BACKGROUND: First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies.
METHODS: Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW.
RESULTS: The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies.
CONCLUSIONS: Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.

BACKGROUND: Gastric cancer is one of the most common malignant tumours of the gastrointestinal tract, which has a significant negative impact on human health.
OBJECTIVE: CCL chemokines play important roles in a variety of tumor microenvironments; nevertheless, gastric cancer has surprisingly limited associations with CCL chemokines.
METHODS: In our study, we comprehensively utilized bioinformatics analysis tools and databases such as cBioPortal, UALCAN, GEPIA, GeneMANIA, STRING, and TRRUST to clarify the clinical significance and biology function of CCL chemokines in gastric cancer.
RESULTS: The mRNA expression levels of CCL1/3/4/5/7/8/14/15/18/20/21/22/26 were up-regulated, while the mRNA expression levels of CCL2/11/13/16/17/19/23/24/25/28 were down-regulated. The chemokine significantly associated with the pathological stage of gastric cancer is CCL2/11/19/21. In gastric cancer, the expression level of CCL chemokines was not associated with disease-free survival, but low expression of CCL14 was significantly associated with longer overall survival. Therein, associated with the regulation of CCL chemokines are only 10 transcription factors (RELA, NFKB1, STAT6, IRF3, REL, SPI1, STAT1, STAT3, JUN and SP1). The major biological process and functional enrichment of CCL chemokines are to induce cell-directed migration.
CONCLUSIONS: These results may indicate that CCL chemokines may be immunotherapeutic targets and promising prognostic biomarkers for gastric cancer.

There exist very limited non-hazardous therapeutic strategies except for surgical resection and lymphadenectomy against gastric cancer (GC) despite being the third leading cause of cancer deaths worldwide. This study proposes an innovative treatment approach against GC using a drug combination strategy that manipulates mitochondrial dynamics in conjunction with the induction of mitochondrial pathology-mediated cell death. Comparative analysis was done with gastric adenocarcinoma and normal cells by qPCR, western blot, microscopic immunocytochemistry, and live cell imaging. In this study, impairment of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission by Mdivi-1 created an imbalance in mitochondrial structural dynamics in indomethacin-treated AGS cells in which mitophagy-regulator protein PINK1 is downregulated. These drug combinations with the individual sub-lethal doses ultimately led to the activation of cell death machinery upregulating pro-apoptotic proteins like Bax, Puma, and Noxa. Interestingly, this combinatorial therapy did not affect normal gastric epithelial cells significantly and also no significant upregulation of death markers was observed. Moreover, the drug combination strategy also retarded cell migration and reduced stemness in GC cells. In summary, this study offers a pioneering specific therapeutic strategy for GC treatment, sparing normal cells providing opportunities for minimal drug-mediated toxicity utilizing mitochondria as a viable and specific target for anti-cancer therapy in gastric cancer.

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.

BACKGROUND: 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.

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.
CONCLUSIONS: 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.

Gastric outlet obstruction often manifests as a result of mural, luminal, or extrinsic compression. Due to capacity of the stomach to distend 2-4 L after food intake, gastric outlet obstruction secondary to a malignant cause goes often undetected clinically until a high-grade obstruction develops. Gastric adenocarcinoma seldom manifests as gastric outlet obstruction secondary to a partially obstructing mass or a stricture that develops due to peptic ulceration. Fatal sequelae and serious complications of gastric outlet obstruction may result when early detection and appropriate intervention such as gastric decompression and surgical resection are delayed. This report describes a rare case of gastric adenocarcinoma causing gastric outlet obstruction diagnosed on ultrasonography in a 40-year-old female.

UNASSIGNED: Gastric adenocarcinoma (GAC) is a deadly tumor. Postoperative complications, including infections, worsen its prognosis and may affect overall survival. Little is known about perioperative complications as well as modifiable and non-modifiable risk factors. Early detection and treatment of these risk factors may affect overall survival and mortality.
UNASSIGNED: We extracted GAC patient\'s data from the Surveillance, Epidemiology, and End Results (SEER) database and analyzed using Pearson\'s Chi-square, Cox regression, Kaplan-Meier, and binary regression methods in SPSS.
UNASSIGNED: At the time of analysis, 59,580 GAC patients were identified, of which 854 died of infection. Overall, mean survival in months was better for younger patients, age < 50 years vs. ≥ 50 years (60.45 vs. 56.75), and in females vs. males (65.23 vs. 53.24). The multivariate analysis showed that the risk of infectious mortality was higher in patients with age ≥ 50 years (hazard ratio (HR): 3.137; 95% confidence interval (CI): 2.178 - 4.517), not treated with chemotherapy (HR: 1.669; 95% CI: 1.356 - 2.056), or surgery (HR: 1.412; 95% CI:1.132 - 1.761) and unstaged patients (HR: 1.699; 95% CI: 1.278 - 2.258). In contrast, the mortality risk was lower in females (HR: 0.658; 95% CI: 0.561 - 0.773) and married patients (HR: 0.627; 95% CI: 0.506 - 0.778). The probability of infection was higher in older patients (odds ratio (OR) of 2.094 in ≥ 50 years), other races in comparison to Whites and Blacks (OR: 1.226), lesser curvature, not other specified (NOS) as a primary site (OR: 1.325), and patients not receiving chemotherapy (OR: 1.258).
UNASSIGNED: Older, unmarried males with GAC who are not treated with chemotherapy or surgery are at a higher risk for infection-caused mortality and should be given special attention while receiving treatment.

Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown. To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.

BACKGROUND: Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus (RGAVCT) have a poor prognosis, with a 5-year survival rate ranging from 18.42%-53.57%. These patients need a reasonable postoperative treatment plan to improve their prognosis.
OBJECTIVE: To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT.
METHODS: We retrospectively collected the clinicopathological data of 530 patients who underwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus. Furthermore, we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by assessing the clinical and pathological features of the patients who met the inclusion criteria. We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses. The subgroups of patients with stages I, II, and III disease who received single-, dual-, or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0.
RESULTS: In all, 530 eligible individuals with RGAVCT were enrolled in this study. The median overall survival (OS) of patients with RGAVCT was 24 months, and the survival rates were 80.2%, 62.5%, and 42.3% at 12, 24, and 59 months, respectively. Preoperative complications, tumor size, T stage, and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model. A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage I or II RGAVCT; however, chemotherapy did have an effect on OS of stage III patients. Stage III patients who were treated with chemotherapy consisting of dual- or triple-agent regimens had better survival than those treated with single-agent regimens, and no significant difference was observed in the survival of patients treated with chemotherapy consisting of dual- or triple-agent regimens.
CONCLUSIONS: For patients with stage III RGAVCT, a dual-agent regimen of postoperative chemotherapy should be recommended rather than a triple-agent treatment, as the latter is associated with increased frequency of adverse events.