Physical frailty deteriorates after a 5-day dexamethasone course in children with acute lymphoblastic leukemia, results of a national prospective study

Background: Dexamethasone 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. Methods: Patients 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. Results: We 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. Conclusion: Physical 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.</p

Sleep disorders and the hypothalamus

As early as the 1920s, pathological studies of encephalitis lethargica allowed Von Economo to correctly identify hypothalamic damage as crucial for the profound associated sleep-related symptoms that helped define the condition. Only over the last 3 decades, however, has the key role of the hypothalamus in sleep-wake regulation become increasingly recognized. As a consequence, a close relation between abnormal sleep symptomatology and hypothalamic pathology is now widely accepted for a variety of medical disorders. Narcolepsy is discussed in some detail as the cardinal primary sleep disorder that is caused directly and specifically by hypothalamic pathology, most notably destruction of hypocretin (orexin)-containing neurons. Thereafter, various conditions are described that most likely result from hypothalamic damage, in part at least, producing a clinical picture resembling (symptomatic) narcolepsy. Kleine-Levin syndrome is a rare primary sleep disorder with intermittent symptoms, highly suggestive of hypothalamic involvement but probably reflecting a wider pathophysiology. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) and Prader-Willi syndrome are also covered as hypothalamic syndromes with prominent sleep-related symptoms. Finally, sleep issues in several endocrine disorders are briefly discussed.</p

Psychometric properties of the Patient-Reported Outcomes Measurement Information System (PROMIS®) pediatric item bank peer relationships in the Dutch general population

Purpose: This study aimed to validate the PROMIS Pediatric item bank v2.0 Peer Relationships and compare reliability of the full item bank to its short form, computerized adaptive test (CAT) and the social functioning (SF) subscale of the Pediatric Quality of Life Inventory (PedsQL™). Methods: Children aged 8–18 (n = 1327), representative of the Dutch population completed the Peer Relationships item bank. A graded response model (GRM) was fit to the data. Structural validity was assessed by checking item-fit statistics (S-X2, p 0.50) was expected between Peer Relationships and the PedsQL SF subscale. Cross-cultural DIF between U.S. and NL was assessed using logistic regression, where an item with McFadden’s pseudo R2 > 0.02 was considered to have DIF. Percentage of participants reliably measured was assessed using the standard error of measurement (SEM) 2SD in the clinically relevant direction. CAT outperformed all other measures in efficiency. Mean T-score of the Dutch general population was 46.9(SD 9.5). Conclusion: The pediatric PROMIS Peer Relationships item bank was successfully validated for use within the Dutch population and reference data are now available

Actigraphic estimates of sleep and the sleep-wake rhythm, and 6-sulfatoxymelatonin levels in healthy Dutch children

Sleep and the sleep-wake rhythm are essential for children’s health and well-being, yet reference values are lacking. This study therefore aimed to assess actigraphic estimates of sleep and the 24-h sleep-wake rhythm, as well as 6-sulfatoxymelatonin (aMT6s) levels in healthy children of different age groups. Additionally, relationships between the outcomes and sex, highest parental educational level (as an indication of socioeconomic status (SES)), and body-mass-index (BMI) were explored. In this cross-sectional study, healthy Dutch children (2–18 years) wore an actigraph (GT3x) for 7 consecutive days, collected first-morning void urine and completed a sleep log and sociodemographic questionnaire. Actigraphically estimated sleep variables were sleep onset latency (SOL), sleep efficiency (SE), total sleep time (TST), and wake after sleep onset (WASO). Non-parametric sleep-wake rhythm variables were intradaily variability (IV); interdaily stability (IS); the activity counts and timing of the least active 5-h period (L5counts and midpoint) and of the most active 10-h period (M10 counts and midpoint); and the relative amplitude (RA), i.e. the ratio of the difference and the sum of M10 and L5 counts. Finally, creatinine-corrected aMT6s levels were obtained by isotope dilution mass spectrometry. Effects of age group (preschool 2–5 years/school-aged 6–12 years/teenager 13–18 years), sex, highest parental educational level and BMI (Z-scores) were explored. Ninety-four children participated, equally divided across age groups (53% boys). Teenagers slept less, but more efficiently, than younger children, while their 24 h sleep-wake rhythm was the least stable and most fragmented (likely due to fragmentation of daytime activity). Additionally, aMT6s levels significantly declined over the age groups. Children from highly educated parents had lower sleep efficiency, but a more stable sleep-wake rhythm. Finally, sex or increase in BMI was not associated with any of the outcomes in this study. In conclusion, this study provides reference values of healthy children across different age groups and different sociodemographic factors. In the future, this information may help to better interpret outcomes in clinical populations

Sleep disorders and the hypothalamus

As early as the 1920s, pathological studies of encephalitis lethargica allowed Von Economo to correctly identify hypothalamic damage as crucial for the profound associated sleep-related symptoms that helped define the condition. Only over the last 3 decades, however, has the key role of the hypothalamus in sleep-wake regulation become increasingly recognized. As a consequence, a close relation between abnormal sleep symptomatology and hypothalamic pathology is now widely accepted for a variety of medical disorders. Narcolepsy is discussed in some detail as the cardinal primary sleep disorder that is caused directly and specifically by hypothalamic pathology, most notably destruction of hypocretin (orexin)-containing neurons. Thereafter, various conditions are described that most likely result from hypothalamic damage, in part at least, producing a clinical picture resembling (symptomatic) narcolepsy. Kleine-Levin syndrome is a rare primary sleep disorder with intermittent symptoms, highly suggestive of hypothalamic involvement but probably reflecting a wider pathophysiology. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) and Prader-Willi syndrome are also covered as hypothalamic syndromes with prominent sleep-related symptoms. Finally, sleep issues in several endocrine disorders are briefly discussed

A cost analysis of individualized asparaginase treatment in pediatric acute lymphoblastic leukemia

Background: Therapeutic drug monitoring (TDM) of asparaginase is necessary to respond to variability in asparaginase activity levels, detect silent inactivation, and distinguish between real allergies and allergic-like reactions with and without asparaginase neutralization, respectively. In this study, the costs of an individualized and fixed asparaginase dosing schedule were compared. Procedure: Patients, treated according to the Dutch Childhood Oncology Group ALL-11 protocol (individualized PEGasparaginase treatment, starting dose: 1,500 IU/m2) or ALL-10 protocol (native Escherichia coli asparaginase followed by 2,500 IU/m2 PEGasparaginase), were included. To focus on TDM of PEGasparaginase, the costs were also calculated excluding patients treated with Erwinia asparaginase and compared to a hypothetical protocol with a fixed dose of 1,500 IU/m2 PEGasparaginase. Direct asparaginase-related medical costs, including costs for asparaginase use (calculated with the absolute dose), TDM, laboratory tests, daycare treatment, and outpatient clinic visits, were calculated. Results: Eighty-three ALL-10 patients and 51 ALL-11 patients were included. The asparaginase-related costs were 30.8% lower in ALL-11 than in ALL-10 ($29,048 vs.$41,960). The ALL-11 costs of nonallergic patients were 20.4% lower, when using TDM, than the hypothetical protocol with a fixed dose of 1,500 IU/m2 ($13,178 vs.$16,551). TDM accounted for 12.4% of the costs. Including asparaginase waste, TDM in ALL-11 will be cost saving if three doses can be prepared out of one vial compared to a fixed dose of 1,500 IU/m2. Conclusions: TDM of asparaginase is cost saving if calculated with the absolute asparaginase dose and will be if the waste is minimalized by preparing multiple doses out of one vial

Risk factors for steroid-induced adverse psychological reactions and sleep problems in pediatric acute lymphoblastic leukemia

Objective: Steroids play an essential role in treating pediatric acute lymphoblastic leukemia (ALL). The downside is that these drugs can cause severe side effects, such as adverse psychological reactions (APRs) and sle

Psychometric properties of the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Sleep-Related Impairment item banks in adolescents

Sleep problems have a high prevalence and negative daytime consequences in adolescents. Current sleep measures for this age group have limitations. The Patient-Reported Outcomes Measurement Information System (PROMIS®) developed sleep item banks for adults. In a previous validation study, these item banks were adapted to a shortened version for adolescents. The current study aimed to further explore the psychometric properties of the 11-item Sleep-Related Impairment and 23-item Sleep Disturbance item banks in Dutch adolescents. We investigated structural validity by testing item response theory assumptions and model fit; measurement invariance by performing differential item functioning analyses; performance as a computerized adaptive test; reliability by marginal reliability estimates and test–retest reliability (intraclass correlation coefficients and limits of agreement); and construct validity by hypothesis testing. Additionally, we provide mean values for the item banks. The study sample consisted of 1,046 adolescents (mean age 14.3 ± 1.6), including 1,013 high-school students and 33 sleep-clinic patients. The Sleep Disturbance-23 showed lack of unidimensionality, but had sufficient test–retest reliability, and could distinguish between adolescents with and without sleep or health issues. The Sleep-Related Impairment-11 showed sufficient unidimensionality and model fit and was thus tested as a computerized adaptive test, demonstrating an equal amount of reliable measures to the full item bank. Furthermore, the Sleep-Related Impairment-11 could distinguish between adolescents with and without sleep or health issues and test–retest reliability was moderate. The use of both item banks in the full form and the use of the Sleep-related Impairment-11 as a computer adaptive test is recommended

A cost-effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic leukemia

Objectives: Erwinia asparaginase is used as a second-line formulation after a neutralizing hypersensitivity reaction to the first-line formulation of asparaginase. Here, we have performed a cost-effectiveness analysis of Erwinia asparaginase treatment. Methods: Children with acute lymphoblastic leukemia treated according to the Dutch Childhood Oncology ALL-10 or ALL-11 protocol were included and initially treated with PEGasparaginase in the intensification phase. The total treatment costs of this treatment phase, quality of life (QoL), and life years saved (LYS) were studied for two scenarios: (a) patients were switched to Erwinia asparaginase treatment after a hypersensitivity reaction, or (b) asparaginase would have been permanently stopped. Results: Sixty-eight patients were included. There was no difference in QoL between patients with and without a hypersensitivity reaction. The mean costs of the intensification phase per patient were $40,925 if PEGasparaginase could be continued,$175,632 if patients had to switch to Erwinia asparaginase, and $21,190 if asparaginase would have been permanently stopped. An extrapolation of the literature suggests that the 5-year event-free survival would be 10.3$1892 for scenario 1 and $872 for scenario 2. Conclusions: Switching to Erwinia asparaginase increases the costs per LYS by$1020, which is modest in view of the total costs. Moreover, when asparaginase treatment can be completed by switching to Erwinia asparaginase, relapses—and consequential costs—will be avoided. Therefore, from a cost perspective, we recommend a switch to Erwinia asparaginase to complete asparaginase treatment