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1.  Decline in physical activity level in the Childhood Cancer Survivor Study cohort 
We aimed to identify demographic and health-related predictors of declining physical activity levels over a four year period among participants in the Childhood Cancer Survivor Study.
Analyses included 7287 ≥5 year childhood cancer survivors and 2107 siblings who completed multiple follow-up questionnaires. Participants were classified as active if they met the Centers for Disease Control and Prevention guidelines for physical activity. Generalized linear models were used to compare participants whose physical activity levels declined from active to inactive over the study to those who remained active. Additionally, selected chronic conditions (CTCAE v4.03 Grade 3 and 4) were evaluated as risk factors in an analysis limited to survivors only.
The median age at last follow-up among survivors and siblings was 36 (range: 21–58) and 38 (range: 21–62) years, respectively. The rate of decline did not accelerate over time among survivors when compared with siblings. Factors that predicted declining activity included BMI ≥30kg/m2 (RR=1.32, 95%CI=1.19–1.46, p<0.01), not completing high school (RR=1.31, 95%CI=1.08–1.60, p<0.01), and female sex (RR=1.33, 95%CI=1.22–1.44, p<0.01). Declining physical activity levels were associated with the presence of chronic musculoskeletal conditions (p=0.034), but not with the presence of cardiac (p=0.10), respiratory (p=0.92) or neurological conditions (p=0.21).
Interventions designed to maximize physical activity should target female, obese, and less educated survivors. Survivors with chronic musculoskeletal conditions should be monitored, counseled and/or referred for physical therapy.
Clinicians should be aware of low activity levels among sub-populations of childhood cancer survivors which may heighten their risk for chronic illness.
PMCID: PMC4119523  PMID: 24842624
children; cancer; survivor; physical; activity
2.  Relations between Posttraumatic Stress and Posttraumatic Growth in Long-Term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Contemporary models of trauma suggest that posttraumatic stress and growth should be related, and that symptoms of stress resulting from a perceived trauma (e.g. childhood cancer) are prerequisite for posttraumatic growth to occur. However, empirical data regarding the relationship of posttraumatic stress and growth have been equivocal. The purpose of this study is to examine the relationship between posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) among adult survivors of childhood cancer.
Survey methods were utilized to collect data from 6162 survivors participating in the Childhood Cancer Survivor Study (CCSS). Non-parametric correlation was examined pair-wise between PTG and PTSS using Spearman’s correlation coefficient with 95% confidence intervals, with non-linear canonical correlation analysis being conducted to examine relationships between subscales. A multivariable partial proportional odds model was also fit for PTG Total quartiles focusing on associations with PTSS Total quartiles while adjusting for sociodemographic and medical variables.
Examination of unadjusted PTSS and PTG total scores revealed a Spearman correlation of 0.11 (p<0.001), with coefficients ranging from 0.03 to 0.17 between total and subscale scores. The non-linear canonical correlation analyses resulted in two Dimensions with Eigenvalues of 0.15 and 0.14, resulting in a fit value of 0.30 and evidence that little variability in the data (15%) was explained by the weighted combinations of the variables.
Although statistically significant, these results do not indicate a robust relationship between PTSS and PTG among adult survivors of childhood cancer. Theories suggesting that PTSS is a prerequisite for PTG should be reconsidered.
PMCID: PMC4158696  PMID: 24799000
3.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
PMCID: PMC4142216  PMID: 24954778
4.  Parent-reported cognition of children with cancer and its potential clinical usefulness 
Cognitive dysfunction is a common concern for children with brain tumors (BTs) or those receiving central nervous system (CNS) toxic cancer treatments. Perceived cognitive function (PCF) is an economical screening that may be used to trigger full, formal cognitive testing. We assessed the potential clinical utility of PCF by comparing parent-reported scores for children with cancer with scores from the general US population.
Children (n = 515; mean age =13.5 years; 57.0 % male) and one of their parents were recruited from pediatric oncology clinics. Most children (53.3 %) had a diagnosis of CNS tumor with an average time since diagnosis of 5.6 years. PCF was evaluated using the pediatric PCF item bank (pedsPCF), which was developed and normed on a sample drawn from the US general pediatric population. Children also completed computer-based neuropsychological tests. We tested relationships between PCF and clinical variables. Differential item functioning (DIF) was used to evaluate measurement bias between the samples.
No item showed DIF, supporting the use of pedsPCF in the cancer sample. PedsPCF differentiated children with (vs. without) a BT, p < 0.01, and groups defined by years since diagnosis, p < 0.01. It significantly (p < 0.05) correlated with computerized neuropsychological tests in 40 of 60 comparisons. Children with BTs were rated as having worse pedsPCF scores than the norm, regardless of years since diagnosis.
PCF significantly differentiated cancer survivors with various clinical characteristics. It is brief and easy to implement. PCF should be considered for routine care of pediatric cancer survivors.
PMCID: PMC3967001  PMID: 24197478
Perceived cognitive function; Item bank; Pediatric cancer; Brain tumor; Item response theory; Quality of life
5.  Regional Brain Glucose Metabolism and Neurocognitive Function in Adult Survivors of Childhood Cancer Treated with Cranial Radiation 
The objective of this study was to examine associations between regional brain metabolism, as measured by 18F-FDG PET, and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation.
Thirty-eight adult survivors of ALL were randomly selected from a large cohort treated with cranial radiation therapy (19 with 18 Gy and 19 with 24 Gy of exposure). At a mean age of 26.4 (range, 22.3–37.4) years, and 23.5 (range, 20.4–32.8) years since diagnosis, patients underwent comprehensive neurocognitive evaluations and brain 18F-FDG PET imaging during a resting condition. 18F-FDG PET images were analyzed stereotactically, and pixel values were normalized to global activity. Predefined region-of-interest and voxel-based correlation analyses were performed.
Compared with national norms, survivors demonstrated lower vocabulary (P < 0.001), reading (P < 0.001), mathematics (P < 0.001), working memory (P < 0.001), oral naming speed (P < 0.001), and cognitive flexibility (P < 0.001). Metabolic activity was higher in basal gangliar structures for those treated with 24 Gy of cranial radiation therapy (P = 0.04). Metabolic activity was positively correlated with oral naming speed in both lateral frontal lobes (ρ = 0.48 and 0.47 for right and left frontal regions, respectively, P < 0.01) and negatively correlated with cognitive flexibility in the sections of the basal ganglia (P < 0.01 for both caudate and putamen).
Neurocognitive impairment in long-term survivors of ALL treated with cranial radiation appears to be associated with increased metabolic activity in frontal cerebral cortical and subcortical regions in the basal ganglia, suggesting decreased efficiency of the frontostriatal brain circuit.
PMCID: PMC4366940  PMID: 25315244
18F-FDG PET; childhood cancer survivor; neurocognitive function
6.  Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2014;32(9):949-959.
Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.
Patients and Methods
Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.
Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.
MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
PMCID: PMC3948096  PMID: 24550419
7.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
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.
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.
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).
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.
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
8.  Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols 
The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user’s capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population’s level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations.
PMCID: PMC4362220  PMID: 25852494
tDCS; clinical trials; attention deficit hyperactivity disorder; depression; multiple sclerosis; palliative care
9.  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.
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.
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.
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).
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
PMCID: PMC3871511  PMID: 24248696
10.  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.
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.
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.
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.
PMCID: PMC3842908  PMID: 24190124
11.  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.
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.
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.
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.
A large proportion of survivors suffered from many symptom classes, which was associated with HRQOL impairment.
PMCID: PMC3821013  PMID: 24127449
12.  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.
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.
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.
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).
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.
PMCID: PMC3928631  PMID: 23775832
Leukemia; fMRI; memory; survivors; glucocorticoid; retrosplenium
13.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
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.
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.
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.
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.
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
14.  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.
PMCID: PMC3721186  PMID: 23584707
children with special health care needs; chronic condition; family impact; fatigue; quality of life
15.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
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.
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).
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.
PMCID: PMC3696633  PMID: 23680033
16.  Emotional distress among adult survivors of childhood cancer 
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.
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.
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.
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.
PMCID: PMC4098755  PMID: 24459073
emotional distress; childhood cancer; survivorship; late effects
17.  Evaluation of Memory Impairment in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Cranial Radiotherapy 
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.
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.
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).
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.
PMCID: PMC3687368  PMID: 23584394
18.  Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia 
Journal of Clinical Oncology  2013;31(17):2182-2188.
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.
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).
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.
PMCID: PMC3731978  PMID: 23650422
19.  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.
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.
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.
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).
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.
PMCID: PMC3995451  PMID: 23143294
CNS malignancies; survivorship; quality of life; environmental access
20.  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.
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.
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.
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).
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.
PMCID: PMC3494805  PMID: 22848025
psychoactive medication; neurocognition; survivorship
21.  Prevalence and Predictors of Prescription Psychoactive Medication Use in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
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).
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.
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.
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.
PMCID: PMC3568188  PMID: 23224753
psychoactive medication; quality of life; survivorship
22.  Oxidative Stress and Executive Function in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2009;53(4):551-556.
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.
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 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.
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.
PMCID: PMC3928629  PMID: 19499584
oxidative stress; neurocognitive; leukemia
23.  Parent-perceived child cognitive function: results from a sample drawn from the US general population 
This paper reports the development and evaluation of a perceived cognitive function (pedsPCF) item bank reported by parents of the pediatric US general population.
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).
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%.
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.
PMCID: PMC3885608  PMID: 20652814
Perceived cognitive function; Children; Brain tumor; Neuro-oncology; Item bank
24.  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.
PMCID: PMC3845091  PMID: 22856670
Cerebral Spinal Fluid; Childhood Leukemia; Neurocognitive; Phospholipids
25.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
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.
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.
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.
PMCID: PMC3462045  PMID: 22949149

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