260 Chapter 8 In children, nocebo-effects can be severe and often anticipatory. For example, children with juvenile idiopathic arthritis who receive methotrexate and experience nausea as side effect, can become nauseous even before they start their next dose methotrexate upon entering the hospital.79 During ALL maintenance treatment, children usually know when the ‘DexaDays’ will start again: this fact and the behavioral and anticipatory adjustment of the family members, may give rise to intensified behavioral changes. Furthermore, all patients described in this thesis already had received at least twelve dexamethasone courses before they were included. The experiences from patients and parents in the preceding dexamethasone courses could have influenced the perception of the measured dexamethasone-induced problems. Therefore, it would be interesting to measure dexamethasone-induced problems during the first encounter with dexamethasone, to explore whether a negative first experience contributes to dexamethasone-induced problems further in maintenance, especially since dexamethasone is currently used in induction of the ALLTogether1 protocol, similar to the previously applied DCOG ALL-9 protocol. Steroid receptor function in steroid-induced cytotoxicity While previously studying the influence of hydrocortisone on dexamethasone-induced cytotoxicity, for safety purposes, we found that hydrocortisone potentiated the cytotoxic effect of both prednisolone and dexamethasone in steroid sensitive ALL cell lines.80 In this thesis, we describe that hydrocortisone is an extremely potent steroid to induce steroidinduced cell death (Chapter 7). This steroid-induced cell death can be achieved solely by activation of the mineralocorticoid receptor (MR). Furthermore, dexamethasone was able to induce cell death through activation of the MR, highlighting that the MR is potentially capable of inducing leukemic cell death after activation by steroid treatment. The fact that hydrocortisone is a potent anti-leukemic steroid is of interest. Since several studies showed better overall and event free survival and less central nervous system relapses using dexamethasone compared to prednisone, dexamethasone became the preferred steroid during maintenance therapy in most treatment protocols.81-84 It is still debated whether these advantages of dexamethasone are due to a higher equivalent cytotoxic dose than the generally presumed factor seven, or due to higher CNS penetration.85 The downside of dexamethasone compared to prednisone is an overall increased toxicity.86,87 Apart from intrathecal therapy, hydrocortisone has not been used in the treatment of ALL, possibly due to the shorter biological half-life, consequential logistic dosing challenges, and higher mineralocorticoid activity.57 However, hydrocortisone seems to penetrate the cerebrospinal fluid, and has a favorable toxicity profile.88 Although our PDX model and patient samples did not confirm that hydrocortisone was more cytotoxic than dexamethasone or prednisone, it was at least equal, and it may therefore still be of
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