A Recombinant Human Adenovirus Type 5 (H101) Combined With Chemotherapy for Advanced Gastric Carcinoma: A Retrospective Cohort Study

BackgroundThis retrospective cohort study aimed to evaluate the clinical outcomes of H101 combined with chemotherapy for advanced gastric carcinoma (GC) patients.MethodsThe advanced GC patients, who were treated with H101 and/or chemotherapy, were enrolled and divided into three groups according to treatment method. The clinical characteristics of patients, clinical short-term and long-term outcomes, followed up, and complication were analyzed.ResultsA total of 95 patients (30 patients in group A were treated with H101, 33 in group B patients were treated with chemotherapy, 32 patients in group C were treated with H101 combined with chemotherapy) were retrospectively reviewed. The disease control rate (DCR) and overall response rate (ORR) were significantly greater in group C (81.3% and 50.0%) than in groups A (63.3% and 30.0%) and B (66.7% and 33.3%, all p < 0.05). The 1- and 2-year survival rates and progression-free survival were significantly greater in group C than in groups A and B (all p < 0.05). There was no significant difference in complication among the three groups. At dose levels of 0.5 × 1012 vp/day, 1.0 × 1012 vp/day, and 1.5 × 1012 vp/day, complications were not increased as increased of dose.ConclusionsH101 combined with chemotherapy may be a potential therapeutic option for patients with advanced GC, and prospective studies with proper assessment of toxicity will be needed in the future.

Development and validation of a prognostic scoring model for mortality risk stratification in patients with recurrent or metastatic gastric carcinoma

Background Survival times differ among patients with advanced gastric carcinoma. A precise and universal prognostic evaluation strategy has not yet been established. The current study aimed to construct a prognostic scoring model for mortality risk stratification in patients with advanced gastric carcinoma. Methods Patients with advanced gastric carcinoma from two hospitals (development and validation cohort) were included. Cox proportional hazards regression analysis was conducted to identify independent risk factors for survival. A prognostic nomogram model was developed using R statistics and validated both in bootstrap and external cohort. The concordance index and calibration curves were plotted to determine the discrimination and calibration of the model, respectively. The nomogram score and a simplified scoring system were developed to stratify patients in the two cohorts. Results Development and validation cohort was comprised of 401 and 214 gastric cancer patients, respectively. Mucinous or non-mucinous histology, ECOG score, bone metastasis, ascites, hemoglobin concentration, serum albumin level, lactate dehydrogenase level, carcinoembryonic antigen level, and chemotherapy were finally incorporated into prognostic nomogram. The concordance indices were 0.689 (95% CI: 0.664 ~ 0.714) and 0.673 (95% CI: 0.632 ~ 0.714) for bootstrap and external validation. 100 and 200 were set as the cut-off values of nomogram score, patients in development cohort were stratified into low-, intermediate- and high-risk groups with median overall survival time 15.8 (95% CI: 12.2 ~ 19.5), 8.4 (95% CI: 6.7 ~ 10.2), and 3.9 (95% CI: 2.7 ~ 5.2) months, respectively; the cut-off values also worked well in validation cohort with different survival time in subgroups. A simplified model was also established and showed good consistency with the nomogram scoring model in both of development and validation cohorts. Conclusion The prognostic scoring model and its simplified surrogate can be used as tools for mortality risk stratification in patients with advanced gastric carcinoma.

Safety Analysis of Apatinib Combined with Chemotherapy in the Treatment of Advanced Gastric Carcinoma: A Randomised Controlled Trial

Objective. To study the safety of apatinib combined with chemotherapy in the treatment of advanced gastric carcinoma (GCA). Methods. 74 patients with advanced GCA treated in the oncology department of Weifang People’s Hospital (January 2019–January 2020) were enrolled in this study and equally split into study group (SG) and reference group (RG) according to the odd and even admission numbers. RG underwent chemotherapy alone, while SG received apatinib combined with chemotherapy. The clinical indicators of serum matrix metalloproteinase 9 (MMP-9), serum interleukin-2 receptor (SIL-2R), and immune cell level were detected in the two groups before and after treatment to analyze the therapeutic effect of different treatment methods on patients with advanced gastric carcinoma. Results. No obvious differences in gender ratio, average age, average BMI, pathological staging, pathological types, organ metastasis types, and residence were observed between the two groups ( P > 0.05 ). The short-term follow-up results showed that the disease control rate (DCR) in SG was markedly higher compared with RG ( P < 0.05 ). The MMP-9 and SIL-2R levels in both groups after treatment decreased ( P < 0.05 ), and the levels in SG after treatment were notably lower compared with RG ( P < 0.001 ). Compared with RG, CD3+, CD4+, and CD4+/CD8+ levels in SG after treatment were notably higher ( P < 0.001 ), while the CD8+ level was notably lower ( P < 0.001 ). The median progression-free survival (MPFS) and overall survival (OS) in SG were markedly higher compared with RG ( P < 0.001 ). The GQOLI-74 scores in both groups after treatment increased ( P < 0.001 ), and the GQOLI-74 score in SG after treatment was markedly higher compared with RG ( P < 0.001 ). The total incidence of adverse reactions was lower in SG than in RG ( P < 0.05 ). Conclusion. Apatinib combined with chemotherapy is superior to chemotherapy alone in effectively improving treatment outcomes in patients with advanced GCA.

Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling

Background Currently, resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy. Here, we sought to investigate the function of activating transcription factor 3 (ATF3) n GC chemoresistance. Methods Expression of ATF3 was determined in GC cell lines (MNK45, SGC7901, and BGC823) and cisplatin (DDP)-resistant cells (SGC7901/DDP and BGC823/DDP). Biological informatics was performed to analyze ATF3 expression and prognosis in GC patients. Cisplatin resistance was evaluated. Ferroptosis was detected after ATF3 transfection of cells. The underlying molecular mechanism was also investigated. Results Transcripts of ATF3 were decreased in GC cells and GC tissues. Kaplan–Meier plotter analysis revealed that ATF3 expression was positively related to the overall survival of GC patients. In particular, lower levels of ATF3 were observed in cisplatin-resistant SGC7901/DDP and BGC823/DDP relative to their parental cells. Notably, ATF3 elevation sensitized cisplatin-resistant cells to cisplatin. Mechanically, compared with parental cells, SGC7901/DDP and BGC823/DDP cells exhibited lower ferroptosis evident by lower ROS, MDA and lipid peroxidation and higher intracellular GSH levels. However, ATF3 elevated ferroptosis in SGC7901/DDP and BGC823/DDP cells. Intriguingly, ATF3 overexpression together with ferroptosis activator erastin or RSL3 treatment further enhanced ferroptosis and cisplatin resistance; however, the ferroptosis suppressor liproxstatin-1 reversed the function of ATF3 in ferroptosis and cisplatin resistance. Additionally, cisplatin-resistant cells exhibited stronger activation of Nrf2/Keap1/xCT signaling relative to parental cells, which was restrained by ATF3 up-regulation. Importantly, restoring Nrf2 signaling overturned ATF3-mediated ferroptosis and cisplatin resistance. Conclusion ATF3 may sensitize GC cells to cisplatin by induction of ferroptosis via blocking Nrf2/Keap1/xCT signaling, supporting a promising therapeutic approach for overcoming chemoresistance in GC.

HER2 status in gastric adenocarcinoma: Comparison between matched endoscopic biopsy and gastrectomy specimens

Purpose: To evaluate the concordance between HER2 status in matched endoscopic biopsy and gastrectomy specimens of gastric adenocarcinoma patients. Patients and Methods: Fifty-five gastric adenocarcinoma patients were diagnosed by upper GI endoscopic biopsy and treated with gastrectomy. HER2 status was assessed by immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) on both endoscopic biopsy and gastrectomy specimens. HER2-positive status was defined as a score IHC 3+, or IHC 2+ with a positive result in FISH. Data were collected from June, 2014 to July, 2016 in HCMC Oncology Hospital. Results: HER2-positive status was identified in 9.6%. The concordance in HER2 status between matched endoscopic biopsy and surgical specimens was 98% (Kappa=0.879). Conclusion: There was a very high concordance in HER2 status between the results performed with surgical specimens and matched endoscopic specimens. HER2 status assessed on endoscopic biopsy specimens could be reliable for treatment decisions using anti-HER2 agents in patients with advanced gastric carcinoma.

Clinical Effectiveness of Neoadjuvant Chemotherapy in Gastric Carcinoma and Exploration of Perioperative Imaging Assessment Parameters

Background and Aims. Due to the difficulty in clinical staging, a simple and feasible perioperative assessment approach for guiding personalized neoadjuvant chemotherapy (NAC) is lacking. We investigated the clinical value of NAC in advanced gastric carcinoma (GC) and the concordance between perioperative imaging and postoperative pathological assessments. Methods. This study included 62 patients with advanced GC who received NAC between January 2012 and December 2018. The preoperative and postoperative T stages, postoperative pathological tumor regression grade (TRG), and changes in computed tomography (CT) values after NAC were assessed. Follow-ups were conducted to obtain the median survival time (MST), and Kaplan–Meier survival curves were plotted. Results. The T stages significantly differed between before and after NAC ( p = 0.001 ). The MST of patients in the TRG0 group was significantly different from that of patients in the TRG1+2 and TRG3 groups ( p = 0.223 ). The percentages of positive lymph nodes were 0%, 24.17%, and 27.64% in the TRG0, TRG1+2, and TRG3 groups, respectively. TRG was correlated with changes in CT values before and after NAC, and the extent of change was associated with patient prognosis. Conclusions. Perioperative imaging can be used to assess the short-term effectiveness of NAC for patients with GC.

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive GC patients with advanced disease. However, subsequent studies on HER2 targeted therapies in this setting failed to meet their primary endpoints, and not all HER2-positive GC patients benefit from targeted approaches. More recently, novel HER2-directed treatments have been investigated, including trastuzumab deruxtecan (T-Dxd); following the results of the DESTINY-Gastric01 study, T-Dxd received its first U.S. Food and Drug Administration (FDA) approval on 15 January 2021 for the treatment of adults with unresectable, locally advanced, or metastatic GC who have received a prior trastuzumab-based regimen. In this review, we discuss the current HER2-targeted treatments for GC in the advanced disease setting, mainly focusing on emerging new treatments and future research directions.