Surgery (RMH) - Research Publications

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Author: Chow, Sing Ken × Author: Corcoran, Niall × Author: Peters, Justin × End date: 2024 × Start date: 2020 ×

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    Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression
    Mangiola, S ; McCoy, P ; Modrak, M ; Souza-Fonseca-Guimaraes, F ; Blashki, D ; Stuchbery, R ; Keam, SP ; Kerger, M ; Chow, K ; Nasa, C ; Le Page, M ; Lister, N ; Monard, S ; Peters, J ; Dundee, P ; Williams, SG ; Costello, AJ ; Neeson, PJ ; Pal, B ; Huntington, ND ; Corcoran, NM ; Papenfuss, AT ; Hovens, CM (BMC, 2021-07-22)
    BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
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    Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy
    Cmero, M ; Kurganovs, NJ ; Stuchbery, R ; McCoy, P ; Grima, C ; Ngyuen, A ; Chow, K ; Mangiola, S ; Macintyre, G ; Howard, N ; Kerger, M ; Dundee, P ; Ruljancich, P ; Clarke, D ; Grummet, J ; Peters, JS ; Costello, AJ ; Norden, S ; Ryan, A ; Parente, P ; Hovens, CM ; Corcoran, NM (LIPPINCOTT WILLIAMS & WILKINS, 2021-06)
    PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.
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    The utility of magnetic resonance imaging in prostate cancer diagnosis in the Australian setting
    Tay, JYI ; Chow, K ; Gavin, DJ ; Mertens, E ; Howard, N ; Thomas, B ; Dundee, P ; Peters, J ; Simkin, P ; Kranz, S ; Finlay, M ; Heinze, S ; Kelly, B ; Costello, A ; Corcoran, N (WILEY, 2021-11)
    OBJECTIVES: To investigate the utility of Magnetic Resonance Imaging (MRI) for prostate cancer diagnosis in the Australian setting. PATIENTS AND METHODS: All consecutive men who underwent a prostate biopsy (transperineal or transrectal) at Royal Melbourne Hospital between July 2017 to June 2019 were included, totalling 332 patients. Data were retrospectively collected from patient records. For each individual patient, the risk of prostate cancer diagnosis at biopsy based on clinical findings was determined using the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator, with and without incorporation of MRI findings. RESULTS: MRI has good diagnostic accuracy for clinically significant prostate cancer. A PI-RADS 2 or lower finding has a negative predictive value of 96% for clinically significant cancer, and a PI-RADS 3, 4 or 5 MRI scan has a sensitivity of 93%. However, MRI has a false negative rate of 6.5% overall for clinically significant prostate cancers. Pre- biopsy MRI may reduce the number of unnecessary biopsies, as up to 50.0% of negative or ISUP1 biopsies have MRI PI-RADS 2 or lower. Incorporation of MRI findings into the ERSPC calculator improved predictive performance for all prostate cancer diagnoses (AUC 0.77 vs 0.71, P = .04), but not for clinically significant cancer (AUC 0.89 vs 0.87, P = .37). CONCLUSION: MRI has good sensitivity and negative predictive value for clinically significant prostate cancers. It is useful as a pre-biopsy tool and can be used to significantly reduce the number of unnecessary prostate biopsies. However, MRI does not significantly improve risk predictions for clinically significant cancers when incorporated into the ERSPC risk calculator.