Search

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.

BACKGROUND Neuroblastoma survivors may be at elevated risk for psychological impairments because of their young age at diagnosis and neurotoxic treatment, but this is not well described. METHODS A total of 859 ≥5-year survivors of neuroblastoma younger than 18 years (diagnosed in 1970-1999), who had a median age at diagnosis of 0.8 years (range: 0.0-7.3 years) and a median follow-up of 13.3 years (range: 8.0-17.9 years), were compared with 872 siblings of childhood cancer survivors who were younger than 18 years with the parent-reported Behavior Problem Index (BPI) for psychological functioning. Age- and sex-adjusted multivariate log-binomial models were used to identify factors associated with impairment in BPI domains (scores worse than the sibling 10th percentile). The impact of psychological impairment on educational outcomes was examined among survivors. RESULTS Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19% vs 14%; P = .003), headstrong behavior (19% vs 13%; P

Purpose Infection-related outcomes associated with asplenia or impaired splenic function in survivors of childhood cancer remains understudied. Methods Late infection-related mortality was evaluated in 20,026 5-year survivors of childhood cancer (diagnosed < 21 years of age from 1970 to 1999; median age at diagnosis, 7.0 years [range, 0 to 20 years]; median follow-up, 26 years [range, 5 to 44 years]) using cumulative incidence and piecewise-exponential regression models to estimate adjusted relative rates (RRs). Splenic radiation was approximated using average dose (direct and/or indirect) to the left upper quadrant of the abdomen (hereafter, referred to as splenic radiation). Results Within 5 years of diagnosis, 1,354 survivors (6.8%) had a splenectomy and 9,442 (46%) had splenic radiation without splenectomy. With 62 deaths, the cumulative incidence of infection-related late mortality was 1.5% (95% CI, 0.7% to 2.2%) at 35 years after splenectomy and 0.6% (95% CI, 0.4% to 0.8%) after splenic radiation. Splenectomy (RR, 7.7; 95% CI, 3.1 to 19.1) was independently associated with late infection-related mortality. Splenic radiation was associated with increasing risk for late infection-related mortality in a dose-response relationship (0.1 to 9.9 Gy: RR, 2.0; 95% CI, 0.9 to 4.5; 10 to 19.9 Gy: RR, 5.5; 95% CI, 1.9 to 15.4; ≥ 20 Gy: RR, 6.0; 95% CI, 1.8 to 20.2). High-dose alkylator chemotherapy exposure was also independently associated with an increased risk of infection-related mortality (RR, 1.9; 95% CI, 1.1 to 3.4). Conclusion Splenectomy and splenic radiation significantly increase risk for late infection-related mortality. Even low- to intermediate-dose radiation exposure confers increased risk, suggesting that the spleen is highly radiosensitive. These findings should inform long-term follow-up guidelines for survivors of childhood cancer and should lead clinicians to avoid or reduce radiation exposure involving the spleen whenever possible.

BACKGROUND: Pulmonary transit time (PTT) obtained from contrast-echocardiography is a marker of global cardiopulmonary function. Pulmonary blood volume (PBV), derived from PTT, may be a non-invasive surrogate for left-sided filling pressures, such as pulmonary artery wedge pressure (PAWP). We sought to assess the relationship between PBV obtained from contrast-echocardiography and PAWP. METHODS: Participants were adult survivors of childhood cancer that had contrast-echocardiography performed nearly simultaneously with right-heart catheterization. PTT was derived from time-intensity curves of contrast passage through the right-ventricle (RV) and left atrium (LA). PBV relative to overall stroke volume (rPBV) was estimated from the product of PTT and heart rate during RV-LA transit. PAWP was obtained during standard right-heart catheterization. The Spearman correlation coefficient was used to assess the relationship between rPBV and PAWP. RESULTS: The study population consisted of 7 individuals who had contrast-echocardiography and right-heart catheterization within 3 hours of each other. There was a wide range of right atrial (1–17 mmHg), mean pulmonary artery (18–42 mmHg), and PAW pressures (4–26 mmHg) as well as pulmonary vascular resistance (< 1 to 6 Wood Units). We observed a statistically significant correlation between rPBV and PAWP (r = 0.85; p = 0.02). CONCLUSION: Relative PBV derived from contrast-echocardiography correlates with PAWP. If validated in larger studies, rPBV could potentially be used as an alternative to invasively determined left-sided filling pressure.

Background The objective of the current study was to characterize and identify factors associated with perceptions of risk of infertility among adult male survivors of childhood cancer. Methods A total of 1233 adult male survivors from the Childhood Cancer Survivor Study who were without a history of disease recurrence or subsequent malignancy reported their perceptions of their risk of infertility compared with men never diagnosed with cancer. Survivors were a median age of 37.8 years (range, 22.0-58.7 years) and were 28.4 years from their diagnosis (range, 21.4-39.2 years). Multivariable logistic regression evaluated factors associated with perceptions of risk. Results Overall, 35.9% of the survivors (443 of 1233 survivors) reported perceptions of their risk of infertility that were discordant with their actual risk based on previous cancer treatment exposures. Discordant perceptions were equally common among men exposed to gonadotoxic therapies (36.3%; 311 of 857 men) and those with no history of gonadotoxic exposure (35.1%; 132 of 376 men). Survivors who fathered children (odds ratio [OR], 4.14; 95% confidence interval [95% CI], 2.74-6.24), had no survivor-focused health care (OR, 3.07; 95% CI, 1.57-5.99), were nonwhite (OR, 2.28; 95% CI, 1.10-4.75), and were of lower income were more likely to report no increased risk of infertility after gonadotoxic treatment. Perceptions of increased risk of infertility among men with no history of gonadotoxic treatment were predicted by never having fathered a child (OR, 1.88; 95% CI, 1.17-3.03), recent participation in survivor-focused health care (OR, 2.11; 95% CI, 1.01-4.42), and higher educational achievement. Conclusions Many male survivors of childhood cancer are unaware of how their cancer treatments could impact their reproductive health, underscoring the need for all patients to receive education regarding their risk of infertility throughout the continuum of cancer care. Cancer 2018;124:2447-55. © 2018 American Cancer Society.

PURPOSE: To describe and compare the prevalence of mental health access, preference, and use among pediatric cancer survivors and their siblings. To identify factors associated with mental health access and use among survivors. METHODS: 698 survivors in the Childhood Cancer Survivor Study (median age=39.4; median years from diagnosis=30.8) and 210 siblings (median age=40.4) were surveyed. Outcomes included having mental health insurance coverage, delaying care due to cost, perceived value of mental health benefits, and visiting a mental health provider in the past year. RESULTS: There were no differences in mental health access, preferences, and use between survivors and siblings (p>0.05). Among respondents with a history of distress, most reported not having seen a mental health provider in the past year (80.9% survivors vs. 77.1% siblings; p=0.60). Uninsured survivors were more likely to defer mental health services due to cost (24.6% vs. 8.4%; p

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

BACKGROUND Survivors of childhood cancer are at risk of nonsurgical premature menopause (NSPM). To the authors' knowledge, risk factors for NSPM and its impact on reproduction remain poorly defined. METHODS The menopausal status of 2930 survivors diagnosed between 1970 and 1986 (median age, 6 years [range, birth-20 years]) who were aged > 18 years at the time of the current study (median age, 35 years [range, 18-58 years]) was compared with 1399 siblings. NSPM was defined as the cessation of menses ≥6 months in duration occurring 5 years after diagnosis and before age 40 that was not due to pregnancy, surgery, or medications. Among survivors, multivariable logistic regression identified risk factors for NSPM. Pregnancy and live birth rates were compared between survivors with and without NSPM. RESULTS A total of 110 survivors developed NSPM (median age, 32 years [range, 16-40 years]), with a prevalence at age 40 years of 9.1% (95% confidence interval [95% CI], 4.9%-17.2%); the odds ratio (OR) was 10.5 (95% CI, 4.2-26.3) compared with siblings. Independent risk factors included exposure to a procarbazine dose ≥4000 mg/m2 (OR, 8.96 [95% CI, 5.02-16.00]), any dose of ovarian radiation (OvRT) (OvRT

Cardiovascular disease (CVD), which includes cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction, is a major concern for long-term survivors of childhood cancer. There is clear evidence of increased risk of CVD largely attributable to treatment exposures at a young age, most notably anthracycline chemotherapy and chest-directed radiation therapy, and compounded by traditional cardiovascular risk factors accrued during decades after treatment exposure. Preclinical studies are limited; thus, it is a high priority to understand the pathophysiology of CVD as a result of anticancer treatments, taking into consideration the growing and developing heart. Recently developed personalized risk prediction models can provide decision support before initiation of anticancer therapy or facilitate implementation of screening strategies in at-risk survivors of cancer. Although consensus-based screening guidelines exist for the application of blood and imaging biomarkers of CVD, the most appropriate timing and frequency of these measures in survivors of childhood cancer are not yet fully elucidated. Longitudinal studies are needed to characterize the prognostic importance of subclinical markers of cardiovascular injury on long-term CVD risk. A number of prevention trials across the survivorship spectrum are under way, which include primary prevention (before or during cancer treatment), secondary prevention (after completion of treatment), and integrated approaches to manage modifiable cardiovascular risk factors. Ongoing multidisciplinary collaborations between the oncology, cardiology, primary care, and other subspecialty communities are essential to reduce therapeutic exposures and improve surveillance, prevention, and treatment of CVD in this high-risk population.

Summary Background Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer. Methods The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age-matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked-point-process regression was used for inferential cumulative burden analysis. Findings Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54·5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45·5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99·9% (95% CI 99·9–99·9) for grade 1–5 CHCs and 96·0% (95% CI 95·3–96·8%) for grade 3–5 CHCs. By age 50 years, a survivor had experienced, on average, 17·1 (95% CI 16·2–18·1) CHCs of any grade, of which 4·7 (4·6–4·9) were CHCs of grade 3–5. The cumulative burden in matched community controls of grade 1–5 CHCs was 9·2 (95% CI 7·9–10·6; p vs total study population) and of grade 3–5 CHCs was 2·3 (1·9–2·7, p vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1–5 CHCs at age 50 years was highest in survivors of CNS malignancies (24·2 [95% CI 20·9–27·5]) and lowest in survivors of germ cell tumours (14·0 [11·5–16·6]). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs. Interpretation The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population. Funding The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.

BACKGROUND Medulloblastoma survivors are at risk for social deficits, yet underlying mechanisms are poorly understood. METHODS Facial affect recognition was assessed in 50 medulloblastoma survivors treated with craniospinal radiation (median[range] 21.4[12.5–30.9] years old, 11.0[5.7–22.6] years since diagnosis) and 56 non-cancer age-, sex-, and race-matched controls. Brain activation and connectivity in core regions/nodes of the face perception network (fusiform gyri, occipital gyri, superior temporal sulcus) were examined using structural and functional neuroimaging. Structural networks were constructed from diffusion tensor imaging (DTI) data and individual node strength and efficiency were assessed. Functional MRI (fMRI) was conducted using a 1-back facial affect recognition task with assessment of regional differences in task-related cerebral blood flow (BOLD). Standardized neurocognitive testing was completed with 24 hours of brain imaging. RESULTS Medulloblastoma survivors performed worse on a behavioral measure of facial affect recognition (P=0.003) compared to matched controls. During the facial affect recognition task, controls demonstrated greater BOLD activation of the left and right fusiform gyri and the left and right middle occipital gyri compared to survivors (P’s CONCLUSIONS Medulloblastoma survivors have deficits in facial affect recognition and reduced activation and efficiency in brain regions comprising the face perception network compared to matched controls. Interventions targeting this specific skill and neural network may improve social functioning in survivors.

Rationale: Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using magnetic resonance imaging (MRI), the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether 11C-methionine positron emission tomography ([11C]MET -PET), a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. Methods: We evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities, where PHGG tumor recurrence was of concern during follow-up visits with [11C]MET -PET. We performed quantitative and qualitative assessments of both [11C]MET-PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival we plotted the time from development of the imaging changes against survival. Results: Qualitative evaluation of [11C]MET-PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for [11C]MET-PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI (P =

BACKGROUND Children with Down syndrome (DS) are at increased risk of developing acute leukemia and are more prone to acute toxicities. We studied the incidence and severity of chronic health conditions among survivors of childhood leukemia with DS compared with those without DS. METHODS Chronic health conditions reported by questionnaire were compared between 154 pediatric leukemia survivors with DS and 581 without DS, matched by leukemia, age at diagnosis, race/ethnicity, sex, radiation location and chemotherapy exposure using Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects were selected from 7139 5-year survivors of leukemia in the Childhood Cancer Survivor Study. RESULTS Risk of at least 1 late onset chronic health condition (grade 1-5) was similar in the DS population compared with the non-DS group (HR, 1.1; 95% CI, 0.7-1.5). Serious chronic health conditions (grade 3-5) were more common in DS survivors (HR, 1.7; 95% CI, 1.1-2.6), as were ≥ 3 chronic health conditions (grades 1-5) (HR, 1.7; 95% CI, 1.2-2.4). The 25-year cumulative incidence of any condition (grades 1-5) was 83% for DS survivors and 69% for non-DS survivors. CONCLUSION Leukemia survivors with DS have therapy-related chronic health conditions comparable to those of similarly treated survivors without DS, with a few notable exceptions: 1) an increased risk of cataracts, hearing loss, and thyroid dysfunction compared with survivors without DS (though these are known risks in the DS population), 2) decreased risk of second cancers, and 3) increased risk of severe or multiple conditions. Practitioners should be aware of these risks during and after therapy. Cancer 2017. © 2017 American Cancer Society.

Background Neurocognitive impairment in survivors of childhood cancer may be associated with direct neurotoxicity, as well as indirect effects of systemic health complications. We evaluated associations among treatment exposures, chronic health conditions, and neurocognitive outcomes in adult survivors of childhood cancer. Methods Participants included 5507 adult survivors of childhood cancer (47.1% male; mean [SD] age = 31.8 [7.6] years at evaluation; 23.1 [4.5] years postdiagnosis) in the Childhood Cancer Survivor Study who completed a self-report measure of neurocognitive function. Cardiac, pulmonary, and endocrine chronic health conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Structural equation modeling was used to examine a priori hypothesized causal pathways among cancer treatment, subsequent chronic health conditions, and neurocognitive outcomes. Multivariable models were used to estimate relative risk for associations of treatments and chronic conditions on neurocognitive function. All statistical tests were two-sided. Results One-third of survivors with a grade 2 or higher chronic condition reported impairments in task efficiency and memory. In addition to direct effects of cranial radiation, path analyses and multivariable models demonstrated direct effects of cardiopulmonary (β = 0.10, P = .002; relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.12 to 1.44) and endocrine (β = 0.07, P = .04; RR = 1.14, 95% CI = 1.02 to 1.28) conditions on impaired task efficiency. We identified similar effects of cardiopulmonary condition on memory (P = .01) and emotional regulation (P = .01). Thoracic radiation was associated with impaired task efficiency (P = .01) and emotional regulation (P = .01) through endocrine morbidity. Conclusions Non-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors' neurocognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer.

Objective To evaluate concurrent and longitudinal associations between psychosocial functioning and physical activity in adolescent and young adult survivors of early childhood cancer. Methods Adolescent survivors of early childhood cancer (diagnosed before age four) participating in the Childhood Cancer Survivor Study completed the Coping Health and Illness Profile–Adolescent Edition (CHIP-AE; n = 303; mean age at survey: 17.6 years). A subset of these survivors (n = 248) completed a follow-up survey an average of 6.0 years later (range: 4-10). Logistic regression identified associations between psychosocial functioning in adolescence and physical activity levels in adolescence and young adulthood. Results Survivors reported low physical activity as adolescents (46.1% scored below CHIP-AE cut-point) and young adults (40.8% below Centers for Disease Control guidelines). Poor physical activity during adolescence was associated with female sex (OR = 2.06, 95% CI, 1.18-3.68), parents with less than a college education (OR = 1.91, 95% CI, 1.11-3.32), previous treatment with cranial radiation (OR = 3.35, 95% CI, 1.69-6.88), TV time (OR = 1.77, 95% CI, 1.00-3.14), and limitations of activity due to health or mobility restrictions (OR = 8.28, 95% CI, 2.87-30.34). Poor diet (OR = 1.84, 95% CI, 1.05-3.26) and low self-esteem (OR = 1.80, 95% CI, 0.99-3.31) during adolescence were associated with lower odds of meeting Centers for Disease Control physical activity guidelines in young adulthood. Conclusion These findings provide targets for future interventional studies to improve physical activity in this high-risk population.

Background Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Methods Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1-38.9), median age at last evaluation 30.3 years (range, 6.1-56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. Results From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6-16.7; motor impairment HR: 7.6; 95% CI: 5.8-9.9; hearing loss HR: 18.4; 95% CI: 13.1-25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2-3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8-3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9-5.4), and stroke (HR: 14.9; 95% CI: 10.4-21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6-3.2), meningioma (HR: 2.6; 95% CI: 1.1-6.5), and stroke (HR: 2.0; 95% CI: 1.1-3.4). Conclusions CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666–74. ©2016 AACR.

BACKGROUND Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551–60. © 2017 American Cancer Society.

Background Dorsal midbrain syndrome (also known as Parinaud syndrome and pretectal syndrome) is a well-known complication of tumors of the pineal region. However, there are few reports regarding outcomes, especially in children. The purpose of this study was to report the ophthalmic outcomes in a group of children with pineal tumors treated at a single institution. Methods The medical records of pediatric patients diagnosed with pineal region tumors and evaluated at our ophthalmology clinic were studied retrospectively. Descriptive statistics were used to assess rate of dorsal midbrain syndrome, defined as one or more of the following: limitation of upgaze, pupillary light-near dissociation, and convergence retraction nystagmus. Treatment outcomes were recorded. Results A total of 35 subjects (age range, 5 months to 20 years) were included, 18 (51%) of whom were found to have dorsal midbrain syndrome. Of those 18, 16 patients (89%) had limitation of upgaze, 15 (83%) had pupillary light-near dissociation, and 9 (50%) had convergence-retraction nystagmus. Convergence insufficiency was noted in 5 patients (28%); exotropia (either intermittent or constant), in 9 (50%). Improvement in dorsal midbrain syndrome findings following treatment was seen in 7 of 17 patients (41%), but only 2 (12%) experienced complete resolution. Treatment consisted of surgery, radiation, and/or chemotherapy. Conclusions In our study cohort of children with pineal tumors have a high incidence of dorsal midbrain syndrome. Most cases had residual findings after treatment.

We compared health-related quality of life (HRQOL) between adult survivors of childhood cancer and siblings by investigating the mediating role of emotional distress on HRQOL assessment, and examining the extent to which emotional distress affected the item responses of HRQOL measures given the same underlying HRQOL (i.e., measurement non-invariance). Cancer survivors (7103) and siblings (390) enrolled in Childhood Cancer Survivor Study who completed the SF-36 measuring HRQOL and the Brief Symptom Inventory-18 measuring anxiety, depression, and somatization were analyzed. Multiple Indicators & Multiple Causes modeling was performed to identify measurement non-invariance related to emotional distress on the responses to HRQOL items. Mediation analysis was performed to test the effects of cancer experience on HRQOL accounting for the mediating role of emotional distress. Twenty-nine percent, 40%, and 34% of the SF-36 items were identified with measurement non-invariance related to anxiety, depression, and somatization, respectively. Survivors reported poorer HRQOL than siblings in all domains (ps

Background: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. Methods: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970–1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. Results: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs 1 year from menarche (HR=1.80, CI 1.19–2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause

Background: Long-term survivors of childhood Hodgkin lymphoma (HL) are at significant risk for cardiovascular, pulmonary, and endocrine morbidity in addition to subsequent cancers. Emerging evidence suggests that HL survivors may also experience persistent neurocognitive impairment, however the prevalence of neurocognitive impairment has not been well characterized. Further, little work has been done to examine how specific treatments or comorbidities are associated with these impairments. Methods: The current study included 1,760 survivors (52.0% female, mean[sd] 37.5 [6.0] years old, 23.6 [4.7] years from diagnosis) of childhood Hodgkin lymphoma and 3,180 sibling controls (54.5% female, 33.2 [8.5] years old) from the Childhood Cancer Survivor Study. Participants completed questionnaires assessing four domains of neurocognitive impairment (task efficiency, emotional regulation, organization, and memory). Impairment for each domain was defined as a score worse than the 90th percentile of community controls. Treatment exposures were abstracted from the medical record. Second malignancies (SMN) were self-reported and subsequently confirmed by pathology findings or medical record review. Chronic health conditions were self-reported and systematically graded according to the NCI CTCAE v4.3 (Grade 1 mild, Grade 2 moderate, Grade 3 severe/disabling, Grade 4 life-threatening). Generalized estimating equations were used to calculate risk of impairment in survivors compared with siblings adjusted for age, sex, and race. Among HL survivors, multivariable log-binomial regression was used to calculate risk of impairment associated with demographic, clinical, and treatment factors. Separate models examined risk associated with Grade 2+ chronic health conditions adjusted for age, sex, and race. Results: 10.8% of HL survivors reported impaired task efficiency (vs. 7.7% in siblings), 16.6% emotional regulation (vs. 11.5% in siblings), 12.1% organization (vs. 10.3% in siblings), and 8.1% memory (vs. 5.7% in siblings). Compared with siblings, survivors reported significantly higher risk of impairment in each of the four neurocognitive domains after adjusting for age, sex, and race (Table). Female survivors had elevated risk of impairment on emotional regulation (RR [95%CI] 1.4 [1.1,1.9)) and memory (2.0 [1.3,3.0]). Compared with white survivors (91.8% of the population), non-white survivors had higher risk of impairment in task efficiency (2.1 [1.2, 3.5]) and emotional regulation (1.7 [1.0,2.7]). Current smokers (12.3%) had higher risk of impairment in task efficiency (1.9 [1.2, 3.1]), emotional regulation (2.5 [1.7,3.7]), and memory (1.7 [1.0,3.0]). Having a late-relapse (>5 years from diagnosis) or a second malignancy (20.0%) was associated with elevated risk of impairment in task efficiency (1.6 [1.06,2.3]). While not statistically significant, anthracycline exposure (39.8%) was associated with higher risk of impairment in task efficiency (1.3 [0.7,2.2]) and memory (1.6 [0.9,3.0]). No statistically significant associations were noted for bleomycin, corticosteroids, or chest radiation. HL survivors with pulmonary morbidity (8.5%) had a higher risk of impairment on task efficiency (1.9 [1.2,3.0]) compared to those without. Cardiovascular conditions (32.9%) were associated with elevated risk of impairment in all domains (RR range from 1.5 to 2.1, all p Conclusions: Survivors experienced significantly more neurocognitive impairment compared to sibling controls. Among survivors, potentially modifiable risk factors such as smoking and chronic health conditions were associated with neurocognitive impairment while treatment exposures showed little association. Mitigation or prevention of smoking and chronic health conditions may improve neurocognitive functioning in HL survivors Table Disclosures No relevant conflicts of interest to declare.

PURPOSE Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes. PATIENTS AND METHODS In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality. RESULTS The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes. CONCLUSION Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.

IMPORTANCE: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. OBJECTIVES: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. DESIGN, SETTING, AND PARTICIPANTS: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. EXPOSURES: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for subsequent breast cancer by ER status. RESULTS: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER–], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER– (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m(2), 1.23; 95% CI, 1.09-1.39; P

Treatment-induced high-grade gliomas (TIHGGs) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy used to treat pediatric cancer. We assembled a cohort of 33 TIHGGs from multiple institutions. The primary antecedent malignancies were medulloblastoma, acute lymphoblastic leukemia, astrocytoma, and ependymoma. We performed methylation profiling, RNA-seq, and genomic sequencing (whole-genome or whole-exome) on TIHGG samples. Methylation profiling revealed that TIHGGs cluster primarily with the pediatric receptor tyrosine kinase I subtype (26/31 samples). Common TIHGG copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, Ch. 4 loss, Ch. 6q loss, and Ch. 13 and Ch. 14 loss; focal alterations include PDGFRA and CDK4 gain and loss of CDKN2A and BCOR. Relative to de novo pediatric high-grade glioma (pHGG), BCOR loss (p=0.004) and CDKN2A loss (p=0.005) were significantly increased. Transcriptomic analysis identified two distinct TIHGG subgroups, one with a lesser mutation burden (0.12 mut/Mb), Ch. 1p loss/1q gain (5/6 samples), and stem cell characteristics, and one with a greater mutation burden (1.08 mut/Mb, pPDGFRA and CDK4. In vitro drug screening in one primary, patient-derived TIHGG cell line from each expression subgroup identified microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors as potentially effective therapies. This study provides a comprehensive molecular profile of TIHGG, including mechanistic insights to TIHGG oncogenesis, and identifies potentially effective therapeutic modalities for further investigation.

Author(s): Mueller, Sabine; Kline, Cassie N; Buerki, Robin A; Chen, Yan; Yasui, Yutaka; Howell, Rebecca; Oeffinger, Kevin C; Leisenring, Wendy M; Robison, Leslie L; Armstrong, Gregory T; Fullerton, Heather J; Krull, Kevin R | Abstract: BackgroundPoor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).MethodsThe CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.ResultsAmong 14,358 participants (median age, 39.7nyears), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).ConclusionsStroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.

PURPOSE: To examine the association between posttraumatic stress symptoms (PTSS), neurocognitive and psychosocial late-effects, health behaviors, and healthcare utilization in long-term survivors of childhood cancer. METHODS: Participants included individuals (N=6844; 52.5% female; mean [SD] age at diagnosis =7.6[5.8], at follow-up =34.9[7.5]) in the Childhood Cancer Survivor Study (CCSS). Follow-up included the Posttraumatic Stress Scale, Brief Symptom Inventory-18, Short-form 36 Health-related quality of life (HRQOL) survey, CCSS Neurocognitive Questionnaire, and questions about sociodemographics, physical health, health behaviors and healthcare utilization. Modified Poisson regression and multinomial logistic regression models examined associations between post-traumatic stress symptoms (PTSS) and neurocognitive, HRQOL, health behavior, and healthcare outcomes when adjusting for sociodemographics, disease, and treatment. RESULTS: Long-term survivors with PTSS (N= 995, 14.5%) reported more impairment in mental (relative risk [RR] 3.42, 95% confidence interval [CI] 3.05–3.85) and physical (RR=2.26, CI= 1.96–2.61) HRQOL. PTSS was also associated with increased impairment in task efficiency (RR=3.09, CI=2.72–3.51), working memory (RR=2.55, CI= 2.30–2.83), organization (RR=2.11, CI= 1.78–2.50) and emotional regulation (RR=3.67, CI=3.30–4.09). Survivors with PTSS were significantly more likely to attend cancer-specific health visits in the past 2-years (OR=1.89, CI=1.50–2.39), and showed greater likelihood of either high frequency (OR= 1.89, CI= 1.50–2.39) or complete lack of (OR=1.63, CI=1.32–2.01) primary care visits compared to survivors without PTSS. CONCLUSIONS: Survivors with PTSS reported significantly more psychosocial and neurocognitive late effects, and were more likely to engage in variable use of healthcare. IMPLICATIONS FOR CANCER SURVIVORS: PTSS is associated with additional challenges for a population vulnerable to adverse late effects. Inclusion of integrative services during follow up visits may benefit functional outcomes.

Background The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. Methods A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Results By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. Conclusions Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

Summary Background Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer. Methods The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15–20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs. Findings Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34–50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5–6·2) and among 5804 childhood cancer survivors (median age 34 years; 27–42), it was 6·2 (5·8–6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4–5·1] vs 6·8 [6·2–7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3–5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7–4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9–6·3] for childhood cancer survivors), and at increased risk of developing grade 3–5 cardiac (4·3 [3·5–5·4] and 5·6 [4·5–7·1]), endocrine (3·9 [2·9–5·1] and 6·4 [5·1–8·0]), and musculoskeletal conditions (6·5 [3·9–11·1] and 8·0 [4·6–14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors. Interpretation Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3–5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors. Funding National Cancer Institute and American Lebanese-Syrian Associated Charities.

Context: Direct assessment of Leydig cell function in adult survivors of childhood cancer has been limited. Objectives: To describe the prevalence of, and risk factors for, Leydig cell failure (LCF) and associated adverse health outcomes. Design: Retrospective cohort with cross-sectional health outcomes analysis. Patients: 1534 participants (median age 30.8 years; range 18.1-63.8) evaluated at a median of 22.0 years (range 7.5-49.8) after cancer diagnosis. Survivors with LH/FSH deficiency were excluded. Main Outcome Measure: LCF was defined as serum total testosterone < 250 ng/dL (8.67 nmol/L) combined with LH >8.6 IU/L; compensated LCF by testosterone ≥ 250 ng/dL and LH >8.6 IU/L. Polytomous logistic regression evaluated associations between demographic and treatment-related risk factors and LCF or compensated LCF. Log-binomial regression examined associations between these diagnoses and risk of diabetes mellitus, dyslipidemia, abdominal obesity, frailty, erectile dysfunction, and psychological distress. Piecewise exponential models analyzed the association between mortality and LCF/compensated LCF. Results: The prevalence of LCF and compensated LCF was 8.0% (95% confidence interval (CI) 6.7%-9.4%) and 22.8% (95% CI 20.7%-25.0%), respectively. Individuals aged 36-45.9 years (odds ratio (OR) 3.8, 95% CI 1.9-7.9) or ≥46 years (OR 4.9, 95% CI 2.2-11.1) at the time of study had a significantly higher risk of LCF than those 18-25 years old. Participants treated with direct testicular radiotherapy at doses >0-19.9 (OR 81.6, 95% CI 24.9-266.7) or ≥ 20 Gy (OR >999, 95% CI 109.9->999) had a higher risk of LCF than those not exposed to this treatment. Individuals treated with alkylating agents at cyclophosphamide equivalent doses 4000-7999 mg/m2 (OR 3.6, 95% CI 1.9-6.9) or 8000-11999 mg/m2 (OR 3.7, 95% CI 1.9-7.3) or ≥ 12000 mg/m2 (OR 8.7, 95% CI 4.7-16.4) had a higher risk of LCF than those not exposed to these agents. LCF was independently associated with abdominal obesity (prevalence ratio (PR) 1.6, 95% CI 1.2-2.1), diabetes mellitus (PR 2.9, 95% CI 1.8-4.6), erectile dysfunction (PR 1.8, 95% CI 1.4-2.5), frailty (PR 2.5, 95% CI 1.2-5.3) and mortality (PR 4.8, 95% CI 2.3-10.1). For compensated LCF, the risk factor associations were similar to those found for LCF; however, no significant associations were found with adverse physical or psychosocial outcomes. Conclusion: In adult survivors of childhood cancer, older age, direct testicular radiotherapy and high dose alkylating agents were associated with LCF, which was associated with poor general health outcomes. Further studies are needed to investigate the role of sex hormone replacement in mitigating such outcomes.

Objective Sleep disorders are associated with psychological and physical health, although reports in long-term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes. Methods Survivors (n = 1933; median [IQR] age = 35 [30, 41]) and siblings (n = 380; age = 33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately 5 years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes. Results Survivors were more likely to report poor sleep efficiency (30.8% vs 24.7%; prevalence ratio [PR] = 1.26; 95% confidence interval, 1.04-1.53), daytime sleepiness (18.7% vs 14.2%; PR = 1.31 [1.01-1.71]), and sleep supplement use (13.5% vs 8.3%; PR = 1.56 [1.09-2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR = 1.70 [1.40-2.07]), restricted sleep time (PR = 1.35 [1.12-1.62]), fatigue (PR = 2.11 [1.92-2.32]), daytime sleepiness (PR = 2.19 [1.71-2.82]), snoring (PR = 1.85 [1.08-3.16]), and more sleep medication (PR = 2.86 [2.00-4.09]) and supplement use (PR = 1.89[1.33-2.69]). Survivors reporting symptoms of insomnia (PR = 1.46 [1.02-2.08]), fatigue (PR = 1.31 [1.01-1.72]), and using sleep medications (PR = 2.16 [1.13-4.12]) were more likely to develop migraines/headaches. Conclusions Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes.

PURPOSE The impacts of radiotherapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk for late-onset cardiac disease in survivors of childhood cancer remain unresolved. PATIENTS AND METHODS We determined the rates of severe to fatal cardiac disease in 24,214 5-year survivors in the Childhood Cancer Survivor Study diagnosed between 1970 and 1999 at a median age of 7.0 years (range, 0 to 20.9 years), with a median attained age of 27.5 years (range, 5.6 to 58.9 years). Using piecewise exponential models, we evaluated the association between cardiac disease rates and demographic and treatment characteristics. RESULTS The cumulative incidence of cardiac disease 30 years from diagnosis was 4.8% (95% CI, 4.3 to 5.2). Low to moderate radiotherapy doses (5.0 to 19.9 Gy) to large cardiac volumes (≥ 50% of heart) were associated with an increased rate of cardiac disease (relative rate, 1.6; 95% CI, 1.1 to 2.3) compared with survivors without cardiac radiotherapy exposure. Similarly, high doses (≥ 20 Gy) to small cardiac volumes (0.1% to 29.9%) were associated with an elevated rate (relative rate, 2.4; 95% CI, 1.4 to 4.2). A dose-response relationship was observed between anthracycline chemotherapy and heart failure with younger children (age ≤ 13 years) at the greatest risk for heart failure after comparable dosing. CONCLUSION These observations support advances in radiation field design and delivery technology to reduce cardiac dose/volume and should guide future treatment protocols. They also inform clinical practice guidelines for post-therapy surveillance and risk-reducing strategies.

PURPOSE Treatment of medulloblastoma has evolved from surgery and radiotherapy to contemporary multimodal regimens. However, the impact on long-term health outcomes remains unknown. METHODS Cumulative incidence of late mortality (5 or more years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of medulloblastoma diagnosed between 1970 and 1999. Outcomes were evaluated by treatment exposure, including historical therapy (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), high risk (CSI ≥ 30 Gy + chemotherapy), standard risk (CSI < 30 Gy + chemotherapy), and by treatment decade (1970s, 1980s, 1990s). Rate ratios (RRs) and 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS Among 1,311 eligible survivors (median age, 29 years [range, 6 to 60 years]; median time from diagnosis, 21 years [range, 5 to 44 years]), the 15-year cumulative incidence rate of all-cause late mortality was 23.2% (diagnosed 1970s) versus 12.8% (1990s; P = .002), with a recurrence-related mortality rate of 17.7% versus 9.6% ( P = .008). Lower late mortality rates as a result of other health-related causes were not observed. Among 997 survivors who completed a baseline survey, the 15-year cumulative incidence of SNs was higher among survivors with multimodal therapy (standard risk, 9.5%; historical, 2.8%; P = .03). Survivors treated in the 1990s had a higher cumulative incidence of severe, disabling, life-threatening, and fatal chronic health conditions (56.5% in 1990s v 39.9% in 1970s; P < .001) and were more likely to develop multiple conditions (RR, 2.89; 95% CI, 1.31 to 6.38). However, survivors of standard-risk therapy were less likely to use special education services than high-risk therapy survivors (RR, 0.84; 95% CI, 0.75 to 0.93). CONCLUSION Historical changes in medulloblastoma therapy that improved 5-year survival have increased the risk for SNs and debilitating health conditions for survivors yet reduced the need for special education services.

Importance Anthracyclines are part of many effective pediatric cancer treatment protocols. Most pediatric oncology treatment groups assume that the hematologic toxicity of anthracycline agents is equivalent to their cardiotoxicity; for example, Children’s Oncology Group substitution rules consider daunorubicin and epirubicin isoequivalent to doxorubicin, whereas mitoxantrone and idarubicin are considered 4 to 5 times as toxic as doxorubicin. Objective To determine optimal dose equivalence ratios for late-onset cardiomyopathy between doxorubicin and other anthracyclines or the anthraquinone mitoxantrone. Design, Setting, and Participants This multicenter cohort study of childhood cancer survivors who survived 5 or more years analyzed data pooled from 20 367 participants in the Childhood Cancer Survivor Study treated from 1970 to 1999, 5741 participants in the Dutch Childhood Oncology Group LATER study diagnosed between 1963 and 2001, and 2315 participants in the St Jude Lifetime study treated from 1962 to 2005. Exposures Cumulative doses of each agent (the anthracyclines doxorubicin, daunorubicin, epirubicin, and idarubicin; and the anthraquinone mitoxantrone) along with chest radiotherapy exposure were abstracted from medical records. Main Outcomes and Measures Cardiomyopathy (severe, life-threatening, or fatal) by 40 years of age. Agent-specific Cox proportional hazards models evaluated cardiomyopathy risk, adjusting for chest radiotherapy, age at cancer diagnosis, sex, and exposure to anthracyclines or to an anthraquinone. An agent-specific cardiomyopathy equivalence ratio (relative to doxorubicin) was estimated for each dose category as a ratio of the hazard ratios, and then a weighted mean determined the overall agent-specific equivalence ratio across all dose categories. Results Of 28 423 survivors (46.4% female; median age at cancer diagnosis 6.1 years [range, 0.0-22.7 years]), 9330 patients received doxorubicin, 4433 received daunorubicin, 342 received epirubicin, 241 received idarubicin, and 265 received mitoxantrone. After a median follow-up of 20.0 years (range, 5.0-40.0 years) following receipt of a cancer diagnosis, 399 cardiomyopathy cases were observed. Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone. Outcomes were too rare to generate idarubicin-specific estimates. Ratios based on a continuous linear dose-response relationship were similar for daunorubicin (0.5 [95% CI, 0.4-0.7]) and epirubicin (0.8 [95% CI, 0.3-1.4]). The relationship between mitoxantrone and doxorubicin appeared better characterized by a linear exponential model. Conclusions and Relevance In a large data set assembled to examine long-term cardiomyopathy risk in childhood cancer survivors, daunorubicin was associated with decreased cardiomyopathy risk vs doxorubicin, whereas epirubicin was approximately isoequivalent. By contrast, the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk.

BACKGROUND Survivors of childhood cancer are at risk of neurocognitive impairment, emotional distress, and poor health-related quality of life (HRQOL); however, the effect of race/ethnicity is understudied. The objective of this study was to identify race/ethnicity-based disparities in neurocognitive, emotional, and HRQOL outcomes among survivors of childhood cancer. METHODS Self-reported measures of neurocognitive function, emotional distress (the Brief Symptom Inventory-18), and HRQOL (the Medical Outcomes Study Short Form-36 health survey) were compared between minority (Hispanic, n = 821; non-Hispanic black [NHB], n = 600) and non-Hispanic white (NHW) (n = 12,287) survivors from the Childhood Cancer Survivor Study (median age, 30.9 years; range, 16.0-54.1 years). By using a sample of 3055 siblings, the magnitude of same-race/same-ethnicity survivor-sibling differences was compared between racial/ethnic groups, adjusting for demographic and treatment characteristics and current socioeconomic status (SES). RESULTS No clear pattern of disparity in neurocognitive outcomes by race/ethnicity was observed. The magnitude of the survivor-sibling difference in the mean score for depression was greater in Hispanics than in NHWs (3.59 vs 1.09; P = .004). NHBs and Hispanics had greater survivor-sibling differences in HRQOL than NHWs for mental health (NHBs: -5.78 vs -0.69; P = .001; Hispanics: -3.87 vs -0.69; P = .03), and social function (NHBs: -7.11 vs -1.47; P

Background The impact of growth hormone deficiency (GHD) on neurocognitive function is poorly understood in survivors of childhood acute lymphoblastic leukemia (ALL). This study examined the contribution of GHD to functional outcomes while adjusting for cranial radiation therapy (CRT). Methods Adult survivors of ALL (N = 571; 49% female; mean age, 37.4 years; age range, 19.4-62.2 years) completed neurocognitive tests and self-reported neurocognitive symptoms, emotional distress, and quality of life. GHD was defined as a previous diagnosis of GHD or a plasma insulin-like growth factor1 level less than -2.0 standard deviations for sex and age at the time of neurocognitive testing. Hypothyroidism, hypogonadism, sex, age at diagnosis, CRT dose, and intrathecal and high-dose intravenous methotrexate were included as covariates in multivariable linear regression models. Results Of the 571 survivors, 298 (52%) had GHD, and those with GHD received higher doses of CRT (P = .002). Survivors who had GHD, irrespective of prior growth hormone treatment, demonstrated poorer vocabulary (z-score, -0.84 vs -0.61; P = .02), processing speed (z-score, -0.49 vs -0.30; P = .04), cognitive flexibility (z-score, -1.37 vs -0.94; P = .01), and verbal fluency (z-score, -0.74 vs -0.44; P = .001), and they self-reported more neurocognitive problems and poorer quality of life compared with survivors who did not have GHD. Multivariable and mediation models revealed that GHD was associated with small effects on quality of life (general health, P = .01; vitality, P = .01; mental health, P = .01); and CRT dose accounted for the lower neurocognitive outcomes. Conclusions Adult survivors of childhood ALL who receive CRT are at risk for GHD, although poor neurocognitive outcomes are determined by CRT dose and not by the presence of GHD.

Malignant disease and its treatment carry huge burdens for patients. Some are immediate, in that the disease itself presents as a life threatening event, or the treatment may result in immediate and devastating toxicity. More often the treatment of cancer is associated with more subtle or late events, yet these may impact the quality of life for cancer survivors in a variety of ways. In addition to the physical sequelae of cancer or its treatment, cancer survivors often experience consequences in the form of social or mental incapacity. Session III of this Colloquium on Cardio-Oncology focuses on some of these concerns, both from the perspective of health care providers who strive to minimize the burdens, but also from the viewpoint of the patient him or herself who must deal with the price that must often be paid for increased survival or cure.

Background Although paediatric astrocytoma has an excellent 5-year survival rate, survivors remain at risk for morbidity and late mortality. This study aimed to estimate the risk of late mortality, chronic conditions, poor health status and social impairment in ageing paediatric astrocytoma survivors. Methods We longitudinally evaluated 1182 5-year astrocytoma survivors diagnosed between 1970 and 1986 and 4023 siblings enrolled in a retrospective cohort study. Kaplan–Meier estimates of late mortality and cumulative incidence of serious chronic conditions were estimated. Cox regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) for development of chronic conditions, and generalised linear models provided relative risks (RRs) of the poor health status and social outcomes. Results At 30 years from diagnosis, cumulative late mortality was 22.1% (CI 20.0–24.3%), primarily due to disease progression or recurrence. Compared with siblings, survivors were at increased risk of serious chronic conditions (HR 4.6, CI 3.8–5.5). Survivors reported higher rates of poor general health (RR 3.3, CI 2.8–3.8), poor mental health (RR 1.9, CI 1.7–2.1), functional impairment (RR 9.0, CI 7.7–10.5) and activity limitation (RR 3.6, CI 3.1–4.2) and lower rates of college graduation (RR 0.75, CI 0.69–0.82), marriage (RR 0.62, CI 0.58–0.66), employment (RR 0.75, CI 0.72–0.79) and household income ≥$40,000 (RR 0.68, CI 0.64–0.73). Even survivors without radiation exposure had elevated risk of chronic conditions, poor health status and social impairment compared with siblings. Conclusions Survivors of paediatric astrocytoma are at high risk for long-term complications of their disease and its treatment. They require lifelong monitoring for late effects.

Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study (CCSS): 48 obese (BMI ≥30.0 kg/m(2)) and 48 normal weight (BMI = 18.5–24.9 kg/m(2)). The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. The false discovery rate (FDR) was used to account for multiple testing. In exploratory analyses, we also tested for interaction between cranial radiotherapy (CRT) status and selected CpG sites to evaluate differences by CRT exposure. Thirty-nine loci were associated (FDR

10026 Background: The impact of childhood and adolescent cancer on the long-term financial outcomes of survivors is poorly understood. We compared financial hardship between survivors and siblings enrolled in the CCSS and identified survivors at elevated risk. Methods: Survivors treated for cancer at age < 21 years in 1970-1999 and siblings responded to a survey (23 binary-response questions) at age ≥26 years administered in 2017-2019. Principal component analysis with promax rotation extracted 3 factors with eigenvalues > 1 and KR-20 reliability coefficients > 0.7, retaining items with factor loadings > 0.4. These factors were behavioral hardship (8 items, e.g., forgone needed medical care), material hardship/financial sacrifices (8 items, e.g., problems paying medical bills) and psychological hardship (3 items, e.g., worry about having enough money to pay rent/mortgage). Factor scores were calculated by adding the item responses and dividing by their standard deviation. Multiple linear regression examined the association of sociodemographic and cancer treatment variables with factor scores. Results: Among 3349 survivors (49% male; median age [range] 40.2 [26.0-67.4] years) and 976 siblings (42% male, median age 46.5 [ 26.1-69.2] years), survivors were more likely to report being sent to debt collection (29.5 vs 21.4%), problems paying medical bills (20.0 vs 11.9%), foregoing needed medical care (13.3 vs 7.7%) and worry/stress about paying their mortgage (32.8 vs 23.2%) or having enough money to buy nutritious meals (25.0 vs 16.2%), all P < 0.001. Survivors reported greater hardship than siblings on all 3 factors: behavioral hardship (standardized mean score 0.51 vs 0.36), material hardship/financial sacrifices (0.63 vs 0.44), psychological hardship (0.69 vs 0.44), all P < 0.001. Behavioral hardship was increased by female gender (regression coefficient [ꞵ] 0.17, 95% CI 0.10-0.25), < high school (ꞵ 0.45, CI 0.12-0.79) or < college (ꞵ 0.18, CI 0.09-0.26) education, no (ꞵ 1.14, CI 0.93-1.35) or public (ꞵ 0.23, CI 0.10-0.35) health insurance, being divorced/separated (ꞵ 0.28, CI 0.10-0.46) and ≥250mg/m2 anthracycline chemotherapy (ꞵ 0.09, CI 0.00-0.19). The same variables were significantly associated with the other two hardship factors, but total body irradiation and cranial radiation also contributed to the risk of material hardship/financial sacrifices, and ≥8g/m2 cyclophosphamide equivalent dose and cranial radiation contributed to psychological hardship. Conclusions: Survivors of childhood and adolescent cancer are at elevated risk for financial hardship as compared to sibling controls. Those at highest risk can be defined using a combination of sociodemographic and treatment variables. This information can be used to inform targeted intervention strategies to reduce the risk of poor financial outcomes in this vulnerable population.

10044 Background: Survival rates for neuroblastoma vary widely based on risk group. Therapies have evolved over the past four decades to de-intensify treatment for individuals with low/intermediate risk disease and intensify therapy for those with high risk disease. Risk stratification is predicted to result in differential outcomes in late morbidity and mortality; the magnitude of these differences has not been well studied. Methods: We evaluated late mortality, subsequent malignant neoplasms (SMN) and chronic health conditions (CHC) graded according to CTCAE v4.03 among 491 5-year CCSS survivors of neuroblastoma diagnosed 1987-1999 at ≥1 year of age. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n=182]; intermediate [n=70]; high [n=239]). Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) of SMN were calculated using rates from NCHS and SEER, respectively. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. Results: Among survivors (48% male; median age 22 years, range 7-42; median follow-up 19 years, range 5-29), 80.4% with low risk disease were treated with surgery alone, while 77.8% with high risk disease received surgery, radiation, chemotherapy ± transplant. The 15-year cumulative incidence of all-cause mortality was 9.2% (CI: 7.1-11.4), with a recurrence-related mortality of 7.3% (CI: 5.3-9.3) and SMN-related mortality of 0.3% (CI: 0-0.7). All-cause mortality was significantly higher in all risk groups: (low, SMR=5.8 [CI: 2.6-13.0]; intermediate, SMR=5.7 [CI: 1.4-23.5]; high, SMR=38.6 [CI: 27.9-53.5]). The risk of SMN was elevated among high risk survivors (SIR=25.1, CI: 16.7-37.6), but did not differ from the US population for survivors of low or intermediate risk disease. Table describes the HR of CHCs (grades 1-5 and 3-5) in survivors, by risk group, as compared with siblings, as well as categories of CHCs for which survivors were at increased risk. Conclusions: Long-term survivors of neuroblastoma have a high risk of late morbidity and mortality; risk is particularly pronounced among survivors of high risk disease. Vigilant lifelong medical surveillance will be required for this relatively young population as they age.[Table: see text]

10043 Background: This study examines temporal patterns in HRQL among adult survivors of childhood cancer, and socio-demographic, lifestyle and health status predictors of decline in HRQL. Methods: Adult survivors of childhood cancer (4755, 55.2% female, 86.9% non-Hispanic white) completed baseline (T0) and follow-up (T1 in 2003, T2 in 2014) surveys (median[SD] age 32.4[7.5] at T1, time since diagnosis to T1 23.0[4.5], T1-T2 interval 11.7[0.6] years). Socio-demographic (e.g., age, sex, educational attainment, annual family income), lifestyle (physical inactivity, smoking) and health status predictors were collected at T0 and T1. Chronic conditions graded ≥2 by CTCAE defined as presence, and mental and cognitive status with ≥1SD from norms defined as poor. SF-36 Physical and Mental Component Summary (PCS/MCS; mean 50/SD 10) at T1 and T2 classified HRQL as optimal (≥40) or suboptimal ( < 40). Multivariable logistic regression identified risk factors (T0, T1 or status change T0-T1) of decreased HRQL (i.e., optimal to suboptimal) using a backward selection method (p < 0.1), adjusting for sex, race, age at T1 and years between T1-T2. The sample was randomly split into training (80%) and test (20%) datasets to develop and validate prediction models; Area Under the ROC Curve (AUC) evaluated model performance. Results: From T1-T2, 8.1% and 8.3% of survivors reported decreased PCS and MCS. AUCs of training/test models were 0.75/0.74 for decreased PCS and 0.72/0.68 for decreased MCS. Risk factors at T0 or T1 predicting decreased PCS included female sex (OR 1.67, 95%CI 1.25-2.24), younger age (OR 1.04, 95%CI 1.02-1.06), < college/vocational education (OR 1.59, 95%CI 1.02-2.46), family income < $20,000 (OR 2.00, 95%CI 1.21-3.30), obesity (OR 1.97, 95%CI 1.32-2.92), chronic health conditions (neurologic OR 2.47, 95%CI 1.69-3.60; musculoskeletal OR 2.27, 95%CI 1.42-3.64; endocrinological OR 2.25, 95%CI 1.44-3.52; gastrointestinal OR 1.89, 95%CI 1.32-2.69; pulmonary OR 1.66, 95%CI 1.06-2.59; cardiovascular OR 1.53, 95%CI 1.14-2.06) and depression (OR 1.79, 95%CI 1.20-2.67). Risk factors at T0 or T1 predicting decreased MCS included unemployment (OR 1.68, 95%CI 1.19-2.38), smoking (OR 2.03, 95%CI 1.37-3.00), physical inactivity (OR 1.48, 95%CI 1.05-2.09), poor mental health (depression OR 4.29, 95%CI 2.44-7.55; somatization OR 1.63, 95%CI 1.05-2.53) and poor cognitive status (task efficiency OR 1.90, 95%CI 1.34-2.68; organization OR 1.67, 95%CI 1.12-2.48). Conclusions: Nearly 10% of childhood cancer survivors have significant late-onset decline in HRQL. Chronic health conditions predict decreased physical HRQL, whereas smoking, physical inactivity and poor mental health predict decreased mental HRQL. Interventions targeting modifiable lifestyle and health conditions should be considered to prevent decreased HRQL for childhood cancer survivors.

10047 Background: Kidney failure (need for dialysis or kidney transplantation, or death due to kidney disease) is a rare but serious late effect for survivors of childhood cancer. We aimed to develop a model using demographic and treatment characteristics to predict individual risk of kidney failure among five-year survivors of childhood cancer. Methods: CCSS survivors without kidney failure at five years after cancer diagnosis (n = 25,483) were assessed for subsequent kidney failure by age 40. Outcomes were self-reported and corroborated by the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5045) served as a comparator. Piecewise exponential models with backward selection estimated the relationships between potential predictors and kidney failure and were converted to integer risk scores. Additional results from the St. Jude Lifetime Cohort Study (SJLIFE, n = 2490) and the National Wilms Tumor Study (NWTS, n = 6760) validated the models. Results: Among CCSS survivors, 204 developed late kidney failure. We developed a model with sex, race/ethnicity, age at cancer diagnosis, nephrectomy, exposure to specific chemotherapy, any abdominal radiation, presence of genitourinary anomalies, and early-onset hypertension (Table). Risk scores achieved an area under the curve (AUC) and concordance (C) statistic of 0.65 and 0.68 for kidney failure by age 40. Validation cohort AUC and C statistics were 0.83/0.86 for SJLIFE (8 cases) and 0.61/0.63 for NWTS (91 cases). An alternative model with specific chemotherapy doses and kidney-specific radiation dosimetry had similar AUC and C statistic (0.67/0.70). Integer risk scores were collapsed to form statistically distinct low (score

10017 Background: Racial, ethnic, and socioeconomic disparities are documented in outcomes for childhood cancer survivors. Understanding whether childhood cancer modifies established disparities in cardiovascular risk factors (CVRFs) in the general population would inform strategies to reduce health inequities among survivors. Methods: The CCSS is a retrospectively constructed cohort with prospective follow-up consisting of 25,579 five year survivors of childhood cancer diagnosed between 1970 and 1999. We estimated the incidence of self-reported Common Terminology Criteria for Adverse Events (CTCAE) grade >2 CVRFs (hypertension, diabetes, dyslipidemia, and obesity) and multiple (>2) CVRFs among survivors. Multivariable Poisson regression estimated the rate ratios (RR) of CVRFs by race/ethnicity, adjusted for key treatment exposures and sociodemographics. Results: Within the CCSS cohort, there were 20,416 non-Hispanic White (NHW), 1625 non-Hispanic Black (NHB), and 2043 Hispanic survivors with the cumulative incidence estimates of each CVRF at age 40 displayed in Table. Survivors who self-reported “Other” or mixed race were excluded for this analysis (n=1495). NHB survivors were more likely to report hypertension (unadjusted RR 1.3; 95% Confidence Interval [CI] 1.0-1.6), diabetes (RR 1.6; 95% CI 1.0-2.4), obesity (RR 1.6; 95% CI 1.4-1.9), and multiple CVRF (RR 1.3; 95% CI 1.2-1.5), whereas Hispanic survivors were more likely to report diabetes (RR 1.7; 95% CI 1.2-2.4), obesity (RR 1.4; 95% CI 1.2-1.5), and multiple CVRFs (RR 1.1; 95% CI 1.0-1.3) compared with NHW survivors. These observed disparities in risks of CVRFs remained nearly unchanged even after adjustment for sociodemographic factors (age, sex, household income, education, marital status, employment, and insurance) and treatment exposures (Yes/No for anthracyclines, alkylators, and chest radiation). Conclusions: NHB and Hispanic adult survivors demonstrate a higher burden of CVRF compared with NHW survivors, particularly diabetes and obesity. The associated morbidity of these conditions and established increase they incur in risk of more severe cardiovascular disease emphasizes the need for interventions to mitigate CVRFs to promote health equity among these survivors.[Table: see text]

10027 Background: Thoracic radiotherapy (RT) is a risk factor for cardiac disease among survivors of childhood cancer based on studies considering RT doses to the entire heart. Dose to specific cardiac substructures may provide more precise dose-response associations to guide RT planning. We report associations between RT dose to cardiac substructures and risk of specific cardiac outcomes. Methods: We determined the cumulative incidences of CTCAE grade 3 – 5 coronary artery disease (CAD), heart failure (HF), and valvular disease (VD) among 25,481 5-year childhood cancer survivors diagnosed 1970 – 1999 in the CCSS. Median age at diagnosis was 6.1 years (0 – 20 years) and at last follow-up 29.8 years (5.6 – 65.9 years). For the 12,228 individuals receiving RT, fields were reconstructed on an age scaled computational phantom. Mean doses to the entire heart, cardiac chambers, valves, and left main, anterior descending (LAD), circumflex, and right coronary (RCA) arteries were estimated. Adjusted piecewise exponential models (including cumulative anthracycline dose) evaluated associations between mean RT dose to each structure and outcomes. Results: At 30 years from diagnosis, the cumulative incidences of grades 3 – 5 CAD, HF, and VD were 2.3% (95% CI 2.0 – 2.5), 2.6% (95% CI 2.4 – 2.9), and 0.6% (95% CI 0.5 – 0.8) respectively. Low dose RT (mean 5 – 9.9 Gy) to the RCA (relative rate [RR] = 2.6, 95% CI 1.6 – 4.1, p < 0.001), LAD (RR = 1.9, 95% CI 1.1 – 3.3, p = 0.019), and left ventricle (RR = 2.2, 95% CI 1.3 – 3.7, p = 0.002) was associated with increased risk of CAD relative to those not exposed; mean dose of 5 – 9.9 Gy to the entire heart was not (RR = 1.1, 95% CI = 0.8 – 1.6, p = 0.59). Table shows the associated cumulative incidences of CAD for these structures. Mean RT doses of 5 – 9.9 Gy to the aortic valve (RR = 4.6, 95% CI 1.5 – 14.0, p = 0.008) and tricuspid valve (RR = 5.5, 95% CI 2.0 – 15.1, p = 0.001) were associated with risk of VD compared to those with no RT; mean heart dose 5 – 9.9 Gy was not (RR = 0.6, 95% CI = 0.2 – 1.3, p = 0.16). No cardiac structure was significantly associated with an increased risk of HF at a mean dose of 5 – 9.9 Gy. Mean RT doses below 5 Gy were not associated with increased risks of CAD, HF, or VD; doses ≥10 Gy to nearly all substructures and the entire heart were. Conclusions: Low dose RT to the coronary arteries and cardiac valves (5 – 9.9 Gy) from RT is associated with increased risk of CAD and VD, respectively. Sensitivity to low dose RT may vary across the heart and doses to specific structures may be more predictive of late cardiac disease than whole heart dose. These data can guide RT planning to prioritize substructures for avoidance.[Table: see text]

10048 Background: The impact of treatment era and chronic health conditions on health-related unemployment among childhood cancer survivors has not been studied. Methods: Childhood cancer survivors (age ≥25 years) enrolled in the CCSS (3,420 diagnosed in the 1970s, 3,564 in the 1980s, and 2,853 in the 1990s) were matched 1:5 on sex, race/ethnicity, census bureau division, age, and year of survey to the Behavioral Risk Factor Surveillance System (BRFSS), a nationally representative population. Among survivors, health-related unemployment was defined as self-reported unemployment due to illness/disability and for BRFSS participants as self-reported inability to work. To standardize follow-up, health-related unemployment was assessed either in 2002-05 or 2014-16 for both cohorts. Sex stratified standardized prevalence ratio (SPR) and relative SPR (rSPR) with 95% confidence intervals (CI) for health-related unemployment were estimated using multivariable generalized linear models, with BRFSS background rates to assess the impact of treatment era and moderate to severe health conditions (per the Common Terminology Criteria for Adverse Events). Results: Prevalence of health-related unemployment in survivors (median age 9 years [range 0-20] at diagnosis and 33 years [25-54] at follow-up) was significantly higher compared to BRFSS participants (females: 11.3% vs 3.7%; SPR 3.0, 95% CI 2.7-3.3; males: 10.5% vs 3.0%; SPR 3.5, 95% CI 3.1-3.9). Health-related unemployment risks declined among survivors in more recent decades (ptrend< 0.001) for females: 1970s SPR 3.8, 95% CI 3.2-4.5, 1980s SPR 2.9, 95% CI 2.5-3.5, 1990s SPR 2.5, 95% CI 2.1-3.0; and males: 1970s SPR 3.6, 95% CI 2.9-4.4, 1980s SPR 3.8, 95% CI 3.1-4.7, 1990s SPR 3.0, 95% CI 2.5-3.7. Among survivors, multivariable models identified associations between presence of specific health conditions and elevated health-related unemployment (Table) adjusting for all statistically significant health conditions, race/ethnicity, treatment era, age at survey, and diagnosis. Among females, rSPR for endocrine conditions differed between 1970s and 1990s (interaction p = 0.04); fewer significant health conditions remained in the final model for males. Conclusions: While prevalence for health-related unemployment has declined over time, childhood cancer survivors remain at higher risk compared to the general population. These elevated risks are associated with chronic health conditions and affect female survivors more than male survivors.[Table: see text]

12073 Background: The direct impact of a major cardiovascular (CV) event on mortality among childhood cancer survivors is not well described. We hypothesized that mortality following a major CV event would be higher among survivors compared with siblings and that mortality would be influenced by primary cancer treatment. Methods: The CCSS cohort has conducted longitudinal follow-up of 25,658 survivors of childhood cancer and 5,051 siblings. All-cause and CV-cause specific mortality after a first event of heart failure (HF), coronary artery disease (CAD), or stroke occurring at least 5 years after cancer diagnosis, was estimated using the Kaplan-Meier method. The relative hazards (HR) and 95% confidence intervals (CI) between survivors and siblings as well as the influence of demographic (sex, age, race/ethnicity) and cancer treatment factors were estimated via Cox regression. Results: In total, 1780 survivors and 91 siblings experienced a serious CV event. Total deaths included 706 survivors (271 cardiac causes, 381 non-cardiac causes, 54 unknown causes) and 14 siblings. Survivors were a median age of 31.5 years (range 6.5-61.5) and 20.0 years (range 5.0-44.6) since cancer diagnosis at time of CV event. After a CV event, estimated 10- and 20-y all-cause mortality was significantly higher among survivors than siblings (Table). The HR for all-cause mortality was significantly higher among survivors than siblings after HF (HR 5.2, CI 2.1-13.0), CAD (HR 4.2, CI 2.0-9.0), and stroke (HR 4.6, CI 1.5-14.6). HF and stroke-specific mortality were not significantly increased among survivors versus siblings, in contrast to CAD-specific mortality (HR 3.5, CI 1.1-11.0). Among survivors, heart dose from radiotherapy (per 10 Gy) was associated with increased all-cause and cause-specific mortality after HF (HR 1.2, CI 1.0-1.3; HR 1.3, CI 1.0-1.7), all-cause mortality after CAD (HR 1.2, CI 1.0-1.3), and cause-specific mortality after stroke (HR 2.5, CI 1.2-4.9). Brain dose from radiotherapy was associated with increased all-cause mortality (HR 1.1, CI, 1.0-1.2, per 10 Gy) after stroke. Anthracycline dose was not associated with increased overall or cause-specific mortality risk after a CV event. Conclusions: After a CV event, mortality is higher among survivors than siblings. In survivors, mortality is primarily driven by non-cardiac causes. CAD and prior radiotherapy exposure to the heart and brain also influenced mortality.[Table: see text]

10045 Background: Survivors of childhood cancer have functional limitations and health-related morbidity consistent with an accelerated aging phenotype. We characterized aging using a Deficit Accumulation Index (DAI) which examines the accumulation of multiple aging-related deficits readily available from medical records and self-report. DAI’s are used as surrogates of biologic aging and are validated to predict mortality in adult cancer patients. Methods: We included childhood cancer survivors (N = 3,758, mean age 30 [SD 8], 22 [9] years post diagnosis, 52% male) and community controls (N = 575, mean age 34 [10] 44% male) who completed clinical assessments and questionnaires and who were followed for mortality through December 31st, 2018 (mean follow-up 6.1 [3.1] years). Using the initial SJLIFE clinical assessment, a DAI score was generated as the proportion of deficits out of 44 items related to aging, including chronic conditions (e.g. hearing loss, hypertension), psychosocial and physical function, and activities of daily living. The total score ranged 0 to 1; scores > 0.20 are robust, while moderate and large clinically meaningful differences are 0.02 and 0.06, respectively. Linear regression compared the DAI in survivors and controls with an age*survivor/control interaction and examined treatment associations in survivors. Cox-proportional hazards models estimated risk of death associated with DAI. All models were adjusted for age, sex, and race. Results: Mean [SD] of DAI was 0.17 [0.11] for survivors and 0.10 [0.08] for controls. 32% of survivors had a DAI above the 90th percentile of the control distribution (p < 0.001). After adjustment for covariates, survivors had a statistically and clinically meaningfully higher DAI score than controls (β = 0.072 95%CI 0.062, 0.081; p < 0.001). When plotted against age, the adjusted DAI at the average age of survivors (30 years) was 0.166 (95% CI 0.160,0.171), which corresponded to 60 years of age in controls, suggesting premature aging of 30 years. The mean difference in DAI between survivors and controls increased with age from 0.06 (95% CI 0.04, 0.07) at age 20 to 0.11 (95% CI 0.08, 0.13) at age 60, consistent with an accelerated aging phenotype (p = 0.014). Cranial radiation, abdominal radiation, cyclophosphamide, platinum agents, neurosurgery, and amputation were each associated with a higher DAI (all p≤0.001). Among survivors, a 0.06 increase in DAI was associated with a 41% increased risk of all-cause mortality (HR 1.41 95%CI 1.32, 1.50; p < 0.001). Conclusions: Survivors of childhood cancer experience significant age acceleration that is associated with an increased risk of mortality; longitudinal analyses are underway to validate these findings. Given the ease of estimating a DAI, this may be a feasible method to quickly identify survivors for novel and tailored interventions that can improve health and prevent premature mortality.