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Purpose: The treatment of ovarian cancer continues to pose a challenge especially through the development of platinum-resistant disease and still has the highest mortality rate among gynecologic cancers. Patients are usually diagnosed with advanced stages where complete cytoreduction and standard platinum-based chemotherapy are the mainstay of treatment. Advances into the molecular underpinnings of DNA damage repair highlighted BRCA 1/2 and other related genes as key regulators of platinum sensitivity. Our study characterizes clinical features and outcomes associated with BRCA mutations in a cohort of ovarian cancer patients., Methods: Patient data from our Institute was retrospectively extracted for all patients that were tested for the presence of BRCA germline or somatic mutations through next generation sequencing between May 2016 and August 2018., Results: Eighty-eight patients were included in the present analysis. Advanced FIGO stage IIIC-IV was common at presentation (71.6%), with 58% of patients undergoing primary debulking surgery. BRCA mutant cases represented 44% and were associated with a significantly higher frequency for complete pathologic response, first and second platinum sensitive relapse and a significantly longer overall survival for advanced stage cases treated with neoadjuvant chemotherapy. Mean age at presentation was significantly lower in the BRCA mutated (52 years) compared to BRCA wildtype patients (54.2 years, p=0.045)., Conclusions: Upfront knowledge of BRCA status is encouraged, given the recent advent of targeted therapies and for the decision regarding optimal sequence of available therapeutic strategies.

Purpose: Ovarian cancer has the poorest survival rate among gynaecological malignancies. Besides the comparison of different therapeutic strategies aimed to improve outcomes, studies have also begun to focus on aspects of cost-effectiveness of these strategies. In this context, we proposed to evaluate the survival impact, costs and cost-effectiveness of two primary treatment options, primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT), in patients with advanced ovarian cancer treated in a tertiary cancer center of the North-Western Romania., Methods: The study included patients with stages IIIC and IV ovarian cancer treated at the "Prof. Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, between 2008-2011, by either PDS or NACT. Survival was the measure of the effectiveness of the two treatments. A cost-effectiveness analysis was carried out by estimating the incremental cost-effectiveness ratio (ICER) and the average cost-effectiveness ratio (ACER)., Results: There was no significant difference in overall survival between the two treatment groups. The median costs for the NACT subgroup were 3580.41 € compared to 2990.19 € for the PDS subgroup, with an incremental cost of 590.22 €. The effectiveness measured in years of survival was 3.34 years for NACT and 3.57 years for PDS. The corresponding median ICER was -2566.17 €/year of survival. ACER was higher for NACT compared to PDS (1071.98 vs. 837.59 €/year of survival)., Conclusions: Despite the higher costs, NACT did not prove to be a more effective therapeutic strategy in terms of survival of patients with stage IIIC/IV ovarian cancer. Altogether, our results state that NACT might be less cost-effective than PDS.

Purpose: The heterogeneous phenotype of epithelial ovarian cancer (EOC) explains the unpredictable behaviour in terms of response to therapy, time to progression and survival. In this context, CD146, a cell adhesion molecule, has been focused on as a marker of poor prognosis in various solid cancers, being also capable to modulate the activity of endothelial cells. Therefore, we proposed to investigate its role in serous ovarian carcinoma., Methods: The study included 101 patients diagnosed with EOC and treated within "Ion Chiricuta" Oncology Institute by optimal surgical debulking followed by platinum-based chemotherapy. Clinico-pathological characteristics were collected from patient files. CD146 expression was assessed by immunohistochemistry in serous ovarian carcinoma primary tumours, taking into account both staining intensity and the percentage of positive tumor cells. Expression of CD146 in endothelial cells of tumour microvessels was also evaluated. CD34 immunostaining was used for intratumoral microvessel density estimation., Results: CD146 positivity in tumor cells was objectified in 49.5% of samples and 37.1% presented a high CD146 endothelial expression. Our analysis showed that CD146 was as reliable as CD34 for microvascular density estimation. The distribution of cases according to CD146 tumor expression was similar regardless of age, initial serum CA125 level, FIGO stage, presence/absence of malignant ascites. Multivariate analysis confirmed that expression of CD146 in tumor cells was a negative prognostic factor for overall survival, significantly asociated with a higher risk of chemotherapy resistance., Conclusions: Although CD146 immunoreactivity in tumor cells did not correlate with the routinely used clinico-pathological parameters, expression of CD146 in tumor cells was an independent pronostic factor for survival in serous ovarian carcinomas. Moreover, CD146 might be regarded as a novel biomarker of tumor neovasculature.

Purpose: Ovarian cancer continues to be the most lethal gynecologic malignancy, with a complex tumor microenvironment (TME). We investigated the immunohistochemical (IHC) expression of toll like receptors (TLRs) 4,5,7 and 9 together with CD68 and CD 163 as markers for tumor-associated macrophages (TAM) in relation to clinicopathological data., Methods: Data from 102 patients with serous ovarian cancer treated between 2006 and 2011 was retrospectively reviewed. A TLR IHC score was developed and CD68, CD163 density scores were calculated as the mean number of positive cells from three 0.5 mm2 areas., Results: Advanced-stage disease (FIGO IIIC-IV) was present in 65.7% of cases. A TLR4 score above median was associated with peritoneal carcinomatosis (odds ratio/OR) 3.02, p=0.019) or ascites (OR 2.5, p=0.041). In FIGO stage IIIC-IV patients with a platinum-free interval (PFI) >12 months had, in comparison with patients with PFI ≤12 months, a higher CD68 density score (191.9 ± 95.2 vs. 152.7 ± 69.4, p=0.066) and a lower CD163 density score (106.7 ± 73.3 vs. 154.5 ± 73.9, p=0.011). In early-stage ovarian cancer patients, TLR9 positivity was associated with a higher overall survival than in patients with absent expression (110.2 vs. 22 months, p<0.001), while advanced-stage patients with TLR7 positivity had a lower overall survival than patients with negative TLR7 (38.3 vs. 66.2 months, p=0.01)., Conclusions: Our data shows that TLRs and TAM are important prognostic markers and future studies are needed to better comprehend the immune response in ovarian cancer.

Pupose: Nestin and CD133 are regarded as putative markers of cancer stem cells (CSCs) and related to poor prognosis in various cancer sites. Since few studies have focused on their role in ovarian cancer, we aimed to investigate their predictive value and association with neoangiogenesis., Methods: Immunohistochemical analysis for nestin and CD133 was performed on 85 serous ovarian carcinoma tumor samples using tissue microarray technique. Nestin immunoreactivity was detected in both tumor and endothelial cells, whilst CD133 was only identified in tumor cells. CD34 endothelial expression was used to assess intratumor microvessel density (MVD)., Results: Of the tissue samples 49.4% were nestin-positive and 24.7% were positive for CD133. In both univariate and multivariate analysis nestin or CD133 expressions in tumor cells were not significantly associated with clinicopathological parameters (age, serum CA125, peritoneal carcinomatosis, malignant ascites, tumor grade). However, in multivariate analysis nestin expression in tumor cells proved to be an independent prognostic factor, associated with poorer survival and time to progression (p=0.025 and p=0.05, respectively). This has not been achieved for CD133. Furthermore, a significant concordance between nestin endothelial expression (nestin-determined MVD) and CD34-determined MVD was achieved., Conclusion: In addition to the well-known clinicopathological characteristics, tumor expression of nestin might be a valuable prognostic factor for survival in patients with advanced ovarian cancer. With regard to its endothelial expression, nestin might be as reliable as CD34 for quantifying tumor angiogenesis. Further investigation is justified in order to better clarify the role of these biomarkers.

Purpose: The tumor microenvironment in ovarian cancer (OC) seems to play an important role, and besides tumor cells, biomarkers can derive from endothelial cells. We investigated CDCP1 and ADAM12 expression in relation with other clinical and pathological characteristics in OC patients., Methods: We retrospectively evaluated patient files between 2006-2011. A histochemical score was developed to evaluate tumor staining, the microvessel density (MVD), and stromal expression patterns for both ADAM12 and CDCP1. A CD34 antibody was used to assess tumor MVD., Results: 102 patients were selected and 83% had FIGO stage III/IV. A high CDCP1 tumor score correlated significantly with a shorter overall survival (OS) (p<0.01). Cases with positive CDCP1 had an elevated CD34 MVD (p<0.01). An absent/low ADAM12 tumor score correlated with significantly improved OS (p<0.01). Mean CD34 MVD was higher in cases with positive ADAM12 MVD (p=0.012)., Conclusions: Our results indicate that both tumor markers are negative prognostic factors for overall survival and additional studies are required to validate their future potential.

Ovarian cancer (OC) is the second most common gynecological cancer and the deadliest in industrialized countries, with poor outcomes that indicate an urgent need to provide a greater insight into the molecular mechanisms underlying OC. Insights into the complex tumor microenviroment show that besides tumor islets, OC biomarkers can derive from newly formed blood vessels that have endothelial cells with a different molecular signature in comparison with their normal counterparts. In this view, recent research has been able to highlight promising candidates such as CDCP1 and ADAM12. Our present review summarises their implications in cancer progression with a focus on OC.