scholarly journals Nucleotide Oligomerization Domain-like receptor 4 (NLR4) Gene Expression and Interleukin 1-β (IL 1-β) Level in Urine Samples Before and After Intravesical BCG Therapy For Treatment of Bladder Cancer

2021 ◽  
Vol 22 (6) ◽  
pp. 1141-1154
Author(s):  
Ahmed Samar Abd Elmoaty Eissa ◽  
Ossama Rasslan ◽  
Lamia Fouad ◽  
Fahim Hisham Abdelmajeed ◽  
Amira Esmail Abdel-Hamid
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Fold Increase ◽  
Urine Samples ◽  
Expression Level ◽  
Muscle Invasive Bladder Cancer ◽  
Bcg Therapy ◽  
Muscle Invasive ◽  
Surgical Sample

Bladder cancer is the 7th most commonly diagnosed cancer in males worldwide and the 11th when both genders are considered. Seventy five per cent of bladder cancer cases are non-muscle invasive bladder cancer (NMIBC). Bacillus Calmette–Gu rin (BCG) immunotherapy remains the standard intravesical agent for NMIBC. The exact mechanism by which BCG prevents recurrence is unknown. The aim of this study was to evaluate NLR4 gene expression and IL-1β as possible prognostic indicators for NMIBC recurrence and BCG treatment failure, and to detect the difference in their levels among muscle invasive bladder cancer (MIBC) and NMIBC that may aid in primary differentiation between cases. This study was conducted in 30 patients who had NMIBC and 17 patients who had MIBC. Urine samples were obtained in sterile cups before operation. From NMIBC cases, four more samples were obtained as mentioned below. Evaluation of NLR4 gene expression was performed in pre-surgical sample for MIBC and in 4 samples for NMIBC: pre-surgical sample, sample collected 4 hours after the 3rd dose of BCG instillation, and samples collected during follow up (3 and 6 months post-surgically). There was statistical significant increase in NLRP4 expression levels in NMIBC (CT=0.87±1.48) compared to MIBC (CT=2.82±2.07). As far as we searched, no published results were found regarding comparative gene expression levels between NMIBC and MIBC cases. Gene expression in recurrent cases was higher in pre-surgical urine samples than in non-recurrent cases. The expression level further increased up to 21 fold than the pre-surgical level in the sample taken after injection of the 3rd dose of BCG. This level decreased distinctly to become 1-fold increase over pre-surgical level at the 3rd month follow up then to only 0.9-fold at the 6th month. In non- recurrent cases, gene expression level started pre-surgically in much lower levels than those encountered in recurrent cases. There were 11-fold increase in expression level after 3rd dose of BCG instillation and then decreased to be 5.6 folds higher in the sample taken at 3rd month follow up than in presurgical samples. Gene expression further decreased to become 4.1 fold higher in samples taken at 6 month follow up than the pre-surgical levels. IL-1β levels were estimated for NMIBC and MIBC cases in urine samples pre-surgically and during BCG therapy in case of NMIBC before and 4 hours after the 3rd dose and during 3rd month follow-up of those cases for searching its possible use of for primary differentiation between NMIBC and MIBC, and also as a prognostic factor for possible recurrence in case of NMIBC cases. The level of IL-1β was generally higher in pre-surgical samples (0.62±0.12 pg/ml) when compared to its level before the 3rd dose of BCG induction therapy (0.53±0.13 pg/ml). Its level was distinctly higher four hours after administration of the 3rd dose BCG (1.96±0.62 pg/ml) than both previous levels. Levels decreased bellow pre-surgical level at 3rd month follow up (0.57±0.099 pg/ml). The levels of IL-1β estimated in samples collected four hours after the 3rd dose BCG was higher in cases that showed recurrence later on than non-recurrent cases. The levels decreased in both cases and became higher in non-recurrent cases (0.64±0.05 pg/ml) than in cases already developed recurrence at the 3rd month diagnosed during follow-up (0.45±0.05 pg/ml). To conclude, on following NLRP4 gene expression and IL-1β levels during BCG administration among recurrent and non-recurrent cases of thirty NMIBC cases, there was a significant statistical difference in both levels for the samples collected after the third dose BCG, being higher in patients who showed subsequent recurrence at the 3rd and 6th month of follow-up. If these preliminary reported findings will be confirmed in upcoming larger cohort’s studies, it could be promising in prognosis of such cases, with the possibility of early manipulation of individualized treatment schedule, keeping patients most probably prone to encounter recurrence safe from possible side effects of BCG therapy. The assessment of NLRP4 expression and IL-1β levels could help predict failure of BCG therapy, playing an appreciable role in early deciding radical surgery. When comparing NLRP4 expression and IL-1β levels between MIBC and NMIBC cases, increased values were noted among non-invasive ones. This finding may serve as a possible diagnostic tool, which represents a challenging issue. Hence, cut-off values for gene expression and cytokine level are to be specified.

scholarly journals Uromonitor®as a novel sensitive and specific urine-based test for recurrence surveillance of patients with non-muscle invasive bladder cancer

2018 ◽  
Author(s):  
Cristina Sampaio ◽  
Rui Batista ◽  
Pedro Peralta ◽  
Paulo Conceição ◽  
Amílcar Sismeiro ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Standard Procedure ◽  
Cost Effective ◽  
Urine Samples ◽  
High Rate ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Invasive Approach ◽  
Muscle Invasive

AbstractBladder cancer is the most frequent malignancy of the urinary system and is ranked the seventh most diagnosed cancer in men worldwide. About 70-75% of all newly diagnosed patients with bladder cancer will present disease confined to the mucosa or submucosa, the non-muscle invasive bladder cancer (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to this high rate of recurrence, patients are submitted to an intensive follow-up program that should be maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different non-invasive (both in serum and urine samples) assays have been developed in order to search genetic and protein alterations related to the development, progression and recurrence of bladder cancer.TERTpromoter mutations andFGFR3hotspot mutations are the most frequent somatic alterations in bladder cancer and constitute the most reliable biomarkers for bladder cancer. Based on these findings, an ultra-sensitive assay called Uromonitor®was developed that corresponds to a urine-based assay capable of detecting trace amounts of the two most common alterations in NMIBC,TERTpromoter andFGFR3mutation, in urine samples. The Uromonitor®test was performed in a cohort of 72 patients, firstly diagnosed with bladder cancer and under surveillance for NMIBC, to access its sensitivity and specificity in the detection of NMIBC recurrence. Uromonitor®was shown to be highly sensitive and specific in detecting recurrence of bladder cancer in patients under surveillance of non-muscle invasive bladder cancer.

scholarly journals Fibronectin urothelial gene expression as a new reliable biomarker for early detection of local toxicity secondary to adjuvant intravesical therapy for non-muscle invasive bladder cancer

2021 ◽  
Vol 13 ◽  
pp. 175628722199568
Author(s):  
Fabrizio Di Maida ◽  
Cristina Scalici Gesolfo ◽  
Riccardo Tellini ◽  
Andrea Mari ◽  
Chiara Sanfilippo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Early Detection ◽  
Medical Therapy ◽  
Invasive Bladder Cancer ◽  
Intravesical Therapy ◽  
Muscle Invasive Bladder Cancer ◽  
Local Toxicity ◽  
Bcg Therapy ◽  
Muscle Invasive

Background: A marker of urothelial damage could be helpful for early detection and monitoring of local toxicity due to intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The aim of the study was to investigate the correlation between fibronectin (FN) gene expression in bladder washings and local toxicity secondary to adjuvant intravesical therapy. Materials and methods: Patients undergoing adjuvant intravesical therapy for NMIBC and age-matched healthy patients were enrolled. Real time polymerase chain reaction was performed to analyze FN expression in bladder washings. Local toxicity was classified as: 0–1 mild (no medical therapy), 2 moderate (medical therapy and/or instillation postponed), 3 severe (discontinuation of therapy). Results: Seventy-two patients and 21 controls entered the study. A useful pellet was obtained in 58 patients and 18 controls. Intravesical Bacillus Calmette–Guerin (BCG), Epirubicin and Mitomycin C was offered to 69%, 13.8% and 17.2% of patients respectively. Compared with healthy controls (FN = 1.0 fold), overall median FN expression before adjuvant intravesical therapy was 1.73 fold [interquartile range (IQR) 0.8–2.3], while during therapy median FN expression increased to 3.41 (IQR: 1.6–6.1) fold. Considering 40 intermediate and high-risk patients undergoing intravesical BCG, median FN expression before adjuvant treatment was 1.92 [(IQR: 1.0–2.7) fold, increasing up to 4.1 (IQR: 1.9–6.6) during therapy. In more detail, FN increased during BCG therapy, showing a median expression of 4.22 (IQR: 2.2–5.5) and 6.16 (IQR: 2.6–8.7) fold in presence of grade 2 and 3 toxicity respectively, while remaining more or less stable in asymptomatic patients. After receiver operating characteristic curve analysis, FN value of 3.6 fold resulted, corresponding to 75% sensitivity and 69% specificity to predict grade 2–3 toxicity events (area under the curve 0.74, 95% confidence interval 0.63–0.85, p = 0.001). Conclusion: Our study validated the correlation between FN expression and urothelial damage. BCG seems to induce a urothelial activation with FN overexpression during adjuvant intravesical therapy. Grade of toxicity was related to FN expression.

Gene expression as a predictive marker of outcome for high-risk transitional-cell carcinoma (TCC) of the bladder in patients (pts) randomized to adjuvant chemotherapy with cisplatin-gemcitabine (PG) or observation (OBS) after radical cystectomy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15502-15502
Author(s):  
C. F. Pollera ◽  
G. Pessina ◽  
F. Nelli ◽  
A. Felici ◽  
L. Moscetti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Mrna Expression ◽  
Radical Cystectomy ◽  
Expression Level ◽  
Phase Iii ◽  
Mrna Levels ◽  
Muscle Invasive

15502 Background: A randomized phase III trial comparing PG vs OBS in muscle-invasive TTC of the bladder is currently ongoing. ERCC1 and RRM1 genes are involved in the nucleotide excision repair pathways, and their up-regulation by tumor has been clearly related to resistance of cisplatin and gemcitabine, respectively. Preliminary correlations in patients with bladder cancer randomized to PG were already presented (Proc ASCO 2005, Abstract No: 4589). In the present study, we have examined the predictive value of ERCC1 and RRM1 as markers of tumor progression, as well as their potential correlation with other known prognostic factors also in patients randomized to OBS. Methods: Thirty-nine paraffin-embedded TTC samples of a subset of patients entered the trial were collected. The characteristics were: pT2 23%, pT3 54%, pT4a 23%, pN1–2 46%; G3–4 98%; M/F 10%/90%, median age: 65 years (range 53–74); PG/OBS: 49%/51%. Analysis consisted of real time RT-PCR quantification of mRNA levels of ERCC1 and RRM1. Results: After a median follow-up of 25 months (range 12–51), 17 patients relapsed and 10 deceased. A good correlation was found between mRNA expression levels of both genes. Three-year disease-free survival (DFS) was 74% vs 33% for patients with low and high ERCC1 expression (p=0.03), and 64% vs 22% for those with low and high RRM1 expression (p=0.26), respectively. Comparable result in favour of patients showing lower ERCC1 mRNA levels was found in both groups of patients randomized to PG or obs. Multivariate analysis demonstrated that only the presence of N1–2 and low expression level of ERCC1 were significant prognostic factor for better DFS (HR 4.358, 2.775 and p value = 0.006 and 0.046, respectively). Conclusions: Determination of ERCC1 mRNA expression level in muscle-invasive bladder cancer can make a contribution as an independent predictor of DFS after radical cystectomy. It’s still unclear if quantification of ERCC1 gene expression level could interact with adjuvant chemotherapy. Longer follow-up will help to address this issue (Supported by CNR-MIUR grants 02.00447, 03.00387-ST97). No significant financial relationships to disclose.

scholarly journals Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

2021 ◽  
Vol 9 (3) ◽  
pp. e001941
Author(s):  
Niannian Ji ◽  
Neelam Mukherjee ◽  
Ryan M Reyes ◽  
Jonathan Gelfond ◽  
Martin Javors ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
Percentage Change ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Double Blind ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Muscle Invasive

BackgroundAlthough intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.MethodsA randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.ResultsThirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1–2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: −26% (−51% to 24%) for placebo, 9.6% (−59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (−31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).ConclusionsFour weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

A prospective observational study on oral administration of Ellagic Acid and Annona Muricata in patients affected by non-muscle invasive bladder cancer not undergoing maintenance after 6-week intravesical prophylaxis

2021 ◽  
pp. 039156032110222
Author(s):  
Vincenzo Serretta ◽  
Ettore De Berardinis ◽  
Alchiede Simonato ◽  
Alessio Guarneri ◽  
Nino Dispensa ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Oral Administration ◽  
Ellagic Acid ◽  
Invasive Bladder Cancer ◽  
Prophylactic Effect ◽  
Annona Muricata ◽  
Muscle Invasive Bladder Cancer ◽  
Number Of Patients ◽  
Muscle Invasive

Introduction: BCG and MMC shortage and Covid-19 pandemic, more recently, limit accessibility to maintenance regimen in intravesical prophylaxis against recurrence of non-muscle invasive bladder cancer (NMIBC). Ellagic acid (EA) and Annona muricata (AM) exert antitumor activity against different human tumours. An observational prospective study on the prophylactic effect of oral administration of EA+AM in patients avoiding maintenance regimen is presented. Materials and methods: Patients affected by NMIBC and not undergoing maintenance after a 6-week course of intravesical prophylaxis with MMC or BCG were entered. Tis and very high-risk tumours were excluded. After informed consent, the patients were subdivided in relation to the oral assumption or not of EA (100 mg) plus AM (100 mg), daily for 6 months. All patients were submitted to 3-month cytology and cystoscopy. Results: 162 (90%) of 180 entered patients are evaluable, 90 and 72 receiving or not EA+AM. No difference emerged in patients’ characteristics between the two groups. BCG was given in 86 (54%) and chemotherapy in 74 (46%) patients. The recurrence free rate at 3, 6 and 12 months in patients assuming or not EA was 96.5% versus 84.6% ( p = 0.003), 85.4% versus 64.8% ( p = 0.005) and 74.2% versus 60.6% ( p = 0.246), respectively. The recurrence free survival at 12 months in patients assuming or not EA was 63.0% versus 34.5% ( p < 0.0001). Discussion and conclusions: Our study suffers several limits: not randomized trial although prospective, limited number of patients and short follow-up, nevertheless it shows the prophylactic effect of oral EA+AM in absence of maintenance after intravesical chemotherapy or immunotherapy induction.

Development and Validation of a Prognostic Nomogram Model for Recurrence of Non-Muscle Invasive Bladder Cancer

2021 ◽  
Author(s):  
Sanhe Liu ◽  
Yongzhi Li ◽  
Diansheng Cui ◽  
Yuexia Jiao ◽  
Liqun Duan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Risk Stratification ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Muscle Invasive Bladder Cancer ◽  
Clinicopathologic Characteristics ◽  
Cox Proportional Hazards Regression ◽  
Proportional Hazards Regression ◽  
Muscle Invasive

Abstract BackgroundDifferent recurrence probability of non-muscle invasive bladder cancer (NMIBC) requests different adjuvant treatments and follow-up strategies. However, there is no simple, intuitive, and generally accepted clinical recurrence predictive model available for NMIBC. This study aims to construct a predictive model for the recurrence of NMIBC based on demographics and clinicopathologic characteristics from two independent centers. MethodsDemographics and clinicopathologic characteristics of 511 patients with NMIBC were retrospectively collected. Recurrence free survival (RFS) was estimated using the Kaplan-Meier method and log-rank tests. Univariate Cox proportional hazards regression analysis was used to screen variables associated with RFS, and a multivariate Cox proportional hazards regression model with a stepwise procedure was used to identify those factors of significance. A final nomogram model was built using the multivariable Cox method. The performance of the nomogram model was evaluated with respect to its calibration, discrimination, and clinical usefulness. Internal validation was assessed with bootstrap resampling. X-tile software was used for risk stratification calculated by the nomogram model. ResultsIndependent prognostic factors including tumor stage, recurrence status, and European Association of Urology (EAU) risk stratification group were introduced to the nomogram model. The model showed acceptable calibration and discrimination (area under the receiver operating characteristic [ROC] curve was 0.85; the consistency index [C-index] was 0.79 [95% CI: 0.76 to 0.82]), which was superior to the EAU risk stratification group alone. The decision curve also proved well clinical usefulness. Moreover, all populations could be stratified into three distinct risk groups by the nomogram model. ConclusionsWe established and validated a novel nomogram model that can provide individual prediction of RFS for patients with NMIBC. This intuitively prognostic nomogram model may help clinicians in postoperative treatment and follow-up decision-making.

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