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Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed monospecific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell-associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer.

Background: A major step in cancer formation involves the degradation of the extracellular matrix, mediated by multiple degradative actions of (lysosomal) proteases. Extracellular release of lysosomal proteases (cathepsins) and their inhibitors has been associated with the development and progression of several types of cancer. We investigated whether cathepsins in ovarian cyst fluid (oCF) were associated with disease outcome in patients with epithelial ovarian cancer (EOC)., Materials and Methods: The levels of cathepsin B (CatB), H (CatH), L (CatL) and X (CatX) and their most abundant extracellular inhibitor cystatin C (CysC) were determined in oCF of 50 EOC patients by quantitative ELISAs. The cathepsin levels and ratios between cathepsins and CysC were related to clinicopathological parameters (Mann-Whitney U and Kruskal-Wallis tests) and survival (Cox Regression analysis)., Results: Median (25th-75th percentile) levels of cathepsin B, H, L, X and CysC in oCF were 97 (42-203), 18 (12-32), 61 (37-108), 20 (13-47) and 657 (501-805) ng mL(-1) respectively. Ratio of CysC/CatB was significantly lower for patients with metastatic compared with localised EOC (P = 0.025). Ratios of CysC/CatH and CysC/CatX differed significantly between histological subtypes (P = 0.012 and P = 0.035 respectively) and were significantly higher for high-grade tumours compared with low-grade tumours (P = 0.031 and P = 0.039 respectively). Neither cathepsins nor their ratios were significant predictors of survival for EOC patients., Conclusions: Ratios between CysC and cathepsins in oCF differed significantly between important clinicopathological subgroups. We believe that a complex cascade of proteolytic events, in which cathepsins play different roles, might be responsible for progression and metastasis in EOC.

Introduction: In cancer, an extracellular and membrane bound localization of cathepsins contribute to the invasion of tumor cells at the basement membrane., Methods: This is the first study that explored levels of cathepsins B (CatB), L (CatL) and their inhibitor cystatin C (CysC) in the cystic fluid (CF) of ovarian tumors (n = 110)., Results: CF contained considerable amounts of CatB, CatL and CysC. Remarkable differences in CatB and CatL and CysC CF levels were found between different histopathological tumor subtypes. Levels of CatB and CysC were significantly higher in CF of malignant serous tumors compared to those found in benign serous tumors (p = 0.010 and p = 0.001 respectively), whereas levels of CatL were significantly higher in CF of malignant mucinous tumors compared to those found in benign mucinous tumors (p = 0.035). CatB and CysC showed a strong correlation in the group of patients with malignant serous tumors (p < 0.001; R = 0.921) suggesting that the increase in CatB might be balanced by a corresponding increase in CysC., Conclusion: Further studies are warranted to investigate cathepsins as possible prognostic biomarkers for the aggressiveness of ovarian cancer.

Most ovarian tumors contain ovarian cyst fluid (oCF) which can be easily obtained during surgery. This is the first study that explored if CA 125 in oCF could be of prognostic value for patients with epithelial ovarian cancer (EOC). Of 54 patients with primary EOC, oCF and preoperative serum were collected and clinicopathological data were retrospectively obtained. CA 125 was measured with the commercially available CA 125 assay. CA 125 in oCF (n=54, median: 55,500 U/ml, range: 590-10,200,000 U/ml) was always higher than in the corresponding serum (n=51, median: 179 U/ml, range: 13-11,000 U/ml) (p<0.001) and values were moderately correlated (R=0.337, p=0.016). CA 125 in oCF was associated with histology (p<0.001) and tumor grade (p=0.038). High levels of oCF CA 125 (>median) were significantly associated with a poor disease-free survival (DFS) (log-rank p=0.002 and p=0.005 univariate Cox-regression). Other factors associated with a poor DFS in univariate analysis were advanced FIGO stage, suboptimal debulking (both p<0.001), high tumor grade (p=0.025), serous histology (p=0.003) and high serum (>media) CA 125 (p=0.009). In multivariate analysis, only FIGO stage was of independent predictive value. These findings indicate that, although high levels of oCF CA 125 were significantly associated with a poor survival of EOC patients, CA 125 in oCF was not of independent predictive value and might therefore not be useful as a prognostic biomarker for EOC.

Objective: To evaluate the frequency of metastatic tumors among malignant ovarian neoplasms, the site distribution of the primary malignancies that give rise to ovarian metastasis and the clinicopathologic features of metastatic tumors., Methods: We analyzed a total number of 116 patients diagnosed with metastasis to the ovary between 1985 and 2007 at the Radboud University Nijmegen Medical Centre. The medical records of the patients were reviewed for age at diagnosis, medical history, menopausal state, clinical manifestation, primary tumor, intraoperative findings, and prognosis. The pathology reports were reviewed for macroscopic appearances and histopathologic features., Results: Metastasis to the ovary accounted for 15% of all ovarian malignancies identified in the 22-year period at the Radboud University Nijmegen Medical Centre. The gastrointestinal tract was the most common primary site (39%), followed by breast (28%) and endometrium (20%). There were 22 metastases to the ovary that mimicked a primary ovarian tumor at first clinical presentation, of which the single greatest number of cases (36%) originated from a primary tumor of the large intestine. Ovarian cysts were present in 71% of patients, and most ovaries with metastatic disease were 10 cm in diameter or less. Bilateral ovarian involvement was present in 69% of the patients, including all patients with tumors of the stomach., Conclusion: In case of an ovarian tumor, metastatic disease should always be considered to avoid pitfalls in diagnosis and therapy. The gastrointestinal tract is the most likely location of the primary tumor, followed by breast and endometrium.

We investigated whether epithelial ovarian cancer patients participating in a randomized phase III trial comparing single intraperitoneal (IP) administration of yttrium-90-labeled murine HMFG1 ((90)Y-muHMFG1) plus standard treatment (AT) vs. standard treatment (ST) alone developed IgG ab to MUC1 that had an impact on disease outcome. Serial serum samples from 208 patients in the AT and 199 patients in the ST arm were tested for IgG ab to MUC1 (anti-MUC1 IgG). Anti-MUC1 IgG at weeks 4, 8 and 12 ranked higher in the AT than in the ST arm (p < 0.001). The median (range) area under the curve (AUC) of anti-MUC1 IgG for weeks 1 to 12 was 5.53 (1.51-39.51) and 3.92 (1.17-68.74) for the AT and ST arm, respectively (p < 0.001). An anti-MUC1 IgG AUC > 13 was associated with a benefit in overall survival (OS) and disease-free survival (DFS) in the AT arm in univariate (p = 0.043 and 0.036, respectively), but not in multivariate analysis (Cox proportional hazards regression model). Kaplan-Meier analysis showed a benefit in OS and DFS in patients with an anti-MUC1 IgG AUC > 13 in the AT arm (p = 0.043 and 0.036, respectively), but not in the ST arm. A single IP injection with muHMFG1 did not lead to a survival benefit in the randomized trial, but it induced ab to MUC1 that were associated with an improved disease outcome in patients with highest levels of anti-MUC1 IgG. Immunotherapy against MUC1 could be effective in the treatment of epithelial ovarian cancer.

Background: Human anti-mouse antibody (HAMA)-IgM and IgG in ovarian cancer patients treated with intraperitoneal (i.p.) 90Y-muHMFG1 as consolidating therapy were analyzed for a relationship with outcome of disease., Patients and Methods: Serial serum samples from 208 ovarian cancer patients participating in a phase III trial of i.p. 90Y-muHMFG1 and 25 controls were analyzed for HAMA-IgM and HAMA-IgG. Results were correlated with time to, and location of, disease recurrence., Results: Patients receiving i.p. 90Y-muHMFG1 developed a rapid HAMA-IgM peak (week 4 to 8), followed by a HAMA-IgG peak 2-4 weeks later. HAMA levels in the control group remained unchanged. Early maximum HAMA-IgG peaks were associated with early relapse [hazard ratio (HR), 0.975; 95% confidence interval (CI) 0.956 to 0.995; p=0.012]. Patients with a HAMA-IgG maximum before or at 8 weeks were at significantly higher risk for disease recurrence (HR, 1.6; 95% CI 1.1 to 25;p=0.021) as compared to patients with a HAMA-IgG maximum after 8 weeks., Conclusion: Besides time point of maximum HAMA-IgG, no evident relation could be found between HAMA-IgM or HAMA-IgG development and time to relapse or location of recurrence.

The prognosis for patients with ovarian cancer is still poor and more effective therapeutic modalities are needed. (Radio)immunotherapy using monoclonal antibodies (Mabs) could be one of these approaches. Here, we review the status of (radio)immunotherapy using Mabs for the treatment of ovarian cancer. The Pubmed database was searched for clinical trials investigating the effect of (radio)immunotherapy in ovarian cancer published until October 1, 2007. Keywords for the search were: ovarian cancer, monoclonal antibodies, CA 125, gp38, HER2, HMFG, MUC1, TAG 72 and VEGF. A total of 44 trials on immunotherapy with unconjugated Mabs, Mab vaccination and (radio)immunotherapy directed towards the antigens CA 125, gp38, HER2, MUC1, TAG 72 or VEGF in patients with ovarian cancer were found, reviewed and discussed. Out of these trials, 23 studied immunotherapy with unconjugated Mabs, 5 vaccination with Mabs and 16 trials studied (radio)immunotherapy. The lack of large randomized prospective trials with Mabs directed to tumor-associated antigens expressed on ovarian cancer cells preclude any firm conclusion on the potential of Mabs use in the treatment of ovarian cancer. Oregovomab, directed against CA 125, and bevacizumab, targeting VEGF, are two unconjugated Mabs closest to clinical introduction for the treatment of ovarian cancer. Vaccination with Mab ACA 125 seems promising but these findings need to be confirmed in controlled randomized trials. Sole RIT should be investigated with the appropriate radionuclide and a Mab with high affinity for the specific tumor-associated antigen in the appropriate patient group to determine whether it may have a therapeutic effect. Additionally, appending (radio)immunotherapy with anti-TAG 72 or anti-MUC1 to other treatment strategies such as chemotherapy could also be a strategy worthwhile investigating. The potential of Mabs to complement current treatment paradigms, is encouraging and may bring a significant improvement to the overall therapeutic outcomes currently being achieved in ovarian cancer.

Objective: To investigate the influence of human anti-mouse antibodies (HAMA) on serial CA 125 measurements in serum of patients with epithelial ovarian cancer following single intraperitoneal (IP) therapy with Yttrium-90-labeled human milk fat globule 1 murine monoclonal antibody ((90)Y-muHMFG1) as part of a large international randomized phase III trial., Methods: We monitored CA 125 concentrations in longitudinally collected serum samples from 224 patients after IP (90)Y-muHMFG1 (study group) and from 223 patients who received standard treatment (control group). Serum samples of 22 study patients with increased CA 125 concentrations were selected and subjected to affinity chromatography to study HAMA interference in CA 125 measurements., Results: CA 125 serum concentrations at weeks 1, 4 and 8 were significantly higher in the study group than in the control group. In the first 8 weeks after IP (90)Y-muHMFG1 administration significantly more patients of the study group (144/224) demonstrated CA 125 concentrations above the upper limit of normal of 23 U/mL, as compared to those of the control group (37/223). Affinity chromatography of serum with high CA 125 values in the first 8 weeks confirmed HAMA interference in CA 125 measurements while after 24 weeks this HAMA interference could no longer be detected., Conclusions: This is the first study to demonstrate that clinical trials applying murine monoclonal antibodies may be flawed by a transient HAMA effect, which should be considered when monitoring ovarian cancer patients with CA 125 measurements.

Chondroitin sulfate (CS) is abundantly present in the tumor stroma, and tumor-specific CS modifications might be potential targets to influence tumor development. We applied the phage display technology to select antibodies that identify these tumor-specific CS modifications. Antibody GD3G7 was selected against embryonic glycosaminoglycans, and it reacted strongly with CS-E (rich in GlcA-GalNAc4S6S units). In ovarian adenocarcinomas, strong expression of this CS-E epitope was found in the extracellular matrix, and occasionally on tumor cells. No expression was found in normal ovary and cystadenomas. Differential expression was found in ovarian carcinoma cell lines, which correlated with the gene expression of the GalNAc4S-6st enzyme, involved in biosynthesis of CS-E. Vascular endothelial growth factor (VEGF)-sensitive fenestrated (in normal tissues) and tumor blood vessels were both identified by antibody GD3G7, which might implicate a role for CS-E in VEGF biology. VEGF bound to CS-E and antibody GD3G7 could compete for binding of VEGF to CS-E. In conclusion, antibody GD3G7 identified rare CS-E-like structures that were strongly expressed in ovarian adenocarcinomas. This antibody might therefore be instrumental for identifying tumor-related CS alterations.

The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n=5) and the responders (n=19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p<0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies., (Copyright (c) 2005 Wiley-Liss, Inc.)

To evaluate the frequency of metastatic tumors among malignant ovarian neoplasms, the site distribution of the primary malignancies that give rise to ovarian metastasis and the clinicopathologic features of metastatic tumors.We analyzed a total number of 116 patients diagnosed with metastasis to the ovary between 1985 and 2007 at the Radboud University Nijmegen Medical Centre. The medical records of the patients were reviewed for age at diagnosis, medical history, menopausal state, clinical manifestation, primary tumor, intraoperative findings, and prognosis. The pathology reports were reviewed for macroscopic appearances and histopathologic features.Metastasis to the ovary accounted for 15% of all ovarian malignancies identified in the 22-year period at the Radboud University Nijmegen Medical Centre. The gastrointestinal tract was the most common primary site (39%), followed by breast (28%) and endometrium (20%). There were 22 metastases to the ovary that mimicked a primary ovarian tumor at first clinical presentation, of which the single greatest number of cases (36%) originated from a primary tumor of the large intestine. Ovarian cysts were present in 71% of patients, and most ovaries with metastatic disease were 10 cm in diameter or less. Bilateral ovarian involvement was present in 69% of the patients, including all patients with tumors of the stomach.In case of an ovarian tumor, metastatic disease should always be considered to avoid pitfalls in diagnosis and therapy. The gastrointestinal tract is the most likely location of the primary tumor, followed by breast and endometrium. [ABSTRACT FROM AUTHOR]