Joanie Mayer Hope

LPA receptor 2 mediates LPA-induced endometrial cancer invasion.

OBJECTIVE We have previously shown that lysophosphatidic acid (LPA) promotes the ovarian cancer metastatic cascade. In this study, we evaluated the role of LPA on endometrial cancer invasion. METHODS Transient mRNA knockdown was accomplished using pre-designed siRNA duplexes against LPA receptor 2 (LPA2) and human matrix metalloproteinase-7 (MMP-7). RT-PCR was used to characterize LPA receptor and MMP-7 expression. Analysis of in vitro invasion was performed with rat-tail collagen type I coated Boyden chambers. Gelatin zymography was used to evaluate the MMP activity in cell culture conditioned media. Cell-cell and cell-matrix attachment was also assessed upon LPA2 knockdown to further illuminate the LPA2 cascade. RESULTS LPA increases HEC1A cellular invasion at physiologic concentrations (0.1-1 muM). Of the four principle LPA receptors, LPA2 is predominantly expressed by HEC1A cells. Transient transfection of LPA2 siRNA reduced LPA2 mRNA expression in HEC1A cells by 93% (P<0.01). Silencing LPA2 eliminated the LPA-stimulated increase in invasion (P<0.05) and reduced LPA-induced MMP-7 secretion/activation, without significantly affecting cell-cell or cell-matrix adhesion. Silencing MMP-7 reduced overall invasion but did not eliminate LPAs pro-invasive effect on HEC1A cells, as compared to negative control (P<0.05). Gelatin zymography confirmed that LPA2 and MMP-7 knockdown reduced MMP-7 activation in HEC1A conditioned media. CONCLUSION LPA2 mediates LPA-stimulated HEC1A invasion and the subsequent activation of MMP-7.

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

OBJECTIVES We previously demonstrated that sphingosine 1-phosphate (S1P) bimodally regulates epithelial ovarian cancer (EOC) cell invasiveness: low-concentration S1P stimulates invasion similar to lysophophatidic acid (LPA), while high-concentration S1P inhibits invasion. In this study, we investigated the mechanisms through which S1P affects EOC cell proteolysis, invasion, and adhesion in two cultured epithelial ovarian cancer cell lines. METHODS G-protein Gi was inhibited by pertussis toxin (PTX) and GTP binding protein Rac by NSC23766. S1P conditioned media of DOV13 and OVCA429 cells were evaluated via gel zymography, fluorometric gelatinase assay, urokinase plasminogen activator (uPA) activity assay, and Western Blot for MT1-MMP. Cell invasion was analyzed in Matrigel chambers. Membrane-N-cadherin was localized via fluorescence microscopy. RESULTS Zymography revealed pro-MMP2 in conditioned media of EOC cells regardless of treatment. Gelatinase activity was increased by low-concentration S1P. In DOV13 cells this effect was Gi and Rac dependent. In all OVCA429 and control DOV13 cells, PTX enhanced gelatinolysis, suggesting an MMP2-inhibitory pathway via Gi. MT1-MMP was decreased Gi-dependently by high-concentration S1P. Rac inhibition significantly counteracted low-S1P enhancement and high-S1P reduction of DOV13 invasiveness; and uPA activity in conditioned media of invading cells correlated significantly. Immunohistochemistry revealed Gi-dependent clustering of membrane-N-cadherin in DOV13 cells treated with 0.5 microM S1P or 10 microM LPA. CONCLUSIONS S1P influences EOC invasion by regulating ECM-proteolysis and cell-cell attachment via MMP2, uPA, and membrane-N-cadherin. Furthermore, this study illustrates that the net effect of S1P on each of these processes reflects a complex interplay of multiple GPCR pathways involving Gi and downstream Rac.

Spherical Tissue Sampling in 3-Dimensional Power Doppler Angiography : A New Approach for Evaluation of Ovarian Tumors

The purpose of this study was to evaluate the usefulness of virtual spherical tissue sampling using 3‐dimensional (3D) ultrasound power Doppler angiography to enhance differentiation between normal and pathologic ovaries.

The Role of Palliative Surgery in Gynecologic Cancer Cases

The decision to undergo major palliative surgery in end-stage gynecologic cancer is made when severe disease symptoms significantly hinder quality of life. Malignant bowel obstruction, unremitting pelvic pain, fistula formation, tumor necrosis, pelvic sepsis, and chronic hemorrhage are among the reasons patients undergo palliative surgeries. This review discusses and summarizes the literature on surgical management of malignant bowel obstruction and palliative pelvic exenteration in gynecologic oncology.

Three-dimensional power Doppler angiography of cyclic ovarian blood flow

Objective. The purpose of this study was to assess the vascular indices generated by 3‐dimensional (3D) power Doppler angiography by evaluating the cyclic changes in the vascularity of normal ovaries, including those that were ovulating, nonovulating, and hormonally suppressed. Methods. In this prospective longitudinal observational study, a cohort of premenopausal regularly menstruating women with no known ovarian disease underwent 3D power Doppler imaging every 2 to 3 days for the duration of 1 menstrual cycle. Four indices were generated: vascularization index (VI), flow index (FI), vascularization‐flow index (VFI), and mean grayness. Comparisons of vascularity were made between ovulating, nonovulating, and hormonally suppressed ovaries. Normal ranges were established and graphed longitudinally. Results. Eighteen participants (36 ovaries) ages 28 to 45 years underwent an average of 10 examinations, yielding 368 acquired ovarian volumes for analysis. Seven participants used hormonal contraception. The VI, FI, and VFI were closely correlated (Pearson product moment correlation coefficients, 0.52–0.95). The vascular indices of ovulating ovaries were significantly higher than those of nonovulating ovaries (VI, FI, and VFI, all P < .001), with the largest discrepancies during the luteal phase. Hormonally suppressed ovaries had significantly lower vascularity throughout the cycle (VI, P < .002; FI, P < .001; VFI, P < .007). The vascular indices of all groups appeared to drop during the late follicular period and then rise again. Conclusions. The VI would suffice as the principal vascular parameter for 3D power Doppler analysis. Preovulatory scans may be more useful for distinguishing pathologic vascularization. Hormonally suppressed ovaries have significantly lower vascularity throughout the cycle. Normal‐appearing ovaries with vascular indices above the normal ranges established by these data may warrant further investigation.

Current status of maintenance therapy for advanced ovarian cancer

Even after countered with and responding to maximal surgical and chemotherapy efforts, advanced ovarian cancer usually ultimately recurs. One strategy employed to forestall recurrence is maintenance chemotherapy, an extension of treatment following a complete response to conventional measures. Many agents have been studied and many more are currently under investigation in maintenance regimens. While phase III data suggest that taxane maintenance prolongs progression-free survival, no overall survival benefit has been established. This article reviews the current status of maintenance therapy for advanced ovarian cancer, including phase III evidence and new and upcoming trials.

Advancing Women’s Cancer Care

Prognostic Model for FIGO Stage I Epithelial Ovarian Cancer The choice to give adjuvant chemotherapy to patients with stage I epithelial ovarian cancer is currently based on the substage (IC) and grade (G2–3) of the disease. At the opening plenary session, Dr. Andreas Obermair from Brisbane, Australia, introduced a new prognostic index (ECO-1) for stratifying patients with surgical stage I epithelial ovarian cancer. The ECO-1 score is based on points assigned for preoperative CA125 1 30 (3 points), advanced age at diagnosis (3 points), substage IC (1 point) and grade 2 or 3 (1 point). Based on retrospective data from 600 patients, ECO-1 scores of 0–1, 3–6 and 7–8 corresponded to 5-year survival rates of 97, 89 and 73%, respectively (p ! 0.0001). The authors concluded that patients with ECO-1 scores ̂ 2 have a very good prognosis and, confirming results of previous trials, likely obtain no additional survival benefit from adjuvant chemotherapy.

OP16.08: Virtual 3D power Doppler angiographic spherical tissue sampling for evaluation of ovarian pathology

Methods: Digitally stored B-mode sonographic images, from a random sample of 98 women with an adnexal mass submitted to surgery after B-mode transvaginal sonography, were evaluated by five different examiners with different degree of experience. Masses in which the echo features were highly characteristic of a given pathology, such as endometrioma, cystic teratoma, hemorrhagic cyst, hydrosalpinx, benign mucinous cystoadenoma, serous cyst, and peritoneal cysts were categorized as benign. Any cystic mass containing excrescences, thick septations, multiple irregular septations or solid mass (thick wall, thick septations, thick papillary projections, solid areas or mostly solid component) in which the echo architecture was not highly suggestive of benign histology was categorized as malignant. Intraobserver and interobserver agreement according to the level of experience was assessed by calculating the kappa index. Results: Of the 98 cases randomly selected, definitive histologic diagnoses were as follows: 70 (71%) benign and 28 (29%) malignant masses. Intraobserver agreement was good or very good for all examiners with different degrees of experience (kappa = 0.72–1). Interobserver agreement was good for all expert operators (kappa = 0.69–0.75). Interobserver agreement between experts and highly experienced operators was moderate or good (kappa = 0.51–0.63). Interobserver agreement between moderately experienced operators and experts was fair to moderate (kappa = 0.29–0.46). Interobserver agreement between moderately and highly experienced operators was fair (kappa = 0.33). Conclusions: Our results indicate that typical malignant patterns are very highly reproducible even in moderately experienced examiners. More experience was associated with better interobserver agreement.