Gastric Cancer最新文献

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.

Background: The INTEGRATE trials evaluated regorafenib in advanced gastric and esophagogastric junction cancer (AGOC), a poor prognosis population. In INTEGRATE 1 (I1, phase 2), regorafenib improved progression-free survival (PFS) without a clear excess decline in health-related quality of life (HRQoL). INTEGRATE 2a (I2a, phase 3) demonstrated an overall survival (OS) benefit, alone and in a pre-specified pooled analysis with I1.

Aim: To evaluate HRQoL outcomes from I2a and the pooled analysis with I1.

Methods: HRQoL was assessed at baseline, day 1 of each cycle, and every 8 weeks until progression, using EORTC QLQ-C30, EORTC STO22, and the participant Disease and Treatment Assessment (PtDATA). The primary endpoint was deterioration-free survival (DetFS), defined as time to a ≥ 10-point decline in QLQ-C30 physical function (DetFSPF) or global health status (DetFSGHS), progression, or death. Secondary analyses used linear mixed models (LMM). Tertiary analyses used logistic regression to evaluate symptom and side-effect prevalence (PtDATA). Pooled analyses adjusted for trial effects.

Results: Of 251 I2a participants, 240 contributed HRQoL data. Regorafenib was superior on DetFSPF (HR = 0.75, 95% CI 0.58-0.99, p = 0.03) and DetFSGHS (HR = 0.68, 95% CI 0.52-0.89, p = 0.004). LMM showed no appreciable differences in HRQoL trajectories. Rash, hand-foot syndrome, numbness, and coping difficulties were more frequent with regorafenib. Pooled analyses confirmed these findings.

Conclusion: Regorafenib modestly prolonged survival in AGOC without clear HRQoL deterioration. Despite more frequent toxicities, overall HRQoL was preserved. Regorafenib may offer a net clinical benefit when survival and HRQoL preferences are considered.

Background: Immune checkpoint inhibitors (ICIs) play a pivotal role in the treatment of advanced gastric cancer (GC). However, the biomarkers used to predict ICI efficacy are limited due to their reliance on single or static tumor characteristics. This study aims to develop a machine learning (ML) model that incorporates dynamic changes in clinlabomics data to optimize the predictive accuracy of ICI efficacy.

Methods: This multicenter, retrospective study utilized nine ML to construct the model. Participants were further stratified into low-risk and high-risk groups based on the predicted efficacy of ICI. Kaplan-Meier survival curves and RNA-sequencing were used for differential analysis.

Results: This study enrolled 377 patients with advanced GC who underwent first-line ICI treatment across eleven hospitals between January 2018 and May 2023. Among them, 220 patients from Qilu Hospital of Shandong University were selected for the development model. The remaining ten hospitals contributed to two external test cohorts. Ten dynamic clinlabomics features were identified. The XGBoost demonstrated optimal performance in predicting ICI response, achieving an AUC of 0.863 in the training cohort, and 0.790-0.842 in the validation and two external cohorts. Notably, the model exhibited strong predictive capabilities compared to single point-in-time and previously proposed model. In the subgroup analysis, the low-risk subtype demonstrated a significantly improved prognosis and exhibited characteristics of "hot tumors". A web tool was generated: https://ici-therapeutic-efficacy-predictor-ztwwfwek2uckbmhxlnsayq.streamlit.app/ .

Conclusions: The dynamic clinlabomics model can effectively predict the ICI efficacy in advanced GC. The model was validated using multicenter data and provides new evidence to optimize treatment decisions.

Background: Minimally invasive surgery (MIS) is increasingly used for gastric cancer; however, its application to remnant gastric cancer (RGC) remains technically challenging due to adhesions and altered anatomy. Large-scale comparative data on the safety and effectiveness of MIS versus open surgery for RGC are limited. This retrospective study aimed to evaluate the short-term outcomes of MIS versus open completion total gastrectomy for RGC.

Methods: We retrospectively analyzed data from 3337 patients who underwent completion total gastrectomy for RGC between January 2018 and December 2022 using the National Clinical Database of Japan. After applying predefined inclusion criteria, we performed one-to-one propensity score matching to balance baseline characteristics between the MIS and open surgery groups and compared short-term surgical outcomes.

Results: After matching, 540 patient pairs were included in the analysis. MIS was associated with a significantly longer operative time (median 344 vs. 248.5 min; P < 0.001) but reduced blood loss (median 70 vs. 290 mL; P < 0.001). The incidence of anastomotic leakage was higher in the MIS group (9.8% vs. 6.3%; P = 0.034). Postoperative hospital stay was numerically shorter in the MIS group (median 13 vs. 14 days; P = 0.065). Overall complication, reoperation, and mortality rates were comparable between groups.

Conclusions: MIS for RGC showed comparable short-term outcomes to those of open surgery in a nationwide analysis, with advantages including reduced blood loss. However, the increased risk of anastomotic leakage highlights the need for careful patient selection and ongoing technical refinement.

Background: The renin-angiotensin system (RAS) has been increasingly recognized to be associated with carcinogenesis and cancer progression. There is extensive preclinical evidence suggesting the benefits of RAS-inhibiting drugs, such as angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), in preventing the progression of gastric cancer (GC). However, clinical evidence supporting the positive effects of ARBs and ACEIs on GC prognosis is currently limited. The purpose of this study is to investigate their effects in a Finnish cohort.

Methods: This is a retrospective national cohort study, where cancer patient registry data were linked to prescription purchase records for ARBs and ACEIs. The effect of ARB/ACEI in the post-diagnostic period on overall mortality was assessed using Cox regression analysis. Disease-specific mortality associations were evaluated with the Fine and Gray model.

Results: We included 2246 histologically confirmed GC patients diagnosed between 2011 and 2016. Follow-up continued until the end of 2023. In the main analysis, a protective effect of ARB use was associated with a significant reduction in overall mortality (adjusted hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.69-0.94, p = 0.007). Furthermore, the effect was greater for those with higher ARB dosage. A similar finding was not observed with ACEI use. For disease-specific survival, both ARB and ACEI use had a significant protective effect (adjusted HR 0.75, 95% CI 0.62-0.90 p = 0.002 and adjusted HR 0.76, 95% CI 0.63-0.93, P = 0.007, respectively).

Conclusions: Our study adds to the evidence that ARB use might have a beneficial impact on survival among GC patients.