Probiotic treatment induced change of inflammation related metabolites in IBS-D patients/double-blind, randomized, placebo-controlled trial.

There have been many studies suggesting that probiotics are effective in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). However, its mechanism of action as well as prediction of response is still to be elucidated. In the present study, to find out metabolomic characteristics of probiotic effect in IBS-D, we compared IBS symptom changes and metabolomic characteristics in the subjects' urine samples between multi-strain probiotics (one strain of Lactobacillus sp. and four strains of Bifidobacterium sp.) group (n = 32) and placebo group (n = 31). After 8 weeks' administration (3 times/day), dissatisfaction in bowel habits and stool frequencies were significantly improved. Also, probiotics group had significantly changed seven metabolites including palmitic acid methyl ester (PAME) and 4,6-dihydroxyquinoline, 4-(2-aminophenyl)-2,4-dioxobutanoic acid (DOBA). According to IBS-SSS and IBS-QoL questionnaires, IBS-SSS responders showed higher PAME levels and IBS-QoL responders showed lower DOBA levels. This suggests potential role of these metabolites as a biomarker to predict probiotics effect in IBS-D patients.

Statins and metachronous recurrence after endoscopic resection of early gastric cancer: a nationwide Korean cohort study.

BACKGROUND: Statins have shown to reduce the risk of various cancers. However, their effects on metachronous recurrence (MR) after endoscopic resection (ER) for early gastric cancer (EGC) are unknown. We evaluate their effects on MR development after ER for EGC. METHODS: We selected 11,568 patients who received ER for EGC from 2002 to 2011 from the Korean National Health Insurance database and classified into 2 groups: control and statins using propensity score matching. Metachronous recurrence was defined as the second ER or gastrectomy performed 6 months after the first ER. RESULTS: Mean follow-up period was 8.8 ± 3.1 years. Statins showed a significantly lower incidence of MR than the control group (12.5% vs 2.2%, respectively, P < 0.01). After conducting competing risk analyses and time-dependent cox regression analysis considering immortal time bias, statins still showed a lower incidence rate of MR compared to that observed in the control group. For the multivariate analysis, statins remained significant (HR 0.17; 95% CI 0.13-0.24, P < 0.01). In the dose-response analysis, an inverse dose-response relationship was identified between MR and statins (P < 0.01). CONCLUSION: Statins was significantly associated with a reduced risk of MR after ER for EGC with an inverse dose-response relationship.

Helicobacter pylori Eradication Can Reverse the Methylation-Associated Regulation of miR-200a/b in Gastric Carcinogenesis.

Background/Aims: Epigenetic change is one of the mechanisms that regulates the expression of microRNAs (miRNAs) and is known to play a role in Helicobacter pylori-associated gastric carcinogenesis. We aimed to evaluate the epigenetic changes of miR-200a/b in H. pylori-associated gastric carcinogenesis and restoration after eradication. Methods: The expression and methylation levels of miR-200a/b were evaluated in gastric cancer (GC) cell lines, human gastric mucosa of H. pylori-negative and -positive controls, and H. pyloripositive GC patients. Next, the changes in the expression and methylation levels of miR-200a/b were compared between H. pylori -eradication and H. pylori -persistence groups at 6 months. Real-time reverse transcription-polymerase chain reaction was conducted to investigate the miRNA expression levels, and MethyLight was performed to assess the methylation levels. Results: In the GC cell lines, the level of miR- 200a/b methylation decreased and the level of expression increased after demethylation. In the human gastric mucosa, the miR-200a/b methylation levels increased in the following group order: H. pylori-negative control group, H. pylori-positive control group, and H. pylori-positive GC group. Conversely, the miR-200a/b expression levels decreased in the same order. In the H. pylori -persistence group, no significant changes were observed in the methylation and expression levels of miR-200a/b after 6 months, whereas the level of methylation decreased and the level of expression of miR-200a/b increased significantly 6 months in the H. pylori-eradication group. Conclusions: Epigenetic alterations of miR-200a/b may be implicated in H. pylori -induced gastric carcinogenesis. This field defect for cancerization is suggested to be improved by H. pylori eradication.

Synergistic Effect of Lymphatic Invasion and Venous Invasion on the Risk of Lymph Node Metastasis in Patients with Non-Curative Endoscopic Resection of Early Gastric Cancer.

BACKGROUND: Although additive radical surgery is recommended for patients with non-curative endoscopic resection for early gastric cancer (EGC), lymph node (LN) metastasis or remnant tumor is detected in only about 10% of patients. Therefore, we aimed to identify patients who required surgery by identifying significant risk factors for LN metastasis and evaluate long-term outcomes in patients with non-curative endoscopic resection. METHODS: We retrospectively analyzed the database of Seoul National University Hospital to identify patients who underwent endoscopic resection for EGC from June 2005 to December 2016. RESULTS: Three hundred and twenty-nine patients did not meet the criteria for curative resection after endoscopic resection. Among them, 140 patients underwent additional surgery and 171 patients refused surgery and regularly received follow-up. In the surgery group, LN metastasis was found in 12.1% of patients. Logistic regression analysis revealed that the rate of LN metastasis was significantly higher in patients with lymphatic invasion (LI) (odds ratio [OR] 5.84, p = 0.014) and venous invasion (VI) (OR 5.66, p = 0.006). We analyzed LN metastasis based on LI and VI in the surgical group. LN metastasis was significantly increased in the positive LI and VI groups compared with the negative LI and VI groups (OR 68.32; 95% confidence interval, 4.74-984.82; p = 0.002). CONCLUSIONS: Both LI and VI were significant predictors of LN metastasis. The risk of LN metastasis was augmented when both LI and VI were positive. Therefore, LI and VI should be evaluated separately in patients with non-curative endoscopic resection. Additive surgery should be recommended for patients with LI and/or VI.

Determining the current indications for endoscopic submucosal dissection in patients with Lauren mixed-type early gastric cancer.

BACKGROUND AND AIM: Recent study showed that early gastric cancer (EGC) with Lauren mixed-type (MT) histology is associated with worse prognosis. We aimed to evaluate the clinicopathologic features and prognostic significance of Lauren MT-EGCs that meets the criteria for endoscopic submucosal dissection (ESD). METHODS: We reviewed 2665 patients with EGC who underwent surgery between 2010 and 2015. The clinicopathologic features and invasiveness including lymph node metastasis (LNM) and lymphovascular invasion (LVI) of MT-EGC were compared with those of intestinal type and diffuse type by Lauren histology. RESULTS: Among 2665 patients, EGCs in 241 (9%) patients were classified as MT. Tumor size was larger and depth of invasion was greater than other histology. Among patients with MT-EGC, 16.6% (40/241) showed LNM and 22.8% (55/241) showed lymphatic invasion, which were significantly higher than that of patients with other Lauren types (8.2% and 15.3% in intestinal type and 9.1% and 8.7% in diffuse type, P < 0.001). This finding remained significant even after adjusting for depth of invasion. However, when we analyzed the patient groups who met the absolute or expanded criteria of ESD, no significant difference was observed in the rates of LNM or LVI or cancer mortality by Lauren classification. CONCLUSION: Mixed-type early gastric cancer (MT-EGC) exhibited larger tumor size, greater depth of invasion, and higher risk of LNM and LVI. However, among the patients who met the absolute or expanded criteria of ESD, no significant difference was observed in LNM, LVI, and gastric cancer mortality risk.

Clinical outcomes of early gastric cancer with non-curative resection after pathological evaluation based on the expanded criteria.

Additional surgical resection should be considered for the patients with pathological findings beyond the expanded criteria with the risk for LN metastasis. However, close observation without additional surgery may be applied because of various reasons. We aimed to determine the clinical outcomes of early gastric cancer beyond the expanded criteria after endoscopic resection according to the pathological extent. A total of 288 patients with 289 lesions beyond the expanded criteria of endoscopic submucosal dissection for early gastric cancer were analyzed between 2005 and 2016, and classified into two groups according to additional treatment: observation (n = 175 patients, 175 lesions) and surgery (n = 113 patients, 114 lesions). The depth of tumor invasion was greater and the tumor-positive vertical margin and lymphatic and venous invasion were more common in the surgery group than in the observation group (P<0.001). Residual, synchronous, and metachronous tumors were more common in the observation group; however, the occurrence of regional lymph node and distant metastasis did not differ between the groups. Overall survival and 5-year disease-specific survival did not differ between the groups (observation vs surgery, 88.6 vs 93.8%; P = 0.259, 98.2 vs 100%; P = 0.484, respectively), but the 5-year disease-free survival was lower in the observation group (73.5 vs 97.9%; P<0.001). On multivariate analysis, tumor-positive lateral margin was a risk factor for residual tumor and lymphatic and venous invasion were risk factors for regional lymph node metastasis. In conclusion, the clinical course of beyond the expanded criteria of endoscopic submucosal dissection for early gastric cancer showed good prognosis over 98% in 5-year disease specific survival. If additional surgery cannot be performed, a close follow-up with endoscopy and abdominal computed tomography can be considered as an alternative for carefully selected patients without lymphatic and vascular invasion.

There might be a distinctive clinical phenotype of constipation with non-cardiac chest pain which responds to combination laxatives: A retrospective, longitudinal symptom analysis.

Proton pump inhibitor (PPI)-refractory non-cardiac chest pain (NCCP) is often resolved when constipation was relieved. This study aimed to investigate the clinical features of patients with both NCCP and constipated functional bowel disorders (FBD).Among 692 consecutive patients diagnosed with functional constipation or irritable bowel syndrome with constipation and underwent anorectal manometry (ARM) in our hospital, PPI-refractory NCCP was present in 37. The clinical course of various torso symptoms including NCCP and ARM findings were retrospectively evaluated.The mean age was lower in the NCCP than in the non-NCCP group (57.4 vs 61.3 years, respectively, P = .042). Back pain (16.2% vs 2.0%, P < .001) and sharp abdominal pain (13.5% vs 0.9%, P < .001) were more common in the NCCP group. Increased resting pressure (16.2% vs 6.9%, P = .036) and squeezing pressure (62.2% vs 50.7%, P = .049) of the anal sphincter, increased urgency volume (40.5% vs 23.2%, P = .004), and maximal volume (25.7% vs 15.0%, P = .032) for rectal sensation were more frequently observed in the NCCP group. After taking laxatives for 1 to 3 months, 81.1% of patients with NCCP reported improvement.Subjects with NCCP showed decreased rectal sensation more frequently at anorectal manometry. Majority of patients with NCCP reported improvement of symptom upon relief of constipation. Constipation might be a therapeutic target in patients with NCCP related to constipated functional bowel disorders.

Exploring the possibility of endoscopic submucosal dissection for clinical submucosal invasive early gastric cancers.

BACKGROUND: The current standard treatment modality for clinical submucosal invasive (cT1b) early gastric cancer (EGC) is surgery. However, there are discrepancies in T staging between pre- and post-operative findings, and in cases of overestimation, patients may lose the opportunity to preserve the stomach. The aim of this study was to analyze surgical outcomes of cT1b EGC and determine the pre-treatment factors favoring ESD. METHODS: Patients who underwent gastrectomy for cT1b EGC with a tumor size of 30 mm or less in diameter and differentiated-type histology were retrospectively reviewed from January 2010 to December 2014. According to the final surgical pathologic results, two groups were classified: patients whose pathologic results qualified for current ESD indication (ESD-qualified group, n = 203) and patients whose pathologic results made them ineligible for ESD (ESD-disqualified group, n = 261). The preoperative clinical characteristics were compared. RESULTS: Forty-three percent of the patients (203/464) who underwent gastrectomy for cT1b EGC qualified for ESD; their endoscopic lesion tended to be smaller than 20 mm in size and located in the distal part of stomach. In addition, the ESD-qualified group showed a significantly higher proportion of well-differentiated tubular adenocarcinoma on endoscopic biopsy and of the flat/depressed type in the endoscopic evaluation. CONCLUSION: Forty-three percent of the patients with cT1b EGC who underwent gastrectomy had a chance to preserve their stomach by ESD. Therefore, pre-treatment factors such as endoscopic lesion size, location, histology, and gross type should be considered for treatment modality selection for cT1b EGC.

Asthma under control is inversely related with erosive esophagitis among healthy adults.

BACKGROUND: Some recent studies suggested that reflux esophagitis is positively correlated with asthma. However, there are debates on this issue. The aim of this study is to clarify the true association between reflux esophagitis and asthma in a large population. METHODS: Medical records of subjects who received health surveillance checkup between January 2005 and December 2011 were reviewed. Their endoscopic findings, medical history, body mass index, and smoking history were analyzed. Erosive esophagitis was defined as endoscopically detected mucosal break at the Z-line, irrespective of reflux symptom. Information about asthma history was obtained from their questionnaires and medical records. RESULTS: Out of the total 15,999 patients, 986 had erosive esophagitis and 376 had asthma. In this population, erosive esophagitis was inversely related with asthma in univariable analysis (OR, 0.586; 95% CI, 0.342-1.003, p = 0.049). In multivariable analysis, asthma was demonstrated as an independent negative risk factor for erosive esophagitis (OR, 0.472; 95% CI, 0.257-0.869, p = 0.016), under adjustment with age (OR, 1.000; 95% CI, 0.994-1.006, p = 0.977), male sex (OR, 2.092; 95% CI, 1.683-2.601, p < 0.001), body mass index (OR, 1.115; 95% CI, 1.090-1.141, p < 0.001), smoking (OR, 1.584; 95% CI, 1.318-1.902, p < 0.001), and urban residence (OR, 1.363; 95% CI, 1.149-1.616, p < 0.001). Likewise, erosive esophagitis was shown to be an independent negative risk factor for asthma (OR, 0.558; 95% CI, 0.324-0.960, p = 0.035) under adjustment with age (OR, 1.025; 95% CI, 1.015-1.034, p <0.001), male sex (OR, 0.861; 95% CI, 0.691-1.074, p = 0.185), and body mass index (OR, 1.067; 95% CI, 1.030-1.106, p < 0.001) in multivariable analysis. CONCLUSIONS: Contrary to previous studies, this large scale data showed inverse association between erosive esophagitis and asthma. Further studies investigating the clear mechanism of this phenomenon are warranted.

Clinical features and outcomes in spontaneous intramural small bowel hematoma: Cohort study and literature review.

BACKGROUND/AIMS: Spontaneous intramural small bowel hematoma (SISBH) is an extremely rare complication of anticoagulant or antiplatelet therapy. We assessed the clinical characteristics and outcomes of patients with SISBH according to the anatomical location of the hematoma. METHODS: From January 2003 to February 2016, medical records for all patients hospitalized for SISBH at 2 tertiary referral hospitals were retrospectively reviewed. The primary outcome was requirement for surgery. RESULTS: A total of 37 patients were enrolled. The mean age was 74.1 years. Among them, 33 patients (89.2%) were taking anticoagulant and/or antiplatelet agents. Duodenal intramural hematoma was detected in 4 patients (10.8%), jejunal in 16 (43.2%), and ileal in 17 (45.9%). Compared to jejunal and ileal involvement, duodenal intramural hematoma was significantly associated with high Charlson comorbidity index and low levels of white blood cells, hemoglobin, and platelets in the blood. SISBH in the duodenum was related to thrombocytopenia in 3 patients following systemic chemotherapy for malignancy. All patients with SISBH showed clinical improvement with conservative therapy. Mean length of hospital stay was 9.35 days. Independent predictors of a hospital stay of more than 7 days were body weight less than 60 kg (odds ratio [OR], 12.213; 95% confidence interval [CI], 1.755-84.998; P=0.011) and a history of cerebrovascular accidents (OR, 6.667; 95% CI, 1.121-39.650; P=0.037). CONCLUSIONS: Compared to jejunal and ileal involvement, thrombocytopenia may result in spontaneous duodenal intramural hematoma among patients who are treated with systemic chemotherapy for malignancies. Patients with SISBH have excellent clinical outcomes with conservative therapy regardless of the anatomical location of the hematoma.

Clinical Implication and Risk Factors for Malignancy of Atypical Gastric Gland during Forceps Biopsy.

Background/Aims: Although forceps biopsy is performed for suspicious gastric tumors during endoscopy, it is difficult to determine treatment strategies for atypical gastric glands due to uncertainty of the diagnosis. The aim of this study was to investigate clinical implications and risk factors for predicting malignancy in atypical gastric glands during forceps biopsy. Methods: We retrospectively reviewed medical records of 252 patients with a diagnosis of atypical gastric gland during forceps biopsy. Predictors of malignancy were analyzed using initial endoscopic findings and clinical data. Results: The final diagnosis for 252 consecutive patients was gastric cancer in 189 (75%), adenoma in 26 (10.3%), and gastritis in 37 (14.7%). In the multivariate analysis, lesion sizes of more than 10 mm (odds ratio [OR], 3.021; 95% confidence interval [CI], 1.480 to 6.165; p=0.002), depressed morphology (OR, 3.181; 95% CI, 1.579 to 6.406, p=0.001), and surface nodularity (OR, 3.432; 95% CI, 1.667 to 7.064, p=0.001) were significant risk factors for malignancy. Conclusions: Further evaluation and treatment should be considered for atypical gastric gland during forceps biopsy if there is a large-sized (>10 mm) lesion, depressed morphology, or surface nodularity.

Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial.

BACKGROUND AND AIMS: Whether eradication of Helicobacter pylori reduces the incidence of metachronous gastric cancer (MGC) is still debatable. We aimed to evaluate the long-term effect of H pylori eradication on the development of MGC after endoscopic gastric tumor resection. METHODS: We undertook an open-label, prospective, randomized controlled trial at a tertiary hospital in Seoul, Korea. Participants were recruited during April 2005 to February 2011 and followed until December 2016. We assigned 898 patients with H pylori infection treated with endoscopic resection (ER) for gastric dysplasia or early gastric cancer to receive (n =442) or not receive (n =456) eradication therapy using a random-number chart. Eradication group patients received oral omeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg twice daily for a week, whereas control group patients received no H pylori treatment. The primary outcome was the incidence of MGC (intention-to-treat analysis). RESULTS: The 877 patients who attended ≥1 follow-up examination (eradication group, 437; control group, 440) were analyzed. Median follow-up was 71.6 months (interquartile range, 42.1-90.0). MGC developed in 18 (4.1%) eradication and 36 (8.2%) control group patients (log-rank test, P = .01). In our yearly analysis, the effect of eradication showed a significant difference in 5 years after allocation (log-rank test, P = .02). The adjusted hazard ratio for the control group was 2.02 (95% CI, 1.14-3.56; P = .02), compared with the eradication group. CONCLUSIONS: H pylori eradication significantly reduces the incidence of MGC after ER of gastric tumors and should be considered for H pylori-positive gastric tumor patients treated with ER. (Clinical trial registration number: NCT01510730.).

Seasonal changes in surface ozone over South Korea.

Recently, the surface ozone concentration in the Korean peninsula has been increasing more rapidly than in the past, and seasonal changes are appearing such as increases in the number of ozone alerts in springtime. We examined changes in the timing of annual maximum South Korean O3 levels by fitting a sine function to data from 54 air-quality monitoring sites over a 10-year period (2005-2014). The analytical results show that the date of maximum ozone concentration at 23 points in the last 10 years has been advanced by about 2.1 days per year (E-sites), while the remaining 31 points have been delayed by about 2.5 days per year (L-sites). We attribute these differences to seasonal O3 changes: E-sites show a larger increase in O3 level in March-April (MA) than in June-July (JJ), while L-sites show a larger increase in JJ than in MA. Furthermore, these shifts are significantly larger in magnitude than those reported for Europe and North America. We also examined one possible reason for these seasonal differences: the relationship between O3 and precursors such as NO2 and CO. E-sites showed a rapid decrease in NO2 (NO) concentration in MA over the last decade. As a result, the ozone concentration at E-sites seems to have increased due to the absence of ozone destruction by NOx titration in early spring. In L-Sites, the concentrations of ozone precursors such as NO2 and CO in JJ showed a smaller decrease than those at other sites. Therefore, in L-sites, relatively large amounts of ozone precursors were distributed in JJ, implying that more ozone was generated. We suggest that shifts in the South Korean O3 seasonal cycle are due to changes in early spring and summer NO2 (NO) and CO levels; this should be tested further by modeling studies.

Comparison of Tight Junction Protein-Related Gene mRNA Expression Levels between Male and Female Gastroesophageal Reflux Disease Patients.

Background/Aims: Male predominance has been observed in the erosive reflux disease (ERD), but reverse finding in nonerosive reflux disease (NERD). This suggests sex-specific medicine approach is needed but its mechanism is remained to be elucidated. We aimed to compare clinical characteristics and mRNA expression levels of tight junction-related proteins between male and female gastroesophageal reflux disease (GERD). Methods: Sixteen healthy controls, 45 ERD, and 14 NERD patients received upper endoscopies and completed questionnaires. Quantitative real-time polymerase chain reactions of occludin (OCLN), zonal occludens (ZO) 1, claudin-1 (CLDN1) and claudin-4 (CLDN4), and neurokinin 1 receptor (NK1R) were performed in the distal esophageal mucosal specimen. These results were analyzed by sex. Results: Female GERD patients were affected more by reflux symptoms than males. The impairment of overall quality of life was more prominent in female patients with reflux symptoms than male patients (5.6±0.2 vs 4.9±0.6, p=0.009). The levels of OCLN mRNA expression were significantly lower in the male ERD group. On the other hand, those of CLDN1, CLDN4, and NK1R except ZO-1 were significantly higher in the male ERD group. Conclusions: We demonstrated that female ERD/NERD patients were affected more by GERD and male ERD patients showed significant changes of tight junction protein mRNA expression levels.

Clinical efficacy of endoscopic ultrasonography for decision of treatment strategy of gastric cancer.

BACKGROUND: Accurate preoperative tumor staging of gastric cancer is indispensable with expansion of indications for laparoscopic surgery and endoscopic resection. It is important to distinguish mucosal cancer (T1a) in smaller lesion and differentiate early gastric cancer (EGC) in larger lesion considering endoscopic resection indication and laparoscopic surgery indication. We evaluated the clinical outcomes of endoscopic ultrasonography (EUS) for the decision of treatment strategy of gastric cancer compared with pathological staging. METHODS: The patients who underwent EUS and surgical or endoscopic resection for gastric cancer were retrospectively reviewed between September 2005 and February 2016. The depth of tumor invasion (T staging) by EUS was compared with the pathological staging after endoscopic or surgical resection. RESULTS: A total of 6084 patients were finally analyzed. The accuracy rates for T1a and EGC were 75.0 and 89.4%, respectively. The overall accuracy of T staging by EUS was 66.3% when divided by T1a, T1b, and over T2. The accuracy of EUS prior to endoscopic resection was 75.1% in absolute indication and 73.1% in expanded criteria, respectively. The accuracy rates for T1a with lesion ≤ 2 cm in miniprobe EUS and EGC with lesion > 2 cm in conventional EUS were 84.6 and 83.2%, respectively. In multivariate analysis, presence of ulcer, large tumor size, and radial EUS were associated with overestimation, and small tumor size and miniprobe were associated with underestimation in T staging. CONCLUSIONS: EUS showed the high accuracy of 84.6% for T1a in lesion ≤ 2 cm in miniprobe EUS and 83.2% for EGC in lesion > 2 cm in conventional EUS, respectively. EUS can be a complementary diagnostic method to determine endoscopic or surgical treatment modality.

Continuous Use of Thienopyridine May Be as Safe as Low-Dose Aspirin in Endoscopic Resection of Gastric Tumors.

Background/Aims: Current guidelines recommend withholding antiplatelets for 5-7 days before high-risk endoscopic procedures. We investigated whether this reduces post-endoscopic submucosal dissection (ESD) bleeding. Methods: Gastric ESD cases with antiplatelets were retorospectively reviewed. Withholding antiplatelets for 5-7 days before ESD was defined as cessation and 0-4 days as continuation. The rate and risk of post-ESD bleeding according to the types and cessation of antiplatelets were assessed. Results: Among the 215 patients (117 adenoma and 98 early gastric cancer), 161 patients were on single (94 aspirin, 56 thienopyridine, and 11 other agents), 51 on dual, and 3 on triple antiplatelets. Post-ESD bleeding rates were 12.8% in aspirin users, 3.6% in thienopyridine, 27.5% in dual, 33.3% in triple therapy, and 9.7% in the cessation and 15.0% in the continuation group. Multiple antiplatelets (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.01 to 5.76) and specimen size ≥ 5.5 cm (OR, 2.84; 95% CI, 1.04 to 7.73) were the risk of bleeding, while continuation of thienopyridine (OR, 0.23; 95% CI, 0.05 to 1.09) and antiplatelets (OR, 1.83; 95% CI, 0.68 to 4.94) did not increase the risk of bleeding. Conclusions: Continuing thienopyridine and aspirin did not increase the risk of post-ESD. Multiple antiplatelet therapy and a large specimen size were independent risk factors of post-ESD bleeding.

Helicobacter pylori Is Associated with miR-133a Expression through Promoter Methylation in Gastric Carcinogenesis.

BACKGROUND/AIMS: To investigate whether Helicobacter pylori eradication can reverse epigenetic silencing of microRNAs (miRNAs) which are associated with H. pylori-induced gastric carcinogenesis. METHODS: We examined expression and promoter methylation of miR-34b/c, miR-133a, let-7a, and let-7i in gastric cancer cell line, before/after demethylation. Among them, epigenetically controlled miRNAs were identified. Their expression and promoter methylation was examined in human tissues of H. pylori-positive gastric cancer (T), H. pylori-positive gastritis (H), and H. pylori-negative controls (C). We also compared changes of miRNA expression and promoter methylation in H. pylori-positive patients who were endoscopically treated for early gastric cancer, between baseline and 1 year later according to eradication status. RESULTS: In gastric cancer cell line, miR-34b/c and miR-133a showed epigenetic silencing. In human tissues, miR-34b/c and miR-133a showed serial increase of promoter methylation in order of C, H, and T (all, p＜0.01), and the miR-133a expression showed serial decrease (C vs H, p=0.02; H vs T, p=0.01; C vs T, p＜0.01) while miR-34b and miR-34c expressions did not. H. pylori eradication induced decrease of methylation (p＜0.01) and increase of miR-133a expression (p=0.03), compared with noneradication group. CONCLUSIONS: This result suggests H. pylori eradication could reverse methylation-silencing of miR-133a which is involved in H. pylori-induced gastric carcinogenesis.

Long-Term Effects of Helicobacter pylori Eradication on Metachronous Gastric Cancer Development.

BACKGROUND/AIMS: Gastric mucosal atrophy and intestinal metaplasia due to Helicobacter pylori infection are the main precursor lesions of gastric cancer. The aim of this study was to evaluate the long-term effects of H. pylori eradication on the progression of precancerous lesions to metachronous cancer after endoscopic resection of early gastric cancer (EGC). METHODS: Patients who underwent endoscopic resection of EGC were retrospectively reviewed. Changes in precancerous lesions and development of metachronous cancer were compared according to H. pylori eradication and final infection status. RESULTS: In total, 565 patients were followed for over 5 years after endoscopic resection of EGC. The grade of atrophy on corpus was significantly lower in the H. pylori-eradicated group than in the persistent group during follow-up (p=0.029). In patients ＜70 years of age, the cumulative incidence rate of metachronous cancer was significantly lower in the H. pylori-eradicated group than in the persistent group (p=0.018). Age was an independent risk factor for metachronous cancer development. CONCLUSIONS: H. pylori eradication might prevent the development of metachronous cancer in patients ＜70 years of age by delaying the progression of precancerous lesions after endoscopic resection of EGC.

Helicobacter pylori-induced modulation of the promoter methylation of Wnt antagonist genes in gastric carcinogenesis.

BACKGROUND: This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis. METHODS: The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs. RESULTS: The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P < 0.001). SFRP1, -2, and DKK3 gene expression was stepwise downregulated from H. pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P < 0.05). Among the Wnt antagonists, only the degrees of methylation and downregulation of DKK3 were significantly reduced after H. pylori eradication (P < 0.05). CONCLUSION: Epigenetic silencing of SFRP and DKK family genes may facilitate the formation of an epigenetic field during H. pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation.

Novel risk stratification for metachronous recurrence after curative endoscopic submucosal dissection for early gastric cancer.

BACKGROUND AND AIMS: This study stratified the risk of developing metachronous gastric cancer (MGC) after curative endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) to enable customization of endoscopic surveillance for MGC. METHODS: A total of 1115 patients who underwent curative ESD based on the expanded criteria for differentiated EGC from 2005 to 2014 at a single tertiary hospital were enrolled in this retrospective cohort study. They were followed up with annual endoscopy for a median of 50.1 months. Helicobacter pylori and histologic intestinal metaplasia (IM) were evaluated. The Kaplan-Meier method and Cox regression analysis were used for risk stratification. RESULTS: Three risk groups were identified: group 1 comprised patients with a synchronous neoplasm; group 2 comprised male patients with corpus IM; and group 3 comprised male patients without corpus IM or female patients. The 5- and 7-year cumulative risks (95% confidence interval [CI]) for metachronous recurrence were 15.1% (95% CI, 7.7-22.5) and 26.1% (95% CI, 14.9-37.3), respectively, in group 1; 5.6% (95% CI, 3.1-8.1) and 9.3% (95% CI, 5.4-13.2), respectively, in group 2; and 3.8% (95% CI, 1.6-6.0) and 4.9% (95% CI, 2.4-7.4), respectively, in group 3 (P < .001 by log-rank test). The incidence of MGCs increased constantly even after 5 years in groups 1 and 2 but not in group 3. There was not enough evidence to show an association between H pylori eradication and metachronous recurrence in the data. CONCLUSIONS: Meticulous annual endoscopic surveillance for MGC for more than 5 years is recommended for patients with synchronous neoplasm. Endoscopic surveillance may also be extended beyond 5 years in male patients with corpus IM.