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Background: Despite advances in treatments for gastric cancer (GC), new targets are needed to enhance treatment, especially when mesenchymal‐epithelial transition (MET) amplification is involved. Therefore, we investigated the genomic features of MET‐amplified GC and efficacy of anti‐MET therapy. Methods: Genomic features were investigated in 2284 patients (cohort 1) and 438 patients in the Cancer Genome Atlas (TCGA cohort). RNA data were obtained from TCGA for expression analysis. Clinical responses of 71 patients (cohort 2) were investigated. Survival rates were compared by Kaplan–Meier and log‐rank tests. Results: In cohort 1, 95 (4.2%) exhibited MET amplifications. In TCGA cohort, 15 (3.4%) exhibited MET amplifications. The five top mutated genes were TP53, CDH1, ARID1A, KMT2D and PIK3CA in cohort 1 and TTN, TP53, MUC16, LRP1B and SYNE1 in TCGA cohort. TP53, PIK3CA, KRAS and GNAS showed significant single nucleotide variants (SNVs) in cohort 1, and TP53 SNVs were significant in TCGA cohort. Fifteen and 18 genes showed significant copy number variations (CNVs) between the MET‐ and non‐MET‐amplified groups in cohort 1 and TCGA cohort, respectively. The PI3K pathway was significantly activated in Chinese patients with MET‐amplified GC (p = 0.002). TP53 expression is negatively associated with MET amplification. Real‐world data obtained with cohort 2 revealed that anti‐MET treatment significantly affected overall survival (OS) (p = 0.002), whereas CNVs did not affect progression‐free or OS even when treatment lines were considered. Conclusions: MET‐amplified GC has a distinctive mutation landscape. Our findings provide valuable information for clinicians who treat patients with MET‐amplified GC. [ABSTRACT FROM AUTHOR]

Background: The clinicopathological features of MET‐amplified gastric cancer (GC) and real‐world data on the efficacy of MET‐targeted therapies remain unknown. Pulmonary lymphangitis carcinomatosis (PLC) is a peculiar manifestation of GC, whose management has not been thoroughly described. Methods: This study analyzed patients diagnosed with MET‐amplified GC or GC with PLC at any time point of the disease course from 2011 to 2021 in two centers. Clinicopathological features and survival outcomes of MET‐amplified GC were analyzed. The clinical and molecular implications of GC with PLC were discussed. Results: Fifty‐eight patients with MET‐amplified GC and 20 patients with GC accompanied by PLC were finally enrolled for analysis (including 13 overlapped patients). GC with PLC was more common in female patients (p = 0.010), diagnosed at a younger age (p = 0.002), presented with a higher baseline ECOG PS (p = 0.016), and was more likely to develop lung metastasis (p < 0.001), and serous effusion (p = 0.026) than GC without PLC. Patients with primary MET‐amplified GC had a worse prognosis than those with secondary MET‐amplified GC (p = 0.005). The application of anti‐MET therapy was associated with numerically prolonged survival, but the association was not statistically significant (p = 0.07). MET amplification was concentrated in patients with PLC, in which anti‐MET therapies elicited a high response rate. Conclusions: MET‐targeted therapies are efficacious in real‐world populations with MET‐amplified GC. Patients with PLC have distinct clinical and molecular features and might benefit from MET‐targeted therapies. [ABSTRACT FROM AUTHOR]

Purpose: The prognosis of diffuse‐type gastric cancer (DGC) is poorer than that of intestinal type, but S‐1 is a potential treatment option in DGC. This study explored the maximal tolerated dose (MTD) and the recommended dose for phase II study (RP2D) of nab‐paclitaxel combined with S‐1 (AS regimen) as adjuvant chemotherapy in stage III DGC. Methods: Patients with stage III DGC were recruited into this phase I dose‐escalation study between July 2019 and June 2020 in Zhongshan Hospital. Nab‐paclitaxel and S‐1 (80–120 mg/day, d1‐14, q3w) were administrated for 6 cycles, and then 8 cycles of S‐1 monotherapy were applied. The patients received nab‐paclitaxel at 180, 220, or 260 mg/m2 according to the 3 + 3 design based on dose‐limiting toxicity (DLT). The primary endpoint was RP2D. Secondary endpoints were the 1‐year disease‐free survival (DFS) rate and adverse events (AEs). Results: One case experienced DLT in 180‐mg/m2 dose group, subsequently three additional subjects were enrolled. DLT was not observed in the 220‐ and 260‐mg/m2 dose groups (both n = 3). Therefore, the MTD has not reached, and the RP2D of nab‐paclitaxel would be 260 mg/m2. Five participants showed progressive disease, with three and two participants in the 180‐ and 220‐mg/m2 dose groups, respectively. The 6‐, 12‐, and 18‐month DFS rates were 100%, 63.6%, and 50.9%, respectively. The most frequently observed AEs were neutropenia (83.3%) and leukopenia (66.7%). Conclusion: The RP2D of nab‐paclitaxel as adjuvant chemotherapy in DGC was 260 mg/m2. The AS regimen had a tolerable AE profile in stage III DGC. [ABSTRACT FROM AUTHOR]

Purpose: Alpha-fetoprotein-producing gastric cancer (AFPGC) and hepatoid adenocarcinoma of stomach (HAS) are rare types of gastric cancer, with specific clinical manifestations and poor prognosis. The standardized treatment process of such cancers remains elusive. We aim to investigate the efficacy of immunotherapy combined with chemotherapy on patients with AFPGC or HAS. Patients and Methods: AFPGC and HAS patients who underwent immunotherapy and/or chemotherapy as the first-line treatment at our institute from June 2016 to December 2018 were enrolled in this observational study. Their clinicopathological characteristics, serum AFP level and treatment methods were collected. The progression-free survival (PFS) and overall survival (OS) were analyzed and compared between patients who received immunotherapy plus chemotherapy and those received chemotherapy. Results: A total of 21 patients with advanced AFPGC or HAS were included in the study and the median follow-up time was 28.0 months. Of the 21 patients, 7 patients received immunotherapy of PD-1 antibody (nivolumab) plus chemotherapy and 14 patients as control received chemotherapy with or without Herceptin/Apatinib. The median progression-free survival (mPFS) time was 5.0 months (4.3 months in the control group and 22.0 months in the immunotherapy group). The median overall survival (mOS) time of the control group was 16.0 months (14.0 months in chemotherapy alone subgroup, 20.0 months in chemotherapy plus Apatinib or Herceptin subgroup), while the mOS of patients receiving immunotherapy was not reached. Conclusion: This study suggested PD-1 checkpoint inhibitor plus chemotherapy could benefit AFPGC and HAS patients. Its mechanism of action warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: To compare the prognosis of adjuvant SOX (S-1 and oxaliplatin) vs XELOX (capecitabine and oxaliplatin) chemotherapy in Chinese patients with gastric cancer (GC) after D2 gastrectomy. Methods: This was a real-world study of patients with GC (stages II–III) who underwent D2 gastrectomy and received adjuvant SOX or XELOX between 01/2010 and 06/2017 in Zhongshan Hospital affiliated to Fudan University. The patients were matched by propensity score matching. The primary and secondary endpoints were disease-free survival (DFS) and overall survival (OS), respectively. Adverse events (AEs) were compared. Results: A total of 552 patients were included. The median follow-up time was 24.9 months. There were no differences in DFS (median, 44.4 vs 41.2 months; HR=1.17, 95% CI: 0.92– 1.48) and OS (median, 61.5 vs 65.3 months; HR=1.01, 95% CI: 0.73– 1.39) between the XELOX and SOX groups. Both DFS and OS had no significant differences between SOX and XELOX for all subgroups based on sex (P=0.949, P=0.990), age (P=0.303, P=0.392), Lauren type (P=0.362, P=0.573), type of gastrectomy (P=0.607 P=0.989), and pathological TNM stage (P=0.899, P=0.888). A total of 86 patients in the SOX subgroup (34.2%) experienced AEs, similar to the rate found in the XELOX subgroup (104 patients or 41.4%; P=0.098). Discussion: The results suggested that adjuvant SOX chemotherapy has similar survival benefits compared to XELOX chemotherapy in Chinese patients with pathological stage II or III GC after D2 gastrectomy. [ABSTRACT FROM AUTHOR]

High‐throughput messenger RNA (mRNA) analysis has become a powerful tool for exploring tumor recurrence or metastasis mechanisms. Here, we constructed a signature to predict the recurrence risk of Stages II and III gastric cancer (GC) patients. A least absolute shrinkage and selection operator method Cox regression model was utilized to construct the signature. Using this method, a 16‐mRNA signature was identified to be associated with the relapse‐free survival of Stages II and III GCs in training dataset GSE62254 (n = 194). Then this signature was validated in an independent Gene Expression Omnibus cohort GSE26253 (n = 297) and a dataset of The Cancer Genome Atlas (TCGA; n = 235). This classifier could successfully screen out the high‐risk Stages II and III GCs in the training cohort (hazard ratio [HR] = 40.91; 95% confidence interval [CI] = 5.58–299.7; p <.0001). Analysis in two independent validation cohorts yielded consistent results (GSE26253: HR = 1.69, 95% CI = 1.17–2.43,; p =.0045; TCGA: HR = 2.01, 95% CI = 1.13–3.56, p =.0146). Cox regression analyses revealed that the risk score derived from this signature was an independent risk factor in Stages II and III GCs. Besides, a nomogram was constructed to serve clinical practice. Through gene set variation analysis, we found several gene sets associated with chemotherapeutic drug resistance and tumor metastasis significantly enriched in high‐risk patients. In summary, this 16‐mRNA signature can be used as a powerful tool for prognostic evaluation and help clinicians identify high‐risk patients. [ABSTRACT FROM AUTHOR]

Background: The indistinctive effects of antiangiogenesis agents in gastric cancer (GC) can be attributed to multifaceted gene dysregulation associated with angiogenesis. Angiopoietin‐like (ANGPTL) proteins are secreted proteins regulating angiogenesis. They are also involved in inflammation and metabolism. Emerging evidences have revealed their various roles in carcinogenesis and metastasis development. However, the mRNA expression profiles, prognostic values, and biological functions of ANGPTL proteins in GC are still elucidated. Methods: We compared the transcriptional expression levels of ANGPTL proteins between GC and normal gastric tissues using ONCOMINE and TCGA‐STAD. The prognostic values were evaluated by LinkedOmics and Kaplan–Meier Plotter, while the association of expression levels with clinicopathological features was generated through cBioPortal. We conducted the functional enrichment analysis with Metascape. Results: The expression of ANGPTL1/3/6 was lower in GC tissues than in normal gastric tissues. High expression of ANGPTL1/2/4 was correlated with short overall survival and post‐progression survival in GC patients. Upregulated ANGPTL1/2 was correlated with higher histological grade, non‐intestinal Lauren classification, and advanced T stage, while ANGPTL4 exhibited high expression in early T stage, M1 stage, and non‐intestinal Lauren classification. Conclusions: Integrative bioinformatics analysis suggests that ANGPTL1/2/4 may be potential therapeutic targets in GC patients. Among them, ANGPTL2 acts as a GC promoter, while ANGPTL1/4's role in GC is still uncertain. [ABSTRACT FROM AUTHOR]

Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer. [ABSTRACT FROM AUTHOR]