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Background: Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes., Methods: Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0-53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0-70.0] years, 55.7% female) completed in-person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form-36 physical/mental summary scores, social attainment)., Results: Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%-29.4%) than controls (2.9%, CI 1.4-4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure <15 mg/m 2 versus none (OR 4.38, CI 1.06-18.08) and etoposide exposure >2036 mg/m 2 versus none (OR 12.61, CI 2.19-72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01-1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68-11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10-0.84, Sensory: OR 0.35, CI 0.13-0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22-5.72)., Conclusions: In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

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.

In this study, the social determinants of patient-reported outcomes (PROs) in young survivors of childhood cancer aged <18 years are researched. This cross-sectional study investigated social determinants associated with poor PROs among young childhood cancer survivors. We included 293 dyads of survivors receiving treatment at St. Jude Children's Research Hospital who were <18 years of age during follow-up from 2017 to 2018 and their primary caregivers. Social determinants included family factors (caregiver-reported PROs, family dynamics) and county-level deprivation (socioeconomic status, physical environment via the County Health Rankings & Roadmaps). PROMIS measures assessed survivors' and caregivers' PROs. General linear regression tested associations of social determinants with survivors' PROs. We found that caregivers' higher anxiety was significantly associated with survivors' poorer depression, stress, fatigue, sleep issues, and reduced positive affect ( p < 0.05); caregivers' sleep disturbances were significantly associated with lower mobility in survivors ( p < 0.05). Family conflicts were associated with survivors' sleep problems ( p < 0.05). Residing in socioeconomically deprived areas was significantly associated with survivors' poorer sleep quality ( p < 0.05), while higher physical environment deprivation was associated with survivors' higher psychological stress and fatigue and lower positive affect and mobility ( p < 0.05). Parental, family, and neighborhood factors are critical influences on young survivors' quality of life and well-being and represent new intervention targets.

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.)

Phase IV clinical trials are designed to monitor long-term side effects of medical treatment. For instance, childhood cancer survivors treated with chest radiation and/or anthracycline are often at risk of developing cardiotoxicity during their adulthood. Often the primary focus of a study could be on estimating the cumulative incidence of a particular outcome of interest such as cardiotoxicity. However, it is challenging to evaluate patients continuously and usually, this information is collected through cross-sectional surveys by following patients longitudinally. This leads to interval-censored data since the exact time of the onset of the toxicity is unknown. Rai et al. computed the transition intensity rate using a parametric model and estimated parameters using maximum likelihood approach in an illness-death model. However, such approach may not be suitable if the underlying parametric assumptions do not hold. This manuscript proposes a semi-parametric model, with a logit relationship for the treatment intensities in two groups, to estimate the transition intensity rates within the context of an illness-death model. The estimation of the parameters is done using an EM algorithm with profile likelihood. Results from the simulation studies suggest that the proposed approach is easy to implement and yields comparable results to the parametric model., Competing Interests: Competing interests The authors declare that they have no competing interests. C.Qian is a current employee of AbbVie Inc. AbbVie Inc. is neither aware of nor a participant in this research work. All opinions in this manuscript represent the author’s own view.

Thoracic radiation is associated with significant cardiopulmonary morbidities in survivors of long-term Hodgkin lymphoma and may affect neurocognitive outcomes. Survivors (N = 204; 52.5% female; mean [standard deviation] age, 36.6 [8.01] years) treated with thoracic radiation and age-, sex-, and race/ethnicity-matched community controls (N = 205; 51.7% female; age, 36.7 [9.17] years) completed standardized neurocognitive testing, echocardiography, pulmonary function tests, and vascular studies during the same visit. Treatments were abstracted from medical records. Cardiac (ie, left ventricular ejection fraction [LVEF], global longitudinal strain [GLS]), vascular (ie, large and small artery elasticity [SAE]), pulmonary (ie, diffusing capacity of the lungs for carbon monoxide [DLCO] and forced expiratory volume [FEV1]), and chronic health conditions were evaluated for associations with age-adjusted neurocognitive performance using multivariable linear regression. Compared with controls, survivors had lower performance (P < 0.05) in visuomotor (0.11 vs 0.41), visual processing speed (0.25 vs 0.64), short-term recall (-0.24 vs 0.12), and flexibility (-0.04 vs 0.28). Survivors had lower pulmonary (FEV1, DLCOcorr), cardiac (LVEF, GLS), and vascular function (SAE) than controls (all P < 0.001). FEV1 was associated with visuomotor (P = .008) and visual processing speed (P = .05), and flexibility (P = .05). GLS was associated with short-term recall (P = .03). SAE was associated with flexibility (P = .007). Neurocognitive outcomes were also associated with moderate-to-severe neurologic chronic conditions (P < .05). Findings suggest a link between subclinical cardiopulmonary and vascular findings, neurologic morbidity, and neurocognitive impairments. Prevention of health morbidity may benefit neurocognitive outcomes., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Identification of biomarkers by integrating multiple omics together is important because complex diseases occur due to an intricate interplay of various genetic materials. Traditional single-omics association tests neither explore this crucial interomics dependence nor identify moderately weak signals due to the multiple-testing burden. Conversely, multiomics data integration imparts complementary information but suffers from an increased multiple-testing burden, data diversity inherent with different omics features, high-dimensionality, and so forth. Most of the available methods address subtype classification using dimension-reduction techniques to circumvent the sample size issue but interacting multiomics biomarker identification methods are unavailable. We propose a two-step model that first investigates phenotype-omics association using logistic regression. Then, selects disease-associated omics using sparse principal components which explores the interrelationship of multiple variables from two omics in a multivariate multiple regression framework. On the basis of this model, we developed a multiomics biomarker identification algorithm, interacting omics search (ioSearch), that jointly tests the effect of multiple omics with disease and between-omics associations by using pathway information that subsequently reduces the multiple-testing burden. Further, inference in terms of p values potentially makes it an easily interpretable biomarker identification tool. Extensive simulation demonstrates ioSearch as statistically powerful with a controlled Type-I error rate. Its application to publicly available breast cancer data sets identified relevant omics features in important pathways., (© 2023 Wiley Periodicals LLC.)

Background: Exercise intolerance among childhood cancer survivors substantially increases risk for early mortality, reduced cognitive function, poor quality of life, emotional distress, and sub-optimal participation in social roles. Fortunately, exercise intolerance is modifiable, even among individuals with impaired cardiopulmonary and neuromuscular health. This study aims to evaluate the impact of tailored exercise intervention remotely supervised by fitness professionals in survivors with exercise intolerance. Telehealth-based delivery of the intervention aims to enhance uptake by removing the burden of travel and allowing participants to gain confidence with exercise and physical activity at home., Methods: This is an ongoing single-blind, two-arm, prospective, clinical trial that will randomize 160 participants 1:1 to intervention (n = 80) and attention control (n = 80) groups. The intervention group receives an individually tailored exercise prescription based on results from baseline assessments performed remotely via a Health Insurance Portability and Accountability Act-compliant virtual platform and personal preferences for aerobic exercise. Each prescription includes aerobic and strengthening components designed to progress gradually to 150-300-min of moderate aerobic activity and twice weekly strengthening exercises over 20-weeks. The first two weeks are supervised for 6 sessions, tapering to twice/week for weeks 3-4, once/week for weeks 5-8, every other week for weeks 9-16 and once midway between weeks 17-20. The schedule is modifiable depending on participant need, adherence, and response to exercise. Each session is approximately one hour., Conclusion: This study tests the efficacy of an individually prescribed, virtually supervised exercise intervention on exercise intolerant childhood cancer survivors., Clinicaltrials: gov registration: NCT04714840., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Background: Childhood cancer survivors are at elevated risk for poor health-related quality-of-life (HRQOL). Identification of potentially modifiable risk factors associated with HRQOL is needed to inform survivorship care., Methods: Participants included 4294 adult childhood cancer survivors from the St. Jude Lifetime Cohort Study who completed a survey and clinical assessment at entry into the survivorship cohort (baseline) and follow-up (median interval: 4.3 years) between 2007 and 2019. The SF-6D compared utility-based HRQOL of survivors to an independent sample from the U.S. Medical Expenditures Panel Survey. Chronic health conditions (CHCs) were graded using modified Common Terminology Criteria for Adverse Events. General linear models examined cross-sectional and temporal associations of HRQOL with CHC burden (total and by organ-system), adjusting for potential risk factors., Findings: Survivors reported poorer HRQOL compared to the general population (effect size [d] = -0.343). In cross-sectional analyses at baseline, significant non-demographic risk factors included higher total CHC burden (driven by more severe cardiovascular [d = -0.119, p = 0.002], endocrine [d = -0.112, p = 0.001], gastrointestinal [d = -0.226, p < 0.001], immunologic [d = -0.168, p = 0.035], neurologic [d = -0.388, p < 0.001], pulmonary [d = -0.132, p = 0.003] CHCs), public (d = -0.503, p < 0.001) or no health insurance (d = -0.123, p = 0.007), current smoking (d = -0.270, p < 0.001), being physically inactive (d = -0.129, p < 0.001), ever using illicit drugs (d = -0.235, p < 0.001), and worse diet quality (d = -0.004, p = 0.016). In temporal analyses, poorer utility-based HRQOL at follow-up was associated with risk factors at baseline, including higher total CHC burden (driven by cardiovascular [d = -0.152, p = 0.002], endocrine [d = -0.092, p = 0.047], musculoskeletal [d = -0.160, p = 0.016], neurologic [d = -0.318, p < 0.001] CHCs), public (d = -0.415, p < 0.001) or no health insurance (d = -0.161, p = 0.007), current smoking (d = -0.218, p = 0.001), and ever using illicit drugs (d = -0.217, p < 0.001)., Interpretation: Adult survivors report worse utility-based HRQOL than the general population, and potentially modifiable risk factors were associated with HRQOL. Interventions to prevent the early onset of CHCs, promote healthy lifestyle, and ensure access to health insurance in the early survivorship stage may provide opportunities to improve HRQOL., Funding: The research reported in this manuscript was supported by the U.S. National Cancer Institute under award numbers U01CA195547 (Hudson/Ness), R01CA238368 (Huang/Baker), R01CA258193 (Huang/Yasui), R01CA270157 (Bhakta/Yasui), and T32CA225590 (Krull). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies., Competing Interests: All authors declare that they have no competing interests., (© 2023 The Authors.)

Background: The prevalence of diastolic dysfunction has not been systematically evaluated in a large population of survivors of childhood cancer using established guidelines and standards., Objectives: This study sought to assess the prevalence and progression of diastolic dysfunction in adult survivors of childhood cancer exposed to cardiotoxic therapy., Methods: Comprehensive, longitudinal echocardiographic examinations of adult survivors of childhood cancer ≥18 years of age and ≥10 years from diagnosis in SJLIFE (St. Jude Lifetime Cohort Study) were performed. Diastolic dysfunction was defined based on 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines., Results: Among 3,342 survivors, the median (25th-75th percentiles [quartile (Q)1-Q3]) age at diagnosis was 8.1 years (Q1-Q3: 3.6-13.7 years), 30.1 years (Q1-Q3: 24.4-37.0 years) at the baseline echocardiography evaluation (Echo 1), and 36.6 years (Q1-Q3: 30.8-43.6 years) at the last follow-up echocardiography evaluation (1,435 survivors) (Echo 2). The proportion of diastolic dysfunction was 15.2% (95% CI: 14.0%-16.4%) at Echo 1 and 15.7% (95% CI: 13.9%-17.7%) at Echo 2, largely attributable to concurrent systolic dysfunction. Less than 5% of survivors with preserved ejection fraction had diastolic dysfunction (2.2% at Echo 1, 3.7% at Echo 2). Using global longitudinal strain assessment in adult survivors with preserved ejection fraction (defined with a cutpoint worse than -15.9%), the proportion of diastolic dysfunction increased to 9.2% at baseline and 9.0% at follow-up., Conclusions: The prevalence of isolated diastolic dysfunction is low among adults who received cardiotoxic therapies for childhood cancer. The inclusion of left ventricular global longitudinal strain significantly increased the identification of diastolic dysfunction., Competing Interests: Support to St. Jude Children’s Research Hospital was provided by National Cancer Institute grant U01 CA195547 (Drs Ness and Hudson [principal investigators]), the Cancer Center Support grant P30 CA21765 (Dr Roberts [principal investigator), and the American Lebanese-Syrian Associated Charities. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas., Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?, Methods: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys., Results: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups., Conclusion: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

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.

Background: Over 50% of childhood cancer survivors are exercise intolerant, with maximal aerobic capacities comparable to individuals decades older, suggesting early physiologic ageing. In addition, 36% of survivors are obese. Optimal exercise capacity provides a foundation to support daily function and healthy body habitus and is associated with benefits to cognition, cardiovascular health, and longevity. Cellular senescence and inflammation are key mechanisms that drive age-related disease, quantifiable as biomarkers in peripheral blood., Aims: This study aimed to evaluate associations between p16 INKa , a biomarker of cellular senescence, and inflammation and exercise capacity among adult survivors of childhood cancer., Materials and Methods: Eligible survivors were recruited from the St. Jude Lifetime (SJLIFE) Cohort Study. Exercise capacity was assessed by maximal oxygen uptake (VO 2 , ml/kg/min) obtained via cardiopulmonary exercise testing using a modified Bruce protocol. Body fat (%) was determined from dual energy x-ray absorptiometry (DEXA). Peripheral blood samples were used to evaluate log 2 p16 INK4a mRNA expression, a biomarker of cellular senescence, and inflammation with high sensitivity C-reactive protein (hs-CRP) levels. Multivariable regression evaluated associations between p16 INK4a , hs-CRP, body fat, and exercise capacity., Results: Participants included 185 five-year childhood cancer survivors (mean age 36.6 [range 20.1 - 55.7] years, 44% male, 77% non-Hispanic white, 53% leukemia/lymphoma). Compared to males, females had lower peak VO 2 (mean ± SD, 22.5 ± 8.2 vs. 28.8 ± 7.7 ml/kg/min, p<0.01), higher p16 INK4a expression (9.6 ± 1.2 vs. 9.2 ± 1.2 fold, p=0.02), and hs-CRP concentration (5.9 ± 8.4 vs. 3.3 ± 3.9 mg/L, p=0.01). Among females (n=103), hs-CRP concentration (β -0.2, 95% CI -0.34 to -0.05, p=0.01) and p16 INK4a expression (β-5.32, 95% CI 10.42 to -0.22, p=0.04) were inversely associated and statistically significant with peak exercise capacity, with a significant interaction between p16 INK4a expression and body fat (β 0.15, 95% CI 0.02 to 0.28, p=0.03). Among males (n=82), p16 INK4a expression (β -1.01, 95% CI -2.14 to 0.12, p=0.08), and body fat (β -0.54, 95% CI -0.70 to -0.38, p<0.01) were inversely associated with peak exercise capacity., Conclusion: Inflammation and p16 INK4a expression, a biomarker of cellular senescence, are associated with lower exercise capacity in childhood cancer survivors, suggesting potential targets or outcome measures for interventions designed to prevent or remediate accelerated physiologic ageing in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goodenough, Wogksch, Kundu, Lear, Thomas, Srivastava, Wang, Armstrong, Hudson, Robison and Ness.)

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: Adult survivors of childhood acute lymphoblastic leukemia (ALL) have impaired adaptive physical function and poor health-related quality of life (HRQoL). Obesity may contribute to these impairments by increasing the physiological cost of walking. Due to treatment exposures during ALL therapy, survivors' cost of walking may be more impacted by obesity than the general population. Therefore, we examined associations between obesity, persistent motor neuropathy, and energy cost of walking; and examined associations between energy cost of walking, adaptive physical function, and HRQoL, in adult survivors of childhood ALL vs. community controls., Methods: Obesity was measured via body mass index (BMI) and body fat percentage. The physiological cost index (PCI) was calculated from the six-minute walk test. Adaptive physical functioning was measured using two tests: the timed up and go (TUG) test and the physical performance test. Persistent motor neuropathy was measured using the modified total neuropathy score; HRQoL was measured using the Short-Form-36 questionnaire. The associations between obesity and PCI were evaluated using multivariable linear regressions in adult survivors of childhood ALL ( n  = 1,166) and community controls ( n  = 491). Then, the associations between PCI, adaptive physical functioning and peripheral neuropathy were examined using multivariable linear regressions. Finally, to determine the association between obesity, and neuropathy on PCI, while accounting for potential lifestyle and treatment confounders, a three model, sequential linear regression was used., Results: Obese individuals (BMI > 40 kg/m 2 and excess body fat percentage [males: >25%; females: >33%]) had higher PCI compared to those with normal BMI and body fat percentage (0.56 ± 0.01 vs. 0.49 ± 0.009 beats/meter p  < .01; and 0.51 ± 0.007 vs. 0.48 ± .0006 beats/meter p  < .01, respectively). Treatment exposures did not attenuate this association. Increased PCI was associated with longer TUG time in survivors, but not community controls (6.14 ± 0.02 s vs. 5.19 ± 0.03 s, p  < .01). Survivors with PCI impairment >95th percentile of community controls had lower HRQoL compared to un-impaired ALL survivors: 46.9 ± 0.56 vs. 50.4 ± 1.08, respectively ( p  < .01)., Conclusion: Obesity was associated with increased PCI. Survivors with high PCI had disproportionately worse adaptive physical function and HRQoL compared to controls. Survivors with increased energy costs of walking may benefit from weight loss interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Wogksch, Finch, Nolan, Smeltzer, Mzayek, Goodenough, Pui, Inaba, Mulrooney, Kaste, Brinkman, Lanctot, Srivastava, Jefferies, Armstrong, Robison, Hudson and Ness.)

Background: Patients with pediatric leukemia and sickle cell disease are at risk for developing osteonecrosis (ON), a disease that can result in pain, loss of function, and disability. Hip core decompression surgery is an option aimed to prevent femoral head collapse and avoid future arthroplasty., Objective: Describe functional outcomes and gait quality among a young population with hip ON before and after hip core decompression., Methods: Study included participants with hip ON secondary to treatment for hematologic malignancy or sickle cell disease, between 8 and 29 years old, requiring hip core decompression surgery. At one-year follow-up, 13 participants (9 male, median age 17 years) completed the Functional Mobility Assessment (FMA), range of motion, and GAITRite ® testing., Results: Participants demonstrated improved mobility and endurance on the FMA at 1-year post-operatively compared to pre-operatively, with higher scores for time on the Timed Up and Go (mean FMA score = 2.92 [SD = 1.32] vs. 2.07 [SD = 1.70]), time on the Timed Up and Down Stairs (3.69 [0.85] vs. 2.92 [1.66]), and 9-Minute Walk Test scores for distance walked (2.69 [0.63] vs. 2.23 [0.93]) and heart rate (4.54 [0.66] vs. 3.31 [1.38]). GAITRite ® analysis also showed improvements in many gait parameters at one-year follow-up., Limitations: Cancer treatment complications other than ON could have contributed to results, not all eligible participants agreed to participate, and follow-up was only one year., Conclusions: Young patients with hip ON demonstrated improvements in functional mobility, endurance, and gait quality one year following hip core decompression., Competing Interests: Conflicts of Interest: All authors have declared no conflicts of interest.

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: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes., Methods: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored., Results: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12)., Conclusions: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further., (© 2021 American Cancer Society.)

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: Childhood cancer survivors are at elevated risk for motor and/or sensory neuropathy. The study aims to evaluate the concordance between self-report peripheral neuropathy compared with clinically ascertained peripheral neuropathy, and to identify factors associated with misclassification of peripheral neuropathy among survivors., Methods: The concordance between self-report and clinically ascertained peripheral neuropathy was evaluated among 2,933 5+ years old childhood cancer survivors (mean age 33.3, SD = 8.9). The sensitivity, specificity, and accuracy of self-report peripheral motor neuropathy (PMN) and peripheral sensory neuropathy (PSN) were calculated with reference to clinically assessed peripheral neuropathy., Results: Female survivors were more likely than male survivors to have clinically ascertained PMN (8.4% vs. 5.6%, P = 0.004). For females, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (43.2%, 90.3%, and 85.2%, respectively), with kappa of 0.304. For males, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (38.8%, 90.5%, and 86.3%, respectively) with kappa of 0.242. Age at diagnosis, emotional distress, and reporting pain in legs in the past 4 weeks were associated with an increased risk for false-positive reporting of peripheral neuropathy. Race (White), age at assessment, and emotional distress were associated with increased risk for false-negative reporting of peripheral neuropathy., Conclusions: Agreement between self-report and clinically ascertained peripheral neuropathy was poor in survivors. Choosing self-report versus clinical ascertained peripheral neuropathy should be carefully considered., Impact: The current study identifies the need for a self-report questionnaire that accurately assesses symptoms of peripheral neuropathy among cancer survivors., (©2021 American Association for Cancer Research.)

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.)

Clinical trials with survival endpoints are typically designed to enroll patients for a specified number of years, (usually 2-3 years) with another specified duration of follow-up (usually 2-3 years). Under this scheme, patients who are alive or free of the event of interest at the termination of the study are censored. Consequently, a patient may be censored due to insufficient follow-up duration or due to being lost to follow-up. Potentially, this process could lead to unequal censoring in the treatment arms and lead to inaccurate and adverse conclusions about treatment effects. In this article, using extensive simulation studies, we assess the impact of such censorings on statistical procedures (the generalized logrank tests) for comparing two survival distributions and illustrate our observations by revisiting Mukherjee et al.'s 1 findings of cardiovascular events in patients who took Rofecoxib (Vioxx).

Background: Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated., Methods: Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross-sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement., Results: For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross-sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P < .05), attention (attention span and risk taking; all P < .05), and processing speed (visual motor coordination, visual speed, and motor speed; all P < .05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P = .01) and slower motor speed (P = .02), which persisted throughout the treatment., Conclusions: Overweight/obesity was significantly associated with neurocognitive impairment during long-term follow-up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk., (© 2021 American Cancer Society.)

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.)

Background: It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions., Methods: We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA., Results: By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10 -8 ). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA)., Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.

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 exposed to cardiotoxic therapies are at significant cardiovascular risk. The utility of cardiac biomarkers for identifying the risk of future cardiomyopathy and mortality is unknown., Methods: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were assessed in 1213 adults 10 or more years from a childhood cancer diagnosis; 786 were exposed to anthracycline chemotherapy and/or chest-directed radiation therapy (RT). NT-proBNP values above age- and sex-specific 97.5th percentiles were considered abnormal. Generalized linear models estimated cross-sectional associations between abnormal NT-proBNP and anthracycline or chest RT doses as risk ratios with 95% confidence intervals (CIs). A Poisson distribution estimated rates and a Cox proportional hazards model estimated hazard ratios (HRs) for future cardiac events and death., Results: At a median age of 35.5 years (interquartile range, 29.8-42.5 years), NT-proBNP and cTnT were abnormal in 22.5% and 0.4%, respectively. Exposure to chest RT and exposure to anthracycline chemotherapy were each associated with a dose-dependent increased risk for abnormal NT-proBNP (P for trend <.0001). Among exposed survivors with no history of Common Terminology Criteria for Adverse Events-graded cardiomyopathy and with normal systolic function, survivors with abnormal NT-proBNP had higher rates per 1000 person-years of cardiac mortality (2.93 vs 0.96; P < .0001) and future cardiomyopathy (32.10 vs 15.98; P < .0001) and an increased risk of future cardiomyopathy (HR, 2.28; 95% CI, 1.28-4.08) according to a multivariable assessment., Conclusions: Abnormal NT-proBNP values were prevalent and, among survivors who were exposed to cardiotoxic therapy but did not have a history of cardiomyopathy or current systolic dysfunction, identified those at increased risk for future cardiomyopathy. Further longitudinal studies are needed to confirm this novel finding., (© 2020 American Cancer Society.)

Background: Childhood cancer survivors are at risk for cardiovascular morbidity and mortality that is not fully explained by cancer-directed therapies. We examined the contribution of emotional stress and distress to cardiac health in adult survivors of childhood cancer., Methods: Participants included 3,267 adult survivors enrolled in the St. Jude Lifetime Cohort Study [median (range) 29.9 (18.1-64.5) years of age; 7.7 (0-24.8) years at diagnosis; 48.4% female]. Survivors completed comprehensive medical assessments and standardized measures of depression, anxiety, posttraumatic stress symptoms (PTSS), and perceived stress. Cardiovascular-related conditions included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia, myocardial infarction (severity graded 0-4), and metabolic syndrome (yes/no). Multivariable modified Poisson models examined associations between symptoms of stress/distress and cardiovascular outcomes. Longitudinal associations between stress/distress and new-onset cardiovascular outcomes, defined as a change from grade ≤1 at initial evaluation to grade ≥2 at follow-up (median 3.9 years) were examined in 1,748 participants., Results: In multivariable cross-sectional models, stress/distress was associated with hypertension [risk ratio (RR) = 1.24; 95% confidence interval (CI), 1.07-1.43], dyslipidemia (RR = 1.29; 95% CI, 1.03-1.61), and metabolic syndrome (RR = 1.35; 95% CI, 1.17-1.54) independent of known cardiovascular risk factors. In longitudinal models, stress/distress was associated with new-onset dysrhythmia (RR = 2.87; 95% CI, 1.21-6.78), perceived stress with hypertension (RR = 1.42; 95% CI, 1.04-1.95), and PTSS and anxiety with dyslipidemia (RR = 1.72; 95% CI, 1.13-2.62; RR = 1.54; 95% CI, 1.01-2.35, respectively)., Conclusions: Stress/distress is independently associated with adverse cardiovascular outcomes among childhood cancer survivors., Impact: Improving psychological health may serve as a potential intervention target for optimizing cardiac health among childhood cancer survivors., (©2020 American Association for Cancer Research.)

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.)

For the analysis of ultrahigh-dimensional data, the first step is often to perform screening and feature selection to effectively reduce the dimensionality while retaining all the active or relevant variables with high probability. For this, many methods have been developed under various frameworks but most of them only apply to complete data. In this paper, we consider an incomplete data situation, case II interval-censored failure time data, for which there seems to be no screening procedure. Basing on the idea of cumulative residual, a model-free or nonparametric method is developed and shown to have the sure independent screening property. In particular, the approach is shown to tend to rank the active variables above the inactive ones in terms of their association with the failure time of interest. A simulation study is conducted to demonstrate the usefulness of the proposed method and, in particular, indicates that it works well with general survival models and is capable of capturing the nonlinear covariates with interactions. Also the approach is applied to a childhood cancer survivor study that motivated this investigation., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.)

Background: We aimed to characterize body composition, metabolic impairments, and physical performance among survivors of pediatric abdominal and pelvic solid tumors., Methods: Participants included 431 survivors of abdominal or pelvic tumors [median attained age = 29.9 (range: 18.7-55.1) years]. Relative lean mass and fat mass were assessed with dual X-ray absorptiometry. Metabolic outcomes [insulin resistance (IR), high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides] were based on laboratory values and medication usage. General linear regression evaluated associations between treatment and lifestyle with body composition; binomial regression evaluated associations between body composition and metabolic outcomes and physical performance., Results: Lean mass was lower than values from the National Health and Nutrition Examination Survey (NHANES) in males (Z-score = -0.67 ± 1.27; P < 0.001) and females (Z-score = -0.72 ± 1.28; P < 0.001). Higher cumulative abdominal and pelvic radiation doses were associated with lower lean mass among males [abdominal: β = -0.22 (SE) ± 0.07; P = 0.002 and pelvic: β = -0.23 ± 0.07; P = 0.002] and females (abdominal: β = -0.30 ± 0.09; P = 0.001 and pelvic: β = -0.16 ± 0.08; P = 0.037). Prevalence of IR (40.6% vs. 33.8%; P = 0.006), low HDL (28.9% vs. 33.5%; P = 0.046), and high triglycerides (18.4% vs. 10.0%; P < 0.001) was increased among survivors relative to NHANES. Compared with survivors with normal/high lean mass and normal/low fat mass, survivors with normal/high lean mass and high fat mass had an increased risk of IR ( P < 0.001), low HDL ( P < 0.001), reduced quadriceps strength at 60°/second ( P < 0.001) and 300°/second ( P < 0.001), and reduced distance covered in the 6-minute walk ( P < 0.01)., Conclusions: Abdominal/pelvic radiotherapy is associated with body composition changes that can adversely influence metabolic outcomes and performance status among survivors., Impact: Interventions targeting body composition may facilitate management of cardiovascular disease risk in this population., (©2020 American Association for Cancer Research.)

Background: Because of unknown features of the COVID-19 and the complexity of the population affected, standard clinical trial designs on treatments may not be optimal in such patients. We propose two independent clinical trials designs based on careful grouping of patient and outcome measures., Methods: Using the World Health Organization ordinal scale on patient status, we classify treatable patients (Stages 3-7) into two risk groups. Patients in Stages 3, 4 and 5 are categorized as the intermediate-risk group, while patients in Stages 6 and 7 are categorized as the high-risk group. To ensure that an intervention, if deemed efficacious, is promptly made available to vulnerable patients, we propose a group sequential design incorporating four factors stratification, two interim analyses, and a toxicity monitoring rule for the intermediate-risk group. The primary response variable (binary variable) is based on the proportion of patients discharged from hospital by the 15 th day. The goal is to detect a significant improvement in this response rate. For the high-risk group, we propose a group sequential design incorporating three factors stratification, and two interim analyses, with no toxicity monitoring. The primary response variable for this design is 30 day mortality, with the goal of detecting a meaningful reduction in mortality rate., Results: Required sample size and toxicity boundaries are calculated for each scenario. Sample size requirements for designs with interim analyses are marginally greater than ones without. In addition, for both the intermediate-risk group and the high-risk group, the required sample size with two interim analyses is almost identical to analyses with just one interim analysis., Conclusions: We recommend using a binary outcome with composite endpoints for patients in Stage 3, 4 or 5 with a power of 90% to detect an improvement of 20% in the response rate, and a 30 day mortality rate outcome for those in Stage 6 or 7 with a power of 90% to detect 15% (effect size) reduction in mortality rate. For the intermediate-risk group, two interim analyses for efficacy evaluation along with toxicity monitoring are encouraged. For the high-risk group, two interim analyses without toxicity monitoring is advised.

Background: Adult survivors of childhood osteosarcoma and Ewing sarcoma are at risk of developing therapy-related chronic health conditions. We characterized the cumulative burden of chronic conditions and health status of survivors of childhood bone sarcomas., Methods: Survivors ( n = 207) treated between 1964 and 2002 underwent comprehensive clinical assessments (history/physical examination, laboratory analysis, and physical and neurocognitive testing) and were compared with community controls ( n = 272). Health conditions were defined and graded according to a modified version of the NCI's Common Terminology Criteria for Adverse Events and the cumulative burden estimated., Results: Osteosarcoma and Ewing sarcoma survivors [median age 13.6 years at diagnosis (range 1.7-24.8); age at evaluation 36.6 years (20.7-66.4)] demonstrated an increased prevalence of cardiomyopathy (14.5%; P < 0.005) compared with controls. Nearly 30% of osteosarcoma survivors had evidence of hypertension. By age 35 years, osteosarcoma and Ewing sarcoma survivors had, on average, 12.0 (95% confidence interval, 10.2-14.2) and 10.6 (8.9-12.6) grade 1-4 conditions and 4.0 (3.2-5.1) and 3.5 (2.7-4.5) grade 3-4 conditions, respectively, compared with controls [3.3 (2.9-3.7) grade 1-4 and 0.9 (0.7-1.0) grade 3-4]. Both survivor cohorts exhibited impaired 6-minute walk test, walking efficiency, mobility, strength, and endurance ( P < 0.0001). Accumulation of ≥4 grade 3-4 chronic conditions was associated with deficits in executive function [RR: osteosarcoma 1.6 (1.0-2.4), P = 0.049; Ewing sarcoma 2.0 (1.2-3.3), P = 0.01] and attention [RR: osteosarcoma 2.3 (1.2-4.2); P = 0.008]., Conclusions: Survivors of osteosarcoma and Ewing sarcoma experience a high cumulative burden of chronic health conditions, with impairments of physical function and neurocognition., Impact: Early intervention strategies may ameliorate the risk of comorbidities in bone sarcoma survivors., (©2020 American Association for Cancer Research.)

Purpose: This cross-sectional study compared breastfeeding outcomes among childhood cancer survivors to those of women in the general population and evaluated whether breastfeeding is adversely affected by cancer treatment or endocrine-related late effects., Methods: A self-reported survey ascertained breastfeeding practices and incorporated items from the questionnaires used in the Infant Feeding Practices Study II (IFPS II) to allow comparison with the general population. Among 710 eligible survivors, 472 (66%) responded. The participants were predominantly non-Hispanic White (84%), married (73%), and had some college or less (60%). The mean maternal age at the time of birth of the first child after cancer treatment was 24 years (SD 24.3 ± 4.8)., Results: Fewer survivors planned to breastfeed than did IFPS II controls (67% vs. 82%, P < .0001), and fewer survivors initiated breastfeeding (66% vs. 85%, P < .0001). The median breastfeeding duration was shorter among survivors, with early undesired weaning occurring sooner in the survivor group (1.4 months, interquartile range (IQR) 0.5-3.5 months) than in the IFPS II group (2.7 months, IQR 0.9-5.4 months). A higher proportion of survivors reported an unfavorable breastfeeding experience (19% vs. 7.5%, P < .0001) and early, undesired weaning (57.5%, 95% CI 51-64) than did IFPS II participants (45.2%, 95% CI 44-47, P = .0164). Among survivors who expressed intention and chose to breastfeed, 46% endorsed disrupted lactation related to physiologic problems with high risk in those overweight/obese., Conclusions: Survivors are at risk of negative breastfeeding experiences; however, lactation outcomes were not significantly associated with cancer diagnosis, treatments, or endocrine complications., Implications for Cancer Survivors: Prior research has not examined the association of cancer treatments and clinically validated late effects with lactation outcomes in a clinically diverse childhood cancer survivor cohort. Findings from this study suggest that childhood cancer survivors, especially those who are overweight/obese, are at risk of having negative breastfeeding experiences. Early undesired weaning, physiologic problems related to lactation and misconceptions about breastfeeding, especially fears of passing on cancer through breastmilk, highlight the need for counseling and specialized support to optimize lactation outcomes in this vulnerable population.

Importance: Exercise intolerance is associated with increased risk for morbidity and mortality in childhood cancer survivors. However, an association between exercise intolerance and psychosocial outcomes has not been fully explored., Objective: To examine the associations between exercise intolerance and emotional distress, attainment of social roles, and health-related quality of life in childhood cancer survivors., Design, Setting, and Participants: A cross-sectional study including 1041 adult survivors of childhood cancer and 286 community controls in the St Jude Lifetime Cohort was conducted at St Jude Children's Research Hospital. The study was performed from April 1, 2012, to March 15, 2020., Exposures: Exercise intolerance was defined as relative peak oxygen uptake less than 85% of age- and sex-estimated levels from maximal cardiopulmonary exercise testing., Main Outcomes and Measures: Emotional distress was measured with the 18-item Brief Symptom Inventory-18, which includes overall Global Severity Index and depression, anxiety, and somatization subscales. Participants with T scores greater than or equal to 63 were classified as having elevated levels of distress. Social attainment was evaluated using patient-reported educational, employment, and marital status. Health-related quality of life was examined with the Medical Outcomes Survey Short Form-36. Participants with T scores less than or equal to 40 were classified as reporting poor health-related quality of life., Results: Of the 1041 participants, 528 were women (50.7%). The prevalence of exercise intolerance among survivors (mean [SD] age, 35.5 [9.2] years) was higher than that among controls (age, 34.5 [10.0] years) (survivors: 634 [60.9%] vs controls: 75 [26.2%], P < .001). After adjusting for age at diagnosis and cardiopulmonary exercise testing, sex, race/ethnicity, smoking, physical activity, and exercise intolerance were associated with an increased risk for anxiety (prevalence rate ratio [PRR], 1.95; 95% CI, 1.20-3.16), somatization (PRR, 1.86; 95% CI, 1.23-2.80), and unemployment (PRR, 1.76; 95% CI, 1.23-2.52); an inverse association was noted with having a college degree (PRR, 0.67; 95% CI, 0.50-0.88). Exercise intolerance was associated with an increased the risk for scoring less than or equal to 40 on the physical component summary of the Medical Outcomes Survey Short Form-36 (PRR, 3.69; 95% CI, 2.34-5.84). These associations persisted when either cancer treatment exposures or chronic health conditions were added to the model., Conclusions and Relevance: The findings of this study suggest that exercise intolerance is independently associated with emotional distress, attainment of social roles, and health-related quality of life of long-term survivors of childhood cancer. The results also suggest that improving physiologic capacity may benefit general health and wellness, as well as emotional health, ability to participate in social roles, and health-related quality of life.

Background: Glucocorticoids used to treat childhood leukemia and lymphoma can result in osteonecrosis, leading to physical dysfunction and pain. Improving survival rates warrants research into long-term outcomes among this population., Objective: The objective of this study was to compare the physical function and quality of life (QOL) of survivors of childhood cancer who had an osteonecrosis history with that of survivors who had no osteonecrosis history and with that of people who were healthy (controls)., Design: This was a cross-sectional study., Methods: This study included St Jude Lifetime Cohort Study participants who were ≥ 10 years from the diagnosis of childhood leukemia or lymphoma and ≥ 18 years old; 135 had osteonecrosis (52.5% men; mean age = 27.7 [SD = 6.08] years) and 1560 had no osteonecrosis history (52.4% men; mean age = 33.3 [SD = 8.54] years). This study also included 272 people who were from the community and who were healthy (community controls) (47.7% men; mean age = 35.1 [SD = 10.46] years). The participants completed functional assessments and questionnaires about QOL., Results: Survivors with osteonecrosis scored lower than other survivors and controls for dorsiflexion strength (mean score = 16.50 [SD = 7.91] vs 24.17 [SD = 8.61] N·m/kg) and scored lower than controls for flexibility with the sit-and-reach test (20.61 [SD = 9.70] vs 23.96 [SD = 10.73] cm), function on the Physical Performance Test (mean score = 22.73 [SD = 2.05] vs 23.58 [SD = 0.88]), and mobility on the Timed "Up & Go" Test (5.66 [SD = 2.25] vs 5.12 [SD = 1.28] seconds). Survivors with hip osteonecrosis requiring surgery scored lower than survivors without osteonecrosis for dorsiflexion strength (13.75 [SD = 8.82] vs 18.48 [SD = 9.04] N·m/kg), flexibility (15.79 [SD = 8.93] vs 20.37 [SD = 10.14] cm), and endurance on the 6-minute walk test (523.50 [SD = 103.00] vs 572.10 [SD = 102.40] m)., Limitations: Because some eligible survivors declined to participate, possible selection bias was a limitation of this study., Conclusions: Survivors of childhood leukemia and lymphoma with and without osteonecrosis demonstrated impaired physical performance and reported reduced QOL compared with controls, with those requiring surgery for osteonecrosis most at risk for impairments. It may be beneficial to provide strengthening, flexibility, and endurance interventions for patients who have pediatric cancer and osteonecrosis for long-term function., (© 2020 American Physical Therapy Association.)

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.