Surgery (RMH) - Research Publications

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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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    A phase 1b open-label study of sodium selenate as a disease-modifying treatment for possible behavioral variant frontotemporal dementia
    Vivash, L ; Malpas, CB ; Meletis, C ; Gollant, M ; Eratne, D ; Li, Q-X ; McDonald, S ; O'Brien, WT ; Brodtmann, A ; Darby, D ; Kyndt, C ; Walterfang, M ; Hovens, CM ; Velakoulis, D ; O'Brien, TJ (WILEY, 2022-01-01)
    Introduction: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.
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    Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer
    Pechlivanis, M ; Campbell, BK ; Hovens, CM ; Corcoran, NM (MDPI, 2022-01-01)
    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.
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    Sodium selenate as a disease-modifying treatment for mild-moderate Alzheimer's disease: an open-label extension study
    Vivash, L ; Malpas, CB ; Hovens, CM ; Brodtmann, A ; Collins, S ; Macfarlane, S ; Velakoulis, D ; O'Brien, TJ (BMJ PUBLISHING GROUP, 2021-12-01)
    INTRODUCTION: Sodium selenate is a potential disease-modifying treatment for Alzheimer's disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification. METHODS: An open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression. RESULTS: Sixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 score increased 1.8 points over 12 months. DISCUSSION: Chronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.
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    Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial
    Vivash, L ; Bertram, KL ; Malpas, CB ; Marotta, C ; Harding, IH ; Kolbe, S ; Fielding, J ; Clough, M ; Lewis, SJG ; Tisch, S ; Evans, AH ; O'Sullivan, JD ; Kimber, T ; Darby, D ; Churilov, L ; Law, M ; Hovens, CM ; Velakoulis, D ; O'Brien, TJ (BMJ PUBLISHING GROUP, 2021-12-01)
    INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).
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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, 2021-06-01)
    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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    Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression
    Chow, K ; Herrera, P ; Stuchbery, R ; Peters, JS ; Costello, AJ ; Hovens, CM ; Corcoran, NM (WILEY, 2019-06-01)
    OBJECTIVE: To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era. PATIENTS AND METHODS: Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen-deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12 months (early), BCR at 12-60 months (intermediate), and BCR at >60 months (late), after RP. Clinicopathological characteristics were analysed using the Student's t-test, Mann-Whitney U-test, or chi-squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time-points. RESULTS: In all, 2312 patients were included in the final analysis with up to 12 years of follow-up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group ≥2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5 years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43-3.20; P <0.001). CONCLUSION: This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation.
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    Ductal adenocarcinoma of the prostate: A systematic review and meta-analysis of incidence, presentation, prognosis, and management.
    Ranasinha, N ; Omer, A ; Philippou, Y ; Harriss, E ; Davies, L ; Chow, K ; Chetta, PM ; Erickson, A ; Rajakumar, T ; Mills, IG ; Bryant, RJ ; Hamdy, FC ; Murphy, DG ; Loda, M ; Hovens, CM ; Corcoran, NM ; Verrill, C ; Lamb, AD (Wiley, 2021-01)
    Context: Ductal adenocarcinoma (DAC) is relatively rare, but is nonetheless the second most common subtype of prostate cancer. First described in 1967, opinion is still divided regarding its biology, prognosis, and outcome. Objectives: To systematically interrogate the literature to clarify the epidemiology, diagnosis, management, progression, and survival statistics of DAC. Materials and methods: We conducted a literature search of five medical databases from inception to May 04 2020 according to PRISMA criteria using search terms "prostate ductal adenocarcinoma" OR "endometriod adenocarcinoma of prostate" and variations of each. Results: Some 114 studies were eligible for inclusion, presenting 2 907 170 prostate cancer cases, of which 5911 were DAC. [Correction added on 16 January 2021 after the first online publication: the preceding statement has been corrected in this current version.] DAC accounts for 0.17% of prostate cancer on meta-analysis (range 0.0837%-13.4%). The majority of DAC cases were admixed with predominant acinar adenocarcinoma (AAC). Median Prostate Specific Antigen at diagnosis ranged from 4.2 to 9.6 ng/mL in the case series.DAC was more likely to present as T3 (RR1.71; 95%CI 1.53-1.91) and T4 (RR7.56; 95%CI 5.19-11.01) stages, with far higher likelihood of metastatic disease (RR4.62; 95%CI 3.84-5.56; all P-values < .0001), compared to AAC. Common first treatments included surgery (radical prostatectomy (RP) or cystoprostatectomy for select cases) or radiotherapy (RT) for localized disease, and hormonal or chemo-therapy for metastatic disease. Few studies compared RP and RT modalities, and those that did present mixed findings, although cancer-specific survival rates seem worse after RP.Biochemical recurrence rates were increased with DAC compared to AAC. Additionally, DAC metastasized to unusual sites, including penile and peritoneal metastases. Where compared, all studies reported worse survival for DAC compared to AAC. Conclusion: When drawing conclusions about DAC it is important to note the heterogenous nature of the data. DAC is often diagnosed incidentally post-treatment, perhaps due to lack of a single, universally applied histopathological definition. As such, DAC is likely underreported in clinical practice and the literature. Poorer prognosis and outcomes for DAC compared to AAC merit further research into genetic composition, evolution, diagnosis, and treatment of this surprisingly common prostate cancer sub-type. Patient summary: Ductal prostate cancer is a rare but important form of prostate cancer. This review demonstrates that it tends to be more serious at detection and more likely to spread to unusual parts of the body. Overall survival is worse with this type of prostate cancer and urologists need to be aware of the presence of ductal prostate cancer to alter management decisions and follow-up.
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    The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited
    Deek, MP ; Van der Eecken, K ; Phillips, R ; Parikh, NR ; Velho, PI ; Lotan, TL ; Kishan, AU ; Maurer, T ; Boutros, PC ; Hovens, C ; Abramowtiz, M ; Pollack, A ; Desai, N ; Stish, B ; Feng, FY ; Eisenberger, M ; Carducci, M ; Pienta, KJ ; Markowski, M ; Paller, CJ ; Antonarakis, ES ; Berlin, A ; Ost, P ; Tran, PT (ELSEVIER, 2021-10-14)
    BACKGROUND: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical. OBJECTIVE: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC). RESULTS AND LIMITATIONS: The frequency of driver mutations in TP53 (p =  0.01), WNT (p =  0.08), and cell cycle (p =  0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p =  0.002), and time to CRPC (95.6 vs 155.8 mo; p =  0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p =  0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p =  0.004) and DNA double-strand break repair (IRR 1.61; p <  0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p =  0.03) and the development of CRPC (HR 1.71; p =  0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined. CONCLUSIONS: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration. PATIENT SUMMARY: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.