Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients.

BACKGROUND: Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in ß-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. METHODOLOGY/PRINCIPAL FINDINGS: We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated ß-catenin, ß-catenin and GSK3ß. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. CONCLUSIONS/SIGNIFICANCE: Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets.

Predictors of transfusion requirements for cardiac surgical procedures at a blood conservation center.

BACKGROUND: Previous studies defining perioperative risk factors for allogeneic transfusion requirements in cardiac surgery were limited to highly selected cardiac surgery populations or were associated with high transfusion rates. The purpose of this study was to determine perioperative risk factors and create a formula to predict transfusion requirements for major cardiac surgical procedures in a center that practices a multimodality approach to blood conservation. METHODS: We performed an observational study on 307 consecutive patients undergoing coronary artery bypass grafting, valve, and combined (coronary artery bypass grafting and valve) procedures. An equation was derived to estimate the risk of transfusion based on preoperative risk factors using multivariate analysis. In patients with a calculated probability of transfusion of at least 5%, intraoperative predictors of transfusion were identified by multivariate analysis. RESULTS: Thirty-five patients (11%) required intraoperative or postoperative allogeneic transfusions. Preoperative factors as independent predictors for transfusions included red blood cell mass, type of operation, urgency of operation, number of diseased vessels, serum creatinine of at least 1.3 mg/dL, and preoperative prothrombin time. Intraoperative factors included cardiopulmonary bypass time, three or fewer bypass grafts, lesser volume of acute normovolemic hemodilution removed, and total crystalloid infusion of at least 2,500 mL. The derived formula was applied to a validation cohort of 246 patients, and the observed transfusion rates conformed well to the predicted risks. CONCLUSIONS: A multimodality approach to blood conservation in cardiac surgery resulted in a low transfusion rate. Identifying patients' risks for transfusion should alter patient management perioperatively to decrease their transfusion rate and make more efficient use of blood resources.