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PubMed | Karolinska Institutet, Portuguese Oncology Institute, Dana-Farber Cancer Institute, University of Warwick and 28 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain 38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.


Bruyere F.,CHU Bretonneau | Namdarian B.,Royal Melbourne Hospital | Corcoran N.M.,Royal Melbourne Hospital | Pedersen J.,TissuPath Pty Ltd. | And 5 more authors.
Urologic Oncology: Seminars and Original Investigations | Year: 2010

Background: Epithelial-mesenchymal transition (EMT) is known to play an important role in the development of tumor invasion and progression in tumors of epithelial origin. Objectives: Our aim was to investigate the role of Snail transcription repressor family members in human bladder pathogenesis. Material and methods: We evaluated levels of Snail and Slug in 87 patients who received transurethral resection of a transitional cell carcinoma at our institution during the period from June 1999 until November 2003. Immunohistochemistry was performed on tissue microarrays, and expression correlated with pathological variables and clinical outcomes. Degree and intensity of Snail and Slug staining was quantified by immunohistochemistry. Results: There was no apparent enrichment in strong vs. weak staining for either Snail (43.7% vs. 56.3%) or Slug (46% vs. 54%) in the superficial bladder tumors. Univariate analysis determined that tumor focality and Snail expression were significantly associated with tumor recurrence (P < 0.05). Only for tumor focality did such a relationship exist when assessing tumor progression. Multivariate analysis using the Cox's proportional hazards model revealed similar results to that of the univariate analysis. Snail expression (P = 0.038) and tumor focality (P = 0.011) were independent and significant prognostic factors for tumor recurrence in all patients. However, only tumor focality was an independent predictor of tumor progression (P = 0.034). Conclusions: High expression of Snail in superficial bladder tumors is a strong predictor of tumor recurrence enhancing risk stratification and prognostication. © 2010 Elsevier Inc.


Gorrell R.J.,University of Melbourne | Gorrell R.J.,Murdoch Childrens Research Institute | Gorrell R.J.,Monash University | Wijburg O.L.C.,University of Melbourne | And 7 more authors.
Infection and Immunity | Year: 2013

The natural immune response to Helicobacter pylori neither clears infection nor prevents reinfection. However, the ability of secretory antibodies to influence the course of H. pylori infection has not been determined. We compared the natural progression of H. pylori infection in wild-type C57BL/6 mice with that in mice lacking the polymeric immunoglobulin receptor (pIgR) that is essential for the secretion of polymeric antibody across mucosal surfaces. H. pylori SS1-infected wild-type and pIgR knockout (KO) mice were sampled longitudinally for gastrointestinal bacterial load, antibody response, and histological changes. The gastric bacterial loads of wild-type and pIgR KO mice remained constant and comparable at up to 3 months postinfection (mpi) despite SS1-reactive secretory IgA in the intestinal contents of wild-type mice at that time. Conversely, abundant duodenal colonization of pIgR KO animals contrasted with the near-total eradication of H. pylori from the intestine of wild-type animals by 3 mpi. H. pylori was cultured only from the duodenum of those animals in which colonization in the distal gastric antrum was of sufficient density for immunohistological detection. By 6 mpi, the gastric load of H. pylori in wild-type mice was significantly lower than in pIgR KO animals. While there was no corresponding difference between the two mouse strains in gastric pathology results at 6 mpi, reductions in gastric bacterial load correlated with increased gastric inflammation together with an intestinal secretory antibody response in wild-type mice. Together, these results suggest that naturally produced secretory antibodies can modulate the progress of H. pylori infection, particularly in the duodenum. ©2013, American Society for Microbiology.


Sherwin J.C.,TissuPath Pty Ltd. | Mirmilstein G.,University of Melbourne | Pedersen J.,TissuPath Pty Ltd. | Lawrentschuk N.,University of Toronto | And 2 more authors.
Journal of Urology | Year: 2010

Purpose: Digital image analysis software to review histopathology specimens is advancing uropathology by objectivity and reproducibility. Subjective pathologist assessed prostate tumor volume calculations correlate with known prognostic factors at radical prostatectomy. We ascertained whether image analysis software calculations of prostate tumor volume correlate with such prognostic factors, particularly positive surgical margins. Materials and Methods: Prostate tumor volume was calculated using digital image analysis software in 851 sequential radical prostatectomy specimens. Results were correlated with clinicopathological data by logistic regression. Results: Median prostate tumor volume was 2.2 cc (IQR 0.9-3.8). Median peripheral and transition zone tumor volume was 1.9 and 0.6 cc, respectively. Transition zone tumors were noted in 236 specimens (27.8%) and positive surgical margins occurred in 244 (28.7%). Tumors with extensive positive surgical margins had larger image analysis software assessed prostate tumor volume (p = 0.029) and peripheral zone volume (p = 0.007) than those with only focal positive surgical margins. On univariate analysis positive surgical margin tumors were larger and had seminal vesicle invasion, extraprostatic extension, perineural invasion and higher preoperative prostate specific antigen than those without positive surgical margins (each p <0.001). A linear relationship existed between image analysis software determined prostate tumor volume, and increasing tumor stage, Gleason score and prostate specific antigen (p for trend <0.001). On multivariate analysis tumor volume and tumor volume as a percent of prostate volume predicted positive surgical margins. Conclusions: Prostate tumor volume determined objectively by image analysis software correlates with positive surgical margins, as do prognostic variables such as extraprostatic extension, seminal vesicle invasion, perineural invasion, peripheral zone volume and Gleason score greater than 7. Objective digital image analysis software assessment appears to be a valid form to determine prostate tumor volume at radical prostatectomy. It is a useful adjunct to other histopathological analyses. © 2010 American Urological Association Education and Research, Inc.


Becher D.,University of Melbourne | Deutscher M.E.,University of Melbourne | Simpfendorfer K.R.,University of Melbourne | Wijburg O.L.,University of Melbourne | And 4 more authors.
European Journal of Immunology | Year: 2010

Helicobacter pylori is recognised as the chief cause of chronic gastritis, ulcers and gastric cancer in humans. With increased incidence of treatment failure and antibiotic resistance, development of prophylactic or therapeutic vaccination is a desirable alternative. Although the results of vaccination studies in animal models have been promising, studies in human volunteers have revealed problems such as 'post-immunisation gastritis' and comparatively poor responses to vaccine antigens. The focus of this study was to compare the gastric and systemic cellular immune responses induced by recombinant attenuated Salmonella Typhimurium-based vaccination in the C57BL/6 model of H. pylori infection. Analysis of lymphocyte populations in the gastric mucosa, blood, spleen, paragastric LN and MLN revealed that the effects of vaccination were largely confined to the parenchymal stomach rather than lymphoid organs. Vaccine-induced protection was correlated with an augmented local recall response in the gastric mucosa, with increased proportions of CD4+ T cells, neutrophils and reduced proportions of CD4+ Treg. CD4+ T cells isolated from the stomachs of vaccinated mice proliferated ex vivo in response to H. pylori antigen, and secreted Th1 cytokines, particularly IFN-γ. This detailed analysis of local gastric immune responses provides insight into the mechanism of vaccine-induced protection. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Wong C.K.E.,Epworth Hospital | Namdarian B.,Royal Melbourne Hospital | Chua J.,Epworth Hospital | Chin X.,Epworth Hospital | And 10 more authors.
British Journal of Cancer | Year: 2012

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. © 2012 Cancer Research UK 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.,University of British Columbia | Corcoran N.M.,Royal Melbourne Hospital | Hovens C.M.,Royal Melbourne Hospital | Metcalfe C.,University of British Columbia | And 8 more authors.
BJU International | Year: 2012

Objective To determine the impact of surgical margin status on the risk of significant biochemical recurrence (prostate-specific antigen [PSA] doubling time <3, <6 or <9 months) after prostatectomy. Materials and Methods Patients undergoing radical prostatectomy with complete clinical and pathological data and detailed PSA follow-up were identified from two prospectively recorded databases. Patients were stratified according to their risk of occult systemic disease (low risk: PSA < 10 ng/dL, pT2 stage and Gleason score ≤6; intermediate risk: PSA 10-20 ng/dL, pT2 stage and/or Gleason score 7; high: PSA > 20 ng/dL or pT3-4 stage or Gleason score 8-10) and the impact of a positive surgical margin (PSM) within each stratum determined by univariable and multivariable analysis. Results Of 1514 patients identified, 276 (18.2%), 761 (50.3%) and 477 (31.5%) were classified as having low-, intermediate- and high-risk disease respectively. A total of 370 (24.4%) patients had a PSM and with a median follow-up of 22.2 months, and 165 (7%) patients had a biochemical recurrence. Sufficient PSA data was available to calculate PSA doubling times in 151/165 patients (91.5%). The PSM rate rose significantly, from 11% in low-risk to 43% in high-risk disease (P < 0.001), with similar positive associations noted with tumour grade, stage and serum PSA (P < 0.001). Patients with low-risk disease had essentially identical risks of significant biochemical recurrence over the study period, regardless of surgical margin status. By contrast, in patients with both intermediate- and high-risk disease, a PSM was a strong predictor of significant biochemical recurrence on univariable analysis. On multivariable analysis, howver, PSM predicted significant disease recurrence in intermediate-risk disease only. Conclusions PSM is a risk factor for significant biochemical recurrence only in intermediate risk disease. © 2012 BJU INTERNATIONAL.


PubMed | Royal Melbourne Hospital and TissuPath Pty Ltd
Type: Journal Article | Journal: Canadian Urological Association journal = Journal de l'Association des urologues du Canada | Year: 2015

The ability of perineural invasion (PNI) in radical prostatectomy (RP) specimens to predict biochemical recurrence (BCR) is unclear. This study investigates this controversial question in a large cohort.A retrospective analysis was undertaken of prospectively collected data from 1497 men who underwent RP (no neoadjuvant therapy) for clinically localized prostate cancer. The association of PNI at RP with other clinicopathological parameters was evaluated. The correlation of clinicopathological factors and BCR (defined as prostate-specific antigen [PSA] >0.2 ng/mL) was investigated with univariable and multivariable Cox regression analysis in 1159 men.PNI-positive patients were significantly more likely to have a higher RP Gleason score, pT3 disease, positive surgical margins, and greater cancer volume (p < 0.0005). The presence of PNI significantly correlated with BCR on univariable (hazard ratio 2.30, 95% confidence interval 1.50-3.55, p < 0.0005), but not multivariable analysis (p = 0.602). On multivariable Cox regression analysis the only independent prognostic factors were preoperative PSA, RP Gleason score, pT-stage, and positive surgical margin status. These findings are limited by a relatively short follow-up time and retrospective study design.PNI at RP is not an independent predictor of BCR. Therefore, routine reporting of PNI is not indicated. Future research should be targeted at the biology of PNI to increase the understanding of its role in prostate cancer progression.


PubMed | Royal Melbourne Hospital, TissuPath Pty Ltd and New York University
Type: | Journal: Urology | Year: 2016

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.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 Massons 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.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).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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