Austin Academic Centre - Theses
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ItemAcute severe ulcerative colitis: clinical and translational studies( 2019)Acute Severe Ulcerative Colitis (ASUC) is a life-threatening condition that affects 20% of people with ulcerative colitis at some point in their life. Intravenous corticosteroids are first line therapy; however, approximately one-third do not respond, prompting the need for medical salvage treatment such as infliximab. Despite this, 20-30% of patients require life changing surgery to remove the large bowel with stoma formation within three months of presentation. Infliximab has been used as medical salvage therapy for over 15 years; however, the ideal dosing strategy is unknown. This thesis aims to identify the optimal infliximab induction strategy in ASUC; to improve clinical response rates to infliximab and reduce colectomy rates, and; to explore clinical and experimental predictors and mechanisms of treatment response. A systematic review and meta-analysis was undertaken to examine the efficacies of different infliximab induction strategies. A retrospective study was performed to assess biomarkers of response to infliximab. This thesis is built upon a clinical study which aims to determine the optimal infliximab induction strategy in ASUC by comparing high dose strategies to standard dose induction, in order to improve clinical outcomes in ASUC. Nested within this clinical trial are exploratory studies assessing biomarkers of steroid response. This study is also aligned with research examining the immunological processes driving ASUC in order to identify new mechanisms of disease and biomarkers of treatment response. In summary, this thesis describes the implementation of the largest randomised controlled trial currently being undertaken globally to identify the optimal use of infliximab salvage therapy in ASUC. Comprehensive and longitudinal data collection will allow for the investigation of novel clinical, biochemical and immunological predictors of response to therapy.
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ItemAn integrated eHealth strategy to optimise outpatient disease and psychological management in inflammatory bowel disease( 2019)The increasing incidence of inflammatory bowel disease (IBD) over the past decade has resulted in increased health care resource utilisation and longer specialist outpatient waiting lists. IBD is associated with an increased prevalence of psychological morbidity and adversely affects quality of life, societal interaction and functioning. Electronic-health or ‘eHealth’ technologies incorporating self-management strategies to manage patients remotely such as telemedicine, web-based interventions, and smart-phone applications may offer a solution to streamline outpatient management, by detecting earlier changes in patient well-being (disease activity, medication status and psychological health) and providing greater access to personalised care in real-time. However, whether eHealth technologies offer any significant benefit over traditional outpatient based IBD care remains to be proven. This thesis encompasses a framework and the design of a decision support tool which aims to improve the outpatient management of IBD patients by proving that eHealth monitoring of patients with mild-to-moderate ulcerative colitis, stratified for disease activity and psychological distress and treated according to a fixed regime of eHealth directed self-management, is an effective model of care compared with IBD clinic-led outpatient management. A colloquium was initially held to obtain key stakeholders’ perspectives on the role of an eHealth tool to facilitate decision support for IBD. Retrospective studies were then undertaken to establish the extent to which gastroenterologists adhere to evidence based international guidelines in clinical practice. A cost analysis study was conducted to describe the current cost of care and to compare the costs associated with treating active disease compared to disease in remission. A cross-sectional study was then undertaken to establish the relationship between patient-reported outcomes and disease activity. Patient perspectives regarding the potential value of an eHealth intervention for outpatient IBD management were then explored. Finally, clinical algorithms were developed for disease activity, psychological wellbeing and preventive care and incorporated into a decision support tool which was assessed for feasibility, usability and acceptability compared to standard IBD care. In summary, this is the first prospective study to demonstrate that an eHealth tool to facilitate decision support significantly improves the delivery of quality care and promotes shared decision-making in patients with mild-to-moderate ulcerative colitis.
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ItemManagement choices in prostate cancer( 2018)The thesis examines two main issues in prostate cancer management. Firstly, the role of imaging modalities including multiparametric MRI prostate and PSMA PET scan in the detection and surveillance of prostate cancer. Secondly, the thesis explores the role of local treatment for men with oligometastatic disease utilising clinical research and critical appraisal of the recent literature. These controversial areas within prostate cancer management are then discussed with regards to future directions and the implications of new technology on patient care.
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ItemLennox-Gastaut syndrome: a secondary network epilepsy( 2018)Lennox-Gastaut syndrome (LGS) is a severe epilepsy that usually begins in childhood. Diverse aetiologies can cause LGS, including structural and genetic abnormalities. However, the electroclinical phenotype that emerges from these aetiologies is remarkably consistent across patients and includes tonic seizures and generalised interictal epileptiform discharges on scalp electroencephalography (EEG). Frequent epileptic activity is thought to contribute to cognitive impairment in LGS (‘epileptic encephalopathy’). The mechanisms by which diverse aetiologies lead to LGS, and by which epileptic activity causes impaired cognition, are poorly understood. This thesis aimed to determine the brain regions underlying epileptic activity in LGS, and to assess how LGS may alter functional organisation of brain networks that support cognition. Simultaneous EEG with functional magnetic resonance imaging (EEG-fMRI) was performed in 38 patients, including 11 children with recent-onset LGS and 27 older patients with longstanding LGS. To limit motion during scanning, younger patients were anaesthetised with low-dose isoflurane and remifentanil. Data from the older patients, who tolerated scanning without anaesthesia, were compared to resting-state fMRI in 29 age-matched healthy controls. The primary hypothesis was that LGS reflects abnormal expression of a shared network that is ‘secondary’ to the specific aetiology of LGS. Five studies were performed. Study 1 examined technical feasibility of anaesthetised fMRI in children with LGS. Resting-state networks previously described in non-anaesthetised subjects were observable in the anaesthetised patients with LGS, demonstrating that isoflurane-remifentanil anaesthesia can extend the utility of fMRI to young and intellectually disabled patients while retaining interpretability of fMRI. Study 2 explored brain areas underlying interictal epileptiform discharges in LGS using EEG-fMRI. In both anaesthetised and non-anaesthetised patient groups, discharges recruited widespread areas of frontal, parietal, and temporal cortex, as well as the thalamus and brainstem. Activation was similar across individual patients with structural, genetic, and unknown aetiologies of LGS. Further analysis using dynamic causal modelling suggested a cortically driven process underlying discharges. Study 3 explored network mechanisms of impaired cognition in LGS by comparing resting-state functional connectivity between patients and healthy controls, focusing on corticocortical interactions. Patients showed abnormal integration and segregation of major cognition-related networks, including the executive-control and default-mode networks. Altered connectivity persisted during periods without epileptic activity on patients’ in-scanner EEG, potentially contributing to pervasively impaired cognition in LGS. Study 4 tested thalamocortical circuits and found abnormally enhanced connectivity in LGS, maximally involving mediodorsal and ventrolateral nuclei. Finally, study 5 examined neural changes accompanying successful treatment of LGS by re-scanning one patient who experienced seizure remission following resection of a cortical lesion. After surgery, the patient showed reversal of abnormal network patterns seen in non-operated patients, with improved network integration and segregation. This thesis provides a new way of conceptualising LGS as a ‘secondary network epilepsy’, where the syndrome’s characteristic epileptological and cognitive features reflect abnormal expression of a shared brain network, rather than the specific initiating aetiology. The epileptic process in LGS is cortically driven, affects specific thalamic subregions, and may be reversible with early surgical intervention.
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ItemPattern of lymph node metastasis in colorectal cancer liver metastasis( 2018)Background Hepatic resection is the standard treatment for resectable colorectal liver metastasis. There is evidence that lymphatics play a role in disease recurrence post-surgery. The aim of this retrospective study is to assess patterns of lymph node recurrence after liver resection. Methods Patients who had liver resection for colorectal cancer metastasis between 1 January 2010 and 31 December 2014 at 2 institutions in Melbourne, Australia were included. Data was collected from databases located at the 2 surgical centres. Results Seventy-four patients were included in the study. Follow-up period was for a mean of 32.7 months. Lymph node recurrences were seen in 39.2% of patients during follow-up. Initial recurrence sites after hepatectomy was mainly in visceral-site only. Lymph node recurrences became more prominent during subsequent Recurrence Stages (RSs) of follow-up (RS1 – 22.4%, RS2 – 50.0%, RS3 – 50.0%, RS4 – 71.4%, RS5 – 66.7%, and RS6 – 0%). No predictive factor showed statistically significant relation to development of nodal recurrences. Nodal recurrences had a propensity to occur at sites other than the perihepatic and peripancreatic nodal groups. Conclusion Lymph node recurrences after hepatic resection for liver metastases usually occur subsequent to a visceral-site only metastasis. There is no predictive factor as to which nodal group would be involved due to the complexity of liver lymphatic drainage. Formal systematic perihepatic lymphadenectomy would not appear to help with disease control.
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ItemPrediction and assessment of pathological complete response following neoadjuvant chemoradiotherapy for locally advanced rectal cancer( 2017)Introduction The management of patients with rectal cancer who develop a pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) presents an ongoing challenge to clinicians. Some authors have suggested that the presence of a clinical complete response may allow patients to be spared the morbidity and potential risks of surgery through adoption of a ‘watch and wait’ policy with surgery only in the setting of clinical failure. However clinical response and pathological response are not always wellcorrelated and widespread adoption of this regimen is limited by accurate methods to assess and confirm the presence of a pCR without a surgical specimen. Method A systematic review of the literature has been performed to identify methods to predict and assess a pathological complete response to nCRT. The first part of the literature review focuses on factors predictive of a pCR, specifically clinical features, radiological features and histological and molecular markers. The second part of the literature review aims to determine methods to accurately assess the presence of a pCR following neoadjuvant treatment. Following this an institutional database was interrogated to determine clinical and radiological features associated with prediction and assessment of a pCR and a multimodal predictive model has been developed. Molecular analysis has been performed to identify genetic influences on pCR. The role of radiological imaging in the assessment of pCR will be explored and the prognostic and clinical significance of metabolic response assessment by 18F FDG PET CT has been investigated in detail. Results Assessment Histology and clinical assessment remain the most effective methods of assessment of pCR with histology considered the gold standard. Clinical assessment is limited to low rectal tumours and is open to significant inter-rater variability while histological examination requires a surgical specimen for accurate assessment. Radiological assessment of pCR demonstrates the greatest potential for assessment of pCR without the need for surgery with diffusion weighted MRI and 18F FDG PET CT providing the greatest accuracy. It is likely that improved accuracy will be achieved with multimodal assessment of response combining the benefits of clinical, serological, endoscopic and radiological methods of response assessment. Prediction Clear methods to predict pCR prior to the commencement of therapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular signatures hold the greatest potential to predict response however adoption of this technology is limited by poor concordance of biomarkers between cohorts. Conclusion Accurate prediction and determination of a complete pathological response is paramount if a non-operative approach is to be undertaken with confidence in oncological outcomes. A variety of methods are available but currently they lack sufficient sensitivity and specificity to define management. Despite a large volume of research the ability to predict which patients are likely to sustain a pCR and accurately assess those patient who have a pCR remains elusive. Further research into models incorporating both prediction and assessment into decision-making is required.