Gastric Cancer最新文献

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.

This review provides a comprehensive analysis of phase-specific management strategies for type 2 diabetes (T2D) in patients undergoing gastric cancer (GC) surgery, encompassing the preoperative, intraoperative and postoperative phases within the context of oncodiabetology. In the preoperative phase, predicting T2D remission and evaluating antidiabetic medications while considering their adverse event profiles are important. These medications include metformin and sodium-glucose cotransporter 2 inhibitors, which may help prevent both T2D progression and GC advancement. Regarding surgical approaches, Roux-en-Y reconstructions are associated with better T2D remission rates than Billroth I/II reconstructions, likely because of enhanced glucose metabolism. The considerable effects of gastrectomy and reconstruction on glucose levels have led to the development of a new surgical approach, known as oncometabolic surgery. This approach integrates oncologic treatment with metabolic benefits and has gained attention as a promising strategy for managing T2D in patients undergoing GC surgery. In the postoperative phase, glucose monitoring, individualized medication adjustments, weight management, and patient education are essential for maintaining remission and preventing relapse. A comprehensive, stage-specific approach to glycemic care is crucial for improving both metabolic and oncologic outcomes in patients with GC.

Background: Despite significant advancements in cancer treatment, gastric cancer (GC) continues to have a high incidence and mortality rate. Antibody-drug conjugates (ADCs) are emerging as a viable treatment option for GC. Glypican-1 (GPC1), a cell surface proteoglycan, has garnered interest for its role in tumor growth and its potential as a biomarker. This study evaluated the efficacy of an ADC comprising a humanized anti-GPC1 monoclonal antibody conjugated with monomethyl auristatin E (GPC1-ADC) to target GPC1 in GC.

Methods: GPC1 expression was assessed in GC cell lines and tissues. The cytotoxic efficacy and mechanism of action of GPC1-ADC were evaluated through comprehensive in vitro assays. In vivo efficacy was further assessed in xenograft mouse models, focusing on tumor growth inhibition and its performance against peritoneal dissemination.

Results: In vitro, GPC1-ADC exhibited significant cytotoxicity against GPC1-positive cell lines by inducing cell cycle arrest and apoptosis. Additionally, GPC1-ADC demonstrated promising bystander-killing activity via cancer-associated fibroblasts, highlighting its potential to target the heterogeneous tumor microenvironment characteristic of GC. In vivo, GPC1-ADC significantly inhibited tumor growth and demonstrated substantial therapeutic effects in a peritoneal dissemination model. Immunohistochemical analysis of tumor specimens from GC patients revealed that 90.2% of differentiated types and 66.7% of poorly differentiated types exhibited high GPC1 expression. High GPC1 expression in tumor samples was significantly associated with poorer progression-free and overall survival.

Conclusions: Our findings suggest that GPC1-targeting ADCs represent a promising therapeutic option for GPC1-positive GC.

Background: The purpose of this study was to examine the eligibility criteria in phase 3 randomized controlled trials (RCTs) in gastric cancer.

Methods: The analysis included 207 RCTs of systemic treatments, started between 2009 and 2024, and registered at the WHO International Clinical Trials Registry Platform (ICTRP).

Results: 93 (44.9%) trials had an upper age limit of 85 years of age or lower (coprimary outcome). In multivariable analysis, these limits were less likely in RCTs with the sites located in North America (adjusted odds ratio [aOR], 0.06; 95% confidence interval [CI] 0.01-0.26; p < 0.001). Only 3 (1.4%) trials were specifically dedicated to older patients. 138 (66.7%) trials excluded patients with Eastern Cooperative Oncology Group (ECOG) score > 1 (coprimary outcome); these criteria were more likely in more recent trials (aOR, 4.49; 95% CI 2.11-9.94; p < 0.001). However, the odds of excluding individuals with ECOG score > 1 were not significantly associated with any type of the investigational treatment including chemotherapy (p > 0.05). Moreover, many trials excluded patients with brain metastases (n = 91; 44%) and those with comorbidities, most frequently liver disorders (n = 170; 82.1%). None of the RCTs excluded patients based on frailty.

Conclusions: The eligibility criteria in phase 3 RCTs in gastric cancer are fairly strict. Recommendations presented in this article will allow the investigators to improve the enrollment of some clinically relevant populations of patients, especially older persons, individuals with inadequate performance status, and those with comorbidities, without substantially compromising the safety of trials participants.