Chloroquine Combined with Imatinib Overcomes Imatinib Resistance in Gastrointestinal Stromal Tumors by Inhibiting Autophagy via the MAPK/ERK Pathway.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. However, up to 40-50% of GISTs develop secondary resistance after an average of 24 months of imatinib treatment. It has been reported that autophagy can promote the survival of GIST cells and induce drug resistance. Presently, the specific mechanism of autophagy in GISTs with imatinib resistance is not clear. MATERIALS AND METHODS: The cell-counting kit (CCK)-8 method and flow cytometry were used for in vitro drug sensitivity testing and autophagy level detection. Detection of the apoptosis level was by flow cytometry with the annexin V Kit. Western blotting was used to analyze the role of autophagy and apoptosis in GIST cells with CQ alone, imatinib alone, or in combination, and to analyze MAPK pathway expression. In vitro results were confirmed by in vivo experiments using the mice model. Hematoxylin and eosin and immunohistochemical staining were used to detect the pathological characteristics and immunophenotype of the transplanted tumor. Detection of KIT and PDGFRA gene mutations in the transplanted imatinib-resistant GIST was done by denaturing high performance liquid chromatography (DHPLC) and direct sequencing. ERK and KIT expression and regulation levels were detected by Western blotting. RESULTS: In vitro and vivo experiments, the autophagy level of imatinib-resistant cells was higher than that of normal cells; CQ combined with imatinib can promote apoptosis by blocking autophagy of imatinib-resistant cells. In the meanwhile, we found that the phosphorylation level of ERK may be related to autophagy. CONCLUSION: Our data suggest that autophagy through the MAPK/ERK pathway may play a pivotal role in imatinib-resistant GIST proliferation. Moreover, combining an autophagy inhibitor with imatinib may be a potential valuable strategy in overcoming acquired resistance in GIST patients.

Hyperthermic intraperitoneal chemotherapy combined with systemic chemotherapy for gastric cancer peritoneal carcinomatosis: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The prognosis of gastric cancer peritoneal carcinomatosis (GCPC) remains poor despite recent advances in systemic chemotherapy (SC) with an average survival less than 6 months. Current evidence supporting the utility of hyperthermic intraperitoneal chemotherapy (HIPEC) combined with SC for GCPC is limited. We plan to provide a systematic review and meta-analysis of randomized controlled trials to evaluate the comparative effects and safety of HIPEC combined with SC in the management of GCPC. METHODS: Randomized controlled trials evaluating HIPEC combined with SC versus SC as first-line treatment for GCPC will be searched in MEDLINE, EMBASE, Web of Science, the Cochrane Library, ClinicalTrials.gov, and Google Scholar, from database inception to April 30, 2020. Data on study design, participant characteristics, intervention details, and outcomes will be extracted. Primary outcomes to be assessed are: median progression-free survival; secondary outcomes are: median survival time, 1- year survival rate, 2-year survival rate, objective response rate, and adverse events. Meta-analysis will be performed using RevMan V.5.3 statistical software. Data will be combined with a random effect model. Study quality will be assessed using the Cochrane Risk of Bias Tool. Heterogeneity will be assessed, and if necessary, a subgroup analysis will be performed to explore the source of heterogeneity. RESULTS: The results will provide useful information about the effectiveness and safety of HIPEC combined with systemic chemotherapy regimens in patients with gastric cancer peritoneal carcinomatosis. CONCLUSION: The findings of the study will be disseminated through peer-reviewed journal. THE REGISTRATION NUMBER: INPLASY202050006. DOI NUMBER: 10.37766/inplasy2020.5.0006.

A two centers study of postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX regimens for gastric cancer after D2 resection: a cohort study.

OBJECTIVE: Currently, radical surgery with D2 lymphadenectomy has become the standard operation mode of patients in East Asian countries who suffer from resectable gastric cancer. Our target is to compare the efficacy of postoperative adjuvant chemotherapy with S-1 versus SOX/XELOX regimens for gastric cancer after D2 resection. METHODS: We selected 186 patients with gastric cancer who underwent D2 resection in Hangzhou First People's Hospital and Hangzhou Cancer Hospital from June 2014 to June 2017. All patients were followed up for more than 3 years. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS) and toxicity. RESULTS: The 3-year DFS of monotherapy group and combined group were, respectively, 50.7% and 64.0%, while the 3-year OS were, respectively, 62.7% and 71.2%. The 3-year DFS and OS of the combined group were higher than the monotherapy group, but the differences had no statistical significance (3-year DFS: P = 0.071; 3-year OS: P = 0.224). Subgroup analysis showed that the DFS of patients with stage III gastric cancer in monotherapy group was significantly lower than the combined group, with the difference that had statistical significance (P = 0.030), while there was no significant difference in OS (P = 0.186). Most toxic and side effects seen in both groups had no significant differences, while the incidence of hand-foot syndrome and peripheral neurotoxicity in combined group was significantly higher than that in the monotherapy group (P < 0.001). CONCLUSION: For patients with advanced gastric cancer who underwent D2 resection, compared with S-1 regimen, there is prolonged disease-free survival trend with SOX/XELOX regimen, while there is no significant overall survival benefit.