Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.

BACKGROUND & AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

IQGAP3 signalling mediates intratumoral functional heterogeneity to enhance malignant growth.

BACKGROUND: The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear. OBJECTIVE: We define the function of IQGAP3 in gastric cancer (GC) development and progression. DESIGN: We studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours. RESULTS: Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFß1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFß/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions. CONCLUSION: IQGAP3 knockdown suppressed the RAS-TGFß signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.

Effectiveness of an Artificial Intelligence-Assisted App for Improving Eating Behaviors: Mixed Methods Evaluation.

BACKGROUND: A plethora of weight management apps are available, but many individuals, especially those living with overweight and obesity, still struggle to achieve adequate weight loss. An emerging area in weight management is the support for one's self-regulation over momentary eating impulses. OBJECTIVE: This study aims to examine the feasibility and effectiveness of a novel artificial intelligence-assisted weight management app in improving eating behaviors in a Southeast Asian cohort. METHODS: A single-group pretest-posttest study was conducted. Participants completed the 1-week run-in period of a 12-week app-based weight management program called the Eating Trigger-Response Inhibition Program (eTRIP). This self-monitoring system was built upon 3 main components, namely, (1) chatbot-based check-ins on eating lapse triggers, (2) food-based computer vision image recognition (system built based on local food items), and (3) automated time-based nudges and meal stopwatch. At every mealtime, participants were prompted to take a picture of their food items, which were identified by a computer vision image recognition technology, thereby triggering a set of chatbot-initiated questions on eating triggers such as who the users were eating with. Paired 2-sided t tests were used to compare the differences in the psychobehavioral constructs before and after the 7-day program, including overeating habits, snacking habits, consideration of future consequences, self-regulation of eating behaviors, anxiety, depression, and physical activity. Qualitative feedback were analyzed by content analysis according to 4 steps, namely, decontextualization, recontextualization, categorization, and compilation. RESULTS: The mean age, self-reported BMI, and waist circumference of the participants were 31.25 (SD 9.98) years, 28.86 (SD 7.02) kg/m2, and 92.60 (SD 18.24) cm, respectively. There were significant improvements in all the 7 psychobehavioral constructs, except for anxiety. After adjusting for multiple comparisons, statistically significant improvements were found for overeating habits (mean -0.32, SD 1.16; P<.001), snacking habits (mean -0.22, SD 1.12; P<.002), self-regulation of eating behavior (mean 0.08, SD 0.49; P=.007), depression (mean -0.12, SD 0.74; P=.007), and physical activity (mean 1288.60, SD 3055.20 metabolic equivalent task-min/day; P<.001). Forty-one participants reported skipping at least 1 meal (ie, breakfast, lunch, or dinner), summing to 578 (67.1%) of the 862 meals skipped. Of the 230 participants, 80 (34.8%) provided textual feedback that indicated satisfactory user experience with eTRIP. Four themes emerged, namely, (1) becoming more mindful of self-monitoring, (2) personalized reminders with prompts and chatbot, (3) food logging with image recognition, and (4) engaging with a simple, easy, and appealing user interface. The attrition rate was 8.4% (21/251). CONCLUSIONS: eTRIP is a feasible and effective weight management program to be tested in a larger population for its effectiveness and sustainability as a personalized weight management program for people with overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT04833803; https://classic.clinicaltrials.gov/ct2/show/NCT04833803.

Correction: Effectiveness of an Artificial Intelligence-Assisted App for Improving Eating Behaviors: Mixed Methods Evaluation.

[This corrects the article DOI: 10.2196/46036.].

A 10-year experience with anastomotic leaks in upper gastrointestinal surgery-Retrospective cohort study.

BACKGROUND: Anastomotic leak (AL) in upper gastrointestinal (UGI) surgery continues to be a diagnostic challenge. We seek to identify clinical parameters that predict AL and examine the effectiveness of investigations in evaluating AL following UGI surgeries. METHODS: 592 patients underwent UGI surgeries with an anastomosis between January 2011 and January 2021. Data on patient characteristics, surgery, postoperative investigations and outcomes were prospectively collected and analysed. RESULTS: The overall occurrence of AL was 6.4 %. Tachycardia >120 BPM (OR 6.959, 95 % CI 1.856-26.100, p = 0.004) and leukocyte count >19 × 109/L (OR 3.327, 95 % CI 1.009-10.967, p = 0.048) were independent predictors of AL. On multivariate analysis, patients whose anastomosis was deemed high risk and had pre-emptive investigation done postoperatively to exclude a leak were less likely to require intervention and were more likely to be managed conservatively (66.7 % vs 14.3 %, p = 0.025). Methylene blue test, oral contrast study and Computed Tomography scan with intravenous and oral contrast had 50.0 %, 20.0 % and 9.1 % false negative results, while esophagogastroduodenoscopy had none. There was no misdiagnosed AL when more than 1 investigation (n = 15, 39.5 %) were performed. CONCLUSION: Our study demonstrates that the presence of a triad including desaturation, tachycardia and leucocytosis predicts for AL following UGI surgery and for confirmation of a leak, evaluation with 2 or more investigation is needed. A practice of evaluating high risk anastomosis prior to commencement of feeding decreased the need for surgical intervention and improves success of conservative treatment.

Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. DESIGN: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. RESULTS: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. CONCLUSION: Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.

Real-World Validation of a Computer-Aided Diagnosis System for Prediction of Polyp Histology in Colonoscopy: A Prospective Multicenter Study.

INTRODUCTION: Computer-aided diagnosis (CADx) of polyp histology could support endoscopists in clinical decision-making. However, this has not been validated in a real-world setting. METHODS: We performed a prospective, multicenter study comparing CADx and endoscopist predictions of polyp histology in real-time colonoscopy. Optical diagnosis based on visual inspection of polyps was made by experienced endoscopists. After this, the automated output from the CADx support tool was recorded. All imaged polyps were resected for histological assessment. Primary outcome was difference in diagnostic performance between CADx and endoscopist prediction of polyp histology. Subgroup analysis was performed for polyp size, bowel preparation, difficulty of location of the polyps, and endoscopist experience. RESULTS: A total of 661 eligible polyps were resected in 320 patients aged ≥40 years between March 2021 and July 2022. CADx had an overall accuracy of 71.6% (95% confidence interval [CI] 68.0-75.0), compared with 75.2% (95% CI 71.7-78.4) for endoscopists ( P = 0.023). The sensitivity of CADx for neoplastic polyps was 61.8% (95% CI 56.9-66.5), compared with 70.3% (95% CI 65.7-74.7) for endoscopists ( P < 0.001). The interobserver agreement between CADx and endoscopist predictions of polyp histology was moderate (83.1% agreement, κ 0.661). When there was concordance between CADx and endoscopist predictions, the accuracy increased to 78.1%. DISCUSSION: The overall diagnostic accuracy and sensitivity for neoplastic polyps was higher in experienced endoscopists compared with CADx predictions, with moderate interobserver agreement. Concordance in predictions increased this diagnostic accuracy. Further research is required to improve the performance of CADx and to establish its role in clinical practice.

Single-incision transgastric resection for gastric gastrointestinal stromal tumors in anatomically challenging locations.

Surgical resection is the mainstay treatment for resectable gastrointestinal stromal tumors (GISTs). However, resection in anatomically challenging locations, such as near the gastroesophageal junction, lesser curve and fundus, remain technically challenging. We herein report the outcomes of the largest series of patients who underwent single-incision transgastric resection of an intraluminal gastric GIST. Our reduced-port resection technique for intraluminal GISTs in these anatomically challenging locations involves a single incision in the left hypochondrium, deepened to access the gastric lumen, with the surgery completed in a transgastric manner. A total of 22 patients received surgery with this technique at the National University Hospital in Singapore from November 2012 to September 2020. The median operative time was 101 (range 50-253) min, with no conversions to open surgery, median lesion size 3.6 (range 1.8-8.2) cm and median postoperative length of stay 5 (range 1-13) days. There was no 30-day mortality and no recurrence during the follow-up period. Our laparoscopic approach for reduced-port transgastric excision of intraluminal GISTs allows for adequate surgical clearance, convenient extraction and secure gastrostomy closure with low morbidity.

Surgical outcomes and quality of life assessment of esophagectomy for cancer with colon conduit via retrosternal route.

PURPOSE: Colon conduit is an alternative to a gastric conduit for esophagectomy in patients that stomach is not available. Surgical technique is complex and has a high risk of morbidities and mortality. Outcomes of patients are still lacking in the literature, thus aims of this study are to evaluate the safety, feasibility and long-term functional outcomes of patients who underwent esophagectomy for cancer with colon conduit via retrosternal route. METHODS: Twenty-six patients underwent operation between August 2016 and June 2021 for malignancies. Minimally invasive esophagectomy and laparotomy were performed in accordance with the 2017 Japan Esophageal Society's guidelines. Colonic interposition was used for esophageal replacement. Outcomes were technical success, complications assessed using Clavien-Dindo classification, and patient's quality of life (QOL) based on EORTC-QOL-OES18 questionnaire. RESULTS: Mean age was 56.0 ± 9.9 years and 21 patients (80.8%) were men. Mean operating time was 432 ± 66 min. Technical success was 100%. The average number of resected lymph nodes was 26 ± 14. Twelve patients (46.2%) experienced postoperative complications: 7/12 were classified as grade I-II, 3/12 as grade III, 1/12 as grade IV, and 1/12 as grade V (death). Patient's QOL improved during the follow-up period with median (25-75th percentiles) global EORTC-QOL-OES18 score was 29 (17-34); 13 (9-21), and 9 (6-16) at 3, 6, and 12 months, respectively. During the follow-up period, there were 4 late complications, 3 lymphatic recurrences, 5 distant metastases, and 6 deaths. CONCLUSIONS: Colon conduit via retrosternal route after esophagectomy is feasible, safe, and could provide acceptable long-term functional outcomes.

Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP).

OBJECTIVE: To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS: A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS: There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS: We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.

Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition.

OBJECTIVES: Epigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours. DESIGN: Alternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes. RESULTS: APBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using 'humanised mice' harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032). CONCLUSION: These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants.

BACKGROUND: Metabolic-bariatric surgery delivers substantial weight loss and can induce remission or improvement of obesity-related risks and complications. However, more robust estimates of its effect on long-term mortality and life expectancy-especially stratified by pre-existing diabetes status-are needed to guide policy and facilitate patient counselling. We compared long-term survival outcomes of severely obese patients who received metabolic-bariatric surgery versus usual care. METHODS: We did a prespecified one-stage meta-analysis using patient-level survival data reconstructed from prospective controlled trials and high-quality matched cohort studies. We searched PubMed, Scopus, and MEDLINE (via Ovid) for randomised trials, prospective controlled studies, and matched cohort studies comparing all-cause mortality after metabolic-bariatric surgery versus non-surgical management of obesity published between inception and Feb 3, 2021. We also searched grey literature by reviewing bibliographies of included studies as well as review articles. Shared-frailty (ie, random-effects) and stratified Cox models were fitted to compare all-cause mortality of adults with obesity who underwent metabolic-bariatric surgery compared with matched controls who received usual care, taking into account clustering of participants at the study level. We also computed numbers needed to treat, and extrapolated life expectancy using Gompertz proportional-hazards modelling. The study protocol is prospectively registered on PROSPERO, number CRD42020218472. FINDINGS: Among 1470 articles identified, 16 matched cohort studies and one prospective controlled trial were included in the analysis. 7712 deaths occurred during 1·2 million patient-years. In the overall population consisting 174 772 participants, metabolic-bariatric surgery was associated with a reduction in hazard rate of death of 49·2% (95% CI 46·3-51·9, p<0·0001) and median life expectancy was 6·1 years (95% CI 5·2-6·9) longer than usual care. In subgroup analyses, both individuals with (hazard ratio 0·409, 95% CI 0·370-0·453, p<0·0001) or without (0·704, 0·588-0·843, p<0·0001) baseline diabetes who underwent metabolic-bariatric surgery had lower rates of all-cause mortality, but the treatment effect was considerably greater for those with diabetes (between-subgroup I2 95·7%, p<0·0001). Median life expectancy was 9·3 years (95% CI 7·1-11·8) longer for patients with diabetes in the surgery group than the non-surgical group, whereas the life expectancy gain was 5·1 years (2·0-9·3) for patients without diabetes. The numbers needed to treat to prevent one additional death over a 10-year time frame were 8·4 (95% CI 7·8-9·1) for adults with diabetes and 29·8 (21·2-56·8) for those without diabetes. Treatment effects did not appear to differ between gastric bypass, banding, and sleeve gastrectomy (I2 3·4%, p=0·36). By leveraging the results of this meta-analysis and other published data, we estimated that every 1·0% increase in metabolic-bariatric surgery utilisation rates among the global pool of metabolic-bariatric candidates with and without diabetes could yield 5·1 million and 6·6 million potential life-years, respectively. INTERPRETATION: Among adults with obesity, metabolic-bariatric surgery is associated with substantially lower all-cause mortality rates and longer life expectancy than usual obesity management. Survival benefits are much more pronounced for people with pre-existing diabetes than those without. FUNDING: None.

Gastro-esophageal reflux disease (GERD) after peroral endoscopic myotomy (POEM).

BACKGROUND: Peroral endoscopic myotomy (POEM) is gaining traction as a minimally invasive treatment of achalasia. Increased reflux is reported after POEM but the incidence, type and severity of reflux are not fully understood. We aimed to study the prevalence and nature of reflux after POEM and correlate reflux with endoscopy and pH-impedance findings. METHODS: This is a prospective cohort study of achalasia patients undergoing POEM since 2014. Data from Eckardt and GERD symptom scores, high-resolution oesophageal manometry (HRM) and gastroscopy were performed pre-procedure and repeated at 1-year follow-up. Data from 24-h pH-impedance, if performed, were also recorded. A standardized questionnaire was used to determine the severity and frequency of heartburn symptoms and the composite score for each patient was calculated. RESULTS: 58 patients underwent POEM between January 2014 and October 2018. The efficacy of POEM at 1 year was 93.0%. We observed reduction of median Integrated Relaxation Pressure (IRP) from 23.5 ± 33.1 mmHg to 13.4 ± 7.71 mmHg (p = 0.005) and mean Eckardt score improved from 6.09 ± 2.43 points to 1.16 ± 1.70 points (p < 0.001). At 1 year, 43.1% (n = 25) had symptomatic reflux. Of the 40 patients who underwent repeated gastroscopy, 60.0% (n = 24) had endoscopic evidence of oesophagitis with seven patients (18%) diagnosed with Grade C or D oesophagitis. 43.1% (n = 25) of patients had pH-impedance done post-POEM off PPIs. 14 patients (56%) had increased acid exposure. Sixteen percent of reflux episodes were acidic and 77.3% were weakly acidic. CONCLUSION: POEM was an effective treatment for achalasia. However, GERD was common after POEM with incidence of 43% on symptom score, 60% on endoscopy and 56% on pH-impedance test. Post-POEM reflux appeared to be predominantly acidic in nature. Routine surveillance for GERD after POEM is recommended.

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population.

OBJECTIVE: An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. DESIGN: We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. RESULTS: We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). CONCLUSION: We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov (Registration number: NCT04329299).

Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homoeostasis and repair.

OBJECTIVE: Tissue stem cells are central regulators of organ homoeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. DESIGN: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridisation. We performed lineage tracing and transcriptomic analysis of Iqgap3 +isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumours from patient samples. RESULTS: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homoeostasis. Iqgap3+isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. CONCLUSION: IQGAP3 is a major regulator of stomach epithelial tissue homoeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.

Structured Training for Laparoscopic Appendectomy for Residents (STAR Trial)-A Randomized Pilot Study.

OBJECTIVE: Laparoscopic appendectomy is a common operation that is frequently performed by junior surgical residents. We investigated the effect of a structured training program on the proficiency of junior residents in acquiring skills necessary in this operation. DESIGN AND PARTICIPANTS: This is a randomized pilot trial. Between December 2014 and July 2018, twenty junior residents were recruited for this study. 11 were randomized to receive a structured training program of supervised, task-specific training. Each resident subsequently performed ten cases of laparoscopic appendectomy with their performance assessed for the last 5. The GOALS scale was used as the primary endpoint. Secondary endpoints were perioperative outcomes. The effect of intervention on these outcomes were evaluated assuming a linear mixed effect multi-level model. The study was single-blinded as the assessors did not know which group each resident belonged to. RESULTS: There were no statistically significant differences in the total GOALS score or any of its individual domains. After adjusting for the number of operations done within the trial, the mean difference between the total GOALS score was 0.07 (95% CI -0.76 to 0.90, P=0.866). Blood loss, hospital stay and postoperative complication rates were similar. There was suggestion of a shorter operative time (effect estimate -9.03, 95% CI -19.56 to 1.50) in the intervention arm although statistical significance was not achieved. No avoidable adverse events due to this study were recorded. CONCLUSION: Structured training program did not significantly improve surgical performance and outcomes in laparoscopic appendectomy in this pilot trial. Despite these findings, residents can still potentially mount their learning curves in laparoscopy earlier in a safe environment with such a program which is especially important in the era of minimally invasive surgery.

Opportunistic upper endoscopy during colonoscopy as a screening strategy for countries with intermediate gastric cancer risk.

BACKGROUND AND AIM: Screening upper endoscopy can detect esophagogastric (OG) cancers early with improved outcomes. Recent cost-utility studies suggest that opportunistic upper endoscopy at the same setting of colonoscopy might be a useful strategy for screening of OG cancers, and it may be more acceptable to the patients due to cost-saving and convenience. We aim to study the diagnostic performance of this screening strategy in a country with intermediate gastric cancer risk. METHODS: A retrospective cohort study using a prospective endoscopy database from 2015 to 2017 was performed. Patients included were individuals age > 40 who underwent opportunistic upper endoscopy at the same setting of colonoscopy without any OG symptoms. Neoplastic OG lesions are defined as cancer and high-grade dysplasia. Pre-neoplastic lesions include Barrett's esophagus (BE), intestinal metaplasia (IM), and atrophic gastritis (AG). RESULTS: The study population involved 1414 patients. Neoplastic OG lesions were detected in five patients (0.35%). Pre-neoplastic lesions were identified in 174 (12.3%) patients. IM was found in 146 (10.3%) patients with 21 (1.4%) having extensive IM. The number needed to scope to detect a neoplastic OG lesion is 282.8 with an estimated cost of USD$141 400 per lesion detected. On multivariate regression, age ≥ 60 (RR: 1.84, 95% CI: 1.29-2.63) and first-degree relatives with gastric cancer (RR: 1.64, 95% CI: 1.06-2.55) were independent risk factors for neoplastic or pre-neoplastic OG lesion. CONCLUSION: For countries with intermediate gastric cancer risk, opportunistic upper endoscopy may be an alternative screening strategy in a selected patient population. Prospective trials are warranted to validate its performance.

DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia.

OBJECTIVE: Intestinal metaplasia (IM) is a premalignant stage that poses a greater risk for subsequent gastric cancer (GC). However, factors regulating IM to GC progression remain unclear. Previously, activated DNA damage response (DDR) signalling factors were shown to engage tumour-suppressive networks in premalignant lesions. Here, we interrogate the relationship of DDR signalling to mutational accumulation in IM lesions. DESIGN: IM biopsies were procured from the gastric cancer epidemiology programme, an endoscopic surveillance programme where biopsies have been subjected to (epi)genomic characterisation. IM samples were classified as genome-stable or genome-unstable based on their mutational burden/somatic copy-number alteration (CNA) profiles. Samples were probed for DDR signalling and cell proliferation, using the markers γH2AX and MCM2, respectively. The expression of the gastric stem cell marker, CD44v9, was also assessed. Tissue microarrays representing the GC progression spectrum were included. RESULTS: MCM2-positivity increased during GC progression, while γH2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γH2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γH2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γH2AX levels, elevated CD44v9 expression and modest promoter hypermethylation of DNA repair genes WRN, MLH1 and RAD52. CONCLUSIONS: Our data suggest that IM lesions with active DDR will likely experience a longer latency at the premalignant state until additional hits that override DDR signalling clonally expand and promote progression. These observations provide insights on the factors governing IM progression.

Pouch Versus No Pouch Following Total Gastrectomy: Meta-analysis of Randomized and Non-randomized Studies.

OBJECTIVE: The aim of the study was to assess the impact of pouch reconstruction on perioperative outcomes, postprandial symptoms, nutritional and anthropometric parameters, and overall quality of life after total gastrectomy for gastric malignancy. SUMMARY BACKGROUND DATA: The short-term perioperative risks and longer term functional value of creating a small-bowel reservoir after total gastrectomy are contended. METHODS: A search for randomized and non-randomized studies comparing reconstruction with or without a pouch was conducted. Treatment effects were computed using pairwise random-effects meta-analysis and meta-regression, and the systematic review was conducted in accordance with PRISMA and MOOSE guidelines. RESULTS: A total of 17 randomized trials and 8 observational studies involving 1621 participants were included. Pouch creation is associated with an increased operation time [259.3 vs 235.8 min; weighted mean difference (WMD) 23.5, 95% confidence interval (CI) 9.8-37.2], but not hospitalization duration. There was no difference in overall postsurgical complications, including anastomotic leak and abdominal abscess. Pouch formation markedly reduces the risk of dumping syndrome at 3 to 6 months [8.1% vs 32.4%; risk ratios (RR) 0.36, 95% CI, 0.21-0.60] and 12 to 24 months (2.8% vs 23.6%; RR 0.27, 95% CI, 0.16-0.46). The functional advantages of pouch reconstruction persist at 1 to 2 years, with aggregated data indicating considerably lower risks of esophagitis and heartburn (63% relative reduction), dumping syndrome (73% relative reduction), and food intake disturbance (50% relative reduction). At 12 to 24 months, albumin levels (40.5 vs 37.9 g/L; WMD 2.59, 95% CI, 1.35-3.84) and body mass index (22.2 vs 20.9 kg/m; WMD 1.28, 95% CI, 0.61-1.94) are significantly higher among participants with a pouch. CONCLUSIONS: Pouch creation improves long-term functional and nutritional outcomes after total gastrectomy, without greater perioperative morbidity.

Laparoscopic versus open appendectomy in pediatric patients with complicated appendicitis: a meta-analysis.

BACKGROUND: Acute appendicitis is a common condition in the pediatric population. In patients with uncomplicated appendicitis, laparoscopic appendectomy (LA) is preferred as compared to open appendectomy (OA). However, in patients with complicated appendicitis (CA), as defined as suppurative, gangrenous or perforated appendicitis, or appendicitis with periappendicular abscess formation, the decision to perform OA or LA remains unclear. METHODS: The PRISMA guidelines were adhered to. An electronic database search from 1997 to 2017 was performed using the Cochrane, Medline, PubMed, Scopus, Ovid, Embase, and Web of Knowledge databases. Data analysis, including subgroup analysis of randomized-control trials, was performed using RevMan 5.3. Assessment of methodological and statistical heterogeneity, as well as publication bias of the included studies, was performed. RESULTS: Six randomized-control trials (296 LA versus 373 OA) and 33 case-control trials (3106 LA versus 4149 OA) were analyzed. Compared to OA, LA has a shorter length of stay (WMD = - 0.96, 95% CI - 1.47 to - 0.45) and a lower rate of surgical site infection (OR 0.37, 95% CI 0.25-0.54), although the rates of intraabdominal abscess formation were similar (OR 1.01, 95% CI 0.71-1.43). LA was also shown to have lower readmission rates, lower incidences of postoperative ileus or intestinal obstruction, lower incidence of reoperation, as well as a shorter time taken to oral intake. Operative time for OA was shorter than LA (WMD = 12.44, 95% CI 2.00-22.87). CONCLUSION: While studies in the past have associated LA with higher rates of intraabdominal abscess in patients with CA, our meta-analysis has shown that they were similar. Considering this, together with other improved postoperative outcomes, LA should be the procedure of choice in pediatric patients presenting with CA.