Search

Background: Role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in ovarian cancer is largely unclear. It was shown that mesothelial expression mediates tumour cell invasion and is associated with metastases in advanced ovarian cancer. Material and methods: In our prospective study we measured preoperative serum sVCAM-1 in 37 patients with advanced ovarian cancer and evaluated correlation with disease recurrence. Serum samples were obtained prior to surgery, ascites was collected during the surgery and all analysed by flow cytometric bead-based assay. ROC analysis was used to identify a cut-off value for sVCAM-1. Survival curves were calculated using Kaplan-Meier method. The association between sVCAM-1 and survival was investigated with Cox regression models, adjusting for age at surgery. A p of Results: Mean sVCAM-1 serum concentration in all patients before operation was 1564.68 ± 435.65 ng/ml while mean ascites level was 801.84 ±244.35 ng/ml. Follow up period was minimum 27 and the maximum 58 months. Patients were divided in two groups according to time to recurrence. Group A: 20 patients with disease progress or relapse within 12 months (mean serum level 1660.54±417.93 ng/ml; mean ascites level 827.92±290.36) and group B: 17 patients with tumour relapse after more than 12 months (mean serum level 451.91±441.15ng/ml; mean ascites level 771.16±179.93). There was a correlation between serum and ascites concentrations in group A and not in the patients from group B. The statistically significant difference was observed in serum concentration but not in ascites concentrations of sVCAM-1, There were no differences in grade, histology and stage of the tumour between the groups. sVCAM-1 and age resulted correlated (Spearman r=0.32, p=0.048). In Cox regression models after adjusting for age at surgery, sVCAM-1 above 1,400 ng/ml was associated with impaired DFS (hazard ratio 3.824; 95% confidence interval 1.460 to 9.374; p=0.003) and impaired OS (hazard ratio 13.394; 95% confidence interval 1.693 to 105.3985; p=0.014. Conclusions: This is the first study demonstrating that higher serum sVCAM-1 concentrations at the time of diagnosis might be predictive for early relapse. Serum sVCAM-1 can be potential marker for ovarian cancer follow-up.

In parallel to medical treatment of ovarian cancer, methods for the early detection of cancer tumors are being sought. In this contribution, the use of non-invasive static (SLS) and dynamic light scattering (DLS) for the characterization of extracellular nanoparticles (ENPs) in body fluids of advanced serous ovarian cancer (OC) and benign gynecological pathology (BP) patients is demonstrated and critically evaluated. Samples of plasma and ascites (OC patients) or plasma, peritoneal fluid, and peritoneal washing (BP patients) were analyzed. The hydrodynamic radius (Rh) and the radius of gyration (Rg) of ENPs were calculated from the angular dependency of LS intensity for two ENP subpopulations. Rh and Rg of the predominant ENP population of OC patients were in the range 20–30 nm (diameter 40–60 nm). In thawed samples, larger particles (Rh mostly above 100 nm) were detected as well. The shape parameter ρ of both particle populations was around 1, which is typical for spherical particles with mass concentrated on the rim, as in vesicles. The Rh and Rg of ENPs in BP patients were larger than in OC patients, with ρ ≈ 1.1–2, implying a more elongated/distorted shape. These results show that SLS and DLS are promising methods for the analysis of morphological features of ENPs and have the potential to discriminate between OC and BP patients. However, further development of the methodology is required.

Ovarian cancer has the highest mortality rate among all gynecologic cancers, with most patients presenting with advanced stage tumors. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time up to 80 % of others develop chemoresistance, rendering recurrent disease incurable. Moreover, according to latest EMSO-ESGO (European Society for Medical Oncology – European Society for Gynecological Oncology) consensus conference manuscript on ovarian cancer, there are currently no validated molecular predictive biomarkers for platinum resistance. Recent studies suggest that the copper efflux transporters ATP7A and ATP7B play an important role in platinum resistance. In addition, by exploring their role in mediating resistance, new pathways of platinum resistance emerge, such as lysosomal storage disorders, which might be explored in the future as a new target to circumvent platinum resistance. This review outlines a challenging clinical hurdle in ovarian cancer therapy due to platinum resistance, links between the essential trace element copper and cytotoxic platinum-based medicines, and enigmatic mechanisms of ATP7A and ATP7B mediating platinum resistance. It then presents clinical studies showing a significant association of ATP7A and ATP7B with response to cisplatin/carboplatin and prognosis. Based on the results of in vitro assays, disease-relevant animal models, and clinical studies to date, it may be concluded that APT7A and ATP7B deserve further development as predictive markers of platinum resistance in ovarian cancer. Both transporters could play a particularly important role in early estimation of therapy response to identify platinum-resistant tumors and to adjust the treatment of ovarian cancer patients accordingly.

The aim of the study was to analyze the overall survival (OS) and progression free survival (PFS) of patients with high grade and advanced stage epithelial ovarian cancer (EOC) with at least 60 months of follow-up treated in a single gynecologic oncology institute. We compared primary debulking surgery (PDS) versus neoadjuvant chemotherapy plus interval debulking surgery (NACT + IDS) stratifying data based on residual disease with the intent to identify the rationale for therapeutic option decision and the role of laparoscopic evaluation of resectability for that intention. Patients and methods. This is observational retrospective study on consecutive patients with diagnosis of high grade and International Federation of Gynecology and Obstetrics (FIGO) stage III/IV EOC referred to our center between January 2008 and May 2012. We selected only patients with a follow-up of at least 60 months. Primary endpoint was to compare PDS versus NACT + IDS in term of progression free survival (PFS) and overall survival (OS). Secondary endpoints were PFS and OS stratifying data according to residual disease after surgery in patients receiving PDS versus NACT + IDS. Finally, through Cox hazards models, we tested the prognostic value of different variables (patient age at diagnosis, residual disease after debulking, American Society of Anesthesiologists (ASA) stage, number of adjuvantchemotherapy cycles) for predicting OS. Results. A total number of 157 patients were included in data analysis. Comparing PDS arm (108 patients) and NACT + IDS arm (49 patients) we found no significant differences in term of OS (41.3 versus 34.5 months, respectively) and PFS (17.3 versus 18.3 months, respectively). According to residual disease we found no significant differences in term of OS between NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0 or residual disease = 1, as well as no significant differences in PFS were found comparing NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0; contrarily, median PFS resulted significantly lower in PDS patients receiving optimal debulking (residual disease = 1) in comparison to NACT + IDS patients receiving complete debulking (residual disease = 0). PDS arm was affected by a significant higher rate of severe post-operative complications (grade 3 and 4). Diagnostic laparoscopy before surgery was significantly associated with complete debulking. Conclusions. We confirm previous findings concerning the non-superiority of NACT + IDS compared to PDS for the treatment of EOC, even if NACT + IDS treatment was associated with significant lower rate of post-operative complications. On the other hand, selecting patients for NACT + IDS, based on laparoscopic evaluation of resectabilty prolongs the PFS and does not worse the OS compared to the patients not completely debulked with PDS. Na odločitev o vrsti zdravljenja bolnikov z napredovalim melanomom lahko pomembno vpliva status mutacij v genih za BRAF, NRAS IN c-KIT. Pogostost mutacij in njihove medsebojne povezave s histološkimi značilnostmi tumorskih tkiv na slovenski populaciji do sedaj še niso bili raziskani. Bolniki in metode. Analizo smo izvedli retrospektivno. Mutacije BRAF, NRAS in c-KIT smo določili na 230 patoloških vzorcih bolnikov, ki smo jih nameravali zdraviti s sistemsko terapijo zaradi metastatskega melanoma na Onkološkem Inštitutu Ljubljana med leti 2013 in 2016. Zbrali smo histološke značilnosti primarnih tumorjev in klinične podatke bolnikov ter jih testirali na medsebojno povezanost z mutacijskim statusom. Rezultati. Povprečna starost 230 bolnikov je bila 59 let (razpon 25%85). Moških je bilo 141 (61,3 %) in žensk 89 (38,7 %). Ugotovili smo 129 (56,1 %) mutacij BRAF, 31 (13,5 %) NRAS in 3 (1,3 %) c-KIT mutacij v tkivnih vzorcih. Med 129 bolniki z mutacijami BRAF je imelo 114 (88,4 %) bolnikov mutacijo V600E in 15 (11,6 %) mutacijo V600K. Bolniki z BRAF mutacijami so bili ob diagnozi mlajši (52 v primerjavi s 59 let, p < 0,05), bolniki z NRAS mutacijami starejši (61 v primerjavi s 55 leti, p < 0,05). Število mutacij c-KIT je bilo prenizko za smiselno testiranje na medsebojne povezanosti, je pa bil eden izmed treh melanomov s c-KIT mutacijo melanom sluznice. Zaključki. Rezultati analize so v skupini slovenskih bolnikov z metastatskim melanomom odkrili visok delež mutacij BRAF ter nizek delež mutacij NRAS in c-KIT v primerjavi s predhodno objavljenimi raziskavami v Evropi in Severni Ameriki. Eden od glavnih vzrokov so specifične značilnosti naše študijske populacije, ki niso bile enake kot značilnosti celotne populacije bolnikov z melanomom.

Background. Vascular cell adhesion molecule-1 (VCAM-1) is associated with ovarian cancer progression but the origin of its soluble form (sVCAM-1) in serum is not well investigated. The purpose of this study was to elucidate whether the concentration of sVCAM-1 in serum correlates with the concentration in ascites, that represents local tumour environment, and with systemic inflammation, various clinicopathological characteristics, and patient outcome. Patients and methods. Thirty-six patients with advanced ovarian cancer were included in the study. Serum for sVCAM-1 analysis was obtained prior to surgery. Ascites samples were collected at the beginning of the operation. Clinical data were collected from patients’ medical records. sVCAM-1 in samples was analysed by flow cytometric bead-based assay. The mean follow-up period was 11 months (range 0-23) from the time of surgery. Results. Serum sVCAM-1 concentrations are positively correlated to ascites sVCAM-1 concentrations. There was a weakly positive correlation of serum sVCAM-1 with tumour size and no correlation with inflammatory tumour markers, FIGO stage or grade. Higher concentrations of sVCAM-1 were associated with poor disease outcome (death from ovarian cancer) in almost all cases before chemotherapy was started. Conclusions. This is the first study demonstrating that serum concentrations of sVCAM-1 in advanced ovarian cancer patients correlate with sVCAM-1 concentrations in ascites, thus expressing the biologic potential of malignant disease to metastasis, rather than systemic inflammation. Higher serum and ascites sVCAM-1 concentrations might have predictive potential for different biologic behaviour.

Background Determination of the tumor marker concentration in peritoneal fluid (PF) may help to assess its potential to detect small concentration changes between benign ovarian pathology and early stage ovarian cancer. Peritoneal washing, which can also be obtained when PF is absent, is already included in the International Federation of Gynecology and Obstetrics (FIGO) staging classification for ovarian cancer but sampling has not yet been standardized. Since our aim was to evaluate the relationship between marker concentration in PF and washing, standardization of the sampling protocol was a prerequisite to ensure reliable results. Methods Thirty-three women with non-malignant pathology of the reproductive organs were included in the study. We used three promising tumor markers for evaluation of the marker concentration in local fluid: osteopontin (sOPN), splice variant 6 of sCD44 (sCD44-v6) and vascular cell adhesion molecule-1 (sVCAM-1). After aspiration of PF, washing of the uterus, ovaries and pelvic peritoneum was performed with saline solution. Patients were divided into two groups based on the solution volume: A-20 ml and B-50 ml. To determine the efficiency of washing in relation to solution volume, washing was repeated three times. Concentrations of markers in samples were determined using flow cytometry. Results Mean concentrations of markers were significantly higher (P

Ovarian cancer is one of the most aggressive and lethal cancers in women. There is currently no accurate noninvasive diagnostic test for ovarian cancer; most patients are diagnosed at an advanced stage, presenting with peritoneal metastasis and ascites. Although ovarian cancer patients often respond initially to chemotherapy, recurrence is almost always accompanied by chemoresistance. The identification of proteins that are abundantly and predominantly expressed in ovarian cancer is therefore relevant to diagnosis, tumor imaging, and targeted therapies. Proteins with high secretion rates or proteins that are extensively cleaved from the cell surface, specifically from tumor cells, are a potential source of circulating biomarkers for ovarian cancer. The process of surface protein shedding as observed in ascites-derived tumor cells from ovarian cancer patients is also relevant to tumor invasion and metastasis, as exemplified by the role of cadherin. Additionally, proteins, as well as lipids, DNA, and RNA, can reach the blood in microvesicles that are shed from tumor cells. A roughly fivefold increase in their blood concentration is reported in ovarian cancer patients. Tumor-derived vesicles are fully equipped to facilitate the escape of tumor cells from immune surveillance. At the same time, they are involved in the establishment of an optimal environment for metastatic tumor cells. On the basis of the role of tumor microvesicles in tumor progression, another door has been opened to a new ovarian cancer therapy. This review addresses the relevance of secretion and shedding of microvesicles and membrane surface protein from tumor cells for biomarker discovery, cancerogenesis, and new therapies in ovarian cancer.

Background Despite advances in surgery and combination chemotherapy, ovarian cancer is first in terms of death rates of gynaecological malignancies. More than 90% of ovarian cancers arise from surface epithelium and the serous histological subtype is the most commonly diagnosed epithelial ovarian carcinoma. Extensive seeding of the peritoneal cavity by tumour cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. Currently CA-125 is the most widely used biomarker in the evaluation and management of women with epithelial ovarian cancer. However, in approximately 15% of these patients CA-125 is not indicative of disease status or progression. Therefore, an alternative tumour marker would be useful. Osteopontin is a secreted, integrin-binding glykophosphoprotein which is overexpressed in ovarian cancer cells and thus may serve as a serum biomarker. By combining the data from blood and fluid from the proximity of the tumour we might be more likely to discover a protein biomarker secreted from the tumour rather than deriving from another part of the body.