Parental Sleep, Distress, and Quality of Life in Childhood Acute Lymphoblastic Leukemia:A Longitudinal Report from Diagnosis up to Three Years Later

This study assessed sleep, distress and quality of life (QoL) in parents of children with acute lymphoblastic leukemia (ALL) from diagnosis to three years after, and the impact of sleep and distress on QoL. Additionally, this study explored determinants of sleep and distress. Parents completed the MOS Sleep, Distress Thermometer for Parents and SF-12 at four-five months (T0), one year (T1), two years (T2), and three years (T3) after diagnosis. The course of outcomes and longitudinal impact of clinically relevant sleep problems (>1SD above reference’s mean) and clinical distress (score ≥ 4) on QoL Z-scores were assessed with linear mixed-models. Determinants of sleep and distress were assessed with multinomial mixed-models. Parents (81% mothers) of 139 patients (60% males; 76% medium-risk (MR)) participated. Distress and QoL gradually restored from T0 to T3. Sleep problems improved, but were still elevated at T3: 33% reported clinically relevant sleep problems, of which 48% in concurrence with distress. Over time, presence of sleep problems or distress led to lower mental QoL Z-scores (SD-score −0.2 and −0.5, respectively). Presence of both led to a cumulatively lower Z-score (SD-score −1.3). Parents in the latter group were more likely to report insufficient social support, parenting problems, a chronic illness, pain for their child, having a child with MR-ALL, and being closer to diagnosis. In conclusion, parental well-being improves over time, yet sleep problems persist. In combination with ongoing distress, they cumulatively affect QoL. Special attention should be given to parents who are vulnerable to worse outcomes

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

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

Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia:a national, prospective, longitudinal study in the Netherlands

OBJECTIVES: Health-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse, which is now reflected by the stratification of patients into three risk groups who receive treatment of differing intensities. This study is the first to evaluate the longitudinal course of HRQoL in light of these adjustments and identify determinants of HRQoL. DESIGN: Two prospective, national cohort studies (add-on studies within the two most recent treatment protocols for children with ALL (ALL-10 and ALL-11)). SETTING: Dutch paediatric oncology hospitals between October 2006 and October 2009 (ALL-10) and between August 2013 and July 2017 (ALL-11).PARTICIPANTS: Patients with ALL (2-18 years) are treated according to the ALL-10 or ALL-11 treatment protocol. Patients treated according to the ALL-10 protocol only completed a cancer-specific QoL measure and patients treated according to the ALL-11 protocol completed both a cancer-specific and generic QoL measure (see below). OUTCOME MEASURES: HRQoL, assessed with parent-proxy questionnaires (PedsQL Generic and Cancer module) within the first 5 months (T0), at 1 year (T1), 2 years (T2) and 3 years (T3) after diagnosis. The proportion of patients with clinically relevant generic HRQoL impairment was compared with healthy norm values. Multivariable mixed model analyses were used to evaluate the development of HRQoL over time and its medical and sociodemographic determinants (collected on enrolment). RESULTS: Of the ALL-10 cohort, 132 families participated and of the ALL-11 cohort, 136 families participated (268 total). Thus, cancer-specific HRQoL assessments were available for 268 patients (median age 5.3 years (IQR 6.15), 56.0% boys, 69.0% medium-risk ALL), and generic HRQoL assessments for 136 patients (median age 4.8 years (IQR 6.13), 60.3% boys, 75.0% medium-risk ALL). Generic HRQoL improved between timepoints T0 and T3 (total score B 16.1, 95% CI 12.2 to 20.1, p&lt;0.001), but did not restore to normal 1 year after the end of treatment: 28.0% of children remained impaired compared with 16% in the general population (p=0.003). Cancer-specific HRQoL generally improved from T0 to T2 (Pain B 11.3, 95% CI 7.1 to 15.5; Nausea B 11.7, 8.4 to 15.1; Procedural Anxiety B 19.1, 14.8 to 23.4; Treatment Anxiety B 12.8, 9.5 to 16.0; Worry B 3.5, 0.6 to 6.3; Communication B 8.5, 5.0 to 11.9; all p&lt;0.001 except for Worry (p=0.02)), while Physical Appearance and Cognitive Functioning remained stable. Higher treatment intensity and experiencing pain or simultaneous chronic illness were associated with lower HRQoL over time for multiple subscales. CONCLUSIONS: HRQoL impairment is prevalent during and after ALL treatment. Patients with standard-risk ALL and reduced treatment intensity have better HRQoL than patients in higher risk groups. Systematic monitoring of HRQoL is of utmost importance in order to provide timely psychosocial interventions and supportive care.</p

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpos

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

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia

Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is an update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 6, 2014), MEDLINE/PubMed (from 1945 to June 2014), and EMBASE/Ovid (from 1980 to June 2014). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 to 2013), and ongoing trial databases (the ISRCTN register and the NIH register via http://www.controlled-trials.com in June 2014). All study designs, except case reports and patient series with fewer than 10 children, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which another review author checked. We identified eight studies (total of 218 children), including two randomised controlled trials (RCTs), that assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, we could not pool results. All of the studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all children in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCTs, the occurrence and duration of adrenal insufficiency did not differ between the prednisone and dexamethasone arms. In one study, it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. Furthermore, one of the studies evaluated the presence of infections or stress episodes, or both as a risk factor for adrenal insufficiency. The authors found no relationship between the presence of infection/stress and adrenal insufficiency. We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available, we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.Finally, it would be relevant to further investigate the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpos

Gender-specific differences in parental health-related quality of life in childhood cancer

Background: Parents of children with cancer are at risk for impaired health-related quality of life (HRQoL). Most prior research has focused on the HRQoL of mothers. The aim of this study is to describe HRQoL in mothers and fathers, and determine the influence of sociodemographic, medical, and psychosocial factors. Procedure: In a cross-sectional study, both parents completed questionnaires on sociodemographics, distress, and HRQoL. Parental HRQoL was compared to healthy population values. Differences between mothers and fathers were evaluated with multilevel analysis. Gender-specific HRQoL determinants were assessed via multiple linear regression analysis. Results: Parents (202 mothers, 150 fathers; comprising 121 couples) of 231 children with different cancer diagnoses (mean time since diagnosis 3.3 ± 1.4 years, 90% posttreatment) participated. Compared to healthy women and men, mothers and fathers reported significantly impaired HRQoL on the following domains: cognitive functioning, sleep, daily activities, and vitality (Cohen's d = 0.3-0.9). Additionally, maternal HRQoL was reduced on the domains gross motor functioning, pain, social functioning, sexuality, and depressive emotions. Mothers scored worse than fathers on six of 12 domains. Risk factors for adverse outcomes in both parents were higher distress, emotional and parenting problems, little social support, medication use, and active treatment of the child. Other determinants in mothers were non-Dutch background and unemployment, while lower HRQoL in fathers was predicted by their child's diagnosis type, shorter time since diagnosis, and treatment intensity. Conclusion: These outcomes illustrate the need for family-centered care. Future interventions aimed at improving parental functioning should take into account gender-specific differences in HRQoL to reach optimal efficacy

Concurrencia de problemas de sueño y sufrimiento: prevalencia y determinantes en padres de niños con cáncer

Background: Parents of children with cancer are at risk for sleep problems. If these problems persist, an important perpetuating factor might be ongoing parental distress. Objective: 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. Method: 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. Results: 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]). Conclusions: 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