Gastric Adenocarcinoma Patients Research Articles

Prognostic value analysis and survival model construction of different treatment methods for advanced intestinal type gastric adenocarcinoma

BackgroundIntestinal-type gastric adenocarcinoma, representing 95 % of gastric malignancies, originates from the malignant transformation of gastric gland cells. Despite its prevalence, existing methods for prognosis evaluation of this cancer subtype are inadequate. This study aims to enhance patient-specific prognosis evaluation by analyzing the clinicopathological characteristics and prognostic risk factors of intestinal-type gastric adenocarcinoma patients using data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI). MethodsWe extracted clinical data for patients diagnosed with intestinal-type gastric adenocarcinoma between 2010 and 2015 from the SEER database, selecting 257 cases based on predefined inclusion and exclusion criteria. Independent risk factors for overall survival (OS) and cancer-specific survival (CSS) were identified using a Cox regression model. A nomogram model for predicting OS or CSS was developed from the Cox risk regression analysis and validated through the consistency index (C-index), ROC curve, and calibration curve. ResultsAge, primary tumor resection, chemotherapy, lymph node metastasis, and tumor size were identified as independent prognostic factors for OS and CSS (P < 0.05). The nomogram model, constructed from these indicators, demonstrated superior predictive consistency for OS and CSS compared to the AJCC-TNM staging system. ROC curve analysis confirmed the model's higher accuracy, and calibration curve analysis indicated good agreement between the nomogram's predictions and actual observed outcomes. ConclusionThe nomogram model derived from SEER database analyses accurately predicts OS and CSS for patients with intestinal-type gastric adenocarcinoma. This model promises to facilitate more tailored treatments in clinical practice.

Neoadjuvant Chemotherapy Does Not Improve Survival in cT2N0M0 Gastric Adenocarcinoma Patients: A Multicenter Propensity Score Analysis.

According to current international guidelines, stage cT2N0M0 gastric adenocarcinoma warrants preoperative chemotherapy followed by surgery. However, upfront surgery is often preferred in clinical practice, depending on patient clinical status and local treatment preferences. The aim of the present study was to assess the impact of neoadjuvant chemotherapy in overall survival (OS) and disease-free survival (DFS) of cT2N0M0 patients. A retrospective analysis was performed among 32 centers, including gastric adenocarcinoma patients operated between January 2007 and December 2017. Patients with cT2N0M0 stage were divided into upfront surgery (S) and neoadjuvant chemotherapy followed by surgery (CS) groups. Inverse probability of treatment weighting (IPTW) was used to compensate for baseline differences between the groups. Among the 202 patients diagnosed with cT2N0M0 stage, 68 (33.7%) were in the CS group and 134 (66.3%) were in the S group. CS patients were younger (mean age 62.7±12.8 vs. 69.8±12.1 years for S patients; p<0.001) and had a better health status (World Health Organization performance status=0 in 60.3% of CS patients vs. 34.5% of S patients; p=0.006). During follow-up, recurrence occurred in 27.2% and 19.6% of CS and S patients, respectively, after IPTW (p=0.32). Five-year OS was similar between CS and S patients (78.9% vs. 68.3%; p=0.42), as was 5-year DFS (70.4% vs. 68.5%; p=0.96). Neoadjuvant chemotherapy was associated with neither OS nor DFS in multivariable analysis after IPTW. Patients with cT2N0M0 gastric adenocarcinoma did not present a survival or recurrence benefit if treated with perioperative chemotherapy followed by surgery as opposed to surgery alone.

Bioinformatics Analysis Reveals Prognostic Significance of the Macrophage Marker Gene Signature in Gastric Adenocarcinoma.

Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor microenvironment. Herein, single-cell RNA sequencing (scRNA-seq) profiles from the Gene Expression Omnibus (GEO) and bulk RNA-seq data from the Cancer Genome Atlas (TCGA) database were utilized to construct a macrophage marker gene signature (MMGS) to predict the prognosis of GAC patients. Subsequently, a risk score model based on the MMGS was built to predict the prognosis of GAC patients; further, this was validated in the GEO cohort. The risk score categorized patients into the high- and low-risk groups. A nomogram model based on the risk score and clinic-pathological characteristics was developed. Seven genes, ABCA1, CTHRC1, GADD45B, NPC2, PLTP, PRSS23, and RNASE1, were included in the risk score model. Patients with a low-risk score showed a better prognosis. The MMGS had good sensitivity and specificity for predicting the prognosis inGAC patients. The risk score was an independent prognostic factor. The constructed nomogram exhibited favorable predictability and reliability for predicting GAC prognosis. In conclusion, the risk score model based on the seven MMGSs performed well in the predicting prognosis of GAC patients. Our study may provide new insights into clinical decision-making for the personalized treatment of patients with gastric cancer (GC).

Preoperative Risk Stratification for Gastric Cancer: The Establishment of Dual-Energy CT-Based Radiomics Using Prospective Datasets at Two Centers

ObjectiveTo evaluate the performance of dual-energy CT (DECT)-based radiomics models for identifying high-risk histopathologic phenotypes - serosal invasion (pT4a), lymph node metastasis (LNM), lymphovascular invasion (LVI) and perineural invasion (PNI) in gastric cancer. Material and MethodsThis prospective bi-center study recruited histologically confirmed gastric adenocarcinoma patients who underwent triple-phase enhanced DECT before gastrectomy between January 2021 and July 2023. Radiomics features were extracted from polychromatic/monochromatic (40keV, 100 keV)/iodine images at arterial/venous/delay phase, respectively. Predictive features were selected in the training dataset using logistic regression classifier, and trained models were applied to the external validation dataset. Performances of clinical models, conventional contrast enhanced CT (CECT) models and DECT models were evaluated using areas under the receiver operating characteristic curve (AUCs). ResultsIn total, 503 patients were recruited: 396 at training dataset (60.1 ± 10.8 years, 110 females, 286 males) and 107 at validation dataset (61.4 ± 9.5 years, 29 females, 78 males). DECT models dichotomizing pT4a, LNM, LVI, and PNI achieved AUCs of 0.891, 0.817, 0.834, and 0.889, respectively, in the validation dataset, similar with the CECT models. In the training dataset, compared with the CECT model, the DECT model provided increased performance for identifying pT4a, LNM, LVI (all P＜0.05), and similar performance for stratifying PNI (P = 0.104). The DECT models was associated with patient disease-free survival (all P ＜0.05). ConclusionDECT radiomics can stratify patients preoperatively according to high-risk histopathologic phenotypes for gastric cancer and are associated with patient disease-free survival in the training dataset.

State of the art and upcoming trends in claudin-directed therapies in gastrointestinal malignancies.

Claudins, components of tight cell junctions in epithelial and endothelial cells, have emerged as a therapeutic target in gastrointestinal (GI) malignancies, particularly claudin 18.2 (CLDN18.2). Zolbetuximab, a chimeric anti-CLDN18.2 monoclonal antibody (mAb), is currently under FDA review and may emerge as the first claudin targeted therapy approved. Phase 3 trials show that zolbetuximab in combination with front-line fluoropyrimidine plus oxaliplatin improves survival in advanced CLDN18.2 positive (≥75% of tumor cells) gastric adenocarcinoma (GAC) patients. Many other therapies (mAbs; CART; bispecific; ADCs) are under investigation. CLDN18.2 will be an important target in GAC. Early understanding of how to target CLDN18.2 based on the level of expression (high, moderate, low) will be the key to success in this area. Studying these as separate entities should be considered. Resistance patterns, loss of CLDN18.2 expression, role in the refractory setting, and if any role in localized disease are questions that remain. Other targets for claudin that target claudin six and four are under investigation. Their role in GI malignancies will soon be further clarified.

CT radiomics based on the peritumoral adipose region of gastric adenocarcinoma for preoperative prediction of lymph node metastasis

PurposeTo construct and validate CT radiomics model based on the peritumoral adipose region of gastric adenocarcinoma to preoperatively predict lymph node metastasis (LNM). Methods and Methods293 consecutive gastric adenocarcinoma patients receiving radical gastrectomy with lymph node dissection in two medical institutions were stratified into a development set (from Institution A, n = 237), and an external validation set (from Institution B, n = 56). Volume of interest of peritumoral adipose region was segmented on preoperative portal-phase CT images. The least absolute shrinkage and selection operator method and stepwise logistic regression were used to select features and build radiomics models. Manual classification was performed according to routine CT characteristics. A classifier incorporating the radiomics score and CT characteristics was developed for predicting LNM. Area under the receiver operating characteristic curve (AUC) was used to show discrimination between tumors with and without LNM, and the calibration curves and Brier score were used to evaluate the predictive accuracy. Violin plots were used to show the distribution of radiomics score. ResultsAUC values of radiomics model to predict LNM were 0.938, 0.905, and 0.872 in the training, internal test, and external validation sets, respectively, higher than that of manual classification (0.674, all P values < 0.01). The radiomics score of the positive LNM group were higher than that of the negative group in all sets (both P-values < 0.001). The classifier showed no improved predictive power compared with the radiomics signature alone with AUC values of 0.916 and 0.872 in the development and external validation sets, respectively. Multivariate analysis showed that radiomics score was an independent predictor. ConclusionsRadiomics model based on peritumoral adipose region could be a useful approach for preoperative LNM prediction in gastric adenocarcinoma.

Robotic versus laparoscopic gastrectomy for gastric cancer: A Western propensity score matched analysis.

Robot-assisted gastrectomy (RG) has been shown to be safe and feasible in the treatment of gastric cancer (GC). However, it is unclear whether RG is equivalent to laparoscopic gastrectomy (LG), especially in the Western world. Our objective was to compare the outcomes of RG and LG in GC patients. We reviewed all gastric adenocarcinoma patients who underwent curative gastrectomy by minimally invasive approach in our institution from 2009 to 2022. Propensity score matching (PSM) analysis was conducted to reduce selection bias. DaVinci Si platform was used for RG. A total of 156 patients were eligible for inclusion (48 RG and 108 LG). Total gastrectomy was performed in 21.3% and 25% of cases in LG and RG, respectively. The frequency of stage pTNM II/III was 48.1%, and 54.2% in the LG and RG groups (p = 0.488). After PSM, 48 patients were matched in each group. LG and RG had a similar number of dissected lymph nodes (p = 0.759), operative time (p = 0.421), and hospital stay (p = 0.353). Blood loss was lower in the RG group (p = 0.042). The major postoperative complicationsrate was 16.7% for LG and 6.2% for RG (p = 0.109). The 30-day mortality rate was 2.1% and 0% for LG and RG, respectively (p = 1.0). There was no significant difference between the LG and RG groups for disease-free survival(79.6% vs. 61.2%, respectively; p = 0.155) and overall survival (75.9% vs. 65.7%, respectively; p = 0.422). RG had similar surgical and long-term outcomes compared to LG, with less blood loss observed in RG.

Robotic gastrectomy was reliable option for overweight patients with gastric cancer: a propensity score matching study.

The role of minimally invasive surgery using robotics versus laparoscopy in resectable gastric cancer patients with a high body mass index (BMI) remains controversial. A total of 482 gastric adenocarcinoma patients with BMI ≥ 25 kg/m2 who underwent minimally invasive radical gastrectomy between August 2016 and December 2019 were retrospectively analyzed, including 109 cases in the robotic gastrectomy (RG) group and 321 cases in the laparoscopic gastrectomy (LG) group. Propensity score matching (PSM) with a 1:1 ratio was performed, and the perioperative outcomes, lymph node dissection, and 3-year overall survival (OS) and disease-free survival (DFS) rates were compared. After PSM, 109 patients were included in each of the RG and LG groups, with balanced baseline characteristics. Compared with the LG group, the RG group had similar intraoperative estimated blood loss [median (IQR) 30 (20-50) vs. 35 (30-59) mL, median difference (95%CI) - 5 (- 10 to 0)], postoperative complications [13.8% vs. 18.3%, OR (95%CI) 0.71 (0.342 to 1.473)], postoperative recovery, total harvested lymph nodes [(34.25 ± 13.43 vs. 35.44 ± 14.12, mean difference (95%CI) - 1.19 (-4.871 to 2.485)] and textbook outcomes [(81.7% vs. 76.1%, OR (95%CI) 1.39 (0.724 to 2.684)]. Among pathological stage II-III patients receiving chemotherapy, the initiation of adjuvant chemotherapy in the RG group was similar to that in the LG group [median (IQR): 28 (25.5-32.5) vs. 32 (27-38.5) days, median difference (95%CI) - 3 (- 6 to 0)]. The 3-year OS (RG vs. LG: 80.7% vs. 81.7%, HR = 1.048, 95%CI 0.591 to 1.857) and DFS (78% vs. 76.1%, HR = 0.996, 95%CI 0.584 to 1.698) were comparable between the two groups. RG conferred comparable lymph node dissection, postoperative recovery, and oncologic outcomes in a selected cohort of patients with BMI ≥ 25 kg/m2.

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.

Abstract 1730: Unraveling the oncogenic potential of KDM2A with gastric organoids

Abstract Background: Gastric adenocarcinoma (GAC), prevalent and often lethal, imposes a serious global health challenge. Therefore, it is critical to identify novel oncogenes (drivers) that can be therapeutically targeted. Of epigenetic modifications, histone lysine methylation is a hallmark of epigenetic and transcriptional regulation of gene expression. Therefore, investigating the involvement of histone methylation modifiers in GAC is paramount to gaining a comprehensive understanding of the disease but also to discover novel targets. Our analysis of the GAC genome indicates that these epigenetic modifiers are amplified in GAC. Objective and Hypothesis: The overall objective is to define the oncogenic role of KDM2A in GAC pathogenesis and progression. The central hypothesis is that KDM2A promotes GAC by upregulating the expression of oncogenic proteins via the activation of epigenomic signatures/pathways.KDM2A (FBXL11) is a histone lysine demethylase that demethylates H3K36me2 and represses target genes involved in various biological processes, including cell proliferation, DNA damage repair, and stem cell maintenance. Previously, we reported that KDM2A was necessary for the tumorigenic and metastatic capabilities of non-small lung cancer cells through transcriptionally repressing the expression of DUSP3 and HDAC3, which led to activation of ERK signaling and upregulation of cell cycle-associated genes. Results: Our analysis of the GAC genome indicates that KDM2A is one of the top demethylases frequently amplified and overexpressed (14%). In addition, KDM2A expression was significantly higher in GAC samples than in normal tissues, and high expression of KDM2A was associated with poor survival in GAC patients. To examine the effect of KDM2A knockdown on characteristics of GAC, we used gastric organoids generated from KDM2Aflox/flox mouse stomach. We expressed wild-type (Flag-KDM2A) and catalytic mutant (Flag-KDM2A-mut) in these organoids. Ectopic expression of KDM2A wild-type, but not mutant, increased the proliferation of organoids. We showed that KDM2A knockdown decreased the proliferation and invasion of two GAC cells, GA0518 and AGS. In addition, we determine the effect of overexpression of KDM2A on cell proliferation by comparing the control organoids to KDM2A overexpressed using IHC staining of Ki-67 (a proliferation marker) and other activated oncogenic signaling PI3KCA/mTOR/AKT, EGFR. We showed that GA5018 cells were very sensitive to the KDM2A inhibitor (daminozide) alone and in combination with erlotinib (EGFRi inhibitor) and RAD001 (RAD1 mTOR inhibitor). Significance and Innovation: In contrast to advances in cellular signaling pathways in GAC pathogenesis, how GAC development is epigenetically regulated remains largely unknown. Our results from using organoids indicate that KDM2A is an oncoprotein. Citation Format: Shilpa S. Dhar, Calena Brown, Constantin Zod, Jaffer A. Ajani, Min Gyu Lee. Unraveling the oncogenic potential of KDM2A with gastric organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1730.

Abstract 5939: Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib

Abstract Background: Current treatments for primary metastatic or recurrent gastric adenocarcinoma (GAC) primarily involve combination chemotherapy, but the median survival time remains under a year. Nab-paclitaxel has displayed significant antitumor activity in preclinical GAC studies. GAC often exhibits overexpression of various growth factors and their receptors, which play a critical role in its pathophysiology. Aberrant activation of the HGF/c-Met pathway has been reported in up to 50% of GAC patients. We investigated the therapeutic potential of merestinib, a novel inhibitor targeting c-Met, along with Axl and DDR1/2 pathways, in combination with nab-paclitaxel in GAC preclinical models. Methods: Animal survival studies were conducted using peritoneal dissemination xenografts in NOD/SCID mice implanted with MKN-45 cells. Tumor growth was assessed in subcutaneous xenografts using MKN-45 and SNU-1 cells in NOD/SCID mice. IHC analyses were performed to evaluate tumor cell proliferation and microvessel density. In vitro cell proliferation and protein expression were assessed using the WST-1 assay and Western blot analysis, respectively. Results: Animal survival significantly improved with nab-paclitaxel (118%) and merestinib (41%) individually. The combination of merestinib with nab-paclitaxel (153%) resulted in further increased animal survival. In MKN-45 xenografts with high c-Met expression, a substantial reduction in tumor growth was observed with nab-paclitaxel and merestinib, showing a synergistic response. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3 (tumor regression). In low c-Met expressing SNU-1 xenografts, the effect of merestinib and nab-paclitaxel was less pronounced compared to MKN-45 xenografts. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 219 mm3, 105 mm3, 131 mm3, and 57 mm3. Tumor cell proliferation and microvessel density corroborated the tumor growth study results. Nab-paclitaxel and merestinib reduced in vitro cell proliferation, with an additive effect in combination. The reduction in cell proliferation by nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% in MKN-45, 59%, 50%, and 82% in SNU-1, and 53%, 19%, and 66% in gastric fibroblasts. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased the expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. Conclusion:Merestinib has strong antitumor activity in GAC, especially when administered with nab-paclitaxel, demonstrating a synergistic effect. These results provide compelling evidence for the potential clinical relevance of this combination therapy in improving the survival of GAC patients. Citation Format: Quinn Kaurich, Jennifer Huang, Sazzad Hassan, Urs von Holzen, Niranjan Awasthi. Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5939.

Abstract 3725: Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma

Abstract Peritoneal carcinomatosis (PC) in gastric adenocarcinoma (GAC) lead to a short median survival (≤6 months). Pre-metastatic niche (PMN) formation, in a distant organ to prepare for tumor seeding and colonization, has long been recognized. However, the precise molecular and mechanistic contributions of exosomes in PMN formation of PC remain unclear. We identify that exosomes promote PMN formation in the peritoneal cavity by patient-derived orthotopic mouse model. Using an in-depth proteomic profiling of paired ascites cells and ascites-derived exosomes from PC patients, we discover that Galectin-3 as the exosomal payload is responsible for PC by promoting PMN formation in both patient-derived orthotopic model and syngeneic mouse model. Inhibition of exosomal Galectin-3 reverses PC. Furthermore, exosomal Galectin-3 activates cancer-associated fibroblasts (CAFs), which further activate the CXCL12/CXCR4 axis to orchestrate the immunosuppressive PMN. Simultaneous inhibition of exosomal Galectin-3, CXCR4, and PD-1 leads to tumor regression and durable anti-tumor responses. Thus, this study provides a rationale for the novel clinical strategy for GAC patients with PC. Citation Format: Yibo Fan, Shumei Song, Melissa Pool Pizzi, Katsuhiro Yoshimura, Jody V. Vykoukal, Samir Hanash, Jaffer Ajani. Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3725.

Bile acids serve as endogenous antagonists of the Leukemia inhibitory factor (LIF) receptor in oncogenesis

The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.

Incidence, risk and prognosis of second primary malignancy of patients with gastric adenocarcinoma

Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Screening the Biomarkers and Related Medicines for Gastric Adenocarcinoma.

To search for potential biomarkers and available medicines for gastric adenocarcinoma. Experimental study. Place and Duration of the Study: Scientific Research Section, Shenzhen Longhua District Central Hospital, Shenzhen, China, from January to April 2023. Datasets were retrieved from the Gene Expression Omnibus (GEO). Differential gene expression analysis between gastric adenocarcinoma and normal samples was conducted using GEO2R. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed via the Enrichr website. Protein-protein interaction (PPI) networks were established using the STRING website. The central hub genes were identified using the cytoHubba plugin integrated within Cytoscape. Finally, the GEPIA2 and QuartataWeb websites were employed to validate the expression levels of the hub genes and to identify potential medicines for gastric adenocarcinoma. In total, 133 DEGs were identified. GO analysis revealed that these DEGs predominantly participate in processes such as cell adhesion, positive regulation of cell proliferation, and extracellular matrix organisation. In the KEGG pathways, DEGs were significantly enriched in gastric acid secretion, protein digestion and absorption, and ECM-receptor interaction. Following the construction of the PPI network, 10 central hub genes were identified and validated using GEPIA2. Notably, among these hub genes, SERPINE1 demonstrated a significant association with the prognosis of gastric adenocarcinoma, and potential therapeutic agents were subsequently predicted. SERPINE1 and potential therapeutic agents hold promise to enhance personalised diagnosis and treatment for gastric adenocarcinoma patients in the future. Biomarkers, Gastric adenocarcinoma, Bioinformatics, Differentially Expressed Genes (DEGs).

A ubiquitination-related risk model for predicting the prognosis and immunotherapy response of gastric adenocarcinoma patients.

Ubiquitination is crucial for the growth of cancer. However, the role of ubiquitination-related genes (URGs) in stomach adenocarcinoma (STAD) remains unclear. Differentially expressed URGs (DE-URGs) were examined in the whole TCGA-STAD dataset, and the prognosis-related genes were discovered from the The Cancer Genome Atlas (TCGA) training set. Prognostic genes were discovered using selection operator regression analysis and absolute least shrinkage (LASSO). A multivariate Cox analysis was further employed, and a polygene-based risk assessment system was established. Signatures were verified using the Gene Expression Omnibus (GEO) database record GSE84433 and the TCGA test set. Using the MEXPRESS dataset, a detailed analysis of gene expression and methylation was carried out. Using the DAVID database, DE-URG function and pathway enrichment was examined. The identified 163 DE-URGs were significantly associated with pathways related to protein ubiquitination, cell cycle, and cancer. A prognostic signature based on 13 DE-URGs was constructed, classifying patients into two risk groups. Compared to low-risk patients, people at high risk had considerably shorter survival times. Cox regression analyses considered prognostic parameters independent of age and risk score and were used to generate nomograms. Calibration curves show good agreement between nomogram predictions and observations. Furthermore, the results of the MEXPRESS analysis indicated that 13 prognostic DE-URGs had an intricate methylation profile. The enhanced Random Forest-based model showed greater efficacy in predicting prognosis, mutation, and immune infiltration. The in vitro validation, including CCK8, EdU, Transwell, and co-culture Transwell, proved that RNF144A was a potent oncogene in STAD and could facilitate the migration of M2 macrophages. In this research, we have created a genetic model based on URGs that can appropriately gauge a patient's prognosis and immunotherapy response, providing clinicians with a reliable tool for prognostic assessment and supporting clinical treatment decisions.

Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer with peritoneal metastasis.

281 Background: Although anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy has shown promising antitumor activity in advanced gastric adenocarcinoma (GC), the evidence of conversion therapy for initially GC with peritoneal metastasis is limited. This study aimed to clarify the clinical outcomes of conversion therapy for such patients. Methods: In this retrospective single institution cohort study, we analyzed 83 GC patients with peritoneal metastasis who received first-line anti-PD-1 antibody and chemotherapy and/or target therapy (trastuzumab) between November 2019 and June 2023. In patients who respond well to treatment, when preoperative imaging studies, multidisciplinary team discussions, and staged laparoscopy indicated the absence of peritoneal metastasis and the possibility of R0 resection, patients were offered conversion surgery. In this study, palliative surgery was not included. Patients were divided into two groups: conversion therapy group and palliative therapy group. Results: All patients underwent staging laparoscopy at their initial visit and underwent at least 2 treatment cycle, with a median follow-up time of 20.3 (16-24.6) months. Of the 83 patients, 32 patients presented a clinical response and underwent re-laparoscopy. Negative peritoneal metastasis and peritoneal cytology were confirmed in 25 patients who proceeded to undergo the conversion surgery. Compared with palliative therapy group, surgery group had a significantly better median progression-free survival (PFS) (20.3 vs 5.1 months; p &lt; 0.001) and a prolonged median overall survival (OS) (33.4 vs 11.7 months; p &lt; 0.001). In the surgery group, 24 (96%) of 25 patients were performed laparoscopic gastrectomy radical laparoscopic gastrectomy with more than D2 lymph node dissection (only one patient underwent open gastrectomy), 19 (76%) patients achieved R0 resection, 2 (8%) patients achieved pathologic complete response (pCR) and 4 (16%) patients reached tumor regression grade (TRG) 0-1. It was observed that patients with PCI score ≤ 2 experienced a longer median OS in comparison to those with PCI scores &gt; 2 ( unreached vs 28.5 months, P &lt; 0.031). And multivariate analysis associated with PFS among surgery cases identified signet ring cell carcinoma as an independent adverse prognostic factor (HR 4.66; 95% CI 1.19–18.22; p = 0.027). No serious treatment-related adverse events resulted in termination of treatment or death. Conclusions: Conversion surgery following first-line anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy represented a promising treatment strategy for GC patients with peritoneal metastasis. When immunochemotherapy is effective, active second-look staging laparoscopy should be performed to clarify the possibility of conversion surgery.

Survival of GEJ and gastric adenocarcinoma patients admitted at Imam Khomeini and Aram oncology clinic and treated with preoperative EOX chemotherapy

Objective: We aimed to investigate safety and efficacy of preoperative chemotherapy using EOX regime in patients with locally advanced gastric and GEJ cancer who were admitted at Imam-Khomeini Oncology clinic and Aram clinic.&#x0D; Method: We performed a mix-cohort study in 51 gastric cancer patients. In the beginning, we performed contrast thorax and abdominal CT scan or ECO cardiograph to determine cancer staging. After that, each patient received 3-weeks EOX regime in 6 cycle. After each three cycles follow-up CT scan was performed to assess any possible progression. Response to the treatment, Overall survival, and Progression-Free Survival were the main outcomes that we evaluated in the current study. We used Kaplan-Meier approach and Cox regression to address survival rate and its prognostic factors&#x0D; Results: Overall, 72.5% percent were male and mean age of study participants was 57.6. Complete response rate was observed in 11.1%, while 51.1% showed partial response. Median of overall survival and Progression-Free Survival was estimated 35.0 and 28.0 month, respectively. The 5-year overall survival was 74.2% and for PFS it was estimated at 57.7%.&#x0D; Conclusion: Preoperative chemotherapy using EOX regime could increase survival rate among patients with gastric and GEJ cancer.

Decoding the expression pattern of MUC3A in gastric adenocarcinoma: unveiling the key to successful immunotherapy

ABSTRACT Aims Despite the promise of immunotherapy for gastric adenocarcinoma, resistance is common, necessitating the validation of new targets. Based on our previous bioinformatics analysis, the MUC3A antigen emerged as a promising candidate for immunotherapy against gastric adenocarcinoma. However, a comprehensive understanding of its expression at protein level remains elusive, despite its crucial role in determining clinical response. We also sought to establish a connection between the expression pattern and relevant clinical variables of the disease, whenever feasible. Methods Immunohistochemistry was used to determine the percentage of MUC3A-positive tumor cells in primary (PT) and metastatic tumor (MT) sites of 190 gastric adenocarcinoma patients. We also evaluated the association between MUC3A expression and variables such as Lauren classification, history of neoadjuvant chemotherapy and/or radiotherapy, and overall patient survival. Results Median MUC3A expression was 50% in PT and 70% in MT sites, exhibiting a positive correlation. MT intestinal type showed significantly higher MUC3A expression compared to other types. Neoadjuvant therapy history did not affect MUC3A expression. Higher MUC3A expression correlated with improved survival. Conclusions Based on our previous bioinformatics data and the consistently high expression of MUC3A on gastric tumor cells, we propose advancing experimental aspects of anti-MUC3A immunotherapy for gastric adenocarcinoma.

Development and validation of a nomogram to predict pathological complete response in patients with locally advanced gastric adenocarcinoma treated with neoadjuvant chemotherapy in combination with PD-1 antibodies.

Currently, the survival benefits of combining neoadjuvant chemotherapy with programmed death 1 (PD-1) antibody immunotherapy in advanced gastric adenocarcinoma remain controversial. Emerging evidence suggests that the survival benefits of neoadjuvant therapy in advanced gastric adenocarcinoma hinge upon the attainment of pathological complete response (pCR). Therefore, the prediction of pCR in patients undergoing neoadjuvant chemotherapy combined with PD-1 antibody immunotherapy holds significant importance and is beneficial for the individualized treatment of gastric cancer (GC) patients. Clinical and pathological characteristics of patients with GC who received neoadjuvant chemotherapy combined with PD-1 inhibitor (camrelizumab) therapy and radical gastrectomy between January 2019 and December 2020 at the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital were retrospectively analyzed. A total of 52 patients were enrolled in the study, with all subjects assigned to the training set. The neoadjuvant regimen consisted of a combination of PD-1 inhibitor and fluorouracil analogues plus oxaliplatin, comprising two drugs. The patients were divided into a pCR group and a non-pCR group according to pCR occurrence. Multifactor logistic regression analysis was applied to determine the correlation between each factor and pCR. A prediction model was developed based on the results of the logistic regression analysis. The predictive performance of the model was evaluated using the receiver operating characteristic curves. Internal verification was completed via the bootstrapping method. The pCR was observed in 10 out of 52 patients (19.2%). The results of binary logistic regression multivariate analysis showed that cN stage [odds ratio (OR): 0.215; P=0.03], combined positive score (CPS) (OR: 6.364; P=0.026), and tumor diameter (OR: 0.112; P=0.026) were independent predictors of pCR. The nomogram prediction model for the pCR was plotted with a concordance index of 0.923 [95% confidence interval (CI): 0.8441-1]. Neoadjuvant chemotherapy combined with PD-1 antibodies may be the preferred option for patients with advanced gastric adenocarcinoma who have a small tumor diameter, no or few lymph node metastases, and high CPS. The presented nomogram model exhibits the potential to predict pCR in advanced gastric adenocarcinoma patients, showcasing satisfactory predictive performance and potentially facilitating the implementation of personalized treatment strategies.