The importance of ERα and ERβ gene polymorphisms in PCOS

Estrogens act through binding to estrogen receptor α (ERα) and β (ERβ). Studies in knockout mice have shown that the absence of ERα leads to the polycystic ovary syndrome (PCOS) phenotype. Furthermore, the expression of ERβ gene is lower in follicles derived from women with PCOS compared with healthy women. The aim of this study was to investigate the importance of ERα and ERβ gene polymorphisms in PCOS. A cohort of 180 women with PCOS and 140 healthy controls were recruited, and the PvuII and XbaI polymorphisms of ERα, as well as, the AluI and RsaI polymorphisms of ERβ were genotyped. No difference was found in the distribution of these polymorphisms between patients and healthy controls. However, in PCOS women, carriers of TC and TT genotypes of PvuII polymorphism had lower fasting glucose to insulin ratio compared with carriers of CC genotype (p = 0.029). In addition, the presence of AA genotype of XbaI polymorphism was associated with lower levels of follicle-stimulating hormone (FSH) compared with the presence of AG and GG genotypes (p = 0.03). The association of ERα polymorphisms with insulin resistance indices and FSH levels emphasizes the importance of ERα as a genetic modifier of the PCOS phenotype.     

A nationwide study of ovarian serous borderline tumors in Denmark 1978–2002. Risk of recurrence,and development of ovarian serous carcinoma

Objective

Absolute risk and risk factors for recurrence and ovarian serous carcinoma following ovarian serous borderline tumors (SBTs) is not well-established.

A multicenter phase II study of gemcitabine, paclitaxel, and cisplatin in chemonaïve advanced ovarian cancer

OBJECTIVES: The objectives of this multicenter phase II study were to evaluate the effects of gemcitabine-paclitaxel-cisplatin combination chemotherapy on response rate, survival, and toxicity in patients with advanced epithelial ovarian cancer (AEOC). METHODS: Chemonaive AEOC patients with bidimensionally measurable disease or an elevated serum cancer antigen 125 level received cisplatin (70 mg/m(2)) on day 1 and paclitaxel (80 mg/m(2)) and gemcitabine (1000 mg/m(2)) on days 1 and 8, every 3 weeks. RESULTS: Between October 2000 and September 2001, 46 patients were enrolled. Sixteen patients underwent debulking surgery prior to chemotherapy. In 45 evaluable patients, overall response rate was 64.4% (7 CR and 22 PR). Median time-to-progression was 13.4 months (95% CI, 9.6-17.4 months); median progression-free survival was 12.3 months (95% CI, 8.8-15.6 months); median overall survival was 26.0 months (95% CI, 18 months-not reached); and 1-year survival was 74% (95% CI, 60-88%). The relative dose intensities of gemcitabine, paclitaxel, and cisplatin were 81.4%, 80.2%, and 89.8%, respectively. Grade 3/4 neutropenia was the predominant hematologic toxicity observed (73.9% of patients) followed by grade 3/4 leukopenia (56.5%), anemia (45.7%), thrombocytopenia (23.9%), and febrile neutropenia/neutropenic sepsis (26.1%). The predominant grade 3 nonhematologic toxicities were alopecia (43.5%) and diarrhea (19.6%). Grade 4 nonhematologic toxicities were nausea/vomiting, constipation, and uremia (2.2% each). Two treatment-related deaths occurred (neutropenic sepsis and uremia). CONCLUSION: Gemcitabine-paclitaxel-cisplatin combination chemotherapy is active with manageable toxicity in chemonaive patients with advanced ovarian cancer and should be explored in larger phase III trials.     

Migfilin, α-parvin and β-parvin are differentially expressed in ovarian serous carcinoma effusions,primary tumors and solid metastases

ObjectiveThe objective of this study is to analyze the expression and clinical role of integrin-linked kinase (ILK), α-parvin, β-parvin and migfilin in advanced-stage serous ovarian carcinoma.MethodsExpression of these 4 proteins was investigated in 205 effusions and in 94 patient-matched solid lesions (33 primary tumors and 61 solid metastases) using immunohistochemistry. Protein expression was analyzed for association with clinicopathologic parameters and survival.ResultsILK, α-parvin, β-parvin and migfilin were expressed in tumor cells in 53%, 2%, 28% and 53% of effusions and 57%, 20%, 83% and 25% of solid lesions, respectively. Statistical analysis showed significantly higher α-parvin and β-parvin expression in primary carcinomas (p = 0.02 and p = 0.001, respectively) and solid metastases (p = 0.001 and p < 0.001, respectively), compared to effusions, with opposite findings for migfilin (p = 0.006 and p = 0.008 for primary carcinomas and solid metastases, respectively). ILK expression was comparable at all anatomic sites. β-Parvin expression in effusions was associated with better response to chemotherapy at diagnosis (p = 0.014), with no other significant association with clinicopathologic parameters or survival. Expression in primary tumors and solid metastases was similarly unrelated to clinicopathologic parameters or survival.ConclusionsThis study provides further evidence to our previous observations that the adhesion profile of ovarian serous carcinoma cells in effusions differs from their counterparts in primary carcinomas and solid metastases. β-Parvin may be a novel marker of chemoresponse in metastatic ovarian carcinoma.     

The clinical significance of the expression of the metastasis suppressor gene KAI1 in epithelial ovarian carcinoma

It was reported that impairment of cell adhesionplays a vital role in tumor progression,particularly ininvasive and metastatic properties[1].KAI1is a re-cently identified metastasis suppressor gene.It belongsto transmembrane4superfamily(TM4SF),which in-volved in tumor cells growth,adhesion and motility.Itwas noted later that KAI1protein expression was down-regulated during the progression of human prostatecancer[2].Down regulation of KAI1was reported to beassociated with an increased rate…     

VEGF,PIGF and HIF-1α in placentas of early- and late-onset pre-eclamptic patients

Abstract

Purpose: The aim of this study was to compare the VEGF, PIGF, and HIF-1α levels in the placentas of early- and late-onset pre-eclamptic patients, which are thought to be important in pathophysiology of pre-eclampsia.

Material and method: Pre-eclamptic early-onset (n?=?22) and late-onset (n?=?24) pregnant women and a control group of healthy pregnant women (n?=?22) were recruited for this case–control study. A semi-quantitative immunohistochemical analysis of VEGF, PIGF and HIF-1α was performed in cross-sections of the placentas of the subjects, after which results were compared.

Results: Levels of VEGF and PIGF in the placentas of pre-eclamptic patients were found to be lower than the levels in the placentas of healthy pregnant women (p?<?0.001 and p?=?0.025, respectively), whereas the levels of HIF-1α were found significantly higher (p?<?0.001). No difference was observed in terms of VEGF, PIGF and HIF-1α in a comparison of the early- and late-onset pre-eclampsia groups (p?>?0.05).

Conclusion: The results of the study indicated that there is no relationship between the time of onset of pre-eclampsia and the placental changes that occur in these factors.     

Prognostic significance of the estrogen receptor beta (ERβ) isoforms ERβ1, ERβ2, and ERβ5 in advanced serous ovarian cancer

Objective

In the present study we have examined the pattern of expression of the full length estrogen receptor β (ERβ1) and two ERβ splice variant isoforms (ERβ2, ERβ5) in well-characterized advanced serous ovarian cancers.

Methods

Immunohistochemistry was performed with ERβ1, ERβ2, and ERβ5 antibodies and results were correlated with pathological and clinical follow-up data. Expression of ERβ isoforms in a panel of ovarian cancer cell lines and human tumor xenografts was also assessed.

Results

Immunohistochemical staining revealed cellular compartment-specific distribution for each isoform in malignant ovarian tissues exhibiting both nuclear staining and cytoplasmic staining. Patients with cytoplasmic ERβ2 expression had significantly worse outcome (p = 0.006 at the multivariate analysis), the 5-year survival rate being nearly 28% for patients who did express cytoplasmic ERβ2, and 60% in negative patients. Cytoplasmic ERβ2 expression was also found to be significantly associated with chemoresistance. In concordance with clinical results both nuclear and cytoplasmic expressions were observed for the three isoforms in the cancer cell lines and human tumor xenografts tested.

Conclusions

This is the first study to uncover an unfavorable prognostic role of ERβ2 in advanced serous ovarian cancer. If anomalies of ERβ2 cytoplasmic expression could be demonstrated to represent an independent unfavorable prognostic marker and/or a marker predicting chemoresistance in advanced serous ovarian cancer, its immunohistochemical assessment at the time of surgery, could help to recognize candidates for clinical trials of new interventions.     

Platelet-derived growth factor receptor alpha (PDGFRα) targeting and relevant biomarkers in ovarian carcinoma

Objective

Platelet-derived growth factor receptor alpha (PDGFRα) is believed to be associated with cell survival. We examined (i) whether PDGFRα blockade enhances the antitumor activity of taxanes in ovarian carcinoma and (ii) potential biomarkers of response to anti-PDGFRα therapy.

Methods

PDGFRα expression in 176 ovarian carcinomas was evaluated with tissue microarray and correlated to survival outcome. Human-specific monoclonal antibody to PDGFRα (IMC-3G3) was used for in vitro and in vivo experiments with or without docetaxel. Gene microarrays and reverse-phase protein arrays with pathway analyses were performed to identify potential predictive biomarkers.

Results

When compared to low or no PDGFRα expression, increased PDGFRα expression was associated with significantly poorer overall survival of patients with ovarian cancer (P = 0.014). Although treatment with IMC-3G3 alone did not affect cell viability or increase apoptosis, concurrent use of IMC-3G3 with docetaxel significantly enhanced sensitization to docetaxel and apoptosis. In an orthotopic mouse model, IMC-3G3 monotherapy had no significant antitumor effects in SKOV3-ip1 (low PDGFRα expression), but showed significant antitumor effects in HeyA8-MDR (high PDGFRα expression). Concurrent use of IMC-3G3 with docetaxel, compared with use of docetaxel alone, significantly reduced tumor weight in all tested cell lines. In protein ontology, the EGFR and AKT pathways were downregulated by IMC-3G3 therapy. MAPK and CCNB1 were downregulated only in the HeyA8-MDR model.

Conclusion

These data identify IMC-3G3 as an attractive therapeutic strategy and identify potential predictive markers for further development.     

Conservative treatment of a young patient with thyroid carcinoma in adult ovarian teratoma – case report

The cystic mature teratomas, including dermoid cysts, are one of the most frequently occurring benign ovarian tumors diagnosed in female patients. The process of neoplastic transformation in mature dermoid cysts is applicable only to 1–2% of cases. In our article, we present a rare case of thyroid carcinoma development in adult teratoma in 21-year-old patient. The young age, certain pathomorphological features and clinical data (small size of neoplastic lesion, correct values of tumour markers, unilateral character, regular levels of thyreoglobulin and absence of any significant deviations in imaging examinations), were the basis for attempting to apply the conservative treatment both in the scope of gynecological surgery and in the supplemental endocrinological therapy. In the patient, the one-sided adnexectomy was performed, considering pathological lesions on the adnexa, as well as the other ovary dermoid cyst was enucleated, without the hysteroctomy procedure. Considering the lack of any morphological lesions and functional changes relating to thyroid gland, the treatment was not radicalised in this scope, either. At present, one year after the primary operation treatment, the patient does not manifest any disease symptoms, whereas the other ovary, in the follow-up ultrasound examinations, shows normal size and echostructure. The thyroid-stimulating hormone (TSH) suppression keeps being applied.     

What's new in the pathogenesis and prevention of ovarian hyperstimulation syndrome?

Several pathophysiological mechanisms have been proposed for the development of ovarian hyperstimulation syndrome (OHSS), such as activation of the ovarian renin--prorenin--angiotensin system, release of ovarian cytokines and nitric oxide, but numerous reports now attest to the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen, as an important mediator of the syndrome. Luteinizing hormone (LH) or human chorionic gonadotrophin (hCG) regulates VEGF production by the ovary. Formation of multiple follicles, as seen in regimens of ovarian stimulation used for in vitro fertilization (IVF), and intensified sensitivity towards human menopausal gonadotrophin (hMG) and hCG, as seen in women with polycystic ovaries (PCO) or polycystic ovary syndrome (PCOS), result in increased serum VEGF concentrations, probably due to enhanced VEGF production by the ovaries. It is possible that the hypersecretion of VEGF in women with PCO is due to an increase in the number of VEGF secreting cells or that the cells individually hypersecrete VEGF. This hypothesis was tested by in vitro studies on granulosa lutein cells. After the cells were stimulated with gonadotrophins and hCG, VEGF production was higher in granulosa cells obtained from women with PCO compared with those obtained from women with normal ovaries under similar culture conditions. The studies performed in vivo and in vitro were consistent with increased VEGF expression as a constitutive feature of PCO. Increased VEGF may be responsible for the fluid shift from the vascular bed to the extravascular space, which characterizes OHSS. Prevention of OHSS focuses on predicting the possibility of developing OHSS. Markers such as serum oestradiol concentrations and number of follicles on the day of hCG administration, the presence of PCO and the number of oocytes retrieved may be subject to inter-observer and inter-operator variations. As individual markers of OHSS, each of these factors predicts less than a quarter of cases of the syndrome. It has been shown that a combination of pretreatment diagnosis of PCO along with number of follicles on the day of hCG administration and 'VEGF rise' gives the highest prediction rates for the risk of developing OHSS. Neither pathogenesis nor prevention and treatment of OHSS are specific. Therefore, at present, OHSS remains a condition that cannot be avoided altogether.     

Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with Paclitaxel-Platinum?

OBJECTIVE: Recurrent ovarian carcinoma is considered an incurable disease and second-line chemotherapy is administered for extension of survival and palliation. The impact of continued antineoplastic treatment in patients with stable disease without a demonstrable response is uncertain. The aim of this analysis was to assess the value of a stabilization of the tumor size in second-line chemotherapy as an indicator of survival. METHODS: Retrospective, single-institution study of 487 consecutive patients with primary epithelial ovarian carcinoma. Inclusion criteria: (1) FIGO stage IC-IV epithelial ovarian carcinoma; (2) first-line chemotherapy with Paclitaxel and a Platinum-compound; (3) refractory, persistent, or recurrent disease diagnosed by imaging methods; and (4) intravenous second-line chemotherapy with single Topotecan or Paclitaxel-Carboplatin. Univariate and multivariate analyses of survival with the World Health Organization (WHO) tumor response parameter included as a time-dependent variable were performed. RESULTS: The response rates were (N = 100): complete response (CR) 27%, partial response (PR) 14%, stable disease (SD) 41% and progressive disease (PD) 18%. In a multivariate Cox regression analysis of survival, SD was found to be an independent prognostic factor for survival and the death hazard ratio was 0.37 (SD versus PD; 95% CI: 0.16-0.86; P = 0.02). There was no statistically significant difference in survival between patients with PR and SD (P = 0.09). CONCLUSION: In second-line chemotherapy of ovarian cancer, patients demonstrating SD have a survival benefit compared to patients with PD measured by the WHO tumor response criteria.     

Palliative care in ovarian carcinoma patients—a personalized approach of a team work: a review

Most ovarian cancer patients are diagnosed in an advanced stage; and after the initial treatment experience disease recurrence, which eventually becomes palliative. Many questions arise in this setting including how to address patients in the palliative setting, how to discuss end-of-life issues, and how to manage symptoms. In this review, we discuss the timing and setting of end-of-life discussion in the context of end-stage ovarian cancer. We review the approach to relieving disease burden by improving and decreasing symptoms. These symptoms include recurrent ascites, bowel obstruction, pain, pulmonary effusion, and deep vein thrombosis.     

Calprotectin,RAGE and TNF-α in hypertensive disorders in pregnancy: expression and significance

Objective  

To investigate the expression of calprotectin, the receptor of advanced glycation end products (RAGE) and tumor necrosis factor-α (TNF-α) in hypertensive disorders in pregnancy as well as the significance of their expression.     

Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-α in normal pregnancies and in pregnancies complicated by preeclampsia

Objectives.?The aim of this study was to investigate the relationship of maternal and umbilical cord interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) serum levels with the existence and severity of preeclampsia. A particular objective was the comparison of normal umbilical serum levels to preeclamptic values.

Materials and Methods.?The study group consisted of 24 patients with third trimester singleton pregnancies complicated by preeclampsia (15 severe and 9 mild preeclampsia). The gestational age-matched 19 healthy pregnant women were compared by study group. Maternal and umbilical serum IL-6, IL-8, and TNF-α were calculated by using enzyme-linked immunosorbent assay.

Results.?Significantly increased maternal and umbilical serum levels of IL-6, IL-8, and TNF-α were found in preeclamptic patient group in comparison with the control group. Maternal serum IL-8 and TNF-α concentration were significantly higher in patients with severe preeclampsia than in mild preeclampsia. Increased umbilical serum levels of IL-6 and IL-8 were found in severe preeclampsia than in mild preeclampsia. There were significantly higher levels of maternal serum IL-8 and TNF-α in patients with preeclampsia with IUGR than in patients with preeclampsia with normal fetal growth.

Conclusion.?Our findings suggest that increased concentrations of IL-6, IL-8, and TNF-α in the maternal and umbilical serum play a significant role in pathogenesis of preeclampsia. Alterations in maternal and umbilical serum levels of IL-6, IL-8, and TNF-α may also play role in preeclampsia complicated by intrauterine growth retardation. These associations may offer insight into the etiology and pathogenesis of preeclampsia.     

Expressions of HLA class Ⅰ and CD80 in human epithelial ovarian carcinomas

Ｈｕｍａｎｅｐｉｔｈｅｌｉａｌｏｖａｒｉａｎｃａｒｃｉｎｏｍａｓ(ＥＯＣ)ａｒｅｖｅｒｙａｇｇｒｅｓｓｉｖｅｔｕｍｏｒｓｗｉｔｈｐｏｏｒｐｒｏｇｎｏｓｉｓ .Ｉｔｉｓａｓｓｕｍｅｄｔｈａｔｔｕｍｏｒｃｅｌｌｓｍｉｇｈｔｓｕｒｖｉｖｅｂｙｅｓｃａｐｉｎｇｔｈｅｉｍｍｕｎｅｓｕｒｖｅｉｌ ｌａｎｃｅ .Ｍａｊｏｒｈｉｓｔｏｃｏｍｐａｔｉｂｉｌｉｔｙｃｏｍｐｌｅｘ(ＭＨＣ)ｍｏｌｅｃｕｌｅｓａｓｗｅｌｌａｓｔｈｅｃｏ ｓｔｉｍｕｌａｔｏｒｙｍｏｌｅｃｕｌｅＣＤ80ａｐｐｅａｒｔｏｐｌａｙａｎｉｍｐｏｒｔａｎｔｒｏ…