Publications by authors named "Elena I Braicu"

21 Publications

  • Page 1 of 1

Discovery of Prognostic Markers for Early-Stage High-Grade Serous Ovarian Cancer by Maldi-Imaging.

Cancers (Basel) 2020 Jul 22;12(8). Epub 2020 Jul 22.

Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.

With regard to relapse and survival, early-stage high-grade serous ovarian (HGSOC) patients comprise a heterogeneous group and there is no clear consensus on first-line treatment. Currently, no prognostic markers are available for risk assessment by standard targeted immunohistochemistry and novel approaches are urgently required. Here, we applied MALDI-imaging mass spectrometry (MALDI-IMS), a new method to identify distinct mass profiles including protein signatures on paraffin-embedded tissue sections. In search of prognostic biomarker candidates, we compared proteomic profiles of primary tumor sections from early-stage HGSOC patients with either recurrent (RD) or non-recurrent disease (N = 4; each group) as a proof of concept study. In total, MALDI-IMS analysis resulted in 7537 spectra from the malignant tumor areas. Using receiver operating characteristic (ROC) analysis, 151 peptides were able to discriminate between patients with RD and non-RD (AUC > 0.6 or < 0.4; < 0.01), and 13 of them could be annotated to proteins. Strongest expression levels of specific peptides linked to Keratin type1 and Collagen alpha-2(I) were observed and associated with poor prognosis (AUC > 0.7). These results confirm that in using IMS, we could identify new candidates to predict clinical outcome and treatment extent for patients with early-stage HGSOC.
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http://dx.doi.org/10.3390/cancers12082000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463791PMC
July 2020

BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis.

J Natl Cancer Inst 2020 Dec;112(12):1190-1203

Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Background: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data.

Methods: Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided.

Results: 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling.

Conclusion: BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
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http://dx.doi.org/10.1093/jnci/djaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735770PMC
December 2020

Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment.

EMBO J 2020 03 3;39(6):e104013. Epub 2020 Feb 3.

Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.
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http://dx.doi.org/10.15252/embj.2019104013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073464PMC
March 2020

EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM.

Mol Cancer Res 2020 02 8;18(2):278-286. Epub 2019 Nov 8.

Department of Obstetrics and Gynecology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM-expressing tumors compared with patients with low EZH2 and low-ATM-expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance. IMPLICATIONS: Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0141DOI Listing
February 2020

Incidence and Pattern of Spread of Lymph Node Metastasis in Patients With Low-grade Serous Ovarian Cancer.

Anticancer Res 2019 Oct;39(10):5617-5621

Department of Gynecology, Virchow Campus Clinic, Charité Medical University Berlin, Berlin, Germany

Background/aim: Involvement of lymph nodes (LNs) and their surgical resection in low-grade ovarian cancer remains a field of discussion. The aim of this study was to determine the incidence and pattern of distribution of lymph node metastases in patients with low-grade serous ovarian cancer.

Patients And Methods: A retrospective analysis was carried out in patients with primary low-grade serous ovarian cancer who underwent primary surgery including systematic lymphadenectomy. Analysis of the affected LNs along with pattern of lymphatic spread was performed.

Results: Thirty-seven patients who underwent systematic pelvic and para-aortal LN dissection were identified. The median age was 48 years (range=26-76 years). The majority of patients had International Federation of Gynecology and Obstetrics stage III (89.2%). A median of 41 (range=10-97) LNs were resected. LN metastases were found in 27 (72.9%) patients. In 15 (55.5%) patients, both pelvic and para-aortic LNs were affected concomitantly, in isolated para-aortal and pelvic lymph nodes in three (11.1%) and eight (29.6%) patients, respectively. The most frequently affected region was the right obturator fossa, found in 14 (51.8%) patients, followed by the left obturator fossa in 11 (40.7%) patients.

Conclusion: Low-grade serous ovarian cancer exhibits a high percentage of lymphatic spread, with more confinement to the pelvic compared to the para-aortic region.
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http://dx.doi.org/10.21873/anticanres.13757DOI Listing
October 2019

Dilution of Molecular-Pathologic Gene Signatures by Medically Associated Factors Might Prevent Prediction of Resection Status After Debulking Surgery in Patients With Advanced Ovarian Cancer.

Clin Cancer Res 2020 01 16;26(1):213-219. Epub 2019 Sep 16.

Department of Gynecology and Gynecologic Oncology, Kliniken-Essen-Mitte, Germany.

Purpose: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome.

Experimental Design: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status.

Results: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology.

Conclusions: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722525PMC
January 2020

Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation.

Nat Commun 2019 03 18;10(1):1194. Epub 2019 Mar 18.

Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.

Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility. Here we use human fallopian tube organoids and genital Ctr serovars D, K and E for long-term in vitro analysis. The epithelial monolayer responds with active expulsion of the bacteria into the lumen and with compensatory cellular proliferation-demonstrating a role of epithelial homeostasis in the defense against this pathogen. In addition, Ctr infection activates LIF signaling, which we find to be an essential regulator of stemness in the organoids. Infected organoids exhibit a less differentiated phenotype with higher stemness potential, as confirmed by increased organoid forming efficiency. Moreover, Ctr increases hypermethylation of DNA, which is an indicator of accelerated molecular aging. Thus, the chronic organoid infection model suggests that Ctr has a long-term impact on the epithelium. These heritable changes might be a contributing factor in the development of tubal pathologies, including the initiation of high grade serous ovarian cancer.
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http://dx.doi.org/10.1038/s41467-019-09144-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423033PMC
March 2019

Morphology and tumour-infiltrating lymphocytes in high-stage, high-grade serous ovarian carcinoma correlated with long-term survival.

Histopathology 2018 Dec 7;73(6):1002-1012. Epub 2018 Oct 7.

Tumorbank Ovarian Cancer Network, Berlin, Germany.

Aims: Advanced-stage ovarian high-grade serous carcinoma (HGSC) is a poor-prognosis cancer; however, a small and poorly characterised subset of patients shows long-term survival. We aimed to establish a cohort of HGSC long-term survivors for histopathological and molecular analysis.

Methods And Results: Paraffin blocks from 151 patients with primary FIGO III/IV HGSC and progression-free survival (PFS) >5 years were collected within the Tumorbank Ovarian Cancer (TOC) Network; 77 HGSC with a PFS <3 years were used as a control group. A standardised analysis of histological type and morphological features was performed. Ki67 index, tumour-infiltrating lymphocytes (TILs) and major histocompatibility complex expression (MHC1/2) were determined by immunohistochemistry. A total of 117 of 151 tumours (77.5%) in the long-term survivor group fulfilled the World Health Organisation (WHO) criteria of HGSC after review, and of these, 83 patients (70.9%) fulfilled all clinical criteria for inclusion into our cohort. Tumours of long-term survivors had significantly higher CD3 and CD8 TILs and were more frequently positive for MHC2 than controls (P = 0.004, P = 0.025, P = 0.048). However, there were also long-term survivors (up to 20%) with low TILs or low MHC expression. TILs and MHC had no impact on survival in long-term survivors. Morphological and Ki67 analysis revealed no differences between long-term survivors and controls.

Conclusions: HGSC from long-term survivors have higher-level T cell infiltration and antigen-presentation capacity; however, this is not a prerequisite for an excellent prognosis. Histopathological criteria are not capable to identify these patients. Further extensive clinical and molecular characterisation of this enigmatic subgroup is ongoing to understand the reasons of long-term survival in HGSC.
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http://dx.doi.org/10.1111/his.13711DOI Listing
December 2018

Proteomic and Bioinformatic Studies for the Characterization of Response to Pemetrexed in Platinum Drug Resistant Ovarian Cancer.

Front Pharmacol 2018 8;9:454. Epub 2018 May 8.

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Proteomics and bioinformatics are a useful combined technology for the characterization of protein expression level and modulation associated with the response to a drug and with its mechanism of action. The folate pathway represents an important target in the anticancer drugs therapy. In the present study, a discovery proteomics approach was applied to tissue samples collected from ovarian cancer patients who relapsed after the first-line carboplatin-based chemotherapy and were treated with pemetrexed (PMX), a known folate pathway targeting drug. The aim of the work is to identify the proteomic profile that can be associated to the response to the PMX treatment in pre-treatement tissue. Statistical metrics of the experimental Mass Spectrometry (MS) data were combined with a knowledge-based approach that included bioinformatics and a literature review through ProteinQuest™ tool, to design a protein set of reference (PSR). The PSR provides feedback for the consistency of MS proteomic data because it includes known validated proteins. A panel of 24 proteins with levels that were significantly different in pre-treatment samples of patients who responded to the therapy vs. the non-responder ones, was identified. The differences of the identified proteins were explained for the patients with different outcomes and the known PMX targets were further validated. The protein panel herein identified is ready for further validation in retrospective clinical trials using a targeted proteomic approach. This study may have a general relevant impact on biomarker application for cancer patients therapy selection.
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http://dx.doi.org/10.3389/fphar.2018.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952181PMC
May 2018

Diagnostic markers for the detection of ovarian cancer in BRCA1 mutation carriers.

PLoS One 2017 15;12(12):e0189641. Epub 2017 Dec 15.

Department of Obstetrics and Gynecology, Cancer Comprehensive Center, Medical University Vienna, Vienna, Austria.

Background: Screening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers.

Methods: Using a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation.

Results: Using the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%. The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065).

Conclusion: We have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731824PMC
January 2018

The ascites N-glycome of epithelial ovarian cancer patients.

J Proteomics 2017 03 8;157:33-39. Epub 2017 Feb 8.

Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité Medical University, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address:

Epithelial ovarian cancer (EOC) is worldwide the sixth most lethal form of cancer occurring in women. More than one third of ovarian patients have ascites at the time of diagnosis and almost all of them have it when recurrence occurs. Although its effect on tumor cell microenvironment remains poorly understood, its presence is correlated with bad diagnosis. In previous studies, we proposed a novel glycan-based biomarker for the diagnosis of EOC, which showed an improved sensitivity and specificity at any stage of the disease and an improved discrimination between malignant and benign ovarian tumors. In this work, we report for the first time the N-glycome profiles of ascitic fluid from primary serous EOC patients and compare them with the serum N-glycomes of the same patients as well as of healthy controls. N-Glycans were digested from equivalent amount of ascites and serum from 18 EOC patients and from serum of 20 age-matched controls and measured by MALDI-TOF-MS. Ascites N-glycome showed increased antennarity, branching, sialylation and Lewis motives compared to healthy serum. In addition, a correlation was established between ascites volume and degree of sialylation.

Significance: Malignant ascitic fluid is the build-up of large volumes of fluid in the peritoneal cavity secondary to cancer. At least one-third of ovarian cancer patients develop ascites, a generally voluminous fluid containing cells of tumor origin, in the course of cancer and almost all when recurrence occurs. The proteome of ascites is known to be as complex as that of serum and contains high amount of proteins shed from inflammatory cells as well as from tumor cells. Although many attempts have been made to provide molecular insight into the proteomic and peptidomic content of malignant ascites, no data about the N-glycome of the ascitic fluid fraction from cancer patients has been reported to date. In this study, the N-glycosylation profile of ascites from 20 patients suffering from epithelial ovarian cancer (EOC) was analyzed by MALDI-TOF-mass spectrometry and compared to the pathologically modified N-glycan pattern obtained from serum of the same patients as well as to the pattern of serum from healthy individuals. Significant quantitative differences were observed in the ascites of EOC patients when compared to the serum of healthy subjects. The glycome of ascites shows typical features of inflammatory conditions, what was also found in the serum of patients suffering from EOC when compared to healthy serum. In addition, a correlation was established between ascites volume and degree of sialylation, showing that the high-volume ascites contains a higher amount of sialylated structures than the low-volume ascites.
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http://dx.doi.org/10.1016/j.jprot.2017.02.001DOI Listing
March 2017

Predictive and Prognostic Value of sPRR in Patients with Primary Epithelial Ovarian Cancer.

Anal Cell Pathol (Amst) 2016;2016:6845213. Epub 2016 Aug 31.

Department of Gynecology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany.

. The purpose of the present study was to analyze the predictive and prognostic role of soluble (pro)renin receptor (sPRR) as a biomarker for clinicopathological outcome in patients with primary epithelial ovarian cancer (EOC). As part of the renin-angiotensin system (RAS) whose activity is known to increase in ovarian cancer patients, the relation of sPRR and ovarian cancer should be further investigated. . In this study 197 patients with primary EOC in our institution from 2000 to 2011 were included. sPRR was determined by enzyme-linked immunosorbent assay (ELISA) in preoperative taken blood sera. Associations with clinicopathological outcome were analyzed and serum levels of sPRR in patients have been compared to those in healthy specimen. Kaplan-Meier and logistic/Cox regression assessed the impact of the markers on progression-free survival (PFS) and overall survival (OS). . There have been no correlations proved of sPRR levels with neither clinicopathological factors nor prognostic data. Also the distribution of sPRR in patients and controls was normal. . sPRR seems to have no predictive, prognostic, or diagnostic value in EOC. As several factors of the RAS which might indicate cancer events have been shown, sPRR seems not to be affected.
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http://dx.doi.org/10.1155/2016/6845213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021861PMC
August 2016

Y-box protein-1/p18 as novel serum marker for ovarian cancer diagnosis: A study by the Tumor Bank Ovarian Cancer (TOC).

Cytokine 2016 09 29;85:157-64. Epub 2016 Jun 29.

Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany. Electronic address:

Introduction: The cold shock Y-box binding protein-1 (YB-1) fulfills important roles in regulating cell proliferation and differentiation. Overexpression occurs in various tumor cells. Given the existence of extracellular YB-1 we set out to determine the diagnostic, predictive and prognostic role of serum YB-1/p18 for patients with primary epithelial ovarian cancer (EOC).

Methods: The protein fragment YB-1/p18 was quantified by sandwich ELISA in serum samples from 132 healthy female volunteers and 206 patients with histological diagnosis of primary EOC. The ELISA sensitivity and specificity to detect EOC were calculated using receiver operating curves. Survival data were calculated using Kaplan Maier curves.

Results: Median age at the time of diagnosis was 60years and follow-up ended with a mean of 44.8month. 188 (91%) patients were diagnosed at advanced stages (FIGO III/IV) and 188 patients (91%) suffered from high-grade serous ovarian carcinoma. YB-1/p18 levels were significantly decreased in older patients (p=0.021). Significantly lower serum levels of YB-1/p18 were detected in the EOC cohort when compared to the control group (p<0.0001, AUC=0.827; 95% CI, 0.787-0.867). Using the expression of serum YB-1/p18 in early stages I and II cases these could be differentiated from control cases (p<0.0001, AUC=0.816; 95% CI 0.704-0.929). No other significant associations between clinical prognostic factors and YB-1/p18 serum levels were detected. Immunoblotting results with serum samples suggest that masking of epitopes by the YB-1/p18 fragment in multiprotein-complexes under non reducing conditions leads to the observed reduced ELISA readings in the EOC cohort.

Conclusions: The quantification of fragment YB-1/p18 derived from cold shock protein YB-1 in serum samples could be useful for the early diagnosis of EOC.
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http://dx.doi.org/10.1016/j.cyto.2016.06.021DOI Listing
September 2016

Role of IGF-I in Primary Ovarian Cancer - A Study of the OVCAD European Consortium.

Anticancer Res 2016 Mar;36(3):1015-22

Gynecological Tumor Center and European Competence Center for Ovarian Cancer, Charité-Universitätsmedizin Berlin, Berlin, Germany Ovarian Cancer Tumor Bank (TOC), Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background/aim: IGF-I (insulin growth factor 1) is crucially involved in cellular proliferation. Moreover, deregulation of IGF-I has been shown to be relevant in the carcinogenesis of various tumor entities. However, the impact of IGF-I in epithelial ovarian cancer (EOC) is unclear. In the present study, we investigated the predictive and prognostic role of circulatory IGF-I in primary EOC patients.

Patients And Methods: In the FP6 European Project "OVCAD", 275 consecutive primary EOC patients were enrolled. Patients were eligible if radical cytoreductive surgery and platinum-based chemotherapy were performed. Plasma IGF-I was detected using ELISA.

Results: Increased plasma IGF-I levels were more frequently found in well-differentiated epithelial ovarian carcinoma (p=0.0047). A weak correlation was observed between IGF-I levels and CA-125 in patients with serous EOC (p=0.04). No association between IGF-I expression and other clinico-pathological parameters was observed.

Conclusion: IGF-I is overexpressed in patients with well-differentiated EOC. Further studies are warranted to elucidate the role of IGF-I in this sub-group of patients.
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March 2016

Serum glycome profiling: a biomarker for diagnosis of ovarian cancer.

J Proteome Res 2013 Sep 29;12(9):4056-63. Epub 2013 Jul 29.

Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité Medical University, Augustenburger Platz 1, 13353 Berlin, Germany.

During the development of cancer, changes in cellular glycosylation are observed, indicating that alterations of the glycome occur in extracellular fluids as well as in serum and could therefore serve as tumor biomarkers. In the case of epithelial ovarian cancer (EOC), common tumor markers such as CA125 are known to have poor specificity; therefore, better biomarkers are needed. The aim of this work was to identify new potential glycan biomarkers in EOC-patients. N-Glycans were cleaved from serum glycoproteins from 63 preoperative primary EOC-patients along with 33 age-matched healthy women, permethylated, and analyzed using MALDI-TOF mass spectrometry. A value named GLYCOV was calculated from the relative areas of the 11 N-glycan biomarkers revealed by SPSS statistical analyses, namely four high-mannose and seven complex-type fucosylated N-glycans. GLYCOV diagnosed primary EOC with a sensitivity of 97% and a specificity of 98.4% whereas CA-125 showed a sensitivity of 97% and a specificity of 88.9%. Our study is the first one to compare glycan values with the established tumor marker CA125 and to give better results. Therefore, the N-glycome could potentially be used as a biomarker.
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http://dx.doi.org/10.1021/pr400405xDOI Listing
September 2013

Clinical outcome of patients with advanced ovarian cancer after resection of liver metastases.

Anticancer Res 2012 Oct;32(10):4517-21

Departments of General, Charité, Campus Virchow Clinic, University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany.

Aim: Hepatic resection has become the standard treatment for patients with primary or metastatic liver malignancies. The aim of our study was to evaluate the clinical outcome of hepatic resection in patients with advanced ovarian cancer (AOC).

Patients And Methods: All patients undergoing hepatic resection for AOC in our institution between 11/1991 and 02/2007 were evaluated by a validated intraoperative documentation tool.

Results: Seventy patients were evaluated (median age=59 years; range=29-76 years). Forty-one (58.6%) patients underwent liver resection; 29 patients had unresectable disease. Additional multivisceral procedures performed were: colic resection (51.4%), small bowel resection (32.9%), gastric resection (5.7%), pancreatic resection (4.3%), splenectomy (5.7%). The median survival of patients with R0 resection was 42 months (95% confidence interval (CI)=17-66 months), 4 months for R1, 6 months (95% CI=0-11 months) for R2, and 5 months (95% CI=0-9 months) for those without liver resection. In multivariate analysis, postoperative residual tumor mass was the strongest predictor of survival.

Conclusion: Our data indicate that complete macroscopical tumor resection remains the strongest predictor of survival in patients with liver metastases from AOC.
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October 2012

The N-terminally truncated p53 isoform Δ40p53 influences prognosis in mucinous ovarian cancer.

Int J Gynecol Cancer 2012 Mar;22(3):372-9

Department of Gynecology and Obstetrics, Medical University Innsbruck, Innsbruck, Austria.

Objective: The tumor suppressor p53 generates the N-terminally truncated isoforms Δ40p53 and Δ133p53 that possess the ability to modulate p53 function in vitro. The aim of the present study was to evaluate the clinical relevance of p53 isoforms in the main histological subtypes of ovarian cancer.

Methods: Δ40p53, Δ133p53, and full-length p53 (FLp53) expression was determined in 45 mucinous, 30 endometrioid, and 91 serous ovarian cancer specimens as well as 42 normal ovarian tissues using reverse transcriptase-quantitative polymerase chain reaction. In a subgroup of mucinous ovarian cancer cases, Δ40p53 expression was examined using Western blot analysis. A functional yeast-based assay and subsequent sequencing were performed to analyze the p53 mutational status.

Results: In endometrioid cancer specimens, Δ133p53 expression was significantly lower than in mucinous and serous cases (P = 0.016) or in normal tissues (P = 0.004). Mucinous cancer samples showed elevated Δ40p53 expression as compared with normal ovarian tissues (P = 0.003). In addition, high Δ40p53 expression constituted an independent prognostic marker for recurrence-free but not for overall survival in patients with mucinous ovarian cancer (hazard ratio, 0.267; 95% confidence interval, 0.094-0.756 [P = 0.013]; hazard ratio, 0.453, 95% confidence interval, 0.193-1.064 [P = 0.069]). Western blot analysis confirmed the presence of p53β and Δ40p53α in a subset of patients with mucinous ovarian cancer. Expression of p53 isoforms was not associated with p53 mutational status or clinicopathologic parameters.

Conclusions: We show that expression of p53 isoforms differs in histological subtypes, thus supporting the hypothesis that histological subtypes represent distinct disease entities. In addition, we provide first evidence for a favorable role of Δ40p53 in patients with mucinous ovarian cancer.
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http://dx.doi.org/10.1097/IGC.0b013e31823ca031DOI Listing
March 2012

MDM2 SNP309 modifies the prognostic significance of the p53 mutational status in patients with ovarian cancer.

Oncol Rep 2012 Mar 23;27(3):673-7. Epub 2011 Nov 23.

Department of Gynecology and Obstetrics, Medical University Innsbruck, A-6020 Innsbruck, Austria.

A single nucleotide polymorphism (SNP309) of MDM2 causes elevated MDM2 levels and an attenuation of p53 function. The aim of the present study was to examine the clinical relevance of the MDM2 SNP309 in ovarian cancer.MDM2 SNP309 genotype was analyzed in 198 patients with primary ovarian cancer. MDM2 expression was investigated using immunohistochemistry. A functional yeast-based assay and subsequent sequencing were performed to determine p53 mutational status. Of the patients, 44.4% (88 of 198) exhibited the common variant (T/T), 40.9% (81 of 198) the heterozygous variant (T/G) and 14.7% (29 of 198) the homozygous variant (G/G) MDM2 SNP309 genotype. MDM2 SNP309 was not associated with p53 mutational status, MDM2 expression, clinicopathological parameters or prognosis. In patients with the T allele (T/T and T/G genotype), p53 wild type carcinomas were associated with significantly improved recurrence-free (p<0.001) and overall survival (p<0.001) as compared to p53 mutant carcinomas. In contrast, p53 mutational status did not possess prognostic relevance in G/G carriers. A possible functional impairment of the p53 pathway caused by the G/G genotype of the MDM2 SNP309 may modify the association between p53 mutational status and prognosis in ovarian cancer.
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http://dx.doi.org/10.3892/or.2011.1560DOI Listing
March 2012

An intracellular targeted antibody detects EGFR as an independent prognostic factor in ovarian carcinomas.

BMC Cancer 2011 Jul 14;11:294. Epub 2011 Jul 14.

Institute of Pathology, University Hospital Charité Berlin, Germany.

Background: In ovarian cancer, the reported rate of EGFR expression varies between 4-70% depending on assessment method and data on patient outcome are conflicting.

Methods: In this study we investigated EGFR expression and its prognostic value in a cohort of 121 invasive ovarian carcinomas, using a novel antibody against the intracellular domain of the receptor. We further evaluated an association between EGFR, the nuclear transporter CRM1 as well as COX-2. Furthermore, we evaluated EGFR expression in ten ovarian cancer cell lines and incubated cancer cells with Leptomycin B, a CRM1 specific inhibitor.

Results: We observed a membranous and cytoplasmic EGFR expression in 36.4% and 64% of ovarian carcinomas, respectively. Membranous EGFR was an independent prognostic factor for poor overall survival in ovarian cancer patients (HR 2.7, CI 1.1-6.4, p = 0.02) which was also found in the serous subtype (HR 4.6, CI 1.6-13.4, p = 0.004). We further observed a significant association of EGFR with COX-2 and nuclear CRM1 expression (chi-square test for trends, p = 0.006 and p = 0.013, respectively). In addition, combined membranous EGFR/COX-2 expression was significantly related to unfavorable overall survival (HR 7.2, CI 2.3-22.1, p = 0.001).In cell culture, we observed a suppression of EGFR protein levels after exposure to Leptomycin B in OVCAR-3 and SKOV-3 cells.

Conclusions: Our results suggest that the EGFR/COX-2/CRM1 interaction might be involved in progression of ovarian cancer and patient prognosis. Hence, it is an interesting anti-cancer target for a combination therapy. Further studies will also be needed to investigate whether EGFR is also predictive for benefit from EGFR targeted therapies.
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http://dx.doi.org/10.1186/1471-2407-11-294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149030PMC
July 2011

Vascular endothelial growth factor C mRNA expression is a prognostic factor in epithelial ovarian cancer as detected by kinetic RT-PCR in formalin-fixed paraffin-embedded tissue.

Virchows Arch 2009 Dec 13;455(6):461-7. Epub 2009 Nov 13.

Institute of Pathology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.

Vascular endothelial growth factor C (VEGF-C) is a well described chemotactic and growth factor for lymphatic endothelial cells. Its inhibition leads to suppression of lymphatic and distant metastases in mouse models. In ovarian cancer, the relationship between VEGF-C expression and tumor behavior has not yet been determined by a quantitative method in vivo. Therefore, we used a new technique of RNA extraction from formalin-fixed paraffin-embedded tissue samples and determined the expression levels of VEGF-C mRNA in a study group of 97 ovarian cancer patients. Expression levels were correlated with clinicopathological features and patient survival. High VEGF-C expression was associated with worse overall (p = 0.0393) and progression-free (p = 0.0155) patient survival. In the subgroups of serous tumors and high-grade tumors, VEGF-C mRNA was still a negative indicator for patient survival (p = 0.0190 and 0.0311, respectively). A trend was observed among patients with high clinical stage (p = 0.0634). In multivariate survival analysis VEGF-C mRNA retained its prognostic influence on progression-free survival (p = 0.006, HR = 0.319 with a 95% confidence interval of 0.142-0.720). High VEGF-C expression was further associated with an increased residual tumor mass after primary cytoreductive surgery. We found no correlation of VEGF-C expression with tumor grade, FIGO stage, lymph node, or distant metastases. Our study demonstrates that high VEGF-C expression is associated with aggressive tumor behavior in ovarian cancer. mRNA extracted from paraffin-embedded tumor samples is suitable for VEGF-C gene expression studies.
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http://dx.doi.org/10.1007/s00428-009-0851-6DOI Listing
December 2009