Sir Peter MacCallum Department of Oncology - Theses

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    How information technology improves the quality and efficiency of medical care and research
    Khor, Richard Chen-Tze ( 2018)
    In 2007, the concept of rapid learning healthcare was proposed in the United States of America health system in a response to increasing healthcare costs. Its aim was to accelerate knowledge discovery through a systematic approach to integrating electronic medical records design with analysis infrastructure to rapidly and continuously assess health system performance. The delivery of healthcare is becoming increasingly performed and documented within the electronic domain, and large databases of healthcare-related information being created as a by-product. This has led to an unprecedented level of access to detailed and structured clinical data that could be used to accelerate research. In a rapid learning healthcare system, the high level of integration from electronic record to policy would ensure that each patient and each click of the mouse would drive innovation. The attraction of rapid learning was not to supplant the traditional clinical trial paradigm, but to augment its effectiveness with accelerated analysis of real-world outcomes. The rapid learning concept relied heavily on electronic medical records, administrative systems and disease registries as data sources to power analyses. Electronic health record penetrance in Australia has lagged that achieved in the USA, primarily because of financial assistance provided as part of the HITECH act in the USA. However, one exception is seen in oncology, where radiotherapy is exclusively prescribed electronically. Additionally, there has been a significant shift toward electronic chemotherapy prescribing due to the clinical risk associated with manual systems. Perhaps in oncology there is an opportunity to replicate the successes of data-driven health research achieved elsewhere. The objective of the work contained in this thesis is to develop practical methods to expand and discover the infrastructure required to implement rapid learning health care in the Australian oncology context. Ultimately, the aim is to increase the quality and efficiency of medical care and research by harnessing novel information technology (IT) methods. In addition to leveraging existing secondary databases for health services research and creating high impact linkages with state-level cancer registries, advanced IT methods could also be used to automate manual data extraction tasks in a timely and cost-effective fashion. The integration of these methods into routine clinical practice has enormous implications for tracking patient care quality, and accelerating research by utilising all data by-products of health care.  
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    The impact of sex differences on host and tumour prognostic factors in patients with non-small cell lung cancer
    Wainer, Zoe ( 2018)
    Epidemiological studies demonstrate that women live longer than men following diagnosis of non-small cell lung cancer (NSCLC) even after controlling for prognostic factors. This study examines the one biological trait all patients have, sex, and seeks to understand and generate new knowledge with respect to the impact of sex on survival. Patient and tumour characteristics of women and men are examined from presentation and diagnosis, to staging, with specific focus on the impact of these factors on outcomes in NSCLC treated surgically with curative intent. The study also explores how to include sex differences in medical research more generally. Aim and research question The aim is to examine the impact on survival of the association of sex with the following recognised prognostic patient and tumour characteristics: • age • performance status • smoking history • positron emission tomography maximum standardised uptake value • tumour, node, metastasis (TNM) staging The research question is: “What is the impact of sex on validated and putative prognostic factors in non-small cell lung cancer and how can we translate understandings in sex differences in lung cancer to facilitate a more targeted research and therapeutic approach to improve patient outcomes?” This is answered by sex disaggregated analysis of the prognostic value of host and tumour factors from a detailed clinical dataset, including patient outcomes, and compared to an independent population level validation dataset. Finally, I examine international examples of success in sex differences medical research more broadly, and the policy landscape that is preventing translation of both the findings in lung cancer, and sex differences in health and disease across the health care continuum in Australia. Method A detailed surgical database was developed from patients treated surgically with curative intent from the Peter MacCallum Cancer Centre and St Vincent’s Hospital Melbourne from 2000-2010. An additional cohort of patients was identified and analysed from the Surveillance, Epidemiology and End Results (SEER) database, the US population level database. The SEER database was matched to the Melbourne cohort with respect to surgical treatment with curative intent and date of surgery, to ensure continuity with clinical protocols. Extensive clinical data were collected to allow analyses of the impact of sex differences on prognostic variables in three key areas: 1. Host factors (sex, age, smoking and performance status) 2. The maximum standardised uptake value on Positron Emission Tomography 3. TNM staging The patient outcome was disease specific five-year survival. During this research, a new edition of TNM staging was developed resulting in two different editions of TNM staging being used, with the 7th edition in chapter 3 and 4 and 8th edition in chapter 5. Data were analysed with IBM SPSS Statistics software (SPSS) version 21 (Chapter 4), version 22 (Chapter 3) and versions 25 and R (Chapter 5). Findings There are biological differences between women and men in the disease process in early NSCLC. These differences span elements from patient characteristics to survival outcomes. Irrespective of the parameter examined, male sex was a consistent negative prognostic factor. However, the prognostic value of previously identified tumour and host characteristics was equally valid for men and women. Whilst the finding of poorer survival in men with NSCLC is not new, researchers and clinicians have assumed that this was because women are less likely to smoke; due to ethnicity (there is a distinct variant of NSCLC which is less aggressive and occurs more commonly in women of Asian descent); because women are more likely than men to get adenocarcinoma, with its better survival profile compared with squamous cell cancer; and that women are likely to seek treatment at an earlier stage. The research presented in this thesis demonstrates that these assumptions do not fully explain the observed survival differences. Whilst the observations are correct superficially, the causality is false. Survival differences between men and women persist irrespective of ethnicity, histology and disease stage. These findings have important implications for research design, translation, clinical guidelines and practice. Significance A better understanding of the impact of patient and tumour sex on tumour characteristics has the potential to improve understanding of the biology of lung cancer and may lead to different staging and treatment approaches. Understanding the impact of sex on patient response to treatment may improve patient outcomes for men and women by improving selection of therapies tailored to each sex. In addition, novel targets for therapeutics may be identified. This thesis presents a comprehensive delineation of the differences in survival between men and women with NSCLC. These differences raise important questions with respect to the accuracy and efficacy of TNM staging when applied to clinical decision-making for both sexes and indicate that current therapeutic decision-making driven by stage should be reviewed. There is a significant possibility that the oncological community may be over-treating women and under-treating men. Publications from this study may provide direction for future clinical trials, redefine staging, assist in changing clinical practice by more accurate prediction of tumour behaviour, and support the move to individualised treatment.
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    The role of nature in cancer patients' experiences of health and recovery
    Blaschke, Sarah-May ( 2017)
    This thesis explores the role of nature in cancer patients’ experiences of health and recovery. Using a 2-Phase mixed-method approach, the investigation aimed to generate new theoretical understanding about cancer patients’ use of nature and how they find nature engagement helpful or not when confronting cancer diagnosis. The project’s translational focus was to produce expert recommendations for nature-based care opportunities in oncology contexts based on patient-reported data. First, a systematic literature review and meta-synthesis was conducted to describe the existing qualitative research evidence base relating to nature experiences and nature-based interventions for cancer populations specifically. The aim was to describe current knowledge about the role of nature in cancer patients’ lives. From eleven eligible publications, seven inter-related core themes were identified as follows: connecting with what is valued; being elsewhere, seeing and feeling differently; exploration, inner and outer excursions; home and safe; symbolism, understanding and communicating differently; benefitting from old and new physical activities; and, enriching aesthetic experiences. Next, an in-depth investigation of cancer patients’ own experiences with nature used primary data to develop a new Grounded Theory describing the underlying and intrapsychic mechanisms of cancer patients’ phenomenal nature experiences. Based on qualitative data collected from semi-structured interviews with 20 cancer patients (9 female), the resulting theory model explores the unique role nature plays when diagnosed with cancer. It constitutes a core category and two inter-related themes, which explain a normalization process in which patients moved towards a state of 'new-normal' (Core Category). Nature functioned in this process as a support structure that repositioned patients and nurtured their inner and outer capacities to respond and connect more effectively (Theme A). Once enabled and comforted, participants could engage survival and reconstructive manoeuvres and explore the consequences of cancer in their present lives and possible futures (Theme B). A dynamic relationship was shown between moving away while, simultaneously, advancing towards the cancer reality in order for patients to incorporate their cancer experiences into a shifting normality. From a place of comfort and safety, patients felt supported to deal differently and more creatively with the threat and demands of cancer diagnosis, treatment, and outlook. The descriptively rich interview data provided further insights into patients’ own recommendations for nature engagement in the oncology context, which were extracted from the transcriptions using deductive content analysis and were consolidated into patient recommendations for nature-based care opportunities. These incorporated using nature for vital sensory stimulation and engagement, using nature for personal space and freedom to enable private and social exploration, using views of nature for distraction and comfort, and accessing nature for physical activity and movement. Three critical factors were determined to avoid adverse experiences: determining appropriate health-care expenditure and resourcing on nature-based interventions, selection of appropriate nature-based design materials, and exercising caution around demanding nature engagement and harsh weather conditions. A questionnaire survey study was conducted following an environmental intervention in an oncology waiting room to assess patient, visitor, and staff responses to design changes, which included the addition of artificial plant materials. Based on 143 returned survey questionnaires consisting of 73 cancer patients, 13 staff, 52 carers, and five ‘other’, it was found that the environmental intervention positively impacted patients, staff, and carers’ perceptions of the oncology waiting room environment. Patients, staff, and carers mostly accepted artificial plants as an alternative design solution to real plants. Comments included positive appraisals and occasional adverse reactions to artificial plants. No significant differences were found between patient, staff, and carer reactions. Insights gleaned from the initial, exploratory phase formed the basis for a second phase investigation comprising an international online Delphi study. The aim was to solicit knowledge from relevant experts drawn from a range of healthcare practitioners, management, designers, and researchers to determine feasible opportunities for, and barriers to, providing helpful nature engagement in oncology settings. Two hundred potential panellists were identified and sent an invitation to participate. Thirty-eight experts were recruited who represented 7 countries: Australia (19), USA (8), UK (3), New Zealand (2), Canada (2), Denmark (3), and Sweden (1). This study followed a structured, iterative feedback process that queried and synthesized expert opinion. Cancer patients’ own recommendations, extracted from phase 1, were used as a starting point for the Delphi panel to brainstorm and develop their own ideas about appropriate nature-based opportunities in oncology settings and the barriers to their provision. In total, 250 separate suggestions for opportunities and 205 suggestions for barriers were collected. Further analysis condensed these into 55 unique items (35 opportunities, 20 barriers). The Delphi panel’s list of recommendations included “Window views from clinical areas onto nature […]” as the highest rated opportunity, and “Building design and site constraints […]” as the highest rated barrier to providing nature-based supports for oncology care. Finally, a synthesis of findings from the overall investigation, which constitutes six publications, is provided to summarize and outline the salient findings and discern the study’s limitations in order to suggest pathways for future research. This synthesis produced a conceptual framework consolidating new theoretical understanding and empirical content from patient and expert-reported data about nature-based care opportunities in the oncology setting. The thesis findings provide evidence for multiple uses of nature as a supportive aid in the cancer care context. Concrete recommendations have resulted to guide the application of nature based concepts in future oncology setting design and may be considered when developing additional supportive care services. The findings may assist healthcare practitioners, designers, researchers, and patients themselves to creatively and practically participate in future oncology care practice and design.
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    Identification of cooperating oncogenic lesions in Myc-driven lymphoma
    Lefebure, Marcus Patrick Henry ( 2017)
    MYC is a potent oncogene that is deregulated in nearly 50% of all human malignancies and as such, is considered an attractive molecular target for inhibition. However, MYC is rarely mutated, has no enzymatic activity that can be pharmacologically exploited and is expressed by normal cells leading to the current view that MYC is “undruggable” and indeed, its pharmacological inhibition has proved elusive. Therefore, discovering genes and pathways that interact with oncogenic MYC signalling and identifying them as potential therapeutic targets in cancers with ectopic MYC expression is of high clinical importance. The Eμ-Myc mouse has been utilised extensively as a faithful model of MYC-driven B cell lymphomagenesis. The Eμ-Myc transgene mimics the t(8;14) translocation apparent in Burkitt’s lymphoma, where ectopic Myc expression is driven by the Eμ- (IGH) promoter elements. Despite being driven by a single oncogene, Eμ-Myc lymphomas demonstrate remarkable heterogeneity indicating that the pathway to frank clonal neoplasia relies on oncogenic Myc signalling and the acquisition of at least one other mutation that cooperates with Myc. Hence, the Eμ-Myc model is a powerful tool in identifying MYC-cooperative genes and pathways. However, to date there has only been partial characterisation of the secondary, tertiary and quaternary mutations that can cooperate with Myc in driving Eμ-Myc lymphomagenesis. To identify somatically acquired Myc-cooperative lesions, massive-parallel sequencing was applied to spontaneous Eμ-Myc B cell lymphomas. Whole genome sequencing was used to map three copies of the Eμ-Myc transgene to chromosome 19 in the germline corresponding with an adjacent chromosome 19 segmental copy number gain. The chromosome 19 amplicon is in a region syntenic to an oncogenic region frequently amplified in human B cell malignancies. The chromosome 19 amplicon was demonstrated to undergo additional somatic gain in 50% of Eμ-Myc lymphoma. In addition to the identification of mutations in genes already implicated in Eμ-Myc lymphoma (Trp53, Cdkn2a, Nras, Kras), whole exome sequencing identified high frequency protein truncating mutations in Bcl6-co-repressor (Bcor). Furthermore, co-occurring tertiary driver lesions involving Cdkn2a (p19ARF) deletion and either Bcor or Ras mutations were identified in clonal Eμ-Myc lymphomas. RNAi and CRISPR-Cas9 mediated knockdown/knockout of Bcor in Eμ-Myc foetal liver hematopoietic stem cells reconstituted into recipient mice demonstrated significantly reduced latency of disease onset, validating Bcor as a tumor suppressor gene in the Eμ-Myc model. Gene-expression profiling of these Eμ-Myc tumours with forced Bcor-loss identified a reliable signature of Bcor loss that was distinct to Trp53 mutation signatures and was redolent of Tgfβ-pathway activation signature. The Eμ-Myc model of lymphoma has been heavily utilised but never fully genomically characterised until now. By applying next generation sequencing technology to a first generation animal model of cancer, this thesis challenges several persisting assumptions made about Eμ-Myc lymphoma. Firstly, data herein suggests that both oncogenic Myc expression along with the chromosome 19 amplification is the initiating driver event in Eμ-Myc lymphoma. This has obvious implications for the conclusions drawn in many publications predicated on the assumption that ectopic Myc expression is the exclusive initiating oncogenic lesion in Eμ-Myc lymphoma. Secondly, the discovery that homozygous deletion of Cdkn2a does not totally attenuate selective pressure for the acquisition of tertiary driver mutations indicates the significance of Cdkn2a deletion in Eμ-Myc lymphoma is overestimated. Thus, deductions made about the cooperative mechanism between CDKN2A and how it opposes proliferative MYC-signalling in human neoplastic transformation may need to be revisited. Finally, the identification of biologically functional high frequency Bcor mutations in Eμ-Myc lymphoma has defined a novel pathway that is potentially capable of restraining oncogenic MYC activity. That Bcor inactivation is reminiscent of Tgfβ-pathway enhancement is suggestive of perturbation of the oncogene induced senescence pathway. If this is the pathway through which Bcor exerts its tumour suppressive activity then it is feasible that dissection of this pathway will lead to the identification of novel therapeutic targets that can be selectively exploited in human malignancies in which MYC is oncogenically deregulated.
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    An investigation of type-1 interferon and the immune response against breast cancer metastasis
    Rautela, Jai ( 2016)
    Breast cancer is a highly prevalent disease that, like many cancers, lacks effective therapies aimed at treating and preventing metastasis. Harnessing the host immune system to recognise and eliminate malignant cells has recently emerged as an effective therapeutic strategy in many cancers. However, response rates to these approved immunotherapies remain modest in the absence of a more detailed understanding of tumour immunity. The type I interferons are a family of cytokines that have long been understood to enhance the immune response to cancers, though their clinical application has led to underwhelming results in numerous types of cancer. This thesis provides new evidence that proposes the re-visitation of cancer immunotherapies that stimulate the type I interferon pathway. We show that host-derived type interferon is critical for the suppression of breast cancer metastasis through natural- killer cell activation. Induction of a type I IFN response by administering agents that mimic a viral infection (poly(I:C), a double-stranded RNA analog) proved to be powerful anti-metastatic agents in multiple pre-clinical models of triple-negative breast cancer (TNBC). This was linked to widespread immune activation which conferred NK cells with enhanced cytotoxic function to eliminate disseminated tumour cells. The efficacy of this novel immunotherapeutic approach was also found to rely upon the treatment setting in which it was used. Evidence is presented that demonstrates administration prior to primary tumour removal (neo-adjuvant therapy) as the only effective therapeutic regimen. We propose that such immunotherapies are most effective at eliminating circulating and early disseminated cells rather than established metastatic lesions. This provides some explanation to the inefficacy of previous interferon trials that were conducted in patients with late-stage metastatic disease. It also calls into question whether other immunotherapies could be used earlier in cancer treatment to maximise the chances of a clinical response. Finally, we uncover that expression of IRF9, a key transcription factor in the type-I interferon signaling pathway, accurately predicts TNBC patient prognosis. Loss of IRF9 in a patient’s primary tumour predicted significantly poorer overall survival due to metastatic spread. As we show that tumour cells are not directly responsible for the poly(I:C)-induced interferon response, we propose that patients with IRF9-negative TNBC could benefit from neo-adjuvant interferon-based immunotherapy.
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    Exploring the nature and impact of taste dysfunction in people receiving chemotherapy
    Boltong, Anna Gaye ( 2013)
    Self-reported ‘taste’ problems are common in people receiving chemotherapy and have implications for nutritional and psychosocial domains. Taste refers to the perception derived when chemical molecules stimulate taste receptor fields in the oral cavity whereas flavour perception involves at least three independent sensory systems including taste, smell and texture. Conflation of the terms taste and flavour contributes to clinician confusion and reduces the opportunity to develop effective strategies to address taste problems in cancer patients. The research reported in this thesis aimed to characterise the extent to which taste function and food hedonics contribute to the eating and drinking experience in people receiving chemotherapy and to investigate how this is managed in the clinical setting. There was a mixed methods approach to this program of research that was comprised of three separate studies, in two phases, designed to: Phase 1, qualitative 1. Describe current practice surrounding taste function and food hedonics in the clinical oncology setting (Study 1); 2. Understand the experience and consequences of altered taste function and food hedonics for people receiving chemotherapy (Study 2); and Phase 2, quantitative 3. Describe the patterns of altered taste function and food hedonics across the chemotherapy treatment trajectory (Study 3). In the Phase 1 studies, patient and clinician interviews were used to explore a) clinician practice regarding the management of taste problems and b) patient and carer descriptions, experiences and consequences of taste changes. This qualitative phase informed the quantitative phase of the research: a longitudinal study of 52 women receiving chemotherapy for breast cancer that assessed taste function, appetite and food liking six times from before chemotherapy to 2 months after chemotherapy and investigated whether changes in these outcomes were associated with dietary intake, nutritional status or social dining activity. Phase 1 findings demonstrated that ‘taste’ problems refer to a raft of issues related to the wider aspects of flavour including changes to the sense of smell or touch, or to problems with appetite or food liking. Clinicians have limited capacity to distinguish between these scenarios. These changes shaped what patients chose to eat, drink, cook and purchase, and influenced how they dined and how they felt. A need for new approaches to classifying and describing flavour problems was identified and a requirement for better quality information and evidence with which to guide patients was indicated. In Phase 2, patterns of taste and hedonic changes were characterised in an unprecedented fashion across the treatment trajectory. Findings from Phase 2 analyses showed taste function and food hedonics were adversely influenced with greatest change closest to chemotherapy administration, followed by a gradual return to baseline measures. Problems resolved by 2 months after completion of chemotherapy. Change from baseline in ability to correctly identify all tastants was significant early in the third chemotherapy cycle (difference = 18.2%; 95% CI = 2.7, 32.9; p = 0.02) and final chemotherapy cycle (difference = 19.6%; 95% CI = 3.0, 35.1; p = 0.02). Decreased liking of sweet food (chocolate) was observed in the early (d = 0.77; p = 0.002) and middle stages of the third chemotherapy cycle (d = 0.70; p = 0.003) and early in the final chemotherapy cycle (d = 0.89; p = 0.001). Appetite was significantly decreased from baseline early in both the third and final chemotherapy cycles (d = 1.02; p < 0.001 respectively). Associations were found between taste and hedonic changes and dietary intake, nutritional status and social dining. Change in ability to correctly identify tastants was associated with reduced energy intake (r = 0.32; p = 0.005) early in the third chemotherapy cycle. At this assessment point, decreased liking of a sweet food item was also associated with reduced energy intake (r = 0.35; p = 0.001). Appetite loss was associated with reduced energy (r = 0.35; p = 0.001) and protein intake (r = 0.36; p = 0.001) early in a chemotherapy cycle, decrease in BMI over the study period (r = 0.36; p = 0.001), and change in overall nutritional status as assessed by PG-SGA score (r = 0.18; p = 0.09). Early in the final chemotherapy cycle, small-sized but non-significant associations were seen between taste change and social dining episodes (r = 0.22, p = 0.09) and between appetite loss and social dining episodes (r = 0.18, p = 0.16). Clinicians are ill equipped to support patients who report taste problems due to an absence of assessment tools or classification symptoms to identify problems described colloquially as ‘taste’. An emerging taxonomy of taste arising from this research goes some way to address the need for a classification system linking patient language to specific sensory or hedonic disturbances. Research findings will be used to guide the development of more specific pre-chemotherapy education material for patients.