Psychiatric disorders in childhood cancer survivors: A retrospective matched cohort study of inpatient hospitalisations and community-based mental health services utilisation in Western Australia.

OBJECTIVE: We examined the impact of long-term mental health outcomes on healthcare services utilisation among childhood cancer survivors in Western Australia using linked hospitalisations and community-based mental healthcare records from 1987 to 2019. METHOD: The study cohort included 2977 childhood cancer survivors diagnosed with cancer at age < 18 years in Western Australia from 1982 to 2014 and a matched non-cancer control group of 24,994 individuals. Adjusted hazard ratios of recurrent events were estimated using the Andersen-Gill model. The cumulative burden of events over time was assessed using the method of mean cumulative count. The annual percentage change in events was estimated using the negative binomial regression model. RESULTS: The results showed higher community-based service contacts (rate/100 person-years: 30.2, 95% confidence interval = [29.7-30.7] vs 22.8, 95% confidence interval = [22.6-22.9]) and hospitalisations (rate/1000 person-years: 14.8, 95% confidence interval = [13.6-16.0] vs 12.7, 95% confidence interval = [12.3-13.1]) in childhood cancer survivors compared to the control group. Childhood cancer survivors had a significantly higher risk of any event (adjusted hazard ratio = 1.5, 95% confidence interval = [1.1-2.0]). The cumulative burden of events increased with time since diagnosis and across age groups. The annual percentage change for hospitalisations and service contacts significantly increased over time (p < 0.05). Substance abuse was the leading cause of hospitalisations, while mood/affective and anxiety disorders were common causes of service contacts. Risk factors associated with increased service events included cancer diagnosis at age < 5 years, leukaemia diagnosis, high socioeconomic deprivation, and an attained age of < 18 years. CONCLUSIONS: The elevated utilisation of healthcare services observed among childhood cancer survivors emphasises the need for periodic assessment of psychiatric disorders, particularly in high-risk survivors, to facilitate early management and optimise healthcare resources.

School and educational support programmes for paediatric oncology patients and survivors: A systematic review of evidence and recommendations for future research and practice.

OBJECTIVES: The Psychosocial Standards of Care (PSSC) in paediatric oncology prescribe the minimum standards for education support. It is unknown, however, if published education support programmes for children with cancer meet the PSSC standards for education support. Successful implementation of standards for education support is challenging but may be achieved with guidance. We aimed to (1) review education support programmes for childhood cancer patients and survivors against the PSSC standards and (2) provide practical recommendations for future research and implementation of education support programmes. METHODS: We searched PsycINFO, PubMed, CINAHL, EMBASE, and Educational Resources Information and Center databases. We reviewed the education support programmes using five evaluation criteria derived from the PSSC and summarised the structure of identified programmes. We examined the features and limitations of programmes that met all evaluation criteria. RESULTS: We identified 20 education support programmes in paediatric oncology, including peer programmes (n = 3), teacher programmes (n = 5), and school re-entry programmes (SRPs n = 12). We found that three SRPs met all evaluation criteria and that SRP components were timed according to the child's position on the cancer trajectory (e.g., diagnosis and treatment, school re-entry, and follow up throughout schooling). The supporting evidence of the programmes, however, is unclear due to the lack of adequately designed studies. CONCLUSIONS: SRPs provide a promising structure for future education support programmes. We recommend strategies for developing and evaluating education support that adheres to the PSSC and adapts to international and local contexts.

Late mortality from other diseases following childhood cancer in Australia and the impact of intensity of treatment.

BACKGROUND: People who receive treatment for cancer during childhood often experience subsequent complications of therapy, known as late effects, which can lead to an increased risk of death. PROCEDURE: Using deidentified population-based data from the Australian Childhood Cancer Registry for children aged 0-14 diagnosed with cancer during the period 1983-2011 and who survived for a minimum of 5 years, we examined disease-related deaths (other than cancer recurrence or second primary cancers) that occurred up to 31 December 2016. Risk of death relative to the general population was approximated using standardised mortality ratios (SMRs). Treatment received was stratified according to the intensity of treatment rating, version 3 (ITR-3). RESULTS: During the study period, 82 noncancer disease-related deaths were recorded among 13 432 childhood cancer survivors, four times higher than expected (SMR = 4.43, 95% CI = 3.57-5.50). A clear link to treatment intensity was observed, with the relative risk of noncancer disease-related mortality being twice as high for children who underwent 'most intensive' treatment (SMR = 5.94, 95% CI = 3.69-9.55) compared to the 'least intensive' treatment group (SMR = 2.98, 95% CI = 1.42-6.24; Ptrend  = .01). Thirty-year cumulative mortality from noncancer disease-related deaths was estimated at 1.4% (95% CI = 1.1-1.9) after adjusting for competing causes of death such as cancer, accidents, or injuries. CONCLUSIONS: Although childhood cancer survivors are at increased relative risk of death from noncancer diseases, particularly those who undergo more intensive treatment, the cumulative mortality within 30 years of diagnosis remains small. Knowledge of late effects can guide surveillance of survivors and treatment modification, without wanting to compromise the high rates of survival.

Long-term health-related quality of life in young childhood cancer survivors and their parents.

PURPOSE: Few studies have investigated the health-related quality of life (HRQoL) of young childhood cancer survivors and their parents. This study describes parent and child cancer survivor HRQoL compared to population norms and identifies factors influencing child and parent HRQoL. METHODS: We recruited parents of survivors who were currently <16 years, and >5 years postdiagnosis. Parents reported on their child's HRQoL (Kidscreen-10), and their own HRQoL (EQ-5D-5L). Parents rated their resilience and fear of cancer recurrence and listed their child's cancer-related late effects. RESULTS: One hundred eighty-two parents of survivors (mean age = 12.4 years old and 9.7 years postdiagnosis) participated. Parent-reported child HRQoL was significantly lower than population norms (48.4 vs. 50.7, p < .009). Parents most commonly reported that their child experienced sadness and loneliness (18.1%). Experiencing more late effects and receiving treatments other than surgery were associated with worse child HRQoL. Parents' average HRQoL was high (0.90) and no different to population norms. However 38.5% of parents reported HRQoL that was clinically meaningfully different from perfect health, and parents experienced more problems with anxiety/depression (43.4%) than population norms (24.7%, p < .0001). Worse child HRQoL, lower parent resilience, and higher fear of recurrence was associated with worse parent HRQoL. CONCLUSIONS: Parents report that young survivors experience small but significant ongoing reductions in HRQoL. While overall mean levels of HRQoL were no different to population norms, a subset of parents reported HRQoL that was clinically meaningfully different from perfect health. Managing young survivors' late effects and improving parents' resilience through survivorship may improve HRQoL in long-term survivorship.

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.

Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.

Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors.

BACKGROUND: There is growing impetus for increased genetic screening in childhood cancer survivors. Family history-taking is a critical first step in determining survivors' suitability. However, the family history-taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown. PROCEDURE: Fifty-four providers completed semistructured interviews in total, which included eight tertiary providers representing nine hospitals across two countries (63% male, 63% oncologists, 37% nurses) and 46 primary care providers (PCPs) nominated by a survivor (59% male, 35% regional practice). We used content analysis and descriptive statistics/regression to analyze the data. RESULTS: Few tertiary (38%) or primary (35%) providers regularly collected survivors' family histories, often relying on survivors/parents to initiate discussions. Providers mostly took two-generation pedigrees (63% tertiary and 81% primary). Primary providers focused on adult cancers. Lack of time, alternative priorities, and perceived lack of relevance were common barriers. Half of all tertiary providers felt moderately comfortable discussing genetic cancer risk to children of survivors (88% felt similarly discussing risks to other relatives). Most primary providers lacked confidence: 41% felt confident regarding risks to survivors' children and 48% regarding risks to other relatives. CONCLUSIONS: While family history-taking will not identify all survivors suitable for genetics assessment, recommendations for regular history-taking are not being implemented in tertiary or primary care. Additional PCP-targeted genetic education is warranted given that they are well placed to review family histories of pediatric cancer survivors.

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.

Neuroimaging manifestations of paediatric histiocytoses.

Histiocytoses are rare multi-system disorders marked by abnormal histiocyte cell proliferation, affecting children with diverse clinical presentations. Classified into five groups in 2016, including Langerhans-related (L), cutaneous (C), malignant (M), Rosai-Dorfman disease (R) and haemophagocytic lymphohistiocytosis (H), newer entities such as ALK-positive histiocytosis have also emerged, heralding the era of molecular (sub)classification. Common entities include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD) and haemophagocytic lymphohistiocytosis (HLH). This pictorial essay aids radiologists in recognising and differentiating paediatric histiocytoses based on unique neuroimaging features.

Hospitalizations and Cost of Inpatient Care for Physical Diseases in Survivors of Childhood Cancer in Western Australia: A Longitudinal Matched Cohort Study.

BACKGROUND: The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalization trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982 to 2014. METHODS: Hospitalization records for 2,938 CCS and 24,792 comparisons were extracted from 1987 to 2019 (median follow-up = 12 years, min = 1, max = 32). The adjusted hazard ratio (aHR) of hospitalization with 95% confidence intervals (CI) was estimated using the Andersen-Gill model for recurrent events. The cumulative burden of hospitalizations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalization was estimated using the generalized linear models. RESULTS: We identified a higher risk of hospitalization for all-cause (aHR, 2.0; 95% CI, 1.8-2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR, 15.0; 95% CI, 11.3-19.8) and blood diseases (aHR, 6.9; 95% CI, 2.6-18.2). Characteristics associated with higher hospitalization rates included female gender, diagnosis with bone tumors, cancer diagnosis age between 5 and 9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalization costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, P < 0.05). CONCLUSIONS: The CCS population faces a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. IMPACT: Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on CCS and hospital services.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus.

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects. However, none are specific to pediatrics. We have addressed this gap in the literature by undertaking a rigorous Delphi consensus approach across 11 domains of cardio-oncology care using an Australian and New Zealand expert group. The expert group consisted of pediatric and adult cardiologists and pediatric oncologists. This Delphi consensus provides an approach to perform risk and baseline assessment, screening, and follow-up, specific to the cancer therapeutic. This review is a useful tool for clinicians involved in the cardio-oncology care of pediatric oncology patients.

The lived experience of children and adolescents with cancer.

BACKGROUND: The lived experience of children and adolescents diagnosed with cancer differs greatly from that of the adult cancer patient. A diagnosis of cancer disrupts almost every developmental life stage and continues to affect the child, and potentially their whole family, throughout adulthood. OBJECTIVE: While it is important to recognise the potential for post-traumatic growth, a considerable proportion of children and adolescents will experience poorer psychological, social, educational and quality-of-life outcomes. Parents, particularly mothers, have been shown to experience levels of post-traumatic distress even greater than that of survivors. As such, there exists a critical need to provide family-centred support from diagnosis through to long-term survivorship or bereavement. DISCUSSION: Ongoing surveillance, proactive management of chronic health conditions, and health behaviour education are critical to survivors' lifelong wellbeing and can be facilitated locally by general practitioners with support from tertiary healthcare teams in a shared-care arrangement.

Examining health-related quality of life in pediatric cancer patients with febrile neutropenia: Factors predicting poor recovery in children and their parents.

BACKGROUND: The impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes. METHOD: Data on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0-3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL. FINDINGS: For children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group. INTERPRETATION: Approximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relationship stress were predictive of chronic group membership for both parents and children. These families may benefit from increased financial and psychosocial support during anti-cancer treatment. FUNDING: National Health and Medical Research Council Grant (APP1104527).

Diagnostic Yield of Initial and Consecutive Blood Cultures in Children With Cancer and Febrile Neutropenia.

BACKGROUND: The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics. METHODS: Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken. RESULTS: A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P < .001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures. CONCLUSIONS: In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.

Genetics-related service and information needs of childhood cancer survivors and parents: a mixed-methods study.

Genetics in paediatric oncology is becoming increasingly important in diagnostics, treatment and follow-up care. Genetic testing may offer a possibility to stratify survivors follow-up care. However, survivors' and parents' preferences and needs for genetics-related services are largely unknown. This mixed-methods study assessed genetics-related information and service needs of survivors and parents. Six hundred and twenty-two participants (404 survivors: mean age: 26.27 years; 218 parents of survivors: mean age of child: 13.05 years) completed questionnaires. Eighty-seven participants (52 survivors; 35 parents) also completed in-depth telephone interviews. We analysed data using multivariable logistic regression and qualitative thematic analyses. Thirty-six of 50 families who were offered cancer-related genetic testing chose to undergo testing. Of those not offered testing, 11% of survivors and 7.6% of parents indicated that they believed it was 'likely/very likely' that the survivor had inherited a gene fault. Twenty-nine percent of survivors and 36% of parents endorsed access to a genetics specialist as important in their care. Survivors (40.9%) and parents (43.7%) indicated an unmet need for information about genetics and childhood cancer. Parents indicated a higher unmet need for information related to the survivors' future offspring than survivors (p < 0.001). Many survivors and parents have unmet needs for genetics-related services and information. Greater access to services and information might allow survivors at high risk for late effects to detect and prevent side effects early and improve medical outcomes. Addressing families' needs and preferences during survivorship may increase satisfaction with survivorship care.

Cardiovascular Testing Detects Underlying Dysfunction in Childhood Leukemia Survivors.

PURPOSE: Childhood leukemia survivors commonly develop late-onset cardiovascular disease after treatment with anthracyclines. Resting echocardiogram is the standard procedure for monitoring cardiac health but this method may not be sensitive enough to detect subclinical injury. Exercise echocardiography may provide a viable alternative. METHODS: Nineteen (9 males; age, 19 ± 3 yr) anthracycline-treated survivors of childhood leukemia and 17 (8 males) healthy individuals of similar age (22 ± 2 yr) were recruited. All survivors had normal resting echocardiography upon recruitment. Exercise echocardiography was performed using contemporary imaging techniques. Flow-mediated dilation (FMD), body composition, and cardiorespiratory fitness (V˙O2peak) were assessed to determine predisposition to additional disease. RESULTS: Mitral valve peak flow velocity in late diastole (interaction, P = 0.007) increased from rest in survivors (P = 0.023) and controls (P = 0.020) immediately postexercise but did not recover again in the survivors (exercise-recovery, P = 0.784) after recuperation. Consequently, E/A ratio (interaction, P < 0.001) was lower in the survivors at recovery (P < 0.001). Survivors had reduced FMD (7.88 ± 1.70 vs 9.65 ± 2.83; P = 0.030), maximal and recovery HR (P = 0.001; P < 0.001), minute ventilation (P < 0.001), and V˙O2peak (absolute, 2.64 ± 0.62 vs 3.14 ± 0.74 L·min, P = 0.034; relative, 36.78 ± 11.49 vs 45.14 ± 6.80 mL·kg·min; P = 0.013) compared with controls. They also had higher total body fat (percentage, P = 0.034; mass, P = 0.024) and fat mass in the central (P = 0.050), peripheral (P = 0.039) and visceral (P < 0.001) regions. Survivors matched controls with regard to height (173.0 ± 7.8 cm vs 173.8 ± 9.1 cm; P = 0.796), body mass (76.16 ± 19.05 kg vs 70.07 ± 13.96 kg; P = 0.287) and body mass index (25.2 ± 5.1 vs 22.9 ± 2.7; P = 0.109). CONCLUSIONS: Exercise echocardiography unmasked subclinical diastolic dysfunction that may indicate late anthracycline toxicity in apparently healthy survivors of childhood leukemia. Presence of secondary risk factors indicates increased predisposition to comorbidities and highlights the importance of assessing cardiovascular health during follow-up.

Early markers of cardiovascular injury in childhood leukaemia survivors treated with anthracycline chemotherapy.

BACKGROUND: Cardiovascular disease (CVD) is the leading non-malignant cause of death in childhood cancer survivors. Heightened risk of CVD is often attributable to treatment with anthracycline chemotherapy. Anthracycline-mediated cardiac injury may lie latent for years following cessation of treatment and is therefore often not detected until disease is advanced and aggressive therapy is required. Symptomatic CVD may be preceded by subclinical cardiac and vascular dysfunction. This study aimed to determine whether such dysfunction could be detected in healthy, anthracycline-treated survivors of childhood leukaemia. METHODS: Cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement and endothelial function were used to characterise pre-clinical stages of CVD. Twenty-two long-term (>5 years survival; age 21 ± 3 years) childhood leukaemia survivors were assessed. All survivors were asymptomatic and had normal resting echocardiography. To exclude potential confounding effects of radiotherapy, no survivors had received this treatment. Twenty-two similarly aged (25 ± 3 years) gender-matched controls were recruited for comparison. RESULTS: Left ventricular ejection fraction was lower in the survivors (55.0 ± 4.6%) compared to the controls (59.4 ± 6.2%; p = 0.010). Further, five survivors (23%) had clinically reduced (<50%) left ventricular ejection fraction. Normalised left ventricular end systolic volume was augmented in survivors (40.0 ± 9.1 mL·m2 vs. 34.5 ± 7.5 mL·m2; p = 0.038). Cardiac MRI did not show any late gadolinium enhancement. High resolution, ultrasound-derived flow mediated dilation was impaired in survivors (6.7 ± 2.1% vs. 8.60 ± 1.91%, p = 0.005). CONCLUSIONS: We detected subclinical changes in cardiovascular structure and function indicative of early disease in anthracycline-treated childhood leukaemia survivors with normal echocardiography. Early detection and characterisation of underlying disease allows for timely intervention and improved outcomes in this at-risk population.

Use of bevacizumab as a single agent or in adjunct with traditional chemotherapy regimens in children with unresectable or progressive low-grade glioma.

In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity.