Paraneoplastic thrombocytosis in ovarian cancer.

BACKGROUND: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer.

The objective of this study was to evaluate the role of an in vitro drug resistance assay to platinum and taxane in the management of advanced epithelial ovarian, fallopian and primary peritoneal cancer. All patients with FIGO Stage IIIc and IV who received postoperative chemotherapy with platinum and taxane for more than 4 courses after the initial cytoreductive surgery between 1995 and 2008 were evaluated. Patients who received neoadjuvant chemotherapy were not included. An in vitro drug resistance assay (EDR Assay, Oncotech, Tustin, CA) was used to determine drug resistance for each patient's tumor tissue. Level of drug resistance was described as extreme (EDR), intermediate (IDR), or low (LDR). Response to chemotherapy and survival were correlated to the EDR Assay. Of the 335 patients who underwent primary cytoreductive surgery, 173 cases met the criteria for statistical evaluation. The 58 patients (33.5%) whose tumors had LDR to both platinum and taxane had statistically improved progression-free survival and overall survival (OS) compared with the 115 patients (66.5%) who demonstrated IDR or EDR to platinum and/or taxane (5-year OS rates, 41.1% vs. 30.9%, p = 0.014). The 5-year OS rates for the 28 (16.2%) cases that had optimal cytoreduction with LDR to both platinum and taxane was significantly improved over the 62 (35.8%) cases that were suboptimally cytoreduced with IDR or EDR to platinum and/or taxane (54.1% vs. 20.4%, respectively, p < 0.001). In conclusion, LDR to both platinum and taxane chemotherapy, as determined by an in vitro drug resistance assay, independently predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer, especially in those patients who undergo optimal primary cytoreduction.

Prediction of Chemotherapy Response With Platinum and Taxane in the Advanced Stage of Ovarian and Uterine Carcinosarcoma: A Clinical Implication of In vitro Drug Resistance Assay.

OBJECTIVES: To evaluate the role of an in vitro drug resistance assay to predict the response to platinum and taxane combination chemotherapy in advanced ovarian and uterine carcinosarcoma. METHODS: We evaluated all patients with FIGO stage II-IV ovarian and FIGO stage III-IV uterine carcinosarcoma, who received platinum and taxane chemotherapy after initial cytoreductive surgery between January 1, 1995 and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics, clinicopathologic data, response to chemotherapy, and follow-up outcomes were abstracted from the medical records. In vitro drug resistance assay results (Extreme Drug Resistance [EDR] Assay, Oncotech Inc, Tustin, CA) were evaluated. Response to chemotherapy was then compared with the assay results. RESULTS: There were 51 cases in which in vitro drug resistance assay results were available, of which 17 (33.3%) received combination chemotherapy with platinum and taxane. For these 17 cases, the primary site of disease was ovary in 12 cases and uterus in the other 5 cases. Overall response rate for these 17 cases was 70.6%. Chemotherapy response in the presence of EDR to at least 1 of the 2 drugs (EDR-PT) was significantly lower than non-EDR-PT (37.5% vs. 100%, P = 0.009). Sensitivity, specificity, positive predictive value, and negative predictive value for chemotherapy response in non-EDR-PT were 75%, 100%, 100%, and 62.5%, respectively. EDR-PT showed a significantly lower progression-free survival (1-year progression-free survival rate, 28.6% vs. 100%, P = 0.01) and overall survival (5-year overall survival rate, 26.9% vs. 57.1%, P = 0.033). CONCLUSIONS: Use of an in vitro drug resistance assay was a feasible test to predict the chemotherapy response and survival outcome in advanced ovarian and uterine carcinosarcoma.

Localization of heparin cofactor II in injured human skin: a potential role in wound healing.

The physiologic function of the serpin heparin cofactor II (HCII) is not fully understood. We have hypothesized that HCII functions as an extravascular inhibitor of thrombin. Thrombin formed at a site of injury has been hypothesized to contribute to migration and proliferation of fibroblasts and smooth muscle cells involved in wound healing. To begin to test our hypothesis, we examined the immunohistochemical localization of HCII in human skin and compared it to that of the closely related serpin, antithrombin (ATIII). In skin specimens with acute wounds, there was diffuse HCII and ATIII staining in areas of hemorrhage. In healing skin wounds ATIII was primarily associated with mast cells, while HCII was associated with mononuclear phagocytes in the dermis. Blood monocytes isolated from healthy donors also stained for HCII protein. However, in situ hydridization and RT-PCR studies failed to show significant HCII mRNA expression either in macrophages in wounded skin or in peripheral blood leukocytes. HCII localization is not due to nonspecific uptake of plasma proteins, since ATIII had a very different distribution in wounded skin. These findings support the notion that HCII could function as an extravascular thrombin inhibitor and might play a role in the regulation of wound healing.