Exploring the immune escape mechanisms in gastric cancer patients based on the deep AI algorithms and single-cell sequencing analysis.

Gastric cancer is a prevalent and deadly malignancy, and the response to immunotherapy varies among patients. This study aimed to develop a prognostic model for gastric cancer patients and investigate immune escape mechanisms using deep machine learning and single-cell sequencing analysis. Data from public databases were analysed, and a prediction model was constructed using 101 algorithms. The high-AIDPS group, characterized by increased AIDPS expression, exhibited worse survival, genomic variations and immune cell infiltration. These patients also showed immunotherapy tolerance. Treatment strategies targeting the high-AIDPS group identified three potential drugs. Additionally, distinct cluster groups and upregulated AIDPS-associated genes were observed in gastric adenocarcinoma cell lines. Inhibition of GHRL expression suppressed cancer cell activity, inhibited M2 polarization in macrophages and reduced invasiveness. Overall, AIDPS plays a critical role in gastric cancer prognosis, genomic variations, immune cell infiltration and immunotherapy response, and targeting GHRL expression holds promise for personalized treatment. These findings contribute to improved clinical management in gastric cancer.

Global Ring Study to Investigate the Comparability of Total Assay Performance of Commercial Claudin 18 Antibodies for Evaluation in Gastric Cancer.

Claudin 18.2 (CLDN18.2), the dominant isoform of CLDN18 in gastric tissues, is a highly specific tight junction protein of the gastric mucosa with variably retained expressions in gastric and gastroesophageal junction cancers. Additionally, CLDN18.2-targeted treatment with zolbetuximab, in combination with chemotherapy, has recently been assessed in 2 phase-III studies of patients with HER2-negative, locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma. These trials used the investigational VENTANA CLDN18 (43-14A) RxDx immunohistochemistry (IHC) assay on the Ventana BenchMark platform to identify patients eligible for CLDN18.2-targeted treatment. We report the findings of a global ring study evaluating the analytical comparability of concordance of the results of 3 CLDN18 antibodies (Ventana, LSBio, and Novus) stained on 3 IHC-staining platforms (Ventana, Dako, and Leica). A tissue microarray (TMA), comprising 15 gastric cancer cases, was stained by 27 laboratories across 11 countries. Each laboratory stained the TMAs using at least 2 of the 3 evaluated CLDN18 antibodies. Stained TMAs were assessed and scored using an agreed IHC-scoring algorithm, and the results were collated for statistical analysis. The data confirmed a high level of concordance for the VENTANA CLDN18 (43-14A; Ventana platform only) and LSBio antibodies on both the Dako and Leica platforms, with accuracy, precision, sensitivity, and specificity rates all reaching a minimum acceptable ≥85% threshold and good-to-excellent levels of concordance as measured by Cohen's kappa coefficient. The Novus antibody showed the highest level of variability against the reference central laboratory results for the same antibody/platform combinations. It also failed to meet the threshold for accuracy and sensitivity when used on either the Dako or Leica platform. These results demonstrated the reliability of IHC testing for CLDN18 expression in gastric tumor samples when using commercially available platforms with an appropriate methodology and primary antibody selection.

Overall Volume of Upper Gastrointestinal Surgery Positively Impacts Gastric Cancer Outcomes at Centers with Low Gastrectomy Volume.

BACKGROUND: The relationship between hospital volume and surgical mortality is well documented. However, complete centralization of surgical care is not always feasible. The present study investigates how overall volume of upper gastrointestinal surgery at hospitals influences patient outcomes following resection for gastric adenocarcinoma. PATIENTS AND METHODS: National Cancer Database (2010-2019) patients with pathologic stage 1-3 gastric adenocarcinoma who underwent gastrectomy were identified. Three cohorts were created: low-volume hospitals (LVH) for both gastrectomy and overall upper gastrointestinal operations, mixed-volume hospital (MVH) for low-volume gastrectomy but high-volume overall upper gastrointestinal operations, and high-volume gastrectomy hospitals (HVH). Chi-squared tests were used to analyze sociodemographic factors and surgical outcomes and Kaplan-Meier method for survival analysis. RESULTS: In total, 26,398 patients were identified (LVH: 20,099; MVH: 539; HVH: 5,760). The 5-year survival was equivalent between MVH and HVH for all stages of disease (MVH: 56.0%, HVH 55.6%; p = 0.9866) and when stratified into early (MVH: 69.9%, HVH: 65.4%; p = 0.1998) and late stages (MVH: 24.7%, HVH: 32.0%; p = 0.1480), while LVH had worse survival. After matching patients, postoperative outcomes were worse for LVH, but there was no difference between MVH and HVH in terms of adequate lymphadenectomy, margin status, readmission rates, and 90-day mortality rates. CONCLUSIONS: Despite lower gastrectomy volume for cancer, postoperative gastrectomy outcomes at centers that perform a high number of upper gastrointestinal cancer surgeries were similar to hospitals with high gastrectomy volume. These hospitals offer a blueprint for providing equivalent outcomes to high volume centers while enhancing availability of quality cancer care.

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. METHODS: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). RESULTS: Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49-0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62-0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87-1.53; p = 0.34). CONCLUSIONS: In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells.

Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori-induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC-I) molecules HLA-E and HLA-C-ligands of the major NK cell inhibitory receptors NKG2A and killer-cell Ig-like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM-1 and CD2, and of the adhesion molecules LFA-1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA-C surface expression on AGS cells. H. pylori infection enhanced HLA-C protein synthesis, which could explain H. pylori-induced HLA-C surface expression. H. pylori infection enhanced HLA-C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori-induced HLA-C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA-C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA-C-specific inhibitory receptors.

Neoadjuvant chemotherapy for resectable gastric cancer is associated with better outcomes than neoadjuvant chemoradiation.

INTRODUCTION: National Comprehensive Cancer Network Guidelines recommend neoadjuvant chemotherapy (CTx) or chemoradiation (CRTx) for advanced resectable gastric cancer, irrespective of the tumor location. The aim of this study is to compare survival benefits between neoadjuvant CTx and CRTx using the National Cancer Database (NCDB). METHODS: Using the NCDB, we retrospectively reviewed patients who underwent gastrectomy after neoadjuvant CRTx or CTx between 2004 and 2018. RESULTS: The cohort included 14 266 patients, with 6458 (45.3%) receiving neoadjuvant CTx and 7808 (54.7%) receiving neoadjuvant CRTx. Both treatment groups exhibited significant differences in various demographic and clinical factors, including sex, age, race, tumor locations, stages, and adjuvant treatment (all p < 0.001). While the complete pathological response was more prevalent in the CRTx group (p < 0.001), overall survival (OS) was significantly extended in the CTx group (p < 0.001). Subgroup survival analyses, accounting for tumor location and clinical/pathological stage, consistently revealed longer OS in the CTx group (p < 0.001). The direct comparison showed an approximately 20%-30% improved 5-year OS in the CTx group across the majority of American Joint Committee on Cancer (AJCC) T/N category tables. Multivariate analysis confirmed neoadjuvant CTx was an independent protective factor (hazard ratio = 0.811; p < 0.001). A nomogram for OS based on multivariate analysis was also proposed, revealing a significant improvement in the c-index compared to the current AJCC staging (0.654 vs. 0.596). CONCLUSIONS: Patients undergoing neoadjuvant CRTx demonstrated significantly shorter survival compared to patients undergoing CTx at the same stage. The current AJCC staging may lead to an overestimation of survival in patients with neoadjuvant CRTx.

A prognostic risk model based on lactate metabolism and transport-related lncRNAs for gastric adenocarcinoma.

BACKGROUND: Increased lactate levels and metastasis in tumours are strongly associated with dismal outcomes. But prognostic value of lactate metabolism and transport-related lncRNAs in gastric adenocarcinoma (GA) patients remains unaddressed. METHODS: Gene expression data of GA were provided by The Cancer Genome Atlas. Lactate metabolism and transport-related gene data were accessed from GSEA. LncRNAs related to lactate metabolism and transport were identified by correlation analysis. A prognostic model was built by regression analysis. Validity of prognostic model was confirmed through survival analysis and receiver operating characteristic (ROC) curve. Immunity of each risk group was evaluated by immune correlation analysis .LncRNA-mRNA network was built by correlation analysis using Cytoscape software. RESULTS: A 12-gene prognostic model based on lactate metabolism and transport-related lncRNAs was built in GA. Median riskscore was utilized to classify GA samples into high- and low-risk groups. Survival analysis and ROC curves demonstrated validity of prognostic model. Most immune checkpoint molecules and TIDE scores were lower in the low-risk group. LINC01303 and LINC01545 may be the key prognostic factors in patients with GA. CONCLUSION: This study successfully built a prognostic model of lactate metabolism and transport-related lncRNAs in GA. The findings guide prognostic management of GA patients.

Prevalence, clinical characteristics and treatment outcomes of oxyntic gland neoplasm: a single-center retrospective study.

BACKGROUND: Oxyntic gland neoplasm (OGN) is a rare subtype of gastric cancer. The aim of this study is to evaluate the prevalence, clinicopathological features, effectiveness and safety of endoscopic treatment, as well as the prognosis of OGN. METHODS: We retrospectively analyzed the data of patients pathologically diagnosed with OGN at our hospital from November 1, 2019 to May 1, 2023. RESULTS: A total of 36 patients with 45 lesions were identified, resulting in a disease frequency of 0.047% (36/76,832). The mean age was 55.0 ± 7.5 years, with a male-to-female ratio of about 1:1.12. Most lesions were ≤10 mm in size (84.4%), located in the upper third of the stomach (73.3%), exhibited slight elevation (75.5%), appeared whitish (55%), had dilated blood vessels on the surface (75.5%). 16 and 21 lesions were treated by precutting endoscopic mucosal resection (EMR-P) and endoscopic submucosal dissection (ESD), respectively. No significant differences were found between EMR-P and ESD in terms of en bloc resection rate (100% vs 100%, p = 1.000), complete resection rate (100% vs 90.5%, p = 0.495), and curative resection rate (93.8% vs 90.5%, p = 1.000). No complications such as bleeding and perforation were observed. No recurrence or metastasis was observed during the follow-up period. CONCLUSIONS: OGN is a rare tumor with unique clinical, endoscopic, and pathological characteristics. EMR-P and ESD are deemed safe and effective for treating OGNs. The relatively faster and easier EMR-P seems at least non-inferior to ESD, especially for removal of smaller OGNs. The overall prognosis is favorable.

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

BACKGROUND: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. METHODS: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. RESULTS: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. CONCLUSION: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

High expression of NOTCH2 in gastric adenocarcinoma: A novel early diagnostic target.

BACKGROUND AND AIM: NOTCH2 is overexpressed in gastric cancer (GC), and its enhanced activity is significantly correlated with worse tumor characteristics. We aim to analyze the clinicopathologic correlation between NOTCH2 and the molecular typing of GC by immunohistochemistry and by transcriptional sequencing. METHODS: In this immunohistochemical study, we detected NOTCH2, EBER, P53, HER2, MLH1, MSH2, PMS2, and MSH6 and evaluated the association of NOTCH2 with clinical and histopathological features in a large single-institutional series of gastric adenocarcinomas (n = 488). The correlation was also investigated between immunohistochemical results and survival outcomes. RESULTS: High NOTCH2 expression (2+/3+) was found in 139/488 (27.5%) samples analyzed. NOTCH2 expression was correlated with early stage T1 (P < 0.0001), GC in the fundus (P = 0.0364), and positive P53 status (P = 0.0019). We did not find an association between NOTCH2 and HER2, microsatellite instability, EBER, and overall survival. Through RNA sequencing, it was revealed that NOTCH2 plays an important biological function in the pathogenesis and development of GC. CONCLUSIONS: Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.

Comparable long-term survival outcomes after endoscopic and gastrectomy treatment of pT1acN0M0 gastric adenocarcinoma in patients who met the expanded criteria.

BACKGROUND: Whether the Western pT1acN0M0 gastric cancer (GC) patients who met the Japanese expanded criteria could be the candidates for endoscopic treatment (ET) remains unclear because of unknown long-term survival outcomes. METHODS: A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program was performed. The survival differences between pT1acN0M0 gastric adenocarcinoma patients who received ET or gastrectomy treatment (GT) were evaluated using multivariate survival analysis. RESULTS: A total of 314 pT1acN0M0 gastric adenocarcinoma patients who met the expanded criteria were included, 46 patients received ET and 268 patients received GT. pT1acN0M0 gastric adenocarcinoma patients met the expanded criteria underwent ET experienced a similar hazard of cancer-specific death compared with those underwent GT both in the multivariate Cox survival analysis (adjusted hazard ratio [HR]; 1.18, 95% confidence interval [CI] 0.40-3.49; P = 0.766) and the multivariate competing risk model (subdistribution HR [SHR], 1.12, 95% CI 0.38-3.29; P = 0.845). The result that pT1acN0M0 gastric adenocarcinoma patients met the expanded criteria underwent ET experienced comparable survival outcomes to those who underwent GT did not change even compared with those who underwent GT with > 15 lymph nodes examined (adjusted HR, 1.55, 95% CI 0.44-5.49; P = 0.499; SHR, 1.47, 95% CI 0.44-4.88; P = 0.532). CONCLUSIONS: The ET can be considered in Western pT1acN0M0 gastric adenocarcinoma patients who met the Japanese expanded criteria. However, a prospective study should be warranted.

Gastrointestinal manifestations in patients with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a systematic review with analysis of individual patient data.

BACKGROUND AND AIM: Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome characterized by fundic gland polyps (FGP) as well as an increased risk of gastric cancer. The syndrome has been recognized as a clinical entity for less than a decade. A clinical suspicion may be complex and can vary from incidental findings of FGPs at gastroscopy to obstructive symptoms with dyspepsia and vomiting. The diagnosis is established by genetic detection of a pathogenic variant in the promotor 1B region of the APC gene. As of yet there are no established clinical criteria for the diagnosis. To increase knowledge of the condition and to discuss possible genetic testing and surveillance strategies, we performed a systematic review of all reported patients with GAPPS. METHODS: This review was organized according to PRISMA guidelines. The search, which was conducted on September 7th, 2023, was applied to MEDLINE and restricted to only humans and papers in the English language. Only the studies on patients/families with GAPPS verified by identification of a pathogenic variant in the APC promoter 1B were included. RESULTS: Twelve publications with a total of 113 patients were identified. In all instances the diagnosis was genetically verified with reports of four different variants within the APC promotor 1B region. Eighty-eight patients (90.1%) had gastric polyps, of these seven patients had low-grade dysplasia and five patients had both low- and high-grade dysplasia. Thirty-seven patients (45.7%) underwent gastrectomy. There were no reports of duodenal polyps (0%). Gastric cancer was found in 31 patients (30.1%) with a median age of 48 years (range 19-75). Twenty-six patients died (23.2%) of which 19 had developed gastric cancer (73.1%). One patient was diagnosed with metastatic colorectal cancer (2.2%) and died at 73 years of age. Nineteen patients had colorectal manifestations with < 20 polyps (41.3%). CONCLUSION: Patients with a pathogenic variant in the APC promoter 1B region have an increased risk of gastric polyposis and early-onset gastric cancer. However, there is considerable variation in clinical expression and penetrance, which makes decisions on surveillance and the timing of prophylactic gastrectomy challenging.

Hypoxia-based critical gene biomarkers as prognostic reporters for gastric adenocarcinoma.

BACKGROUND: Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients. METHODS: Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non-negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package "oncoPredict" was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression. RESULTS: Hypoxia-score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution-based algorithms for immune infiltration, Hypoxia-score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high-risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low-risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia-score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia-score in single-cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single-cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees. CONCLUSION: The Hypoxia-score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.

Unraveling the immunogenic cell death pathways in gastric adenocarcinoma: A multi-omics study.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal (GI) system. However, the lack of reliable biomarkers has made its diagnosis, prognosis, and treatment challenging. Immunogenic cell death (ICD) is a type of programmed cell death that is strongly related to the immune system. However, its function in GC requires further investigation. METHOD: We used multi-omics and multi-angle approaches to comprehensively explore the prognostic features of ICD in patients with stomach adenocarcinoma (STAD). At the single-cell level, we screened genes associated with ICD at the transcriptome level, selected prognostic genes related to ICD using weighted gene co-expression network analysis (WGCNA) and machine learning, and constructed a prognostic model. In addition, we constructed nomograms that incorporated pertinent clinical features and provided effective tools for prognostic prediction in clinical settings. We also investigated the sensitivity of the risk subgroups to both immunotherapy and drugs. Finally, in addition to quantitative real-time polymerase chain reaction, immunofluorescence was used to validate the expression of ICD-linked genes. RESULTS: Based on single-cell and transcriptome WGCNA analyses, we identified 34 ICD-related genes, of which 11 were related to prognosis. We established a prognostic model using the least absolute shrinkage and selection operator (LASSO) algorithm and identified dissimilarities in overall survival (OS) and progression-free survival (PFS) in risk subgroups. The nomograms associated with the ICD-related signature (ICDRS) demonstrated a good predictive value for clinical applications. Moreover, we detected changes in the tumor microenvironment (TME), including biological functions, mutation landscapes, and immune cell infiltration, between the high- and low-risk groups. CONCLUSION: We constructed an ICD-related prognostic model that incorporated features related to cell death. This model can serve as a useful tool for predicting the prognosis of GC, targeted prevention, and personalized medicine.

Medical image segmentation of gastric adenocarcinoma based on dense connection of residuals.

BACKGROUND AND OBJECTIVE: Accurate segmentation of gastric cancer based on CT images of gastric adenocarcinoma is crucial for physicians to screen gastric diseases, clinical diagnosis, preoperative prediction, and postoperative evaluation plans. To address the issue of the inability of the segmentation algorithm to depict the correct boundaries due to unclear gastric contours in the lesion area and the visible irregular band-like dense shadow extending to the perigastric region, a 3D medical image segmentation model 3D UNet based on residual dense jumping method is proposed. METHODS: In the method we proposed, Residual Dense Block, which is applied to the image super-resolution module to remove CT artifacts, and Residual Block in ResNet are further fused. The quality of CT images is improved by Residual Dense Skip Block, which removes banded dense shadows, preserves image details and edge information, captures features, and improves the segmentation performance of gastric adenocarcinoma. The Instance Normalization layer position is modified to select the best result. Different loss functions are also combined in order to obtain the best gastric adenocarcinoma segmentation performance. RESULTS: We tested the model on a hospital-provided gastric adenocarcinoma dataset. The experimental results show that our model outperforms the existing methods in CT gastric adenocarcinoma segmentation, in which the method combining the hybrid loss function of Dice and CE obtains an average dice score of 82.3%, which is improved by 5.3% and 3.8% compared to TransUNet and Hiformer, respectively, and improves the cross-merge rate to 70.8%, compared to nnFormer, nnUNet by 1% and 0.9%, respectively. CONCLUSIONS: The residual jump connection structure indeed improves segmentation performance. The proposed method has the potential to be used as a screen for gastric diseases and to assist physicians in diagnosis.

An In Vitro Study on the Cytotoxic, Antioxidant, and Antimicrobial Properties of Yamogenin-A Plant Steroidal Saponin and Evaluation of Its Mechanism of Action in Gastric Cancer Cells.

Yamogenin is a steroidal saponin occurring in plant species such as Asparagus officinalis, Dioscorea collettii, Trigonella foenum-graecum, and Agave sp. In this study, we evaluated in vitro cytotoxic, antioxidant, and antimicrobial properties of yamogenin. The cytotoxic activity was estimated on human colon cancer HCT116, gastric cancer AGS, squamous carcinoma UM-SCC-6 cells, and human normal fibroblasts with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The amount of apoptotic and dead AGS cells after treatment with yamogenin was estimated with flow cytometry. Also, in yamogenin-treated AGS cells we investigated the reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activity level of caspase-8 and -9, and gene expression at mRNA level with flow cytometry, luminometry, and RT-PCR, respectively. The antioxidant properties of yamogenin were assessed with DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays. The antimicrobial potential of the compound was estimated on Staphylococcus aureus, Bacillus cereus, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Helicobacter pylori, Campylobacter coli, Campylobacter jejuni, Listeria monocytogenes, Lactobacillus paracasei, and Lactobacillus acidophilus bacteria strains. Yamogenin showed the strongest cytotoxic effect on AGS cells (IC50 18.50 ± 1.24 µg/mL) among the tested cell lines. This effect was significantly stronger in combinations of yamogenin with oxaliplatin or capecitabine than for the single compounds. Furthermore, yamogenin induced ROS production, depolarized mitochondrial membrane, and increased the activity level of caspase-8 and -9 in AGS cells. RT-PCR analysis revealed that this sapogenin strongly up-regulated TNFRSF25 expression at the mRNA level. These results indicate that yamogenin induced cell death via the extrinsic and intrinsic way of apoptosis. Antioxidant study showed that yamogenin had moderate in vitro potential (IC50 704.7 ± 5.9 µg/mL in DPPH and 631.09 ± 3.51 µg/mL in ABTS assay) as well as the inhibition of protein denaturation properties (with IC50 1421.92 ± 6.06 µg/mL). Antimicrobial test revealed a weak effect of yamogenin on bacteria strains, the strongest one being against S. aureus (with MIC value of 350 µg/mL). In conclusion, yamogenin may be a potential candidate for the treatment and prevention of gastric cancers.

Identification of histopathological classification and establishment of prognostic indicators of gastric adenocarcinoma based on deep learning algorithm.

The aim of this study is to establish a deep learning (DL) model to predict the pathological type of gastric adenocarcinoma cancer based on whole-slide images(WSIs). We downloaded 356 histopathological images of gastric adenocarcinoma (STAD) patients from The Cancer Genome Atlas database and randomly divided them into the training set, validation set and test set (8:1:1). Additionally, 80 H&E-stained WSIs of STAD were collected for external validation. The CLAM tool was used to cut the WSIs and further construct the model by DL algorithm, achieving an accuracy of over 90% in identifying and predicting histopathological subtypes. External validation results demonstrated the model had a certain generalization ability. Moreover, DL features were extracted from the model to further investigate the differences in immune infiltration and patient prognosis between the two subtypes. The DL model can accurately predict the pathological classification of STAD patients, and provide certain reference value for clinical diagnosis. The nomogram combining DL-signature, gene-signature and clinical features can be used as a prognostic classifier for clinical decision-making and treatment.

Immunohistochemical Human Epidermal Growth Factor Receptor 2 (HER2) Expression Pattern in Gastric Adenocarcinomas in a Nigerian Tertiary Hospital.

BACKGROUND AND OBJECTIVE: The demonstration of HER2 in gastric adenocarcinoma (GA) tissues by immunohistochemistry assists in deciding whether targeted therapy would optimise the treatment of GA patients who are HER2 positive. However, this has not been extensively studied in our patients hence the need for this study. METHODS: Recipient tissue microarray blocks were constructed from donor archival formalin fixed paraffin embedded gastric tumour tissue from 80 patients seen over a period of 17 years in a retrospective descriptive study. Slides cut from these blocks were stained with antihuman HER2 antibody by immunohistochemistry and scored using the trastuzumab in gastric adenocarcinomas (ToGA) trial criteria. Data on age, gender, site of lesion and histological subtype of the gastric adenocarcinomas were also retrieved and reviewed. RESULTS: Eighty cases (52 males and 28 females; male to female ratio of 1.9:1), 55.65 ±13.50 years (modal age group 60-69 years), were studied. Most tumours (91.2%) involved the distal parts (pylorus, antrum and body) with a few (8.8%) involving the proximal part (cardia and fundus) of the stomach. HER2 was overexpressed in a total of 6 (7.5%) cases only. Two of seven (28.6%) proximal tumours showed HER2 positivity whereas only 4 of 73 (5.5%) of the distal tumours showed HER2 positivity. CONCLUSION: We had only a slightly lower HER2 overexpression rate than in studies from many other parts of the world. The observed overexpression was significantly higher in proximal than distally located tumours suggesting that distal tumours are less likely to respond to Trastuzumab than proximal tumours. The known association of distal gastric tumours with Helicobacter pylori infection probably provides for a possible difference in the molecular aetiopathogenesis of GAs by site of occurrence. The exact mechanisms for proximal gastric carcinogenesis remain to be more clearly elucidated. More studies, including clinical trials with larger sample sizes, are recommended to elucidate this differential expression of HER2 in gastric adenocarcinoma.

CONTEXTE ET OBJECTIF: La démonstration de la présence de HER2 dans les tissus d'adénocarcinome gastrique (AG) par immunohistochimie aide à décider si une thérapie ciblée optimiserait le traitement des patients atteints d'AG HER2 positif. Cependant, cela n'a pas été largement étudié chez nos patients, d'où la nécessité de cette étude. MÉTHODES: Des blocs de microarray de tissus destinataires ont été construits à partir de tissus tumoraux gastriques inclus en paraffine d'archives provenant de 80 patients vus sur une période de 17 ans, dans le cadre d'une étude descriptive rétrospective. Les lames découpées à partir de ces blocs ont été colorées avec un anticorps anti-HER2 humain par immunohistochimie et évaluées selon les critères de l'essai trastuzumab dans les adénocarcinomes gastriques (ToGA). Les données sur l'âge, le sexe, le site de la lésion et le sous-type histologique des adénocarcinomes gastriques ont également été récupérées et examinées. RÉSULTATS: Quatre-vingts cas (52 hommes et 28 femmes ; rapport hommes-femmes de 1,9:1), 55,65 ± 13,50 ans (groupe d'âge modal 60-69 ans), ont été étudiés. La plupart des tumeurs (91,2 %) ont touché les parties distales (pylore, antre et corps) avec quelques-unes (8,8 %) touchant la partie proximale (cardia et fundus) de l'estomac. HER2 a été surexprimé dans un total de 6 cas seulement (7,5 %). Deux des sept tumeurs proximales (28,6 %) ont montré une positivité HER2, tandis que seulement 4 des 73 tumeurs distales (5,5 %) ont montré une positivité HER2. CONCLUSION: Nous avons eu un taux de surexpression de HER2 légèrement inférieur à celui observé dans de nombreuses autres régions du monde. La surexpression observée était significativement plus élevée dans les tumeurs proximales que dans les tumeurs distales, suggérant que les tumeurs distales sont moins susceptibles de répondre au trastuzumab que les tumeurs proximales. L'association connue des tumeurs gastriques distales avec l'infection par Helicobacter pylori fournit probablement une différence potentielle dans l'étiopathogenèse moléculaire des AG par site d'occurrence. Les mécanismes exacts de la carcinogenèse gastrique proximale restent à élucider plus clairement. Davantage d'études, y compris des essais cliniques avec des tailles d'échantillons plus importantes, sont recommandées pour élucider cette expression différentielle de HER2 dans l'adénocarcinome gastrique. MOTS-CLÉS: Adénocarcinome gastrique, expression de HER2, Immunohistochimie, Thérapie ciblée.

Population-based investigation of common and deviating patterns of gastric cancer and oesophageal cancer incidence across populations and time.

BACKGROUND: The subtypes of gastric cancer (GC) and oesophageal cancer (EC) manifest distinct epidemiological profiles. Here, we aim to examine correlations in their incidence rates and to compare their temporal changes globally, both overall and by subtype. METHODS: Long-term incidence data were obtained from population-based registries available from the Cancer Incidence in Five Continents series. Variation in the occurrence of EC and GC (overall and by subtype) was assessed using the GC:EC ratio of sex-specific age-standardised rates (ASR) in 2008-2012. Average annual per cent changes were estimated to assess temporal trends during 1998-2012. RESULTS: ASRs for GC and EC varied remarkably across and within world regions. In the countries evaluated, the GC:EC ratio in men exceeded 10 in several South American countries, Algeria and Republic of Korea, while EC dominated in most sub-Saharan African countries. High rates of both cardia gastric cancer and oesophageal squamous cell carcinoma (ESCC) were observed in several Asian populations. Non-cardia gastric cancer rates correlated positively with ESCC rates (r=0.60) and negatively with EAC (r=-0.79). For the time trends, while GC incidence has been uniformly decreasing by on average 2%-3% annually over 1998-2012 in most countries, trends for EC depend strongly on histology, with several but not all countries experiencing increases in EAC and decreases in ESCC. CONCLUSIONS: Correlations between GC and EC incidence rates across populations are positive or inverse depending on the GC subsite and EC subtype. Multisite studies that include a combination of populations whose incidence rates follow and deviate from these patterns may be aetiologically informative.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.