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Cumulative burden of chronic health conditions and neurocognitive and physical function were examined among survivors of childhood acute myeloid leukemia (AML) treated with hematopoietic cell transplant (HCT; n = 66) or conventional therapy (CT; n = 67). Survivors and controls underwent a comprehensive clinical assessment, and health conditions were graded using a modified version of the Common Terminology Criteria for Adverse Events. By age 40 years, HCT and CT survivors had an average 17.4 (95% confidence interval [CI] 14.6-20.1) and 9.3 (7.7-11.1) grade 1-4 conditions versus 3.8 (3.3-4.2) in community controls. Compared to controls, HCT survivors had a higher prevalence of hypertriglyceridemia (45.5% vs. 18.3%), hypercholesterolemia (47.0% vs. 30.9%), hypothyroidism (27.3% vs. 4.0%), and primary hypogonadism (p < 0.001). CT survivors had a higher prevalence of cardiomyopathy (11.9% vs. 2.7%) and hypertension (53.7% vs. 44.3%). Neurocognitive impairment was elevated across all domains compared to controls but did not differ by treatment modality. Compared to controls, a higher proportion of HCT survivors had impairments in strength and endurance; whereas flexibility and mobility impairments were noted among CT survivors. Despite successful advances in childhood AML therapy, many therapeutic exposures remain unchanged. These findings support ongoing investigations of novel therapies and strategies to ameliorate the risk of late morbidities.

OBJECTIVE This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score

Survivors of childhood cancer are at risk of experiencing fatigue, pain, lower levels of physical activity, increased engagement in risky health behavior, and poor social adjustment, after finishing treatment. Risks are more pronounced for survivors of specific diagnoses or receiving specific treatment protocols. Interventions to address these outcomes are in their infancy. Future research should focus on exploring the antecedents and consequences of these outcomes. In the meantime, researchers and cancer centers should attempt to provide high-quality and accessible health information to survivors through various media outlets to encourage healthy behaviors.

Long-term survivors of childhood Hodgkin lymphoma (HL) experience a high burden of chronic health morbidities. Correlates of neurocognitive and psychosocial morbidity have not been well established. A total of 1760 survivors of HL (mean ± SD age, 37.5 ± 6.0 years; time since diagnosis, 23.6 ± 4.7 years; 52.1% female) and 3180 siblings (mean age, 33.2 ± 8.5 years; 54.5% female) completed cross-sectional surveys assessing neurocognitive function, emotional distress, quality of life, social attainment, smoking, and physical activity. Treatment exposures were abstracted from medical records. Chronic health conditions were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.3 (1 = mild, 2 = moderate, 3 = severe/disabling, and 4 = life-threatening). Multivariable analyses, adjusted for age, sex, and race, estimated relative risk (RR) of impairment in survivors vs siblings and, among survivors, risk of impairment associated with demographic, clinical, treatment, and grade 2 or higher chronic health conditions. Compared with siblings, survivors had significantly higher risk (all, P < .05) of neurocognitive impairment (eg, memory, 8.1% vs 5.7%), anxiety (7.0% vs 5.4%), depression (9.1% vs 7%), unemployment (9.6% vs 4.4%), and impaired physical/mental quality of life (eg, physical function, 11.2% vs 3.0%). Smoking was associated with a higher risk of impairment in task efficiency (RR, 1.56; 95% confidence interval [CI], 1.02-2.39), emotional regulation (RR, 1.84; 95% CI, 1.35-2.49), anxiety (RR, 2.43; 95% CI, 1.51-3.93), and depression (RR, 2.73; 95% CI, 1.85-4.04). Meeting the exercise guidelines of the Centers for Disease Control and Prevention was associated with a lower risk of impairment in task efficiency (RR, 0.70; 95% CI, 0.52-0.95), organization (RR, 0.60; 95% CI, 0.45-0.80), depression (RR, 0.66; 95% CI, 0.48-0.92), and multiple quality of life domains. Cardiovascular and neurologic conditions were associated with impairment in nearly all domains. Survivors of HL are at elevated risk for neurocognitive and psychosocial impairment, and risk is associated with modifiable factors that provide targets for interventions to improve long-term functional outcomes.

OBJECTIVE To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

PURPOSE This study compared the measurement properties for multiple modes of survey administration, including postal mail, telephone interview, and Web-based completion of patient-reported outcomes (PROs) among survivors of childhood cancer. METHODS The population included 6,974 adult survivors of childhood cancer in the Childhood Cancer Survivor Study who completed the Brief Symptom Inventory-18 (BSI-18), which measured anxiety, depression, and somatization symptoms. Scale reliability, construct validity, and known-groups validity related to health status were tested for each mode of completion. The multiple indicators and multiple causes technique was used to identify differential item functioning (DIF) for the BSI-18 items that responded through a specific survey mode. The impact of the administration mode was tested by comparing differences in BSI-18 scores between the modes accounting for DIF effects. RESULTS Of the respondents, 58%, 27%, and 15% completed postal mail, Web-based, and telephone surveys, respectively. Survivors who were male; had lower education, lower household income, or poorer health status; or were treated with cranial radiotherapy were more likely to complete a telephone-based survey compared with either a postal mail or Web-based survey (all P < .05). Scale reliability and validity were equivalent across the 3 survey options. One, 2, and 5 items from the anxiety, depression, and somatization domains, respectively, were identified as having significant DIF among survivors who responded by telephone ( P < .05). However, estimated BSI-18 domain scores, especially depression and anxiety, between modes did not differ after accounting for DIF effects. CONCLUSION Certain survivor characteristics were associated with choosing a specific mode for PRO survey completion. However, measurement properties among these modes were equivalent, and the impact of using a specific mode on scores was minimal.

Survivors of childhood cancer may be at risk of experiencing pain, and a systematic review would advance our understanding of pain in this population. The objective of this study was to describe: 1) the prevalence of pain in survivors of childhood cancer, 2) methods of pain measurement, 3) associations between pain and biopsychosocial factors, and 4) recommendations for future research. Data sources for the study were articles published from January 1990 to August 2019 identified in the PubMed, PsycINFO, EMBASE, and Web of Science data bases. Eligible studies included: 1) original research, 2) quantitative assessments of pain, 3) articles published in English, 4) cancers diagnosed between birth and age 21 years, 5) survivors at 5 years from diagnosis and/or at 2 years after therapy completion, and 6) a sample size >20. Seventy-three articles were included in the final review. Risk of bias was considered using the Cochrane risk of bias tool. The quality of evidence was evaluated according to Grading of Recommendations Assessment Development and Evaluation (GRADE) criteria. Common measures of pain were items created by the authors for the purpose of the study (45.2%) or health-related quality-of-life/health status questionnaires (42.5%). Pain was present in from 4.3% to 75% of survivors across studies. Three studies investigated chronic pain according the definition in the International Classification of Diseases. The findings indicated that survivors of childhood cancer are at higher risk of experiencing pain compared with controls. Fatigue was consistently associated with pain, females reported more pain than males, and other factors related to pain will require stronger evidence. Theoretically grounded, multidimensional measurements of pain are absent from the literature.

Objective Children with acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits, and examining individual variability is essential to understand these risks. This study evaluated latent longitudinal trajectories and risk factors of neurocognitive outcomes in childhood ALL. Methods There were 233 participants with ALL who were enrolled on a phase 3, risk-stratified chemotherapy-only clinical trial (NCT00137111) and who completed protocol-directed neurocognitive assessments [47.6% female, mean (SD) = 6.6 (3.7) years]. Measures of sustained attention, learning/memory, and parent ratings of attention were completed during and after treatment. Longitudinal latent class analyses were used to classify participants into distinct trajectories. Logistic regression was used to identify predictors of class membership. Results Within the overall group, attention performance was below age expectations across time (Conners Continuous Performance Test detectability/variability, p Conclusions Most patients with ALL have stable neurocognitive profiles. Smaller groups have significant impairments shortly after diagnosis or have worsening performance over time. A tiered assessment approach, which includes consideration of individual and clinical risk factors, may be useful for monitoring neurocognitive functioning during treatment and survivorship.

BackgroundSurvivors of childhood acute myeloid leukemia (AML) are vulnerable to medical late effects of treatment; however, less is known about their psychosocial outcomes. This study evaluated neurocognitive and psychosocial outcomes in long-term AML survivors treated with bone marrow transplantation (BMT) or intensive chemotherapy (IC) without BMT.MethodsAML survivors (N = 482; median age at diagnosis = 8 [range = 0-20] years; median age at evaluation = 30 [range = 18-49] years) treated with BMT (n = 183) or IC (n = 299) and sibling controls (N = 3190; median age at evaluation = 32 [range = 18-58] years) from the Childhood Cancer Survivor Study were compared on emotional distress (Brief Symptom Inventory-18), neurocognitive problems (Childhood Cancer Survivor Study Neurocognitive Questionnaire), health-related quality of life (SF-36), and social attainment. Outcomes were dichotomized (impaired vs nonimpaired) using established criteria, and relative risks (RRs) were estimated with multivariable Poisson regression, adjusted for age at evaluation and sex.ResultsAML survivors were more likely than siblings to report impairment in overall emotional (RR = 2.19, 95% confidence interval [CI] = 1.51 to 3.18), neurocognitive (RR = 2.03, 95% CI = 1.47 to 2.79), and physical quality of life (RR = 2.71, 95% CI = 1.61 to 4.56) outcomes. Survivors were at increased risk for lower education (RR = 1.15, 95% CI = 1.03 to 1.30), unemployment (RR = 1.41, 95% CI = 1.16 to 1.71), lower income (RR = 1.39, 95% CI = 1.17 to 1.65), and not being married or having a partner (RR = 1.33, 95% CI = 1.17 to 1.51). BMT-treated survivors did not differ statistically significantly from IC-treated on any outcome measure.ConclusionsAML survivors are at increased risk for psychosocial impairment compared with siblings; however, BMT does not confer additional risk for psychosocial late effects compared with treatment without BMT.

Background: Adult survivors of childhood osteosarcoma and Ewing sarcoma are at risk of developing therapy-related chronic health conditions. We characterized the cumulative burden of chronic conditions and health status of survivors of childhood bone sarcomas. Methods: Survivors (n = 207) treated between 1964 and 2002 underwent comprehensive clinical assessments (history/physical examination, laboratory analysis, and physical and neurocognitive testing) and were compared with community controls (n = 272). Health conditions were defined and graded according to a modified version of the NCI's Common Terminology Criteria for Adverse Events and the cumulative burden estimated. Results: Osteosarcoma and Ewing sarcoma survivors [median age 13.6 years at diagnosis (range 1.7–24.8); age at evaluation 36.6 years (20.7–66.4)] demonstrated an increased prevalence of cardiomyopathy (14.5%; P < 0.005) compared with controls. Nearly 30% of osteosarcoma survivors had evidence of hypertension. By age 35 years, osteosarcoma and Ewing sarcoma survivors had, on average, 12.0 (95% confidence interval, 10.2–14.2) and 10.6 (8.9–12.6) grade 1–4 conditions and 4.0 (3.2–5.1) and 3.5 (2.7–4.5) grade 3–4 conditions, respectively, compared with controls [3.3 (2.9–3.7) grade 1–4 and 0.9 (0.7–1.0) grade 3–4]. Both survivor cohorts exhibited impaired 6-minute walk test, walking efficiency, mobility, strength, and endurance (P < 0.0001). Accumulation of ≥4 grade 3–4 chronic conditions was associated with deficits in executive function [RR: osteosarcoma 1.6 (1.0–2.4), P = 0.049; Ewing sarcoma 2.0 (1.2–3.3), P = 0.01] and attention [RR: osteosarcoma 2.3 (1.2–4.2); P = 0.008]. Conclusions: Survivors of osteosarcoma and Ewing sarcoma experience a high cumulative burden of chronic health conditions, with impairments of physical function and neurocognition. Impact: Early intervention strategies may ameliorate the risk of comorbidities in bone sarcoma survivors.

Patient-reported outcomes among survivors of pediatric hematopoietic stem cell transplant (HSCT) are understudied. We compared symptom prevalence, health-related quality of life (HRQOL), and risk factors in adult survivors of childhood hematologic malignancies treated with HSCT to those treated with conventional therapy and noncancer controls. Survivors of childhood hematologic malignancies (HSCT N = 112 [70% allogeneic, 30% autologous]; conventionally treated N = 1106) and noncancer controls (N = 242) from the St. Jude Lifetime Cohort Study completed surveys assessing 10 symptom domains and SF-36 HRQOL summary scores. Chronic health conditions (CHCs) were validated by clinical assessment. Multivariable logistic regression reveals that compared with noncancer controls, HSCT survivors endorsed a significantly higher symptom prevalence in sensation (OR = 4.7, 95% confidence interval [CI], 2.6-8.4), motor/movement (OR = 4.3, 95% CI, 1.6-11.0), pulmonary (OR = 4.6, 95% CI, 1.8-11.8), and memory domains (OR = 4.8, 95% CI, 2.5-9.2), and poorer physical HRQOL (OR = 6.9, 95% CI, 2.8-17.0). HSCT and conventionally treated survivors had a similar prevalence of all symptom domains and HRQOL (all P > .05); however, HSCT survivors had a significantly higher cumulative prevalence for specific symptoms: double vision (P = .04), very dry eyes (P < .0001), and trouble seeing when wearing glasses (P < .0001). Occurrence of organ-specific CHCs, instead of transplant receipt, was significantly associated with a higher prevalence of all symptom domains (all P < .05) in adult survivors of childhood cancer, except for pain and anxiety domains. This study found that patient-reported outcomes were equally impaired between HSCT and conventionally treated survivors, but poorer in both groups compared with noncancer controls. Poor patient-reported outcomes in all survivors of childhood hematologic malignancies correlated with the presence of CHCs, whether treated with conventional therapy or HSCT.

Background The objective of this study was to characterize the prevalence and risk of pain, pain interference, and recurrent pain in adult survivors of childhood cancer in comparison with siblings. Methods This study analyzed longitudinal data from survivors (n = 10,012; 48.7% female; median age, 31 years [range, 17-57 years]; median time since diagnosis, 23 years) and siblings (n = 3173) from the Childhood Cancer Survivor Study. Survivors were diagnosed between 1970 and 1986 at 1 of 26 participating sites. Associations between risk factors (demographics, cancer-related factors, and psychological symptoms) and pain, pain interference, and recurrent pain (5 years apart) were assessed with multinomial logistic regression. Path analyses examined cross-sectional associations between risk factors and pain outcomes. Results Twenty-nine percent of survivors reported moderate to severe pain, 20% reported moderate to extreme pain interference, and 9% reported moderate to severe recurrent pain. Female sex, a sarcoma/bone tumor diagnosis, and severe/life-threatening chronic medical conditions were associated with recurrent pain. Depression and anxiety were associated with increased risk for all pain outcomes. Poor vitality mediated the effects of anxiety on high pain and pain interference (root mean square error of approximation, 0.002). Conclusions A large proportion of adult survivors report moderate to severe pain and pain interference more than 20 years after their diagnosis. Increased screening and early intervention for pain interference and recurrent pain are warranted.

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16-17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ+ thalassaemia; n = 52 HbSS/HbSβ0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ+ thalassaemia; n = 8 HbSS/HbSβ0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ0 thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.

PURPOSE To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty. METHODS Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition. RESULTS The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; v 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m2, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for. CONCLUSION Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.

Background: To the authors' knowledge, few studies to date have examined long-term neurocognitive outcomes in survivors of childhood soft-tissue sarcoma. Methods: A total of 150 survivors (41% of whom were female with a mean current age of 33 years [SD, 8.9 years] and a time since diagnosis of 24 years [SD, 8.7 years]) and 349 community controls (56% of whom were female with a mean current age of 35 years [SD, 10.2 years]) completed comprehensive neuropsychological testing, echocardiography, electrocardiography, pulmonary function tests, endocrine evaluation, and physical examination. Patient-reported outcomes of health-related quality of life (HRQOL) and social attainment were collected. Survivors were compared with norms and controls on neurocognitive outcomes using general linear models, and on HRQOL and social attainment using modified Poisson models. The impacts of treatment and chronic health conditions on outcomes were examined using multivariable general linear models (effect size was expressed as unstandardized β estimates that reflected the unit of change from a mean of 0 and an SD of 1) and modified Poisson models (effect size expressed as relative risks). Results: Compared with controls and population norms, survivors demonstrated lower performance on measures of verbal reasoning (mean z score, −0.45 [SD, 1.15]; P

Background Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. Methods Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P Results Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent–level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error–corrected P = .004 to .008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P Conclusions These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits.

Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS.Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties.Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21-3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01-3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment.Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time.Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

Patient-reported outcome measures (PROMs) are subjective assessments of health status or health-related quality of life. In childhood cancer survivors, PROMs can be used to evaluate the adverse effects of cancer treatment and guide cancer survivorship care. However, there are barriers to integrating PROMs into clinical practice, such as constraints in clinical validity, meaningful interpretation, and technology-enabled administration of the measures. This article discusses these barriers and proposes 10 important considerations for appropriate PROM integration into clinical care for choosing the right measure (considering the purpose of using a PROM, health profile vs. health preference approaches, measurement properties), ensuring survivors complete the PROMs (data collection method, data collection frequency, survivor capacity, self- vs. proxy reports), interpreting the results (scoring methods, clinical meaning and interpretability), and selecting a strategy for clinical response (integration into the clinical workflow). An example framework for integrating novel patient-reported outcome (PRO) data collection into the clinical workflow for childhood cancer survivorship care is also discussed. As we continuously improve the clinical validity of PROMs and address implementation barriers, routine PRO assessment and monitoring in pediatric cancer survivorship offer opportunities to facilitate clinical decision making and improve the quality of survivorship care.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR014) of the Conference Proceedings. Citation Format: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park. Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B004.

Background: Childhood cancer survivors are a growing population at elevated risk for premature aging and age-related chronic health conditions (CHCs) compared to the general population. In the general population, diet affects many hallmarks of aging, including inflammation, metabolic dysfunctions, and molecular and epigenetic changes. We examined associations between dietary patterns and risk of premature aging in adult survivors of childhood cancer. Methods: Adult survivors (18-65 years old, mean [SD] age 31 [8.4] years) of childhood cancer enrolled in SJLIFE between 2007 and 2017 completed a 110-item food frequency questionnaire at enrollment (n=2,904). Sociodemographic, cancer, cancer treatments, and health history were abstracted from medical records; CHCs were clinically validated. Factor analysis was performed to identify dietary patterns specific to the study population. Premature aging was assessed using the Deficit Accumulation Index (DAI) based on 45 age-related CHCs and categorized into low (0.35) aging risk groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multinomial logistic regressions adjusting for potential confounders, such as sociodemographics, health behaviors, and cancer treatments. Individuals’ factor scores of each pattern were grouped into quintiles, and a median score of each quintile was entered as a continuous term in regression models. Results: 20% of survivors were at medium- and 8% were at high-risk for premature aging. Survivors at high-risk for premature aging were more likely to be female, smokers, have low socioeconomic status, and have received radiation therapy to head and neck, chest, spine, or abdomen compared to those at low premature aging risk. Three dietary patterns were identified: 1) plant-based, 2) fast-food, and 3) Western contemporary. A plant-based diet was characterized by greater intakes of vegetables, fruits, whole grains, and fish. A higher plant-based diet pattern score was associated with a lower risk of premature aging (OR=0.76, 95% CI: 0.62-0.94 for the high-risk group; OR=0.91, 95% CI: 0.79-1.04 for the medium-risk group). A fast-food diet was characterized by greater intakes of sweets, processed meat, refined grains, potato, high-fat dairy, and soda. A fast-food diet was related to a non-significant increased risk of premature aging (OR=1.20, 95% CI: 0.91-1.57 for the high-risk group; OR=1.18, 95% CI: 0.98-1.43 for the medium-risk group). A Western contemporary diet characterized by greater intakes of meat, pasta/rice, pizza, Mexican food, and fruit juice was associated with an increased risk of premature aging (OR=1.36, 95% CI: 1.05-1.78 for the high-risk group; OR=1.04, 95% CI: 0.87-1.26 for the medium-risk group). Conclusion: Our findings suggest that diet plays a role in aging, and a diet rich in plant-based foods may mitigate the risk of premature aging in childhood cancer survivors. Citation Format: Yikyung Park, Mei Wang, Tuo Lan, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness. Cancer survivor-specific dietary patterns and risk of premature aging in adult survivors of childhood cancer: St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A019.

Background: In the general population, sugar intake is associated with a wide range of adverse health conditions related to premature aging, including obesity, diabetes, and cardiovascular disease. Childhood cancer survivors are at increased risk of premature aging and mortality compared to their healthy peers and may be especially vulnerable to adverse consequences of excess sugar intake. Objective: To examine the association between sugar and sugar-sweetened beverage intake and premature aging in childhood cancer survivors. Method: A total of 3,322 adult survivors of childhood cancer (age range 18-65 years; mean age: 31 years) in SJLIFE self-reported their typical diet using the 110-item Block Food Frequency Questionnaire. Added sugars included all sugars added to foods during preparation or processing. Total sugar-sweetened beverages are the sum of regular and diet soda and fruit-flavored drinks. Survivors’ sociodemographics, cancer histories, and health conditions were abstracted from medical records. Premature aging was assessed using the Deficit Accumulation Index (DAI) that was a ratio of the number of age-related chronic health conditions each survivor had out of 45 conditions total. The DAI was categorized into low (0.35) aging risk groups. Multinomial logistic regressions (reference: low aging risk group) adjusting for confounders, including sociodemographics, lifestyle factors, cancer treatments, and overall diet quality, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Survivors’ average total sugar intake was 120 g/day and added sugar intake was 71 g/day. 41% of survivors consumed sugar-sweetened beverages ≥1 time/day, and 26% consumed soda daily; 75% of soda consumed was regular (vs. diet). Survivors with higher consumption of sugar and sugar-sweetened beverages were more likely to be non-Hispanic Black and have lower educational attainment and income. Total sugar intake was associated with a significantly increased risk of premature aging (per 25 g/1,000 kcal increment, OR=1.31 [95% CI: 1.00-1.70] in the medium-risk group; OR=1.52 [95% CI: 1.03-2.25] in the high-risk group). Added sugar intake was associated with a 19% (OR=1.19, 95% CI: 1.07-1.31, per 20 g/1,000 kcal increment) and an 18% (OR=1.18, 95% CI: 1.02-1.37) increased risk of premature aging in the medium- and high-risk group, respectively. Consuming ≥2 servings/day (vs. ≤ 1/week) of total sugar-sweetened beverage was also related to an increased risk of premature aging (OR=1.54 [95% CI: 0.83-2.83] in the medium-risk group; OR=6.71 [95% CI: 2.95-15.2] in the high-risk group). Regular soda, but not diet soda, consumption was associated with premature aging risk. Conclusion: Higher consumption of sugar and sugar-sweetened beverages was associated with an increased risk of premature aging in childhood cancer survivors. Intervention efforts to reduce sugar intake among this vulnerable population are needed. Citation Format: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park. Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR014.

PURPOSE: Pediatric low-grade glioma therapy has evolved to delay or eliminate radiation. The impact of therapy changes on long-term outcomes remains unknown. METHODS: Cumulative incidence of late mortality (death >5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, CTCAE grading criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed 1970-1999. Outcomes were evaluated by diagnosis decade and by treatment exposures received ≤5 years following diagnosis (surgery-only, chemotherapy ± surgery, and cranial radiation ± surgery or chemotherapy). Relative risk (RRs) with 95%CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 2,684 eligible survivors (age at diagnosis (median [range]), 7 years [0-20 years]; time from diagnosis, 24 years [5-48 years]), exposure to cranial radiation decreased [51% (1970s), 45% (1980s), 25% (1990s)] along with late tumor recurrence (>5 & ≤15 years from diagnosis) [9.8% (1970s), 8.8% (1980s), 5.0% (1990s)]. The 15-year cumulative incidence of late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p

BACKGROUND Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age

Background: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors. Methods: This study included 203 API 5-year survivors [age at follow-up: 29.2 (SD = 6.3) years] and 12,186 NHW survivors [age at follow-up 31.5 (SD = 7.3) years] from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment. Results: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors [mean 54.11 (SD = 8.98) vs. 51.32 (SD = 10.12); P < 0.001]. NHW survivors were less likely to have attained at least a college degree than API survivors [OR = 0.50; 95% confidence interval (CI) = 0.34–0.73]. API survivors were more likely than NHW survivors to be never-married (OR = 2.83; 95% CI = 1.93–4.13) and to live dependently (OR = 3.10; 95% CI = 2.02–4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P < 0.05). Conclusions: We observed differences in social attainment between API and NHW survivors, although statistically significant differences in neurocognitive and emotional outcomes were not identified. Impact: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.

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

Background The effect of chemotherapy on brain development in long-term survivors of pediatric acute lymphoblastic leukemia (ALL) was systematically reviewed. Methods A systematic search of Pubmed, Scopus, and PsycINFO databases was conducted to identify articles published between January 2000 and February 2020 that implemented magnetic resonance imaging to assess brain structure and function in pediatric ALL survivors (diagnosed younger than 21 years of age). The review included articles that were published on children diagnosed with ALL between 0 and 21 years of age and treated with chemotherapy-only protocols. Articles meeting the inclusion criteria described survivors on average of 5 years or more from diagnosis and were peer-reviewed articles and original studies. Results The search yielded 1975 articles with 23 articles meeting inclusion criteria. The review revealed that survivors had statistically significant alterations in brain anatomy, most commonly a smaller hippocampus and impaired microstructural white matter integrity in frontal brain regions. Survivors also had impaired brain function including lower brain network efficiency and altered resting state connectivity. Survivors also displayed widespread reductions in brain activation (ie, frontal, temporal, parietal brain regions) during cognitive tasks. Conclusion Although the neurotoxic effects of cancer treatment are reduced in the absence of cranial radiation, survivors treated on chemotherapy-only protocols still display long-term alterations in brain structure and function, which contribute to lifelong neurocognitive late effects.

Childhood cancersurvivors may be differentially impacted by coronavirus disease 2019 (COVID‐19). From April to June of 2020, we examined psychosocial/health concerns in 4148 adult survivors and 571 siblings. Although more survivors reported concerns about getting sick (p = .002) and needing hospitalization (p = .003) in general, survivors and siblings were comparably concerned about being infected with and the consequences of COVID‐19. Cranial radiation was associated with social isolation (relative risk [RR] = 1.3, CI = 1.1–1.7), and central nervous system (CNS) tumors were associated with unemployment due to COVID‐19 (RR = 1.7, CI = 1.2–2.2). Some survivors appear more vulnerable and may require more support to meet health care and vocational needs during COVID‐19, though siblings also perceive substantial risk.

BACKGROUND Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment-related exercise intolerance and neurocognitive deficits. This analysis aimed to identify the association between exercise intolerance and neurocognitive impairments in ALL survivors. METHODS Cardiopulmonary exercise testing, results from a 2-hour standardized neuropsychological assessment, and self-report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO2 ) and neuropsychological test and self-reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status. RESULTS Compared with controls, survivors had worse rpkVO2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual-motor speed, memory span, and reading and math measures (all P

PURPOSE: Improved therapies for pediatric central nervous system (CNS) tumors have increased survival rates, however, many survivors experience significant long-term functional limitations. Survivors of pediatric CNS tumors can experience deficits in social attainment. The aim of this review was to systematically amalgamate findings pertaining to social attainment (i.e., educational attainment, marriage, employment outcomes) in survivors of pediatric CNS tumors. METHODS: PubMed(Web-based), PsycINFO(EBSCO), EMBASE(Ovid), and Web of Science(Thomson Reuters) were used to identify articles published between January 2011 and September 2018. Eligible studies reported outcomes for survivors of pediatric CNS tumors diagnosed before age 21 years, and >5 years from diagnosis and/or >2 years off therapy. All data were independently abstracted by two reviewers. Random-effects meta-analyses were performed using Review Manager 5.0. RESULTS: The search yielded 7,021 unique publications. Forty-six were included in the current review. Meta-analyses revealed survivors of CNS tumors were significantly more likely to have completed compulsory education only (OR = 1.87, 95% CI = 1.66, 2.12, p < 0.00001), less likely to be married (OR = 4.70, 95% CI = 3.89, 5.68, p

PURPOSE The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study. PATIENTS AND METHODS Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029). RESULTS LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors. CONCLUSION Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.

Observational data have shown that some cancer survivors develop chronic conditions like frailty, sarcopenia, cardiac dysfunction, and mild cognitive impairment earlier and/or at a greater burden than similarly aged individuals never diagnosed with cancer or exposed to systemic or targeted cancer therapies. In aggregate, cancer- and treatment-related physical, cognitive, and psychosocial late- and long-term morbidities experienced by cancer survivors are hypothesized to represent accelerated or accentuated aging trajectories. However, conceptual, measurement, and methodological challenges have constrained efforts to identify, predict, and mitigate aging-related consequences of cancer and cancer treatment. In July 2018, the National Cancer Institute convened basic, clinical, and translational science experts for a think tank titled “Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors.” Through the resulting deliberations, several research and resource needs were identified, including longitudinal studies to examine aging trajectories that include detailed data from before, during, and after cancer treatment; mechanistic studies to elucidate the pathways that lead to the emergence of aging phenotypes in cancer survivors; long-term clinical surveillance to monitor survivors for late-emerging effects; and tools to integrate multiple data sources to inform understanding of how cancer and its therapies contribute to the aging process. Addressing these needs will help expand the evidence base and inform strategies to optimize healthy aging of cancer survivors.

Context Childhood cancer survivors experience chronic health conditions that impact health-related quality of life (HRQOL) and participation in optimal physical activity. Objective The study aimed to determine independent effects of endocrine and metabolic disorders on HRQOL and physical activity. Design, Setting, and Patients Retrospective cohort with longitudinal follow-up of survivors of childhood cancer enrolled in the North American Childhood Cancer Survivor Study. Main Outcome Measures Medical Outcomes Short Form-36 estimated HRQOL, and participation in physical activity was dichotomized as meeting or not meeting recommendations from the Centers for Disease Control and Prevention. Log binomial regression evaluated the association of each endocrine/metabolic disorder with HRQOL scales and physical activity. Results Of 7287 survivors, with a median age of 32 years (range, 18 to 54 years) at their last follow-up survey, 4884 (67%) reported one or more endocrine/metabolic disorders. Survivors with either disorder were significantly more likely to be male, older, have received radiation treatment, and have experienced other chronic health conditions. After controlling for covariates, survivors with any endocrine/metabolic disorder were more likely to report poor physical function risk ratio (RR, 1.25; 95% CI, 1.05 to 1.48), increased bodily pain (RR, 1.27; 95% CI, 1.12 to 1.44), poor general health (RR, 1.49; 95% CI, 1.32 to 1.68), and lower vitality (RR, 1.21; 95% CI, 1.09 to 1.34) compared with survivors without. The likelihood of meeting recommended physical activity was lower among survivors with growth disorders (RR, 0.90; 95% CI, 0.83 to 0.97), osteoporosis (RR, 0.87; 95% CI, 0.76 to 0.99), and overweight/obesity (RR, 0.92; 95% CI, 0.88 to 0.96). Conclusion Endocrine and metabolic disorders are independently associated with poor HRQOL and suboptimal physical activity among childhood cancer survivors.

To examine prevalence and predictors of neurocognitive outcomes, social attainment, emotional distress, and health-related quality of life (HRQOL) in long-term survivors of pediatric Wilms tumor (WT). One hundred fifty-eight WT survivors (59% female; mean [SD] age 33 [9.1] years; time since diagnosis 29 [9.1] years) and 354 community controls (55.6% female; 35 [10.2] years) completed comprehensive neuropsychological testing and physical examination, including echocardiography/electrocardiography, pulmonary function tests, and endocrine evaluation. Self-report of emotional distress, HRQOL, and social attainment were collected. Impairment was defined in relation to both controls and normative data. Generalized linear models were developed to examine impact of treatment and chronic health conditions on outcomes. WT survivors performed poorer than norms and controls in 6 of 16 cognitive variables and 1 of 8 HRQOL variables, with scores ranging from − 0.64 (mathematics) to − 0.21 (verbal fluency) standard deviations below expectations. Compared to controls, WT survivors were less likely to graduate college (odds ratio 2.23, 95% confidence interval 1.46–3.41) and had more moderate to severe neurologic conditions (18.4% vs 8.2%, p

10007 Background: Therapy for pediatric low-grade glioma has evolved to delay or eliminate the need for cranial radiation. The impact of this change in approach on long-term outcomes remains unknown. Methods: Cumulative incidence of late mortality (death ≥5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, graded using CTCAE criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed between 1970 and 1999. Outcomes were evaluated by diagnosis decade (1970s, 1980s, 1990s) and by treatment exposure in the first five years from diagnosis [surgery only, chemotherapy (with or without surgery), and cranial radiation (with or without surgery or chemotherapy)]. Relative Risk (RRs) with 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. Results: Among 2,684 eligible survivors (median age at diagnosis, 7 years [range, 0 to 20 years]; median time from diagnosis, 24 years [range, 5 to 48 years]), the proportion exposed to cranial radiation decreased from 51% (1970s) to 45% (1980s) and 25% (1990s) while the rate of recurrence within > 5 years but ≤15 years of diagnosis decreased from 9.8% (1970s) to 8.8% (1980s) and 5.0% (1990s). The 15-year cumulative incidence rate of all-cause late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p < 0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence rates of severe, disabling or life-threatening (grade 3-5) CHCs also decreased between 1970 and 1999: 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p < 0.0001). Lower rates of SN were not observed. In a multivariable analysis adjusted for age at diagnosis, attained age, race, sex and diagnosis decade, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality (RR 0.86, 95% CI 0.74-0.99), grade 3-5 CHCs (RR 0.65, 95% CI 0.51-0.82) and SN (RR 0.64, 95% CI 0.44-0.94). In addition, when treatment exposure was added to the multivariable model, the effect of diagnosis decade was attenuated and no longer significant. Exposure to radiation or chemotherapy both increased risk compared to surgery alone: all-cause mortality (radiation RR 4.95, 95% CI 3.79-6.47; chemotherapy RR 2.88, 95% CI 1.85-4.48), grade 3-5 CHCs (radiation RR 4.02, 95% CI 3.28-4.94; chemotherapy RR 1.66, 95% CI 1.13-2.45), SNs (radiation RR 4.02, 95% CI 3.06-6.13, chemotherapy RR 2.08, 95% CI 1.03-4.23)). The effect of delayed radiation (> 1year to ≤5 years from diagnosis) on all-cause late mortality, grade 3-5 CHCs, or SNs was not different compared to radiation within one year of diagnosis. Conclusions: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.

12095 Background: Survivors of childhood cancer are at increased risk for early development of CHCs, including metabolic syndrome (MetS), low bone mineral density (LBMD), and gastrointestinal (GI) disease. Dietary modification is often recommended for prevention and/or treatment of these CHCs in non-cancer populations. However, associations between diet quality and severity of CHCs in adult survivors of childhood cancer are not well known. Methods: Adult survivors (≥10 years post-diagnosis) of childhood cancer who completed a clinical evaluation and Block Food Frequency Questionnaire were included. Diet quality was estimated using the Mediterranean diet score (aMED), with scores ranging from 0 to 9 (increased scores represent higher adherence to diet). CHCs were graded (modified CTCAE) and classified as “low” (grade ≤1 for LBMD and GI; grade ≤2 for MetS) or “high” (grade 2-4 for LBMD and GI; grade 3-4 for MetS). A multivariable linear regression model was used to estimate the mean aMED score by “low” or “high” disease category, with adjustment for age at evaluation, sex, race, education, total energy intake, adjusted BMI, physical activity, smoking, and alcohol consumption. Results: 2,822 survivors of childhood cancer (52.4% male, 83.1% non-Hispanic white) were included. The most prevalent diagnosis was acute lymphoblastic leukemia (34.1%). Time from primary diagnosis was 24.2±8.5 years and age at recruitment was 32.5±8.7 years. Lower adherence to aMED diet was associated with “high” MetS and LBMD, but not GI disease. See the Table for aMED multivariate-adjusted diet quality scores by CHC. Conclusions: In this cross-sectional analysis, MetS and LBMD were associated with poor adherence to the aMED diet. Although longitudinal investigation of associations between diet quality and CHCs in survivors of childhood cancer are needed to determine causal association between diet quality and CHCs in childhood cancer survivors, dietary interventions in early or late cancer survivors may help prevent development or progression of specific treatment related chronic conditions. [Table: see text]

PURPOSE: Survivors of pediatric glioma are at risk of developing physical and neurocognitive sequelae secondary to their tumor and its treatment. The contribution of these conditions to attainment of functional independence has not previously been examined. METHODS: 1,284 adult survivors of pediatric glioma (48% male, median [range] 30 [18-51] years at assessment, 22 [15-34] years since diagnosis) completed the CCSS Neurocognitive Questionnaire with impairment defined as scores > 90th %ile of sibling norms. Treatment exposures were categorized as surgery only, chemotherapy (± surgery), or cranial radiation (± chemotherapy/surgery). Self-reported chronic health conditions (CHCs) were graded by organ system using NCI’s CTCAE v4.3. Latent class analysis utilized six factors (employment, marital status, independent living, driver’s license, assistance with routine needs, assistance with personal care needs) to identify classes of functional independence. Multivariable modified Poisson regression evaluated relative risk (RR) of neurocognitive impairment between the classes, adjusting for sex, race, age at assessment, and age at diagnosis. Path analysis explored the impact of treatment exposures on functional independence, mediated by Grade 2-4 CHCs and neurocognitive impairment. RESULTS: Three latent classes of functional independence were identified: independent (58%), moderately independent (20%), and non-independent (22%). Compared to the independent class, non-independent survivors were at elevated risk for impaired task efficiency (RR=3.86, 95% CI, 2.97-5.01), memory (RR=2.39, 95% CI, 1.91-2.98), organization (RR=2.04, 95% CI, 1.64-2.54), and emotional regulation (RR=1.67, 95% CI, 1.30-2.15). Path analysis revealed significant direct paths from cranial radiation (β=0.14), impaired task efficiency (β=0.42), and sensorimotor (β=0.22) and endocrine conditions (β=0.24) to non-independence. Cranial radiation also was indirectly associated with non-independence through impaired task efficiency (β=0.06), and sensorimotor (β=0.06) and endocrine conditions (β=0.10). CONCLUSIONS: Neurocognitive impairment and chronic health conditions partially mediate the association between treatment exposures and attainment of independence in adulthood, identifying potential intervention targets to promote independence in long-term survivors.

10051 Background: Chronic health conditions are prevalent among adult survivors of childhood cancer. The impact of health on maintaining full-time (FT) employment, a common indicator of socioeconomic independence, has not been studied in this population. Methods: Self-reported employment status (FT, part-time [PT], unemployed [any reason], not in labor force) was assessed at two timepoints (2002-04 [T1] and 2015-16 [T2]) in adult (≥25y old) survivors of childhood cancer diagnosed between 1970-86. Sex-stratified Poisson regression, adjusted for race and ages at diagnosis and T2, was used to study associations between timing and severity of chronic health conditions (graded per the CTCAE v4.03) and transitions from FT to PT or unemployed. Results: Survivors employed FT at T1 (males=1712, median age [min-max]: 34y [25-53]; females=1337, 33y [25-53]) who reported employment status at T2 were included. At T2 (median time from T1 11.5y [9.4-13.8]), 83% males and 70% females remained employed FT, but 4% and 10% transitioned to PT, and 11% and 12% to unemployed (additional 2% and 8% left the labor force), respectively. Male and female survivors with grade 2 or 3-4 neurologic conditions acquired before T1 or between T1-T2 were at a higher risk of moving from FT to PT or unemployed compared to those with grade 0-1 conditions. Males and females with grade 3-4 respiratory conditions prior to T1 and cardiac and musculoskeletal conditions acquired between T1-T2 were also at higher risk for moving to PT or unemployed (Table). Additional predictors for males included grade 2 vision (before T1 RR 2.3, 95% CI 1.5-3.3; between T1-T2 RR 1.7, 95% CI 1.1-2.7) and endocrine (before T1 RR 1.4, 95% CI 1.1-1.9; between T1-T2 RR 1.7, 95% CI 1.3-2.3) conditions. Conclusions: A substantial portion of adult survivors of childhood cancer with health conditions of varying severity leave FT employment. Increased awareness of all stakeholders may facilitate access to clinical counseling and occupational provisions for flexible and supportive work accommodations to reduce work-related barriers for childhood cancer survivors. [Table: see text]

10014 Background: The impact ofmodifiable lifestyle and cardiovascular risk factors (CVRFs) on risk for late mortality in adult survivors of childhood cancer is not well established. Methods: All-cause and health-related late (>5 years from cancer diagnosis) mortality (HRM; excludes death from primary cancer and external causes) were evaluated in five-year survivors diagnosed

10020 Background: Survivors of pediatric cancer, including those without CNS-directed treatment, are at risk of neurocognitive impairment and peripheral or autonomic neuropathies; conditions that co-occur in non-cancer populations. Using the St. Jude Lifetime Cohort, we investigated associations between these sequelae to inform contributors to long-term cancer-related neurocognitive impairment. Methods: Clinically assessed survivors of pediatric cancer (N=2,138, mean age 31 [SD 13], 23[11] years from diagnosis, 51% male) not treated with CNS-directed therapy completed neurocognitive testing. Modified total neuropathy score peripheral sensory and motor subscales were combined with functional tasks and severity graded using a modified NCI CTCAE. Cardiac autonomic neuropathy was defined as impaired heart rate reserve (th percentile) associated with grade 2+ sensory, motor or autonomic neuropathy. Path analysis examined if pain with daily interference mediated associations between motor or sensory neuropathy and neurocognitive impairment. Results: 838 (39%) survivors had autonomic, 115 (5.4%) had motor and 162 (7.6%) had sensory neuropathy. Compared to those with no neuropathy, survivors with motor or sensory neuropathy had a higher risk of impairment in sustained attention, visual-motor processing speed, short- and long-term memory, and executive function (Table, p’s

e22024 Background: Physical and psychological symptoms co-occur among survivors of childhood cancer, and subgroups with high symptom burden may be at increased risk for problematic healthcare utilization (HCU). Methods: Childhood Cancer Survivor Study participants (N = 17,231; Mean [SD] age = 27.4 [5.98]; 79% non-Hispanic White; 48% female) self-reported sensory, motor, cardiac, respiratory, pain, gastrointestinal, fatigue, memory, depression, and anxiety symptoms at baseline evaluation and latent class analysis identified symptom profiles. Chronic health conditions (CHCs) at baseline (graded per CTCAE 1-2 [mild or moderate; reference] vs 3-4 [severe-life threatening or disabling). HCU (no health care, general care, oncology-focused, long-term follow-up, emergency room visit) for the past 2 years was assessed 6.3 median years after baseline. Logistic regressions examined associations between class membership and follow-up HCU, adjusted for sex, age, health insurance and CHCs. Results: Five symptom classes were identified: 1) Global symptoms (global; 7.7%); 2) emotional distress and pain (distress-pain; 13.3%); 3) neurologic and pain (neuro-pain; 10.6%); 4) cardiopulmonary and pain (cardio-pain; 5.3%); 5) non-elevated symptoms (norm; 63.1%). Bone tumor survivors had higher risk of falling into global, neuro-pain and cardio-pain groups (p’s < .001), and CNS tumor survivors had higher risk of falling into global and neuro-pain group (all p < .001) compared to leukemia survivors. Radiation, Grade 3-4 CHCs, female sex, and older age increased risk of global, distress-pain, neuro-pain and cardio-pain membership compared to norm (all p’s < .001). Oncology-focused care was more common in cardio-pain and global symptom groups, while long-term follow-up care was more common in neuro-pain and global groups (Table). All elevated symptoms groups were more likely to have emergency room visits compared to norm group. Conclusions: Adjusting for insurance, CHCs and older age, elevated symptoms are associated with future emergency room use. Pain is prevalent in all high symptom groups, and suggests an important intervention target.[Table: see text]

e24147 Background: Psychosocial late effects of childhood cancer are often studied in isolation despite high rates of co-morbidity. We examined patterns of psychosocial morbidity and their associations with subsequent chronic health conditions, quality of life, and mortality in adult survivors of childhood cancer. Methods: St. Jude Lifetime Cohort participants (n = 4,009; median[range] 30.6[18.0-64.8] years of age; 20.4[5.5-52.3] years from diagnosis; 51% female) completed baseline questionnaires. Latent class analysis characterized psychosocial morbidity using 18 individual indicators across four domains: functional independence (e.g., independent living), emotional health (e.g., depressive symptoms), health behaviors (e.g., alcohol use), and socioeconomic status (e.g., employment). Generalized linear models, adjusted for age, sex, and race/ethnicity, examined longitudinal associations between class membership at cohort entry and persistent/new onset Grade 2-4 chronic health conditions from baseline to follow-up (n = 2,355, median f/u = 5.8 years). In separate adjusted models, associations with persistently poor/worsening quality of life at follow-up [SF-36 t-score

Background: Childhood cancer survivors are at elevated risk for motor and/or sensory neuropathy. The study aims to evaluate the concordance between self-report peripheral neuropathy compared with clinically ascertained peripheral neuropathy, and to identify factors associated with misclassification of peripheral neuropathy among survivors. Methods: The concordance between self-report and clinically ascertained peripheral neuropathy was evaluated among 2,933 5+ years old childhood cancer survivors (mean age 33.3, SD = 8.9). The sensitivity, specificity, and accuracy of self-report peripheral motor neuropathy (PMN) and peripheral sensory neuropathy (PSN) were calculated with reference to clinically assessed peripheral neuropathy. Results: Female survivors were more likely than male survivors to have clinically ascertained PMN (8.4% vs. 5.6%, P = 0.004). For females, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (43.2%, 90.3%, and 85.2%, respectively), with kappa of 0.304. For males, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (38.8%, 90.5%, and 86.3%, respectively) with kappa of 0.242. Age at diagnosis, emotional distress, and reporting pain in legs in the past 4 weeks were associated with an increased risk for false-positive reporting of peripheral neuropathy. Race (White), age at assessment, and emotional distress were associated with increased risk for false-negative reporting of peripheral neuropathy. Conclusions: Agreement between self-report and clinically ascertained peripheral neuropathy was poor in survivors. Choosing self-report versus clinical ascertained peripheral neuropathy should be carefully considered. Impact: The current study identifies the need for a self-report questionnaire that accurately assesses symptoms of peripheral neuropathy among cancer survivors.

BACKGROUND Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated. METHODS Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross-sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement. RESULTS For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross-sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P < .05), attention (attention span and risk taking; all P < .05), and processing speed (visual motor coordination, visual speed, and motor speed; all P < .05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P = .01) and slower motor speed (P = .02), which persisted throughout the treatment. CONCLUSIONS Overweight/obesity was significantly associated with neurocognitive impairment during long-term follow-up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk.

BACKGROUND To examine associations between phenotypes of short sleep duration and clinically assessed health conditions in long-term survivors of childhood cancer. METHODS Survivors recruited from the St. Jude Lifetime Cohort (n = 911; 52% female; mean age 34 years; 26 years postdiagnosis) completed behavioral health surveys and underwent comprehensive physical examinations. Sleep was assessed with the Pittsburgh Sleep Quality Index. Short sleep was defined as ≤6 h per night with phenotypes of short sleep including poor sleep efficiency (

Background: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact. Methods: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes. Results: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9–12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1–34.6) and sarcomas (PR, 11.5; 95% CI, 9.1–14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8–24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5–2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1–1.2), anxiety (PR, 2.5; 95% CI, 2.2–2.9), depression (PR, 2.1; 95% CI, 1.9–2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90–0.94) and employment (PR, 0.8; 95% CI, 0.8–0.9). Conclusions: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes. Impact: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.