Real-world data for cancer medicines research in Australia: Bridging the evidence gap

Robust evidence is needed to support the development, registration, subsidy and use of cancer therapies. Randomised controlled trials form a cornerstone of cancer medicines research by generating evidence about the efficacy of therapies in selected patient populations. However, their implementation is resource- and cost-intensive, and they often have limited generalisability to patients treated in routine care. Real-world evidence leverages data collected about patients receiving routine care, outside of clinical trial settings. This thesis comprises four studies that use Australian real-world data to explore the potential of real-world evidence to address evidence gaps that are not met by conventional clinical trials, using lung and breast cancer as illustrative examples. These evidence gaps relate to differences in patients, management and outcomes between clinical trials and real-world practice. First, using linked health administrative data for clients of the Australian Department of Veterans’ Affairs, we determined that most adults aged ≥65 years with advanced lung cancer would not be suitable for clinical trial participation and nearly 90% did not receive systemic cancer treatment. This demonstrates the limited generalisability of clinical trial evidence and resultant evidence gap for older adults with lung cancer. Second, we assessed how real-world patients compare with participants in immunotherapy trials, using data from a prospective, multicentre database of lung cancer patients. Only 30% of real-world lung cancer patients would be eligible for landmark immunotherapy trials, and this would be almost doubled by broadening clinical trial eligibility criteria. Third, we used national, population-wide medicines dispensing data to study real-world trastuzumab use and outcomes among patients with HER2-positive early breast cancer. Although only two-thirds of patients completed the recommended 12-month course of treatment, survival outcomes were similar to those reported in clinical trials. Finally, we studied cardiac monitoring practices among patients receiving trastuzumab for HER2-positive early breast cancer in a nation-wide cohort. Adherence to guidelines varied by year and geography, suggesting areas for improvements in cancer care at a population level. This thesis illustrates the ways in which observational research using Australian real-world data provides opportunities to complement and enhance cancer research centred on clinical trials. Maximising the potential of real-world evidence research is key to developing a robust evidence base for optimising cancer medicines use and outcomes in Australia

The effects of asymmetric vs. symmetric probability of targets following probe and irrelevant stimuli in the complex trial protocol for detection of concealed information with P300

The complex trial protocol (CTP, [J.P. Rosenfeld, E. Labkovsky, M. Winograd, M.A. Lui, C. Vandenboom & E. Chedid (2008), The complex trial protocol (CTP): a new, countermeasure-resistant, accurate P300-based method for detection of concealed information. Psychophysiology, 45, 906–919.]) is a sensitive, new, countermeasure-resistant, P300-based concealed information protocol in which a first stimulus (Probe or Irrelevant) is followed after about 1.4–1.8 s by a Target or Non-Target second stimulus within one trial. It has been previously run with a potentially confounding asymmetric conditional probability of Targets following Probes vs. Irrelevants. This present study compared asymmetric vs. symmetric conditional probability groups and found no significant differences in detection rates or Probe-minus-Irrelevant P300 differences between groups. Group differences were seen in error rates and reaction times (RT) to second stimuli. These differences were, however, not diagnostic for deception vs. truth-telling, and were attributable to response perseveration

Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

<p>Abstract</p> <p>Background</p> <p>We previously found that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of multiple sclerosis (MS) (Carlson et al. J.Neuroimmunology 2006, 149:40). This suggests that COX-2 may contribute to death of oligodendrocytes.</p> <p>Objective</p> <p>The goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.</p> <p>Methods</p> <p>The potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes <it>in vitro</it>. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death.</p> <p>Results</p> <p>COX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death <it>in vitro</it>. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA). Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a significant decrease in sensitivity to KA induced death.</p> <p>Conclusions</p> <p>COX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.</p

A Toll-Like Receptor 7, 8, and 9 Antagonist Inhibits Th1 and Th17 Responses and Inflammasome Activation in a Model of IL-23-Induced Psoriasis

Psoriasis is a chronic inflammatory skin disease that involves the induction of T-helper 1 (Th1) and T-helper 17 (Th17) cell responses and the aberrant expression of proinflammatory cytokines, including IL-1β. Copious evidence suggests that abnormal activation of Toll-like receptors (TLRs) contributes to the initiation and maintenance of psoriasis. We have evaluated an antagonist of TLR7, 8, and 9 as a therapeutic agent in an IL-23-induced psoriasis model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the ear or dorsum. IL-23-induced increase in ear thickness was inhibited in a dose-dependent manner by treatment with antagonist. Histological examination of ear and dorsal skin tissues demonstrated a reduction in epidermal hyperplasia in mice treated with the antagonist. Treatment with antagonist also reduced the induction of Th1 and Th17 cytokines in skin and/or serum, as well as dermal expression of inflammasome components, NLRP3 and AIM2, and antimicrobial peptides. These results indicate that targeting TLR7, 8, and 9 may provide a way to neutralize multiple inflammatory pathways that are involved in the development of psoriasis. The antagonist has the potential for the treatment of psoriasis and other autoimmune diseases

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF ( Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P \u3e .05. Conclusions and Relevance: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. Trial Registration: clinicaltrials.gov Identifier: NCT02188784

Associations between attitudes towards and reported intakes of sugars, low/no-calorie sweeteners, and sweet-tasting foods in a UK sample.

Public health initiatives are currently aiming to lower free sugar intakes for health benefits, but attitudes towards sugars, their alternatives such as low/no-calorie sweeteners (LNCS), and towards sweet-tasting foods may be hampering efforts. This work investigated associations between attitudes towards and the reported intakes of sugars, LNCS and sweet-tasting foods, and identified latent attitude profiles in subpopulations of adults in the United Kingdom. A total of 581 adults completed a questionnaire assessing their usual intake of sugars, LNCS and sweet-tasting foods, attitudes towards these foods and various demographic characteristics. Six principal components explained 39.1% of the variance in the attitude responses, named: 'Personal Impact', 'Personal Management', 'Apathy', 'Negativity', 'Perceived Understanding' and 'Perceived Nonautonomy'. Personal Impact was negatively associated with reported consumption of sugar-food and sweet-tasting food groups more frequently (smallest β = -0.24, p < .01). Personal Management was positively associated with reporting adding sugar and consuming sugar-food and sweet-tasting food groups more frequently (smallest β = 0.14, p < .01). Three latent classes of participants with distinct patterns of attitudes were identified, labelled: 'Feeling Ill-equipped' (n = 52), 'Actively Engaged' (n = 162) or 'Unopinionated' (n = 367). Individuals who were classed as Actively Engaged reported adding LNCS more frequently than those classed as Feeling Ill-equipped (t(212) = -2.14, p<.01), who reported consuming sweet-tasting food groups more frequently than those classed as Unopinionated (t(417) = 2.65, p < .01). These findings suggest the need for personalised approaches within public health initiatives, to reduce free sugar intakes

Mitosis in circulating tumor cells stratifies highly aggressive breast carcinomas.

BACKGROUND: Enumeration of circulating tumor cells (CTCs) isolated from the peripheral blood of breast cancer patients holds promise as a clinically relevant, minimally invasive diagnostic test. However, CTC utility has been limited as a prognostic indicator of survival by the inability to stratify patients beyond general enumeration. In comparison, histological biopsy examinations remain the standard method for confirming malignancy and grading malignant cells, allowing for cancer identification and then assessing patient cohorts for prognostic and predictive value. Typically, CTC identification relies on immunofluorescent staining assessed as absent/present, which is somewhat subjective and limited in its ability to characterize these cells. In contrast, the physical features used in histological cytology comprise the gold standard method used to identify and preliminarily characterize the cancer cells. Here, we superimpose the methods, cytologically subtyping CTCs labeled with immunohistochemical fluorescence stains to improve their prognostic value in relation to survival. METHODS: In this single-blind prospective pilot study, we tracked 36 patients with late-stage breast cancer over 24 months to compare overall survival between simple CTC enumeration and subtyping mitotic CTCs. A power analysis (1-β = 0. 9, α = 0.05) determined that a pilot size of 30 patients was sufficient to stratify this patient cohort; 36 in total were enrolled. RESULTS: Our results confirmed that CTC number is a prognostic indicator of patient survival, with a hazard ratio 5.2, p = 0.005 (95 % CI 1.6-16.5). However, by simply subtyping the same population based on CTCs in cytological mitosis, the hazard ratio increased dramatically to 11.1, p \u3c 0.001 (95 % CI 3.1-39.7). CONCLUSIONS: Our data suggest that (1) mitotic CTCs are relativity common in aggressive late-stage breast cancer, (2) mitotic CTCs may significantly correlate with shortened overall survival, and (3) larger and more defined patient cohort studies are clearly called for based on this initial pilot study