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

John D. Kelly; Tim J. Dudderidge; Alex Wollenschlaeger; Odu Okoturo; Keith Burling; Fiona Tulloch; Ian Halsall; Teresa Prevost; Andrew Toby Prevost; Joana Carvalho Vasconcelos; Wendy Robson; Hing Y. Leung; Nikhil Vasdev; Robert S. Pickard; Gareth H. Williams; Kai Stoeber

doi:10.1371/journal.pone.0040305

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

John D. Kelly, Tim J. Dudderidge, Alex Wollenschlaeger, Odu Okoturo, Keith Burling, Fiona Tulloch, Ian Halsall, Teresa Prevost, Andrew Toby Prevost, Joana Carvalho Vasconcelos, Wendy Robson, Hing Y. Leung, Nikhil Vasdev, Robert S. Pickard, Gareth H. Williams, Kai Stoeber

Cicely Saunders Institute of Palliative Care, Policy & Rehabilitation

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

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 (R) 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.

Original language	English
Article number	e40305
Pages (from-to)	-
Number of pages	9
Journal	PL o S One
Volume	7
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0040305
Publication status	Published - 9 Jul 2012

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Kelly, J. D., Dudderidge, T. J., Wollenschlaeger, A., Okoturo, O., Burling, K., Tulloch, F., Halsall, I., Prevost, T., Prevost, A. T., Carvalho Vasconcelos, J., Robson, W., Leung, H. Y., Vasdev, N., Pickard, R. S., Williams, G. H., & Stoeber, K. (2012). Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22. PL o S One , 7(7), -. Article e40305. https://doi.org/10.1371/journal.pone.0040305

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

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 (R) 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.",

author = "Kelly, {John D.} and Dudderidge, {Tim J.} and Alex Wollenschlaeger and Odu Okoturo and Keith Burling and Fiona Tulloch and Ian Halsall and Teresa Prevost and Prevost, {Andrew Toby} and {Carvalho Vasconcelos}, Joana and Wendy Robson and Leung, {Hing Y.} and Nikhil Vasdev and Pickard, {Robert S.} and Williams, {Gareth H.} and Kai Stoeber",

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Kelly, JD, Dudderidge, TJ, Wollenschlaeger, A, Okoturo, O, Burling, K, Tulloch, F, Halsall, I, Prevost, T, Prevost, AT , Carvalho Vasconcelos, J, Robson, W, Leung, HY, Vasdev, N, Pickard, RS, Williams, GH & Stoeber, K 2012, 'Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22', PL o S One , vol. 7, no. 7, e40305, pp. -. https://doi.org/10.1371/journal.pone.0040305

TY - JOUR

T1 - Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22

AU - Kelly, John D.

AU - Dudderidge, Tim J.

AU - Wollenschlaeger, Alex

AU - Okoturo, Odu

AU - Burling, Keith

AU - Tulloch, Fiona

AU - Halsall, Ian

AU - Prevost, Teresa

AU - Prevost, Andrew Toby

AU - Carvalho Vasconcelos, Joana

AU - Robson, Wendy

AU - Leung, Hing Y.

AU - Vasdev, Nikhil

AU - Pickard, Robert S.

AU - Williams, Gareth H.

AU - Stoeber, Kai

PY - 2012/7/9

Y1 - 2012/7/9

N2 - 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 (R) 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.

AB - 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 (R) 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.

U2 - 10.1371/journal.pone.0040305

DO - 10.1371/journal.pone.0040305

M3 - Article

SN - 1932-6203

VL - 7

SP - -

JO - PL o S One

JF - PL o S One

IS - 7

M1 - e40305

ER -

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

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