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Importance: Symptom burden and its characteristics among survivors of pediatric cancers aged 8 to 18 years remain understudied., Objective: To examine the prevalence of symptom burden among young childhood cancer survivors and identify associations with sociodemographic, clinical, and psychological resilience skills, and health-related quality of life (HRQOL)., Design, Setting, and Participants: A cross-sectional analysis using data collected from November 1, 2017, to January 31, 2019, in a survivorship clinic at a US-based comprehensive cancer center was conducted. Participants included 302 dyads of children aged 8 to 18 years who survived at least 5 years beyond diagnosis and their primary caregivers. Data analysis was performed from March 13, 2023, to February 29, 2024., Exposures: Diagnosis, caregiver-reported family conflict, self-reported caregiver anxiety, neighborhood-level social vulnerability, and survivor-reported meaning and purpose., Main Outcomes and Measures: Novel symptom-level burden, integrating the attributes of severity and daily activity interference using the pediatric version of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, global cumulative symptom burden, and HRQOL using the EuroQol-5D. Multinomial logistic regression identified characteristics associated with symptom burden; linear regression assessed symptom burden and HRQOL associations., Results: Among 302 survivors (mean [SD] age, 14.2 [2.9] years, mean [SD] time since diagnosis, 10.9 [2.9] years; 153 [50.7%] male), 186 (62.0%) had low, 77 (25.7%) moderate, and 37 (12.3%) high global cumulative symptom burden. Greater caregiver anxiety was associated with moderate (risk ratio [RR], 1.56; 95% CI, 1.09-2.24) global symptom burden. Greater neighborhood deprivation was associated with moderate global symptom burden (RR, 4.86; 95% CI, 1.29-18.26). Survivors with greater meaning/purpose were less likely to have moderate (RR, 0.42; 95% CI, 0.29-0.61) and high (RR, 0.27; 95% CI, 0.16-0.46) global symptom burden. The burden of individual symptoms displayed similar patterns. Low (Cohen d, -0.60; 95% CI, -0.87 to -0.32) and moderate/high (d, -0.98; 95% CI, -1.53 to -0.43) general pain, moderate/high numbness (d, -0.99; 95% CI, -1.69 to -0.29), and moderate/high worry (d, -0.55; 95% CI, -0.99 to -0.11) were associated with lower HRQOL., Conclusions and Relevance: In this cross-sectional study of young childhood cancer survivors, symptom burden was prevalent. Caregiver anxiety and disparity-related neighborhood factors were associated with greater symptom burden, whereas meaning and purpose was a protective factor. Greater specific symptom burden contributed to poorer HRQOL. The findings suggest that interventions targeting resilience and neighborhood adversity may alleviate symptom burden and improve HRQOL.

Purpose: To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction (LVEF) at highest risk of future treatment-related cardiomyopathy., Methods: St Jude Lifetime Cohort participants ≥5 years from diagnosis, at increased risk for cardiomyopathy per the International Guideline Harmonization Group (IGHG), with an LVEF ≥50% on baseline echocardiography (n = 1,483) underwent measurement of GLS (n = 1,483) and NT-proBNP (n = 1,052; 71%). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for postbaseline cardiomyopathy (modified Common Terminology Criteria for Adverse Events ≥grade 2) incidence in association with echocardiogram-based GLS (≥-18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles). Prediction performance was assessed using AUC in models with and without GLS and NT-proBNP and compared using DeLong's test for IGHG moderate- and high-risk individuals treated with anthracyclines., Results: Among survivors (median age, 37.6; range, 10.2-70.4 years), 162 (11.1%) developed ≥grade 2 cardiomyopathy 5.1 (0.7-10.0) years from baseline assessment. The 5-year cumulative incidence of cardiomyopathy for survivors with and without abnormal GLS was, respectively, 7.3% (95% CI, 4.7 to 9.9) versus 4.4% (95% CI, 3.0 to 5.7) and abnormal NT-proBNP was 9.9% (95% CI, 5.8 to 14.1) versus 4.7% (95% CI, 3.2 to 6.2). Among survivors with a normal LVEF, abnormal baseline GLS and NT-proBNP identified anthracycline-exposed, IGHG-defined moderate-/high-risk survivors at a four-fold increased hazard of postbaseline cardiomyopathy (HR, 4.39 [95% CI, 2.46 to 7.83]; P < .001), increasing to a HR of 14.16 (95% CI, 6.45 to 31.08; P < .001) among survivors who received ≥250 mg/m 2 of anthracyclines. Six years after baseline, AUCs for individual risk prediction were 0.70 for models with and 0.63 for models without GLS and NT-proBNP ( P = .022)., Conclusion: GLS and NT-proBNP should be considered for improved identification of survivors at high risk for future cardiomyopathy.

Background: Hearing loss is prevalent following ototoxic therapy for childhood cancer. Associations between hearing loss, self-perceived hearing handicap, and functional outcomes have not been examined in survivors., Methods: Adult survivors treated with platinum or head and neck radiotherapy with hearing loss were recruited. A total of 237 survivors (median age at survey = 37.0 years [range = 30.0-45.0 years]; median = 29.1 years [range = 22.4-35.0 years] since diagnosis; median = 4.0 years [range = 2.9-7.7 years] from last audiogram to survey) completed the Hearing Handicap Inventory for Adults and questionnaires on social and emotional functioning and hearing aid use. Hearing loss severity was defined according to Chang criteria. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between hearing loss, hearing handicap, functional outcomes, and hearing aid use with adjustment for sex, race, age at hearing loss diagnosis, and age at survey., Results: Two-thirds of survivors had severe hearing loss, which was associated with increased likelihood of hearing handicap (mild-moderate handicap: OR = 2.72, 95% CI = 1.35 to 5.47; severe handicap: OR = 5.99, 95% CI = 2.72 to 13.18). Survivors with severe hearing handicap had an increased likelihood of social isolation (OR = 8.76, 95% CI = 3.62 to 21.20), depression (OR = 9.11, 95% CI = 3.46 to 24.02), anxiety (OR = 17.57, 95% CI = 3.77 to 81.84), reduced personal income (OR = 2.82, 95% CI = 1.46 to 5.43), and less than full-time employment (OR = 2.47, 95% CI = 1.30 to 4.70). Survivors who did not use a recommended hearing aid were twice as likely to have less than full-time employment (OR = 2.26, 95% CI = 1.10 to 4.61) and reduced personal income (OR = 2.24, 95% CI = 1.08 to 4.63) compared with survivors who wore a hearing aid., Conclusion: Self-perceived hearing handicap beyond measured hearing loss is associated with reduced functional outcomes. Assessment of hearing handicap may facilitate targeted interventions in adult survivors with hearing loss., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors., Methods: Prevalence of prediabetes (fasting plasma glucose 100-125 mg/dL or hemoglobin A1c 5.7%-6.4%) and diabetes was clinically assessed in 3,529 adults ≥5 years from childhood cancer diagnosis and 448 controls stratified by age. Cox proportional hazards regression estimated progression from prediabetes to diabetes, and risk of future cardiac events, stroke, CKD, and death., Results: Among survivors, median age 30 years (IQR, 18-65), and the prevalence of prediabetes was 29.2% (95% CI, 27.7 to 30.7) versus 18.1% (14.5 to 21.6) in controls and of diabetes was 6.5% (5.7 to 7.3) versus 4.7% (2.7 to 6.6). By age 40-49 years, more than half of the survivors had prediabetes (45.5%) or diabetes (14.0%). Among 695 survivors with prediabetes and longitudinal follow-up, 68 (10%; median follow-up, 5.1 years) progressed to diabetes. After adjustment for demographic factors and body composition, risk of progression was associated with radiation exposure to the pancreatic tail ≥10 Gy (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.8]) and total-body irradiation (4.4 [1.5 to 13.1]). Compared with survivors with normal glucose control, adjusting for relevant treatment exposures, those with prediabetes were at increased risk of future myocardial infarction (HR, 2.4 [95% CI, 1.2 to 4.8]) and CKD (2.9 [1.04 to 8.15]), while those with diabetes were also at increased risk of future cardiomyopathy (3.8 [1.4 to 10.5]) or stroke (3.4 [1.3 to 8.9])., Conclusion: Prediabetes is highly prevalent in adult survivors of childhood cancer and independently associated with an increased risk of future cardiovascular and kidney complications. Prediabetes, a modifiable risk factor among childhood cancer survivors, represents a new target for intervention that may prevent subsequent morbidity and mortality.

Background: Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors., Methods: Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls., Results: Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non-high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio [HR] = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy., Conclusions: Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies., Methods: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress., Results: Among CNS-treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non-independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non-independent (5.7%). In contrast to 50% of non-CNS-treated survivors and 60% of siblings, a fourth fully independent class of CNS-treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70-3.68), seizure (OR = 9.70, 95% CI: 7.37-12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16-3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40-3.88) were associated with non-independence among CNS-treated survivors. Non-independence was associated with emotional distress symptoms., Interpretation: CNS-treated survivors do not attain full independence comparable to non-CNS-treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment-related neurological sequalae., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis)., Methods: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov., Findings: 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001)., Interpretation: Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden., Funding: American Lebanese Syrian Associated Charities and US National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Cancer-related worry (CRW; concerns related to cancer and its late effects) is prevalent among childhood cancer survivors. Elevated CRW has been associated with self-reported suboptimal physical activity. The aim of this investigation was to describe associations between CRW and objectively assessed physical activity in childhood cancer survivors., Methods: CRW was assessed at a baseline evaluation using six survey items. Weekly minutes of moderate and vigorous physical activity were captured by actigraphy 5.25 (3.8-8.0) yr later. Factor analysis was used to identify types of worry; multiple regression determined independent associations between CRW and moderate and vigorous physical activity adjusting for sex, race, diagnosis, age at baseline, anxiety level at baseline, self-reported physical activity at baseline, and pain interference at baseline., Results: Participants ( n = 1223) were an average of 30.9 (SD, 6.9) yr at baseline and 36.1 (SD, 7.1) yr at follow-up. Thirty-seven percent were survivors of leukemia, 26% of non-CNS solid tumors, 19% of lymphoma, 11% of CNS tumors, and 6% of other malignancies. Two types of CRW were identified: "body-focused" and "general fear." Body-focused CRW ( β = -19.6, P = 0.012), endorsing pain interference ( β = -27.7, P = 0.002) at baseline, and having a diagnosis of CNS tumor ( β = -41.3, P = 0.0003) or non-CNS solid tumor ( β = -19.4, P = 0.02) were negatively associated with physical activity at follow-up., Conclusions: CRW related to bodily function and appearance is associated with decreased physical activity. Clinicians should consider the potential negative impact of CRW on physical activity levels and provide behavioral counseling., (Copyright © 2023 by the American College of Sports Medicine.)

Background: Childhood cancer survivors experience reduced physiologic reserve, or frailty, earlier and more frequently than peers. In other populations, frailty is impacted by one's neighborhood. This study's purpose was to evaluate associations between neighborhood characteristics and frailty in childhood cancer survivors., Methods: Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were analyzed. Pre-frailty/Frailty was defined as having 1-2/≥3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion from direct assessments. Neighborhood characteristics [e.g., access to exercise opportunities and healthy food, neighborhood socioeconomic status (nSES), and rurality/urbanicity] were determined using publicly available geospatial data. Nested multivariable logistic regression models identified associations between neighborhood characteristics and pre-frailty/frailty, adjusting for chronic health conditions, individual health behaviors and socio-demographics, and high-risk cancer treatment exposures., Results: For our cohort (N = 3,806, 46.79% female, 81.40% white, mean age 33.63±9.91 years), compared with non-frail survivors (n = 2,573; 67.6%), pre-frail (n = 900; 23.6%) and frail survivors (n = 333; 8.7%) were more likely to live in neighborhoods with decreased exercise opportunities (frail OR: 1.62, 1.26-2.09), reduced healthy food access (pre-frail OR: 1.28, 1.08-1.51; frail OR: 1.36, 1.06-1.75), and lower nSES (pre-frail OR: 1.31, 1.12-1.52; frail OR: 1.64, 1.30-2.07). Participants had 8% increased odds (95% confidence interval, 2%-14%) of being pre-frail/frail if they lived in "resource poor" neighborhoods as opposed to "resource rich" neighborhoods after adjusting for other pre-frailty/frailty risk factors., Conclusions: The neighborhood a childhood cancer survivor resides in as an adult is associated with pre-frailty/frailty., Impact: This study provides valuable information for creating interventions using neighborhood-level factors to mitigate frailty and improve health outcomes in survivors. See related commentary by Bhandari and Armenian, p. 997., (©2023 American Association for Cancer Research.)

Purpose: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS., Methods: Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at < 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties., Results: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P < 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P < 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21-3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01-3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment., Conclusions: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time., Implications for Cancer Survivors: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Associations between modifiable chronic health conditions (CHCs), social determinants of health, and late mortality (defined as death occurring ≥5 years after diagnosis) in childhood cancer survivors are unknown., Objective: To explore associations between modifiable CHCs and late mortality within the context of social determinants of health., Design, Setting, and Participants: This longitudinal cohort study used data from 9440 individuals who were eligible to participate in the St Jude Lifetime Cohort (SJLIFE), a retrospective cohort study with prospective clinical follow-up that was initiated in 2007 to characterize outcomes among childhood cancer survivors. Eligible individuals had survived 5 or more years after childhood cancer diagnosis, were diagnosed between 1962 and 2012, and received treatment at St Jude Children's Research Hospital were included in mortality estimates. A total of 3407 adult SJLIFE participants (aged ≥18 years) who completed an on-campus assessment were included in risk factor analyses. Vital status, date of death, and cause of death were obtained by linkage with the National Death Index (coverage from inception to December 31, 2016). Deaths occurring before inception of the National Death Index were obtained from the St Jude Children's Research Hospital Cancer Registry. Data were analyzed from June to December 2022., Exposures: Data on treatment exposures and causes of death were abstracted for individuals who were eligible to participate in the SJLIFE study. Information on modifiable CHCs (dyslipidemia, hypertension, diabetes, underweight or obesity, bone mineral deficiency, hypogonadism, hypothyroidism, and adrenal insufficiency, all graded by the modified Common Terminology Criteria for Adverse Events), healthy lifestyle index (smoking status, alcohol consumption, body mass index [calculated as weight in kilograms divided by height in meters squared], and physical activity), area deprivation index (ADI; which measures neighborhood-level socioeconomic disadvantage), and frailty (low lean muscle mass, exhaustion, low energy expenditure, slowness, and weakness) was obtained for participants., Main Outcomes and Measures: National Death Index causes of death were used to estimate late mortality using standardized mortality ratios (SMRs) and 95% CIs, which were calculated based on US mortality rates. For the risk factor analyses (among participants who completed on-campus assessment), multivariable piecewise exponential regression analysis was used to estimate rate ratios (RRs) and 95% CIs for all-cause and cause-specific late mortality., Results: Among 9440 childhood cancer survivors who were eligible to participate in the SJLIFE study, the median (range) age at assessment was 27.5 (5.3-71.9) years, and the median (range) duration of follow-up was 18.8 (5.0-58.0) years; 55.2% were male and 75.3% were non-Hispanic White. Survivors experienced increases in all-cause mortality (SMR, 7.6; 95% CI, 7.2-8.1) and health-related late mortality (SMR, 7.6; 95% CI, 7.0-8.2). Among 3407 adult SJLIFE participants who completed an on-campus assessment, the median (range) age at assessment was 35.4 (17.9-69.8) years, and the median (range) duration of follow-up was 27.3 (7.3-54.7) years; 52.5% were male and 81.7% were non-Hispanic White. Models adjusted for attained age, sex, race and ethnicity, age at diagnosis, treatment exposures, household income, employment status, and insurance status revealed that having 1 modifiable CHC of grade 2 or higher (RR, 2.2; 95% CI, 1.2-4.0; P = .01), 2 modifiable CHCs of grade 2 or higher (RR, 2.6; 95% CI, 1.4-4.9; P = .003), or 3 modifiable CHCs of grade 2 or higher (RR, 3.6; 95% CI, 1.8-7.1, P < .001); living in a US Census block with an ADI in the 51st to 80th percentile (RR, 5.5; 95% CI, 1.3-23.5; P = .02), an ADI in the 81st to 100th percentile (RR, 8.7; 95% CI, 2.0-37.6; P = .004), or an unassigned ADI (RR, 15.7; 95% CI, 3.5-70.3; P < .001); and having frailty (RR, 2.3; 95% CI, 1.3-3.9; P = .004) were associated with significant increases in the risk of late all-cause death. Similar associations were observed for the risk of late health-related death (1 modifiable CHC of grade ≥2: RR, 2.2 [95% CI, 1.1-4.4; P = .02]; 2 modifiable CHCs of grade ≥2: RR, 2.5 [95% CI, 1.2-5.2; P = .01]; 3 modifiable CHCs of grade ≥2: RR, 4.0 [95% CI, 1.9-8.4; P < .001]; ADI in 51st-80th percentile: RR, 9.2 [95% CI, 1.2-69.7; P = .03]; ADI in 81st-100th percentile: RR, 16.2 [95% CI, 2.1-123.7; P = .007], unassigned ADI: RR, 27.3 [95% CI, 3.5-213.6; P = .002]; and frailty: RR, 2.3 [95% CI, 1.2-4.1; P = .009])., Conclusions and Relevance: In this cohort study of childhood cancer survivors, living in a Census block with a high ADI and having modifiable CHCs were independently associated with an increased risk of late death among survivors of childhood cancer. Future investigations seeking to mitigate these factors will be important to improving health outcomes and developing risk-stratification strategies to optimize care delivery to childhood cancer survivors.

Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5'-cytosine-phosphate-guanine-3' (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH-CpG associations ( P < 9 × 10 -8 ), 25 of which were validated in survivors of African ancestry ( P < 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking-related genes (e.g., CLDND1 and CPOX ). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors' health.

Purpose: To examine self-reported (30-day) sleep versus nightly actigraphy-assessed sleep concordance in long-term survivors of childhood cancer., Methods: Four hundred seventy-seven participants enrolled in the St. Jude Lifetime Cohort (53.5% female, median (range) age 34.3 (19.3-61.6) years, 25.4 (10.9-49.3) years from diagnosis) completed the Pittsburgh Sleep Quality Index and ≥ 3 nights of actigraphy. Participants had neurocognitive impairment and/or a self-reported prolonged sleep onset latency (SOL). Self-reported 30-day sleep and nightly actigraphic sleep measures for sleep duration, SOL, and sleep efficiency (SE) were converted into ordinal categories for calculation of weighted kappa coefficients. General linear models estimated associations between measurement concordance and late effects., Results: Agreements between self-reported and actigraphic measures were slight to fair for sleep duration and SOL measures (k w  = 0.20 and k w  = 0.22, respectively; p < 0.0001) and poor for SE measures (k w  = 0.00, p = 0.79). In multivariable models, severe fatigue and poor sleep quality were significantly associated with greater absolute differences between self-reported and actigraphy-assessed sleep durations (B = 26.6 [p < 0.001] and B = 26.8 [p = 0.01], respectively). Survivors with (versus without) memory impairment had a 44-min higher absolute difference in sleep duration (B = 44.4, p < 0.001). Survivors with, versus without, depression and poor sleep quality had higher absolute discrepancies of SOL (B = 24.5 [p = 0.01] and B = 16.4 [p < 0.0001], respectively). Poor sleep quality was associated with a 12% higher absolute difference in SE (B = 12.32, p < 0.0001)., Conclusions: Self-reported sleep and actigraphic sleep demonstrated discordance in our sample. Several prevalent late effects were statistically significantly associated with increased measurement discrepancy. Future studies should consider the impacts of late effects on sleep assessment in adult survivors of childhood cancer., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Adult survivors of childhood cancer are at risk of developing sleep and neurocognitive problems, yet few efficacious interventions exist targeting these prevalent late effects. Melatonin has known sleep-promoting effects; however, it has not been well studied among childhood cancer survivors., Method: Survivors (n = 580; mean age = 33.5 years; 26 years post-diagnosis) from the St. Jude Lifetime Cohort were randomized (1:1) to a six-month double-blind placebo-controlled trial of 3 mg time-release melatonin within three strata (stratum 1: neurocognitive impairment only; stratum 2: neurocognitive and sleep impairment; stratum 3: sleep impairment only). Neurocognitive performance was assessed at baseline and post-intervention using standardized measures. Sleep was assessed via self-report and actigraphy. Independent sample t tests compared mean change scores from baseline to six months. Post-hoc analyses compared the prevalence of clinically significant treatment responders among melatonin and placebo conditions within and across strata., Results: Intent-to-treat analyses revealed no statistically significant differences in neurocognitive performance or sleep from baseline to post-intervention. However, among survivors with neurocognitive impairment only, a larger proportion randomized to melatonin versus placebo demonstrated a treatment response for visuomotor speed (63% vs 41%, P = 0.02) and nonverbal reasoning (46% vs 28%, P = 0.04). Among survivors with sleep impairment only, a larger proportion treated with melatonin demonstrated a treatment response for shifting attention (44% vs 28%, P = 0.05), short-term memory (39% vs 19%, P = 0.01), and actigraphy-assessed sleep duration (47% vs 29%, P = 0.05)., Conclusion: Melatonin was not associated with improved neurocognitive performance or sleep in our intent-to-treat analyses; however, a subset of survivors demonstrated a clinically significant treatment response., (© 2021 Wiley Periodicals LLC.)

Background: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy., Methods: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed., Results: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15-2.68)., Conclusions: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance., (© 2021 American Cancer Society.)

Background: Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail., Methods: Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates., Results: Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32)., Conclusions: Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cancer-related worry (CRW) is common among cancer survivors; however, little is known about factors associated with CRW or its impact on health behaviors in adult survivors of childhood cancer., Methods: Survivors in the St. Jude Lifetime Cohort Study (n = 3211; 51% male; mean age, 31.2 years [SD, 8.4 years]; mean time after diagnosis, 22.8 years [SD, 8.3 years]) underwent medical evaluations and completed ratings of CRW, psychological symptoms, and health behaviors. Multivariable modified Poisson regression models examined associations between CRW and treatment exposures, chronic health conditions, psychological symptoms, and health behaviors., Results: Sixty-four percent of survivors (95% confidence interval [CI], 62.6-65.9) reported worry about subsequent malignancy, 45% (95% CI, 43.5-46.9) reported worry about physical problems related to cancer, and 33% (95% CI, 31.2-34.4) reported worry about relapse. Multiple psychological symptoms, treatment exposures, and chronic conditions significantly increased the risk of CRW. Survivors reporting CRW were at increased risk for substance use, inadequate physical activity, and increased health care utilization after adjustments for chronic conditions. For example, with adjustments for chronic conditions, those who endorsed CRW were more likely to have ≥5 cancer-related physician visits, ≥5 physician visits related to cancer, and ≥5 calls to a physician's office in the previous 2 years in comparison with survivors who were not worried. CRW was also associated with an increased risk of current tobacco use, past marijuana use, and current marijuana use., Conclusions: A substantial proportion of adult survivors of childhood cancer reported CRW associated with increased health care utilization. CRW may serve as an intervention target to promote well-being and adaptive health behaviors., (© 2021 American Cancer Society.)

Background: To examine associations between phenotypes of short sleep duration and clinically assessed health conditions in long-term survivors of childhood cancer., Methods: Survivors recruited from the St. Jude Lifetime Cohort (n = 911; 52% female; mean age 34 years; 26 years postdiagnosis) completed behavioral health surveys and underwent comprehensive physical examinations. Sleep was assessed with the Pittsburgh Sleep Quality Index. Short sleep was defined as ≤6 h per night with phenotypes of short sleep including poor sleep efficiency (<85%), prolonged sleep onset latency (SOL; ≥30 min), and wake after sleep onset (≥3 times per week). Covariates included childhood cancer treatment exposures, demographics, body mass index, and physical inactivity. Separate modified Poisson regression models were computed for each health category to estimate relative risks (RR) and 95% confidence intervals (CI). Multinomial logistic regression models examined associations between sleep and an aggregated burden of chronic health conditions., Results: Short sleep duration was reported among 44% (95% CI 41%-47%) of survivors. In multivariable models, short sleep duration alone was associated with pulmonary (RR = 1.35, 95% CI 1.08-1.69), endocrine (RR = 1.22, 95% CI 1.06-1.39) and gastrointestinal/hepatic conditions (RR = 1.46, 95% CI 1.18-1.79), and anxiety (RR 3.24, 95% CI 1.64-6.41) and depression (RR = 2.33, 95% CI 1.27-4.27). Short sleep with prolonged SOL was associated with a high/severe burden of health conditions (OR = 2.35, 95% CI 1.12-4.94)., Conclusions: Short sleep duration was associated with multiple clinically ascertained adverse health conditions. Although the temporality of these associations cannot be determined in this cross-sectional study, sleep is modifiable and improving sleep may improve long-term health in survivors., (© 2021 Wiley Periodicals LLC.)

Purpose: Early identification of childhood cancer survivors at high risk for treatment-related cardiomyopathy may improve outcomes by enabling intervention before development of heart failure. We implemented artificial intelligence (AI) methods using the Children's Oncology Group guideline-recommended baseline ECG to predict cardiomyopathy., Material and Methods: Seven AI and signal processing methods were applied to 10-second 12-lead ECGs obtained on 1,217 adult survivors of childhood cancer prospectively followed in the St Jude Lifetime Cohort (SJLIFE) study. Clinical and echocardiographic assessment of cardiac function was performed at initial and follow-up SJLIFE visits. Cardiomyopathy was defined as an ejection fraction < 50% or an absolute drop from baseline ≥ 10%. Genetic algorithm was used for feature selection, and extreme gradient boosting was applied to predict cardiomyopathy during the follow-up period. Model performance was evaluated by five-fold stratified cross-validation., Results: The median age at baseline SJLIFE evaluation was 31.7 years (range 18.4-66.4), and the time between baseline and follow-up evaluations was 5.2 years (0.5-9.5). Two thirds (67.1%) of patients were exposed to chest radiation, and 76.6% to anthracycline chemotherapy. One hundred seventeen (9.6%) patients developed cardiomyopathy during follow-up. In the model based solely on ECG features, the cross-validation area under the curve (AUC) was 0.87 (95% CI, 0.83 to 0.90), whereas the model based on clinical features had an AUC of 0.69 (95% CI, 0.64 to 0.74). In the model based on ECG and clinical features, the cross-validation AUC was 0.89 (95% CI, 0.86 to 0.91), with a sensitivity of 78% and a specificity of 81%., Conclusion: AI using ECG data may assist in the identification of childhood cancer survivors at increased risk for developing future cardiomyopathy., Competing Interests: Rebecca M. HowellResearch Funding: MD Anderson Cancer Center John L. JefferiesHonoraria: Genzyme, Amicus Therapeutics, Pfizer, Abbott Diagnostics, Stealth Biotherapeutics, Novartis, ChiesiConsulting or Advisory Role: Abbott Diagnostics, Amicus Therapeutics, Chiesi, Medtronic, CHF Solutions, Stealth Biotherapeutics, Pfizer, NovartisSpeakers' Bureau: Genzyme, PfizerResearch Funding: Medtronic, Myokardia, Sanofi, Innolife, Novartis, Lilly, CHF Solutions, RegeneronTravel, Accommodations, Expenses: Genzyme, Abbott Diagnostics, Amicus Therapeutics, Novartis, Medtronic, Chiesi, PQBypass Deo Kumar SrivastavaConsulting or Advisory Role: GENERAL DYNAMICS Information Technology Peer Review and Science Management Melissa M. HudsonConsulting or Advisory Role: Oncology Research Information Exchange Network, Princess Máxima CenterNo other potential conflicts of interest were reported.

Background: Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors., Methods: Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0-23); age at last follow-up, 35 years (range, 18-66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2-4 events) and cardiovascular risk factors., Results: Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy ( n = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01-1.88; P = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26-1.92; P < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06-1.59; P = 0.01)]., Conclusions: Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies., Impact: These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer., (©2020 American Association for Cancer Research.)

Introduction: There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction., Aim: To estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL)., Methods: Female survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores <10th percentile of controls were classified with sexual dysfunction. Logistic regression evaluated associations between survivor characteristics and sexual dysfunction, and between sexual dysfunction and QOL., Outcomes: Sexual dysfunction was defined by scores <10th percentile of noncancer controls on the SFQ overall, as well as the domains of arousal, interest, orgasm, and physical problems, while QOL was measured by scores on the SF-36 with both physical and mental summary scales., Results: Sexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45-54 vs 18-24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score <40 on the physical (21.1% vs 12.7%, P = .01) and mental health (36.5% vs 18.2%, P < .01) summary scales of the SF-36. Only 2.9% of survivors with sexual dysfunction reported receiving intervention., Clinical Implications: Health care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention., Strengths & Limitations: Strengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction., Conclusion: Sexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions. Bjornard KL, Howell CR, Klosky JL, et al. Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study. J Sex Med 2020;17:1981-1994., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality., Methods: Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake < 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality., Results: Survivors (mean age ± standard deviation [SD], 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min; P for all < .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio [OR], 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second < 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction < 53% was not associated with exercise intolerance., Conclusion: Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.

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 posttraumatic 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.

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/m 2 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.

Purpose: To describe perceptions of infertility risk among adult survivors of childhood cancer, to test the concordance of survivors' risk perceptions and their adult fertility status, and to identify explanatory factors (sociodemographic factors, gonadotoxic treatments, reproductive history, sexual dysfunction) associated with these outcomes., Patients and Methods: Adult childhood cancer survivors (N = 1,067; without children or a history of pregnancies) completed questionnaires that asked about infertility risk perceptions and participated in physical evaluations, including biomarkers of gonadal functioning (eg, semen analysis, blood hormone levels, menses). Multivariable regression models tested associations between explanatory factors and risk perceptions as well as concordance of perceptions and fertility status., Results: Most childhood cancer survivors (61.9%) perceived themselves at increased risk for infertility, which was significantly associated with sociodemographic factors (older age, white ethnicity, being married/partnered, higher education), gonadotoxic treatments, fertility concerns, previous unsuccessful attempts to conceive, and sexual dysfunction (all P < .05). Laboratory-evaluated impaired gonadal function was found in 24.3% of female and 55.6% of male survivors, but concordance with survivors' risk perceptions was low (Cohen's κ < .19). Most survivors with discordant perceptions overestimated risk (ie, perceived being at risk, though fertility status seemed normal; 19.7% of male and 43.6% of female survivors), whereas a minority underestimated risk (ie, perceived no risk but were impaired/infertile; 16.3% of male and 5.3% of female survivors). Factors related to discordance included sociodemographics, gonadotoxic treatments, fertility concerns, and sexual dysfunction (all P < .05)., Conclusion: Although childfree survivors may correctly consider themselves at risk for infertility on the basis of their previous treatments, such risk perceptions were discordant from laboratory-evaluated fertility status among many survivors in adulthood. Thus, repeated fertility-related communication throughout survivorship is essential, because treatment-indicated risk does not equal fertility status after treatment. Offering fertility testing to those who were at risk and/or those with fertility-related concerns is recommended.

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., (© 2019 John Wiley & Sons, Ltd.)

Background: Survivors of childhood cancer are at significant risk for serious chronic health conditions and subsequent cancers because of their prior treatment exposures. However, little is known about survivors' perceptions of their future health risks., Methods: This study examined self-reported levels of concern about future health and subsequent cancer in 15,620 adult survivors of childhood cancer (median age, 26 years; median time since diagnosis, 17 years) and 3991 siblings in the Childhood Cancer Survivor Study. The prevalence of concerns was compared between survivors and siblings, and the impact of participant characteristics and treatment exposures on concerns was examined with multivariable modified Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs)., Results: A substantial proportion of survivors were not concerned about their future health (31%) or developing cancer (40%). The prevalence of concern in survivors was modestly higher (RR for future health, 1.12; 95% CI, 1.09-1.15) or similar (RR for subsequent cancer, 1.02; 95% CI, 0.99-1.05) in comparison with siblings. Survivors exposed to high doses of radiation (≥20 Gy) were more likely to report concern (RR for future health, 1.13; 95% CI, 1.09-1.16; RR for subsequent cancer, 1.14; 95% CI, 1.10-1.18), but 35% of these high-risk survivors were not concerned about developing cancer, and 24% were not concerned about their future health., Conclusions: A substantial subgroup of survivors were unconcerned about their future health and subsequent cancer risks, even after exposure to treatments associated with increased risk. These survivors may be less likely to engage in beneficial screening and risk-reduction activities. Cancer 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Objective: To examine the potential mediating role of body image dissatisfaction on the association between treatment-related scarring/disfigurement and psychological distress in adult survivors of childhood cancer., Methods: Participants included 1714 adult survivors of childhood cancer (mean [SD] age at evaluation = 32.4 [8.0] years, time since diagnosis = 24.1 [8.1] years) enrolled in the St. Jude Lifetime Cohort Study. Survivors completed measures of body image, emotional distress, and posttraumatic stress symptoms (PTSS). Body image dissatisfaction (BID) was categorized into 2 groups (cancer-related and general) based on factor analysis. Using causal mediation analysis, we estimated the proportion of psychological distress associated with treatment-related scarring/disfigurement that could be eliminated by resolving BID through a hypothetical intervention., Results: Among survivors with scarring/disfigurement of the head, a sizable proportion of the relative excess of psychological distress could be eliminated if BID was successfully treated (males: [cancer-related BID: depression: 63%; anxiety: 100%; PTSS: 52%]; [general BID: depression: 70%; anxiety: 100%; PTSS: 42%]; females: [cancer-related BID: depression: 20%; anxiety; 36%; PTSS: 23%]; [general BID: depression: 32%; anxiety: 87%; PTSS: 38%]). The mediating effect of BID was less pronounced for the association between scarring/disfigurement of the body and psychological distress for both males and females., Conclusions: Body image dissatisfaction mediates the association treatment-related scarring/disfigurement and psychological distress among adult survivors of childhood cancer, particularly among survivors with scarring/disfigurement of the head and male survivors. Successful treatment of body image dissatisfaction has the potential to eliminate a substantial proportion of psychological distress related to scarring/disfigurement among adult survivors of childhood cancer., (Copyright © 2017 John Wiley & Sons, Ltd.)

Context: Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited., Objective: To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes., Design: Cross-sectional., Setting: The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center., Patients: Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis., Main Outcome Measure: POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED)., Results: The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI., Conclusion: High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes., (Copyright © 2017 Endocrine Society)

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 ., (©2016 American Association for Cancer Research.)

Background: The objective of this study was to describe perceptions and associated risk factors of the impact of cancer on functional outcomes, including social relationships, exercise, finances, and religion, among adult survivors of childhood cancer., Methods: Evaluable participants included 3001 adult survivors (mean age, 32.5 years; range, 18.3-63.8 years; 24.1 years from diagnosis; 50.8% male; 84.9% Caucasian) who were enrolled in the St. Jude Lifetime Cohort study. Perceptions of the impact of cancer were assessed using the Brief Cancer Impact Assessment (BCIA). Regression models were used to evaluate risk factors for functional outcomes., Results: The median response on the BCIA was a perception that cancer had minimal impact on the domains assessed. Approximately 33.1% to 46.6% of survivors indicated this response across the 4 subscales, although responses ranged from very positive to very negative impact. Other than diagnosis (with survivors of brain tumors generally indicating a more negative impact of cancer, with subscale estimates of -1.25 for caregiving and finance and -1.01 for social and emotional and an odds ratio of 1.83 for exercise and diet), most variability was because of demographic factors, including sex, age, race, education, and employment., Conclusions: The current findings highlight that many long-term adult survivors perceive minimal impact of childhood cancer on functional aspects of adulthood, including caregiving, finances, exercise, social-emotional relationships, and religion. This suggests that survivors may not be focusing on the influence of likely physical and psychological late effects of their disease in their day-to-day lives. For those who do perceive a negative impact, variability in responses suggests that there are of survivors who may benefit from interventions focused on the achievement of functional goals. Cancer 2017;123:1625-1634. © 2017 American Cancer Society., (© 2016 American Cancer Society.)

Background: Health complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co-occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co-occurring RHBs., Methods: Latent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership., Results: Three RHB clusters were identified: a low-risk cluster, an insufficiently active cluster, and a high-risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj ], 1.17; 95% confidence interval [95% CI], 1.06-1.27) and were less likely to be in the high-risk cluster (ORadj , 0.79; 95% CI, 0.69-0.88). Risk factors for membership in the high-risk cluster included psychological distress (ORadj , 2.76; 95% CI, 1.98-3.86), low educational attainment (ORadj , 7.49; 95% CI, 5.15-10.88), income <$20,000 (ORadj , 2.62; 95% CI, 1.93-3.57), being divorced/separated or widowed (ORadj , 1.36; 95% CI, 1.03-1.79), and limb amputation (ORadj , 1.52; 95% CI, 1.03-2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure., Conclusions: RHBs co-occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747-2756. © 2016 American Cancer Society., Competing Interests: No conflicts of interest to declare., (© 2016 American Cancer Society.)

Purpose: This study describes the prevalence and predisposing factors for potentially modifiable unmet emotional, care/support, and information needs among adult survivors of childhood malignancies., Methods: A randomly selected/stratified sample of participants in the Childhood Cancer Survivor Study (CCSS) responded to the CCSS-Needs Assessment Questionnaire (CCSS-NAQ) (n = 1189; mean [SD] current age, 39.7 [7.7], range = 26-61 years; 60.9 % women; mean [SD] years since diagnosis, 31.6 [4.7]). Survivors self-reported demographic information, health concerns, and needs; diagnosis/treatment data were obtained from medical records. Adjusted proportional risk ratios (prevalence ratios, PRs) were used to evaluate 77 separate needs., Results: Fifty-four percent of survivors reported unmet psycho-emotional, 41 % coping, and 35 % care/support needs; 51, 35, and 33 %, respectively, reported unmet information needs related to cancer/treatment, the health care system, and surveillance. Female sex and annual income <$60K were associated with multiple needs; fewer needs were linked to diagnosis/years since/or age at diagnosis. Having moderate/extreme cancer-related anxiety/fear was associated with all needs, including a >6-fold increased prevalence for help dealing with "worry" (PR = 6.06; 95 % confidence interval [CI], 3.79-9.69) and anxiety (PR = 6.10; 95 % CI, 3.82-9.72) and a >5-fold increased prevalence for "needing to move on with life" (PR = 5.56; 95 % CI, 3.34-9.25) and dealing with "uncertainty about the future" (PR = 5.50; 95 % CI, 3.44-8.77). Radiation exposure and perceived health status were related to 42 and 29 needs, respectively., Conclusions: Demographic factors, disease/treatment characteristics, and intrapersonal factors can be used to profile survivors' unmet emotional, care/support, and information needs., Implications for Cancer Survivors: These data can be used to enhance provider-survivor communication, identify at-risk subsamples, and appraise core intervention content.

Genome-wide association studies (GWAS) have successfully identified many common genetic variants associated with complex diseases over the past decade. The 'gold standard' method for validating the top single nucleotide polymorphisms (SNPs) identified in GWAS is to independently replicate the findings in similar or diverse large-scale external cohorts. However, for rare diseases, it can be difficult to find an external validation cohort within a reasonable timeframe. In such situations, resampling methods, such as the two-step iterative resampling (TSIR) approach have been used to identify SNPs associated with the outcome of interest. However, the TSIR approach involves choosing several parameters in each step, which can influence the performance of the approach. In this paper, we undertook extensive simulation studies to assess the effect of choice of different parameters on the type I error and power for both binary and continuous phenotypes and also compared the TSIR approach with the traditional one-stage (OS) and two-stage (TS) GWAS analysis. We illustrate the usefulness of the TSIR approach by applying it to a GWAS of childhood cancer survivors. Our results indicate that the TSIR approach with an at least 70:30 split and a cutoff of discovering and replicating SNPs at least 20 times in 100 replications provides conservative type I error control and has near 'optimal' power for internally validated SNPs. Its performance is comparable with the TS GWAS for which an external validation cohort is available with only slight reduction in power in some situations. It has almost the same power as OS GWAS with conservative type I error which leads to fewer false positive findings. TSIR is a powerful and efficient method for identifying and internally validating SNPs for GWAS when independent cohorts for external validation may not be available.

Background: Survivors of pediatric cancer have elevated risks of mortality and morbidity. Many late adverse effects associated with cancer treatment (eg, second cancers and cardiac and pulmonary disease) are also associated with cigarette smoking, and this suggests that survivors who smoke may be at high risk for these conditions., Methods: This study examined the self-reported smoking status for 9397 adult survivors of childhood cancer across 3 questionnaires (median time interval, 13 years). The smoking prevalence among survivors was compared with the smoking prevalence among siblings and the prevalence expected on the basis of age-, sex-, race-, and calendar time-specific rates in the US population. Multivariable regression models examined characteristics associated with longitudinal smoking patterns across all 3 questionnaires., Results: At the baseline, 19% of survivors were current smokers, whereas 24% of siblings were current smokers, and 29% were expected to be current smokers on the basis of US rates. Current smoking among survivors dropped to 16% and 14% on follow-up questionnaires, with similar decreases in the sibling prevalence and the expected prevalence. Characteristics associated with consistent never-smoking included a higher household income (relative risk [RR], 1.16; 95% confidence interval [CI], 1.08-1.25), higher education (RR, 1.32; 95% CI, 1.22-1.43), and receipt of cranial radiation therapy (RR, 1.08; 95% CI, 1.03-1.14). Psychological distress (RR, 0.86; 95% CI, 0.80-0.92) and heavy alcohol drinking (RR, 0.64; 95% CI, 0.58-0.71) were inversely associated. Among ever-smokers, a higher income (RR, 1.17; 95% CI, 1.04-1.32) and education (RR, 1.23; 95% CI, 1.10-1.38) were associated with quitting, whereas cranial radiation (RR, 0.86; 95% CI, 0.76-0.97) and psychological distress (RR, 0.80; 95% CI, 0.72-0.90) were associated with not having quit. The development of adverse health conditions was not associated with smoking patterns., Conclusions: Despite modest declines in smoking prevalence, the substantial number of consistent current smokers reinforces the need for continued development of effective smoking interventions for survivors., (© 2015 American Cancer Society.)

Background: The objective of this study was to identify treatment and genetic factors associated with obesity among childhood cancer survivors., Methods: Participants included 1996 survivors who previously received treatment for cancer at St. Jude Children's Research Hospital and who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years). Obesity was defined as a body mass index ≥30 kg/m(2) . The factors associated with adult obesity were identified by subgroup-specific (cranial radiation [CRT] exposure status) multivariable logistic regression. Single nucleotide polymorphisms (SNPs) associated with obesity were identified by subgroup-specific, exploratory, genome-wide association analyses using a 2-stage resampling approach with a type I error rate of 5 × 10(-6) ., Results: Forty-seven percent of survivors who received CRT and 29.4% of those who did not receive CRT were obese at evaluation. In multivariable analyses, abdominal/pelvic radiation exposure was associated with decreased prevalence of obesity among survivors regardless of CRT status (P < .0001). The odds of obesity were increased among survivors who received CRT who had also received glucocorticoids (P = .014) or who were younger at diagnosis (P = .013). Among the survivors who had received CRT, 166 SNPs were associated with obesity. The strongest association was observed with reference SNP rs35669975 (P = 3.3 × 10(-8) ) on segment 33.3 of the long arm of chromosome 13 (13q33.3), approximately 30 kb downstream of FAM155A (family with sequence similarity 155, member A). SNPs within the glycine receptor α3 (GLRA3) gene and near the sex-determining region Y box 11 (SOX11) and cadherin 18 type 2 (CDH18) genes also were identified. These genes have been implicated in neural growth, repair, and connectivity., Conclusions: Obesity in childhood cancer survivors remains associated with previous exposure to CRT and glucocorticoids. Genetic variants related to neural connectivity may modify the risk of obesity among survivors who receive CRT. Validation of these findings in independent cohorts is required., (© 2015 American Cancer Society.)

Background: Childhood cancer survivors (CCSs) are at risk for obesity. The purpose of this project was to determine which clinical measures of body composition are most accurate among CCSs in comparison with dual-energy x-ray absorptiometry (DXA)., Methods: The agreement between the body mass index (BMI), skinfold percent body fat, and waist-to-height ratio (WHtR) and DXA was evaluated among 1361 CCSs (mean age, 32.4 ± 7.7 years) 10 or more years after the diagnosis. The sensitivity and specificity of BMI, skinfold, and WHtR obesity classifications were calculated with respect to DXA. Log-binomial regression, stratified by sex, was used to evaluate treatment-related factors for misclassification as nonobese by BMI, skinfolds, and WHtR., Results: The mean body fat values were 23.3% ± 7.7% (males) and 32.3% ± 8.1% (females) for skinfolds and 26.9% ± 7.4% (males) and 38.4% ± 7.7% (females) for DXA. Pearson correlations between skinfolds and DXA were high (R = 0.83 for males, R = 0.84 for females). Skinfolds incorrectly classified 34.5% of obese males and 27.3% of obese females. BMI measures were the least sensitive with false-negative rates of 46.4% (males) and 53.1% (females). Males exposed to abdominal/pelvic radiation were at increased risk for misclassification as nonobese by BMI (relative risk, 1.57; 95% confidence interval, 1.25-1.95). The percentages classified as obese were highest with DXA (males, 63.1%; females, 84.8%) and lowest with BMI (males, 35.7%; females, 39.7%). Although skinfolds and WHtR underestimated the percentage classified as obese in comparison with DXA, the differences were not as large., Conclusions: Findings suggest that skinfolds and WHtR are better than BMI for obesity classification in CCSs. Clinicians should be aware of the high risk of misclassifying obese CCSs as nonobese., (© 2015 American Cancer Society.)

Introduction: The purpose of this investigation was to determine the efficacy of two evidence-based tobacco quitlines in adult survivors of childhood cancer who regularly smoke cigarettes., Methods: A total of 519 adult survivors of childhood cancer were randomized to either Proactive + 4 weeks of medication (Counselor-initiated intervention, n = 260) or a Reactive + 2 weeks of medication (Participant-initiated intervention, n = 259) condition. Both conditions received telephone counseling to quit smoking as well as nicotine replacement therapy. The primary outcome was biochemically verified (i.e. cotinine) point prevalence smoking cessation at 12 months follow-up., Results: Participants randomized to the Proactive + 4 weeks of medication condition self-reported a higher rate of cessation than those survivors in the Reactive + 2 weeks of medication condition at 8 weeks (33.2% vs. 17.0%, p < .001), but cessation rates were not significantly different at 12 months (23.0% vs. 18.7%, p = .29). However, 80% of participants claiming abstinence failed biochemical verification, indicating marked falsification of self-reported smoking status. Adjusted cessation rates were less than 2% in both intervention conditions., Conclusions: Our results indicate that neither a Proactive + 4 weeks of medication or Reactive + 2 weeks of medication quitline significantly impacted long-term smoking cessation rates. Our results further indicate that self-reports of smoking status are unreliable in survivors of childhood cancer, a population in considerable need of tobacco abstinence. Rates of smoking cessation may be markedly overestimated in studies of childhood cancer survivors that rely on self-reports of tobacco abstinence, and future studies need to include biochemical verification of tobacco status in this population., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The purpose of the study (conducted 2010-2013) was to determine the efficacy of two common types of tobacco quitlines in adult cancer survivors who regularly smoked cigarettes., Method: Adult onset cancer survivors in Memphis, Tennessee (n=427, 67% female, 60% Caucasian) were randomized either to a Proactive (i.e., counselor-initiated calls) or Reactive (i.e., participant-initiated calls) quitline. Both conditions also received nicotine replacement therapy. The primary outcome was biochemically-verified (i.e., salivary cotinine) smoking cessation., Results: While 12-month self-reported abstinence was consistent with other published studies of smoking cessation (22% and 26% point prevalence abstinence for Proactive and Reactive conditions, respectively), 48% of participants who were tested for cotinine failed biochemical verification, indicating a considerable falsification of self-reported cessation. Adjusted cessation rates were less than 5% in both intervention conditions., Conclusion: Our results are consistent with other studies indicating that traditional smoking cessation interventions are ineffective among cancer survivors. Moreover, self-reports of cessation were unreliable in cancer survivors participating in a quitline intervention, indicating that future studies should include biochemical verification. Given the importance of smoking cessation among cancer survivors and low cessation rates in the current study, it may be necessary to design alternative interventions for this population. ClinicalTrials.gov identifier: NCT00827866., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Survivors of childhood cancer treated with central nervous system (CNS)-directed therapy may be at risk for poor health care utilization because of neurocognitive deficits. This study examined associations between neurocognitive function and adherence to routine and risk-based medical evaluations in adult survivors exposed to CNS-directed therapy., Methods: Neurocognitive function and health care utilization were assessed in 1304 adult survivors of childhood cancer enrolled in the St. Jude Lifetime Cohort Study. Adherence to recommended care was defined as meeting guidelines published by the Children's Oncology Group. Multivariate models were used to evaluate associations between neurocognitive function and health screenings. Established predictors of health care utilization were included as covariates. Odds ratios (ORs) or prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for variables maintained in the final models., Results: Adherence to recommended medical care was higher for routine care (general physician care, 57.6%; dental care, 49.1%) versus specialized care (survivor-focused care, 21.9%; echocardiogram, 19.9%). Higher intelligence was predictive of general physician care (OR, 1.74; 95% CI, 1.41-2.15) and survivor-focused care (OR, 1.44; 95% CI, 1.13-1.83) in comparison with no care, whereas better executive function skills were associated with reduced dental care (PR, 0.94; 95% CI, 0.91-0.98). Echocardiogram monitoring was not associated with neurocognition. Possible late effects of cancer treatment (pain and reduced cardiorespiratory fitness) were associated with an increased likelihood of receiving specialized medical care., Conclusions: Survivors with reduced global cognition are at risk for poor health care utilization. Educational practices regarding recommended health care should be personalized to ensure comprehension by survivors with neurocognitive impairment., (© 2014 American Cancer Society.)

Purpose: To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies., Patients and Methods: Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness., Results: The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness., Conclusion: Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes., (© 2015 by American Society of Clinical Oncology.)

Background: Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS., Methods: CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income., Results: Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines., Conclusions: Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS., (© 2014 American Cancer Society.)

Background: Adult survivors of childhood cancer are at risk for suicide ideation, although longitudinal patterns and rates of recurrent suicide ideation are unknown. This study investigated the prevalence of late report (ie, after initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality., Methods: Participants included 9128 adult survivors of childhood cancer and 3082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18 instrument. Mortality data was ascertained from the National Death Index., Results: Survivors were more likely to report late (odds ratio [OR] =1.9, 95% confidence interval [CI] =1.5-2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8-3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3-2.7; recurrent: OR=1.9, 95% CI=1.2-2.9). Suicide ideation was associated with increased risk for all-cause mortality (hazard ratio=1.3, 95% CI=1.03-1.6) and death by external causes (hazard ratio=2.4, 95% CI=1.4-4.1)., Conclusions: Adult survivors of childhood cancer are at risk for late-report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions., (© 2013 American Cancer Society.)

Purpose: Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality., Methods: Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death., Results: The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2)., Conclusion: The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.

Objectives: To ascertain prevalence of peripheral sensory and motor neuropathy, and to evaluate impairments in relation to function., Design: St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer., Setting: A children's research hospital., Participants: Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥ 18 years, ≥ 10 years postdiagnosis, and no history of cranial radiation. Survivors (N=531) were included in the evaluation with a median age of 32 years and a median time from diagnosis of 25 years., Interventions: Not applicable., Main Outcome Measures: Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the Modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific z scores of ≤-1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the Timed Up & Go test (mobility), and the Sensory Organization Test (balance)., Results: The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio [OR]=1.66; 95% confidence interval [CI], 1.04-2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR=1.62; 95% CI, .97-2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99; 95% CI, .99-4.0) and mobility (OR=1.65; 95% CI, .96-2.83)., Conclusions: Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Importance: Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions., Objective: To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer., Design, Setting, and Participants: Presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1713 adult (median age, 32 [range, 18-60] years) survivors of childhood cancer (median time from diagnosis, 25 [range, 10-47] years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012., Main Outcomes and Measures: Age-specific cumulative prevalence of adverse outcomes by organ system., Results: Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% [95% CI, 60.4%-69.8%]), auditory (hearing loss, 62.1% [95% CI, 55.8%-68.2%]), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% [95% CI, 59.5%-64.6%]), cardiac (any cardiac condition, such as heart valve disorders, 56.4% [95% CI, 53.5%-59.2%]), and neurocognitive (neurocognitive impairment, 48.0% [95% CI, 44.9%-51.0%]) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% [95% CI, 10.8%-15.3%]), skeletal (osteoporosis, 9.6% [95% CI, 8.0%-11.5%]), renal (kidney dysfunction, 5.0% [95% CI, 4.0%-6.3%]), and hematopoietic (abnormal blood cell counts, 3.0% [95% CI, 2.1%-3.9%]) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition., Conclusions and Relevance: Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.

Event history studies occur in many fields including economics, medical studies, and social science. In such studies concerning some recurrent events, two types of data have been extensively discussed in the literature. One is recurrent event data that arise if study subjects are monitored or observed continuously. In this case, the observed information provides the times of all occurrences of the recurrent events of interest. The other is panel count data, which occur if the subjects are monitored or observed only periodically. This can happen if the continuous observation is too expensive or not practical, and in this case, only the numbers of occurrences of the events between subsequent observation times are available. In this paper, we discuss a third type of data, which is a mixture of recurrent event and panel count data and for which there exists little literature. For regression analysis of such data, we present a marginal mean model and propose an estimating equation-based approach for estimation of regression parameters. We conduct a simulation study to assess the finite sample performance of the proposed methodology, and the results indicate that it works well for practical situations. Finally, we apply it to a motivating study on childhood cancer survivors., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer., Procedure: Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study (CCSS) using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors' report of prescription medication use., Results: Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR = 1.80, 95% CI = 1.47-2.21), organization (OR = 1.83, 95% CI = 1.48-2.25), memory (OR = 1.53, 95% CI = 1.27-1.84), and emotional regulation (OR = 2.06, 95% CI = 1.70-2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR = 2.46, 95% CI = 1.29-4.69; OR = 2.82, 95% CI = 1.61-4.93, respectively) and memory (OR = 2.08, 95% CI = 1.13-3.82; OR = 2.69, 95% CI = 1.59-4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory, and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS)., Conclusions: These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained., (Copyright © 2012 Wiley Periodicals, Inc.)