Usefulness of narrow-band imaging for the detection of remnant sessile-serrated adenoma (SSA) tissue after endoscopic resection: the KASID multicenter study.

BACKGROUND: A sessile-serrated adenoma (SSA) has a high risk for incomplete resection. Little is known regarding how to immediately detect remnant SSA tissue after endoscopic resection. We investigated the usefulness of narrow-band imaging (NBI) to detect remnant SSA tissue after endoscopic mucosal resection (EMR). METHODS: We performed a prospective randomized study on 138 patients who had suspicious SSA on colonoscopy at five centers. After EMR on the suspected SSA determined on the endoscopic morphology, all lesions were randomized into two inspection methods, NBI and white light endoscopy (WLE), to detect remnant tissue on the resected margin. If remnant tissue was detected, an additional resection was performed. Finally, we obtained quadrant biopsies on the resection margin to evaluate the incomplete resection. The proportion of incomplete resection was calculated by combining the detection of remnant tissue and the positivity of SSA cells on the final quadrant biopsies. The primary outcome was the proportion of remnant tissue detection, and the secondary outcome was the proportion of incomplete resection of SSA. RESULTS: In all, 145 lesions from 138 patients were removed. The diagnostic rate of SSA was 87.6% (127/145). After randomization, NBI inspection was performed on 69 lesions, and WLE inspection was performed on 76 lesions. The histologic diagnostic rate of SSA was 89.9% (62/69) in the NBI group and 85.5% (65/76) in the WLE group (p > 0.05). There were no significant differences in the detection of remnant tissue (12.9% (8/62) vs. 15.4% (10/65), p > 0.05), the proportion of SSA in remnant tissue (11.3% (7/62) vs. 12.3% (8/65), p > 0.05), or the proportion of incomplete resection (6.5 (4/62) vs. 10.8 (7/65), p > 0.05) between the NBI and WLE inspection groups, respectively. CONCLUSION: NBI was not superior to WLE for detecting remnant SSA tissue after EMR and could not decrease the proportion of incomplete resection of SSA.

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.

Long-term evolution of direct healthcare costs for inflammatory bowel diseases: a population-based study (2006-2015).

Introduction: We explored the long-term evolution of direct healthcare costs for inflammatory bowel diseases (IBD) using a population-level database in a country with an escalating burden of IBD. Methods: We searched the database of the Korean National Health Insurance Claims, which covers more than 97% of the South Korean population. An IBD diagnosis was defined as the combination of a billing code for Crohn's disease (CD: K50.xx) or ulcerative colitis (UC: K51.xx) and at least one claim for IBD-specific drugs. Between 2006 and 2015, a total of 59,447 patients (CD: 17,677; UC: 41,770) were included. Results: The total and mean cost per capita increased significantly over time. In the last year of the study (2015), the cost for anti-tumor necrosis factor (TNF) therapy accounted for 68.8% (CD) and 48.8% (UC) of the total cost. Age at diagnosis (<20 years vs. ≥30 years) and anti-TNF use were independent predictors of increased total IBD cost. Anti-TNF therapy was the strongest predictor of high-cost outliers (designated as the top 20 percentile of the total costs) for IBD (OR: 160.4; 95% CI: 89.0-289.2). The mean cost among patients with newly diagnosed CD increased significantly over the 8-year follow-up period (p = .03), while costs associated with UC remained stable. Only medication costs increased significantly during the follow-up period for CD. Conclusions: Over the past 10 years, the increased usage of anti-TNF agents has been the key driver of IBD-related healthcare costs. Long-term cost-cutting strategies for patients with CD are warranted.

Ras association domain family 1 isoform A suppresses colonic tumor cell growth through p21WAF1 activation in a p53-dependent manner.

BACKGROUND AND AIM: Despite the frequent loss of Ras association domain family 1 isoform A (RASSF1A) expression in various cancers, the precise mechanism underlying its tumor-suppressive effect is not fully understood. To elucidate the growth-inhibitory role for RASSF1A in colorectal tumorigenesis, this study investigated the RASSF1A regulation of the p53-p21WAF1 pathway. METHODS: Ras association domain family 1 isoform A effect on cellular growth was tested in three human colon cancer cell lines by flow cytometry, cell counting, and [3 H]-thymidine incorporation assay. HCT116 p53+/+ and p53-/- isogenic sublines were utilized to determine the p53 dependence of RASSF1A effect on p21WAF1 . Cycloheximide chase experiment and immunoprecipitation assay were carried out to define RASSF1A effect on p53 stability and mouse double minute 2 (MDM2) homolog ubiquitination. RESULTS: Ras association domain family 1 isoform A expression inhibits colonic cell proliferation by preventing the G1 to S phase transition of the cell cycle. The RASSF1A-induced G1 cell cycle arrest is accompanied by the increase in the level of p21WAF1 mRNA expression. The p21WAF -inducing activity of RASSF1A was substantially higher in HCT116 p53+/+ cell compared with isogenic p53-/- cells. The cycloheximide chase assay revealed that RASSF1A expression leads to p53 stabilization and MDM2 homolog degradation. Using p53-/- and p21WAF1-/- subline cells, this study finally validated a crucial role of the p53-p21WAF1 axis in RASSF1A-mediated growth inhibition. CONCLUSIONS: RASSF1A suppresses colonic tumor growth through the activation of the p53-p21WAF1 pathway. This finding supports that RASSF1A could be a valuable marker for the assessment of colorectal cancer development and progression.

Bidirectional alteration of Cav-1 expression is associated with mitogenic conversion of its function in gastric tumor progression.

BACKGROUND: Expression of caveolin-1 (Cav-1) is frequently altered in many human cancers and both tumor suppression and promotion functions of Cav-1 have been suggested based on its expression status. However, it remains unanswered how Cav-1 provokes opposite effects in different cancers or different phases of tumor progression. METHODS: To explore the implication of Cav-1 alteration in gastric tumorigenesis, the expression and mutational status of Cav-1 and its effects on tumor cell growth were characterized. RESULTS: A substantial fraction of primary tumors and cell lines displayed abnormally low or high Cav-1 mRNA expression, indicating the bidirectional alteration of Cav-1 in gastric cancers. While allelic imbalance and mutational alterations of the Cav-1 gene were rarely detected, aberrant promoter hyper- or hypo-methylation showed a tight correlation with bidirectional alteration of its expression. Abnormally low and high Cav-1 expression was more frequently observed in early and advanced cancers, respectively, suggesting the oncogenic switch of its function in tumor progression. Cell cycle progression, DNA synthesis, and colony forming ability were markedly decreased by Cav-1 transfection in low-expressing tumor cells but by its depletion in high-expressing cells. Interestingly, Cav-1 exerted opposite effects on MEK-ERK signaling in these two cell types through the reciprocal regulation of the RAF-ERK negative feedback loop. A feedback inhibition of RAF by ERK was stimulated by restoration of Cav-1 expression in low-expressing cells but by it depletion in high-expressing cells. As predicted, the opposite effects of Cav-1 on both tumor cell growth and inhibitory RAF phosphorylation were abolished if ERK is depleted. CONCLUSION: Bidirectional alteration of Cav-1 is linked to its opposite effects on gastric tumor cell growth, which stem from the reciprocal control on the RAF-ERK negative feedback loop.

Clinical Outcomes between P1 and P0 Lesions for Obscure Gastrointestinal Bleeding with Negative Computed Tomography and Capsule Endoscopy.

BACKGROUND: A simple classification for the relevance of lesions (P0, P1, and P2; no bleeding potential, less likely to bleed, and more likely to bleed, respectively) based on capsule endoscopy (CE) findings has been used. This study aimed at investigating rebleeding rates and predictive factors of P0 and P1 lesions after obtaining negative findings in both, CE and computed tomography (CT), for patients with obscure gastrointestinal bleeding (OGIB). METHODS: Among 193 patients resulted in negative CE findings defined as P0 or P1 lesions, 84 patients with negative results on CT images were enrolled in this study. The rebleeding rates and predictive factors were assessed in the P0 and P1 groups. RESULTS: Overall rebleeding rate in patients with negative CT and CE was 17.9%; 18.4% in the P0 group; 17.4% in the P1 group within a median follow-up duration of 18.5 months. In the P0 and P1 groups, the cumulative rebleeding rates were 9.2%, 25.4%, and 25.4%, and 6.9%, 11.8%, and 18.6% at 12, 24, and 60 months, respectively (p = 0.97). There were no independent rebleeding associated factors in the P0 group, whereas Charlson comorbidity index (CCI) (hazard ratio (HR) = 2.019, 95% confidence interval (CI): 1.158-3.519, p = 0.013), and initial low hemoglobin (Hb) level (<8 g/dL) (HR = 15.085, 95% CI: 1.182-192.514, p = 0.037) were independent predictive factors responsible for rebleeding in the P1 group. CONCLUSIONS: Despite having negative findings on CT and CE, patients with OGIB have a significant potential rebleeding risk. Although there was no significant difference in rebleeding rates between the P0 and P1 groups on CE, the P1 group, with CCI or low initial Hb level, should be cautiously observed after the first bleeding episode.

The role of platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in ulcerative colitis.

BACKGROUND/AIMS: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) can serve as biomarkers for diagnosing and assessing disease activity in ulcerative colitis (UC). We investigated their clinical significance in UC. METHODS: We analyzed 48 patients with UC who underwent measurement of fecal calprotectin (FC) and endoscopy and 96 age- and sex-matched healthy controls. NLR and PLR were compared between the patients and healthy controls. The endoscopic activity was divided into 2 groups: group 1 (mild to moderate inflammation) and group 2 (severe inflammation) according to the Mayo endoscopic subscore in UC. RESULTS: To diagnose UC, the optimal cutoff of NLR and PLR was 2.26 (sensitivity 54.2%; specificity 90.6%; positive likelihood ratio 5.778, 95% confidence interval [CI] 2.944-11.339; area under the curve [AUC] 0.774, 95% CI, 0.690-0.859) and 179.8 (sensitivity 35.4%; specificity 90.6%; positive likelihood ratio 3.778, 95% CI 1.821-7.838; AUC 0.654, 95% CI 0.556-0.753), respectively. The optimal cutoff to differentiate group 1 and group 2 was 3.44, 175.9, and 453 µg/g for NLR, PLR, and FC, respectively (sensitivity, 63.6% vs. 90.9% vs. 81.8%; specificity, 81.1% vs. 78.4% vs. 73.0%; positive likelihood ratio, 3.364 vs. 4.205 vs. 3.027; AUC, 0.714 vs. 0.897 vs. 0.813). PLR had the highest AUC and positive likelihood ratio. CONCLUSIONS: NLR and PLR help differentiate patients with UC from healthy controls. NLR, PLR, and FC indicate endoscopic activity and may reflect intestinal mucosal conditions.

Esophageal Involvement and Determinants of Perception of Esophageal Symptoms Among South Koreans With Systemic Sclerosis.

Background/Aims: Our study aims to characterize esophageal motor function; evaluate the relationships among esophagogastroduodenoscopy (EGD), high-resolution manometry (HRM), and 24-hour esophageal multichannel intraluminal impedance monitoring combined with pH-metry (MII-pH); and elucidate the determinants of esophageal symptom perception in South Koreans with systemic sclerosis (SSc). Methods: We reviewed prospectively collected HRM (n = 46), EGD (n = 41), and MII-pH (n = 37) data from 46 consecutive patients with SSc (42 females; mean age 50.1 years) who underwent esophageal tests between June 2013 and September 2018. Results: The most common HRM diagnosis was normal (39.1%), followed by ineffective esophageal motility (23.9%) and absent contractility (21.7%). Erosive esophagitis was observed in 12.2% of total SSc patients, with a higher frequency in patients with absent contractility than those with normal motility (44.5% vs 0.0%, P = 0.01). Pathologic acid exposure was observed in 6 patients (20.0%) and positive symptom association in 18 patients (60.0%) in MII-pH tests of symptomatic patients. The proportion of SSc patients with esophageal symptoms not explained by reflux or mucosal or motor esophageal abnormalities was 33.0%. Conclusions: Esophageal involvement among South Koreans with SSc was characterized by heterogeneous motility patterns, with a higher prevalence of normal motility and lower prevalence of erosive esophagitis. Reflux hypersensitivity or functional heartburn might be partly attributed to the perception of esophageal symptoms in SSc patients who have neither gastroesophageal reflux disease nor esophageal dysmotility.

Unmet Psychosocial Needs of Patients with Newly Diagnosed Ulcerative Colitis: Results from the Nationwide Prospective Cohort Study in Korea.

Background/Aims: Limited data are available regarding psychosocial distress at the time of diagnosis of ulcerative colitis (UC). We investigated the psychosocial burden and factors related to poor health-related quality of life (HRQL) among patients newly diagnosed with moderate-to-severe UC who were affiliated with the nationwide prospective cohort study. Methods: Within the first 4 weeks of UC diagnosis, all patients were assessed using the Hospital Anxiety and Depression Scale (HADS), Work Productivity and Activity Impairment questionnaire, Inflammatory Bowel Disease Questionnaire (IBDQ), and 12-Item Short Form (SF-12) health survey. A multiple linear regression model was used to identify factors associated with HRQL. Results: Between August 2014 and February 2017, 355 patients completed questionnaires. Significant mood disorders requiring psychological interventions, defined by a HADS score ≥11, were identified in 16.7% (anxiety) and 20.6% (depression) of patients. Patients with severe disease were more likely to have presenteeism, loss of work productivity, and activity loss than those with moderate disease (all p<0.05). Significant mood disorders had the strongest negative relationship with total IBDQ score, which indicates disease-specific HRQL (ß coefficient: -22.1 for depression and -40.0 for anxiety, p<0.001). The scores of all SF-12 dimensions, which indicate general HRQL, were remarkably decreased in the study population compared indirectly with previously reported scores in the general population. The Mayo score, C-reactive protein level, and white blood cell count showed significant negative associations with the IBDQ score (p<0.05). Conclusions: Psychosocial screening and timely interventions should be incorporated into the initial care of patients newly diagnosed with UC.

TGF-ß1 protects colon tumor cells from apoptosis through XAF1 suppression.

Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine that functions as a growth suppressor in normal epithelial cells and early stage tumors, but acts as a tumor promoter during malignant progression. However, the molecular basis underlying the conversion of TGF­ß1 function remains largely undefined. X­linked inhibitor of apoptosis­associated factor 1 (XAF1) is a pro­apoptotic tumor suppressor that frequently displays epigenetic inactivation in various types of human malignancies, including colorectal cancer. The present study explored whether the anti­apoptotic effect of TGF­ß1 is linked to its regulatory effect on XAF1 induction in human colon cancer cells under stressful conditions. The results revealed that TGF­ß1 treatment protected tumor cells from various apoptotic stresses, including 5­fluorouracil, etoposide and γ­irradiation. XAF1 expression was activated at the transcriptional level by these apoptotic stresses and TGF­ß1 blocked the stress­mediated activation of the XAF1 promoter. The study also demonstrated that mitogen­activated protein kinase kinase inhibition or extracellular signal­activated kinase (Erk)1/2 depletion induced XAF1 induction, while the activation of K­Ras (G12C) led to its reduction. In addition, TGF­ß1 blocked the stress­mediated XAF1 promoter activation and induction of apoptosis. This effect was abrogated if Erk1/2 was depleted, indicating that TGF­ß1 represses XAF1 transcription through Erk activation, thereby protecting tumor cells from apoptotic stresses. These findings point to a novel molecular mechanism underlying the tumor­promoting function of TGF­ß1, which may be utilized in the development of a novel therapeutic strategy for the treatment of colorectal cancer.

Clarithromycin resistance and female gender affect Helicobacter pylori eradication failure in chronic gastritis.

BACKGROUND/AIMS: The eradication rate of the first-line triple therapy (a proton pump inhibitor, clarithromycin, and amoxicillin) for Helicobacter pylori infection has gradually decreased in Korea. We evaluated whether clinical parameters, clarithromycin resistance, and CYP2C19 genotype can affect the eradication failure. METHODS: A total of 203 patients with H. pylori-positive chronic gastritis were consecutively enrolled. They received clarithromycin-based triple therapy for 7 days. A clarithromycin resistance test was performed by detection of A2142G and A2143G point mutations in H. pylori 23S rRNA. The CYP2C19 genotype was examined for polymorphism G681A of exon 5 and G636A of exon 4 by polymerase chain reaction with restriction fragment length polymorphism. Eradication was assessed by a 13C-urea breath test 4 weeks after treatment. RESULTS: Of 203 patients, 190 completed the study. The eradication rate was 64.0% according to intention-to-treat analysis and 68.4% by per-protocol analysis. CY-P2C19 genotypes were identified as follows: 75 poor metabolizers, 75 intermediate metabolizers, and 40 rapid metabolizers. Nonetheless, this polymorphism was not significantly associated with eradication failure (p = 0.682). Clarithromycin resistance was detected in 33/190 patients (17.4%), and their eradication rate was zero. Clarithromycin resistance (odds ratio [OR], 19.13; 95% confidence interval [CI], 9.35 to 35.09) and female gender (OR, 1.73; 95% CI, 1.15 to 4.25) were significantly associated with eradication failure. The other clinical parameters such as age, cigarette smoking, alcohol intake, the body mass index, hypertension, and diabetes were not significantly associated with eradication. CONCLUSION: Clarithromycin resistance and female gender are factors affecting H. pylori eradication failure in patients with chronic gastritis.