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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. Source


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. Source


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. Source


Hong K.H.,Royal Melbourne Hospital | Namdarian B.,Royal Melbourne Hospital | Corcoran N.M.,Royal Melbourne Hospital | Corcoran N.M.,Peter MacCallum Cancer Center | And 9 more authors.
Pathology | Year: 2011

Aims: To assess if accurately determined tumour volume variables could serve as independentpredictors of early biochemical recurrence in high riskprostate cancerpatients who underwent radical prostatectomy. Methods: Tumour volume variables were calculated by digitalplanimetry in 269prostatectomy specimens ofpatients with high riskprostate cancer. The associations to biochemical progression of tumour volume and clinicoPathological variables, including age,pre-operativeprostate specific antigen (PSA) levels, final Gleason score,Pathological T stage, and surgical margins, were examined using univariate and multivariate Coxproportional hazards analyses. Results: Median tumour volume was 3.7 ml [interquartile range (IQR) 2.1-6.1 mL] and median follow-up time was 12 months (IQR 6-24 months). Biochemical recurrence occurred in 64 men (24%) during thisperiod, with a median time to recurrence of 7.5 months (IQR 3.0-15.5 months). On univariate analysis all of the tumour volume variables were strongly correlated with the clinicoPathological variables, as well as biochemical recurrence (p<0.001). On multivariate analysis, we found that tumour volume variables served as independentpredictors ofpSAprogression whilst other routinely reportedPathological variables did not. Conclusion: Accurately assessing tumour volume in the high risk setting may aid in identifyingpatients at greatest risk of developing early biochemical recurrence and most in need of adjuvant therapy. © 2011 Royal College ofpathologists of Australasia. Source


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. Source

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