Proteomic Heterogeneity of the Extracellular Matrix Identifies Histologic Subtype-Specific Fibroblast in Gastric Cancer.

Gastric cancer (GC) is a highly heterogeneous disease regarding histologic features, genotypes, and molecular phenotypes. Here, we investigate extracellular matrix (ECM)-centric analysis, examining its association with histologic subtypes and patient prognosis in human GC. We performed quantitative proteomic analysis of decellularized GC tissues that characterizes tumorous ECM, highlighting proteomic heterogeneity in ECM components. We identified 20 tumor-enriched proteins including four glycoproteins, serpin family H member 1 (SERPINH1), annexin family (ANXA3/4/5/13), S100A family (S100A6/8/9), MMP14, and other matrisome-associated proteins. In addition, histopathological characteristics of GC reveals differential expression in ECM composition, with the poorly cohesive carcinoma-not otherwise specified (PCC-NOS) subtype being distinctly demarcated from other histologic subtypes. Integrating ECM proteomics with single-cell RNA sequencing, we identified crucial molecular markers in the PCC-NOS-specific stroma. PCC-NOS-enriched matrisome proteins and gene expression signatures of adipogenic cancer-associated fibroblasts (CAFadi) are closely linked, both associated with adverse outcomes in GC. Using tumor microarray analysis, we confirmed the CAFadi surface marker, ATP binding cassette subfamily A member 8 (ABCA8), predominantly present in PCC-NOS tumors. Our ECM-focused analysis paves the way for studies to determine their utility as biomarkers for patient stratification, offering valuable insights for linking molecular and histologic features in GC.

Cumulative exposure to impaired fasting glucose and gastrointestinal cancer risk: A nationwide cohort study.

BACKGROUND: Impaired fasting glucose (IFG) is associated with the risk of various cancers, but the cumulative effect of IFG on gastrointestinal cancer risk remains unclear. This study evaluated the association between the cumulative exposure to IFG and gastrointestinal cancer risk. METHODS: The authors extracted data from the Korean National Health Insurance Service and health examination data sets. Among individuals ≥40 years old who were free of diabetes or cancer, 1,430,054 who underwent national health examinations over 4 consecutive years from 2009 to 2012 were selected and followed up until gastrointestinal cancer diagnosis, death, or December 31, 2019. The IFG exposure score (range, 0-4) was based on the number of IFG diagnoses over 4 years. RESULTS: The median follow-up duration was 6.4 years. Consistent normoglycemia for 4 years was found in 44.3% of the population, whereas 5.0% had persistent IFG and 50.7% had intermittent IFG. Compared to the group with an IFG exposure score of 0, groups with IFG exposure scores of 1, 2, 3, and 4 had a 5%, 8%, 9%, and 12% increased risk of gastrointestinal cancer, respectively (score 1: adjusted hazard ratio [aHR], 1.05; 95% confidence interval [CI], 1.01-1.08; score 2: aHR, 1.08; 95% CI, 1.04-1.12; score 3: aHR, 1.09; 95% CI, 1.05-1.14; score 4: aHR, 1.12; 95% CI, 1.06-1.19). Persistent IFG exposure was also associated with higher risks of individual cancer types (colorectum, stomach, pancreas, biliary tract, and esophagus). CONCLUSIONS: Cumulative exposure to IFG is associated with an increased risk of developing gastrointestinal cancer, in a dose-dependent manner. PLAIN LANGUAGE SUMMARY: Hyperglycemia, including both diabetes and prediabetes, has been associated with an increased risk of various cancers. However, the cumulative effect of impaired fasting glucose on the risk of developing gastrointestinal cancer remains unclear. A frequent diagnosis of impaired fasting glucose was dose-dependently associated with a higher risk of developing overall gastrointestinal cancer. Furthermore, risks of individual cancer types increased with persistent impaired fasting glucose. Early detection of hyperglycemia and strict glycemic control can lower the risk of gastrointestinal cancer by reducing hyperglycemic burden. Additionally, for some individuals, lifestyle changes such as managing metabolic syndrome or abstaining from alcohol may also be helpful.

An artificial intelligence system for comprehensive pathologic outcome prediction in early gastric cancer through endoscopic image analysis (with video).

BACKGROUND: Accurate prediction of pathologic results for early gastric cancer (EGC) based on endoscopic findings is essential in deciding between endoscopic and surgical resection. This study aimed to develop an artificial intelligence (AI) model to assess comprehensive pathologic characteristics of EGC using white-light endoscopic images and videos. METHODS: To train the model, we retrospectively collected 4,336 images and prospectively included 153 videos from patients with EGC who underwent endoscopic or surgical resection. The performance of the model was tested and compared to that of 16 endoscopists (nine experts and seven novices) using a mutually exclusive set of 260 images and 10 videos. Finally, we conducted external validation using 436 images and 89 videos from another institution. RESULTS: After training, the model achieved predictive accuracies of 89.7% for undifferentiated histology, 88.0% for submucosal invasion, 87.9% for lymphovascular invasion (LVI), and 92.7% for lymph node metastasis (LNM), using endoscopic videos. The area under the curve values of the model were 0.992 for undifferentiated histology, 0.902 for submucosal invasion, 0.706 for LVI, and 0.680 for LNM in the test. In addition, the model showed significantly higher accuracy than the experts in predicting undifferentiated histology (92.7% vs. 71.6%), submucosal invasion (87.3% vs. 72.6%), and LNM (87.7% vs. 72.3%). The external validation showed accuracies of 75.6% and 71.9% for undifferentiated histology and submucosal invasion, respectively. CONCLUSIONS: AI may assist endoscopists with high predictive performance for differentiation status and invasion depth of EGC. Further research is needed to improve the detection of LVI and LNM.

Lower risk of depression after smoking cessation and alcohol abstinence in patients with gastric cancer who underwent gastrectomy: A population-based, nationwide cohort study.

BACKGROUND: Although depression is associated with poor treatment outcomes in patients with cancer, little is known about whether lifestyle modifications could help prevent depression. The authors aimed to identify the effect of lifestyle modifications, including smoking cessation, alcohol abstinence, and starting regular physical activity, on new-onset depression in patients with gastric cancer who underwent surgery. METHODS: By using the Korean National Health Insurance Service database, patients with gastric cancer who underwent surgery between 2010 and 2017 were identified. Self-reported lifestyle behaviors within 2 years before and after surgery were analyzed using the health examination database. Patients were classified according to changes in lifestyle behaviors, and their risk of new-onset depression was compared. RESULTS: Among 18,902 patients, 2302 (12.19%) developed depression (26.00 per 1000 person-years). Smoking cessation (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.66-0.91) and alcohol abstinence (HR, 0.79; 95% CI, 0.69-0.90) were associated with reduced risk of depression development compared with persistent smoking and persistent drinking, respectively. Starting regular physical activity was not associated with risk of depression. When lifestyle behaviors after gastrectomy were scored from 0 to 3 points (1 point each for not smoking, not drinking, and being physically active), the risk of depression tended to decrease as lifestyle scores increased from 0 points (reference) to 1 point (HR, 0.69; 95% CI, 0.55-0.83), 2 points (HR, 0.60; 95% CI, 0.50-0.76), and 3 points (HR, 0.55; 95% CI, 0.45-0.68). CONCLUSIONS: Smoking cessation and alcohol abstinence are associated with reduced risk of developing depression in patients with gastric cancer who undergo surgery.

A Randomized Controlled Trial of Fibrin Glue to Prevent Bleeding After Gastric Endoscopic Submucosal Dissection.

INTRODUCTION: This study evaluated the efficacy of fibrin glue for preventing postendoscopic submucosal dissection (ESD) bleeding in high-risk patients for bleeding (expected iatrogenic ulcer size ≥40 mm or receiving antithrombotic therapy). METHODS: A multicenter, open-label, randomized controlled trial was performed at 4 tertiary medical centers in South Korea between July 1, 2020, and June 22, 2022. Patients with gastric neoplasm and a high risk of post-ESD bleeding were enrolled and allocated at 1:1 to a control group (standard ESD) or a fibrin glue group (fibrin glue applied to iatrogenic ulcers after standard ESD). The primary outcome was overall bleeding events within 4 weeks. The secondary outcomes were acute bleeding (within 48 hours post-ESD) and delayed bleeding (48 hours to 4 weeks post-ESD). RESULTS: In total, 254 patients were randomized, and 247 patients were included in the modified intention-to-treat population (125 patients in the fibrin glue group and 122 patients in the control group). Overall bleeding events occurred in 12.0% (15/125) of the fibrin glue group and 13.1% (16/122) of the control group ( P = 0.791). Acute bleeding events were significantly less common in the fibrin glue group than in the control group (1/125 vs 7/122, P = 0.034). Delayed bleeding events occurred in 11.2% (14/125) in the fibrin glue group and 7.3% (9/122) in the control group ( P = 0.301). DISCUSSION: This trial failed to show a preventive effect of fibrin glue on overall post-ESD bleeding in high-risk patients. However, the secondary outcomes suggest a potential sealing effect of fibrin glue during the acute period.

Gastric mucosal swab as an alternative to biopsy for Helicobacter pylori detection.

BACKGROUND AND AIMS: Gastric mucosal swab may be a more sensitive sampling method than a biopsy since Helicobacter pylori (H. pylori) resides within the mucus layer. We compared the diagnostic performance of the rapid urease test (RUT) and bacterial load of H. pylori between swabs and tissue biopsy. METHODS: Overall, 276 RUTs (138 swab-RUTs (S-RUT) and 138 tissue-RUTs (T-RUT)) were performed. To diagnose H. pylori infection, RUT, H. pylori PCR, and 16S ribosomal RNA gene sequencing of tissue and swab were used, and its infection was defined as at least two positives of the six test results. The diagnostic performances of RUTs and the H. pylori bacterial load using qPCR were compared between swab and biopsy. RESULTS: The positivity rates of S-RUT and T-RUT were 35.5% (49/138) and 25.4% (35/138), respectively. The sensitivity, specificity, and accuracy of S-RUT were 98.0%, 100.0%, and 99.2%, while those of T-RUT were 70.0%, 100%, and 89.1%, respectively. The sensitivity and accuracy were significantly higher for S-RUT than for T-RUT (p < 0.05). In the patients with atrophic gastritis and intestinal metaplasia, S-RUT showed significantly higher sensitivity than T-RUT. qPCR showed that the swab contained a significantly higher H. pylori bacterial load than tissue biopsy (22.92-fold and 31.61-fold in the antrum and body (p < 0.05), respectively). CONCLUSIONS: Gastric mucosal swabs showed higher RUT accuracy and H. pylori bacterial load than a tissue biopsy. This may be an alternative to a biopsy when diagnosing H. pylori infection during endoscopy is necessary. (ClinicalTrials.gov, NCT05349578).

Risk assessment of metachronous gastric cancer development using OLGA and OLGIM systems after endoscopic submucosal dissection for early gastric cancer: a long-term follow-up study.

BACKGROUND: Metachronous gastric cancer (MGC) may develop in patients undergoing curative endoscopic submucosal dissection for early gastric cancer. As gastritis and intestinal metaplasia are notable precursors to gastric cancer, we assessed MGC risk using the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia assessment (OLGIM) systems. METHODS: This retrospective cohort study classified the OLGA and OLGIM stages for 916 patients who had undergone endoscopic submucosal dissection for early gastric cancer between 2005 and 2015. MGC development was followed up until 2020 and risk factors were evaluated using the Cox proportional hazards regression analysis. RESULTS: During a median follow-up of 94 months, MGC developed in 120 subjects. OLGA stages II ~ IV were significantly associated with increased MGC risk (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.05-3.19; HR 2.31, 95% CI 1.22-4.38; HR 2.36, 95% CI 1.16-4.78) in multivariable analysis, even after adjusting for the well-known positive predictor of Helicobacter pylori eradication. OLGIM stages II ~ IV also showed significant association (HR 2.86, 95% CI 1.29-6.54; HR 2.94, 95% CI 1.34-6.95; HR 3.64, 95% CI 1.60-8.29). 5-year cumulative incidence increased with each stage. Helicobacter pylori-eradicated patients with OLGIM stages 0 ~ II had significantly less MGC than non-eradicated patients (4.5% vs 11.8%, p = 0.022), which was not observed with OLGIM stages III ~ IV. CONCLUSIONS: High OLGA and OLGIM stages are independent risk factors for metachronous gastric cancer, with the OLGIM staging system being a better predictor. Patients with OLGIM stages 0 ~ II are a subgroup that may benefit more from Helicobacter pylori eradication.

Decision to perform additional surgery after non-curative endoscopic submucosal dissection for gastric cancer based on the risk of lymph node metastasis: a long-term follow-up study.

BACKGROUND: Radical surgery after non-curative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) may be excessive, since only 5-10% of patients have lymph node metastasis (LNM). This study investigated the suitability of the eCura system for determining the need for radical surgery after non-curative ESD. METHODS: We retrospectively investigated 343 patients who underwent non-curative ESD for EGC from 2006 to 2021 at a tertiary hospital in Korea. These patients were divided into surgery (n = 191) and observation (n = 152) groups based on whether they underwent additional surgery post-ESD. Each group was further classified into low-risk (eCura score 0-1), intermediate-risk (eCura score 2-4) and high-risk (eCura score 5-7). All patients were regularly followed-up at least annually after the initial treatment. The cumulative overall and recurrence-free survival rates were calculated for each category and compared between the surgery and observation groups. RESULTS: No significant differences in overall survival were found between the surgery and observation groups in low-risk (p = 0.168) and intermediate-risk patients (p = 0.306); however, high-risk patients had better 5-year overall survival rate in the surgery group than in the follow-up group (95.2% vs. 71.4%, p < 0.001). The 5-year recurrence-free survival rate was higher in the surgery group than in the observation group for low-risk (100% vs. 84.3%; p = 0.034), intermediate-risk (96.1% vs. 88.4%; p = 0.081) and high-risk patients (100% vs. 83.3%; p = 0.023). CONCLUSIONS: Follow-up without additional surgery after non-curative ESD can be a reasonable option for low-risk and even intermediate-risk patients according to the eCura system. However, surgery is warranted for eCura high-risk patients.

Metachronous gastric neoplasm beyond 5 years after endoscopic resection for early gastric cancer.

BACKGROUND AND AIMS: The natural course of early gastric cancer (EGC) following endoscopic submucosal dissection (ESD) remains unclear. This study aimed to clarify the long-term clinical outcomes and risk factors of metachronous gastric neoplasm (MGN) 5 years after ESD for EGC. METHODS: We performed a retrospective analysis of patients who underwent ESD for EGC from July 2005 to October 2015 in Seoul National University Hospital. Long-term clinical outcomes and risk factors of MGN after 5 years post-ESD were evaluated. RESULTS: Among the 2059 patients who underwent ESD for EGC, 1102 were followed up for > 5 years. MGN developed in 132 patients 5 years after ESD. During the median follow-up period of 85 months, the cumulative incidences of MGN and metachronous gastric cancer were 11.7, 16.9, and 27.0 and 7.6, 10.8, and 18.7% after 5, 7, and 10 years, respectively. In multivariable analysis, male sex (odds ratio 1.770; P = 0.042), severe intestinal metaplasia (odds ratio 1.255; P = 0.000), tumor-positive lateral margin (odds ratio 2.711; P = 0.008), < 5 mm lateral safety margin (odds ratio 1.568; P = 0.050), and synchronous adenoma (odds ratio 2.612; P = 0.001) were positive predictive factors, and successful eradication of Helicobacter pylori (odds ratio 0.514; P = 0.024) was a negative predictive factor for MGN after 5 years post-ESD. CONCLUSION: The cumulative MGN incidence was high even 5 years post-ESD for EGC. Meticulous long-term endoscopic follow-up is mandatory, especially in male patients with underlying intestinal metaplasia, tumor-positive lateral margins, lateral safety margins of < 5 mm, and synchronous adenomas.

Safety of pylorus-preserving gastrectomy for gastric cancer combined with antral high-risk lesions: a comparison with endoscopic submucosal dissection.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is a surgical treatment option for cT1N0M0 gastric cancer located in the middle third of the stomach. However, data for the long-term post-PPG clinical outcomes related to metachronous gastric neoplasms (mGNs) in the residual stomach are currently lacking. Therefore, we aimed to evaluate the safety of PPG by focusing on mGNs. METHODS: In this single-center, retrospective study, we reviewed the data for 362 patients who underwent PPG with a 3-cm antral cuff and 139 who underwent endoscopic submucosal dissection (ESD) for middle-third gastric cancer between January 2013 and December 2015. The histopathologic features of the antrum in the ESD group, which could not be determined in the PPG group, were analyzed to investigate the risk factors for mGNs. The estimated and actual incidence of mGNs in the antrum were compared in the PPG group. RESULTS: The incidence of mGNs was 6.5% (9/139) in the ESD group. The presence of a synchronous adenoma (odds ratio [OR], 8.46; 95% confidence interval [CI], 1.55-46.34), carcinoma (OR, 15.71; 95% CI, 2.67-92.56) and moderate-to-severe intestinal metaplasia (OR, 9.77; 95% CI, 1.14-83.92) were associated with a higher risk of overall mGNs. However, when confined to the antrum, no significant association was observed between these factors and mGNs. In the ESD group, 2 of 9 mGNs (1.4%) were located at the 3-cm antral cuff. In the PPG group, both mGNs (0.6%) were located in the proximal remnant stomach. CONCLUSION: Pylorus-preserving gastrectomy was a safe therapeutic option with regard to the occurrence of metachronous adenomas or carcinomas in our series. Despite the low mGN incidence in the 3-cm antral cuff after PPG, the presence of synchronous neoplasms or moderate-to-severe intestinal metaplasia was a risk factor for mGNs in the ESD group; thus, further studies on longer antral cuffs with long-term follow-up are needed.

Histamine-2 Receptor Antagonists and Proton Pump Inhibitors Are Associated With Reduced Risk of SARS-CoV-2 Infection Without Comorbidities Including Diabetes, Hypertension, and Dyslipidemia: A Propensity Score-Matched Nationwide Cohort Study.

BACKGROUND: This study aimed to identify the effect of histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) use on the positivity rate and clinical outcomes of coronavirus disease 2019 (COVID-19). METHODS: We performed a nationwide cohort study with propensity score matching using medical claims data and general health examination results from the Korean National Health Insurance Service. Individuals aged ≥ 20 years who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between 1 January and 4 June 2020 were included. Patients who were prescribed H2RA or PPI within 1 year of the test date were defined as H2RA and PPI users, respectively. The primary outcome was SARS-CoV-2 test positivity, and the secondary outcome was the instance of severe clinical outcomes of COVID-19, including death, intensive care unit admission, and mechanical ventilation administration. RESULTS: Among 59,094 patients tested for SARS-CoV-2, 21,711 were H2RA users, 12,426 were PPI users, and 24,957 were non-users. After propensity score matching, risk of SARS-CoV-2 infection was significantly lower in H2RA users (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.74-0.98) and PPI users (OR, 0.62; 95% CI, 0.52-0.74) compared to non-users. In patients with comorbidities including diabetes, dyslipidemia, and hypertension, the effect of H2RA and PPI against SARS-CoV-2 infection was not significant, whereas the protective effect was maintained in patients without such comorbidities. Risk of severe clinical outcomes in COVID-19 patients showed no difference between users and non-users after propensity score matching either in H2RA users (OR, 0.89; 95% CI, 0.52-1.54) or PPI users (OR, 1.22; 95% CI, 0.60-2.51). CONCLUSION: H2RA and PPI use is associated with a decreased risk for SARS-CoV-2 infection but does not affect clinical outcome. Comorbidities including diabetes, hypertension, and dyslipidemia seem to offset the protective effect of H2RA and PPI.

Deep learning model for diagnosing gastric mucosal lesions using endoscopic images: development, validation, and method comparison.

BACKGROUND AND AIMS: Endoscopic differential diagnoses of gastric mucosal lesions (benign gastric ulcer, early gastric cancer [EGC], and advanced gastric cancer) remain challenging. We aimed to develop and validate convolutional neural network-based artificial intelligence (AI) models: lesion detection, differential diagnosis (AI-DDx), and invasion depth (AI-ID; pT1a vs pT1b among EGC) models. METHODS: This study included 1366 consecutive patients with gastric mucosal lesions from 2 referral centers in Korea. One representative endoscopic image from each patient was used. Histologic diagnoses were set as the criterion standard. Performance of the AI-DDx (training/internal/external validation set, 1009/112/245) and AI-ID (training/internal/external validation set, 620/68/155) was compared with visual diagnoses by independent endoscopists (stratified by novice [<1 year of experience], intermediate [2-3 years of experience], and expert [>5 years of experience]) and EUS results, respectively. RESULTS: The AI-DDx showed good diagnostic performance for both internal (area under the receiver operating characteristic curve [AUROC] = .86) and external validation (AUROC = .86). The performance of the AI-DDx was better than that of novice (AUROC = .82, P = .01) and intermediate endoscopists (AUROC = .84, P = .02) but was comparable with experts (AUROC = .89, P = .12) in the external validation set. The AI-ID showed a fair performance in both internal (AUROC = .78) and external validation sets (AUROC = .73), which were significantly better than EUS results performed by experts (internal validation, AUROC = .62; external validation, AUROC = .56; both P < .001). CONCLUSIONS: The AI-DDx was comparable with experts and outperformed novice and intermediate endoscopists for the differential diagnosis of gastric mucosal lesions. The AI-ID performed better than EUS for evaluation of invasion depth.

Tumorigenic mechanisms of estrogen and Helicobacter pylori cytotoxin-associated gene A in estrogen receptor α-positive diffuse-type gastric adenocarcinoma.

BACKGROUND: Diffuse-type gastric cancer (DGC), for which Helicobacter pylori infection is a causal factor, is associated with poor prognosis among young women, possibly due to female hormones such as estrogen. We aimed to identify the carcinogenesis induced by estrogen and H. pylori in DGC. METHODS: We screened and selected estrogen receptor alpha (ERα)-positive (MKN45) and ERα-negative (SNU5) DGC cell lines. H. pylori strain 60190 and its isogenic mutant strain lacking cytotoxin-associated gene A (60190ΔCagA) were used to infect MKN45 cells. And the cytotoxin-related gene A (CagA) cDNA which was cloned into pSP65-SR-HA (cagA-pSP65SRa) vector was used to transfect MKN45 cells. Tumor samples were used for DGC organoid culture. RESULTS: In MKN45 cells, we found that estradiol promotes epithelial-mesenchymal transition (EMT) and stemness phenotypes via HOTAIR expression. These effects were further enhanced by the addition of CagA secreted by H. pylori but were reversed by co-treatment with fulvestrant (ICI 182,780), a selective ER degrader. We also validated the effect of estrogen on DGC organoids. ERα expression was associated with tumor invasion and HOTAIR expression in DGC patients with overt H. pylori infection. CONCLUSIONS: These findings may explain the rapid DGC progression in young women with physiologically high levels of estrogen and suggest that fulvestrant with ovarian function suppression could serve as a tumor-suppressive agent in premenopausal patients with DGC.

Gastric subepithelial tumor: long-term natural history and risk factors for progression.

BACKGROUND: Subepithelial tumors are often detected incidentally during upper gastrointestinal endoscopy. However, their natural history and clinical management have yet to be clearly established. The aim of this study was to evaluate the natural history and risk factors for progression of gastric SETs. METHODS: The study retrospectively reviewed the medical records of patients who were diagnosed with gastric SET using upper gastrointestinal endoscopy between January 2005 and December 2017. Tumor progression was defined by a ≥ 25% increase in diameter. RESULTS: Among 3237 patients, 1859 underwent serial upper gastrointestinal endoscopy for more than six months. Endoscopic ultrasonography was further performed in 733 (39.43%) patients. Resection was performed in 73 (3.93%) patients. Tumor progressed in 138 (7.42%) patients over a mean follow-up period of 59.41 months (range, 5-215 months). In progressed tumors, the mean initial size was 15.01 mm (range, 2-50 mm) and the mean size increment was 12.86 mm (range, 3-50 mm). Large initial tumor size (OR: 1.03, 95% CI: 1.01-1.05), surface ulcer or erosion (OR: 2.47, 95% CI: 1.21-5.06), lobulated shape (OR: 3.76, 95% CI: 2.00-7.06), and middle-third location (OR: 1.65, 95% CI: 1.08-2.52) were significant risk factors for tumor progression. Large SETs had higher rates of progression and tended to grow faster than smaller tumors (r = 0.44, p < 0.001). CONCLUSIONS: The majority of gastric SETs did not increase in size during the long-term follow-up. Serial endoscopy may be sufficient as a follow-up tool for small SETs with intact overlying mucosa without lobulated shape.

Identification of gaze pattern and blind spots by upper gastrointestinal endoscopy using an eye-tracking technique.

BACKGROUND: The lesion detection rate of esophagogastroduodenoscopy (EGD) varies depending on the degree of experience of the endoscopist and anatomical blind spots. This study aimed to identify gaze patterns and blind spots by analyzing the endoscopist's gaze during real-time EGD. METHODS: Five endoscopists were enrolled in this study. The endoscopist's eye gaze tracked by an eye tracker was selected from the esophagogastric junction to the second portion of the duodenum without the esophagus during insertion and withdrawal, and then matched with photos. Gaze patterns were visualized as a gaze plot, blind spot detection as a heatmap, observation time (OT), fixation duration (FD), and FD-to-OT ratio. RESULTS: The mean OT and FD were 11.10 ± 11.14 min and 8.37 ± 9.95 min, respectively, and the FD-to-OT ratio was 72.5%. A total of 34.3% of the time was spent observing the antrum. When observing the body of the stomach, it took longer to observe the high body in the retroflexion view and the low-to-mid body in the forward view. CONCLUSIONS: It is necessary to minimize gaze distraction and observe the posterior wall in the retroflexion view. Our results suggest that eye-tracking techniques may be useful for future endoscopic training and education.

WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma.

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Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer.

BACKGROUND: Patients with early gastric cancers that are limited to gastric mucosa or submucosa usually have an advanced loss of mucosal glandular tissue (glandular atrophy) and are at high risk for subsequent (metachronous) development of new gastric cancer. The long-term effects of treatment to eradicate Helicobacter pylori on histologic improvement and the prevention of metachronous gastric cancer remain unclear. METHODS: In this prospective, double-blind, placebo-controlled, randomized trial, we assigned 470 patients who had undergone endoscopic resection of early gastric cancer or high-grade adenoma to receive either H. pylori eradication therapy with antibiotics or placebo. Two primary outcomes were the incidence of metachronous gastric cancer detected on endoscopy performed at the 1-year follow-up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3-year follow-up. RESULTS: A total of 396 patients were included in the modified intention-to-treat analysis population (194 in the treatment group and 202 in placebo group). During a median follow-up of 5.9 years, metachronous gastric cancer developed in 14 patients (7.2%) in the treatment group and in 27 patients (13.4%) in the placebo group (hazard ratio in the treatment group, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.03). Among the 327 patients in the subgroup that underwent histologic analysis, improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% of the patients in the treatment group and in 15.0% of those in the placebo group (P<0.001). There were no serious adverse events; mild adverse events were more common in the treatment group (42.0% vs. 10.2%, P<0.001). CONCLUSIONS: Patients with early gastric cancer who received H. pylori treatment had lower rates of metachronous gastric cancer and more improvement from baseline in the grade of gastric corpus atrophy than patients who received placebo. (Funded by the National Cancer Center, South Korea; ClinicalTrials.gov number, NCT02407119 .).

Long-term natural history after endoscopic resection for gastric dysplasia.

BACKGROUND AND STUDY AIMS: Natural history after endoscopic resection (ER) for gastric dysplasia is still unclear. The aim of this study was to evaluate the long-term clinical outcomes and risk factors after ER for gastric dysplasia between control and cases with synchronous or metachronous gastric neoplasm. METHODS: A total of 1090 patients who had undergone ER for gastric dysplasia and been followed up for at least one year from December 2002 to December 2013 were finally analyzed. Risk factors affecting the development of synchronous or metachronous neoplasm (SMN) and long-term clinical outcomes after ER for gastric dysplasia were evaluated. RESULTS: Synchronous and metachronous neoplasms had developed in 126 (11.6%) and 133 patients (12.2%) during the mean follow-up duration of 63.6 months, respectively. Five-year and 10-year risk of metachronous neoplasm were 9.8% and 27.2%, respectively. Median duration to the development of metachronous neoplasm was 103.1 months. While age (P < 0.001) and mucosal atrophy (P = 0.09) of index cases were associated with the development of synchronous neoplasm, age (P = 0.017), incomplete resection (P = 0.025), and intestinal metaplasia (P = 0.017) of background mucosa of index cases were significantly related to the development of metachronous neoplasm in multivariate analysis. Cumulative incidence of SMN was not significantly different among H. pylori negative, eradicated, and persistent group. CONCLUSIONS: Age, incomplete ER, and background intestinal metaplasia of index gastric dysplasia were significantly associated with metachronous recurrence. Endoscopic surveillance for metachronous recurrence after ER for gastric dysplasia is mandatory for longer than 10 years.

CDK5RAP3 as tumour suppressor negatively regulates self-renewal and invasion and is regulated by ERK1/2 signalling in human gastric cancer.

BACKGROUND: Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance. METHODS: We examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft. RESULTS: We show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA. CONCLUSIONS: Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.

Nationwide antibiotic resistance mapping of Helicobacter pylori in Korea: A prospective multicenter study.

INTRODUCTION: The eradication rates for Helicobacter pylori have decreased in Korea although the prevalence of this bacterium has also decreased. Antibiotic resistance is likely to be a crucial factor in H. pylori eradication success, and we therefore mapped these resistance patterns nationwide in Korea. MATERIALS AND METHODS: Five hundred and ninety adult subjects were prospectively enrolled from 2017 to 2018 from 15 centers across six geographic areas of Korea. A total of 580 biopsy tissues had been sampled from these patients during an upper endoscopy and were frozen at -80°C and delivered to a central laboratory. The agar dilution method was used to determine the minimum inhibitory concentration of amoxicillin, clarithromycin, metronidazole, tetracycline, ciprofloxacin, and levofloxacin for each H. pylori isolate. RESULTS: The culture success rate was 60.2% (349/580). Resistance rates against clarithromycin, metronidazole, amoxicillin, tetracycline, levofloxacin, and ciprofloxacin were 17.8%, 29.5%, 9.5%, 0%, 37.0%, and 37.0%, respectively. The geographic distribution of metronidazole and quinolone resistance was highly variable. Some subjects had multiple H. pylori strains in the antrum and body of the stomach and showed a heterogeneous resistance profile between these anatomic areas. The H. pylori multidrug resistance (MDR) rate was 25.2% (88/349) among amoxicillin, clarithromycin, metronidazole, tetracycline, and quinolone and 11.2% (39/349) among four of these major antibiotics except for quinolone. The Seoul and Chungcheong areas showed a relatively lower MDR rate. CONCLUSION: The antibiotic resistance of H. pylori differs by drug and geographic area in Korea. Detailed nationwide antibiotic resistance mapping is needed to develop an effective H. pylori eradication strategy.