Gastric Cancer最新文献

Background: Gastric cancer (GC) presents challenges in predicting treatment responses due to its patient-specific heterogeneity. Recently, liquid biopsies have emerged as a valuable data modality, offering essential cellular and molecular insights while facilitating the capture of time-sensitive information. This study aimed to leverage artificial intelligence (AI) technology to analyze longitudinal liquid biopsy data.

Methods: We collected a dataset from longitudinal liquid biopsies of 91 patients at Peking Cancer Hospital, spanning from July 2019 to April 2022. This dataset included 1895 tumor-related cellular images and 1698 tumor marker indices. Subsequently, we introduced the Dynamic-Aware Model (DAM) to predict responses to GC treatment. DAM incorporates dynamic data through AI-engineered components, facilitating an in-depth longitudinal analysis.

Results: Utilizing threefold cross-validation, DAM exhibited superior performance compared to traditional cell-counting methods, achieving an AUC of 0.807 in predicting GC treatment responses. In the test set, DAM maintained stable efficacy with an AUC of 0.802. Besides, DAM showed the capability to accurately predict treatment responses based on early treatment data. Moreover, DAM's visual analysis of attention mechanisms identified six dynamic visual features related to focus areas, which were strongly associated with treatment-response.

Conclusions: These findings represent a pioneering effort in applying AI technology to interpret longitudinal liquid biopsy data and employ visual analytics in GC. This approach provides a promising pathway toward precise response prediction and personalized treatment strategies for patients with GC.

Background: Immune checkpoint inhibitors (ICIs) are becoming more prominent in the treatment of gastric cancer (GC). However, predictive biomarkers of response to ICIs in HER2-negative patients remain incompletely understood.

Methods: A total of 47 patients diagnosed with HER2-negative advanced GC who underwent ICI regimens were eligible for this study. Plasma samples with paired white blood cells prior to treatments were collected from these 47 patients. Variations of circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing followed by its significance analysis.

Results: A total of 658 somatic mutations involving 203 genes were identified in all ctDNA. Mutations in MEN1, MLH1, CEBPA, ATR, GNAQ, and FOXL2 genes were more frequent in responders (P < 0.05). Compared with wild-type patients, patients with CEBPA or IRS2 mutations had prolonged median progression-free survival (mPFS, P = 0.0056). Patients with co-occurring mutations in IRS2/CEBPA, IRS2/POLD1, TP53/PIK3CA, or POLD1/CEBPA had longer mPFS compared with others (P = 0.003; 0.006; 0.0166; 0.0315; respectively). Both alteration of CDKN2A alone and co-mutations with MSH6 were significantly associated with superior overall survival (OS, P = 0.0289; 0.0355; respectively). In addition, higher on-treatment ctDNA concentration or variant allele frequency (VAF) were associated with poorer response (P < 0.05). Additionally, the increased molecular alterations of POLE, FGFR2 and MDC1 seemed to indicate the acquired resistance to ICIs.

Conclusions: Variation signatures captured by ctDNA as well as the kinetics of ctDNA could predict the clinical benefits of ICB in HER2-negative GC patients, which was worth further validated in large cohort.

Background: Gastric cancer with peritoneal metastasis is associated with a poor prognosis. Current treatments, including the first-line therapy of combination chemotherapy with nivolumab for advanced recurrent gastric cancer, have shown limited efficacy against peritoneal dissemination. In this study, we evaluated neoantigen (neoAg)-mRNA lipid nanoparticle (LNP) as a potential agent in combination with anti-PD-1 therapy, focusing on its effects on neoAg-specific CD8⁺ T cell responses and antitumor efficacy in a murine gastric cancer model.

Methods: The mRNA, comprising a tandem minigene encoding three neoAgs identified from the murine gastric cancer YTN16 cell line, was synthesized by in vitro transcription and encapsulated within LNPs. NeoAg-specific CD8⁺ T cells in the spleens and tumors were assessed by flow cytometry. The antitumor efficacy of the neoAg-mRNA-LNP vaccine, alone or in combination with anti-PD-1 antibody, was evaluated in both subcutaneous and peritoneal metastasis models of YTN16.

Results: The neoAg-mRNA-LNP vaccine induced significantly higher frequencies of neoAg-specific CD8⁺ T cells than the neoAg-dendritic cell vaccine, confirming its enhanced immunogenicity. NeoAg-mRNA-LNP vaccination led to robust tumor regression, achieving complete eradication in all treated mice, especially when combined with anti-PD-1 therapy. This effect was associated with an increase in neoAg-specific progenitor-exhausted and intermediate-exhausted CD8⁺ T cells. In a peritoneal metastasis model, neoAg-mRNA-LNP monotherapy prevented peritoneal dissemination when administered prophylactically, and combination therapy with anti-PD-1 effectively suppressed tumor growth in a therapeutic setting.

Conclusions: NeoAg-mRNA-LNP vaccines elicit potent neoAg-specific CD8⁺ T cell responses and show enhanced antitumor efficacy with anti-PD-1 therapy in gastric cancer with peritoneal metastasis.

Background: Excessive surgical stress induces inflammatory cytokine release, negatively impacting prognosis in patients with malignancies. This study aimed to determine whether the anti-inflammatory effect of a corticosteroid (CS) would improve prognosis when administered intraoperatively to patients with resectable gastric cancer.

Methods: In this multicenter, randomized, open-label, phase II/III study, patients with cStage II-III gastric cancer were randomized to CS administration or non-administration (control) groups. Patients in the CS group received 5 mg/kg of methylprednisolone just before the skin incision during surgery. The primary endpoints were the highest postoperative serum level of C-reactive protein (CRP_max) in the phase II portion, and recurrence-free survival (RFS) in the phase III portion.

Results: Between December 2016 and February 2019, 410 patients were enrolled. In the phase II portion, CRP_max was significantly lower in the CS group than in the control group (mean, 10.7 vs 14.3 mg/dL, respectively; P = 0.009). In the phase III portion, 3-year RFS rates in the CS (n = 202) and control (n = 204) groups were 67.2% and 63.0%, respectively, indicating no significant difference (hazard ratio, 0.807 [95% confidence interval, 0.590-1.105]; log-rank P = 0.182). Subgroup analysis showed that both histological type and clinical stage had significant interactions with RFS, suggesting a potential survival benefit of CS administration in patients with differentiated histological-type or cStage III gastric cancer.

Conclusions: Intraoperative CS administration mitigated postoperative CRP elevation but did not result in significantly improved survival in patients with cStage II-III gastric cancer. The study is registered with UMIN-CTR, number UMIN000024465.

Background: Nivolumab plus chemotherapy has shown efficacy in clinical trials for advanced or recurrent gastric cancer (GC). However, real-world utilization data are limited. In this study, we aimed to assess the effectiveness, safety, and treatment status of first line nivolumab plus chemotherapy in Japanese patients with treatment-naïve advanced or recurrent GC.

Methods: Untreated patients with advanced or recurrent GC who initiated nivolumab plus chemotherapy as first line treatment from November 2021 to June 2023 across 23 Japanese sites were enrolled in this observational study (G-KNIGHT). This report focused on the objective response rate (ORR), real-world progression-free survival (rwPFS), and the treatment-related adverse event (TRAE) incidence. Furthermore, subgroup analyses for ORR and rwPFS were conducted for patients stratified by various factors including age and the programmed cell death ligand 1 (PD-L1) combined positive score (CPS).

Results: Among 527 patients (median age, 70.3 years; 25.2% aged ≥ 75 years; 65.5% male; 84.3% with advanced GC), the median follow-up period was 10.4 (interquartile range, 6.7-15.2) months. The ORR was 65.6% (95% confidence interval [CI], 59.9-70.9%). The median rwPFS (months, 95% CI) was 6.9 (6.2-7.6); by subgroups: age < 75 years, 6.7 (6.0-7.5); age ≥ 75 years, 7.4 (6.2-8.6); PD-L1 CPS < 1, 7.5 (6.5-9.0); CPS 1-5, 6.2 (5.5-8.0); and CPS ≥ 5, 7.0 (6.2-8.2). TRAEs occurred in 91.3% of patients, with 40.4% experiencing grade ≥ 3 events.

Conclusions: This large-scale real-world study supports the effectiveness and safety of nivolumab plus chemotherapy in untreated Japanese patients with advanced or recurrent GC.

Background: Gastrointestinal stromal tumors (GISTs) are commonly driven by primary mutations in KIT or PDGFRA. Imatinib is the first-line therapy for GISTs. However, secondary mutations frequently emerge during imatinib treatment, contributing to resistance and influencing the efficacy of subsequent tyrosine kinase inhibitors, such as sunitinib and regorafenib. This study aimed to investigate the clinical relevance of both primary and secondary KIT mutations in treating and prognosing unresectable or recurrent GISTs.

Methods: Ninety patients with unresectable or recurrent GISTs treated at our institution between 2000 and 2017 were retrospectively analyzed. Genetic testing was performed before the initial drug administration to guide first-line imatinib therapy based on the primary mutation profile. In 64 imatinib-resistant patients, additional genetic testing was conducted on tissues obtained from resistant lesions. Treatment response and prognosis were compared across mutational profiles.

Results: The most common primary mutation was KIT exon 11 (76.7%), followed by exon 9 (12.2%). Patients with exon 9 mutations showed superior progression-free survival with sunitinib than those with exon 11 mutations. Among patients with exon 11 primary mutations, secondary mutations were identified in 79.2%, predominantly in KIT exon 13/14 (47.9%) or 17/18 (31.3%). Sunitinib was more effective in patients with secondary exon 13/14 mutations, whereas regorafenib was significantly more effective in those with exon 17/18 mutations.

Conclusions: Secondary KIT mutations play a crucial role in imatinib resistance and the efficacy of second- and third-line therapies. Genetic profiling at the initial diagnosis and at the time of resistance may provide more personalized and effective treatment strategies.

Background: Our Kaplan-Meier analysis reveals that gastric cancer patients with high androgen receptor (AR) expression demonstrate poorer survival outcomes compared to those with low AR expression, particularly in patients with characteristics typical of EBV-positive gastric cancer. However, the molecular mechanisms driving this seemingly contradictory relationship have remained poorly understood, as our experimental findings suggest AR signaling actually suppresses tumor growth in EBVaGC.

Methods: The study utilized AR-positive EBV-infected gastric cancer cell lines treated with dihydrotestosterone (DHT) to investigate molecular pathways. Comprehensive analyses included examination of apoptosis, miRNA expression, signaling pathways, DNA methylation patterns, and viral gene expression. In vivo validation was performed using xenograft models with MKN1-EBV and SNU719 cells to assess tumor growth and immune response.

Results: DHT treatment triggered early apoptosis through upregulation of pro-apoptotic miRNAs, particularly miR-204-5p, while activating the PI3K-Akt pathway and enhancing DNA damage response through increased phosphorylation of key proteins. The treatment reduced DNMT3A expression, leading to genome-wide DNA demethylation and increased expression of both lytic (BZLF1) and latent (EBNA1, LMP1) EBV genes. Xenograft studies confirmed these findings, showing reduced tumor growth, increased lymphocyte infiltration, and enhanced viral gene expression specifically in AR-positive tumors.

Conclusion: The study reveals that AR signaling suppresses EBV-positive gastric cancer by modulating both cellular apoptosis and EBV reactivation through epigenetic mechanisms. These findings suggest that AR agonists might have therapeutic potential in treating AR-positive EBV-associated gastric cancer.

Background: Gastric neuroendocrine carcinoma (NEC) is a rare and aggressive malignancy for which no standard treatment has been established for locoregional disease. This multicenter retrospective study aimed to evaluate the prognostic relevance and therapeutic efficacy of lymph node dissection in this setting.

Methods: A total of 118 patients with gastric NEC or mixed adenoneuroendocrine carcinoma (MANEC) who underwent gastrectomy with lymph node dissection were analyzed. Survival outcomes, clinicopathological factors, and the therapeutic value index of each lymph node station were assessed. Lymph node involvement was classified using both the pathological N category and the extent of nodal involvement based on the dissection area (pND).

Results: The 5-year overall survival and 3-year recurrence-free survival rates were 56.7% and 63.4%, respectively. Prognostic stratification using pND provided clearer separation than using the conventional pN category. Multivariate analysis identified older age, female sex, and pND2 (metastasis to D2 area nodes) as independent unfavorable prognostic factors. The therapeutic value index for lymph nodes in the D1 area was high (35.0, based on 5-year overall survival), whereas the index for D2 nodes was markedly lower (6.8). Notably, these indices remained consistent across histological subtypes, showing similar values between NEC and MANEC. Postoperative chemotherapy and surgical complications did not significantly affect survival outcomes.

Conclusions: Perigastric (D1) lymph node dissection appears to provide meaningful survival benefit in locoregional gastric NEC, whereas the additional value of D2 dissection is limited. These findings support consideration of a more selective surgical approach, though further validation is needed.

Background: Boron neutron capture therapy selectively delivers the boron isotope ¹⁰B to tumors, where neutron irradiation induces a nuclear reaction that generates particle radiation, eradicating cancer cells. Imatinib and other drug therapies remain standard treatments for recurrent and unresectable gastrointestinal stromal tumors; however, their efficacy is limited by drug resistance. Therefore, developing novel therapeutic strategies for unresectable gastrointestinal stromal tumors is essential. This study aimed to investigate the therapeutic potential of boron neutron capture therapy for recurrent and unresectable gastrointestinal stromal tumors.

Methods: The GIST-T1 cell line and its imatinib-resistant variant (GIST-T1/IM-R) were utilized to assess boronophenylalanine uptake and evaluate boron neutron capture therapy efficacy in both in vitro and in vivo models.

Results: Boronophenylalanine was substantially incorporated into GIST-T1 and GIST-T1/IM-R cells. Boron neutron capture therapy significantly reduced survival fractions in both cell lines compared to neutron irradiation alone. In the GIST-T1 mouse model, high boronophenylalanine uptake was observed 3 h post-administration, resulting in significant tumor growth suppression following boron neutron capture therapy. Elevated expression of cleaved PARP, Caspase-3, Caspase-8, and γH2AX significantly increased in GIST-T1 tumors post-boron neutron capture therapy.

Conclusions: The results indicate that boron neutron capture therapy suppresses tumor growth by inducing extrinsic apoptosis through severe DNA damage. This study suggests that boron neutron capture therapy is a promising alternative treatment for gastrointestinal stromal tumors, particularly for cases exhibiting resistance to conventional therapies.

Background: Gastric cancer (GC) exhibits high mortality and poor prognosis, with ferroptosis playing a critical role in its progression. More recent research suggests that PROM2 are closely associated with MVBs (Multivesicular Bodies) which is essential to ferroptosis, and may represent key molecules involved in the resistance of tumor cells to ferroptosis.

Methods: The study employed RSL3-induced ferroptosis models to analyze mitochondrial damage, ROS accumulation, and iron dysregulation. PROM2 expression was assessed under varying RSL3 concentrations and durations. Co-immunoprecipitation and structural modeling elucidated the CRM1-PROM2 interaction. Clinical correlations were evaluated using GC tissue samples. In vivo animal experiments tested the effects of PROM2 and CRM1 inhibition on tumor growth.

Results: RSL3 inhibits cell proliferation and induces ferroptosis in GC cells, concomitant with increased PROM2 expression. PROM2 Knockdown potentiates ferroptosis sensitivity and augments RSL3-induced cell death. Clinically, elevated PROM2 correlates with poor prognosis in GC patients. In vivo, PROM2 inhibition suppresses xenograft tumor growth and enhances ferroptosis susceptibility. Mechanistically, PROM2 interacts with CRM1 whose inhibition by LMB (Leptomycin B) impairs cell proliferation and promotes ferroptosis. Nucleocytoplasmic translocation of PROM2 is CRM1-dependent, and CRM1 expression positively correlates with PROM2 in GC tissues. CRM1 depletion synergizes with RSL3 to suppress tumor growth in xenograft models.

Conclusions: These findings delineate a CRM1-PROM2 signaling axis that governs ferroptosis sensitivity in GC, wherein CRM1-mediated nuclear export of PROM2 during ferroptosis represents a critical regulatory node. Targeting this axis may offer novel diagnostic and therapeutic strategies for GC and other malignancies.