The evolution of prostate cancer from normal epithelium via the preneoplastic lesion of high-grade prostatic intraepithelial neoplasia to invasive carcinoma is characterised by a number of particular genomic abnormalities that are predominantly generated in the preneoplastic phase. Whilst there are numerous candidates for the cause of these alterations, telomere dysfunction is thought to be a major contributor. Telomeres are the terminal ends of human chromosomes, and when dysfunctional can lead to break-fusion-bridge cycles and multi-polar mitoses that generate numerical and structural chromosomal instability. The results presented reinforce the association of telomere dysfunction with the generation of certain markers of genomic instability such as abnormalities of the arms of chromosome 8. Furthermore, this work clarifies that the TMPRSSS2-ERG aberrations are not telomere related phenomena and are associated with a genomic deletion in a proportion of cases. Similarly, the PTEN microdeletions did not appear to have an association with telomere attrition. A previously unrecognised association between the telomere length in various types of prostatic epithelia and adjacent stroma is defined, suggesting evidence of a micro-environmental field effect in the generation of prostatic neoplasia. Finally, when examined retrospectively, it appears that telomere attrition, both in the HPIN epithelium and the stroma has independent prognostic value in the diagnosis of prostate cancer after a previous diagnosis of HPIN. Taken together, the research presented suggests important avenues for further research to determine the nature of barriers to the evolution of prostatic carcinogenesis such as oncogene- and telomere-induced senescence that may be exploited for therapeutic gain. These understandings may also help tailor management for prostate cancer such as risk stratification for men with HPIN and the use of targeted agents such as AKT inhibitors and telomerase inhibitors. In more advanced disease, translational application of this work has enabled a clinical trial of cytarabine in the treatment of metastatic hormone refractory prostate cancer.

Background: Life expectancy (LE) estimation is an important part of both screening and treatment decision-making for potentially curable prostate cancer. Clinicians’ estimation of patient life expectancy is typically made using population-based life tables and intuition and it is often inaccurate. This study explores methods to improve LE prediction by formally considering patient co-morbid illness status, in addition to age, in the development of a LE prediction tool. Methods: We conducted a population-based retrospective cohort study of patients from the Ontario Cancer Registry who were curative treatment candidates, identified between 1990-1998. We analyzed data on three sub-populations of this cohort, and we used LE estimates from the Ontario Life Tables. Each model utilized Cox proportional hazards analysis, and/or the declining exponential approximation of LE, to estimate the survival experience of potential curative treatment candidates, including the impact due to both age and co-morbid illness status. We developed five separate models, tested them using a random subset of the cohort study sample, and compared their predictive accuracy by measuring both discriminative ability and calibration to determine the ‘best’ model. We also conducted a supplementary analysis using logistic regression to develop a model to predict the probability of 10-year survival. Results: The ‘best’ of our models demonstrated a c-index of 0.65 and very good calibration. Further analysis revealed that our ‘best’ model violated the Cox PH assumption for age and it’s predictions consistently over-estimated observed LE. Supplementary analysis of the logistic regression prediction model demonstrated a c-index of 0.70. Conclusions: Our exploration of methods to predict LE resulted in modest predictive accuracy. However, based on the results of the logistic regression model, we conclude that the results of our LE prediction models are reasonable, and obtaining a high level of predictive accuracy may not be possible given just age and co-morbidities as predictors. Further studies should continue to explore these and other methods for LE prediction. External validation of the ‘best’ model from the current study is required before the model and its accompanying LE reference tables can be recommended for use in a clinical setting for screening or treatment decision-making. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2011-04-07 19:11:34.216

Prostate brachytherapy, a treatment for prostate cancer, was a procedure that typically involved placing radioactive sources in a cancerous prostate using percutaneous needles. The placement of these sources determined the dose that the prostate and healthy tissues surrounding it received. However, because a needle could bend, tissue could deform, and a patient could move, each source may have been displaced from its planned position. This source misplacement could later cause some cancer to be spared or healthy organs to be further damaged. To better understand patterns of source misplacement, and eventually reduce the phenomenon, this work matched and registered implanted sources with their planned positions. Each implant was registered to its plan using a sequence of four successive registrations. A rough initial registration was first found, using features known in the planned dataset and estimated from the implanted dataset. Second, subsets of sources were reconstructed in the implanted dataset. The implanted sources were next matched to the planned sources using the subsets as constraints. Finally, the optimal rigid transformation between the implants and the plan was found. The algorithm was tested on both simulated and clinical datasets. Simulations placed limits on how properties of the subsets affected registration accuracy. When tested on 9 clinical datasets, the algorithm found 100% of correct plan-implant source matches within seconds on commonly available computers. When the implanted strands were reconstructed as sine waves, 97% of t strands had an amplitude of less than 2mm. The clinical accuracy result generally agreed with simulation: subsets with amplitudes less than 2mm were expected to produce an accuracy >90%. The high accuracy of the algorithm may enable its use in finding patterns of source misplacement. The fast run-time of the algorithm may additionally make it useful for use in a clinical setting. / Thesis (Master, Computing) -- Queen's University, 2011-12-23 13:28:07.348

No description available.

No description available.

<p>Prostate cancer (PCa) is the most common non-cutaneous cancer in men with an estimated almost 30,000 deaths occurring in the United States in 2014. Currently, the most widely utilized methods for screening men for prostate cancer include the digital rectal exam and prostate specific antigen analysis; however, these methods lack either high sensitivity or specificity, requiring needle biopsy to confirm the presence of cancer. The biopsies are conventionally performed with only B-mode ultrasound visualization of the organ and no targeting of specific regions of the prostate, although recently, multi-parametric magnetic resonance imaging has shown promise for targeting biopsies. Earlier work has demonstrated the feasibility of acoustic radiation force impulse (ARFI) imaging and shear wave elasticity imaging (SWEI) to visualize cancer in the prostate, however multiple challenges with both methods have been identified.</p><p>The aim of this thesis is to contribute to both the technical development and clinical applications of ARFI and SWEI imaging using the latest advancements in ultrasound imaging technology.</p><p>The introduction of the Siemens Acuson SC2000 provided multiple technological improvements over previous generations of ultrasound scanners, including: an improved power supply, arbitrary waveform generator, and additional parallel receive beamforming. In this thesis, these capabilities were utilized to improve both ARFI and SWEI imaging and reduce acoustic exposure and acquisition duration. However, the SC2000 did not originally have radiation force imaging capabilities; therefore, a new tool set for prototyping these sequences was developed along with rapid data processing and display code. These tools leveraged the increasing availability of general purpose computing on graphics processing units (GPUs) to significantly reduce the data processing time, facilitating real-time display for ultrasonic research systems.</p><p>These technical developments for both acquisition and processing were applied to investigate new methods for ARFI and SWEI imaging. Specifically, the power supply on the SC2000 allowed for a new type of multi-focal zone ARFI images to be acquired, which are shown to provide improved image quality over an extended depth of field. Additionally, a new algorithm for SWEI image processing was developed using an adaptive filter based on a maximum a posteriori estimator, demonstrating increases in the contrast to noise ratio of lesion targets upwards of 50%.</p><p>Finally, the optimized ARFI imaging methods were integrated with a transrectal ultrasound transducer to acquire volumetric in vivo data in patients undergoing robotic radical prostatectomy procedures in an ongoing study. When the study was initiated, it was recognized that the technological improvements of Siemens Acuson SC2000 allowed for the off-axis response to the radiation force excitation to be concurrently recorded without impacting ARFI image quality. This volumetric SWEI data was reconstructed retrospectively using the approaches developed in this thesis, but the images were low quality. A further investigation identified multiple challenges with the SWEI sequence, which should be addressed in future studies. The ARFI image volumes were very high quality and are currently being analyzed to assess the accuracy of ARFI to visualize prostate anatomy and clinically significant prostate cancer tumors. After a blinded evaluation of the ARFI image volumes for suspicion of prostate cancer, three readers correctly identified 63% of all clinically significant tumors and 74% of clinically significant tumors in the posterior region, showing great promise for using ARFI in the context of prostate cancer visualization for targeting biopsies, focal therapy, and watchful waiting.</p> / Dissertation

We demonstrate here that ultrasound-stimulated microbubbles can lead to enhanced cell death within tumors when combined with radiation. The aim of this study was to investigate different ultrasound parameters in conjunction with different concentrations of microbubbles with regards to this effect. Prostate xenograft tumors in Severe Combined Immunodeficient mice were subjected to ultrasound treatment that involved various peak negative pressures (250 kPa, 570 kPa, and 750 kPa), microbubble concentrations (8 µL/kg, 80 µL/kg, and 1000 µL/kg), and different radiation doses (0 Gy, 2 Gy, and 8 Gy). Twenty-four hours after treatment, tumors were excised and assessed for cell death. Histological analyses demonstrated that increases in radiation dose, microbubble concentration, and ultrasound pressure promoted apoptotic cell death and cellular disruption within tumors. Comparable increases in ceramide, a cell death mediator, were identified using immunohistochemistry. We also demonstrate that clinically-utilized microbubble concentrations combined with ultrasound can induce an enhancement in cell death.

We demonstrate here that ultrasound-stimulated microbubbles can lead to enhanced cell death within tumors when combined with radiation. The aim of this study was to investigate different ultrasound parameters in conjunction with different concentrations of microbubbles with regards to this effect. Prostate xenograft tumors in Severe Combined Immunodeficient mice were subjected to ultrasound treatment that involved various peak negative pressures (250 kPa, 570 kPa, and 750 kPa), microbubble concentrations (8 µL/kg, 80 µL/kg, and 1000 µL/kg), and different radiation doses (0 Gy, 2 Gy, and 8 Gy). Twenty-four hours after treatment, tumors were excised and assessed for cell death. Histological analyses demonstrated that increases in radiation dose, microbubble concentration, and ultrasound pressure promoted apoptotic cell death and cellular disruption within tumors. Comparable increases in ceramide, a cell death mediator, were identified using immunohistochemistry. We also demonstrate that clinically-utilized microbubble concentrations combined with ultrasound can induce an enhancement in cell death.

Prostate cancer (CaP) is the 2nd most common cancer in North American men. Tumour management strategies are appropriate for early stage disease, but advanced disease has a poor prognosis and requires prompt treatment. Therefore, research into delay of tumour progression and efficacious treatment of aggressive cancer are of interest. Ganglioside was assessed for its role in altering markers of metastatic potential and susceptibility of CaP to adenovirus-mediated gene therapy. Healthy (RWPE-1) and malignant (DU-145, PC-3) prostate cells were cultured with or without mixed ganglioside. Differences in growth, ganglioside and integrin densities, and adenoviral infectivity were assessed between treatment and control groups. Ganglioside decreased (p<0.01) growth of PC-3 cells relative to untreated control. Ganglioside decreased (p<0.01) GD1a and increased (p<0.04) integrin densities in malignant prostate cells, suggesting ganglioside may increase metastatic potential of CaP. Ganglioside significantly increased adenovirus entry in PC-3 cells, thereby improving susceptibility of CaP to adenovirus-mediated gene therapy. / Nutrition and Metabolism

Prostate cancer is the most common cancer among Swedish men, but the aetiology of this disease is largely unknown. There is evidence for a linkage between chronic inflammation and prostate cancer. The mechanisms causing prostate inflammation and how this could promote tumour development and progression are however largely unknown. Chronic inflammatory infiltrates are common findings in prostate tissue samples and infection is proposed to be one possible cause for this inflammation. Inflammatory cells release free radicals, cytokines, and growth factors that facilitate increased cell proliferation, DNA damage, mutations, and angiogenesis. However, the present literature on the presence of microbes in prostate tissue and their possible linkage to inflammation and cancer development is limited. Therefore, the aim of this thesis was to investigate if microorganisms are present in prostate tissue and to evaluate their role in inducing prostatitis and prostate epithelial neoplasia. The presence of microorganisms (virus, bacteria and fungi) was studied in clinical prostate tissue samples to evaluate whether or not the occurrences of microorganisms were different in patients that later developed cancer compared with matched controls that did not. Viruses, bacteria and fungi were found in prostate tissues. Out of eight different viruses investigated, EBV and JC virus were detected, but there were no differences in occurrence in the case group compared to the control group. The fungus Candida albicans was present in a very small proportion of the prostate tissue samples. The predominant bacterium was Propionibacterium acnes and the second most prevalent was Escherichia coli. The presence of Propionibacterium acnes was associated with inflammation and subsequent prostate cancer development. Propionibacterium acnes was further evaluated for its capacity to induce an inflammatory response both in vitro and in vivo. Live Propionibacterium acnes induced a strong immune reaction in prostate epithelial cells in vitro with up-regulation of inflammatory genes and secretion of pro-inflammatory cytokines. Infection with Propionibacterium acnes in rat prostate resulted in a lobe specific inflammation with the most intense inflammation in the dorso-lateral prostate, lasting up to 3 months post-inoculation. Propionibacterium acnes inflammation was also associated with altered epithelial cell morphology, signs of DNA damage and increased cell proliferation. Taken together, this thesis shows that different viruses and bacteria can be found in prostate tissue. Propionibacterium acnes, the most abundant among the bacteria detected and more prevalent in the cancer than in the control group, exhibits strong prostatitis promoting properties both in vitro and in vivo. In addition, Propionibacterium acnes can induce some of the epithelial changes known to occur during prostate neoplasia formation. This thesis therefore suggests that Propionibacterium acnes induced chronic prostatitis could promote prostate cancer development. Further studies are needed to elucidate the molecular interplay linking Propionibacterium acnes induced inflammation and the formation of a pre-neoplastic state that could evolve into prostate cancer.