Nodal downstaging to ypN0 after neoadjuvant chemotherapy positively impacts on survival of cT4N+ GC/GEJ patients.

BACKGROUND: The prognostic value of histomorphologic regression in primary gastric and gastroesophageal cancers (GC/GEJ) has been previously established, however, the impact of lymph node (LN) regression on survival still remains unclear. METHODS: A prospectively maintained database was reviewed to identify cT4N+ gastric and gastroesophageal cancers (GC/GEJ) after NAC (neoadjuvant chemotherapy). Patients were categorized into two groups based on LN status: cN+/ypN0 (downstaged N0) and cN+/ypN+ (persistent N+), long-term survival were analyzed using Kaplan-Meier survival estimates. RESULTS: In total, 125 patients with cT4N+ GC/GEJ underwent NAC followed by surgery were enrolled. A total of 39 patients (31.2%) had cN+/ypN0 (ypN0) disease, 86 patients (68.8%) had cN+/ypN+ (ypN+) disease. Prognosis in ypN+ patients was significantly worse than those in ypN0 group for 3- and 5-year overall survival (OS) (p < 0.05). The 3-year OS was 83%, 44% in ypN0 and ypN+ group, respectively. The 5-year OS was 75%, 35% in ypN0 and ypN+ group, respectively. Multivariable analysis suggested that multivisceral resection (hazard ratio [HR] = 0.33, 95% confidence interval [CI]: 0.14-0.76, p = 0.009), and ypN+ (HR = 3.42, 95% CI: 1.15-10.13, p =0.027) were independent prognostic factors for OS. CONCLUSION: Nodal downstaging is an important hallmark representing the effectiveness of NAC for GC/GEJ, and it positively impacts on survival of these patients.

Combined use of lysyl oxidase, carcino-embryonic antigen, and carbohydrate antigens improves the sensitivity of biomarkers in predicting lymph node metastasis and peritoneal metastasis in gastric cancer.

The purpose of this study was to determine whether lysyl oxidase (LOX) is a useful marker of metastasis in gastric cancer (GC) patients in combination with tumor markers carcino-embryonic antigen (CEA), carbohydrate antigen 724 (CA724), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125). There were 215 GC patients (67 without metastasis, 102 with lymph node metastasis, and 46 with peritoneal metastasis) who presented to the Affiliated Cancer Hospital of Guangxi Medical University between May 2009 and November 2012 that were enrolled in this study. The LOX expression level and the serum concentration of the four tumor markers were evaluated preoperatively. All patients underwent computed tomography (CT) and ultrasonography (US) before surgery. Statistical analysis, including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC) analysis, and logistic regression analysis, was performed to evaluate the diagnostic value of these markers in predicting metastasis in GC. For predicting lymph node metastasis in GC, the sensitivity of LOX, CEA, CA724, CA199, and CA125 was 44.12, 12.75, 21.57, 23.53, and 15.69 %, respectively, and increased to 79.41 % in combination. For predicting peritoneal metastasis in GC, the sensitivity of these markers was 56.52, 23.91, 34.78, 36.96, and 34.78 %, respectively, and increased to 91.30 % in combination. Combining LOX with CEA, CA724, CA199, and CA125 could increase the sensitivity of predicting lymph nodes metastasis and peritoneal metastasis in GC. Surgeons can use these markers to determine the best treatment options for patients. Additional large-scale, prospective, multicenter studies are urgently needed to further confirm the results of this study.

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ): a multicentre, phase II, single-arm, open-label clinical trial (FRUTINEOGA) protocol.

INTRODUCTION: Curing locally advanced gastric cancer (GC) or gastro-oesophageal junction adenocarcinoma (GEJ) with surgery alone is challenging. Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients with locally advanced GC/GEJ, and SOX is the most common neoadjuvant regimen in China. The generally good tolerability in patients and fruquintinib's low potential for drug-drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. A combination of fruquintinib, S-1 and oxaliplatin can be a promising neoadjuvant treatment for locally advanced GC/GEJ. In this phase II study, we aim to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC/GEJ. METHODS AND ANALYSIS: The FRUTINEOGA trial is a prospective, multicentre, phase II, single-arm, open-label clinical trial that will enrol 54 patients. Eligible patients will be registered, enrolled and receive 2-4 cycles of fruquintinib plus SOX, after which surgery will be performed and tumour regression will be evaluated. The primary endpoint is the pathological remission rate, and the secondary endpoints are disease-free survival, overall survival, objective response rate, major pathological response rate and R0 resection rate. ETHICS AND DISSEMINATION: Written informed consent will be required from all patients enrolled, and it will be provided by them. The study protocol received approval from the independent ethical review committee of Guangxi Medical University Cancer Hospital, Wuming Hospital of Guangxi Medical University and Wuzhou Red Cross Hospital, Wuzhou Gongren Hospital (approval number: CS2021(96)). We will submit the finalised paper for publication on completing the analyses. This study will provide valuable insights to clinicians regarding the safety and efficacy of incorporating fruquintinib into SOX as neoadjuvant treatment for locally advanced GC/GEJ. The findings have the potential to inform future research proposals and may guide the use of fruquintinib in the neoadjuvant setting for locally advanced GC/GEJ. TRIAL REGISTRATION NUMBER: NCT05122091.

Comprehensive multi-omics analysis of pyroptosis for optimizing neoadjuvant immunotherapy in patients with gastric cancer.

Background: Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Patients and Methods: Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. Results: GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (BATF2, PTPRJ, RGS1, and VCAN), is a reliable and independent biomarker for GC. PRSlow is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRSlow marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Conclusion: Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.

The role of senescence genes in the treatment, prognosis, and tumor microenvironment of gastric cancer.

AIM: Gastric cancer (GC) has a high incidence and poor prognosis. Senescence genes are suggested to participate in immune cell infiltration, thus affecting the immunotherapy of GC. In this research, we established a senescence-related GC model to explore and verify the role of senescence genes in the prognosis, treatment, and tumor microenvironment (TME) of GC. METHODS: The TCGA GC (TCGA-STAD) dataset was used to screen key senescence genes from differentially expressed genes (DEGs). A prognostic risk model was trained utilizing the TCGA-STAD dataset and validated using an external GEO dataset. The CIBERSORT algorithm was run to explore the relationship between senescence genes and TME. The chemotherapy drug sensitivities in GC patients were calculated utilizing R package pRRophetic. RESULTS: A total of 37 senescence-related DEGs were obtained. Five key senescence-related genes were further screened to establish a senescence-related risk model based on Cox regression. The survival status of GC patients in the high-risk group was found to be worse than that in the low-risk group. According to the results of gene set enrichment analysis, the senescence-related risk was mainly associated with cytokine activity, immune mechanism, and related pathways. By analyzing the sensitivity of common chemotherapy drugs in GC patients, it was revealed that the sensitivities of high-risk patients to Dasatinib, Lapatinib, and Pazopanib were lower than those of low-risk patients. The CIBERSORT algorithm was executed to analyze the TME in the high-risk group, revealing elevated levels of CD8 T cells, Macrophages M2, and resting Mast cells. In addition, decreased levels of resting memory CD4 T cells , resting NK cells, activated Dendritic cells, and activated Mast cells were also observed. CONCLUSION: Senescence genes were related to the prognosis, response to chemotherapy drugs, and TME of GC. Our senescence-related risk model could forecast the survival of patients, their response to chemotherapy drugs, and the TME to a certain extent.

Tumor Immunophenotyping-Derived Signature Identifies Prognosis and Neoadjuvant Immunotherapeutic Responsiveness in Gastric Cancer.

The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype-related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG-3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in-house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune-activated, and IPSHigh is immune-silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti-PD-1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

LTBP2 Knockdown Promotes Ferroptosis in Gastric Cancer Cells through p62-Keap1-Nrf2 Pathway.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Ferroptosis is a new type of peroxidation-driven and iron-dependent cell death. However, the biological functions and exact regulatory mechanisms of ferroptosis in GC remain elusive. Here, we performed RNAi and gene transfection, cell viability assay, lipid peroxidation assay, reactive oxygen species (ROS) assay, glutathione assay, qRT-PCR, Western blotting, and transmission electron microscopy (TEM) to study ferroptosis in gastric cancer. The results revealed that silencing latent transforming growth factor ß binding proteins (LTBP2) can significantly inhibit GC cell proliferation and decrease cellular GSH levels, reduce GPX4 activity, and increase ROS generation and malondialdehyde (MDA) levels, leading to ferroptosis in GC cells. In addition, we demonstrate that suppression of LTBP2 could regulate the p62-Keap1-Nrf2 pathway, thereby downregulating the GPX4 and xCT expression and upregulating the PTGS2 and 4HNE expression. Our findings described a new role of LTBP2 in regulating ferroptosis, which heralds the prospect of ferroptosis-mediated cancer therapy.

Circular RNA Profiling Reveals That circRNA_104433 Regulates Cell Growth by Targeting miR-497-5p in Gastric Cancer.

BACKGROUND: The role and mechanism of hsa_circRNA_104433 in gastric cancer (GC) are further elucidated. MATERIALS AND METHODS: CircRNA_104433 was selected by circRNA microarrays and GEO database. qRT-PCR was used to analyze the expression of circRNA_104433 in GC. The role of circRNA_104433 in GC cells was evaluated based on cell cycle progression, cell proliferation, cell apoptosis, and tumor xenograft experiment assay. To explore the mechanisms of circRNA_104433 in GC TCGA database, STRING version, qRT-PCR and luciferase assay were performed. Furthermore, the prognostic value of CDC25A in GC was determined based on the GEO database. RESULTS: The level of circRNA_104433 showed upregulation in GC tissues, and the expression of it showed a positive correlation with the degree of differentiation and the size of the tumor. Knockdown of circRNA_104433 inhibited cell cycle transition, and cell proliferation, while promoted cell apoptosis in GC. CircRNA_104433 directly binds to miR-497-5p, which directly regulates CDC25A. The median survival period of GC patients with high expression levels of CDC25A was 21.3 months, which was shorter than those with low group expression of CDC25A (35.9 months). The cell cycle proteins CDK1, CDK2, CCNB1, PKMYT1, CDC20, CHEK1 and CDC25A were coexpressed with CDC25A. CONCLUSION: These findings suggested that knockdown of circRNA_104433 expression suppressed tumor development in GC.

Targeting snoRNAs as an emerging method of therapeutic development for cancer.

The relevance of the dysregulation of snoRNAs in human cancer has been widely investigated and has challenged the view that snoRNAs merely function as house-keeping genes for the posttranscriptional modification of rRNAs. Accumulating evidence has shown the intimate connection between snoRNAs and proliferation, apoptosis, invasion and migration of tumor cells via manual intervention patterns of snoRNA expression. In this review, we focused on how snoRNAs are dysregulated and its regulation of the formation and development of cancer. We summarized the non-classical functions of snoRNAs in the context of their regulations of the signaling pathways involving PI3K-AKT and K-Ras and p53-dependant manner. Under these novel functions and characteristics, snoRNAs can act as potential and feasible biomarkers for diagnosis. Simultaneously, these promising therapeutic strategies should be considered to counteract the perturbations of snoRNAs.

The accuracy of magnifying narrow band imaging (ME-NBI) in distinguishing between cancerous and noncancerous gastric lesions: A meta-analysis.

BACKGROUND: Previous clinical trials have demonstrated the diagnostic accuracy of magnifying narrow-band (ME-NBI) for gastric cancerous lesions, but the results are inconsistent. The purpose of this meta-analysis is to investigate the accuracy of ME-NBI in distinguishing between cancerous and noncancerous gastric lesions. METHODS: Systematic literature searches were conducted until October 2016 in PubMed, Embase by 2 independent reviewers. Meta-analysis was performed to calculate the pooled sensitivity, specificity. Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data. Meta-analytic method was used to construct summary receiver operating characteristic curves, and pooled sensitivity, specificity were calculated. RESULTS: Nine studies enrolling 5398 lesions were included. The pooled sensitivity, specificity were 88% (95% confidence interval [CI]: 78-93%), 96% (95% CI: 91-98%), respectively. The area under the curve (AUC) was 0.97. There was a large heterogeneity between the included studies. Studies with lesions ≤ 10 mm still had a high pooled sensitivity of 81% (95% CI: 73-90%) and specificity of 97% (95% CI: 95-100%). Studies which analyzed resected specimens had a sensitivity of 91% (95 CI: 82-99%) and specificity of 88% (95% CI: 83-94%), and studies which analyzed biopsied specimens had a sensitivity of 85% (95 CI: 74-96%) and specificity of 99% (95% CI: 98-99%). CONCLUSIONS: ME-NBI is highly accurate and consistent to distinguish between gastric cancerous and noncancerous lesions.

Postoperative morbidity and mortality in patients receiving neoadjuvant chemotherapy for locally advanced gastric cancers: A systematic review and meta-analysis.

AIM: To investigate the postoperative morbidity and mortality for neoadjuvant chemotherapy (NAC) plus surgery compared with surgery alone. METHODS: PubMed and Embase were searched to capture the incidence of any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, and postoperative mortality in randomized clinical trials comparing NAC plus surgery with surgery alone. The meta-analyses were performed with a random effects model. RESULTS: Nine relevant studies were included. Comparing NAC with surgery alone, there were no increases in any postoperative complications, pulmonary complications, anastomotic leakage, surgical site infections, or postoperative mortality attributable to NAC. Sensitivity analysis suggested a possible increased risk of any postoperative complications compared with surgery alone: the risk difference 0.056 (95% confidence interval -0.032 to 0.145). Severe complications such as anastomotic leakage and pulmonary complications were similar in the 2 groups. CONCLUSIONS: NAC for gastric cancer does not increase the risk of postoperative morbidity and mortality compared with surgery alone.