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  • br Conclusion A urinary integrated panel


    Conclusion: A urinary integrated panel of methylation and miRNA markers is a promising approach to identify AS patients at risk for reclassification. Our 3-marker panel, with its high negative predictive value, would be beneficial to identify and preclude AS patients with truly indolent cancer and to personalize monitoring strategies for AS patients. 2019 Elsevier Inc. All rights reserved.
    Keywords: Prostate cancer; Biomarkers; DNA methylation; miRNA; Active surveillance; Urinary biomarkers
    The authors have no conflict of interest to declare.
    This work was funded by the Ontario Institute of Cancer ResearchPersonalized Medicine Research Fund No. 10Nov-412, Prostate Cancer Canada No. 2011-700, and PCC Movember TAG No. 2014-01 (BB). The Ontario Student Opportunity Trust Funds Awards (FZ), Ontario Graduate Scholarships (FZ, RSCL, and EO-M), and University of Toronto Fellowships (FZ, RSCL).
    E-mail address: [email protected] (B. Bapat). 1These authors contributed equally to this work
    1. Introduction
    Prostate cancer (CaP) is the most common malignancy diagnosed in men [1]. Most CaP patients are diagnosed with low-grade, localized tumors with good prognosis [2]. However, a subset of these patients will experience disease progression and/or harbor occult aggressive tumors that may become life threatening.
    Current standards for diagnosis and prognosis include palpating the prostate tumor through digital rectal exams (DRE), measuring circulating prostate specific antigen (PSA), histological assessment of prostate tissue biopsies with the Gleason grading system, and multiparametric (mp) MRI where available. DRE is routinely used for detection of CaP in men over 50 but can only detect large tumors in the posterior of the prostate, and as such cannot identify aggressive tumors before they Adrucil have grown to be palpable. Due to its high sensitivity, measurement of cir-culating PSA has led to >50% increase in the diagnosis of CaP [3]. However, PSA cannot reliably differentiate between indolent, low-risk CaP and aggressive, high-risk tumors. Consequently, many patients with elevated PSA but without CaP or with clinically insignificant, low-risk CaP undergo unnecessary invasive biopsies. Prostate biopsies are stratified by the Gleason Grade Groups (GG), which are based on the Gleason patterns ranging from 1 to 5. GG1 (pattern 3+3 or lower) tumors are con-sidered low-risk, with a small chance of metastasis. GG2&3 (pattern 3 + 4 and 4 + 3 respectively) tumors are intermediate risk with the latter being at higher risk, and GG4&5 (patterns 4 + 4 and above) are high-risk tumors. Although histologic assessment remains the gold standard for CaP diagnosis and prognostication, the biopsy proce-dure is highly invasive and has many associated morbid-ities such as pain, bleeding, infections and even hospitalizations [4,5]. Additionally, biopsies sample less than 1% [6] of the prostate by volume and may miss occult high-grade tumors or CaP altogether. MpMRI has been shown to effectively reduce the number of prostate biopsies through improved detection of patients with GG2&3 disease and reduction in the number of GG1 diagnoses [7]. However, MRI availability and cost are prohibitive, and consensus regarding the effectiveness of monitoring low-risk patients using mpMRI remains inconclusive [8]. To avoid overtreatment, CaP patients diagnosed with low-risk, localized tumors are often enrolled in an Active Surveillance (AS) program instead of being subjected to definitive treatment such as radical prostatectomy or radiation. AS patients are monitored with repeated PSA measurements, DREs, multiparametric magnetic resonance imaging (mpMRI) if available, and periodic prostate biopsies [9,10]. If signs of disease pro-gression are found, including rapid increase in PSA, GG increase with repeat biopsy, and/or detection of a signifi-cant tumor by mpMRI, patients are considered to have “reclassified” with higher-risk disease and are offered