Publications by authors named "Raphaële R L van Litsenburg"

36 Publications

The association between vincristine-induced peripheral neuropathy and health-related quality of life in children with cancer.

Cancer Med 2021 Nov 1;10(22):8172-8181. Epub 2021 Nov 1.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric oncology, Amsterdam, The Netherlands.

Purpose: Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR-induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health-related quality of life (HR-QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR-QoL in children starting treatment for cancer.

Methods: Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score (ped-mTNS). Assessment of HR-QoL was done with self- and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL).

Results: In total, N = 86 children were included. HR-QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = -8.96 and 95% confidence interval (CI) -14.48 to -3.43; p = 0.002, estimated PedsQL Generic Total score (self-reported): 85.16, β = -8.38 (95% CI: -13.76 to -3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = -9.94 [95%CI: -16.44 to -3.45], p = 0.003; hurt: estimated score [self-report] 97.57, β = -19.15 [95%CI: -26.82 to -11.48], p < 0.001).

Conclusion: VIPN results in a significant reduction of HR-QoL in children under treatment for a malignancy, which means that VIPN is important for the well-being of pediatric oncology patients. Therefore, this study underlines the importance of optimizing treatment with VCR, thereby aiming to reduce VIPN while maintaining efficacy.
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http://dx.doi.org/10.1002/cam4.4289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607258PMC
November 2021

Disparities in pediatric psychosocial oncology utilization.

Pediatr Blood Cancer 2021 Nov 14;68(11):e29342. Epub 2021 Sep 14.

Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

Background: Integratedbehavioral health models have been proposed as care delivery approaches to mitigate mental health disparities in primary care settings. However, these models have not yet been widely adopted or evaluated in pediatric oncology medical homes.

Methods: We conducted a retrospective cohort study of 394 children with newly diagnosed cancer at Dana-Farber/Boston Children's Cancer and Blood Disorders Center (DF/BCH) from April 2013 to January 2017. Baseline sociodemographic characteristics and psychiatry utilization outcomes at 12 months following diagnosis were abstracted from the medical record. The severity of household material hardship (HMH), a concrete poverty exposure, at diagnosis and race/ethnicity were characterized by parent report using the Psychosocial Assessment Tool 2.0 (PAT). Associations between sociodemographic characteristics and receipt of psychiatry consultation were assessed with multivariable logistic regression models.

Results: Among 394 children, 29% received a psychiatric consultation within 12 months postdiagnosis. Of these, 88% received a new psychiatric diagnosis, 76% received a psychopharmacologic recommendation, and 62% received a new behavioral intervention recommendation. In multivariable logistic regression adjusting for age, cancer diagnosis, and PAT total score, there was no statistically significant association between HMH severity or household income and psychiatry utilization. Children who identified as racial/ethnic minorities were significantly less likely to receive a psychiatry consultation (OR = 0.48, 95% CI = 0.27-0.84).

Conclusions: In a pediatric oncology medical home with an integrated behavioral health model, socioeconomic status was not associated with disparate psychiatry utilization. However, there remained a profound racial/ethnic disparity in psychiatry utilization, highlighting the need for additional research and care delivery intervention.
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http://dx.doi.org/10.1002/pbc.29342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463506PMC
November 2021

Sleep disorders and the hypothalamus.

Handb Clin Neurol 2021 ;182:369-385

Department of Neurology, James Cook University Hospital, Middlesbrough, United Kingdom.

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.
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http://dx.doi.org/10.1016/B978-0-12-819973-2.00025-3DOI Listing
July 2021

From statistics to clinics: the visual feedback of PROMIS® CATs.

J Patient Rep Outcomes 2021 Jul 10;5(1):55. Epub 2021 Jul 10.

Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam Reproduction and Development, Amsterdam Public Health, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Postbox 22660, 1100 DD, Amsterdam, The Netherlands.

Background: To reduce the burden of completing Patient-Reported Outcome Measures (PROMs), PROMIS® Computerized Adaptive Tests (CATs) are being implemented in pediatric clinical practice. We aimed to develop recommendations for visual feedback options for PROMIS CATs on individual item and domain score level as an evidence-based feedback recommendation for PROMIS CATs is lacking.

Methods: Focus groups were held with clinicians who use the KLIK PROM portal. Literature-based feedback options were provided to initiate group discussion. Data was analyzed using thematic coding method. Additionally, a questionnaire was sent out to assess patients' (12-18y) and parents' (child 0-18y) preference for individual item feedback. Data was analyzed using descriptive statistics.

Results: Six focus groups were held (N = 28 clinicians). Regarding individual item feedback, showing the complete item bank, with only responses to administered items in traffic light colors was preferred. For domain scores, line graphs were preferred, including numerical (T-)scores, reference and cut-off lines, and traffic light colors. Separate graphs per domain, ranked in order of importance and harmonization of directionality ('higher = better') were considered important. Questionnaire results (N = 31 patients/N = 131 parents) showed that viewing their own item responses was preferred above receiving no item feedback by 58.1% of the patients and 77.1% of the parents.

Conclusions: Based on the outcomes and after discussion with the Dutch-Flemish PROMIS National Center, recommendations for PROMIS CAT feedback options were developed. PROMIS CATs can now be used in clinical practice to help clinicians monitor patient outcomes, while reducing the burden of completing PROMs for patients significantly.
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http://dx.doi.org/10.1186/s41687-021-00324-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272760PMC
July 2021

Psychometric properties of the Patient-Reported Outcomes Measurement Information System (PROMIS®) Pediatric Anger Scale in the Dutch general population.

Psychol Assess 2021 Jul 1. Epub 2021 Jul 1.

Department of Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam Reproduction and Development, Amsterdam Public Health, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam.

This study aimed to validate the PROMIS® pediatric v2.0 Anger scale in the Dutch general population, provide reference data, and compare reliability and relative efficiency between the full-length scale, its short-form, computerized adaptive test (CAT), and Pediatric Quality of Life Inventory (PedsQLTM) emotional functioning (EF) subscale scores. Children (N = 1,328), representative of the Dutch population, were asked to complete the PROMIS pediatric Anger scale (8-18 years) and PedsQLTM (8-17 years). A graded response model (GRM) was fit to the data. Structural validity was assessed by checking item-fit statistics (S-X2, p < .001 = misfit). For construct validity, a moderate correlation (Pearson's r > 0.50) was expected between the Anger scale and PedsQLTM EF subscale score. Dutch mean T score based on the U.S. model was calculated to provide reference data and cut-offs. Standard error of measurement (SE(θ)) was used to assess reliability (SE(θ) < .32 = .90 reliability). Relative efficiency was calculated (1 - SE(θ)2/N items) to compare how good the measures performed relative to the amount of items administered. In total, 527 children completed the PROMIS pediatric Anger scale, of which 482 completed the PedsQLTM. Structural validity was sufficient as no items displayed misfit (S-X2 = 22.9-40.3, p > .001). The Anger scale score correlated moderately (Pearson's r = .64) with the PedsQLTM EF subscale score. Dutch mean T score was 44.20 (SD = 11.39), with cut-offs of >52.2 for moderate and ≥62.3 for severe symptoms. Reliable measurements were obtained at the population mean and >2SD in the clinically relevant direction. CAT outperformed all other measures in efficiency. The PROMIS pediatric Anger scale displayed sufficient psychometric properties within the Dutch population and reference data are available. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0001051DOI Listing
July 2021

Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia.

Lancet Haematol 2021 Jul;8(7):e513-e523

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.
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http://dx.doi.org/10.1016/S2352-3026(21)00136-8DOI Listing
July 2021

Does the guided online cognitive behavioral therapy for insomnia "i-Sleep youth" improve sleep of adolescents and young adults with insomnia after childhood cancer? (MICADO-study): study protocol of a randomized controlled trial.

Trials 2021 Apr 26;22(1):307. Epub 2021 Apr 26.

Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht, 3584 CS, The Netherlands.

Background: Adolescents and young adults who had childhood cancer are at increased risk for insomnia, due to being critically ill during an important phase of their life for the development of good sleep habits. Insomnia is disabling and prevalent after childhood cancer (26-29%) and negatively impacts quality of life, fatigue, pain, and general functioning and is often associated with other (mental) health problems. Insomnia and a history of childhood cancer both increase the risk of adverse health outcomes, posing a double burden for adolescents who had childhood cancer. The first-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBT-I). However, access to this type of care is often limited. The guided online CBT-I treatment "i-Sleep" has been developed to facilitate access via online care. i-Sleep is shown effective in adult (breast cancer) patients, but it is unknown if iCBT-I is effective in pediatric oncology.

Methods/design: We developed a youth version of i-Sleep. Our aim is to evaluate its effectiveness in a national randomized-controlled clinical trial comparing iCBT-I to a waiting-list control condition at 3 and 6 months (n = 70). The intervention group will be also assessed at 12 months to see whether the post-test effects are maintained. Adolescents and young adults aged 12-30 years with insomnia, diagnosed with (childhood) cancer, currently at least 6 months since their last cancer treatment will be eligible. Outcomes include sleep efficiency (actigraphic), insomnia severity (self-report), sleep and circadian activity rhythm parameters, fatigue, health-related quality of life, perceived cognitive functioning, chronic distress, depressive and anxiety symptoms, and intervention acceptability.

Discussion: Insomnia is prevalent in the pediatric oncology population posing a double health burden for adolescents and young adults who had childhood cancer. If guided iCBT-I is effective, guidelines for insomnia can be installed to treat insomnia and potentially improve quality of life and the health of adolescents and young adults who had childhood cancer.

Trial Registration: NL7220 (NTR7419; Netherlands Trial register). Registered on 2 August 2018.
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http://dx.doi.org/10.1186/s13063-021-05263-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077706PMC
April 2021

Risk factors for steroid-induced adverse psychological reactions and sleep problems in pediatric acute lymphoblastic leukemia: A systematic review.

Psychooncology 2021 07 6;30(7):1009-1028. Epub 2021 Apr 6.

Princess Maxima Center, CS Utrecht, The Netherlands.

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 sleep problems, which can compromise health-related quality of life. This study aimed to systematically review literature to identify risk factors for steroid-induced APRs and sleep problems in children with ALL.

Methods: A systematic search was performed in six databases. Titles/abstracts were independently screened by two researchers. Data from each included study was extracted based on predefined items. Risk of bias and level of evidence were assessed, using the Quality in Prognosis Studies tool and the Grading of Recommendations Assessment, Development and Evaluation tool, respectively.

Results: Twenty-four articles were included. APR measurement ranged from validated questionnaires to retrospective record retrieval, sleep measurement included questionnaires or actigraphy. Overall, quality of evidence was very low. Current evidence suggests that type/dose of steroid is not related to APRs, but might be to sleep problems. Younger patients seem at risk for behavior problems and older patients for sleep problems. No studies describing parental stress or medical history were identified. Genetic susceptibility associations remain to be replicated.

Conclusions: Based on the current evidence, conclusions about risk factors for steroid-induced adverse psychological reactions or sleep problems in children with ALL should be drawn cautiously, since quality of evidence is low and methods of measurement are largely heterogeneous. A standardized registration of steroid-induced APRs/sleep problems and risk factors is warranted for further studies in children with ALL.
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http://dx.doi.org/10.1002/pon.5654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359839PMC
July 2021

Severe Fatigue Is Common Among Pediatric Patients with Primary Immunodeficiency and Is Not Related to Disease Activity.

J Clin Immunol 2021 08 17;41(6):1198-1207. Epub 2021 Mar 17.

Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Surface mail: HP KE.04.133.1, Post box 85090, 3508 AB, Utrecht, The Netherlands.

Purpose: Fatigue is a distressing symptom commonly reported among pediatric patients with primary immunodeficiency (PID). However, the relationship between fatigue and disease activity is currently unknown.

Methods: In this cross-sectional study, we examined the prevalence of severe fatigue, the effect of fatigue on health-related quality of life (HRQoL), and the effects of disease activity and comorbidity on fatigue severity among pediatric patients 2-18 years of age with PID. Fatigue and HRQoL were assessed using the pediatric quality of life inventory multidimensional fatigue scale (PedsQL MFS) and generic core scales (PedsQL GCS), respectively. Linear regression analyses and an analysis of covariance were used to compare the fatigue scores with the scores obtained from a healthy control group. Data were adjusted for age and sex.

Results: Of the 91 eligible patients, 79 were assessed (87% participation rate), with a mean age of 10.4 ± 4.4 years. Pediatric patients with PID reported significantly higher fatigue levels compared to healthy peers, with an 18.9% prevalence of severe fatigue. Moreover, higher fatigue levels were inversely associated with HRQoL in all domains and directly associated with school absences. We found that severe fatigue was comparable between common variable immunodeficiency (CVID), combined immunodeficiency (CID), and selective immunoglobulin A deficiency (SIgAD) patients, but was not reported in the X-linked agammaglobulinemia (XLA) patients studied. Finally, fatigue severity was not significantly associated with disease activity or comorbidity.

Conclusions: Nearly 20% of pediatric patients with PID reported experiencing severe fatigue, and fatigue was reported among a wide range of PID subcategories. In addition, severe fatigue negatively affected the patient's quality of life and daily functioning, but was not associated with disease activity or comorbidity. Thus, targeting severe fatigue might be a promising strategy for improving the overall well-being and quality of life of pediatric patients with PID.
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http://dx.doi.org/10.1007/s10875-021-01013-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310837PMC
August 2021

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

Qual Life Res 2021 Jul 19;30(7):2061-2070. Epub 2021 Feb 19.

Child and Adolescent Psychiatry & Psychosocial Care, Amsterdam Reproduction and Development, Amsterdam Public Health, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Postbus 22660, 1100 AD, Amsterdam, The Netherlands.

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-X, p < 0.001 = misfit). For construct validity, a moderately strong correlation (> 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 R > 0.02 was considered to have DIF. Percentage of participants reliably measured was assessed using the standard error of measurement (SEM) < 0.32 as a criterion (reliability of 0.90). Relative efficiency ((1-SEM)/n) was calculated to compare how well the instruments performed relative to the amount of items administered.

Results: In total, 527 (response rate: 39.7%) children completed the PROMIS v2.0 Peer Relationships item bank (n = 15) and the PedsQL™ (n = 23). Structural validity of the Peer Relationships item bank was sufficient, but one item displayed misfit in the GRM model (S-X < 0.001); 5152R1r ("I played alone and kept to myself"). The item 733R1r ("I was a good friend") was the only item that displayed cross-cultural DIF (R = 0.0253). The item bank correlated moderately high (r = 0.61) with the PedsQL SF subscale Reliable measurements were obtained at the population mean and > 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.
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http://dx.doi.org/10.1007/s11136-021-02781-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233291PMC
July 2021

Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis.

Nat Hum Behav 2021 01 16;5(1):113-122. Epub 2020 Nov 16.

Research Institute of Child Development and Education, University of Amsterdam, Amsterdam, the Netherlands.

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1-100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40-69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the 'acceptable' sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8-10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6-19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5-2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.
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http://dx.doi.org/10.1038/s41562-020-00965-xDOI Listing
January 2021

A meta-analysis of accelerometer sleep outcomes in healthy children based on the Sadeh algorithm: the influence of child and device characteristics.

Sleep 2021 04;44(4)

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Amsterdam, the Netherlands.

Study Objectives: Children often experience sleep problems, with a negative impact on mood, behavior, cognitive function, and other aspects of mental and physical health. Accelerometers are widely used to assess sleep, but general reference values for healthy children do not yet exist. The aim of this meta-analysis was to determine mean values for wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST) and sleep onset latency (SOL), and to determine the effect of child and accelerometer-characteristics.

Methods: A search included studies with healthy children, 0-18 years, reporting WASO, SE, TST, and/or SOL, calculated with the Sadeh algorithm. Meta-analyses with random effects produced pooled estimate means per outcome. Meta-regression analyses determined the effect of age, sex, placement site and accelerometer type.

Results: Eighty-three studies (9,068 participants) were included. Pooled means were 63 min (95% CI 57 to 69) for WASO, 88% (95% CI 87 to 89) for SE, 477 min (95% CI 464 to 491) for TST and 19 min (95% CI 17 to 22) for SOL. Heterogeneity was high (95%-99%). TST decreased with age and there was an age-effect on SOL. SE differed between wrist and ankle (used in age 0-24 months) placement, and between piezoelectric and MEMS-type accelerometers. No differences were found between boys and girls, although this number of studies was small.

Conclusions: We found differences in almost all investigated outcomes and heterogeneity was high. Therefore, we advise to use a study-specific control sample until more robust reference values are available. Future research should narrow the methodological heterogeneity and produce larger datasets, needed to establish these reference values.
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http://dx.doi.org/10.1093/sleep/zsaa231DOI Listing
April 2021

Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses.

Pediatr Blood Cancer 2020 11 10;67(11):e28697. Epub 2020 Sep 10.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.

Background: During maintenance treatment, Dutch pediatric patients with medium-risk (MR) acute lymphoblastic leukemia (ALL) receive intravenous chemotherapy and cyclic dexamethasone. Dexamethasone affects child's sleep and behavior. Standard-risk (SR) patients only receive oral chemotherapy, without dexamethasone. Effects of stratified therapy on parents are not well known. This study compares parental sleep, distress and quality of life (QoL) with the general population, between MR and SR groups, and on- and off-dexamethasone (MR group).

Procedure: One year after diagnosis, parents of MR patients completed the Medical Outcomes Study (MOS) sleep, distress thermometer for parents and Short Form-12 (SF-12) twice; once on-dexamethasone and once off-dexamethasone. SR parents completed one measurement. Sleep problems, distress and QoL scores (off-dexamethasone) were compared to reference values and between MR and SR. Score differences on- and off-dexamethasone were assessed by multilevel regression analysis.

Results: Parents (80% mothers) of 121 patients (57% males; 75% MR, 25% SR) completed 191 measurements. Compared to reference values, parents reported more sleep disturbances, higher distress, and lower mental QoL. Additionally, MR parents reported clinical distress (score ≥ 4), whereas SR parents (on average) did not (mean 4.8 ± 2.4 vs 3.5 ± 2.4, P = .02). Within the MR group, outcomes did not significantly differ on- and off-dexamethasone.

Conclusions: Parents of ALL patients report sleep problems, high distress, and QoL impairment. Within the MR group, parental functioning did not differ on- and off-dexamethasone. However, MR parents reported clinical distress more often than SR parents, possibly reflecting differences in prognostic estimates and treatment burden. This perhaps includes the overall strain of cyclic dexamethasone. This study highlights the need for psychosocial support throughout treatment, regardless of risk stratification.
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http://dx.doi.org/10.1002/pbc.28697DOI Listing
November 2020

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

J Sleep Res 2021 04 16;30(2):e13029. Epub 2020 Mar 16.

Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1111/jsr.13029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047882PMC
April 2021

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

Chronobiol Int 2020 05 4;37(5):660-672. Epub 2020 Mar 4.

Princess Máxima Center for Pediatric Oncology , Utrecht, The Netherlands.

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.
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http://dx.doi.org/10.1080/07420528.2020.1727916DOI Listing
May 2020

High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy.

Pediatr Blood Cancer 2020 04 15;67(4):e28165. Epub 2020 Jan 15.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Objective: To assess sleep problems (prevalence and predictors) in pediatric patients with acute lymphoblastic leukemia (ALL) after the most intensive phase of therapy (induction).

Methods: Patients (≥2 years) treated according to the Dutch ALL-11 protocol were included. Sleep was measured using parent-reports and self-reports (Children's Sleep Habits Questionnaire; CSHQ) and actigraphy. Parental sleep (Medical Outcome Study Sleep Scale) and distress and parenting problems (Distress Thermometer for Parents) were assessed with questionnaires. Z-scores were calculated for total CSHQ scores using age-appropriate scores of healthy Dutch children. The prevalence of sleep problems (defined as a Z-score > 1) in patients with ALL was compared to healthy children (chi-square tests). Actigraphic sleep estimates were collected in healthy Dutch children (n = 86, 2-18 years) for comparison with patients (linear regression). Determinants of parent-reported child sleep (total CSHQ Z-score) were identified with regression models.

Results: Responses were collected for 124 patients (response rate 67%), comprising 123 parent-reports, 34 self-reports, and 69 actigraphy assessments. Parents reported sleep problems in 38.0% of the patients compared to 15.2% in healthy children (P < .001). Patients reported fewer sleep problems themselves: 12.1% compared to 15.8% in healthy children (P = .33). Total time in bed (B (95% CI): 22.89 (9.55-36.22)) and total sleep time (B (95% CI):16.30 (1.40-31.19)), as derived from actigraphy, were significantly longer in patients. More parent-reported child sleep problems were predicted by parenting problems, more parental sleep problems, bedroom sharing, and child's sleep medication use (explained variance: 27.4%).

Conclusions: Systematic monitoring of child and parental sleep and implementation of effective interventions may be a gateway to improve quality of survival in pediatric ALL.
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http://dx.doi.org/10.1002/pbc.28165DOI Listing
April 2020

Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.

Sleep 2020 06;43(6)

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Study Objectives: To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue.

Methods: A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients.

Results: In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant.

Conclusions: Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.
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http://dx.doi.org/10.1093/sleep/zsz320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294409PMC
June 2020

Causes of early death and treatment-related death in newly diagnosed pediatric acute myeloid leukemia: Recent experiences of the Dutch Childhood Oncology Group.

Pediatr Blood Cancer 2020 04 23;67(4):e28099. Epub 2019 Dec 23.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: With the current more effective treatment regimens for pediatric acute myeloid leukemia (AML), research on early death (ED), treatment-related mortality (TRM), and toxicity becomes increasingly important. The aim of this study was to give an overview of the frequency, clinical features, and risk factors associated with ED and TRM in first complete remission (CR1) during the last three consecutive treatment protocols of the Dutch Childhood Oncology Group (DCOG) between 1998 and 2014.

Methods: Incidence and risk factors associated with ED and TRM in CR1 were retrospectively studied in 245 patients treated according to the Dutch ANLL-97/AML-12 (n = 118), AML-15 (n = 60), or DB AML-01 (n = 67) protocols.

Results: The incidence of ED was, respectively, 5.1%, 6.7%, and 3.0% excluding deaths before treatment (P = NS), and 7.4%, 11.1%, and 4.4% including deaths before the onset of treatment. Severe underweight at initial diagnosis was significantly associated with more frequent ED. When relapse was included as a competing risk, cumulative incidence of death in CR1 were 5.9%, 5.0%, and 4.6% for ANLL97, AML15, and DB01, respectively (P = NS). The most important cause of TRM included infectious and SCT-related complications.

Conclusion: We report relatively stable rates of ED and TRM in CR1 in the latest completed DCOG protocols for newly diagnosed AML patients. The most important causes of TRM were SCT- or infection-related, warranting further evaluation and awareness.
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http://dx.doi.org/10.1002/pbc.28099DOI Listing
April 2020

Determinants of health-related quality of life proxy rating disagreement between caregivers of children with cancer.

Qual Life Res 2020 Apr 9;29(4):901-912. Epub 2019 Dec 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Purpose: Proxy reports of health-related quality of life (HRQoL) are commonly used in pediatric oncology. However, it is not known if caregivers' reports differ. This study therefore aims to compare paternal and maternal proxy reports, and explore determinants of couple disagreement (sociodemographic and medical characteristics, and parental QoL and distress).

Methods: Both parents completed the PedsQL generic (child's HRQoL), Short Form-12 (own QoL) and Distress Thermometer for Parents. To assess agreement in child HRQoL, intra-class correlation coefficients (ICCs) were calculated. Differences between fathers/mothers were assessed with paired t tests. Systematic disagreement patterns were visualized with Bland-Altman plots. Characteristics of parental couples with a mean proxy difference in the highest quartile (highest proxy score minus lowest proxy score) were explored with multiple logistic regression analysis.

Results: Parents of 120 children with cancer (87% post-treatment, mean age 11.0 ± 5.7 years) participated. No significant differences were found between paternal and maternal proxy scores, and agreement was good on all scales (ICCs 0.65-0.83). Bland-Altman plots revealed no systematic disagreement patterns, but there was a wide range in magnitude of the differences, and differences went in both directions. Couples with a mean proxy difference (irrespective of which direction) in the highest quartile (± 20 points) were more likely to have a child in active treatment, with retinoblastoma or relapsed disease, and to diverge in their own QoL.

Conclusions: If proxy reports of only one parent are available, clinicians may reasonably assume that paternal and maternal reports are interchangeable. However, if in doubt, respondent's sex is not of major importance, but clinicians should be aware of patient's and family's characteristics.
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http://dx.doi.org/10.1007/s11136-019-02365-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142061PMC
April 2020

A call to action for expanded sleep research in pediatric oncology: A position paper on behalf of the International Psycho-Oncology Society Pediatrics Special Interest Group.

Psychooncology 2020 03 3;29(3):465-474. Epub 2019 Nov 3.

St. Jude Children's Research Hospital, Department of Psychology, Memphis, Tennessee.

Sleep and circadian rhythms are closely related to physical and psychosocial well-being. However, sleep and circadian rhythm disruptions are often overlooked in children with cancer, as they are frequently considered temporary side effects of therapy that resolve when treatment ends. Yet, evidence from adult oncology suggests a bidirectional relationship wherein cancer and its treatment disrupt sleep and circadian rhythms, which are associated with negative health outcomes such as poor immune functioning and lower survival rates. A growing body of research demonstrates that sleep problems are prevalent among children with cancer and can persist into survivorship. However, medical and psychosocial outcomes of poor sleep and circadian rhythmicity have not been explored in this context. It is essential to increase our understanding because sleep and circadian rhythms are vital components of health and quality of life. In children without cancer, sleep and circadian disturbances respond well to intervention, suggesting that they may also be modifiable in children with cancer. We present this paper as a call to (a) incorporate sleep or circadian rhythm assessment into pediatric cancer clinical trials, (b) address gaps in understanding the bidirectional relationship between sleep or circadian rhythms and health throughout the cancer trajectory, and (c) integrate sleep and circadian science into oncologic treatment.
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http://dx.doi.org/10.1002/pon.5242DOI Listing
March 2020

Concurrence of sleep problems and distress: prevalence and determinants in parents of children with cancer.

Eur J Psychotraumatol 2019 22;10(1):1639312. Epub 2019 Jul 22.

Pediatric Oncology-Hematology, Cancer Center Amsterdam, Amsterdam UMC, Emma Children's Hospital, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. : The aim of this study is to assess the prevalence of sleep problems and the concurrence with distress in parents of children treated for cancer, and to identify predictors of this symptom clustering. : Parents completed the Medical Outcomes Study (MOS) Sleep Scale and Distress Thermometer for Parents (DT-P). Clinically relevant sleep problems were defined as a score >1SD above the norm and clinical distress as a thermometer score above the established cut-off of 4. Four parent categories were constructed: neither sleep problems nor distress; no distress but sleep problems; no sleep problems but distress; both sleep problems and distress. Predictive determinants (sociodemographic, medical, psychosocial) for each category were assessed with multilevel multinomial logistic regression. : Parents (202 mothers and 150 fathers) of 231 children with different cancers participated. Mean time since diagnosis was 3.3 ± 1.4 years (90% off-treatment). The prevalence of sleep problems was 37%. Fifty percent of parents reported neither sleep problems nor distress, 9% had only sleep problems, 13% only distress, and 28% reported both. Compared to parents without sleep problems or distress, parents who reported both were more likely to report parenting problems (OR 4.4, [2.2-9.1]), chronic illness (OR 2.8, [1.2-6.5]), insufficient social support (OR 3.7, [1.5-9.1]), pre-existent sleep problems (OR 6.2, [2.0-18.6]) and be female (OR 1.8, [1.1-4.2]). : Sleep problems are common in parents of children treated for cancer, and occur mostly in the presence of clinical distress. Future research must show which interventions are most effective in this group: mainly targeted at sleep improvement or with prominent roles for stress management or trauma processing.
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http://dx.doi.org/10.1080/20008198.2019.1639312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691919PMC
July 2019

Longitudinal development of cancer-related fatigue and physical activity in childhood cancer patients.

Pediatr Blood Cancer 2019 12 22;66(12):e27949. Epub 2019 Aug 22.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Purpose: Cancer-related fatigue is one of the most distressing side effects of childhood cancer treatment. Physical activity can decrease fatigue and has positive effects on other health outcomes. Most research on physical activity pertains to adults, and the few studies that focus on children have limited follow-up time. This study evaluates cancer-related fatigue in children and its association with physical activity over a one-year time period.

Methods: Sixty-eight children with cancer (7-18 years) were recruited during or within the first year after treatment. Physical activity (Actical activity monitor) and cancer-related fatigue (Pediatric Quality-of-Life Questionnaire Multidimensional Fatigue Scale (PedsQL-MFS), self- and parent- reports) were assessed at baseline, 4 months, and 12 months. PedsQL-MFS scores were compared with Dutch norms. Longitudinal association of cancer-related fatigue with physical activity was evaluated (No. NTR 1531).

Results: Generally, PedsQL-MFS scores were worse than norms at baseline and 4 months, and recovered by 12 months except for the parent-proxy scores in adolescents. Younger children (≤12 years) self-reported comparable or better scores than norms. Physical activity generally improved over time, but patients mostly remained sedentary. During follow-up, increased physical activity was associated with less cancer-related fatigue.

Conclusion: Cancer-related fatigue in children improves over time, and increased physical activity is associated with less cancer-related fatigue. Given the sedentary lifestyle of this population, the positive effect of physical activity on cancer-related fatigue, and the many other health benefits of an active lifestyle, it is important to stimulate physical activity in childhood cancer patients and survivors.
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http://dx.doi.org/10.1002/pbc.27949DOI Listing
December 2019

High occurrence of sleep problems in survivors of a childhood brain tumor with neurocognitive complaints: The association with psychosocial and behavioral executive functioning.

Pediatr Blood Cancer 2019 11 16;66(11):e27947. Epub 2019 Aug 16.

Princess Màxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: Survivors of childhood brain tumors are prone to sleep and neurocognitive problems. Effective interventions to improve neurocognitive functioning are largely lacking. In general, sleep problems are negatively related to neurocognitive functioning, but this relationship is unclear in survivors of childhood brain tumors. Therefore, the occurrence of sleep problems, potential risk factors, and the relation between sleep and executive functioning were evaluated.

Procedure: Baseline data of a randomized controlled trial on the effectiveness of neurofeedback were used. Childhood brain tumor survivors 8-18 years of age with parent-reported neurocognitive complaints ≥2 years after treatment were eligible. Parents completed the Sleep Disturbance Scale for Children. Executive functioning was assessed by parents and teachers (Behavior Rating Inventory of Executive Functioning). Multiple linear regression analyses were used to examine sociodemographic and medical characteristics and emotional difficulties and hyperactivity/inattention (Strength and Difficulties Questionnaire) as potential risk factors for sleep problems, and to assess the association between sleep and executive functioning.

Results: Forty-eight percent of survivors (n = 82, 7.0 ± 3.6 years post diagnosis, age 13.8 ± 3.2 years) had sleep problems and scored significantly worse than the norm on the subscales Initiating and Maintaining Sleep, Excessive Somnolence, and the total scale (effect sizes 0.58-0.92). Emotional problems and/or hyperactivity/inattention were independent potential risk factors. Sleep problems were associated with worse parent-reported executive functioning.

Conclusions: Sleep problems occur among half of childhood brain tumor survivors with neurocognitive problems, and are associated with worse executive functioning. Future studies should focus on the development of sleep interventions for this population, to improve sleep as well as executive functioning.
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http://dx.doi.org/10.1002/pbc.27947DOI Listing
November 2019

Health-Related Quality of Life of Adolescents with Cancer During the First Year of Treatment.

J Adolesc Young Adult Oncol 2019 10 3;8(5):616-622. Epub 2019 Jul 3.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Adolescents with cancer (aged 12-18 years) are at risk for impaired health-related quality of life (HRQoL). Little is known about this population during treatment. This study aimed to (1) determine the HRQoL of adolescents with cancer during the first year of treatment and compare them with age-matched peers and (2) obtain insight into cancer-specific HRQoL of adolescents during the first year of treatment. Participants were part of a larger study focused on routine monitoring of electronic reported outcomes in standard pediatric oncology care. Adolescents completed the pediatric quality of life inventory (PedsQL) 4.0 and the PedsQL Cancer Module 3.0. Mean generic HRQoL scale scores were compared between the groups using multivariate analysis of covariance. Cancer-specific item scores were dichotomized and percentages were calculated to determine the proportion of adolescents reporting presence or absence of problems. A total of 73 (mean []  14.71, standard deviation [] = 1.85) adolescents with cancer ( = 14.71,  = 1.85,  = 3.51 months,  = 2.8) and 268 healthy peers ( = 14.23,  = 1.51) participated. Adolescents with cancer reported significantly lower generic HRQoL scores on all domains than their peers ( <0.05,  0.01-0.42). Most frequently reported cancer-specific HRQoL problems were pain (hurt joint/muscle, 42.9%), nausea (during medical treatments [47.1%]; food not tasting good [54.3%]; food and smells [61.4%]), worry (about relapse [45.7%]; about side effects [52.9%]), cognitive problems (paying attention [47.1%]), and physical appearance (not good looking [47.1%]). Adolescents with cancer showed impaired HRQoL during treatment on both physical and psychosocial domains. Close monitoring of physical and psychosocial symptoms during treatment is, therefore, important.
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http://dx.doi.org/10.1089/jayao.2019.0017DOI Listing
October 2019

Fatigue in childhood chronic disease.

Arch Dis Child 2019 11 7;104(11):1090-1095. Epub 2019 Jun 7.

Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Objectives: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL).

Design And Setting: Cross-sectional study in two children's hospitals.

Patients: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic.

Outcome Measures: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method.

Results: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains.

Conclusions: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.
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http://dx.doi.org/10.1136/archdischild-2019-316782DOI Listing
November 2019

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

Pediatr Blood Cancer 2019 01 23;66(1):e27458. Epub 2018 Sep 23.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

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% lower without intensive asparaginase treatment if asparaginase is stopped after a reaction. Thus, the costs per LYS were $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.
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http://dx.doi.org/10.1002/pbc.27458DOI Listing
January 2019

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

Pediatr Blood Cancer 2017 Dec 2;64(12). Epub 2017 Aug 2.

Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

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/m ) or ALL-10 protocol (native Escherichia coli asparaginase followed by 2,500 IU/m 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/m 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/m ($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/m .

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.
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http://dx.doi.org/10.1002/pbc.26651DOI Listing
December 2017

Determinants of quality of life during induction therapy in pediatric acute lymphoblastic leukemia.

Support Care Cancer 2014 Dec 11;22(12):3235-42. Epub 2014 Jul 11.

Department of Pediatrics, VU University Medical Center Amsterdam, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands,

Purpose: Improvement in survival of pediatric acute lymphoblastic leukemia (ALL) has increased the attention to quality of life (QoL) . QoL is impaired during maintenance treatment, but little is known about QoL during induction therapy. Identification of patients with poor QoL during induction will provide opportunities for early interventions, and may subsequently improve future QoL. This national multi-center study aimed to assess QoL and its determinants during ALL induction treatment.

Methods: Proxy reports of the Child Health Questionnaire (CHQ) and the PedsQL cancer version were collected. Child, treatment, and parental characteristics were analyzed as potential determinants in a multiple regression model.

Results: One hundred thirty parents of children participated (response rate 82 %), median child age was 5.7 years and 48 % were female. QoL, as measured with the CHQ, was significantly lower than the norm, the effect sizes were large, and the differences were clinically relevant. Physical QoL was more often affected than psychosocial QoL. Regression models could be constructed for 4/ 10 CHQ scales and 6/ 8 PedsQL cancer scales, accounting for 7 to 36 % of the variance in scores. Impaired QoL was most often associated with older children, girls, and time since diagnosis. Also, father respondents seem to have a lower QoL perception compared to mother respondents although this needs to be confirmed in future research.

Conclusions: Specific counseling for subsets of patients with a higher risk of low QoL during the early phases of therapy is warranted.
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http://dx.doi.org/10.1007/s00520-014-2349-2DOI Listing
December 2014

Health status utilities in pediatrics: a systematic review of acute lymphoblastic leukemia.

Med Decis Making 2014 01 25;34(1):21-32. Epub 2013 Jul 25.

Department of Pediatrics, VU University Medical Center Amsterdam, Amsterdam, the Netherlands (AK, RJBJG)

Background: Measuring utilities and health-related quality of life (HRQL) in children is challenging due to their cognitive abilities and changing developmental stages.

Purpose: . To identify methodological issues on utility measurements in children, we performed a systematic review on utilities measured with a single instrument, the Health Utilities Index (HUI), in pediatric acute lymphoblastic leukemia (ALL). The secondary goal was to facilitate future cost-utility analyses without the need for time-consuming assessments. Data Sources. PubMed, Embase, Cochrane Library, CINAHL, and PsycINFO were searched from inception to June 2012. Studies had to report on utility scores in pediatric ALL, either on or after treatment, to be included.

Results: . Fifteen studies were included. Most studies had methodological shortcomings, which mainly concerned

Study Design: and definition and representativeness of the study group. Utility scores were dependent on treatment variables, and there generally was an improvement in HRQL as treatment or survivorship advanced. In general, proxy-respondents were less reliable for subjective phenomena than for observable conditions. HUI2 and HUI3 scores were not interchangeable. Limitations. Studies may have been missed because no validated search method for utility studies exists, due to language bias or the exclusion of non-peer-reviewed papers.

Conclusions: . Most studies in this review were methodologically suboptimal. Future developments should focus on including developmentally appropriate items for the whole pediatric age group. Adding disease-specific domains may enhance the sensitivity and responsiveness of instruments. Efforts should be undertaken to elicit valuation of health states from older children and teenagers as much as possible. For now, it remains difficult to make valid and informed decisions on the financing of interventions until health state valuation in children has become more methodologically robust.
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http://dx.doi.org/10.1177/0272989X13497263DOI Listing
January 2014

Cost-analysis of treatment of childhood acute lymphoblastic leukemia with asparaginase preparations: the impact of expensive chemotherapy.

Haematologica 2013 May 12;98(5):753-9. Epub 2013 Feb 12.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands.

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.
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http://dx.doi.org/10.3324/haematol.2012.073510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640120PMC
May 2013
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