What women with ovarian cancer think and know about genetic testing

ObjectivesFew women with ovarian cancer undergo genetic testing for the Breast and Ovarian Cancer susceptibility genes, BRCA1 and BRCA2. With the prospect of BRCA-directed therapeutics, we investigated ovarian cancer patients' knowledge and willingness to undergo genetic testing.MethodsAll ovarian cancer patients seen in the Gynecology Center of a cancer center and a private clinic were asked to complete an anonymous questionnaire regarding knowledge and willingness to undergo BRCA testing. Women who had prior genetic testing were asked not to participate. Data was analyzed using Fisher's exact test.ResultsTwo-hundred and thirty seven ovarian cancer patients voluntarily completed the questionnaire. Fifty-five percent (131/237) of participants had not heard of BRCA testing. Of Caucasian respondents, 51% were unaware of BRCA testing, compared to 70% of Hispanic and 88% of African American respondents (p = 0.008). Awareness was correlated with education (p < 0.001). Eighty-nine percent of participants were willing to be tested if it would directly affect their therapy and 86.9% would be tested to benefit their family. Seventy-four percent of patients would pay 20% of the cost of testing, only 25.1% would pay in full.ConclusionsA majority of women with ovarian cancer are not aware of the availability of BRCA testing. This lack of awareness is more profound in minorities. Despite lack of knowledge, most patients would undergo testing if it would impact their care. However, cost may be a barrier. Given the willingness of patients to undergo testing and the possibility of targeted therapy, clinicians who care for these patients should work to make appropriate genetic counseling referrals.     

The biological and biochemical effects of CP-654577, a selective erbB2 kinase inhibitor,on human breast cancer cells

Aberrant expression or activity of epidermal growth factor receptor (EGFr) or the closely related p185(erbB2) can promote cell proliferation and survival and thereby contribute to tumorigenesis. Specific antibodies and low molecular-weight tyrosine kinase inhibitors of both proteins are in clinical trials for cancer treatment. CP-654577 is a potent inhibitor selective for p185(erbB2), relative to EGFr tyrosine kinase, and selectively reduces erbB2 autophosphorylation in intact cells. Treatment of SKBr3 human breast cancer cells with CP-654577 reduces the levels of the activated form of mitogen-activated protein kinase, increases the levels of cyclin-dependent kinase inhibitor p27(kip1) and reduces expression of cyclins D and E. These biochemical changes result in a reduced level of phosphorylated retinoblastoma protein and an inhibition of cell-cycle progression at G(1). Apoptosis is triggered in both SKBr3 and another high erbB2-expressing cell line, BT474, by exposure to 1 micro M CP-654577, but this effect is not observed in MCF7 cells that express low erbB2. Levels of activated Akt, an important positive regulator of cell survival, are reduced within 2 h of exposure to 250 nM CP-654577, and this may contribute to the increased apoptosis. These biochemical effects are distinct from those produced by Tarceva, a selective EGFr inhibitor. The antitumor activity of CP-654577 was investigated in athymic mice bearing s.c. tumors from Fischer rat embryo fibroblasts transfected with erbB2. CP-654577 produced a dose-dependent reduction of p185(erbB2) autophosphorylation and inhibited the growth of these tumors. CP-654577 warrants further evaluation in tumors with high expression of p185(erbB2) and may differ from selective EGFr inhibitors or nonselective dual EGFr/erbB2 inhibitors in efficacy and therapeutic index.     

Cervical Concentrations of Interleukin-10 and Interleukin-12 Do Not Correlate with Plasma Levels

Human papillomavirus (HPV) infects the transformation zone of the cervix and is the primary cause of cervical cancer. The infection is localized to the cervix and mucosal immunity is likely to be an important determinant for viral clearance. Previous studies of immunity to HPV have measured immune markers in the blood, but the relationship of systemic immunity to cervical immunity is poorly understood. In this study of 70 women enrolled in the ASCUS-LSIL Triage Study (ALTS), a clinical trial for management of low-grade cytologic abnormalities of the cervix, we collected paired plasma and cervical secretions to investigate the relationship between cervical concentrations of interleukin-10 (IL-10) and interleukin-12 (IL-12) and plasma levels. Neither IL-10 ( = 0.11), or IL-12 ( = –0.04) nor the ratio of IL-12 to IL-10 ( = 0.06) were correlated between blood and cervical secretions. Except for weak correlations of IL-10 among nonsmokers ( = 0.35, P = 0.019) and those in day 18–27 of their menstrual cycle ( = 0.51, P = 0.015), this lack of correlation persisted in all subgroups defined by genital inflammation or infection, current oral contraceptive use, heme contamination and volume of collected secretions, HPV16 seropositivity, and repeat HPV infection and/or cytologic abnormalities. The lack of correlation and high concentrations in cervical secretions indicate that the cervical IL-10 and IL-12 concentrations exceed what could be expected from blood as a principle source of IL-10 and IL-12 and suggest that cytokine concentrations in cervical secretions are predominantly the result of local cytokine production.     

Cerebral white matter contains PDGF-responsive precursors to O2A cells

Cells dissociated from the cerebral white matter of immature rats were maintained in monolayer culture. Treatment with platelet-derived growth factor (PDGF) caused a large increase in the numbers of "O2A" oligodendroglial precursor cells (which bind the monoclonal antibody A2B5) and subsequently in the numbers of galactocerebroside (galC)-positive oligodendroglia. A2B5-negative "pre-O2A cells" in cerebral white matter cultures in which O2A cells and oligodendroglia had been killed by antibody-dependent complement-mediated cytolysis were induced by PDGF to proliferate and to differentiate into O2A cells and subsequently into oligodendroglia and type 2 astroglia. The most mature pre-O2A phenotype in these cultures was a small, round, process-bearing cell which expressed vimentin but not glial fibrillary acidic protein or galC. Cells of this phenotype were not observed upon PDGF treatment of immature rat optic nerve monolayer cultures from which O2A cells and oligodendrocytes had been depleted, and PDGF also failed to elicit the accumulation of O2A cells and oligodendroglia in such cultures.     

An immunomagnetic-based method for the purification of ovarian cancer cells from patient-derived ascites.

OBJECTIVE: Primary ovarian cancer cells obtained from fresh tumor have many advantages over established cell lines. Therefore, a procedure for the specific and efficient purification of such neoplastic cells is critical. We report an effective immunomagnetic method for the isolation of tumor cells from the ascitic fluid of patients diagnosed with ovarian adenocarcinoma. METHODS: This procedure incorporates the use of monoclonal antibody (mAb) CC49, which recognizes the tumor-associated glycoprotein 72 (TAG-72). TAG-72 is highly expressed on ovarian tumor cell surfaces with little or no reactivity with normal tissues. Also used in this protocol are immunomagnetic beads, which bind to the CC49 mAb via a secondary antibody. When ovarian cancer cells adhere to the magnetic beads, a magnetic field is used to separate the tumor cells from all other cellular components. RESULTS: Using ascitic fluid from five patients, we found that preparations before purification contained between 38 and 52% neoplastic cells. Using our method, we produced preparations that were between 63 and 96% pure for cancer cells, thus obtaining an average increase in tumor cell enrichment of 86%. CONCLUSION: We, therefore, believe this method is preferable for producing high yields of pure ovarian neoplastic cells. We are now employing this technique in our laboratory to provide a stringent and pure template for our studies on gene transfer to primary ovarian cancer cells.     

Current strategies in gene therapy for ovarian cancer

The application of gene therapy strategies for ovarian cancer has employed various viral and nonviral vectors. Thus far, adenovirus has been the most promising vehicle for gene replacement but the use of non DNA-based viruses is also being explored. Recent novel advances in gene therapy approaches include refinement of vector targeting and the use of site-specific promoters and conditionally replicative adenoviral vectors. Although several clinical trials have documented the relative safety of gene therapy in ovarian cancer patients, few significant clinical responses have been effected. However, advances in the field are occurring rapidly and this strategy does appear promising for the treatment of ovarian cancer.     

Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway

Lysophosphatidic acid (LPA) is an important intercellular signaling molecule involved in a myriad of biological responses. Elevated concentrations of LPA are present in the ascites and plasma of ovarian cancer patients suggesting a role for LPA in the pathophysiology of ovarian cancer. We have demonstrated previously that oleoyl (18:1) LPA at concentrations present in ascites induces the secretion of urokinase plasminogen activator (uPA) from ovarian cancer cells, possibly linking LPA to cellular invasion. In this study we sought to elucidate which signaling pathway(s) are involved in LPA-mediated secretion of uPA from ovarian cancer cells. Specific inhibitors were utilized to determine if interference with the p38(MAPK), p42/44(MAPK), and PI3K pathways functionally blocked LPA-mediated uPA secretion. LPA stimulation of ovarian cancer cells markedly increased the phosphorylation and activity of p38(MAPK), p42/p44(MAPK), and PI3K. Both tyrosine phosphorylation and Src kinase activity were required for optimal activation of signaling by LPA including phosphorylation of p38(MAPK). Inhibition of p38(MAPK) signaling by SB202190 completely abrogated LPA-induced uPA secretion, while inhibition of the p42/44(MAPK) or PI3K pathways with PD98059 or wortmannin and LY294002, respectively, decreased but did not completely block uPA secretion. In contrast, inhibitors of phospholipase D or the p70S6 kinase pathway did not alter LPA-induced uPA secretion. Further, tyrosine phosphorylation and functional Src were required for optimal uPA secretion. Finally, LPA induces uPA secretion from ovarian cancer cells predominantly through the LPA2 receptor, with LPA3 contributing to this process. These results indicate that the p38(MAPK) signaling pathway is required for optimal LPA-dependent uPA secretion from ovarian cancer cells.     

Unicornuate uterus with a rudimentary horn and ovarian dysgerminoma. A case report

BACKGROUND: Several documented cases of endometrial and cervical carcinoma arising in unicornuate uteri have been described; however, ovarian malignancy occurring in conjunction with this müllerian anomaly has not been reported. CASE: An 18-year-old woman had a unicornuate uterus, noncommunicating rudimentary horn and homogeneous, solid, right ovarian mass found to be a dysgerminoma at surgery. CONCLUSION: Müllerian anomalies are unlikely to predispose women to ovarian malignancies. However, it is essential to keep in mind that women with such anomalies, though presenting at a young age, could still have cervical, uterine or even ovarian malignancies.     

Guided vs. non-guided insertion of Ambu AuraGain™ in edentulous patients

Die Anaesthesiologie - Supraglottic airway devices perform more poorly and have lower oropharyngeal leak pressure in edentulous patients than in patients with teeth. The Ambu Aura Gain is...