275 English summary A ENGLISH SUMMARY Glucocorticoids, such as dexamethasone and prednisone, are indispensable components in the treatment of childhood acute lymphoblastic leukemia (ALL). Dexamethasone is currently the preferred glucocorticoid in most treatment protocols and is administered during maintenance therapy for five days every 3-4 weeks, during 1,5 year of ALL treatment. Besides the positive anti-leukemic effect, dexamethasone can induce various undesirable side effects. Patients and parents often report neurobehavioral and sleep problems as harmful side effects, which generally negatively affect quality of life. Increased feeling of hunger, dyslipidemia and adiposity are also well-known side effects of dexamethasone. The inter-patient variability in all these side effects is high and no clear risk factors are known. The first aim of this thesis was to increase current knowledge on the prevalence and determinants of dexamethasone-induced side effects in children with ALL. We first performed a systematic literature review to identify previously described risk factors for steroid-induced neurobehavioral and sleep problems in children with ALL (Chapter 2). Overall, the quality of evidence was very low. Available literature suggested that type or dose of steroid is not related to neurobehavioral problems, but might be to sleep problems. Younger patients seem at risk for behavioral problems, whereas older patients are at risk for sleep problems. No studies describing parental stress or medical history were identified, and genetic susceptibility associations remain to be replicated. We furthermore performed a prospective cohort study in 105 children (3.0-18.8 years) with ALL (Chapters 3 and 4). Clinically relevant dexamethasone-induced neurobehavioral and sleep problems were reported by parents in 70 (67%) and 61 (59%) patients respectively. We identified parenting stress, and not dexamethasone pharmacokinetics, genetic variation, patient and parent demographics, or disease and treatment characteristics, as a significant determinant for parent-reported dexamethasone-induced neurobehavioral and sleep problems. Parenting stress may be a modifiable target to reduce these problems in the future. We also found that merely five days of dexamethasone lead to direct and significant increase in leptin (a fat hormone that regulates satiety), hunger scores and fat mass (Chapter 5). We found no correlations between these measurements, which may suggest a dexamethasone-induced state of acute leptin resistance. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and leptin resistance might play a role.
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