Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse. METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission. TRIAL REGISTRATION NUMBER: NCT05667766.

Melatonin does not reduce delirium severity in hospitalized older adults: Results of a randomized placebo-controlled trial.

BACKGROUND: Delirium is common in older inpatients, causing distress, cognitive decline, and death. Current therapies are unsatisfactory, limited by lack of efficacy and adverse effects. There is an urgent need for effective delirium treatment. Sleep wake cycle is disturbed in delirium; endogenous Melatonin is perturbed, and exogenous Melatonin is a safe and effective medication for sleep disorders. This study aims to determine the effect of oral Melatonin 5 mg immediate release (IR) nightly for five nights on the severity of delirium in older (≥65 years) medical inpatients. METHODS: This was a double-blinded, randomized controlled trial in general internal medicine units of a tertiary teaching hospital. Older inpatients with Confusion Assessment Method positive, hyperactive or mixed delirium within 48 h of admission or onset of in-hospital delirium were included. The primary outcome was change in delirium severity measured with the Memorial Delirium Assessment Scale (MDAS). A previous pilot trial showed 120 participants randomized 1:1 to Melatonin or Placebo would provide 90% power to demonstrate a 3-point reduction in the MDAS. RESULTS: One hundred and twenty participants were randomized, 61 to Melatonin 5 mg and 59 to Placebo. The medication was well tolerated. The mean MDAS improvement was 4.9 (SD 7.6) in the Melatonin group and 5.4 (SD 7.2) in the Placebo group, p-value 0.42, a non-significant difference. A post-hoc analysis showed length of stay (LOS) was shorter in the intervention group (median 9 days [Interquartile Range (IQR) 4, 12] vs. Placebo group 10 [IQR 6, 16] p-value = 0.033, Wilcoxon Rank Sum test). CONCLUSIONS: This trial does not support the hypothesis that Melatonin reduces the severity of delirium. This may be due to no effect of Melatonin, a smaller effect than anticipated, an effect not captured on a multidimensional delirium assessment scale, or a type II statistical error. Melatonin may improve LOS; this hypothesis should be studied.

Integrating Cardio-Oncology Across the Research Pipeline, Policy, and Practice in Australia-An Australian Cardiovascular Alliance Perspective.

Over 18 million people worldwide were diagnosed with cancer in 2020, including over 150,000 people in Australia. Although improved early detection and treatment have increased the survival rates, cardiotoxic treatment and inadequate management of cardiovascular risk factors have resulted in cardiovascular disease (CVD) being one of the leading causes of non-cancer-related death and disability among cancer survivors. International guidelines outline the standards of care for CVD risk surveillance and management. However, Australian cardio-oncology policies and clinical guidelines are limited. There is increasing growth of cardio-oncology research in Australia and support from leading Australian professional bodies and advocacy and research networks, including the Cardiac Society of Australia and New Zealand, the Clinical Oncology Society of Australia, the National Heart Foundation of Australia, and the Australian Cardiovascular Alliance (ACvA). Thus, opportunities to drive multidisciplinary cardio-oncology initiatives are growing, including grant funding, position statements, and novel research to inform new policies. The ACvA has a unique flagship structure that spans the translational research pipeline from drug discovery to implementation science. This article aims to highlight how multidisciplinary cardio-oncology innovations could intersect with the seven ACvA flagships, and to showcase Australian achievements in cardio-oncology thus far. We summarise eight key priority areas for future cardio-oncology research that emerged. These strategies will strengthen cardio-oncology research and care in Australia, and drive new guidelines, policies, and government initiatives to ensure equity in health outcomes for all cardio-oncology patients.

Promoting positive physical activity behaviours in children undergoing acute cancer treatment: feasibility of the CanMOVE intervention.

BACKGROUND: Supporting children and adolescents with cancer to be physically active can improve medium- and long-term health outcomes. OBJECTIVE: To assess the feasibility of CanMOVE, a 10-week complex, theoretically-informed, behaviour change intervention to promote physical activity for children and adolescents undergoing acute cancer treatment. METHODS: A feasibility study using a single-group, repeated measures, mixed methods design. Participants completed CanMOVE, which included provision of a Fitbit (child/adolescent and carer) and structured support from a physical therapist. Feasibility domains of demand, acceptability, implementation, practicality, limited efficacy, and integration were evaluated. Data sources included service level data, objective assessment of physical activity, physical function, and health-related quality of life; and qualitative data collected via semi-structured interviews with participants and focus groups with staff. RESULTS: Twenty children/adolescents (median age 13yrs, interquartile-range 9-14) with a mix of cancer diagnoses, 20 parents, and 16 clinicians participated. There was high demand with 95% enrolment rate. CanMOVE was acceptable for participants. All feasibility thresholds set for implementation were met. Under practicality, there were no serious adverse events related to the intervention. Limited efficacy data indicated CanMOVE showed positive estimates of effect in influencing child/adolescent physical activity behaviour, physical function, and health-related quality of life. Positive impacts were also seen in parent and staff attitudes towards physical activity promotion. To improve integration into the clinical setting, it was suggested the duration and scope of CanMOVE could be expanded. CONCLUSION: CanMOVE was feasible to implement in a paediatric cancer setting. CanMOVE is appropriate to be tested in a large-scale trial.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia.

BACKGROUND: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is transforming care for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). There are limited pediatric-specific data concerning the infection risks associated with CD19 CAR-T therapy and the adequacy of current antimicrobial prophylaxis guidelines for these patients. METHODS: We describe the antimicrobial prophylaxis used and the types of infectious occurring in the first 100 days following CAR-T therapy for relapsed or refractory B-cell ALL in children and adolescents (≤18 years) at our centre. RESULTS: Twenty-seven patients received their first CAR-T infusion (CTI) during the study period. Almost all patients (96%) had a comprehensive Infectious Diseases review prior to CTI, which informed a personalised prophylaxis or fever/sepsis plan in six (22%). Overall, six (22%) patients had one or more infections during the study period including five (19%, 0.9 per 100 days-at-risk) from days 0-30 and three (n = 20, 15%, 0.6 per 100 days-at-risk) from days 31-100. Bacterial blood stream infections were the most common type of infection encountered during both time periods, and one patient had probable pulmonary aspergillosis. There were no infection-related deaths. CONCLUSION: Our study contributes important information on the spectrum of infections encountered in pediatric patients with B-ALL post CAR-T therapy. Overall, the burden of infectious complications post CAR-T therapy in our cohort is lower than previously reported in the literature. Results suggest that our prophylaxis recommendations are effective in this population.

A systematic review of knowledge, attitude and practice of pharmacogenomics in pediatric oncology patients.

Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.

Physician-defined severe toxicities occurring during and after cancer treatment: Modified consensus definitions and clinical applicability in the evaluation of cancer treatment.

Overall survival after cancer is increasing for the majority of cancer types, but survivors can be burdened lifelong by treatment-related severe toxicities. Integration of long-term toxicities in treatment evaluation is not least important for children and young adults with cancers with high survival probability. We present modified consensus definitions of 21 previously published physician-defined Severe Toxicities (STs), each reflecting the most serious long-term treatment-related toxicities and representing an unacceptable price for cure. Applying the Severe Toxicity (ST) concept to real-world data required careful adjustments of the original consensus definitions, translating them into standardized endpoints for evaluating treatment-related outcomes to ensure that (1) the STs can be classified uniformly and prospectively across different cohorts, and (2) the ST definitions allow for valid statistical analyses. The current paper presents the resulting modified consensus definitions of the 21 STs proposed to be included in outcome reporting of cancer treatment.

Density of antibiotic use and infectious complications in pediatric allogeneic hematopoietic cell transplantation.

BACKGROUND: Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo-HCT), can have adverse effects and select for antibiotic resistance. Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions. METHODS: Retrospective, single-center cohort of children undergoing first allo-HCT (n = 125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo-HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections. RESULTS: At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range [IQR] 20-30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1-7 days). Piperacillin-tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%). CONCLUSION: Pediatric HCT patients receive prolonged courses of broad-spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.

Australia and New Zealand Transplant and Cellular Therapies (ANZTCT) position statement: COVID-19 management in patients with haemopoietic stem cell transplant and chimeric antigen receptor T cell.

Patients with post-haemopoietic stem cell transplant or chimeric antigen receptor T -cell (CAR-T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally.

Promoting positive physical activity behaviors for children and adolescents undergoing acute cancer treatment: Development of the CanMOVE intervention using the Behavior Change Wheel.

Background: Increasing participation in physical activity has the potential to improve outcomes for children and adolescents with cancer during treatment and into survivorship. The aim of this study is to outline the theoretical process behind development of CanMOVE, a behavior change intervention designed to increase physical activity for children and adolescents with cancer. Study design: This study followed a theoretical design process consistent with the Behavior Change Wheel to inform the design of a complex intervention. Materials and methods: The three stages of the Behavior Change Wheel intervention design process include: (1) understanding physical activity behavior within the pediatric cancer setting, (2) identifying potential intervention functions, and (3) identifying appropriate behavior change and implementation strategies. Qualitative and behavior change literature relevant to the pediatric cancer treatment setting were used to inform each stage. Results: An individualized and flexible approach to physical activity promotion that considers intrinsic factors specific to the child/adolescent and their environment is required. Fifteen behavioral change strategies were identified to form the intervention components of CanMOVE. Implementation strategies were identified to build motivation, opportunity and capacity toward increasing physical activity behaviors. Key intervention components of CanMOVE include standardized assessment and monitoring (physical activity, physical function, and health-related quality of life), provision of an activity monitor to both child/adolescent and parent, and one-on-one capacity building sessions with a healthcare professional. Capacity building sessions include education, goal setting, an active supervised physical activity session, barrier identification and problem solving, and action planning. Conclusion: CanMOVE is a novel approach to physical activity promotion in the pediatric cancer treatment setting. The use of a theoretical intervention design process will aid evaluation and replication of CanMOVE when it is assessed for feasibility in a clinical setting. The design process utilized here can be used as a guide for future intervention development.

Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia.

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. METHODS: Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. RESULTS: Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. CONCLUSIONS: It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.

Non-neutropenic fever in children with cancer: Management, outcomes and clinical decision rule validation.

INTRODUCTION: Fever and infection are an important complication of childhood cancer therapy. Most research and guideline development has focussed on febrile neutropenia, with a paucity directed at non-neutropenic fever (NNF). We describe the clinical presentation, management and outcomes of NNF in children with cancer, and externally validate the Esbenshade Vanderbilt (EsVan) clinical decision rules (CDR) to predict bacteraemia. METHOD: Using a prospective database, retrospective data were collected on consecutive NNF episodes (fever ≥38.0°C and absolute neutrophil count >1.0 cells/mm3 ). Sensitivity, specificity and area under the receiver operator characteristic curve (AUC-ROC) of the CDR were compared to derivation study. RESULTS: There were 203 NNF episodes occurring in 125 patients. Severe sepsis was uncommon (n = 2, 1%) and bacteraemia occurred in 10 (4.9%, 95% confidence interval [CI]: 2.7%-8.8%) episodes. A confirmed or presumed bacterial infection requiring antibiotics occurred in 31 (15%) patients. Total 202 (99%) episodes received at least one dose of intravenous broad-spectrum antibiotic and 141 (70%) episodes were admitted to hospital. Six (3%) episodes required intensive care unit (ICU)-level care and there were no infection-related deaths. The EsVan 1 rule had an AUC-ROC of 0.67, 80% were identified as low risk, and sensitivity and specificity were 50% and 81.5%, respectively, for a risk threshold of 10%. CONCLUSIONS: Serious infection and adverse outcome are uncommon in children with NNF. Many children did not have a bacterial cause of infection identified, but were still treated with broad-spectrum antibiotics and admitted to hospital. National clinical practice guidelines should be developed for this important cohort to enable risk stratification and optimise antibiotic management. Further research is required to determine appropriateness of EsVan CDR in our cohort.

Clinical Utility of Bronchoalveolar Lavage in Pediatric Oncology Patients.

BACKGROUND: Lower airway sampling is important in the assessment of lower respiratory tract infection in children with cancer or posthematopoietic stem cell transplant and can be done via bronchoalveolar lavage (BAL). Clinicians can struggle with balancing the benefits of BAL against the risks. This study aimed to define the diagnostic and clinical utility of BAL in this population. METHODS: A single-center retrospective review of BAL performed in children with cancer or posthematopoietic stem cell transplant. Data extracted included demographics, BAL method and results and antimicrobial treatment. Variables significantly associated with diagnostic yield, diagnostic impact (confirmation or exclusion of infection), and clinical impact (any change in antimicrobial or nonantimicrobial therapy) were assessed in both univariate and multivariate analysis. RESULTS: Seventy-three BAL episodes were included. In 26 (35.6%) episodes, a pathogen was identified on BAL. Forty-nine (67%) BAL episodes had a diagnostic impact and 15 (21%) had a clinical impact. Late BAL (>72 hours) compared with early BAL (odds ratio 3.27; 95% CI: 1.03-10.86), and flexible bronchoscopy compared with nonbronchoscopic lavage (odds ratio 6.10; 95% CI: 1.90-24.0), were more likely to have a diagnostic impact on multivariate analysis. No associations were found for clinical impact. CONCLUSIONS: One-third of BAL episodes identified a pathogen, two-thirds had a diagnostic impact, and almost a quarter of episodes impacted antimicrobial prescribing. The method and timing of BAL may be important, with flexible bronchoscopy 6-fold more likely and late BAL 3-fold more likely to have a diagnostic impact.

COVID-19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non-malignant haematological conditions: Australian and New Zealand Children's Haematology/Oncology Group consensus statement.

INTRODUCTION: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. RECOMMENDATIONS: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged ≥ 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. ENDORSED BY: The Australian and New Zealand Children's Haematology/Oncology Group.

Australia and New Zealand Transplant and Cellular Therapies COVID-19 vaccination consensus position statement.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives of all adult and paediatric allogeneic bone marrow transplant and cellular therapy (TCT) centres as well as representatives from autologous transplant only centres in Australia and New Zealand collaborated with infectious diseases specialists with expertise in TCT on this consensus position statement regarding COVID-19 vaccination in TCT patients in Australia and New Zealand. It is our recommendation that TCT patients, should have expedited access to high-efficacy COVID-19 vaccines given that these patients are at high risk of morbidity and mortality from COVID-19 infection. We also recommend prioritising vaccination of TCT healthcare workers and household members of TCT patients. Vaccination should not replace other public health measures in TCT patients given the effectiveness of COVID-19 vaccination in TCT patients is unknown. Furthermore, given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.

The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of paediatric cancer patients.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Treatment and Outcomes for Central Nervous System Tumors in Australian Adolescents and Young Adults: A Population-Based National Study.

Purpose: While central nervous system (CNS) tumors account for only 10% of adolescent and young adult (AYA) cancers, they are the leading cause of cancer death in this age group. Using national data for Australia, we describe the presentation, treatment, and survival for AYAs diagnosed with CNS tumors. Methods: A population-based study of 15-24 year-olds diagnosed with CNS tumors (low- and high-grade glioma [LGG, HGG], medulloblastoma [MB], primitive neuroectodermal tumors [PNET], ependymoma [EP]) or other (e.g., low-grade neuronal tumor) between 2007 and 2012. Clinical details were extracted from hospital medical records for each patient. Treatment centers were classified as pediatric or adult services. Results: Two hundred seventy-five patients (129 LGG, 77 HGG, 23 MB, 10 PNET, 19 EP, 17 other) were identified, with 17% treated at pediatric hospitals. Symptoms (headache [53%], nausea [31%]) were present for a median of 3 weeks before consulting a health professional. Of LGG patients, 15% had radiotherapy (RT) and 12% chemotherapy (CT). Of HGG patients, 81% had RT and 75% CT. All MB and PNET were managed with surgery, and 74% of MB and 80% of PNET had both RT and CT. Treatment did not differ by treatment center type. Five-year survival for LGG and EP was over 80%, but was 42% for HGG and 20% for PNET. Conclusions: This national, population-based study indicates similar treatment for AYA patients with CNS tumors between pediatric and adult services. Poor outcomes for HGG and PNET patients highlight the need for clinical trials of novel approaches for these tumors.

Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness.

BACKGROUND: Pediatric cancer survivors are at increased risk of cardiac dysfunction and heart failure. Reduced peak oxygen consumption (peak VO2) is associated with impaired cardiac reserve (defined as the increase in cardiac function from rest to peak exercise) and heart failure risk, but it is unclear whether this relationship exists in pediatric cancer survivors. This study sought to investigate the presence of reduced peak VO2 in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac haemodynamics and systolic function during exercise. METHODS: Twenty pediatric cancer survivors (8-24 years; 10 male) treated with anthracycline chemotherapy ± radiation underwent cardiopulmonary exercise testing to quantify peak VO2, with a value < 85% of predicted defined as impaired peak VO2. Resting cardiac function was assessed using 2- and 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate, stroke volume index (SVI) and cardiac index (CI) using exercise cardiovascular magnetic resonance (CMR). RESULTS: Twelve of 20 survivors (60%) had reduced peak VO2 (70 ± 16% vs. 97 ± 14% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired peak VO2. However, those with reduced peak VO2 had diminished cardiac reserve, with a lesser increase in CI and SVI during exercise (Interaction P < 0.01 for both), whilst the heart rate response was similar (P = 0.71). CONCLUSIONS: Whilst exercise intolerance is common among pediatric cancer survivors, it is poorly explained by resting measures of cardiac function. In contrast, impaired exercise capacity is associated with impaired haemodynamics and systolic functional reserve measured during exercise. Consequently, measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure.