Bladder cancer is the fourth most common cancer

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1 ADULT UROLOGY SENSITIVITY AND SPECIFICITY OF COMMONLY AVAILABLE BLADDER TUMOR MARKERS VERSUS CYTOLOGY: RESULTS OF A COMPREHENSIVE LITERATURE REVIEW AND META-ANALYSES YAIR LOTAN AND CLAUS G. ROEHRBORN ABSTRACT Objectives. To determine the clinical utility of urine-based bladder tumor markers (UBBTMs) and cytology in the treatment of patients with transitional cell carcinoma on the basis of their statistical performance. Methods. A comprehensive literature review was performed using Medline (1966 to current) and other search engines. Data regarding the statistical performance of UBBTMs were double extracted and rectified. Studies addressing comparable patient populations were combined and hierarchical Bayesian meta-analyses performed to calculate the sensitivity and specificity of commonly used UBBTMs, as well as urinary cytology. Patient populations were stratified by tumor stage and grade when data were presented in an extractable fashion. Results. The literature review yielded 54 publications, 338 distinct patient groups (controls, screening population, patients with cancer, strata based on grade and stage) and more than 10,000 patients. The number of groups varied from 1 to 18, and the number of patients ranged from less than 100 to more than 1500 for the various markers. All UBBTMs have better sensitivity compared with cytology, especially for low-grade/stage disease, but do not match cytology regarding specificity. In patients with grade 1 and 2 tumors, several UBBTMs are significantly superior statistically in terms of sensitivity compared with cytology. The sensitivity for transitional cell carcinoma in situ (Tis) is surprisingly poor for all UBBTMs. Conclusions. UBBTMs can be used for follow-up of low-grade/stage tumors but should not replace cystoscopy. All UBBTMs have better sensitivity than cytology and could potentially replace routine cytology during patient follow-up. UROLOGY 61: , , Elsevier Science Inc. Bladder cancer is the fourth most common cancer in men (6%) and the eighth most common cancer in women (2%), accounting in men for 3% of cancer deaths in Of the estimated 56,500 cases for 2002, 1 the vast majority will be superficial transitional cell carcinoma, an imminently treatable disorder. Despite the success in removing these tumors initially by transurethral resection, the recurrence rate is 30% to 70%, and the progression rate to invasive cancer is 10% to 30%. 2 5 Close monitoring of patients is essential for early detection of these recurrences. The current standard of From the Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Reprint requests: Claus G. Roehrborn, M.D., Department of Urology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, J8-130, Dallas, TX Submitted: August 1, 2001, accepted (with revisions): August 27, 2002 care at most institutions consists of cystoscopy and urine cytology every 3 months for the first 2 years after the first occurrence of bladder cancer and at a reduced interval in subsequent years. 6 This approach is costly and requires multiple invasive procedures per year for each patient, having led to the term nuisance tumor for this neoplasm. In recent years, numerous urine-based bladder tumor markers (UBBTMs) have been evaluated to determine whether less invasive follow-up for patients with bladder cancer is feasible. An ideal marker would be office-based, rapid, inexpensive, and exhibit high specificity and sensitivity in the target population. Cytology, which is commonly used in conjunction with cystoscopy, has been shown to have a low sensitivity for low-grade tumors Among the assays evaluated in the past years are the bladder tumor antigen (BTA) test, BTA TRAK, BTA stat, urinary nuclear matrix pro- 2003, ELSEVIER SCIENCE INC /03/$30.00 ALL RIGHTS RESERVED PII S (02)

2 Marker TABLE I. Overall median sensitivity and specificity for commonly used UBBTMs with 95% confidence intervals based on hierarchical Bayesian meta-analyses. Studies (n) Sensitivity (%) Patients (n) Specificity (%) Patients (n) Cytology ( ) ( ) 1512 NMP ( ) ( ) 1579 BTA test ( ) ( ) 1398 BTA stat ( ) ( ) 1596 BTA TRAK ( ) ( ) 743 FDP ( ) ( ) 605 Hgb dipstick ( ) ( ) 322 CYFRA 21-1 (CK 19) ( ) ( ) 245 UBC (CK 8/18) ( ) ( ) 313 BCA (CK 8,18) ( ) ( ) 205 CK ( ) ( ) 83 TPA (CK 8,18,19) TPS (CK 8/CK 18) Telomerase ( ) ( ) 168 BCLA Chemiluminescent Hgb HA ( ) ( ) 313 HAase HA-HAase Immunocyt test Beta-HCG KEY: UBBTMs urine-based bladder tumor markers; NMP22 nuclear matrix protein 22; BTA bladder tumor antigen; FDP fibrin degradation product; Hgb hemoglobin; UBC urinary bladder cancer; CK cytokeratin; BCA bladder cancer antigen; TPA tissue polypeptide antigen; TPS tissue polypeptide-specific (antigen); BCLA-4 bladder cancer nuclear matrix protein; HA hyaluronic acid; HAase hyaluronidase; HCG human chorionic gonadotropin. Numbers in parentheses are the 95% confidence intervals. In cases with only one study/group only the median value is reported. tein 22 (NMP22), fibrin degradation product (FDP), autocrine motility factor receptor, bladder cancer nuclear matrix protein (BCLA-4), cytokeratin 20, telomerase, hyaluronic acid, hyaluronidase, Immunocyt, urinary bladder cancer (UBC) test, CYFRA 21-1, chemiluminescent hemoglobin, hemoglobin dipstick, urinary tissue polypeptidespecific (TPS) antigen, bladder cancer antigen (BCA), beta-human chorionic gonadotropin, tissue polypeptide antigen (TPA), and microsatellite analysis. No consensus regarding the relevance of UBBTMs to clinical practice has been established. To evaluate the use of UBBTMs for the surveillance of the bladder, we researched relevant published studies and calculated the sensitivity and specificity of widely available UBBTMs overall, as well as by stage and grade. MATERIAL AND METHODS A comprehensive literature review was performed using Medline (1966 to current) and other search engines. Data regarding the statistical performance of UBBTMs were double extracted and rectified. Studies addressing comparable patient populations were combined by hierarchical Bayesian metaanalyses to calculate the sensitivity and specificity of commonly used tumor markers, as well as urinary cytology. In contrast to standard Bayesian meta-analyses, the hierarchical model is a random effects model allowing for subtle differences in the studied population and target outcomes. 15 Additional stratification by tumor stage and grade was done when data were presented in an extractable fashion. The overall sensitivity and specificity, as well as the sensitivity by grade and stage, were calculated by the hierarchical Bayes method (FAST*PRO, Eddy). RESULTS The literature review yielded 54 publications, 338 distinct patient groups (controls, screening population, patients with cancer, strata based on grade and stage), and more than 10,000 patients. The number of groups varied from 1 to 18, and the number of patients ranged from less than 100 to more than 1500 for the various markers. Table I shows the overall sensitivity and specificity of, as well as the number of publications and groups identified for each marker. The BTA stat, BTA test, NMP22, and cytology were evaluated more commonly than the other markers. The newer BTA stat and BTA TRAK tests are more sensitive than the older BTA test. BTA stat, BTA TRAK, and NMP22 demonstrated similar sensitivity and specificity. All UBBTMs are more sensitive than cytology, and overall their specificity is inferior to cytology. Several markers were only evaluated in a limited number of patients at a single center. Fig- 110 UROLOGY 61 (1), 2003

3 Of those UBBTMs that are superior to cytology in grade 1 and 2 tumors in terms of sensitivity (NMP22, BTA stat, BTA TRAK, CYFRA, and telomerase), BTA stat and CYFRA are significantly inferior to cytology in terms of specificity. BTA TRAK and telomerase are superior in terms of sensitivity, at least for grade 1 and 2 disease, and equivalent in terms of sensitivity in grade 3 tumors and in terms of specificity. Assays for microsatellite instability found loss of heterozygosity or alterations in microsatellite analysis with a sensitivity of 83% to 95% in small groups of patients (n 12 to 21) Controls in two of these studies revealed a specificity of 89% 19 and 100%. 17 FIGURE 1. Overall (A) sensitivity and (B) specificity for cytology and UBBTMs with more than one study reported (see Appendix). Median and 95% confidence intervals shown; dashed line indicates upper 95% for cytology. Asterisk indicates statistical superiority over cytology. CK/ck cytokeratin. ure 1 shows a comparison graph for sensitivity (Fig. 1A) and specificity (Fig. 1B) for cytology versus those UBBTMs for which more than one study group was available. As indicated by the nonoverlapping confidence intervals, the UBBTMs BTA stat, BTA TRAK, CYFRA, BCA, cytokeratin 20, telomerase, and hyaluronic acid are statistically superior to cytology in terms of overall sensitivity. However, none of the UBBTMs are superior in terms of specificity, BTA stat and CYFRA are statistically inferior to cytology, and UBC and hyaluronic acid are equivalent (ie, within the 95% confidence interval for cytology; Fig. 1B). Table II and Figure 2 list the sensitivity by grade and stage. Of the UBBTMs, NMP22, BTA stat, BTA TRAK, CYFRA, and telomerase are significantly superior compared with cytology in patients with grade 1 and grade 2 tumors. However, none of the markers is superior to cytology in patients with grade 3 tumors (Fig. 2B). The results in patients with transitional cell carcinoma in situ (Table III) were superior compared with cytology for almost all markers, with the exception of the BTA test and the hemoglobin dipstick. However, the number of patients with transitional cell carcinoma in situ was relatively small for all groups. COMMENT Transitional cell carcinoma is a cancer with very high recurrence rates and frequently progresses, especially at higher stages and grades. 2 5 The results of Holmäng et al. 20 suggest that detecting bladder cancer earlier will decrease the rate of progression. Patients with cancer progression have significantly higher mortality. 21 The treatment of patients with bladder cancer requires close surveillance at a high cost to society and discomfort to the patient. Although cystoscopy is currently considered the reference standard for the surveillance and detection of bladder cancer, many researchers have evaluated multiple different assays to find an ideal UBBTM. Despite these efforts, the clinical role of currently available UBBTMs has not been defined. A systematic review of the current literature for the various assays revealed that the sensitivity overall and by stage and grade is better for most available UBBTMs compared with cytology. There are good reasons to consider the use of UBBTMs to replace cytology in the monitoring of bladder cancer. Cytology is currently used widely as an adjunct to cystoscopy. The current role of cytology is the detection of lesions not visually recognized by cystoscopy such as carcinoma in situ and upper tract lesions. Cytology is not a point of care test and is costly compared with most commonly available tumor markers. 13 Cytology also has poor interobserver and intraobserver reproducibility. 22,23 Several of the current markers, such as the BTA stat, FDP, and UBC rapid test, provide immediate results as a point of contact test, with minimal ambiguity, higher sensitivity, and lower cost than cytology. Markers such as NMP22 and BTA TRAK are more widely available but require specimens to be sent out to a laboratory and are not point of contact tests. Other markers require more technical expertise and do not provide immediate results, but are less expensive and more sensitive than cytology. 13 UROLOGY 61 (1),

4 TABLE II. Median sensitivity by grade and stage for commonly used UBBTMs with 95% confidence intervals based on hierarchical Bayesian meta-analyses Marker Studies (n) G1 G2 G3 Ta T1 >T2 Cytology ( ) 0.26 ( ) 0.64 ( ) 0.15 ( ) 0.46 ( ) 0.55 ( ) NMP ( ) 0.71 ( ) 0.79 ( ) 0.60 ( ) 0.85 ( ) 0.89 ( ) BTA test ( ) 0.50 ( ) 0.79 ( ) 0.33 ( ) 0.62 ( ) 0.80 ( ) BTA stat ( ) 0.73 ( ) 0.94 ( ) 0.57 ( ) 0.82 ( ) 0.91 ( ) BTA trak ( ) 0.70 ( ) 0.92 ( ) 0.57 ( ) 0.93 ( ) 0.90 ( ) FDP ( ) 0.56 ( ) 0.92 ( ) 0.56 ( ) Hgb dipstick ( ) 0.42 ( ) 0.76 ( ) 0.25 ( ) CYFRA 21-1 (CK 19) ( ) 0.97 ( ) 0.99 ( ) UBC (CK 8/18) ( ) 0.73 ( ) 0.74 ( ) 0.62 ( ) 0.63 ( ) 0.84 ( ) BCA (CK 8,18) CK TPA (CK 8,18,19) Telomerase ( ) 0.82 ( ) 0.93 ( ) 0.74 ( ) Chemiluminescent Hgb HA HAase HA-HAase Immunocyt Abbreviations as in Table I. Numbers in parentheses are the 95% confidence intervals. In cases with only one study/group, only the median value is reported.

5 FIGURE 2. Sensitivity for (A) grade 1, (B) grade 2, and (C) grade 3 for cytology and UBBTMs with more than one study reported (see Appendix). Median and 95% confidence intervals shown; dashed line indicates upper 95% for cytology. Asterisk indicates statistical superiority over cytology. CK/ck cytokeratin. Specificity is lower for most markers compared with cytology. Most studies included exclusion criteria to improve the specificity of the assays. Typically, patients with infection and intravesical therapy within the last month were excluded. Sharma et al. 24 noted six exclusion criteria that resulted in a specificity of 95.6% and 91.5% for NMP22 and BTA stat, respectively, values comparable to cytology. Although using exclusion criteria makes UBBTMs more advantageous in surveillance for patients with bladder cancer, this is a disadvantage for screening patients with microscopic hematuria in whom the diagnosis is uncertain. A concern with UBBTMs that was echoed in published reports is the high rate of false-positive findings. This results in unnecessary additional testing and patient anxiety. Several studies used exclusion criteria to minimize this problem. Likewise, several investigators suggest that these false-positive findings may indicate premalignant changes predating a finding of recurrent malignancy. 8,9,25,26 Giannopoulos et al. 8 followed up patients who had no evidence of disease for a mean of 13.2 months after their false-positive NMP22 test and found that those patients had a 57% recurrence rate compared with the 11% recurrence rate for patients with truenegative test results (P 0.032). Currently, the sensitivity of UBBTMs is not sufficiently high to replace cystoscopy as the reference standard. Vriesema et al., 27 using a standard gamble method, found that 89% of their patients would prefer cystoscopy as the diagnostic method if a bladder tumor marker s sensitivity were less than 90%. Several assays have been tested to improve sensitivity. Konety et al. 28 reported on the use of BCLA-4 to test for six nuclear matrix proteins that are found exclusively in tumors and found a 96% sensitivity for cancer detection. Likewise, assays testing for different cytokeratins have also shown a higher sensitivity than more commonly used markers such as BTA stat, BTA TRAK, and NMP22. Although these markers may not be ready to replace cystoscopy, there may be a role for modified protocols that increase the intervals between cystoscopies and alternate with tumor marker testing. Millan-Rodriguez et al. 2 showed that low-risk tumors had only a 37% recurrence and 0% progression rate compared with the 54% recurrence and 15% progression rates in high-risk tumors. Lowstage tumors may be ideal candidates for longer intervals between cystoscopies, and tumor markers may be used in the interim periods to detect recurrences earlier. Likewise, for tumors that are more likely to progress (ie, high stage/grade), the sensitivities of common tumor markers are high, so fewer of these tumors would be missed. Lotan and Roehrborn 29 have found that the use of a modified surveillance protocol alternating tumor marker testing with cystoscopy is more cost effective than cystoscopy and cytology every 3 months, regardless of the UBBTM sensitivity and specificity. We realize the shortcomings of our analyses. When evaluating the published studies, a few markers such as cytology, BTA stat, BTA test, BTA TRAK, FDP, and NMP22 have been evaluated in a large number of patients and others have been evaluated by only a few studies. Several studies UROLOGY 61 (1),

6 TABLE III. Median sensitivity in patients with Tis for commonly used UBBTMs with 95% confidence intervals based on hierarchical bayesian meta-analyses Marker Studies (n) TIS (median 95% CI) Patients (n) Cytology ( ) 45 NMP ( ) 23 BTA test ( ) 45 BTA stat ( ) 46 BTA TRAK ( ) 18 FDP ( ) 16 Hgb dipstick ( ) 17 CYFRA 21-1 (Ck 19) UBC (Ck 8/18) ( ) 4 BCA (Ck 8,18) CK TPA (Ck 8,18,19) Telomerase ( ) 14 Chemiluminescent Hgb HA HAase HA-HAase Immunocyt KEY: CI confidence interval; other abbreviations as in Table I. In cases with only one study/group only the median value is reported. were retrospective and others were blinded, multicenter prospective studies. The exclusion criteria used were different in the various studies. When larger numbers of healthy patients were used, the specificity for the tumor markers was higher. The patient groups compared were also different in that some investigators used the assays for screening and others for surveillance. The cutoff values for several markers such as BTA TRAK and NMP22 were optimized by the researchers and varied from the manufacturer s recommended cutoff points. As far as cytology is concerned, different studies defined a positive cytology test by different criteria and most used voided cytology rather than bladder washing, which has been shown to be more sensitive. 13 Although there are shortcomings to our metaanalyses, a comprehensive evaluation of the role of bladder tumor markers in the monitoring of patients with bladder cancer has not been done. This study surveyed the current published reports and compared the various UBBTMs with cytology. There is a need for the additional evaluation of potential markers in multicenter studies to determine whether the use of exclusion criteria can increase the specificity and whether new markers can demonstrate better sensitivity. Likewise, there is good evidence to suggest replacing the use of cytology with UBBTMs. CONCLUSIONS Currently available UBBTMs can be used for the follow-up of low-grade/stage tumors but should not replace cystoscopy. All UBBTMs have better sensitivity than cytology and could potentially replace routine cytology during follow-up. BTA stat and telomerase are significantly more sensitive compared with cytology in grade 1 and 2 tumors and equivalent in grade 3 tumors and equivalent in terms of specificity. More studies need to be performed to evaluate new markers for improved sensitivity and to determine the appropriate exclusion criteria that will improve specificity. REFERENCES 1. Jaemal A, Thomas A, Murray T, et al: Cancer statistics CA Cancer J Clin 52: 23 47, Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al: Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 164: , Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: progression and recurrence. J Urol 130: , Rubben H, Lutzeyer W, Fischer N, et al: Natural history and treatment of low and high risk superficial bladder tumors. J Urol 139: , Herr HW: Intravesical BCG: current results, natural history and implications for urothelial cancer prevention. J Cell Biochem Suppl 161: , Messing ECW: Urothelial tumors of the urinary tract, in Walsh PC, Retik AB, Vaughan ED Jr, et al (Eds): Campbells 114 UROLOGY 61 (1), 2003

7 Urology, 7th ed. Philadelphia, WB Saunders, 1998, Vol 3, pp Del Nero A, Esposito N, Curro A, et al: Evaluation of urinary level of NMP22 as a diagnostic marker for stage ptapt1 bladder cancer: comparison with urinary cytology and BTA test. Eur Urol 35: 93 97, Giannopoulos A, Manousakas T, Mitropoulos D, et al: Comparative evaluation of the BTA stat test, NMP22, and voided urine cytology in the detection of primary and recurrent bladder tumors. Urology 55: , Leyh H, Marberger M, Conort P, et al: Comparison of the BTA stat test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer. Eur Urol 35: 52 56, Leyh H, Hall R, Mazeman E, et al: Comparison of the Bard BTA test with voided urine and bladder wash cytology in the diagnosis and management of cancer of the bladder. 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Urology 54: , Sharma S, Zippe CD, Pandrangi L, et al: Exclusion criteria enhance the specificity and positive predictive value of NMP22 and BTA stat. J Urol 162: 53 57, Ellis WJ, Blumenstein BA, Ishak LM, et al, for the Multi Center Study Group: Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors. Urology 50: , Klein A, Zemer R, Buchumensky V, et al: Expression of cytokeratin 20 in urinary cytology of patients with bladder carcinoma. Cancer 82: , Vriesema JL, Povcki MH, Kiemeney LN, et al: Patient opinion of urinary tests versus flexible urethrocystoscopy in follow-up examination for superficial bladder cancer: utility analysis. Urology 56: , Konety BR, Nguyen TS, Brenes G, et al: Clinical usefulness of the novel marker BLCA-4 for the detection of bladder cancer. J Urol 164: , Lotan Y, and Roehrborn CG: Cost effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy in the follow-up of patients with transitional cell carcinoma of the bladder: a decision analytical approach. J Urol 167: 75 79, Cytology References APPENDIX 1. Buchumensky V, Klein A, Zemer R, et al: Cytokeratin 20: a new marker for early detection of bladder cell carcinoma? J Urol 160(6 Pt 1): , Comment in: J Urol 160(6 Pt 1): , 1998 and J Urol 162: , Del Nero A, Esposito N, Curro A, et al: Evaluation of urinary level of NMP22 as a diagnostic marker for stage pta-pt1 bladder cancer: comparison with urinary cytology and BTA test. Eur Urol 35: 93 97, D Hallewin MA, and Baert L: Initial evaluation of the bladder tumor antigen test in superficial bladder cancer. J Urol 155: , Published erratum: J Urol 155: 2041, 1996; Comment in: J Urol 155: , 1996 and J Urol 157: 627, Ellis WJ, Blumenstein BA, Ishak LM, et al, for the Multi Center Study Group: Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors. Urology 50: , Ianari A, Sternberg CN, Rossetti A, et al: Results of Bard BTA test in monitoring patients with a history of transitional cell cancer of the bladder. Urology 49: , Johnston B, Morales A, Emerson L, et al: Rapid detection of bladder cancer: a comparative study of point of care tests. J Urol 158: , Comment in: J Urol 158: , Landman J, Chang Y, Kavaler E, et al: Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer. Urology 52: , Leyh H, Marberger M, Conort P, et al: Comparison of the BTA stat test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer. Eur Urol 35: 52 56, Leyh H, Hall R, Mazeman E, et al: Comparison of the Bard BTA test with voided urine and bladder wash cytology in the diagnosis and management of cancer of the bladder. Urology 50: 49 53, Leyh H, and Mazeman E: Bard BTA test compared with voided urine cytology in the diagnosis of recurrent bladder cancer. Eur Urol 32: , Pode D, Shapiro A, Wald M, et al: Noninvasive detection of bladder cancer with the BTA stat test. J Urol 161: , Comment in: J Urol 161: , Ramakumar S, Bhuiyan J, Besse JA, et al: Comparison of UROLOGY 61 (1),

8 J Urol 161: , Comment in: J Urol 161: , 1999; J Urol 162: , 1999; and J Urol 162: , Sarosdy MF, devere White RW, Soloway MS, et al: Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer. J Urol 154(2 Pt 1): , Comment in: J Urol 154(2 Pt 1): , 1995 and J Urol 156: , Schmetter BS, Habicht KK, Lamm DL, et al: A multicenter trial evaluation of the fibrin/fibrinogen degradation products test for detection and monitoring of bladder cancer. J Urol 158(3 Pt 1): , Sozen S, Biri H, Sinik Z, et al: Comparison of the nuclear matrix protein 22 with voided urine cytology and BTA stat test in the diagnosis of transitional cell carcinoma of the bladder. Eur Urol 36: , Van der Poel HG, Van Balken MR, Schamhart DH, et al: Bladder wash cytology, quantitative cytology, and the qualitative BTA test in patients with superficial bladder cancer. Urology 51: 44 50, Zippe C, Pandrangi L, Potts JM, et al: NMP22: a sensitive, cost-effective test in patients at risk for bladder cancer. Anticancer Res 19: , Zippe C, Pandrangi L, and Agarwal A: NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J Urol 161: 62 65, Comment in: J Urol 161: 66, 1999 and J Urol 162: , NMP22 References 1. Landman J, Chang Y, Kavaler E, et al: Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer. Urology 52: , Del Nero A, Esposito N, Curro A, et al: Evaluation of urinary level of NMP22 as a diagnostic marker for stage pta-pt1 bladder cancer: comparison with urinary cytology and BTA test. Eur Urol 35: 93 97, Giannopoulos A, Manousakas T, Mitropoulos D, et al: Comparative evaluation of the BTA stat test, NMP22, and voided urine cytology in the detection of primary and recurrent bladder tumors. Urology 55: , Mian C, Lodde M, Haitel A, et al: Comparison of the monoclonal UBC-ELISA test and the NMP22 ELISA test for the detection of urothelial cell carcinoma of the bladder. Urology 55: , Miyanaga N, Akaza H, Ishikawa S, et al: Clinical evaluation of nuclear matrix protein 22 (NMP22) in urine as a novel marker for urothelial cancer. Eur Urol 31: , Ramakumar S, Bhuiyan J, Besse JA, et al: Comparison of J Urol 161: , Comment in: J Urol 161: , Comment in: J Urol 162: , 1999 and J Urol 162: , Serretta V, Lo Presti D, Vasile P, et al: Urinary NMP22 for the detection of recurrence after transurethral resection of transitional cell carcinoma of the bladder: experience on 137 patients. Urology 52: , Iles RK, Persad R, Trivedi M, et al: Urinary concentration of human chorionic gonadotrophin and its fragments as a prognostic marker in bladder cancer. Br J Urol 77: 61 69, Soloway MS, Briggman V, Carpinito GA, et al: Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol 156(2 Pt 1): , Stampfer DS, Carpinito GA, Rodriguez-Villanueva J, et al: Evaluation of NMP22 in the detection of transitional cell carcinoma of the bladder. J Urol 159: , Published erratum: J Urol 159: 1650, Comment in: J Urol 159: , Witjes JA, van der Poel HG, van Balken MR, et al: Urinary NMP22 and karyometry in the diagnosis and follow-up of patients with superficial bladder cancer. Eur Urol 33: , Zippe C, Pandrangi L, Potts JM, et al: NMP22: a sensitive, cost-effective test in patients at risk for bladder cancer. Anticancer Res 19: , Sozen S, Biri H, Sinik Z, et al: Comparison of the nuclear matrix protein 22 with voided urine cytology and BTA stat test in the diagnosis of transitional cell carcinoma of the bladder. Eur Urol 36: , Abbate I, D Introno A, Cardo G, et al: Comparison of nuclear matrix protein 22 and bladder tumor antigen in urine of patients with bladder cancer. Anticancer Res 18: , Sanchez-Carbayo M, Herrero E, Megias J, et al: Comparative sensitivity of urinary CYFRA 21-1, urinary bladder cancer antigen, tissue polypeptide antigen, tissue polypeptide antigen and NMP22 to detect bladder cancer. J Urol 162: , Comment in: J Urol 162: , BCLA-4 References 1. Konety BR, Nguyen TS, Brenes G, et al: Clinical usefulness of the novel marker BLCA-4 for the detection of bladder cancer. J Urol 164(3 Pt 1): , Comment in: J Urol 164(3 Pt 1): , BTA Test References 1. Landman J, Chang Y, Kavaler E, et al: Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer. Urology 52: , Sarosdy MF, Hudson MA, Ellis WJ, et al: Improved detection of recurrent bladder cancer using the Bard BTA stat test. Urology 50: , Sarosdy MF, devere White RW, Soloway MS, et al: Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer. J Urol 154(2 Pt 1): , Comment in: J Urol 154(2 Pt 1): , 1995 and J Urol 156: , Takashi M, Schenck U, Kissel K, et al: Use of diagnostic categories in urinary cytology in comparison with the bladder tumour antigen (BTA) test in bladder cancer patients. Int Urol Nephrol 31: , Del Nero A, Esposito N, Curro A, et al: Evaluation of urinary level of NMP22 as a diagnostic marker for stage pta-pt1 bladder cancer: comparison with urinary cytology and BTA test. Eur Urol 35: 93 97, D Hallewin MA, and Baert L: Initial evaluation of the bladder tumor antigen test in superficial bladder cancer. 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9 tests. J Urol 158: , Comment in: J Urol 158: , Murphy WM, Rivera-Ramirez I, Medina CA, et al: The bladder tumor antigen (BTA) test compared to voided urine cytology in the detection of bladder neoplasms. J Urol 158: , Comment in: J Urol 158: , Schamhart DH, de Reijke TM, van der Poel HG, et al: The Bard BTA test: its mode of action, sensitivity and specificity, compared to cytology of voided urine, in the diagnosis of superficial bladder cancer. Eur Urol 34: , The United Kingdom and Eire Bladder Tumour Antigen Study Group: The use of the bladder-tumour associated analyte test to determine the type of cystoscopy in the follow-up of patients with bladder cancer. Br J Urol 79: , Comment in: Br J Urol 81: 180, 1998 and Br J Urol 81: , Van der Poel HG, Van Balken MR, Schamhart DH, et al: Bladder wash cytology, quantitative cytology, and the qualitative BTA test in patients with superficial bladder cancer. Urology 51: 44 50, BTA stat References 1. 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