BackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and... Show moreBackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors.MethodsPatients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or >= three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2.ResultsWe included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2.ConclusionPhysical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy. After a 5-day dexamethasone course. Physical frailty increased with 13.5% in pediatric ALL patients. A poorer physical state at start of a dexamethasone course (lower muscle mass, muscle strength, or slower movement ability) was prognostic for developing frailty after a dexamethasone course.image Show less
Koning, A.S.C.A.M.; Meulen, M. van der; Schaap, D.; Satoer, D.D.; Vinkers, C.H.; Rossum, E.F.C. van; ... ; Dekkers, O.M. 2023
Context Synthetic glucocorticoids are widely used to treat patients with a broad range of diseases. While efficacious, glucocorticoids can be accompanied by neuropsychiatric adverse effects... Show moreContext Synthetic glucocorticoids are widely used to treat patients with a broad range of diseases. While efficacious, glucocorticoids can be accompanied by neuropsychiatric adverse effects.Objective This systematic review and meta-analysis assesses and quantifies the proportion of different neuropsychiatric adverse effects in patients using synthetic glucocorticoids.Methods Six electronic databases were searched to identify potentially relevant studies. Randomized controlled trials, cohort studies, and cross-sectional studies assessing psychiatric side effects of glucocorticoids measured with validated questionnaires were eligible. Risk of bias was assessed with RoB 2, ROBINS-I, and AXIS appraisal tool. For proportions of neuropsychiatric outcomes, we pooled proportions, and when possible, differences in questionnaire scores between glucocorticoid users and nonusers were expressed as standardized mean differences (SMD). Data were pooled in a random-effects logistic regression model.Results We included 49 studies with heterogeneity in study populations, type, dose, and duration of glucocorticoids. For glucocorticoid users, meta-analysis showed a proportion of 22% for depression (95% CI, 14%-33%), 11% for mania (2%-46%), 8% for anxiety (2%-25%), 16% for delirium (6%-36%), and 52% for behavioral changes (42%-61%). Questionnaire scores for depression (SMD of 0.80 [95% CI 0.35-1.26]), and mania (0.78 [0.14-1.42]) were higher than in controls, indicating more depressive and manic symptoms following glucocorticoid use.Conclusion The heterogeneity of glucocorticoid use is reflected in the available studies. Despite this heterogeneity, the proportion of neuropsychiatric adverse effects in glucocorticoid users is high. The most substantial associations with glucocorticoid use were found for depression and mania. Upon starting glucocorticoid treatment, awareness of possible psychiatric side effects is essential. More structured studies on incidence and potential pathways of neuropsychiatric side effects of prescribed glucocorticoids are clearly needed. Show less
Hulst, A.M. van; Verwaaijen, E.J.; Berg, S.A.A. van den; Litsenburg, R.R.L. van; Grootenhuis, M.A.; Fiocco, M.; ... ; Akker, E.L.T. van den 2023
Background & aims: Children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone during treatment, which induce acute side effects. The aims of the current study were to... Show moreBackground & aims: Children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone during treatment, which induce acute side effects. The aims of the current study were to determine the influence of a five-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep and fatigue and to explore associations between these changes.Methods: Pediatric ALL patients were included during maintenance treatment. Data was collected before (T1) and after (T2) a five-day dexamethasone course (6 mg/m(2)/day). BMI, fat mass (bioelectrical impedance analysis) and leptin were assessed on both timepoints, as well as parent-reported questionnaires regarding hunger, fatigue and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin.Results: We included 105 children with median age 5.4 years (range 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue and sleep deteriorated after five days of dexamethasone (p < 0.001), in contrast to BMI (p = 0.12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio (OR) 1.51, 95%-confidence interval (95%-CI) 1.28-1.77), higher fat mass (OR 1.19, 95%-CI 1.07-1.33) and earlier maintenance week (OR 0.96, 95%-CI 0.92-0.99).Conclusions: Five days of high dose dexamethasone treatment lead to direct and significant changes in leptin, hunger scores and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role. Show less
Simple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced.... Show moreSimple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced. The use of high dose systemic corticosteroids around docetaxel infusion appeared to decrease the incidence of HSR and fluid retention and has been applied in daily practice ever since. However, there is little evidence that supports this high dose of dexamethasone. Furthermore, the application of high-dosed corticosteroids can lead to undesirable adverse effects. In this phase 1 study, we aim to evaluate the impact of reducing the dose of dexamethasone as an adjunct to docetaxel on the incidence of HSR and fluid retention in patients with prostate or breast cancer. Background: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Patients and methods: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Results: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. Conclusions: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome. Show less
Miah, I.P.; Blanter, A.; Tank, Y.; Zwet, E.W. van; Rosendaal, F.R.; Peul, W.C.; ... ; Gaag, N.A. van der 2022
The main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy... Show moreThe main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy is applied. Recent trials revealed dexamethasone therapy to be an ineffective treatment in symptomatic patients with chronic subdural hematoma. Whether the efficacy of dexamethasone therapy differs in radiological hematoma subtypes is unknown. The aim of this substudy was to identify which hematoma subtype might be favorable for dexamethasone therapy. As part of a randomized controlled trial, symptomatic chronic subdural hematoma patients received 19-days dexamethasone therapy. The primary outcome measure was the change in hematoma size as measured on follow-up computed tomography (CT) after 2 weeks of dexamethasone in six hematoma (architectural and density) subtypes: homogeneous total, laminar, separated and trabecular architecture types, and hematoma without hyperdense components (homogeneous hypodense, isodense) and with hyperdense components (homogeneous hyperdense, mixed density). We analyzed hematoma thickness, midline shift, and volume using multi-variable linear regression adjusting for age, sex and baseline value of the specific radiological parameter. From September 2016 until February 2021, 85 patients were included with a total of 114 chronic subdural hematoma. The mean age was 76 years and 25% were women. Larger decrease in hematoma thickness and midline shift was revealed in hematoma without hyperdense components compared with hematoma with hyperdense components (adjusted [adj.] b -2.2 mm, 95% confidence interval [CI] -4.1 to -0.3 and adj. b -1.3 mm, 95% CI -2.7 to 0.0 respectively). Additional surgery was performed in 57% of patients with the highest observed rate (81%) in separated hematoma. Largest hematoma reduction and better clinical improvement was observed in chronic subdural hematoma without hyperdense components after dexamethasone therapy. Evaluation of these parameters can be part of an individualized treatment strategy. Show less
Miah, I.P.; Blanter, A.; Tank, Y.; Zwet, E.W. van; Rosendaal, F.R.; Peul, W.C.; ... ; Gaag, N.A. van der 2022
The main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy... Show moreThe main treatment strategy for chronic subdural hematoma is surgical intervention. When a conservative pharmacological approach is considered in symptomatic patients, mainly dexamethasone therapy is applied. Recent trials revealed dexamethasone therapy to be an ineffective treatment in symptomatic patients with chronic subdural hematoma. Whether the efficacy of dexamethasone therapy differs in radiological hematoma subtypes is unknown. The aim of this substudy was to identify which hematoma subtype might be favorable for dexamethasone therapy. As part of a randomized controlled trial, symptomatic chronic subdural hematoma patients received 19-days dexamethasone therapy. The primary outcome measure was the change in hematoma size as measured on follow-up computed tomography (CT) after 2 weeks of dexamethasone in six hematoma (architectural and density) subtypes: homogeneous total, laminar, separated and trabecular architecture types, and hematoma without hyperdense components (homogeneous hypodense, isodense) and with hyperdense components (homogeneous hyperdense, mixed density). We analyzed hematoma thickness, midline shift, and volume using multi-variable linear regression adjusting for age, sex and baseline value of the specific radiological parameter. From September 2016 until February 2021, 85 patients were included with a total of 114 chronic subdural hematoma. The mean age was 76 years and 25% were women. Larger decrease in hematoma thickness and midline shift was revealed in hematoma without hyperdense components compared with hematoma with hyperdense components (adjusted [adj.] b -2.2 mm, 95% confidence interval [CI] -4.1 to -0.3 and adj. b -1.3 mm, 95% CI -2.7 to 0.0 respectively). Additional surgery was performed in 57% of patients with the highest observed rate (81%) in separated hematoma. Largest hematoma reduction and better clinical improvement was observed in chronic subdural hematoma without hyperdense components after dexamethasone therapy. Evaluation of these parameters can be part of an individualized treatment strategy. Show less
Koorneef, L.L.; Meulen, M. van der; Kooijman, S.; Sanchez-Lopez, E.; Scheerstra, J.F.; Voorhoeve, M.C.; ... ; Meijer, O.C. 2022
Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin... Show moreSynthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice. Show less
Background: Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor ... Show moreBackground: Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms. Objective: In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone. Main outcome measures: The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured. Results: In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient. Conclusions: Dexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients. Show less
Garcia Couce, J.; Tomas, M.; Fuentes, G.; Que, I.V.; Almirall, A.; Cruz, L.J. 2022
Intra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug... Show moreIntra-articular administration of anti-inflammatory drugs is a strategy that allows localized action on damaged articular cartilage and reduces the side effects associated with systemic drug administration. The objective of this work is to prepare injectable thermosensitive hydrogels for the long-term application of dexamethasone. The hydrogels were prepared by mixing chitosan (CS) and Pluronic-F127 (PF) physically. In addition, tripolyphosphate (TPP) was used as a crosslinking agent. Chitosan added to the mix increased the gel time compared to the pluronic gel alone. The incorporation of TPP into the material modified the morphology of the hydrogels formed. Subsequently, MTS and Live/Dead(R) experiments were performed to investigate the toxicity of hydrogels against human chondrocytes. The in vitro releases of dexamethasone (DMT) from CS-PF and CS-PF-TPP gels had an initial burst and took more time than that from the PF hydrogel. In vivo studies showed that hydrogels retained the fluorescent compound longer in the joint than when administered in PBS alone. These results suggest that the CS-PF and CS-PF-TPP hydrogels loaded with DMT could be a promising drug delivery platform for the treatment of osteoarthritis. Show less
Vrouwe, J.P.M.; Kamerling, I.M.C.; Esdonk, M.J. van; Metselaar, J.M.; Stuurman, F.E.; Pluijm, G. van der; ... ; Osanto, S. 2021
Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate ... Show moreDexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels <= 9.1 mmol/L. Trough plasma concentrations of liposomal- and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t(1/2) similar to 50 h for liposomal dexamethasone), trough concentrations of liposomal- and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow-up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715. Show less
We report on a case of a 50-year-old female patient with primary hyperaldosteronism, in whom adrenal venous sampling was required to differentiate between unilateral and bilateral disease. Because... Show moreWe report on a case of a 50-year-old female patient with primary hyperaldosteronism, in whom adrenal venous sampling was required to differentiate between unilateral and bilateral disease. Because of a history of severe allergy to iodinated contrast media, premedication with glucocorticoids was indicated. Exogenous glucocorticoids, however, can affect measurements of serum cortisol. To avoid this potential confounding effects on the cortisol assay, we decided to use dexamethasone instead of prednisolone or hydrocortisone. A high-dose adrenocorticotropin (ACTH) stimulation test with the simultaneous use of dexamethasone revealed an adequate adrenal cortisol response. ACTH-stimulated adrenal venous sampling showed reliable results, which provided a solid basis for further clinical decision-making. Show less
Miah, I.P.; Herklots, M.; Roks, G.; Peul, W.C.; Walchenbach, R.; Dammers, R.; ... ; Dutch Chronic Subdural Hematoma Re 2019
