A gene-environment-induced epigenetic program initiates tumorigenesis.

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

Effectiveness and Tolerability of Methotrexate Combined with Biologics in Patients with Crohn's Disease: A Multicenter Observational Study.

BACKGROUND: Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn's disease (CD). METHODS: We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. RESULTS: MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). CONCLUSIONS: MTX combination therapy with biologics was effective and tolerable in patients with CD.

Development and validation of a convolutional neural network model for diagnosing Helicobacter pylori infections with endoscopic images: a multicenter study.

BACKGROUND AND AIMS: Insufficient validation limits the generalizability of deep learning in diagnosing Helicobacter pylori infection with endoscopic images. The aim of this study was to develop a deep learning model for the diagnosis of H pylori infection using endoscopic images and validate the model with internal and external datasets. METHODS: A convolutional neural network (CNN) model was developed based on a training dataset comprising 13,403 endoscopic images from 952 patients who underwent endoscopy at Seoul National University Hospital Gangnam Center. Internal validation was performed using a separate dataset comprised of images of 411 individuals of Korean descent and 131 of non-Korean descent. External validation was performed with the images of 160 patients in Gangnam Severance Hospital. Gradient-weighted class activation mapping was performed to visually explain the model. RESULTS: In predicting H pylori ever-infected status, the sensitivity, specificity, and accuracy of internal validation for people of Korean descent were .96 (95% confidence interval [CI], .93-.98), .90 (95% CI, .85-.95), and .94 (95% CI, .91-.96), respectively. In the internal validation for people of non-Korean descent, the sensitivity, specificity, and accuracy in predicting H pylori ever-infected status were .92 (95% CI, .86-.98), .79 (95% CI, .67-.91), and .88 (95% CI, .82-.93), respectively. In the external validation cohort, sensitivity, specificity, and accuracy were .86 (95% CI, .80-.93), .88 (95% CI, .79-.96), and .87 (95% CI, .82-.92), respectively, when performing 2-group categorization. Gradient-weighted class activation mapping showed that the CNN model captured the characteristic findings of each group. CONCLUSIONS: This CNN model for diagnosing H pylori infection showed good overall performance in internal and external validation datasets, particularly in categorizing patients into the never- versus ever-infected groups.

Comparison of the Pharmacokinetics of CT-P13 Between Crohn's Disease and Ulcerative Colitis.

BACKGROUND: We aimed to compare trough infliximab levels and the development of antidrug antibody (ADA) for 1 year between Crohn's disease (CD) and ulcerative colitis (UC) patients who were biologic-naive, and to evaluate their impact on clinical outcomes. METHODS: This was a prospective, multicenter, observational study. Biologic-naive patients with moderate to severe CD or UC who started CT-P13, an infliximab biosimilar, therapy were enrolled. Trough drug and ADA levels were measured periodically for 1 year after CT-P13 initiation. RESULTS: A total of 267 patients who received CT-P13 treatment were included (CD 168, UC 99). The rates of clinical remission (72% vs. 32.3%, P <0.001) at week 54 were significantly higher in CD than in UC. The median trough drug level (µg/mL) was significantly higher in CD than in UC up to week 14 (week 2, 18.7 vs. 14.7, P <0.001; week 6, 12.5 vs. 8.6, P <0.001; week 14, 3.4 vs. 2.5, P =0.001). The median ADA level (AU/mL) was significantly lower in CD than in UC at week 2 (6.3 vs. 6.5, P =0.046), week 30 (7.9 vs. 11.8, P =0.007), and week 54 (9.3 vs. 12.3, P =0.032). Development of ADA at week 2 [adjusted odds ratio (aOR)=0.15, P =0.026], initial C-reactive protein level (aOR=0.87, P =0.032), and CD over UC (aOR=1.92, P <0.001) were independent predictors of clinical remission at week 54. CONCLUSION: Infliximab shows more favorable pharmacokinetics, including high drug trough and low ADA levels, in CD than in UC, which might result in better clinical outcomes for 1-year infliximab treatment in CD patients.

Nomogram for pre-procedural prediction of non-curative endoscopic resection in patients with early gastric cancer.

BACKGROUND: Non-curative resection (non-CR) after endoscopic submucosal dissection (ESD) requires additional surgery due to the possibility of lymph node metastasis (LNM). Therefore, it is important to accurately predict the risk of non-CR to avoid unnecessary preoperative procedures. Thus, we aimed to develop and verify a nomogram to predict the risk of non-CR prior to ESD. METHODS: Patients who underwent ESD for early gastric cancer (EGC) were divided into CR and non-CR groups based on the present ESD criteria. The pre-procedural factors, such as endoscopic features, radiologic findings, and pathology of the lesion, were compared between the groups to identify the risk factors associated with non-CR. A nomogram was developed using multivariate analysis, and its predictive value was assessed using an external validation group. RESULTS: Among 824 patients, 682 were curative (82.7%) and 142 were non-curative (17.3%). By comparing two groups, endoscopic features including redness, whitish mucosal change, fold convergence, and large lesion size; histologic features such as moderately or poorly differentiated or signet ring cell carcinoma; and abnormal CT findings including non-specific lymph node enlargement and fold thickening were identified as significant predictors of non-CR. The nomogram was developed based on these predictors and showed good predictive performance in the external validation, with an area under the curve of 0.87. CONCLUSIONS: We developed a nomogram to predict the risk of non-CR prior to ESD. These predictive factors in addition to the existing ESD criteria can help provide the best treatment option for patients with EGC.

Enrichment of Activated Fibroblasts as a Potential Biomarker for a Non-Durable Response to Anti-Tumor Necrosis Factor Therapy in Patients with Crohn's Disease.

We investigated whether the response to anti-tumor necrosis factor (anti-TNF) treatment varied according to inflammatory tissue characteristics in Crohn's disease (CD). Bulk RNA sequencing (RNA-seq) data were obtained from inflamed and non-inflamed tissues from 170 patients with CD. The samples were clustered based on gene expression profiles using principal coordinate analysis (PCA). Cellular heterogeneity was inferred using CiberSortx, with bulk RNA-seq data. The PCA results displayed two clusters of CD-inflamed samples: one close to (Inflamed_1) and the other far away (Inflamed_2) from the non-inflamed samples. Inflamed_1 was rich in anti-TNF durable responders (DRs), and Inflamed_2 was enriched in non-durable responders (NDRs). The CiberSortx results showed that the cell fraction of activated fibroblasts was six times higher in Inflamed_2 than in Inflamed_1. Validation with public gene expression datasets (GSE16879) revealed that the activated fibroblasts were enriched in NDRs over Next, we used DRs by 1.9 times pre-treatment and 7.5 times after treatment. Fibroblast activation protein (FAP) was overexpressed in the Inflamed_2 and was also overexpressed in the NDRs in both the RISK and GSE16879 datasets. The activation of fibroblasts may play a role in resistance to anti-TNF therapy. Characterizing fibroblasts in inflamed tissues at diagnosis may help to identify patients who are likely to respond to anti-TNF therapy.

Risk of Metachronous Colorectal Advanced Neoplasia and Cancer in Patients With 3-4 Nonadvanced Adenomas at Index Colonoscopy: A Systematic Review and Meta-Analysis.

INTRODUCTION: This systematic review and meta-analysis evaluated the available evidence on the risk of metachronous advanced neoplasia (AN) and colorectal cancer (CRC) in patients with 3-4 nonadvanced adenomas (NAAs). METHODS: We searched MEDLINE, EMBASE, and Cochrane Library databases up to January 2021 for studies evaluating metachronous AN and CRC risk by comparing 3 groups (1-2 vs 3-4 vs ≥5 NAAs) at index colonoscopy. The estimates for risk of metachronous AN and CRC were evaluated using random-effects models. RESULTS: Fifteen studies (n = 36,375) were included. The risk of metachronous AN was significantly higher in the 3-4 NAAs group than in the 1-2 NAAs group (relative risk [RR] 1.264, 95% confidence interval [CI] 1.053-1.518, P = 0.012; I2 = 0%); there was no difference between the ≥ 5 NAAs and 3-4 NAAs groups (RR 1.962, 95% CI 0.972-3.958, P = 0.060; I2 = 68%). The risks of metachronous CRC between the 1-2 NAAs and 3-4 NAAs groups (RR 2.663, 95% CI 0.391-18.128, P = 0.317; I2 = 0%) or the 3-4 NAAs and ≥ 5 NAAs groups (RR 1.148, 95% CI 0.142-9.290, P = 0.897; I2 = 0%) were not significantly different. DISCUSSION: Although the risk of metachronous AN was greater in the 3-4 NAAs group than in the 1-2 NAAs group, the risk of metachronous AN and CRC between the 3-4 NAAs and ≥ 5 NAAs groups was not different. This suggests that further studies on metachronous AN and CRC risk in the 3-4 NAAs group are warranted to confirm a firm ≥5-year interval surveillance colonoscopy.

Association between triglyceride-glucose index and gastric carcinogenesis: a health checkup cohort study.

BACKGROUND: We aimed to investigate the association between the triglyceride-glucose (TyG) index and gastric carcinogenesis, including precancerous conditions such as dysplasia, atrophic gastritis, and intestinal metaplasia. METHODS: Patients who received an upper endoscopic assessment at a medical center were included. The enrolled patients were divided into four categories according to their TyG index quartile (Q). To evaluate the relationship between increase of TyG index and gastric cancer, we analyzed the patients who received a health checkup twice. Moreover, receiver-operating characteristic curve analysis was used to establish cut-off value of the TyG index for gastric cancer. RESULTS: Of 127,564 enrolled patients, 43,525 (34.1%) and 186 (0.1%) were diagnosed with precancerous conditions and gastric cancer, respectively. The odds ratios (ORs) of precancerous conditions given TyG index progressively increased across quartiles: using Q1 as the reference: Q2 (OR = 1.403, P < 0.001), Q3 (OR = 1.646, P < 0.001), and Q4 (OR = 1.656, P < 0.001). The ORs of gastric cancer also increased according to the quartiles: Q2 (OR = 1.619, P = 0.045), Q3 (OR = 2.180, P = 0.004), and Q4 (OR = 2.363, P = 0.001). Moreover, the increase in TyG index between baseline and follow-up tests was more significant in gastric cancer group than in control group (P = 0.001). The optimal cut-off value for predicting gastric cancer was 9.73. CONCLUSIONS: The TyG index may be a novel predictive biomarker for gastric carcinogenesis. Notably, increase in the TyG index is significantly associated with gastric cancer.

Atopic Diseases Are Associated With Development of Inflammatory Bowel Diseases in Korea: A Nationwide Population-based Study.

BACKGROUND & AIMS: The association between atopic diseases and inflammatory bowel diseases (IBD) is unclear. We conducted a nationwide population-based study in Korea to investigate the effect of atopic diseases on the development of IBD. METHODS: A total of 9,923,521 participants, who received a medical check-up in 2009, were included and followed through 2017. The presence of any atopic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma, was evaluated. Patients who developed IBD, including Crohn's disease (CD) and ulcerative colitis (UC), were identified using claims data from National Health Insurance; the association between atopic diseases and the risk of IBD was evaluated using Cox proportional hazard models, and presented as adjusted hazard ratios (aHRs) with 95% CIs. RESULTS: During a mean follow-up period of 7.3 years, 1419 patients (0.014%) developed CD and 5897 patients (0.059%) developed UC. The incidences of CD (per 100,000 person-years) were 3.756, 2.248, and 2.346 in patients with AD, AR, or asthma, respectively. The incidences of UC were 11.952, 9.818, and 9.358 in patients with AD, AR, or asthma, respectively. Multivariable analysis revealed that the aHRs for incident CD in patients with AD, AR, or asthma were 2.02, 1.33, and 1.60 (95% CIs, 1.118-3.663, 1.149-1.529, and 1.193-2.136, respectively) compared with controls. The risks of incident UC in patients with AD, AR, or asthma were 1.51, 1.32, and 1.29 (95% CIs, 1.082-2.104, 1.229-1.410, and 1.115-1.491, respectively) compared with controls. Moreover, an increase in the number of atopic diseases gradually increased the risk for CD and UC; for 1 or 2 or more atopic diseases, the aHRs for CD were 1.35 and 1.65 (95% CIs, 1.171-1.560 and 1.146-2.376), and the aHRs for UC were 1.30 and 1.49 (95% CIs, 1.211-1.392 and 1.249-1.774), respectively. CONCLUSIONS: Based on a nationwide population-based study in Korea, patients with any atopic disease, including AD, AR, or asthma, have an increased risk for CD and UC. The risk for IBD increases with the increase in the number of atopic diseases.

Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. METHODS: We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2-2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/µL, levels of hemoglobin 10 g/dL, or platelet counts below 100 K/µL. RESULTS: Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (P=.005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22-0.81; P = .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P = .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. CONCLUSIONS: In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.

Increased risk of idiopathic pulmonary fibrosis in inflammatory bowel disease: A nationwide study.

BACKGROUND AND AIM: The relationship between inflammatory bowel disease (IBD) and idiopathic pulmonary fibrosis (IPF) remains unclear. We evaluated the risk for developing IPF in patients with IBD using a nationwide population-based study. METHODS: Using claims data from the National Health Insurance service in Korea, patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC), were identified through both the 10th revision of the International Statistical Classification of Diseases and Related Health Problems and rare and intractable disease program codes from January 2010 to December 2013. We compared 38 921 IBD patients with age-matched and sex-matched individuals without IBD in a ratio of 1:3. Patients with newly diagnosed IPF were identified by both the 10th revision of the International Statistical Classification of Diseases and Related Health Problems and rare and intractable disease registration codes. RESULTS: During a mean 4.9-year follow-up, the incidence of IPF in patients with IBD was 33.21 per 100 000 person-years. The overall risk of IPF was significantly higher in IBD patients than in non-IBD controls (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.20-2.20; P = 0.003). In patients with CD, the incidence (per 100 000 person-years) of IPF was 26.04; in controls, the incidence was 9.15 (HR, 2.89; 95% CI, 1.46-5.72; P = 0.002). The incidence of IPF in patients with UC tended to be higher than in controls (36.66 vs 26.54 per 100 000 person-years; 95% CI, 0.99-1.99; HR, 1.41; P = 0.066). The risk of developing IPF in patients with IBD was higher in male patients than in female patients (P = 0.093 in CD; P = 0.147 in UC by interaction analysis). CONCLUSIONS: Patients with IBD, especially CD, have an increased risk of developing IPF.

Novel sulfate tablet PBK-1701TC versus oral sulfate solution for colon cleansing: A randomized phase 3 trial.

BACKGROUND AND AIM: PBK-1701TC is a novel sulfate tablet-based that contains 320 mg of simethicone and delivers 90% of the salt and water delivered by oral sulfate solution (OSS) preparation. This study evaluated the efficacy, safety, and tolerability of PBK-1701TC compared with OSS in bowel preparation for colonoscopy. METHODS: This randomized, multicenter, phase 3 non-inferiority trial included adults aged 19 years or older with a body mass index of 19-30 kg/m2 undergoing colonoscopy at five university hospitals in Korea. The primary efficacy endpoint was successful bowel-cleansing rate, defined as Harefield Cleansing Scale grade A or B as evaluated by blinded central readers. Secondary endpoints included the presence of residual air bubbles. Adverse events and laboratory evaluations were monitored to assess safety. Tolerability was assessed via participant interview. RESULTS: Overall, 235 participants were randomized, and 224 were included in the per-protocol analysis (PBK, 112; OSS, 112). Successful bowel cleansing was achieved for 95.5% (107/112) in the PBK group, which was non-inferior to the OSS group (98.2%, 110/112) with a difference of -2.7% (one sided 97.5% confidence limit, -8.1%). The participants in the PBK group had fewer intraluminal bubbles (0.9% vs 81.3%, P < 0.001) and reported a lower incidence of nausea and vomiting, with better acceptance, taste, and willingness to repeat the regimen than those in the OSS group (all P < 0.05). CONCLUSION: The novel sulfate tablet, PBK-1701TC, was non-inferior to OSS with respect to bowel-cleansing efficacy and exhibited better safety and tolerability in adults undergoing colonoscopy.

Effect of histologic differences between biopsy and final resection on treatment outcomes in early gastric cancer.

BACKGROUND AND STUDY AIMS: Biopsy-based histologic diagnosis is important in determining the treatment strategy for early gastric cancer (EGC). However, there are few studies on how histologic discrepancy may affect patients' treatment outcomes. We aimed to investigate the impact of histopathologic differences between biopsy and final specimens from endoscopic resection (ER) or gastrectomy on treatment outcomes in patients with EGC. We also examined the predictive factors of histologic discrepancy. PATIENTS AND METHODS: We analyzed the data of 1851 patients with EGC treated with ER or gastrectomy. We compared the histology between biopsies and final resected specimens from ER or gastrectomy. We also examined changes in treatment outcomes according to histologic differences. RESULTS: Histologic discrepancy was observed in 11.9% of patients in the ER group and 10.7% of those in the gastrectomy group. In patients treated with ER who showed histologic discrepancy, 80.9% showed differentiated-type EGC (D-EGC) on biopsy but undifferentiated-type-EGC (UD-EGC) after ER, of which 78.9% were non-curative resection. In patients treated with gastrectomy who showed histologic discrepancy, 39% showed UD-EGC on biopsy but showed D-EGC after gastrectomy. A total of these patients had absolute and expanded indications for ER. Moderately differentiated and poorly differentiated adenocarcinoma on biopsy were predictive factors of histologic discrepancy in UD-EGC and D-EGC on final resection, respectively. CONCLUSIONS: About 10% of patients showed histologic discrepancy between biopsy and final resection with ER or gastrectomy. Histologic discrepancy can affect treatment outcomes, such as non-curative resection in ER or missing the opportunity for ER in gastrectomy.

Outcomes and Management Strategies for Capsule Retention: A Korean Capsule Endoscopy Nationwide Database Registry Study.

BACKGROUND: The most concerning complication of capsule endoscopy (CE) is capsule retention (CR) in the gastrointestinal (GI) tract; however, the clinical outcomes and management of patients with CR are still uncertain. AIMS: This study aimed to investigate the clinical outcomes and management of CR. METHODS: The outcomes of CR in multiple centers between October 2002 and June 2018 were retrospectively reviewed. Data on CE indication, findings, and management details were analyzed. RESULTS: A total of 2705 consecutive small-bowel CE procedures were performed. CR was detected in 20 cases (0.7%). The most common site of CR was the small bowel (19 cases), followed by the esophagus (one case). In patients who underwent CE, CR was detected in nine (0.6%) of 1397 patients with obscure GI bleeding. Further, CR occurred in 11 (6.5%) of 169 patients with Crohn's disease based on the final diagnoses after CE. Capsule retrieval was safely performed surgically in nine cases and endoscopically in six cases. The retained capsules dislodged after steroid treatment in two cases, whereas three cases of CR resolved without any intervention. In multivariate analysis, the development of abdominal symptoms after CR was a significant predictive factor for requiring endoscopic or surgical interventions for capsule extraction. CONCLUSIONS: This large multicenter study shows that CR is a rare complication with favorable clinical outcomes. Three-fourths of the patients with CR were managed with endoscopic or surgical intervention, which was required particularly in patients with abdominal symptoms after CR.

Clinical outcomes of endoscopic mucosal resection for rectal neuroendocrine tumor.

BACKGROUND: The incidence of rectal neuroendocrine tumors (NETs) is rapidly increasing because of the frequent use of endoscopic screening for colorectal cancers. However, the clinical outcomes of endoscopic resection for rectal NETs are still unclear. The aim of this study was to assess the rates of histologically complete resection (H-CR) and recurrence after endoscopic mucosal resection (EMR) for rectal NETs. METHODS: A retrospective analysis was performed on patients who underwent EMR for rectal NETs between January 2002 and March 2015 at Seoul National University Hospital. Primary outcomes were H-CR and recurrence rates after endoscopic resection. H-CR was defined as the absence of tumor invasion in the lateral and deep margins of resected specimens. RESULTS: Among 277 patients, 243 (88%) were treated with conventional EMR, 23 (8%) with EMR using a dual-channel endoscope, and 11 (4%) with EMR after precutting. The median tumor size was 4.96 mm (range, 1-22) in diameter, and 264 (95%) lesions were confined to the mucosa and submucosal layer. The en-bloc resection rate was 99% and all patients achieved endoscopically complete resection. The H-CR rates were 75, 74, and 73% for conventional EMR, EMR using a dual-channel endoscope, and EMR after precutting, respectively. Multivariate analysis showed that H-CR was associated with tumor size regardless of endoscopic treatment modalities (p = 0.023). Of the 277 patients, 183 (66%) underwent at least 1 endoscopic follow-up. Three (2%) of these 183 patients had tumor recurrence, which was diagnosed at a median of 62.5 months (range 19-98) after endoscopic resection. There was 1 case of disease-related death, which occurred 167 months after endoscopic treatment because of bone marrow failure that resulted from tumor metastasis. CONCLUSIONS: Although the en-bloc resection rate was 99% in rectal NETs, H-CR rates were 72-74% for various EMR procedures. H-CR may be associated with tumor size regardless of endoscopic treatment modalities.

Nimbolide Inhibits Nuclear Factor-КB Pathway in Intestinal Epithelial Cells and Macrophages and Alleviates Experimental Colitis in Mice.

Nimbolide is a limonoid extracted from neem tree (Azadirachta indica) that has antiinflammatory properties. The effect of nimbolide on the nuclear factor-kappa B (NF-κB) pathway in intestinal epithelial cells (IECs), macrophages and in murine colitis models was investigated. The IEC COLO 205, the murine macrophage cell line RAW 264.7, and peritoneal macrophages from interleukin-10-deficient (IL-10-/- ) mice were preconditioned with nimbolide and then stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide. Dextran sulfate sodium-induced acute colitis model and chronic colitis model in IL-10-/- mice were used for in vivo experiments. Nimbolide significantly suppressed the expression of inflammatory cytokines (IL-6, IL-8, IL-12, and TNF-α) and inhibited the phosphorylation of IκBα and the DNA-binding affinity of NF-κB in IECs and macrophages. Nimbolide ameliorated weight loss, colon shortening, disease activity index score, and histologic scores in dextran sulfate sodium colitis. It also improved histopathologic scores in the chronic colitis of IL-10-/- mice. Staining for phosphorylated IκBα was significantly decreased in the colon tissue after treatment with nimbolide in both models. Nimbolide inhibits NF-κB signaling in IECs and macrophages and ameliorates experimental colitis in mice. These results suggest nimbolide could be a potentially new treatment for inflammatory bowel disease. Copyright © 2016 John Wiley & Sons, Ltd.

Fexofenadine regulates nuclear factor-κB signaling and endoplasmic reticulum stress in intestinal epithelial cells and ameliorates acute and chronic colitis in mice.

The aim of this study was to evaluate the effect of fexofenadine on intestinal inflammation. HCT116 and COLO205 cells were pretreated with fexofenadine and then stimulated with tumor necrosis factor (TNF)-α. Interleukin (IL)-8 expression was determined by real-time reverse-transcription polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. DNA-binding activity of nuclear factor-κB was assessed by electrophoretic mobility shift assay. The molecular markers of endoplasmic reticulum (ER) stress were evaluated by Western blot analysis and PCR. In the acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days with or without fexofenadine. IL-10(-/-) mice were used to evaluate the effect of fexofenadine on chronic colitis. Fexofenadine significantly inhibited the upregulated expression of IL-8 in HCT116 and COLO205 cells stimulated with TNF-α. Fexofenadine suppressed nuclear factor-κB DNA-binding activity. C/EBP homologous protein mRNA expression was enhanced in the presence of TNF-α, and it was dampened by pretreatment of fexofenadine. In addition, the induction of ER stress markers caspase-12 and p-eukaryotic initiation factor 2 (eIF2)-α was significantly suppressed by the pretreatment of fexofenadine. Administration of fexofenadine significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IκB kinase activation was significantly decreased in fexofenadine-pretreated mice. Finally, fexofenadine significantly reduced the severity of colitis and the immunoreactivity of caspase-12 and p-eIF2-α in IL-10(-/-) mice as compared with controls. These results suggest that fexofenadine is a potential therapeutic agent for the treatment of inflammatory bowel disease.

Novel risk stratification for recurrence after endoscopic resection of advanced colorectal adenoma.

BACKGROUND: Advanced colorectal adenoma (ACA) refers to adenomas with the following predictive characteristics: ≥1 cm in diameter, and/or villous component, and/or high-grade dysplasia. ACA has high risk of transforming to colorectal cancer, and the recurrence rate is relatively high. OBJECTIVE: To assess the outcomes of patients with ACA undergoing endoscopic resection and to identify risk factors for local recurrence and development of metachronous advanced neoplasm. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS: From 2005 to 2011, the records of 3625 patients who underwent colonoscopic polypectomy at Seoul National University Hospital were retrospectively reviewed. Patients with synchronous colorectal cancers, inflammatory bowel disease, previous colorectal resection, loss to follow-up, and incomplete resection were excluded. INTERVENTION: Endoscopic resection for ACA. MAIN OUTCOME MEASUREMENTS: Local recurrence and metachronous advanced neoplasm. RESULTS: The study included 917 patients with 1206 ACAs. The median duration of follow-up was 28.5 months (interquartile range, 12.8-51.7). Independent risk factors for local recurrence included ACA with 2 or more predictive characteristics (adjusted hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.11-5.48; P = .027) and piecemeal resection (adjusted HR, 6.96; 95% CI, 1.58-30.71; P = .010). Independent risk factors for metachronous advanced neoplasm were male gender (adjusted HR, 1.65; 95% CI, 1.02-2.65; P = .041), ≥3 adenomas (adjusted HR, 2.56; 95% CI, 1.72-3.82; P < .001), and ≥3 ACAs (adjusted HR, 1.44; 95% CI, 1.01-2.06; P = .045). LIMITATIONS: Retrospective design. CONCLUSION: ACAs with 2 or more predictive characteristics recurred locally at a higher rate than ACAs with 1 predictive characteristic. These results suggest that patients who are found to have ACAs with 2 or more predictive factors at index colonoscopy are at higher risk for local recurrence, and follow-up colonoscopy should be performed sooner.