A body map of somatic mutagenesis in morphologically normal human tissues.

Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.

Infectious pathogens and risk of esophageal, gastric and duodenal cancers and ulcers in China: A case-cohort study.

Infection by certain pathogens is associated with cancer development. We conducted a case-cohort study of ~2500 incident cases of esophageal, gastric and duodenal cancer, and gastric and duodenal ulcer and a randomly selected subcohort of ~2000 individuals within the China Kadoorie Biobank study of >0.5 million adults. We used a bead-based multiplex serology assay to measure antibodies against 19 pathogens (total 43 antigens) in baseline plasma samples. Associations between pathogens and antigen-specific antibodies with risks of site-specific cancers and ulcers were assessed using Cox regression fitted using the Prentice pseudo-partial likelihood. Seroprevalence varied for different pathogens, from 0.7% for Hepatitis C virus (HCV) to 99.8% for Epstein-Barr virus (EBV) in the subcohort. Compared to participants seronegative for the corresponding pathogen, Helicobacter pylori seropositivity was associated with a higher risk of non-cardia (adjusted hazard ratio [HR] 2.73 [95% CI: 2.09-3.58]) and cardia (1.67 [1.18-2.38]) gastric cancer and duodenal ulcer (2.71 [1.79-4.08]). HCV was associated with a higher risk of duodenal cancer (6.23 [1.52-25.62]) and Hepatitis B virus was associated with higher risk of duodenal ulcer (1.46 [1.04-2.05]). There were some associations of antibodies again some herpesviruses and human papillomaviruses with risks of gastrointestinal cancers and ulcers but these should be interpreted with caution. This first study of multiple pathogens with risk of gastrointestinal cancers and ulcers demonstrated that several pathogens are associated with risks of gastrointestinal cancers and ulcers. This will inform future investigations into the role of infection in the etiology of these diseases.

Predicting Incident Adenocarcinoma of the Esophagus or Gastric Cardia Using Machine Learning of Electronic Health Records.

BACKGROUND & AIMS: Tools that can automatically predict incident esophageal adenocarcinoma (EAC) and gastric cardia adenocarcinoma (GCA) using electronic health records to guide screening decisions are needed. METHODS: The Veterans Health Administration (VHA) Corporate Data Warehouse was accessed to identify Veterans with 1 or more encounters between 2005 and 2018. Patients diagnosed with EAC (n = 8430) or GCA (n = 2965) were identified in the VHA Central Cancer Registry and compared with 10,256,887 controls. Predictors included demographic characteristics, prescriptions, laboratory results, and diagnoses between 1 and 5 years before the index date. The Kettles Esophageal and Cardia Adenocarcinoma predictioN (K-ECAN) tool was developed and internally validated using simple random sampling imputation and extreme gradient boosting, a machine learning method. Training was performed in 50% of the data, preliminary validation in 25% of the data, and final testing in 25% of the data. RESULTS: K-ECAN was well-calibrated and had better discrimination (area under the receiver operating characteristic curve [AuROC], 0.77) than previously validated models, such as the Nord-Trøndelag Health Study (AuROC, 0.68) and Kunzmann model (AuROC, 0.64), or published guidelines. Using only data from between 3 and 5 years before index diminished its accuracy slightly (AuROC, 0.75). Undersampling men to simulate a non-VHA population, AUCs of the Nord-Trøndelag Health Study and Kunzmann model improved, but K-ECAN was still the most accurate (AuROC, 0.85). Although gastroesophageal reflux disease was strongly associated with EAC, it contributed only a small proportion of gain in information for prediction. CONCLUSIONS: K-ECAN is a novel, internally validated tool predicting incident EAC and GCA using electronic health records data. Further work is needed to validate K-ECAN outside VHA and to assess how best to implement it within electronic health records.

Conventional versus oblique fiber-sparing endoscopic myotomy for achalasia cardia: a randomized controlled trial (with videos).

BACKGROUND AND AIMS: GERD is common after peroral endoscopic myotomy (POEM). Selective sparing of oblique fibers may reduce the incidence of reflux esophagitis after POEM. In this study, we compared the incidence of GERD between conventional myotomy (CM) versus oblique fiber-sparing (OFS) myotomy in patients with achalasia. METHODS: Eligible patients with type I and II achalasia who underwent POEM from January 2020 to October 2020 were randomized into 2 groups (CM and OFS myotomy). Exclusion criteria were type III achalasia, sigmoid esophagus, and history of Heller's myotomy. The primary study outcome was incidence of reflux esophagitis (at least grade B) in the 2 groups. Secondary outcomes were reflux symptoms, esophageal acid exposure, clinical success, and adverse events. RESULTS: One hundred fifteen patients were randomized into CM (n = 58) and OFS myotomy (n = 57) groups. POEM was technically successful in all patients. Overall, reflux esophagitis was found in 56 patients (48.7%). The incidence of at least grade B esophagitis was similar in both groups (CM vs OFS myotomy: 25.9% vs 31.6%, P = .541). The mean number of reflux episodes (48.2 ± 36.6 vs 48.9 ± 40.3, P = .933), increased esophageal acid exposure >6% (45.5% vs 31.7%, P = .266), and high DeMeester scores (38.6% vs 41.5%, P = .827) were similar in both groups. There was no difference in the rate of symptomatic reflux (GERD questionnaire score >7) or use of proton pump inhibitors at 1 year. CONCLUSIONS: Sparing of sling fibers has no significant impact on the incidence of significant reflux esophagitis after POEM. Novel strategies need to be explored to prevent reflux after POEM. (Clinical trial registration number: NCT04229342.).

Short-Term Prognostic Effect of Comprehensive Complication Index in Patients With Gastric Cardia Adenocarcinoma.

INTRODUCTION: The Clavien-Dindo Classification (CDC) has been traditionally used for assessing postoperative complications. Recently, the Comprehensive Complication Index (CCI) has been introduced as a new tool. However, its prognostic significance in Gastric Cardia Adenocarcinoma (GCA) is yet to be determined. METHODS: The CCI and CDC of 203 patients who underwent radical surgery for GCA at Jinling Hospital from 2016 to 2023 were evaluated. Primary outcome variables included Hospital Length of Stay, duration of intensive care unit stay postoperatively, time to return to normal activities, and total hospitalization cost. The area under the curve was used to measure the correlation strength of the CCI and CDC for these outcomes. RESULTS: The CCI demonstrated superior association strength, indicated by higher area under the curve values for all primary outcome variables compared to the CDC: Hospital Length of Stay (0.956 versus 0.910), intensive care unit stay duration (0.969 versus 0.954), time to return to normal activities (0.983 versus 0.962), and total hospitalization cost (0.925 versus 0.911). CONCLUSIONS: The CCI showed a stronger positive association than the CDC with short-term postoperative complications in GCA. It has potential implications for improving postoperative patient management.

A scoring system to predict the technical difficulty of endoscopic resection for cardial submucosal tumors.

BACKGROUND AND AIM: Endoscopic resection has been successfully used for the removal of digestive submucosal tumors (SMTs). However, the cardia has been considered a challenging location for endoscopic resection due to its narrow lumen and sharp angle. The objective of this study was to establish a clinical scoring model to grade the technical difficulty of endoscopic resection for cardial SMTs. METHODS: A total of 246 patients who suffered cardial SMTs and received endoscopic resection were included in this retrospective study. All of them were randomized into the training cohort (n = 123) or internal validation cohort (n = 123). Potential predictors were analyzed using univariate analysis. Then, covariates with P < 0.05 were selected for the multivariate logistic regression model. The ß coefficients from the logistic regression model were used to create a scoring system for technical difficulty prediction by rounding the score to the nearest integer of the absolute ß coefficient value. RESULTS: The clinical score consisted of the following factors: male gender (2 points), extraluminal growth (3 points), and maximum diameter ≥3 cm (3 points). The scoring model demonstrated good discriminatory power, with an area under the receiver operating characteristic curve of 0.860 and a 95% confidence interval of 0.763-0.958. The model also showed a good goodness of fit in the Hosmer-Lemeshow test (P = 0.979). In the training cohort, the probability of encountering technical difficulty in the easy (score = 0), intermediate (score = 1-3), difficult (score = 4-6), and very difficult (score >6) categories was 0, 6.8%, 33.3%, and 100.0%, respectively; similarly, in the validation cohort, it was 0, 5.6%, 22.2%, and 50.0%, respectively. CONCLUSIONS: This scoring system could serve as a valuable tool for clinicians in predicting the technical difficulty of endoscopic resection for cardial SMTs.

Fibrin sealant for closure of mucosal penetration at the oesophagus or cardia during submucosal tunnelling endoscopic resection for gastrointestinal submucosal tumours.

BACKGROUND AND STUDY AIM: To assess the efficacy and safety of a fibrin sealant for the prevention of leak resulting from mucosal penetration at the esophagus or cardia during a STER procedure to remove gastrointestinal submucosal tumors (SMTs). PATIENTS AND METHODS: Between April 2014 and October 2022, a total of 290 patients with oesophageal or cardiac SMTs underwent STER at our centre. We retrospectively identified patients with oesophageal or cardia SMTs who underwent STER and experienced mucosal penetration of the cardia or oesophagus during the procedure. A total of 31 mucosal penetrations in 30 procedures were included. Of the 31 mucosal penetrations, 12 occurred in the cardia, and the other 19 occurred in the oesophagus. All 31 sites received the fibrin sealant to close the mucosal penetration. Clinical characteristics, procedure-related parameters, detailed data of the mucosal penetrations, and treatment outcomes using the fibrin sealant were reviewed for all 30 patients to assess the efficacy and safety of the fibrin sealant for closure of mucosal penetration at the cardia or oesophagus. RESULTS: For the 31 mucosal penetrations, the mean size was 0.08 ± 0.06 cm2 (range 0.01-0.25 cm2). Mucosal closure using the fibrin sealant was performed successfully in all 31 mucosal penetrations. Of the 31 mucosal penetrations, clips were used in 13 cases. All 30 patients were discharged after a median of 7 days (range 4-20 day) postoperatively. During a mean 62 months (range 6-107 months) follow-up, all 31 mucosal penetrations successfully healed without the occurrence of infection, ulcer, oesophagitis, chest infection or abdominal infection. CONCLUSION: For the closure of mucosal penetration during STER at the cardia or oesophagus, a fibrin sealant is both safe and efficacious. It is necessary to conduct more research on the viability, effectiveness, and safety of using a fibrin sealant to close wider mucosal penetrations.

Long-term outcomes of laparoscopic Heller's myotomy with angle of His accentuation in patients of achalasia cardia.

BACKGROUND: Laparoscopic Heller's myotomy (LHM) is an established treatment for achalasia cardia. Anti-reflux procedures (ARP) are recommended with LHM to reduce the post-operative reflux though the optimal anti-reflux procedure is still debatable. This study reports on the long-term outcomes of LHM with Angle-of-His accentuation (AOH) in patients of achalasia cardia. METHODS: One hundred thirty-six patients of achalasia cardia undergoing LHM with AOH between January 2010 to October 2021 with a minimum follow-up of one year were evaluated for symptomatic outcomes using Eckardt score (ES), DeMeester heartburn (DMH) score and achalasia disease specific quality of life (A-DsQoL) questionnaire. Upper gastrointestinal endoscopy, high resolution manometry (HRM) and timed barium esophagogram (TBE) were performed when feasible and rates of esophagitis and improvement in HRM and TBE parameters evaluated. Time dependent rates of success were calculated with respect to improvement in ES and dysphagia-, regurgitation- and heartburn-free survival using Kaplan-Meier analysis. RESULTS: At a median follow-up of 65.5 months, the overall success (ES ≤ 3) was 94.1%. There was statistically significant improvement in ES, heartburn score and A-DsQoL score (p < 0.00001, p = 0.002 and p < 0.00001). Significant heartburn (score ≥ 2) was seen in 12.5% subjects with 9.5% patients reporting frequent PPI use (> 3 days per week). LA-B and above esophagitis was seen in 12.7%. HRM and TBE parameters also showed a significant improvement as compared to pre-operative values (IRP: p < 0.0001, column height: p < 0.0001, column width: p = 0.0002). Kaplan-Meier analysis showed dysphagia, regurgitation, and heartburn free survival of 75%, 96.2% and 72.3% respectively at 10 years. CONCLUSIONS: LHM with AOH gives a lasting relief of symptoms in patients of achalasia cardia with heartburn rates similar to that reported in studies using Dor's or Toupet's fundoplication with LHM. Hence, LHM with AOH may be a preferred choice in patients of achalasia cardia given the simplicity of the procedure.

How-I-do-it: laparoscopic intragastric submucosal dissection (LISD) for gastric and gastro-oesophageal junction early lesions.

PURPOSE: Laparoscopic intragastric submucosal dissection (LISD) is a novel approach to the resection of gastric lesion that are not amenable to conventional endoscopic approaches. The technique permits favourable access to lesions situated at the cardia and angular notch of the stomach, enables en-bloc resection of large areas of tissue, and can prevent the need of formal gastrectomy or oesophagectomy in selected patients. METHODS: All cases were deemed suitable for LISD by a multidisciplinary team panel following endoscopic assessment (using white light enhancement, chromoendoscopy and magnification endoscopy) that was integrated when needed with EUS, CT scan or PET scan. The surgical technique consisted in a 3-port laparoscopic approach; after establishment of pneumoperitoneum, three gastrotomies were performed to enable port insertion into the stomach. Following establishment of stable pneumogastrium, the area of interest was identified, submucosal hyaluronic acid injection performed to provide a cushion in the plane of dissection, and the excision area was circumferentially marked with cautery. Resection was completed using cautery hook, along a plane parallel to the muscolaris propria. After the specimen was extracted in a retrieval bag, intracorporeal single layer running suture closure of gastrotomies was performed. The abdominal wall closed by layers and tap block performed along with local anaesthetic injection on skin incision. Measures were taken to ensure correct orientation of resected specimens prior to fixation. RESULTS: During the study period that spans from 2014 and 2022, a total of 11 patients underwent LISD for limited lesions of the stomach, 10 were located at gastro-oesophageal junction and one at the angular incisura. Four patients were female, seven males. The median age was 74 (46-79) years. R0 resection rate was 54.5%. Mean operative time was 109 min with very low blood loss (10 ml). Mortality rate was 0%, no immediate major complications (Grade II-V Clavien Dindo), including haemorrhage or perforation, occurred in these cases. Two patients developed dysphagia later that was successfully treated with endoscopic balloon dilatations. Median hospital stay was 3 days and median oral intake was on day 1 post-procedural. CONCLUSIONS: Laparoscopic intragastric submucosal dissection is shown to be a safe and effective intervention for the treatment of early gastric cancers in selected patients having undergone deemed not amenable for endoscopic submucosal resection for their technically challenging location. Its application can serve as route to avoid formal surgery and the associated morbidity.

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma.

OBJECTIVE: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

Construction and testing of a risk prediction classifier for cardia carcinoma.

OBJECTIVES: This research aimed to construct a prediction model for stages II and III cardia carcinoma (CC), and provide an effective preoperative evaluation tool for clinicians. METHODS: CC mRNA expression matrix was obtained from Gene Expression Omnibus and The Cancer Genome Atlas databases. Non-negative matrix factorization was used to cluster data to obtain subgroup information, and weighted gene co-expression network analysis was used to uncover key modules linked to different subgroups. Gene-set enrichment analysis analyzed biological pathways of different subgroups. The related pathways of multiple modules were scrutinized with Kyoto Encyclopedia of Genes and Genomes. Key modules were manually annotated to screen CC-related genes. Subsequently, quantitative real-time polymerase chain reaction assessed CC-related gene expression in fresh tissues and paraffin samples, and Pearson correlation analysis was performed. A classification model was constructed and the predictive ability was evaluated by the receiver operating characteristic curve. RESULTS: CC patients had four subgroups that were associated with brown, turquoise, red, and black modules, respectively. The CC-related modules were mainly associated with abnormal cell metabolism and inflammatory immune pathways. Then, 76 CC-elated genes were identified. Pearson correlation analysis presented that THBS4, COL14A1, DPYSL3, FGF7, and SVIL levels were relatively stable in fresh and paraffin tissues. The area under the curve of 5-gene combined prediction for staging was 0.8571, indicating good prediction ability. CONCLUSIONS: The staging classifier for CC based on THBS4, COL14A1, DPYSL3, FGF7, and SVIL has a good predictive effect, which may provide effective guidance for whether CC patients need emergency surgery.

Epidemiology of Gastric Malignancies 2000-2018 According to Histology: A Population-Based Analysis of Incidence and Temporal Trends.

BACKGROUND & AIMS: Gastric cancer (GC) remains a leading cause of cancer and cancer-related mortality. Recent reports suggest noncardia GC is increasing in certain U.S. POPULATIONS: However, whether these trends are driven by gastric adenocarcinoma (GA) or other histologies, including neuroendocrine tumors (NETs), lymphoma, or gastrointestinal stromal tumors (GISTs), is unclear. METHODS: We analyzed the Surveillance, Epidemiology and End Results-18 cancer registry (2000-2018) to determine age-standardized incidence rates (ASIR) and annual percentage change (APC) trends for histologically-confirmed GCs, stratified by anatomic location (noncardia vs cardia), age group (20-49 vs 50+ years), sex, race, and ethnicity. Joinpoint regression modeling estimated the statistical significance of trend comparisons. RESULTS: Of 74,520 individuals with noncardia GC, most (66.2%) were GA, with the next largest categories being non-mucosa-associated lymphoid tissue (non-MALT) lymphomas (6.9%), GIST (6.7%), NET (6.4%), and MALT lymphoma (5.6%). Noncardia GA ASIR was significantly higher than other histologies and demonstrated the greatest differences by race and ethnicity. APCs for GA and MALT, both Helicobacter pylori-associated cancers, declined significantly over time, which was driven primarily by trends among individuals ≥50 years-old. NET and GIST APCs significantly increased irrespective of age group, with the highest APCs observed among non-Hispanic white individuals. Cardia GC was rarer than noncardia GC and comprised primarily by GA (87.9%). Cardia GC incidence fell during the study period, which was primarily driven by decline in cardia GA. CONCLUSIONS: GA was the most common histology. On the basis of our findings, the rise in noncardia GC among certain U.S. populations appears predominantly driven by NET and GIST, not GA. Further studies are needed to clarify underlying etiologies for these findings.

Trends in the Incidence of Upper Gastrointestinal Cancers Show Changing Dynamics.

Over the last 50 years, there have been shifts in the incidence of gastric and esophageal cancers in the United States, including a decline in noncardia gastric adenocarcinoma (NCGC), and increases in cardia gastric adenocarcinoma (CGC) and esophageal adenocarcinoma (EAC).1,2 Hypotheses for the changing incidences include eradication of Helicobacter pylori, the main causative agent of NCGC, and rising rates of reflux, obesity, and diet, which are risk factors associated with EAC and CGC.1,3.

Transgastric Single-Incision Laparoscopic Resection for a Gastric Submucosal Tumor Located at the Cardia.

INTRODUCTION: Surgical treatment of gastric submucosal tumors (SMTs) located near the gastroesophageal junction can be technically challenging, especially regarding preservation of the integrity and function of the lower esophageal sphincter. We introduce a novel minimally invasive surgery, successfully performed in a patient with a gastric SMT located at the cardia. A 24-year-old lady presenting with acid reflux for 1 year underwent esophagogastroscopy that showed a gastric SMT located at the cardia. Endoscopic ultrasonography showed a 20×19 mm homogeneous hypoechoic lesion originating from the muscularis propria layer. Transgastric single-incision laparoscopic resection of the tumor was performed. CONCLUSION: Transgastric single-incision laparoscopic resection of gastric SMTs is technically feasible and safe. This presents an alternative surgical choice for resection for gastric SMTs located in difficult regions such as the fundus, cardia, or prepyloric antrum.

Diagnosis and treatment for gastro-oesophageal cancer in England and Wales: analysis of the National Oesophago-Gastric Cancer Audit (NOGCA) database 2012-2020.

BACKGROUND: The National Oesophago-Gastric Cancer Audit (NOGCA) captures patient data from diagnosis to end of primary treatment for all patients with oesophagogastric (OG) cancer in England and Wales. This study assessed changes in patient characteristics, treatments received, and outcomes for OG cancer surgery for the period 2012-2020, and examined which factors may have led to changes in clinical outcomes over this time. METHODS: Patients diagnosed with OG cancer between April 2012 and March 2020 were included. Descriptive statistics were used to summarize patient demographics, disease site, type, and stage, patterns of care, and outcomes over time. The treatment variables of unit case volume, surgical approach, and neoadjuvant therapy were included. Regression models were used to examine associations between surgical outcomes (duration of stay and mortality), and patient and treatment variables. RESULTS: In total, 83 393 patients diagnosed with OG cancer during the study period were included. Patient demographics and cancer stage at diagnosis showed little change over time. Altogether, 17 650 patients underwent surgery as part of radical treatment. These patients had increasingly more advanced cancers, and a greater likelihood of pre-existing comorbidity in more recent years. Significant decreases in mortality rates and duration of stay were noted, along with improvements in oncological outcomes (nodal yields and margin positivity rates). Following adjustment for patient and treatment variables, increasing audit year and trust volume were associated, respectively, with improved postoperative outcomes: lower 30-day mortality (odds ratio (OR) 0.93 (95 per cent c.i. 0.88 to 0.98) and OR 0.99 (95 per cent c.i. 0.99-0.99)) and lower 90-day mortality (OR 0.94 (95 per cent c.i. 0.91 to 0.98) and OR 0.99 (95 per cent c.i. 0.99-0.99)), and a reduction in duration of postoperative stay (incidence rate ratio (IRR) 0.98 (95 per cent c.i. 0.97 to 0.98) and IRR 0.99 (95 per cent c.i. 0.99 to 0.99)). CONCLUSION: Outcomes of OG cancer surgery have improved over time, despite little evidence of improvements in early diagnosis. The underlying drivers for improvements in outcome are multifactorial.

Does non-metastatic gastric cancer of the cardia warrant a different treatment strategy?

BACKGROUND: Multimodal treatment strategies with surgery as its centerpiece have been accepted as the standard of care in nonmetastatic cardia gastric cancer (CGC). There remains a lack of consensus regarding the optimal multimodal treatment strategy. METHOD: We queried National Cancer Database from 2004 to 2016 to identify patients with resected nonmetastatic CGC who received perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), or postoperative chemotherapy (POC). A subgroup analysis was performed in optimally treated patients defined as initial chemotherapy within 45 days of diagnosis, resection within 45 days of diagnosis, negative margins, adjuvant chemotherapy within 90 days of resection, and standard radiation dose (45 Gy). Kaplan-Meier, Univariate analysis (UVA), and Multivariable analysis (MVA) were performed. RESULTS: We identified 2387 patients. Median survival was 38.8 months in the PEC group, 36 months in the POCR group, and 32.3 months in the POC group (p = 0.1025). On UVA, patients treated with PEC had an association with improved survival (HR, 0.83; p = 0.037) when compared with POC. On MVA, no significant difference was noted in overall survival (OS) between PEC, POCR, and POC, similar to subgroup analysis of optimally treated cohort. CONCLUSION: OS rate in nonmetastatic CGC is not significantly different between patients receiving PEC, POCR, or POC.

Risk factors of perforation in gastric stromal tumors during endoscopic resection: a retrospective case-control study.

BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.

Genome-wide DNA methylation profiling of gastric cardia cancer.

BACKGROUND AND AIM: Aberrant DNA methylation has been found in various cancer types including gastric cancer, yet the genome-wide DNA methylation profile of gastric cardia cancer (GCC) remains unclear. Therefore, we aimed to profile the DNA methylation pattern of GCC and identify promising diagnostic epigenetic biomarkers. METHODS: We investigated the genome-wide DNA methylation pattern in eight pairs of GCC and adjacent normal tissues using Illumina 850K microarrays. Subsequently, bisulfite-pyrosequencing and quantitative real-time PCR were performed on eight pairs of GCC-adjacent normal tissues for validation. Finally, we performed immunohistochemistry to examine ADHFE1 expression on 126 pairs of GCC-adjacent normal samples. RESULTS: DNA methylome analysis showed global hypomethylation and local hypermethylation of promoter cytosine-phosphate-guanine (CpG) islands (CGIs) in GCC tissues compared with gastric cardia normal mucosa (P < 2.2 × 10-16 ). Differential methylation analysis identified a total of 91 723 differentially-methylated probes (DMPs), and the candidate gene with the largest average DNA methylation difference mapped to ADHFE1 (mean Δß = 0.53). Subsequently, three DMPs in the ADHFE1 promoter were validated by pyrosequencing. Notably, the mean methylation level of the three candidate DMPs (ADHFE1_cg08090772, ADHFE1_cg19283840, and ADHFE1_cg20295442) was negatively associated with ADHFE1 mRNA expression level (Spearman rho = -0.64, P = 0.01). Moreover, both mRNA (P = 0.0213) and protein (P < 0.0001) expression of ADHFE1 were significantly decreased in GCCs compared with the adjacent normal tissues. CONCLUSIONS: Our results reveal DNA methylation aberrations in GCC and that ADHFE1 gene DNA methylation contributes to the risk of GCC, thus providing novel mechanistic insights into gastric cardia cancer carcinogenesis.

Classification of GIST and other benign gastric tumors based on minimally invasive surgical strategy.

PURPOSE: Gastrointestinal mesenchymal tumors (GMTs) include malignant, intermediate malignancy, and benign lesions. The aim is to propose a new surgical classification to guide the intraoperative minimally invasive surgical strategy in case of non-malignant GMTs less than 5 cm. METHODS: Primary endpoint is the creation of a classification regarding minimally invasive surgical technique for these tumors based on their gastric location. Secondary endpoint is to analyze the R0 rate and the postoperative morbidity and mortality rates. Tumors were classified in two groups based on their morphology (group A: exophytic, group B: transmural/intragastric). Each group is then divided based on the tumor location and consequently surgical technique used in subgroup: AI (whole stomach area) and AII (iuxta-cardial and pre-pyloric areas) both for the anterior and posterior gastric wall; BIa (greater curvature on the anterior and posterior wall), BIb (lesser curvature on the anterior wall); BII (iuxta-cardial and pre-pyloric area in the anterior and posterior wall, including the lesser curvature on the posterior wall). RESULTS: Forty-two patients were classified and allocated in each subgroup: 17 in AI, 2 in AII, 5 in BIa, 3 in BIb, and 15 in BII. Two postoperative Clavien-Dindo I complications (4.8%, subgroup BIa and BIb) occurred. One patient (2.4%, subgroup AI) underwent reintervention due to R0 resection. CONCLUSIONS: This classification proved to be able to classify gastric lesions based on their morphology, location, and surgical treatment, obtaining encouraging perioperative results. Further studies with wider sample of patients are required to draw definitive conclusions.

[Application value of CT examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma].

Objective: To investigate the application value of computed tomography (CT) examination of lymph node short diameter in evaluating cardia-left gastric lymph node metastasis in thoracic esophageal squamous cell carcinoma (ESCC). Methods: A total of 477 patients with primary thoracic ESCC who underwent surgical treatment in the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to December 2017 were collected. All of them underwent McKeown esophagectomy plus complete two-field or three-field lymph node dissection. Picture archiving and communication system were used to measure the largest cardia-left gastric lymph node short diameter in preoperative CT images. The postoperative pathological diagnosis results of cardia-left gastric lymph node were used as the gold standard. Receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CT lymph node short diameter in detecting the metastasis of cardia-left gastric lymph node in thoracic ESCC, and determine the optimal cut-off value. Results: The median short diameter of the largest cardia-left gastric lymph node was 4.1 mm in 477 patients, and the largest cardia-left gastric lymph node short diameter was less than 3 mm in 155 cases (32.5%). Sixty-eight patients had cardia-left gastric lymph node metastases, of which 38 had paracardial node metastases and 41 had left gastric node metastases. The lymph node ratios of paracardial node and left gastric node were 4.0% (60/1 511) and 3.3% (62/1 887), respectively. ROC curve analysis showed that the area under the curve of CT lymph node short diameter for evaluating cardia-left gastric lymph node metastasis was 0.941 (95% CI: 0.904-0.977; P<0.05). The optimal cut-off value of CT examination of the cardia-left gastric lymph node short diameter was 6 mm, and the corresponding sensitivity, specificity and accuracy were 85.3%, 91.7%, and 90.8%, respectively. Conclusion: CT examination of lymph node short diameter can be a good evaluation of cardia-left gastric lymph node metastasis in thoracic ESCC, and the optimal cut-off value is 6 mm.