Gastric Cancer最新文献

Peritoneal metastasis (PM) is a major challenge in advanced gastric cancer (GC) with poor prognosis. Normothermic intraperitoneal and systemic treatment (NIPS) has become a promising therapeutic approach. This consensus aims to provide practical recommendations for NIPS treatment for gastric cancer with peritoneal metastasis (GCPM). The GRADE standards were used to rank evidence, and the Delphi method was employed for expert voting. 30 experts from China, Japan, South Korea, and Singapore participated in the development of this consensus. 28 experts participated in the voting process, which produced 29 statements covering diagnostic approaches, patient selection criteria, treatment regimens, management of intraperitoneal port placement, and conversion surgery considerations, and post-surgical treatment strategies in NIPS therapy. Based on current evidence and expert experience, these statements aim to improve the clinical outcomes of NIPS therapy for GCPM patients.

Background: In 2021, anamorelin, a ghrelin receptor agonist, was approved in Japan for cancer cachexia in select cancers, including gastric cancer. However, evidence regarding its efficacy and predictive factors in patients with gastric cancer remains lacking.

Methods: This prospective observational study encompassed 229 patients with unresectable, advanced, or recurrent gastric cancer and cancer cachexia who received anamorelin from 2021 to 2023 at 25 institutions affiliated with Osaka University. Body weight change at 12 weeks was the primary endpoint. Appetite, food intake, treatment compliance, and adverse events comprised the secondary endpoints. Multivariable logistic regression analyses were employed for identifying weight gain predictors.

Results: Of the 229 patients (median age, 73 years), 126 completed the 12-week follow-up. The median anamorelin administration duration was 62 days. The mean weight significantly increased from baseline to 4, 8, and 12 weeks (up to + 0.88 kg, p < 0.001). Moreover, appetite and food intake improved. Multivariable analysis identified baseline body mass index (BMI) < 20 kg/m² and neutrophil-to-lymphocyte ratio (NLR) < 4.0 as independent predictors of significant weight gain at 12 weeks. Treatment was generally well tolerated, with a 41% completion rate; 59% of the participants discontinued mainly owing to disease progression.

Conclusion: In patients with gastric cancer-related cachexia, anamorelin was associated with significant increases in body weight and improvements in appetite. Lower BMI and lower systemic inflammation (NLR < 4.0) were predictive of better response.

Background: TFF2 is a promising yet underexplored biomarker for gastric cancer. We aimed to investigate the relationship between serum TFF2 and gastric cancer, including early gastric cancer, and its interactions with other factors.

Methods: A cross-sectional, population-based study was conducted involving 3986 participants from Wuwei Cohort. The serum levels of TFF2, TFF1, TFF3, PG I, PG II, and Hp IgG were measured. Logistic regression and restricted cubic splines assessed associations and dose-response relationships.

Results: Gastric cancer prevalence rose across serum TFF2 tertiles, from 1.6 to 5.0% (p for trend < 0.001). TFF2 demonstrated the strongest association with gastric cancer, with participants in the highest tertile showing over a fourfold increased risk (OR 4.02, 95% CI 2.25-7.19, p < 0.001) after adjusting for traditional risk factors and other biomarkers. The association remained robust for early gastric cancer, exhibiting over a threefold risk (OR 3.31, 95% CI 1.80-6.08, p < 0.001). RCS analyses confirmed dose-response relationships (p for non-linearity < 0.05). The joint analyses showed that participants in the highest tertiles of both TFF1 and TFF2, or in the lowest tertile of TFF1 and highest tertile of TFF2, had at least an eightfold increased risk of gastric cancer and early gastric cancer compared to those with both biomarkers in the lowest tertile.

Conclusion: Serum TFF2 is a more reliable biomarker for gastric cancer, including early gastric cancer, in the general population. Its strong dose-response association with gastric cancer outcomes and the synergistic effects with TFF1 highlight its potential to improve risk prediction and guide future research.

Background: Since the FLOT4 gastric cancer (GC) trial, the use of adjuvant chemotherapy has been perceived as limited and its added value questioned. We wanted to objectify this perception and reassess the value of adjuvant chemotherapy in a real-world setting.

Methods: In our retrospective cohort study we analyzed real-world data from 147 patients with GC or cancer of the gastroesophageal junction (AEG) who received perioperative FLOT. Data originated from clinical care at the university hospital, local hospitals and medical practices. Clinicopathologic data, survival outcomes, and targetable biomarkers were analyzed.

Results: Median overall survival (OS) and tumor specific survival (TSS) were 19.4 ± 2.9 and 19.9 ± 3.1 months, respectively. 84.4% completed all cycles of neoadjuvant chemotherapy. The pathological complete response rate was 11.8%. Adjuvant chemotherapy was initiated in only 42.9%. Survival rates of patients with marked tumor regression (TRG1) were not improved by adjuvant chemotherapy. Conversely, patients with partial histopathologic response (TRG2) showed a marked trend and those with minimal histopathologic response (TRG3) showed a significantly longer survival with any number of adjuvant chemotherapy cycles (OS: 22.3 ± 2.6 months versus 8.7 ± 2.4 months, p = 0.005; TSS: 22.3 ± 4.5 months versus 8.7 ± 2.4 months, p = 0.016). Targetable biomarkers PD-L1, Claudin 18.2, HER2 and microsatellite instability were detected in 53.4%, 26.2%, 7.8%, and 3.9% of the TRG2/3 patient subset, respectively.

Conclusions: In the real-world setting, adjuvant chemotherapy proved to be a critical turning point of the FLOT regimen. It should be sought-even in a reduced form-in patients with TRG2/3.

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.