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The adaptive immune system is involved in tumor establishment and aggressiveness. Tumors of the ovaries, an immune-privileged organ, spread via transceolomic routes and rarely to distant organs. This is contrary to tumors of non-immune privileged organs, which often disseminate hematogenously to distant organs. Epigenetics-based immune cell quantification allows direct comparison of the immune status in benign and malignant tissues and in blood. Here, we introduce the "cellular ratio of immune tolerance" (immunoCRIT) as defined by the ratio of regulatory T cells to total T lymphocytes. The immunoCRIT was analyzed on 273 benign tissue samples of colorectal, bronchial, renal and ovarian origin as well as in 808 samples from primary colorectal, bronchial, mammary and ovarian cancers. ImmunoCRIT is strongly increased in all cancerous tissues and gradually augmented strictly dependent on tumor aggressiveness. In peripheral blood of ovarian cancer patients, immunoCRIT incrementally increases from primary diagnosis to disease recurrence, at which distant metastases frequently occur. We postulate that non-pathological immunoCRIT values observed in peripheral blood of immune privileged ovarian tumor patients are sufficient to prevent hematogenous spread at primary diagnosis. Contrarily, non-immune privileged tumors establish high immunoCRIT in an immunological environment equivalent to the bloodstream and thus spread hematogenously to distant organs. In summary, our data suggest that the immunoCRIT is a powerful marker for tumor aggressiveness and disease dissemination.

PURPOSE: This prospective study evaluates whether sonoelastography can improve B-mode ultrasonographic sizing of breast tumors. Precise measuring is important for effective therapy planning for breast cancer patients. MATERIALS AND METHODS: The size of 100 surgically excised breast lesions (92 patients: 77 malignant, 23 benign) was compared to preoperative measurements. Lesions were imaged with both ultrasonographic techniques in identical planes. The largest sizes measured with each modality were compared to the largest histopathological measurements. The interobserver variability was also computed from measurements made by two examiners assessing identical planes. RESULTS: Both ultrasonographic measuring techniques underestimate lesion size. The sonoelastography measurements were within ± 5 mm of the histological size in 70.1 % of malignant lesions, and the B-mode measurements in 57.1 % of cases. Sonoelastography leads to more accurate measurements of 13.0 % of cases (statistically not significant). A total of 22 lesions were also imaged by a second examiner. Sonoelastography had 27.3 % less interobserver variability (examiners agreed in 36.4 % of sonoelastography and in 9.1 % of B-mode results). CONCLUSION: In this study there is no significant advantage of sonoelastography, although a tendency is apparent. The low interobserver variability also favors sonoelastography for preoperative diagnostics, since it may be less dependent on the observer than conventional B-mode imaging. The results of this prospective study require validation in a prospective multicenter study with larger case numbers.

Ovarian carcinoma has the highest mortality rate among gynaecological malignancies. In this project, we investigated the hypothesis that molecular markers are able to predict outcome of ovarian cancer independently of classical clinical predictors, and that these molecular markers can be validated using independent data sets. We applied a semi-supervised method for prediction of patient survival. Microarrays from a cohort of 80 ovarian carcinomas (TOC cohort) were used for the development of a predictive model, which was then evaluated in an entirely independent cohort of 118 carcinomas (Duke cohort). A 300-gene ovarian prognostic index (OPI) was generated and validated in a leave-one-out approach in the TOC cohort (Kaplan-Meier analysis, p = 0.0087). In a second validation step, the prognostic power of the OPI was confirmed in an independent data set (Duke cohort, p = 0.0063). In multivariate analysis, the OPI was independent of the post-operative residual tumour, the main clinico-pathological prognostic parameter with an adjusted hazard ratio of 6.4 (TOC cohort, CI 1.8-23.5, p = 0.0049) and 1.9 (Duke cohort, CI 1.2-3.0, p = 0.0068). We constructed a combined score of molecular data (OPI) and clinical parameters (residual tumour), which was able to define patient groups with highly significant differences in survival. The integrated analysis of gene expression data as well as residual tumour can be used for optimized assessment of the prognosis of platinum-taxol-treated ovarian cancer. As traditional treatment options are limited, this analysis may be able to optimize clinical management and to identify those patients who would be candidates for new therapeutic strategies.

Aims: Multidrug resistance is a major impediment in chemotherapeutic treatment of ovarian carcinoma patients. The aim of this study was to investigate the expression of multidrug resistance-associated protein 1 (MRP1) and to assess the possible associations with clinicopathological variables and patient outcome in primary ovarian carcinoma. Methods and results: Tumour specimens from 129 patients were obtained before chemotherapy and analysed by immunohistochemistry on tissue microarrays, and by real-time reverse transcriptase-polymerase chain reaction on RNA extracted from formalin-fixed paraffin-embedded tissue specimens using a new technique. Significantly increased MRP1 protein expression was observed in high-grade tumours (P = 0.005) and advanced International Federation of Gynaecology and Obstetrics stages (P = 0.036). On univariate Kaplan–Meier analysis, patients with higher expression of MRP1 protein had significantly decreased overall survival (P = 0.006). On multivariate Cox regression analysis, MRP1 protein expression retained its significance as an independent negative prognostic marker for overall survival (hazard ratio = 6.52, P = 0.003). Furthermore, MRP1 expression correlated with topoisomerase IIα expression both at mRNA and protein level (P

Purpose: Vascular endothelial growth factor (VEGF), an important regulator of angiogenesis and vascular permeability, is involved in various steps of ovarian carcinogenesis. Gene polymorphisms within the gene encoding VEGF were shown to be independently associated with an adverse outcome in various malignancies. No data are available for ovarian cancer. Experimental Design: In the present multicenter study, we examined three common polymorphisms within the VEGF gene (−634G/C, −1154G/A, and −2578C/A) known to be associated with an increased VEGF production in 563 Caucasian patients with ovarian cancer from Austria and Germany using pyrosequencing. Results were correlated with clinical data. Results: The three investigated polymorphisms did not correlate with any of the investigated clinicopathologic variables. In univariate and multivariate models, no significant correlations between any polymorphism and patients' overall survival were ascertained. Simultaneous carriage of the three homozygous genotypes (i.e., VEGF −634C/C, VEGF −1154G/G, VEGF −2578C/C) known to be associated with increased VEGF expression in an individual patient, however, was independently associated with a shortened overall survival (hazard ratio, 2.1; 95% confidence interval, 1.1-3.9; P = 0.02). Conclusions: We present the first data on VEGF gene polymorphisms in ovarian cancer. Simultaneous carriage of the three investigated homozygous genotypes was shown to be an independent adverse prognosticator of overall survival.

Objective The aim of this study was to evaluate the clinicopahtological significance of telomerase activity and expression of hTERT gene in human ovarian cancer. The potential value of them as indicators for chemotherapy in ovarian cancer cells was also studied. Materials and methods A total of 73 samples and ovarian cancer cell lines HO-8910 and COC 1 were studied. Telomerase activity was detected by PCR-TRAP-ELISA assay and the expression of the hTERT mRNA was analyzed by semi-quantitative RT-PCR. Alteration of the telomerase activity and hTERT mRNA were also analyzed in the ovarian cancer cells treated with different concentration and different time of cisplatin. Cytogenetic analysis was performed to compare the telomere status in the OH-8910 cells pre- and post-cisplatin treatment. The associations between these two markers and cisplatin induced-apoptosis were respectively analyzed in COC 1 cells by the flow cytometry. Results Telomerase activity are highly increased in malignancy (0.795 ± 0.168 A450–655 nm ) than borderline (0.389 ± 0.174 A450–655 nm ), benign tumors (0.236 ± 0.102 A450–655 nm ) and normal ovary (0.213 ± 0.070 A450–655 nm ) ( p 0.05). Twenty samples showed detectable levels of hTERT. The hTERT gene positive lesion showed significantly higher telomerase activity than negative ( p = 0.004). There is a significant correlation between the telomerase activity and expression of hTERT ( r = 0.921). Both telomerase activity and expression of hTERT can reflect the chemotherapeutic effect of cisplatin in a time-dependent and dose-dependent manner. Treatment with 10 μM cisplatin, the hTERT mRNA decreased after 12 h and completely disappeared after 48 h, whereas the telomerase activity did not decrease until 24 h. Results from cytogenetic analysis and flow cytometry assay confirmed that the alterations of these two markers are associated with the anti-cancer treatment of cisplatin. Conclusion Expression of hTERT gene is rate-limiting with the activation of telomerase. Both of they may be useful in the predicting of chemotherapeutic effect in ovarian cancer.

OBJECTIVE : The aim of this study was to evaluate the expression of topoisomerase IIα ( TOP2A ) in epithelial and stromal cells of ovarian cancer. METHODS : TOP2A expression was analyzed in normal ovarian tissue and in laser-microdissected ovarian tumor epithelial and adjacent stromal cells using quantitative real time RT-PCR ( n = 38), RNA in situ hybridization ( n =13), and immunhistochemistry ( n = 69). Results : TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, with stronger hybridization signals in tumor epithelial cells compared to adjacent stromal cells. The same expression pattern was found by immunohistochemistry ( P = .0001). Very interestingly, specific changes of TOP2A were found in recurrent ovarian cancer after platinum-based chemotherapy: TOP2A expression decreased in tumor epithelial cells ( P = .056) of recurrent ovarian cancer, whereas it increased in tumor adjacent stromal cells ( P = .023) compared to primary ovarian cancer. CONCLUSION : TOP2A mRNA and protein expressions in ovarian cancer exhibit specific patterns in tumor epithelial and adjacent stromal cells, which are differentially modulated after platinum-based chemotherapy. These data support the possible importance of the stromal compartment in tumor progression and suggest that tumor stromal cells might be relevant to the development of chemotherapy resistance in ovarian cancer.

The plasminogen activator-plasmin cascade plays a central role in tumor cell invasion and metastasis of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiologic regulator of the plasminogen activation. The PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of different solid tumors. The aim of this article is to give an overview of the function, clinical and prognostic role of PAI-1 in gynaecological malignancies.

Epithelial ovarian cancer is the leading cause of death from gynaecologic malignancies in western countries. In the clinical day treatment decision of the physician (e. g. surgery, chemotherapy) based on individual prognostic factors of the patient with ovarian cancer. The tumor stage at time of diagnosis and the postoperative residual tumor mass are prognostic factors and are unequivocally related to overall survival. Other prognostic factors are identified mostly in small series and are discussed in the literature controversially. This article discussing the value of conventional prognostic factors, as stage, postoperative tumor mass, age, lymph node status, ascites) and newer molecular biological factors, as Her-2-status, PAI-1, MMP, VEGF and CD24.

Objective: Quality of Life (QoL) is increasingly relevant in the field of clinical research. Almost every clinical study analyses different aspects of QoL. The following summary discuss the question What is the value of QoL in recent studies? Results: Comparability of the studies presented was restricted due to use of different QoL definitions and measurement tools, however the following results can be summarised: In the majority of the studies QoL was applied as an outcome-parameter for specific treatment schedules. Other studies dealt with the development and validation of QoL measuring instruments. Only in a few studies was QoL a primary aim of research. The prognostic value of QoL still remains unclear in this field of research. Conclusions: QoL is an eligible outcome-parameter. QoL should be established as a primary goal in the palliative prospective-randomised studies of different treatment options. The prognostic value of QoL should be further investigated. QoL should be measured uniformly with standard instruments. Specific questionnaires (e.g. OV 28 of the EORTC) must be applied to investigate particular features of QoL.

Introduction: Visions of the future are based on expectations and assumptions as to how trends will progress. They are useful for generating better understanding of how best to prepare for the future, for example, for the planning of future investments and technological implementations. Normally such prognoses are based on expert opinion. However, the patient's point of view can deliver useful information as to expectations as well as point to deficits in the present system of managing ovarian cancer. Method: In the context of a mono-institutional, prospective study, 100 patients with a histologically proven ovarian carcinoma were interviewed informally. Results: 46 patients had a primary ovarian carcinoma and 54 of the women had a recurrence of an ovarian carcinoma. The median age of the patients at the time of interview was 59 years. The median time elapsed since first diagnosis was 3 years (ranging from 1 to 15). The distribution of the FIGO-stages was as follows: I:15%, II: 4%, III: 71% and IV: 10% What, in your opinion will the treatment of ovarian cancer be in 2010? The median number of answers was 2 (ranging from 0 to 4). Almost half of the patients hoped that chemotherapy would be easier to cope with in future. A longer life expectancy with a better quality of life was identified by 31% of patients. 26% of patients expect there to be optimised preventative methods. 20% wanted a general use of alternative therapies. How could treatment for women with ovarian cancer be improved in 2010 in comparison with today? The median number of answers was 2 (range from 0 to 4). 35% of patients wanted more time for conversation and explanations about the clinical management, 20% wanted better communication between doctors. Conclusions: Ovarian cancer patients want chemotherapy to be easier to cope with in future and especially more time and space for information, advice and explanation from doctors. The political discussion about the shape and nature of the health system needs to be taken into account when considering these results.

Einleitung: Die Mehrzahl der Patientinnen mit einem Ovarialkarzinom weist zum Zeitpunkt der Primardiagnose ein fortgeschrittenes Stadium auf. Die klinische Stadieneinteilung (FIGO) erfolgt intraoperativ. Die FIGO-Klassifikation birgt jedoch Unscharfen und kann lediglich als Orientierung des Tumorbefalls dienen. Die exakte Stadieneinteilung bei Erstdiagnose stellt aber die Grundlage fur die Beurteilung der Prognose der Erkrankung dar und hat Einfluss auf die adjuvante Behandlung.Methode: Es wurde eine systematische operative und histopathologische Tumordokumentation entwickelt, ferner wurde deren klinische und wissenschaftliche Anwendung gepruft.Ergebnisse: Zwischen September 2000 und Juli 2002 wurden insgesamt 128 Patientinnen mit primarem und rezidiviertem Ovarialkarzinom operiert und prospektiv dokumentiert. Das mediane Alter der Patientinnen bei Erstdiagnose lag bei 55 Jahren. Bei der Mehrzahl der primaren Ovarialkarzinome fand sich ein diffuses Tumorbefallmuster (lokalisiert: 18 [32 %]; zentral: 14 [25 %]; diffus: 24 [43 %]). Bei Patientinnen mit Ovarialkarzinomrezidiv traten die drei definierten Tumorbefallmuster in ahnlicher Verteilung auf (lokalisiert: 19 [28 %]; zentral: 19 [28 %]; diffus: 29 [43 %]). Wahrend beim u berwiegenden Anteil der Patientinnen mit primarem Ovarialkarzinom die hochste Tumorlast im Bereich des Unterbauches lokalisiert war, zeigte sich im Vergleich bei den Rezidiven eine deutliche Verschiebung in den Oberbauch („Etagenwechsel”, p=0,027).Schlussfolgerung: Das „IMO” (Intraoperatives Mapping des Ovarialkarzinoms) stellt ein neues Instrument fur eine detaillierte und objektivierbare Operationsdokumentation dar und dient einem exakteren Staging. Eine derartige Dokumentation kann ferner als wichtiges Instrument der Qualitatskontrolle fungieren und die Erstellung von SOP's (Standard Operation Procedures) unterstutzen. Introduction: The majority of patients diagnosed with ovarian cancer are in an advanced stage of the disease at the time of first diagnosis. The standard clinical staging (FIGO) occurs intraoperatively. The FIGO classification hides ambiguities and is useful as a means of orientation. However, an exact assessment of stage at first diagnosis, can form the basis for the evaluation of diagnostic and prognostic factors and furthermore has influence on adjuvant treatment. Method: We developed a systematic surgical and histopathological tumor documentation instrument, further we investigated its clinical and scientific application. Results: Between September 2000 and July 2002, 128 patients with primary and recurrent ovarian cancer were operated and prospectively documented. The median age of the patients at the time of first diagnosis was 55 years. The majority of patients diagnosed with primary ovarian cancer had a diffuse tumor spread pattern (localised: 18 [32 %]; central: 14 [25 %]; diffuse: 24 [43 %]). In patients diagnosed with recurrent ovarian cancer the three defined tumor spread patterns showed a comparable distribution (localised 19 [28 %]; central: 19 [28 % ]; diffused: 29 [43 %]). While in most of the patients with primary ovarian cancer the highest tumor mass was concentrated in the lower abdomen/ pelvis, in comparison, in patients with recurrent ovarian cancer it was located mostly in the upper abdomen (“change of level”, p=0,027). Conclusions: The IMO (Interoperative Mapping of Ovarian Cancer) represents a new instrument for a detailed and objective documentation of surgical and patholgical rsults of patients with ovarian cancer and helps provide a more precise staging. Potentially this prospective documentation support the developement of SOP's (Standard Operating Procedures) and could be an efficous instrument of quality management.

Topoisomerase IIalpha (Top IIalpha) is a nuclear enzyme that plays a central role in DNA metabolism, and is a molecular target for a variety of chemotherapeutic agents. Top IIalpha has recently gained attention as a biomarker for therapy response and patient survival. In this study, we attempted to assess the feasibility of measuring Top IIalpha gene expression in RNA, isolated from archival formalin-fixed paraffin-embedded tissue specimens, which are used routinely in pathology laboratories. We have employed a new technique on the basis of magnetic particles' separation and purification of nucleic acids, and evaluated both protein and mRNA expressions from the same routinely processed tissue blocks. We investigated the expression of Top IIalpha mRNA and protein by real-time reverse transcription polymerase chain reaction and immunohistochemistry, in a cohort of 133 primary ovarian carcinomas, and evaluated the association between Top IIalpha expression and clincopathological variables as well as patient outcome. Elevated Top IIalpha mRNA expression was observed in high-grade tumors (P=0.003) and advanced stage disease (P=0.011). In univariate Kaplan-Meier analysis, patients with higher expression of Top IIalpha nuclear protein had a significantly decreased overall survival (P=0.045). Interestingly, we detected cytoplasmic protein expression of Top IIalpha in a subset of samples. Cytoplasmic expression of Top IIalpha was associated with the expression of chromosomal region maintenance/exportin 1 (CRM1)-a nuclear export protein (P=0.008). Our study suggests that Top IIalpha overexpression is involved in the progression of ovarian cancer in a subset of the patients. Our results encourage the further evaluation of the prognostic and predictive values of Top IIalpha expression in ovarian carcinoma, which might help to assess the patients' risk profile, and the planning of an individualized therapy.

Cytokines play a major role in promoting the growth and metastatic spread of cancer cells. Interleukin-1 alpha and beta (IL-1) and IL-1 RA are known to be critically involved in carcinogenesis and in various solid tumors. There are limited data on expression of IL-1 alpha, beta and RA in serum and ascites in patients with advanced ovarian cancer. Objectives of this study were to investigate the level of IL-1 alpha, IL-1 beta and IL-1 RA in serum and ascites from patients with ovarian cancer and their impact on the prognosis.Fifty-three women with ovarian cancer (OC) (33 patients with primary OC and 20 with relapsed OC) and 50 women with benign gynaecological diseases as a control group (CG) were enrolled onto this prospective study. IL-1 alpha, beta and RA levels were analyzed in serum and ascites by ELISA technique.The median age was 55 years (range 19-80) in the ovarian cancer group and 40 years (range 15-89) in the controls. The distribution of histological type of ovarian cancer was as follows: serous-papillary 43 (81.1%), 4 (7.5%) mucinous, 3 (5.7%) endometroid and 3 (5.7%) clear cell carcinoma. The concentrations of IL-1 beta and RA in ascites or peritoneal fluid were significantly increased in patients with OC in comparison to the CG, for both cytokines (p0.0001); also the concentration of IL-1 RA in serum was increased in OC (p=0.003) vs. CG. An increased level of IL-1 beta in ascites correlated significantly with a poorer histopathological grading (p=0.038). IL-1 RA concentration in ascites was correlated with advanced FIGO stage (p=0.049) and the IL-1 RA serum level with ascites volume (or =500 ml vs.500 ml) (p=0.046). Patients with IL-1 RA level in ascites lower than the cut off value of 695.6 pg/ml showed a significant better progression-free median survival (24.6 vs. 12.8 months, p=0.008) and postoperative median overall survival (34.6 vs. 17 months, p=0.01) in comparison to patients with an IL-1 RA level in ascites higher than the cut off level. Additionally, a higher expression of IL-1 beta in serum (p=0.004) and ascites (p=0.05) reduced significantly the progression-free survival. In the multivariate analysis, expression of IL-1 RA in ascites was an independent prognostic factor for good progression-free and postoperative overall survival (HR, 0.39 95% CI, 0.18-0.83, p=0.01, HR, 0.36 95% CI, 0.16-0.8, p=0.01).IL-1 RA levels in ascites lower than the cut off value of 695.6 pg/ml are associated with a significant improvement in postoperative and progression-free survival. IL-1 RA shows a prognostic relevance in ovarian cancer.

Purpose: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood. Experimental Design: We developed an algorithm to identify secreted proteins encoded among ∼22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression. Results: We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls. Conclusions: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.

Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. We have used a metabolite profiling approach to test the hypothesis that quantitative signatures of primary metabolites can be used to characterize molecular changes in ovarian tumor tissues. Sixty-six invasive ovarian carcinomas and nine borderline tumors of the ovary were analyzed by gas chromatography/time-of-flight mass spectrometry (GC-TOF MS) using a novel contamination-free injector system. After automated mass spectral deconvolution, 291 metabolites were detected, of which 114 (39.1%) were annotated as known compounds. By t test statistics with P < 0.01, 51 metabolites were significantly different between borderline tumors and carcinomas, with a false discovery rate of 7.8%, estimated with repeated permutation analysis. Principal component analysis (PCA) revealed four principal components that were significantly different between both groups, with the highest significance found for the second component (P = 0.00000009). PCA as well as additional supervised predictive models allowed a separation of 88% of the borderline tumors from the carcinomas. Our study shows for the first time that large-scale metabolic profiling using GC-TOF MS is suitable for analysis of fresh frozen human tumor samples, and that there is a consistent and significant change in primary metabolism of ovarian tumors, which can be detected using multivariate statistical approaches. We conclude that metabolomics is a promising high-throughput, automated approach in addition to functional genomics and proteomics for analyses of molecular changes in malignant tumors. (Cancer Res 2006; 66(22): 10795-804)

Estrogen receptor-related receptor alpha (ERRalpha) was reported to compete with estrogen receptor alpha (ERalpha) in a constitutive manner as an orphan nuclear closely related to (ERalpha). To discuss the role of ERRalpha in the endometrial carcinoma cells, this study was performed. ER-responsive endometrial carcinoma cells Ishikawa and ER-nonresponse HEC-1A cells were treated with different concentration of 17beta-E2 or E2 plus ICI 182780. Semiquantitative reverse transcription-polymerase chain reaction and western blot were performed to analysis the expression of human estrogen receptor-related receptor alpha (hERRalpha). Plasmid PLXSN-hERRalpha was constructed and transfected into cells. Selected in the medium containing high-dose G418, the Ishikawa and HEC-1A cells with stable overexpression of hERRalpha were constructed and renamed as Ishikawa/hERRalpha and HEC-1A/hERRalpha, respectively. To discuss the effect of overexpression of hERRalpha in the cell biological behavior (3-[4,5-dimethylth-lazol-2yl]-2,5-diphenyltetrazolium bromid) (MTT) cell assay was performed. Estrogen downregulates ERRalpha expression in ER-positive Ishikawa cells, while upregulates the expression of ERRalpha in ER-negative HEC-1A cells. In Ishikawa cells, the downregulation of 17beta-E2 in ERRalpha expression cells could be blocked by ICI 182780. A decreasing expression of hERalpha was observed in the ER-responsive cells with overexpression of ERRalpha (Ishikawa/hERRalpha). Overexpression of hERRalpha inhibits the cell proliferation in the ERalpha-responsive Ishikawa cells and stimulated the cell proliferation in the ERalpha-nonresponsive HEC-1A cells. Function of hERRalpha depends on the expression and function of hERalpha. ER-mediated signaling might be the important factor resulting in the hormone-dependent endometrial carcinoma, whereas ERRalpha-mediated pathway might act as the vital role in hormone-independent endometrial carcinoma.

Background Transthyretin (TTR), a traditional biomarker for nutritional and inflammatory status exists in different molecular variants of yet unknown importance. A truncated form of TTR has recently been described to be part of a set of biomarkers for the diagnosis of ovarian cancer. The main aim of the study was therefore to characterize differences in microheterogeneity between ascitic fluid and plasma of women affected with ovarian cancer and to evaluate the tumor site as the possible source of TTR. Methods Subjects were 48 women with primary invasive epithelial ovarian cancer or recurrent ovarian carcinoma. The control group consisted of 20 postmenopausal women. TTR and retinol-binding protein (RBP) levels were measured by enzyme-linked immunoassay (ELISA) and C-reactive protein (CRP) levels by a high-sensitivity latex particle turbidimetric assay. The molecular heterogeneity of TTR was analysed using immunoprecipitation and matrix-associated laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Presence of TTR in tumor tissue was determined with indirect peroxidase immunostaining. Results TTR and RBP (μg/ml) levels in serum were 148.5 ± 96.7 and 22.5 ± 14.8 in affected women compared to 363.3 ± 105.5 and 55.8 ± 9.3 in healthy postmenopausal women (p < 0.01). In ascitic fluid, levels were 1.02 ± 0.24 and 4.63 ± 1.57 μg/ml, respectively. The mean levels of TTR and RBP in serum showed a tendency to decrease with the severity of the disease and were lower in affected women whose CRP levels were > 40 mg/ml (p = 0.08 for TTR; p < 0.05 for RBP). No differences in TTR microheterogeneity were observed between TTR isolated from serum of affected and healthy women or from ascitic fluid. TTR occurred rather consistently in four variants. Mass signals were at 13758 ± 7, 13876 ± 13 (greatest intensity), 13924 ± 21 and 14062 ± 24 Da, representing native, S-cysteinylated, S-cysteinglycinylated and glutathionylated TTR, respectively. Serum of healthy and affected women as well as ascitic fluid contained the truncated fragment of TTR (12828 ± 11 Da). No immunoreactive TTR was observed in the tumor sites. Conclusion The severity of the cancer associated catabolism as well as the inflammation status affect serum TTR and RBP levels. Neither TTR nor its truncated form originates from tumor tissue and its occurrence in ascites may well reflect the filtration from blood into ascitic fluid.

The plasminogen activator-plasmin cascade plays a central role in tumor cell invasion and metastasis of solid tumors. The type-1 plasminogen activator inhibitor (PAI-1) is the major physiologic regulator of the plasminogen activation. The PAI-1 is suggested to play a crucial role in tumor cell invasion and metastasis of different solid tumors. The aim of this article is to give an overview of the function, clinical and prognostic role of PAI-1 in gynaecological malignancies.

Epithelial ovarian cancer is the leading cause of death from gynaecologic malignancies in western countries. In the clinical day treatment decision of the physician (e. g. surgery, chemotherapy) based on individual prognostic factors of the patient with ovarian cancer. The tumor stage at time of diagnosis and the postoperative residual tumor mass are prognostic factors and are unequivocally related to overall survival. Other prognostic factors are identified mostly in small series and are discussed in the literature controversially. This article discussing the value of conventional prognostic factors, as stage, postoperative tumor mass, age, lymph node status, ascites) and newer molecular biological factors, as Her-2-status, PAI-1, MMP, VEGF and CD24.

A subfamily of orphan receptors, estrogen receptor-related receptors (ERRs), has been demonstrated to modulate the transcription of some estrogen responsive genes via variant estrogen response elements (EREs). This study was conducted to determine whether human ERRalpha, ERRbeta, and ERRgamma might be involved in the tumorigenesis of ovarian cancer. RT-PCR was performed to analyze the expression of hERRalpha, hERRbeta, hERRbeta-2, and hERRgamma mRNA in five ovarian cancer cell lines as well as 33 samples of ovarian cancer and 12 samples of normal ovary. Serum CA-125 levels were also analyzed in all samples by ELISA. Progression-free survival and overall survival of patients with different expression of ERRs were analyzed by the Kaplan-Meier method. To analyze the subcellular localization of ERRalpha, a green fluorescent protein (GFP)-reporter plasmid of hERRalpha was constructed and transfected into the ovarian cancer cell line OVCAR-3. Expression of hERRalpha-GFP fusion protein was observed in the nucleus of OVCAR-3 ovarian cancer cell lines. We observed increased expression of hERRalpha mRNA (P = 0.020) and hERRgamma mRNA (P = 0.045) in ovarian cancers compared to normal ovaries. In contrast, hERRbeta was only observed in 9.1% of ovarian cancers. We found a positive correlation between the serum CA-125 levels and hERRalpha expression (P = 0.012), but not hERRbeta and hERRgamma expression. Survival analysis showed that the hERRalpha-positive group has a reduced overall survival (P = 0.015), and the ERRgamma-positive group has a longer progression-free survival (P = 0.020). In multivariate analysis, expression of hERRalpha was an independent prognostic factor for poor survival (relative risk, 3.032; 95% CI, 1.27-6.06). Based on our results, ERRs may play an important role in ovarian cancer. hERRalpha may represent a biomarker of poor prognosis, and hERRgamma may be a new therapeutic target in ovarian cancer.

The majority of patients diagnosed with ovarian cancer are in an advanced stage of the disease at the time of first diagnosis. The standard clinical staging (FIGO) occurs intraoperatively. The FIGO classification hides ambiguities and is useful as a means of orientation. However, an exact assessment of stage at first diagnosis, can form the basis for the evaluation of diagnostic and prognostic factors and furthermore has influence on adjuvant treatment.We developed a systematic surgical and histopathological tumor documentation instrument, further we investigated its clinical and scientific application.Between September 2000 and July 2002, 128 patients with primary and recurrent ovarian cancer were operated and prospectively documented. The median age of the patients at the time of first diagnosis was 55 years. The majority of patients diagnosed with primary ovarian cancer had a diffuse tumor spread pattern (localised: 18 [32 %]; central: 14 [25 %]; diffuse: 24 [43 %]). In patients diagnosed with recurrent ovarian cancer the three defined tumor spread patterns showed a comparable distribution (localised 19 [28 %]; central: 19 [28 % ]; diffused: 29 [43 %]). While in most of the patients with primary ovarian cancer the highest tumor mass was concentrated in the lower abdomen/ pelvis, in comparison, in patients with recurrent ovarian cancer it was located mostly in the upper abdomen ("change of level", p=0,027).The IMO (Interoperative Mapping of Ovarian Cancer) represents a new instrument for a detailed and objective documentation of surgical and pathological results of patients with ovarian cancer and helps provide a more precise staging. Potentially this prospective documentation support the development of SOP's (Standard Operating Procedures) and could be an efficacious instrument of quality management.