Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Post-diagnosis physical activity and sedentary behaviour and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

Low physical activity and high sedentary behaviour have been clearly linked with colorectal cancer development, yet data on their potential role in colorectal cancer survival is limited. Better characterisation of these relationships is needed for the development of post-diagnosis physical activity and sedentary behaviour guidance for colorectal cancer survivors. We searched PubMed and Embase through 28 February 2022 for studies assessing post-diagnosis physical activity, and/or sedentary behaviour in relation to all-cause and cause-specific mortality and recurrence after colorectal cancer diagnosis. Total and recreational physical activity were assessed overall and by frequency, duration, intensity, and volume using categorical, linear, and non-linear dose-response random-effects meta-analyses. The Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel interpreted and graded the likelihood of causality. We identified 16 observational studies on 82,220 non-overlapping patients from six countries. Physical activity was consistently inversely associated with colorectal cancer morbidity and mortality outcomes, with 13%-60% estimated reductions in risk. Sedentary behaviour was positively associated with all-cause mortality. The evidence had methodological limitations including potential confounding, selection bias and reverse causation, coupled with a limited number of studies for most associations. The CUP Global Expert panel concluded limited-suggestive evidence for recreational physical activity with all-cause mortality and cancer recurrence. Total physical activity and its specific domains and dimensions, and sedentary behaviour were all graded as limited-no conclusion for all outcomes. Future research should focus on randomised trials, while observational studies should obtain objective and repeated physical activity measures and better adjustment for confounders.

Post-diagnosis adiposity and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The adiposity influence on colorectal cancer prognosis remains poorly characterised. We performed a systematic review and meta-analysis on post-diagnosis adiposity measures (body mass index [BMI], waist circumference, waist-to-hip ratio, weight) or their changes and colorectal cancer outcomes. PubMed and Embase were searched through 28 February 2022. Random-effects meta-analyses were conducted when at least three studies had sufficient information. The quality of evidence was interpreted and graded by the Global Cancer Update Programme (CUP Global) independent Expert Committee on Cancer Survivorship and Expert Panel. We reviewed 124 observational studies (85 publications). Meta-analyses were possible for BMI and all-cause mortality, colorectal cancer-specific mortality, and cancer recurrence/disease-free survival. Non-linear meta-analysis indicated a reverse J-shaped association between BMI and colorectal cancer outcomes (nadir at BMI 28 kg/m2). The highest risk, relative to the nadir, was observed at both ends of the BMI distribution (18 and 38 kg/m2), namely 60% and 23% higher risk for all-cause mortality; 95% and 26% for colorectal cancer-specific mortality; and 37% and 24% for cancer recurrence/disease-free survival, respectively. The higher risk with low BMI was attenuated in secondary analyses of RCTs (compared to cohort studies), among studies with longer follow-up, and in women suggesting potential methodological limitations and/or altered physiological state. Descriptively synthesised studies on other adiposity-outcome associations of interest were limited in number and methodological quality. All the associations were graded as limited (likelihood of causality: no conclusion) due to potential methodological limitations (reverse causation, confounding, selection bias). Additional well-designed observational studies and interventional trials are needed to provide further clarification.

Risk of increased mortality in underweight survivors: A brief report from the Childhood Cancer Survivor Study.

BACKGROUND: Approximately 1 in 10 adult survivors of childhood cancer is underweight. Although the consequences of being overweight or obese have been well described, outcomes among childhood cancer survivors who are underweight are unknown. OBJECTIVE: To determine whether underweight status increases the risk of mortality. PROCEDURE: Cohort study: Marginal models with generalized estimating equations to evaluate the associations between body mass index (BMI), serious or life-threatening chronic conditions, and death in the setting of long-term follow-up questionnaires and National Death Index search. PARTICIPANTS: C. EXPOSURE: Underweight status, defined as body mass index (BMI) < 18.5 kg/m2 compared with ideal body weight. Based on available literature on body weight and mortality from the general population, ideal body weight was defined as BMI 22.0-24.9 kg/m2. MAIN OUTCOMES: Overall mortality and cancer-specific mortality. RESULTS: Of 9454 survivors (median age 35 years old (range, 17-58), an average of 17.5 years from diagnosis), 627 (6.6%) participants were underweight at baseline or follow-up questionnaire. Of 184 deaths, 29 were among underweight survivors. Underweight status was more common among females (9.1% vs. 4.5%, p < .01) and participants with younger age at diagnosis (8.2% for < 5 years vs. 6.1% for ≥5 years, p < .01), lower household income (8.9% for < $20,000 vs. 6.0% for ≥ $20,000, p < .01), or a history of serious chronic condition (p = .05). After adjustment for these factors, in addition to prior smoking and a history of radiation therapy, the risk of all-cause mortality within two years of BMI report was increased (OR 2.85; 95% CI: 1.63-4.97; p < .01) for underweight survivors, compared with ideal-weight survivors. CONCLUSIONS: Childhood cancer survivors who are underweight are at increased risk for late mortality that appears unrelated to smoking status, recognized chronic disease, or subsequent malignancy. Whether targeted nutritional interventions would ameliorate this risk is unknown.

Chronic Health Conditions and Longitudinal Employment in Survivors of Childhood Cancer.

Importance: Employment is an important factor in quality of life and provides social and economic support. Longitudinal data on employment and associations with chronic health conditions for adult survivors of childhood cancer are lacking. Objective: To evaluate longitudinal trends in employment among survivors of childhood cancer. Design, Setting, and Participants: Retrospective cohort study of 5-year cancer survivors diagnosed at age 20 years or younger between 1970 and 1986 enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS). Sex-stratified employment status at baseline (2002 to 2004) and follow-up (2014 to 2016) was compared with general population rates from the Behavioral Risk Factor Surveillance System cohort. Data were analyzed from July 2021 to June 2022. Exposures: Cancer therapy and preexisting and newly developed chronic health conditions. Main Outcomes and Measures: Standardized prevalence ratios of employment (full-time or part-time, health-related unemployment, unemployed, not in labor force) among adult (aged ≥25 years) survivors between baseline and follow-up compared with the general population. Longitudinal assessment of negative employment transitions (full-time to part-time or unemployed at follow-up). Results: Female participants (3076 participants at baseline; 2852 at follow-up) were a median (range) age of 33 (25-53) years at baseline and 42 (27-65) years at follow-up; male participants (3196 participants at baseline; 2557 at follow-up) were 33 (25-54) and 43 (28-64) years, respectively. The prevalence of full-time or part-time employment at baseline and follow-up was 2215 of 3076 (71.3%) and 1933 of 2852 (64.8%) for female participants and 2753 of 3196 (85.3%) and 2079 of 2557 (77.3%) for male participants, respectively, with declining standardized prevalence ratios over time (female participant baseline, 1.01; 95% CI, 0.98-1.03; follow-up, 0.94; 95% CI, 0.90-0.98; P < .001; male participant baseline, 0.96; 95% CI, 0.94-0.97; follow-up, 0.92; 95% CI, 0.89-0.95; P = .02). While the prevalence of health-related unemployment increased (female participants, 11.6% to 17.2%; male participants, 8.1% to 17.1%), the standardized prevalence ratio remained higher than the general population and declined over time (female participant baseline, 3.78; 95% CI, 3.37-4.23; follow-up, 2.23; 95% CI, 1.97-2.51; P < .001; male participant baseline, 3.12; 95% CI, 2.71-3.60; follow-up, 2.61; 95% CI, 2.24-3.03; P = .002). Among survivors employed full-time at baseline (1488 female participants; 1933 male participants), 285 female participants (19.2%) and 248 male participants (12.8%) experienced a negative employment transition (median [range] follow-up, 11.5 [9.4-13.8] years). Higher numbers and grades of chronic health conditions were significantly associated with these transitions. Conclusions and Relevance: In this retrospective analysis of adult survivors of childhood cancer, significant declines in employment and increases in health-related unemployment among cancer survivors compared with the general population were identified. A substantial portion of survivors in the midcareer age range fell out of the workforce. Awareness among clinicians, caregivers, and employers may facilitate clinical counseling and occupational provisions for supportive work accommodations.

Using an mHealth approach to collect patient-generated health data for predicting adverse health outcomes among adult survivors of childhood cancer.

Introduction: Cancer therapies predispose childhood cancer survivors to various treatment-related late effects, which contribute to a higher symptom burden, chronic health conditions (CHCs), and premature mortality. Regular monitoring of symptoms between clinic visits is useful for timely medical consultation and interventions that can improve quality of life (QOL). The Health Share Study aims to utilize mHealth to collect patient-generated health data (PGHD; daily symptoms, momentary physical health status) and develop survivor-specific risk prediction scores for mitigating adverse health outcomes including poor QOL and emergency room admissions. These personalized risk scores will be integrated into the hospital-based electronic health record (EHR) system to facilitate clinician communications with survivors for timely management of late effects. Methods: This prospective study will recruit 600 adult survivors of childhood cancer from the St. Jude Lifetime Cohort study. Data collection include 20 daily symptoms via a smartphone, objective physical health data (physical activity intensity, sleep performance, and biometric data including resting heart rate, heart rate variability, oxygen saturation, and physical stress) via a wearable activity monitor, patient-reported outcomes (poor QOL, unplanned healthcare utilization) via a smartphone, and clinically ascertained outcomes (physical performance deficits, onset of/worsening CHCs) assessed in the survivorship clinic. Participants will complete health surveys and physical/functional assessments in the clinic at baseline, 2) report daily symptoms, wear an activity monitor, measure blood pressure at home over 4 months, and 3) complete health surveys and physical/functional assessments in the clinic 1 and 2 years from the baseline. Socio-demographic and clinical data abstracted from the EHR will be included in the analysis. We will invite 20 cancer survivors to investigate suitable formats to display predicted risk information on a dashboard and 10 clinicians to suggest evidence-based risk management strategies for adverse health outcomes. Analysis: Machine and statistical learning will be used in prediction modeling. Both approaches can handle a large number of predictors, including longitudinal patterns of daily symptoms/other PGHD, along with cancer treatments and socio-demographics. Conclusion: The individualized risk prediction scores and added communications between providers and survivors have the potential to improve survivorship care and outcomes by identifying early clinical presentations of adverse events.

Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement.

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Multilevel Characteristics of Cumulative Symptom Burden in Young Survivors of Childhood Cancer.

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

Seroprevalence of Measles (Rubeola) Antibodies in Childhood Cancer Survivors.

Background: Measles is reemerging as a public health threat, raising important questions about disease vulnerability among childhood cancer survivors. This secondary analysis assessed the seroprevalence of anti-measles immunoglobulin G (IgG) antibodies as a marker of immune status in survivors of childhood cancer and associated demographic/treatment variables. Method: Participants were childhood cancer survivors who were free of active disease, having routine blood studies drawn, and could provide documentation of having received two doses of measles, mumps, and rubella vaccine before their cancer diagnosis. Patient record review documented demographic and treatment variables. Antimeasles (rubeola) IgG antibody seroprevalence was assessed by enzyme immunoassay for vaccine-specific antibodies. Results: Of 270 survivors evaluated, 110 (42%) were female, 196 (75%) were White, and 159 (61%) were leukemia/lymphoma survivors. Of these 262, 110 (42%) had negative measles seroprevalence, suggesting loss of immunity. Conclusion: Measles antibody surveillance and the need for reimmunization for survivors of childhood cancer survivors outside the transplant setting remains controversial. Our analysis indicates that a substantial proportion of survivors lose vaccine-related immunity to measles. Pediatric oncology nurses play important roles in educating cancer survivors regarding their risk of measles infection, evaluating the need for reimmunization, correcting misinformation about vaccine safety and effectiveness, and working to optimize community herd-based immunity.

Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

Multilevel Social Determinants of Patient-Reported Outcomes in Young Survivors of Childhood Cancer.

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

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.

Associations between mitochondrial copy number, exercise capacity, physiologic cost of walking, and cardiac strain in young adult survivors of childhood cancer.

PURPOSE: Childhood cancer survivors are at risk for cardiac dysfunction and impaired physical performance, though underlying cellular mechanisms are not well studied. In this cross-sectional study, we examined the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN, a proxy for mitochondrial function) and markers of performance impairment and cardiac dysfunction. METHODS: Whole-genome sequencing, validated by quantitative polymerase chain reaction, was used to estimate mtDNA-CN in 1720 adult survivors of childhood cancer (48.5% female; mean age = 30.7 years, standard deviation (SD) = 9.0). Multivariable logistic regression was performed to evaluate the associations between mtDNA-CN and exercise intolerance, walking inefficiency, and abnormal global longitudinal strain (GLS), adjusting for treatment exposures, age, sex, and race and ethnicity. RESULTS: The prevalence of exercise intolerance, walking inefficiency, and abnormal GLS among survivors was 25.7%, 10.7%, and 31.7%, respectively. Each SD increase of mtDNA-CN was associated with decreased odds of abnormal GLS (adjusted odds ratio (OR) = 0.88, p = 0.04) but was not associated with exercise intolerance (OR = 1.02, p = 0.76) or walking inefficiency (OR = 1.06, p = 0.46). Alkylating agent exposure was associated with increased odds of exercise intolerance (OR = 2.25, p < 0.0001), walking inefficiency (OR = 2.37, p < 0.0001), and abnormal GLS (OR = 1.78, p = 0.0002). CONCLUSIONS: Increased mtDNA-CN is associated with decreased odds of abnormal cardiac function in childhood cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: These findings demonstrate a potential role for mtDNA-CN as a biomarker of early cardiac dysfunction in this population.

St. Jude Survivorship Portal: sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors.

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and 400 million genetic variants from over 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry.

Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.

PURPOSE: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D. PATIENTS AND METHODS: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci. RESULTS: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 × 10-8). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 × 10-9). CONCLUSION: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.

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.

Hypogonadism and neurocognitive outcomes among childhood cancer survivors.

OBJECTIVE: Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors. DESIGN: Cross-sectional study using retrospective cohort. METHODS: In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes. RESULTS: The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2-2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P < .01) and indirect (from P < .01) impact on impairment in visual processing speed among females. Males demonstrated direct (P = .03) and indirect (P = .04) impact of hypogonadism on motor processing speed. CONCLUSION: Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function.

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.