The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.)

RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms. Cancer Res; 70(9); 3687–96. ©2010 AACR.

OBJECTIVE: To examine the prognostic performance of the revised 2018 International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging schema. METHODS: We used the National Cancer Database to identify women with cervical cancer diagnosed from 2004 to 2015. Using clinical and pathologic data, each patient's stage was classified using three staging schemas: American Joint Committee on Cancer 7th edition, FIGO 2009 and FIGO 2018. The FIGO 2018 revised staging classifies stage IB tumors into three substages based on tumor size (IB1–IB3) and classifies patients with positive lymph nodes (pathologically or clinically detected) as stage IIIC1 (positive pelvic nodes) or IIIC2 (positive para-aortic nodes). Five-year survival rates were estimated for each stage grouping. We sought to determine whether the 2018 FIGO staging system was able to offer improved 5-year survival rate differentiation compared with older staging schemas. RESULTS: A total of 62,212 women were identified. The classification of stage IB tumors into three substages improved discriminatory ability. Five-year survival in the FIGO 2018 schema was 91.6% (95% CI 90.4–92.6%) for stage IB1 tumors, 83.3% (95% CI 81.8–84.8%) for stage IB2 neoplasms, and 76.1% (95% CI 74.3–77.8%) for IB3 lesions. In contrast, for women with stage III tumors, higher FIGO staging was not consistently associated with worse 5-year survival rates: stage IIIA (40.7%, 95 CI 37.1–44.3%), stage IIIB (41.4%; 95% CI 39.9–42.9%), stage IIIC1 (positive pelvic nodes) was 60.8% (95% CI 58.7–62.8%) and stage IIIC2 37.5% (95% CI 33.3–41.7%). CONCLUSION: The FIGO 2018 staging schema provides improved discriminatory ability for women with stage IB tumors; however, classification of all women with positive lymph nodes into a single stage results in a very heterogeneous group of patients with highly variable survival rates.