Bladder Tumor Markers Research Articles

Identification of Hydroxysteroid Dehydrogenase Type 1 As a Potential Bladder Tumor Marker.

The 17beta-hydroxysteroid dehydrogenase type 1 (HSD17B) family has been implicated in the prognosis and treatment prediction of various malignancies; however, its association with bladder cancer (BLCA) remains unclear. This study aimed to evaluate the potential of HSD17B1, as a prognostic biomarker, for the survival of patients with BLCA and to determine its effectiveness as a supplemental biomarker for BLCA. A series of bioinformatics techniques were applied to investigate the expression of HSD17B1 in different types of cancer and its potential association with the prognosis of BLCA patients using diverse databases. The UALCAN, Human Protein Atlas, cBioPortal, Metascape, GEPIA, MethSurv, and TIMER were employed to analyze expression differences, mutation status, enrichment analysis, overall survival, methylation, and immune-infiltrating cells. The real-time reverse transcription-PCR (qRT-PCR) was implemented to detect the messenger ribonucleic acid (mRNA) expression levels of HSD17B1 in vitro. Elevated mRNA and protein levels of HSD17B1, surpassing normal levels, were observed in BLCA samples. In addition, the BLCA patients with higher mRNA expression level of HSD17B1 significantly reduced the overall survival. Also, several immune infiltrating cells, including mast cell resting CIBERSORT-ABS, have been identified as tumor-associated biomarker genes, with the potential to significantly influence the immunological environment. Finally, qRT-PCR analysis revealed a significant upregulation of HSD17B1 mRNA expression level in the cancer cells compared to the human 293T cells, which was consistent with the bioinformatics data. There is a strong correlation between the elevated HSD17B1 expression and positive prognosis in patients with BLCA. Therefore, HSD17B1 can be used as a prognostic biomarker in these patients.

Comet-FISH analysis of urothelial cells. A screening opportunity for bladder cancer?

ABSTRACT Introduction Bladder cancer (BCa) is the most frequent cancer of the urinary tract, with more than 500,000 reported cases and nearly 200,000 related deaths yearly. Cystoscopy is the standard examination used for the initial diagnosis and follow-up of BCa in the noninvasive stage. However, the American Cancer Society does not include BCa screening in its list of recommended cancer screenings. Areas covered Recently, several urine-based bladder tumor markers (UBBTMs) that identify genomic, transcriptomic, epigenetic, or protein alterations have been introduced, some of which have been approved by the Food and Drug Administration (FDA) to improve its diagnosis and surveillance. Several biomarkers have been found in the tissues and blood of individuals with BCa or predisposed to develop the disease, further enriching our information. Expert opinion From a prevention perspective, alkaline Comet-FISH could be a valuable tool with broad potential for clinical application. Furthermore, a comet assay could be more beneficial for diagnosing and monitoring bladder cancer and determining individual susceptibility. Thus, we recommend further studies to understand the potential of this combined assay in the general population as a potential screening test and in patients initiated into the diagnostic process.

Biomarkers for Bladder Cancer: Present Challenges and Recent Developments

Bladder cancer is the most common carcinoma of the urinary system. Early detection and diagnosis of bladder cancer is a major challenge. Urine cytology has low sensitivity and specificity, especially for low-grade tumors. Cystoscopy is the gold standard for the detection and follow-up of bladder tumors. However, it is an expensive and invasive procedure and can fail to detect many bladder lesions such as carcinoma in situ (CIS). It is thus an unmet need to identify a robust set of biomarkers, which can improve the current diagnostic practice. During the last one decade, several bladder tumor markers have been identified for diagnosis, however, none of these diagnostic markers offer sufficient sensitivity and specificity to be routinely used in the clinics. Recent advancement in mass spectrometry (MS)-based quantitative proteomics has emerged as a powerful method to discover wide range of proteins in complex biological samples. In this review, we summarize the status of biomarkers currently identified and used for bladder cancer diagnosis.

Metabonomic diagnosis of bladder cancer: what are the advantages and considerations?

Bladder cancer (BC) is the fifth most common cancer and is one of the leading causes of death worldwide [1]. The 5-year survival rate for BC is approximately 94% if detected early; thus timely diagnosis and intervention of BC increase patient’s survival rate dramatically [2]. However, BC has a high recurrence rate and patients are subjected to life-long surveillance. As a result, the lifetime economic burden per BC patient is higher than other cancer types. Currently, the standard diagnoses of BC are cystoscopy and urinary cytology [3]. While cystoscopy is clinically reliable, it is expensive, invasive and associated with a definite risk of morbidity. On the other hand, noninvasive urinary cytology demonstrates poor sensitivity in detecting low-grade BC (4–31%) [4]. In recent years, several proteinaceous urinebased bladder tumor markers (UBBTMs) have been evaluated for the diagnosis of BC, such as bladder tumor antigen (BTA), NMP22, FDP and ImmunoCyt [5]. However, the specificity and sensitivity of current molecular biomarkers are not adequate to replace cystoscopy [6]. Therefore, there is an impetus to develop sensitive and specific noninvasive biomarkers for the diagnosis and surveillance of BC. Dysregulated molecular pathways, associated with tumor genes, secrete specific modulated levels of metabolites into biological fluids that may be detectable prior to clinical symptoms, rendering them potential early biomarkers for cancer diagnosis. Metabonomics measures the dynamic multiparametric responses of systems biological metabolome to genetic modifications or pathophysiological stimuli such as cancers [7]. It allows scientists to survey global dysregulated metabolic pathways and gain holistic insights into cancer etiology and progression. Significant progress has been made using modern metabonomics techniques to characterize BC patients, identify marker metabolites and generate new knowledge in disease biology and potential therapeutic targets [5].

Multiplex Protein Signature for the Detection of Bladder Cancer in Voided Urine Samples

Accurate urine assays for bladder cancer detection would benefit patients and health care systems. Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples. In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort. We performed a case-control, phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders. The urinary concentration of 8 biomarkers (IL-8, MMP-9 and 10, PAI-1, VEGF, ANG, CA9 and APOE) was assessed by enzyme-linked immunosorbent assay. Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values, eg sensitivity and specificity. Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer. The 7 biomarkers were assessed in a new model, which had an AUROC of 0.88 (95% CI 0.84-0.93), and 74% sensitivity and 90% specificity. In contrast, the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39% and 54%, respectively. Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls. The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays.

Cost-Effectiveness of Fluorescence In Situ Hybridization in Patients with Atypical Cytology for the Detection of Urothelial Carcinoma

Patients with atypical cytology and equivocal or negative cystoscopy pose a challenge due to uncertainty about the presence of cancer. We determined the cost-effectiveness of using fluorescence in situ hybridization assays to determine the need for biopsy in patients with atypical cytology and equivocal or negative cystoscopy. Data from 2 large prospective studies evaluating the usefulness of fluorescence in situ hybridization in the setting of atypical cytology to detect urothelial carcinoma were combined. The data were used to calculate sensitivity and specificity for the UroVysion fluorescence in situ hybridization assay in various clinical scenarios. Cost data were obtained from our institution and Medicare reimbursement rates. Evaluations with or without bladder biopsy and with or without upper tract evaluation were considered. The study included 263 patients with atypical cytology and equivocal (62) or negative (201) cystoscopy. In patients with equivocal cystoscopy (assuming biopsy was performed in the operating room) biopsy based on fluorescence in situ hybridization results saved $1,740 per patient ($3,267 vs $1,527 per patient) and avoided 42 biopsies compared to biopsy in all patients. If office based biopsies were used then cost savings using fluorescence in situ hybridization results were $95 per patient. Among patients with negative cystoscopy biopsy based on fluorescence in situ hybridization resulted in costs savings of $2,241 per patient, avoiding 167 biopsies, compared to biopsy in all patients. Assuming office based biopsy, the cost savings were $216 per patient. The decision to perform biopsy based on fluorescence in situ hybridization assay in patients with atypical cytology and equivocal or negative cystoscopy was associated with a significant decrease in bladder cancer associated costs.

Diagnostic Potential of Urinary α1-Antitrypsin and Apolipoprotein E in the Detection of Bladder Cancer

The ability to reliably diagnose bladder cancer in voided urine samples would be a major advance. Using high throughput technologies, we identified a panel of bladder cancer associated biomarkers with potential clinical usefulness. In this study we tested 4 potential biomarkers for the noninvasive detection of bladder cancer. We examined voided urine specimens from 124 patients, including 63 newly diagnosed with bladder cancer and 61 controls. Concentrations of proteins were assessed by enzyme-linked immunosorbent assay, including α1-antitrypsin, apolipoprotein E, osteopontin and pentraxin 3. Data were compared to the results of urinary cytology and the BTA Trak® enzyme-linked immunosorbent assay based bladder cancer detection assay. We used the AUC of ROC curves to compare the usefulness of each biomarker to detect bladder cancer. Urinary levels of α1-antitrypsin, apolipoprotein E and bladder tumor antigen were significantly increased in subjects with bladder cancer. α1-Antitrypsin (AUC 0.9087, 95% CI 0.8555-0.9619) and apolipoprotein E (AUC 0.8987, 95% CI 0.8449-0.9525) were the most accurate biomarkers. The combination of α1-antitrypsin and apolipoprotein E (AUC 0.9399) achieved 91% sensitivity, 89% specificity, and a positive and negative predictive value of 89% and 90%, respectively. Multivariate regression analysis highlighted only apolipoprotein E as an independent predictor of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004). Alone or in combination, α1-antitrypsin and apolipoprotein E show promise for the noninvasive detection of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004). Larger, prospective studies including more low grade, low stage tumors are needed to confirm these results.

Discovery of Potential Bladder Cancer Biomarkers by Comparative Urine Proteomics and Analysis

ObjectiveWe searched for bladder tumor markers by analyzing urine samples from patients with bladder cancer and from normal controls. MethodsProteins in urine samples of patients with bladder cancer and with normal controls were systematically examined by 2-dimensional electrophoresis combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The expression of the protein apolipoprotein A-I (apoA-I) was confirmed by Western blot analysis and further evaluated. ResultsWe successfully obtained the 2-dimensional electrophoresis gel maps of urinary proteins in patients with bladder cancer and in normal controls. Thirty differentially expressed protein spots were successfully matched by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Combined with the SWISS-PROT database, only 14 proteins (beta-2-microglobulin, fatty acid–binding protein adipocyte, gelsolin, isoform 1 of gelsolin, myoglobin, isoform 2 of fibrinogen alpha chain, apoA-I, prostaglandin D2 synthase 21 kDa [brain], protein AMBP, transthyretin, keratin type II cytoskeletal 1, type II cytoskeletal 8, putative uncharacterized protein ALB, putative uncharacterized protein MASP2 [fragment]) were identified, including 2 putative proteins. Furthermore, apoA-I was confirmed by Western blot analysis, and the high level of apoA-I was found in urine samples from patients with bladder tumors compared with normal controls. ConclusionsAnalysis of urinary proteome may be a feasible, noninvasive, and efficient strategy for searching for potential bladder tumor biomarkers. A significant relationship of expressed apoA-I was established between bladder cancer and normal controls. We concluded that 14 differential spots included the apoA-I and would be potential urinary biomarkers for the diagnosis and surveillance of bladder cancer.

Research progress in bladder cancer markers and its detection methods

Bladder cancer is the most common type of tumor in the urinary system in China. Its incidence has been increasing and the disease has a high rate of recurrence. The gold standard for detecting and following up bladder cancer is cystoscopy and cytology. However, cystoscopy is expensive and invasive,and cytology is low sensitive.With further understanding cancer in molecular biology,numerous bladder tumor markers have been recently found. Tumor markers play very important role in the diagnosis of cancer,the judgement of invasion,metastasis,therapy effecta,as well as predietion and prognosis.The aim of this review is to discuss the advancement of hiomarkers for bladder cancer. Key words: Urinary bladder neoplasms; Tumor markers; Diagnosis

Rationale for an early detection program for bladder cancer

Introduction:A total of 356,557 new cases were diagnosed annually worldwide in 2009, it was estimated that 52,810 new patients were to be diagnosed with bladder cancer and there were 10,180 projected deaths from the disease in the USA. Despite being the fourth commonest cancer in men, we do not have an early detection/screening program for bladder cancer. The review was aimed at looking at the evidence for the rationale for an early detection program for bladder cancer.Materials and Methods:A detailed search on bladder cancer epidemiology, diagnosis, pathology, tumor markers, treatment outcomes, screening, morbidity and mortality of bladder cancer was carried out on Pubmed central/Medline. Original articles, review articles, monograms, book chapters on bladder cancer, text books on urological oncology, oncology and urology were reviewed. The latest information for new articles before publication was last accessed in June 2010.Discussion and Conclusions:Bladder cancer is the fourth commonest cancer in men, the annual death rate from this disease is significant and every year there is an increase in its incidence globally. The prognosis of bladder cancer is stage and grade dependent; the lower the stage (T2 or less) the better is the survival. Delay in the diagnosis and treatment does alter the overall outcome. Therefore, there is a clear need for early detection of bladder cancer and screening program. Although we do not have an ideal marker for bladder cancer, it is time we maximize the potential of markers such as UroVysion, NMP22 along with cytology to start such a program. May be as a first step the early detection and screening program could be started in high-risk population. It is not worth waiting till we find the best marker as it would be unfair to our patients. The fear of unnecessary tests and treatment in bladder cancer after its detection in screening program is without any substance. The cost-effectiveness of such a program is certainly comparable to that is used for colon or breast and for prostate as well.

Abstract 4619: Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer

Abstract Bladder cancer is a significant healthcare problem in the USA with a high recurrence rate. More than 90% of bladder cancers are transitional cell carcinomas (TCC). About 75% of TCC present as superficial tumors, of which 50-70% of tumors will recur and roughly 10-20% will progress to aggressive invasive disease. Early detection of bladder cancer is essential for removing the tumor with preservation of the bladder, avoiding metastasis and hence improving prognosis and long-term survival. Urine-based detection of bladder cancer biomarkers aim to reduce the use of current invasive procedure; cystoscopy for diagnosis and surveillance of bladder cancer. No single bladder tumor marker has emerged as the generally accepted test of choice when compared to cystoscopy. As a result, there is a growing need to identify new biomarkers to further develop urine-based bladder cancer diagnostic tests. The oncoprotein DEK is one such candidate biomarker for bladder cancer. Human DEK was first characterized as part of a DEK-CAN fusion resulting from chromosomal translocation in a subset of patients with acute myeloid leukemia. Subsequent studies identified DEK as an over expressed gene in several malignancies including bladder cancer. However, there are no reports to show the presence of the DEK protein in urine of bladder cancer patients. To evaluate if DEK is a biomarker for bladder cancer, we analyzed the expression of DEK protein in 26 TCC tumor tissues and adjacent normal tissue by western blot analysis using a monoclonal DEK antibody. Our results indicate that DEK is expressed in 85% of analyzed tumors but not in normal tissues. As urine contains both cells exfoliated from normal and cancerous urothelium as well as proteins from either secretion or cell lysis, we determined if the DEK protein is present in urine of bladder cancer patients. We analyzed approximately 30 urine samples from patients with active bladder cancer, other malignant urogenital disease and healthy individuals. Urine samples were precipitated with acetone and re-suspended precipitates were analyzed for DEK expression by western blot analysis using polyclonal DEK antibody. We are the first to show that DEK is present in the urine of bladder cancer patients with assay specificity of 86% and sensitivity of 84%. Overall, our data suggest that DEK protein is a biomarker for bladder cancer and the presence of DEK protein in urine of bladder cancer patient can be explored as a diagnostic test for bladder cancer. Successful development of a sensitive test that detects DEK protein in urine samples will allow clinicians to monitor patients with history of bladder cancer and for screening of high-risk populations, such as smokers or workers exposed to industrial bladder carcinogens and reduce the use of invasive cystoscopy, increase patient compliance and survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4619.

Bikunin Loss in Urine as Useful Marker for Bladder Carcinoma

We searched for bladder tumor markers by analyzing urine samples from patients with bladder cancer and normal individuals. Proteins in urine samples of patients with cancer and normal subjects were systematically examined by 2-dimensional electrophoresis combined with matrix assisted laser desorption ionization time-of-flight mass spectrometry. Of the proteins bikunin expression was confirmed by Western blot analysis and further evaluated. To correlate urinary bikunin levels with clinical significance we examined urine samples from patients with bladder cancer and normal controls for bikunin expression in parallel with pro-urolinase-plasminogen activator, which was previously shown to be associated with advanced bladder carcinoma. A significant relationship was established between the low level and absence of bikunin, and pro-urolinase-plasminogen activator in urine samples from patients with bladder tumors. Analysis of urinary proteomes may be a feasible, noninvasive and efficient strategy for searching for potential bladder tumor biomarkers. We identified bikunin loss in urine as a potential bladder carcinoma marker.

Bladder Cancer Screening in a High Risk Asymptomatic Population Using a Point of Care Urine Based Protein Tumor Marker

We evaluated whether screening high risk asymptomatic individuals with a bladder tumor marker can lead to earlier detection and resultant down staging of bladder cancer. Subjects at high risk for bladder cancer based on age and smoking or occupational status were solicited from 2 well patient clinics from March 2006 to November 2007. NMP22 BladderChek testing was performed on voided urine samples. Those with positive test results underwent office cystoscopy and cytology testing. Participants were contacted for followup at 12 months after study enrollment to evaluate for unrecognized bladder cancer. A total of 1,175 men and 327 women underwent BladderChek testing. Mean participant age was 62.5 years (range 46 to 92). Based on 10-year or greater smoking history 1,298 participants were enrolled while 513 were enrolled based on a greater than 15-year high risk occupation for bladder cancer. Positive BladderChek testing was observed in 85 (5.7%) participants and 69 agreed to undergo cystoscopy. Three types of lesions were diagnosed including multifocal, high grade Ta (1); Ta, low grade tumor (1) and marked atypia (1). Followup was available in 1,309 subjects. Mean followup was 12 months (range 0.9 to 25.5) and 2 of 1,309 participants had low grade noninvasive bladder cancer. Evaluation of patient records revealed that 73.4% of participants had urinalysis within 3 years before screening. NMP22 BladderChek for screening an asymptomatic, high risk population can detect noninvasive cancers but the low prevalence of bladder cancer in this population did not permit assessment of intervention efficacy. Frequent use of urinalyses in high risk persons may attenuate future efforts to study the effects of bladder cancer screening tests.

Bladder Tumor Markers: A Review of the Literature

Bladder cancer is among the top eight most frequent cancers. Its natural history is related to a combination of factors that impact on its aggressiveness. Cystoscopy and urine cytology are the currently used techniques for the diagnosis and surveillance of non-invasive bladder tumors. The sensitivity of urine cytology for diagnosis is not high, particularly in low-grade tumors. The combination of voided urine cytology and new diagnostic urine tests would be ideal for the diagnosis and follow-up of bladder cancer. However, in order to have some clinical utility, new diagnostic and/or prognostic markers should achieve better predictive capacity that the currently used diagnostic tools. None of the markers evaluated over the last years showed remarkable sensitivity or specificity for the identification of any of the diverse types of bladder cancer in clinical practice. The limitations of the known prognostic markers have led to the research of new molecular markers for early detection of bladder cancer. This research focused in particular on the discovery of biomarkers capable of reducing the need for periodic cystoscopies or, ideally, offering a non-invasive examination instead. In this review, we will examine various new markers of bladder cancer and their value in the diagnosis and follow-up of non-muscleinvasive bladder cancer. When compared with urine cytology, which showed the highest specificity, most of these markers demonstrated an increased sensitivity.

Bladder tumor markers: from hematuria to molecular diagnostics – where do we stand?

Bladder cancer is a common malignancy in the USA. Currently, the detection of initial tumors and recurrent disease is based on evaluation of voided urinary specimens, often followed by cystoscopy. With the high rate of recurrence, cystoscopies are regularly repeated with the aim of halting progression of the disease. For patients, this process is fraught with anxiety, pain and high cost. As a result, intense work is being done in the field of bladder tumor markers with the goal of identifying bladder cancer earlier, both in the initial diagnosis and in recurrences of known tumor. The possibility of identifying a marker that could noninvasively differentiate benign and malignant causes of hematuria, and identify recurrences prior to their pathologic progression is the objective of this area of research. Currently, a large number of tumor markers exist, each scrutinized in both the laboratory and in clinical trials. Here we present many of the most widely used and tested markers. Background details are provided as to the mechanism of detection of malignant cells, the results of recent trials and future directions of study. Some novel modalities for tumor detection are also presented. The next few years will no doubt bring newer markers and lead to the elimination of others. Studies continue to refine the role of these markers in clinical practice, but their ultimate efficacy will need to be borne out in large-scale clinical trials in a multitude of settings.

Economic Impact of Tumor Markers in Bladder Cancer Surveillance

Bladder cancer invokes the highest cost per patient from diagnosis to death and is the fifth most expensive cancer to treat overall, exceeding $3.4 billion annually. Current surveillance regimens require intense follow-up contributing to high cost and emotional burden. Bladder tumor markers hold the promise to reduce these costs, yet have not been widely adopted in oncological practice. We assessed the cost-effectiveness of bladder tumor markers in surveillance routines. A MEDLINE search of all available literature concerning bladder tumor markers and cost-effectiveness was performed. We reviewed retrospective and prospective studies, reviews, opinion papers, decision analyses, and cost-effectiveness analyses. Bladder tumor markers exist in various stages of development and efficacy. Sensitivity and specificity values have been reported across a wide range, with tumor markers generally possessing a higher sensitivity and lower specificity than urine cytology. Several cost-effectiveness analyses have shown tumor markers significantly lower the cost of bladder cancer surveillance when using a modified regimen that lengthens intervals between cystoscopies. However, many of the studies rely on overconfident sensitivity and specificity estimates and do not incorporate data specific to recurrent bladder cancer. No comprehensive study incorporating utility analysis has been performed. Bladder tumor markers cannot definitively replace cystoscopy in surveillance regimens given the current evidence. Recent reports suggest potential for tumor markers to control the financial and emotional cost of bladder cancer care and improve quality of life. Until prospective analyses incorporating quality of life outcomes are performed, wider adoption of bladder tumor markers will be hampered.

Bladder tumor markers: a review of the literature

Bladder cancer is among the top eight most frequent cancers. Its natural history is related to a combination of factors that impact on its aggressiveness. Cystoscopy and urine cytology are the currently used techniques for the diagnosis and surveillance of non-invasive bladder tumors. The sensitivity of urine cytology for diagnosis is not high, particularly in low-grade tumors. The combination of voided urine cytology and new diagnostic urine tests would be ideal for the diagnosis and follow-up of bladder cancer. However, in order to have some clinical utility, new diagnostic and/or prognostic markers should achieve better predictive capacity that the currently used diagnostic tools. None of the markers evaluated over the last years showed remarkable sensitivity or specificity for the identification of any of the diverse types of bladder cancer in clinical practice. The limitations of the known prognostic markers have led to the research of new molecular markers for early detection of bladder cancer. This research focused in particular on the discovery of biomarkers capable of reducing the need for periodic cystoscopies or, ideally, offering a non-invasive examination instead. In this review, we will examine various new markers of bladder cancer and their value in the diagnosis and follow-up of non-muscleinvasive bladder cancer. When compared with urine cytology, which showed the highest specificity, most of these markers demonstrated an increased sensitivity.

Telomerase and other novel approaches to bladder cancer detection.

The current protocols in place for bladder cancer screening are cystoscopy and urine cytology. Cytology does not have an adequate sensitivity in low-grade malignancy and has limited utility in the screening and management of bladder cancer patients. Urine tumor markers aimed at detection of cancer via voided urine are an attractive alternative to cytology. Currently, FDA-approved tumor marker assays lack the characteristics of an ideal test and have yet to revolutionize bladder cancer detection. Novel tumor markers, not yet FDA-approved, have the potential to change disease management algorithms that currently include voided urine cytology. Telomerase, an enzyme present in greater than 80% of all cancer cells, has the potential to be a successful bladder tumor marker for cancer surveillance and monitoring.

Defining the role of NMP22 in bladder cancer surveillance

Despite advances in treatment and knowledge of its pathogenesis, urothelial carcinoma of the bladder remains a significant cause of morbidity and mortality. Experience with the natural course of bladder cancer has revealed that early diagnosis of primary and recurrent disease improves patient prognosis. In this regard, cystoscopy (usually in combination with urinary cytology) has long been regarded as the gold standard for the diagnosis and surveillance of bladder cancer. However, the disadvantages inherent to cystoscopy, including invasiveness and cost, have stimulated a search for alternative methods for detecting urothelial malignancy. The ideal alternative test would duplicate the high accuracy of cystoscopy for detecting bladder tumors while eschewing its invasiveness, attendant morbidity, and high cost. The vast majority of bladder cancers arise from the urothelium, which continually sheds cells as well as intracellular contents into the urine, thereby providing a potential source of cancer-specific markers. Voided cytology and urinalysis are established tests that have been the standard tools for detection of such substances. The last decade has seen the rise of a myriad of novel urine-based bladder tumor markers, including bladder tumor antigen, urinary bladder cancer antigen, fibronectin, telomerase, and nuclear matrix proteins (e.g., NMP22). The NMP22 assay in particular has been the subject of considerable study and has demonstrated some promise as a potential adjunct to cystoscopy and cytology. Through a critical review of the literature, we seek to define the role, if any, of NMP22 in the follow-up of patients with a previous history of urothelial carcinoma of the bladder.

Evaluation of Urine NMP22 Point-of-Care Test for the Screening of Bladder Cancer

Screening of high-risk patients using bladder tumor markers can offer an advantage of early detection and saving medical costs. For these purpose many tumor markers have been developed to supplement invasive cystoscopy. Our study evaluated the NMP22 point-of-care test (NMP22 POCT), which is one of the tumor makers, comparing with the standard urine cytology for the diagnosis of bladder cancer. From January to September 2005, 232 patients who had undergone a cystoscopy due to bladder cancer associated symptoms including hematuria and dysuria were enrolled in this study. Urine specimens were collected for NMP22 POCT and cytology. NMP22 POCT and urine cytology were compared for sensitivity and specificity. In addition, we evaluated urine stick test and microscopy to explain some false-positive results in NMP22 POCT. Superficial transitional cell carcinoma was diagnosed in 10 patients. The sensitivity of NMP22 test was 60% (95% confidence interval [CI], 26.2-87.8%), whereas that of cytology was 33.3% (95% CI, 7.5-70.1%); however, the difference was not significant. The specificity of NMP22 test was 69.8% (95% CI, 63.3-75.8%), compared with 99.0% (95% CI, 96.5-99.9%) for cytology (P<0.001). The presence of microscopic RBCs in urine specimen was significantly associated with the lower specificity of NMP22 POCT (P=0.02). NMP22 POCT was significantly less specific than urine cytology. To be useful as a bladder cancer screening test, the NMP22 test should have a higher specificity.