261 General discussion 8 value as an additional steroid to induce cell death, or as an alternative therapy for those patients who do not tolerate dexamethasone or prednisone due to extreme side effects. However, the short half-life (1-3 hours) would require frequent administration, or modifiedrelease prescriptions could be used. Still, this should first be explored in clinical trials. Our study was the first to compare the cytotoxic activity of dexamethasone, prednisolone and hydrocortisone in equivalent concentrations (500 micromolar (µM) to 8.19*10-8 µM) in ALL cell lines with either a functional GR or MR, thereby comparing both receptors in their abilities to induce cell death. Previous studies in ALL cell lines only looked into cytotoxic activity of different steroids without distinguishing between GR and MR activity, and most studies or trials so far, did not consider hydrocortisone as a potent steroid.89-92 We found that dexamethasone is a potent steroid to induce cell death through MR activation, however, a somewhat similar experiment in CV-1 cells (monkey kidney cells) transfected with human GR or MR, showed that dexamethasone had a high glucocorticoid potency, but only minor mineralocorticoid potency.89 This indicates that the MR and GR may exert different mechanisms in different cell types. A recent case report using brain tissue from an eight-year-old patient who died from a brain tumor whilst using high-dose dexamethasone suggests that dexamethasone is able to bind the MR sufficiently to induce partial nuclear translocation.58 Nevertheless, it is unknown whether this binding actually regulates gene transcription and subsequent effects. This needs further investigation in neural cell lines or, preferably, in brain tissue from more glucocorticoid-treated, resistant and sensitive subjects. Future directions: implementation of our findings Based on the findings described in this thesis, the most important question which arises is: Can we use the intervention with hydrocortisone or placebo in clinical care to reduce dexamethasone-induced neurobehavioral problems? In a recent expert consensus paper regarding placebo- and nocebo-effects, the importance of making optimal use of placeboeffects to achieve better treatment outcomes is strongly advocated in adults.93 Studies evaluating the use of open-label placebo showed its effect in children with functional abdominal pain or ADHD.75,94-96 To our knowledge, the use of open-label placebo has not been evaluated so far in the pediatric oncology setting. Besides open-label placebo, hydrocortisone could also be considered as an effective intervention, bearing in mind that it might increase feeling of hunger. As we realized that introducing open-label placebo in children with cancer is a novel strategy, we discussed this clinical implementation extensively with different stakeholders, including several feedback loop conversations (Figure 1).
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