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Dietmar Pils,
Dan Tong,
Gudrun Hager,
Eva Obermayr,
Stefanie Aust,
Georg Heinze,
Maria Kohl,
Eva Schuster,
Andrea Wolf,
Jalid Sehouli,
Ioana Braicu,
Ignace Vergote,
Toon Van Gorp,
Sven Mahner,
Nicole Concin, Paul Speiser,
Robert Zeillinger
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ABSTRACT: BACKGROUND: The immune system is a key player in fighting cancer. Thus, we sought to identify a molecular 'immune response signature' indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC. METHODS: Comparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC. RESULTS: Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%. CONCLUSIONS: The combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.
BMC Cancer 04/2013; 13(1):178. · 3.01 Impact Factor
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Stefanie Aust,
Peter Horak,
Dietmar Pils,
Sophie Pils,
Christoph Grimm,
Reinhard Horvat,
Dan Tong,
Bernd Schmid, Paul Speiser,
Alexander Reinthaller,
Stephan Polterauer
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ABSTRACT: BACKGROUND: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a coregulator of the estrogen receptors (ERs) alpha and beta, is a potential proto-oncogene in hormone dependent gynecological malignancies. To better understand the role of PELP1 in epithelial ovarian cancer (EOC), the protein expression and prognostic significance of PELP1 was evaluated together with ERalpha and ERbeta in EOC tissues. METHODS: The expression of PELP1, ERalpha, and ERbeta was characterized in tumor tissues of 63 EOC patients. The prognostic value was calculated performing log-rank tests and multivariate Cox-Regression analysis. In a second step, validation analysis in an independent set of 86 serous EOC patients was performed. RESULTS: Nuclear PELP1 expression was present in 76.2% of the samples. Prevalence of PELP1 expression in mucinous tumors was significantly lower (37.5%) compared to serous (85.7%) and endometrioid tumors (86.7%). A significant association between PELP1 expression and nuclear ERbeta staining was found (p=0.01). Positive PELP1 expression was associated with better disease-free survival (DFS) (p=0.004) and overall survival (OS) (p=0.04). The combined expression of ERbeta+/PELP1+ revealed an independent association with better DFS (HR 0.3 [0.1-0.7], p=0.004) and OS (HR 0.3 [0.1-0.7], p=0.005). In the validation set, the combined expression of ERbeta+/PELP1+ was not associated with DFS (HR 0.7 [0.4-1.3], p=0.3) and OS (HR 0.7 [0.3-1.4], p=0.3). CONCLUSION: Positive immunohistochemical staining for the ER coregulator PELP1, alone and in combination with ERbeta, might be of prognostic relevance in EOC.
BMC Cancer 03/2013; 13(1):115. · 3.01 Impact Factor
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Stefanie Aust,
Sophie Pils,
Stefan Polterauer,
Reinhard Horvat,
Dan Cacsire Castillo-Tong,
Dietmar Pils,
Grazyna Dudek,
Bernd Schmid, Paul Speiser,
Alexander Reinthaller,
Christoph Grimm
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ABSTRACT: In epithelial ovarian cancer (EOC), literature on the prognostic value of B-cell lymphoma 2 (Bcl-2) is limited and inconsistent. Little is known about the expression patterns and the prognostic value of prosurvival proteins of the Bcl-2-associated athanogene (BAG) family proteins interacting with Bcl-2. The major aim of this study was to further define the expression pattern and the prognostic role of Bcl-2 together with BAG-1, BAG-3, and BAG-4 proteins in EOC patients receiving platinum/taxane-based chemotherapy. A tissue array was constructed comprising 63 EOC patients. The expression and the prognostic value of Bcl-2, BAG-1, BAG-3, and BAG-4 in EOC were evaluated by immunohistochemistry and multivariate analysis. A positive cytoplasmic staining for Bcl-2 was observed in 23.8% of EOC samples and in all histologic subtypes. BAG-1, BAG-3, and BAG-4 were detected in tumor cell nuclei and cytoplasm. Interestingly, all patients presenting with a positive Bcl-2 staining showed additional positive nuclear and cytoplasmic BAG-4 expression (P=0.014). Expression of Bcl-2, or the BAG family proteins, independent of nuclear or cytoplasmic localization, had no significant impact on either disease-free or overall survival, both in univariate and multivariate survival analyses with the limitation of a small cohort of cases. In this study, no association between Bcl-2 expression in EOC tumor tissue and prognosis was found. Similarly, nuclear and cytoplasmic expression of the prosurvival proteins of the BAG family had no significant impact on patients' outcome.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 02/2013; · 1.63 Impact Factor
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Radoslav Chekerov,
Ioana Braicu,
Dan Cacsire Castillo-Tong,
Rolf Richter,
Isabelle Cadron,
Sven Mahner,
Linn Woelber,
Christian Marth,
Toon Van Gorp, Paul Speiser,
Robert Zeillinger,
Ignace Vergote,
Jalid Sehouli
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ABSTRACT: INTRODUCTION: The Sixth Framework Program European Union project OVCAD, "Ovarian Cancer-Diagnosis of a Silent Killer," aimed to investigate new predictors for early detection of minimal residual disease in epithelial ovarian cancer (EOC). Here we present the main pathologic, surgical, and chemotherapy characteristics of the OVCAD patient cohort. METHODS: Between February 2005 and December 2008, 5 European gynecologic cancer centers (WP2 group) enrolled prospective 275 consecutive patients with EOC into this translational study. Inclusion criteria were as follows: advanced International Federation of Obstetrics and Gynecology II to IV stage, cytoreductive surgery, platinum-based chemotherapy, and collected tumor samples. WP2 coordinated the implementation, screening, and recruiting of the patients and tumor samples into a Web-based data bank according established standard operating procedures. RESULTS: Median age at the time of diagnosis was 58 years. Most patients presented advanced high-grade EOC: International Federation of Obstetrics and Gynecology III/IV (94.5%), grade 2/3 (96%), serous histology (86.2%), ascites (76%), peritoneal carcinomatosis (67.6%), and lymph node involvement (52%). The most common surgical procedures were omentectomy (92.4%), bilateral salpingo-oophorectomy (90.9%), hysterectomy (77.3%), pelvic (69.5%) and paraaortic (66.9%) lymphadenectomy, and large (37.7%) or small bowel resection (13.4%). Patients were treated commonly with platinum-based therapy (98.2%). The macroscopic cytoreduction rate was 68.4%. After a median follow-up of 37 months, 70 patients (25.5%) developed a platinum-resistant recurrence. Biological materials such as tumor and paraffin tissue, ascites, and blood samples were collected consecutively. CONCLUSIONS: The implementation of the OVCAD cohort demonstrated the feasibility and advantages of an open, prospective, and multicenter recruitment inside a translational research study. Essential was the predefinition of all inclusion criteria, standard operating procedures, and Web-based software, which enabled the prospective patient recruitment and tissue sampling, minimizing institutional bias and variability in the quality of the biological samples. The translational concept of the OVCAD study does not conflict with the state-of-the-art surgical and chemotherapy management and guaranteed an improved outcome of patients with EOC.
International Journal of Gynecological Cancer 02/2013; 23(2):268-275. · 1.65 Impact Factor
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ABSTRACT: OBJECTIVE: The study aims at identifying novel markers for circulating tumor cells (CTCs) in patients with epithelial ovarian cancer (EOC), and at evaluating their impact on outcome. METHODS: Microarray analysis comparing matched EOC tissues and peripheral blood leucocytes (N=35) was performed to identify novel CTC markers. Gene expression of these novel markers and of EpCAM was analyzed using RT-qPCR in blood samples taken from healthy females (N=39) and from EOC patients (N=216) before primary treatment and six months after adjuvant chemotherapy. All samples were enriched by density gradient centrifugation. CTC positivity was defined by over-expression of at least one gene as compared to the healthy control group. RESULTS: CTC were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two thirds were identified by overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. The presence of CTCs at baseline correlated with the presence of ascites, sub-optimal debulking, and elevated CA-125 and HE-4 levels, whereas CTC during follow-up occurred more often in older and platinum resistant patients. PPIC positive CTCs during follow-up were significantly more often detected in the platinum resistant than in the platinum sensitive patient group, and indicated poor outcome independent from classical prognostic parameters. CONCLUSIONS: Molecular characterization of CTC is superior to a mere CTC enumeration or even be the rationale for CTC diagnostics at all. Ultimately CTC diagnostics may lead to more personalized treatment of EOC, especially in the recurrent situation.
Gynecologic Oncology 09/2012; · 3.89 Impact Factor
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Stefanie Aust,
Anna Bachmayr-Heyda,
Dan Tong,
Silvia Darb-Esfahani,
Carsten Denkert,
Radoslav Chekerov,
Jalid Sehouli,
Sven Mahner,
Toon Van Gorp,
Ignace Vergote, Paul Speiser,
Reinhard Horvat,
Robert Zeillinger,
Petra Pateisky,
Dietmar Pils
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ABSTRACT: BACKGROUND: The role of the tumor necrosis factor receptor associated protein 1 (TRAP1) -- supposed to be involved in protection of cells from apoptosis and oxidative stress -- has just started to be investigated in ovarian cancer. TRAP1 has been shown to be estrogen up-regulated in estrogen receptor alpha (ERalpha) positive ovarian cancer cells. The clinical impact of TRAP1 is not clear so far and the significance of ERalpha expression as therapeutic and prognostic marker is still controversial. Therefore, we investigated the importance of TRAP1 together with ERalpha in regard to clinicopathological parameters, chemotherapy response, and survival.Methods and resultsExpressions of TRAP1 and ERalpha were evaluated by immunohistochemical staining of tissue microarrays comprised of 208 ovarian cancer samples. TRAP1 was highly expressed in 55% and ERalpha was expressed in 52% of all cases. High TRAP1 expression correlated significantly with ERalpha (p < 0.001) but high TRAP1 expression was also found in 42% of ERalpha negative cases. High TRAP1 expression correlated significantly with favorable chemotherapy-response (HR = 0.48; 95%CI 0.24-0.96, p=0.037) and showed a significant impact on overall survival (OS) (HR = 0.65; 95%CI 0.43-0.99, p = 0.044). ERalpha expression was a favorable prognostic factor for OS in univariate and multivariate analyses. Interestingly, the combined pattern (ERalpha positive and/or TRAP1-high) revealed the strongest independent and significant positive influence on OS (HR = 0.41; 95%CI 0.27-0.64). CONCLUSION: Immunohistochemical evaluation of TRAP1 together with ERalpha provides significant prognostic information. TRAP1 alone is significantly associated with chemotherapy response and overall survival, rendering TRAP1 as interesting scientific and therapeutic target.
Molecular Cancer 09/2012; 11(1):69. · 3.99 Impact Factor
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ABSTRACT: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2-3). We aimed to estimate the efficacy of a treatment with imiquimod, a topical immune-response modulator, in patients with CIN 2-3.
Fifty-nine patients with untreated CIN 2-3 were randomly allocated to a 16-week treatment with self-applied vaginal suppositories containing either imiquimod or placebo. The main outcome was efficacy, defined as histologic regression to CIN 1 or less after treatment. Secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance, and tolerability. Assuming a two-sided 5% significance level and a power of 80%, a sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2-3 regression.
Histologic regression was observed in 73% of patients in the imiquimod group compared with 39% in the placebo group (P=.009). Complete histologic remission was higher in the imiquimod group (47%) compared with the placebo group (14%) (P=.008). At baseline, all patients tested positive for high-risk HPV. Human papillomavirus clearance rates were increased in the imiquimod group (60%) compared with the placebo group (14%) (P<.001). In patients with HPV-16 infection, complete remission rates were 47% in the imiquimod group compared with 0% in the placebo group (P=.003). Microinvasive cancer was observed in three of 59 (5% [1-14%]) patients, all within the placebo group. Topical imiquimod treatment was well tolerated, and no high-grade side effects were observed.
Topical imiquimod is an efficacious and feasible treatment for patients with CIN 2-3.
Obstetrics and Gynecology 07/2012; 120(1):152-9. · 4.73 Impact Factor
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Dietmar Pils,
Gudrun Hager,
Dan Tong,
Stefanie Aust,
Georg Heinze,
Maria Kohl,
Eva Schuster,
Andrea Wolf,
Jalid Sehouli,
Ioana Braicu,
Ignace Vergote,
Isabelle Cadron,
Sven Mahner,
Gerda Hofstetter, Paul Speiser,
Robert Zeillinger
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ABSTRACT: Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced-stage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P ≤ 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P ≤ 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02306.x, 2012).
Cancer Science 04/2012; · 3.33 Impact Factor
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ABSTRACT: To evaluate a reverse-hybridisation assay (strip assay) designed for the sensitive detection of 10 mutations in codons 12 and 13 of the KRAS gene. The strip assay relies on mutant-enriched PCR followed by reverse-hybridisation of biotinylated amplification products to oligonucleotide probes immobilised as an array of parallel lines on nitrocellulose test strips.
The strip assay was used to analyse genomic DNA isolated from 120 formalin-fixed paraffin-embedded (FFPE) ovarian tissue samples. The samples were analysed in parallel using a biochip-based protocol (biochip assay) covering the same mutation spectrum, and results were compared with respect to sensitivity, specificity and operational input.
The strip assay identified 19 (16%) of 120 FFPE samples to carry a KRAS mutation; results were in agreement with those obtained by biochip hybridisation. Both assays had an analytical sensitivity of 1% when performed on FFPE-extracted DNA with approximately the same operational input needed for post-PCR processing. In contrast to the biochip assay, strip assay hybridisation may be automated to a large extent.
The strip assay is an accurate and sensitive tool for the low to medium throughput detection of KRAS mutation in genomic DNA isolated from FFPE tissue.
Journal of clinical pathology 03/2011; 64(3):252-6. · 2.43 Impact Factor
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ABSTRACT: ATP-binding Cassette (ABC) transporters are thought to cause multiple drug resistance (MDR) in various carcinomas. Gene expression data from individual transporters in ovarian cancer tissue is contradictory and also scarce for some of them. RNA levels of a panel of ABC transporters were collected and analyzed to get a more detailed overview which transporters are of importance in resistance to chemotherapeutic agents in ovarian carcinoma.
Real-time PCR was used to determine RNA expression levels of 9 ABC transporters in 50 benign tissue samples and 50 recurrent ovarian cancer samples. Genes exhibiting a significant difference between those two groups were further evaluated in 50 primary cancer samples. Data were analyzed with receiver operating characteristic (ROC) curves and multiple Wilcoxon-Mann-Whitney U-tests with Shaffer correction.
Gene expression of four transporters (ABCC1, ABCC2, ABCC3, and ABCB3) was significantly elevated in recurrent cancer lesions compared to benign tissue. Expression levels of these 4 ABC transporters were further analyzed in primary ovarian cancer lesions. A significant difference between primary and recurrent tumor tissue was found in all four genes. Changes in gene expression between benign samples and primary lesions were minor and not relevant.
Four of the examined ABC transporters are likely to play a role in the MDR of ovarian carcinoma. Gene expression of these transporters seems only up regulated through chemotherapy. The thesis that MDR in ovarian cancer is acquired through therapy itself and not present ab initio is supported by these findings.
Gynecologic Oncology 11/2009; 117(2):198-201. · 3.89 Impact Factor
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ABSTRACT: Cervical biopsy often causes discomfort and pain. To compare local anesthesia (1% lidocaine) with forced coughing as pain relief, we quantified the actual pain experienced during cervical punch biopsies.
For a prospective trial conducted at the Medical University of Vienna, 68 women undergoing cervical punch biopsies for assessment of abnormal cervical smears were randomized in 2 pain relief treatment groups. Patients' discomfort was assessed immediately after taking the biopsy using at 10-cm visual analog scale.
No statistically significant difference was found between pain scores recorded for the 2 groups (P = .47, 95% confidence interval [CI], -0.4 to 1.3 cm). However, when local anesthesia was applied, the examination was significantly prolonged by a median of 2.11 min (P < .001; 95% CI, 1.6-2.8).
Forced coughing during cervical biopsies reduces patients' discomfort to the same extent as local anesthesia, but is associated with a significantly reduced examination time.
American journal of obstetrics and gynecology 10/2008; 199(6):641.e1-3. · 3.28 Impact Factor
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ABSTRACT: To evaluate whether C-reactive protein (CRP) serum levels can be used as a prognostic parameter in patients with cervical cancer.
In the present study, CRP serum levels were measured in 215 patients with cervical cancer. CRP serum levels were measured prior to therapy for cervical cancer and were correlated to clinical data.
The median CRP serum level in patients with cervical cancer was 0.5 mg/dl (interquartile range 0.5-0.9 mg/dl). CRP serum levels were significantly associated with advanced tumor stage (p<0.001), lymph node involvement (p=0.01) and patients' age (p=0.01), but not with histological grade (p=0.1) and histological type (p=0.9). In a univariate and multivariate analysis CRP serum levels, tumor stage, and lymph node involvement, but not histological grade, histological type and patients' age were associated with overall and disease-free survival.
CRP serum levels can be used as additional prognostic parameter in patients with cervical cancer.
Gynecologic Oncology 11/2007; 107(1):114-7. · 3.89 Impact Factor
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ABSTRACT: p16, a member of the INK4a family of cyclin-dependent kinase inhibitors, is known as a negative regulator of cell cycle progression and differentiation. Although p16 has been shown to be a promising biomarker for the detection of cervical intraepithelial neoplasia, few data have been published on vulvar cancer. Using immunohistochemistry, we evaluated the expression of p16 in 80 cases of invasive vulvar squamous cell carcinoma. Results were correlated with clinicopathologic parameters and survival data to determine the prognostic significance of p16 in vulvar cancer. p16 expression was detected in 34 of 80 (43%) cases of invasive vulvar squamous cell carcinoma. The expression was localized to the cytoplasm and the nuclei of the tumor cells. Correlations between p16 expression status and any clinicopathologic variables failed to be of statistical significance. In a univariate analysis, groin lymph node status, tumor stage, and tumor grade were associated with disease-free and overall survival, respectively. Patients positive for p16 expression showed a significantly longer disease-free and overall survival by univariate analysis. p16 expression was not associated with survival in a multivariate Cox-regression model. Our data add on those published in the literature and suggest that p16 may be of prognostic significance in invasive vulvar squamous cell carcinoma.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 10/2007; 15(3):279-83. · 1.63 Impact Factor
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ABSTRACT: To determine whether the cyclooxygenase (COX)-2 inhibitor rofecoxib increases the regression rates of cervical intraepithelial neoplasia (CIN) grade II and III.
A prospective, randomized, placebo-controlled, double-blind study with rofecoxib 25 mg daily for 6 [corrected] months as active treatment for patients with CIN II and III was started in May 2004 [corrected] and was halted after rofecoxib withdrawal in October 2004 [corrected]
A total of 16 patients with CIN II (n=9) and CIN III (n=7) were included in our study. Eight and eight patients received rofecoxib and placebo, respectively. Regression rates in the rofecoxib and placebo arm were statistically not significant (25% versus 12.5%) after a mean of 87 (46.3) days of treatment. No severe side effects were noted during the therapy; no dropouts were recorded.
A conservative treatment of CIN II and III is feasible. Inhibitors of COX, especially COX-2, were seen as candidates for cancer chemoprevention. Our study was halted after rofecoxib was withdrawn. The results obtained should be added to those already published for planning future studies on medical therapies for high grade CIN.
European Journal of Obstetrics & Gynecology and Reproductive Biology 05/2006; 125(2):251-4. · 1.97 Impact Factor
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ABSTRACT: The enzyme matrix metalloproteinase (MMP)-1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP-1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women.
The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data.
No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involvement (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient's age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04).
Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.
Gynecologic Oncology 04/2006; 100(3):506-10. · 3.89 Impact Factor
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ABSTRACT: Besides its important role in immune response and inflammatory processes the cytokine interleukin-6 (IL-6) is crucially involved in carcinogenesis. A common polymorphism within the gene encoding IL-6 (IL6) is known to alter IL-6 protein expression and has been associated with patients' prognosis in various malignancies. No data are available with respect to vulvar cancer. Therefore, we determined the prognostic potential of the common -174(G-->C) single nucleotide polymorphism in the promoter region of IL6 in a series of patients with this disease.
The IL6 promoter polymorphism was investigated in 81 Caucasian patients with surgically treated squamous cell vulvar cancer using pyrosequencing. Results were correlated with clinical data.
No association was ascertained between the IL6 promoter polymorphism and the investigated clinicopathologic parameters, ie, tumor stage, lymph node involvement, tumor grade, and patient's age at diagnosis. In an univariate analysis, lymph node involvement and patients' age at diagnosis were associated with patient prognosis. In a multivariate analysis, including tumor stage and lymph node involvement as established prognostic factors and the IL6 promoter polymorphism, lymph node involvement, and the presence of at least one mutant allele, but not tumor stage, were associated with increased disease-free and overall survival.
Our data suggest that the IL6 -174(G-->C) promoter polymorphism might serve as an additional prognostic parameter in patients with vulvar cancer.
Journal of the Society for Gynecologic Investigation 12/2005; 12(8):617-20. · 2.26 Impact Factor
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ABSTRACT: Thrombospondin-1 (TSP-1) is a multifunctional matricellular glycoprotein involved in several mechanisms critical to the formation and progression of solid tumors including cell adhesion, proliferation, migration, invasion, and angiogenesis. The present study was designed to investigate the expression of TSP-1 in invasive vulvar squamous cell carcinoma.
A total of 75 invasive vulvar squamous cell carcinomas were evaluated for TSP-1 expression by immunohistochemistry. Results were correlated with the clinicopathologic parameters including tumor stage, groin lymph node status, tumor grade, patient's age, patients' disease-free, and overall survival.
TSP-1 expression was detected in 35/75 (46.7%) specimens of invasive vulvar squamous cell carcinomas. The expression of TSP-1 was generally localized to the cytoplasm and occasionally seen in the nucleus. An increased TSP-1 expression was detected in patients with an advanced tumor stage (P = 0.01) and a positive groin lymph nodes status (P = 0.01). Tumor stage and groin lymph node status were associated with patients' disease-free and overall survival. All other parameters failed to be of prognostic significance.
We are the first to report on the immunohistochemical expression of TSP-1 in invasive vulvar squamous cell carcinoma. Increased TSP-1 expression was associated with an advanced tumor stage and a positive groin lymph node status, suggesting its pro-angiogenic potential in vulvar carcinogenesis.
Gynecologic Oncology 11/2005; 99(1):80-3. · 3.89 Impact Factor
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ABSTRACT: Metastatic relapse due to early dissemination of tumor cells is associated with poor prognosis for epithelial cancer. The molecular characterization of these single cells or cell clusters that have evaded the tumor is indispensable in order to evaluate their biological behavior and metastatic potential. In this study, we established a sensitive immunomagnetic method to isolate rare cancer cells from peripheral blood based on their expression of epithelial- or tumor-cell-specific markers.
Low numbers of cells of breast cancer cell lines - ZR-75-1, MCF-7, HBL-100 - were spiked into peripheral blood specimens of healthy volunteers. Enrichment of tumor cells was performed using either pre-coupled HEA and/or ErbB2 microbeads or a mixture of three monoclonal antibodies against HEA, ErbB2 and EGFR.
The recovery rate of spiked tumor cells correlated with the expression of the corresponding antigens. ZR-75-1 cells high expressing all three genes could be isolated to 60-71%. MCF-7 cells, which hardly express EGFR, showed a significant better recovery by using two specific antibodies in combination (50-68%) than one pre-coupled bead alone (31-42%). HBL-100 cells little expressing HEA could not be isolated with HEA microbeads and only to 27% in combination with ErbB2 beads -in contrast the use of an antibody cocktail achieved 38%.
As tumor and epithelial specific cell marker antigens are expressed differently in disseminated tumor cells, the immunomagnetic enrichment from peripheral blood is most robust and reliable when using a combination of specific antibodies compared to single antibodies.
Gynecologic Oncology 09/2005; 98(2):211-6. · 3.89 Impact Factor
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ABSTRACT: To determine whether SCC-Ag serum levels can be used as a prognostic parameter in surgically treated early stage vulvar cancer.
SCC-Ag serum levels were measured preoperatively in 61 surgically staged patients with squamous cell vulvar cancer (UICC pT1 and pT2). Results were correlated to clinical data.
Mean (standard deviation) SCC-Ag serum levels in patients with vulvar cancer were 1.5 (1.99) ng/mL. SCC-Ag serum levels were significantly higher in patients with pT2 vulvar cancer (2.2 [2.6] ng/mL) compared with patients with pT1 vulvar cancer (1.0 [1.2] ng/mL, P = 0.034). SCC-Ag serum levels were not associated with lymph node involvement (P = 0.1), tumor grade (P = 0.6), and patients' age (P = 0.5). Multivariate Cox regression models considering tumor stage, lymph node involvement, patients' age, and SCC-Ag serum levels as covariates showed that lymph node involvement (P = 0.04 and P = 0.01) and tumor stage (P = 0.006 and P = 0.009), but not SCC-Ag serum levels (P = 0.8 and P = 0.6), and patients' age (P = 0.08 and P = 0.22) are prognostic factors for disease-free and overall survival, respectively.
SCC-Ag serum levels cannot be used as an additional prognostic parameter in patients with surgically treated early stage vulvar cancer.
Gynecologic Oncology 07/2005; 97(3):904-7. · 3.89 Impact Factor
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ABSTRACT: A relatively high incidence of pelvic and paraaortic lymph node metastases is found in patients with pT1 and pT2 ovarian cancer. This paper investigates the clinicomorphological parameters and the expression of various biological markers in these tumors in order to define possible risk factors for lymphatic dissemination.
In a retrospective study we identified 51 patients with pT1 and pT2 ovarian cancer. All patients underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and systemic pelvic +/- paraaortal lymphadenectomy. The incidence of lymph node metastases in these patients and the clinicomorphological parameters of their tumors were examined. Immunohistochemistry was used to determine the expression levels of the cell proliferation marker Ki-67, the cell adhesion molecules CD44s and CD44v6, and the oncoprotein HER2/neu of the tumors and their respective lymph node metastases.
Lymph node involvement was found in 5 of 26 patients with pT1 ovarian cancer and in 6 of 25 patients with pT2 ovarian cancer. Serous adenocarcinoma was associated with a significantly higher incidence of lymph node metastases than other histological types (chi(2) = 4.7, P = 0.03). No correlation was found between tumor grade and the lymph node status. High Ki-67 expression was significantly correlated with spread to the lymph nodes (chi(2) = 4.2, P = 0.04), whereas expression of CD44s, CD44v6, and HER2/neu was not related to the lymph node status. Survival analyses showed no difference in disease-free and overall survival in patients with lymph node metastases compared to those without lymph node metastases. No association was seen among histological type, tumor grade, and immunohistochemically detected Ki-67, CD44s, CD44v6, and HER2/neu expression on the one hand and disease-free and overall survival on the other hand.
Our data suggest that in early stage ovarian cancer the serous histological type and tumors showing a high Ki-67 expression carry a high risk of lymph node metastases. With respect to prognosis our data showed a minor role for Ki-67, CD44s, CD44v6, and HER2/neu expression and the occurrence of lymph node metastases in pT1 and pT2 ovarian cancer.
Gynecologic Oncology 05/2003; 89(1):9-15. · 3.89 Impact Factor
