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Background: Anthracycline-induced cardiac toxicity is a cause of significant morbidity and early mortality in survivors of childhood cancer. Current strategies for predicting which children are at greatest risk for toxicity are imperfect and diagnosis of cardiac injury is usually made relatively late in the natural history of the disease. This study aims to identify genomic, biomarker and imaging parameters that can be used as predictors of risk or aid in the early diagnosis of cardiotoxicity.Methods: This is a prospective longitudinal cohort study that recruited two cohorts of pediatric cancer patients at six participating centres: (1) an Acute Cohort of children newly diagnosed with cancer prior to starting anthracycline therapy (n = 307); and (2) a Survivor Cohort of long-term survivors of childhood cancer with past exposure to anthracycline (n = 818). The study team consists of three collaborative cores. The Genomics Core is identifying genomic variations in anthracycline metabolism and in myocardial response to injury that predispose children to treatment-related cardiac toxicity. The Biomarker Core is identifying existing and novel biomarkers that allow for early diagnosis and prognosis of anthracycline-induced cardiac toxicity. The Imaging Core is identifying echocardiographic and cardiac magnetic resonance (CMR) imaging parameters that correspond to early signs of cardiac dysfunction and remodeling and precede global dysfunction and clinical symptoms. The data generated by the cores will be combined to create an integrated risk-prediction model aimed at more accurate identification of children who are most susceptible to anthracycline toxicity.Discussion: We aim to identify genomic risk factors that predict risk for anthracycline cardiotoxicity pre-exposure and imaging and biomarkers that facilitate early diagnosis of cardiac injury. This will facilitate a personalized approach to identifying at-risk children with cancer who may benefit from cardio- protective strategies during therapy, and closer surveillance and earlier initiation of medications to preserve heart function after cancer therapy.Trial Registration: NCT01805778 . Registered 28 February 2013; retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.Methods: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.Findings: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001).Interpretation: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.Funding: National Cancer Institute and the American Lebanese-Syrian Associated Charities. [ABSTRACT FROM AUTHOR]