Delayed diagnosis of ovarian cancer (OC) is usually a cause of its high mortality. OC counts for one of the most aggressive gynecological malignancies. Noninvasive biomarkers may be used to help with diagnostic and treatment decisions in OC management. The incidence and clinical significance of occult OC cells (circulating tumor cells-CTCs) in the peripheral blood of patients with newly diagnosed or nondiagnosed OC at the time of surgical intervention were examined in our study. The objective of the study was to isolate and cultivate CTCs in OC patients (mainly stage IIIB-C) by a recently introduced size-based separation method (MetaCell(®)). CTCs were successfully isolated in patients with OC capturing cells with proliferation potential. The cells were enriched in good fitness, which enabled the short term in vitro culture of the CTCs. The CTCs may be used for further downstream applications (e.g. gene expression analysis) even if in the majority of the in vitro CTC cultures no confluence was reached. The CTCs were detected in 77 out of 118 patients (65.2%). CTC positivity was given to the relationship with different disease stage parameters with special focus on CA125 marker levels. The results show that the information on CTC presence may provide new and independent prognosis staging information to the patient description. Several interesting relationships of CA125, age and ascites presence are reported. As shown in our patient sample, patients with ascites tend to have higher CA125 levels, even if the CTCs were not found in the peripheral blood. It suggests that hematogenous dissemination is fully represented by the CTCs while lymphogenic dissemination is represented by elevated CA125. In this context, easy access to CTCs provided by the method applied in our study, both at the time of diagnosis and relapse, may become an increasingly valuable tool in future. This methodology may provide an opportunity for more personalized medicine where treatment for OC may be guided by information from an individual's CTC molecular profile.

Department of Cell and Molecular Biology 3rd Faculty of Medicine Charles University PragueRuska 87 100 97 Prague Czech Republic; Department of Laboratory Genetics University Hospital Kralovske VinohradySrobarova 50 100 34 Prague Czech Republic

Department of Cell and Molecular Biology 3rd Faculty of Medicine Charles University PragueRuska 87 100 97 Prague Czech Republic; Department of Pathology Masaryk's Hospital in Usti nad Labem Krajska zdravotni a s Socialni pece 3316 12A 40113 Usti nad Labem Czech Republic

Department of Gynecology and Obstetrics University Hospital Kralovske Vinohrady Srobarova 50 100 34 Prague Czech Republic

Department of Laboratory Genetics University Hospital Kralovske Vinohrady Srobarova 50 100 34 Prague Czech Republic

Department of Laboratory Genetics University Hospital Kralovske VinohradySrobarova 50 100 34 Prague Czech Republic; Department of Histology and Embryology Wroclaw Medical UniversityWrocław Poland

Division of Surgical Oncology Gynaecological Oncology Chemotherapy and Department of Oncology Wroclaw Medical University Plac Hirszfelda 12 53 413 Wrocław Poland

Division of Surgical Oncology Gynaecological Oncology Chemotherapy and Department of Oncology Wroclaw Medical UniversityPlac Hirszfelda 12 53 413 Wrocław Poland; Lower Silesian Oncology CentreWroclaw Plac Hirszfelda 12 53 413 Wroclaw Poland

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. PubMed

Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician. 2009;80:609–616. PubMed

Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10:6897–904. PubMed

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91. PubMed

de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–9. PubMed

Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, Matera J, Repollet M, Doyle GV, Terstappen LW, Hayes DF. Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006;12:6403–9. PubMed

Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher HI. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13:7053–8. PubMed

Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006;12:4218–24. PubMed

Shaffer DR, Leversha MA, Danila DC, Lin O, Gonzalez-Espinoza R, Gu B, Anand A, Smith K, Maslak P, Doyle GV, Terstappen LW, Lilja H, Heller G, Fleisher M, Scher HI. Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13:2023–9. PubMed

Romero-Laorden N, Olmos D, Fehm T, Garcia-Donas J, Diaz-Padilla I. Circulating and disseminated tumor cells in ovarian cancer: a systematic review. Gynecol Oncol. 2014;133:632–9. PubMed

Bast RC Jr, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR Jr, Knapp RC. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med. 1983;309:883–887. PubMed

Kenemans P, van Kamp GJ, Oehr P, Verstraeten RA. Heterologous double-determinant immunoradiometric assay CA 125 II: reliable second-generation immunoassay for determining CA 125 in serum. Clin Chem. 1993;39:2509–2513. PubMed

Rustin GJ, Nelstrop AE, Tuxen MK, Lambert HE. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol. 1996;7:361–364. PubMed

Meyer T, Rustin GJ. Role of tumour markers in monitoring epithelial ovarian cancer. Br J Cancer. 2000;82:1535–1538. PubMed PMC

Gupta D, Lis CG. Role of CA125 in predicting ovarian cancer survival-a review of the epidemiological literature. J Ovarian Res. 2009;2:13. PubMed PMC

Menon U, Jacobs IJ. Ovarian cancer screening in the general population. Curr Opin Obstet Gynecol. 2001;13:61–64. PubMed

Verheijen RH, Mensdorff-Pouilly S, van Kamp GJ, Kenemans P. CA 125: fundamental and clinical aspects. Semin Cancer Biol. 1999;9:117–124. PubMed

Skates SJ, Menon U, MacDonald N, Rosenthal AN, Oram DH, Knapp RC, Jacobs IJ. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J. Clin. Oncol. 2003;21:206s–210s. PubMed

Duffy MJ, Bonfrer JM, Kulpa J, Rustin GJ, Soletormos G, Torre GC, Tuxen MK, Zwirner M. CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679–691. PubMed

Rustin GJ, Bast RC Jr, Kelloff GJ, Barrett JC, Carter SK, Nisen PD, Sigman CC, Parkinson DR, Ruddon RW. Use of CA-125 in clinical trial evaluation of new therapeutic drugs for ovarian cancer. Clin Cancer Res. 2004;10:3919–3926. PubMed

Bobek V, Matkowski R, Gürlich R, Grabowski K, Szelachowska J, Lischke R, Schützner J, Harustiak T, Pazdro A, Rzechonek A, Kolostova K. Cultivation of circulating tumor cells in esophageal cancer. Folia Histochem Cytobiol. 2014;52:171–7. PubMed

Cegan M, Kolostova K, Matkowski R, Broul M, Schraml J, Fiutowski M, Bobek V. In vitro culturing of viable circulating tumor cells of urinary bladder cancer. Int J Clin Exp Pathol. 2014;7:7164–71. PubMed PMC

Yeung TL, Leung CS, Yip KP, Au Yeung CL, Wong ST, Mok SC. Cellular and molecular processes in ovarian cancer metastasis. Am J Physiol Cell Physiol. 2015;309:C444–56. PubMed PMC

Liberko M, Kolostova K, Bobek V. Essentials of circulating tumor cells for clinical research and practice. Crit Rev Oncol Hematol. 2013;88:338–56. PubMed

Poveda A, Kaye SB, McCormack R, Wang S, Parekh T, Ricci D, Lebedinsky CA, Tercero JC, Zintl P, Monk BJ. Circulating tumor cells predict progression free survival and overall survival in patients with relapsed/recurrent advanced ovarian cancer. Gynecol Oncol. 2011;122:567–72. PubMed

Fan T, Zhao Q, Chen JJ, Chen WT, Pearl ML. Clinical significance of circulating tumor cells detected by an invasion assay in peripheral blood of patients with ovarian cancer. Gynecol Oncol. 2009;112:185–91. PubMed PMC

udson PL, Geller MA, Bliss RL, Boente MP, Downs LS Jr, Argenta PA, Carson LF. Preoperative detection of peripherally circulating cancer cells and its prognostic significance in ovarian cancer. Gynecol Oncol. 2003;91:389–94. PubMed

Marth C, Kisic J, Kaern J, Tropé C, Fodstad Ø. Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer. 2002;94:707–12. PubMed

Braun S, Schindlbeck C, Hepp F, Janni W, Kentenich C, Riethmuller G, Pantel K. Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic relapse. J. Clin. Oncol. 2001;19:368–75. PubMed

Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett. 2007;253:180–204. PubMed

Zhong XY, Kaul S, Eichler A, Bastert G. Evaluating GA733-2 mRNA as a marker for the detection of micrometastatic breast cancer in peripheral blood and bone marrow. Arch Gynecol Obstet. 1999;263:2–6. PubMed

Lambrechts AC, van’t Veer LJ, Rodenhuis S. The detection of minimal numbers of contaminating epithelial tumor cells in blood or bone marrow: use, limitations and future of RNAbased methods. Ann Oncol. 1998;9:1269–76. PubMed

Kruger WH, Jung R, Detlefsen B, Mumme S, Badbaran A, Brandner J, Renges H, Kroger N, Zander AR. Interference of cytokeratin-20 and mammaglobin-reverse-transcriptase polymerase chain assays designed for the detection of disseminated cancer cells. Med Oncol. 2001;18:33–8. PubMed

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