Biologically Active Tissue Factor-Bearing Larger Ectosome-Like Extracellular Vesicles in Malignant Effusions from Ovarian Cancer Patients: Correlation with Incidence of Thrombosis

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF+ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis.

Clinical efficacy and safety of apatinib combined with oral VP-16 for the treatment of advanced ovarian cancer: Preliminary evaluation of a clinical drug regimen

To investigate the clinical efficacy and safety of apatinib in combination with oral VP-16 for the treatment of chemotherapy-resistant advanced ovarian carcinoma. Twenty-seven advanced ovarian carcinoma patients were treated with oral VP-16 chemotherapy combined with oral apatinib mesylate (500 mg/d). CA125, VEGF, and CEA were examined every 3-4 weeks, and tumour changes were monitored by CT every 8-12 weeks. PFS was obtained by follow-up after discharge. For all patients, the ORR (including CR and PR) was 25.0%, and the DCR (including CR, PR and SD) was 75.0%. CEA and CA199 significantly decreased (p<0.05), but the decrease in VEGF was not significant. The average PFS was 5.13 months. The ECOG score had a significant effect on PFS (p<0.05), while there were no significant differences in PFS based on age (p=0.394). The main side effects of this regimen were hypertension, proteinuria, hand-foot syndrome and myelosuppression, which were tolerated by patients after active symptomatic treatment. Apatinib combined with oral VP-16 is an effective regimen for the treatment of chemotherapy-resistant advanced ovarian cancer. This combination therapy should be widely used in clinical practice.