Dataset Information

Nuclear Factor-?B Overexpression is Correlated with Poor Outcomes after Multimodality Bladder-Preserving Therapy in Patients with Muscle-Invasive Bladder Cancer.

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 (NF?B; 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 NF?B 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, NF?B and p16 independently remained significant. The investigational in vitro study demonstrated that irradiation induces up-regulation of NF?B signaling. Irradiated bladder cancer cells showed increased invasion capability and clonogenic survival; inhibition of NF?B signaling by an NF?B inhibitor, SC75741, or RNA interference reversed the observed increases. NF?B 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. NF?B may be a putative molecular target to help with outcome stratification.

SUBMITTER: Chiang Y

PROVIDER: S-EPMC6912291 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Nuclear Factor-κB Overexpression is Correlated with Poor Outcomes after Multimodality Bladder-Preserving Therapy in Patients with Muscle-Invasive Bladder Cancer.

Chiang Yun Y Wang Chung-Chieh CC Tsai Yu-Chieh YC Huang Chao-Yuan CY Pu Yeong-Shiau YS Lin Chia-Chi CC Cheng Jason Chia-Hsien JC

Journal of clinical medicine 20191113 11

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 metallopro ...[more]

PMID: 31766169

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Project description:OBJECTIVE:Bladder-preserving trimodal therapy is recognized as a promising alternative treatment for muscle-invasive bladder cancer. We report the updated outcomes of muscle-invasive bladder cancer patients that were treated using our treatment protocol, which involves radiotherapy delivered with a real-time tumor-tracking radiotherapy system. METHODS:Thirty-eight patients who were diagnosed with T2-T4N0M0 bladder cancer between 1998 and 2016 and had clinically inoperable disease or refused to undergo surgery were enrolled. The treatment protocol included maximal transurethral resection followed by whole-bladder radiotherapy (40 Gy). Concurrent nedaplatin-based chemotherapy was administered to patients with adequate renal function. At the time of the first evaluation (via transurethral resection of the tumor bed), fiducial markers were endoscopically inserted into the bladder wall around the tumor. A boost of 25 Gy was administered using the real-time tumor-tracking radiotherapy system. The second evaluation (via transurethral resection of the tumor bed) was performed 6 months after the start of treatment. The Kaplan-Meier method and Cox hazards analysis were used to analyze overall survival and cancer-specific survival. RESULTS:The median duration of the follow-up period was 28 months (range: 3-161 months). The 5- and 10-year overall survival rates were 54.9 and 41.2%, respectively. Twenty-five (65.8%) and twenty (74.1%) patients had achieved complete responses to chemoradiation at the first and second evaluations, respectively. In univariate and multivariate analyses, performance status was found to be significantly associated with overall survival [P = 0.03, hazard ratio: 3.48, 95% confidence interval: 1.15-10.6] and cancer-specific survival [P = 0.02, hazard ratio: 4.57, 95% confidence interval: 1.32-16.9], and sex was shown to be significantly associated with cancer-specific survival [P = 0.03, hazard ratio: 3.07, 95% confidence interval: 1.09-8.30]. CONCLUSIONS:Our bladder-preserving trimodal therapy protocol, which involves the use of a real-time tumor-tracking radiotherapy system, produced an acceptable overall survival rate. This therapy is a reasonable alternative for patients that are medically unfit for or do not want to undergo cystectomy.

Project description:Background and purposeBladder radiotherapy is a management option for carefully selected patients with muscle-invasive bladder cancer. However, the inability to visualize the tumor site during treatment and normal bladder movement limits targeting accuracy and increases collateral radiation. A means to accurately and reliably target the bladder during radiotherapy is needed.Materials and methodsEighteen consecutive patients with muscle-invasive bladder cancer (T1-T4) elected bladder-preserving treatment with maximal transurethral resection (TUR), radiation and concurrent chemotherapy. All underwent endoscopic placement of 24-K gold fiducial markers modified with micro-tines (70 [2.9×0.9 mm.]; 19 [2.1×0.7 mm.) into healthy submucosa 5-10 mm. from the resection margin, using custom-made coaxial needles. Marker migration was assessed for with intra-op bladder-filling cystogram and measurement of distance between markers. Set-up error and marker retention through completion of radiotherapy was confirmed by on-table portal imaging.ResultsBetween 1/2007 and 7/2012, a total of 89 markers (3-5 per tumor site) were placed into 18 patients of mean age 73.6 years. Two patients elected cystectomy before starting treatment; 16/18 completed chemo-radiotherapy. All (100%) markers were visible with all on-table (portal, cone-beam CT), fluoroscopy, plain-film, and CT-scan imaging. In two patients, 1 of 4 markers placed at the tumor site fell-out (voided) during the second half of radiotherapy. All other markers (80/82, 98%) were present through the end of radio-therapy. No intraoperative (e.g. uncontrolled bleeding, collateral injury) or post-operative complications (e.g. stone formation, urinary tract infection, post-TUR hematuria >48 hours) occurred. Use of micro-tined fiducial tumor-site markers afforded a 2 to 6-fold reduction in bladder-area targeted with high-dose radiation.DiscussionPlacement of the micro-tined fiducial markers into the bladder was feasible and associated with excellent retention-rate and no complications. All markers were well-visualized during radiotherapy with all imaging modalities. Bladder fiducial markers improve targeting accuracy, and may increase treatment efficacy and reduce morbidity from collateral radiation.

Project description:ContextThere is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR.ObjectiveTo elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results.Evidence acquisitionWe performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis.Evidence synthesisMedian CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities.ConclusionsWe demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space.Patient summaryIn this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

Project description:BackgroundHuman apurinic/apyrimidinic (AP) endonuclease 1 (APE1) plays a critical role in DNA base excision repair (BER) pathway and has been reported to be overexpressed in multiple cancers. Previously, we have shown that histone chaperone FACT complex (Facilitates Chromatin Transcription, a heterodimer of SSRP1 and SPT16 proteins) facilitates the chromatin access and DNA repair function of APE1, and their expression levels are correlated with promoting drug resistance in cancer. FACT inhibitor has been introduced in phase I and II clinical trials for chemosensitization of advanced solid cancers. However, the expression profile and prognostic significance of APE1 and FACT complex in bladder cancer remains largely unknown.MethodsRetrospectively, 69 bladder cancer samples were retrieved and submitted for immunohistochemical staining of APE1 and SSRP1. Expression profile including cytoplasmic and nuclear staining of APE1 and expression level of SSRP1 was examined and semi-quantified to render a H-score. The prognostic significance of APE1 and SSRP1 was evaluated by Kaplan-Meier survival analysis in our cohort and R2 database.ResultsAPE1 expression is elevated in bladder cancer compared to normal adjacent tissues. Compared with low grade tumors, high grade tumors show a shift in the staining pattern including higher intensity and positive cytoplasmic staining. Carcinoma in situ has a similar staining pattern to high grade tumors. APE1 and SSRP1 staining intensity increases as tumor progresses with stage. There is a correlation between APE1 and SSRP1 staining in invasive bladder cancer (Spearman r = 0.5466, p < 0.0001). The increased expression of APE1 and SSRP1 is associated with poor survival in Kaplan-Meier analysis in our cohort and in R2-TCGA bladder cancer database.ConclusionsThe expression levels of APE1 and SSRP1 are significantly elevated in bladder cancer as compared to normal adjacent tissues. APE1 correlates with SSRP1 expression in high grade tumors. Overexpression of APE1 and SSRP1 is associated with poor survival in bladder cancer. This suggests the usage of FACT inhibitor curaxins in muscle invasive bladder cancer to target FACT complex and APE1 to improve chemosensitization after further validation.

Dataset Information

Nuclear Factor-?B Overexpression is Correlated with Poor Outcomes after Multimodality Bladder-Preserving Therapy in Patients with Muscle-Invasive Bladder Cancer.

Publications

Nuclear Factor-κB Overexpression is Correlated with Poor Outcomes after Multimodality Bladder-Preserving Therapy in Patients with Muscle-Invasive Bladder Cancer.

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