Gastric Cancer Death Research Articles

PAR1 Is a Candidate Target for the Treatment of Peritoneal Dissemination in Gastric Cancer.

Peritoneal dissemination (PD) is a frequent cause of death in gastric cancer (GC), and there is evidence of an association between protease-activated receptor-1 (PAR1) and the development of PD. This study hypothesized that PD in GC might be influenced by PAR1. The cytotoxic effect of paclitaxel (PTX) on PAR1-transfected MKN45 (MKN45/PAR1) cells was analyzed using the MTT assay, and IC50 values were determined. In female athymic nude mice, MKN45/PAR1 cells were suspended in 0.05 ml phosphate-buffered saline (PBS) medium and inoculated into the stomach mid-wall. In each group, intraperitoneal injections of PBS, PTX, SCH79797 (PAR1-antagonist), or PTX plus SCH79797 were administered on days 8, 15, and 22 following tumor inoculation. At 56 days after tumor inoculation, mice were examined for both abdominal tumor nodule status and size and weight of the tumors. The IC50 of PTX for MKN45/PAR1 cells was 0.0697 μM and that of SCH79797 was 0.0145 μM. Mean survival of the MKN45/PAR1 mice in the PBS group was 28.75 days, whereas survival times for the mice treated with SCH79797, PTX, or a combination of PTX and SCH79797 were 31.2, 49.2, and 48.5 days, respectively. Tumor weight was smaller in the group receiving PTX and SCH79797 intraperitoneally compared with that in the PBS group (1,086±127.2 mg vs. 33.2±19.9 mg; p<0.001). The PAR1 antagonist was found to inhibit PD in a PAR1-expressing GC cell line. PAR1 may serve as a promising therapeutic target for managing PD in gastric cancer, as it plays a crucial role in its progression.

Gastric cancer in Spain: evaluating productivity loss and economic impact

Introduction In 2018, gastric cancer (GC) was estimated to account for over 1.03 million new cases globally, making it one of the most frequently diagnosed malignancies. In Spain, about 6,913 new cases were diagnosed in 2022. GC is an aggressive cancer originating in the stomach and ranks fifth in cancer incidence and third in cancer-related deaths worldwide. Despite treatment, only 25% of patients survive more than 5 years after diagnosis. Methods To estimate the economic impact of premature mortality due to GC, the human capital method was employed. This approach involved collecting data on mortality rates, average salaries, and unemployment rates. The study spanned a 10-year period, from 2013 to 2022, to integrate the latest and most pertinent data for analysis. The goal was to quantify the economic consequences GC-related deaths, providing valuable information for policy makers and healthcare professionals. Results GC caused 51,814 deaths over the study period with a slight annual decline, predominantly affecting men. Approximately 23% of deaths occurred among people of working age, amounting to a total of 122,632 YPLL. In economic terms, GC deaths accounted for costs of €1,239.34 million in 2013, rising to €1,242.04 million by 2021, for a total of €11,469.07 million over the study period. Conclusions The incidence of gastrointestinal cancers has decline in some types, but they remain a substantial public health challenge. These findings underline the significant health and economic challenges posed by GC, highlighting the need for targeted interventions to mitigate its impact on both individuals and healthcare systems.

Exploring copper metabolism-induced cell death in gastric cancer: a single-cell RNA sequencing study and prognostic model development

BackgroundGastric cancer (GC) is the third leading cause of cancer-related deaths globally. Despite advancements in treatment, the overall 5-year survival rate remains below 30%, particularly in advanced stages. Copper metabolism, vital for various cellular processes, has been linked to cancer progression, but its role in GC, especially at the single-cell level, is not well understood.ObjectiveThis study aims to investigate copper metabolism in GC by integrating single-cell RNA sequencing (scRNA-seq) data and developing a prognostic model based on copper metabolism-related gene (CMRG) expression. The study explores how copper metabolism affects the tumor microenvironment and identifies potential therapeutic targets.MethodsscRNA-seq data from gastric cancer and normal tissues were analyzed using the Seurat package. Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP) were used for dimensionality reduction and clustering. Non-negative matrix factorization (NMF) was employed for T cell subpopulation analysis. A high-dimensional weighted gene co-expression network analysis (HdWGCNA) identified key molecular features. LASSO regression and Random Survival Forest (RSF) techniques were used to create and validate a prognostic model. Survival analysis, immune microenvironment assessment, and drug sensitivity analysis were conducted.ResultsSixteen cell clusters and nine distinct cell types were identified, with T cells showing significant roles in cell communication. The NMF analysis of CD8 +T cells revealed five copper metabolism-related subtypes. The prognostic model based on nine CMRGs indicated significant survival differences between high- and low-risk groups. High-risk patients showed shorter survival times, increased immune cell infiltration, and altered immune responses. Drug sensitivity analysis suggested higher efficacy of certain drugs in high-CMRG patients.

Multi-omics features of immunogenic cell death in gastric cancer identified by combining single-cell sequencing analysis and machine learning

Gastric cancer (GC) is a prevalent malignancy with high mortality rates. Immunogenic cell death (ICD) is a unique form of programmed cell death that is closely linked to antitumor immunity and plays a critical role in modulating the tumor microenvironment (TME). Nevertheless, elucidating the precise effect of ICD on GC remains a challenging endeavour. ICD-related genes were identified in single-cell sequencing datasets and bulk transcriptome sequencing datasets via the AddModuleScore function, weighted gene co-expression network (WGCNA), and differential expression analysis. A robust signature associated with ICD was constructed using a machine learning computational framework incorporating 101 algorithms. Furthermore, multiomics analysis, including single-cell sequencing analysis, bulk transcriptomic analysis, and proteomics analysis, was conducted to verify the correlation of these hub genes with the immune microenvironment features of GC and with GC invasion and metastasis. We screened 59 genes associated with ICD and developed a robust ICD-related gene signature (ICDRS) via a machine learning computational framework that integrates 101 different algorithms. Furthermore, we identified five key hub genes (SMAP2, TNFAIP8, LBH, TXNIP, and PIK3IP1) from the ICDRS. Through single-cell analysis of GC tumor s, we confirmed the strong correlations of the hub genes with immune microenvironment features. Among these five genes, LBH exhibited the most significant associations with a poor prognosis and with the invasion and metastasis of GC. Finally, our findings were validated through immunohistochemical staining of a large clinical sample set, and the results further supported that LBH promotes GC cell invasion by activating the epithelial–mesenchymal transition (EMT) pathway.

Programmed cell death in Helicobacter pylori infection and related gastric cancer.

Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.

Curcumin Induces Autophagy-mediated Ferroptosis by Targeting the PI3K/AKT/mTOR Signaling Pathway in Gastric Cancer.

As a very common malignancy of the digestive system, the incidence and mortality rates of gastric cancer (GC) are increasing year by year. The critical role of ferroptosis in cancer development has been well-documented. The polyphenol compound curcumin shows prominent anti-tumor effects in multiple cancer types, including GC. However, whether curcumin participates in GC tumorigenesis by regulating ferroptosis remains unknown. Gastric cancer cells AGS and HGC-27 were treated with curcumin (0, 10, and 20 μM). Cell viability and death were evaluated through CCK-8 and LDH release assays. LC3B expression in cells was estimated through immunofluorescence staining. Intracellular ferrous iron (Fe2+), GSH, MDA, and lipid ROS levels were assessed by corresponding assay kits. The cellular levels of autophagy markers (ATG5, ATG7, Beclin 1, and LC3B), ferroptosis markers (ACSL4, SLC7A11, and GPX4), and phosphorylated (p)-PI3K, p-AKT, and p-mTOR were determined through western blotting. Curcumin attenuated cell viability but stimulated cell death in GC cells. Curcumin enhanced autophagy in GC cells, as demonstrated by the increased levels of ATG5, ATG7, Beclin 1, and LC3B. Besides, curcumin upregulated iron, MDA, GSH, and ACSL4 levels while downregulated lipid ROS, SLC7A11, and GPX4 levels, suggesting its stimulation on ferroptosis in GC cells. Curcumin decreased p-PI3K, p-AKT, and p-mTOR levels in cells. Importantly, the ferroptosis inhibitor ferrostatin-1 overturned the impacts of curcumin on GC cell viability, death, and ferroptosis. Curcumin suppresses GC development by inducing autophagy-mediated ferroptosis by inactivating the PI3K/AKT/mTOR signaling.

Induction of ferroptosis by brucine suppresses gastric cancer progression through the p53-mediated SLCA711/ALOX12 axis

Increasing evidence indicates important antiproliferative and anti-inflammatory roles of brucine in various diseases. However, the mechanism through which brucine causes the cell death of gastric cancer (GC) remains unclear. In the current research, we looked into whether brucine inhibits GC progression. GC cell migration and proliferation were assessed in response to brucine using Transwell, scratch, and the Cell Counting Kit-8 (CCK-8) assays. To assess the expression of proteins linked to ferroptosis, western blotting was used. An in vivo experiment was conducted to investigate if brucine decreases tumor growth. The CCK-8 experiment demonstrated that brucine reduced AGS and MKN45 cell viability in a way that was dose- and time-dependent. Brucine dramatically promoted cell death in AGS and MKN45 cells according to flow cytometry. In addition, brucine reduced AGS and MKN45 cells’ ability to migrate. According to Western blot investigations, brucine elevated p53 and ALOX12 expression, while suppressing the expression of SLC7A11 in AGS and MKN45 cells. Notably, silencing p53 reversed brucine-induced ferroptotic cell death. Additionally, brucine was shown to decrease tumor weight and volume in in vivo experiments. Moreover, malondialdehyde (MDA) and Fe2+ levels decreased in response to brucine treatment. Furthermore, in tumors treated with brucine, p53 and ALOX12 expression increased, whereas SLCA711 expression decreased. In summary, we demonstrated that brucine regulates the p53/SLCA711/ALOX12 axis to cause ferroptosis in GC cells. The results of this study lend support to the idea of treating GC with brucine.

Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer.

Gastric cancer is one of the most common malignant tumors in the world, and its occurrence and development involve complex biological processes. Iron death, as a new cell death mode, has attracted wide attention in recent years. However, the regulatory mechanism of iron death in gastric cancer and its effect on lipid peroxidation metabolism remain unclear. To explore the role of iron death in the development of gastric cancer, reveal its relationship with lipid peroxidation, and provide a new theoretical basis for revealing the molecular mechanism of the occurrence and development of gastric cancer. The process of iron death in gastric cancer cells was simulated by cell culture model, and the occurrence of iron death was detected by fluorescence microscopy and flow cytometry. The changes of gene expression related to iron death and lipid peroxidation metabolism were analyzed by high-throughput sequencing technology. In addition, a mouse model of gastric cancer was established, and the role of iron death in vivo was studied by histology and immunohistochemistry, and the level of lipid peroxidation was detected. These methods comprehensively and deeply reveal the regulatory mechanism of iron death on lipid peroxidation metabolism in the occurrence and development of gastric cancer. Iron death was significantly activated in gastric cancer cells, and at the same time, associated lipid peroxidation levels increased significantly. Through high-throughput sequencing analysis, it was found that iron death regulated the expression of several genes related to lipid metabolism. In vivo experiments demonstrated that increased iron death in gastric cancer mice was accompanied by a significant increase in lipid peroxidation. This study confirmed the important role of iron death in regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. The activation of iron death significantly increased lipid peroxidation levels, revealing its regulatory mechanism inside the cell.

Diabetes and gastric cancer incidence and mortality in the Asia Cohort Consortium: A pooled analysis of more than a half million participants.

Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes. A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses. Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag. Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis.

Immunoinformatics-Based Designing of Novel and Potent Multi-Epitope PSA D15 and Cag11 Immunogens for Helicobacter pylori Immunodiagnostic Assay Development.

Helicobacter pylori (H. pylori) strain is the most genetically diverse pathogenic bacterium and now alarming serious human health concern ranging from chronic gastritis to gastric cancer and human death all over the world. Currently, the majority of commercially available diagnostic assays for H. pylori is a challenging task due to the heterogeneity of virulence factors in various geographical regions. In this concern, designing of universal multi-epitope immunogenic biomarker targeted for all H. pylori strains would be crucial to successfully immunodiagnosis assay and vaccine development for H. pylori infection. Hence, the present study aimed to explore the potential immunogenic epitopes of PSA D15 and Cag11 proteins of H. pylori, using immunoinformatics web tools in order to design novel immune-reactive multi-epitope antigens for enhanced immunodiagnosis in humans. Through an in silico immunoinformatics approach, high-ranked B-cell, MHC-I, and MHC-II epitopes of PSA D15 and Cag11 proteins were predicted, screened, and selected. Subsequently, a novel multi-epitope PSA D15 and Cag11 antigens were designed by fused the high-ranked B-cell, MHC-I, and MHC-II epitopes and 50S ribosomal protein L7/L12 adjuvant using linkers. The antigenicity, solubility, physicochemical properties, secondary and tertiary structures, 3D model refinement, and validations were carried. Furthermore, the designed multi-epitope antigens were subjected to codon adaptation and in silico cloning, immune response simulation, and molecular docking with receptor molecules. A novel, stable multi-epitope PSA D15 and Cag11 H. pylori antigens were developed and immune simulation of the designed antigens showed desirable levels of immunological response. Molecular docking of designed antigens with immune receptors (B-cell, MHC-I, MHC-II, and TLR-2/4) revealed robust interactions and stable binding affinity to the receptors. The codon optimized and in silico cloned showed that the designed antigens were successfully expressed (CAI value of 0.95 for PSA D15 and 1.0 for Cag11) after inserted into pET-32ba (+) plasmid of the E. coli K12 strain. In conclusion, this study revealed that the designed multi-epitope antigens have a huge immunological potential candidate biomarker and useful in developing immunodiagnostic assays and vaccines for H. pylori infection.

Family history and gastric cancer incidence and mortality in Asia: a pooled analysis of more than half a million participants

BackgroundThe family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case–control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study.MethodsWe included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes.ResultsDuring the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32–1.58), similarly in males (1.44, 1.31–1.59) and females (1.45, 1.23–1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00–1.60) and non-cardia subsites (1.49, 1.35–1.65), and with intestinal- (1.48, 1.30–1.70) and diffuse-type (1.59, 1.35–1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19–1.41).ConclusionsIn this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer.

PlexinA1 promotes gastric cancer migration through preventing MICAL1 protein ubiquitin/proteasome-mediated degradation in a Rac1-dependent manner

Metastasis promotes the development of tumors and is a significant cause of gastric cancer death. For metastasis to proceed, tumor cells must become mobile by modulating their cytoskeleton. MICAL1 (Molecule Interacting with CasL1) is known as an actin cytoskeleton regulator, but the mechanisms by which it drives gastric cancer cell migration are still unclear. Analysis of gastric cancer tissues revealed that MICAL1 expression is dramatically upregulated in stomach adenocarcinoma (STAD) samples as compared to noncancerous stomach tissues. Patients with high MICAL1 expression had shorter overall survival (OS), post-progression survival (PPS) and first-progression survival (FPS) compared with patients with low MICAL1 expression. RNAi-mediated silencing of MICAL1 inhibited the expression of Vimentin, a protein involved in epithelial-mesenchymal transition. This effect correlates with a significant reduction in gastric cancer cell migration. MICAL1 overexpression reversed these preventive effects. Immunoprecipitation experiments and immunofluorescence assays revealed that PlexinA1 forms a complex with MICAL1. Importantly, specific inhibition of PlexinA1 blocked the Rac1 activation and ROS production, which, in turn, impaired MICAL1 protein stability by accelerating MICAL1 ubiquitin/proteasome-dependent degradation. Overexpression of PlexinA1 enhanced Rac1 activation, ROS production, MICAL1 and Vimentin expressions, and favored cell migration. In conclusion, this study identified MICAL1 as an important facilitator of gastric cancer cell migration, at least in part, by affecting Vimentin expression and PlexinA1 promotes gastric cancer cell migration by binding to and suppressing MICAL1 degradation in a Rac1/ROS-dependent manner.

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells.

Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC).Gastric cancer mesenchymal stem cells (GCMSCs)have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA)was performed to explore the glycolysis-related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs-treated GCcells. The therapeutic efficacy of oxaliplatin (OXA)and paclitaxel (PTX)was determined using CCK-8and colony formation assays. Signaling pathways altered by GCMSCs-CMwere revealed by immunoblotting. The expression of TNF-αin GCMSCs and bone marrow mesenchymal stem cells (BMMSCs)was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs-CMtreated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase-3 and Bax expression, and increased levels of Bcl-2, HK2, MDR1, and B7H3 expression. Blocking TNF-αin GCMSCs-CM,B7H3 knockdown or the use of 2-DG,a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs-CM. This study shows that GCMSCs-CMderived TNF-α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

Risk factors for death from other diseases after curative gastrectomy and lymph node dissection for gastric cancer

BackgroundRecent advances in treatment are expected to bring a cure to more patients with gastric cancer (GC). Focusing on the risk of death from other diseases (DOD) has become a crucial issue in patients cured of GC. The aim of this study was to elucidate the risk factors for DOD in patients who underwent curative gastrectomy with lymph node dissection for GC.MethodsWe enrolled 810 patients who underwent curative gastrectomy with lymph node dissection for GC from January 1990 to December 2014 and had no recurrence or death of GC until December 2019. We investigated the risk factors for DOD defined as death excluding death from a malignant neoplasm, accident, or suicide after gastrectomy, focusing on the perioperative characteristics at gastrectomy.ResultsAmong 315 deaths from any cause, 210 died from diseases other than malignancy, accidents and suicide. The leading cause of DOD was pneumonia in 54 patients (25.7%). The actual survival period in 167 patients (79.5%) with DOD was shorter than their estimated life expectancy at gastrectomy. Multivariate analysis revealed that a high Charlson Comorbidity Index score (score 1–2: hazard ratio [HR] 2.192, 95% confidence interval [CI] 1.713–2.804, P < 0.001 and score ≥ 3: HR 4.813, 95% CI 3.022–7.668, P < 0.001), total gastrectomy (HR 1.620, 95% CI 1.195–2.197, P = 0.002) and the presence of postoperative complications (HR 1.402, 95% CI 1.024–1.919, P = 0.035) were significant independent risk factors for DOD after gastrectomy for GC, in addition to age of 70 years or higher, performance status of one or higher and body mass index less than 22.0 at gastrectomy.ConclusionsPneumonia is a leading cause of DOD after curative gastrectomy and lymph node dissection for GC. Paying attention to comorbidities, minimizing the choice of total gastrectomy and avoiding postoperative complications are essential to maintain the long-term prognosis after gastrectomy.

Personalizing age of gastric cancer screening based on comorbidity in China: Model estimates of benefits, affordability and cost-effectiveness optimization

The benefits of gastric cancer screening are related to age and comorbidity status, but reliable estimates are lacking in China. This study aimed to estimate the benefits and affordability of the gastric cancer screening strategy by level of comorbidity to inform decisions to screening age.We assessed six current gastric cancer screening strategies in China using a microsimulation model with different starting and stopping ages and comorbidity profiles, for a total of 378 strategies. 1,000,000 individuals were simulated in the model and followed the alternative strategies. Primary outcomes included gastric cancer incidence, the number of endoscopy and complications, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Future costs and QALYs are discounted by 5% per year. Sensitivity analyses were used to evaluate model uncertainty.Strategies with longer screening durations were associated with higher benefits of life-year gained and gastric cancer deaths averted, but were also accompanied by a large number of endoscopy screening, and complication events. Using the threshold of US$18,575 per QALY gained, at the no, moderate, and severe comorbidity level, the leading cost-effectiveness strategies were the new gastric cancer screening scoring system strategy (NGCS) screening from age 40 years to 60 years (40–60), 40–55-NGCS, and 40–55-NGCS strategy, respectively. The results are robust in sensitivity analyses.Our study illustrates the importance of considering comorbidity conditions and age when determining the starting and stopping screening age for gastric cancer and informs the discussion on personalizing decisions. The trade-off between benefits and harms can also be referenced when necessary.

Abstract C120: Antitumor effect of HER3-DXd, an antibody-drug conjugate targeting HER3, in gastric cancer cell lines

Abstract Background: HER3, one of the HER family members, is expressed across various solid tumors and known to be an important oncogenic driver. HER3-DXd is an antibody-drug conjugate (ADC) that combines patritumab, an anti-HER3 antibody, and deruxtecan, a topoisomerase 1 inhibitor payload through peptide cleavable linker system. HER3-DXd has been shown to have anti-tumor effects in breast, non-small cell lung, and colorectal cancers, in vitro and in vivo, and is being evaluated in phase 2 and phase 3 clinical trials. However, the effect of HER3-DXd in gastric cancer and the mechanism of sensitivity are largely unknown. Methods: Seven gastric cancer cell lines were used (NUGC-4, NCI-N87, SNU-601, SNU-216, SNU-638, SNU-668, and MKN-45). Colony formation assay (CFA) was performed with increasing concentration of HER3-DXd (doses range: 0-100 nM) for 14 days. Cell cycle change and internalization of HER3-DXd bound to HER3 protein in the cell membrane were seen by flow cytometry analysis. Apoptotic cell death was assessed by Annexin-V assay. DNA strand breaks were examined using alkaline comet assay. DNA damage accumulation and TOP1-cleavage complexes (TOP1ccs) were identified using immunofluorescence assay. Results: Seven gastric cancer cell lines showed heterogeneous mRNA expression of HER2 and HER3, which correlated with protein expression. Three cell lines with different sensitivities to HER3-DXd were selected based on CFA. SNU-601 was sensitive to U3-1402 (IC50 value: 11.01 nM), SNU-638 was less sensitive (IC50 value: 50.04 nM), and SNU-668 was insensitive (IC50 value &amp;gt;100 nM). HER3-DXd increased the Annexin-V positive population and the sub-G1 population in SNU-601 and SNU-638 cells. Moreover, cleavage of PARP and caspase-3 were increased in SNU-601 and SNU-638 cells, but not in SNU-668 cells. HER3-DXd was efficiently internalized within 1 hour in all three cells, regardless of their sensitivities to HER3-DXd. Signal transduction through the HER2 and HER3 receptors, which mediates a PI3K-AKT signaling pathway, was inhibited in SNU-601 cells. In SNU-601 and SNU-638 cells, HER3-DXd increased the expression of γ-H2AX and length of the comet tails, which indicate DNA damage. HER3-DXd also induced topoisomerase 1 cleavage complexes (TOP1ccs) in SNU-601 and SNU-638 cells. In contrast, TOP1cc was not observed in resistant SNU-668 cells. Conclusion: HER3-DXd induced formation of TOP1ccs, subsequent DNA damage, and apoptotic cell death in sensitive cell lines, but not in an insensitive cell line. These data indicate that internalized HER3-DXd causes accumulation of DNA damage through TOP1cc formation, which leads to apoptotic cell death in gastric cancer. Citation Format: Hae Min Hwang, So Hyeon Kim, Sujin Ham, Minyoung Lee, Youlim Noh, Yu-Jin Kim, Changyun Lee, Jinyoung Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. Antitumor effect of HER3-DXd, an antibody-drug conjugate targeting HER3, in gastric cancer cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C120.

Decline of gastric cancer mortality in common variable immunodeficiency in the years 2018-2022.

In patients with Common Variable Immunodeficiency, malignancy has been reported as the leading cause of death in adults, with a high risk of B-cell lymphomas and gastric cancer. We conducted a five-year prospective study aiming to update the incidence and mortality of gastric cancer and the incidence of gastric precancerous lesions in 512 CVID patients who underwent a total of 400 upper gastrointestinal endoscopies. In the pre-pandemic period, 0.58 endoscopies were performed per patient/year and in the COVID-19 period, 0.39 endoscopies were performed per patient/year. Histology revealed areas with precancerous lesions in about a third of patients. Patients who had more than one gastroscopy during the study period were more likely to have precancerous lesions. Two patients received a diagnosis of gastric cancer in the absence of Helicobacter pylori infection. The overall prevalence of Helicobacter pylori infection in biopsy specimens was 19.8% and related only to active gastritis. Among patients who had repeated gastroscopies, about 20% progressed to precancerous lesions, mostly independent of Helicobacter pylori. While gastric cancer accounted for one in five deaths from CVID in our previous survey, no gastric cancer deaths were recorded in the past five years, likely consistent with the decline in stomach cancer mortality observed in the general population. However, during the COVID-19 pandemic, cancer screening has been delayed. Whether such a delay or true decline could be the reason for the lack of gastric cancer detection seen in CVID may become clear in the coming years. Due to the high incidence of precancerous lesions, we cannot rely on observed and predicted trends in gastric cancer mortality and strongly recommend tailored surveillance programs.

Chinese Guideline on Risk Management of Gastric Cancer in the General Public(2023 Edition)

The disease burden of gastric cancer is considerable heavy in China, where the annual number of new gastric cancer cases and deaths rank first in the world. It has been shown that risk assessment, screening, and reducing risk factors may effectively reduce gastric cancer development in general population. However, there is currently a lack of practice guidelines on risk management of gastric cancer for the general public in China. This guideline was conducted by the Chinese Gastric Cancer Association (CGCA) and Chinese Society of Upper Gastrointestinal Surgeons (CSUGS). Based on the best research evidence and health expertise, we developed 17 questions and formulated 18 recommendations. These recommendations provide comprehensive guidance for the management of gastric cancer risk in the general public, with the potential to reduce the cancer development and the burden of disease.

Changes in Gastric Pathology after H. pylori Treatment in Community-Driven Research Aimed at Gastric Cancer Prevention.

Community-driven projects have characterized Helicobacter pylori (Hp) infection in Indigenous communities in the Northwest Territories (NT) and Yukon (YT), Canada. These projects address concerns about the frequent diagnosis of Hp infection among community members and its relation to gastric cancer deaths, perceived to occur with alarming frequency in this region. Projects included breath-test screening for Hp infection, gastroscopy with gastric biopsies, and treatment to eliminate Hp infection. Previous project results showed a high prevalence of stomach pathologies associated with increased cancer risk among Hp-positive participants at baseline. This analysis describes changes in precancerous gastric pathologies in project participants who had gastroscopy before baseline treatment during 2008-2013 and again in 2017. Throughout the study period, the same pathologist graded Hp density, active gastritis, chronic gastritis, atrophic gastritis, and intestinal metaplasia using the updated Sydney System. Of 310 participants from three communities with baseline pathology data, 69 had follow-up pathology data. Relative to baseline, the prevalence of Hp infection and precancerous gastric pathology was substantially lower at follow-up; most participants who were Hp-positive at baseline and Hp-negative at follow-up had reduced severity of active, chronic, and/or atrophic gastritis at follow-up. Though follow-up numbers are small, these results yield evidence that successful Hp treatment has the potential to reduce the risk of gastric cancer in Arctic Indigenous communities.

An increasing trend of gastric cancer deaths and inadequate preventive measures in elderly adults.

Japan became the world's first country to cover Helicobacter pylori eradication for chronic gastritis under its National Health Insurance (NHI) system in February 2013. Thereafter, H. pylori eradication dramatically increased and gastric cancer deaths began to decrease in Japan. However, the details of gastric cancer deaths and its prevention in the very elderly have not been fully elucidated. We analyzed the temporal trend of gastric cancer deaths referencing data from Ministry of Health, Labour and Welfare reports and "Cancer Statistics in Japan-2021" and assessed the numbers of H. pylori test and gastric cancer screening using a national database and a report of cancer screening in Shimane Prefecture, respectively. Although gastric cancer deaths in total population have clearly decreased since 2013, those in people aged 80 years and older are still increasing. People aged 80 years and older represent 9% of the total population and accounted for half of all gastric cancer deaths in 2020. The numbers of H. pylori eradication and gastric cancer screening in people aged 80 years and older were 25% and 25% of those in other generations, respectively. In spite of a dramatic increase in H. pylori eradication and a clear decrease in gastric cancer deaths in Japan, gastric cancer deaths in people aged 80 years and older are increasing. This might be due to fewer H. pylori eradication in the elderly than in other generations, indicating the difficulty of gastric cancer prevention in the very elderly.