Surgery (RMH) - Research Publications

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    Active surveillance versus enzalutamide for low-risk prostate cancer - was it really a trial we needed?
    Williams, ISC ; Perera, S ; Murphy, DG ; Corcoran, NM ; Bolton, DM ; Lawrentschuk, N (WILEY, 2022-11)
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    Active involvement of nursing staff in reporting and grading complication-intervention events-Protocol and results of the CAMUS Pilot Nurse Delphi Study
    Soliman, C ; Thomas, BC ; Santaguida, P ; Lawrentschuk, N ; Mertens, E ; Giannarini, G ; Wuethrich, PY ; Wu, M ; Khan, MS ; Nair, R ; Thurairaja, R ; Challacombe, B ; Dasgupta, P ; Malde, S ; Corcoran, NM ; Spiess, PE ; Dundee, P ; Furrer, MA (WILEY, 2022-11)
    OBJECTIVES: The aim of this study is to gain experienced nursing perspective on current and future complication reporting and grading in Urology, establish the CAMUS CCI and quality control the use of the Clavien-Dindo Classification (CDC) in nursing staff. SUBJECTS AND METHODS: The 12-part REDCap-based Delphi survey was developed in conjunction with expert nurse, urologist and methodologist input. Certified local and international inpatient and outpatient nurses specialised in urology, perioperative nurses and urology-specific advanced practice nurses/nurse practitioners will be included. A minimum sample size of 250 participants is targeted. The survey assesses participant demographics, nursing experience and opinion on complication reporting and the proposed CAMUS reporting recommendations; grading of intervention events using the existing CDC and the proposed CAMUS Classification; and rating various clinical scenarios. Consensus will be defined as ≥75% agreement. If consensus is not reached, subsequent Delphi rounds will be performed under Steering Committee guidance. RESULTS: Twenty participants completed the pilot survey. Median survey completion time was 58 min (IQR 40-67). The survey revealed that 85% of nursing participants believe nurses should be involved in future complication reporting and grading but currently have poor confidence and inadequate relevant background education. Overall, 100% of participants recognise the universal demand for reporting consensus and 75% hold a preference towards the CAMUS System. Limitations include variability in nursing experience, complexity of supplemental grades and survey duration. CONCLUSION: The integration of experienced nursing opinion and participation in complication reporting and grading systems in a modern and evolving hospital infrastructure may facilitate the assimilation of otherwise overlooked safety data. Incorporation of focused teaching into routine nursing education will be essential to ensure quality control and stimulate awareness of complication-related burden. This, in turn, has the potential to improve patient counselling and quality of care.
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    Identification and isolation of slow-cycling glioma stem cells
    Furst, L ; Atkins, RJ ; Dinevska, M ; Stylli, SS ; Corcoran, NM ; Hovens, CM ; Mantamadiotis, T ; Vitale, I ; Manic, G ; Galluzzi, L (ELSEVIER ACADEMIC PRESS INC, 2022)
    Cancer stem cells are defined as low-abundance, quiescent cells and are considered a major cellular source of tumor recurrence following therapy, which identifies these cells as important therapeutic targets for difficult-to-treat cancers, including high-grade gliomas. By contrast to the highly proliferative bulk tumor cells, glioma stem cells (GSC) are slow-cycling, and therefore less sensitive to DNA damaging cytotoxic drugs. GSC are also less reliant on aerobic glycolytic metabolism, leading to inadequate clearing of GSC by chemotherapy and radiotherapy. The definition of GSC is based on the expression of specific stem cell protein markers. This method of GSC isolation is successful in isolating cell populations that can reliably recapitulate the tumor. However, cell populations that lack stem marker expression may also be capable of tumor recapitulation. Therefore, robust, reproducible methods for isolating GSC are required to identify and isolate cells with stem cell characteristics. Here, we provide a comprehensive and reproducible protocol for the isolation of slow-cycling GSC. Using this method, GSC isolated retain key characteristics of the cells in situ, including expression of genes associated with cell quiescence and invasive potential, compared to non-quiescent cell populations. Thus, isolation of GSC gated on cell proliferation offers a reliable alternative method for in vitro GSC identification, that adequately mirrors the physiological properties of GSC seen in vivo.
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    Molecular Mechanisms Driving the Formation of Brain Metastases
    Campbell, BK ; Gao, Z ; Corcoran, NM ; Stylli, SS ; Hovens, CM (MDPI, 2022-10)
    Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.
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    Perish and publish: Dynamics of biomedical publications by deceased authors
    Jung, C-HJ ; Boutros, PCM ; Park, DJM ; Corcoran, NMM ; Pope, BJM ; Hovens, CMM ; Wicherts, JM (PUBLIC LIBRARY SCIENCE, 2022-09-14)
    The question of whether it is appropriate to attribute authorship to deceased individuals of original studies in the biomedical literature is contentious. Authorship guidelines utilized by journals do not provide a clear consensus framework that is binding on those in the field. To guide and inform the implementation of authorship frameworks it would be useful to understand the extent of the practice in the scientific literature, but studies that have systematically quantified the prevalence of this phenomenon in the biomedical literature have not been performed to date. To address this issue, we quantified the prevalence of publications by deceased authors in the biomedical literature from the period 1990-2020. We screened 2,601,457 peer-reviewed papers from the full text Europe PubMed Central database. We applied natural language processing, stringent filtering and manual curation to identify a final set of 1,439 deceased authors. We then determined these authors published a total of 38,907 papers over their careers with 5,477 published after death. The number of deceased publications has been growing rapidly, a 146-fold increase since the year 2000. This rate of increase was still significant when accounting for the growing total number of publications and pool of authors. We found that more than 50% of deceased author papers were first submitted after the death of the author and that over 60% of these papers failed to acknowledge the deceased authors status. Most deceased authors published less than 10 papers after death but a small pool of 30 authors published significantly more. A pool of 266 authors published more than 90% of their total publications after death. Our analysis indicates that the attribution of deceased authorship in the literature is not an occasional occurrence but a burgeoning trend. A consensus framework to address authorship by deceased scientists is warranted.
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    PEDAL protocol: a prospective single-arm paired comparison of multiparametric MRI and 18F-DCPFyl PSMA PET/CT to diagnose prostate cancer
    Tran, V ; Hong, A ; Sutherland, T ; Taubman, K ; Lee, S-F ; Lenaghan, D ; Sethi, K ; Corcoran, NM ; Lawrentschuk, N ; Woo, H ; Tarlinton, L ; Bolton, D ; Spelman, T ; Thomas, L ; Booth, R ; Hegarty, J ; Perry, E ; Wong, L-M (BMJ PUBLISHING GROUP, 2022-09)
    INTRODUCTION: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has emerged as valuable imaging to assessing metastatic disease in prostate malignancy. However, there has been limited studies exploring the utility PSMA-PET as primary imaging assessing for index lesions prior to biopsy. The primary objective of this study is to compare the diagnostic accuracy of 18-fluorine PSMA (18F DCFPyL PSMA) PET scans to multiparametric MRI (mpMRI) to detect primary prostate cancer at prostate biopsy. METHODS AND ANALYSIS: The PEDAL trial is a multicentre, prospective, single-arm, paired comparison, non-randomised phase III trial in subjects considered for diagnostic prostate biopsy. Subjects who are eligible for a diagnostic mpMRI prostate will undergo additional same-day 18 F DCFPyl PSMA PET/CT of the chest, abdomen and pelvis. Software coregistration of the mpMRI and PSMA-PET/CT images will be performed. The reporting of the mpMRI prostate, PSMA-PET/CT and PSMA PET/MRI coregistration will be performed blinded. The diagnostic accuracy of PSMA PET/CT alone, and in combination with mpMRI, to detect prostate cancer will be assessed. Histopathology at prostate biopsy will be used as the reference standard. Sample size calculations estimate that 240 subjects will need to be recruited to demonstrate 20% superiority of PSMA-PET/CT. The sensitivity, specificity, positive predictive value and negative predictive value of the combination of mpMRI prostate and PSMA PET/CT compared with targeted and systematic prostate biopsy will be evaluated. It is hypothesised that PSMA PET/CT combined with mpMRI prostate will have improved diagnostic accuracy compared with mpMRI prostate alone for detection of prostate cancer in biopsy-naïve men, resulting in a significant impact on patient management. ETHICS AND DISSEMINATION: This study was approved by the independent Human Research Ethics Committee. Results will be published in peer-reviewed medical journals with eligible investigators will significantly contribute. TRIAL REGISTRATION NUMBER: ACTRN12620000261910.
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    Defining Prostatic Vascular Pedicle Recurrence and the Anatomy of Local Recurrence of Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography
    Dundee, P ; Furrer, MA ; Corcoran, NM ; Peters, J ; Pan, H ; Ballok, Z ; Ryan, A ; Guerrieri, M ; Costello, AJ (ELSEVIER, 2022-07)
    BACKGROUND: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. OBJECTIVE: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. DESIGN SETTING AND PARTICIPANTS: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. INTERVENTION: PSMA PET/CT for BCR following RP. RESULTS AND LIMITATIONS: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. CONCLUSIONS: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. PATIENT SUMMARY: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.
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    Molecular classification of hormone-sensitive and castration-resistant prostate cancer, using nonnegative matrix factorization molecular subtyping of primary and metastatic specimens
    Yuen, KC ; Tran, B ; Anton, A ; Hamidi, H ; Costello, AJ ; Corcoran, NM ; Lawrentschuk, N ; Rainey, N ; Semira, MCG ; Gibbs, P ; Mariathasan, S ; Sandhu, S ; Kadel, EE (WILEY, 2022-06)
    BACKGROUND: Despite the rapidly evolving therapeutic landscape, immunotherapy has demonstrated limited activity in prostate cancer. A greater understanding of the molecular landscape, particularly the expression of immune-related pathways, will inform future immunotherapeutic strategies. Consensus nonnegative matrix factorization (cNMF) is a novel model of molecular classification analyzing gene expression data, focusing on biological interpretation of metagenes and selecting meaningful clusters. OBJECTIVE: We aimed to identify molecular subtypes of prostate cancer using cNMF and correlate these with existing biomarkers to inform future immunotherapeutic strategies. METHODS: A cohort of archival tumor specimens from hormone-sensitive and castration-resistant disease was studied. Whole transcriptomic profiles were generated using TruSeq RNA Access technology and subjected to cNMF. Comprehensive genomic profiling was performed with the FoundationOne assay. NMF subtypes were characterized by gene expression pathways, genomic alterations and correlated with clinical data, then applied to The Cancer Genome Atlas data set. RESULTS: We studied 164 specimens, including 52 castration-resistant and 13 paired primary/metastatic specimens. cNMF identified four distinct subtypes. NMF1 (19%) is enriched for immune-related and stromal-related pathways with transforming growth factor β (TGFβ) signature. NMF2 (36%) is associated with FOXO-mediated transcription signature and AKT signaling, NMF3 (26%) is enriched for ribosomal RNA processing, while NMF4 (19%) is enriched for cell cycle and DNA-repair pathways. The most common gene alterations included TMPRSS22 (42%), TP53 (23%), and DNA-repair genes (19%), occurring across all subtypes. NMF4 is significantly enriched for MYC and Wnt-signaling gene alterations. TMB, CD8 density, and PD-L1 expression were low overall. NMF1 and NMF4 were NMF2 was associated with superior overall survival. CONCLUSIONS: Using cNMF, we identified four molecularly distinct subtypes which may inform treatment selection. NMF1 demonstrates the most inflammatory signature with asuppressive TGFβ signature, suggesting potential benefit with immunotherapy combination strategies targeting TGFβ and PD-(L)1. Prospective studies are required to evaluate the use of this novel model to molecularly stratify patients for optimal treatment selection.
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    The Prostate Cancer Immune Microenvironment, Biomarkers and Therapeutic Intervention
    Zhang, Y ; Campbell, BK ; Stylli, SS ; Corcoran, NM ; Hovens, CM (MDPI AG, 2022-04-10)
    Advanced prostate cancers have a poor survival rate and a lack of effective treatment options. In order to broaden the available treatments, immunotherapies have been investigated. These include cancer vaccines, immune checkpoint inhibitors, chimeric antigen receptor T cells and bispecific antibodies. In addition, combinations of different immunotherapies and with standard therapy have been explored. Despite the success of the Sipuleucel-T vaccine in the metastatic, castrate-resistant prostate cancer setting, other immunotherapies have not shown the same efficacy in this population at large. Some individual patients, however, have shown remarkable responsiveness to these therapies. Therefore, work is underway to identify which populations will respond positively to therapy via the identification of predictive biomarkers. These include biomarkers of the immunologically active tumour microenvironment and biomarkers indicative of high neoantigen expression in the tumour. This review examines the constitution of the prostate tumour immune microenvironment, explores the effectiveness of immunotherapies, and finally investigates how therapy selection can be optimised by the use of biomarkers.
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    Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer
    Pechlivanis, M ; Campbell, BK ; Hovens, CM ; Corcoran, NM (MDPI, 2022-01)
    Prostate cancer (PCa) is a hormone driven cancer, characterised by defects in androgen receptor signalling which drive the disease process. As such, androgen targeted therapies have been the mainstay for PCa treatment for over 70 years. High-risk PCa presents unique therapeutic challenges, namely in minimising the primary tumour, and eliminating any undetected micro metastases. Trials of neoadjuvant androgen deprivation therapy aim to address these challenges. Patients typically respond well to neoadjuvant treatment, showing regression of the primary tumour and negative surgical margins at the time of resection, however the majority of patients relapse and progress to metastatic disease. The mechanisms affording this resistance are largely unknown. This commentary attempts to explore theories of resistance more broadly, namely, clonal evolution, cancer stem cells, cell persistence, and drug tolerance. Moreover, it aims to explore the application of these theories in the PCa setting. This commentary also highlights the distinction between castration resistant PCa, and neoadjuvant resistant disease, and identifies the markers and characteristics of neoadjuvant resistant disease presented by current literature.