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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. [ABSTRACT FROM AUTHOR]

A new report provides compelling evidence of the high prevalence of endocrine disorders in childhood cancer survivors, which begins soon after diagnosis and persists throughout adulthood. This finding highlights the need for awareness and education in primary care, and for specialized physicians to provide health care to adult survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Objective To evaluate associations between prepregnancy lifestyle factors, psychologic distress and adverse pregnancy outcomes among female survivors of childhood cancer. Study Design We examined pregnancies of 1192 female participants from the Childhood Cancer Survivor Study. Generalized linear models, adjusted for age at diagnosis, age at pregnancy, parity, and education were used to calculate the odds ratio (OR) and confidence interval (CI) for associations between prepregnancy inactivity, overweight or obese status, smoking status, risky drinking, psychologic distress and pregnancy outcomes. Interactions between lifestyle factors, psychologic distress, type of cancer and cancer treatment were assessed in multivariable models. Results The median age of study participants at the beginning of pregnancy was 28 years (range, 14–45). Among 1858 reported pregnancies, there were 1300 singleton live births (310 were preterm), 21 stillbirths, 397 miscarriages, and 140 medical abortions. Prepregnancy physical inactivity, risky drinking, distress, and depression were not associated with any pregnancy outcomes. Compared with those who had never smoked, survivors with >5 pack-years smoking history had a higher risk for miscarriage among those treated with >2.5 Gray (Gy) uterine radiation (OR, 53.9; 95% CI, 2.2–1326.1) than among those treated with ≤2.5 Gy uterine radiation (OR, 1.9; 95% CI, 1.2–3.0). There was a significant interaction between smoking and uterine radiation ( P interaction = .01). Conclusion Although most lifestyle factors and psychologic distress were not predictive of adverse pregnancy outcomes, the risk for miscarriage was significantly increased among survivors exposed to >2.5 Gy uterine radiation who had a history of smoking. [ABSTRACT FROM AUTHOR]

Background: We aimed to characterize premature aging as an accumulation of deficits in survivors of pediatric cancer compared to community controls and examine associations with host/treatment factors, neurocognition, and mortality.Methods: Pediatric cancer survivors (N = 4,000, median age 28.6 [IQR 23-35], 20 [15-27] years post-diagnosis) and community controls (N = 638, median age 32 [25-40]) completed clinical assessments, questionnaires, and were followed for mortality through April 30th, 2020 (mean [SD] follow-up 7.0 [3.4] years). A deficit accumulation index (DAI) score was calculated from 44 aging-related items including: self-reported daily function, psychosocial symptoms, and health conditions. Items were weighted from 0 (absent) to 1 (present/most severe), summed and divided by the total yielding a ratio (higher=more deficits). Scores <0.20 are robust and 0.06 is a clinically meaningful difference. Linear regression compared the DAI in survivors and controls with an age*survivor/control interaction. Logistic regression and Cox-proportional hazards estimated the risk of neurocognitive impairment and death. Models were minimally adjusted for age, sex, and race andethnicity.Results: The adjusted mean DAI among survivors at age 30 years was 0.16 corresponding to age 63 in controls (33 years premature aging; β = 0.07 95%CI 0.06-0.08; p<.001). Cranial/abdominal radiation, alkylators, platinum, and neurosurgery were associated with worse DAI (p's≤.001). Higher scores were associated with increased risk of neurocognitive impairment in all domains (p's<.001) and increased risk of death (DAI 0.20-0.35 HR = 2.80, 95%CI 1.97-3.98; DAI ≥0.35 HR = 5.08, 95%CI 3.52-7.34).Conclusion:  Pediatric cancer survivors experience significant premature aging. The DAI may be used to identify survivors at greatest risk of poor health outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVES: We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor. METHODS: Survivors ofWilms tumor (n = 280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow-up of individuals treated for childhood cancer at St. Jude Children's Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n = 625). Health conditions were graded per a modified version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded by using age-adjusted z-scores. Impaired physical function was defined by age- and sexmatched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations. RESULTS: Median age at evaluation was similar between survivors and controls (30.5 years [9.0--58.0] and 31.0 [12.0-70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI: 6.7-8.2) grade 2 to 4 health conditions, compared to 4.2 (CI: 3.9-4.6) and 2.3 (CI: 2.1-2.5), respectively, among controls. Grade 2 to 4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments. CONCLUSIONS: Wilms tumor survivors experience a threefold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance. [ABSTRACT FROM AUTHOR]

Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test ≥7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency. [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]

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]

With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n = 2,231; observed-to-expected replication ratio = 0.70, p = 6.2 × 10−8). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected replication ratio = 0.55, p = 5.6 × 10−15). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors. [ABSTRACT FROM AUTHOR]

Background: Cancer treatment can cause gonadal impairment. Acute ovarian failure is defined as the permanent loss of ovarian function within 5 years of cancer diagnosis. We aimed to develop and validate risk prediction tools to provide accurate clinical guidance for paediatric patients with cancer.Methods: In this cohort study, prediction models of acute ovarian failure risk were developed using eligible female US and Canadian participants in the Childhood Cancer Survivor Study (CCSS) cohort and validated in the St Jude Lifetime Cohort (SJLIFE) Study. 5-year survivors from the CCSS cohort were included if they were at least 18 years old at their most recent follow-up and had complete treatment exposure and adequate menstrual history (including age at menarche, current menstrual status, age at last menstruation, and menopausal aetiology) information available. Participants in the SJLIFE cohort were at least 10-year survivors. Participants were excluded from the prediction analysis if they had an ovarian hormone deficiency, had missing exposure information, or had indeterminate ovarian status. The outcome of acute ovarian failure was defined as permanent loss of ovarian function within 5 years of cancer diagnosis or no menarche after cancer treatment by the age of 18 years. Logistic regression, random forest, and support vector machines were used as candidate methods to develop the risk prediction models in the CCSS cohort. Prediction performance was evaluated internally (in the CCSS cohort) and externally (in the SJLIFE cohort) using the areas under the receiver operating characteristic curve (AUC) and the precision-recall curve (average precision [AP; average positive predictive value]).Findings: Data from the CCSS cohort were collected for participants followed up between Nov 3, 1992, and Nov 25, 2016, and from the SJLIFE cohort for participants followed up between Oct 17, 2007, and April 16, 2012. Of 11 336 female CCSS participants, 5886 (51·9%) met all inclusion criteria for analysis. 1644 participants were identified from the SJLIFE cohort, of whom 875 (53·2%) were eligible for analysis. 353 (6·0%) of analysed CCSS participants and 50 (5·7%) of analysed SJLIFE participants had acute ovarian failure. The overall median follow-up for the CCSS cohort was 23·9 years (IQR 20·4-27·9), and for SJLIFE it was 23·9 years (19·0-30·0). The three candidate methods (logistic regression, random forest, and support vector machines) yielded similar results, and a prescribed dose model with abdominal and pelvic radiation doses and an ovarian dose model with ovarian radiation dosimetry using logistic regression were selected. Common predictors in both models were history of haematopoietic stem-cell transplantation, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and haematopoietic stem-cell transplant. External validation of the model in the SJLIFE cohort produced an estimated AUC of 0·94 (95% CI 0·90-0·98) and AP of 0·68 (95% CI 0·53-0·81) for the ovarian dose model, and AUC of 0·96 (0·94-0·97) and AP of 0·46 (0·34-0·61) for the prescribed dose model. Based on these models, an online risk calculator has been developed for clinical use.Interpretation: Both acute ovarian failure risk prediction models performed well. The ovarian dose model is preferred if ovarian radiation dosimetry is available. The models, along with the online risk calculator, could help clinical discussions regarding the need for fertility preservation interventions in girls and young women newly diagnosed with cancer.Funding: Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer.Methods: The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age-matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked-point-process regression was used for inferential cumulative burden analysis.Findings: Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54·5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45·5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99·9% (95% CI 99·9-99·9) for grade 1-5 CHCs and 96·0% (95% CI 95·3-96·8%) for grade 3-5 CHCs. By age 50 years, a survivor had experienced, on average, 17·1 (95% CI 16·2-18·1) CHCs of any grade, of which 4·7 (4·6-4·9) were CHCs of grade 3-5. The cumulative burden in matched community controls of grade 1-5 CHCs was 9·2 (95% CI 7·9-10·6; p<0·0001 vs total study population) and of grade 3-5 CHCs was 2·3 (1·9-2·7, p<0·0001 vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1-5 CHCs at age 50 years was highest in survivors of CNS malignancies (24·2 [95% CI 20·9-27·5]) and lowest in survivors of germ cell tumours (14·0 [11·5-16·6]). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs.Interpretation: The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population.Funding: The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities. [ABSTRACT FROM AUTHOR]

Background: Poor nutritional intake can exacerbate the chronic disease burden in childhood cancer survivors, whereas a healthful diet serves a protective function. Few studies have provided detailed evaluations of the diet of childhood cancer survivors.Objectives: This study aimed to evaluate diet quality and dietary intakes of key food groups and nutrients in a large cohort of childhood cancer survivors and whether cancer and treatment characteristics have an impact on survivors' long-term intake.Methods: Diet was assessed in 2570 adult survivors of childhood cancer enrolled in the St. Jude Lifetime cohort (mean age = 32.3 y) by using the Block food-frequency questionnaire. The Healthy Eating Index-2010 (HEI-2010) was calculated to quantify diet quality. Cancer diagnosis and treatment exposure were abstracted from medical records. Differences in HEI-2010 by patient characteristics and treatment exposure were examined by using ANCOVA.Results: The mean ± SD HEI-2010 in childhood cancer survivors was 57.9 ± 12.4 of a maximum score of 100. Referenced to Dietary Reference Intakes, survivors consumed inadequate amounts of vitamin D, vitamin E, potassium, fiber, magnesium, and calcium (27%, 54%, 58%, 59%, 84%, and 90% of the recommended intakes) but excessive amounts of sodium and saturated fat (155% and 115% of the recommended intakes) from foods. Survivors diagnosed when <5 y of age had a lower diet quality than did those diagnosed when ≥5 y of age (mean HEI-2010 score: 56.9 compared with 58.2; P = 0.046). Survivors who received higher radiation doses to the abdomen had a lower diet quality than those who received lower doses (mean HEI-2010 scores = 58.9, 57.2, 56.7, and 56.1 for doses of 0, 1-19.9, 20-29.9, and ≥30 Gy, respectively; P = 0.02).Conclusions: Long-term childhood cancer survivors have poor adherence to the 2010 Dietary Guidelines for Americans. Findings reinforce the need to incorporate nutrition into cancer care to improve diet quality and to reduce morbidities. [ABSTRACT FROM AUTHOR]

Background. Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for low lean muscle mass and muscle weakness, which may contribute to inactivity and early development of chronic diseases typically seen in older adults. Although increasing protein intake, in combination with resistance training, improves lean muscle mass in other populations, it is not known whether muscular tissue among survivors of ALL, whose impairments are treatment-related, will respond similarly. Objective. The aim of this study was to evaluate associations among dietary protein intake, resistance training, and lean muscle mass in survivors of ALL and age-, sex-, and race-matched controls. Design. This was a cross-sectional study. Methods. Lean muscle mass was determined with dual-energy x-ray absorptiometry, dietary information with 24-hour recalls, and participation in resistance training with a questionnaire. Participants were 365 survivors of ALL (52% male; 87% white; median age=28.5 years, range=23.6-31.7) and 365 controls with no previous cancer. Results. Compared with controls, survivors of ALL had lower lean muscle mass (55.0 versus 57.2 kg, respectively) and lower percentage of lean muscle mass (68.6% versus 71.4%, respectively) than controls. Similar proportions of survivors (71.1%) and controls (69 7%) met recommended dietary protein intake (0.8 g/kg/d). Survivors (45.4%) were less likely to report resistance training than controls (53.8%). In adjusted models, 1-g higher protein intake per kilogram of body mass per day was associated with a 7.9% increase and resistance training ≥1xwk, with a 2.8% increase in lean muscle mass. Limitations. The cross-sectional study design limits temporal evaluation of the association between protein intake and lean muscle mass. Conclusions. The findings suggest that survivors of childhood ALL with low lean muscle mass may benefit from optimizing dietary protein intake in combination with resistance training. Research is needed to determine whether resistance training with protein supplementation improves lean muscle mass in survivors of childhood ALL. [ABSTRACT FROM AUTHOR]

Promoting physical activity soon after treatment for childhood cancer may benefit health because sedentary lifestyle during curative therapy may perpetuate physical and emotional complications. The primary goals of this study are to evaluate the effects of a 6-month web-based, rewards-based physical activity intervention on fitness, biomarkers of cardiometabolic health, inflammation, adipokine status, quality of life and school attendance, and determine if effect of intervention on markers of cardiometabolic health is mediated by changes in fitness. The primary outcome of interest is fitness (physiological cost index, six-minute walk test) measured at end of intervention. This ongoing study is a two-arm, prospective, randomized design with accrual goals of 192 children for intervention and control groups. Children ≥8 years and < 16 years of age, not meeting recommended levels of physical activity, who completed therapy within the past 12 months are eligible. Both groups receive: 1) educational materials encouraging physical activity, 2) activity monitor, 3) access to web-based interface designed to motivate physical activity, 4) rewards based on physical activity levels, and 5) access to their activity data on the web-interface. Those randomized to intervention: 1) can view others' activity and interact with other participants, and 2) receive rewards based on physical activity levels throughout the intervention (vs. at the end of the intervention for control group). Unique, scalable, and portable physical activity interventions that motivate young survivors are needed. This study will inform future web-based physical activity interventions for children with cancer by demonstrating effects of rewards and social interaction. ClinicalTrials.gov Identifier: NCT03223753 ; COG Identifier: ALTE1631. [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]

There is limited information on body composition, energy balance and fitness among childhood ALL survivors, especially those treated without cranial radiation (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6 ± 5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared to peers (% body fat 26.2 ± 8.2 vs. 22.7 ± 7.1). Survivors without CRT had similar energy balance, but had significantly impaired quadriceps strength (-21.9 ± 6.0 Nm/kg, 60 °/s) and endurance (-11.4 ± 4.6 Nm/kg, 300°/s), exercise capacity (-2.0 ± 2.1 ml/kg/min), low-back and hamstring flexibility (-4.7 ± 1.6 cm), and dorsiflexion range of motion (-3.1 ± 0.9°), and higher modified total neuropathy scores (+1.6 ± 1.1) than peers. Cumulative asparaginase dose ⩾120,000 IU/m2 was associated with impaired flexibility, vincristine dose ⩾39 mg/m2 with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose ⩾8000 mg/m2 with hand weakness, and intrathecal methotrexate dose ⩾225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body composition outcomes. Survivors remain at risk for impaired fitness. [ABSTRACT FROM AUTHOR]

Summary Background Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. Methods We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01–20·3] at diagnosis, 29·0 years [18·4–56·1] at assessment, and a median of 21·0 years [10·5–41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Findings Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m 2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m 2 (SD 7274) in patients with azoospermia, 8480 mg/m 2 (4264) in patients with oligospermia, and 6626 mg/m 2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m 2 CED for azoospermia (OR 1·22, 95% CI 1·11–1·34), and for oligospermia (1·14, 1·04–1·25), but age at diagnosis and age at assessment were not. Interpretation Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m 2 . Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. Funding US National Cancer Institute, American Lebanese Syrian Associated Charities. [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]

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]

Objective To evaluate the influence of the type and treatment of CNS lesion causing central precocious puberty (CPP) on the presentation, hypothalamic-pituitary function and final height. Patients One hundred patients with CPP caused by central nervous system (CNS) lesion. Results The CPP was the presenting symptom of the lesion in 25 (10 boys) and occurred in 75 patients (23 boys) previously treated for lesions. These were optic glioma or astrocytoma ( n = 45), hydrocephalus ( n = 22), hypothalamic hamartoma ( n = 15), suprasellar arachnoid cyst ( n = 10) and others ( n = 8). The percentages of patients with increased height, bone age advance, testicular volume, LH/FSH peaks ratio after gonadotrophin-releasing hormone (GnRH) test and plasma testosterone concentration in boys and oestradiol in girls varied from one aetiology to another. The boys with hamartoma were significantly taller and had greater bone age advance, LH peak and testosterone than boys with optic glioma. The girls with hamartoma and suprasellar arachnoid cyst were significantly younger and had greater LH peak than girls in the other groups. All patients treated for optic glioma had hypothalamic–pituitary deficiencies, including GH (100%), thyrotrophin (71·4%), corticotrophin (12·5%) and pubertal (34·3%) deficiencies. Sixty percent of those with suprasellar cysts lacked GH. Final height was below −2 SD in 15/59 (25%) patients, including 5/11 not treated with GnRH analogue , 3/5 not treated with GH despite GH deficiency, and 2 with hydrocephalus as a result of meningomyelocele. Conclusions The type of CNS lesion influences the presentation of CPP. This is probably caused by differences in the mechanisms inducing puberty and to the hypothalamic-pituitary deficiencies associated with the CPP as a result of a lesion and/or its treatment. [ABSTRACT FROM AUTHOR]

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

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

Childhood cancer survivors are at risk for developing endocrine disorders, including deficits in growth hormone, thyroid hormone and sex hormones. The influence these hormones have on cell growth and metabolism has raised concerns regarding the safety of their use as treatments in survivors of childhood cancer and brain tumors. This article offers a summary of current knowledge, controversies and areas for future research pertaining to this area.

Background: Thyroid function abnormalities can occur after treatment for childhood cancer. Evidence for the management of thyroid dysfunction among asymptomatic childhood cancer survivors (CCS) is lacking. We used a Delphi consensus methodology to expand guidelines for screening asymptomatic CCS at risk for thyroid dysfunction and explore recommendations for the clinical management of abnormal results., Procedure: A Delphi panel of 40 expert physicians representing oncology, endocrinology, and primary care participated in three rounds of anonymous, iterative questionnaires formatted as clinical scenarios. Consensus is defined as ≥ 90% of panelists agree with recommendation and disagreement as < 70% agree., Results: Panelists reached consensus that CCS treated with radiation including neck, total body, whole brain, brain including the hypothalamic-pituitary axis (HPA), and therapeutic meta-iodobenzylguanidine (MIBG) should have annual, lifelong screening using serum thyroid-stimulating hormone (TSH) and free T4 starting within one year off-treatment (98%). Panelists disagreed on continuing to screen CCS for thyroid dysfunction after immunotherapy associated with acute thyroid injury (31%-50%). There was also disagreement on indications for brain (17%-43%) or thyroid (50%-65%) imaging, laboratory tests to assess the HPA (29%-75%), and TSH threshold to initiate treatment of subclinical hypothyroidism. Lack of evidence was the most frequent rationale panelists offered for not recommending additional testing or medications. Panelists' recommendations did not vary by geography, specialty, or survivorship clinical experience., Conclusions: Consensus was reached on most recommendations for screening and management of cancer treatment-related thyroid dysfunction. Screening after completion of thyroid-toxic immunotherapy, indications for imaging, and treatment of subclinical hypothyroidism are areas of disagreement for further investigation., (© 2022 Wiley Periodicals LLC.)

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

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

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking., (© 2021. The Author(s).)

Cumulative burden of chronic health conditions and neurocognitive and physical function were examined among survivors of childhood acute myeloid leukemia (AML) treated with hematopoietic cell transplant (HCT; n = 66) or conventional therapy (CT; n = 67). Survivors and controls underwent a comprehensive clinical assessment, and health conditions were graded using a modified version of the Common Terminology Criteria for Adverse Events. By age 40 years, HCT and CT survivors had an average 17.4 (95% confidence interval [CI] 14.6-20.1) and 9.3 (7.7-11.1) grade 1-4 conditions versus 3.8 (3.3-4.2) in community controls. Compared to controls, HCT survivors had a higher prevalence of hypertriglyceridemia (45.5% vs. 18.3%), hypercholesterolemia (47.0% vs. 30.9%), hypothyroidism (27.3% vs. 4.0%), and primary hypogonadism (p < 0.001). CT survivors had a higher prevalence of cardiomyopathy (11.9% vs. 2.7%) and hypertension (53.7% vs. 44.3%). Neurocognitive impairment was elevated across all domains compared to controls but did not differ by treatment modality. Compared to controls, a higher proportion of HCT survivors had impairments in strength and endurance; whereas flexibility and mobility impairments were noted among CT survivors. Despite successful advances in childhood AML therapy, many therapeutic exposures remain unchanged. These findings support ongoing investigations of novel therapies and strategies to ameliorate the risk of late morbidities., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Study Question: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)?, Summary Answer: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy., What Is Known Already: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability., Study Design, Size, Duration: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391)., Participants/materials, Setting, Methods: To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis., Main Results and the Role of Chance: Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00)., Limitations, Reasons for Caution: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function., Wider Implications of the Findings: Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer., Study Funding/competing Interest(s): This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Hypothalamic-pituitary (HP) dysfunctions are commonly reported complications in survivors of childhood cancer. These include growth hormone deficiency, luteinizing hormone/follicle-stimulating hormone deficiency, thyroid-stimulating hormone deficiency, adrenocorticotropic hormone deficiency, central precocious puberty, hyperprolactinemia, and central diabetes insipidus. Local tumor invasion and surgical or radiation-induced injury represent the highest risk factors. New treatment modalities, such as immunotherapy and molecular targeted therapy have the potential to cause autoimmune hypophysitis. Untreated HP dysfunctions are associated with adverse physical and psychosocial consequences and reduced quality of life. Systematic and periodic endocrine assessments optimize early diagnosis and timely treatment and may improve long-term health outcomes., (© 2021 S. Karger AG, Basel.)

Endocrine late effects, including reproductive disorders and secondary thyroid cancer, have been reported in up to 50 %childhood cancer survivors (CCS) more than 5 years after treatment. Most endocrine disorders are amenable to treatment; awareness of symptoms is therefore of great importance. Recognition of these symptoms may be delayed however because many are nonspecific. Timely treatment of endocrine disorders improves quality of life in CCS and prevents possible consequences, such as short stature, bone and cardiovascular disorders, and depression. At-risk CCS must therefore be regularly and systematically monitored. This article provides a summary of the most commonly reported endocrine late effects in CCS., Competing Interests: Disclosure H.M. van Santen has received speakers fees from Pfizer BV and Ferring BV. The remaining authors have nothing to disclose., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors., Procedure: Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis., Results: Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P = 0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality., Conclusions: HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes., (© 2020 Wiley Periodicals LLC.)

Background: We modeled height after craniospinal irradiation (CSI) in pediatric patients with central nervous system (CNS) embryonal tumors to identify factors that impair stature., Procedure: During 1996-2012, 212 pediatric patients (131 male) with CNS embryonal tumors received postoperative CSI: 23.4 Gy (n = 147) or ≥36 Gy (n = 65), similar postirradiation chemotherapy, and were followed for at least 5 years without tumor progression or other event. The group was further characterized by age at CSI and hormone-replacement therapy received. Models were developed to identify factors associated with growth impairment and estimate final height., Results: With median follow up of 10.2 years (range 5.0-20.4 years), the mean final height z-scores at 18 years of age, compared to United States standards, were -1.3 for female and -1.5 for male survivors. Younger age at the time of CSI, higher CSI dose, and female sex were associated with height impairment. Factors associated with higher growth rates before 15 years of age were older age at CSI, male sex, CSI dose < 36 Gy, replacement therapy for growth hormone (GH) and central adrenal insufficiency, and white race. Growth after age 15 in male survivors was associated with treatment of gonadotropin deficiency. Linear mixed-effects models were developed using clinical factors to estimate final height, demonstrate the unique growth curve of this cohort, and interactions between clinical variable and radiation dose., Conclusions: CSI significantly impaired height at current doses used to treat standard- or high-risk CNS embryonal tumors. Measures to reduce the impact of CSI on height should be sought, with our models serving as benchmarks., (© 2020 Wiley Periodicals LLC.)

Exposure to high doses of alkylating agents is associated with increased risk of impaired spermatogenesis among nonirradiated male survivors of childhood cancer, but there is substantial variation in this risk. Here we conducted a genetic study for impaired spermatogenesis utilizing whole-genome sequencing data from 167 nonirradiated male childhood cancer survivors of European ancestry from the St. Jude Lifetime Cohort treated with cyclophosphamide equivalent dose (CED) ≥4,000 mg/m 2 . Sperm concentration from semen analysis was assessed as the primary outcome. Common variants (MAF > 0.05) were adjusted for age at cancer diagnosis, CED, and top principal components. Rare/low-frequency variants (MAF ≤ 0.05) were evaluated jointly by various functional annotations and 4-kb sliding windows. A novel locus at 7q21.3 containing TAC1 / ASNS was associated with decreased sperm concentration (rs7784118: P = 3.5 × 10 -8 ). This association was replicated in two independent samples of SJLIFE survivors of European ancestry, including 34 nonirradiated male survivors treated with 0 < CED < 4,000 mg/m 2 ( P = 3.1 × 10 -4 ) and 24 male survivors treated with CED ≥4,000 mg/m 2 and radiotherapy <40 Gray ( P = 0.012). No association was observed among survivors not exposed to alkylating agents included in the CED ( P > 0.29). rs7784118 conferred 3.48- and 9.73-fold increases in risk for clinically defined oligospermia and azoospermia and improved prediction of normospermic, oligospermic, and azoospermic states by 13.7%, 5.3%, and 21.7%. rs7784118 was associated with decreased testosterone level, increased levels of follicle stimulating and luteinizing hormones, and 8.52-fold increased risk of Leydig cell failure. Additional research is warranted to determine how this SNP influences spermatogenesis and to assess its clinical utility in characterizing high-risk survivors and guiding intervention strategies. SIGNIFICANCE: The identified genetic markers harbor potential clinical utility in characterizing high-risk survivors and guiding intervention strategies including pretreatment patient counseling and use of fertility preservation services., (©2020 American Association for Cancer Research.)

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

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

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

Hematopoietic stem cell transplantation (HSCT) is used in children to treat a variety of malignant and nonmalignant hematologic conditions and certain inborn errors of metabolism. Survivors of HSCT are markedly affected by disease and treatment toxicity. Endocrine complications are among the most commonly reported chronic health conditions in this population. In this review, we summarize the most common endocrine late effects after pediatric HSCT. We also highlight the importance of systematic and longitudinal evaluations to achieve early diagnoses and treatment for these conditions and improve the long-term health outcomes for patients who received HSCT as children.

Background: Treatment for childhood acute lymphoblastic leukemia has evolved over the past five decades, with moderation of traditional chemotherapy and radiotherapy and the introduction of targeted immune-based and cellular-based therapies. The affect of these changes on late health outcomes has not been assessed. Using data from the The St Jude Lifetime (SJLIFE) Cohort, we aimed to characterise the magnitude of morbidity and patterns of late health outcomes among survivors of childhood acute lymphoblastic leukaemia treated over time., Methods: The St Jude Lifetime (SJLIFE) Cohort is a retrospective cohort study with prospective follow-up and ongoing data accrual designed to facilitate longitudinal, clinically-based assessment of health outcomes among survivors of paediatric malignancies. 980 survivors included in this analysis were diagnosed with paediatric acute lymphoblastic leukaemia at St Jude Children's Research Hospital (SJCRH) between Aug 28, 1963, and July 19, 2003, were aged 18 years old and older at enrolment, had a minimum follow-up of 10 years after diagnosis, and completed an initial on-campus SJLIFE assessment as of data cutoff (June 30, 2015). 272 community control participants, matched to survivors on 5-year age blocks in each sex, were recruited for comparison. Cumulative chemotherapy and radiation dose exposures and major medical events during and after therapy were retrieved from the medical records of the survivors. History or physical examination, laboratory analysis, physical fitness, and neurocognitive testing were done. Health conditions were graded according to a modified version of the Common Terminology Criteria for Adverse Events. Neurocognitive domains of attention (Trial Making Test Part A and Conner's Continuous Performance Test-II) and executive function (Trail Making Test Part B, Controlled Oral Word Association Test, and Wechsler Adult Intelligence Scale-III Digit Span Test Backward) were measured and age-adjusted Z scores were calculated. Mean cumulative count was used to calculate the age-standardised cumulative burden of health conditions over time. This cohort study is registered at ClinicalTrials.gov, number NCT00760656., Findings: 980 survivors of acute lymphoblastic leukaemia (50% women, median age at diagnosis 5 years [IQR 3·1-9·1 years], and median time from diagnosis of 30·0 years [22·7-36·3]) had a median age of 35·8 years (29·4-42·9) at assessment compared with 35·1 years (28·7-42·6) for 272 controls. Survivors had significantly more growth hormone deficiency, hypogonadism, and neuropathy than controls. By age 30 years, survivors of acute lymphoblastic leukaemia had, on average, 5·4 (95% CI 5·1-5·8) grade 1-4 health conditions, including 3·2 (2·9-3·4) grade 2-4 health conditions, compared with 2·0 (CI 1·7-2·2) grade 1-4 and 1·2 (1·03-1·4) grade 2-4 health conditions among controls. The cumulative burden of grade 2-4 health conditions involved multiple organ systems for survivors treated on protocols between 1962-91, but after elimination of cranial radiotherapy for children with acute lymphoblastic leukaemia, conditions now predominately include musculoskeletal and endocrine disorders for survivors on protocols between 1991-2007., Interpretation: Although changes in paediatric acute lymphoblastic leukaemia treatment protocols have improved overall survival, the burden of late morbidity remains high for these patients. We show that the pattern of late toxic effects has markedly changed over time, with survivors having a reduction in health conditions that are immediately life-threatening, however, maintaining health status and quality of life for survivors of paediatric acute lymphoblastic leukaemia requires continued medical surveillance, counselling, and lifestyle modifications., Funding: US National Cancer Institute and the American Lebanese Syrian Associated Charities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown., Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS)., Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways., Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

Single-nucleotide polymorphisms (SNPs) contributing to interactions between regulatory elements that modulate gene transcription may explain some of the uncharacterized variation for complex traits. We explored this hypothesis among 856 adult survivors of pediatric cancer exposed to curative treatments that adversely affect bone mineral density (BMD). To restrict our search to interactions among SNPs in regulatory elements, our analysis considered 75523 SNPs mapped to putative promoter or enhancer regions. In anticipation that power to detect higher order epistasis would be low using an exhaustive search and a Bonferroni-corrected threshold for genome-wide significance (e.g., P < 5.6 × 10 -14 ), a novel non-exhaustive statistical algorithm was implemented to detect chromosome-wide three-way regulatory interactions. We used a permutation-based evaluation statistic to identify candidate SNP interactions with stronger associations with BMD than expected. Of the six regulatory 3-SNP interactions identified as candidate interactions (P < 3.5 × 10 -11 ) among cancer survivors exposed to treatments, five were replicated in an independent cohort of survivors (N = 1428) as modifiers of treatment effects on BMD (P < 0.05). Analyses with publicly available bioinformatics data revealed that SNPs contributing to replicated interactions were enriched for gene expressions (P = 3.6 × 10 -4 ) and enhancer states (P < 0.05) in cells relevant for bone biology. For each replicated interaction, implicated SNPs were within or directly adjacent to 100-kb windows of genomic regions that plausibly physically interact in lymphoblastoid cells. Our study demonstrates the utility of a hypothesis-driven approach in revealing epistasis associated with complex traits.