Australian Prostate Cancer Research Center at Epworth

Richmond, Australia

Australian Prostate Cancer Research Center at Epworth

Richmond, Australia
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Namdarian B.,Royal Melbourne Hospital | Wong E.,Australian Prostate Cancer Research Center at Epworth | Galea R.,Research Division | Pedersen J.,TissuPath Pty Ltd. | And 9 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2013

Objectives: Epithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. Our aim was to investigate the role of tight junction proteins, Par3/Par6/atypical protein kinase C (APKC), Discs large (Dlg), and Scribble in human bladder pathogenesis. Methods: We evaluated levels of APKC, Dlg, and Scribble in 92 superficial bladder tumors using tissue microarrays and immunohistochemistry, and correlated expression with pathologic variables and clinical outcomes. Results: There was a slight apparent enrichment in strong vs. weak staining for APKC (54.9% vs. 45.1%), Dlg (65.7% vs. 34.3%), and a marked enrichment for Scribble (75% vs. 25%) in the superficial bladder tumors. Univariate analysis determined that both tumor focality and APKC expression were significantly associated with tumor recurrence (P < 0.05). Multivariate analysis using the Cox's proportional hazards model revealed that only APKC (P = 0.025) as well as tumor focality (P = 0.018) were independent and significant prognostic factors for tumor recurrence in all patients. We found that no immunohistochemical staining of any of the cell polarity proteins significantly predicted for tumor progression on either univariate or multivariate analysis. Conclusions: Loss of APKC expression in superficial bladder tumors is a strong predictor of tumor recurrence. © 2013 Elsevier Inc.

Corcoran N.M.,University of British Columbia | Corcoran N.M.,Royal Melbourne Hospital | Corcoran N.M.,Australian Prostate Cancer Research Center at Epworth | Casey R.G.,University of British Columbia | And 15 more authors.
BJU International | Year: 2012

OBJECTIVES: • To analyse the performance of PSA density (PSAD) as a predictor of Gleason score upgrade in a large cohort stratified by Gleason score. • We and others have shown that an upgrade in Gleason score between initial prostate biopsy and final radical prostatectomy (RP) pathology is a significant risk factor for recurrence after local therapy. PATIENTS AND METHODS: • Patients undergoing RP with matching biopsy information were identified from two prospective databases. • Patients were analysed according to the concordance between biopsy and final pathology Gleason score in three paired groups: 6/>6, 3 + 4/>3 + 4, 7/>7. • Receiver-operating characteristic (ROC) curves were generated stratified by Gleason score, and the area under the curve (AUC) calculated. • Logistic regression models were fitted to identify significant predictors of tumour upgrade. RESULTS: • From 1516 patients, 435 (29%) had an upgrade in Gleason score. ROC analysis showed a decline in AUC with increasing biopsy Gleason score, from 0.64 for biopsy Gleason score 6, to 0.57 for Gleason score 7. • In logistic regression models containing pretreatment variables, e.g. clinical stage and number of positive cores, for Gleason score 6 and 3 + 4, PSAD was the strongest predictor of subsequent tumour upgrade (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.18-1.83, P = 0.001 and OR 1.37, 95% CI 1.14-1.67, P = 0.002, respectively). • Surprisingly, in tumours upgraded from Gleason score 7 to > 7, PSAD was not predictive even on univariable analysis, whereas clinical stage and number of positive cores were significant independent predictors. To explore the relationship between serum PSA and Gleason score, tumour volume was calculated in 669 patients. • There was a strong association between Gleason score and tumour volume, with the median volume of Gleason score 7 and Gleason score >7 tumours being approximately twice and four-times that of Gleason score 6 tumours, respectively (P < 0.001). • In contrast, the median serum PSA level per millilitre tumour volume decreased significantly with increasing grade, from 5.4 ng/mL for Gleason score 6 to 2.1 ng/mL for > 7 (P < 0.001). CONCLUSIONS: • There is a strong correlation between Gleason score and tumour volume in well/intermediate differentiated tumours, and as they produce relatively high amounts of PSA per unit volume of cancer, high PSAD is the strongest single predictor of tumour undergrading. • However, as higher grade tumours produce less PSA per unit volume, PSAD loses its predictive ability, and other clinical markers of tumour volume such as palpable disease and numbers of positive cores become more predictive. © 2011 BJU International.

Atkins R.J.,Royal Melbourne Hospital | Ng W.,Royal Melbourne Hospital | Stylli S.S.,Royal Melbourne Hospital | Hovens C.M.,Royal Melbourne Hospital | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2015

Glioblastoma multiforme (GBM) is a malignant and incurable glial brain tumour. The current best treatment for GBM includes maximal safe surgical resection followed by concomitant radiotherapy and adjuvant temozolomide. Despite this, median survival is still only 14-16 months. Mechanisms that lead to chemo- and radio-resistance underpin treatment failure. Insights into the DNA repair mechanisms that permit resistance to chemoradiotherapy in GBM may help improve patient responses to currently available therapies. © 2014 Elsevier Ltd. All rights reserved.

Corcoran N.M.,Prostate Center at Vancouver General Hospital | Corcoran N.M.,Royal Melbourne Hospital | Corcoran N.M.,Australian Prostate Cancer Research Center at Epworth | Hong M.K.H.,Royal Melbourne Hospital | And 13 more authors.
BJU International | Year: 2011

Study Type - Prognosis (retrospective cohort) Level of Evidence 2b OBJECTIVE To determine the effect of an upgrade in Gleason score between initial prostate biopsy and final prostatectomy specimen on the risk of postoperative biochemical recurrence. PATIENTS AND METHODS A total of 1629 patients with paired biopsy and radical prostatectomy histology were identified from two prospectively recorded prostate cancer databases. Information on key clinical and pathological characteristics as well as prostate-specific antigen follow-up was recorded. Patients who experienced an upgrade in their Gleason score were compared with corresponding patients with concordant tumours of the lower and higher grade. Kaplan-Meier curves and multivariate models were generated to examine the impact of Gleason score upgrade on the risk of postoperative biochemical recurrence. RESULTS Overall, 466 patients (28.6%) experienced an upgrade in their Gleason score post radical prostatectomy, in 88.4% of cases involving a change in a single Gleason score point. Patients upgraded from Gleason 6 (3 + 3) to Gleason 7 (3 + 4) had pathological characteristics that were very similar to Gleason 7 (3 + 4) concordant tumours, with an identical risk of biochemical recurrence. In contrast, patients upgraded from Gleason score 6 (3 + 3) to Gleason 7 (4 + 3) had tumours with pathological characteristics intermediate between the two concordant groups, which was mirrored by their risk of biochemical recurrence. Patients with Gleason 7 tumours who experienced a change in the predominant pattern from 3 + 4 to 4 + 3 had tumours that resembled Gleason 7 (4 + 3) concordant tumours, with a similar risk of biochemical recurrence. In contrast, patients upgraded from Gleason 7 to Gleason >7 had tumours with intermediate pathological characteristics, and a risk of biochemical recurrence that was significantly different to concordant tumours of the lower and higher grade. In multivariate models, a change in Gleason score was an independent predictor of biochemical recurrence in the preoperative setting only. Although a difference in Gleason score was an independent predictor of recurrence in concordant tumours in models based on postoperative variables, an upgrade in Gleason score in discordant tumours was not, with differences in co-segregated adverse pathological characteristics being more predictive. CONCLUSIONS Patients experiencing an upgrade in their Gleason score between biopsy and final specimen exhibit significantly more aggressive pathological features than corresponding concordant tumours, and a higher risk of biochemical recurrence post radical prostatectomy. As Gleason score can be more accurately assessed preoperatively than other prognostic tumour features, continued effort is required to identify those most at risk of upgrading, and to refine biopsy strategies to reduce sampling error. © 2011 BJU Internationl.

Atkins R.J.,Royal Melbourne Hospital | Stylli S.S.,Royal Melbourne Hospital | Luwor R.B.,Royal Melbourne Hospital | Kaye A.H.,Royal Melbourne Hospital | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2013

Glioblastoma multiforme (GBM) is the most frequently occurring and devastating human brain malignancy, retaining almost universal mortality and a median survival of only 14 months, even with recent advances in multimodal treatments. Gliomas are characterised as being both highly resistant to chemo- and radiotherapy and highly invasive, rendering conventional interventions palliative. The continual dismal prognosis for GBM patients identifies an urgent need for the evolutionary development of new treatment modalities. This includes molecular targeted therapies as many signaling molecules and associated pathways have been implicated in the development and survival of malignant gliomas including the protein kinase, glycogen synthase kinase 3 beta (GSK-3β). Here we review the activity and function of GSK-3β in a number of signaling pathways and its role in gliomagenesis. © 2013 Elsevier Ltd. All rights reserved.

Costello A.J.,Royal Melbourne Hospital | Costello A.J.,Australian Prostate Cancer Research Center at Epworth | Dowdle B.W.,Royal Melbourne Hospital | Namdarian B.,Royal Melbourne Hospital | And 4 more authors.
BJU International | Year: 2011

OBJECTIVE • To characterize the immunohistochemical nature of sympathetic and parasympathetic nerves surrounding the prostate. MATERIALS AND METHODS • Using serial sectioning, four male cadavers were investigated using a combination of haematoxylin and eosin staining and immunohistochemistry. Both the sympathetic and parasympathetic contributions to the autonomic nervous system in the periprostatic region were assessed by staining analysis, the number of nerves fibres was quantified, their position relative to the prostate recorded and their function inferred. • The fascial architecture of the neurovascular bundle (NVB) was also quantified. RESULTS • Approximately 27.8% of all nerve fibres identified were found on the anterior half of the prostate, above the 3 to 9 o'clock level. At the base, mid, and apex of prostate, parasympathetic fibres accounted for 4%, 5% and 6.8% of the nerves located on the anterolateral aspect of the prostate, respectively. • Sympathetic nerves found above the 3 to 9 o'clock level represented ≈15% of the total number of nerves. • When staining the periprostatic fascia, the classical NVB exhibited a distinct fascial architecture with three separate compartments. CONCLUSIONS • A tiny minority of nerves in the anterior periprostatic region are functionally significant parasympathetic nerves. • There is little anatomical evidence to support higher incisions in the lateral prostatic fascia to spare cavernous nerve fibres, although such approaches may reduce the risk of traction injury on the more posterolaterally located NVB. • The presence of distinct fascial compartments in the NVB is also confirmed. © 2010 the authors. bju international.

Corcoran N.M.,Vancouver General Hospital | Corcoran N.M.,Royal Melbourne Hospital | Corcoran N.M.,Australian Prostate Cancer Research Center at Epworth | Hovens C.M.,Royal Melbourne Hospital | And 15 more authors.
BJU International | Year: 2012

Objective To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies. Patients and Methods Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database. Tumour volumes were measured in serial whole-mount sections with image analysis software as part of routine histological assessment. Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed. Results In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified. Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher. Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade. Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade. On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96-0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4-2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01-9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis. Conclusions Under-graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error. Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade. © 2011 BJU International.

Corcoran N.M.,Royal Melbourne Hospital | Corcoran N.M.,Australian Prostate Cancer Research Center at Epworth | Gleave M.E.,University of British Columbia
Histopathology | Year: 2012

The therapeutic approach to advanced prostate cancer has seen greater changes in the last 7 years than it did in the preceding 70. Although only one of the newly approved agents that improve overall survival is a targeted agent, it is a validation of the method of pathway analysis and drug design in delivering novel, clinically usable agents. As our knowledge of the molecular circuitry of tumour invasion, metastases and treatment resistance has become more refined, the number of new, potentially useful, targets has grown exponentially. This is reflected in the vast array of diverse targeted agents that are currently being evaluated in human trials. In this review, we briefly describe some of the key pathways that are involved in the evolution of the prostate cancer 'lethal phenotype', and review the clinical activity of some of the newly approved targeted therapies or those in advanced phases of clinical development. © 2011 Blackwell Publishing Limited.

Clarebrough E.E.,University of Melbourne | Challacombe B.J.,Royal Melbourne Hospital | Briggs C.,University of Melbourne | Namdarian B.,Royal Melbourne Hospital | And 6 more authors.
Journal of Urology | Year: 2011

Purpose: An accurate, complete understanding of the prostate neuroanatomy is required to optimize nerve sparing techniques during radical prostatectomy. However, the precise topography and function of the periprostatic nerves remain contentious and there is uncertainty about which nerve sparing technique is most optimal. We accurately quantified the distribution, precise localization and cross-sectional area of periprostatic neural tissue using cadaveric specimens. Materials and Methods: We analyzed 13 cadaveric hemipelves using hematoxylin and eosin stained sections from the base, mid zone and apex of each prostate. Each section was digitized and divided into 6 sectors numbered clockwise. Analysis was performed using National Institutes of Health ImageJ software to calculate the total periprostatic neural cross-sectional area per sector. Results: Calculating the total neural cross-sectional area highlighted a decrease from prostate base to mid zone to apex of 24.7, 19.7 and 13.7 mm2, respectively. Most neural tissue was located in the posterolateral region. However, the proportion surrounding the anterior part of the prostate increased toward the apex with a median of 6.0% and 7.6% at the base and mid zone regions, respectively, increasing to 11.2% at the apex. Conclusions: Simple numerical nerve quantification may be insufficient to accurately describe the periprostatic neural distribution. Calculating nerve bundle cross-sectional area confirmed that most neural tissue is in the posterolateral region, although the proportion located anterior increases from base to apex. Thus, higher release of the periprostatic fascia may be indicated toward the apex. © 2011 American Urological Association Education and Research, Inc.

Atkins R.J.,Royal Melbourne Hospital | Dimou J.,Royal Melbourne Hospital | Paradiso L.,Royal Melbourne Hospital | Morokoff A.P.,Royal Melbourne Hospital | And 4 more authors.
Journal of Clinical Neuroscience | Year: 2012

Gliomas are aggressive brain tumours that, despite advances in multimodal therapies, continue to portend a dismal prognosis. Glioblastoma multiforme (GBM) represents the most aggressive glioma and patients have a median survival of 14 months, even with the best available treatments. The phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3 beta (GSK-3β) and Wnt/β-catenin pathways are dysregulated in a number of cancers, and these two pathways share a common node protein, GSK-3β. This protein is responsible for the regulation/degradation of β-catenin, which reduces β-catenin's translocation to the nucleus and influences the subsequent transcription of oncogenes. The non-specific small-molecule GSK-3β inhibitor, lithium chloride (LiCl), and the specific Akt inhibitor, AktX, were used to treat U87MG and U87MG.Δ2-7 human glioma cell lines. LiCl treatment significantly affected cell morphology of U87MG and U87MG.Δ2-7 cells, while also increasing levels of phospho-GSK-3β in a dose-dependent manner. Increased cell proliferation was observed at low-to-mid LiCl concentrations as determined by MTT cell growth assays. Treatment of U87MG and U87MG.Δ2-7 cells with AktX resulted in reduced levels of phospho-GSK-3β through its inhibition of Akt, in addition to decreased levels of phosphorylated (active) Akt in a dose-dependent fashion. We have shown in this study that GSK-3β regulation by phosphorylation is important for cell morphology and growth, and that LiCl enhances growth of U87MG and U87MG.Δ2-7 cells by inhibiting GSK-3β through its phosphorylation, whereas AktX reduces growth via activation of GSK-3β by inhibiting Akt's kinase activity. © 2012 Elsevier Ltd. All rights reserved.

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