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The primary objective of this study was to analyse Tetranectin (TN) expression in tumour tissues and TN serum concentration in 758 women with epithelial ovarian tumours. The second was to evaluate, whether TN tissue expression levels correlate with clinico-pathological parameters and prognosis of the disease. Using tissue arrays we analysed the expression levels in tissues from 166 women with borderline ovarian tumours (BOTs) and 592 women with ovarian cancer (OC). A panel of three antibodies was used for immunohistochemistry: a polyclonal and two monoclonal antibodies. Serum TN was measured using the polyclonal antibody A-371. Univariate survival analyses stratified for chemotherapy showed that positive tissue TN as demonstrated by the polyclonal antibody indicated a significantly longer overall survival (OS) (p = 0.0001) as well as cancer specific survival (CSS) (p < 0.0001). High serum TN was likewise found to imply longer OS (p < 0.0001) and CSS (p < 0.0001), whereas tissue staining with the two monoclonal antibodies failed to demonstrate any significant correlation with either survival type. Univariate Kaplan-Meier survival analysis performed on all OC cases showed a significantly longer OS (p = 0.0009) and CSS (p = 0.0006) for women with TN positive tumour tissue and in women with high serum TN levels (p < 0.0001 for both). However, in the multivariate Cox regression analysis, only serum TN was found to be an independent prognostic factor for OS (p = 0.01) and not for CSS (p = 0.08). In conclusion, our results predict that a positive TN expression of both tumour tissue and serum points to a more favourable outcome for OC patients., (© 2015 APMIS. Published by John Wiley & Sons Ltd.)

The primary objective of this study was to assess the expression of MIB-1 (Ki-67) in tumour tissues from 808 patients with epithelial ovarian tumours. The second was to evaluate, whether MIB-1 (Ki-67) tissue expression levels correlate with clinicopathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the MIB-1 (Ki-67) expression levels in tissues from 202 women with borderline ovarian tumours (BOT) (177 stage I, 5 stage II, 19 stage III, 1 stage IV) and 606 ovarian cancer (OC) patients (177 stage I, 64 stage II, 311 stage III, 54 stage IV). Using a 10% cut-off level for MIB-1 (Ki-67) overexpression, 12% of the BOTs and 51% of the OCs were positive for MIB-1 (Ki-67) expression. The frequency of MIB-1 (Ki-67) expression-positive OC increased with increasing FIGO stage (p = 0.003), increasing histological grade (p ≤ 0.0001), and a significantly different distribution of MIB-1 (Ki-67) positive and negative tumours were found in adenocarcinoma NOS, serous adenocarcinomas, mucinous adenocarcinomas, endometrioid adenocarcinomas, non-epithelial and clear-cell carcinomas (p = 0.016). Univariate Kaplan-Meier survival analysis performed on all OC cases showed a significant shorter disease specific survival in patients with positive MIB-1 (Ki-67) expression in the tumour tissue (p ≤ 0.0001). In a Cox survival analysis including 606 FIGO stages I to IV OC cases, FIGO stage (II vs I: HR = 3.00, 95% CI: 1.81-4.99, III-I: HR = 6.41, 95% CI: 3.90-10.50, IV vs I: HR = 12.69, 95% CI: 7.21-22); age at diagnosis pr.10 years (HR = 1.27, 95% CI: 1.15-1.40), residual tumour after surgery (HR = 1.95, 95% CI: 1.40-2.73) and MIB-1 (Ki-67) expression (HR = 1.31, 95% CI: 1.08-1.60) had a significant independent impact on survival. Histological grade (p = 0.14) and histological tumour type (p = 0.35) had no significant independent impact on survival. In conclusion, our results predict that an increased level of MIB-1 (Ki-67) expression in tumour tissue, points to a less favourable outcome for OC patients., (© 2013 APMIS. Published by John Wiley & Sons Ltd.)

To evaluate if heterogeneity of tissue cancer antigen 125 (CA125) expression is present in epithelial serous adenocarcinomas. Furthermore, to investigate whether there is a correlation between levels of CA125 tissue expression, serum level of CA125, stage, and grade. A total of 10 patients diagnosed with serous ovarian adenocarcinomas were included. Preoperative blood samples were collected to determine serum CA125 levels. Tumor tissue from primary surgery was collected and processed for immunohistochemical analyses. CA125 was expressed in varying degrees in tumor tissues from all patients. Mean tissue CA125 expression for each patient ranged from 36% to 98%. Intrapatient variations in tissue expression ranged from 10% to 90% point. No significant correlations between levels of CA125 tissue expression, serum level of CA125, stage, and grade were found. We found that the tissue expression of CA125 is heterogenic. Although most patients had a high mean expression, it covers a large intrapatient variation in expression. This suggests that if using CA125 as a tissue marker and anti-CA125 (oregovomab) as immunotherapy treatment in future studies, it will be necessary to take heterogeneity into consideration and examine a larger number of biopsies. Therefore, the study demonstrates the need for heterogeneity studies in future translational research., (© 2012 The Authors APMIS © 2012 APMIS.)

The primary objective of this study was to assess the expression of cyclin E in tumour tissues from 661 patients with epithelial ovarian tumours. The second was to evaluate whether cyclin E tissue expression levels correlate with clinico-pathological parameters and prognosis of the disease. Using tissue arrays (TA), we analysed the cyclin E expression levels in tissues from 168 women with borderline ovarian tumours (BOT) (147 stage I, 4 stage II, 17 stage III) and 493 Ovarian cancer (OC) patients (127 stage I, 45 stage II, 276 stage III, 45 stage IV). Using a 10% cut-off level for cyclin E overexpression, 20% of the BOTs were positive with a higher proportion of serous than mucinous tumours. Sixty-two per cent of the OCs were positive for cyclin E expression with the highest percentage found in clear cell carcinomas. Results based on univariate and multivariate survival analyses with a 10% cut-off value showed that cyclin E had no independent prognostic value. In conclusion, we found cyclin E expression in tumour tissue to be of limited prognostic value to Danish OC patients., (© 2012 The Authors APMIS © 2012 APMIS.)

The purpose of the study was to determine the expression of BCl-2 in epithelial ovarian tumors and to correlate expression levels with selected clinicopathologic parameters, time to progression and prognosis of the disease. Using tissue arrays (TA), we analyzed BCl-2 expression in tissues from 191 women diagnosed with low malignant potential ovarian tumors (LMP) and from 582 patients diagnosed with ovarian cancer (OC). Using 30% as cutoff level for BCl-2 overexpression, 5% of LMPs were positive with a higher proportion of serous ovarian tumor of LMP, compared to mucinous ovarian tumor of LMP (p = 0.02). Women with a BCl-2-positive LMP tumor were older than women with a BCl-2 negative tumor (p = 0.02). Ten percent of OCs were positive for BCl-2 expression (>or=30%). No significant association was found between BCl-2 expression levels and histologic type of tumors (serous vs mucinous, p = 0.19). A 30% cutoff value or a percentage scale showed that BCl-2 expression had no prognostic value, both in univariate and in multivariate survival analyses. No difference in time to progression was observed between patients with BCl-2-positive and negative tumors. These data suggest that BCl-2 expression may not be of important clinical value in the treatment of Danish OC patients.

The clinical roles played by normal and altered p53 in cancer are under intensive investigation, but larger studies describing the pattern as well as the prognostic value are still needed. The aim of this study was, using tissue array (TA), to examine the overexpression of p53 protein in 774 epithelial ovarian tumour tissues from Danish women and to evaluate whether p53 tissue expression levels correlate with clinicopathological parameters and prognosis. The distribution of p53 expression levels at different stages of disease, in different histological subtypes, and the prognostic value of p53 tissue expression were examined. Overall, p53 was expressed in 24/189 (13%) low malignant potential ovarian tumours (LMP) and in 278/585 (48%) ovarian cancers (OC). No significant difference in frequency of p53 tissue expression in LMP tissue was noted with increasing tumour stage (p=0.98). By contrast, there was a significant increase in the frequency of p53 tissue expression in OC with increasing FIGO stage (p<0.00001). Multivariate Cox regression analysis found that less than 20% tissue expression of p53 was associated with longer OC disease-specific survival. Tissue p53 expression may be of prognostic value in women with OC.

The level of the soluble urokinase plasminogen activator receptor (suPAR) is elevated in tumour tissue from several types of cancer. This is the first study aiming to predict the prognosis for survival by the use of a pre-chemotherapeutic plasma suPAR value in 71 patients with recurrent epithelial ovarian cancer (REOC). For determination of suPAR, pre-chemotherapeutic blood samples from the patients with REOC were processed into plasma (EDTA) within one working day from venipuncture. The plasma suPAR level is not correlated with performance status (p=0.41), FIGO stage (p=0.09), treatment-free interval (TFI) of 12 months (p=0.26), site of recurrence (peritoneum, p=0.50 or pelvis, p=0.44), age (p=0.43), or serum CA125 (p=0.09). Univariate as well as multivariate analyses cannot demonstrate that high pre-chemotherapeutic levels of plasma suPAR (p=0.22, p=0.80) are associated with shorter survival of REOC patients. Multivariate analysis showed that only TFI of 12 months (p=0.001) and performance score status of 2 (p=0.02) were independent prognostic factors. Our study indicates that pre-chemotherapeutic measurement of plasma suPAR level in REOC patients may not be useful to identify a subgroup of patients with poor prognosis.

Soluble tetranectin (TN) was measured preoperatively in serum from 567 patients with primary colorectal cancer and levels were tested for association with prognosis. The prognostic significance of TN was also compared to that of plasminogen-activator inhibitor-1 (PAI-1), urokinase plasminogen activator (uPAR) and carcinoembryonic antigen (CEA). Significantly shorter survival was found for patients with TN levels below a cut-off point of 7.5 mg/l compared to patients with levels above, as illustrated by Kaplan-Meier curves. By Cox analyses, log TN, log soluble uPAR as well as log CEA were found to have an independent prognostic value for survival (log TN: HR = 0.47, 95% CI: 0.29-0.76); log soluble uPAR: HR = 1.65, 95% CI: 1.18-2.31; log CEA: HR = 1.I1, 95% CI: 1.03-1.20). Based on the multivariate model, a patient with a combination of low levels of TN and PAI-1 and elevated levels of soluble uPAR and CEA had a 2.43 increased risk as compared to a patient with median levels of these biochemical markers. Significant correlations were found with Dukes' stages for all the biochemical markers and between the respective biochemical markers. The findings confirm that TN is a strong prognostic factor in patients with colorectal cancer. TN may be valuable as a prognostic variable in future studies evaluating new treatment strategies for colorectal cancer.

The p53 gene, a tumour suppressor gene located on the short arm of chromosome 17 (17p13), is frequently mutated in various human tumours. Accumulation of p53 protein in neoplastic cells and its release following tumour necrosis can lead to development of circulating autoantibodies (AAb) against p53. Earlier studies of ovarian cancer (OC) patients reported different frequencies of p53 AAb and conclusions regarding the clinical and prognostic value of these AAb have not been in agreement. We therefore analysed for the presence of p53 AAb in a total of 227 preoperative serum samples from 193 OC patients and 34 patients with ovarian borderline tumours, and, in addition, serum samples from 86 healthy controls. An enzyme-linked immunosorbent assay (ELISA) was used to measure serum IgG antibodies against p53. The p53 protein used in the assay was produced as a hexahistidine-tagged fusion protein by baculovirus-infected Spodoptera frugiperda cells. Cut-off values for p53 AAb were evaluated, and correlations of p53 AAb with clinical-, biochemical data and survival were examined. We found a low sensitivity for p53 AAb alone, and no major additional effect of the detection rate of CA125 was found. No significant associations were found between p53 AAb and clinical stage, age, histological subtype and radicality after primary surgery. In contrast, we found significantly elevated CA125 levels in p53 AAb-positive patients compared to lower CA125 levels in p53 AAb-negative patients (p=0.003). No significant differences were found between p53 AAb-positive and p53 AAb-negative patients in the univariate and multivariate survival analyses. In conclusion, in a screening study for OC serum p53 AAb levels are of no diagnostic value, even if combined with the tumour marker CA125. The presence of increased serum p53 AAb in patients with diagnosed OC could not be correlated with any clinical data and preoperative serum p53 AAb status had no evident value.