Medicine (RMH) - Theses
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ItemMycobacterium ulcerans on the Bellarine Peninsula: turning observations into science( 2015)The Bellarine Peninsula in south-eastern Australia has been experiencing an epidemic of M. ulcerans since 1998.[1] It affects local residents, but also visitors from outside the endemic region, with more than 50% of cases managed at the local referral health service, Barwon Health. Since 1998 an electronic database (Epi info 6, Centers for Disease Control and Prevention, Atlanta, Ga, USA), designed and implemented by the author and approved by the Barwon Health Ethics Committee, has been established that prospectively records clinical, epidemiological and treatment information on all cases of M. ulcerans managed by staff of Barwon Health. All data has been collected and entered into the database by the author. During the period 1998 until 2014 the management of M. ulcerans in Barwon Health gradually evolved, largely based on observations obtained by clinicians in Barwon Health during their management of patients with M. ulcerans. The analysis of the data collected has been used to confirm and document these observations on a scientific level and to influence the ongoing evolution of clinical practice. These finding have been further disseminated, helping to influence a change of clinical practice in the management of M. ulcerans both throughout Australia and internationally. The results of this research (turning observations into science) are presented in this thesis and include the following important components: 1. The determination that antibiotics are effective in the treatment of M. ulcerans in Australian patients. This has resulted in nearly universal cures achieved with antibiotic treatment of the disease, the performance of more conservative and less reconstructive surgery, less hospitalizations, lower long-term morbidity and reduced cost of care. (Chapters 1, 2 and 3) 2. The demonstration that all oral antibiotic combinations are effective, better tolerated and less toxic than previously administered injectable antibiotics. This also allowed treatment to be given from home and avoided hospitalization. (Chapters 1, 2 and 3) 3. The first demonstration that fluoroquinolone antibiotics are an effective and safe antibiotic that can be used in combination with other known effective antibiotics in M. ulcerans treatment in humans. This has increased the options for safe and effective oral antibiotic treatment. (Chapters 1, 2 and 3) 4. The first study to describe successful outcomes in the treatment of M. ulcerans in selected patients with antibiotic treatment durations shorter than the current WHO and Australian recommended 8 weeks. This has offered significant benefits in terms of reducing toxicity and improving adherence associated with M. ulcerans antibiotic treatment. (Chapter 4) 5. The first clinical reports of the occurrence of paradoxical reactions resulting from the antibiotic treatment of M. ulcerans. This lead to the realization that previously perceived treatment failures were incorrect and instead were occurring as a result of the effectiveness of antibiotic treatment. This has lead to a dramatic change in management of M. ulcerans leading to a reduction in the need for further surgery, reconstructive surgery and the need to change or prolong M. ulcerans antibiotic treatment regimens. (Chapter 5) 6. A comprehensive description of the incidence, clinical spectrum, diagnostic features and treatment of paradoxical reactions associated with the antibiotic treatment of M. ulcerans. This provided information that will aid clinicians in recognizing, diagnosing and managing paradoxical reactions when treating patients with M. ulcerans. (Chapter 6) 7. The determination of risk factors for the development of paradoxical reactions that may minimize the occurrence and impact of paradoxical reactions during M. ulcerans treatment. It also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 6) 8. The first described use of corticosteroids to treat severe paradoxical reactions occurring during the antibiotic treatment of M. ulcerans. This has lead to a reduced need for further surgery and reconstructive surgery as well as minimizing long-term morbidity from the disease. (Chapter 7) This research has been extended to Africa and to HIV coinfected patients where the first reported safe and effective use of prednisolone to manage a severe paradoxical reaction in an HIV-infected patient was described. (Chapter 14) 9. The determination of risk factors for treatment failure if surgery without antibiotics is used for treatment of M. ulcerans. This allows an improved selection of patients if surgery alone is considered in the treatment of M. ulcerans, but also provides important prognostic information for clinicians managing M. ulcerans. (Chapter 8) 10. A comprehensive description of the clinical features and diagnosis of M. ulcerans in an Australian population. This provided important information to aid health practitioners identify, diagnose and treat M. ulcerans. (Chapter 9) 11. A comprehensive description of the clinical features, diagnosis and risk factors of the severe oedematous form of M. ulcerans. This provided important information that will increase the awareness of odematous M. ulcerans disease, and improve the understanding of its clinical presentation and risk factors. This should allow clinicians to diagnose and treat early oedematous forms of M. ulcerans which will have a major impact on the morbidity and cost of this form of disease. (Chapter 10) 12. The use of available evidence, best practice and expert opinion to develop the first guidelines for the management of M. ulcerans/HIV co-infection. These will be an important aid in managing the complex issues relating to the clinical care of patients in endemic areas where these infections are increasingly found to co-exist. (Chapter 12) 13. The use of field experience, best practice and available evidence to propose a research agenda to improve the effectiveness, accessibility, acceptability and feasibility of care for M. ulcerans in Africa, including in those populations co-infected with tuberculosis or HIV. (Chapters 13 and 15)
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ItemImproving the outcome of patients with lymphoproliferative disorders( 2014)Lymphoproliferative disorders (LPD) collectively form the commonest category of haematologic malignancy in Australia. Most patients are not cured and improvements in treatments are urgently needed. Within this thesis I have taken two broad approaches to this problem. Optimising standard therapies 1. Using PET-CT in identify patients at risk of early disease relapse The identification of patients at highest risk of failing existing therapies is a rational starting point to improve outcomes. Using clinical datasets from Peter MacCallum Cancer Centre, I studied the ability of PET-CT to identify patients at risk of disease relapse. Theoretically, early detection of relapse when tumour burden may increase the probability of successful salvage therapy and ultimate cure. Therefore I reviewed the outcomes and method of detecting relapse patterns in patients with de novo DLBCL and transformed indolent lymphoma. No clear benefit from a surveillance strategy was demonstrated, meaning that patients can be spared the anxiety and radiation of scanning. I also explored the role of PET-CT in primary mediastinal B-cell lymphoma and found negative end of treatment PET-CT was predictive of excellent progression-free survival, but positive scans require histologic confirmation prior to escalation of therapy. 2. Central nervous system (CNS) relapse in aggressive NHL This complication is typically rapidly fatal and identifying patients at increased risk In the first study I analysed a group of high-risk patients with DLBCL and found that the addition of high dose systemic methotrexate and/or cytarabine was associated with lower rates of CNS relapse compared with intrathecal prophylaxis alone. This finding highlights the benefits obtaining when a customised therapeutic approach is used. In a second study, by collaborating through a large, international multicentre network I collated a large series of patients with mantle cell lymphoma who developed CNS relapse. Within this, I identified blastoid histology, high mantle cell lymphoma international prognostic index, raised serum lactate dehydrogenase and poor performance status as risk factors for CNS involvement. Developing new therapies The second half of this thesis focuses on the development of novel therapeutic strategies. 3. NMP and anti-CD20 monoclonal antibodies in lymphoma N-methyl-2-pyrrolidone (NMP) shares biologic properties with the established anti-cancer immune modulating drug lenalidomide, which is active with rituximab in lymphoma. I have shown that NMP has in vitro enhancement of rituximab-mediated induction of antibody dependent cellular cytotoxicity on lymphoma cell lines. The promising pre-clinical activity of this combination will be assessed in future clinical trials. 4. Rational clinical trial design using immunotherapies Finally, I designed three early phase clinical trial protocols using immunotherapies: 1) oral NMP in myeloma, 2) intra-tumoral αgalactoceramide and CpG and 3) ISCOMAB and rituximab, in indolent B-cell lymphoma. These clinical trial protocols combine correlative scientific with clinical endpoints and are now ready for activation.