The burden of cardiovascular disease and risk for subsequent major adverse cardiovascular events in survivors of childhood cancer: a prospective, longitudinal analysis from the St Jude Lifetime Cohort Study.

BACKGROUND: The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors. METHODS: This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing. FINDINGS: 9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0-31·4) from the date of primary cancer diagnosis (4311 [44.9%] were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9-19·5) compared with 0·9% (0·0-2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23-0·29) events per survivor compared with 0·009 (0·000-0·021) events per community control participant. Increasing cumulative burden of grade 1-4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1-6·0; p<0·0001; two conditions: 6·6, 4·6-9·5; p<0·0001; and three conditions: 7·7, 5·1-11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias [RR 1·5, 95% CI 1·2-2·0; p=0·0017]), grade 2 left ventricular systolic dysfunction (2·2, 1·6-3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2-4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1-2 hypertriglyceridaemia, or grade 1-2 vascular stenosis. INTERPRETATION: Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events. FUNDING: The US National Cancer Institute and the American Lebanese Syrian Associated Charities.

Translating a motivational interviewing intervention for childhood cancer survivors into an eHealth tool: A user-centered design process.

Childhood cancer survivors have a higher risk of developing cardiomyopathy than members of the general population. Screening echocardiograms can facilitate early detection and treatment of cardiomyopathy. Furthermore, motivational interviewing can increase uptake of cardiac screening. However, such approaches are time- and resource-intensive, which limits their reach to the survivors who need them. We describe how we utilized a user-centered design process to translate an in-person motivational interviewing intervention into an eHealth tool to improve cardiac screening among childhood cancer survivors. We used an iterative, three-phase, user-centered design approach: (i) setting the stage (convening advisory boards and reviewing the original intervention), (ii) content programming and development (writing and programming intervention text and flow), and (iii) intervention testing (research team testing and cognitive interviews.) For cognitive interviews, participants were recruited via institutional participant registries and medical records. Data were analyzed using rapid qualitative analysis. During Phase 1, we identified survivor and provider advisors and outlined elements of the in-person intervention to change for the eHealth tool. During Phases 2 and 3, advisors recommended several modifications that guided the final intervention content and flow. Examples include: acknowledging potential hesitation or apprehension surrounding medical screenings, addressing barriers and facilitators to obtaining screening, and improving the tool's usability and appeal. In Phase 3, cognitive interview participants suggested additional refinements to the intervention language. This translation process shows that continued in-depth engagement of community advisors and iterative testing can improve the applicability of an eHealth to survivors' lived experiences and social contexts.

Childhood cancer survivors have a higher-than-average risk for developing heart damage compared to the general population. One-on-one interviews aimed at educating survivors about the importance of screening for heart damage can increase engagement in screening, but these programs are often too resource-intensive to be made available to large groups of survivors. Programs delivered using digital technology, like websites and smartphone apps, can be a more accessible alternative. In this article, we describe how we translated an in-person counseling program into a digital tool. We convened advisors who were childhood cancer survivors and healthcare providers to review the tool throughout the three-phase translation process: (i) setting the stage (convening advisory boards and reviewing original intervention), (ii) content programming and development (writing, and programming intervention text and flow), and (iii) intervention testing (research team testing and cognitive interviews.). Our translation process shows that continuously engaging with advisory boards and testing apps with participants can improve health programs in line with communities' diverse perspectives.

Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.

Lifestyle and Subsequent Malignant Neoplasms in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study.

INTRODUCTION: This study aimed to assess longitudinal associations between lifestyle and subsequent malignant neoplasms (SMNs) in young adult childhood cancer survivors. METHODS: Members of the St. Jude Lifetime Cohort (SJLIFE) aged ≥18 years and surviving ≥5 years after childhood cancer diagnosis were queried and evaluated for physical activity, cardiorespiratory fitness (CRF), muscle strength, body mass index (BMI), smoking, risky drinking, and a combined lifestyle score. Time to first SMN, excluding nonmalignant neoplasms and nonmelanoma skin cancer, was the outcome of longitudinal analysis. RESULTS: Survivors (n = 4072, 47% female, 29% smokers, 37% risky drinkers, 34% obese, and 48% physically inactive) had a mean (SD) time between baseline evaluation and follow-up of 7.0 (3.3) years, an age of 8.7 (5.7) years at diagnosis, and an age of 30 (8.4) years at baseline lifestyle assessment. Neither individual lifestyle factors nor a healthy lifestyle score (RR 0.8, 0.4-1.3, p = 0.36) were associated with the risk of developing an SMN. CONCLUSIONS: We did not identify any association between lifestyle factors and the risk of SMN in young adult childhood cancer survivors.

Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6-6.44 years biologically older compared to controls and 5-16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging.

Systemic Biological Mechanisms of Neurocognitive Dysfunction in Long-Term Survivors of Childhood Hodgkin Lymphoma.

PURPOSE: Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about the underlying mechanisms. EXPERIMENTAL DESIGN: HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. RESULTS: HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P's < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P's < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P's < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed. CONCLUSIONS: Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.

Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital.

PURPOSE: The intraventricular route of chemotherapy administration, via an Ommaya Reservoir (OmR) improves drug distribution in the central nervous system (CNS) compared to the more commonly used intrathecal administration. We retrospectively reviewed our experience with intraventricular chemotherapy, focused on methotrexate, in patients with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL). METHODS: Twenty-four patients (aged 7 days - 22.2 years) with 26 OmR placements were identified for a total of 25,009 OmR days between 1990 and 2019. Methotrexate cerebrospinal fluid (CSF) concentrations (n = 124) were analyzed from 59 courses of OmR therapy in 15 patients. Twenty-one courses involved methotrexate dosing on day 0 only, whereas 38 courses involved booster dosing on days 1, 2, or both. We simulated the time CSF methotrexate concentrations remained > 1 µM for 3 days given various dosing regimens. RESULTS: CSF methotrexate exposure was higher in those who concurrently received systemic methotrexate than via OmR alone (p < 10- 7). Our simulations showed that current intraventricular methotrexate boosting strategy for patients ≥ 3 years of age maintained CSF methotrexate concentrations ≥ 1 µM for 72 h 40% of the time. Alternatively, other boosting strategies were predicted to achieve CSF methotrexate concentrations ≥ 1 µM for 72 h between 46 and 72% of the time. CONCLUSIONS: OmR were able to be safely placed and administer intraventricular methotrexate with and without boost doses in patients from 7 days to 22 years old. Boosting strategies are predicted to increase CSF methotrexate concentrations ≥ 1 µM for 72 h.

Health Care Transitions Among Adolescents and Young Adults With Cancer.

Survivors of adolescent and young adult (AYA) cancers, defined as individuals diagnosed with a primary malignancy between age 15 and 39 years, are a growing population with unique developmental, psychosocial, and health-related needs. These individuals are at excess risk of developing a wide range of chronic comorbidities compared with the general population and, therefore, require lifelong, risk-based, survivorship care to optimize long-term health outcomes. The health care needs of survivors of AYA cancers are particularly complicated given the often heterogeneous and sometimes fragmented care they receive throughout the cancer care continuum. For example, AYA survivors are often treated in disparate settings (pediatric v adult) on dissimilar protocols that include different recommendations for longitudinal follow-up. Specialized tools and techniques are needed to ensure that AYA survivors move seamlessly from acute cancer care to survivorship care and, in many cases, from pediatric to adult clinics while still remaining engaged in long-term follow-up. Systematic, age-appropriate transitional practices involving well-established clinical models of care, survivorship care plans, and survivorship guidelines are needed to facilitate effective transitions between providers. Future studies are necessary to enhance and optimize the clinical effectiveness of transition processes in AYA cancer survivors.

Dietary patterns and their associations with sociodemographic and lifestyle factors in adult survivors of childhood cancer: a cross-sectional study.

BACKGROUND: Little is known about the specific dietary patterns in adult survivors of childhood cancer. OBJECTIVES: We aimed to identify dietary patterns specific to childhood cancer survivors and examine their associations with sociodemographic and lifestyle factors. METHODS: Adult survivors of childhood cancer (mean:31 ± 8 y; n = 3022) and noncancer controls (n = 497) in the St. Jude Lifetime Cohort self-reported diet over the past 12 mo using a validated food frequency questionnaire. Factor analysis with 48 predefined food groups was performed to identify foods consumed together. Subsequently, cluster analysis with energy-adjusted factor scores was used to categorize survivors into a mutually exclusive dietary pattern. Dietary patterns were the primary outcomes. Multivariable multinomial logistic regressions were used to cross-sectionally examine associations between sociodemographic and lifestyle factors and dietary patterns in cancer survivors. RESULTS: Among the 4 dietary patterns identified, the fast-food pattern (36 %) was the most common, followed by the Western contemporary (30 %), the plant-based (20 %), and the animal-based (14 %) patterns in childhood cancer survivors. By contrast, the plant-based (38 %) and fast-food patterns (29 %) were prevalent in controls. In survivors, male sex, younger age, lower educational attainment, and physical inactivity were associated with the fast-food, Western contemporary, or animal-based pattern. Compared with non-Hispanic White survivors consuming the plant-based diet, non-Hispanic Black survivors were 2-5 times more likely to consume the fast-food [odds ratio (OR:= 2.76; 95 % CI: 1.82, 4.18) or the animal-based diet (OR: 5.61; 95 % CI: 3.58, 8.78)]. Moreover, survivors residing in the most deprived area were 2-3 times more likely to consume the fast-food, Western contemporary, or animal-based diet. CONCLUSIONS: Unhealthy dietary patterns are prevalent in adult survivors of childhood cancer, especially those with lower socioeconomic status and racial minorities. Interventions to improve diet and health in childhood cancer survivors need to concurrently address disparities that contribute to adherence to healthy dietary practices. This trial was registered at clinicaltrials.gov as NCT00760656 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT00760656).

Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy.

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/m2 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.

Plant Foods Intake and Risk of Premature Aging in Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort (SJLIFE).

PURPOSE: To identify dietary factors that are related to premature aging in adult survivors of childhood cancer, we examined the associations between plant food intakes and age-related deficit accumulation. METHODS: A total of 3,322 childhood cancer survivors (age 18-65 years, mean = 31, standard deviation = 8.4) in the St Jude Lifetime Cohort had total fruit, total vegetables and subgroups, whole grains, refined grains, nuts/seeds, and nutrients intake assessed using a food frequency questionnaire. Premature aging at baseline was assessed by the deficit accumulation index (DAI) and categorized as low, medium, and high risk. Multinomial logistic regressions (reference: low risk) adjusting for confounders estimated odds ratios (ORs) and 95% CIs. Multivariable linear regression of a continuous intake against a continuous DAI was also performed. RESULTS: Dark green vegetable (ORhigh v low = 0.47 [95% CI, 0.28 to 0.78] per 1/2 cup/1,000 kcal increment) and nuts/seeds intakes (ORhigh v low = 0.71 [95% CI, 0.47 to 1.08] per 1 oz/1,000 kcal increment; coefficientlinear = -0.0115, P = .02) were associated with a lower risk of premature aging. Conversely, refined grain intake was related to an increased risk of premature aging (ORhigh v low = 1.33 [95% CI, 0.99 to 1.78], per 1 oz/1,000 kcal increment; coefficientlinear = 0.0093, P = .005). Fruit and whole grain intakes were not associated with premature aging risk. Among nutrients abundant in plant foods, dietary folate intake was associated with a lower risk of premature aging (ORhigh v low = 0.89 [95% CI, 0.80 to 0.99] per 50 mcg/1,000 kcal increase). Beta-carotene, lutein/zeaxanthin, and vitamin E intakes from foods were also related to a modestly lower, but not statistically significant, risk of premature aging. CONCLUSION: Specific plant foods are associated with lower risk of premature aging, providing targets for the interventions to promote healthy aging in childhood cancer survivors.

Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report.

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.

Lifestyle and subsequent meningioma in childhood cancer survivors: A report from the St. Jude Lifetime Cohort study.

BACKGROUND: Lifestyle is associated with meningioma risk in the general population. AIMS: We assessed longitudinal associations between lifestyle-associated factors and subsequent meningiomas in childhood cancer survivors. METHODS AND RESULTS: Childhood cancer survivors age ≥18 years in the St. Jude Lifetime Cohort Study were evaluated for body composition, self-reported physical activity, cardiopulmonary fitness, muscle strength, smoking, and alcohol consumption at baseline. Time to first meningioma analyses were performed, adjusted for sex, age at diagnosis and baseline assessment, treatment decade, and childhood cancer treatment exposures. The study included 4,072 survivors (47% female; [mean (SD)] 9 (6) years at diagnosis; 30 (8.5) years at the start of follow-up, with 7.0 (3.3) years of follow-up). 30% of the participants were survivors of acute lymphoblastic leukemia and 29% of the participants had received cranial radiation. During follow-up, 90 participants developed ≥1 meningioma, of whom 73% were survivors of acute lymphoblastic leukemia, with cranial radiation being the strongest risk factor (relative risk [RR] 29.7, 95% confidence interval [CI] 10.6-83.2). Muscle strength assessed by knee extension was associated with a lower risk of developing a meningioma in the adjusted analyses (RR 0.5, 95% CI 0.2-1.0, p = 0.04 for quartiles 3-4 vs. 1). No other lifestyle-associated variable was associated with subsequent meningioma. CONCLUSION: Independent of cranial radiation, muscle strength was associated with a lower risk of developing a subsequent meningioma in childhood cancer survivors.

Trends in physical functioning in acute lymphoblastic leukemia and non-Hodgkin lymphoma survivors across three decades.

PURPOSE: The impact of changes in therapy for childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on the prevalence of physical performance limitations and participation restrictions among survivors is unknown. We aimed to describe the prevalence of reduced function among ALL and NHL survivors by treatment era. METHODS: Participants included survivors of childhood ALL and NHL, and a cohort of their siblings, participating in the Childhood Cancer Survivor Study (CCSS). Physical function was measured using questionnaire. The prevalence of reduced function was compared to siblings using generalized estimating equations, overall and stratified by treatment decade. Associations between organ system-specific chronic conditions (CTCAE v4.03) and function were also evaluated. RESULTS: Among 6511 survivors (mean age 25.9 years (standard deviation 6.5)) and 4127 siblings, risk of performance limitations (15.2% vs. 12.5%, prevalence ratio [PR] = 1.5, 95%CI = 1.3-1.6), restrictions in personal care (2.0% vs. 0.6%, PR = 3.1, 95% CI = 2.0-4.8), routine activities (5.5% vs. 1.6%, PR = 3.6, 95% CI = 2.7-4.8), and work/school attendance (8.8% vs. 2.1%, PR = 4.5, 95% CI = 3.6-5.7) was increased in survivors vs. siblings. The prevalence of survivors reporting reduced function did not decrease between the 1970s and 1990s. The presence of neurological and cardiovascular conditions was associated with reduced function regardless of treatment decade. CONCLUSIONS: Despite changes in therapy, the prevalence of poor physical function remained constant between the 1970s and 1990s. The CCSS clinical trial registration number is NCT01120353 (registered May 6, 2010). IMPLICATIONS FOR CANCER SURVIVORS: Our findings support screening for reduced physical function so that early interventions to improve physical performance and mitigate chronic disease can be initiated.

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer.

Importance: Survivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer. Objective: To examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL). Design, Setting, and Participants: This cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children's Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry. Exposures: The DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher. Main Outcomes and Measures: Genome-wide DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data. Results: This study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (ß = 3.66; 95% CI, 2.47-4.85; P < .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (ß = 1.77; 95% CI, 0.84-2.69; P < .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (ß = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (ß = 4.95; 95% CI, 2.14-7.75; P < .001). There were no associations between mean LTL residual and the DAI. Conclusions and Relevance: This cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.

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.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

Neurocognitive impairment associated with chronic morbidity in long-term survivors of Hodgkin Lymphoma.

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.

Improving quality and quantity of life for childhood cancer survivors globally in the twenty-first century.

The contributions of cooperative groups to performing large-cohort clinical trials and long-term survivorship studies have facilitated advances in treatment, supportive care and, ultimately, survival for patients with paediatric cancers. As a result, the number of childhood cancer survivors in the USA alone is expected to reach almost 580,000 by 2040. Despite these substantial improvements, childhood cancer survivors continue to have an elevated burden of chronic disease and an excess risk of early death compared with the general population and therefore constitute a large, medically vulnerable population for which delivery of high-quality, personalized care is much needed. Data from large survivorship cohorts have enabled the identification of compelling associations between paediatric cancers, cancer therapy and long-term health conditions. Effectively translating these findings into clinical care that improves the quality and quantity of life for survivors remains an important focus of ongoing research. Continued development of well-designed clinical studies incorporating dissemination and implementation strategies with input from patient advocates and other key stakeholders is crucial to overcoming these gaps. This Review highlights the global progress made and future efforts that will be needed to further increase the quality and quantity of life-years gained for childhood cancer survivors.

Adherence to healthy diet and risk of cardiovascular disease in adult survivors of childhood cancer in the St. Jude Lifetime Cohort: a cross-sectional study.

BACKGROUND: Whether diet has beneficial effects on cardiovascular disease (CVD) in childhood cancer survivors as in the general population is unknown. Therefore, we examined associations between dietary patterns and risk of CVD in adult survivors of childhood cancer. METHODS: Childhood cancer survivors, 18-65 years old in the St Jude Lifetime Cohort (1882 men and 1634 women) were included in the analysis. Dietary patterns were defined by the adherence to the Healthy Eating Index (HEI)-2015, Dietary Approaches to Stop Hypertension (DASH), and alternate Mediterranean diet (aMED) based on a food frequency questionnaire at study entry. CVD cases (323 in men and 213 in women) were defined as participants with at least one grade 2 or higher CVD-related diagnosis at baseline. Multivariable logistic regression adjusted for confounders was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of CVD. RESULTS: Greater adherence to HEI-2015 (OR=0.88, 95% CI: 0.75-1.03, per 10 score increment), DASH (OR=0.85, 95% CI: 0.71-1.01, per 10 score increment), and aMED (OR=0.92, 95% CI: 0.84-1.00, each score increment) were, albeit trending towards significance, associated with a lower risk of CVD in women. HEI-2015 was associated with a non-significantly lower risk of CVD in men (ORQ5 vs. Q1=0.80, 95% CI: 0.50-1.28). These dietary patterns were also associated with a lower risk of CVD in survivors with high underlying CVD risk. CONCLUSIONS: As recommended to the general population, a diet rich in plant foods and moderate in animal foods needs to be a part of CVD management and prevention in childhood cancer survivors.