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ANTONIO RUSSO

FIBRONECTIN (FN) AND UROTHELIAL DAMAGE SECONDARY TO ADJUVANT INTRAVESICAL THERAPY

  • Autori: Carità, G.; Alonge, V.; Scurria, S.; Gattuso, S.; Russo, A.; Caruso, S.; D'Arienzo, M.; Serretta, V.
  • Anno di pubblicazione: 2014
  • Tipologia: Proceedings (TIPOLOGIA NON ATTIVA)
  • OA Link: http://hdl.handle.net/10447/99975

Abstract

Introduction and Objectives: Intravesical chemotherapy has been proven effective in preventing recurrence of low-risk non-muscle invasive bladder cancer (NMIBC). BCG is recognised as the best conservative treatment for intermediate and high risk NMIBC. Maintenance for at least one year is required to ameliorate the efficacy of adjuvant therapy. Discomfort and toxicity often cause interruption of adjuvant therapy, BCG particularly. Almost 50% of the patients undergoing BCG does not complete one year. A biomarker of urothelium damage would be helpful for timely detection of toxicity in order to ameliorate patient’s tolerance and compliance. The aim of the present study was to evaluate the gene expression of Fibronectin (FN) in bladder washing in relation with local toxicity due to adjuvant intravesical therapy. Patients and Methods: Out of 26 asymptomatic patients undergoing intravesical prophylaxis with mitomycin (40 mg/40 ml), epirubicin (80 mg/50 ml) or BCG Connaught (81 mg/50 ml) and 10 volunteers as control group, 62 samples of bladder washing were collected before, during and after therapy. The samples were analyzed by isolation of cellular RNA using a miRNeasy Mini Kit (Qiagen®). FN gene expression was analyzed by RT-PCR. The ΔΔCt method after normalization with endogenous reference 18s rRNA was adopted. An average Ct value for each RNA was obtained for triplicate reactions. Local toxicity was classified into 3 grades: 0-1. mild (no medical therapy); 2. moderate (medical therapy); 3. severe (instillation postponed for 1-2 weeks or intravesical solution of hyaluronic acid and chondroitin sulphate administered). Results: FN gene expression, compared to controls, was increased 1.1 fold after TUR and before intravesical therapy. During therapy it remained unchanged (1.0 fold). However it was increased 1.1 fold in absence of local toxicity, but to a median value of 3.6 fold in presence of severe toxicity. Particularly, the mean values, compared to controls, were 2.4 (range: 0.3-6.1), 1.1 (range: 0.1-2.3), 9.3 (range: 0.2-45.2), before therapy, in absence and in presence of local toxicity, respectively. Of interest, patients receiving intravesical hyaluronic acid and chondroitin sulphate solution showed a median FN gene expression of 0.2 fold (range 0.1- 0.7), decreasing from 3 to 0.6 and from 4 to 0.2 fold in two patients contemporary with symptomatic relief. Discussion: Few studies have correlated the gene expression of FN to bladder urothelial damage, in interstitial cystitis (1). FN plays an important role on BCG activity (2). A marker of topical toxicity would be helpful to improve the tolerance and to reduce the drop-out rates of intravesical therapy. The measurement in bladder washing is a simple and direct evaluation of urothelial FN gene activity. This method avoids all the bias due to the evaluation of FN protein expression in urine. The overexpression of FN gene indicates the presence of urothelial damage and activation of repairing processes. Normal and downexpression indicate the absence or healing of urothelial damage. Preliminarily, our study shows a significant correlation between FN gene expression on bladder washing and local toxicity. Furthermore, FN seems to be reduced by the intravesical administration of intravesical hyaluronic acid and chondroitin sulphate solution. Conclusion: FN gene expression in bladder washing emerges as a simple and promising marker of urothelial damage. Further and larger studies should be justified. Acknowledgements: We wish to thank IBSA for unrestricted grant and the GSTU Foundation for administrative support. 1 Blalock EM et al: Gene expression analysis of urine sediment: evaluation for potential noninvasive markers of interstitial cystitis/bladder pain syndrome. J Urol 187: 725, 2012. 2 Eissa S et al: Diagnostic value of fibronectin and mutant p53 in the urine of