Medicine and Health Sciences Commons^™

About Dying And Death: Thanatology's Place In Medical Curriculum, Jill Dombroski

Electronic Thesis and Dissertation Repository

This study explored how healthcare providers engage in advance care planning and end-of-life care conversations. The research explored what shapes their understanding and the extent to which concepts from thanatology they intuitively bring in, explicitly bring in, and maybe fail to recognize. To achieve this, constructivist grounded theory (CGT) methodology guided the design, data collection, analysis, and interpretation of the findings, which allowed for iteration across interviews and analysis with existing theories and data in the literature. The CGT design encouraged further engagement with the literature in an ongoing iterative fashion as well as with the analysis of the data. …

Sarcopenia In Head And Neck Cancer: A Prognostic Analysis, Nedeljko Jovanovic

Electronic Thesis and Dissertation Repository

Introduction: In head and neck cancer (HNC), loss of skeletal muscle mass (SMM), or sarcopenia, is a strong prognostic factor for outcomes. However, inconsistencies in its assessment limit our understanding of the relationship between sarcopenia and nutrition-related outcomes. This project evaluated the significance of sarcopenia as described in the literature and as demonstrated in a cohort of HNC patients.

Methods: A scoping review was first conducted followed by a retrospective cohort study with data collected from 194 oropharyngeal carcinoma patients treated with definitive radiation/chemoradiation. Sarcopenia was assessed from computed tomography (CT) imaging at the third cervical vertebra (C3) and the …

The Molecular Landscape Of Early-Stage Breast Cancer With Lymph Node Metastasis, Farhad Ghasemi

Electronic Thesis and Dissertation Repository

Axillary lymph nodes (ALNs) are the primary site of metastasis in breast cancer, and their involvement has implications in disease staging, prognostication, and treatment decisions. A non-invasive modality of assessing the risk of ALN metastasis can improve care in patients with early-stage breast cancer by omitting the morbidity and costs associated with axillary surgery.

This thesis explores the molecular landscape of early-stage breast cancers with ALN metastasis and shows the potential of tumour molecular signatures in predicting ALN involvement. After a systematic review of the literature, we use data from The Cancer Genome Atlas (TCGA) to develop molecular signatures correlated …

Anticancer Effects And Mechanisms Of Cfi-400945 And Radiation In Breast Cancer, Sierra M. Pellizzari

Electronic Thesis and Dissertation Repository

Breast cancer is a leading cause of death in women and development of new treatments is essential. Polo-like Kinase 4 (PLK4) controls centriole duplication and its inhibition by CFI-400945 induces genomic instability and aneuploidy. Radiation therapy (RT) also induces aneuploidy leading to cell death, although development of radioresistance is common. We hypothesized that CFI-400945 and RT act synergistically in breast cancer. Colony formation assays identified synergistic anticancer effects of CFI-400945 and RT, with combinatorial effects also observed for RT with either siRNA inhibition of PLK4 or with the PLK4 inhibitor Centrinone B. This suggests that the antiproliferative effect of these …

Incidence Of Cancer And Stage At Diagnosis Among People With Recent-Onset Psychotic Disorders, Jared C. Wootten

Electronic Thesis and Dissertation Repository

Evidence on cancer incidence in people with psychotic disorders, compared to the general population, is equivocal, although those with psychotic disorders so have more advanced stage of cancer at the time of diagnosis. The objective of this thesis was to compare cancer incidence and stage at diagnosis for people with psychotic disorders, relative to the general population. Our systematic review did not observe a significant difference in overall cancer incidence among people diagnosed with psychotic disorders (RR = 1.08, 95% CI: 1.00 to 1.16), however people with psychotic disorders were more likely to be present with advanced stage cancer at …

Addressing Bias In Non-Experimental Studies Assessing Treatment Outcomes In Prostate Cancer, David E. Guy

Electronic Thesis and Dissertation Repository

We evaluated the ability of matching techniques to balance baseline characteristics between treatment groups using non-experimental data. We identified a set of balance diagnostics that assessed key differences in baseline covariates with potential for confounding. These diagnostics were used in a novel systematic approach to developing and evaluating models for use in propensity score matching that optimized balance and data retention. We then compared the performance of propensity score and coarsened exact matching strategies in optimizing balance and data retention, using non-experimental data from a pan-Canadian prostate cancer database. Both matching techniques balanced baseline covariates adequately and retained approximately 70% …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

Functional Role Of Dream And Dyrk1a In High-Grade Serous Ovarian Cancer Cell Dormancy, Pirunthan Perampalam

Electronic Thesis and Dissertation Repository

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer. The majority of women are disproportionately diagnosed at an advanced stage (stage III-IV) of the disease when tumours have progressed beyond the ovaries or fallopian tubes and into the peritoneal cavity. Survival rates at late-stage are as low as 25% and chemoresistant disease recurrence is common, affecting up to 90% of patients. Multicellular clusters called spheroids contribute to dormancy, chemoresistance, and metastases and are a major challenge to treatment of HGSOC. Spheroid cells undergo reversible quiescence to evade chemotherapy in a process mediated by the mammalian DREAM …

An Exploration Of Facial Skin Scarring, Its Impact And Contemporary Evaluation, Michael G. Brandt

Electronic Thesis and Dissertation Repository

Facial skin cancer secondary to surgical treatment may be distressing due to the malignancy itself and from the consequences of its treatment. A visible postsurgical scar is an obvious reminder of the condition. This investigation sought to broaden our understanding of facial scarring and develop a novel tool for its objective evaluation. To this end, skin cancer as the most common etiology of facial scarring was reviewed. The scar scale literature was evaluated in the context of assessing scars through a biopsychosocial lens. Finally, the development of a novel scar scale was presented. Thirty-four individuals completed 13,056 ratings using a …

Pan-Cancer Analysis Of Telomerase Reverse Transcriptase (Tert) Isoforms, Mathushan Subasri

Electronic Thesis and Dissertation Repository

Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are further complicated by their highly diverse expression. In this thesis, I characterized TERT expression across normal and neoplastic tissues using TCGA and GTEx RNA-sequencing data. In doing so, I demonstrated the global overexpression and splicing shift towards full-length TERT in neoplastic tissue. Furthermore, my studies identified tumour subtype expression differences possibly regulated by subtype-specific characteristics, detailed heterogeneity …

Neoadjuvant Stereotactic Ablative Radiotherapy To Treat Early Stage Breast Cancer Patients: The Role Of Dce-Mri, Matthew Mouawad

Electronic Thesis and Dissertation Repository

The current standard of breast conserving therapy is lumpectomy followed by whole breast radiotherapy which is prohibitively long for many patients (4-6 weeks). In addition, the need for treating the whole breast has been questioned. The London Regional Cancer Program is enrolling early stage breast cancer patients in a prospective Phase I/II clinical trial (SIGNAL) to assess the safety/efficacy of neoadjuvant stereotactic ablative radiotherapy (SABR) to the tumour alone to reduce treatment times. This provides a unique opportunity to assess tumour response to SABR using non-invasive imaging. Patients received a pre-SABR dynamic contrast-enhanced (DCE)-MRI to guide target volume delineation. A …

Translational Control Of Stress Induced Breast Cancer Plasticity, Michael Jewer

Electronic Thesis and Dissertation Repository

Cancer cell plasticity, whereby stem-cell-like properties are acquired in response to stress, represents a major challenge in cancer treatment. Using cell line and patient-derived xenograft (PDX) models, we demonstrate that translational reprogramming occurs in response to stresses such as hypoxia and chemotherapy which elicits stem cell properties in breast cancer. Other stresses like chemotherapy demonstrate the translational inhibition that has been well characterized as an integral hypoxic cellular response. The inhibition of translation is primarily regulated at initiation by mTOR/4E-BP1 and PERK/eIF2α signalling. We identify previously undescribed 5’ untranslated regions (5’UTRs) of plasticity-associated genes like NANOG, SNAIL and NODAL. …

Elucidating Mechanisms Of Innate And Acquired Resistance To Pi3ka Inhibition In Head And Neck Squamous Cell Carcinoma, Kara M. Ruicci

Electronic Thesis and Dissertation Repository

The phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signalling pathway is aberrantly activated in most head and neck squamous cell carcinomas (HNSCCs). PI3K signalling drives cellular proliferation, protein synthesis and cell survival. Although numerous targeted agents are available to inhibit PI3K signalling, results have been variable and factors influencing response to PI3K inhibition (e.g. genomic aberrations, pathway interconnectivity, acquired drug resistance) are not well defined. In this thesis, we employ a multifaceted approach to elucidate the molecular underpinnings of biomarkers of response and mediators of resistance to PI3K inhibition in HNSCC. We began by combining a large panel of HNSCC …

Impact Of Feeding Tube Status On Health Outcomes For Individuals With Oropharyngeal Cancer, Nedeljko Jovanovic

Electronic Thesis and Dissertation Repository

Abstract

This study investigated differences in outcomes related to health, swallowing, and quality of life (QoL) for individuals with oropharyngeal squamous cell carcinoma (OPSCC) receiving either radiotherapy (RT) alone, or concomitant chemoradiotherapy (CRT). Differences were assessed based on whether patients received a feeding tube (FT group) or not (NFT group). Measures including the Functional Oral Intake Scale (FOIS), Performance Status Scale for Head and Neck Cancer (PSS-HN), M.D. Anderson Dysphagia Inventory (MDADI), and weight were collected for 126 individuals at baseline, and at 3, 6, and 12 months post-treatment. Data were analyzed to identify potential prognostic differences between the groups, …

Oncoplastic Surgery: Is It Time To Change? From Innovation To Adoption Using Mentorship Program, Eman Khayat

Electronic Thesis and Dissertation Repository

Oncoplastic surgery is considered the standard of care for breast cancer therapy in numerous Western World countries, particularly in Europe. Despite the advancement of knowledge, Canada still lags in adoption of oncoplasty into the standard surgical practice. In our study, a mentorship program was used to introduce oncoplastic surgery to practicing breast surgeons at LHSC. The change in perception and adoption of oncoplastic surgery were evaluated using semi-structured interviews, before and after the intervention, by qualitative thematic analysis method. Mentorship program was validated as a superior method of learning new surgical techniques by practicing surgeons, demonstrating acceptance of different levels …

Acute Pharmacologic Modulation Of Glioblastoma Ph Monitored By Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Mohammed Albatany

Electronic Thesis and Dissertation Repository

The response of tumor intracellular pH (pH_i) to a pharmacological challenge could help identify aggressive cancer. In addition, tumor pH_i may influence cell proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is sensitive to cellular pH. More specifically, a CEST method called amine and amide concentration-independent detection (AACID) produces images weighted by intracellular pH (pH_i) and can be used to study pharmacologic pH modulation in tumours.

The overall goal of this thesis was to maximize the magnitude of intracellular tumour acidification using pharmacologic agents. Several …

Prostate Cancer Microparticles In Men Undergoing Radical Prostatectomy, Malcolm James Dewar

Electronic Thesis and Dissertation Repository

Objectives: To determine changes in prostate microparticle (PMP) concentrations in men with prostate cancer (PCa) after digital rectal examination (DRE), after radical prostatectomy (RP), and at follow-up.

Materials and Methods: 22 men were recruited before RP. Four blood specimens were collected – baseline (specimen 1), post-DRE (specimen 2), immediately post-RP (specimen 3), and follow-up (specimen 4). Pre- and post-DRE urine was collected (Specimen A and B respectively). Flow cytometric analysis of biofluids was performed with fluorescent-labeled antibodies against prostate-specific membrane antigen (PSMA) and polysialic acid. Total MP (TMP) and dual positive (PMP) events per µl of plasma or urine were …

The Application Of Self-Administered Nutrition Screening Tools And Evaluations Of The Impact Of Malnutrition On Quality Of Life In Individuals With Head And Neck Cancer, Mark J. P. Lynch

Electronic Thesis and Dissertation Repository

Abstract

Background: Individuals with head and neck cancer (HNCa) are at an increased risk of malnutrition. Therefore, self-administered nutrition screens which attempt to address their nutritional concerns may yield benefits for treatment outcomes and quality of life (QOL).

Methods: 34 participants (26 men, 8 women) completed one demographic and two QOL surveys, two nutrition self-screening tools, a nutrition assessment and an ease-of-use questionnaire. Results of the screens were compared to those of the assessment, and relationships between QOL, nutrition status, and demographics were examined.

Results: 32.3% of participants were identified as nutritionally compromised. The sensitivity and specificity for the PG-SGA …

Minimizing The Impact Of Disease While Maximizing Quality Of Life: An Exploration Of Resilience In Head And Neck Cancer Survivors, Chelsea A. Macdonald

Electronic Thesis and Dissertation Repository

Introduction: Individuals with head and neck cancer (HNCa) face myriad biopsychosocial challenges. Even after treatment completion, these challenges may continue to cause diminished quality of life (QoL). Resilience may serve to minimize the impact of HNCa and, thus, maximize QoL. The purpose of this study was to identify resilience in HNCa survivors and explore its potential relationship with QoL.

Methods: Thirty-one HNCa survivors completed three validated, self-report questionnaires pertaining to the collection of resilience and QoL data. Descriptive, correlational, and observational analyses were performed.

Results: Resilience was identified in the HNCa survivors and a positive correlation was found between resilience …

Developments In Pet-Mri For Radiotherapy Planning Applications, John Christian Patrick

Electronic Thesis and Dissertation Repository

The hybridization of magnetic resonance imaging (MRI) and positron emission tomography (PET) provides the benefit of soft-tissue contrast and specific molecular information in a simultaneous acquisition. The applications of PET-MRI in radiotherapy are only starting to be realised. However, quantitative accuracy of PET relies on accurate attenuation correction (AC) of, not only the patient anatomy but also MRI hardware and current methods, which are prone to artefacts caused by dense materials. Quantitative accuracy of PET also relies on full characterization of patient motion during the scan. The simultaneity of PET-MRI makes it especially suited for motion correction. However, quality assurance …

Translational Study Of Liver Cancer And Hypertrophy: Translich, Mauro Enrique Tun Abraham

Electronic Thesis and Dissertation Repository

Abstract

Background: Associating liver partition with portal vein ligation for staged-hepatectomy (ALPPS) is a technique for inducing accelerated hypertrophy in patients with insufficient future liver remnant (FLR). It remains unknown whether this hypertrophy may lead to rapid cancer cell dissemination and/or alteration of immune cell/function reconstitution in the FLR. We aimed to determine if the rapid hypertrophy during ALPPS procedure results in more circulating tumour cell (CTCs) dissemination and whether the FLR remains immunologically competent in patients with CRLM.

Methods: In our prospective, observational, 2-arm study, we assessed the utility of CTCs as an evaluation tool for disease dissemination. Moreover, …

Investigating Stromal Contributions To The Regulation Of Cancer Progression, Krista M. Vincent

Electronic Thesis and Dissertation Repository

Tumours are not insular masses of proliferating cells, rather tumour cells evolve within a complex local environment complete with matrix, stromal, and immune components. Therefore, successful tumour growth and eventual metastasis is not determined solely by tumour cells themselves, but also by the fitness advantage or disadvantage conferred by their local environment. However, many of our current cancer models are composed solely of tumour cell isolates. As tumour fitness is dependent on the entire local cellular context, we were interested in characterizing the accuracy of cell lines as models of the tumour microenvironment, with a focus on the secreted Frizzled-related …

Assessment Of Post-Treatment Imaging Changes Following Radiotherapy Using Magnetic Susceptibility Techniques, Jean-Guy Belliveau

Electronic Thesis and Dissertation Repository

Radiation therapy (RT) is a common treatment for brain neoplasms and is used alone or in combination with other therapies. The use of RT has been found to be successful in controlling tumors and extending the overall survival of patients; however, there are many unanswered questions regarding radiotherapy effects in the normal brain surrounding or infiltrated by tumor. Changes to the vascular and parenchyma have been documented, and more recently inflammatory mechanisms have been postulated to play a role in radiation injury. Traditional imaging techniques used within the clinic (CT and MRI) are often lacking in their ability to differentiate …

Optimizing Respiratory Gated Intensity Modulated Radiation Therapy Planning And Delivery Of Early-Stage Non-Small Cell Lung Cancer, Ilma Xhaferllari

Electronic Thesis and Dissertation Repository

Stereotactic ablative body radiotherapy (SABR) is the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC) patients. However, thoracic tumours are susceptible to respiratory motion and, if unaccounted for, can potentially lead to dosimetric uncertainties. Respiratory gating is one method that limits treatment delivery to portions of the respiratory cycle, but when combined with intensity-modulated radiotherapy (IMRT), requires rigorous verification. The goal of this thesis is to optimize respiratory gated IMRT treatment planning and develop image-guided strategies to verify the dose delivery for future early-stage NSCLC patients.

Retrospective treatment plans were generated for various IMRT delivery techniques, including …

Non-Invasive Imaging For The Assessment Of Cardiac Dose And Function Following Focused External Beam Irradiation, Omar El-Sherif

Electronic Thesis and Dissertation Repository

Technological advances in imaging and radiotherapy have led to significant improvement in the survival rate of breast cancer patients. However, a larger proportion of patients are now exhibiting the less understood, latent effects of incidental cardiac irradiation that occurs during left-sided breast radiotherapy. Here, we examine the utility of four-dimensional computed tomography (4D-CT) for the accurate assessment of cardiac dose; and a hybrid positron emission tomography (PET) magnetic resonance imaging (MRI) system to longitudinally study radiation-induced cardiac effects in a canine model.

Using 4D-CT and deformable dose accumulation, we assessed the variation caused by breathing motion in the estimated dose …

Oncolytic Virus Therapy For The Treatment Of Metastatic Ovarian Cancer, Jessica Tong

Electronic Thesis and Dissertation Repository

The management of patients with epithelial ovarian cancer (EOC) faces two major challenges which standard treatments fail to effectively address: 1) Diffuse metastasis as a consequence of late stage diagnosis and 2) intra-tumoral heterogeneity, which fuels tumor evolution and drives the acquisition of chemotherapeutic resistance. In this thesis, we tested new therapeutic strategies using a 3-dimensional in vitro spheroid culture model that mimics key steps of epithelial ovarian cancer metastasis; and another model that mimics both temporal and cellular heterogeneity by establishing multiple cell lines from a single patient over the course of disease progression. Using these models, we investigated …

Phase Ii Clinical Trial Of Concurrent Neoadjuvant Chemotherapy With Radiotherapy In Locally Advanced Breast Cancer, Muriel Brackstone

Electronic Thesis and Dissertation Repository

Locally advanced breast cancer (LABC) represents 15% of all non-metastatic breast cancers, with an overall poor prognosis, despite current guidelines that recommend neoadjuvant chemotherapy followed by surgery and adjuvant radiation. Therefore, a novel treatment paradigm using concurrent neoadjuvant chemoradiotherapy was proposed. A clinical trial was designed, where 32 LABC patients were treated with q3 weekly 5-fluorouracil, epirubicin and cyclophosphamide for three cycles, followed by weekly docetaxel for 9 weeks with concurrent regional radiation (45+5.4Gy) for the first 6 weeks. Patients subsequently underwent modified radical mastectomies. Pathological complete responses (pCR) and 3 year overall survival rates were compared to a matched …

Interpretation Of Mutations, Expression, Copy Number In Somatic Breast Cancer: Implications For Metastasis And Chemotherapy, Stephanie Dorman

Electronic Thesis and Dissertation Repository

Breast cancer (BC) patient management has been transformed over the last two decades due to the development and application of genome-wide technologies. The vast amounts of data generated by these assays, however, create new challenges for accurate and comprehensive analysis and interpretation. This thesis describes novel methods for fluorescence in-situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next generation DNA- and RNA-sequencing, to improve upon current approaches used for these technologies. An ab initio algorithm was implemented to identify genomic intervals of single copy and highly divergent repetitive sequences that were applied to FISH and aCGH probe design. FISH …

Development Of A Small Animal Conformal Irradiator With Dual Energy X-Ray Computed Tomography Imaging For Kilovoltage Dosimetry, Michael D. Jensen

Electronic Thesis and Dissertation Repository

External beam radiotherapy has become technically sophisticated with image guided radiation therapy (IGRT) and intensity modulated radiation therapy (IMRT). These technologies allow for precise delivery of radiation to geometric targets in cancer patients. However, many questions remain on how to best define targets based on biological information, such as functional imaging, and how to combine radiation with other cancer therapies. To help answer these questions, small animal preclinical studies are needed to generate data to inform clinical trials. However, the precise radiation delivery capabilities of IGRT and IMRT have not been available in the preclinical labs. To enable translational experiments …

Design Of Novel Sensors And Instruments For Minimally Invasive Lung Tumour Localization Via Palpation, Anish Srinivasan Naidu

Electronic Thesis and Dissertation Repository

Minimally Invasive Thoracoscopic Surgery (MITS) has become the treatment of choice for lung cancer. However, MITS prevents the surgeons from using manual palpation, thereby often making it challenging to reliably locate the tumours for resection. This thesis presents the design, analysis and validation of novel tactile sensors, a novel miniature force sensor, a robotic instrument, and a wireless hand-held instrument to address this limitation. The low-cost, disposable tactile sensors have been shown to easily detect a 5 mm tumour located 10 mm deep in soft tissue. The force sensor can measure six degrees of freedom forces and torques with temperature …