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.

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.

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.

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.

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.

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.

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.

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.

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.

Physical activity for children undergoing acute cancer treatment: A qualitative study of parental perspectives.

BACKGROUND: Little is known about how to facilitate participation in physical activity among children receiving acute cancer treatment. OBJECTIVE: To understand the parental perspectives on physical activity for children during acute cancer treatment and explore strategies to overcome physical inactivity. METHODS: A qualitative study was completed. Data were collected via semistructured interviews with parents of children (aged 4-18 years) who were in their first nine months of cancer treatment. Data were analyzed thematically. RESULTS: Twenty parents were interviewed. A childhood cancer diagnosis and subsequent treatment were described as setting in motion a spiral of physical inactivity. Parents identified movement restrictions as a result of commencing treatment and the hospital environment as factors initiating this decline. Parents described the subsequent impact of movement restrictions on their child over time including loss of independence, isolation, and low motivation. These three consequences further contributed to an inability and unwillingness to be physically active. Parents responded in a variety of ways to their child's inactivity, and many were motivated to overcome the barriers to physical activity yet exhibited a reduced capacity to do so. Suggested intervention strategies highlighted the need for comprehensive support from the organization providing treatment. CONCLUSIONS: Reasons for reduced physical activity in children receiving acute treatment for cancer are complex and multifactorial. Inactivity cannot be addressed by children and parents alone but requires support from the oncology team through changes to the environment, services, and policies to promote physical activity. These findings may be used to inform targeted, effective, and feasible physical activity interventions.

Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance.

INTRODUCTION: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. MAIN RECOMMENDATIONS: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. ENDORSED BY: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.

Do Australian adolescents' and young adults' experiences of cancer care influence their quality of life?

OBJECTIVE: To examine the relationship between the cancer care experiences of adolescents and young adults (AYAs) and their quality of life. METHODS: Two hundred and nine AYAs completed a cross-sectional, self-report survey distributed through the population-based cancer registries in 2 Australian states (New South Wales and Victoria). Eligible AYAs were 15 to 24 years old when diagnosed with any cancer (excluding early-stage melanoma) and were 3 to 24 months post-diagnosis. Questions examined whether particular care experiences occurred for the patient at different points in the cancer care pathway, including diagnosis, treatment, inpatient care, and at the end of treatment. Quality of life was assessed using the Functional Assessment of Cancer Therapy-General scale. RESULTS: Positive experiences of care at diagnosis, during treatment, during inpatient stays, and when finishing treatment were associated with higher functional, emotional, and social well-being. However, these associations generally became nonsignificant when communication and support experiences were included in the model. Inpatient experiences positively influenced emotional well-being over and above the effect of communication and support experiences. CONCLUSIONS: The results suggest that, for most AYAs' quality of life outcomes, positive experiences of age-appropriate communication and emotional support may underpin the effect of positive experiences of care throughout the cancer care pathway. The results support the need for communication and support tailored to an AYA audience, as recognised by recent Australian and international guidelines on the care of AYAs with cancer.

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients.

Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

Factors influencing the provision of fertility counseling and impact on quality of life in adolescents and young adults with cancer.

PURPOSE: This study investigated the impact of fertility-related discussions on Adolescent and Young Adult (AYA) cancer patients' quality of life (QoL) and the factors influencing provision of these discussions. METHODS: Recruitment was conducted through population-based state cancer registries. Eligible AYAs were 15-24 years at diagnosis, 3-24 months postdiagnosis, with any cancer (except early stage melanoma). As part of a larger survey, AYAs were asked about their experiences of fertility-related discussions and QoL (FACT-G). RESULTS: Of the 207 AYAs returning surveys (29% response rate) 88% reported a discussion about infertility risks, 75% reported a discussion about preservation options and 59% were offered a referral to a fertility specialist. Patients attending health services with an AYA focus were more likely than those attending other types of centers to report discussions of fertility preservation (FP) options (85% versus 67%) and referrals (75% versus 49%). Social well-being was positively related to discussions about preservation options and being provided fertility risk information in a sensitive, supportive manner. CONCLUSIONS: Providing a sensitive and proactive discussion about fertility-related risks may benefit AYAs' well-being. Services with an AYA focus are fulfilling their mandate of ensuring optimal fertility-related care for AYA cancer patients.

Chemotherapy-related cardiotoxicity: are Australian practitioners missing the point?

BACKGROUND: It has long been established that cardiotoxicity occurs as a result of exposure to certain chemotherapeutics, particularly anthracyclines. Historically, clinicians equate cardiotoxicity with a poor prognosis, in a small percentage of patients and deem long-term surveillance as optional. Emerging evidence suggests that anthracycline cardiotoxicity (ACT) is a life-long risk with an incidence approaching 20%. AIMS: To elucidate the incidence of anthracycline cardiotoxicity within a current paediatric oncology survivor cohort. METHODS: Participants were identified through the Haematology-Oncology database at the Royal Children's Hospital, Melbourne. Patients were identified from a retrospective audit of outpatient attendances between January 2008 and December 2015. Patients with a cancer diagnosis exposed to anthracyclines were eligible for the study. Patient demographics and echocardiogram findings were recorded with patients subcategorised according to degree of ACT. More significant ACT defined as fractional shortening (FS) <24% and less significant if FS 24-28% or a decline in baseline ejection fraction of >10%. RESULTS: Two hundred and eighty-six of a total 481 identified patients were eligible for study inclusion. Twenty patients displayed significant ACT with FS <24%. Ten patients had a FS 24-28% and 25 patients with a decline in ejection fraction from baseline of >10%. Overall, 6.6% demonstrated significant cardiac complications, whilst 19.6 % demonstrated some degree of ACT and decline in myocardial function. When stratified for cumulative anthracycline dose, the incidence of severe cardiac dysfunction was 5.1% (<250 mg/m2 ) and 25% (>250 mg/m2 ) CONCLUSION: This study demonstrates, in keeping with modern literature, the higher incidence of anthracycline associated cardiac toxicity and a need for better surveillance and follow up.

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.

Pharmacogenomic studies of fertility outcomes in pediatric cancer survivors - A systematic review.

For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.

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.