Gastric Cancer最新文献

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.

Background and aim: Aberrant DNA methylation persists in the gastric mucosa after Helicobacter pylori (H. pylori) eradication and may contribute to the development of post-eradication gastric cancer (PEGC). We aimed to comprehensively investigate both DNA hypermethylation and hypomethylation and their relevance to cancer risk.

Methods: Genome-wide DNA methylation profiling was performed using Infinium MethylationEPIC BeadChips with tumor tissue and non-cancerous mucosa from PEGC patients. Public datasets, including The Cancer Genome Atlas (TCGA)-STAD and H. pylori-negative controls, were integrated to identify recurrently hyper- and hypomethylated loci. Representative gene methylation levels were validated using bisulfite pyrosequencing. Correlation analyses were conducted to link DNA methylation with gene expression.

Results: Non-cancerous mucosa from PEGC patients exhibited substantial CpG island (CGI) hypermethylation. In parallel, we detected 4081 CpG sites recurrently hypomethylated in GC, many of which were also hypomethylated in non-cancerous mucosa from PEGC patients. The majority of hypomethylated sites were located outside of CGIs, often near oncogenes such as CDH17, HNF4A and CD44, and showed inverse correlations with gene expression. CGI hypermethylation and CpG hypomethylation were positively correlated across samples.

Conclusions: CGI hypermethylation and non-CGI hypomethylation are tightly linked and may co-emerge during the early stages of gastric carcinogenesis. Their concurrent presence in non-cancerous mucosa from PEGC patients suggests a coordinated epigenetic landscape contributing to residual cancer risk after H. pylori eradication.

Background: The incidence of esophagogastric junction (EGJ) cancer is increasing worldwide. Siewert type II EGJ cancer encompasses intestinal and gastric phenotypes; however, the molecular profiles and clinicopathological features remain unclear.

Methods: Overall, 922 patients who underwent surgical resection for EGJ or gastric cancer from 2014 to 2023 were analyzed. The tumors were classified into intestinal and gastric phenotypes using immunohistochemistry. Molecular profiling was conducted using whole-exome sequencing, and clinicopathological features, mutational patterns, immune responses, and survival outcomes were investigated.

Results: The intestinal phenotype exhibited frequent TP53 mutations and high NOX1 expression. High NOX1 expression was correlated with increased CD4 + and CD20 + lymphocyte infiltration. The intestinal phenotype was associated with better relapse-free survival (RFS) than the gastric phenotype. Metastatic patterns varied, with peritoneal and lymph node metastases being more common in the gastric and intestinal phenotypes, respectively. High NOX1 expression was an independent prognostic factor for RFS.

Conclusions: EGJ cancers with intestinal and gastric phenotypes demonstrate distinct molecular and immune profiles that influence prognosis. The intestinal phenotype, characterized by TP53 mutations, high NOX1 expression, increased immune cell infiltration, and better survival outcomes, may impact EGJ cancer prognosis and could guide future diagnostic and therapeutic approaches.

Background: Homologous recombination repair (HRR) gene mutations contribute to genomic instability. However, their clinical value in immune checkpoint inhibitor (ICI)-based treatments in gastric cancer remains unclear. Therefore, this study aims to investigate the efficacy of nivolumab plus chemotherapy according to the HRR mutation status in patients with advanced gastric cancer.

Methods: This single-center study included patients with gastric cancer with available panel sequencing results who were treated with first-line nivolumab plus chemotherapy (n = 115) or chemotherapy alone (n = 172). Mutation status of 17 HRR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, RAD52, RAD54L, and XRCC2) was assessed using targeted next-generation sequencing.

Results: Among patients treated with nivolumab plus chemotherapy, 36.5% had HRR mutations, with BRCA2 mutation being the most common mutation (11.3%). Compared to those of the no-HRR mutation group, the HRR mutation group exhibited a higher objective response rate, longer progression-free survival (PFS) (median 12.8 vs. 6.5 months; hazard ratio HR 0.57), and overall survival (OS) (median not reached vs. 14.2 months; HR 0.40) with nivolumab plus chemotherapy. Patients with HRR mutations treated with nivolumab plus chemotherapy showed favorable PFS and OS compared to those treated with chemotherapy alone. However, this difference was not observed in patients without HRR mutations.

Conclusions: HRR mutations were associated with favorable survival outcomes in patients treated with nivolumab plus chemotherapy. Our findings suggest that HRR mutations may serve as a potential predictive biomarker for first-line ICI-based chemotherapy in gastric cancer.

Background: We developed and validated a prognostic model incorporating readily accessible clinicopathological data and specific patient-reported outcomes (PROs).

Methods: We used data from two randomized trials comparing regorafenib to placebo: AGITG INTEGRATE IIa (n = 251) for model development and AGITG INTEGRATE (n = 152) for validation. Candidate variables were chosen from a systematic literature review and expert consultation. Significant prognostic factors in the multivariable model were identified using univariable Cox proportional hazards models with a p-value of < 0.1. Multivariable Cox proportional hazards models were developed using clinicopathological and PRO variables, with model selection refined using least absolute shrinkage and selection operator (LASSO). The model's discrimination and calibration were assessed using concordance indices (C-statistics) and calibration plots.

Results: Univariable analysis identified 9 clinicopathological variables and 4 PRO domains that were prognostic for overall survival: body mass index (BMI), ECOG performance status, number of metastatic sites, liver involvement, treatment with regorafenib, neutrophil-lymphocyte ratio (NLR), LDH, albumin, CA 19-9, appetite loss, constipation, fatigue, and pain. The initial multivariable model (M1) incorporated geographic region (Asia vs non-Asia), performance status, number of metastatic sites, treatment with regorafenib, NLR, BMI, LDH, CA 19-9, and albumin. The preferred multivariable model (M2), including the abovementioned variables plus the 4 PROs, demonstrated superior discriminative ability with higher C-statistic values than models without PROs. Plots supported the model's calibration.

Conclusions: Incorporating PROs into prognostic models for AGOC improved the accuracy of survival predictions. Further research is needed to validate its use in routine clinical practice.

Background: COP9 Signalosome Subunit 5 (COPS5) is a deubiquitinating enzyme that induces chemotherapy resistance. The role of COPS5 amplification in patients with gastric cancer (GC) and its therapeutic potential in HER2-amplified GC models have not been explored.

Methods: The Cancer Genome Atlas (TCGA) data were analyzed to assess the clinical relevance of COPS5 amplification in patients with GC. Functional studies using HER2-amplified GC cell lines and xenograft models evaluated the effects of COPS5 inhibition (CSN5i-3), alone or in combination with trastuzumab.

Results: In the curated stomach adenocarcinoma cohort (n = 294) from TCGA datasets, COPS5 amplification was significantly more frequent in patients with HER2 amplification (10.5% vs. 2.7%, P = 0.040) and was associated with worse disease-free survival after surgery (median 12.6 vs. 45.2 months, P = 0.012) and overall survival (median 21.4 months vs. not reached, P = 0.004). In HER2-amplified GC cell lines, CSN5i-3 treatment synergized with the antiproliferative effect of trastuzumab. Mechanistically, COPS5 knockout enhanced PTEN expression by ubiquitin-mediated SNAIL degradation, suppressing the AKT downstream pathway. The combination effect was dependent on PTEN expression. Accordingly, COPS5 knockout enhanced the efficacy of AKT inhibitors. In a xenograft model, the combination of CSN5i-3 and trastuzumab demonstrated synergistic antitumor effects compared to monotherapy.

Conclusions: COPS5 amplification was significantly more prevalent in patients with HER2 amplification and was associated with poor outcomes after surgery. The synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the inhibition of the AKT pathway, warranting further clinical studies in patients with HER2-positive GC.