A pilot study of urinary microRNA as a biomarker for urothelial cancer

Objective: MicroRNAs (miRNAs) are part of a class of small ribonucleic acid (RNAs). They are important regulatory molecules, involved in several cell processes, such as developmental timing, stem cell division and apoptosis. Dysregulated miRNAs have been identified in several human malignancies, including bladder cancer tissue samples, and may confer a “tumour signature” that can be exploited for diagnostic purposes. We report on a prospective pilot study investigating the diagnostic capability of miRNAs in the urine of patients with urothelial cancer.Methods: Voided urine samples were collected from patients with urothelial carcinoma just prior to bladder tumour resection, as well as age-matched healthy control patients. Pathology demonstrated both low- and high-grade cancer. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed on the RNA extracts using primers for 4 miRNAs shown previously to be dysregulated in solid urothelial carcinomas with RNU6B as the endogenous control. Standard urine cytology was performed on all samples in a blinded fashion.Results: Two miRNAs of interest were dysregulated in the urine from cancer patients with miR-125b showing an average 10.42-fold decrease (p < 0.01) and miR-126 showing an average 2.70-fold increase (p = 0.30) in the cancer samples compared to the normal controls. The sensitivity and specificity of the cytology on the same urine samples were 50% and 80%, respectively. Using these 2miRNAs only, a decision-tree prediction model was generated for a validation cohort of patients yielding a specificity of 100% and a sensitivity of 80%.Discussion: This preliminary study of candidate urinary miRNA inpatients with low- and high-grade urothelial cancer demonstrated a significantly improved diagnostic accuracy over cytology. These results provide rationale for further studies on discovery and validation of candidate miRNAs in voided urine and may potentially lead to the development of a non-invasive and sensitive test for bladder cancer diagnosis and prognosis.

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The negative predictive value of a negative repeat urinalysis in patients presenting with haematuria: A review of 1138 patients

Journal of Clinical Urology ◽

10.1177/2051415817711633 ◽

2017 ◽

Vol 10 (5) ◽

pp. 471-475

Author(s):

Benjamin Zak Starmer ◽

Amal Singh ◽

Stephen Bromage

Keyword(s):

Negative Predictive Value ◽

Predictive Value ◽

Urothelial Cancer ◽

Urine Culture ◽

Bladder Tumour ◽

High Grade ◽

Microscopic Haematuria ◽

Positive Urine Culture ◽

Positive Urine ◽

The One

Objective: Haematuria may be transient for a number of benign conditions, particularly a urinary-tract infection (UTI). We set out to determine if a negative repeat urinalysis at the time of urological assessment for patients with haematuria could predict negative investigations and whether investigations could be tailored by this test. Methods: This was a retrospective analysis of records for all patients attending a haematuria clinic between 16 September 2013 and 12 September 2014. This included patients with visible and non-visible (microscopic) haematuria. Results: There were 1138 patients, 599 with visible haematuria (VH) and 460 with non-visible haematuria (NVH). Seventy-two patients were excluded. A total of 546 patients had a positive repeat urinalysis for blood; 438 patients had a negative repeat urinalysis when tested at the haematuria clinic, 298/599 for VH and 140/460 NVH. For those who had negative repeat urinalysis, urothelial cancer was found in 15/298 VH and 1/140 NVH. The one patient with negative repeat urinalysis and NVH was found to have a grade 2 (high grade) bladder tumour. The negative predictive value for a negative repeat urinalysis in transient haematuria was 0.95 for VH and 0.99 for NVH. Twenty-nine patients with VH and repeat negative urinalysis on assessment had a positive urine culture suggesting a UTI as a cause. None of these patients was found to have urothelial cancer ( p = 0.0413). Conclusion: Patients who experience transient VH and subsequent repeat negative urinalysis in the absence of infection have a 5% chance of urothelial cancer and should still be investigated. For those with transient NVH, the probability of finding a urothelial cancer is <1%, although we did find a high-grade bladder tumour in this group. If patients have a positive urine culture and a negative repeat urinalysis following treatment, they could be spared haematuria investigations.

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Pathology outcomes in patients with transurethral bladder tumour resection in a Turkish population: A retrospective analysis

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2018.1.8 ◽

2018 ◽

Vol 90 (1) ◽

pp. 8

Author(s):

Salih Budak ◽

Cem Yücel ◽

Mehmet Zeynel Keskin ◽

Mehmet Yoldas ◽

Erdem Kısa ◽

...

Keyword(s):

Bladder Cancer ◽

Histopathological Examination ◽

Tnm Classification ◽

Bladder Tumour ◽

Treatment Strategies ◽

Turkish Population ◽

Tumour Resection ◽

Pathology Report ◽

Study Results ◽

Rare Tumours

Objectives: Transurethral bladder tumour resection (TURBT) is the common surgical method used in the diagnosis, staging and treatment of patients with bladder tumour. Most of the rare tumours other than the urothelial carcinomas of the bladder are in advanced stage on diagnosis and necessitate aggressive treatment. In our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region. Materials and methods: We retrospectively evaluated 815 patients who underwent TURBT surgery between January 2010 and March 2016 in our clinic with a diagnosis of bladder cancer and at least 1 year follow-up. Patients with tumour histopathological examination including histological tumour type, grade and were reported. Thirty-nine patients with an unclear pathology report (neighboring organ invasion, cautery artifact, etc) and 17 patients whose data could not be accessed were excluded from the study. The patients who had received chemotherapy or radiotherapy due to any type of malignancy (23) were also excluded from the study. Results: The outcomes of 736 patients operated in our clinics due to bladder tumour were evaluated. The mean age was 65.2 ± 8.4; 135 were female and 601 were male. Among them 711 patients with urothelial carcinoma were reported (94.2%). According to TNM classification, stage Ta was observed in 270 patients (37.9%), stage T1 in 297 (41.7%), and stage T2 in 144 (20.3%). Non-urothelial cancers were reported in 25 cases (3.3%). Conclusion: The incidence of bladder carcinoma varies between regions. The results of our study are similar to those of the western countries. Increased smoking and exposure to environmental carcinogenetic agents may lead to altered incidences and histological types of bladder tumours. Revision of regional tumour records may be useful to develop and evaluate future treatment strategies.

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Urinary expression of let-7c cluster as non-invasive tool to assess the risk of disease progression in patients with high grade non-muscle invasive bladder Cancer: a pilot study

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01550-w ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Manuela Spagnuolo ◽

Manuela Costantini ◽

Mariaconsiglia Ferriero ◽

Marco Varmi ◽

Isabella Sperduti ◽

...

Keyword(s):

Bladder Cancer ◽

Pilot Study ◽

Disease Progression ◽

Invasive Bladder Cancer ◽

High Grade ◽

Muscle Invasive Bladder Cancer ◽

Non Invasive ◽

Risk Of Disease ◽

Muscle Invasive

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Combined cytotoxic effect of UV-irradiation and TiO2microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells

Photochemical & Photobiological Sciences ◽

10.1039/c4pp00272e ◽

2015 ◽

Vol 14 (3) ◽

pp. 583-590 ◽

Cited By ~ 17

Author(s):

Roghayeh Imani ◽

Peter Veranič ◽

Aleš Iglič ◽

Mateja Erdani Kreft ◽

Meysam Pazoki ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Uv Irradiation ◽

Cytotoxic Effect ◽

Urothelial Cancer ◽

Low Grade ◽

High Grade ◽

Urothelial Cells ◽

Efficient Approach

Paper shows that internalization of the TiO2microbeads followed by the UV-irradiation is an efficient approach for killing cancer urothelial cells. Additionally, differentiation dependent differences in the sensitivity of the cells to the UV-irradiation are shown, and a model of photocatalytic treatment of thein vivobladder cancer is presented.

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Assessment of the diagnostic value of microsatellite instability in the urine of bladder cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.384 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 384-384

Author(s):

Hussein Mustafa Khaled ◽

Abdel-Rahman Zekri ◽

Mai B Mohamed ◽

Fatma M Diab ◽

Mona Abdellateif ◽

...

Keyword(s):

Bladder Cancer ◽

Microsatellite Instability ◽

Tumor Tissue ◽

High Sensitivity ◽

Diagnostic Value ◽

Urine Samples ◽

Tissue Samples ◽

Predictive Values ◽

Promising Tool ◽

Sensitivity Specificity

384 Background: Microsatellite alterations in urine sediments have proved to be a promising tool for detection of bladder cancer (BC) due to its high sensitivity and specificity. Methods: We assessed the possible prognostic and predictive values of microsatellite alterations in tissue samples and urine sediments obtained from Egyptian patients with BC, and their utility as diagnostic, prognostic and predictive value. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were assessed using 13 microsatellite markers in tumor tissue and urine sediments of 30 patients with BC. The concordance between MSI in tissue and urine samples was determined. Results: We found that MSI was more frequent than LOH (100% and 46.7%; respectively). D16S310, MBP and IFN-α showed the highest MSI frequency in urine samples (70%, 70% and 66.67%; respectively), while MBP, ACTBP2 and D9S171 (66.67%, 63.33%, and 60%; respectively) were the most frequently detected in tumor tissue. All markers correlated significantly with the pathological subtypes (more frequent in TCC) and hematuria. The concordance between tissue and urine was statistically significant for , D9S171, D16S476, FGA and ACTBP2 (P = 0.04, 0.015, 0.02 and 0.007; respectively). When we combined D16S476 and D9S171, the sensitivity, specificity, PPV and NPV reached (80.0%, 75.0%, 82.8% and 71.4%; respectively) for diagnosis of BC . Conclusions: Thus MSI in urine sediments could be a sensitive and reliable method for diagnosis of BC.

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Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex

Cell Death and Disease ◽

10.1038/s41419-021-03836-z ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Scott J. Weir ◽

Prasad Dandawate ◽

David Standing ◽

Sangita Bhattacharyya ◽

Prabhu Ramamoorthy ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Urothelial Cancer ◽

Phase 1 ◽

Intraperitoneal Administration ◽

Presenilin 1 ◽

Proliferation Index ◽

High Grade ◽

Lower Stage

AbstractCiclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

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Differential expression of FGFRs signaling pathway components in bladder cancer: A step toward personalized medicine

Balkan Journal of Medical Genetics ◽

10.1515/bjmg-2017-0026 ◽

2017 ◽

Vol 20 (2) ◽

pp. 75-81 ◽

Cited By ~ 1

Author(s):

Z Ousati Ashtiani ◽

J Tavakkoly-Bazzaz ◽

SA Salami ◽

MR Pourmand ◽

F Mansouri ◽

...

Keyword(s):

Bladder Cancer ◽

Pilot Study ◽

Growth Factor ◽

Personalized Medicine ◽

Fibroblast Growth Factor ◽

Real Time ◽

Expression Patterns ◽

Fibroblast Growth ◽

Tissue Samples ◽

Over Expression

AbstractVariations Improper activation and inappropriate expression of fibroblast growth factor receptors (FGFRs) in cancer suggests that they can act as therapeutic targets. Fibroblast growth factor receptor inhibitors are currently employed in clinical trials of different cancers. Regarding the essence and the importance of the personalized medicine, mainly mirrored by remarkable inter-individual variations in different populations, we aimed to perform a pilot study to addressFGFR1andFGFR3expression levels and their correlation with the clinicopathological features in Iranian patients with bladder cancer (BC). Paired tumor and adjacent non tumor tissue samples along with their clinico-pathological parameters were obtained from 50 cases diagnosed with BC in different stages and grades. The mRNA expressions ofFGFR1andFGFR3in tissue samples were determined by real-time polymerase chain reaction (real-time PCR). The expression levels ofFGFR3were significantly higher in tumor tissues when compared to adjacent normal tissues (p= 0.007), regardless of the stages and grades of the tumor. Over expression was associated with cigarette smoking (p= 0.037) and family history for cancer (p= 0.004). Decreased expression ofFGFR1was observed, remarkably evident in high-grade tumors (p= 0.047), while over expression was detected in low-grade samples. This pilot study clearly suggests that in Iranian BC patientsFGFR1andFGFR3expression patterns are different, and also highly distinctive with regard to the tumor’s stage and grade. Such particular expression patterns may indicate their special values to be employed for interventional studies aiming targeted therapy. Further studies with a larger sample size are needed to validate our results.

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Association of FGFR alterations with FGFR 1-4 gene expression in TUR biopsies and matched NMP22 urine levels in early bladder cancer of the prospective real world clinico-pathological register trial: BRIDGister.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16533 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16533-e16533

Author(s):

Ralph M. Wirtz ◽

Frank Friedersdorff ◽

Elke Veltrup ◽

Ergin Kilic ◽

Richard Watts ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Mrna Expression ◽

Real World ◽

Standardized Test ◽

Urine Samples ◽

Tissue Samples ◽

Basal Marker ◽

Commercial Kits ◽

Urine Levels

e16533 Background: The objective of the present study was to identify molecular charactersitics associated with FGFR positive tumors in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB at the pilot center of the multicentric BRIDGister Real World Experience trial that are helpful for patient management and prognosis. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 28 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). Relative gene expression of subtyping markers (KRT5, KRT0) as well as FGFR1, FGFR2, FGFR3, FGFR4, ERBB2 was centrally tested by standardized test systems (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed by commercially available urine tests (UBC Rapid, BTA stat, NMP22). Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 28 patients (median age: 73, male 71% vs female 29%) of diverse clinical stages (Benign lesions/no tumor 21%, pTa 32%, pT1 21%, pT2 21%) and WHO 1973 grade (G1 7%, G2 43%, G3 21%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 9 out of 28 patients exhibited FGFR alterations (32%). FGFR positive tumors were associated with high expression of FGFR3 mRNA (r = 5.951, p = 0.0011) but low FGFR1 mRNA as well as FGFR4 mRNA (r = -0.3882, p = 0.0412 and r = -0.6305, p = 0.0004, respectively). Interestingly, FGFR alteration was positively associated with the basal marker KRT5 (r = 0.3929, p = 0.0386), but not with luminal KRT20 mRNA expression (r = -0.0208, p = 0.9179). Moreover FGFR3 altered bladder cancer was associated with elevated NMP22 levels in pretreatment urine (r = 0.3978, p = 0.0361). Conclusions: In early bladder cancer FGFR3 alterations are tightly associated with a characteristic FGFR mRNA signature. Mutation/Fusion of FGFR3 results in high FGFR3 but low FGFR1 and FGFR4 mRNA expression, which might be i.a. relevant for the response to FGFR inhibition and important to predict outcome of FGFR inhibitors. Morever FGFR alteration was associated with elevated NMP22 urine levels, which might be helpful for detecting and monitoring FGFR altered bladder cancer in a non invasive fashion. These results warrant further investigation and its impact on outcome prediction (BCG responsiveness, recurrence, proegression, etc) will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.

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