Four bladder tumor markers have a disappointingly low sensitivity for small size and low grade recurrence.

PURPOSE: We determine the sensitivity and specificity of 3 bladder tumor markers in urine, including NMP22 assay (Matritech, Newton, Massachusetts), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and UBC antigen (IDL Biotech, Sollentuna, Sweden), and bladder wash cytology for new and recurrent bladder cancer. We examine whether tumor size, grade, and stage influence sensitivity and specificity of the markers. MATERIALS AND METHODS: A total of 304 samples in 250 patients were studied. There were 174 patients who had a history of bladder cancer, including 93 with and 81 without recurrent tumor at cystoscopy. The other group of patients consisted of 66 with newly diagnosed bladder tumor and 64 investigated for microscopic hematuria that was found to be idiopathic. BTA stat was assayed according to manufacturer instructions. NMP22 and UBC were measured in urine with an enzyme-linked immunosorbent assay. A cutoff level of 4 for NMP22 and 1 for UBC was chosen to get the same specificity for new tumors as BTA stat (75%) RESULTS: There was a highly significant difference (p <0.001) in all markers between patients with new bladder tumors and those without. The difference was less pronounced for tumor recurrence for NMP22, UBC and BTA stat (p=0.002, 0.016 and 0.244, respectively). The difference between new and recurrent tumors disappeared when corrected for tumor size, grade and stage. The sensitivity for new tumors was 65%, 75% and 60% for NMP22, BTA stat and UBC, respectively. Cytology had a sensitivity of 41% for new tumors at a specificity of 94%. The specificity for recurrence was 64% for NMP22, 54% BTA stat and 72% UBC. The sensitivity was 45% for NMP22, 55% BTA stat and 40% UBC. CONCLUSIONS: Tumor size, grade and stage have a strong impact on sensitivity, and specificity for all 3 tested tumor markers as well as bladder wash cytology. The tumor markers or any combination of them cannot replace followup cystoscopy, mainly because most recurrences are small. The role of the markers for screening high risk populations and as a complement to followup cystoscopy remains to be evaluated.     

Comparison of BTA stat and NMP22 tests in the detection of bladder cancer

OBJECTIVE: This study aimed to compare the BTA (bladder tumour antigen) stat and urinary nuclear matrix protein (NMP22) tests in the detection of bladder cancer. MATERIAL AND METHODS: The office-based qualitative BTA stat and the laboratory-based quantitative NMP22 tests were studied in the same urine samples obtained from 49 patients with a high suspicion of bladder cancer and 20 healthy subjects. RESULTS: A tumour was identified in 36 patients after the cystoscopy. BTA stat demonstrated a sensitivity of 89%, which was superior to the sensitivity of 66.6% with the NMP22 test in detecting the bladder cancer (p < 0.02). The sensitivities for grade I tumours with BTA stat and NMP22 were 55.5% and 33.3%, respectively. The sensitivity of BTA stat was 100% for tumour categories except for the pTa and grade I tumours. No positive result was observed with both tests among the healthy subjects. The specificities for BTA stat and NMP22 were 78.7% and 69.6%, respectively. CONCLUSIONS: The BTA stat test was significantly more sensitive than the NMP22 test in the detection of bladder cancer. Although the sensitivity of BTA stat was not sufficient to replace cystoscopy, its ease and low cost may play a role in reducing the number of control cystoscopies, especially in patients with low risk of progression.     

Tumor marker tests in bladder cancer

The gold standard for detecting bladder cancer is cystoscopy which identifies nearly all papillary and sessile lesions. However, it is an invasive procedure causing some discomfort for patients. Urine cytology is the standard non-invasive marker with very high specificity, but unfavourable poor sensitivity for Ta, G1, and T1 bladder tumors. To improve early detection of bladder cancer as well as to monitor treatment response and tumor recurrence, bladder tumor markers are eligible. An ideal bladder cancer test would have the potential to replace or delay cystoscopy in the follow-up of bladder cancer patients. In recent years, the FDA approved non-invasive tumor marker tests ImmunoCyt / uCyt+, BTA TRAK, BTA stat, NMP22, NMP22 BladderChek, and UroVysion have been investigated. The tests demonstrated higher sensitivity for diagnosis of bladder cancer compared to urine cytology. Overall, the mean sensitivity and mean specificity was 64-80% and 71-95% and the mean positive and negative predictive values to detect malignancy were 49-84% and 79-95%, respectively. BTA TRAK, BTA stat, NMP22, and NMP22 BladderChek assays are limited by false-positive results in patients with benign urological diseases such as hematuria, urocystitis, renal calculi or urinary tract infections. Due to low specificity BTA TRAK, BTA stat, NMP22, and NMP22 BladderChek should not be used without first ruling out benign or malignant genitourinary disease other than bladder cancer. With the exception of UroVysion achieving 80% sensitivity and 94% specificity, none of these non-invasive tests revealed a high sensitivity and specificity at the same time, which is a main demand to be made on an ideal tumor marker. Insufficient sensitivity along with limited specificity does not allow replacing cystoscopy in diagnosis of bladder cancer or treatment decisions based on a positive test result.     

NMP 22, BTA stat test and cytology in the diagnosis of bladder cancer: a comparative study

OBJECTIVE: To evaluate the usefulness of the NMP 22 and BTA stat test in the diagnosis and follow-up of bladder cancer and to compare these tests to cytology and cystoscopy, routine diagnostic methods. METHODS: 150 patients followed up for bladder cancer or symptoms suggestive of bladder cancer underwent cystoscopy after cytology, NMP 22 and BTA stat test using a recently voided urine sample. In suspect cases, TUR and histopathological analysis were performed. RESULTS: Bladder cancer was proven in 76 patients and excluded in 74. For NMP 22 we have used the cutoff value recommended by the manufacturer (10 U/ml) and that obtained by our receiver-operating characteristic curve (6 U/ml). Sensitivity was 84.21% for NMP 22 at the cutoff value of 6 U/ml and 76.32% with 10 U/ml; 72.37% for BTA stat test; 69.74% for cytology, and 100% for cystoscopy. Specificity was 86.49% for NMP 22 at a cutoff value of 6 U/ml and 90.54% at 10 U/ml; 89.19% for the BTA stat test; 93.24% for cytology and 89.19% for cystoscopy. NMP 22 sensitivity for grades 1, 2, and 3 was 68.75, 75.86 and 100%, respectively, at a cutoff value of 6 U/ml, and 50, 68.97 and 96.77%, respectively, at a cutoff level of 10 U/ml; for BTA stat the sensitivity was 56.25% in G1, 62.07% in G2 and 90.32% in G3, and for cytology the sensitivity was 43.75, 62.07 and 90.32%, respectively. The sensitivity of NMP 22 was 68.75% in stage Ta, 84.78% in T1 and 100% in T2-T4 at a cutoff level of 6 U/ml and 50, 80.43 and 92.86%, respectively, at a cutoff level of 10 U/ml; BTA stat sensitivity was 50% in Ta, 73.91% in T1 and 92.86% in T2-T4; and in cytology the results were 37.50, 73.91 and 85.71%, respectively. Using the McNemar test, there was only a significant difference between the sensitivity of NMP 22 at a cutoff level of 6 U/ml and cytology in the overall sample. CONCLUSIONS: The high sensitivity of the NMP 22 and BTA stat test in combination with the data obtained from the parameters used for the evaluation of the test demonstrate their usefulness in the diagnosis and follow-up of bladder cancer. NMP 22 at a cutoff value of 6 U/ml is significantly more sensitive than cytology and consequently a thoroughly valid diagnostic tool in the diagnosis of bladder cancer which may substitute voided urine cytology.     

NMP22与BTA stat检测在膀胱肿瘤诊断中的应用

目的评价NMP22和BTAstat诊断膀胱肿瘤的价值.方法对82例临床怀疑膀胱肿瘤的患者,在膀胱镜检查前将尿样分为3份,分别进行NMP22、BTAstat和脱落细胞学检测,分析比较3种方法的敏感性、特异性和阳性预测价值.结果82例中病理证实膀胱肿瘤32例,其他疾病50例.NMP22诊断膀胱肿瘤敏感性为87.5%,与BTAstat(65.6%)、细胞学(21.9%)比较,差别有显著性意义(P<0.05).3种方法诊断特异性分别为84.0%、64.0%和100.0%.阳性预测值分别为77.8%、53.9%和100.0%.结论NMP22是一种简单、敏感、非侵袭性的早期诊断膀胱肿瘤的肿瘤标记物.     

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.

OBJECTIVE: To assess sensitivity, specificity, accuracy, positive predictive value and negative predictive value of nuclear matrix protein 22 (NMP22) test, BTA stat test and cytology in the urine of patients with a spectrum of urologic conditions, including bladder cancer. METHODS: A total of 140 patients (40 with bladder cancer) provided a urine sample which was divided into appropriate aliquots for each of the tests cited above. The endoscopist, pathologist, cytologist and the person performing BTA stat test and NMP22 test were blinded as to the results of the other tests. RESULTS: Receiver-operating characteristics curve interpretation determined that 12.0 U/ml was an optimal reference value for NMP22 to detect transitional cell carcinoma of the bladder in this patient group. Comparative results demonstrate a clear superiority of NMP22 and BTA stat tests in sensitivity in bladder cancer detection (p < 0.01), while cytology and NMP22 were better than BTA stat test in specificity (p < 0.05). CONCLUSIONS: NMP22 and BTA stat test results represented significant improvement over urinary cytology for detection of transitional cell carcinoma. The sensitivities of NMP22 and BTA stat tests for detection of transitional cell carcinoma in this group of patients were as much as twice that of cytology. When the cutoff value of urinary NMP22 was set at 12.0 U/ml, NMP22 was more accurate than the other tests (p < 0.05).     

The usefulness of urinary FDP in the diagnosis of bladder cancer: comparison with NMP22, BTA and cytology

PURPOSE: We assessed the utility of urine fibrin/fibrinogen degradation products (FDP) as the screening test for bladder cancer. MATERIALS AND METHODS: Single voided specimens were obtained from 87 consecutive patients (61 men and 26 women, mean age 70.7) on cystoscopy, and FDP, NMP22, BTA and cytology test were performed for the same specimens. Final diagnosis of bladder cancer was made by histological examination, which were compared with the results of above four screening methods. RESULTS: Histologically confirmed bladder cancer was found in 14 cases. Overall sensitivity of urinary FDP, NMP22, BTA and cytology were 79, 64, 36 and 36%, respectively. While the sensitivity of FDP was significantly higher than that of BTA and cytology, no significant difference was found between FDP and NMP22. Overall specificity of these four methods were 69, 78, 92 and 90%, respectively. The specificity of FDP and NMP22 were significantly lower than that of BTA and cytology, but satisfactory as a screening test. The sensitivity of the four methods for low-grade and non-invasive tumors were 70, 50, 30 and 10% (G1 or G2, n = 10), and 75, 58, 33 and 25% (Ta or T1, n = 12), respectively. FDP might have a high sensitivity for even low-grade and non-invasive tumors. CONCLUSIONS: FDP in voided urine is a good screening method for bladder cancer because of its high sensitivity for low-grade and non-invasive tumors, and its diagnostic ability could be superior to NMP22.     

Human complement factor H related protein test for monitoring bladder cancer

PURPOSE: The BTA stat test is a rapid, noninvasive, qualitative urine test that detects bladder tumor associated antigen (human complement factor H related protein) in urine. We compared BTA stat test to voided urine cytology in patients monitored for bladder cancer in a prospective trial, and determined whether this test is effective in detection of recurrence not seen by regular cystoscopy. MATERIALS AND METHODS: A total of 445 consecutive patients with bladder cancer were studied. A voided urine sample was obtained before cystoscopy and divided for culture, cytology and BTA stat testing. In cases of a positive BTA stat test but negative cystoscopy, excretory urography or renal ultrasound, random biopsies and collected ureteral urine samples for ureteral cytology were obtained. The overall sensitivity and specificity as well as positive and negative predictive values for BTA stat test, cytology and their combination were calculated. RESULTS: Of the 445 patients 118 (26.5%) had bladder cancer recurrence on cystoscopy, which was detected by BTA stat test and cytology in 63 (53.4%) and 21 (17.8%), respectively. Of the remaining 327 patients not having recurrent tumor on cystoscopy 81 (24.8%) had a positive BTA stat test. Excretory urography or renal ultrasound and random biopsies in 48 (59.3%) of these patients revealed 7 recurrences, making the total number of recurrent tumors 125 of 412 (30.3%). The overall sensitivities and specificities for the BTA stat test, cytology and their combination were 56.0%, 19.2%, 60.0% and 85.7%, 98.3% and 85.0%, respectively. CONCLUSIONS: The sensitivity for detection of recurrent tumor on BTA stat test is superior to that of voided urine cytology in all bladder cancer categories, whereas the specificity of voided urine cytology is higher than that for BTA stat test. However, a sixth of the patients with apparent false-positive BTA stat test results chosen for further investigation had recurrent tumors that were not found on routine cystoscopy. Although the sensitivity and specificity were highest when both tests were used, the differences were not significant overall. Therefore, the BTA stat test could potentially replace urine cytology for followup of superficial bladder cancer.     

几种新瘤标对膀胱癌早期诊断价值的比较

目的：比较几种新瘤标对膀胱移行细胞癌早期诊断的价值。方法：对322例肉眼或镜检血尿、膀胱刺激症状或发现膀胱占位者，在作膀胱镜检查前行尿液中细胞角蛋白20(CK20)、核基质蛋白(NMP22)、ImmunoCyt、膀胱肿瘤抗原(BTA stat)检测和常规尿细胞学检查，比较它们的敏感性和特异性。结果：经膀胱镜和病理检查诊断膀胱移行细胞癌149例，其中浅表性肿瘤110例，浸润性39例；G181例，G246例．G322例。CK20、NMP22、ImmunoCyt、BTA stat、尿细胞学和膀胱镜检的敏感性分别为90．6％、85．2％、82．6％、65．8％、30．2％和94．6％，特异性分别为83．6％、84．0％、78．1％、64％、100％和100％。结论：新瘤标CK20、NMP22、ImmunoCyt具有较高的敏感性，与BTA stat和尿细胞学比较，差异有统计学意义，可用于膀胱肿瘤的早期诊断。     

CAN URINE BOUND DIAGNOSTIC TESTS REPLACE CYSTOSCOPY IN THE MANAGEMENT OF BLADDER CANCER?

Purpose

We compare the diagnostic value of NMP22 [dagger] and BTA stat [double dagger] testing, and QUANTICYT [section] computer assisted dual parameter image analysis to cytology and cystoscopy in patients who had symptoms suggestive of transitional cell cancer or were being followed after treatment for that disease.[dagger] Matritech, Inc., Newton, Massachusetts.[double dagger] Bard Diagnostics, Redmond, Washington.[section] Gentian Scientific Software, Niawier, The Netherlands.

Materials and Methods

We prospectively evaluated voided urine and/or barbotage specimens from 291 patients a mean of 65.2 years old. All voided urine samples were evaluated by quick staining and standard cytology, the BTA stat 1-step qualitative assay (which detects a bladder tumor associated antigen) and the NMP22 test (which detects a nuclear mitotic apparatus protein). In addition, barbotage specimens were evaluated by QUANTICYT computer assisted dual parameter image analysis. All patients underwent subsequent cystoscopy and biopsy evaluation of any suspicious lesion. Sensitivity, specificity, and the predictive value of positive and negative results were determined in correlation with endoscopic and histological findings.

Results

In 91 patients with histologically proved transitional cell carcinoma overall sensitivity was 48, 57, 58, 59 and 59% for the NMP22 test, the BTA stat test, rapid staining cytology of barbotage samples, rapid staining cytology of voided urine specimens and image analysis, respectively. For histological grades 1 to 3 underlying transitional cell carcinoma sensitivity was 17, 61 and 90% for urinary cytology, 48, 58 and 63% for the BTA stat test, and 52, 45 and 50% for the NMP22 test, respectively. Specificity was 100% for cytology, 93% for image analysis, 70% for the NMP22 test and 68% for the BTA stat test.

Conclusions

Immunological markers are superior to cytological evaluation and image analysis for detecting low grade transitional cell carcinoma but they have low specificity and sensitivity in grade 3 transitional cell carcinoma. Urine bound diagnostic tools cannot replace cystoscopy.     

THE BLADDER TUMOR ANTIGEN (BTA) TEST COMPARED TO VOIDED URINE CYTOLOGY IN THE DETECTION OF BLADDER NEOPLASMS

Purpose

Tests to detect recurrent bladder neoplasms are limited and none is consistently accurate. Recent studies suggest that the bladder tumor antigen (BTA*) test, an agglutination reaction for basement membrane complexes, is superior to voided urine cytology in clinical practice. We compared BTA and voided urine cytology to bladder washings and cystoscopy, emphasizing diagnostic yield among patients with causes of basement membrane complexes other than bladder cancer.

Materials and Methods

Random voided urine specimens from 67 patients with a history of bladder neoplasms were collected before cystoscopy and bladder washing. Urine also was obtained from 34 patients with inflammatory bladder conditions including 5 with a history of prostate cancer. Each urine was tested for BTA according to a commericial kit. Positive results were indicated by yellow on a test pad. Blinded to all other results, each urine and each bladder washing were examined microscopically, and a positive test had malignant/suspicious cells. Bladder biopsies were performed when endoscopic lesions were seen. Specimens were grouped into 4 categories: group 1-biopsy proved bladder neoplasm, group 2-history of bladder cancer but not biopsy proved, group 3-history of prostate cancer and group 4-no history of urological cancer.

Results

Voided urine cytology was positive in 54% of specimens from patients with biopsy proved bladder neoplasms compared to 29% for BTA. Relative yield for voided urine cytology versus BTA was not changed if all group 2 cases having a positive bladder washing and positive cystoscopy were assumed to have bladder cancer, nor was relative yield altered by subsequent short-term followup. Of voided urine specimens 14% from group 1 patients and 41% from group 2 patients had scant cells. Overall diagnostic yield was superior for bladder washing. False-positive BTA occurred in 7 of 34 patients with no history of urological or prostate cancer. There were no false-positive voided urine cytology interpretations in these groups.

Conclusions

BTA is not superior to voided urine cytology in detecting bladder neoplasms and may be limited by false-positive reactions in patients with other causes of basement membrane complexes in urine. Voided urine samples may be limited by high frequency of hypocellularity. Of 34 patients with a hypocellular urine specimen 4 had biopsy proved bladder cancer. Bladder washing yields best results but requires instrumentation. No test, including cystoscopy, is accurate always.     

Newly diagnosed bladder cancer: the relationship of initial symptoms,degree of microhematuria and tumor marker status

PURPOSE: We recorded initial symptoms and evaluated the frequency and intensity of hematuria in patients with newly diagnosed bladder cancer. We also evaluated and compared the sensitivity of bladder wash cytology, NMP22 (Matritech, Newton, Massachusetts), BTA Stat (Bion Diagnostic Sciences, Redmond, Washington) and UBC antigen (IDL Biotech, Sollentona, Sweden) with hematuria dipsticks and flow cytometry for determining the size of erythrocytes in urine. MATERIALS AND METHODS: Urine samples were collected from 92 patients with newly diagnosed bladder cancer, 64 with idiopathic microhematuria and 42 with nephritis. Urine was analyzed for NMP22, BTA Stat, UBC and erythrocytes size using flow cytometry. Bladder wash cytology was done at cystoscopy. Urine was analyzed for microhematuria with hematuria dipsticks at home for 7 consecutive days immediately before the operation and in the hospital on the day of surgery. RESULTS: Sensitivity was 75% for NMP22, 78% for BTA Stat, 64% for UBC and 61% for flow cytometry at 73% specificity. Cytology had 42% sensitivity at 97% specificity. Tumor size, grade and stage had a statistically significant influence on NMP22, BTA Stat, UBC and cytology. Of the patients 75% had microhematuria on the day of the operation and 75% had hematuria at least 1 of 7 days when tested at home the last week before transurethral bladder resection. The 70% of all patients with macroscopic hematuria as the initial symptom did not seem to differ from those without the condition in tumor size, grade, stage or tumor marker levels. CONCLUSIONS: Flow cytometry was not well enough able to distinguish patients with bladder cancer from controls. The sensitivity of all tested markers, including hematuria dipsticks, was high for large and high grade, high stage tumors. Further studies are needed to evaluate whether a marker could be used to determine priority among patients referred due to microhematuria.     

Exclusion criteria enhance the specificity and positive predictive value of NMP22 and BTA stat.

PURPOSE: The limitation of current urinary tumor markers is the low specificity and positive predictive value, which clinically manifests as a high false-positive rate. We analyzed the false-positive data of 2 urinary tumor markers, NMP22 and the BTA stat tests. We examined the clinical categories of the false-positive results, established relative exclusion criteria, and recalculated the specificity and positive predictive value after using the exclusion criteria. MATERIALS AND METHODS: A total of 278 symptomatic patients who presented to a urology clinic were asked to submit a single voided urine sample. Each sample was divided into 3 aliquots of which 1 was stabilized with the NMP22 test kit stabilizer and assayed for NMP22, 1 was tested for BTA stat and 1 was sent for cytological examination. All patients subsequently underwent office cystoscopy and bladder biopsy if indicated. RESULTS: Of the 278 symptomatic patients 112 presented with microscopic hematuria, 77 gross hematuria and 89 chronic symptoms of urinary frequency or dysuria. Of 34 cases (12%) of histologically confirmed bladder cancer NMP22 detected 28 (82.4%), BTA stat 23 (67.7%) and cytology only 10 (29.4%). When atypical cytologies were considered positive, cytology then detected 19 cases (55.9%). Elevated NMP22 values were positive in 28 cases and false-positive in 44 for a specificity of 82% and a positive predictive value of 38.9%. Similarly, BTA stat test was positive in 23 cases and false-positive in 43 for a specificity of 82.4% and a positive predictive value of 34.9%. When atypical cytologies were considered positive, the specificity and positive predictive value were 93% and 55.9%. Greater than 80% of the false-positive results were clinically categorized as benign inflammatory or infectious conditions, renal or bladder calculi, recent history of a foreign body in the urinary tract, bowel interposition segment, another genitourinary cancer or an instrumented urinary sample. A category of "no known pathology" was included in analysis as a control. History of ureteral stents or any bowel interposition segment had a 100% false-positive rate. Exclusion of all 6 clinical categories improved the specificity and positive predictive value of NMP22 (95.6%, 87.5%) and BTA stat (91.5%, 69.7%), and was similar to urinary cytology. CONCLUSIONS: Awareness and exclusion of the categories of false-positive results can increase the specificity and enhance the clinical usefulness of NMP22 and BTA stat tests. Similarly, treating an atypical cytology as positive can enhance the sensitivity and usefulness of urinary cytology.     

Comparisons of voided urine cytology, nuclear matrix protein-22 and bladder tumor associated antigen tests for bladder cancer of geriatric male patients in Taiwan, China

Aim： To compare the results of bladder tumor associated antigen （BTA TRAK）, nuclear matrix protein 22 （NMP 22） and voided urine cytology （VUC） in detecting bladder cancer. Methods： A total of 135 elderly male and 50 healthy volunteers enrolled in this study were classified into three groups： （i） 93 patients with bladder cancer; （ii） 42 patients with urinary benign conditions; and （iii） 50 healthy volunteers. BTA TRAK and NMP 22 kits were used to detect bladder cancer. Voided urine cytology was used to compare the sensitivity and specificity of the screening tests. Results： The sensitivity and specificity of cytology, BTA TRAK and NMP 22 were 24% and 97%, 51% and 73%, 78% and 73%, respectively. The level of NMP 22 increased with tumor grading. The BTA TRAK kit has the lowest sensitivity among the screening tests. The NMP 22 with the best sensitivity can be an adjunct to cytology for evaluating bladder cancer. Conclusion： The NMP 22 test has a better correlation with the grading of the bladder cancer than BTA TRAK. As cytology units are typically not available in hospitals or in outpatient clinics, NMP 22 might be a promising tool for screening bladder cancer.     

Tumor markers in the diagnosis of primary bladder cancer. A systematic review

PURPOSE: We systematically reviewed the available evidence, and obtained and compared summary estimates of the sensitivity and specificity of cytology and the urine based markers bladder tumor antigen, BTA stat (Polymedco, Redmond, Washington), BTA TRAK (Polymedco), NMP22 (Matritech, Cambridge, Massachusetts), telomerase and fibrin degradation product in detecting primary bladder cancer. MATERIALS AND METHODS: Studies on the diagnosis of primary bladder cancer published from 1990 through November 2001 in English and German were retrieved from MEDLINE and EMBASE data bases. In our research we included studies that evaluated 1 or more of the markers, used cystoscopy as the reference standard and allowed the construction of a 2 x 2 contingency table for a per patient analysis. The data plus items on study and clinical characteristics were extracted by 2 observers. Sensitivity and specificity for each marker were estimated using a bivariate random effect meta-analysis. A multivariable analysis was performed to explain study variation. RESULTS: A total of 42 studies were included in our review. Only 2 studies were available on fibrin degradation product, hence a meta-analysis was not possible. Cytology had the best specificity at 94% (95% CI: 90% to 96%). This figure was significantly better than that of the other markers except for telomerase (specificity 86% [71% to 94%]). Telomerase had the best sensitivity (75% [71% to 79%]) but it was not significantly better than that of BTA stat (70% [66% to 74%]). Case control designs yielded lower values for sensitivity for the tumor markers cytology, bladder tumor antigen and BTA stat. CONCLUSIONS: Cytology has the best specificity and telomerase the best sensitivity. However, none of the markers studied here is sensitive enough to be recommended for daily routine.     

SCREENING AND MONITORING FOR BLADDER CANCER: REFINING THE USE OF NMP22

PURPOSE: While detecting bladder cancer, bladder tumor markers demonstrate improved sensitivity compared with urinary cytology but the current limitation is the low specificity and positive predictive value, that is high false-positive rate. We examined the clinical categories of the false-positive results, established relative exclusion criteria, and recalculated the specificity and positive predictive value of this assay with these criteria. MATERIALS AND METHODS: A total of 608 patients considered at risk for bladder cancer presented to a urology clinic and submitted a single urine sample. Of the 608 patients 529 (87%) presented with de novo hematuria or chronic voiding symptoms without a diagnosis of bladder cancer. There were 79 (13.0%) patients being monitored with a known history of bladder cancer. Each urine sample was examined via cytology, urinalysis, culture and NMP22 protein assay. All patients underwent office cystoscopy, and transurethral resection and/or biopsy if a bladder tumor was suspected. RESULTS: Of the 608 patients 226 (37.2%) presented with microscopic hematuria, 143 (23.5%) with gross hematuria and 239 (39.3%) had chronic symptoms of urinary frequency or dysuria. There were 52 (8.6%) patients who had histologically confirmed bladder cancer. Of these 52 cancers NMP22 detected 46 (88.5%), whereas cytology identified only 16 (30.8%). When atypical cytology was considered positive, cytology detected 32 (61.5%) cases. In the 135 patients with increased NMP22 values the 46 identified tumors were accompanied by 89 false-positive values yielding a specificity of 83.9% and a positive predictive value of 34.1%. These false-positive results were divided into 6 clinical categories. Exclusion of these categories improved the specificity and positive predictive value of NMP22 to 99.2% and 92.0%, respectively, yielding results similar to urinary cytology (99.8% and 94.1%). CONCLUSIONS: Awareness and exclusion of the categories of false-positive results can increase the specificity and positive predictive value of NMP22, enhancing the clinical use of this urinary tumor marker.     

Effect of intravesical instillations on the human complement factor H related protein (BTA stat) test.

OBJECTIVES: The BTA stat is a rapid, non-invasive, qualitative urine test that detects bladder tumor-associated antigen (human complement factor H related protein) in urine. The sensitivity of this test is superior to that of urine cytology in detecting primary and recurrent tumors of the urinary bladder. Intravesical instillations are widely used to avoid recurrences and even progression. The objective of this study was to evaluate the effect of intravesical treatments on the BTA stat Test. METHODS: 501 consecutive patients followed up for bladder cancer were studied, of which 490 were eligible for analysis. Three hundred and twenty-seven (66.7%) of the patients had no history of intravesical treatments, whereas the remaining 163 (33.3%) had received treatments: 66 (40.5%) at the time of evaluation. A voided urine sample was obtained prior to cystoscopy and split for culture and BTA stat testing. The overall sensitivity and specificity were calculated and compared to the patients with no, past and present instillations. RESULTS: The overall sensitivity for the BTA stat Test was 56.6%, and the specificity was 76.4%. The specificity of the BTA stat Test was 80.7, 70.7 and 65.3% in those with no, past or present intravesical instillation treatments, respectively. The difference in specificity between those with no and present instillations was significant (p = 0.023), whereas the notable difference between those with no and past instillations did not reach significance (p = 0.076), nor was the difference between patients with past and present instillations significant (p = 0.558). Present instillation of mitomycin C had the strongest adverse effect on the test as the specificity was only 25.0%, whereas past treatment did not interfere with testing. The adverse effect of BCG treatment on testing extended. CONCLUSION: The overall specificity of the test is decreased in patients receiving intravesical treatments, whereas past treatments did not interfere with testing in general. However, the adverse effect of BCG on testing seems to extend, and therefore it is suggested that the BTA stat Test should not be used in patients having received BCG, and in those with present instillation of any type.     

Comparative evaluation of the BTAstat test, NMP22, and voided urine cytology in the detection of primary and recurrent bladder tumors

OBJECTIVES: This prospective study was undertaken to evaluate the diagnostic efficacy of the BTAstat test and nuclear matrix protein (NMP22) compared with voided urine cytology (VUC) in the detection of primary and recurrent bladder cancer. METHODS: A total of 147 patients provided a single voided urine sample for the BTAstat test, NMP22, and cytology prior to cystoscopy. Eighty-five of them had no bladder cancer history, whereas the remaining 62 were monitored for superficial bladder cancer. A group of 21 healthy age-matched volunteers were also enrolled in the study. RESULTS: Bladder cancer was confirmed histologically in 99 patients, of which 62 had primary tumors and 37 had recurrent ones. The overall sensitivity and specificity were 71.7% and 56.5% for the BTAstat test, 62.6% and 73. 9% for NMP22, and 38.4% and 94.2% for VUC. The optimal threshold value for NMP22 calculated with receiver operating characteristics curve, was 8 U/mL. BTAstat test was significantly more sensitive than VUC in detecting bladder cancer in all stage and grade subgroups, except GIII. On the contrary, NMP22 was significantly more sensitive than VUC only in stage Ta, grade I and II patients. BTAstat test had higher but not significantly different sensitivity than NMP22. CONCLUSIONS: Our data indicate a superiority of both BTAstat test and NMP22 over VUC in the detection of bladder cancer. Comparing BTAstat test with NMP22, the former proved to be more sensitive, whereas the latter was more specific. Ruling out diseases with potential interference can increase the overall specificity of both tests. False-positive results of either test in patients followed up for bladder cancer seem to correspond to future recurrences.     

Clinical use of urinary markers for the detection and prognosis of bladder carcinoma: a comparison of immunocytology with monoclonal antibodies against Lewis X and 486p3/12 with the BTA STAT and NMP22 tests

PURPOSE: The noninvasive detection of urothelial carcinoma remains challenging. We prospectively evaluated urine markers for bladder carcinoma. We compared the NMP22 (Matritech, Cambridge, Massachusetts) and BTA Stat (Bard Diagnostics, Redmond, Washington) tests with immunocytology using mAbs 486p3/12 and BG7 against Lewis X antigen. MATERIALS AND METHODS: The NMP22 and BTA Stat tests were performed in urine samples and immunocytology with mAbs 486p3/12 and BG7 staining were performed in bladder washing specimens in 146 samples of 115 patients undergoing transurethral resection for suspected bladder carcinoma (70) or 45 undergoing followup cystoscopy for a history of bladder carcinoma (76). Bladder carcinoma was detected in 54 patients, including stages pTa in 25, pT1 in 20, pT2 in 8 and carcinoma in situ in 1, while 61 had no evidence of bladder carcinoma. The cutoff was 10 units per ml. for the NMP22, 30% positive cells for 486p3/12 and 5% positive cells for the Lewis X tests. RESULTS: BTA Stat was positive in 65 samples (44.5%) and NMP22 was positive in 69 (47.3%). Immunocytology with mAbs 486p3/12 and BG7 against Lewis X was positive in 52 (35.6%) and 109 (74.7%) samples, respectively. Sensitivity was 70.3% for BTA Stat, 68.5% for NMP22, 68.5% for 486p3/12 and 94.4% for Lewis X. Specificity was 70.6% for BTA Stat, 65.2% for NMP22, 83.6% for 486p3/12 and 36.9% for Lewis X. Area under the receiver operating characteristics curve was 0.6804 for NMP22, 0.7226 for Lewis X and 0.8002 for 486p3/12. False-positive results on BTA Stat in 2 of 22 patients (9%), on NMP22 in 2 of 25 (8%), on 486p3/12 in 3 of 11 (27%) and on Lewis X in 4 of 43 (9.3%) were associated with tumor recurrence. Furthermore, negative results on BTA Stat in 2 of 39 patients (2%), on NMP22 in 2 of 36 (0.5%), on Lewis X in 0 of 18 (0%) and on 486p3/12 in 1 of 50 (2%) was associated with tumor recurrence during followup. CONCLUSIONS: Immunocytology with mAbs against Lewis X showed higher sensitivity than all commercially available tests evaluated. Because of its high sensitivity and high negative predictive value, it may be useful for screening in a high risk population. Patients with a false-positive 486p3/12 test results are at increased risk for tumor recurrence compared with those with negative results.     

BTA quantitative assay and NMP22 testing compared with urine cytology in the detection of transitional cell carcinoma of the bladder

PURPOSE: Both BTA TRAK and NMP22 urine concentrations have shown a sensitivity superior to urine cytology in the detection of bladder cancer. We compared these tumor markers with urine cytology performed on 3 consecutive samples and evaluated by an expert cytopathologist. PATIENTS AND METHODS: The investigations were conducted on 94 patients undergoing a diagnostic cystoscopy for a high suspicion of bladder cancer (group 1) and on 102 patients with previous history of transitional cell carcinoma awaiting a follow-up cystoscopy (group 2). Biopsy specimens were obtained also from tumor negative patients. Immunoassays for BTA TRAK and NMP22 were carried out according to standard methods. The choice of the cut-off was based on the ground of sensitivity and specificity curves intersection. Urine cytology results were expressed as positive, negative and 'dubious'. RESULTS: Overall sensitivity was 56% for NMP22 (cut-off 11 U/ml) and 57% for BTA TRAK (cut-off 60 U/ml). When dubious results were considered as positive cases, urine cytology achieved a sensitivity of 73.3%. Assuming dubious cases as negative results, urine cytology sensitivity resulted 59.3%. When the 2 groups of patients were evaluated separately with different cut-off, there was no significant gain in sensitivity for BTA TRAK and NMP22 over urine cytology. CONCLUSIONS: Urine cytology performed on 3 samples showed the highest sensitivity and specificity. The diagnostic advantage of urine cytology over BTA TRAK and NMP22 was maintained when patients were stratified by tumor grade.