Prior research has suggested that life style factors, such as diet and physical activity, influence prostate cancer (PCa) progression. Metformin intake has been shown to be associated with decreased cancer risk in type II diabetic patients. We hypothesize that a low carbohydrate diet, prolonged aerobic exercise and metformin treatment can all independently slow prostate tumor development and a combination regimen will have an additive benefit. We used LNCaP xenografts to test this hypothesis. Results revealed that a diet low in carbohydrate reduced food consumption and a combination with exercise significantly reduced animal body weights. Ten weeks of metformin did not significantly alter tumor growth rate compared to control animals. Ten weeks of exercise significantly inhibited tumor growth. Out results suggest that dietary carbohydrate alteration or the administration of metformin alone cannot significantly influence prostate tumor progression. A suitable sustained exercise regimen may offer a more protective effect against PCa progression.

Enhanced resistance to radiation could be caused by both chronic hypoxia and acute hypoxic which has been reported in prostate cancer in various studies. Therefore currently used dose prescriptions (70Gy in 35 fractions) for external beam radiation therapy (EBRT) of prostate cancer has been suggested insufficient to provide optimum clinical outcome. In this study, we propose a Biologically Guided Radiation Therapy approach to boost dose in hypoxic prostate tumor regions while sparing the urethra. A previously proposed hypoxia model was modified for prostate cancer and incorporated into treatment plan optimization. The concept of equivalent uniform dose (EUD) was used in the optimization and evaluation of results. CT data from 25 prostate cancer patients who recently received EBRT at the British Columbia Cancer Agency (BCCA) and hypothetical hypoxic regions manually drawn on these CT scans were selected for this study. The results show that our methods could boost dose in target volume to substantially higher levels. EUD of planning target volume increased to more than 80Gy, despite accounting for effects of hypoxia. This increase was achieved with only minor changes in dose in normal tissues, typically less than 5Gy. Notably, urethra sparing was excellent with a EUD around 64Gy. Robustness of the proposed approach is verified against various hypoxic settings. EUD comparison between RT plans in biological guided and conventional approaches using the same RT technique (Volumetric Modulated Arc Therapy) also suggests that biologically guided radiation therapy (BGRT) approach is more suitable for dose painting purposes with the advantage of delivering sufficient dose to hypoxia region in different scenarios and sparing normal tissue better. Furthermore, we also investigated the impact of inter-fraction patient set-up error and intra-fraction organ motion on the high dose gradients achieved with this proposed dose painting method and explored the feasibility of adapting geometrical uncertainties (represented as systematic error and random error) into treatment planning. Image error obtained from EPID images are used to derive systematic uncertainty and random uncertainty. During the geometrical uncertainty adapted optimization, dose matrix in PTV is shifted based on systematic error and convolved with a Gaussian kernel which is pre-calculated using random error. CT sets and organ contours from five patients who enrolled in the previous dose painting i study are selected. For each of them, seven plans are generated using cumulated uncertainty data which was collected after every five fractions. We also present the outcome in terms of equivalent uniform dose (EUD). For four of the patients, EUD history of all seven plans suggests using the proposed optimization method with uncertainty data from the first five fractions, it is possible to achieve the same target coverage of static treatment plans (difference in EUD less than 1Gy). Meanwhile, the elimination of PTV margin also leads to a significant dose reduction (more than 15Gy) in rectum.

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.

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.

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

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No description available.

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