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PubMed | TissuPath Specialist Pathology, Royal Melbourne Hospital and Center for Neural Engineering
Type: | Journal: Scientific reports | Year: 2016

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.


Hong M.K.H.,Royal Melbourne Hospital | Hong M.K.H.,Epworth Hospital | Macintyre G.,University of Melbourne | Macintyre G.,University of Cambridge | And 43 more authors.
Nature Communications | Year: 2015

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood. © 2015, Nature Publishing Group. All rights reserved.


Hong M.K.H.,Royal Melbourne Hospital | Hong M.K.H.,Australian Prostate Cancer Research Center | Yao H.H.I.,Royal Melbourne Hospital | Yao H.H.I.,Australian Prostate Cancer Research Center | And 12 more authors.
BJU International | Year: 2012

OBJECTIVE: • To evaluate the accuracy of calculated prostate volume variables in a radical prostatectomy (RP) cohort, as many recent studies use these measures of prostate size instead of prostate weight. • To determine whether this accuracy could be improved by modifying the mathematical model used in the volume estimation. PATIENTS AND METHODS: • Patients who underwent RP for prostate cancer at our associated institutions had calculated specimen volumes and weights from RP specimens determined at one pathology institution and transrectal ultrasonography (TRUS) volumes were recorded preoperatively ( n = 236). • Correlation analysis was performed and errors were determined for calculated volume variables when compared with prostate weight. • Bland-Altman plots were drawn and concordance coefficients calculated. • Analysis was repeated with smaller prostates mathematically modelled as bullet-shaped rather than ellipsoid ( n = 165). RESULTS: • Although correlation was good for both TRUS and specimen volumes, they equally underestimated prostate weight with a large range of errors and poor concordance coefficients. • Only 22% of TRUS volumes and 11% of calculated specimen volumes were within 10% of weight measurements. • Application of a bullet-shaped mathematical model for prostates < 55 g did not correct the large individual variation seen within these values. CONCLUSION: • Calculated prostate volume variables are prone to a large range of individual error regardless of the mathematical model used and should be avoided in statistical studies involving RP cohorts, and the more accurate prostate weight variable should instead be used as a size variable or correction factor. © 2012 The Authors.


Naeem H.,Victoria University of Melbourne | Naeem H.,University of Melbourne | Wong N.C.,Murdoch Childrens Research Institute | Wong N.C.,Ludwig Institute for Cancer Research | And 8 more authors.
BMC Genomics | Year: 2014

Background: The Illumina HumanMethylation450 BeadChip (HM450K) measures the DNA methylation of 485,512 CpGs in the human genome. The technology relies on hybridization of genomic fragments to probes on the chip. However, certain genomic factors may compromise the ability to measure methylation using the array such as single nucleotide polymorphisms (SNPs), small insertions and deletions (INDELs), repetitive DNA, and regions with reduced genomic complexity. Currently, there is no clear method or pipeline for determining which of the probes on the HM450K bead array should be retained for subsequent analysis in light of these issues.Results: We comprehensively assessed the effects of SNPs, INDELs, repeats and bisulfite induced reduced genomic complexity by comparing HM450K bead array results with whole genome bisulfite sequencing. We determined which CpG probes provided accurate or noisy signals. From this, we derived a set of high-quality probes that provide unadulterated measurements of DNA methylation.Conclusions: Our method significantly reduces the risk of false discoveries when using the HM450K bead array, while maximising the power of the array to detect methylation status genome-wide. Additionally, we demonstrate the utility of our method through extraction of biologically relevant epigenetic changes in prostate cancer. © 2014 Naeem et al.; licensee BioMed Central Ltd.


Styles C.,Peter MacCallum Cancer Center | Ferris N.,Peter MacCallum Cancer Center | Mitchell C.,Peter MacCallum Cancer Center | Murphy D.,Peter MacCallum Cancer Center | And 6 more authors.
Journal of Medical Imaging and Radiation Oncology | Year: 2014

Introduction Prostate cancer is common and may be treated immediately or managed conservatively by observation. We sought to determine how reliable multiparametric MRI is in the detection of intraprostatic prostate cancer and what role it has in risk stratification. Methods The histology from 38 whole mount prostate specimens was compared with preoperative multiparametric 3T MRI studies with an endorectal receiver coil in place. T1-weighted, T2-weighted, diffusion (b values 50 400 800), perfusion (Ve, Kep, Ktrans, area under the curve) and proton spectroscopic sequences were used. Results For cancers greater than 0.5 cc, the detection rate for combined T2-weighted imaging and diffusion-weighted imaging (DWI) was 85%. For cancers 0.1 cc-0.5 cc, the sensitivity was 52%.Per patient, false positive rate was 50% for combined T2-weighted imaging and DWI. Perfusion imaging had a sensitivity of 70% for tumours greater than 0.5 cc but had a per patient false positive rate of 80% influenced by benign prostatic hypertrophy. In only 15 patients could a satisfactory spectroscopy study be obtained. Weak correlation was found between the Gleason score and tumour size (r = 0.51), apparent diffusion coefficient (ADC) (r = -0.30) and (choline + creatine)/citrate ratio (r = 0.41). Conclusion T2-weighted imaging and DWI in combination were the best strategy for detecting prostate cancer and had a sensitivity of 85% for detecting lesions greater than 0.5 cc. At 3T, an ADC threshold of between 1100-1200.10-6 mm 2/s was optimal for diagnosing prostate cancer. There are significant limitations in the use of perfusion and spectroscopy to detect prostate cancer. Magnetic resonance imaging-targeted or guided biopsy post-MRI imaging is likely to be needed in some patients to assist risk stratification. © 2014 The Royal Australian and New Zealand College of Radiologists.


Mills J.,TissuPath Specialist Pathology | Mills J.,Monash University | Oliver A.,TissuPath Specialist Pathology | Oliver A.,University of Delaware | And 12 more authors.
Pathology | Year: 2012

Aims: To assess the prognostic utility of semi-quantiative expression of RhoC protein in whole prostates from patients who had radical prostatectomies for high grade prostate cancer (PCa). Methods: Subjects who had surgery <55 months previously with primary Gleason pattern 4 PCa were identified from practice records, archival tissues were retrieved for review and RhoC immunohistochemistry, and ZAG expression was also assessed as a control. Results: Eighty-nine subjects were included in the study; 57 had a rising prostate specific antigen (PSA) post-operatively ('cases') and 32 did not ('controls'). By univariate analysis, expression of both RhoC and ZAG proteins was greater in controls than cases, but this was significant only for ZAG. By multivariate analysis, Gleason variables (patterns and score), extraprostatic extension and decreased RhoC staining all contributed to predicting PSA failure ( p<0.05). ZAG expression was inversely correlated with Gleason pattern and hence was not independently predictive in our multivariate model. Conclusions: Increased RhoC expression predicted a good outcome after radical prostatectomy. ZAG staining also correlated with a favourable outcome but was not independently predictive due to its relationship with Gleason pattern. © 2012 Royal College of Pathologists of Australasia.


Fankhauser M.,Royal Melbourne Hospital | Tan Y.,Royal Melbourne Hospital | Macintyre G.,Victoria University of Melbourne | Haviv I.,Victoria University of Melbourne | And 10 more authors.
Clinical Cancer Research | Year: 2014

Purpose: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression. Experimental Design: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. Results: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway. Conclusions: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC. ©2014 AACR.


Pedersen J.S.,TissuPath Specialist Pathology | Pedersen J.S.,Monash University | Clarke I.,Monash University | Mills J.,TissuPath Specialist Pathology | Mills J.,Monash University
Histopathology | Year: 2011

Aims: To develop an antibody broadly reactive against mycobacterial species, which will improve detection of mycobacteria in tissue sections by immunohistochemistry (IHC). Methods: A sheep antisera was developed by immunization with multiple mycobacteria, and was tested by IHC against a range of mycobacteria in tissues from many species, as well as negative tissue controls and other bacteria. Results: The sheep antiserum, MAS-01, reacted with all 18 mycobacterial species tested, but did not react with uninfected inflammatory tissues. Although MAS-01 cross-reacted with two microbial genera which are related to mycobacteria (Corynebacteria and Proprionibacteria), it did not with Nocardia or Actinomyces. The antibody was more sensitive than the Ziehl-Neelsen stain for detection of tissue mycobacteria, and shortened the time required to identify these infections. Conclusion: The MAS-01 antiserum will facilitate rapid identification of tissue mycobacterial infection by histopathologists. © 2011 Blackwell Publishing Limited.


PubMed | TissuPath Specialist Pathology
Type: Journal Article | Journal: Histopathology | Year: 2011

To develop an antibody broadly reactive against mycobacterial species, which will improve detection of mycobacteria in tissue sections by immunohistochemistry (IHC).A sheep antisera was developed by immunization with multiple mycobacteria, and was tested by IHC against a range of mycobacteria in tissues from many species, as well as negative tissue controls and other bacteria.The sheep antiserum, MAS-01, reacted with all 18 mycobacterial species tested, but did not react with uninfected inflammatory tissues. Although MAS-01 cross-reacted with two microbial genera which are related to mycobacteria (Corynebacteria and Proprionibacteria), it did not with Nocardia or Actinomyces. The antibody was more sensitive than the Ziehl-Neelsen stain for detection of tissue mycobacteria, and shortened the time required to identify these infections.The MAS-01 antiserum will facilitate rapid identification of tissue mycobacterial infection by histopathologists.


PubMed | Monash University, TissuPath Specialist Pathology, Los Alamos National Laboratory, Cancer Research UK Research Institute and 6 more.
Type: | Journal: Nature communications | Year: 2015

Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

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