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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. [ABSTRACT FROM AUTHOR]

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/m2 versus none (OR 4.38, CI 1.06–18.08) and etoposide exposure >2036 mg/m2 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 p16INKa, 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 (VO2, ml/kg/min) obtained via cardiopulmonary exercise testing using a modified Bruce protocol. Body fat (%) was determined fromdual energy xray absorptiometry (DEXA). Peripheral blood samples were used to evaluate log2 p16INK4a mRNA expression, a biomarker of cellular senescence, and inflammation with high sensitivity C-reactive protein (hs-CRP) levels. Multivariable regression evaluated associations between p16INK4a, 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 VO2 (mean ± SD, 22.5 ± 8.2 vs. 28.8 ± 7.7 ml/kg/min, p<0.01), higher p16INK4a 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 p16INK4a 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 p16INK4a expression and body fat (β 0.15, 95% CI 0.02 to 0.28, p=0.03). Among males (n=82), p16INK4a expression (β -1.01, 95% CI -2.14 to 0.12, p=0.08), and body fat (b -0.54, 95% CI -0.70 to -0.38, p<0.01) were inversely associated with peak exercise capacity. Conclusion: Inflammation and p16INK4a 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (kw = 0.20 and kw = 0.22, respectively; p < 0.0001) and poor for SE measures (kw = 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. [ABSTRACT FROM AUTHOR]

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. Chest radiation therapy increases the risk of concentric left ventricular remodeling as assessed by echocardiography, but anthracycline therapy does not increase the risk of concentric remodeling. Adult survivors of childhood cancer who have concentric remodeling are more likely to have a relative peak oxygen uptake <85% compared with survivors who have normal left ventricular geometry. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Cancer‐related worry is common among long‐term survivors of childhood cancer. It is associated with treatment exposures, chronic medical conditions, psychological and somatic symptoms, and maladaptive health behaviors. Cancer‐related worry is a modifiable construct that can be targeted via psychosocial interventions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. In this longitudinal cohort study including 1213 adult survivors of childhood cancer, nearly 25% have an abnormal N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) value for age and sex at the baseline. Among survivors exposed to cardiotoxic therapy who have a normal ejection fraction at the baseline, those with an abnormal NT‐proBNP value have more than twice the risk of future cardiomyopathy; this is a significant finding. [ABSTRACT FROM AUTHOR]

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

BACKGROUND: The purpose of this study was to examine the prevalence and predictors of social difficulties in adolescent survivors of central nervous system (CNS) tumors. METHODS: Six hundred sixty‐five survivors of CNS tumors (53.8% male and 51.7% treated with cranial radiation therapy [CRT]), who had a current median age of 15.0 years (range, 2.0‐17.0 years) and were a median of 12.1 years (range, 8.0‐17.7 years) from their diagnosis, were compared with 1376 survivors of solid tumors (50.4% male), who had a median age of 15.0 years (range, 12.0‐17.0 years) and were a median of 13.2 years (range, 8.3‐17.9 years) from their diagnosis, and 726 siblings (52.2% male), who had a median age of 15.0 years (range, 12.0‐17.0 years). Social adjustment was measured with parent‐proxy responses to the Behavior Problems Index. Latent profile analysis defined social classes. Multinomial logistic regression, adjusted for age, sex, and age at diagnosis, identified predictors of class membership. Path analyses tested mediating effects of physical limitations, sensory loss, and cognitive impairment on social outcomes. RESULTS: Caregivers reported that survivors of CNS tumors were more likely to have 0 friends (15.3%) and to interact with friends less than once per week (41.0%) in comparison with survivors of solid tumors (2.9% and 13.6%, respectively) and siblings (2.3% and 8.7%, respectively). Latent profile analysis identified 3 social classes for survivors of CNS tumors: well‐adjusted (53.4%), social deficits (16.2%), and poor peer relationships (30.4%). However, 2 classes were identified for survivors of solid tumors and siblings: well‐adjusted (86.2% and 91.1%, respectively) and social deficits (13.8% and 8.9%, respectively). CRT predicted class membership for CNS survivors (odds ratio [OR] for poor peer relationships, 1.16/10 Gy; 95% confidence interval [CI], 1.08‐1.25; OR for social deficits 1.14/10 Gy; 95% CI, 1.04‐1.25; reference, well‐adjusted). Cognitive impairment mediated the association between all social outcomes and CRT (P values <.001). CONCLUSION: Almost 50% of survivors of CNS tumors experience social difficulties; the pattern is unique in comparison with solid tumor and sibling groups. Cognitive impairment is associated with increased risk, and this highlights the need for multitargeted interventions. Almost 50% of survivors of pediatric central nervous system tumors experience social difficulties; the pattern is unique in comparison with solid tumor and sibling groups. Cognitive impairment is associated with increased risk, and this highlights the need for multitargeted interventions. [ABSTRACT FROM AUTHOR]

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

Objective: Disrupted sleep is common in pediatric cancer, which is associated with psychological distress and may impact neural recovery. Information regarding sleep during pediatric brain tumor treatment is limited. This study aimed to describe objective sleep-wake patterns and examine the sleep-mood relation in youth hospitalized for intensive chemotherapy and stem cell rescue.Methods: Participants included 37 patients (M age = 9.6 ± 4.2 years) enrolled on a medulloblastoma protocol (SJMB03) and their parents. Respondents completed a mood disturbance measure on 3 days, and patients wore an actigraph for 5 days as an objective estimate of sleep-wake patterns. General linear mixed models examined the relation between nocturnal sleep and next-day mood, as well as mood and that night's sleep.Results: Sleep duration was deficient, sleep efficiency was poor, and daytime napping was common, with large between-subjects variability. There were minimal mood concerns across all days. The sleep and next-day mood relationship was nonsignificant (P > .05). Greater parent-reported child mood disturbance on day 2 was associated with decreased same-night sleep (P < .001) and greater patient-reported mood disturbance was associated with greater same-night sleep latency (P = .036).Conclusions: Patients with medulloblastoma are vulnerable to disturbed sleep during hospitalization, and mood may be an important correlate to consider. Sleep and mood are modifiable factors that may be targeted to maximize daytime functioning. [ABSTRACT FROM AUTHOR]

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

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

Background: Health complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co-occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co-occurring RHBs.Methods: Latent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.Results: Three RHB clusters were identified: a low-risk cluster, an insufficiently active cluster, and a high-risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj ], 1.17; 95% confidence interval [95% CI], 1.06-1.27) and were less likely to be in the high-risk cluster (ORadj , 0.79; 95% CI, 0.69-0.88). Risk factors for membership in the high-risk cluster included psychological distress (ORadj , 2.76; 95% CI, 1.98-3.86), low educational attainment (ORadj , 7.49; 95% CI, 5.15-10.88), income <$20,000 (ORadj , 2.62; 95% CI, 1.93-3.57), being divorced/separated or widowed (ORadj , 1.36; 95% CI, 1.03-1.79), and limb amputation (ORadj , 1.52; 95% CI, 1.03-2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.Conclusions: RHBs co-occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747-2756. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated.Methods: Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported.Results: Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34).Conclusions: A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample. [ABSTRACT FROM AUTHOR]

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

BACKGROUND Childhood cancer survivors (CCSs) are at risk for obesity. The purpose of this project was to determine which clinical measures of body composition are most accurate among CCSs in comparison with dual-energy x-ray absorptiometry (DXA). METHODS The agreement between the body mass index (BMI), skinfold percent body fat, and waist-to-height ratio (WHtR) and DXA was evaluated among 1361 CCSs (mean age, 32.4 ± 7.7 years) 10 or more years after the diagnosis. The sensitivity and specificity of BMI, skinfold, and WHtR obesity classifications were calculated with respect to DXA. Log-binomial regression, stratified by sex, was used to evaluate treatment-related factors for misclassification as nonobese by BMI, skinfolds, and WHtR. RESULTS The mean body fat values were 23.3% ± 7.7% (males) and 32.3% ± 8.1% (females) for skinfolds and 26.9% ± 7.4% (males) and 38.4% ± 7.7% (females) for DXA. Pearson correlations between skinfolds and DXA were high ( R = 0.83 for males, R = 0.84 for females). Skinfolds incorrectly classified 34.5% of obese males and 27.3% of obese females. BMI measures were the least sensitive with false-negative rates of 46.4% (males) and 53.1% (females). Males exposed to abdominal/pelvic radiation were at increased risk for misclassification as nonobese by BMI (relative risk, 1.57; 95% confidence interval, 1.25-1.95). The percentages classified as obese were highest with DXA (males, 63.1%; females, 84.8%) and lowest with BMI (males, 35.7%; females, 39.7%). Although skinfolds and WHtR underestimated the percentage classified as obese in comparison with DXA, the differences were not as large. CONCLUSIONS Findings suggest that skinfolds and WHtR are better than BMI for obesity classification in CCSs. Clinicians should be aware of the high risk of misclassifying obese CCSs as nonobese. Cancer 2015;121:2036-2043. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

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

BACKGROUND Survivors of childhood cancer treated with central nervous system (CNS)-directed therapy may be at risk for poor health care utilization because of neurocognitive deficits. This study examined associations between neurocognitive function and adherence to routine and risk-based medical evaluations in adult survivors exposed to CNS-directed therapy. METHODS Neurocognitive function and health care utilization were assessed in 1304 adult survivors of childhood cancer enrolled in the St. Jude Lifetime Cohort Study. Adherence to recommended care was defined as meeting guidelines published by the Children's Oncology Group. Multivariate models were used to evaluate associations between neurocognitive function and health screenings. Established predictors of health care utilization were included as covariates. Odds ratios (ORs) or prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated for variables maintained in the final models. RESULTS Adherence to recommended medical care was higher for routine care (general physician care, 57.6%; dental care, 49.1%) versus specialized care (survivor-focused care, 21.9%; echocardiogram, 19.9%). Higher intelligence was predictive of general physician care (OR, 1.74; 95% CI, 1.41-2.15) and survivor-focused care (OR, 1.44; 95% CI, 1.13-1.83) in comparison with no care, whereas better executive function skills were associated with reduced dental care (PR, 0.94; 95% CI, 0.91-0.98). Echocardiogram monitoring was not associated with neurocognition. Possible late effects of cancer treatment (pain and reduced cardiorespiratory fitness) were associated with an increased likelihood of receiving specialized medical care. CONCLUSIONS Survivors with reduced global cognition are at risk for poor health care utilization. Educational practices regarding recommended health care should be personalized to ensure comprehension by survivors with neurocognitive impairment. Cancer 2015;121:774-782. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS. METHODS CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income. RESULTS Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines. CONCLUSIONS Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS. Cancer 2014;120:2742-2750. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

In event history studies concerning recurrent events, two types of data have been extensively discussed. One is recurrent-event data (Cook and Lawless, 2007. The Analysis of Recurrent Event Data. New York: Springer), and the other is panel-count data (Zhao and others, 2010. Nonparametric inference based on panel-count data. Test 20, 1–42). In the former case, all study subjects are monitored continuously; thus, complete information is available for the underlying recurrent-event processes of interest. In the latter case, study subjects are monitored periodically; thus, only incomplete information is available for the processes of interest. In reality, however, a third type of data could occur in which some study subjects are monitored continuously, but others are monitored periodically. When this occurs, we have mixed recurrent-event and panel-count data. This paper discusses regression analysis of such mixed data and presents two estimation procedures for the problem. One is a maximum likelihood estimation procedure, and the other is an estimating equation procedure. The asymptotic properties of both resulting estimators of regression parameters are established. Also, the methods are applied to a set of mixed recurrent-event and panel-count data that arose from a Childhood Cancer Survivor Study and motivated this investigation. [ABSTRACT FROM AUTHOR]

BACKGROUND Adult survivors of childhood cancer are at risk for suicide ideation, although longitudinal patterns and rates of recurrent suicide ideation are unknown. This study investigated the prevalence of late report (ie, after initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality. METHODS Participants included 9128 adult survivors of childhood cancer and 3082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18 instrument. Mortality data was ascertained from the National Death Index. RESULTS Survivors were more likely to report late (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.5-2.5) and recurrent suicide ideation (OR = 2.6, 95% CI = 1.8-3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR = 1.9, 95% CI = 1.3-2.7; recurrent: OR = 1.9, 95% CI = 1.2-2.9). Suicide ideation was associated with increased risk for all-cause mortality (hazard ratio = 1.3, 95% CI = 1.03-1.6) and death by external causes (hazard ratio = 2.4, 95% CI = 1.4-4.1). CONCLUSIONS Adult survivors of childhood cancer are at risk for late-report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions. Cancer 2014;120:271-277. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

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

BACKGROUND: Long-term survivors of childhood cancer are at risk for fatigue, sleep problems, and neurocognitive impairment, although the association between these outcomes has not been previously examined. METHODS: Outcomes were evaluated in 1426 survivors from the Childhood Cancer Survivor Study using a validated Neurocognitive Questionnaire. Relative risks for neurocognitive impairment were calculated using demographic and treatment factors, and survivors' report on the Functional Assessment of Chronic Illness Therapy-Fatigue, the Short Form-36 Vitality Scale, the Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. RESULTS: Neurocognitive impairment was identified in >20% of survivors, using sibling-based norms for comparison. Multivariate logistic regression models revealed that fatigue (risk ratio [RR], 1.34; 95% confidence interval [CI], 1.13-1.59), daytime sleepiness (RR, 1.68; 95% CI, 1.55-1.83), poor sleep quality (RR, 1.23; 95% CI, 1.01-1.49), and decreased vitality (RR, 1.75; 95% CI 1.33-2.30) were all associated with impaired task efficiency. Likewise, fatigue (RR, 1.77; 95% CI, 1.23-2.55), sleepiness (RR, 1.38; 95% CI, 1.14-1.67), and decreased vitality (RR, 3.08; 95% CI, 1.98-4.79) were predictive of emotional regulation problems. Diminished organization was associated with increased sleepiness (RR, 1.80; 95% CI, 1.31-2.48) and decreased vitality (RR, 1.90; 95% CI, 1.37-2.63). Impaired memory was associated with poor sleep quality (RR, 1.45; 95% CI, 1.19-1.76), increased sleepiness (RR, 2.05; 95% CI, 1.63-2.58), and decreased vitality (RR, 2.01; 95% CI, 1.42- 2.86). The impact of fatigue, sleepiness, sleep quality, and vitality on neurocognitive outcomes was independent of the effects of cranial radiation therapy, steroids and antimetabolite chemotherapy, sex, and current age. CONCLUSIONS: Neurocognitive function in long-term survivors of childhood cancer appears particularly vulnerable to the effects of fatigue and sleep disruption. These findings suggest sleep hygiene should be emphasized among survivors, as it may provide an additional mechanism for intervention to improve neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Parents of terminally ill children with cancer frequently ask clinicians when their child will die. Such information helps parents prepare for the child''s death. To identify how parents perceived when their child''s cancer-related death would occur, we conducted a secondary analysis of telephone interviews with 49 bereaved parents 6–10 months after their child''s death to extract their descriptions of this occurrence. The parents knew in advance that their child was going to die, but they described when their child''s death would occur in three different ways: anticipated (parents observed changes that alerted them that death was imminent; n =22, 52.4%), surprising (parents were surprised that their child died on that particular day; n =13, 31.0%), and overdue (parents had been waiting for the end of their child''s apparent suffering; n =7, 16.7%). These categories did not differ by patients'' diagnosis, sex, or location of death but differed slightly by symptom patterns. Parents who reported the occurrence of their child''s death as surprising reported fewer symptom changes on the last day of their child''s life, compared with the last week of life, than did the parents in the other two categories. These findings indicate that parents of children with terminal cancer can perceive when their child''s death would occur very differently: Some are surprised, whereas others feel they have waited too long for their child''s release from suffering. Clinicians can use these descriptions and the associated symptom patterns to help families prepare for their child''s last week and last day. [Copyright &y& Elsevier]

Background: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies.Methods: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed.Results: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria).Conclusions: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy of an interactive intervention in reducing distress related to radiation therapy (RT) among pediatric cancer participants as measured by occurrence of sedation, observed behavioral distress (OBD), and heart rate (HR). Methods Seventy-nine children receiving RT simulation were assigned randomly to a STARBRIGHT Hospital Pals group (i.e., interactive intervention group; IG) or modified control group (MCG). The interactive intervention included filmed modeling, exposure to an interactive Barney character, and passive auditory distraction. Results Children in the IG experienced significantly lower HR when compared with MCG participants. No differences were found in terms of sedation or OBD. Conclusions The interactive intervention was effective at reducing RT-related distress (as measured by HR) and would be a useful tool in pediatric radiation oncology settings. [ABSTRACT FROM AUTHOR]

There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction. 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). 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. 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. 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. 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 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. 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. [ABSTRACT FROM AUTHOR]

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. 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. This study tests the efficacy of an individually prescribed, virtually supervised exercise intervention on exercise intolerant childhood cancer survivors. Clinicaltrials.gov registration: NCT04714840. • Childhood cancer survivors are physically inactive, increasing early mortality risk. • Exercise intolerance, poor quality of life, and emotional distress are also prevalent. • A remotely supervised exercise intervention may improve these outcomes in survivors. • This Telehealth-based protocol aims to improve adherence and confidence with exercise. [ABSTRACT FROM AUTHOR]

Abstract: Background: Positive health-related behaviours are essential for the future wellbeing of childhood cancer survivors, though relatively few maintain healthy behaviours into adulthood. Methods: Neurocognitive function and emotional distress were examined in 6,440 adult survivors from the Childhood Cancer Survivor Study, and used to predict rates of expected health-related behaviours. Covariates included cancer diagnosis, age, sex, body mass index, insurance status, income and antidepressant medication use, and multivariable models were constructed adjusting for these factors. Findings: In multivariable regression models, survivors with neurocognitive problems in task efficiency (RR=0.77, 95% CI=0.72–0.84) were less likely to meet the Centers for Disease Control guidelines for weekly physical activity. Survivors with neurocognitive impairment were more likely to engage in general survivor care (RR=1.20, 95% CI=1.10–1.30), and less likely to engage in dental care (RR=0.92, 95% CI=0.88–0.97). Obese survivors were less likely to report receiving a bone density exam (RR=0.67, 95% CI=0.54–0.82), a mammogram (RR=0.71, 95% CI=0.57–0.89), and a skin exam (RR=0.78, 95% CI=0.68–0.89). Survivors reporting somatisation, i.e. vague physical symptoms associated with anxiety, were more likely to report receiving echocardiograms (RR=1.53, 95% CI=1.32–1.77). Interpretation: These results support the link between neurocognitive and emotional problems and health-related behaviours in adult survivors of childhood cancer. Monitoring neurocognitive and emotional outcomes may help to identify survivors at risk for poor adherence to prescribed health behaviours and health screening exams. [Copyright &y& Elsevier]

Abstract: Fatigue is one of the most debilitating conditions associated with cancer and anticancer therapy. The lack of reliable and valid self-report instruments has prevented accurate assessment of fatigue in pediatric oncology patients. The purpose of this study was to identify the most sensitive and specific score, that is, the “cut score,” on the Fatigue Scale-Child (FS-C) to identify those children with high cancer-related fatigue in need of clinical intervention. We first used Rasch methods to identify the items on the FS-C that distinguished children with high cancer-related fatigue from other children; our findings indicated that the FS-C needed to be reduced from 14 items to 10 items. We then assessed the 10-item FS-C for its psychometric properties and applied the receiver operating characteristics curve analysis to the FS-C responses from 221 children (aged 7–12 years) receiving anticancer treatment. The cut score identified with 75% sensitivity and 73.5% specificity was 12; 73 (33%) patients scored 12 or higher. Findings from this validated instrument provide a needed guide for clinicians to interpret fatigue scores and provide clinical interventions for this debilitating condition to their pediatric patients with cancer. [Copyright &y& Elsevier]