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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  The Relationships Between Fatigue, Quality of Life, and Family Impact Among Children With Special Health Care Needs 
Journal of Pediatric Psychology  2013;38(7):722-731.
Objective To examine the relationships among pediatric fatigue, health-related quality of life (HRQOL), and family impact among children with special health care needs (CSHCNs), specifically whether HRQOL mediates the influence of fatigue on family impact. Methods 266 caregivers of CSHCNs were studied. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, Pediatric Quality of Life Inventory Generic Scale, and Impact on Family Scale were used to measure fatigue, HRQOL, and family impact, respectively. Linear regressions were used to analyze the designated relationships; path analyses were performed to quantify the mediating effects of HRQOL on fatigue–family impact relationship. Results Although greater fatigue was associated with family impact (p < .05), the association was not significant after accounting for HRQOL. Path analyses indicated the direct effect of fatigue on family impact was not significant (p > .05), whereas physical and emotional functioning significantly mediated the fatigue–family impact relationship (p < .001). Conclusion Fatigue is related to family impact among CSHCNs, acting through the impairment in HRQOL.
doi:10.1093/jpepsy/jst016
PMCID: PMC3721186  PMID: 23584707
children with special health care needs; chronic condition; family impact; fatigue; quality of life
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Parent-perceived child cognitive function: results from a sample drawn from the US general population 
Purposes
This paper reports the development and evaluation of a perceived cognitive function (pedsPCF) item bank reported by parents of the pediatric US general population.
Methods
Based on feedback from clinicians, parents, and children, we developed a scale sampling concerns related to children’s cognitive functioning. We administered the scale to 1,409 parents of children aged 7–17 years; of them, 319 had a neurological diagnosis. Dimensionality of the pedsPCF was evaluated via factor analyses and its clinical utility studied by comparing parent ratings in patient groups and symptom cluster defined by the Child Behavior Checklist (CBCL).
Results
Forty-four of 45 items met criteria for unidimensionality. The pedsPCF significantly differentiated samples defined by medication use, repeated grades, special education status, neurologic diagnosis, and relevant symptom clusters with large effect sizes (>0.8). It can predicted children symptoms with the correction rates ranging 79–89%.
Conclusions
We have provided empirical support for the unidimensionality of the pedsPCF item bank and evidence for its potential clinical utility. The pedsPCF is a promising measurement tool to screen children for further comprehensive cognitive tests.
doi:10.1007/s00381-010-1230-y
PMCID: PMC3885608  PMID: 20652814
Perceived cognitive function; Children; Brain tumor; Neuro-oncology; Item bank
17.  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
18.  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
19.  Using three legacy measures to develop a health-related quality of life tool for young adult survivors of childhood cancer 
Background
Little attention has been paid to selecting and developing health-related quality of life (HRQOL) measurement tools for young adult survivors of childhood cancer (YASCC). The primary purpose of this study was to develop a HRQOL tool for YASCC based on three legacy instruments.
Methods
Data collected from 151 YASCC were analyzed. HRQOL was measured using the Medical Outcomes Study SF-36, Quality of Life in Adult Cancer Survivors, and Quality of Life-Cancer Survivor. We used the following stages to develop our HRQOL tool: mapping items from three instruments into a common HRQOL construct, checking dimensionality using confirmatory factor analyses (CFA), and equating items using Rasch modeling.
Results
We assigned 123 items to a HRQOL construct comprised of six generic and eight survivor-specific domains. CFA retained 107 items that meet the assumptions of unidimensionality and local independence. Rasch analysis retained 68 items that satisfied the indices of information-weighted/outlier-sensitive fit statistic mean square. However, items in most domains possess relatively easy measurement properties, whereas YASCC’s underlying HRQOL was on the middle to higher levels.
Conclusions
Psychometric properties of the established tool for measuring HRQOL of YASCC were not satisfied. Future studies need to refine this tool, especially adding more challenging items.
doi:10.1007/s11136-011-0055-9
PMCID: PMC3328688  PMID: 22101901
Childhood cancer; measurement; quality of life; Rasch analysis; young adult survivor
20.  Clinical Ascertainment of Health Outcomes among Adults Treated for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study 
Importance
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions.
Objective
Following systematic exposure-based medical assessments of a large cohort of adult survivors of childhood cancer, determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures.
Design, Setting, and Participants
Presence of health outcomes was ascertained among 1713 adult (median age 32 years, range 18-60) survivors of childhood cancer (median time from diagnosis 25 years, range 10-47) enrolled in the St. Jude Lifetime Cohort Study since 10/1/2007 and followed through 10/31/2012.
Main Outcome Measures
Age-specific cumulative prevalence of adverse outcomes by organ system and sex-adjusted attributable fraction percentages with 95% confidence intervals were calculated.
Results
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary [65.2%(95% CI, 60.4-69.8%)], auditory [62.1%(95% CI, 55.8-68.2%)], endocrine-reproductive [62.0%(95% CI, 59.5-64.6%)], cardiac [56.4(95% CI, 53.5-59.2%)] and neurocognitive [48.0%(95%CI, 44.9-51.0%)] function, whereas abnormalities impacting hepatic [13.0%(95% CI, 10.8-15.3%)], skeletal [9.6%(95% CI, 8.0-11.5%)], renal [5.0%(95% CI, 4.0-6.3%)] and hematopoietic [3.0%(95% CI: 2.1-3.9%)] function were less common. Attributable fractions were highest for endocrine-reproductive disorders [88.4%(95% CI, 80.1-93.3%)] to 100%, but considerably lower for conditions highly prevalent in the general population such as hypertension [9.3%(95%CI, −16.3-29.2%)], dyslipidemia [15.5%(95% CI, 10.2-20.5%)], and obesity [42.1%(95% CI, 34.4-48.9%)]. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at 50 years of age was 21.6%(95% CI, 19.3-23.9%) for cardiomyopathy, 83.5%(95% CI, 80.2-86.8%) for heart valve disorder, 76.8%(95% CI, 73.6-80.0%) for pituitary dysfunction, 81.3%(95% CI, 77.6-85.0%) for pulmonary dysfunction, 86.5%(95% CI, 82.3-90.7%) for hearing loss, 40.9%(95% CI, 32.0-49.8%) for breast cancer, 31.1%(95% CI, 27.3-34.9%) for Leydig cell failure, and 31.9%(95% CI, 28.0-35.8%) for primary ovarian failure. At age 45 years, the estimated cumulative prevalence of any chronic health condition is 95.2% (95% CI 94.8-98.6%) and 80% (95% CI 73.0-86.6%) for a serious, life-threatening or disabling chronic condition.
Conclusion and Relevance
Systematic risk-based medical assessments of adults treated for childhood cancer identified a substantial number of previously undiagnosed problems that are typically prevalent in an older population underscoring the need for ongoing health monitoring and intervention of this population.
doi:10.1001/jama.2013.6296
PMCID: PMC3771083  PMID: 23757085
Childhood cancer; late effects; long-term follow-up; health screening
21.  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
22.  Mathematics Intervention for Prevention of Neurocognitive Deficits in Childhood Leukemia 
Pediatric blood & cancer  2011;59(2):278-284.
Background
Despite evidence that CNS treatment is associated with cognitive and academic impairment, interventions to prevent or mitigate these problems are limited. The purpose was to determine if early intervention can prevent declines in mathematics abilities.
Procedures
Fifty-seven children with ALL were enrolled and randomized to a Mathematics Intervention or Standard Care. Subjects completed neurocognitive assessments prior to the intervention, post intervention, and one year later. Parents received written results and recommendations for use with their school. The Mathematics Intervention was based on Multiple Representation Theory and delivered individually over one year.
Results
Thirty-two of 57 subjects completed the study and were included in data analyses. These 32 subjects completed all neurocognitive assessments and, for those in the intervention group, 40–50 hours of the mathematics intervention. There were no group differences on relevant demographic variables; risk stratification; number of intrathecal methotrexate injections or high dose systemic methotrexate. Significant improvements in calculation and applied mathematics from baseline to post-intervention (p = 0.003 and 0.002, respectively) and in visual working memory from baseline to one year follow-up (p = 0.02) were observed in the Intervention but not the Standard Care group. Results from repeated measures ANOVA demonstrated significant between group differences for applied mathematics (F[2, 29] 12.47, p<0.001) and visual working memory (F[2 29]= 5.53, p=0.009).
Conclusions
The Mathematics Intervention improved mathematics abilities and visual working memory compared to standard care. Future studies are needed to translate the Mathematics Intervention into a “virtual” delivery method more readily available to parents and children.
doi:10.1002/pbc.23354
PMCID: PMC3246526  PMID: 21938763
mathematics intervention; childhood leukemia; prevention; neurocognitive sequelae
23.  Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study 
Neuro-Oncology  2012;14(8):1018-1025.
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
doi:10.1093/neuonc/nos123
PMCID: PMC3408256  PMID: 22661588
Childhood Cancer Survivor Study; glutathione S-transferase polymorphisms; medulloblastoma; neuropsychological impairment; radiation therapy
24.  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
25.  Perceived Positive Impact of Cancer Among Long-term Survivors of Childhood Cancer: a report from the Childhood Cancer Survivor Study 
Psycho-oncology  2011;21(6):630-639.
Background
Investigations examining psychosocial adjustment among childhood cancer survivors have focused primarily on negative effects and psychopathology. Emergent literature suggests the existence of positive impact or adjustment experienced after cancer, as well. The purpose of this study is to examine the distribution of Perceived Positive Impact (PPI) and its correlates in young adult survivors of childhood cancer.
Methods
6,425 survivors and 360 siblings completed a comprehensive health survey, inclusive of a modified version of the Posttraumatic Growth Inventory (PTGI) as a measure of PPI. Linear regression models were used to examine demographic, disease and treatment characteristics associated with PPI.
Results
Survivors were significantly more likely than siblings to report PPI. Endorsement of PPI was significantly greater among female and non-white survivors, and among survivors exposed to at least one intense therapy, a second malignancy or cancer recurrence. Survivors diagnosed at older ages and fewer years since diagnosis were more likely to report PPI. Income, education and marital/relationship status appeared to have varied relationships to PPI depending upon the subscale being evaluated.
Conclusions
The existence and variability of PPI in survivors in this study suggest that individual characteristics, inclusive of race, gender, cancer type, intensity of treatment, age at diagnosis and time since diagnosis, have unique and specific associations with different aspects of perceived positive outcomes of childhood cancer.
doi:10.1002/pon.1959
PMCID: PMC3697081  PMID: 21425388
Psychosocial; childhood cancer; trauma; event centrality; survivors

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