Publications by authors named "Anthony J Costello"

133 Publications

Articles on robotic surgery.

ANZ J Surg 2021 11;91(11):2238-2240

Department of Surgery and Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ans.16982DOI Listing
November 2021

Robotics in Australian urology contemporary practice and future perspectives.

ANZ J Surg 2021 11;91(11):2241-2245

Department of Urology, The University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1111/ans.17161DOI Listing
November 2021

A review of simulation training and new 3D computer-generated synthetic organs for robotic surgery education.

J Robot Surg 2021 Sep 3. Epub 2021 Sep 3.

Department of Surgery, The University of Melbourne, Parkville, VIC, Australia.

We conducted a comprehensive review of surgical simulation models used in robotic surgery education. We present an assessment of the validity and cost-effectiveness of virtual and augmented reality simulation, animal, cadaver and synthetic organ models. Face, content, construct, concurrent and predictive validity criteria were applied to each simulation model. There are six major commercial simulation machines available for robot-assisted surgery. The validity of virtual reality (VR) simulation curricula for psychomotor assessment and skill acquisition for the early phase of robotic surgery training has been demonstrated. The widespread adoption of VR simulation has been limited by the high cost of these machines. Live animal and cadavers have been the accepted standard for robotic surgical simulation since it began in the early 2000s. Our review found that there is a lack of evidence in the literature to support the use of animal and cadaver for robotic surgery training. The effectiveness of these models as a training tool is limited by logistical, ethical, financial and infection control issues. The latest evolution in synthetic organ model training for robotic surgery has been driven by new 3D-printing technology. Validated and cost-effective high-fidelity procedural models exist for robotic surgery training in urology. The development of synthetic models for the other specialties is not as mature. Expansion into multiple surgical disciplines and the widespread adoption of synthetic organ models for robotic simulation training will require the ability to engineer scalability for mass production. This would enable a transition in robotic surgical education where digital and synthetic organ models could be used in place of live animals and cadaver training to achieve robotic surgery competency.
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http://dx.doi.org/10.1007/s11701-021-01302-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415702PMC
September 2021

Loss of in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

JCO Precis Oncol 2021 Jun 22;5. Epub 2021 Jun 22.

Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.

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 , a key regulator of EMT reprogramming.

Conclusion: We show that EMT characterizes acutely resistant prostate tumors and that deletion of , a key transcriptional regulator of EMT, correlates with clinical response.
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http://dx.doi.org/10.1200/PO.20.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238292PMC
June 2021

The modified International Society of Urological Pathology system improves concordance between biopsy and prostatectomy tumour grade.

BJU Int 2021 Jul 26. Epub 2021 Jul 26.

Department of Urology, Melbourne Health, Royal Melbourne Hospital, Australia.

Objectives: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI).

Patients And Methods: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups.

Results: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding.

Conclusion: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.
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http://dx.doi.org/10.1111/bju.15556DOI Listing
July 2021

Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression.

BMC Cancer 2021 Jul 22;21(1):846. Epub 2021 Jul 22.

Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia.

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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http://dx.doi.org/10.1186/s12885-021-08529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296706PMC
July 2021

MSH2-deficient prostate tumours have a distinct immune response and clinical outcome compared to MSH2-deficient colorectal or endometrial cancer.

Prostate Cancer Prostatic Dis 2021 Dec 9;24(4):1167-1180. Epub 2021 Jun 9.

Departments of Surgery and Urology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes.

Methods And Results: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours.

Conclusions: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.
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http://dx.doi.org/10.1038/s41391-021-00379-4DOI Listing
December 2021

Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival.

Eur J Cancer 2021 05 5;148:440-450. Epub 2021 Mar 5.

Department of Surgery, University of Melbourne, Parkville, Victoria, Australia; Urology Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia; Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia; Department of Urology, Frankston Hospital, Frankston, Victoria, Australia.

Background: Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival.

Methods: Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8).

Results: A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH.

Conclusions: The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.
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http://dx.doi.org/10.1016/j.ejca.2020.12.030DOI Listing
May 2021

Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.

Genome Med 2020 08 17;12(1):72. Epub 2020 Aug 17.

Department of Surgery, University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, 3050, Australia.

Background: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown.

Methods: We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival.

Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014).

Conclusions: CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
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http://dx.doi.org/10.1186/s13073-020-00770-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430029PMC
August 2020

Considering the role of radical prostatectomy in 21st century prostate cancer care.

Nat Rev Urol 2020 03 21;17(3):177-188. Epub 2020 Feb 21.

Department of Urology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.

The practice of radical prostatectomy for treating prostate cancer has evolved remarkably since its general introduction around 1900. Initially described using a perineal approach, the procedure was later popularized using a retropubic one, after it was first described as such in 1948. The open surgical method has now largely been abandoned in favour of the minimally invasive robot-assisted method, which was first described in 2000. Until 1980, the procedure was hazardous, often accompanied by massive blood loss and poor outcomes. For patients in whom surgery is indicated, prostatectomy is increasingly being used as the first step in a multitherapeutic approach in advanced local, and even early metastatic, disease. However, contemporary molecular insights have enabled many men to safely avoid surgical intervention when the disease is phenotypically indolent and use of active surveillance programmes continues to expand worldwide. In 2020, surgery is not recommended in those men with low-grade, low-volume Gleason 6 prostate cancer; previously these men - a large cohort of ~40% of men with newly diagnosed prostate cancer - were offered surgery in large numbers, with little clinical benefit and considerable adverse effects. Radical prostatectomy is appropriate for men with intermediate-risk and high-risk disease (Gleason score 7-9 or Grade Groups 2-5) in whom radical prostatectomy prevents further metastatic seeding of potentially lethal clones of prostate cancer cells. Small series have suggested that it might be appropriate to offer radical prostatectomy to men presenting with small metastatic burden (nodal and or bone) as part of a multimodal therapeutic approach. Furthermore, surgical treatment of prostate cancer has been reported in cohorts of octogenarian men in good health with minimal comorbidities, when 20 years ago such men were rarely treated surgically even when diagnosed with localized high-risk disease. As medical therapies for prostate cancer continue to increase, the use of surgery might seem to be less relevant; however, the changing demographics of prostate cancer means that radical prostatectomy remains an important and useful option in many men, with a changing indication.
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http://dx.doi.org/10.1038/s41585-020-0287-yDOI Listing
March 2020

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial.

Int J Cancer 2020 01 28;146(1):161-168. Epub 2019 Jun 28.

Icon Cancer Centre, Richmond, VIC, Australia.

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1-59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8-29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08-0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4-5 vs. 1-3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.
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http://dx.doi.org/10.1002/ijc.32509DOI Listing
January 2020

Prostatic nerve subtypes independently predict biochemical recurrence in prostate cancer.

J Clin Neurosci 2019 May 13;63:213-219. Epub 2019 Feb 13.

Department of Surgery, Division of Urology, University of Melbourne, Royal Melbourne Hospital, Australia; Urology Unit, Department of Surgery, Peninsula Health, Australia; Australian Prostate Cancer Research Centre Epworth, Richmond, Australia.

Objective: To describe nerve subtypes involved by perineural invasion (PNI) in prostate cancer and their relationship with clinicopathological parameters and recurrence risk.

Methods: 141 prostatectomy specimens from men with localized prostate cancer and known perineural invasion were analyzed. Index tumor blocks were stained for perineural invasion and sympathetic/parasympathetic markers. For 98 patients with complete staining, nerves from up to three hotspot regions of intraprostatic perineural invasion were classified according to autonomic subtype and perineural invasion status. Findings were correlated with prospectively collected clinicopathological data. Biochemical recurrence predictors were tested in univariable and multivariable models.

Results: Most intra-prostatic nerves contained sympathetic and parasympathetic fibres, irrespective of perineural invasion status. A fraction was purely sympathetic (5% PNI, 2% non-PNI) or double-negative (non-adrenergic, non-nitrergic; 1% PNI, 1% non-PNI). Perineural invasion nerve count was associated with higher pathological stage. Although total perineural invasion or non-perineural invasion nerve count did not predict biochemical recurrence, two subtypes were found to be independent predictors: pure sympathetic non-perineural invasion nerves (HR 6.79, p = 0.03) and non-adrenergic, non-nitrergic PNI nerves (HR 10.56, p < 0.005).

Conclusions: Pure sympathetic nerve density without tumour invasion and perineural invasion specifically involving non-adrenergic, non-nitrergic fibres are independent predictors of biochemical recurrence post prostatectomy, supporting a role for the autonomic nervous system in prostate cancer progression.
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http://dx.doi.org/10.1016/j.jocn.2019.01.052DOI Listing
May 2019

Preparation of fluorescent in situ hybridisation probes without the need for optimisation of fragmentation.

MethodsX 2019 27;6:22-34. Epub 2018 Nov 27.

Departments of Surgery and Urology, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia.

DNA-fluorescence in situ hybridisation (DNA-FISH) allows visualisation of chromosome organisation and rearrangement. FISH probes are pools of short fluorescently labelled DNA fragments that are often produced from template plasmids that contain large genomic inserts. For effective sample penetration and target hybridisation it is critical that probe fragments are between 200 and 500bp. Production of these short probes requires significant optimisation and can be confounded access to expensive sonication equipment or inherent sequence features that influence enzymatic fragmentation or amplification. Here we demonstrate that effective FISH probes can be prepared without the need for optimisation of fragmentation using a cocktail of two the 4bp recognition sequence restriction enzymes CviQI and AluI.
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http://dx.doi.org/10.1016/j.mex.2018.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308247PMC
November 2018

Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression.

BJU Int 2019 06 19;123(6):976-984. Epub 2018 Oct 19.

Departments of Urology and Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria,, Australia.

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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http://dx.doi.org/10.1111/bju.14556DOI Listing
June 2019

Ga-labeled Prostate-specific Membrane Antigen Ligand-positron-emission Tomography: Still Just the Tip of the Iceberg.

Urology 2018 Oct 28;120:187-191. Epub 2018 Jun 28.

The Royal Melbourne Hospital, Melbourne, Australia; University of Melbourne, Victoria, Australia; Australian Prostate Centre, Melbourne, Australia.

Objectives: To assess the performance of Ga-labeled prostate-specific membrane antigen ligand-positron-emission tomography (Ga-PSMA PET) for positive lymph nodes on imaging after curatively intended radical prostatectomy.

Patients And Methods: Seventeen patients with biochemical recurrence after radical prostatectomy undergoing robot-assisted salvage lymphadenectomy for positive lymph nodes on imaging were included in this single surgeon study. The performance of Ga-PSMA PET was assessed on per patient, per lesion, per landing site and per laterality level using sensitivity, specificity, and negative and positive predictive value analysis.

Results: A total of 34 positive nodes were detected on Ga-PSMA PET with a median of 2 nodes per patient (IQR 1-3 nodes per patient). Sixty six nodes were pathologically disease positive from 14 patients, with a median of 2 positive nodes per patient (IQR 1-6). Three patients had no pathologically detectable disease. On a per patient basis, the positive predictive value was 82%. Sensitivity, specificity, and negative predictive value were not able to be calculated as all patients had disease recurrence with a detectable prostate-specific antigen.On a "per lesion" basis, the sensitivity, specificity, positive predictive value, and negative predictive value were 36.7%, 96.9%, 73.5%, and 86.7%, respectively.

Conclusion: Our study indicates that sensitivity of Ga-PSMA PET in the salvage setting is not yet sufficient to detect all sites of metastasis. Therefore, imaging-guided metastasis targeted treatment is likely to fail given the likely concomitant imaging negative more widespread disease.
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http://dx.doi.org/10.1016/j.urology.2018.06.029DOI Listing
October 2018

Obesity suppresses tumor attributable PSA, affecting risk categorization.

Endocr Relat Cancer 2018 05;25(5):561-568

Departments of Urology and Surgery, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia.

Obesity is linked with more aggressive prostate cancer and higher rates of disease recurrence post treatment. It is unclear if this is due to specific tumor-promoting effects of obesity or diagnostic bias. Patients undergoing prostatectomy were categorized according to their body mass index (BMI). Expected prostate-specific antigen (PSA) levels were calculated for each patient based on tumor characteristics. The effect of obesity on the accuracy of pre-treatment risk categorization was determined, and mediation analysis was used to identify the contribution of biologic vs non-biologic mechanisms to the observed increased risk of biochemical recurrence. Residual tumor-promoting effects were estimated in a survival model controlling for diagnostic error. The following results were obtained. The analysis included 1587 patients. Despite similar rates of adverse pathological features at prostatectomy, biochemical recurrence rates were significantly higher in very obese patients, which persisted after adjustment for stage, grade and PSA. Tumor volume however correlated significantly with BMI ( = 0.004), and the difference in predicted and observed 'tumor-attributable' PSA (Delta-PSA) in very obese patients was greater than three times higher than that of healthy patients ( = 0.0067). Regression analysis indicated that the effect of BMI on tumor volume was fully mediated indirectly by its effect on PSA. Inclusion of this diagnostic error as a covariate in the survival analysis attenuated the effect of BMI on recurrence. In conclusion, being very obese suppresses tumor-associated PSA resulting in a diagnostic bias that is responsible for errors in risk classification, and potentially contributes to a delay in initial presentation.
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http://dx.doi.org/10.1530/ERC-17-0466DOI Listing
May 2018

Periprostatic fat tissue transcriptome reveals a signature diagnostic for high-risk prostate cancer.

Endocr Relat Cancer 2018 05 28;25(5):569-581. Epub 2018 Mar 28.

Australian Prostate Cancer Research Centre Epworth, Richmond, Victoria, Australia.

Evidence suggests that altered adipose tissue homeostasis may be an important contributor to the development and/or progression of prostate cancer. In this study, we investigated the adipose transcriptional profiles of low- and high-risk disease to determine both prognostic potential and possible biological drivers of aggressive disease. RNA was extracted from periprostatic adipose tissue from patients categorised as having prostate cancer with either a low or high risk of progression based on tumour characteristics at prostatectomy and profiled by RNA sequencing. The expression of selected genes was then quantified by qRT-PCR in a cross-validation cohort. In the first phase, a total of 677 differentially transcribed genes were identified, from which a subset of 14 genes was shortlisted. In the second phase, a 3 gene (, , ) signature was refined and evaluated using recursive feature selection and cross-validation, obtaining a promising discriminatory utility (area under curve 0.72) at predicting the presence of high-risk disease. Genes implicated in immune and/or inflammatory responses predominated. Periprostatic adipose tissue from patients with high-risk prostate cancer has a distinct transcriptional signature that may be useful for detecting its occult presence. Differential expression appears to be driven by a local immune/inflammatory reaction to more advanced tumours, than any specific adipose tissue-specific tumour-promoting mechanism. This signature is transferable into a clinically usable PCR-based assay, which in a cross-validation cohort shows diagnostic potential.
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http://dx.doi.org/10.1530/ERC-18-0058DOI Listing
May 2018

Robotic-assisted radical cystectomy with intracorporeal urinary diversion versus open: early Australian experience.

ANZ J Surg 2018 10 8;88(10):1028-1032. Epub 2018 Jan 8.

Department of Urology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

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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http://dx.doi.org/10.1111/ans.14361DOI Listing
October 2018

3D modelling of radical prostatectomy specimens: Developing a method to quantify tumor morphometry for prostate cancer risk prediction.

Pathol Res Pract 2017 Dec 27;213(12):1523-1529. Epub 2017 Sep 27.

Division of Urology, Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville and Australian Prostate Cancer Research Centre at Epworth Hospital, Richmond, VIC, Australia.

Prostate cancer displays a wide spectrum of clinical behaviour from biological indolence to rapidly lethal disease, but we remain unable to accurately predict an individual tumor's future clinical course at an early curable stage. Beyond basic dimensions and volume calculations, tumor morphometry is an area that has received little attention, as it requires the analysis of the prostate gland and tumor foci in three-dimensions. Previous efforts to generate three-dimensional prostate models have required specialised graphics units and focused on the spatial distribution of tumors for optimisation of biopsy strategies rather than to generate novel morphometric variables such as tumor surface area. Here, we aimed to develop a method of creating three-dimensional models of a prostate's pathological state post radical prostatectomy that allowed the derivation of surface areas and volumes of both prostate and tumors, to assess the method's accuracy to known clinical data, and to perform initial investigation into the utility of morphometric variables in prostate cancer prognostication. Serial histology slides from 21 prostatectomy specimens covering a range of tumor sizes and pathologies were digitised. Computer generated three-dimensional models of tumor and prostate space filling models were reconstructed from these scanned images using Rhinoceros 4.0 spatial reconstruction software. Analysis of three-dimensional modelled prostate volume correlated only moderately with weak concordance to that from the clinical data (r=0.552, θ=0.405), but tumor volume correlated well with strong concordance (r=0.949, θ=0.876). We divided the cohort of 21 patients into those with features of aggressive tumor versus those without and found that larger tumor surface area (32.7 vs 3.4cc, p=0.008) and a lower tumor surface area to volume ratio (4.7 vs 15.4, p=0.008) were associated with aggressive tumor biology.
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http://dx.doi.org/10.1016/j.prp.2017.09.022DOI Listing
December 2017

Changing face of robot-assisted radical prostatectomy in Melbourne over 12 years.

ANZ J Surg 2018 Mar 18;88(3):E200-E203. Epub 2017 Sep 18.

Division of Cancer Surgery, Department of Genitourinary Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: This study aims to characterize the trends in disease presentation for robot-assisted radical prostatectomy (RARP) over a 12-year period in Melbourne, Australia.

Methods: All patients undergoing an RARP between 2004 and October 2016 while under the care of six high-volume surgeons were included in this study. Data were collected prospectively regarding patient demographics and clinical details of their cancer.

Results: Over the 12-year time span of the study, 3075 men underwent an RARP with a median age of 63.01 years. Temporal analysis demonstrated that the median age of patients undergoing prostatectomy advanced with time with the median age in 2016 being 65.51 years compared with 61.0 years in 2004 (P < 0.001). There was also a significant trend to increased D'Amico risk groups over time with the percentage procedures for high-risk patients increasing from 12.6% to 28.10% from 2004 to 2016 (P < 0.001). Upgrade rates between biopsy and pathological Gleason grade scoring significantly trended down over the period of the study (P < 0.001). There was also a shift to increased pathological stage over the 12 years with 22.1% of men having T3 disease in 2004 compared with 49.8% in 2016.

Conclusion: Our analysis demonstrates increasing treatment of older men with higher risk tumours, consistent with international trends. While this largely reflects a shift in case selection, further work is needed to assess whether the stage shift may relate partially to a decline in screening and increased presentation of higher risk disease.
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http://dx.doi.org/10.1111/ans.14169DOI Listing
March 2018

Editorial Comment.

J Urol 2017 09 24;198(3):606. Epub 2017 May 24.

Department of Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1016/j.juro.2017.03.146DOI Listing
September 2017

Comparing nodal versus bony metastatic spread using tumour phylogenies.

Sci Rep 2016 Sep 22;6:33918. Epub 2016 Sep 22.

Departments of Urology and Surgery, Royal Melbourne Hospital and University of Melbourne, Parkville 3050 Victoria, Australia.

The role of lymph node metastases in distant prostate cancer dissemination and lethality is ill defined. Patients with metastases restricted to lymph nodes have a better prognosis than those with distant metastatic spread, suggesting the possibility of distinct aetiologies. To explore this, we traced patterns of cancer dissemination using tumour phylogenies inferred from genome-wide copy-number profiling of 48 samples across 3 patients with lymph node metastatic disease and 3 patients with osseous metastatic disease. Our results show that metastatic cells in regional lymph nodes originate from evolutionary advanced extraprostatic tumour cells rather than less advanced central tumour cell populations. In contrast, osseous metastases do not exhibit such a constrained developmental lineage, arising from either intra or extraprostatic tumour cell populations, at early and late stages in the evolution of the primary. Collectively, this comparison suggests that lymph node metastases may not be an intermediate developmental step for distant osseous metastases, but rather represent a distinct metastatic lineage.
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http://dx.doi.org/10.1038/srep33918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031992PMC
September 2016

High-resolution Map of Somatic Periprostatic Nerves.

Urology 2016 11 26;97:160-165. Epub 2016 Aug 26.

Departments of Urology and Surgery, University of Melbourne, The Royal Melbourne Hospital, Australia; Australian Prostate Cancer Centre, Epworth Hospital, Australia.

Objective: To generate a high-resolution map of periprostatic somatic nerves. Periprostatic nerves are at risk of injury during radical prostatectomy; this study aimed to establish the location of somatic nerves with respect to the prostate and the neurovascular bundle.

Materials And Methods: Hemiprostates from patients in whom a wide local excision was performed were evaluated. Representative sections from the base, midzone, and apex of the prostate were stained with Masson's trichrome and antineuronal nitric oxide synthase antibodies, to identify myelinated and parasympathetic nerves, respectively. Somatic nerves were identified as neuronal nitric oxide synthase negative myelinated nerves. Stained slides were scanned (40× objective) for digital analysis. Location of nerves was described with reference to 6 equal sectors per hemiprostate.

Results: Somatic nerves account for almost 5% of all nerve fibers in the periprostatic tissue. This study found a mean somatic nerve count of 5.83, 5.25, and 3.67 at the level of the prostate base, midzone, and apex, respectively. These nerves are most frequently located either anteriorly or in the region of the neurovascular bundle (posterolateral).

Conclusion: Somatic nerves in the periprostatic region are at risk of injury during radical prostatectomy. Further research is required to clarify their functional relevance.
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http://dx.doi.org/10.1016/j.urology.2016.08.027DOI Listing
November 2016

An online psychological intervention can improve the sexual satisfaction of men following treatment for localized prostate cancer: outcomes of a Randomised Controlled Trial evaluating My Road Ahead.

Psychooncology 2017 07 26;26(7):975-981. Epub 2016 Sep 26.

Department of Urology, The Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: Prostate cancer treatment often results in significant psycho-sexual challenges for men following treatment; however, many men report difficulty in accessing appropriate care.

Methods: A randomized controlled trial was undertaken to assess the efficacy of a 10-week self-guided online psychological intervention called My Road Ahead (MRA) for men with localized prostate cancer in improving sexual satisfaction. Participants were randomized to 1 of 3 conditions MRA alone or MRA plus online forum, or forum access alone. Pre, post, and follow-up assessments of overall sexual satisfaction were conducted. Mixed models and structural equation modeling were used to analyze the data.

Results: One hundred forty-two men (mean age 61 y; SD = 7) participated. The majority of participants had undergone radical prostatectomy (88%) and all men had received treatment for localized prostate cancer. Significant differences were obtained for the 3 groups (P = .026) and a significant improvement in total sexual satisfaction was observed only for participants who were allocated to MRA + forum with a large effect size (P = .004, partial η  = 0.256). Structural equation modeling indicated that increases in sexual function, masculine self-esteem, and sexual confidence contributed significantly to overall sexual satisfaction for the MRA + forum plus forum condition.

Conclusions: This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men with prostate cancer. The findings indicate the potential for MRA to deliver support that men may not otherwise receive and also highlight the importance of psychological intervention to facilitate improved sexual outcomes.
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http://dx.doi.org/10.1002/pon.4244DOI Listing
July 2017

Routinely reported 'equivocal' lymphovascular invasion in prostatectomy specimens is associated with adverse outcomes.

BJU Int 2017 04 31;119(4):567-572. Epub 2016 Aug 31.

Departments of Urology and Surgery, The Royal Melbourne Hospital and University of Melbourne, Parkville, Vic., Australia.

Objective: To evaluate the significance of routinely reported 'equivocal' lymphovascular invasion (LVI) in prostatectomy specimens of patients with clinically localized prostate cancer.

Materials And Methods: Prospectively collected data from men who underwent prostatectomy for clinically localized prostate cancer were retrospectively reviewed. Rates of adverse pathological features and biochemical recurrence (BCR) were compared between tumours positive, negative or 'equivocal' for LVI. Multivariable Cox regression analysis was performed to identify independent predictors of BCR.

Results: Of 1 310 consecutive cases, LVI was present definitively in 82 (6.3%) and equivocally in 43 (3.3%) cases. Similar to definitive LVI, equivocal LVI was significantly associated with other adverse pathological features, including advanced stage, higher Gleason grade and positive surgical margins. BCR occurred more frequently in patients with tumours that were equivocal (61%) or positive for LVI (71%) than in patients with negative results (14.7%). In addition, patients with both definitive and equivocal LVI had a significantly shorter BCR-free survival time compared with those with negative LVI. Multivariable Cox regression analysis indicated that the presence of either definitive or equivocal LVI were independent predictors of disease recurrence (hazard ratio [HR] 3.32, 95% confidence interval [CI] 2.3-4.8; P <0.001 vs HR 1.66, 95% CI 1.05-2.65; P = 0.032, respectively).

Conclusion: In this single-institution study, equivocal LVI had a similar association with adverse pathological features and rate of BCR to that of definitive LVI. If our observations are validated in an independent cohort, consideration should be given to the inclusion of equivocal LVI as part of routine pathological reporting.
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http://dx.doi.org/10.1111/bju.13594DOI Listing
April 2017

Reduction in expression of the benign AR transcriptome is a hallmark of localised prostate cancer progression.

Oncotarget 2016 May;7(21):31384-92

Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.

Background: Despite the importance of androgen receptor (AR) signalling to prostate cancer development, little is known about how this signalling pathway changes with increasing grade and stage of the disease.

Objective: To explore changes in the normal AR transcriptome in localised prostate cancer, and its relation to adverse pathological features and disease recurrence.

Design: Publically accessible human prostate cancer expression arrays as well as RNA sequencing data from the prostate TCGA. Tumour associated PSA and PSAD were calculated for a large cohort of men (n=1108) undergoing prostatectomy.

Outcome Measurements And Statistical Analysis: We performed a meta-analysis of the expression of an androgen-regulated gene set across datasets using Oncomine. Differential expression of selected genes in the prostate TCGA database was probed using the edgeR Bioconductor package. Changes in tumour PSA density with stage and grade were assessed by Student's t-test, and its association with biochemical recurrence explored by Kaplan-Meier curves and Cox regression.

Results: Meta-analysis revealed a systematic decline in the expression of a previously identified benign prostate androgen-regulated gene set with increasing tumour grade, reaching significance in nine of 25 genes tested despite increasing AR expression. These results were confirmed in a large independent dataset from the TCGA. At the protein level, when serum PSA was corrected for tumour volume, significantly lower levels were observed with increasing tumour grade and stage, and predicted disease recurrence.

Conclusions: Lower PSA secretion-per-tumour-volume is associated with increasing grade and stage of prostate cancer, has prognostic relevance, and reflects a systematic perturbation of androgen signalling.
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http://dx.doi.org/10.18632/oncotarget.8915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058764PMC
May 2016

Prognosis of node-positive bladder cancer in 2016.

Minerva Urol Nefrol 2016 Apr 3;68(2):125-37. Epub 2016 Mar 3.

Department of Surgery, Peter MacCallum Cancer Centre, East Melbourne, Australia -

Introduction: Lymph node (LN) positive bladder cancer is a serious disease associated with a poor prognosis. Nevertheless even after radical cystectomy and lymph node dissection alone long-term oncologic control has been reported in a subset of these patients. Efforts have been made to stratify LN-positive patients according to various prognostic factors to make more individualized risk estimations. This review attempts to summarize the existing data on prognostic determinants in node-positive bladder cancer.

Evidence Acquisition: A literature search of the English literature was performed in October 2015 on PubMed using the search terms "bladder cancer", "node-positive" and "prognosis/outcome". Papers were only selected when separate information on the node-positive subpopulation was available. Data from prospective studies, meta-analysis or multi-institutional were selected primarily.

Evidence Synthesis: Current 2010 TNM classification of nodal disease seems to have limited prognostic value. Several other nodal parameters such as number of positive nodes, number of resected nodes, LN density and extracapsular extension have been extensively evaluated and show potential in distinguishing prognostic subgroups. Although node-positive bladder cancer is often seen as systemic disease local tumor characteristics such as T stage and histological variants seem to remain important. Molecular markers are promising in stratifying patients with bladder cancer but need further validation in a specific node-positive subgroup. Neo-adjuvant chemotherapy seems to improve the prognosis of clinical node-positive patients and evaluation of response could help in selecting patients who benefit from consolidating surgery. Although retrospective studies convincingly suggest improved clinical outcome with adjuvant chemotherapy for pathological node-positive patients, these findings are not consistently confirmed in recent prospective studies.

Conclusions: Future research should aim at the incorporation of prognostic variables into clinically applicable nomograms and identification of the subgroup of patients who will benefit from adjuvant treatments.
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April 2016

A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance.

Br J Cancer 2016 Feb 26;114(4):454-62. Epub 2016 Jan 26.

Department of Surgery, Division of Urology, Royal Melbourne Hospital, The University of Melbourne, Parkville, Melbourne, Victoria, Australia.

Background: The objective of this study was to determine whether microRNA (miRNA) profiling of urine could identify the presence of urothelial carcinoma of the bladder (UCB) and to compare its performance characteristics to that of cystoscopy.

Methods: In the discovery cohort we screened 81 patients, which included 21 benign controls, 30 non-recurrers and 30 patients with active cancer (recurrers), using a panel of 12 miRNAs. Data analysis was performed using a machine learning approach of a Support Vector Machine classifier with a Student's t-test feature selection procedure. This was trained using a three-fold cross validation approach and performance was measured using the area under the receiver operator characteristic curve (AUC). The miRNA signature was validated in an independent cohort of a further 50 patients.

Results: The best predictor to distinguish patients with UCB from non-recurrers was achieved using a combination of six miRNAs (AUC=0.85). This validated in an independent cohort (AUC=0.74) and detected UCB with a high sensitivity (88%) and sufficient specificity (48%) with all significant cancers identified. The performance of the classifier was best in detecting clinically significant disease such as presence of T1 Stage disease (AUC=0.92) and high-volume disease (AUC=0.81). Cystoscopy rates in the validation cohort would have been reduced by 30%.

Conclusions: Urinary profiling using this panel of miRNAs shows promise for detection of tumour recurrence in the surveillance of UCB. Such a panel may be useful in reducing the morbidity and costs associated with cystoscopic surveillance, and now merits prospective evaluation.
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http://dx.doi.org/10.1038/bjc.2015.472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815774PMC
February 2016
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