A survey of current practices in post-polypectomy surveillance in Korea.

BACKGROUND/AIMS: We investigated the clinical practice patterns of post-polypectomy colonoscopic surveillance among Korean endoscopists. METHODS: In a web-based survey conducted between September and November 2021, participants were asked about their preferred surveillance intervals and the patient age at which surveillance was discontinued. Adherence to the recent guidelines of the U.S. Multi-Society Task Force on Colorectal Cancer (USMSTF) was also analyzed. RESULTS: In total, 196 endoscopists completed the survey. The most preferred first surveillance intervals were: a 5-year interval after the removal of 1-2 tubular adenomas < 10 mm; a 3-year interval after the removal of 3-10 tubular adenomas < 10 mm, adenomas ≥ 10 mm, tubulovillous or villous adenomas, ≤ 20 hyperplastic polyps < 10 mm, 1-4 sessile serrated lesions (SSLs) < 10 mm, hyperplastic polyps or SSLs ≥ 10 mm, and traditional serrated adenomas; and a 1-year interval after the removal of adenomas with highgrade dysplasia, >10 adenomas, 5-10 SSLs, and SSLs with dysplasia. In piecemeal resections of large polyps ( > 20 mm), surveillance colonoscopy was mostly preferred after 1 year for adenomas and 6 months for SSLs. The mean USMSTF guideline adherence rate was 30.7%. The largest proportion of respondents (40.8%-55.1%) discontinued the surveillance at the patient age of 80-84 years. CONCLUSIONS: A significant discrepancy was observed between the preferred post-polypectomy surveillance intervals and recent international guidelines. Individualized measures are required to increase adherence to the guidelines.

Forecasting the future prevalence of inflammatory bowel disease in Korea through 2048: an epidemiologic study employing autoregressive integrated moving average models.

BACKGROUND AND AIM: The global inflammatory bowel disease (IBD) escalation has precipitated an increased disease burden and economic impact, particularly in Asia. This study primarily aimed to predict the future prevalence of IBD in Korea and elucidate its evolution pattern. METHODS: Using a validated diagnostic algorithm, we analyzed data from the Korean National Health Insurance Service between 2004 and 2017 to identify patients with IBD. We predicted the number and prevalence of patients with IBD from 2018 to 2048 with the autoregressive integrated moving average method. A generalized linear model (GLM) was also employed to identify factors contributing to the observed trend in IBD prevalence. RESULTS: Our prediction model validation demonstrated an acceptable error range for IBD prevalence, with a 2.45% error rate and a mean absolute difference of 2.61. We foresee a sustained average annual increase of 4.51 IBD cases per 100 000, culminating in a prevalence of 239.73 per 100 000 by 2048. The forecasted average annual percent change was 6.17% for males and 2.75% for females over the next 30 years. The GLM analysis revealed that age, gender and time significantly impact the prevalence of IBD, with notable disparities observed between genders in specific age groups for both Crohn's disease and ulcerative colitis (all interaction P < 0.05). CONCLUSIONS: Our study forecasts a notable increase in Korean IBD prevalence by 2048, particularly among males and the 20-39 age group, highlighting the need to focus on these high-risk groups to mitigate the future disease burden.

Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2.

BACKGROUND AND AIMS: Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations. METHODS: Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term. RESULTS: We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers). CONCLUSIONS: This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.

A risk prediction model for hepatocellular carcinoma in non-alcoholic fatty liver disease without cirrhosis: HCC prediction for non-cirrhotic NAFLD.

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC), HCC risk in non-cirrhotic NAFLD received little attention. We aimed to develop and validate an HCC risk prediction model for non-cirrhotic NAFLD. METHODS: A nationwide cohort of non-cirrhotic NAFLD patients in Korea was recruited to develop a risk prediction model and validate it internally (n = 409 088). A model using a simplified point system was developed by Cox proportional hazard model. K-fold cross-validation assessed the accuracy, discrimination and calibration. The model was validated externally using a hospital cohort from Asan Medical Center (n = 8721). RESULTS: An 11-point HCC risk prediction model for non-cirrhotic NAFLD was developed using six independent factors of age, sex, diabetes, obesity, serum alanine aminotransferase level and gamma-glutamyl transferase level (c-index 0.75). The average area under receiver operating curves (AUROCs) of the model was 0.72 at 5 years and 0.75 at 10 years. In the external validation cohort, the AUROCs were 0.79 [95% confidence interval [CI], 0.59-0.95] at 5 years and 0.84 (95% CI, 0.73-0.94) at 10 years. The calibration plots showed the expected risks corresponded well with the observed risks. Risk stratification categorized patients into the low (score 0-6), moderate (7, 8) and high (9-11; estimated incidence rate >0.2%/year) risk groups. CONCLUSIONS: A novel HCC risk prediction model for non-cirrhotic NAFLD patients was developed and validated with fair performance. The model is expected to serve as a simple and reliable tool to assess HCC risk and assist precision screening of HCC.

Assessing Active Bowel Inflammation in Crohn's Disease Using Intestinal Ultrasound: Correlation With Fecal Calprotectin.

AIM: To analyze the correlation between intestinal ultrasound (IUS) and serum and fecal biomarkers, and the characteristics of small bowel disease, for the assessment of active bowel inflammation. METHODS: Patients with Crohn's disease (CD) who underwent an initial IUS examination between July 2018 and November 2022 at our institution were included retrospectively. We divided small and large bowels into seven segments, and recorded the presence of active inflammation according to following criteria: bowel wall thickness ≥ mm with ≥1 of feature of active disease on IUS. The correlations between IUS-assessed activity and serum C-reactive protein (CRP, mg/dL) and fecal calprotectin (FC, µg/g) levels were analyzed. RESULTS: A total of 127 patients were included (mean age: 32.42 ± 12.07, M:F = 90:37, median disease duration 6 years [0-35]). Of them, 78 showed active bowel inflammation (61.4%), with inflammation distal to the terminal ileum being the most common disease location (n = 61, 78.2%). FC and serum CRP levels were significantly correlated with the number of segments with active inflammation (rho = 0.58, 0.48), number of segments with complications (r = 0.35, 0.31), and US activity score (r = 0.62, 0.54). With FC cutoff values of 100 and 150 µg/g, the concordance rates for patients with active small bowel disease were 78.7% (26/33) and 72.7% (24/33), respectively, which were better than those for other disease locations. CONCLUSIONS: Disease activity determined by IUS was significantly correlated with the biomarkers, with a better concordance rate in patients with active small bowel disease than in those with other disease locations with FC cut-off values of 100 and 150 µg/g.

Ideal Timing of Discontinuation of Antiplatelet Agents Before Gastric Endoscopic Submucosal Dissection for Reducing Delayed Bleeding.

BACKGROUND AND AIMS: This study aimed to evaluate whether the use of antiplatelet agents increases the risk of bleeding after gastric endoscopic submucosal dissection (ESD) and to determine the appropriate time to discontinue antiplatelet agents to minimize complications. METHODS: This retrospective observational study utilized a collected dataset of patients who underwent ESD for gastric adenoma and cancer between January 2010 and December 2020. Patients were classified into three groups according to antiplatelet agent use and discontinuation status. We investigated the risk of post-ESD bleeding with different interruption times and antiplatelet agent types. RESULTS: Of 1879 patients, 1389 were non-users, 190 were in the continuous group, and 203 were in the interrupted group. The rates of overall and delayed bleeding were significantly higher in patients who continued or were interrupted within three days before ESD than in the non-users and interrupted group (6.3% vs. 1.2%, p < 0.001, 6.3% vs. 2.5%, p = 0.01, respectively). Significant differences in delayed bleeding between the continuous and interrupted groups decreased with longer cessation periods. In multivariate analysis, continuous antiplatelet agents were still the strongest risk factor for bleeding (OR 2.81, 95% CI 1.14-6.90). Lower third location and longer procedure times were also independent risk factors for post-ESD bleeding (OR 2.75; 95% CI 1.08-6.97; OR 1.02; 95% CI 1.01-1.02). CONCLUSION: Continuous antiplatelet agent use increases the risk of delayed bleeding after gastric ESD. Therefore, the optimal timing of interruption, rather than the type of antiplatelet agent, should be considered to avoid an additional risk of bleeding and thromboembolism.

Anti-NMDAR encephalitis in Crohn's disease undergoing long-term infliximab treatment: A case report.

Infliximab, a chimeric monoclonal antibody against anti-tumor necrosis factor-α (TNF-α), has revolutionized the management of inflammatory bowel disease. However, a recent nested case-control study showed that anti-TNF-α therapy exposure in patients with autoimmune diseases is associated with an increased risk of inflammatory central nervous system (CNS) events. A 27-year-old man diagnosed with Crohn's disease at 17 years of age was referred to our clinic for suffering with Wernicke's aphasia and the right-hand weakness over two weeks. Nine years of treatment for Crohn's disease with infliximab anti-TNF-α therapy was well tolerated. An initial MRI revealed diffuse leptomeningeal enhancement along the bilateral cerebral sulci without any parenchymal abnormalities. Cerebrospinal fluid (CSF) and serum N-methyl-D-aspartate receptor (NMDAR) antibody testing yielded positive results. Anti-NMDAR encephalitis was diagnosed, and the patient was treated with rituximab. A follow-up brain MRI showed new multiple cerebral lesions in the left insular cortex and subcortical white matter of the left frontal and temporal gyri. Approximately 8 months after symptom onset, the CSF and serum NMDAR antibody converted to negative. Twelve months later, the patient fully recovered from anti-NMDAR encephalitis without any neurological deficits and is currently being treated with the anti-interleukin 12/23 agent ustekinumab for Crohn's disease. This is the first report of not only a patient with infliximab-associated anti-NMDAR encephalitis in Crohn's disease but also of an inflammatory non-demyelinating CNS event during long-term suppression of TNF-α. Our case highlights the need for clinicians to recognize the possibility of a paradoxical autoimmune response occurring with novel biological therapies.

Sessile serrated lesion presenting as large pedunculated polyp in the rectum: A case report.

RATIONALE: Sessile serrated lesions (SSLs) are serrated polyps (SP) with the typical serrated architecture of the crypt lining epithelium. SSL has an important clinical implication because they are recognized as precursor lesion of sporadic colorectal cancer (CRC) through "serrated pathway." SSLs usually appear flat to sessile, and are located in the right colon. PATIENT CONCERNS: A 69-year-old man was referred to a tertiary medical center because of intermittent hematochezia for 2 years. DIAGNOSIS: Colonoscopy revealed a large, pedunculated polyp in the rectum. The polyp surface was slightly reddish in color and the elongated stalk was covered with almost normal mucosa. Histopathological examination of the resected specimens revealed the typical features of SSL with low-grade dysplasia. INTERVENTION: Endoscopic mucosal resection using a detachable snare was performed on the tumor for definite diagnosis and treatment. OUTCOMES: There was no evidence of immediate or delayed bleeding after endoscopic mucosal resection, and the hemoglobin level normalized after a 1-year follow-up. LESSONS: We report a rare case of a large pedunculated polyp with typical histological features of SSLs in the rectum. Endoscopists should always consider SSLs at any location even with unusual morphological findings.

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.

Nationwide validation study of diagnostic algorithms for inflammatory bowel disease in Korean National Health Insurance Service database.

BACKGROUND AND AIM: We conducted a nationwide validation study of diagnostic algorithms to identify cases of inflammatory bowel disease (IBD) within the Korea National Health Insurance System (NHIS) database. METHOD: Using the NHIS dataset, we developed 44 algorithms combining the International Classification of Diseases (ICD)-10 codes, codes for Rare and Intractable Diseases (RID) registration and claims data for health care encounters, and pharmaceutical prescriptions for IBD-specific drugs. For each algorithm, we compared the case identification results from electronic medical records data with the gold standard (chart-based diagnosis). A multiple sampling test verified the validation results from the entire study population. RESULTS: A random nationwide sample of 1697 patients (848 potential cases and 849 negative control cases) from 17 hospitals were included for validation. A combination of the ICD-10 code, ≥ 1 claims for health care encounters, and ≥ 1 prescription claims (reference algorithm) achieved excellent performance (sensitivity, 93.1% [95% confidence interval 91-94.7]; specificity, 98.1% [96.9-98.8]; positive predictive value, 97.5% [96.1-98.5]; negative predictive value, 94.5% [92.8-95.8]) with the lowest error rate (4.2% [3.3-5.3]). The multiple sampling test confirmed that the reference algorithm achieves the best performance regarding IBD diagnosis. Algorithms including the RID registration codes exhibited poorer performance compared with that of the reference algorithm, particularly for the diagnosis of patients affiliated with secondary hospitals. The performance of the reference algorithm showed no statistical difference depending on the hospital volume or IBD type, with P-value < 0.05. CONCLUSIONS: We strongly recommend the reference algorithm as a uniform standard operational definition for future studies using the NHIS database.

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.

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.

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.

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.