World J Oncol
World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc
Journal website http://www.wjon.org

Original Article

Volume 4, Number 3, June 2013, pages 151-157


Nuclear Matrix Protein 22 in Voided Urine Cytology Efficacy in Risk Stratification for Carcinoma of Bladder

Monica Sankhwara, Rajender Singhb, Satya Narayan Sankhwara, f, Madhu Mati Goelc, Amita Jaind, Pushp Lata Sankhware

aDepartment of Urology King George Medical University, Lucknow, India
bDepartment of Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil Palace Lucknow, India
cDepartment of Pathology, King George Medical University Lucknow, India
dDepartment of Microbiology, King George Medical University, Lucknow, India
eDepartment of Obstetrics and Gynaecology, King George Medical University, Lucknow, India
fCorresponding author: Satya Narayan Sankhwar, Department of Urology, King George Medical University, Lucknow, India

Manuscript accepted for publication June 13, 2013
Short title: Nuclear Matrix Protein 22
doi: https://doi.org/10.4021/wjon677w

Abstract▴Top 

Background: To investigate the nuclear matrix protein NMP22 in voided urine for detection of malignancy in patients with risk factors of symptoms of bladder cancer.

Methods: January 2009 to December 2012, participants included 1,331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria, patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner.

Results: Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%, 95% confidence interval (CI), 44.1-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8-87.6%) compared with 99.2% (95% CI, 98 initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ.

Conclusion: The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cytoscopy, with test results available during the patient visit.

Keywords: Bladder cancer; NMP22; Urine cytology; Cystoscopy; Hematuria

Introduction▴Top 

Carcinoma of the urinary bladder, the fourth most common cancer in men and the ninth most common cancer in women, results in significant morbidity and mortality. Most patients with bladder cancer receive the diagnosis after they present with gross or microscopic hematuria. At initial diagnosis, approximately 70% of patients have bladder cancers that are confined to the epithelium or sub-epithelial connective tissue [1]. Cigarette smoking is an established cause of bladder cancer, accounting for approximately 50% of the disease burden in the United States and other Western countries [2]. The incidence of bladder cancer is higher in men, individuals older than 60 years, and those exposed to carcinogens in their occupation or environment. Cigarette smoking is the most common risk factor and doubles the risk of bladder cancer, accounting for approximately 50% of the bladder cancer deaths in men and 30% in women [2]. Hematuria and irritative voiding symptoms are the most common symptoms among patients with urinary tract malignancy. Hematuria in bladder cancer can be intermittent, and its degree does not correlate with the severity of underlying disease [3].

A combination of methods is used to evaluate patients at risk for bladder cancer because no single procedure is 100% sensitive. Flexible cystoscopy is an excellent to because it is low risk and generally can be done in the physician’s office under local anesthesia. However, accuracy can be reduced by poor visualization caused by inflammatory conditions or bleeding, and flat urothelial lesions such as severe dysplasia and carcinoma in situ may be difficult to distinguish from normal bladder tissue [4, 5]. For this reason, voided urine cytology is frequently used as an adjunctive noninvasive test, but it is expensive, subjective, and has low sensitivity.

We investigated whether a new, noninvasive urine-based test for the nuclear matrix, protein NMP22 proteomic marker, using monoclonal antibodies in a point of care format, has clinical utility as an aid in diagnosis of bladder cancer and compared its ability to detect cancer with that of voided urine cytology.

Methods▴Top 

Patients with cancers other than of the bladder provided a urine specimen for NMP22 protein analysis during a routine visit and did not have endoscopy or voided cytology evaluations. Each patient evaluated for bladder cancer provided a voided urine sample before undergoing cytoscopy. One protein of each sample was sent for routine cytological examinations, either within the institution or at a reference laboratory, according to the standard practice at each participating facility. An aliquot of the remaining specimen was tested for the presence of NMP22 protein by a member of the clinic staff. Each device was identified by study identification number so that the physicians who performed the subsequent cystoscopy were blinded to the NMP22 test results, and the staff members who performed the NMP22 assay were blinded to cystoscopy test results. Technicians who conducted the cytological examinations were physically distant from both the cystoscopy and NMP22 evaluation, and laboratory reports arrived after the cystoscopies had been completed and documented.

NMP22 assay

Staff members at each office performed the NMP22 assay per protocol by adding 4 drops of voided urine to the sample well of the point of care device. Positive or negative results were read 30 to 50 minutes later in the test window. A built-in control indicated that the assay was complete. There were no other procedural steps.

The IMMP22 point of care device (NMP22 flow immunochromatographic qualitative assay. It detects elevated amount of the nuclear mutotin apparatus protein, which is a abundant component of the nuclear matrix proteins make up the internal structural framework of the nucleus [6, 7] and are associated with such functions as DIMA replication and RNA synthesis [8, 9], as well as regulation and coordination of gene expression [10-12], in tumor cells, nuclear mitotic apparatus protein, which is present in the inter phase nuclear and associated with the organization of mitotic spindles during cell division [13], is elevated concordant with structural/morphological changes characteristic of malignant cell nuclei. Nuclear matrix protein expression varies with cell type of origin [14, 15]. In individuals with bladder cancer nuclear mitotic apparatus protein is released into the urine during cell death. Unlike cytological examination its detection is not dependent on recovery of intact cells. A microtiter plate immunoassay was developed for this protein previously [16].

Two different monoclonal antibodies are used in the NMP22 point of care assay, one as a capture antibody, and one as a reporter. To perform the test, fresh unprocessed urine is added to the sample well of the device and allowed to react with the colloidal gold-conjugated reported antibody. If NMP22 protein is present in the urine, it will interact with the reporter conjugate to form an immune complex. The reaction mixture flows through the membrane, which contains zones of immobilized antibodies. In the test zone, antigen-conjugate complexes are trapped by the capture antibody, forming a visible line if the concentration of NMP22 protein in the urine is a greater than 10 U/mL. A procedural control zone contains an immobilized IgG-specific antibody that will capture the conjugated antibody independently in the presence or absence of the antigen, thereby always producing a visible control line in the window to demonstrate that each device is working properly [17, 18].

Diagnostic criteria

All patients with risk factors or symptoms of bladder cancer underwent cystoscopy. They were considered positive for malignancy if 1 or more tumors were observed during initial cystoscopy or within the subsequent 3 months. Nine patients with no malignancy found during their initial cystoscopy had a subsequent endoscopy due to continued suspicion, such as increased symptoms. Removed tumors were defined as malignant based on pathological examination. Tumors that were seen endoscopically but not removed were considered positive for malignancy and designated stage (TX) and grade (GX). Reasons that neoplasia were not removed included concurrent health problems that made patients poor candidates for surgery and advanced age. Patients were considered negative for cancer if no tumor(s) was seen endoscopically, or if tissue was biopsied and defined as nonmalignant on the basis of histopathological examination [19, 20].

Statistical analysis

Sensitivity of the NMP22 test to detect the presence of bladder with true-positive test results (positive NMP22 test result and tumor) divided by the total number of patients with malignancy, as detected by endoscopy. Specificity was defined as the percentage of patients with a negative NMP22 test result who were not diagnosed with tumors. Corresponding 95% confidence intervals (CIs) were calculated for both sensitivity and specificity were calculated for comparison. A positive cytology test result was defined as one in which malignant or dysplastic cells were present.

Result▴Top 

Characteristics of the patients

Demographic and baseline characteristics of the individuals with risk factors or symptoms of bladder cancer are summarized in Table 1.

Table 1.
Click to view
Table 1. Patient’s Demographics and Baseline Characteristics
 

Among the 1,331 patients who had cystoscopies, 79 (6%) and cancer, 685 (51%) were diagnosed with 1 or more benign urological conditions, and 567 (43%) had no cystoscopic evidence or urinary tract disease. The mean age of the patients with bladder tumors was 65.8 years (range, 21 - 86 years), and they comprised 3 times as many mean as women. Staging information was available for the 72 cancers that were surgically removed. The 7 tumors seen during cystoscopy but not excised were categorized as TX. Of the cancers with pathological staging data, 62 were superficial (stages Ta, Tis, or T1), and 10 were muscle invasive (T2-T3). Pathological determination of grade was available for 70 of the 72 removed tumors. Of these, 27 were well differentiated (low grade), 18 were moderately differentiated (medium grade), and 25 were poorly differentiated (high grade). A total of 27 cancers were muscle invasive (T2 or T3) and/or poorly differentiated (high grade). No patients had detectable metastases or involvement of regional lymph nodes. The NMP22 test results were available for all patients with risk factors (1,331), and cytology test results for 1,287 of the patients with risk factors, including 76 of the 79 diagnosed with cancer.

Detection

Initial cystoscopy alone detected 88.6% (70/79) of the cancers. The remaining 9 malignancies were identified during subsequent cystoscopies conducted due to continued suspicion, such as increased symptoms within 3 months of the initial evaluation. The NMP22 assay was positive in 55.7% (44/79), and cytology test results of malignant or dysplastic cells were found in 15.8% (12/76).

The NMP22 test was significantly more sensitive than voided urine cytology when compared using the McNemar x test (x = 24.6, P < 0.001). This difference remains significant after taking into account the inherent variability among the investigational sites using an adjusted McNemar x test (x = 7.0, P = 0.008). This significant difference is also reflected by the CIs for the sensitivity proportions since they do not overlap, at 55.7% (85% CI, 44.1-66.7%) for the NMP22 test vs 15.8% (95% CI, 7.6-24.0%) for cytology. The positive predictive values of the NMP22 assay and cytology were 19.7% (95% CI, 14.5-25.0%) and 94.9% (95% CI, 93.6-96.1%), respectively (Table 2).

Table 2.
Click to view
Table 2. Sensitivity of NMP22 Assay and Voided Cytology by Stage and Grade of Cancer (n = 72)
 

The same methods were used to compare the specificity proportions and demonstrated that cytology was significantly more specific than the proteomic assay (x2 = 149.6 P < 0.001), at 99.2% (95% CI, 98.7-99.7%) vs 85.7% (95 CI, 83.8-87.6%), respectively. The difference remains significant after taking variability among the sites into account (adjusted McNemar test x2 = 9.0, P = 0.003). The negative predictive values of the IMMP22 assay and cytology were 96.8% (95% CI, 95.6-97.8%) and 94.9% (95% CI, 93.6-96.1%), respectively.

Ten of the 79 malignancies were muscle invasive. Initial cystoscopy visualized 6 (60%) of these, compared with the NMP22 test, which identified 9 (90%) with elevated protein marker. By comparison, voided cytology was positive in only 2 (22%) of the 9 patients with muscle-invasive disease for whom test results were available. The NMP22 assay was also positive for a patient diagnosed with carcinoma in situ after an initial cystoscopic report of benign disease. Thus, a total of 4 potentially life-threatening tumors (T2 G2 of the ureter; T2 G3, Tis G3, and T3 G2 of the bladder) were detected by the NMP22 test but not visualized in the first cystoscopy. Once of the 4 tumor was located in the ureter and therefore outside the viewing area of the cystoscope. Urine tests are often added to an evaluation to identify urinary tract tumors such as this. The combination of the NMP22 test and cystoscopy detected 93.7% of malignancies vs 88.6% for initial cystoscopy alone (P = 0.26). Cytology detected 2 of the 4 cancers not seen in the initial endoscopy, but which were positive by the NMP22 assay. Among the most aggressive malignancies, those that were poorly differentiated (high grade) and/or muscle invasive (stage T2 or T3), the NMP22 test result was positive in 74% (20/27) compared with cytology, which was positive in 39% (10/26). Of the superficial cancers (Ta, Tis, T1) that were moderately or well differentiated (medium of low grade), with 5% (2/41) for cytology. Overall, the point-of-care assay detected 32 malignancies missed by cytology: 11 Ta, 10T1, 4T2, 2 T3, 1 Cis, and 4 TX. Voided cytology was positive in only 2 cancer patients for whom the NMP22 test result was negative, both T1 G3.

The specificity of the NMP22 assay was 90.3% among individuals with symptoms but with no evidence of urinary tract disease seen during cytoscopy, and 85.7% overall (Table 3).

Table 3.
Click to view
Table 3. Specificity of NMP22 Assay
 

All risk patients in the study were undergoing an evaluation for bladder cancer that included cytoscopy, so false-positive test results did not require any additional procedures. Cytology demonstrated a specificity of 99.2% among patients with symptoms and was not performed for individuals with non-bladder cancer. Of the 39 patients with active cancers other than bladder, the NMP22 assay was negative in 86.8% (33/38) and positive in 13.2% (5/38).

Discussion▴Top 

Prognosis and survival of individuals with bladder cancer are related to the stage of the malignancy at the time of detection. Approximately 50% of patients with muscle-invasive disease at first diagnosis demonstrate a recurrence within 2 years of surgery, despite apparently adequate surgical resection. The majority of these patients will experience a cancer-related death within 5 years of diagnosis [21]. By comparison, tumors treated while still confined to the epithelium have lower recurrence rates and progress to higher stages and grades less often, thereby improving patients longterm outcome [22, 23]. In addition, early stage disease can be treated by bladder-sparing thereby rather than cystectomy, the standard for advanced disease, which impacts quality of life as well as survival.

The direct cost of treatment for patients with metastatic genitourinary cancer has been estimated to be more than 6 times greater than for those patients with localized disease for the same period of time [24]. The challenge therefore is to improve detection of bladder cancer without adding increased risk or discomfort to the patient.

Cystoscopy is integral to the diagnosis of bladder cancer, allowing the physician to visualize the bladder wall directly. The sensitivity of cystoscopy is very good, but hematuria and other conditions can obscure lesions, and flat neoplasia can be confused with erythema. As seen in this study, even later-stage cancers are sometimes missed during endoscopy. The precise rate of false-negative during cystoscopy test results is difficult to determine, but estimates range from 10% to 40% [25]. In this study it was 11.4%. For this reason, physicians frequently use multiple tools to aid in diagnosis of bladder cancer, including urinalyses and imaging of the upper tract.

Voided cytology has been a widely accepted adjunctive test to cystoscopy because it is noninvasive. This method involves visual assessment of morphological changes and therefore (low-grade) tumors or both are less likely to exfoliate cells spontaneously because the strong intercellular attachments are better preserved, and the degree of morphological departure from normal is less, making recognition difficult [26-28]. This results in low sensitivity, approximately 15% to 30% in early stage cancers [29, 30]. The high specificity of cytology is offset by low sensitivity, ambiguous test results, expense, and time lag to obtain reports.

We found that the NMP22 test is a useful adjunctive tool in the evaluation of patients at risk for bladder cancer and that it identified several malignancies missed by initial than for cytology (85.7% vs 15.8%), with test results available during the patient visit. The NMP22 protein is the only tumor marker approved by the FDA as an aid in the initial diagnosis of bladder cancer, and the test has been waived under the Clinical Laboratory Improvement Act so it can be performed in any physician’s office. The cost of urine tests varies by location. The average Medicare reimbursement for voided cytology is approximately $56, compared with $24 for the NMP22 point of care assay [31].

Among study patients with the highest risk for bladder cancer, men older than 60 years with a history of smoking, the positive predictive value of the NMP22 test was 37%. This is higher than the 20% to 30% predictive value typically reported for prostate specific antigen in men who have an elevated risk of prostate cancer, those with levels between 4 to 10 ng/mL [32-35].

Conclusion

In conclusion, the NMP22 assay may be useful adjunct to cystoscopy for diagnosing bladder cancer. Studies in different patient populations are necessary to further define the role of this assay in patients with risk factors and symptoms suggestive of possible bladder cancer.

Conflict of Interest

The authors indicated no potential conflicts of interest.


References▴Top 
  1. Shariat SF, Karam JA, Lotan Y, Karakiewizc PI. Critical evaluation of urinary markers for bladder cancer detection and monitoring. Rev Urol. 2008;10(2):120-135.
    pubmed
  2. Tao L, Xiang YB, Wang R, Nelson HH, Gao YT, Chan KK, Yu MC, et al. Environmental tobacco smoke in relation to bladder cancer risk—the Shanghai bladder cancer study [corrected]. Cancer Epidemiol Biomarkers Prev. 2010;19(12):3087-3095.
    doi pubmed
  3. Grossfeld GD, Litwin MS, Wolf JS Jr, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy—part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57(4):604-610.
    doi
  4. Frimberger D, Zaak D, Hofstetter A. Endoscopic fluorescence diagnosis and laser treatment of transitional cell carcinoma of the bladder. Semin Urol Oncol. 2000;18(4):264-272.
    pubmed
  5. Hudson MA, Herr HW. Carcinoma in situ of the bladder. J Urol. 1995;1533 Pt 1:564-572.
    pubmed
  6. Berezney R, Coffey DS. Identification of a nuclear protein matrix. Biochem Biophys Res Commun. 1974;60(4):1410-1417.
    doi
  7. Fey EG, Krochmalnic G, Penman S. The nonchromatin substructures of the nucleus: the ribonucleoprotein (RNP)-containing and RNP-depleted matrices analyzed by sequential fractionation and resinless section electron microscopy. J Cell Biol. 1986;102(5):1654-1665.
    doi pubmed
  8. Kumara-Siri MH, Shapiro LE, Surks MI. Association of the 3,5,3'-triiodo-L-thyronine nuclear receptor with the nuclear matrix of cultured growth hormone-producing rat pituitary tumor cells (GC cells). J Biol Chem. 1986;261(6):2844-2852.
    pubmed
  9. Pardoll DM, Vogelstein B, Coffey DS. A fixed site of DNA replication in eucaryotic cells. Cell. 1980;19(2):527-536.
    doi
  10. Zeitlin S, Parent A, Silverstein S, Efstratiadis A. Pre-mRNA splicing and the nuclear matrix. Mol Cell Biol. 1987;7(1):111-120.
    pubmed
  11. Nakayasu H, Berezney R. Mapping replicational sites in the eucaryotic cell nucleus. J Cell Biol. 1989;108(1):1-11.
    doi
  12. Berrios M, Osheroff N, Fisher PA. In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction. Proc Natl Acad Sci U S A. 1985;82(12):4142-4146.
    doi pubmed
  13. Lydersen BK, Pettijohn DE. Human-specific nuclear protein that associates with the polar region of the mitotic apparatus: distribution in a human/hamster hybrid cell. Cell. 1980;22(2 Pt 2):489-499.
    doi
  14. Miller TE, Beausang LA, Winchell LF, Lidgard GP. Detection of nuclear matrix proteins in serum from cancer patients. Cancer Res. 1992;52(2):422-427.
    pubmed
  15. Partin AW, Getzenberg RH, CarMichael MJ, Vindivich D, Yoo J, Epstein JI, Coffey DS. Nuclear matrix protein patterns in human benign prostatic hyperplasia and prostate cancer. Cancer Res. 1993;53(4):744-746.
    pubmed
  16. Soloway MS, Briggman V, Carpinito GA, Chodak GW, Church PA, Lamm DL, Lange P, 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. 1996;156(2 Pt 1):363-367.
    pubmed
  17. US Food and Drug Administration Premarket Approval (PMA) Database: MA 940035 S002. Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/PMA.cfm?ID=7413. Accessed August 18, 2004.
  18. US Food and Drug Administration Premarket Approval (PMA) Database: MA 940035. Available at; http:/www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/PMA.cfm?ID=7411. Accessed August 18, 2004.
  19. American Joint Committee on Cancer. Cancer Staging Manual. 5th Edition. Philadelphia, Pa: American Joint Committee on Cancer; 1997.
  20. Durkalski VL, Palesch YY, Lipsitz SR, Rust PF. Analysis of clustered matched-pair data. Stat Med. 2003;22(15):2417-2428.
    doi pubmed
  21. Lerner SP, Skinner DG. Radical cystectomy for bladder cancer. In: Vogelzany WJ, Scardino PT, Shipley WV, Coffey DS, eds. Comprehensive Textbook of Genitourinary Oncology. 2nd ed. New York, NY: Lippicott Williams & Wilkins; 2000; 425-447.
  22. Holmang S, Hedelin H, Anderstrom C, Johansson SL. The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol. 1995;153(6):1823-1826, discussion 1826-1827.
  23. Heney NM, Ahmed S, Flanagan MJ, Frable W, Corder MP, Hafermann MD, Hawkins IR. Superficial bladder cancer: progression and recurrence. J Urol. 1983;130(6):1083-1086.
    pubmed
  24. Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A. The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol. 1989;141(2):350-355.
    pubmed
  25. Zaak D, Kriegmair M, Stepp H, Baumgartner R, Oberneder R, Schneede P, Corvin S, et al. Endoscopic detection of transitional cell carcinoma with 5-aminolevulinic acid: results of 1012 fluorescence endoscopies. Urology. 2001;57(4):690-694.
    doi
  26. Schneeweiss S, Kriegmair M, Stepp H. Is everything all right if nothing seems wrong? A simple method of assessing the diagnostic value of endoscopic procedures when a gold standard is absent. J Urol. 1999;161(4):1116-1119.
    doi
  27. Kriegmair M, Baumgartner R, Knuchel R, Stepp H, Hofstadter F, Hofstetter A. Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. J Urol. 1996;155(1):105-109, discussion 109-110.
    doi
  28. Farrow GM. Urine cytology in the detection of bladder cancer: a critical approach. J Occup Med. 1990;32(9):817-821.
    doi pubmed
  29. Badalament RA, Hermansen DK, Kimmel M, Gay H, Herr HW, Fair WR, Whitmore WF Jr, et al. The sensitivity of bladder wash flow cytometry, bladder wash cytology, and voided cytology in the detection of bladder carcinoma. Cancer. 1987;60(7):1423-1427.
    doi
  30. Brown FM. Urine cytology. It is still the gold standard for screening?. Urol Clin North Am. 2000;27(1):25-37.
    doi
  31. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med. 2003;348(23):2330-2338.
    doi pubmed
  32. Andriole GL, Catalona WJ. Using PSA to screen for prostate cancer. The Washington University experience. Urol Clin North Am. 1993;20(4):647-651.
    pubmed
  33. Brawer MK, Chetner MP, Beatie J, Buchner DM, Vessella RL, Lange PH. Screening for prostatic carcinoma with prostate specific antigen. J Urol. 1992;147(3 Pt 2):841-845.
    pubmed
  34. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, Petros JA, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324(17):1156-1161.
    doi pubmed
  35. Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer. The United States experience. Urol Clin North Am. 1997;24(2):299-306.
    doi


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