Expression of urokinase-type plasminogen activator system in non-metastatic prostate cancer
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ORIGINAL ARTICLE
Expression of urokinase‑type plasminogen activator system in non‑metastatic prostate cancer Shoji Kimura1,2 · David D’Andrea1 · Takehiro Iwata1,3 · Beat Foerster1,4 · Florian Janisch1,5 · Mehdi Kardoust Parizi1,6 · Marco Moschini1,7,8 · Alberto Briganti8 · Marko Babjuk9 · Piotr Chlosta10 · Pierre I. Karakiewicz11 · Dmitry Enikeev12 · Leonid M. Rapoport12 · Veronica Seebacher13 · Shin Egawa2 · Mohammad Abufaraj1,14 · Shahrokh F. Shariat1,12,15,16,17 Received: 6 August 2019 / Accepted: 23 November 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract Purpose To investigate the prognostic role of expression of urokinase-type plasminogen activator system members, such as urokinase-type activator (uPA), uPA-receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in patients treated with radical prostatectomy (RP) for prostate cancer (PCa). Methods Immunohistochemical staining for uPA system was performed on a tissue microarray of specimens from 3121 patients who underwent RP. Cox regression analyses were performed to investigate the association of overexpression of these markers alone or in combination with biochemical recurrence (BCR). Decision curve analysis was used to assess the clinical impact of these markers. Results uPA, uPAR, and PAI-1 were overexpressed in 1012 (32.4%), 1271 (40.7%), and 1311 (42%) patients, respectively. uPA overexpression was associated with all clinicopathologic characteristics of biologically aggressive PCa. On multivariable analysis, uPA, uPAR, and PAI-1 overexpression were all three associated with BCR (HR: 1.75, p 50 ng/ml, missing preoperative PSA, surgical margin status, lymphovascular invasion status, lymph-node status, and RP Gleason score. This left 3121 patients for this study. None of the patients had received neoadjuvant androgen deprivation, and chemo- or radiation therapy. None of the patients had clinically evident metastatic disease at the time of RP.
Pathological evaluation and immunohistochemical staining All RP specimens were evaluated according to a standard pathological procedure and assigned stage and grade based
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World Journal of Urology
on the American Joint Committee on Cancer TNM staging system and the International Society of Urological Pathology, respectively. Lymphovascular invasion was defined as the invasion of vessel walls by tumor cells and/or the presence of tumor emboli within a definite endothelial-lined space, at a distance from tumors, or in the prostatic parenchyma surrounding the tumor [19]. Positive surgical margin was defined as the explicit presence of tumor cells at the inked margin of the RP specimen. Immunohistochemical staining for uPA, uPAR, and PAI-1 on a tissue microarray of tumor cores was performed as previously described [16]. Briefly, staining of the serial section from the same paraffin-embedded microarray tissue blocks was performed on the Dako Autostainer (Carpinteria) using mouse monoclonal antibodies against uPA (dilution 1:100), PAI-1 (dilution 1:50), and uPAR (dilution 1:
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