Expression of Tissue Factor in Epithelial Ovarian Carcinoma Is Involved in the Development of Venous Thromboembolism.

OBJECTIVES: Our 2007 study of 32 patients with ovarian cancer reported the possible involvement of tissue factor (TF) in the development of venous thromboembolism (VTE) before treatment, especially in clear cell carcinoma (CCC). This follow-up study further investigated this possibility in a larger cohort. METHODS: We investigated the intensity of TF expression (ITFE) and other variables for associations with VTE using univariate and multivariate analyses in 128 patients with epithelial ovarian cancer initially treated between November 2004 and December 2010, none of whom had received neoadjuvant chemotherapy. Before starting treatment, all patients were ultrasonographically screened for VTE. The ITFE was graded based on immunostaining of surgical specimens. RESULTS: Histological types were serous carcinoma (n = 42), CCC (n = 12), endometrioid carcinoma (n = 15), mucinous carcinoma (n = 53), and undifferentiated carcinoma (n = 6). The prevalence of VTE was significantly higher in CCC (34%) than in non-CCC (17%, P = 0.03). As ITFE increased, the frequencies of CCC and VTE increased significantly (P < 0.001 and P = 0.014, respectively). Multivariate analysis identified TF expression and pretreatment dimerized plasmin fragment D level as significant independent risk factors for VTE development. These factors showed particularly strong impacts on advanced-stage disease (P = 0.021). CONCLUSIONS: The 2007 cohort was small, preventing multivariate analysis. This study of a larger cohort yielded stronger evidence that the development of VTE in epithelial ovarian cancer may involve TF expression in cancer tissues.

Clinicopathologic implications of DNA mismatch repair status in endometrial carcinomas.

OBJECTIVE: Endometrial carcinoma is the most common malignancy in women with Lynch syndrome caused by mismatch repair (MMR) deficiency. We investigated the clinicopathologic significance of deficient MMR and Lynch syndrome presumed by MMR analyses in unselected endometrial carcinomas. METHODS: We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients. Based on these results, tumors were categorized as sporadic or probable Lynch syndrome (PLS). Clinicopathologic variables and prognosis were compared according to MMR status and sporadic/PLS classification. RESULTS: Deficient MMR showed only trends towards favorable overall survival (OS) compared with intact MMR (p=0.13), whereas PLS showed significantly better OS than sporadic (p=0.038). Sporadic was significantly associated with older age, obesity, deep myometrial invasion, and advanced stage (p=0.008, 0.01, 0.02 and 0.03), while PLS was significantly associated with early stage and Lynch syndrome-associated multiple cancer (p=0.04 and 0.001). The trend towards favorable OS of PLS was stronger in advanced stage than in early stage (hazard ratio, 0.044 [95% CI 0-25.6] vs. 0.49 [0.063-3.8]). In the subset receiving adjuvant therapies, PLS showed trends towards favorable disease-free survival compared to sporadic by contrast with patients receiving no adjuvant therapies showing no such trend (hazard ratio, 0.045 [95% CI 0-20.3] vs. 0.81 [0.095-7.0]). CONCLUSIONS: The current findings suggest that analyzing MMR status and searching for Lynch syndrome may identify a subset of patients with favorable survival and high sensitivity to adjuvant therapies, providing novel and useful implications for formulating the precision medicine in endometrial carcinoma.

High Pretreatment Plasma D-dimer Levels Are Associated With Poor Prognosis in Patients With Ovarian Cancer Independently of Venous Thromboembolism and Tumor Extension.

OBJECTIVE: Elevated plasma D-dimer (DD) is associated with decreased survival among patients with breast, lung, and colon cancers. The present study clarifies the prognostic significance of pretreatment plasma DD levels in patients with epithelial ovarian cancer (EOC). METHODS: We investigated pretreatment DD levels and other variables for overall survival using univariate and multivariate analyses in 134 consecutive patients with EOC stages II to IV who were initially treated between November 2004 and December 2010. RESULTS: The median follow-up period was 53 (7-106) months. Univariate analysis significantly associated elevated pretreatment DD (≥2.0 µg/mL) levels to poor 5-year overall survival rates irrespective of previously treated venous thromboembolism (72.2% vs 52.6%, P = 0.039). Cancer antigen 125 levels of 200 U/mL or higher (P = 0.011), distant metastases (P = 0.0004), residual tumors (P < 0.0001), and International Federation of Gynecology and Obstetrics stage III/IV (P = 0.0033) were also poor prognostic factors. Multivariate analysis independently associated DD levels of 2.0 µg/mL or higher (P = 0.041), distant metastases (P = 0.013), and residual tumors (P < 0.0001) with poor overall survival. CONCLUSIONS: High pretreatment DD levels are associated with poor overall survival in patients with EOC independently of venous thromboembolism and tumor extension and might comprise a promising prognostic biomarker for patients with EOC.

Moesin overexpression is a unique biomarker of adenomyosis.

Adenomyosis is characterized by extension of endometrial glands and stromal cells into the myometrium. Here we proved that 'moesin' is a unique biomarker of adenomyosis. We selected two cases of adenomyosis that had been surgically resected and fixed with formalin. Proteins were extracted from the infiltrating adenomyosis lesions and normal endometrium by tissue microdissection. The extracted proteins were examined using a LC-MS/MS system and the expression profiles of each region were compared. Two hundred and sixty proteins were detected, among which 73 were expressed more in adenomyosis than in normal endometrium. Among these proteins, we focused on overexpression of moesin in adenomyosis. Expression of moesin estimated semiquantitatively using an immunohistochemistry score was higher in adenomyosis than in normal endometrium. In particular, moesin was significanly overexpressed in stromal cells of adenomyosis than in those of normal endometrium. Relative to normal endometrium, moesin was also overexpressed at the RNA level in 9 of 14 cases of adenomyosis and at the protein level in all 14 cases. We also detected activated (phosphorylated) moesin in adenomyosis lesions. The present findings suggest that moesin is characteristically overexpressed and activated in adenomyosis, and that moesin activation may be related to extension of adenomyosis in the myometrium.

Safety and efficacy of substituting nedaplatin after carboplatin hypersensitivity reactions in gynecologic malignancies.

AIM: Repeated treatment with carboplatin increases the incidence of hypersensitivity reactions. Current managements for carboplatin hypersensitivity reactions involve premedication, desensitization, and replacing agents. However, preventive effects for recurrent reactions by the former two methods are still limited, and substituting non-platinum agent can attenuate efficacy against platinum-sensitive diseases. The aim of this study was to evaluate the safety and efficacy of substituting nedaplatin, another platinum compound, as a strategy to deal with carboplatin hypersensitivity reactions in gynecologic cancers. MATERIAL AND METHODS: Patients who experienced carboplatin hypersensitivity reactions and subsequently switched to nedaplatin between 2001 and 2009 were identified through our database. The incidence and severity of nedaplatin hypersensitivity were examined. Response to nedaplatin therapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and serum CA-125 levels. RESULTS: Forty-six of 570 patients (8.1%) experienced carboplatin hypersensitivity reactions, and the increased cycle numbers of carboplatin-based regimens correlated with the high incidence of hypersensitivity (≤6, 0.9% vs ≥7, 19.2%). Of these 46 patients, 38 subsequently switched to nedaplatin-based regimens (ovarian, tubal or peritoneal carcinoma, 30; endometrial carcinoma, 6; cervical carcinoma, 2). Three of the 38 patients (7.9%) eventually developed hypersensitivity against nedaplatin, and all their reactions were grade 2. The response rate to nedaplatin therapy among 32 evaluable patients was 31.3%. CONCLUSION: Replacing carboplatin with nedaplatin provided a safe and efficacious approach to manage carboplatin hypersensitivity. To the authors' knowledge, this study is the first to indicate the usefulness of nedaplatin after carboplatin hypersensitivity reactions. Further evaluations are warranted to confirm our finding.