Filters
Availability
Publication Year
Resource Type
Faculty
School/Institute
Publication Search Results
Sort
Results per page
1 - 10 of 19
-
-
-
-
-
-
-
-
-
(2007)ThesisOptimisation of the conventional tripartite of pancreatic cancer (PC) treatment have led to significant improvements in mortality, however further knowledge of the underlying molecular processes is still required. Transcript profiling of mRNA expression of over 44K genes with microarray technology demonstrated upregulation of secreted frizzled related protein 4 (sFRP4) and β-catenin in PC compared to normal pancreata. Their pathway – Wnt signalling is integral to transcriptional regulation and aberrations in these molecules are critical in the development of many human malignancies. Immunohistochemistry protocols were evaluated by two independent blinded examiners for antigen expression differences associated with survival patterns in 140 patients with biopsy verified PC and a subset of 23 normal pancreata with substantial observer agreement (kappa value 0.6-0.8). A retrospective cohort was identified from 6 Sydney hospitals between 1972-2003 and archival formalin fixed tissue was collected together with clinicopathological data. Three manual stepwise regression models were fitted for overall, disease-specific and relapse-free survival to determine the value of significant prognostic variables in risk stratification. The models were fitted in a logical order using a careful strategy with step by step interpretation of the results. Immunohistochemistry demonstrated increased sFRP4 membranous expression (> 10%) in 49/95 PC specimens and this correlated with improved overall survival (HR:0.99;95%CI:0.97-6.40;LRchi2=134.75; 1df; ρ< 0.001). Increased sFRP4 cytoplasmic staining (> 2/3) in 46/85 patients increased the disease-specific survival (HR:0.52;95%CI:0.31-0.89;LR test statistic =248.40;1df;ρ< 0.001). Increasing β-catenin membranous expression (< _60%) in 26/116 patients was associated with an increased risk of overall death (HR:3.18;95%CI:1.14-8.89;LR test statistic =4.61;1df,ρ< 0.05). Increasing cytoplasmic expression in 65/114 patients was protective and was associated with prolonged survival on univariate, but not multivariate analysis (Disease specific survival HR:0.75;95%CI:0.56-1.00;logrank chi2=3.91;1df; ρ=0.05). Increased nuclear β-catenin expression in 65/114 patients was associated with prolonged survival (disease-specific HR:0.92;95%CI:0.83-1.02; LR test statistic= 49.72;1df;ρ< 0.001). At the conclusion, 12 patients (8.6%) remained alive, 122 died of their disease (68 males versus 54 females). They were followed for a median of 8.7 months (range 1.0-131.3) months. The median age was 66.5 years (range 34.4-96.0, standard deviation 10.9) years. Pancreatic resection was achieved in 79 patients with 46.8% achieving RO resection. The 30 day post-operative mortality was 2.1%. The overall 1 year survival rate was (33.7% ; 95%CI: 25.78-33.79) with a 5 year survival of (2.87%, 95%CI: 2.83-6.01) and a median survival of (8.90 months; 95%CI: 7.5-10.2). The median disease-specific survival was (9.40; 95%CI: 7.9-10.5 months) and the median time to relapse was 1.2 months (95%CI 1.0-1.2 months). A central tenet of contemporary cancer research is that an understanding of the genetic and molecular abnormalities that accompany the development and progression of cancer is critical to further advances in diagnosis, treatment and eventual prevention. High throughput tissue microarrays were used to study expression of two novel tumour markers in a cohort of pancreatic cancer patients and identified sFRP4 and β-catenin as potential novel prognostic markers.
-
(2007)ThesisAtherosclerosis, the leading cause of mortality in Western societies, affects large elastic arteries, causing focal deposition of proliferative inflammatory and lipid-laden cells within the artery. Several risk factors have been causally implicated in the reaction to injury hypothesis first described by Ross in 1969. The injury sustained by endothelial cells may be either mechanical or chemical. Environmental factors have a role in the production of chemical agents that are injurious to the endothelium. Mechanical stresses such as wall tensile stress are proportional to systemic blood pressure and pulse pressure. Essentially, these systemic pressures are fairly evenly distributed throughout the circulation. However, atherosclerotic lesions characteristically occur at focal sites within the human vasculature; at or near bifurcations, within the ostia of branch arteries and at regions of marked or complex curvature, where local haemodynamic abnormalities occur. The most discussed haemodynamic factor seems to be low or highly oscillating wall shear stress which exists on the outer wall of bifurcations and on the inner aspect of curving vessels. The magnitude of these haemodynamic forces may not be great but the subtleties of their variable spatial distribution may help to explain the multifocal distribution of atherosclerotic plaques. With the altered haemodynamics there is endothelial injury and phenotypic changes in the endothelium result, which in turn lead to endothelial cell dysfunction. These haemodynamic variables are difficult to measure directly in vivo. In this work a novel model is developed utilising human autologous vein bypass grafts as a surrogate vessel for the observation of pathological structural changes in response to altered haemodynamics. The influence of haemodynamic factors (such as wall shear stress) in the remodeling of the vein graft wall and the pathogenesis of Myointimal Hyperplasia (MIH) and resultant wall thickening in femoral bypass grafts is analysed. The haemodynamic determinants of MIH (which have been established in many animal models) are similar to those implicated in atherosclerosis. The accelerated responses of the vein (Intimal hyperplasia develops much more rapidly than atherosclerotic lesions in native vessels) make it an ideal model to expediently examine the hypothesised relationships prospectively in an in vivo setting. Furthermore, the utilisation of in vivo data acquired from non-invasive diagnostic methods (such as Magnetic Resonance Angiography (MRA) and Duplex ultrasound) combined with the application of state-of-the-art Computational Fluid Dynamic (CFD) techniques makes the model essentially non-invasive. The following hypotheses are examined: 1) regions of Low shear and High tensile stress should develop disproportionately greater wall thickening, 2) regions of greater oscillatory blood flow should develop greater wall thickening, and 3) regions of lower wall shear should undergo inward (or negative) remodelling and result in a reduction in vessel calibre. The conclusions reached are that abnormal haemodynamic forces, namely low Time-averaged Wall Shear Stress, are associated with subsequent wall thickening. These positive findings have great relevance to the understanding of vein graft MIH and atherosclerosis. It was also evident that with non-invasive data and CFD techniques, some of the important haemodynamic factors are realistically quantifiable (albeit indirectly). The detection of parameters known to be causal in the development of graft intimal hyperplasia or other vascular pathology may improve ability to predict clinical problems. From a surgical perspective this might be employed to facilitate selection of at-risk grafts for more focused postoperative surveillance and reintervention. On a broader stage the utilisation of such analyses may be useful in predicting individuals at greater risk of developing atherosclerotic deposits, disease progression, and the likelihood of clinical events such as heart attack, stroke and threat of limb loss.