patients was reduced compared with those from control subjects ( p < 0.001). Long-term cultured organoids (≥6 passages) derived from controls and CD patients showed an indistinguishable microscopic appearance and culturing behavior. Under TNFα-enriched conditions (30 ng/mL), the organoid reconstitution rate and cell viability of CD patient-derived organoids were significantly lower than those of the control organoids ( p < 0.05 for each). The number of EdU+ cells was significantly lower in TNFα-treated organoids derived from CD patients than in TNFα-treated control organoids ( p < 0.05). In a wound healing assay, the unhealed area in TNFα-treated CD patient-derived organoids was significantly larger than that of TNFα-treated control organoids ( p < 0.001). The wound healing ability of CD patient-derived organoids is reduced in TNFα-enriched conditions, due to reduced cell proliferation. Epithelial regeneration ability may be impaired in patients with CD.

Background/aims: The treatment goal of ulcerative colitis (UC) has been changed to achieve endoscopic remission (ER). However, there is insufficient clinical evidence to determine whether a step-up treatment should be performed to achieve ER in clinical remission (CR) without ER, and there are inadequate data on the need to consider the distribution and severity of residual inflammation. This retrospective study aimed to evaluate the prognostic significance of the distribution and severity of residual inflammation in UC patients in CR., Methods: A total of 131 UC patients in CR who underwent endoscopic evaluation for more than three times between January 2000 and December 2018 were reviewed. The patients were allocated by the endoscopic healing state and the distribution of inflammation to ER (n=31, 23.7%), residual nonrectal inflammation with patchy distribution (NRI) (n=17, 13.0%) or residual rectal involvement with continuous or patchy distribution (RI) (n=83, 63.3%) groups. We reviewed clinical characteristics, endoscopic findings, and factors associated with poor outcome-free survival (PFS)., Results: In UC patients in CR, PFS was significantly higher in the ER and NRI groups than in the RI group (p=0.003). Patients in the ER and NRI groups had similar PFS (p=0.647). Cox proportional hazard model showed only RI (hazard ratio, 5.76; p=0.027) was associated with a higher risk of poor outcome., Conclusions: We suggest that escalation of treatment modalities may be selectively performed in consideration of the residual mucosal inflammation pattern, even if ER has not been achieved, in UC patients with CR.

Background/aims: Although balloon-assisted enteroscopy (BAE) enables endoscopic visualization of small bowel (SB) involvement in Crohn's disease (CD), there is no data on the changes in outcomes over time. We therefore investigated the changes in BAE use on CD patients over different time periods in terms of its role and clinical outcomes., Methods: We used a multicenter enteroscopy database to identify CD patients with SB involvement who underwent BAE (131 procedures, 116 patients). We compared BAE-related factors and outcomes between the first period (70 procedures, 60 patients) and the second period (61 procedures, 56 patients). The specific cutoff point for dividing the two periods was 2007, when BAE guidelines were introduced., Results: Initial diagnosis of SB involvement in CD was the most common indication for BAE during each period (50.0% vs 31.1%, p=0.034). The largest change was in the number of BAE uses for stricture evaluation and/or treatment, which increased significantly in the latter period (2.9% vs 21.3%, p=0.002). The diagnostic yield in patients with suspected CD was 90.7% in the first period and 95.0% in the second (p=0.695). More endoscopic interventions were performed in the second period than in the first (5.1% vs 17.6%, p=0.041). Enteroscopic success rates were high throughout (100% in the first period vs 80.0% in the second period, p>0.999). In the first and second periods, therapeutic plans were adjusted in 62.7% and 61.4% of patients, respectively., Conclusions: The overall clinical indications, outcomes, and effectiveness of BAE were constant over time in CD patients with SB involvement, with the exception that the frequency of enteroscopic intervention increased remarkably.

Background: SAMP1/YitFcsJ (SAMP1) mice spontaneously develop terminal ileitis resembling human Crohn disease. SAMP1 mice have exhibited alteration of epithelial cell lineage distribution and an overall proliferation of the crypt cell population; however, it has not been evaluated whether epithelial differentiation is impaired because of dysfunction of intestinal stem cells (ISCs) or their niche factors., Methods: Using the intestine of SAMP1 mice aged 10 to 14 weeks, morphometric alterations in the crypt-villus architecture, ISCs, crypt cells, and differentiated cells; organoid formation capacity of intestinal crypts; and niche signaling pathways were analyzed and compared with those of age-matched control AKR/J (AKR) mice., Results: The ileum of SAMP1 mice showed increased depth of intestinal crypts and decreased surface area of the villi compared with those in the ileum of AKR mice. The number of ISCs in the ileal crypts did not differ between SAMP1 and AKR mice; however, the number of Paneth cells decreased and the number of transient amplifying cells increased. The organoid formation rate of the ileal crypts of SAMP1 mice decreased significantly compared with that of AKR mice. The performance of RNA sequencing for intestinal crypts found that the expression of ISC niche factors, such as Wnt3, Dll1, and Dll4, was decreased significantly in the ileal crypts of SAMP1 mice compared with those of AKR mice. Among the ISC niche signals, the Notch signaling-related genes tended to be downregulated. In particular, immunocytochemistry revealed that the expression of Paneth cell-expressing Notch ligand Dll4 was significantly decreased in the intestinal tissue and organoids of SAMP1 mice compared with those of AKR mice., Conclusions: Depletion of niche factors for ISCs contributes to the alteration of epithelial differentiation in SAMP1 mice., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Endoscopic resection is highly effective treatment option for rectal neuroendocrine tumors (NETs) as they usually present as small localized tumors. However, there are no well-established surveillance strategies following endoscopic resection. We established our own protocol for the surveillance of rectal NETs after endoscopic resection since 2013. This study aimed to assess the outcome and to optimize the surveillance strategies after endoscopic resection., Methods: We retrospectively analyzed the data of patients with endoscopically treated rectal NETs between January 2013 and April 2018 at Samsung Medical Center. We analyzed 337 patients with a median follow-up duration of 35.0 months (min-max: 12.0-88.3)., Results: A total of 329 (97.6%) patients had tumors ≤ 1 cm in size, and eight (2.4%) patients had tumors > 1 cm in diameter. Synchronous rectal NETs were diagnosed in nine (2.7%) patients. Thirteen (3.9%) patients were identified as having positive resection margins. Regardless of the salvage treatment, none of these patients developed recurrence. Metachronous rectal NETs were diagnosed in nine (2.7%) patients. Metachronous lesions were associated with the number of synchronous lesions at initial diagnosis (P < 0.001, hazard ratio = 1.75, 95% confidence interval = 1.38-2.23). Extracolonic metastasis was not detected in this study., Conclusion: Although initial screening for detecting metastatic lesions using computed tomography is recommended, repeated imaging for detecting extracolonic recurrence was not necessary for small non-metastatic rectal NETs. However, regular endoscopic follow-up seems reasonable, especially in case of synchronous rectal NETs, for detecting metachronous rectal NETs., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Routine prophylaxis for venous thromboembolism (VTE) in Asian IBD patients has been controversial. We aimed to estimate the risk of VTE of Asian patients at different phases of IBD by incorporating patient-specific risk factors. In this cohort study, we analyzed the National Health Insurance claims data between 2012 and 2016 for the entire Korean population. We calculated incidence rates and hazard ratios for VTE. The overall VTE risk was higher in patients with IBD [adjusted hazard ratio (aHR), 2.06; 95% confidence interval (CI), 1.66-2.55], than in controls. When we compare the risk of VTE by different disease phases, the risk of VTE was the highest during post-operation period after IBD-related bowel surgery (aHR, 39.7; 95% CI 9.87-159.3), followed by during hospitalized periods with flare (aHR, 27.2; 95% CI 14.9-49.65) and during hospitalized periods with non-flare (aHR, 16.23; 95% CI 10.71-24.58). The incidence rate (per 1000 person-years) was 15.26 during hospitalized periods with a flare and 9.83 during hospitalized periods with non-flare. According to age groups, the incidence rate (per 1000 person-years) during hospitalized periods with flare was 14.53 in young patients (20-39 years) and 34.58 in older patients (60-80 years). During hospitalized periods with non-flare, the incidence rate was 3.55 in young patients and 23.61 in older patients. The prophylaxis of VTE for Asian patients with IBD should be recommended in older patients admitted to hospital and be considered in young patients who are hospitalized with a flare.

Background/aims: Although localized lymphoid hyperplasia (LLH) of the rectum is occasionally observed, its clinical implications are unclear. This study aimed to investigate the clinical course and significance of LLH of the rectum., Methods: We identified 65 patients diagnosed with LLH of the rectum using a histopathologic examination and who received follow-up endoscopies between January 2009 and June 2015. Patients with a history of inflammatory bowel disease, lymphoma, familial adenomatous polyposis, or uncontrolled malignancy and patients who underwent scar biopsy after endoscopic resection or surgery were excluded. Endoscopic findings and clinical courses were analyzed., Results: During the median follow-up of 31 months (interquartile range, 19 to 40 months), 81.5% (53/65) of LLHs of the rectum were resolved. Clinically significant diseases, including ulcerative colitis (UC, n=5) and mucosa-associated lymphoid tissue (MALT) lymphoma (n=1), were diagnosed in 9.2% of patients (6/65). The other six patients showed no significant changes in the lesion (n=3) or a waxing and waning appearance (n=3). According to endoscopic findings, all of the 47 polypoid types showed resolution or waxing and waning patterns. Five of the 11 nodular types (45.5%) developed into UC. One of the seven submucosal tumor (SMT)-like types (14.3%) developed into MALT lymphoma., Conclusions: LLH of the rectum with persistent symptoms or the endoscopic appearance of the nodular or SMT-like type may lead to clinically significant disease. Risk stratification according to endoscopic findings and careful surveillance are required for these lesions.

Background: Self-expandable metallic stent (SEMS) is widely used for malignant colorectal obstruction. Recently, SEMS has been used for palliative option for colorectal obstruction caused by extracolonic malignancy (ECM)., Aim: To evaluate the efficacy of SEMS for colorectal obstruction caused by ECM, and to identify the factors associated with stent occlusion., Methods: Seventy-two patients who were treated with uncovered SEMS insertion for malignant colorectal obstructions caused by colorectal metastasis or peritoneal seeding of ECM at Samsung Medical Center between April 2012 to March 2016 were enrolled. We analyzed technical and clinical outcomes of stent insertion, the factors associated with stent occlusion and long term outcomes after stent insertion., Results: Technical success rate was determined as 90.3% with a clinical success rate of 87.7%. Stent occlusion developed in 28.1%, with a median duration of 51 d. Further, 81.3% with stent occlusion could be treated with secondary stent insertion. Clinical failure was observed to be related to the male sex ( P = 0.020) and right colon obstruction ( P = 0.017). Stent length ≤ 10 cm was found to be associated with stent occlusion ( P = 0.003). Median survival time after stent insertion was 4.7 mo and 40.4% were able to receive their oncological treatments after stent insertion without surgery., Conclusion: Uncovered SEMS is effective for the treatment of colorectal obstruction caused by ECM, considering life expectancy of patients with ECM., Competing Interests: Conflict-of-interest statement: The authors declare no potential financial interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: An association between Helicobacter pylori infection and colorectal neoplasia has been reported in cross-sectional studies., Goals: We examined the association between H. pylori infection and the development of advanced colorectal neoplasia (AN) in a screening cohort., Study: We identified 3753 adults, who underwent screening and subsequent surveillance colonoscopies. The primary outcome was the development of metachronous AN, as confirmed by surveillance colonoscopy. H. pylori infection status was assessed by an H. pylori-specific immunoglobulin G antibody test. Sensitivity analysis was also performed by H. pylori infection status on the basis of histology., Results: During a median follow-up of 41 months, the incidence of AN was 3.2% and 1.7% in participants with and without H. pylori infection, respectively. In multivariable analysis adjusted for age, body mass index, smoking status, alcohol intake, family history of colorectal cancer, and baseline adenoma characteristics, the hazard ratio [95% confidence interval (CI)] for metachronous AN was 1.74 (1.11-2.73) in participants with H. pylori seropositivity, compared with those without H. pylori seropositivity. The association was consistent with H. pylori infection status on the basis of histology (adjusted hazard ratio, 3.51; 95% CI, 1.64-7.51). In the subgroup analysis, the positive association was observed in both no-adenoma and adenoma removal subgroups., Conclusions: In a cohort study, H. pylori infection was associated with an increased risk of AN development. This association was consistent in both the serological and histologic assessment of H. pylori infection. Prospective studies are necessary to determine whether H. pylori eradication can reduce the risk of colorectal neoplasia.

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.

With the development of capsule endoscopy (CE) and device-assisted enteroscopy (DAE), the incidence of small-bowel tumors has increased and the characteristics of these tumors have changed. In addition, the diagnostic and therapeutic approaches for small-bowel tumors have diversified. CE is a simple, noninvasive method that aid in the visualization the entire small bowel. CE is considered the initial approach for small-bowel tumors. DAE can be used to perform endoscopic procedures such as bleeding control, polypectomy, stent insertion, and tattooing, as well as for diagnosis through visualization or tissue sampling. Therapeutic intervention with DAE is particularly useful in polyposis syndromes such as familial adenomatous polyposis and Peutz-Jeghers syndrome. This review will discuss the roles of CE and DAE in the diagnosis and treatment of small-bowel tumors.

This study investigated changes in the intestinal microbiota during 8-week infliximab maintenance therapy in inflammatory bowel disease (IBD) patients in clinical remission. Microbial compositional differences were analyzed according to the trough level of infliximab (TLI) and mucosal healing (MH) status. 16S rRNA gene-based microbiome profiling was performed on 10 and 74 fecal samples from 10 healthy volunteers and 40 adult IBD patients, respectively. Fecal sampling occurred at 1-2 weeks (1W) and 7-8 weeks (7W) after infliximab infusion. TLI was measured by ELISA at 8 weeks, immediately before the subsequent infusion; MH was evaluated by endoscopy within 3 months. There were no significant changes in microbial composition, species richness, or diversity indices between 1W and 7W. However, 7W samples from the patients with TLI ≥ 5 μg/mL showed an increased species richness compared with patients with TLI < 5 μg/mL, and patients with MH showed increased diversity compared with non-MH patients. Beta-diversity analysis showed clustering between samples in the MH and non-MH groups. LEfSe analysis identified differential composition of Faecalibacterium prausnitzii group according to TLI and MH. In conclusion, these results suggest the potential of fecal microbiota as a response indicator.

Background and Aim: Appropriate bowel cleansing before colonoscopy is an important factor in increasing the detection rate of lesions. Low-volume polyethylene glycol (PEG) plus ascorbic acid (PEG-Asc) reduces the dosage of bowel preparation agent, but still presents discomfort to patients. The primary aim of the present study was to compare the efficacy of bowel cleansing between 2 L PEG-Asc (control) and 1 L PEG-Asc with bisacodyl suppository (suppository) groups, and the secondary aim was to investigate complications and tolerability between the two groups., Methods: This was a single-center prospective randomized controlled study. We identified 168 patients scheduled for colonoscopy between August 2017 and January 2018 and randomly assigned them to the control or to the suppository groups. Efficacy of bowel cleansing was assessed using the Boston Bowel Preparation Scale (BBPS), and side-effects were surveyed using questionnaires., Results: No significant difference was detected in baseline characteristics including insertion and withdrawal times, and adenoma detection rates between the two groups. Total BBPS score was 7.93 ± 1.06 and 7.74 ± 1.02 in the control and suppository groups, respectively (P = 0.22). Incidence of abdominal pain and nausea was not statistically different, whereas that of sleep disturbance and anal discomfort was higher in the control group. (P = 0.00)., Conclusions: One liter PEG-Asc with bisacodyl suppository resulted in an equivalent bowel-cleansing outcome with reduced patient discomfort compared to 2 L PEG-Asc. Therefore, PEG-Asc with bisacodyl suppository represents a potential alternative and increases patient compliance with bowel preparation., (© 2019 Japan Gastroenterological Endoscopy Society.)

Aims: NOD2 and CD1d play a key role in innate immunity by recognizing conserved molecular patterns of pathogens. While NOD2-/- and CD1d-/- mice display structural and functional alterations in Paneth cells, animal studies have reported no impact of NOD2 or CD1d deficiency on experimental colitis. NOD2 mutations increase the susceptibility to inflammatory bowel diseases and the CD1d bound to α-galactosylceramide [α-GalCer] alleviates intestinal inflammation. We evaluated the effect of CD1d modulation on experimental colitis in NOD2-/- mice., Methods: The effect of CD1d augmentation and depletion in NOD2-/- mice was assessed in a dextran sodium sulphate [DSS]-induced colitis model via administration of α-GalCer and construction of NOD2-/-CD1d-/- mice. The structural and functional changes in Paneth cells were evaluated using transmission electron microscopy and pilocarpine administration. Colitogenic taxa were analysed in the faeces of NOD2-/-CD1d-/- mice using 16S rRNA gene sequencing., Results: In NOD2-/- mice, α-GalCer alleviated and CD1d depletion [NOD2-/-CD1d-/- mice] aggravated colitis activity and histology compared with co-housed littermates NOD2-/-, CD1d-/- and wild-type mice after administration of 3% DSS. In NOD2-/-CD1d-/- mice, the ultrastructure and degranulation ability of secretary granules in Paneth cells were altered and the intestinal microbial composition differed from that of their littermates. Faecal microbiota transplantation [FMT] with NOD2-/-CD1d-/- mice faeces into wild-type mice aggravated DSS-induced colitis, while FMT with wild-type mice faeces into NOD2-/-CD1d-/- mice alleviated DSS-induced colitis. Acetatifactor muris was identified only in NOD2-/-CD1d-/- mice faeces and the oral gavage of A. muris in wild-type mice aggravated DSS-induced colitis., Conclusion: CD1d modulates colonic inflammation in NOD2-/- mice by altering the intestinal microbial composition comprising A. muris., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Acid suppressants such as histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are effective in preventing gastrointestinal (GI) bleeding in nonsteroidal anti-inflammatory drugs (NSAIDs) users. Despite widespread acid suppressant use, there remain concerns about several potential risks of long-term use. Therefore, we investigated whether gastroprotective agents (GPAs) other than acid suppression therapy are effective in preventing NSAID-related GI injury. To this end, we studied 9,133 patients with osteoarthritis or rheumatoid arthritis who used NSAIDs for ≥1 month. A decrease of 2 g/dL or more in the hemoglobin level was considered a GI injury indicator. The GPAs included acid suppressants and other mucoprotective agents. Acid suppressants included PPIs and H2RAs. Other mucoprotective agents included misoprostol, rebamipide, and eupatilin. During a median follow-up period of 27 (range, 4.3-51.3) weeks, occult GI bleeding occurred in 1,191 (13%) patients. A comparison of patients who used GPAs concomitantly with that of nonusers in a multivariable analysis revealed the hazard ratios (HRs; 95% confidence intervals [CIs]) for occult GI bleeding were 0.30 (0.20-0.44), 0.35 (0.29-0.43), 0.47 (0.23-0.95), 0.43 (0.35-0.51), and 0.98 (0.86-1.12) for PPIs, H2RAs, misoprostol, rebamipide, and eupatilin, respectively. Compared to PPI co-treatment, H2RA, misoprostol, rebamipide, and eupatilin co-treatments were associated with occult GI bleeding HRs (95% CIs) of 1.19 (0.79-1.79), 1.58 (0.72-3.46), 1.44 (0.96-2.16), and 3.25 (2.21-4.77), respectively. Our findings suggest that mucoprotective agents, such as rebamipide and misoprostol, as well as acid suppressants, are effective in reducing the risk for GI injury in NSAID users.

Background/aim: The objective of this study is to identify clinical predictors of primary non-response (PNR) and secondary loss of response (LOR), in Crohn's disease (CD) patients treated with anti-tumor necrosis factor α (anti-TNF) agents. Methods: This retrospective, longitudinal, and observational cohort study included 283 patients with CD who received anti-TNF treatments from November 2006 to July 2017 at Samsung Medical Center, Seoul, Korea. Results: A total of 212 patients with CD were eligible and based on clinical responses, divided into three groups: PNR, LOR, and responder groups. PNR occurred in 13 patients (6.1%). C-Reactive protein (CRP) level at initiation of anti-TNF (baseline CRP) was a possible predictor of PNR compared to the non-PNR group (baseline CRP >1 mg/dl, OR = 4.34, 95% CI = 1.06-17.83, p   =  .042). During maintenance therapy, incidence of LOR was 12.2% at 1-year, 23.6% at 2-years, 36.3% at 3-years, and 52.1% at 5-years. Combining baseline CRP level and CRP reduction rate [(CRP at 12-14 weeks-baseline CRP)/baseline CRP] was a possible predictor of 1-year LOR compared to the responder group (baseline CRP >1 mg/dl and CRP reduction rate > -70%, OR = 18.86, 95% CI = 3.40-104.55, p   =  .001). In the Cox hazard proportional model, a combination of baseline CRP level and CRP reduction rate was possible predictors of long-term LOR during maintenance therapy (baseline CRP >1 mg/dl and CRP reduction rate > -70%, HR = 5.84, 95% CI = 2.75-12.41, p   <  .001). Conclusions: Baseline CRP level and CRP reduction rate might be clinical predictors for PNR or LOR to anti-TNF in patients with CD, and could guide proper therapeutic interventions in patients with CD.

Although colorectal cancer (CRC) is considered one of the most preventable cancers, no non-invasive, accurate diagnostic tool to screen CRC exists. We explored the potential of urine nuclear magnetic resonance (NMR) metabolomics as a diagnostic tool for early detection of CRC, focusing on advanced adenoma and stage 0 CRC. Urine metabolomics profiles from patients with colorectal neoplasia (CRN; 36 advanced adenomas and 56 CRCs at various stages, n = 92) and healthy controls (normal, n = 156) were analyzed by NMR spectroscopy. Healthy and CRN groups were statistically discriminated using orthogonal projections to latent structure discriminant analysis (OPLS-DA). The class prediction model was validated by three-fold cross-validation. The advanced adenoma and stage 0 CRC were grouped together as pre-invasive CRN. The OPLS-DA score plot showed statistically significant discrimination between pre-invasive CRN as well as advanced CRC and healthy controls with a Q2 value of 0.746. In the prediction validation study, the sensitivity and specificity for diagnosing pre-invasive CRN were 96.2% and 95%, respectively. The grades predicted by the OPLS-DA model showed that the areas under the curve were 0.823 for taurine, 0.783 for alanine, and 0.842 for 3-aminoisobutyrate. In multiple receiver operating characteristics curve analyses, taurine, alanine, and 3-aminoisobutyrate were good discriminators for CRC patients. NMR-based urine metabolomics profiles significantly and accurately discriminate patients with pre-invasive CRN as well as advanced CRC from healthy individuals. Urine-NMR metabolomics has potential as a screening tool for accurate diagnosis of pre-invasive CRN.

Background/aims: The quality of bowel preparation is important for optimal colonoscopy. It is influenced by medical and personal factors. We aimed to evaluate the effect of bowel habit on the quality of bowel preparation and to identify predictors of inadequate bowel preparation among bowel habit factors., Methods: From June 2017 to September 2017, 90 volunteers were enrolled in this study. Each participant answered a questionnaire consisting of multiple questions about personal bowel habits, including stool form, frequency of bowel movements per week, duration, and degree of straining for bowel movement. Then, all volunteers underwent colonoscopic exam. Eleven endoscopists performed colonoscopies and used the Boston Bowel Preparation Scale (BBPS) as the index for bowel preparation. Two expert endoscopists simultaneously reviewed all colonoscopic images to confirm the final BBPS. Univariate and multivariate logistic regression analyses were performed to verify the correlation between bowel preparation adequacy and bowel habit., Results: : Among the 90 participants, 20 (22.2%) had inadequate bowel preparation (total BBPS ≤6 or any segmental BBPS ≤1). In univariate analysis, infrequent bowel movement (0-2/week) (odds ratio [OR], 12.60; 95% confidence interval [CI], 1.22 to 129, p=0.03) and moderate straining (more than 1/4 of defecations) (OR, 4.40; 95% CI, 1.44 to 13.39; p=0.01) were significantly associated with inadequate bowel preparation. However, only moderate straining was significantly associated with inadequate bowel preparation in multivariate analysis (OR, 3.99; 95% CI, 1.26 to 12.65; p=0.02)., Conclusions: Straining is a significant predictor for inadequate bowel preparation. For patients with straining during bowel movements, an intensified preparation regimen should be considered.

Endoscopic submucosal dissection (ESD) is a useful procedure for the treatment of superficial gastrointestinal neoplasm. Compared with endoscopic mucosal resection (EMR), ESD has several benefits, which include resectability of various difficult lesion, accurate histologic assessment of specimen, and lower recurrence rate. However, the risk of procedure- related complications is higher with ESD than with EMR. Moreover, because the colon has a thin wall and limited endoscopic maneuverability, ESD is considered a more challenging and risky procedure when performed in the colon than in the stomach. ESD-related complications are more likely to occur. The significant complications associated with ESD are bleeding, perforation, coagulation syndrome and stenosis, most of which can be treated and prevented by endoscopic intervention and preparation. Therefore, it is important to know how to occur and manage the ESD related complication.

Objectives: Individuals with advanced adenomas or three or more adenomas have a higher risk of metachronous advanced neoplasia (AN) and are recommended to undergo surveillance colonoscopy at shorter intervals. However, it is questionable whether patients with multiple (three or more) non-advanced diminutive adenomas should be considered as high-risk., Methods: We analyzed 5482 patients diagnosed with one or more adenomas during their first colonoscopy screening and who underwent a follow-up colonoscopy. Patients were categorized into four groups based on adenoma characteristics at baseline: Group 1, 1-2 non-advanced adenomas; Group 2, ≥3 non-advanced, diminutive (1 to 5 mm) adenomas; Group 3, ≥3 non-advanced, small (6-9 mm) adenomas; and Group 4, advanced adenomas., Results: During a median follow-up of 38 months, the incidence of metachronous AN at surveillance colonoscopy was 5.6%. The incidence of AN was 3.9% in group 1, 5.9% in group 2, 10.6% in group 3, and 22.1% in group 4. The adjusted hazard ratios (HRs) [95% confidence intervals (CIs)] for metachronous AN between group 2, group 3, and group 4, and low risk group 1 were 1.71 (0.99-2.94), 2.76 (1.72-4.44), and 5.23 (3.57-7.68), respectively. Compared with group 4, the adjusted HRs (95% CIs) for group 1, group 2, and group 3 were 0.19 (0.13-0.28), 0.32 (0.18-0.59), and 0.52 (0.31-0.89), respectively., Conclusions: We found that patients with three or more non-advanced diminutive adenomas had a borderline increased risk of metachronous AN compared with patients with low risk adenomas.

Background and Aims: In individuals with either no or 1 to 2 nonadvanced adenomas, future risks of advanced colorectal neoplasia (AN) vary according to clinical risk factors. However, little is known about the association between the adenoma detection rate (ADR) and the risk for metachronous AN in patients with low-risk adenomas., Methods: We identified 7171 participants with no or 1 to 2 nonadvanced adenomas at first-time screening colonoscopy. The risk of metachronous AN was investigated at surveillance colonoscopy, according to clinical characteristics and the ADR., Results: In multivariate analysis the risk for metachronous AN was strongly associated with increasing age, male sex, increasing number of adenomas, and the ADR of the endoscopist. With the ADR modeled as a continuous variable, each 1.0% increase in the rate of ADR predicted a 3.0% decrease in the risk of metachronous AN (adjusted odds ratio [OR], .97; 95% confidence interval [CI], .95-.99). With the ADR modeled using a binary cut-off (32%), the risk of metachronous AN was reduced in patients of endoscopists with an ADR ≥32% (adjusted OR, .53; 95% CI, .35-.83). Moreover, the risk of metachronous AN was reduced (adjusted OR, .66; 95% CI, .46-.95) in patients of endoscopists with an ADR in the highest tertile, compared with patients of endoscopists with ADRs in the lowest tertile. The impact of ADR on metachronous AN was significant for patients with low-risk adenomas rather than patients with no adenoma., Conclusions: In patients with low-risk adenomas, the ADR of the endoscopist was inversely associated with the risk of metachronous AN., (Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: The survival benefit of extensive colectomy is controversial in Lynch syndrome, and risk factors for metachronous colorectal cancer (CRC) after segmental colectomy are unclear., Objective: The aim of this study was to investigate the survival outcome and risk of metachronous CRC after surgery in Lynch syndrome patients diagnosed with their first CRC., Methods: Overall, 106 patients with Lynch syndrome who underwent surgery for CRC were included in the study. The demographics, genotype, clinicopathological characteristics of the index CRC, and follow-up data were reviewed from a single-institution Lynch syndrome database., Results: Of 30 patients who underwent extensive surgery, no metachronous CRC was developed during a mean follow-up of 68.1 months. Of 76 patients who underwent segmental colectomy, 13 (17.1 %) developed metachronous CRC during a mean follow-up of 77.2 months. The cumulative risk of metachronous CRC was 8.4 % at 5 years and 20.4 % at 10 years after segmental colectomy. No difference in overall and CRC-specific survival was observed between segmental colectomy and extensive colectomy (p = 0.277 and p = 0.659, respectively). A 25 cm or longer resection of bowel decreased the risk of metachronous CRC after segmental colectomy compared with less extensive resection (hazard ratio 0.10, 95 % confidence interval 0.01-0.86). Annual surveillance colonoscopy did not decrease the risk of metachronous CRC compared with less frequent surveillance colonoscopy. Although not statistically significant, none of the MSH6 gene mutation carriers were diagnosed with metachronous CRC., Conclusions: Although no survival benefit was identified, surgeons and patients might consider extensive colectomy to prevent metachronous CRC in Lynch syndrome patients regardless of their clinicopathological characteristics.

Global obesity epidemic demands more effective therapeutic treatments and better understanding of obesity pathophysiology. Since obesity results from energy imbalance, accurate quantification of energy intake and energy expenditure (EE) becomes an essential prerequisite to phenotype the cause for obesity development. Indirect calorimetry has long been used as one of the most established methods in EE quantification by detecting changes in levels of O 2 consumption and CO 2 production. In this article, we describe procedures and important considerations for an effective measurement using indirect calorimetry.

Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background and Aim: Previous studies addressed the outcome of balloon-assisted enteroscopy (BAE) were based on its early experience. This procedure is operator-dependent and requires learning curve. Therefore, the accumulated BAE experience over the last decade might affect its pattern of use and outcome. In order to evaluate the changes of BAE practice over time, we compared the indications, diagnostic yield, and complication rate between the early and late stages of BAE implementation., Methods: This multicenter study analyzed BAE-related factors of 1,108 BAE procedures performed in 860 patients and compared the BAEs performed in early stage (Jan. 2004-Aug. 2008, n=543 procedures) to those performed in late stage (Sept. 2008-Feb. 2013, n=565 procedures)., Results: The most common indication for BAE was obscure gastrointestinal bleeding (58.3%). In the early stage, BAE to assess unexplained symptoms/signs was more common (18.8% vs. 9.7%), whereas BAE to confirm abnormal findings of imaging studies was more common in late stage (9.4% vs. 18.8%, P<0.001). Overall diagnostic yield of BAE was 74.6% (95% CI, 72.0%-77.1%). There was no significant difference in the diagnostic yield between the early and late stages (72.2% vs. 77.0%, P=0.073). BAE-associated complications occurred in 12 procedures (1.1%; 95% CI, 0.6%-1.9%). The complication rate decreased significantly in late stage compared to that during early stage (1.8% vs. 0.4%, P=0.020)., Conclusions: BAE is a safe and useful tool for the diagnosis and management of small bowel disease. With time, the indications for BAE have become more specific and the BAE-associated complication rate has decreased. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Background: Genome-wide methylation arrays have revealed aberrant methylation of N-Myc downstream-regulated gene 2 (NDRG2) promoter in colorectal cancer (CRC). This study investigated the role of NDRG2 in colorectal carcinogenesis., Methods: The aberrant promoter methylation, mRNA, and protein expression of NDRG2 were evaluated in 27 pairs of human CRC and adjacent normal tissues and seven human CRC-derived cell-lines. After stable NDRG2 over-expressed RKO and DLD-1 human CRC cell-lines were constructed, in vitro functional assays, including colony formation, cell viability, proliferation, invasion and migration assays, and in vivo xenograft models were performed., Results: The promoter of NDRG2 was methylated in 89% human CRC tissue compared to adjacent normal colonic mucosa (7.4%; P < 0.001). High-level methylation of NDRG2 promoter was more prevalent in proximal CRC (P = 0.022) and advanced T stage (P = 0.039). NDRG2 mRNA and protein expression was down-regulated in 89% and 100% human CRC tissue, respectively. In human CRC cell-lines, the promoter of NDRG2 was methylated aberrantly and mRNA, and protein expression of NDRG2 was down-regulated. NDRG2 mRNA expression was reactivated by 5-aza-2'-deoxycytidine. Colony formation of NDRG2 over-expressing RKO cells was inhibited (P = 0.012), as was the viability, proliferation, and invasion of NDRG2 over-expressing DLD-1 cells (P < 0.001, P = 0.003, and P = 0.044, respectively). Tumor volume in xenograft mice transplanted with NDRG2 over-expressing RKO and DLD-1 cells was smaller than that in controls (P = 0.002 and P = 0.001, respectively)., Conclusions: Epigenetic silencing of NDRG2 induces proliferation and invasion of CRC and may be associated with proximal CRC and advanced T stage. NDRG2 methylation might serve as novel biomarker of CRC., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare disease that is characterized by multiple, recurring small intestinal ulcers with stenosis of unknown causes. The aim of this study was to investigate the clinical characteristics and the treatment outcomes of patients with CMUSE in Korea., Methods: We performed a multicenter study to retrospectively analyze clinical data from 20 patients who suffered from CMUSE between 1984 and 2012. Their clinical characteristics and long-term disease courses were investigated., Results: The most common initial symptom of CMUSE was abdominal pain (14/20, 70 %). Small bowel series (13/20, 65 %), double-balloon enteroscopy (12/20, 60 %), CT enterography (12/20, 60 %), and capsule endoscopy (10/20, 50 %) were used to diagnose CMUSE. The strictures of the patients were located in the jejunum (5/20, 25 %), ileum (7/20, 35 %), and both jejunum and ileum (6/20, 30 %). The number of patients in a state of remission, persistent disease, and relapse at the end of follow-up were 13/20 (65 %), 2/20 (10 %), and 5/20 (25 %), respectively. The median relapse-free survival was of 67.1 months. Seventy-five percent relapse-free survivals for female and male patients were 93 and 9 months, respectively (P = 0.031)., Conclusion: CMUSE is difficult to diagnose and is an easily relapsing disease. Female patients might have a better prognosis than male patients in terms of the relapse-free time.

Background and Study Aims: To suggest an appropriate surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancers, based on incidence and patterns of local, metachronous, and extragastric recurrence., Patients and Methods: Between 2003 and 2011, 1497 consecutive patients with 1539 differentiated-type early gastric cancers meeting absolute or expanded indication criteria underwent curative ESD. They were followed up with esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) under a standardized surveillance protocol. Long-term outcomes were analyzed for 1306 patients with at least 1 year's follow-up., Results: Incidences of residual and synchronous lesions detected within 1 year were 0.13 % and 0.87 %, respectively. During median 47 months of follow-up, there was 1 local recurrence (0.08 %; early gastric cancer) and 47 cases of metachronous recurrence (3.6 %; 44 early gastric cancers, 3 pT2 advanced gastric cancers); all were curatively treated. During a 5-year surveillance, the cumulative incidence curve of metachronous recurrence increased linearly. Median time from ESD to metachronous recurrence was 30 months. There were 2 extragastric recurrences (0.15 %) in lymph nodes, at 5 and 4 years, respectively, after curative ESD for absolute and expanded indications. The patient with the expanded indications underwent a palliative operation and died of gastric cancer progression., Conclusions: There was a constant incidence rate of metachronous recurrence during a 5-year surveillance period and there was extragastric recurrence at least 4 years after ESD of early gastric cancer even for absolute indications. Therefore, annual or biannual surveillance EGD and abdominal CT might be necessary for at least 5 years after curative ESD for early gastric cancers, with absolute as well as expanded indications., (© Georg Thieme Verlag KG Stuttgart · New York.)

The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. Significance statement: Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and NPY-mediated hyperphagia., (Copyright © 2015 the authors 0270-6474/15/3510440-11$15.00/0.)

Background: Patients with Crohn's disease (CD) are frequently exposed to diagnostic radiation, mainly as a result of abdominopelvic computed tomography (APCT) examinations. However, there are limited data on the impact of APCT on clinical management in this population., Aim: To investigate clinical predictors of urgent findings on APCT in patients with CD who presented to the emergency department (ED)., Methods: A retrospective study was performed among patients with CD presenting to 11 EDs with a gastrointestinal complaint. The primary outcome, OPAN (obstruction, perforation, abscess, or non-CD-related urgent findings), included new or worsening CD-related urgent findings or non-CD-related urgent findings that required urgent or emergency treatment. Variables with P < 0.1 in univariate analyses were included in a multivariable logistic regression model., Results: Of the 266 APCTs performed, 103 (38.7 %) had OPAN and 113 (42.5 %) required changes in treatment plan. Stricturing or penetrating disease (odds ratio [OR] 2.72, 95 % confidence interval [CI] 1.21-6.13), heart rate >100 beats/min (OR 2.33, 95 % CI 1.10-4.93), leukocyte count >10,000/mm(3) (OR 4.38, 95 % CI 2.10-9.13), and CRP >2.5 mg/dL (OR 3.11, 95 % CI 1.23-7.86) were identified as the independent predictors of OPAN, whereas biologic agent use (OR 0.37; 95 % CI 0.15-0.90) was identified as the negative predictor in patients with CD., Conclusions: Only 39 % of the APCTs performed in the ED among patients with CD showed urgent findings. Stricturing or penetrating disease, tachycardia, leukocytosis, and high CRP level were predictors of urgent CT findings, while biologic agent use was a negative predictor. To reduce unnecessary radiation exposure, the selection process for CD patients referred for APCT must be improved.

Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GABAergic neurons reduced feeding. LH GABAergic neurons project extensively to the paraventricular hypothalamic nucleus (PVH), and optogenetic stimulation of GABAergic LH → PVH fibers induced monosynaptic IPSCs in PVH neurons, and potently increased feeding, which depended on GABA release. In addition, disruption of GABA-A receptors in the PVH reduced feeding. Thus, we have identified a new feeding pathway in which GABAergic projections from the LH to the PVH promote feeding., (Copyright © 2015 the authors 0270-6474/15/353312-07$15.00/0.)

Background: Before endoscopic resection (ER), a considerable number of undifferentiated early gastric cancer (UD-EGC) cases were initially diagnosed as atypical glands, dysplasia, or differentiated EGC (D-EGC) based on forceps biopsy specimens. As UD-EGC carries a high risk of resection margin involvement, identifying the predictive factors for UD-EGC cases with histologic discrepancy (HD) is of clinical importance., Aims: To investigate the outcomes of ER for UD-EGC and to identify the predictive factors for UD-EGC with HD., Methods: Among 2,194 EGC lesions treated by ER, 59 lesions were finally diagnosed as UD-EGC and 50 UD-EGC cases showed HD. The demographic and endoscopic characteristics were compared between D-EGC and UD-EGC with HD, and the predictive factors for the latter were investigated among cases of forceps biopsy-based diagnosis of atypical glands, dysplasia, or D-EGC., Results: UD-EGC showed significantly higher rate of lateral margin involvement compared to D-EGC (18.6 vs. 3.4%). Among the UD-EGC cases meeting the expanded criteria and not involving additional surgery, no local or extragastric tumor recurrence was observed during the median follow-up of 27.5 months. Multivariate analysis demonstrated that age (≤60 years), female gender, gastric body, flat or depressed type, and tumor size (>2 cm) were independent predictive factors for UD-EGC with HD among cases of forceps biopsy-based diagnosis of atypical glands, dysplasia, or D-EGC., Conclusions: For lesions with predictive factors for UD-EGC with HD, a circumferential mapping biopsy before ER or wide marking during ER could be considered to avoid the potential risk of incomplete resection.

Xenin is a gut hormone that reduces food intake partly by acting through the hypothalamus. However, the mechanism of hypothalamic xenin action is not fully understood. To identify xenin-regulated genes in the hypothalamus, we compared expression levels of metabolism-related genes in the hypothalamus between saline-treated control and xenin-treated mice. Intraperitoneal injection of xenin caused a significant increase in hypothalamic interleukin 1 beta (IL-1β) mRNA levels without causing a significant change in hypothalamic IL-1α mRNA levels. To further examine the possible contribution of IL-1 signaling to xenin's anorexigenic action, the effect of intraperitoneal injection of xenin on food intake was compared between wild-type and type I IL-1 receptor (IL-1RI)-deficient mice. Intraperitoneal administration of xenin (7.5 μg/g b.w.) caused a significant reduction of food intake in wild-type mice, while it failed to reduce food intake in pre-obese IL-1RI-deficient mice. These findings support the role of hypothalamic IL-1β-IL-1RI signaling in the mediation of the anorexigenic effect of xenin., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Aim: Although differences in genetic susceptibility and the clinical features of Crohn's disease (CD) have been reported between Asian and Caucasian patients, the disease course and predictors of CD in Asians remains poorly defined. The study therefore aimed to investigate factors predictive of the clinical outcomes of patients with CD in a Korean population., Methods: This retrospective multicenter cohort study included 728 Korean CD patients from 13 university hospitals. The first CD-related surgery or need for immunosuppressive or biological agents were regarded as the clinical outcomes of interest., Results: A total of 126 (17.3%) CD patients underwent CD-related surgery, while 473 (65.0%) and 196 (26.9%) were prescribed thiopurine drugs and infliximab, respectively. Multivariate Cox regression analysis identified current (hazard ratio [HR] = 1.86; P = 0.018) and former smoking habits (HR = 1.78; P = 0.049), stricturing (HR = 2.24; P < 0.001), and penetrating disease behavior at diagnosis (HR = 3.07; P < 0.001) as independent predictors associated with the first CD-related surgery. With respect to immunosuppressive and biological agents, younger age (< 40 years) (HR = 2.17; P < 0.001 and HR = 2.10; P = 0.006, respectively), ileal involvement (HR = 1.36; P = 0.035 and HR = 2.17; P = 0.006, respectively), and perianal disease (HR = 1.42; P = 0.001 and HR = 1.38; P = 0.038, respectively) at diagnosis were significant predictors for the need of these medications., Conclusions: In Korean patients with CD, stricturing, penetrating disease behavior, and smoking habits at the time of diagnosis are independent predictors for CD-related surgery. It was also identified that younger age (< 40 years), ileal involvement, and perianal disease at diagnosis are predictive of a need for immunosuppressive or biological agents., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Nonampullary sporadic duodenal adenomas (NSDAs) are uncommon mucosal neoplasms with malignant potential. Recently, endoscopic treatment is used for NSDA with increasing frequency., Aims: This study therefore aimed to evaluate the efficacy and safety of endoscopic treatment for NSDA., Methods: A total of 36 NSDAs in 35 consecutive patients were endoscopically eradicated at Samsung Medical Center between October 1994 and May 2011. Data on patient demographics, tumor characteristics, and endoscopic treatment outcomes were obtained and retrospectively analyzed., Results: Of all patients, 19 (52.8 %) were male. The mean age was 56.0 ± 12.2 (SD) years. Of the 36 NSDAs, 23 lesions were removed by endoscopic resection (ER) including endoscopic mucosal resection (EMR, n = 20) and snare polypectomy (n = 3). In the 23 cases treated with ER, en bloc resection was achieved in 20 (87.0 %). All cases undergoing en bloc resection showed tumor-free resection margins. Thirteen lesions were ablated by argon plasma coagulation (APC). During EMR, bleeding occurred in two cases and perforation occurred in one case. One patient bled during APC. All complications were successfully managed with endoscopic treatment without surgical intervention. During a median follow-up period of 11.4 months (range, 1.8-182.4 months), local recurrence occurred in one patient treated with APC (1/10, 10.0 %). Among patients undergoing ER, no local recurrence occurred but one patient treated with EMR experienced metachronous recurrence., Conclusions: Endoscopic treatment, including EMR, snare polypectomy, and APC, was an effective and safe treatment for NSDA. Further multi-center large prospective studies are warranted to establish appropriate treatment guidelines for NSDA.

Background: Percutaneous endoscopic gastrostomy (PEG) is performed to provide nutrition to patients with swallowing difficulties. A multicenter study was conducted to evaluate the predictors of complications and mortality after PEG placement., Methods: This study retrospectively analyzed patients who underwent initial PEG placement between January 2004 and December 2011 at seven tertiary hospitals in the Republic of Korea., Results: All 1,625 patients underwent PEG placement by the pull-string method. The median age of the patients was 66 years, and 1,108 of the patients were men. The median follow-up period was 254 days. The common indications were stroke (31.6%) and malignancy (18.9%). The complication rate was 13.2%. The prophylactic use of antibiotics (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.38-0.88; p = 0.010) reduced the PEG-related infection rate, but the actual usage rate was 81.1%. The use of anticoagulants (OR, 7.26; 95% CI, 2.23-23.68; p = 0.001) and the presence of diabetes mellitus (OR, 4.02; 95% CI, 1.49-10.87; p = 0.006) increased the risk of bleeding, but antiplatelet therapy did not. The procedural, 30-day, and overall mortality rates were 0.2, 2.4 and 14.0%, respectively. Serum albumin levels lower than 31.5 g/L (OR, 8.55; 95% CI, 3.11-23.45; p < 0.001) and C-reactive protein levels higher than 21.5 mg/L (OR, 3.01; 95% CI, 1.27-7.16; p = 0.012) increased the risk of 30-day mortality, and the patients who had both risk factors had a significantly shorter median survival time than those who did not (1,740 vs 3,181 days) (p < 0.001, log-rank)., Conclusions: The findings showed PEG to be a safe and feasible procedure, but the patient's nutritional and inflammatory status should be considered in predicting the outcomes of PEG placement.

Background: Sodium alginate is currently used in medical products, including drugs and cosmetic materials. It can also be used as a submucosal injection material due to its excellent water retention ability. Alginate with a high water retention ability is called alginate hydrogel (AH). The aim of this study was to investigate the usefulness of AH as a submucosal injection material., Methods: To investigate the optimal viscosity of AH as a submucosal injection material, we observed the changes in submucosal height from the initial submucosal height in the stomachs of six miniature pigs for each injection material tested (0.3 % AH, 0.5 % hyaluronic acid, glycerol). All submucosal heights were compared serially over time (3, 5, 10, 20, and 30 min). Both immediate and 1-week delayed tissue reactions were investigated endoscopically in the same living pigs. Histological analyses were performed after the animals had been sacrificed., Results: In a preliminary study, we determined that 0.3 % sodium alginate mixed with BaCl2 (400 μl) was the optimal viscosity of AH as an injection material. Our comparison of submucosal height changes over time showed that there was a significant decrease in submucosal height just 3 min following the injection of hyaluronic acid and glycerol, but that following the injection of AH a significant decrease in submucosal height was observed only after 10 min (p < 0.05). The histological analyses revealed that there were mild capillary dilations with congestion and mild fibrotic changes with some lymphocytic infiltration at the AH injection site., Conclusion: Alginate hydrogel demonstrated long-lasting maintenance of submucosal elevation, safety, and cost-effectiveness in a pig model, which makes it a potential alternative to hyaluronic acid.

The aim of this study was to determine the correlation between microsatellite instability (MSI) and young age in patients with advanced colorectal adenomas. We retrospectively analyzed young patients (≤ 40 years of age) with advanced adenomas (n=84) between January 1996 and December 2006. We randomly selected the control group as patients ≥ 50 years of age with advanced adenomas (n=84) during the same time period. Of these patients, the MSI test and MLH1 immunohistochemistry were performed in the available tissue samples from patients with advanced adenomas. The number of patients who had the two tests was 52 in the young group and 49 in the old group. The monomorphic nature of the BAT26 panel for MSI analysis was used without comparison of normal tissue. MSI was detected in three young patients (n=52) and none of the old patients (n=49). There was no statistical difference between the two groups (P=0.243). All three young patients with MSI had a strong family history of colorectal cancer. MSI analysis was not a useful method of screening for HNPCC in young patients with advanced colorectal adenoma, at least in cases without a family history of colorectal cancer., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Recent studies of diabetic animal models suggest an important role of ICC in the pathogenesis of gastropathy. The aim of this study was to characterize the ultrastructural features of ICC and record the electrical properties in the stomach of patients with type 2 DM. Gastric specimens were obtained from 13 diabetic patients and 6 control subjects with gastric cancer that underwent gastrectomy. All specimens were taken from disease-free areas. The samples were processed for both electron microscopic and electrophysiologic examination. The characteristic ultrastructural changes of the ICC were observed in both the nucleus and cytoplasm in patients with type 2 DM. Wrinkling of the nuclear envelope and changes in the cytoplasm such as dilatation of the endoplasmic reticulum, an increase of autophagic vacuoles, were more frequently observed in the diabetic patients. Apoptosis characterized by nuclear karyorrhexis or pyknosis was observed only in the diabetic patients. Slow waves were recorded in the circular muscle of stomach. In diabetic patients, the mean resting membrane potential was higher and amplitude was lower than controls. These changes of electrical activities of slow waves were accompanied with ultrastructural changes of ICC, particularly the characteristic nuclear changes. In human diabetic patients, the characteristic ultrastructural changes of ICC such as preapoptosis, accompanied with electrical dysrhythmia of slow waves, were observed. These results show several evidence converging to support that degeneration of the ICC may be associated with the pathogenesis of diabetic gastropathy., (Copyright © 2010 Elsevier GmbH. All rights reserved.)