Les options thérapeutiques d'intention curative ont une faible probabilité de succès chez les patients atteints d'un cancer de la prostate avec métastases ganglionnaires. Ainsi, l'obtention d'une méthode de prédiction de la présence ou l'apparition de métastases ganglionnaires est souhaitable. Ce document présente le développement d'un modèle de prédiction de la présence de métastases ganglionnaires à la prostatectomie radicale. Le modèle utilise les marqueurs radiomiques extraits de l'examen FDG-TEP/CT fait en préopératoire. Ces marqueurs issus de la radiomique - définie comme le processus d'extraction quantitative de données exploitables de haute dimension à partir d'images médicales - permettent de quantifier des caractéristiques invisibles à l'œil tels que les paramètres de texture et d'intensité. Dans un premier volet, afin de limiter les erreurs de recalage entre la TEP et le CT, une évaluation de l'extraction des marqueurs radiomiques a été effectuée en comparant la valeur maximale d'absorption standardisée (SUVₘₐₓ) sur l'imagerie TEP. Une méthode de segmentation semi-automatique de la vessie en TEP a été développée de manière à soustraire la vessie de la segmentation de la prostate, ce qui permet une extraction plus juste des marqueurs radiomiques. Dans un second volet, une méthode de sélection des marqueurs radiomiques a été développée afin de réduire les marqueurs redondants et de sélectionner les plus importants, ce qui a permis de sélectionner 17 marqueurs TEP. Lorsque combinés avec l'intelligence artificielle, les marqueurs radiomiques peuvent être utilisés pour la prédiction de différents paramètres cliniques. Un modèle de prédiction utilisant un classificateur par forêts aléatoires a permis d'obtenir des résultats démontrant le potentiel de l'algorithme et des marqueurs radiomiques en FDG-TEP/CT. Une fois couplé aux données cliniques, l'algorithme permet une meilleure prédiction. Une AUC de (79 ± 9) % est obtenue lors de la combinaison du modèle de prédiction avec le stade clinique de la tumeur. / Therapeutic options with curative intent have a low probability of success in patients with prostate cancer with lymph node metastases. Therefore, a method for predicting the presence or development of lymph node metastases is desirable. This document presents the development of a model for predicting the presence of lymph node metastases at radical prostatectomy. The model uses radiomic markers extracted from the preoperative FDG-PET/CT examination. These radiomic markers - defined as the process of quantitatively extracting high-dimensional usable data from medical images - allow the quantification of features invisible to the eye such as texture and intensity parameters. In the first part, to limit the misalignment errors between PET and CT, an evaluation of the extraction of radiomic markers was carried out by comparing the standardized maximum absorption value (SUVₘₐₓ) on PET imaging. A semi-automatic PET bladder segmentation method was developed to subtract the bladder from the prostate segmentation, allowing a more accurate extraction of radiomic markers. In the second phase, a method for selecting radiomic markers was developed to reduce redundant markers and to select the most important ones, resulting in the selection of 17 PET markers. When combined with artificial intelligence, radiomic markers can be used for the prediction of various clinical parameters. A prediction model using a random forest classifier provided results demonstrating the potential of the algorithm and radiomic markers in FDG-PET/CT. Once coupled with clinical data, the algorithm allows a better prediction. AUC of (79 ± 9) % is obtained when combining the prediction model with the clinical stage of tumor.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Tumor biologist have long appreciated that both cell to cell and cell to extracellular matrix (ECM) interactions are involved in the invasive and metastatic events that are characteristic of malignancy. Cancer cell attachment to and invasion of an ECM has been associated with metastatic potential of cell lines of the Dunning rat prostate model. It was postulated that differences observed in the metastatic potential of four Dunning cell lines may correlate with cell-matrix interactions. Four cell lines, highly metastatic ML, MLL, AT-3 and non-metastatic AT-1 were studied. The adhesive, invasive and chemoinvasive capability of each cell line was compared. Cell adhesion was examined by plating the cells on plastic dishes coated with various components of the ECM (fibronectin, laminin and collagen) as well as EHS Natrix (a natural ECM) . Invasion was determined by examining cells ability to traverse a matrigel barrier. Correlations were found between the cells' adhesive and invasive abilities in response to the ECM. These observations suggest that ECM components are highly involved in prostate cancer cell activities and loss may contribute to tumor progression and metastasis.

This study examines the effects of novel antineoplastic agents(isochalcones) on human metastatic prostate cancer cell lines by screening cells for their relative antiproliferative effects, measuring the protein expression levels of specific oncogenes by Western blotting, and evaluating an array of genes ( 5184) to determine possible mechanisms of action of these novel isochalcones. The array data were supported by real-time polymerase chain reaction (PCR) techniques. The antineoplastic agents were screened in human metastatic prostate cancer cell lines (LNCaP, DU145, PC-3, and MDA-PCa-2b) and non-cancerous prostate epithelial cell line PZ-HPV-7 in concentrations ranging from nanomolar to millimolar. The alamar blue exclusion dye assay, a redox indicator, was used to evaluate cell proliferation when compared to the untreated control. DJ52 demonstrated a growth inhibitory effect on LNCaP, PC-3, and DU145 cell lines at the micromolar concentration (p<0.05). Based on these data, 1 x 106 cells were treated, protein isolated, and expression levels of epidermal growth factor (EGF) and omithine decarboxylase (ODC) were measured and compared to theuntreated controls. These data indicated a dose-dependent decrease of expression of EGF and ODC, therefore, suggesting that other key oncogenes may also have a decrease in expression when treated with these novel antineoplastic agents. Therefore, gene arrays were used to identify possible families of genes and/or specific pathways that may be responsible for the antiproliferative effects noted. It was determined that the key families of genes significantly induced by these agents (Pathways 4®) were proapoptotic and cell cycle regulators. ABI 7700 Prism was used to perform quantitative RT-PCR via the AB Sequence Detector® software.

One in two people born after 1960 in the United Kingdom will be diagnosed with some form of cancer during their lifetime. Analysis of cancer at the bulk level means that individual attributes may be averaged, and single cell detection and interrogation techniques are therefore of particular interest. In recent years, significant progress has been made into the label-free detection and discrimination of individual cancer cells using Laser Tweezers Raman Spectroscopy (LTRS). However, methods have invariably involved a high degree of manual intervention, and before this technique can be translated into a clinical setting a greater degree of automation is required.\\Initial work has centred on the construction of a LTRS system for the analysis of individual prostate cancer cells and lymphocytes. A novel method of acquiring cell spectra using a microfluidic flow cell has been developed, and the optimum operating conditions for such a system are elucidated in this thesis. Using the system developed, the discrimination of epithelial prostate cells and lymphocytes has been achieved with a high degree of accuracy while requiring a significant reduction in operator input. Further developments to the system have made it possible to obtain Raman spectra for multiple cell lines in a completely automated manner, with no input required during the acquisition of spectra. \\A motivating factor behind the integration of LTRS with microfluidics is the possibility of a label-free equivalent of the Fluorescent Activated Cell Sorter (FACS), which remains the gold standard for single cell analysis. A number of significant steps toward the development of the Raman equivalent (RACS) are presented in this thesis, including the demonstration of an automated system which is capable of multivariate classification and cell translation in real time. Due to limitations relating to the microfluidic flow cells, it has not been possible to actively sort one cell line from a mixed population. However, the system presented in this thesis represents a considerable level of progress towards this objective.\\In addition to the construction of a LTRS arrangement, a 2D Raman mapping system has been developed for the analysis of adherent prostate cell line. This has allowed a direct comparison between the more common technique of Raman mapping and LTRS, and provides new insights into the level of information which can be obtained using LTRS. This thesis presents results obtained with both systems which enable malignant and normal prostate cell lines to be distinguished based on cytochrome-c levels. While cytochrome-c content has been linked with malignancy previously, this is the first demonstration of this relationship using a LTRS system which could be applied in a high throughput setting.

Prostate Cancer (PC) is associated with disease- and treatment-related side effects that can compromise quality of life (QoL). Psychosocial interventions designed to improve adjustment and quality of life (QoL) for post-treatment PC patients have been conducted with mixed results. Intervention effects are typically analyzed using either mean difference scores or a single estimate of growth parameters (e.g., intercept and slope factors) across groups. These methods assume homogeneity within groups. Evidence suggests, however, considerable variability both in the experience of disease-specific outcomes and in the long-term adjustment and emotional well-being of men with PC. The present study used growth mixture modeling (GMM) to explore the effects of a cognitive behavioral stress management (CBSM) intervention on emotional well-being among men recently treated for localized PC. This methodology allowed examination of intervention effects across unobserved subgroups characterized by different trajectories of emotional well-being and identified factors associated with intervention efficacy.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

A beta-emitting glass seed was proposed for the brachytherapy treatment of prostate cancer. Criteria for seed design were derived and several beta-emitting nuclides were examined for suitability. 142Pr was selected as the isotope of choice. Seeds 0.08 cm in diameter and 0.9 cm long were manufactured for testing. The seeds were activated in the Texas A&M University research reactor. The activity produced was as expected when considering the meta-stable state and epi-thermal neutron flux. The MCNP5 Monte Carlo code was used to calculate the quantitative dosimetric parameters suggested in the American Association of Physicists in Medicine (AAPM) TG-43/60. The Monte Carlo calculation results were compared with those from a dose point kernel code. The dose profiles agree well with each other. The gamma dose of 142Pr was evaluated. The gamma dose is 0.3 Gy at 1.0 cm with initial activity of 5.95 mCi and is insignificant to other organs. Measurements were performed to assess the 2-dimensional axial dose distributions using Gafchromic radiochromic film. The radiochromic film was calibrated using an X-ray machine calibrated against a National Institute of Standards and Technology (NIST) traceable ion chamber. A calibration curve was derived using a least squares fit of a second order polynomial. The measured dose distribution agrees well with results from the Monte Carlo simulation. The dose was 130.8 Gy at 6 mm from the seed center with initial activity of 5.95 mCi. AAPM TG-43/60 parameters were determined. The reference dose rate for 2 mm and 6 mm were 0.67 and 0.02 cGy/s/mCi, respectively. The geometry function, radial dose function and anisotropy function were generated.

Background: The prostate specific antigen (PSA) test has been available for physicians and free of charge to residents in Saskatchewan since 1990. The PSA test witnessed great growth in use indicative of screening but it was unknown who was being tested, how often, which physicians were ordering PSA tests, or what the variation in utilization was in the population. Whether widespread use of the PSA test resulted in a stage shift among newly diagnosed prostate cancers or changed the clinical management of the disease was also unknown. The purpose of this research was to describe in detail how the PSA test is being used in the Saskatchewan population and investigate the impact of testing on the diagnosis and clinical management of prostate cancer during the PSA era.<p> Methods: Individual records were retrieved from the two labs in Saskatchewan capable of analyzing PSA serum samples. The PSA data represented almost all PSA tests in the population for the five-year period 1997-2001. The PSA data included date of the PSA test, a unique identifier of the men tested, test results including total PSA and the free-PSA amount (for November 1999 to December 2001), and an ID of the physician who ordered the test. This data was linked to the population-based Saskatchewan Cancer Registry to determine who had a previous or subsequent prostate cancer diagnosis and to secure tumour characteristics and clinical management data. This combined data was then linked to Saskatchewan Health data files to obtain information about biopsy procedures and to determine the geographic residence of men at the time of their PSA tests. De-identified data was returned for descriptive analysis.<p> Results: Over 60% of men aged 50 and over had at least one PSA test during 1997 to 2001. Even among men 40-49, 27% had at least one PSA test and there were over 5,300 tests done in men under 40 years of age. Sixteen percent of men 40-49 who had PSA tests had more than one and this percentage increased with age to 59.4% for men in their 70s. Over 80% of all PSA tests were ordered by general practitioners and there were significant geographic variations in testing patterns. Knowledge of the free-PSA-ratio, which began in 1999, reduced biopsy rates 4.7% and increased cancer detection 8.7% for men with total PSA test results in the 4.0-10.0ng/ml range, however these rates were also very age specific. The age-adjusted incidence rate of organ confined disease increased from 38.5 per 100,000 to 108.8 per 100,000 from 1985 to 2001. Almost 80% of prostate cancers were detected by needle biopsy in 2001 compared to only 34% in 1985, while 20% of cases in 2001 were treated with radical surgery compared to only 2% for 1985. Mortality rates have remained stable up to 2001.<p> Conclusion: PSA testing is very common in Saskatchewan consistent with extensive screening activity. Conflicting guidelines and the universal availability of the test has resulted in significant inappropriate testing and considerable variation of use. Most prostate cancers are now found by needle biopsy and are organ confined at the time of diagnosis. No benefit in prostate cancer mortality has yet been realized in Saskatchewan from extensive PSA testing.

Background LHRH agonists decrease tumour size/activity by suppressing testosterone in prostate cancer; however, initial injection causes testosterone surge that triggers flare symptoms. Anti-androgen given with agonist may reduce/avoid flare symptoms. When LHRH antagonist/blocker is introduced, testosterone suppression is immediate, but there is uncertainty about significance of flare symptoms without anti-androgen. Objective Systematic review compared significance of flare symptoms avoided and cost utility analysis using modelling comparing incremental value of blocker (degarelix) OR agonist (goserelin)+anti-androgen (bicalutamide) VERSUS agonist alone in prostate cancer patients. Outcome Incremental cost/QALY of bone pain as flare symptom between treatments Results Thirteen studies were reviewed. There was no standard definition for flare symptoms or data on LHRH antagonist versus other treatments on flare. From societal perspective, goserelin+bicalutamide was dominated over goserelin alone and similarly, from public perspective, goserelin+bicalutamide had favourable cost effectiveness profile against goserelin. Conclusion With bone pain as clinical endpoint, LHRH agonist+anti-androgen had favourable cost-effectiveness profile compared to goserelin.