Emir Henic

Cleaved Forms of the Urokinase Plasminogen Activator Receptor in Plasma Have Diagnostic Potential and Predict Postoperative Survival in Patients with Ovarian Cancer

Purpose: To evaluate the plasma level of different forms of soluble urokinase plasminogen activator receptor (suPAR) as discriminators between malignant, borderline, and benign ovarian tumors and as prognostic markers in patients with ovarian cancer. Experimental Design: The different suPAR forms were measured in preoperative plasma samples obtained from 335 patients with adnexal lesions using three different time-resolved fluoresence assays (TR-FIA): TR-FIA 1 measuring intact suPAR, suPAR(I-III), TR-FIA 2 measuring the total amount of suPAR(I-III) and the cleaved form, suPAR(II-III), and TR-FIA 3 measuring the liberated uPAR(I). Tumors were classified as benign (n = 211), borderline (possibly malignant; n = 30), and well (n = 19), moderately (n = 15), and poorly (n = 60) differentiated malignant. Results: All uPAR forms as well as CA125 were statistically significant in univariate analysis discriminating between benign, borderline, and invasive tumors. Restricting the analysis of invasive tumors to early stage (I and II) showed similar results. A combination of CA125 and suPAR(I-III) + suPAR(II-III) discriminated between malignant (all stages) and benign tumors [AUC, 0.94; 95% confidence interval (95% CI), 0.90-0.98] as well as borderline and benign tumors (AUC, 0.78; 95% CI, 0.67-0.89). All suPAR forms were markers for poor prognosis in univariate analyses, and high preoperative plasma level of uPAR(I) is an independent predictor of poor prognosis (hazard ratio, 1.84; 95% CI, 1.15-2.95; P = 0.011) in multivariate analyses including age and CA125. Conclusions: High concentration of plasma uPAR(I) is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The combination of plasma suPAR(I-III) + suPAR(II-III) and CA125 discriminates between malignant and benign tumors with an AUC of 0.94.

The G protein-coupled estrogen receptor 1 (GPER/GPR30) does not predict survival in patients with ovarian cancer

BackgroundEven though ovarian tumors are not generally considered estrogen-sensitive, estrogens may still have an impact on ovarian tumor progression. The recently identified trans-membrane estrogen receptor GPER is involved in rapid estrogen signaling. Furthermore, it binds selective estrogen receptor modulators with agonistic effect, which could explain tamoxifen controversies.MethodsGPER mRNA was assayed with quantitative real-time PCR (qPCR) in 42 primary ovarian tumors and 7 ovarian cancer cell lines. ERα and ERβ mRNA were analyzed for comparison. GPER protein was semi-quantified with densitometric scanning of Western blots and its tissue distribution analyzed with immunohistochemistry (IHC) in 40 ovarian tumors. In addition, IHC was evaluated in a tissue microarray (TMA) of 150 primary malignant ovarian tumors.ResultsAll tumor samples contained GPER mRNA. The content of mRNA was not different between benign and malignant tumors, but one third of malignant samples over-expressed GPER mRNA. The content of ERα mRNA was higher in malignant than in benign tumors, whereas ERβ mRNA was higher in benign than in malignant tumors. GPER mRNA was detected in all seven ovarian cancer cell lines with highest levels in TOV21G and TOV112D cells. Similar expression pattern was seen for ERβ mRNA. Western blot demonstrated GPER protein in all tumor samples. Semi-quantification showed no difference between benign and malignant tumors, but about one third of malignant samples over-expressed GPER protein. GPER staining was localized mainly in epithelial cells. In the TMA study we found no correlation between GPER staining and clinical stage, histological grade or patient survival.ConclusionsGPER mRNA as well as GPER protein is present in both benign and malignant ovarian tumor tissue. About one third of malignant tumors over-expressed both GPER mRNA and protein. This, however, correlated neither with histological or clinical parameters nor with patient survival.

High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer

AbstractThe aim of this study was to assess the clinical value of preoperative blood levels of HE4 as a predictor of overall survival in patients with ovarian cancer and to validate previous data of HE4 and the ROMA algorithm including HE4 and CA125 in discriminating benign and malignant ovarian tumors.Experimental designThe preoperative plasma levels of HE4 and CA125 were analyzed with ELISA in 312 patients with adnexal lesions. Tumors were classified as benign (n= 206), borderline (i.e. low malignant potential tumors) (n= 25), and well (n= 14), moderately (n= 15), and poorly (n= 51) differentiated malignant.ResultsIn univariate Cox regression analyses high levels (dichotomized at the median) of HE4, CA125, increased age (continuous variable), advanced-stage of disease 2–4, histological grade 3 and non-optimal tumor debulking at primary surgery were all significantly associated with shorter overall survival. A multivariate Cox regression model including pre-operative available covariates HE4 and CA125 both dichotomized at median in addition to age as continuous variable showed that high levels of HE4 was an independent prognostic marker for worse prognosis HR 2.02 (95% CI 1.1-3.8). In postmenopausal women the ROMA algorithm gave the highest AUC of 0.94 (95% CI, 0.90-0.97) which was higher than the separate markers HE4 AUC 0.91 (95% CI 0.86-0.95) and CA125 AUC 0.91(95% CI 0.87-0.96).ConclusionsHigh concentration of plasma HE4 is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The algorithm ROMA discriminates in postmenopausal women between malignant and benign tumors with an AUC of 0.94.

Estradiol attenuates EGF-induced rapid uPAR mobilization and cell migration via the G-protein-coupled receptor 30 in ovarian cancer cells.

Epidermal growth factor (EGF) stimulates proliferation and migration in ovarian cancer cells, and high tumor expression of the EGF system correlates with poor prognosis. Epidermal growth factor upregulates urokinase plasminogen activator receptor (uPAR) on the cell surface via 3 distinct mechanisms: rapid mobilization of uPAR from detergent-resistant domains, increased mRNA, and decreased degradation. G-protein-coupled receptor 30 (GPR30) is a newly identified membrane estrogen receptor (ER). The objective of this study was to explore the effects of 17β-estradiol (E2) on uPAR expression and cell migration in ovarian cancer cells and further to identify the ER involved. We used 7 ovarian cancer cell lines, cell migration assay, cellular binding of 125I-uPA, cellular degradation of 125I-uPA/PAI-1 complex, enzyme-linked immunosorbent assay for uPAR, solid-phase enzyme immunoassay for ER&agr;, and quantitative polymerase chain reaction. Estradiol attenuates the stimulatory effect of EGF on cell migration and uPAR expression. Specifically, E2 reduces the very rapid increase of detergent extractable uPAR, which occurs within minutes of EGF stimulation and probably represents mobilization of uPAR from detergent-resistant domains such as lipid rafts. Estradiol influenced neither the amount of uPAR mRNA nor the rate of uPAR degradation or solubilization. The nuclear ER antagonists ICI 182780 and tamoxifen, which are GPR30 agonists, as well as the specifically constructed GPR30 agonist G1, mimicked the effect of E2 on uPAR expression and cell migration. OVCAR-3 cells express mRNA for GPR30. Estradiol attenuates EGF-induced mobilization of ligated uPAR from detergent-resistant domains and subsequent migration in ovarian cancer cells. The response to various ER ligands indicates that this effect is mediated via the membrane ER GPR30.

Vaginal self-sampling without preservative for human papillomavirus testing shows good sensitivity.

BACKGROUND Several strategies have been used to reach non-attending women in organized cervical-cancer-screening programs, with varying success. Self-sampling (SS) for HPV is effective for increasing coverage in screening programs, but requires expensive commercial sampling kits. OBJECTIVE We aimed to evaluate if vaginal SS, without commercial preservatives was adequate for HPV testing. STUDY DESIGN Women with abnormal cervical smears as determined from the organized screening program were invited to a colposcopy clinic. The 121 women were asked to insert a cotton swab into the vagina and rotate it, put the cotton swab into a sterile cryotube, break the upper part of the stick and put the cap on. Thereafter, the gynaecologist collected a liquid based cytology (LBC) sample. The presence of HPV-types in SS and LBC samples was analysed with PCR and luminex-based typing. RESULTS High-risk-HPV (hr-HPV) DNA was found in 65 of the tested 108 SS (60%; 95% CI 0.50-0.69), whereas LBC found hr-HPV in 64/108 samples (59%; 95% CI 0.49-0.69). The agreement between sampling with SS and LBC was good, kappa value 0.67 (95% CI; 0.53-0.81). The sensitivity for SS with hr-HPV to find HSIL was 77% (95% CI; 62-91%), specificity 47% (95% CI; 35-59%) [corrected] and the sensitivity for LBC with hr-HPV to find HSIL was 79% (95% CI 66-93%), specificity 50% (95% CI; 38-62%). [corrected] CONCLUSIONS This new vaginal self-sampling method detects hr-HPV-infections with similar sensitivity as a cervical smear taken by a gynaecologist. This self-sampling method is cost-effective and well tolerated, and the kit is suitable for regular mail transport.

Mannan-binding lectin in women with a history of recurrent vulvovaginal candidiasis.

OBJECTIVES To determine the serum concentration of mannan-binding lectin (MBL), a component of the innate immune system, in women with a history of recurrent vulvovaginal candidiasis (RVVC) and to correlate the result to candida-cultures, contraceptive use, if any, and to different antifungal therapies. STUDY DESIGN Twenty-nine women with a history of RVVC were investigated. Cultures of vulvar and vaginal samples were grown on chromogenic agar. Serum levels of MBL were determined by a sandwich time-resolved immunofluorometric assay, using anti-MBL coated microtiter wells containing samples, which were washed, incubated with biotinylated anti-MBL followed by europium-labeled streptavidin and measured by time-resolved flourometry. RESULTS The median MBL level was higher in the RVVC cases than in 30 women with no history of genital candida infection who served as a comparison group (p=0.006). It was also higher in the candida-positive than in the culture-negative RVVC (p=0.02). The median concentration of MBL was also higher in hormonal contraceptive users as compared to condom-users and those using no contraceptive at all (p=0.03). CONCLUSION The result indicates a role of MBL in RVVC and the production may correlate to vulvar/vaginal colonization by Candida, hormonal contraceptive use, and antifungal therapies.

Follow up with HPV test and cytology as test of cure, 6 months after conization, is reliable

Human papillomavirus (HPV) infection is an objective marker with a high sensitivity for finding cervical dysplasia. The objective of the current study is to investigate whether HPV testing, combined with liquid‐based cytology, is reliable as a test of cure after the loop electrical excision procedure (LEEP).

Deliveries after malignant disease before pregnancy: Maternal characteristics, pregnancy, and delivery complications

PURPOSE Survival after cancer has increased, and the question of risks in later pregnancies has become important. A previous malignancy may affect pregnancy outcome. METHODS Comparison of women with malignant disease before pregnancy with all other women giving birth during 1994-2011. Data were obtained by linkage between Swedish national health registers. Subfertility, evaluated as time to pregnancy, and in vitro fertilization (IVF) before the relevant delivery were studied. The following delivery diagnoses were studied: gestational diabetes, preeclampsia, placenta previa, placenta abruption, placenta retention, bleeding around delivery, and premature rupture of membranes. The rates of cesarean section and vacuum extraction or forceps delivery were also studied. RESULTS We identified 3931 women with 7176 deliveries and with a malignancy diagnosed at least 1 year before the delivery. The total number of deliveries in Sweden in these years was 1,746,870. Overall, an increased risk of subfertility (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.28), use of IVF (OR = 1.36, CI 1.21-1.53), delivery complications (OR = 1.17, 95% CI 1.10-1.24), and rate of caesarean sections (OR = 1.27, 95% CI 1.20-1.34) was observed among women with a history of malignancy compared with other women. CONCLUSION We found an increased risk of subfertility, pregnancy, and delivery complications in women with a history of malignant disease. Further studies are needed to evaluate the risks of specific treatments and to provide these women with reliable information that could affect their family planning.

Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses

Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss.

Congenital malformations in offspring of women with a history of malignancy

BACKGROUND Survival after malignancy has increased and the question of risks, including risk for congenital malformations for the offspring of these women has become important. Data on congenital malformations in such offspring are limited. METHODS We compared congenital malformation in offspring, born 1994 to 2011 of women with a history of malignancy (at least 1 year before delivery) with all other offspring. Adjustment for confounders was mainly made by Mantel-Haenszel methodology. Data were obtained by linkage between Swedish national health registers. RESULTS We identified 71,954 (4.1%) infants with congenital malformation, of which 47,081 (2.7%) were relatively severe (roughly corresponding to major malformation). Among 7284 infants to women with a history of malignancy 204 relatively severe malformations were found (2.8%; odds ratio [OR] = 1.04; 95% confidence interval [CI], 0.91-1.20). After in vitro fertilization, the risk of a relatively severe malformation was significantly increased in women without a history of malignancy (OR = 1.31; 95% CI, 1.24-1.38) and still more in women with such a history (risk ratio = 1.85; 95% CI, 1.08-2.97). However, there were no significant differences neither, for any malformations (OR = 1.04; 95% CI, 0.92-1.16) nor for relatively severe malformations (OR = 1.04; 95% CI, 0.91-1.20), when comparing offspring only after maternal history of malignancy. CONCLUSION No general increase in malformation rate was found in infants born to women with a history of malignancy. A previously known increased risk after in vitro fertilization was verified and it is possible that this risk is further augmented among infants born of women with a history of malignancy. Birth Defects Research 109:224-233, 2017.