Gastric Cancer最新文献

Background: Positive peritoneal cytology (CY1) is classified as stage IV gastric cancer and typically treated with systemic chemotherapy. However, upfront surgery is sometimes performed when CY1 is identified intraoperatively or postoperatively and may improve long-term survival when followed by adjuvant chemotherapy. It remains unclear which patients benefit most from this approach. This study aimed to identify patient subgroups likely to achieve long-term survival with upfront surgery followed by adjuvant chemotherapy.

Methods: We retrospectively analyzed patients diagnosed with P0CY1 who underwent upfront surgery between 2008 and 2020. Prognostic factors for overall survival (OS) and progression-free survival were evaluated using univariate and multivariate analyses.

Results: A total of 147 patients were included; 65% were male, with a median age of 72 years. Macroscopic types 3 and 4 were present in 80% of patients, 91% had pathological T4 tumors, and 63% had lymph node metastasis. Total gastrectomy was performed in 54%, and 81% received adjuvant chemotherapy. Median OS was 27.0 months. Univariate analysis showed age, macroscopic type, tumor size, and adjuvant chemotherapy were significantly associated with OS. Multivariate analysis identified adjuvant chemotherapy tumor size  ≥  80 mm, and macroscopic types 1 and 2 as independent favorable prognostic factors. Among patients receiving adjuvant chemotherapy, those with macroscopic types 1 and 2 had significantly better OS (5-year OS rate: 46%) compared to types 3 and 4.

Conclusions: In P0CY1 gastric cancer, upfront surgery followed by adjuvant chemotherapy may result in long-term survival, particularly in patients with macroscopic types 1 and 2.

Gastric cancer remains a major clinical challenge owing to its insidious onset and marked heterogeneity, which contribute to poor prognosis and limit the effectiveness of chemotherapy‑based systemic therapy. Antibody‑drug conjugates (ADCs) deliver potent cytotoxins to tumor cells with antigen specificity and have emerged as a therapeutic class that can enhance efficacy while reducing off‑target toxicity. Recent trials of ADCs targeting HER2, CLDN18.2, TROP2, CEACAM5/6, and HER3 demonstrate substantial therapeutic activity. Notably, the HER2‑directed agents trastuzumab deruxtecan and disitamab vedotin have improved survival and response in previously treated advanced disease. ADCs targeting CLDN18.2 and TROP2 have also yielded encouraging early results. Accumulating evidence from ongoing programs indicates movement into earlier lines of therapy in advanced gastric cancer, including evaluation in first‑line combination regimens. Broader clinical use has highlighted resistance mechanisms, including antigen loss or heterogeneity, impaired internalization and lysosomal processing, increased drug efflux, and an immunosuppressive tumor microenvironment that limits delivery. This review synthesizes clinical advances in ADC therapy for gastric cancer, delineates resistance biology, and evaluates strategies to overcome therapeutic resistance. Deeper mechanistic insight, biomarker‑guided patient selection, and continued innovation in targets, linkers, payloads, and rational combinations will be critical to overcome resistance and improve outcomes for patients with gastric cancer.

Background: A fibrotic tumor microenvironment (TME) promotes tumor progression by the interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the extracellular matrix (ECM), which enhance tumor cell survival and growth, and by suppressing antitumor immunity. However, how characteristic gene expression and amplification in cancer cells drive the formation of a fibrotic TME in patients with gastric cancer (GC) is unclear.

Methods: We performed genomic and transcriptomic analyses via datasets from The Cancer Genome Atlas and the Asian Cancer Research Group to identify amplified and overexpressed genes associated with the presence of a fibrotic TME in tumors. Syngeneic mouse models of GC and multiplexed immunohistochemistry (IHC) were used to validate the findings of the transcriptomic analysis and investigate the underlying mechanisms.

Results: The Frizzled class receptor 1 (FZD1) gene was frequently amplified and highly expressed in GC patients with fibrotic tumors, and FZD1 expression was related to a poor prognosis. The overexpression of Fzd1 in murine GC tumor cells was significantly associated with enhanced tumor fibrosis and growth and reduced infiltration of CD3⁺ lymphocytes and CD8⁺ T cells into tumors. SLIT2 secretion was increased in Fzd1-overexpressing tumor cells via the canonical WNT-β-catenin pathway, and SLIT2 activated CAFs to produce more ECM through the SLIT2‒ROBO1 axis.

Conclusions: This study highlights the potential of FZD1 as a biomarker for predicting fibrotic status in patients with GC and the SLIT2‒ROBO1 axis as a therapeutic target to reverse a fibrotic and immunosuppressive TME.

Background: Leptomeningeal carcinomatosis (LMC) from gastric cancer is rare but carries a poor prognosis, and its risk factors and clinical presentation remain unclear.

Methods: Among 3850 patients treated with palliative chemotherapy, those with pathologically or cytologically confirmed LMC were included. Responsiveness to intrathecal methotrexate (IT-MTX) was defined as a malignant cell count < 1/μL on ≥ 2 consecutive cerebrospinal fluid analyses. Survival outcomes were compared across subgroups with different clinical presentations.

Results: During a median follow-up of 13.7 months, LMC was diagnosed in 0.8% (32/3850) of patients. At the time of LMC diagnosis, 27 patients were undergoing palliative systemic chemotherapy, 4 were diagnosed with recurrence following curative surgery, and 1 was diagnosed with the initial presentation of metastatic gastric cancer. Multivariate logistic regression analysis revealed that signet ring cell carcinoma (SRC) and/or poorly differentiated adenocarcinoma (PD) was the most relevant risk factor for LMC (adjusted odds ratio 4.78; p = 0.036). Thirty patients received IT-MTX, with responders (n = 23) showing longer overall survival (OS) than non-responders (n = 7) (p = 0.004). Among the 29 patients with available data on extracranial disease control, those with controlled extracranial disease at LMC diagnosis (n = 19) demonstrated significantly better OS following IT-MTX than those with progressive extracranial disease (n = 10) (p = 0.023).

Conclusions: SRC and/or PD is a key risk factor for LMC, which often arises despite controlled extracranial disease, necessitating early evaluation for neurologic symptoms. Survival outcomes depend on IT-MTX response and the status of extracranial disease.

Background: This study assessed the impact of an institutional certification system that was newly introduced by the Japanese Gastric Cancer Association on short-term surgical outcomes in patients with gastric cancer using data from the National Clinical Database.

Methods: A retrospective cohort study of distal gastrectomy and total gastrectomy procedures performed between January 2020 and December 2022 was conducted. The institutions were classified into three categories: type A, type B, and non-certified institutions, in decreasing order of certification stringency. The primary outcome was the incidence of grade ≥ IIIa postoperative complications based on the Clavien-Dindo classification system. The secondary outcome was surgery-related mortality. Logistic regression with risk adjustment, estimated using generalized estimating equations, was used to account for intra-cluster correlation.

Results: There was no significant difference in the risks of distal gastrectomy-related complications across the three institution types. However, type A- (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.31-0.49) and type B-certified institutions (OR 0.59, 95% CI 0.49-0.71) had a significantly lower mortality risk than non-certified ones. On the other hand, Type A- (OR 1.25, 95% CI 1.09-1.44) and type B-certified institutions (OR 1.17, 95% CI 1.03-1.33) had higher risks of postoperative total gastrectomy-related complications than non-certified ones. Nevertheless, type A- (OR 0.41, 95% CI 0.29-0.58) and type B-certified institutions (OR 0.67, 95% CI 0.51-0.88) had significantly lower surgery-related mortality risks than non-certified ones.

Conclusions: Certified institutions demonstrated lower surgical mortality risks, highlighting the benefits of the certification system and the importance of institutional quality.

Background: Extrachromosomal DNA (ecDNA), a form of circular DNA located outside chromosomes, is a common driver of oncogene amplification. Recent pan-cancer studies have associated ecDNA with cancer progression and poor prognosis. Moreover, its relationship with specific genomic features is becoming increasingly evident. However, the clinicopathological characteristics and underlying genomic mechanisms of ecDNA in gastric cancer remain poorly understood.

Methods: We analyzed whole-genome sequencing data from 81 Japanese gastric cancer samples to identify ecDNA using AmpliconArchitect and AmpliconClassifier. Gene expression profiles were obtained through whole-transcriptome RNA sequencing (RNA-seq).

Results: We found that the frequency of ecDNA occurrence was comparable across cancer stages and had a modest impact on prognosis, suggesting that ecDNA is present in early-stage disease and has a limited role in gastric cancer progression. Several immunomodulatory genes were amplified on ecDNA, and the presence of ecDNA harboring these genes was associated with the suppression of cytotoxic T cell responses, indicating a functional link between ecDNA and immune evasion. ecDNA-positive cases more frequently harbored TP53 mutations and were microsatellite stable compared to ecDNA-negative cases. Finally, ecDNA-positive tumors exhibited a high prevalence of single-base substitution signature 17, implicating that oxidative stress, potentially induced by gastric acid, plays a role in the generation of ecDNA in gastric cancer.

Conclusions: These findings provide insights into the clinicogenomic features of ecDNA in gastric cancer and highlight its potential impact on disease progression and immune modulation.

Objective: To develop and validate a nomogram for predicting lymph node metastasis in early gastric cancer according to the characteristics of the tumor microenvironment to optimize treatment strategies.

Methods: Clinicopathological data of 882 early gastric cancer patients from three medical centers were retrospectively collected. Among them, 744 cases from Center 1 were assigned to the training set, and 138 cases from Centers 2 and 3 were the validation set. Tumor-infiltrating lymphocytes (TILs) and tumor-stroma ratio (TSR) were quantified in hematoxylin-eosin stained sections using QuPath software. The number and maturity of tertiary lymphoid structures (TLS) were evaluated through multiplex immunofluorescence. Nomogram prediction models were constructed using independent risk factors identified by univariate and multivariate logistic regression analyses. The performance of the model was evaluated by receiver operating characteristics (ROC) curve, calibration curve, and clinical decision curve analyses.

Results: Lymph node metastasis rates were 19.2% in the training set and 23.9% in the validation set; sex, lymphovascular invasion, TSR, and TLS were identified as independent risk factors. The model achieved an area under the ROC curve of 0.807 [95% confidence interval (CI) 0.766-0.843] in the training set and 0.822 (95% CI 0.721-0.907) in the validation set. The calibration curves indicated good agreement between predicted probabilities and actual incidence rates, and the clinical decision curve analysis revealed a positive clinical net benefit over a broad range of thresholds.

Conclusion: The nomogram developed in this study showed high accuracy, stability, and clinical utility, suggesting its value for guiding treatment decision-making in early gastric cancer.