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Abstract
The aim of this study was to investigate prognostic molecular targets for selecting patients with muscle-invasive bladder cancer undergoing bladder-preserving therapy. Pretreatment biopsy samples from patients with muscle-invasive bladder cancer receiving trimodality bladder-preserving therapy were analyzed for expression levels of p53, p16, human epidermal growth factor receptor-2 (Her-2), epidermal growth factor receptor (EGFR), nuclear factor-kappa B (NFκB; p65), E-cadherin, matrix metalloproteinase-9 (MMP9), meiotic recombination 11 homolog (MRE11), programmed death-1 ligand (PD-L1), and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemical (IHC) staining. The correlations between these molecular markers with local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS) were explored. Biopsy samples from 41 out of 60 patients were evaluated using IHC. Univariate analysis revealed that the high expression of NFκB is associated with significantly worse LPFS, DMFS, and OS, and low expression of p16 is associated with significantly lower LPFS. Upon further multivariate analysis including sex, age, stage, and selected unfavorable factors in the model, NFκB and p16 independently remained significant. The investigational in vitro study demonstrated that irradiation induces up-regulation of NFκB signaling. Irradiated bladder cancer cells showed increased invasion capability and clonogenic survival; inhibition of NFκB signaling by an NFκB inhibitor, SC75741, or RNA interference reversed the observed increases. NFκB expression (p65) is associated with prognostic significance for both LPFS and DMFS in patients treated with bladder-preserving therapy, with consistent impact on cell viability of bladder cancer cells. NFκB may be a putative molecular target to help with outcome stratification.
Highlights
Radical cystectomy is viewed as the standard treatment for muscle-invasive bladder cancer, post-operative urinary diversion may result in major physical and psychological changes with a consequent negative impact on quality of life [1,2,3]
The current study revealed that NFκB overexpression is a negative prognosticator of local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and overall survival (OS), whereas expression of p16 is inversely associated with LPFS in patients with bladder cancer undergoing trimodality bladder-preserving therapy
A previous study on putative IHC biomarkers in pre-treatment biopsy samples of patients with muscle-invasive bladder cancer, who received induction chemoradiation followed by cystectomy, showed that overexpression of NFκB is associated with chemoradiation resistance and lower cancer-specific survival, in line with our result [23]
Summary
Radical cystectomy is viewed as the standard treatment for muscle-invasive bladder cancer, post-operative urinary diversion may result in major physical and psychological changes with a consequent negative impact on quality of life [1,2,3]. Clinical factors, including T3–T4 disease, incomplete tumor resection, hydronephrosis, and pelvic lymph node involvement, are poor prognosticators of bladder-preserving therapy [5,9,10]. Among these factors, patients with hydronephrosis and/or pelvic lymph node involvement are typically contraindicated for bladder preservation. Given the current prognostic factors or selection criteria for patients with bladder-preserving therapy with exclusively clinical factors (T2–T3, absence of carcinoma in situ, hydronephrosis, or lymphadenopathy), the tumor-associated molecular markers might have prognostic implication for successful organ preservation
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