Medicine (St Vincent's) - Theses
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ItemThe relationship between occupational sunlight exposure and non-melanoma skin cancer( 2015)Aims and Background: Australia has the highest incidence of skin cancer in the world and ultraviolet (UV) radiation exposure is the dominant environmental determinant of all major forms of skin cancer. Two recent systematic reviews and meta-analysis of the available epidemiological evidence clearly indicate that occupational ultraviolet radiation (UVR) exposure is a substantial risk factor for the development of non- melanoma skin cancer. This study is an initial attempt to investigate the role of occupational sunlight exposure in the development of non-melanoma skin cancer in men in Australia. Methods: A case-control study was conducted. One hundred cases were recruited from the Skin and Cancer Foundation Inc. Controls included 14 age- and gender-matched subjects nominated by the cases. A questionnaire was administered through face-to- face interviews to collect information on pigmentary and genetic characteristics, occupational and recreational exposure assessment, and time of first diagnosis of non- melanoma skin cancer, confirmed with histopathological diagnosis. Conditional logistic regression models were implemented. Subsequently, a one-way analysis of variance (ANOVA) was used to investigate the relationship of each risk factor with occupational sun exposure. Results: There was insufficient evidence to conclude that there was a relationship between occupational sun exposure and non-melanoma skin cancer, because of the small sample size of matched case-control pairs. As the results for the small sample size of the matched case-control group were not statistically significant, a one-way analysis of variance (ANOVA) was performed to compare the risk factors. Fitzpatrick Skin Type was the only risk factor that showed a statistically significantly different occupational exposure profile (with a P-value of 0.035) but even then the differences were minor and only between skin phototype 2 and 3. There were no significant relationships between occupation exposure and the other risk factors. Conclusion: Unfortunately, analysis of the small number of matched case-control pairs was not statistically significant and it was not possible to draw any conclusions regarding the role of occupational sunlight exposure in the development of non- melanoma skin cancer. We experienced unexpectedly high levels of reluctance from case subjects to propose control subjects to participate in the study, which impacted on data collection and subsequently the study results. It has been well established that solar UVR is a risk factor for skin cancer. Outdoor workers are potentially exposed to high levels of UVR. More epidemiological studies are needed to improve our understanding and awareness of skin cancer as well as aid the development of prevention strategies at workplaces to reduce outdoor workers’ exposure to UVR.
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Item“A tale of two cities”: Studies on host control of chronic hepatitis B infection & Comparative evaluation of methods for quantifying cytokine production( 2016)Globally, an estimated 240 million people are living with chronic hepatitis B (CHB) [1], and the number is approximately 218000 in Australia [2]. Inactive hepatitis B e antigen (HBeAg)-negative patients are the most prevalent group, who are defined by with sustained virological response (SVR). This state is associated with favorable prognosis and low risk of liver complications. Through monitoring the serological markers and immune markers by flow cytometry, as well as advanced techniques such as transcriptome mapping, progress has been made on unveiling the mechanism of host immunological control of the CHB infection. Furthermore, it is of great clinical significance to accurately identify relapse of patients (Chapter 1). Few studies have focused on effectively identifying the treatment-naïve inactive carriers (IC), and we are particularly interested in predicting sustained inactivation through monitoring the serum HBV DNA level and HBsAg titer. Based on a retrospective/longitudinal study, we report that HBV DNA is a better predictor over HBsAg, and it is not beneficial to add HBsAg into the prediction model. The cutoff value of HBV DNA>2.5log IU/mL is effective for identifying IC with the NPV 93.6% for 12 months and 92.3% for 24 months. In another words, IC with baseline HBV DNA load<2.5 log IU/mL is likely to maintain the sustained inactivation for another 1 and 2 years, with a probability over 90% (Chapter 2). We also developed a protocol for effectively selecting peripheral blood mononuclear cells (PBMCs) subpopulations- including monocytes, Natural Killer (NK) cells, and rest of the PBMCs from inactive HBeAg negative patients undergoing clinical relapse after NA therapy cessation. Corresponding selection kits (from Miltenyi Biotec or Stemcell Technologies) were compared, and sample quality and the purification of the sample was analysed. Extracted mRNA samples will undergo expression profiling in the future, expected to pinpoint the biomarkers and unveil the mechanism of the carrier relapse (Chapter 3). For host immunity studies, accurate assessment of cytokine profile is an important perspective. We performed the comparative evaluation of two most commonly used methods for quantifying cytokines, flow cytometry and ELISA, based on the model of TLR stimulated human monocytes. Fundamentally different biological patterns were ascertained regarding cytokines from the two assays, and were mainly evidenced by the more comprehensive information that was available by flow cytometry (Chapter 4). For applying this optimized methodology, which is presenting results from flow cytometry and ELISA in parallel, to CHB studies, we adopted a human hepatocyte cell line, HepG2 (Chapter 5).
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ItemNo Preview AvailableBioimaging in colorectal cancer - prediction of response to neoadjuvant treatment( 2015)Over the last decade the management of colorectal cancer has changed significantly with the benefits of neoadjuvant therapies and new adjuvant treatments becoming apparent. Surgical strategies have also evolved with initial evidence that some patients can be successfully managed with local excision or omission of any surgery at all, resulting in a shift towards the individualisation of cancer management. The management of rectal cancer is based on primary staging assessment which relies on imaging techniques such as CT, MRI and ERUS. Recent advances in technology have improved the accuracy and widened the applications of these techniques. With the progress in medical and surgical treatments for rectal cancer, the optimal management of rectal cancer has become more complex. The evolving ability to tailor optimal treatment to the individual has created new roles for imaging such as prediction of response to treatment, restaging with assessment of response to treatment and prediction of prognosis. Consequently, prediction of response will become an important component of modern pre-operative assessment of rectal cancer to optimise individualisation of medical and surgical treatment. Beyond the established role of primary staging of malignancies, the role of conventional imaging techniques in re-staging following neoadjuvant treatment may be of increasing importance. Novel functional imaging techniques such as FDG-PET, DW (diffusion weighted) MRI are also emerging, the roles of which are yet to be determined. This thesis will examine the current status of bio-imaging and explore new imaging techniques in rectal cancer. At the Peter MacCallum Cancer Centre, we have been routinely performing staging and restaging imaging with CT, MRI and PET for the last 5 years which has resulted in a cohort of patients in whom these imaging techniques can be evaluated. This thesis also aims to evaluate a recent and evolving functional imaging technique- DW-MRI, in the prediction of response of rectal cancer to chemo-radiation.
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ItemIncreasing the hair inductive potential of human dermal papilla cells: stimulating and characterising cell aggregation( 2015)Dermal papilla cells (DPCs) are able to induce hair follicles. DPC tend to aggregate both in vitro and in vivo. This tendency is associated with their ability to induce hair growth. The use of DPCs to treat alopecia is limited because human DPCs lose their hair-inducing activity in culture, whereas ovine DPC do not. The aims of this study were to characterise the molecular phenotype of ovine DPC aggregates, and to determine whether aggregating ovine DPCs secrete factors affecting the aggregative behaviour or inductive potential of human DPCs. Expression of papilla markers in cultured ovine DPCs was characterised. The effects of ovine factors, different culture substrates and medium compositions on aggregative behaviour of human DPCs were determined. Co-cultures of ovine and human papilla cells, separated by a permeable membrane were observed to determine whether the ovine cells secrete soluble factors that affect human cell aggregation. Ovine DPC aggregates expressed 16 papilla markers, showing they have a similar phenotype to papillae in vivo. In co-culture experiments, well-formed aggregates were produced in human:ovine DPC mixtures. In contrast, unmixed human DPCs remained in a monolayer state, indicating that ovine cells are required to initiate aggregation but the human cells are then able to incorporate into aggregates. Both human and ovine DPCs had a higher tendency to aggregate in medium containing 20% (v/v) lamb serum compared to 10% (v/v) foetal calf serum. The effect of co-culturing human with ovine DPCs separated by a permeable membrane gave positive additional effects to human aggregation. In summary, ovine biomolecules show potential for increasing the aggregative behaviour of human DPCs in culture. These biomolecules might eventually be used to treat androgenetic alopecia.
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ItemExamining non-melanoma skin cancer trends in Australia using data from Medicare Australia( 2014)Background: Non-melanoma skin cancers (NMSC) are the most common cancer in Australia, costing the Australian Government $511 million in 2010. NMSC incidence studies have typically utilised face-to-face interview methods that rely on self-reporting of skin cancers. Studies overseas have employed national medical system billing data to examine trends in NMSC. The work in this thesis has adopted this novel approach for evaluating skin cancer trends. Objectives: 1. Determine the completeness of Medicare Australia (MA) in capturing skin cancer cases. 2. Examine the up-to-date incidence rates of NMSC to 2012. 3. Examine rates of recurrent and incompletely excised (residual) NMSC in Australia. Methods: Data from MA, Medicare Benefits Online and Victorian Cancer Registry (VCR) from 2004-2008 were extracted for use in this thesis. MA and VCR melanoma cases were compared. Regression and a paired-samples t-test was performed. NMSC incidence was estimated by determining the number of separate patients treated for a NMSC. The proportion of recurrences and residuals were calculated. Results: Medicare Australia data were found to correlate with the VCR data set. Incidence rates for NMSC were 856 per 105 people in 2012. This incidence was forecast to increase to 1636 per 105 in 2015. 1.54% of NMSC required treatment for a recurrence and 1.26% of NMSC required retreatment for incomplete excision. Conclusion: This thesis has contributed the following: 1. Demonstration of a correlation between MA and VCR melanoma data, suggesting that MA could potentially be used for examining trends in other skin cancers including NMSC. 2. An up-to-date incidence of NMSC in Australia to 2012. 3. Proportion of NMSC that required treatment for residual lesions. 4. Proportion of NMSC that required treatment for recurrent lesions.