A B S T R A C T PurposeTo determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL). Patients and MethodsSurvivors 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 Ն 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. ResultsImpairment 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 Ͻ .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. ConclusionThis 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.

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 MethodsThis 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. ResultsIntelligence 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. ConclusionSurvivors 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.

Background:This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer.Methods:Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported.Results:Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9% anxiety: 4.8% somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2% anxiety: 11.8% somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4–4.5; anxiety: OR=3.0; 95% CI=2.2–4.0; somatisation: OR=5.3; 95% CI=3.9–7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use.Conclusion:Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.

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 χ2 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.

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 MethodsParents 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). ResultsFour 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. ConclusionBehavioral, 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.