<p>Prostate cancer is the most common type of cancer in men in Europe and the USA. Some prostate tumours are regarded as stiffer than the surrounding normal tissue, and therefore it is of interest to be able to reliably measure prostate tissue stiffness. The methods presently used to detect prostate cancer are inexact, and new techniques are needed. In this licentiate thesis resonance sensor technology, with its ability to measure tissue stiffness, was applied to normal and cancerous prostate tissue.</p><p>A piezoelectric transducer element in a feedback system can be set to vibrate at its resonance frequency. When the sensor element contacts an object a change in the resonance frequency is observed, and this feature has been utilized in sensor systems to describe physical properties of different objects. For medical applications it has been used to measure stiffness variations due to various pathophysiological conditions.</p><p>An impression-controlled resonance sensor system was used to quantify stiffness in human prostate tissue in vitro using a combination of frequency change and force measurements. Measurements on prostate tissue showed statistically significant (p < 0.001) and reproducible differences between normal healthy tissue and tumour tissue when using a multivariate parameter analysis. Measured stiffness varied in both the normal tissue and tumour tissue group. One source of variation was assumed to be related to differences in tissue composition. Other sources of error could be uneven surfaces, different levels of dehydration of the prostates, and actual differences between patients.</p><p>The prostate specimens were also subjected to morphometric measurements, and the sensor parameter was compared with the morphology of the tissue with linear regression. In the probe impression interval 0.5–1.7 mm, the maximum coefficient of determination was R2 ≥ 0.60 (p < 0.05, n = 75). An increase in the proportion of prostate stones (corpora amylacea), stroma, or cancer in relation to healthy glandular tissue increased the measured stiffness. Cancer and stroma had the greatest effect on the measured stiffness. The deeper the sensor was pressed, the greater, i.e., deeper, volume it sensed.</p><p>It is concluded that prostate cancer increases the measured stiffness as compared with healthy glandular tissue, but areas with predominantly stroma or many stones could be more difficult to differentiate from cancer. Furthermore, the results of this study indicated that the resonance sensor could be used to detect stiffness variations in human prostate tissue in vitro, and especially due to prostate cancer. This is promising for the development of a future diagnostic tool for prostate cancer.</p>

FGFR4 and β-Klotho in Metastatic Prostate Cancer by Derek LaMar Shenefelt Fibroblast growth factors and fibroblast growth factor receptors have been associated with the aggressiveness and progression of Prostate Cancer (PCa). Also, β-Klotho is a known co-receptor with FGFR4 for FGF19 in the liver however, the role of this co-receptor pair remains unclear in the setting of PCa. I demonstrated that FGFR4 and KLB mRNA and protein are highly expressed in PCa cells when compared to bone marrow stromal cells, a common site of metastasis. I also provide support for the association of FGFR4 and KLB in PCa, suggesting a functional co-receptor pair capable of altering cellular signaling. FGFR4-KLb may also provide some level of protection to PCa cells from chemotherapeutics. This analysis of FGFR4 and KLB expression and signaling in PCa has provided novel insights into phenotypic alterations during PCa progression while also providing new avenues of study to further explore the role and importance of this exciting co-receptor complex.

L'hypertrophie bénigne de la prostate (HBP) est une pathologie qui affecte 50% des hommes dès l'âge de 60 ans et qui conduit à des troubles de la miction. L'HBP se caractérise par une hypertrophie exclusive ou composite de plusieurs compartiments tissulaires de la prostate que sont l'épithélium, le stroma et les fibres musculaires qui définissent respectivement les composantes glandulaire, fibreuse et musculaire de cette pathologie. Il a récemment été montré que les souris dépourvues en récepteurs nucléaires LXR (Liver‐X‐receptor) α (souris lxrα‐/‐) développent une hypertrophie de la prostate dont les signes histologiques évoquent une HBP de type fibreuse. Par ailleurs, un des traitements de l'HBP, vise à éteindre la signalisation androgénique en inhibant la conversion de la testostérone en son métabolite actif, la dihydrotestostérone (DHT). Le phénotype d'hypertrophie de la prostate pourrait donc également s'expliquer par une altération de la signalisation androgénique dans les souris lxrα‐/‐. Dans ce contexte, notre projet de recherche a été centré sur l'étude du rôle des LXR dans l'apparition de l'HBP dans sa composante glandulaire et l'analyse des relations moléculaires associant les signalisations dépendantes de LXRα et du récepteur des androgènes (AR) au sein de la prostate. Le phénotype d'HBP observé dans les souris lxrα‐/‐ résulte d'altérations importantes de l'homéostasie de l'épithélium qui miment la composante glandulaire : 1) une activité sécrétoire accrue ; 2) une altération des processus de sécrétion associée à une altération de l'expression des gènes codant des protéines du transport vésiculaire ; 3) une réponse altérée de certains gènes androgéno‐dépendants associée à une hypersensibilité aux androgènes ; 4) des modifications du réseau paracrine reliant le stroma et l'épithélium. Au final, ces travaux définissent LXRα comme un acteur clé de l'homéostasie prostatique et ouvrent des pistes intéressantes pour la compréhension de l'étiologie de l'HBP chez l'homme. Ces résultats montrent qu'il est possible de moduler la réponse androgénique de la prostate en ciblant LXRα. Ainsi, à plus long terme, l'activation pharmacologique de LXRα constitue une piste potentielle dans le traitement de l'HBP.

<p>Prostate cancer (PCa) is the most common non-cutaneous cancer in men in the United States. Early detection of PCa is essential for improving treatment outcomes and survival rates. However, diagnosis of PCa at an early stage is challenged by the lack of an imaging method that can accurately visualize PCas. Because pathological processes change the mechanical properties of the tissue, elasticity imaging methods have the potential to differentiate PCas from other prostatic tissues. Acoustic radiation force impulse (ARFI) imaging is a relatively new elasticity imaging method that visualizes the local stiffness variations inside soft tissue.</p><p>The work presented in this dissertation investigates the feasibility of prostate ARFI imaging. Volumetric ARFI data acquisition and display methods were developed to visualize anatomic structures and pathologies in <italic>ex vivo </italic>human prostates. The characteristic appearances of various prostatic tissues in ARFI images were identified by correlating ARFI images with McNeal's zonal anatomy and the correlated histological slides, in which prostatic pathologies were delineated by a pathologist blinded to the ARFI images. The results suggest ARFI imaging is able to differentiate anatomic structures and identify suspicious PCa regions in the prostate.</p><p>To investigate the correlation between ARFI displacement amplitudes and the underlying tissue stiffness in the prostate ARFI images, the mechanical properties of prostatic tissues were characterized using a quantitative method, based upon shear wave elasticity imaging (SWEI). Co-registered ARFI and SWEI datasets were acquired in excised prostate specimens to reconstruct the shear moduli of prostatic tissues. The results demonstrated that variations in ARFI displacement amplitudes were inversely related to the underlying tissue stiffness; and the reconstructed shear moduli of prostatic tissues had good agreements with those reported in literature. The study suggests the matched ARFI and SWEI datasets provide complementary</p><p> information about tissue's elasticity. </p><p>To increase the efficiency of the data acquisition, a novel imaging sequence was developed to acquired matched ARFI-SWEI datasets without increasing the number of excitations compared to a conventional ARFI imaging sequence. Imaging parameters were analyzed both theoretically and experimentally. An analytical model was derived to quantify the fundamental accuracy limit in the reconstructed shear modulus, and demonstrated good agreement with the experimental data. The novel sequence was demonstrated in tissue-mimicking phantoms.</p><p>Finally, ARFI imaging sequences were developed in a transrectal probe, and ARFI images were presented from <italic>in vivo</italic> data acquired in patients under radical prostatectomy. The <italic>in vivo</italic> ARFI images demonstrated decreased contrast and resolution as compared to the matched <italic>ex vivo</italic> ARFI data. However, prostate anatomy and some PCa were successfully visualized in the <italic>in vivo</italic> ARFI images. Thus, we conclude that ARFI imaging has the potential to provide image guidance for locating cancerous regions during PCa diagnosis and treatment.</p> / Dissertation

published_or_final_version / Anatomy / Master / Master of Philosophy

Not available / text

Hyperthermia based cancer treatments delivered under various modalities have the potential to become an effective option to eradicate the disease, maintain functionality of infected organs, and minimize complications and relapse. Moreover, hyperthermia therapies are a form of minimally invasive cancer treatment which are key to improving the quality of life post-treatment. Many modalities are available for delivering the heat source. However, the ability to control the energy deposition to prevent damage to adjacent healthy tissue is a limiting factor in all forms of thermal therapies, including cryotherapy, microwave, radio-frequency, ultrasound, and laser. The application of a laser heat source under the guidance of real-time treatment data has the potential to provide unprecedented control over the temperature field induced within the biological domain. The computational infrastructure developed in this work combines a computational model of bioheat transfer based on a nonlinear version of the Pennes equation for heterogeneous media with the precise timing and orchestration of the real-time solutions to the problems of calibration, optimal control, data transfer, registration, finite element mesh refinement, cellular damage prediction, and laser control; it is an example of Dynamic-Data-Driven Applications System (DDDAS) in which simulation models interact with measurement devices and assimilates data over a computational grid for the purpose of producing high-fidelity predictions of physical events. The tool controls the thermal source, provides a prediction of the entire outcome of the treatment and, using intra-operative data, updates itself to increase the accuracy of the prediction. A precise mathematical framework for the real-time finite element solution of the problems of calibration, optimal heat source control, and goal-oriented error estimation applied to the equations of bioheat transfer is presented. It is demonstrated that current finite element technology, parallel computer architecture, data transfer infrastructure, and thermal imaging modalities are capable of inducing a precise computer controlled temperature field within a biological domain. The project thus addresses a set of problems falling in the intersection of applied mathematics, imaging physics, computational science, computer science and visualizations, biomedical engineering, and medical science. The work involves contributions in the three component areas of the CAM program; A, Applicable Mathematics; B, Numerical Analysis and Scientific Computing; and C, Mathematical modeling and Applications. The ultimate goal of this research is to provide the medical community a minimally invasive clinical tool that uses predictive computational techniques to provide the optimal hyperthermia laser treatment procedure given real-time, patient specific data. / text

Prostate-specific antigen (PSA) testing has caused a steep increase in the incidence of prostate cancer, especially the incidence of localised low risk disease. In order to decrease the overdiagnosis accompanied by PSA testing, analysis of inherited genetic variants have been suggested as potential tools for clinical assessment of disease risk. With the aim of minimizing overtreatment and postpone side-effects of curative treatment for low risk prostate cancer, active surveillance, a treatment strategy with initial surveillance and deferred radical prostatectomy at the time of progression has evolved.  The aim of this thesis was to study the validity of PSA (paper I) and inherited genetic variants (paper II) for early diagnosis of prostate cancer, to assess the extent of PSA testing in Sweden (paper III), and to study the safety of deferred radical prostatectomy in localised low to intermediate risk prostate cancer (paper IV). The study designs were i) case-control studies nested within the Västerbotten intervention project (paper I and II), ii) observational study in the Cancer Register of Sweden (paper III), and iii) observational study in the NPCR Follow-up study (paper IV). PSA had a high validity in predicting a prostate cancer diagnosis with an area under the receiver operating characteristics (ROC) curve of 0.86 (95% CI, 0.84 to 0.88). A combined test, including PSA, the ratio of free to total PSA, and 33 single nucleotide polymorphisms (SNPs) in a genetic risk score, increased the area under curve to 0.87 (95% CI, 0.85 to 0.89). The estimated uptake of PSA testing among men aged 55 to 69 years increased from zero to 56% between 1997 and 2007 and there were large variations in the uptake of PSA testing between counties in Sweden. After a median follow-up time of eight years there was no significant difference in presence of any one or more adverse pathology features or prostate cancer specific mortality after primary compared to deferred radical prostatectomy in localised low to intermediate risk prostate cancer. Results from these studies indicate that PSA and the hitherto identified SNPs are not suitable biomarkers in single-test prostate cancer screening. It is possible to estimate the uptake of PSA testing on a population level. Initial surveillance and deferred radical prostatectomy represent a feasible treatment strategy in localised low to intermediate risk prostate cancer.

Prostate cancer continues to be the most commonly diagnosed cancer among men. Brachytherapy has emerged as one of the definitive treatment options for early stage prostate cancer which entails permanent implantation of radioactive seeds into the prostate to eradicate the cancer with ionizing radiation. Successful brachytherapy requires the ability to perform dosimetry -which requires seed localization- during the procedure but such function is not available today. If dosimetry could be performed intraoperatively, physicians could implant additional seeds into the under-dosed portions of the prostate while the patient is still on the operating table. This thesis addresses the brachytherapy seed localization problem with introducing intensity based registration between transrectal ultrasound (TRUS) that shows only the prostate and a 3D seed model drawn from fluoroscopy that shows only the implanted seeds. The TRUS images are first filtered and compounded, and then registered to the seed model by using mutual information. A training phantom was implanted with 48 seeds and imaged. Various ultrasound filtering techniques were analyzed. The effect of false positives and false negatives in ultrasound was investigated by randomly masking seeds from the fluoroscopy volume or adding seeds to that in random locations. Furthermore, the effect of sparse and dense ultrasound data was analyzed by running the registration for ultrasound data with different spacing. The registration error remained consistently below clinical threshold and capture range was significantly larger than the initial guess guaranteed by the clinical workflow. This fully automated method provided excellent registration accuracy and robustness in phantom studies and promises to demonstrate clinically adequate performance on human data. / Thesis (Master, Electrical & Computer Engineering) -- Queen's University, 2008-09-27 12:35:16.691

High grade intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) are two pathological lesions associated with prostate adenocarcinoma. HGPIN is an architectural finding, while ASAP is a term used to describe a lesion that cannot confidently be diagnosed as prostate adenocarcinoma. The mean incidence rate for HGPIN is 7.7% with a median of 5.2% and range of 0-24.6% and the cancer detection rate mean is 18.1%. The mean incidence rate for ASAP is 5.0% with a median of 4.4% and a range of 0.7-23.4%. The mean cancer detection rate is 40.2%. Currently, the incidence and cancer detection rates for HGPIN and ASAP for Winnipeg, Manitoba, have not been published. A retrospective study was conducted on all prostate biopsies collected from the Manitoba Cancer Care Prostate Centre (MCCPC) from 2008 and 2009. Prostate biopsies with a diagnosis of isolated HGPIN and or ASAP and no previous history of cancer were included in this study. In Winnipeg, Manitoba, from 2008-2009, the mean HGPIN incidence rate was 5.0% and the mean cancer detection rate was 46.1%. The mean ASAP incidence rate was 4.6% and the mean cancer detection rate of 48.2%. As a control, the cancer detection rate following a benign diagnosis was also calculated at 33.3%. The mean incidence and cancer detection rates for HGPIN and ASAP for Winnipeg, Manitoba are slightly lower than literature, but still fall within the published range. In addition, the mean ASAP cancer detection rate is similar to the cancer detection rate following a benign diagnosis indicating that, in our study, both a benign finding and a diagnosis of ASAP hold the same predictive value for cancer on a subsequent re-biopsy.