title: The impact of immunohistochemical staining with ezrin-carbonic anhydrase IX and neuropilin-2 on prognosis in patients with metastatic renal cell cancer receiving tyrosine kinase inhibitors.
abstract: The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. In this retrospective study, we evaluated the prognostic role of carbonic anhydrase-IX, ezrin, and neuropilin in metastatic RCC patients. The expression of several biomarkers were measured by immunohistochemistry (IHC) in 45 patients with advanced stage RCC treated with second-line tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) after failure of interferon-alpha between January 2007 and June 2012. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on the survival. Age, ezrin and neuropilin-2 overexpression were found to be statistically significant factors (P < 0.05) for PFS in the univariate analysis. Ezrin and neuropilin-2 overexpression, hemoglobin and albumin level were statistically significant factors (P < 0.05) for OS in the univariate analysis. Multivariate analysis revealed that low expression of ezrin and neuropilin-2 was an independent prognostic factor for PFS and OS. The median PFS was 4 months for patients overexpressing neuropilin-2 versus 11 months for those with lower expression of neuropilin-2 (p = 0.033). The median OS was longer in patients with low levels of neuropilin-2 expression (26 months) compared to patients overexpressing neuropilin-2 (13 months) (p = 0.023). Increased expression of ezrin was associated with poor prognosis in patients treated with TKIs targeting VEGF (PFS, 3 vs 7 months; p = 0.012). High ezrin expression was associated with shorter OS (p = 0.009). This is the first study in the literature showing that neuropilin-2 and ezrin are related with prognosis in patients with advanced RCC.
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Van Education and Research Hospital, Edremit, Van, 65100, Turkey. caretta06@hotmail.com.
authors.forename: Bulent
authors.initials: B
authors.lastname: Cetin
authors.affiliation: Department of Pathology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Ipek Isık
authors.initials: II
authors.lastname: Gonul
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Buyukberber
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Konya Numune State Hospital, Konya, Turkey.
authors.forename: Barıs
authors.initials: B
authors.lastname: Afsar
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Ozge
authors.initials: O
authors.lastname: Gumusay
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey.
authors.forename: Efnan
authors.initials: E
authors.lastname: Algın
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey.
authors.forename: Nedim
authors.initials: N
authors.lastname: Turan
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ozet
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Benekli
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey.
authors.forename: Ugur
authors.initials: U
authors.lastname: Coskun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D039943:Neuropilin-2 / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D000099149:Ezrin
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D003598:Cytoskeletal Proteins; D016898:Interferon-alpha; D039943:Neuropilin-2; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000099149:Ezrin; C089226:CA9 protein, human
keywords: Advanced renal cell carcinoma; Molecular markers; Prognostic factors; Targeted drugs