Gastric Cancer最新文献

Background: Helicobacter (H.) pylori is the major risk factor of gastric cancer (GC). We aimed to estimate the population attributable fraction (PAF) of GC and the number of new GC cases and deaths for GC attributable to H. pylori in different countries worldwide in 2022.

Methods: The PAF was estimated using country-specific pooled prevalence of H. pylori in the period 2000-2010 obtained through a systematic review and meta-analysis and a risk ratio of 5.9 for the association between H. pylori and GC. The absolute number of new GC cases and deaths for GC attributable to H. pylori was calculated using PAF and GC incidence and mortality reported by GLOBOCAN 2022.

Results: The PAF of GC due to H. pylori was calculated for 27 countries. The average PAF was 69.7% ranging from 40.7% in Malaysia to 82.3% in South Africa. The PAF was > 70% in all countries in the analysis in Africa, East Mediterranean region and Latin America, apart from Mexico, and in some countries in Western Pacific region (China, Japan and Korea) and Europe (Poland, Spain and Albania). The largest number of GC cases and deaths for GC attributable to H. pylori was estimated in China (GC: 252,850, deaths:184,666) and Japan (GC: 92,166, deaths: 31,809).

Conclusions: More than two-thirds of new GC cases in the countries in the analysis were attributable to H. pylori in 2022. Our estimates may contribute to better investigate cost-effectiveness of H. pylori screening strategies for GC prevention in different countries worldwide.

Background: Immune checkpoint inhibitors (ICI) are pivotal in cancer treatment. However, not all patients are responsive to current ICI therapies, and new targets are needed. Thus, the HLA-G/ILT2 pathway emerges as one such potential ICI. The present study aimed to analyze the implications of this pathway in cytotoxic T cells from patients with gastric adenocarcinoma.

Methods: Peripheral blood mononuclear cells (PBMCs), and tissue infiltrating lymphocytes were obtained from 16 patients with gastric adenocarcinoma. PBMCs from 17 healthy subjects were used as controls. Cells were subjected to flow cytometry on the one hand and stimulation (assessed by IFNγ production) and proliferation assays, in the presence or absence of HLA-G, on the other.

Results: Despite lower CD3 + counts (p = 0.0036), CD3 + CD8 + ILT2 + (ILT2 + Tc) cells are overrepresented in patients, compared to control subjects (p < 0.0001). These ILT2 + Tc exhibit enhanced anti T-cell receptor (TCR)-stimulated IFNγ production, compared to its counterparts ILT2- Tc (p = 0.0039), which was impaired by the presence of HLA-G (p = 0.0002). Proliferative responses of Tc were significantly reduced by HLA-G (p < 0.0001) after 5 days of stimulation. Finally, simultaneously PD1 and ILT2 staining revealed differential expression patterns between patients.

Conclusions: CD8 + T cells expressing ILT2 are overrepresented in patients with gastric adenocarcinoma, independent of PD-1 expression, and appear particularly susceptible to functional suppression in the presence of HLA-G-positive tumors. These findings highlight the immunomodulatory role of HLA-G in the tumor microenvironment and support its relevance as a potential target for personalized immunotherapeutic strategies.

Background: Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The NF-YA gene codes for the Nuclear-Transcription-Factor-Y-Subunit-A, which is overexpressed in various tumors. In tumors, the relative ratio of the two major NF-YA alternative splicing isoforms, NF-YA long and NF-YA short, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high NF-YA long/NF-YA short ratio, we generated a 158-gene signature that is common to Claudin^low Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD).

Methods: To better classify STAD Claudin^low tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudin^low subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning DeepCC tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots.

Results: The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudin^low expression and with a high NF-YA long/NF-YA short ratio. This Claudin^low subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudin^low STAD cell lines with a high NF-YA long/NF-Y short ratio and validated the expression of selected markers.

Conclusions: Our work supports the notion that three overlapping features-low expression of Claudin-3/4/7, high NF-YA long/NF-YA short ratio and a 158-gene signature-mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.

Objective: This research examines how NF-κB Interacting LncRNA (NKILA) and its functional variant rs2273534 influence gastric cancer (GC) risk, development, and prognosis, along with the molecular pathways involved.

Methods: 840 GC patients and 840 healthy controls participated in a case-control research. Genetic association analyses, molecular experiments (qRT-PCR, Western blot, functional assays), and bioinformatics approaches were employed. Cell-based and animal experiments were employed to validate the oncogenic role of NKILA and its regulatory axis.

Results: Carriers of the NKILA rs2273534 C allele exhibited a markedly higher susceptibility to GC (OR = 1.51, p = 0.003) and an unfavorable prognosis (HR = 1.89, p = 0.016), which was also associated with elevated NKILA expression. Elevated NKILA expression in GC tissues was associated with advanced clinicopathological characteristics. Mechanistically, NKILA promotes the expression of 5'-Oligoadenylate Synthetase 2 (OAS2) through sponging miR-4424, which in turn facilitates proliferation, migration, invasion, and EMT in GC cells. Rescue experiments confirmed that the NKILA/miR-4424/OAS2 axis is crucial for GC malignancy.

Conclusions: The rs2273534 SNP enhances NKILA expression and drives GC progression through the NKILA/miR-4424/OAS2 axis. Our findings highlight rs2273534 as a possible indicator for GC susceptibility and prognosis, offering insights into the oncogenic mechanisms mediated by lncRNAs.

Background: We aimed to reveal the outcomes of endoscopic resection (ER) for locally recurrent early gastric cancer (LRGC) after ER using the data obtained in a Japanese multicenter prospective cohort study of ER for early gastric cancer (EGC) using Web registry (J-WEB/EGC).

Methods: Short-term and long-term outcomes were compared between 125 LRGCs (119 patients) and 9387 primary EGCs of naive stomach (8455 patients) enrolled in this study at 41 centers between July 2010 and June 2012. We calculated 5-year overall survival rates (OS) and disease-specific survival rates (DSS) for LRGC, divided ERs into curative and noncurative resections, and calculated hazard ratios (HR) for all-cause mortality with Cox regression analysis.

Results: For LRGCs and primary EGCs, median resection times were 100 and 77 min (p<0.0001), en-bloc resection rates were 97.6% and 99.5% (p<0.05), and R0 resection rates were 86.4% and 93.3% (p<0.05), respectively. There were no significant differences for adverse events between LRGC and primary EGC. Five-year OS and DSS for LRGC cases were 89.9% and 100%. Compared to curatively resected primary EGC cases, HR for all-cause mortality of curatively resected LRGC, noncuratively resected primary EGC and noncuratively resected LRGC cases were 0.58 (95% CI 0.24-1.41), 1.46 (1.25-1.7) and 3.02 (1.43-6.36), respectively.

Conclusions: A curative ER for LRGC offers the same long-term prognosis as primary EGC. ER for LRGC can offer a secure and radical treatment.

Background: Conditional survival (CS) estimates the probability of future survival based on time already survived. However, evidence regarding postoperative dynamic follow-up in gastric cancer patients after neoadjuvant therapy (NAT) remains limited. This study aimed to evaluate dynamic prognosis and optimize follow-up for locally advanced gastric cancer (LAGC) patients after NAT.

Methods: We retrospectively analyzed 997 LAGC patients who underwent NAT followed by radical gastrectomy across multiple Chinese centers. CS was used to evaluate the probability of surviving for Y years on top of having survived for X years. Prognostic factors for overall survival (OS) and recurrence-free survival (RFS) were identified by Cox regression and incorporated into a model predicting conditional probabilities at 1, 3, and 5 years after surgery. Patients were stratified into high- and low-risk groups using an optimal cut-off of 160 points derived from the RFS nomogram.

Results: The 3-year OS rate was 61.3%. CS increased with longer postoperative survival, with 3-year conditional overall survival (cOS3) rising from 62.2% at 1 year to 89.3% at 5 years. A similar trend was observed for 3-year conditional recurrence-free survival (cRFS3). Independent prognostic factors included preoperative CA19-9 level, tumor size, ypT stage, ypN stage, and perineural invasion (all P < 0.05). Recurrence analysis showed that 68.7% of high-risk patients experienced recurrence, with 91.9% of events occurring within 2 years.

Conclusions: CS enables dynamic assessment of postoperative prognosis in patients with LAGC after NAT, underscoring the importance of intensified early follow-up to facilitate timely detection and intervention for recurrence.

Background: Chronic atrophic gastritis, represented by Helicobacter pylori (H. pylori) or autoimmune gastritis (AIG), has been recognized as a risk factor for gastric carcinoma (GC). Differences in the clinicopathological features of GC with AIG (GC-AIG) based on H. pylori infection status remain unclear.

Methods: This retrospective analysis included 65 cases of GC-AIG in which endoscopic resection or gastrectomy was performed at a single center between 2008 and 2024. The cases were categorized into Group A (H. pylori-naïve GC-AIG) or Group B (H. pylori-infected GC-AIG), and the clinical and pathological data were compared between the groups.

Results: Group A included 18 cases with 25 lesions and Group B included 47 cases with 72 lesions. The median age [interquartile range] was significantly younger in Group A (70 [63-74] years) than in Group B (75 [62-79] years, p = 0.045). Tumors in Group A were more frequently located in the upper and middle stomach, whereas those in Group B were predominantly located in the lower stomach (p = 0.006). Group A had a significantly higher proportion of pure undifferentiated-type adenocarcinoma (Laurén's diffuse type) than Group B (28.0% versus 8.3%, p = 0.027).

Conclusions: H. pylori-naïve GC-AIG is characterized by younger age, a higher prevalence of pure undifferentiated-type adenocarcinoma, and tumors predominantly located in the upper and middle stomach.

Background: The tyrosine kinase inhibitor (TKI) imatinib targets KIT and PDGFRA, offering significant therapeutic benefits in advanced gastrointestinal stromal tumors (GISTs). However, the high rate of recurrence following treatment discontinuation suggests that drug-tolerant persister cells (DTPs) may contribute to therapy resistance. Elucidating the mechanisms underlying DTP survival is critical for the development of curative strategies. This study aimed to investigate the role of yes-associated protein (YAP) in DTP survival and to evaluate the efficacy of combining imatinib with YAP inhibitors as a potential therapeutic approach.

Methods: Imatinib-sensitive GIST cell lines were treated with imatinib to generate DTPs. YAP activity was assessed via western blotting, fluorescence immunostaining, and nuclear-cytoplasmic fractionation. Proliferation and apoptosis assays were conducted to evaluate sensitivity to YAP inhibitors, such as verteporfin. Xenograft mouse models were used to assess the efficacy of combination therapy with imatinib and verteporfin.

Results: DTPs exhibited increased nuclear localization and activity of YAP, which was reversible upon imatinib withdrawal. YAP inhibitors reduced nuclear YAP levels and showed greater efficacy in DTPs than in parental cells. Combination therapy with imatinib and verteporfin significantly suppressed DTP proliferation and induced apoptosis in vitro. In xenograft models, the combination therapy delayed tumor regrowth after treatment cessation compared to imatinib monotherapy.

Conclusions: YAP activity was elevated in GIST DTPs, and YAP inhibitors effectively suppressed this activity. The combination of imatinib and YAP inhibitors enhanced tumor growth suppression. These findings underscore the pivotal role of YAP in DTP survival and demonstrate the therapeutic potential of combining imatinib with YAP inhibitors.