Surgery (RMH) - Research Publications

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    Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer
    Soekmadji, C ; Corcoran, NM ; Oleinikova, I ; Jovanovic, L ; Ramm, GA ; Nelson, CC ; Jenster, G ; Russell, PJ (WILEY, 2017-10-01)
    The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation.
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    Feasibility for active surveillance in biopsy Gleason 3+4 prostate cancer: an Australian radical prostatectomy cohort
    Wong, L-M ; Tang, V ; Peters, J ; Costello, A ; Corcoran, N (WILEY, 2016-04)
    OBJECTIVE: To examine the feasibility of active surveillance for low volume Gleason sum (GS) 3 + 4 disease compared to GS 3 + 3 disease. PATIENTS AND METHODS: Retrospective review of 929 patients, with biopsy proven GS 3 + 3 and 3 + 4 PCa, undergoing upfront radical prostatectomy (RP) was performed. Suitability for AS was adapted from protocols by Royal Marsden Hospital, University of Toronto, and PRIAS by allowing Gleason 3 + 4 disease. The outcomes assessed were adverse pathology at RP (upgrading ≥GS 4 + 3 and/or upstaging ≥pT3) and biochemical recurrence (BCR) after RP. RESULTS: Adverse pathology at RP was compared between GS 3 + 3 vs 3 + 4 groups. When selecting patients using Royal Marsden (n = 714) or University of Toronto (n = 699) protocols, there was statistically significantly more adverse pathology at RP in GS 3 + 4 group (21% vs 31%, P = 0.0028 and 19% vs 33%, P=<0.001 respectively). Using the more stringent PRIAS protocol (n = 198), there was no statistical significant difference in groups. There was no difference in BCR survival between biopsy GS 3 + 3 and 3 + 4 groups, regardless of which AS protocol assessed. Pre-operative PSA and clinical staging were the predictors for BCR. CONCLUSION: Presence of Gleason 3 + 4 at biopsy, when compared to 3 + 3, increases the risk of adverse pathology being present at radical prostatectomy for less stringent selection criteria. When considering AS, a stricter protocol such as PRIAS, limiting PSA density and number of positive cores to ≤2, appears to decrease the risk of adverse pathology. No differences in BCR were seen between biopsy 3 + 3 and 3 + 4 disease, regardless of AS selection criteria.
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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)
    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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    Robotic-assisted radical cystectomy with intracorporeal urinary diversion versus open: early Australian experience
    Chow, K ; Zargar, H ; Corcoran, NM ; Costello, AJ ; Peters, JS ; Dundee, P (WILEY, 2018-10)
    BACKGROUND: The aim of this study was to describe our initial Australian single surgeon experience with robotic-assisted radical cystectomy (RARC) and intracorporeal urinary diversion (ICUD) and to compare the outcomes with open radical cystectomy (ORC). METHODS: Between January 2014 and June 2016, consecutive patients diagnosed with muscle invasive and high-risk non-muscle invasive bladder cancer undergoing radical cystectomy were included. Treatment modalities included either RARC with ICUD or ORC. ICUD consisted of either intracorporeal ileal conduit or orthotopic neobladder formation. Prospectively collected perioperative and oncological outcomes were analysed. RESULTS: Twenty-six RARC and 13 ORC were performed. Median operating times were 362 and 240 min for RARC and ORC, respectively (P < 0.001). Estimated blood loss for RARC was 300 mL compared with 500 mL for ORC (P = 0.01). Post-operative haemoglobin drop was less in the RARC cohort (20% versus 24%, P = 0.03). There was no statistical difference in overall 90-day complication rates (81% versus 62%, P = 0.25) and 90-day major complication rates (19% versus 23%, P = 0.67) between the RARC and ORC groups, respectively. Positive surgical margins for RARC were 4% and 8% for ORC (P = 1.0). CONCLUSION: Early results demonstrate that the safe introduction of RARC with ICUD in Australia is potentially feasible without compromising perioperative and oncological outcomes. Future randomized trial with larger numbers will be required for further analysis in the Australian setting.
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    Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer
    Corcoran, NM ; Hovens, CM ; Michael, M ; Rosenthal, MA ; Costello, AJ (NATURE PUBLISHING GROUP, 2010-08-10)
    BACKGROUND: Angiogenesis is fundamental to the progression of many solid tumours including prostate cancer. Sodium selenate is a small, water-soluble, orally bioavailable activator of PP2A phosphatase with anti-angiogenic properties. METHODS: This was a dose-escalation phase I study in men with asymptomatic, chemotherapy-naïve, castration-resistant prostate cancer. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included establishing the safety, tolerability and pharmacokinetic profile. RESULTS: A total of 19 patients were enrolled. The MTD was 60 mg per day. Dose-limiting toxicity (fatigue and diarrhoea) was observed at 90 mg per day. The most frequently reported treatment-related adverse events across all treatment cohorts were nausea, diarrhoea, fatigue, muscle spasms, alopecia and nail disorders. No grade 4 toxicities were observed and there were no deaths on study. Linear pharmacokinetics was observed. One patient had a PSA response >50%. Median time to PSA progression (for non-responders) was 14.2 weeks. Mean PSA doubling time increased during the main treatment phase from 2.18 months before trial to 3.85 months. CONCLUSION: Sodium selenate is well tolerated at a dose of 60 mg per day with modest single-agent efficacy similar to other anti-angiogenic agents. Further trials in combination with conventional cytotoxic regimens are warranted.
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    Error rates in a clinical data repository: lessons from the transition to electronic data transfer - a descriptive study
    Hong, MKH ; Yao, HHI ; Pedersen, JS ; Peters, JS ; Costello, AJ ; Murphy, DG ; Hovens, CM ; Corcoran, NM (BMJ PUBLISHING GROUP, 2013)
    OBJECTIVE: Data errors are a well-documented part of clinical datasets as is their potential to confound downstream analysis. In this study, we explore the reliability of manually transcribed data across different pathology fields in a prostate cancer database and also measure error rates attributable to the source data. DESIGN: Descriptive study. SETTING: Specialist urology service at a single centre in metropolitan Victoria in Australia. PARTICIPANTS: Between 2004 and 2011, 1471 patients underwent radical prostatectomy at our institution. In a large proportion of these cases, clinicopathological variables were recorded by manual data-entry. In 2011, we obtained electronic versions of the same printed pathology reports for our cohort. The data were electronically imported in parallel to any existing manual entry record enabling direct comparison between them. OUTCOME MEASURES: Error rates of manually entered data compared with electronically imported data across clinicopathological fields. RESULTS: 421 patients had at least 10 comparable pathology fields between the electronic import and manual records and were selected for study. 320 patients had concordant data between manually entered and electronically populated fields in a median of 12 pathology fields (range 10-13), indicating an outright accuracy in manually entered pathology data in 76% of patients. Across all fields, the error rate was 2.8%, while individual field error ranges from 0.5% to 6.4%. Fields in text formats were significantly more error-prone than those with direct measurements or involving numerical figures (p<0.001). 971 cases were available for review of error within the source data, with figures of 0.1-0.9%. CONCLUSIONS: While the overall rate of error was low in manually entered data, individual pathology fields were variably prone to error. High-quality pathology data can be obtained for both prospective and retrospective parts of our data repository and the electronic checking of source pathology data for error is feasible.
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    International multicentre study examining selection criteria for active surveillance in men undergoing radical prostatectomy
    Wong, L-M ; Neal, DE ; Johnston, RB ; Shah, N ; Sharma, N ; Warren, AY ; Hovens, CM ; Goldenberg, SL ; Gleave, ME ; Costello, AJ ; Corcoran, NM (NATURE PUBLISHING GROUP, 2012-10-23)
    BACKGROUND: The controversies concerning possible overtreatment of prostate cancer, highlighted by debate over PSA screening, have highlighted active surveillance (AS) as an alternative management option for appropriate men. Regional differences in the underlying prevalence of PSA testing may alter the pre-test probability for high-risk disease, which can potentially interfere with the performance of selection criteria for AS. In a multicentre study from three different countries, we examine men who were initially suitable for AS according to the Toronto and Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, that underwent radical prostatectomy (RP) in regards to:1.the proportion of pathological reclassification(Gleason score ≥7, ≥pT3 disease),2.predictors of high-risk disease,3.create a predictive model to assist with selection of men suitable for AS. METHODS: From three centres in the United Kingdom, Canada and Australia, data on men who underwent RP were retrospectively reviewed (n=2329). Multivariable logistic regression was performed to identify predictors of high-risk disease. A nomogram was generated by logistic regression analysis, and performance characterised by receiver operating characteristic curves. RESULTS: For men suitable for AS according to the Toronto (n=800) and PRIAS (410) criteria, the rates for upgrading were 50.6, 42.7%, and upstaging 17.6, 12.4%, respectively. Significant predictors of high-risk disease were:•Toronto criteria: increasing age, cT2 disease, centre of diagnosis and number of positive cores.•PRIAS criteria: increasing PSA and cT2 disease.Cambridge had a high pT3a rate (26 vs 12%). To assist selection of men in the United Kingdom for AS, from the Cambridge data, we generated a nomogram predicting high-risk features in patients who meet the Toronto criteria (AUC of 0.72). CONCLUSION: The proportion of pathological reclassification in our cohort was higher than previously reported. Care must be used when applying the AS criteria generated from one population to another. With more stringent selection criteria, there is less reclassification but also fewer men who may benefit from AS.
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    Reply: On the clinical relevance of circulating endothelial cells and platelets in prostate cancer
    Wong, CKE ; Namdarian, B ; Chua, J ; Chin, X ; Speirs, R ; Nguyen, T ; Fankhauser, M ; Pedersen, J ; Costello, AJ ; Corcoran, NM ; Hovens, CM (NATURE PUBLISHING GROUP, 2013-04-02)
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    Levels of a subpopulation of platelets, but not circulating endothelial cells, predict early treatment failure in prostate cancer patients after prostatectomy
    Wong, CKE ; Namdarian, B ; Chua, J ; Chin, X ; Speirs, R ; Nguyen, T ; Fankhauser, M ; Pedersen, J ; Costello, AJ ; Corcoran, NM ; Hovens, CM (NATURE PUBLISHING GROUP, 2012-10-23)
    BACKGROUND: Angiogenesis is one of the hallmarks of cancer driving tumour growth and ultimately metastasis. Circulating endothelial cells (CECs) and circulating endothelial progenitor (CEPs) cells have been reported as candidate surrogate markers for tumour vascularisation. Our aim was to investigate the potential use of these circulating cells levels as predictors of prostate cancer treatment failure and metastasis. METHODS: We examined the levels of CD31(+)CD45(-) cells (CECs) and CD31(+)CD45(-)CD117(+) (CEPs) in s.c. and orthotopic models of human prostate cancers and correlated measurements with tumour size, volume and microvessel density (MVD). We then performed a prospective cohort study in 164 men with localised prostate cancer undergoing prostatectomy. The CD31(+)CD45(-), CD31(+)CD45(-)CD146(+) (CECs) and CD31(+)CD45(intermediate)CD133(+) (CEPs) populations were quantified and subsequently enriched for further characterisation. RESULTS: In preclinical models, levels of CD31(+)CD45(-) cells, but not CEPs, were significantly elevated in tumour-bearing mice and correlated with tumour size, volume and MVD. In our human prospective cohort study, the levels of CD31(+)CD45(-) cells were significantly higher in men who experienced treatment failure within the first year, and on logistic regression analysis were an independent predictor of treatment failure, whereas neither levels of CECs or CEPs had any prognostic utility. Characterisation of the isolated CD31(+)CD45(-) cell population revealed an essentially homogenous population of large, immature platelets representing <0.1% of circulating platelets. CONCLUSION: Elevated levels of a distinct subpopulation of circulating platelets were an independent predictor for early biochemical recurrence in prostate cancer patients within the first year from prostatectomy.
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    Curated MicroRNAs in Urine and Blood Fail to Validate as Predictive Biomarkers for High-Risk Prostate Cancer
    Sapre, N ; Hong, MKH ; Macintyre, G ; Lewis, H ; Kowalczyk, A ; Costello, AJ ; Corcoran, NM ; Hovens, CM ; Medeiros, R (PUBLIC LIBRARY SCIENCE, 2014-04-04)
    PURPOSE: The purpose of this study was to determine if microRNA profiling of urine and plasma at radical prostatectomy can distinguish potentially lethal from indolent prostate cancer. MATERIALS AND METHODS: A panel of microRNAs was profiled in the plasma of 70 patients and the urine of 33 patients collected prior to radical prostatectomy. Expression of microRNAs was correlated to the clinical endpoints at a follow-up time of 3.9 years to identify microRNAs that may predict clinical response after radical prostatectomy. A machine learning approach was applied to test the predictive ability of all microRNAs profiled in urine, plasma, and a combination of both, and global performance assessed using the area under the receiver operator characteristic curve (AUC). Validation of urinary expression of miRNAs was performed on a further independent cohort of 36 patients. RESULTS: The best predictor in plasma using eight miRs yielded only moderate predictive performance (AUC = 0.62). The best predictor of high-risk disease was achieved using miR-16, miR-21 and miR-222 measured in urine (AUC = 0.75). This combination of three microRNAs in urine was a better predictor of high-risk disease than any individual microRNA. Using a different methodology we found that this set of miRNAs was unable to predict high-volume, high-grade disease. CONCLUSIONS: Our initial findings suggested that plasma and urinary profiling of microRNAs at radical prostatectomy may allow prognostication of prostate cancer behaviour. However we found that the microRNA expression signature failed to validate in an independent cohort of patients using a different platform for PCR. This highlights the need for independent validation patient cohorts and suggests that urinary microRNA signatures at radical prostatectomy may not be a robust way to predict the course of clinical disease after definitive treatment for prostate cancer.