255 General discussion 8 treatment, other assessments, e.g. new quantitative biomarkers, are needed.18 Furthermore, to design clinically relevant interventions, investigating other contributing factors for the strongly increased appetite during dexamethasone treatment is of value. Subsequent steps towards elucidating the mechanisms of (short-term) metabolic changes induced by dexamethasone include the measurement of more appetite-regulating hormones with either orexigenic or anorexigenic effects,22-27 in combination with extensive exploration and registration of feeling of hunger, eating behavior and caloric intake through a dietary diary. Measurement of body composition may be considered to be more accurately performed using an air-displacement plethysmograph or a dual energy X-ray absorptiometry (DXA) scan.28,29 These assessments could be performed longitudinally throughout the different treatment phases, since metabolic changes worsen over time.30 Thereafter, targeted interventions, e.g. physical activity programs, may be started to prevent or overcome worsening of metabolic side effects of glucocorticoid treatment. Identification of patients at risk of dexamethasone-induced side effects Neurobehavioral problems Our systematic review of literature suggested younger age as a possible risk factor for behavioral problems (Chapter 2),4 but this was not confirmed in our prospective study (Chapter 4). Parenting stress was the only factor significantly associated with dexamethasone-induced neurobehavioral problems in our national cohort. It is unknown whether parents experienced more stress due to the perceived problems in their child, or vice versa, or whether the association may be bidirectional. A recent study in 7208 healthy children and their primary caregiver supports the bidirectionality of the association between parenting stress and child behavioral problems.31 Regardless, parenting stress may be a modifiable target to influence child problems.32,33 Hence, we propose that future studies should consider parenting stress interventions to explore whether they can improve or prevent dexamethasone-induced neurobehavioral problems in children with ALL. Other possible determinants which influence the inter-patient variability in the development of dexamethasone-induced neurobehavioral problems are worth mentioning. Even though we did not find an association between the candidate Bcl1 single nucleotide polymorphism (SNP) and behavioral problems, still the interpatient variation in behavioral side effects suggests genetic susceptibility. Large scale patient cohorts and replication studies are needed to identify genetic susceptibility and to develop polygenic risk scores.34,35 Furthermore, other factors such as parental coping, family and medical history, as reported in case series and retrospective studies, are conceivably important possible contributing factors for steroidinduced behavioral problems, but they have not been assessed prospectively.36-42 Screening new patients and their families for psychosocial risk at diagnosis is currently part of standard of care in the Princess Máxima Center, using the Psychosocial Assessment Tool (PAT).43
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