Canberra Hospital

IntroductionRegular physical activity at a moderate-to-vigorous intensity is associated with a lower risk of recurrent cardiovascular events and mortality in individuals with coronary heart disease (CHD). Walking is a common form of physical activity; however, there is no evidence-based recommendation for the optimal step cadence (steps per minute) to achieve these intensity levels among individuals with coronary heart disease. Thus, this study aimed to establish the agreement between manually counted step cadence and step cadence assessed by waist- and wrist-worn accelerometers during treadmill walking among individuals with CHD. Next, the study aimed to establish the association between manually counted and accelerometer-assessed step cadence with cardiorespiratory intensity, followed by the development and validation of cadence thresholds for moderate- and vigorous-intensity levels.MethodsParticipants (n = 87) performed a graded treadmill test. Step cadence was counted manually and by a waist- and wrist-worn accelerometer (Actigraph GT3x). Step cadence and oxygen consumption were measured during the final minute of walking at four speeds (3–6 km·h−1). Agreement between manual and accelerometer cadence was established using Bland–Altman analyses. Step cadence thresholds for relative (%VO₂ peak) and absolute (METs) intensity were derived using generalized estimating equations in a training cohort (70%) and validated in a validation cohort (30%).ResultsAccelerometers underestimated the aggregated cadence compared with manual assessments, with a mean difference of −16 and −31 steps/min for waist- and wrist-worn accelerometers, respectively, with a higher level of agreement at higher speeds. Manually assessed cadence thresholds for moderate intensity were 99 (relative) and 92 (absolute) steps/min compared with 61 and 45 steps/min from waist-worn accelerometers. For vigorous intensity, manual and accelerometer thresholds were similar: 116 vs. 112 (relative) and 126 vs. 135 (absolute) steps/min. Both methods effectively identified valid thresholds for moderate and vigorous cardiorespiratory intensity.ConclusionStep cadence is a valid indicator of intensity in CHD populations, with manual and accelerometer methods showing comparable accuracy, despite accelerometer underestimation at lower speeds.Clinical Trial RegistrationAustralian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000605695 (02062023).

Cytomegalovirus (CMV) causes harm in at-risk populations. Selection of seronegative donors has been used to prevent transmission. Leucodepletion reduces the potential for CMV transmission; however, the residual risk is uncertain, leading to variability in practice. This study systematically reviews the risk of CMV transmission in leucodepleted blood products compared to seronegative blood products. A systematic review identified comparative studies of CMV infection rates following transfusion of leucodepleted blood from CMV-negative or unselected donors. Preclinical studies on blood product CMV transmission, reported cases and studies that informed population risk were also reviewed. Meta-analysis was performed on comparative studies. There was no difference in the rate of infection following transfusion of leucodepleted cellular products with or without donor CMV seronegativity selection, with a relative risk of 1.21 (95% confidence interval [CI]: 0.42-3.49). No confirmed cases of CMV transmission were found. Preclinical studies showed a significant reduction in transmissible virus with leucodepletion, although no threshold could be defined. Cell-free CMV is not removed by filtration, and although it may remain a potential source of infection, there was no evidence of transmission through plasma, possibly due to detectable virus not reflecting intact transmissible virus. Selecting CMV-seronegative donors did not reduce the risk of transmission when transfusing leucodepleted blood products because of the high efficiency of filters in removing transmissible cellular virus. This finding suggests CMV donor negative selection does not substantially contribute to donor safety.

Abstract Background Breast cancer is the most commonly diagnosed cancer globally and remains the leading cause of cancer-related death in women. HER2-positive breast cancer, comprising 15-20% of cases, is defined by overexpression of the HER2 tyrosine kinase receptor. While HER2-targeted therapies have transformed clinical outcomes, resistance, recurrence, and metastasis continue to pose significant challenges. Immunotherapy has revolutionised the treatment of several solid tumors by enhancing anti-tumor immunity; however its efficacy in HER2-positive breast cancer has been limited. There is a pressing need for biomarkers that can both track metastatic burden and identify patients most likely to benefit from immunotherapeutic strategies. In this study, we present novel preclinical data from liquid biopsy analyses and propose a biomarker-driven approach targeting the PI3K-mTOR pathway to enhance immune reinvigoration in HER2-positive metastatic breast cancer. Methods Twenty five stage IV HER2-positive metastatic breast cancer (mBC) patients underwent liquid biopsy profiling using an epigenetic biomarker targeting the PI3K-mTOR signaling pathway. We applied digital pathology, Duolink® proximity ligation assays, global immune profiling, and flow cytometry to characterize biomarker expression and immune landscape features. Ex vivo drug screening with PI3K-mTOR inhibitors, including the brain-penetrant paxalisib, was performed to evaluate their effects on mesenchymal phenotypes, disruption of circulating tumor cell (CTC) clusters, and immune reinvigoration. Results We identified a novel epigenetic switch that drives the transition to a more aggressive, drug-resistant mesenchymal phenotype in HER2-positive breast cancer, associated with activation of the nuclear chromatinised PI3K signaling pathway. This phenotype, detectable via liquid biopsy, correlates with metastatic burden and immune exhaustion. In our pilot cohort, we evaluated the interplay between PI3K mutational burden and activation of this mesenchymal epigenetic program. Functional drug response profiling of patient-derived samples demonstrated that dual PI3K-mTOR inhibition not only facilitated mesenchymal-to-epithelial transition but also suppressed key metastatic signatures, including those linked to the highly aggressive persister cell phenotype (p65, FOXQ1, NRF2, and NNMT) and cancer drug resistance (ABCB5, SNAIL, and ALDH1). Importantly, PI3K-mTOR inhibition disrupted metastatic progenitors, including circulating tumor cell (CTC) clusters, and enhanced anti-tumor immune responses, as evidenced by modulation of both progenitor-like and terminally exhausted T cell populations. Conclusions Our preclinical findings support a biomarker-driven therapeutic strategy targeting the PI3K-mTOR pathway to induce epigenetic reprogramming and immune modulation. This dual mechanism may enhance anti-tumor efficacy by converting immunologically 'cold' tumors into 'hot', more immunogenic tumors. By reshaping the tumor microenvironment, this approach has the potential to improve the clinical utility of immunotherapy and expand treatment options for patients with HER2-positive metastatic breast cancer. Citation Format: M. Melino, W. Tu, S. Goh, A. Bain, J. Friend, T. Prasanna, D. Yip, A. Ives, M. Leahy, D. Lewis, M. Nottage, S. Rao. Liquid Biopsy Tracking of PI3K-mTOR Residual Disease Signatures in Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-10-02.

To compare the anatomical and functional outcomes of internal limiting membrane (ILM) flap and conventional ILM peeling in idiopathic full-thickness macular holes (FTMHs). Retrospective cohort study of all eyes treated with vitrectomy and ILM peeling (ILM-P) with or without ILM flap (ILM-F) for primary idiopathic FTMH repair in the Australian and New Zealand Society of Retinal Specialists (ANZSRS) Registry between 2006 and 2023. Propensity score weighting and multivariable regression analysis adjusted for baseline characteristics and covariates, including surgeon grade, lens status, and follow-up duration, were used to evaluate hole closure rate and best corrected visual acuity (BCVA) change at 3 months. Two thousand nine hundred ninety eyes of 2905 patients were included (mean age 69 ± 9 years). One Hundred Ninety-nine eyes underwent ILM-F and 2871 underwent ILM-P. On weighted multivariable regression analysis, ILM-F showed higher odds of hole closure compared to ILM-P (OR = 2.97, 95% CI: 1.08-8.20, p = 0.04). The adjusted closure rate was > 95% across all hole sizes in the ILM-F group, while only falling below 90% for X-large + holes (> 550 μm) in the ILM-P group. No significant difference in BCVA gain was observed between the two groups at 3 months (p = 0.08). The effects of ILM-F compared to ILM-P were consistent across all hole sizes. Although the ILM-F technique was more effective in idiopathic FTMH closure, visual acuity outcomes were comparable to conventional ILM peeling. These findings suggest that ILM-F is not required for the treatment of small and medium FTMHs.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease estimated to affect approximately 30% of children and 10%-15% of adults in Australia. Of those with this condition, one in five is estimated to have moderate-to-severe disease. Treatment guidelines for patients with moderate-to-severe AD recommend adding or switching to a targeted systemic medication if the disease is not well controlled with topical treatment. Without access to these medications, healthcare providers are limited in their ability to effectively treat moderate-to-severe AD. Availability of these guideline-recommended targeted systemic agents varies across the globe because of differences in both approval and reimbursement decisions. Patients in Australia should have funded or subsidised access to these highly effective, well-tolerated medications for moderate-to-severe AD. To highlight the importance of this, and to better understand potential barriers to such access in Australia, we conducted a narrative review of health technology assessment processes and the availability of funded/subsidised targeted systemic therapies for moderate-to-severe AD in patients aged ≥ 12 years in Australia and in countries with comparable healthcare systems, such as the United Kingdom, Canada, New Zealand and France. To provide context for this, we summarised current international guideline-recommended treatment for moderate-to-severe AD and considered healthcare resource utilisation in moderate-to-severe AD, both in Australia and internationally. In Australia, patients only have access to a limited selection of medicines launched globally. This suggests that national healthcare systems should consider updating health technology assessment procedures to better align with the current targeted high-cost therapeutics environment.

Accurately predicting Emergency Department (ED) visits is essential for optimising resource allocation, including staffing adjustments and Operating Room scheduling. Despite the proliferation of AI-driven models, effective ED visit prediction remains challenging due to limited generalisability, susceptibility to overfitting and underfitting, scalability and the complexity of fine-tuning hyper-parameters. To address these challenges, we propose a novel Meta-Learning Gradient Booster (Meta-ED) approach to forecast daily ED visits. Meta-ED leverages a comprehensive dataset spanning 23 years from Canberra Hospital, incorporating exogenous variables such as socio-demographic characteristics, healthcare usage, chronic diseases, diagnoses and climate parameters. Meta-ED combines four foundational learners—CatBoost, Random Forest, Extra Trees and LightGBM—with a Multi-Layer Perceptron (MLP) as the master-level learner, thereby enhancing predictive precision by integrating the strengths of diverse base models. Our comparative analysis, which involved testing 23 models against a set of predefined criteria, demonstrates the superior performance of Meta-ED, achieving an accuracy of 85.7% (95% CI [85.4%, 86.0%]) and outperforming prominent models like XGBoost, Random Forest, AdaBoost, LightGBM and Extra Trees by up to 106.3%. Furthermore, incorporating climate features resulted in a 3.25% improvement in prediction accuracy, effectively capturing seasonal variations that influence patient volumes. These results underscore the potential of Meta-ED to advance predictive analytics in complex healthcare environments.

TPS250 Background: Fluoropyrimidine (FP) is a common chemotherapy class used across multiple tumor streams, including first line colorectal cancer management. Approximately 30% of patients develop serious toxicities with standard doses, potentially requiring hospitalization, intensive care admission and occasionally death. FP chemotherapy is primarily metabolized by dihydropyrimidine dehydrogenase (DPD, encoded by DPYD ), with DPD deficiency accounting for a significant number of serious toxicities. DPYD genotyping is a valid method of indirect measurement of DPD activity and has been implemented into routine care in some regions, enabling genotype-guided dosing. Despite mounting evidence, uptake of DPYD testing in Australia is currently sporadic and typically self-funded by the patient. This study will be the first to provide nation-wide prospective data on the feasibility and effectiveness of DPYD genotyping to direct FP dosing within the Australian health care system. Methods: This is a prospective, single arm, non-randomized study, aiming to recruit 5000 adult patients across Australia with solid organ malignancies intended to receive FP-based chemotherapy for the first time (trial registered 12/13/2023, Australian and New Zealand Cancer Trials Registry ACTRN12623001301651). DPYD genotyping will be performed for the key variants; c.1905+1G>A, ( DPYD *2A, rs3918290), c.2846A>T (rs67376798), c.1679T>G (DPYD*13, rs55886062.1) and c.1236G>A (rs56038477), with dose adjustments performed in accordance with published Australian guidelines. The primary outcome is incidence of serious (CTCAE v5.0 Grade 3+) FP-associated toxicities in the first 60 days in heterozygote DPYD variant carriers who receive a genotype-guided dose-adjustment, compared to: i) current standard of care (as assessed by a retrospective review of 500 consecutive cases); ii) contemporaneous cases without these variants treated with standard doses; and iii) variant carriers in this study that do not receive genotype-guided dosing. Primary endpoint data is anticipated to be completed by Q4 2027. Secondary outcomes include DPYD variant frequency, health economic and cost effectiveness analysis, and impact of dose adjustment on cancer outcomes. To date, 27 sites have been activated, with over 1200 participants enrolled. Completion of this study will inform a standardised approach for DPYD genotyping to minimise FP complications in Australia. Clinical trial information: ACTRN12623001301651 .

Androgen deprivation therapy (ADT) has been pivotal in advanced prostate cancer (PCa) for decades. The introduction of androgen-receptor pathway inhibitors (ARPIs) has transformed treatment paradigms. However, their real-world adoption over time has not been comprehensively characterised. We examined prescribing trends for androgen-directed therapies in Australia over a 29-year period. A retrospective population-based analysis of Pharmaceutical Benefits Scheme (PBS) dispensing data (1996-2024) was performed. PBS-listed anti-androgen therapies-luteinising hormone-releasing hormone (LHRH) agonists (goserelin, leuprorelin, triptorelin), combined androgen blockage (CAB) (LHRH + bicalutamide), ARPIs (enzalutamide, apalutamide, darolutamide, abiraterone)-were included. Annual prescription counts were standardised per 100,000 men. Outcomes included temporal trends, proportional contribution of each drug class, and the effect of ARPI introduction using interrupted time-series (ITS) analysis. Anti-androgen prescriptions rose from 146 to 228,707 between 1996 and 2024, respectively. LHRH monotherapy accounted for > 94% of prescriptions prior to ARPI approval, declining to 51.61% in 2024 despite continued absolute growth (+ 65.16 prescriptions/100,000/year, p < 0.0001). ARPIs expanded following PBS listing, increasing from 2.44% in 2013 to 47.28% in 2024 (+ 131.9 prescriptions/100,000/year, p < 0.0001). ITS modelling demonstrated a significant immediate level increase of + 9.85 percentage points (p < 0.0001) and sustained a post-intervention slope increase of + 3.04 percentage points per year (p < 0.0001) following ARPI introduction, closely mirroring observed proportional and absolute growth 3.44-47.28% between 2013 and 2024, respectively. Australia has transitioned from predominately LHRH-based therapy to widespread use of ARPIs. Health-system structures enabling timely clinical access appears pivotal to the rapid and equitable diffusion of high-value androgen-targeted therapies.

ABSTRACTDDX3X::MLLT10¸ which arises from t(X;10)(p11.4;p12.31), is infrequently observed in adult acute myeloid leukaemia (AML). The clinical and pathological characteristics are also not well characterised, detailed in only two cases published to date. This third case reports the fusion gene in a 27‐year‐old female with acute myelomonocytic leukaemia (AMML) with refractoriness to multiple lines of chemotherapy. Collectively, these cases highlight the genomic heterogeneity of this rare entity, as well as significant unmet clinical needs due to the poor prognosis and chemoresistance observed. These findings may inform future iterations of AML classification and prognostication in adults.