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1.  Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(36):4496-4503.
Purpose
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Methods
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
Results
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
Conclusion
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
doi:10.1200/JCO.2013.52.2268
PMCID: PMC3871511  PMID: 24248696
2.  Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(35):4407-4415.
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.
doi:10.1200/JCO.2012.48.2315
PMCID: PMC3842908  PMID: 24190124
3.  Association Between the Prevalence of Symptoms and Health-Related Quality of Life in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(33):4242-4251.
Purpose
We investigated the association between prevalence of symptoms and health-related quality of life (HRQOL) in adult survivors of childhood cancer enrolled in the St Jude Lifetime Cohort study.
Methods
Eligibility criteria include childhood malignancy treated at St Jude, survival ≥ 10 years from diagnosis, and current age ≥ 18 years. Study participants were 1,667 survivors (response rate = 65%). Symptoms were self-reported by using a comprehensive health questionnaire and categorized into 12 classes: cardiac; pulmonary; motor/movement; pain in head; pain in back/neck; pain involving sites other than head, neck, and back; sensation abnormalities; disfigurement; learning/memory; anxiety; depression; and somatization. HRQOL was measured by using physical/mental component summary (PCS/MCS) and six domain scores of the Medical Outcomes Study 36-Item Short-Form Health Survey. Multivariable regression analysis was performed to investigate associations between symptom classes and HRQOL. Cumulative prevalence of symptom classes in relation to time from diagnosis was estimated.
Results
Pain involving sites other than head, neck and back, and disfigurement represented the most frequent symptom classes, endorsed by 58.7% and 56.3% of survivors, respectively. Approximately 87% of survivors reported multiple symptom classes. Greater symptom prevalence was associated with poorer HRQOL. In multivariable analysis, symptom classes explained up to 60% of the variance in PCS and 56% of the variance in MCS; demographic and clinical variables explained up to 15% of the variance in PCS and 10% of the variance in MCS. Longer time since diagnosis was associated with higher cumulative prevalence in all symptom classes.
Conclusion
A large proportion of survivors suffered from many symptom classes, which was associated with HRQOL impairment.
doi:10.1200/JCO.2012.47.8867
PMCID: PMC3821013  PMID: 24127449
4.  Dexamethasone Exposure and Memory Function in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the SJLIFE Cohort 
Pediatric blood & cancer  2013;60(11):1778-1784.
Background
Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone.
Procedure
Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n=18] vs. prednisone [n=20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure.
Results
Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (p=0.01) and word recognition (p=0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size =1.3), though the small sample size limited statistical significance (p=0.08). Story memory was associated with altered activation in left inferior frontal-temporal brain regions (p=0.007).
Conclusions
Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function.
doi:10.1002/pbc.24644
PMCID: PMC3928631  PMID: 23775832
Leukemia; fMRI; memory; survivors; glucocorticoid; retrosplenium
5.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
Purpose
Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
Patients and Methods
In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
Results
Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E′; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E′]; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DLcocorr; P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E′, although impaired sustained attention and naming speed were associated with DLcocorr. Neurocognitive performance was associated with academic and vocational functioning.
Conclusion
These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.
doi:10.1200/JCO.2012.42.6841
PMCID: PMC3462045  PMID: 22949149
6.  Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2013;31(17):2182-2188.
Purpose
Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome.
Patients and Methods
Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity.
Results
Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01).
Conclusion
These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.
doi:10.1200/JCO.2012.46.7944
PMCID: PMC3731978  PMID: 23650422
7.  Oxidative Stress and Executive Function in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2009;53(4):551-556.
Background
Neurocognitive sequelae following treatment for pediatric acute lymphoblastic leukemia (ALL) has been reported in a significant proportion of survivors, including those treated only with chemotherapy. Early identification of children “at risk” for neurocognitive problems is not yet reliable. Biomarkers of oxidative stress (e.g., oxidated phosphatidylcholine) in cerebral spinal fluid (CSF) have been correlated with intensity of methotrexate (MTX) treatment, suggesting an association with acute central nervous system toxicity.
Procedure
This study examined the association between oxidized CSF phospholipids and executive functions throughout chemotherapy. Measures of oxidative stress and executive functions were examined in 88 children newly diagnosed with ALL. The children were followed over three years with neurocognitive testing and parent ratings of executive functions.
Results
Results demonstrated an association between increased oxidative stress following induction and consolidation and decreased executive function two years later. Younger age at diagnosis was associated with both an increase in oxidative stress and in executive dysfunction; younger age was associated with poorer ability to organize materials in one's environment (r(48) = 0.28, p < 0.05) and with greater oxidated phosphatidylcholine in CSF at the end of chemotherapy ( r(48) = −0.27, p < 0.05). As such, younger age appears to be the most prominent moderator of neurocognitive decline.
Conclusions
These results link functional changes to CSF biomarkers and underscore the importance of monitoring cognitive development in young children treated for ALL. Children with less advanced central nervous system development may be particularly vulnerable to the effects of chemotherapy.
doi:10.1002/pbc.22128
PMCID: PMC3928629  PMID: 19499584
oxidative stress; neurocognitive; leukemia
8.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Background
Adult survivors of childhood cancer are at-risk for suicide ideation, though longitudinal patterns and rates of recurrent suicide ideation are unknown. We investigated the prevalence of late report (i.e. post-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 9,128 adult survivors of childhood cancer and 3,082 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. 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 (HR) =1.3, 95% CI=1.03–1.6) and death by external causes (HR=2.4, 95% CI=1.4–4.1).
Conclusion
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.
doi:10.1002/cncr.28385
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
9.  Chemotherapy-related Changes in Central Nervous System Phospholipids and Neurocognitive Function in Childhood Acute Lymphoblastic Leukemia 
Leukemia & lymphoma  2012;54(3):10.3109/10428194.2012.717080.
Long-term survivors of childhood leukemia are at risk for neurocognitive impairment, though the neurophysiological basis is not well understood. The purpose of this study was to explore associations between changes in cerebrospinal fluid (CSF) phospholipids and neurocognitive function in children undergoing chemotherapy for acute lymphoblastic leukemia. 76 children were followed prospectively from diagnosis. CSF samples were collected during scheduled lumbar punctures and phospholipids were extracted. Neurocognitive evaluations were conducted annually beginning shortly after diagnosis. Concentrations of sphingomyelin (SM) increased following induction (p=0.03) and consolidation (p=0.04), while lysophosphatidylcholine (LPC) increased following induction (p=0.003). Multivariable analyses demonstrated associations between post-induction SM and motor speed at one (p<0.001), two (p=0.001), and three (p=0.02) years following diagnosis. Post-induction LPC was associated with verbal working memory (p=0.007). Results indicate early changes in phospholipids are related to neurocognitive decline and suggest a chemotherapy impact on white matter integrity.
doi:10.3109/10428194.2012.717080
PMCID: PMC3845091  PMID: 22856670
Cerebral Spinal Fluid; Childhood Leukemia; Neurocognitive; Phospholipids
10.  Cerebral white matter integrity and executive function in adult survivors of childhood medulloblastoma 
Neuro-Oncology  2012;14(Suppl 4):iv25-iv36.
Survivors of pediatric medulloblastoma are at risk for neurocognitive dysfunction. Reduced white matter integrity has been correlated with lower intelligence in child survivors, yet associations between specific cognitive processes and white matter have not been examined in long-term adult survivors. Twenty adult survivors of medulloblastoma were randomly recruited from a larger institutional cohort of adult survivors of childhood cancer. Survivors underwent comprehensive neurocognitive evaluations and MRI. Data on brain volume and cortical thickness and diffusion tensor imaging were acquired, including measures of fractional anisotropy, apparent diffusion coefficient, and axial and radial diffusivity. Observed neurocognitive scores were compared with population norms and correlated to MRI indices. Survivors were, on average, 29 years of age and 18 years postdiagnosis. Mean full-scale intelligence quotient was nearly 1 SD below the normative mean (86.3 vs 100, P = .004). Seventy-five percent of survivors were impaired on at least one measure of executive function. Radial diffusivity in the frontal lobe of both hemispheres was correlated with shifting attention (left: rs = −0.67, P = .001; right: rs = −0.64, P = .002) and cognitive flexibility (left: rs = −0.56, P = .01; right: rs = −0.54, P = .01). Volume and cortical thickness were not correlated with neurocognitive function. Neurocognitive impairment was common and involved many domains. Reduced white matter integrity in multiple brain regions correlated with poorer performance on tasks of executive function. Future research integrating diffusion tensor imaging should be a priority to more rigorously evaluate long-term consequences of cancer treatment and to inform cognitive intervention trials in this high-risk population.
doi:10.1093/neuonc/nos214
PMCID: PMC3480251  PMID: 23095827
diffusion tensor imaging; executive function; medulloblastoma; neurocognition
11.  Scarring, Disfigurement, and Quality of Life in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2012;30(20):2466-2474.
Purpose
Childhood cancer survivors are at increased risk for adverse outcomes and chronic medical conditions. Treatment-related scarring, disfigurement, and persistent hair loss, in addition to their long-term impact on psychological distress or health-related quality of life (HRQOL), have received little attention.
Patients and Methods
Self-reported scarring/disfigurement and persistent hair loss were examined in 14,358 survivors and 4,023 siblings from the Childhood Cancer Survivor Study. Multivariable models were used to examine associations with demographic and cancer treatment. The impact of disfigurement and hair loss on HRQOL (ie, Medical Outcomes Short Form–36) and emotional distress (ie, Brief Symptom Inventory–18) was examined.
Results
Survivors reported a significantly higher rate of scarring/disfigurement compared with siblings for head/neck (25.1% v 8.4%), arms/legs (18.2% v 10.2%), and chest/abdomen (38.1% v 9.1%), as well as hair loss (14.0% v 6.3%). In age-, sex-, and race-adjusted models, cranial radiation exposure ≥ 36 Gy increased risk for head/neck disfigurement (relative risk [RR], 2.42; 95% CI, 2.22 to 2.65) and hair loss (RR, 4.24; 95% CI, 3.63 to 4.95). Adjusting for cranial radiation, age, sex, race, education, and marital status, survivor hair loss increased risk of anxiety (RR, 1.60; 95% CI, 1.23 to 2.07), whereas head/neck disfigurement increased risk of depression (RR, 1.19; 95% CI, 1.01 to 1.41). Limitations due to emotional symptoms were associated with head/neck disfigurement (RR, 1.24; 95% CI, 1.10 to 1.41), arm/leg disfigurement (RR, 1.19; 95% CI, 1.05 to 1.35), and hair loss (RR, 1.26; 95% CI, 1.09 to 1.47).
Conclusion
Survivors of childhood cancer are at increased risk for disfigurement and persistent hair loss, which is associated with future emotional distress and reduced quality of life. Future studies are needed to better identify and manage functional outcomes in these patients.
doi:10.1200/JCO.2011.39.3611
PMCID: PMC3397782  PMID: 22614987
12.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Purpose
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Results
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Conclusion
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
doi:10.1200/JCO.2010.34.4267
PMCID: PMC3269951  PMID: 22184380
13.  Symptoms of Attention-Deficit/Hyperactivity Disorder in Long-Term Survivors of Childhood Leukemia 
Pediatric blood & cancer  2011;57(7):1191-1196.
Background
Survivors of childhood acute lymphoblastic leukemia (ALL) sometimes have clinical features that suggest Attention-Deficit/Hyperactivity Disorder (ADHD), though few studies have examined specific symptoms in survivors.
Procedure
Long-term survivors of childhood ALL (n=161) received a neurological examination, while parents completed rating scales to establish formal criteria for ADHD. Symptom profiles were generated and compared across demographic and treatment characteristics, as well as medical tests associated with brain pathology.
Results
Prevalence rates of ADHD were similar in survivors (10.5%) compared to those reported in the general population (7–10%). However, 25.5% of survivors reported symptoms that impair functioning in multiple settings, with attention problems being most common. These symptoms were associated with cranial radiation therapy (CRT) (mean inattentive symptoms [SD] = 3.6 [3.19] for group treated with CRT vs. 1.6 [2.40] for non-CRT group, p=0.0006), and survivors who demonstrated impaired anti-saccades during the neurologic exam (mean inattentive symptoms [SD] = 3.4 [3.29] for those with impaired anti-saccades vs. 1.4 [2.41] for those with normal anti-saccades; p = 0.0004).
Conclusions
The presence of a neurologically-based phenotype of attention problems in survivors of leukemia that is not fully captured by the syndrome of ADHD suggests that treatments specific to childhood ALL should be explored.
doi:10.1002/pbc.22994
PMCID: PMC3140624  PMID: 21280202
ALL; long-term survivor; Attention-Deficit/Hyperactivity Disorder
14.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
Purpose
Survivors of childhood cancer are at increased risk of developing subsequent neoplasms. In long term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms.
Methods
To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. 164 of the survivors had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT), and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms.
Results
Nineteen of the 219 survivors (8.7%) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4% (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review.
Conclusion
Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated.
Implications for Cancer Survivors
The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.
doi:10.1007/s11764-014-0344-8
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
15.  Fatigue, vitality, sleep and neurocognitive functioning in adult survivors of childhood cancer: A Report from the Childhood Cancer Survivor Study 
Cancer  2011;117(11):2559-2568.
Background
Long-term survivors of childhood cancer are at risk for fatigue, sleep problems, and neurocognitive impairment, though the association between these outcomes has not been previously examined.
Methods
Outcomes were evaluated in 1426 survivors from the Childhood Cancer Survivor Study using a validated Neurocognitive Questionnaire. Relative risks for neurocognitive impairment were calculated using demographic and treatment factors, and survivors’ report on the FACIT-Fatigue, the Short Form-36 Vitality Scale (SF-36-V), the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS).
Results
Neurocognitive impairment was identified in over 20% of survivors, using sibling-based norms for comparison. Multivariable logistic regression models revealed that fatigue (RR=1.34, 1.13–1.59), daytime sleepiness (RR=1.68, 1.55–1.83), poor sleep quality (RR=1.23, 1.01–1.49) and decreased vitality (RR=1.75, 95% CI 1.33–2.30) were all associated with impaired task efficiency. Likewise, fatigue (RR=1.77, 1.23–2.55), sleepiness (RR=1.38, 1.14–1.67) and decreased vitality (RR=3.08, 1.98–4.79) were predictive of emotional regulation problems. Diminished organization was associated with increased sleepiness (RR=1.80, 1.31–2.48) and decreased vitality (RR=1.90, 1.37–2.63). Impaired memory was associated with poor sleep quality (RR=1.45, 1.19–1.76), increased sleepiness (RR=2.05, 1.63–2.58), and decreased vitality (RR=2.01, 1.42–2.86). The impact of fatigue, sleepiness, sleep quality and vitality on neurocognitive outcomes was independent of the effects of cranial radiation therapy, steroids and antimetabolite chemotherapy, sex, and current age.
Conclusions
Neurocognitive function in long-term survivors of childhood cancer appears particularly vulnerable to the effects of fatigue and sleep disruption. These findings suggest sleep hygiene should be emphasized among survivors, as it may provide an additional mechanism for intervention to improve neurocognitive outcomes.
doi:10.1002/cncr.25797
PMCID: PMC3135668  PMID: 21484777
Childhood Cancer Survivor Study; CCSS; neurocognitive; sleep; fatigue; vitality
16.  Oxidative Stress and Neurobehavioral Problems in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Chemotherapy 
Summary
Neurobehavioral problems after chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL) have been a recent focus of investigation. This study extended previous research that suggested oxidative stress as a potential mechanism for chemo-therapy-induced central nervous system injury by examining early markers of oxidative stress in relation to subsequent neurobehav-ioral problems. Oxidized and unoxidized components of phosphatidylcholine (PC) were measured in the cerebrospinal fluid of 87 children with ALL at diagnosis, induction, and consolidation. Behavioral assessments were conducted postconsolidation and at the end of chemotherapy. Results revealed a significant association between physiologic reactivity (high vs. low PC changes from diagnosis) and behavioral outcomes (high vs. low pathology). Elevated oxidized PC fraction change was predictive of increased problems with aggression at the end of therapy as well as postconsolidation adaptability. Furthermore, symptoms of hyperactivity systematically changed over time in relation to both unoxidized PC and oxidized PC fraction reactivity. These findings suggest that symptoms of behavioral problems occur early in the course of chemotherapy and that increases in the cerebrospinal fluid PC markers of oxidative stress during induction and consolidation may help to predict certain future behavioral problems.
doi:10.1097/MPH.0b013e3181c9af84
PMCID: PMC3392027  PMID: 20098337
neurobehavioral outcomes; oxidative stress; pediatric leukemia
17.  Neurocognitive functioning and health-related behaviors in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
SUMMARY
Background
Positive health-related behaviors are essential for the future wellbeing of childhood cancer survivors, though relatively few maintain healthy behaviors into adulthood.
Methods
Neurocognitive function and emotional distress were examined in 6,440 adult survivors from the Childhood Cancer Survivor Study, and used to predict rates of expected health-related behaviors. Covariates included cancer diagnosis, age, sex, body mass index, insurance status, income, and antidepressant medication use, and multivariable models were constructed adjusting for these factors.
Findings
In multivariable regression models, survivors with neurocognitive problems in task efficiency (RR=0.77, 95% CI=0.72–0.84) were less likely to meet the Centers for Disease Control guidelines for weekly physical activity. Survivors with neurocognitive impairment were more likely to engage in general survivor care (RR=1.20, 95% CI=1.10–1.30), and less likely to engage in dental care (RR=0.92, 95% CI=0.88–0.97). Obese survivors were less likely to report receiving a bone density exam (RR=0.67, 95% CI=0.54–0.82), a mammogram (RR=0.71, 95% CI=0.57–0.89), and a skin exam (RR=0.78, 95% CI = 0.68–0.89). Survivors reporting somatization, i.e. vague physical symptoms associated with anxiety, were more likely to report receiving echocardiograms (RR=1.53, 95% CI = 1.32–1.77).
Interpretation
These results support the link between neurocognitive and emotional problems and health-related behaviors in adult survivors of childhood cancer. Monitoring neurocognitive and emotional outcomes may help to identify survivors at risk for poor adherence to prescribed health behaviors and health screening exams.
doi:10.1016/j.ejca.2011.03.001
PMCID: PMC3103640  PMID: 21458986
18.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
Background
The impact of childhood cranial radiation therapy (CRT) on stroke risk in adulthood, and the role of modifiable atherosclerotic risk factors, remains poorly defined. We assessed long-term incidence rates and stroke risk factors in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS).
Patients and Methods
CCSS is a multi-institutional retrospective cohort study of 14,358 five-year survivors of childhood cancer and 4,023 randomly selected sibling controls with longitudinal follow up. Age-adjusted incidence rates of self-reported late-occurring (≥ 5 years after diagnosis) first-stroke were calculated. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors.
Results
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% Confidence Interval [CI] 62–96) compared to 9.3 (95% CI 4–23) for siblings. Treatment with CRT increased stroke risk in a dose dependent manner: hazard ratio (HR) 5.9 (95% CI 3.5–9.9) for 30–49 Gy CRT, and 11.0 (7.4–17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4–1.8) at 10 years post-diagnosis and 12% (95% CI 8.9–15.0) at 30 years. Hypertension (HTN) increased stroke hazard by 4-fold (95% CI 2.8–5.5) and in black survivors by 16-fold (95% CI 6.9–36.6).
Conclusion
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
doi:10.1016/j.ijrobp.2013.03.034
PMCID: PMC3696633  PMID: 23680033
19.  Emotional distress among adult survivors of childhood cancer 
Purpose
To estimate the prevalence of emotional distress in a large cohort of adult survivors of childhood cancer and evaluate the interrelationship of risk factors including cancer-related late effects.
Methods
1,863 adult survivors of childhood cancer, median age of 32 years at follow-up, completed comprehensive medical evaluations. Clinically relevant emotional distress was assessed using the Brief Symptom Inventory-18 and was defined as T-scores ≥63. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to identify risk factors for distress. Path analysis was used to examine associations among identified risk factors.
Results
Elevated global distress was reported by 15.1% of survivors. Cancer-related pain was associated with elevated distress (OR 8.72; 95% CI, 5.32 – 14.31). Survivors who reported moderate learning or memory problems were more likely to have elevated distress than survivors who reported no learning or memory problems (OR 3.27; 95% CI, 2.17 – 4.93). Path analysis implied that cancer-related pain has a direct effect on distress symptoms and an indirect effect through socioeconomic status and learning or memory problems. Similar results were observed for learning or memory problems.
Conclusions
Childhood cancer-related morbidities including pain and learning or memory problems appear to be directly and indirectly associated with elevated distress symptoms decades after treatment. Understanding these associations may help inform intervention targets for survivors of childhood cancer experiencing symptoms of distress.
Implications for cancer survivors
A subset of long-term childhood cancer survivors experience significant emotional distress. Physical and cognitive late effects may contribute to these symptoms.
doi:10.1007/s11764-013-0336-0
PMCID: PMC4098755  PMID: 24459073
emotional distress; childhood cancer; survivorship; late effects
20.  Evaluation of Memory Impairment in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Cranial Radiotherapy 
Background
Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood.
Methods
We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging.
Results
Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose–response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT).
Conclusions
Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.
doi:10.1093/jnci/djt089
PMCID: PMC3687368  PMID: 23584394
21.  Adolescent behavior and adult health status in childhood cancer survivors 
Introduction
This study examined the longitudinal association between adolescent psychological problems following cancer treatment and obesity, limited exercise, smoking, and excess sun exposure during adulthood in the Childhood Cancer Survivor Study cohort.
Methods
Participants included 1,652 adolescent survivors of childhood cancer and 406 siblings of cancer survivors, initially evaluated at 12-17 years of age and ≥ 5 years post-diagnosis. A follow-up survey of these participants was conducted roughly 7 years later and included assessment of health status and health behaviors. Logistic regression models were used to assess the association between adolescent psychological problems and adult health behavior outcomes.
Results
During adolescence, survivors demonstrated higher rates of attention deficits, emotional problems, externalizing behavior and social withdrawal compared to sibling controls. Social withdrawal was associated with adult obesity (OR = 1.5, 95% CI = 1.1 - 2.1) and physical inactivity (OR = 1.7, 1.1 - 2.5). Use of stimulant medication during adolescence was also associated with adult obesity (OR = 1.9, 1.1 – 3.2), while antidepressant use was associated with physical inactivity (OR = 3.2, 1.2 – 8.2).
Discussion/Conclusions
Adolescent survivors of childhood cancer display higher rates of psychological problems compared to siblings of cancer survivors. These psychological problems are associated with an increased risk for obesity and poor heath behavior in adulthood, which may increase future risk for chronic health conditions and secondary neoplasms.
Implications
In order to decrease risk of future health problems, adolescent survivors of childhood cancer should be routinely screened and treated for psychological problems following cancer therapy.
doi:10.1007/s11764-010-0123-0
PMCID: PMC3098531  PMID: 20383785
Adolescence; Cancer; Psychological problems; Obesity; Oncology; Childhood Cancer Survivor Study
22.  Restricted Access to the Environment and Quality of Life in Adult Survivors of Childhood Brain Tumors 
Journal of neuro-oncology  2012;111(2):195-203.
Background:
Survivors of pediatric brain tumors are at-risk for late effects which may affect mobility within and access to the physical environment. This study examined the prevalence of and risk factors for restricted environmental access in survivors of childhood brain tumors and investigated the associations between reduced environmental access, health-related quality of life (HRQOL), and survivors’ social functioning.
Methods:
In-home evaluations were completed for 78 brain tumor survivors and 78 population-based controls matched on age, sex, and zip-code. Chi-square tests and multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for poor environmental access and reduced HRQOL.
Results:
The median age of survivors was 22 years at the time of study. Compared to controls, survivors were more likely to report avoiding most dimensions of their physical environment, including a single flight of stairs (p<0.001), uneven surfaces (p<0.001), traveling alone (p=0.01), and traveling to unfamiliar places (p=0.001). Overall, survivors were 4.8 times more likely to report poor environmental access (95% CI, 2.0-11.5, p<0.001). In survivors, poor environmental access was associated with reduced physical function (OR=3.6, 95% CI, 1.0-12.8, p=0.04), general health (OR=6.0, 95% CI, 1.8-20.6, p=0.002), and social functioning (OR=4.3, 95% CI, 1.1-17.3, p=0.03).
Conclusions:
Adult survivors of pediatric brain tumors were more likely to avoid their physical environment than matched controls. Restricted environmental access was associated with reduced HRQOL and diminished social functioning. Interventions directed at improving physical mobility may have significant impact on survivor quality of life.
doi:10.1007/s11060-012-1001-6
PMCID: PMC3995451  PMID: 23143294
CNS malignancies; survivorship; quality of life; environmental access
23.  Psychoactive Medication Use and Neurocognitive Function in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2012;60(3):486-493.
Background
Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer.
Procedure
Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors’ report of prescription medication use.
Results
Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR=1.80, 95% CI=1.47–2.21), organization (OR=1.83, 95% CI=1.48–2.25), memory (OR=1.53, 95% CI=1.27–1.84) and emotional regulation (OR=2.06, 95% CI=1.70–2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR=2.46, 95% CI=1.29–4.69; OR=2.82, 95% CI=1.61–4.93, respectively) and memory (OR=2.08, 95% CI=1.13–3.82; OR=2.69, 95% CI=1.59–4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS).
Conclusions
These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained.
doi:10.1002/pbc.24255
PMCID: PMC3494805  PMID: 22848025
psychoactive medication; neurocognition; survivorship
24.  Prevalence and Predictors of Prescription Psychoactive Medication Use in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Purpose
Childhood cancer survivors are at-risk for late effects which may be managed pharmacologically. The purpose of this study was to estimate and compare the prevalence of psychoactive medication use of adult survivors of childhood cancer and sibling controls, identify predictors of medication use in survivors, and investigate associations between psychoactive medications and health-related quality of life (HRQOL).
Methods
Psychoactive medication use from 1994 to 2010 was evaluated in 10,378 adult survivors from the Childhood Cancer Survivor Study. A randomly selected subset of 3,206 siblings served as a comparison group. Multivariable logistic regression models were used to calculate odds ratios (OR) for baseline and new onset of self-reported psychoactive medication use and HRQOL.
Results
Survivors were significantly more likely to report baseline (22% vs. 15%, p<0.001) and new onset (31% vs. 25%, p<0.001) psychoactive medication use compared to siblings, as well as use of multiple medications (p<0.001). In multivariable models, controlling for pain and psychological distress, female survivors were significantly more likely to report baseline and new onset use of antidepressants (OR=2.66; 95% CI=2.01–3.52; OR=2.02; 95% CI=1.72–2.38, respectively) and multiple medications (OR=1.80; 95% CI=1.48–2.19; OR=1.77; 95% CI=1.48–2.13, respectively). Non-cranial radiation and amputation predicted incident use of analgesics >15 years following diagnosis. Antidepressants were associated with impairment across all domains of HRQOL, with the exception of physical function.
Conclusions
Prevalence of psychoactive medication use was higher among survivors for most medication classes, as was the use of multiple medications. Clinicians should be aware of the possible contribution of psychoactive medications to HRQOL.
doi:10.1007/s11764-012-0250-x
PMCID: PMC3568188  PMID: 23224753
psychoactive medication; quality of life; survivorship
25.  Reliability and Validity of the Childhood Cancer Survivor Study Neurocognitive Questionnaire 
Cancer  2008;113(8):2188-2197.
Background
Up to 40% of childhood cancer survivors may experience neurocognitive impairment in one or more specific domains. As such, regular monitoring has been recommended for patients exposed to cranial irradiation and/or antimetabolite chemotherapy. This study reports the results of a questionnaire developed to identify those survivors who may be experiencing neurocognitive problems.
Methods
Participants for this study were 7,121 members of the Childhood Cancer Survivor Study cohort (6,739 survivors and 382 siblings). These participants completed a new neurocognitive questionnaire designed to assess functions commonly affected by cancer therapy, as well as a standard measure of emotional functioning. A measure of cognitive and emotional functioning was also completed on a subset of the patients roughly seven years prior to the current questionnaire. Responses to the questionnaires among subgroups of survivors were then analyzed to examine the reliability and validity of the new neurocognitive questionnaire.
Results
Four reliable factors were identified that assessed task efficiency, emotional regulation, organization, and memory skills. These neurocognitive factors accurately discriminated between survivors who were at “high risk” for neurocognitive dysfunction, due to neurologic abnormalities or a history of intensive focal cranial irradiation, from healthy “low risk” survivors and siblings.
Conclusions
The questionnaire demonstrated excellent reliability, as well as construct and discriminative validity. It appears to be a practical and efficient tool for monitoring neurocognitive outcomes in adult survivors of pediatric cancer.
Condensed Abstract
Regular monitoring of neurocognitive functioning is recommended for pediatric cancer survivors exposed to cranial irradiation and/or antimetabolite chemotherapy. The Childhood Cancer Survivor Study - Neurocognitive Questionnaire appears to be a practical and efficient tool for such monitoring.
doi:10.1002/cncr.23809
PMCID: PMC2574840  PMID: 18792068
Childhood Cancer Survivor Study; neurocognitive; questionnaire; late effects

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