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Background Adenocarcinoma of the gastroesophageal junction (GEJ) Siewert type II can be resected by transthoracic esophagectomy or transhiatal extended gastrectomy. Both allow for a complete tumor resection, yet there is an ongoing controversy about which surgical approach is superior with regards to quality of life, oncological outcomes and survival. While some studies suggest a better oncological outcome after transthoracic esophagectomy, others favor transhiatal extended gastrectomy for a better postoperative quality of life. To date, only retrospective studies are available, showing ambiguous results. Methods This study is a multinational, multicenter, randomized, clinical superiority trial. Patients ( n = 262) with a GEJ type II tumor resectable by both transthoracic esophagectomy and transhiatal extended gastrectomy will be enrolled in the trial. Type II tumors are defined as tumors with their midpoint between ≤1 cm proximal and ≤ 2 cm distal of the top of gastric folds on preoperative endoscopy. Patients will be included in one of the participating European sites and are randomized to either transthoracic esophagectomy or transhiatal extended gastrectomy. The trial is powered to show superiority for esophagectomy with regards to the primary efficacy endpoint overall survival. Key secondary endpoints are complete resection (R0), number and localization of tumor infiltrated lymph nodes at dissection, post-operative complications, disease-free survival, quality of life and cost-effectiveness. Postoperative survival and quality of life will be followed-up for 24 months after discharge. Further survival follow-up will be conducted as quarterly phone calls up to 60 months. Discussion To date, as level 1 evidence is lacking, there is no consensus on which surgery is superior and both surgeries are used to treat GEJ type II carcinoma worldwide. The CARDIA trial is the first randomized trial to compare transthoracic esophagectomy versus transhiatal extended gastrectomy in patients with GEJ type II tumors. Several quality control measures were implemented in the protocol to ensure data reliability and increase the trial’s significance. It is hypothesized that esophagectomy allows for a higher rate of radical resections and a more complete mediastinal lymph node dissection, resulting in a longer overall survival, while still providing an acceptable quality of life and cost-effectiveness. Trial registration The trial was registered on August 2nd 2019 at the German Clinical Trials Register under the trial-ID DRKS00016923 .

Background This study aimed to investigate the clinical characteristics and esophageal motility of patients with gastric cardia submucosal tumors (SMTs) and the associated changes after endoscopic resection based on high-resolution impedance manometry (HRIM). Methods From our electronic database, we identified patients who underwent pre-operative evaluation of gastric cardia SMTs between 2015 and 2023. All patients completed standardized symptom questionnaires and underwent endoscopic ultrasonography and HRIM. Endoscopic resection via submucosal dissection or submucosal tunnel endoscopic resection was performed, followed by esophagogastroduodenoscopy and HRIM three months later. Esophageal motility on HRIM was compared based on the updated Chicago Classification v4.0. Results Thirty patients (mean age, 47.4 ± 12.8 years; male, 50%) were analyzed. Most patients were asymptomatic (43.3%), while others presented with epigastralgia, regurgitation, chest pain, or dysphagia. On endoscopic ultrasonography, the average tumor size was 16.7 ± 4.5 mm (range, 10.0–30.0 mm), and most tumors originated from the fourth layer (80%). On HRIM, eight patients (26.7%) had abnormal esophageal motility, including five with ineffective esophageal motility (IEM) and three with esophagogastric junction outflow obstruction. Complete resection was achieved in 25 of the 27 patients (92.6%) who underwent endoscopic treatment. Pathology revealed leiomyomas (96%) and gastrointestinal stromal tumors (4%). No significant differences in symptom profiles or HRIM parameters were observed after tumor resection. Three patients with pre-operative IEM exhibited normal motility at the follow-up HRIM. Conclusion Up to 26.7% of patients with gastric cardia SMTs had abnormal esophageal motility on HRIM. Endoscopic resection of these SMTs was effective and safe and appeared to improve esophageal motility in patients with IEM.

ObjectiveEarly 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).DesignscRNA-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.ResultsIntegrative 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.ConclusionOur 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.

BackgroundGastric adenocarcinoma is the second most common cancer-related death globally. Assessing survival trends can help evaluate changes in detection and treatment. We aimed to determine recent prognosis trends in gastric non-cardia and cardia adenocarcinoma in an unselected cohort with complete follow-up.MethodsPopulation-based nationwide cohort study, including 17,491 patients with gastric non-cardia adenocarcinoma and 4698 with cardia adenocarcinoma recorded in the Swedish Cancer Registry in 1990–2013 with follow-up until 2017. Observed and relative 5-year survival was calculated and stratified by resectional surgery and no such surgery. Prognostic factors were evaluated using multivariable Cox regression.ResultsThe relative overall 5-year survival remained stable at 18% for gastric non-cardia adenocarcinoma throughout the study period and increased from 12 to 18% for cardia adenocarcinoma. Concurrently, the proportion of patients who underwent resectional surgery decreased from 49 to 38% for non-cardia adenocarcinoma and from 48 to 33% for cardia adenocarcinoma. The relative postoperative 5-year survival increased from 33 to 44% for non-cardia adenocarcinoma and from 21 to 43% for cardia adenocarcinoma, whereas in nonoperated patients it decreased from 3 to 2% in non-cardia adenocarcinoma and increased from 3 to 5% in cardia adenocarcinoma. Poor prognostic factors were higher tumor stage, older age, and more comorbidity.ConclusionsDespite decreasing resectional rates, the 5-year overall survival has remained unchanged for gastric non-cardia adenocarcinoma and improved for cardia adenocarcinoma over the last two decades in Sweden and is now similar for these sublocations. The postoperative survival has improved for both sublocations, but particularly for cardia adenocarcinoma.

It is recognized that lncRNA BBOX1‐AS1 exerts a crucial oncogenic property in several cancer types. However, the functions and underlying mechanisms of BBOX1‐AS1 in the epithelial–mesenchymal transition (EMT) process of gastric cardia adenocarcinoma (GCA) have remained unclarified. The findings of this study demonstrated that GCA tissues had elevated BBOX1‐AS1 expression levels, which was associated with a worse prognosis in GCA patients. BBOX1‐AS1 dramatically enhanced cell proliferation, invasion, and TGF‐β1‐induced the EMT process in vitro. Further mechanism analysis revealed that BBOX1‐AS1 could combine with CtBP2 and strengthen the interaction of CtBP2 and ZEB1. BBOX1‐AS1 might regulate the E‐cadherin expression through CtBP2/ZEB1 transcriptional complex‐mediated transcriptional repression, further affecting the activation of the Wnt/β‐catenin pathway and the EMT process. Overall, our findings demonstrate that BBOX1‐AS1 might act as an lncRNA associated with EMT for facilitating GCA advancement via interaction with CtBP2 to facilitate the activation of Wnt/β‐catenin pathway and the EMT process, which indicated that it might function as an exploitable treatment target for GCA patients. BBOX1‐AS1, activated by TGF‐β, acts as a downstream effector of TGF‐β signaling to promote the malignant progression of GCA. BBOX1‐AS1 could combine with CtBP2 and strengthen the interaction of CtBP2 and ZEB1. BBOX1‐AS1 might regulate the E‐cadherin expression through CtBP2/ZEB1 transcriptional complex‐mediated transcriptional repression, further affecting the activation of the Wnt/β‐catenin pathway and the EMT process.

Our goal was to develop a prognostic nomogram to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric cardia cancer (GCC). Patients diagnosed with GCC from 2004 to 2015 were screened from the surveillance, epidemiology, and end results (SEER) database. A nomogram was developed based on the variables associated with OS and CSS using multivariate Cox analysis regression models, which predicted 3- and 5-year OS and CSS. The predictive performance of the nomogram was evaluated using the consistency index (C-index), calibration curve and decision curve analysis (DCA), and the nomogram was calibrated for 3- and 5-year OS and CSS. A total of 7,332 GCC patients were identified and randomized into a training cohort (5,231, 70%) and a validation cohort (2,200, 30%). Multivariate Cox regression analysis showed that marital status, race, SEER stage, grade, T stage, N stage, M stage, tumor size, and surgery were independent risk factors for OS and CSS in GCC patients. Based on the multivariate Cox regression results, we constructed prognostic nomograms of OS and CSS. In the training cohort, the C-index for the OS nomogram was 0.714 (95% CI = 0.705–0.723), and the C-index for the CSS nomogram was 0.759 (95% CI = 0.746–0.772). In the validation cohort, the C-index for the OS nomogram was 0.734 (95% CI = 0.721–0.747), while the C-index for the CSS nomogram was 0.780 (95% CI = 0.759–0.801). Our nomogram has better prediction than the nomogram based on TNM stage. In addition, in the training and external validation cohorts, the calibration curves of the nomogram showed good consistency between the predicted and actual 3- and 5-year OS and CSS rates. The nomogram can effectively predict OS and CSS in GCC patients, which may help clinicians personalize prognostic assessments and clinical decisions.

BackgroundLaparoscopic 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.MethodsOne 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.ResultsAt 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.ConclusionsLHM 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.

Objective We aimed to investigate the relationship between the visceral to subcutaneous fat area ratio (V/S ratio) and incidence of early postoperative small bowel obstruction (EPSBO) following total gastrectomy for cardia cancer. Methods We conducted a retrospective analysis among patients with cardia cancer who underwent elective total gastrectomy with esophagojejunostomy Roux-en-Y anastomosis at Nanjing Yimin Hospital between November 2019 and April 2024. Preoperative, intraoperative, and postoperative factors were meticulously monitored. The V/S ratio was calculated using computed tomography scans at the umbilical level with Slice-O-Matic software (Tomovision, Montreal, Canada). Statistical analyses included logistic regression and receiver operating characteristic (ROC) curve analysis. Results Among 175 patients, 27 (15.4%) developed EPSBO. The V/S ratio was significantly higher in the EPSBO group (1.76 ± 1.05 vs. 1.01 ± 0.54). Logistic regression identified the V/S ratio as a significant predictor of EPSBO (odds ratio [OR] = 1.612, 95% [CI]: 1.102–1.605). ROC curve analysis demonstrated high sensitivity (92%) and specificity (100%) for the V/S ratio in predicting EPSBO, with a 0.83 AUC. Conclusions Our findings indicated a higher V/S ratio was a significant predictor of EPSBO following total gastrectomy for cardia cancer. Preoperative assessment of the V/S ratio can inform risk stratification and guide targeted interventions to improve postoperative outcomes.

Background The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. Methods 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. Results MSI-H phenotype was found in 111 of 472 patients (23.5 %). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6 % vs. 35 %, p  < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95 % CI 1.56–4.51, p  < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet-ring cell/mucinous histotypes was observed. Conclusions MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non-cardia tumors.

Although a number of previous studies have noted either positive or no association for body mass index (BMI) and gastric cancer risk, little evidence exists in the Chinese population. We prospectively examined the associations of BMI with risk of gastric cancer in the Linxian General Population Trial cohort, with 29 584 healthy adults enrolled in 1985 and followed through to the end of 2014. Body weight and height were measured during physical examination at baseline and BMI was calculated as weight in kilograms divided by height in meters squared. Body mass index from 138 subjects was missing, and a total of 29 446 participants were included in the final analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. During 30 years of follow‐up, we confirmed 1716 newly diagnosed gastric cardia adenocarcinoma (GCA) cases and 626 new gastric non‐cardia adenocarcinoma (GNCA) cases. Overall, compared to the lowest quartile (BMI <20.32 kg/m2), subjects in the fourth quartile (BMI ≥23.31 kg/m2) subjects had lower risk of developing GNCA (hazard ratio, 0.65; 95% confidence interval, 0.51–0.83). Age‐ and sex‐specific analyses showed that this protective effect was only observed in men and older (52 + years) persons. No associations were observed for BMI with GCA incidence. Higher BMI was associated with decreased risk of GNCA in this population, particularly in men and older persons. Future studies are needed to confirm these findings. The trial is registered with ClinicalTrials.gov: NCT00342654.