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Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22

Title: Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22
Authors: Kelly, JD
Dudderidge, TJ
Wollenschlaeger, A
Okoturo, O
Burling, K
Tulloch, F
Halsall, I
Prevost, T
Prevost, AT
Vasconcelos, JC
Robson, W
Leung, HY
Vasdev, N
Pickard, RS
Williams, GH
Stoeber, K
Item Type: Journal Article
Abstract: Background Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. Methods 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. Results Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62–75%) and 93% negative predictive value (95% CI = 92–95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71–0.79) and 0.72 (95% CI = 0.67–0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88–99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69–74%). Conclusions The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.
Issue Date: 9-Jul-2012
Date of Acceptance: 4-Jun-2012
URI: http://hdl.handle.net/10044/1/40750
DOI: http://dx.doi.org/10.1371/journal.pone.0040305
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS One
Volume: 7
Issue: 7
Copyright Statement: © 2012 Kelly et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
TRANSITIONAL-CELL CARCINOMA
MINICHROMOSOME MAINTENANCE PROTEIN-2
PHOTODYNAMIC DIAGNOSIS
5-AMINOLEVULINIC ACID
UROTHELIAL CANCER
DNA-REPLICATION
FOLLOW-UP
EXPRESSION
MARKERS
NMP22
Aged
Area Under Curve
Biomarkers, Tumor
Carcinoma
Carcinoma, Transitional Cell
Cell Cycle Proteins
False Positive Reactions
Female
Humans
Limit of Detection
Male
Middle Aged
Nuclear Proteins
ROC Curve
Statistics, Nonparametric
Urinary Bladder Neoplasms
Tumor Markers, Biological
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Article Number: e40305
Appears in Collections:School of Public Health