Medicine (Austin & Northern Health) - Theses
Permanent URI for this collection
Search Results
1 - 10 of 26
-
ItemThe Immunological Tumour Microenvironment in Small Cell Lung Cancer and Pulmonary Neuroendocrine Tumours( 2022-11)Background There is a limited understanding of the immunological tumour microenvironment (TME) in pulmonary neuroendocrine tumours (NETs), including well-differentiated (carcinoid) and small cell lung cancer (SCLC). A fuller understanding of the mechanisms by which these tumours escape immune surveillance is required to build on the success using checkpoint inhibitors in pulmonary NETs. This study presents two retrospective cohorts: one of pulmonary carcinoid tumours, and the second of SCLC examining of the IHC analysis of common checkpoints, their correlation with gene expression, and the impact of both on prognosis. In addition, a smaller group of SCLC patients underwent gene expression profiling (GEP), with clustering studies based on T-cell inflammation signatures and their impact on prognosis. Methods Tissue microarrays from 153 histologically-confirmed pulmonary carcinoids and 101 SCLC specimens were scored for IHC staining of immune checkpoints on tumour alone or TME (combined positive score, CPS). Immune checkpoint expression was analysed for impact on overall survival. A subgroup of 30 patients underwent GEP using the Nanostring nCounter Pan-cancer immune panel. Two IFN-G GEP signatures were examined for supervised clustering and impact on survival. Results In carcinoid tumours PD-L1 >5% was seen in 19/153 (12.4%), but only 3/153 (2.0%) expressed PD-L1 >50%. Expression of PD-L1 >5% was more frequent in atypical carcinoid tumours (6/34; 17.7%) than typical carcinoids (13/119; 10.9%; p 0.39 for significance). No significant tumour expression of PD-L2 and TIM3; LAG3 was expressed at low levels (2/153; 1.3%). Checkpoint expression in TME was low, with PD-L1 CPS >10% in 14/153 (9.1%). No significant prognostic impact was seen with checkpoint expression in well-differentiated tumours. PD-L1 was the most frequently expressed checkpoint in SCLC. PD-L1 >5% was seen in 17/101 (16.8%). PD-L2 in 2/101 (1.9%); TIM3 had 1/101 (1.0%); LAG3 in 1/101 (1.0%). Expression was more frequent in the tumour microenvironment with PD-L1 CPS >10% in 18/101 (17.8%); TIM3 CPS >10% in 50/101 (49.5%); LAG3 CPS >10% in 27/101 (26.3%) and PD-L2 CPS >10% in 2/101 (2.0%). 12/101 (11.9%) had co-expression of PD-L1, TIM3 and LAG3. PD-L1 >5% on tumour was associated with improved median OS, 27.7 months vs 12.9 months (p 0.04), as was LAG3 CPS expression, with median OS 18.0 months vs 11.9 months (p 0.02). The greatest improvement in survival was seen in cases with co-expression of checkpoints, median OS 33.0 months vs 12.5 months (p 0.04). Multivariable analysis of survival showed that these differences became non-significant when accounting for stage. Significant heterogeneity was observed in gene expression. Gene expression by mRNA level did not correlate with protein expression by IHC. Supervised clustering with the 18-gene and 28-gene IFN-G GEP signatures showed significant clustering but no significant association with survival. Conclusion Well-differentiated pulmonary NETs express PD-L1 at low rates in typical carcinoids and moderately low rates in atypical carcinoids. PD-L2, LAG3 and TIM3 were not expressed at significant levels on tumour or in the TME. The prognostic impact of checkpoint expression is unclear due to the excellent survival in carcinoid tumours with conventional therapy. In the SCLC cohort, tumour expression of PD-L1 and LAG3 in the TME were associated with improved survival on univariate analysis. Co-expression of immune checkpoints occurred in 16.7% SCLC and was associated with improved survival. These differences were accounted for by stage on multivariable analysis. The cohort showed clustering with T-cell inflamed/IFN-G GEP but there was no significant impact of T-cell inflammation on survival.
-
ItemImproving prognostic and therapeutic precision in high-risk diffuse large B-cell lymphoma( 2022)Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and follows an aggressive clinical course. Standard chemotherapy including rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone (R-CHOP) can be expected to cure ~60% of patients, but those who experience relapse after initial disease control, or have lymphoma which is refractory to front-line combination chemotherapy have limited salvage options and often succumb to their disease. Identification of the clinical and biological factors underlying these poor responses to R-CHOP remains imprecise. One of the most devastating events is dissemination into the central nervous system (CNS), which is usually fatal despite dedicated intensive CNS-penetrating chemotherapy regimens. The objectives of this thesis were to examine the clinical, biological and immunological drivers behind DLBCL refractoriness and relapse in general, with a particular focus on a) the pathobiology and outcomes of CNS dissemination, b) the toxicity of CNS-directed therapy. Clinically, patients with secondary CNS lymphoma (SCNSL) have an aggressive clinical course and the optimal treatment is not defined. This thesis demonstrates that the primary cause of death in these patients is the CNS disease, and subsequently the importance of adding cytarabine to high-dose methotrexate to adequately treat the CNS component. The development of CNS disease, either synchronously at diagnosis or in relapse, occurs for largely unknown reasons. Clinical risk scores for determining CNS risk are imprecise and pathobiological data are lacking to develop rational drug combinations. This thesis compared genetic and functional drivers of secondary CNS DLBCL (SCNSL) samples with primary CNS lymphoma (PCNSL) and systemic-only DLBCL. SCNSL carries multiple aberrations in antigen presentation mechanisms (MHC, B2M, CD58, CIITA) in similar numbers to PCNSL and far more than systemic-only DLBCL suggesting that failure of antigen presentation is a possible mechanism of CNS dissemination with potential therapeutic implications. High-dose methotrexate itself carries substantial toxicity, the underlying risk for which has been undefined. This thesis evaluated the modifiable risk factors for toxicity with high-dose methotrexate and documented the most critical were dose and interacting/nephrotoxic drugs, and suggests how these observations can impact practice. Determining the likelihood of relapse or refractoriness to R-CHOP in systemic DLBCL has been an area of expansive research since the original international prognostic index was published in 1993. With rare exception, improved prognostication has not led to changes in therapy. Real-time assessment of disease response to R-CHOP using FDG-PET has been shown to improve prognostication, but this thesis demonstrates that it can also be used to identify early those who will have refractory disease. Specifically, those with a Deauville score of 5 following 2 cycles of R-CHOP, or a change in the maximum standard uptake value (SUVmax) of <66% following 4 cycles of R-CHOP are highly likely to have refractory disease and should be evaluated for alternative salvage or clinical trial. In order to relapse, DLBCL must escape immune surveillance, and a lack of diversity of the T-cell receptor repertoire at diagnosis has been associated with relapse. Work in this thesis assessed the T-cell diversity in paired diagnostic and relapsed tumour samples. It was observed that these tumour microenvironments become increasingly dysfunctional at relapse though further narrowing of the T-cell receptor repertoire and change in dominant clones, highlighting that it is not only clonal evolution that plays a role in relapse but also defunct immune responses. The high-risk DLBCL groups evaluated in this thesis demonstrate substantial clinical and biological heterogeneity. Identifying and managing the highest risk subgroups remains a challenge that requires comprehensive and multi-faceted approaches to overcome.
-
ItemSpontaneous versus spontaneous timed mode of assisted ventilation in extrathoracic restrictive lung disease( 2017)Restrictive lung disease can be divided into intrathoracic restriction due to parenchymal causes and extrathoracic restriction due to chest wall disease or neuromuscular disease. Patients with extrathoracic lung restriction suffer from shortness of breath, disturbed sleep and eventually type two respiratory failure when their condition progresses. Type two respiratory failure is characterised by hypoxaemia and hypercapnia. Effective treatment of this type of respiratory failure involves ventilatory support in the form of assisted mechanical ventilation. Non-invasive positive pressure ventilation has been a major advance in delivering mechanical ventilation since the late 1980’s. This can be in the form of volume-cycled ventilation or pressure-cycled ventilation. Pressure-cycled ventilation is more commonly practised in Australia and around the world; particularly Europe; according to large multicentre surveys. This can be delivered in spontaneous mode (S) or spontaneous timed mode (ST). There is no current evidence that one mode is superior to the other, and the two modes are roughly equally practised around the world and in Australia according to the available surveys. The aim of this research was to compare S mode to ST mode in a double-blind cross over design over six weeks in 20 patients with stable extrathoracic lung restriction from chest wall and neuromuscular disease. The study aimed to objectively assess adequacy of ventilation, quality of sleep and impact on the patient in psychomotor function, sleepiness as well as patient preference. This was assessed by performing blood gas analysis, sleep studies, psychomotor vigilance testing (PVT) as well as patient questionnaires. We also performed a physiological arm of the study in a subset of patients, assessing the participants for ineffective efforts and poor triggering by inserting an oesophageal balloon and monitoring for markers of effort not followed by a ventilator breath. The oesophageal balloon-catheter system was calibrated for frequency response under different conditions prior to starting this arm of the study and for adequacy of signal acquisition before each sleep study. Due to difficulty in recruitment of participants and some patients withdrawing or failing the safety criteria for the study, a total of 13 patients completed the two arms of the study. The results of this research demonstrated that ST mode was associated with improved nocturnal oxygenation, sleep quality and fewer respiratory events than S mode in patients with stable chest wall and neuromuscular disease. There was no significant difference in daytime hypoventilation as assessed by carbon dioxide measurements. The physiological arm of the study showed that ST mode resulted in fewer ineffective efforts than S mode, the former contributing to better sleep efficiency and correlating well with fewer respiratory events. On the other hand, the mode of ventilation had no significant effect on poor triggering of the ventilator. The participants appeared to be less sleepy on ST than S mode; however, neither mode was associated with pathological sleepiness. There was no significant difference in patient preference between the two modes, nor was there a significant difference in psychomotor function between the modes as assessed by PVT. In conclusion, ST mode of non-invasive positive pressure ventilation was superior to S mode in many aspects of ventilation, sleep quality and impact on the patient. Physiologically there were less ineffective efforts on ST mode, which was related to improved sleep efficiency and the frequency of respiratory events while on ventilation. The participants were less sleepy on ST than S mode, however there was no significant difference between the two modes of non-invasive ventilation on on psychomotor function and patients did not prefer one mode over the other. The sample size of this study was small and less than the original target, due to difficulty in recruitment and the need for participants to present to hospital on three different occasions, a considerable expectation in this relatively frail cohort of patients. The concept of measuring oesophageal pressure in awake patients was also a limiting factor in failure to achieve the target number of participants in the sub-study. This would have impacted the power of the study and the overall significance of some of the results. Based on the results of this study, ST mode of non-invasive ventilation should be utilised rather than S mode in patients with extrathoracic lung restriction due to neuromuscular and chest wall disease. Centre specific preferences and cost need to be taken into account when implementing this recommendation. Acknowledging the difficulties with recruitment, larger (possibly multi-centre) studies of longer duration are required to determine long term health benefits such as hospital admissions and mortality in this population.
-
ItemTracking cerebral amyloid accumulation in ageing, mild cognitive impairment, Alzheimer’s disease and other dementias( 2018)Background Alzheimer’s disease (AD), the most common form of dementia in the elderly, is thought to result from the neurotoxicity of cerebral β-amyloid (Aβ) plaques. Accumulation of Aβ plaques begins years before AD dementia onset; earlier detection might improve diagnostic accuracy, which potentially translates to better clinical outcomes. We assessed the clinical utility of Aβ imaging with 18F-florbetaben (FBB) in mild cognitive impairment (MCI) by evaluating its prognostic accuracy for progression to AD, comparing semi-quantitative assessment with visual scan assessment and exploring the relationships between Aβ plaque deposition, cognition, hippocampal volume and white matter hyperintensities. Methods Forty-five MCI (mean age = 72.7 years, mean Mini-Mental State Examination score = 27.2) underwent FBB positron emission tomography (PET), magnetic resonance imaging and neuropsychological assessment at baseline and two years, and clinical follow-up at four years. Positive FBB PET (FBB+), defined by a cortical to cerebellar cortex standardised uptake value ratio (SUVR) ≥1.45, was compared with visual assessment by five readers. Amnestic MCI (aMCI) was defined by a composite episodic memory (EM) z-score of <−1.5. Correlations were adjusted for age, gender and years of education. Results At baseline, 24 (53%) MCI were FBB+. Regression analyses showed SUVR (r = -0.51, p = 0.0015) and hippocampal volume (r = 0.60, p = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with non-memory-related cognition, and this correlation was particularly associated with high Aβ burden at baseline. Majority reads agreed with SUVR classification (κ 0.96). In two years, 18 (75%) FBB+ progressed to AD compared with two (9.5%) FBB PET negative (FBB−), yielding a predictive accuracy of 83% (95% CI 61% to 94%). Four FBB− developed non-AD dementia. Predictive accuracies of hippocampal volume (58% (95% CI 42% to 73%)) and aMCI status (73% (95% CI 58% to 81%)) were lower. Combinations did not improve accuracy. By four years, 21 (87.5%) FBB+ progressed to AD whereas five (24%) FBB− developed non-AD dementia, yielding a predictive accuracy of 94% (95% CI 74% to 99%). While the strong baseline association between FBB SUVR and EM declined over two years, the association between hippocampal volume and EM became stronger. The association between SUVR and hippocampal volume also strengthened over two years. FBB SUVR increased 2.2%/year in FBB+ with no change in FBB−. Conclusions 18F-florbetaben Aβ imaging facilitates accurate detection of prodromal AD better than hippocampal volume or aMCI status. This supports the notion that biomarkers of amyloid dysregulation employed for identifying patients with incipient AD should be ordered first. In MCI, higher Aβ plaque burden is associated with more severe memory impairment and contributes to early amnestic symptoms independent of hippocampal atrophy. However, as neurodegeneration progresses, and in contrast with the early stages of the disease, hippocampal atrophy, not Aβ plaque burden, seems to drive memory decline. The latter observation might be explained by the neurotoxic effect of soluble fibrillogenic Aβ oligomers on hippocampi, upstream of the formation of Aβ plaque.
-
ItemThe role of androgens acting via the androgen receptor in osteoblasts to regulate bone cell metabolism( 2017)Androgens play a key role in skeletal growth and bone maintenance, however their mechanism of action remains unclear. Androgens exert their actions, at least in part, directly via the androgen receptor (AR). This is evidenced by the bone loss observed in male mice with global deletion of the AR (Kawano, Sato et al. 2003). Previous studies have demonstrated that osteoblasts, the bone forming cells, express the AR, however, it is not known at which stage of osteoblast development androgens act. Therefore, the aim of this thesis was to determine the role of androgens acting directly via its molecular target, the AR in 1) proliferating osteoblasts (pOBLs) and 2) terminally differentiated, mineralising osteoblasts (mOBLs) on bone cell metabolism. To achieve this, the DNA-binding dependent actions of the AR were selectively deleted in pOBLs and mOBLs using the Cre/loxP system. Specifically, a) proliferating osteoblast-androgen receptor knockout mice (pOBL-ARKOs) and b) mineralising osteoblast-androgen receptor knockout mice (mOBL-ARKOs) were generated by breeding female AR floxed mice with male mice in which the expression of Cre-recombinase was under the control of the a) osterix or b) osteocalcin promoter respectively. The effect of deletion of the AR from either the proliferating or mineralisation stage of osteoblast development was extensively characterised in skeletally immature, adult and aging pOBL-ARKO and mOBL-ARKO male mice using microCT, static and dynamic histomorphometry and serum biochemical analysis. Initial characterisation of the pOBL-ARKOs determined that deletion of the AR was not restricted to bone and was also deleted in the brain. Whilst the external genitalia and body weight of pOBL-ARKOs did not differ from wild type control males, it was noted that Osterix-Cre control mice had reduced cortical bone expansion likely due to non-osseous Cre expression. This model was therefore deemed unsuitable for determining the effects of the AR on cortical bone growth and was not investigated further. Male mOBL-ARKOs had decreased femoral trabecular bone volume compared to littermate controls because of a reduction in trabecular number at 6, 12, and 24 weeks of age, indicative of increased bone resorption. The effects of AR inactivation in mineralising osteoblasts was most marked in the young mutant mice at 6 weeks of age when rates of bone turnover are high, with a 35% reduction in trabecular bone volume, decreased cortical thickness, and abnormalities in the mineralisation of bone matrix, characterised by increased unmineralised bone matrix and a decrease in the amount of mineralising surface. This impairment in bone architecture in the mOBL-ARKOs persisted throughout adulthood despite an unexpected compensatory increase in osteoblast activity as reflected by increases in both the extent and rate of mineralisation as measured by mineral apposition rate and bone formation rate at 12 and 24 weeks of age. The presence of osteoidosis despite increased mineralisation in these skeletally mature mOBL-ARKOs is consistent with a role of androgens acting through the AR in mineralising osteoblasts to regulate the coordination of the bone matrix synthesis and mineralisation processes. There was no effect on bone size as determined by periosteal circumference in mOBL-ARKOs, which is consistent with the action of androgens to stimulate periosteal apposition during growth being mediated via the AR in a more immature population of osteoblasts. In conclusion, in this thesis I have provided further significant insight into the mechanism of androgen action via the AR in osteoblasts. I have provided the first evidence for a role of androgens acting via the AR in mineralising osteoblasts to maintain bone by inhibiting bone resorption and the coordination of bone matrix synthesis and its subsequent mineralisation, and that this action is most important during times of bone accrual and high rates of bone remodelling.
-
ItemImplementation and evaluation of Goals of Patient Care medical treatment orders in residential aged care facilities: a mixed methods study( 2017)Background: Systematic reviews demonstrate that Advance Care Planning has many positive effects for residents of residential aged care facilities, including decreased hospitalisation. The proposed residential aged care facility “Goals of Patient Care” form uses shared decision-making to incorporate a resident’s prior Advance Care Planning into medical treatment orders. Where no written Advance Care Plan exists it captures residents’ known values and preferences. This documentation guides healthcare decision-making at a time of clinical deterioration. Method: A mixed methods study design was used incorporating (i) a cluster randomised controlled trial and (ii) an explanatory descriptive study. The cluster randomised controlled trial took place in three pairs of residential aged care facilities over twelve months in 2015-2016. In Intervention facilities Goals of Patient Care discussions and forms were completed by a Medical Practitioner, following a shared decision making process, incorporating Advance Care Plans or preferences. In Control facilities residents had usual care, which frequently included an Advance Care Plan¬¬. The primary hypothesis was that the Goals of Patient Care process was superior to standard Advance Care Planning alone leading to decreased hospitalisation due to clearer documentation of residents' medical treatment plans. The primary outcome was the effect seen on Emergency Department attendances and emergency admissions at six months. Secondary outcomes included change in hospitalisation rates at three and twelve months, total hospital bed days and In-RACF and In-hospital mortality rates. The explanatory descriptive study took place in the Intervention facilities alone twelve months post Goals of Patient Care implementation. Focus groups and semi-structured interviews were conducted to evaluate both Advance Care Planning and Goals of Patient Care from a healthcare professional’s point of view. Open and axial coding of themes was used to analyse this data. Results: Over 70% of patients participated. The facilities were pooled for analysis with 181 residents were randomised to Intervention and 145 to Control. In the cluster randomised controlled trial the primary outcome of a 40% reduction in Emergency Department attendances and emergency admissions compared with Control facilities at six months was not attained with Incident Rate Ratio of 0.74, 95% CI: 0.49–1.14, p=0.170. There was a near 50% change in Cluster 3, but not in Cluster 1 and 2. In the Intervention group 11/61 (20.4%) Emergency Department attendances did not result in admission while in the Control group a significantly higher, 20/54 (32.7%) did not result in hospital admission. There was no difference seen in mortality in the groups at six or twelve months. In terms of secondary outcomes the Intervention resulted in a 40% reduction in Emergency Department attendances and emergency admissions at twelve months with IRR=0.62, 95% CI 0.39-0.99, p=0.043. There was a trend toward decreased total hospital bed days in Intervention versus Control facilities. Mortality rates at all time-points show increased likelihood of dying in the facility rather than hospital, which was the preference for our participants. This was statistically significant at six months with RRR 2.21, p=0.008 95% CI 1.23-3.98. Qualitative analysis identified four major themes; Completing an Advance Care Plan; Activating an Advance Care Plan; End-of-life; GOPC. Both ACP and GOPC was seen as a valuable addition to improve patient care and help residents engage with their own preferences. Barriers to successful ACP included poor health literacy, mistrust, ambivalence to activate the plan by family and varying involvement from General Practitioners. Conclusions: Goals of Patient Care medical treatment orders were not effective in reducing Emergency Department attendances and emergency admissions at six months post intervention. Secondary outcomes did find that Goals of Patient Care medical treatment orders were more effective than standard Advance Care Planning for decreasing hospital transfers and decreasing likelihood of dying outside the facility. The shared decision making process results in medical treatment plans that take better account of both: the resident’s values and preferences; and the medical interventions suitable for their care. Barriers to successful completion and activation of plans still exist and education of all stakeholders would help address these issues.
-
ItemA clinical and electrophysiological study of the effects of 4-aminopyridine on upper limb impairment in multiple sclerosis( 2017)Introduction: Multiple Sclerosis (MS) is a leading cause of disability in Australian adults. Recent decades have seen great advances in disease-modifying therapies for some forms of MS but options for symptomatic therapy remain limited and, in most cases, unsupported by randomized clinical trial evidence. Upper limb dysfunction, visual impairment and fatigue are common and disabling MS symptoms which lack proven symptomatic therapies. Modified-release 4-aminopyridine (fampridine-MR) is licensed in Australia for the symptomatic treatment of walking disability in patients with MS. Its potential for use in other neurological domains, its mode of action, and the reasons for widely variable responses in treated patients, remain unknown. Various clinical and electrophysiological measures can be used to objectively evaluate patients with MS. These include a collection of functional tests of upper limb strength, dexterity and sensation, most of which are seldom conducted as part of routine clinical evaluation. Objective electrophysiological evaluation of Central Nervous System (CNS) conduction can be performed using evoked potential (EP) testing and Transcranial Magnetic Stimulation (TMS). The effect of fampridine-MR on areas of disability other than walking and how this might be reflected by changes in CNS conduction has not been previously fully investigated in the context of blinded randomized controlled trials. As a precursor to the original data, this thesis includes a comprehensive literature review of the diagnosis, pathophysiology and clinical features of MS; currently available disease-modifying and symptomatic treatments; objective clinical and electrophysiological tests used to evaluate of CNS conduction and MS symptoms, and the role of fampridine and related drugs in the treatment of MS symptoms. The original research presented within this thesis will test the following hypotheses: 1. Fampridine-MR treatment is associated with improvements in upper limb impairment, vision and fatigue in patients with multiple sclerosis. 2. Objective electrophysiological measures differ between patients on and off treatment with fampridine, and can be used to predict clinical response. Methods: These hypotheses were tested in two substudies. Study 1 was a small pilot study in patients taking fampridine-MR for walking disability; study 2 was a larger, randomized double-blind placebo-controlled trial in treatment-naïve patients with upper limb impairment. Clinical and electrophysiological measures were made before, during and after the treatment period and compared between groups. A group of healthy control participants was also included for validation of the clinical and electrophysiological measures. The primary clinical outcome measure was improvement in upper limb function using the 9-hole peg test. Secondary clinical outcomes included grip strength, sensory discrimination capacity, visual acuity and fatigue. Electrophysiological outcomes included peripheral nerve conduction, EP’s and TMS parameters. Results: Whilst patients differed from healthy control subjects on the majority of the clinical and electrophysiological measures, treatment with fampridine-MR was not associated with improvement in any of the clinical or electrophysiological measures used. Conclusion: Fampridine-MR was not found to be an effective symptomatic treatment for upper limb impairment, vision or fatigue in patients with MS. The significance of these findings in the context of other published literature and the methodological strengths and limitations of the study are discussed.
-
ItemTreatment strategies to improve outcomes in aggressive lymphomas( 2016)Lymphoma is the 5th most common cancer subtype, comprising 5% of all cancers. There are over 40 different subtypes of lymphoma. Those considered indolent are generally slowly progressive, and most are deemed incurable yet confer median survivals of approximately 10 years. Aggressive lymphomas, by contrast, have a short natural history, often with survival of weeks to months if left untreated. The majority of aggressive lymphomas, including diffuse large B-cell non-Hodgkin lymphoma and Hodgkin lymphoma, are cured with upfront combination chemotherapy, however up to 30% eventually die from disease. The aim of the research projects presented here has been to contribute to the developments and improvements in management of aggressive lymphomas with a focus on diffuse large B cell lymphoma and Hodgkin lymphoma. The topics covered within this thesis explore several strategies for improving outcomes in aggressive lymphomas including dose intensification of firstline combination chemotherapy in diffuse large B-cell lymphoma, incorporating novel targeted therapies into standard treatment regimens, comparing outcomes from firstline chemotherapy in clinical trial Hodgkin lymphoma patients to those treated in routine standard practice, evaluating novel chemotherapy regimens in relapsed lymphoma as well as biomarker-driven identification of high risk groups and adequate follow up of aggressive lymphomas. The findings of the research in the thesis have confirmed the quality of local standards of care in Australia, contributed to global changes in management in aggressive lymphomas and provided a platform for further investigation in improving outcomes from aggressive lymphomas.
-
ItemOptimising the management of patients awaiting liver transplantation( 2016)Liver transplantation is a life-saving therapy for selected patients with end-stage liver disease, hepatocellular carcinoma, acute liver failure and metabolic diseases. However, the successful application of liver transplantation is limited by the imbalance between the demand for and the supply of deceased donor organs. Therefore, processes that optimise the prioritisation of and allocation to patients awaiting liver transplantation are essential. Prediction of the mortality risk of patients waiting for liver transplantation is critical to determine priorities for allocation. A cohort of Australian patients listed for liver transplantation was analysed and medical status, Child-Turcotte-Pugh (CTP) class and model for end-stage liver disease (MELD) were found to be independent predictors of waiting list mortality. Knowledge of the likely future course of patients at the time of listing for liver transplantation, including the period on the waiting list and after delisting for whatever reason, would inform decisions and discussion with patients regarding the survival benefit of listing for liver transplantation. A scoring system, based on variables that are objective, simple to collect and available at the time of listing, was developed. It had predictive ability superior to CTP and MELD scores. Prioritisation of patients on liver transplantation waiting lists and allocation of deceased donor livers has been based on clinical judgement in Australia and New Zealand. MELD score, an objective measure of the degree of liver failure and mortality risk, is a common allocation tool. These methods of prediction of waiting list mortality were examined in a cohort of patients waiting for liver transplantation. MELD score was more likely than clinical judgement to prioritise for allocation patients who subsequently died waiting for a donor liver. An allocation system based on MELD rather than clinical judgement would significantly alter organ allocation in Australia and may reduce waiting list mortality. Most systems of organ allocation for liver transplantation focus on the risk of dying on the waiting list. However, post-transplantation outcomes, which reflect the utility of transplantation, are also important. Allocation by survival benefit aims to allocate to the patient who, with a given organ donor, has the greatest increase in life-years gained by transplantation over remaining on the waiting list. Validation of models of waiting list, donor and recipient risk, that are used to calculate survival benefit, was performed and demonstrated that these generally performed well in a patient population independent of that in which the models were derived. A detailed analysis of allocation in Australia and New Zealand has not been performed previously. Prioritisation is undertaken using clinical judgement informed by MELD score. Allocation decisions take into account acuity and donor quality. Transplant patients overall, recipients of standard criteria and extended criteria grafts and of split or reduced left lobes had a higher acuity than those who remained on the waiting list, but patients selected to receive split right lobes had similar acuity to those who remained on the waiting list. Patients with high MELD scores have a high risk of dying on the waiting list and only have a short window of opportunity for liver transplantation. Inter-regional sharing of livers across Australia and New Zealand for high MELD patients might increase the opportunity to rescue them. A simulation of several models of inter-regional sharing demonstrated that the rules of allocation, such as the MELD threshold above which inter-regional allocation would occur, had important effects on the number of patients potentially rescued and the cost in terms of the number of livers that would be shipped and the increase in shipping distance and cold ischaemia time. This information will inform decision making regarding the implementation of inter-regional sharing for high MELD patients.
-
ItemNovel antibodies for treatment of solid tumours( 2015)This thesis describes three different strategies aimed to optimize the use of novel targeted antibodies for the treatment of metastatic solid tumours, including colorectal cancer and renal cell carcinoma. The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this first study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an anti-GPA33 IgG1-humanised antibody, huA33, in colorectal tumours. Twelve patients were infused with radiolabelled huA33 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in GPA33 tumour antigen expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined. The mean ± SD [131]I-huA33 uptake in whole tumour sections was 5.13±2.71×10(−3) % injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n=5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17×10(−3) %ID, p=0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10×10(−9) vs 3.82 ± 3.67×10(−9) %ID/cell, p=0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between [131]I-huA33 uptake in tumour on a cellular basis and tumour vascularity. In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targeted viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding. For the second strategy, a Phase I imaging and pharmacodynamic study of anti-death receptor 5 (DR5) antibody CS-1008 investigated the impact of CS-1008 dose on the biodistribution, quantitative tumour uptake and anti-tumour response in patients with metastatic colorectal cancer. Pretreated patients with metastatic colorectal cancer were infused with weekly CS-1008 in five dose cohorts. Day 1 and day 36 doses were trace-labeled with Indium-111 ([111]In), followed by whole-body planar and regional SPECT imaging at several time points over 10 days. Nineteen patients were enrolled. [111]In-CS-1008 uptake in tumour was observed in only 12 patients (63%). [111]In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. [111]In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody response was detected. One patient achieved partial response (PR, 3.7 months duration), 8 patients had stable disease (SD), and 10 patients had progressive disease (PD). Disease control rate (SD + PR) in patients with [111]In-CS-1008 uptake in tumour was 58% vs 28% of patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were 1/3 as likely to progress compared to those without antibody uptake (p=0.07). DR5 expression in archived samples did not correlate with [111]In-CS-1008 uptake (p=0.5) or tumour response (p=0.6). In conclusion, DR5 imaging with [111]In-CS-1008 revealed significant inter- and intra-patient heterogeneity of uptake in tumour, is not dose dependent, and is predictive of clinical benefit in the treatment of metastatic colorectal cancer patients. The third strategy examined the safety and tolerability of the combination of cG250 and sunitinib in patients with advanced clear cell renal cell carcinoma. cG250 is an IgG1 kappa chimeric antibody that recognises carbonic anhydrase IX, an antigen present on more than 85% of renal cell carcinoma, but with limited expression in normal tissues. If binding of cG250 to its antigen interrupts signalling, this may lead to synergistic effects with sunitinib. We hypothesized that combination of cG250 and sunitinib would induce beneficial clinical effects by targeting complementary signalling pathways and that sunitinib’s acute effects on tumour vasculature would influence cG250 biodistribution, tumour metabolism and tumour blood flow. Up to 2 cycles of treatment were given to eligible patients who had measurable metastatic or unresectable clear cell renal cell carcinoma with at least one lesion >2 cm assessable by FDG-PET. cG250 was administered at 10 mg/m2/week for 5 weeks (1st and 5th doses tracelabeled with [124]I). Sunitinib was commenced on day 8 of the 1st cycle at 50 mg/day for 4 weeks for sunitinib-naive participants or continued at the same dose for those already receiving sunitinib. Six patients were enrolled and evaluable for toxicity, biodistribution, pharmacokinetics and tumour uptake; 4 patients were evaluable for tumour response. The study was terminated early because dose limiting toxicities (DLTs) occurred in 2 patients: Grade (G) 3 fatigue and G5 cardiogenic shock. These events were considered possibly related to sunitinib. No other G3/4 adverse events (AEs) were reported. No AEs were attributable to cG250. Three patients had SD on CT and stable metabolic disease on FDG-PET, 1 patient had PR on CT and complete metabolic response on FDG-PET. There was a significant decrease in tumour blood flow ranging from 38.5% to 73.2%.[124]I-cG250 showed excellent tumour targeting on PET. No patients developed HACA responses. No differences in biodistribution, tumour uptake or pharmacokinetics were observed between the first and fifth infusion. As expected, the antiangiogenic activity of sunitinib resulted in a significant decrease in quantitative tumour blood flow which was clearly seen as soon as two weeks after its initiation. Despite sunitinib’s acute effects on tumour vasculature, [124]I-cG250 uptake was not affected by tyrosine kinase inhibitor (TKI) treatment in clear cell renal cell carcinoma lesions. These findings may ultimately have implications for the design of studies combining both TKIs and antibody-based treatments.