B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3-and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; Po0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P ¼ 0.02) and a higher incidence of recurrence (P ¼ 0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.
Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular. Cancer Res; 71(3); 645-54. Ó2011 AACR.
BACKGROUND: Limited studies have examined the impact of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) and specifically the category of atypia or follicular lesion of undetermined significance (AUS/FLUS). We studied their effects on reporting rates, subsequent management, and surgical outcome over a 10-year period, 5 years before and after implementation of the BSRTC. METHODS: A retrospective review of thyroid fine-needle aspiration (FNA) reports from 2003 to 2012 was performed. Diagnoses made before BSRTC were reclassified into the most appropriate category.Repeat FNA results for all AUS/FLUS cases were recorded. Surgical follow-up results were matched by side and size of the targeted nodule. Incidental microcarcinomas were not considered "malignant" on excision. Malignancy rates were calculated based on excision and by all aspirated specimens. RESULTS: Initial AUS/FLUS cases increased from 3% to 7% (P 5.001) with implementation of the BSRTC. The nondiagnostic rate decreased from 19% to 10% (P 5.026). Differences in malignancy rates before and after implementation of the BSRTC were not significant for all diagnostic categories. More repeat FNAs and fewer surgical excisions were performed after an initial AUS/FLUS diagnosis. Repeat FNA reclassified 56% of AUS/FLUS cases into a definitive category. The malignancy risks for AUS/FLUS plus benign and AUS/FLUS plus AUS/FLUS repeat FNAs were elevated compared with single benign and AUS/FLUS diagnoses. CONCLUSIONS: AUS/
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