Gastric Cancer最新文献

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: Leptomeningeal carcinomatosis (LMC) is a rare but highly lethal manifestation of gastric cancer. We sought to describe its clinical features and define prognostic factors in a large single-center cohort.

Methods: We retrospectively reviewed 86 patients diagnosed with LMC secondary to gastric cancer at Samsung Medical Center between 2008 and 2024.

Results: The median interval from primary gastric cancer diagnosis to LMC development was 12.0 months (range, 0-106). Common presenting symptoms included headache (73.3%), nausea/vomiting (55.8%), and dizziness (48.8%). Primary gastric cancers were predominantly Borrmann type III (48.2%) or type IV (38.8%) and had an undifferentiated-type (96.5%) histology. Intrathecal (IT) methotrexate-based chemotherapy was administered to 54 patients (62.8%), with or without radiotherapy or systemic chemotherapy. Cytological response was seen in 14/54 patients (25.9%) who received IT chemotherapy. Decompressive therapies, including Ommaya reservoir, external ventricular drainage (EVD) and ventriculoperitoneal (VP) shunt were performed in 71/86 patients (82.6%). The median overall survival from LMC diagnosis was 6.0 weeks (95% confidence interval [CI]: 3.7-8.3). In multivariable analysis, age ≥ 60 years (HR 1.8) and ECOG PS > 2 (HR 2.8) were independent adverse prognostic factors. Univariable subgroup analyses demonstrated prolonged survival with intrathecal chemotherapy (HR 0.5), systemic chemotherapy (HR 0.4), and decompressive procedures (HR 0.3), whereas radiotherapy showed no significant benefit.

Conclusions: The prognosis of gastric cancer patients with LMC remains extremely poor, and older age and poor performance status were independent adverse prognostic factors. As intrathecal chemotherapy, systemic chemotherapy, and decompressive therapies may improve survival, an individualized, multidisciplinary treatment approach is recommended.

Background: In late-line treatment for advanced gastric cancer (AGC), evidence supporting the use of irinotecan in older patients remains limited. We conducted a post-hoc age-subgroup analysis of the phase III RINDBeRG study, which randomized AGC patients previously treated with ramucirumab-based chemotherapy to receive ramucirumab plus irinotecan (RAM + IRI) or irinotecan alone (IRI).

Methods: Patients were classified as elderly (≥ 70 years; n = 83 [RAM + IRI], 80 [IRI]) or non-elderly (< 70 years; n = 117, 113). Efficacy outcomes-including overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)-and safety were compared. Prognostic factors for OS were explored via multivariable Cox regression.

Results: OS and PFS did not differ significantly between age groups. In the RAM + IRI group, median OS was 9.7 vs. 8.9 months (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.63-1.15), and PFS was 4.0 vs. 3.6 months (HR 0.84, CI 0.63-1.12). In the IRI group, OS was 8.5 months in both groups (HR 0.99, CI 0.7-1.34), and PFS was 3.1 vs. 2.2 months (HR 0.87, CI 0.65-1.17). ORRs were 20.5% vs. 14.5% (RAM + IRI) and 18.8% vs. 9.7% (IRI) in elderly vs. non-elderly patients. Grade ≥ 3 adverse events were comparable. Multivariable analysis identified ECOG PS 1, peritoneal metastasis, elevated LDH, modified Glasgow Prognostic Score ≥ 1, and low alkaline phosphatase as poor prognostic factors. Age was not prognostic.

Conclusions: Irinotecan-based therapy offers comparable efficacy and tolerability in older and younger patients with refractory AGC.

Peritoneal metastasis (PM) is a major contributor to poor prognosis in advanced gastric cancer (GC), yet its molecular mechanisms remain insufficiently understood. The results of bioinformatic analysis and clinical sample validation reveal that LncRNA MZF1-AS1 is significantly upregulated in GC tissues, particularly in peritoneal metastases, and is associated with worse overall and post-progression survival. MZF1-AS1 enhances malignant phenotypes and PM of GC cells in vitro and in vivo. Mechanistically, RAB13 is demonstrated as a functional effector of MZF1-AS1 via RNA-seq. MZF1-AS1 enhances RAB13 expression by promoting its mRNA stability, thereby facilitating GC cell proliferation, EMT, migration, invasion, and stemness. Further, RNA pulldown and Mass Spectrometry reveal that MZF1-AS1 directly binds to NSUN2. MZF1-AS1 strengthens the interaction between NSUN2 and RAB13 mRNA, promoting NSUN2-mediated m5C modification and stabilizing RAB13 mRNA. Our findings uncover a novel epi-transcriptomic mechanism by which MZF1-AS1 promotes GC progression via NSUN2-dependent m5C methylation of RAB13 mRNA, offering new insights into PM pathogenesis and highlighting potential therapeutic targets for advanced GC.

Valvuloplastic esophagogastrostomy by a double flap technique has promise for preventing reflux after proximal gastrectomy. However, a short esophageal remnant sometimes strongly complicates the transhiatal procedure for alimentary tract reconstruction. We therefore developed secure robotic techniques for right transthoracic esophagogastrostomy by a double flap technique. To accomplish valvuloplastic esophagogastrostomy by this double flap technique in the right thorax of patients in the prone position, the esophagus and stomach were partially fixed before rotating these two organs to expose the anterior gastric wall side for anastomosis because it was invisible in the right thorax. However, this rotation process was complicated. Doubting that the required anastomosis that was conventionally created in the layout of the ventral esophagus and dorsal stomach in valvuloplastic esophagogastrostomy by a double flap technique protected against reflux, we have considered that, if the anastomosis is created at the posterior gastric wall, it may not be necessary to rotate the remnant esophagus and stomach. We herein describe a modified robotic procedure for right transthoracic valvuloplastic esophagogastrostomy incorporating a double flap technique. In this procedure, the anastomosis is created at the posterior remnant gastric wall under a natural operative view without re-arranging the anastomotic organs. This modified technique simplifies right transthoracic valvuloplastic esophagogastrostomy by a double flap technique without adversely influencing anti-acid reflux mechanisms.