A randomized double-blind placebo-controlled trial of the effectiveness of melatonin on neurocognition and sleep in survivors of childhood cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk of developing sleep and neurocognitive problems, yet few efficacious interventions exist targeting these prevalent late effects. Melatonin has known sleep-promoting effects; however, it has not been well studied among childhood cancer survivors. METHOD: Survivors (n = 580; mean age = 33.5 years; 26 years post-diagnosis) from the St. Jude Lifetime Cohort were randomized (1:1) to a six-month double-blind placebo-controlled trial of 3 mg time-release melatonin within three strata (stratum 1: neurocognitive impairment only; stratum 2: neurocognitive and sleep impairment; stratum 3: sleep impairment only). Neurocognitive performance was assessed at baseline and post-intervention using standardized measures. Sleep was assessed via self-report and actigraphy. Independent sample t tests compared mean change scores from baseline to six months. Post-hoc analyses compared the prevalence of clinically significant treatment responders among melatonin and placebo conditions within and across strata. RESULTS: Intent-to-treat analyses revealed no statistically significant differences in neurocognitive performance or sleep from baseline to post-intervention. However, among survivors with neurocognitive impairment only, a larger proportion randomized to melatonin versus placebo demonstrated a treatment response for visuomotor speed (63% vs 41%, P = 0.02) and nonverbal reasoning (46% vs 28%, P = 0.04). Among survivors with sleep impairment only, a larger proportion treated with melatonin demonstrated a treatment response for shifting attention (44% vs 28%, P = 0.05), short-term memory (39% vs 19%, P = 0.01), and actigraphy-assessed sleep duration (47% vs 29%, P = 0.05). CONCLUSION: Melatonin was not associated with improved neurocognitive performance or sleep in our intent-to-treat analyses; however, a subset of survivors demonstrated a clinically significant treatment response.

The role of body image dissatisfaction in the association between treatment-related scarring or disfigurement and psychological distress in adult survivors of childhood cancer.

OBJECTIVE: To examine the potential mediating role of body image dissatisfaction on the association between treatment-related scarring/disfigurement and psychological distress in adult survivors of childhood cancer. METHODS: Participants included 1714 adult survivors of childhood cancer (mean [SD] age at evaluation = 32.4 [8.0] years, time since diagnosis = 24.1 [8.1] years) enrolled in the St. Jude Lifetime Cohort Study. Survivors completed measures of body image, emotional distress, and posttraumatic stress symptoms (PTSS). Body image dissatisfaction (BID) was categorized into 2 groups (cancer-related and general) based on factor analysis. Using causal mediation analysis, we estimated the proportion of psychological distress associated with treatment-related scarring/disfigurement that could be eliminated by resolving BID through a hypothetical intervention. RESULTS: Among survivors with scarring/disfigurement of the head, a sizable proportion of the relative excess of psychological distress could be eliminated if BID was successfully treated (males: [cancer-related BID: depression: 63%; anxiety: 100%; PTSS: 52%]; [general BID: depression: 70%; anxiety: 100%; PTSS: 42%]; females: [cancer-related BID: depression: 20%; anxiety; 36%; PTSS: 23%]; [general BID: depression: 32%; anxiety: 87%; PTSS: 38%]). The mediating effect of BID was less pronounced for the association between scarring/disfigurement of the body and psychological distress for both males and females. CONCLUSIONS: Body image dissatisfaction mediates the association treatment-related scarring/disfigurement and psychological distress among adult survivors of childhood cancer, particularly among survivors with scarring/disfigurement of the head and male survivors. Successful treatment of body image dissatisfaction has the potential to eliminate a substantial proportion of psychological distress related to scarring/disfigurement among adult survivors of childhood cancer.

Behavioral, Social, and Emotional Symptom Comorbidities and Profiles in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

PURPOSE: In the general population, psychological symptoms frequently co-occur; however, profiles of symptom comorbidities have not been examined among adolescent survivors of childhood cancer. PATIENTS AND METHODS: Parents of 3,893 5-year survivors of childhood cancer who were treated between 1970 and 1999 and who were assessed in adolescence (age 12 to 17 years) completed the Behavior Problems Index. Age- and sex-standardized z scores were calculated for symptom domains by using the Childhood Cancer Survivor Study sibling cohort. Latent profile analysis identified profiles of comorbid symptoms, and multivariable multinomial logistic regression modeling examined associations between cancer treatment exposures and physical late effects and identified symptom profiles. Odds ratios (ORs) and 95% CIs for latent class membership were estimated and analyses were stratified by cranial radiation therapy (CRT; CRT or no CRT). RESULTS: Four symptoms profiles were identified: no significant symptoms (CRT, 63%; no CRT, 70%); elevated anxiety and/or depression, social withdrawal, and attention problems (internalizing; CRT, 31%; no CRT, 16%); elevated headstrong behavior and attention problems (externalizing; CRT, no observed; no CRT, 9%); and elevated internalizing and externalizing symptoms (global symptoms; CRT, 6%; no CRT, 5%). Treatment with ≥ 30 Gy CRT conferred greater risk of internalizing (OR, 1.7; 95% CI, 1.0 to 2.8) and global symptoms (OR, 3.2; 95% CI, 1.2 to 8.4). Among the no CRT group, corticosteroid treatment was associated with externalizing symptoms (OR, 1.9; 95% CI, 1.2 to 2.8) and ≥ 4.3 g/m(2) intravenous methotrexate exposure was associated with global symptoms (OR, 1.5; 95% CI, 0.9 to 2.4). Treatment late effects, including obesity, cancer-related pain, and sensory impairments, were significantly associated with increased risk of comorbid symptoms. CONCLUSION: Behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors of childhood cancer and are associated with treatment exposures and physical late effects. Assessment and consideration of symptom profiles are essential for directing appropriate mental health treatment for adolescent survivors.

Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

PURPOSE: To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol. PATIENTS AND METHODS: This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education. RESULTS: Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue. CONCLUSION: Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.

Long-Term Neurocognitive Functioning and Social Attainment in Adult Survivors of Pediatric CNS Tumors: Results From the St Jude Lifetime Cohort Study.

PURPOSE: To assess the prevalence and severity of neurocognitive impairment in adult survivors of pediatric CNS tumors and to examine associated treatment exposures. PATIENTS AND METHODS: Participants included 224 survivors of CNS tumors who were treated at St Jude Children's Research Hospital (current median age [range], 26 years [19 to 53 years]; time from diagnosis, 18 years [11 to 42 years]) and completed neurocognitive testing. Information on cranial radiation therapy (CRT) doses and parameters of delivery were abstracted from medical records. The prevalence of severe impairment (ie, at least two standard deviations below normative mean) was compared across radiation treatment groups (no CRT, focal irradiation, craniospinal irradiation) using the χ(2) test. Log-binomial models were used to estimate risk ratios (RRs) and corresponding 95% CIs for severe impairment. RESULTS: In multivariable models, craniospinal irradiation was associated with a 1.5- to threefold increased risk of severe impairment compared with no CRT (eg, intelligence: RR = 2.70; 95% CI, 1.37 to 5.34; memory: RR = 2.93; 95% CI, 1.69 to 5.08; executive function: RR = 1.74; 95% CI, 1.24 to 2.45). Seizures were associated with impaired academic performance (RR = 1.48; 95% CI, 1.02 to 2.14), attention (RR = 1.54; 95% CI, 1.12 to 2.13), and memory (RR = 1.44; 95% CI, 1.04 to 1.99). Hydrocephalus with shunt placement was associated with impaired intelligence (RR = 1.78; 95% CI, 1.12 to 2.82) and memory (RR = 1.42; 95% CI, 1.03 to 1.95). Differential follow-up time contributed to variability in prevalence estimates between survivors treated with older nonconformal and those treated with more contemporary conformal radiation therapy methods. Neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living. CONCLUSION: Survivors of pediatric CNS tumors are at risk of severe neurocognitive impairment in adulthood. The prevalence of severe impairment is greater than expected in the general population, even in the absence of CRT, and is associated with disrupted attainment of adult social milestones.

Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma.

IMPORTANCE: This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. OBJECTIVE: To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. MAIN OUTCOMES AND MEASURES: Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. RESULTS: Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, -1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed (-0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). CONCLUSIONS AND RELEVANCE: Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Emotional distress in parents of long-term survivors of childhood acute lymphoblastic leukemia.

OBJECTIVE: The current study investigated the occurrence of emotional distress in parents of long-term survivors of childhood acute lymphoblastic leukemia (ALL) and identified factors associated with parent emotional distress symptoms. METHODS: Parents of 127 long-term survivors of childhood ALL treated on a chemotherapy-only protocol at St. Jude Children's Research Hospital participated in the study. Parents completed standard ratings of emotional distress, caregiver strain, and child physical, emotional, and psychosocial functioning. Multivariable hierarchical linear regression analyses were used to examine associations between symptoms of caregiver strain, survivor functioning, and parent emotional distress. Covariates included parent education, survivor age, survivor sex, and time since childhood cancer diagnosis. RESULTS: On average, few parents reported significant symptoms of emotional distress. Clinically significant levels of anxiety and depression were reported by 7.1% and 3.1% of parents, respectively. Only 3.9% of parents endorsed significant symptoms of posttraumatic stress. Perceived caregiver strain was significantly associated with symptoms of parent anxiety, depression, and posttraumatic stress. Parent-report of child emotional functioning was significantly associated with symptoms of parent anxiety. CONCLUSIONS: Most parents of long-term survivors of ALL exhibit low levels of emotional distress in the context of rates observed in the general population. Perceived caregiver strain was significantly associated with parent emotional distress. Further research is required to examine specific sources of caregiver strain, as well as other risk and protective factors associated with parent emotional distress symptoms.

Predictors of health care utilization in adult survivors of childhood cancer exposed to central nervous system-directed therapy.

BACKGROUND: Survivors of childhood cancer treated with central nervous system (CNS)-directed therapy may be at risk for poor health care utilization because of neurocognitive deficits. This study examined associations between neurocognitive function and adherence to routine and risk-based medical evaluations in adult survivors exposed to CNS-directed therapy. METHODS: Neurocognitive function and health care utilization were assessed in 1304 adult survivors of childhood cancer enrolled in the St. Jude Lifetime Cohort Study. Adherence to recommended care was defined as meeting guidelines published by the Children's Oncology Group. Multivariate models were used to evaluate associations between neurocognitive function and health screenings. Established predictors of health care utilization were included as covariates. Odds ratios (ORs) or prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for variables maintained in the final models. RESULTS: Adherence to recommended medical care was higher for routine care (general physician care, 57.6%; dental care, 49.1%) versus specialized care (survivor-focused care, 21.9%; echocardiogram, 19.9%). Higher intelligence was predictive of general physician care (OR, 1.74; 95% CI, 1.41-2.15) and survivor-focused care (OR, 1.44; 95% CI, 1.13-1.83) in comparison with no care, whereas better executive function skills were associated with reduced dental care (PR, 0.94; 95% CI, 0.91-0.98). Echocardiogram monitoring was not associated with neurocognition. Possible late effects of cancer treatment (pain and reduced cardiorespiratory fitness) were associated with an increased likelihood of receiving specialized medical care. CONCLUSIONS: Survivors with reduced global cognition are at risk for poor health care utilization. Educational practices regarding recommended health care should be personalized to ensure comprehension by survivors with neurocognitive impairment.

Utility of the N-back task in survivors of childhood acute lymphoblastic leukemia.

The N-back task is often used in functional brain imaging studies to activate working memory networks; however, limited information is available on its association to clinical outcomes in children or cancer survivors. A total of 137 survivors of acute lymphoblastic leukemia (ALL; mean current age = 14.3 years, SD = 4.8; time since diagnosis = 7.6 years, SD = 1.6) completed the N-back task and comprehensive neurocognitive testing, including standardized measures of attention, processing speed, and working memory. Results indicated that females demonstrated significantly slower reaction times (0-back p = .02; 1-back p = .03) than males. Survivors <15 years old at the time of testing demonstrated a significant decrease in accuracy as working memory load increased compared to survivors ≥15 years old (p < .001). Performance on the N-back task was associated with nonverbal working memory (rs = .56, p < .001) in survivors ≥15 years of age. For younger survivors, N-back performance was more strongly associated with attention skills. Results suggest the N-back assesses different cognitive constructs at younger compared to older childhood ages. These age differences should be considered in interpreting functional brain imaging results.

Suicide ideation and associated mortality in adult survivors of childhood cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for suicide ideation, although longitudinal patterns and rates of recurrent suicide ideation are unknown. This study investigated the prevalence of late report (ie, after initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality. METHODS: Participants included 9128 adult survivors of childhood cancer and 3082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18 instrument. Mortality data was ascertained from the National Death Index. RESULTS: Survivors were more likely to report late (odds ratio [OR] =1.9, 95% confidence interval [CI] =1.5-2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8-3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3-2.7; recurrent: OR=1.9, 95% CI=1.2-2.9). Suicide ideation was associated with increased risk for all-cause mortality (hazard ratio=1.3, 95% CI=1.03-1.6) and death by external causes (hazard ratio=2.4, 95% CI=1.4-4.1). CONCLUSIONS: Adult survivors of childhood cancer are at risk for late-report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions.

Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study.

PURPOSE: To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion. RESULTS: Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment. CONCLUSION: This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.

Conceptualizing functional cognition in traumatic brain injury rehabilitation.

PRIMARY OBJECTIVE: To conceptualize functional cognitive constructs across the continuum of traumatic brain injury (TBI) recovery, to form the foundation for the Computer Adaptive Measure of Functional Cognition for TBI (CAMFC-TBI). BACKGROUND: TBI often has a profound impact on a survivor's ability to return to previous level of functioning and significantly reduces the overall quality of life for survivors and caregivers. Few assessments are designed to evaluate TBI's impact on cognitive functioning in everyday life. Neuropsychological tests are time consuming and may have questionable ecological validity for predicting functional outcomes. Global functional assessments contain few cognitive items and may lack psychometric rigour. Presently there is a lack of efficient, precise, ecologically valid functional cognitive measures. MAIN OUTCOME AND RESULTS: Studies that used neuropsychological and global functional assessments were reviewed to direct conceptualization of functional cognitive constructs across TBI recovery stages. An advisory panel reviewed study methodology and functional cognitive constructs development. They validated the need for the CAMFC-TBI and the six functional cognitive constructs: attention, memory, processing speed, executive functioning, social communication and emotional management. CONCLUSION: Conceptualizing functional cognitive constructs is the first step in CAMFC-TBI development. Future project stages include item pool development, qualitative testing, field-testing, psychometric analysis and computerized adaptive test programming.

Decreased static and dynamic postural control in children with autism spectrum disorders.

The purpose of this study was to investigate postural control in children with Autism Spectrum Disorders (ASD) during static and dynamic postural challenges. We evaluated postural sway during quiet stance and the center of pressure (COP) shift mechanism during gait initiation for 13 children with ASD and 12 age-matched typically developing (TD) children. Children with ASD produced 438% greater normalized mediolateral sway (p<0.05) and 104% greater normalized anteroposterior sway (p<0.05) than TD children. Consequently, normalized sway area was also significantly greater (p<0.05) in the group with ASD. Similarly, the maximum separation between the COP and center of mass (COM) during quiet stance was 100% greater in the anteroposterior direction (p<0.05) and 146% greater in the resultant direction (p<0.05) for children with ASD. No significant difference was observed in the mediolateral direction, in spite of the 123% greater separation detected in children with ASD. During gait initiation, no group differences were detected in the posterior COP shift mechanism, suggesting the mechanism for generating forward momentum is intact. However, significantly smaller lateral COP shifts (p<0.05) were observed in children with ASD, suggesting instability or an alternative strategy for generating momentum in the mediolateral direction. These results help to clarify some discrepancies in the literature, suggesting an impaired or immature control of posture, even under the most basic conditions when no afferent or sensory information have been removed or modified. Additionally, these findings provide new insight into dynamic balance in children with ASD.