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Background Neurocognitive impairments are sequelae of childhood cancer treatment, however little guidance is given to clinicians on common phenotypes of impairment or modifiable risk factors that could lead to personalized interventions in survivorship. Methods Standardized clinical testing of neurocognitive function was conducted in 2958 (74.1%) eligible survivors, who were at least 5 years postdiagnosis and aged older than 18 years, and 477 community controls. Impairment was examined across 20 measures, and phenotypes were determined by latent class analysis. Multinomial logistic regression was used to estimate risk for phenotype, predicted by cancer diagnosis and treatment exposures, chronic health conditions, and lifestyle, adjusted for sex and age. Associations between phenotypes and social attainment were examined. Results Five neurocognitive phenotypes were identified in survivors (global impairment 3.7%, impaired attention 5.0%, memory impairment 7.2%, processing speed and executive function impairment 9.3%, no impairment 74.8%). Risk of global impairment was associated with severe chronic health condition burden (odds ratio [OR] = 20.17, 95% confidence interval [CI] = 11.41 to 35.63) including cerebrovascular disease (OR = 14.5, 95% CI = 5.47 to 38.44) and cerebrovascular accident (OR = 14.7, 95% CI = 7.50 to 26.40). Modifiable risk factors, such as quitting smoking, reduced risk for global impairment (OR = 0.21, 95% CI = 0.06 to 0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95% CI = 2.86 to 7.21), attention impairment (OR = 2.01, 95% CI = 1.41 to 2.87), processing speed and executive function impairment (OR = 1.90, 95% CI = 1.46 to 2.48), and memory impairment (OR = 2.09, 95% CI = 1.54 to 2.82). Conclusions Results support the clinical utility of neurocognitive phenotyping to develop risk profiles and personalized clinical interventions, such as preventing cerebrovascular disease in anthracycline-treated survivors by preventing hypercholesterolemia, smoking, and sedentary lifestyle, to reduce the risk for global impairment. [ABSTRACT FROM AUTHOR]

Background The Affordable Care Act (ACA) increased private nonemployer health insurance options, expanded Medicaid eligibility, and provided preexisting health condition protections. We evaluated insurance coverage among long-term adult survivors of childhood cancer pre- and post-ACA implementation. Methods Using the multicenter Childhood Cancer Survivor Study, we included participants from 2 cross-sectional surveys: pre-ACA (2007-2009; survivors: n = 7505; siblings: n = 2175) and post-ACA (2017-2019; survivors: n = 4030; siblings: n = 987). A subset completed both surveys (1840 survivors; 646 siblings). Multivariable regression models compared post-ACA insurance coverage and type (private, public, uninsured) between survivors and siblings and identified associated demographic and clinical factors. Multinomial models compared gaining and losing insurance vs staying the same among survivors and siblings who participated in both surveys. Results The proportion with insurance was higher post-ACA (survivors pre-ACA 89.1% to post-ACA 92.0% [+2.9%]; siblings pre-ACA 90.9% to post-ACA 95.3% [+4.4%]). Post-ACA insurance increase in coverage was higher among those aged 18-25 years (survivors: +15.8% vs +2.3% or less ages 26 years and older; siblings +17.8% vs +4.2% or less ages 26 years and older). Survivors were more likely to have public insurance than siblings post-ACA (18.4% vs 6.9%; odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.1 to 2.6). Survivors with severe chronic conditions (OR = 4.7, 95% CI = 3.0 to 7.3) and those living in Medicaid expansion states (OR = 2.4, 95% CI = 1.7 to 3.4) had increased odds of public insurance coverage post-ACA. Among the subset completing both surveys, low- and mid-income survivors (<$40 000 and <$60 000, respectively) experienced insurance losses and gains in reference to highest household income survivors (≥$100 000), relative to odds of keeping the same insurance status. Conclusions Post-ACA, more childhood cancer survivors and siblings had health insurance, although disparities remain in coverage. [ABSTRACT FROM AUTHOR]

Background Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships. Methods We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status. Results Analysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings; P <.001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P =.017) and psychological financial hardship (second quintile, P =.009; third quintile, P =.014). Lower psychological financial hardship was associated with individual factors including greater household income (≥$60 000 income, P <.001) and being single (P =.048). Conclusions Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships. [ABSTRACT FROM AUTHOR]

Background Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates. Methods Childhood cancer survivors (≥5 years from diagnosis; n = 12 340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep outcomes between survivors and siblings and evaluated cancer history and chronic health conditions (CHC) for associations with sleep outcomes, adjusting for age (at diagnosis and current), sex, race/ethnicity, and body mass index. Results Survivors were more likely to report clinically elevated composite PSQI scores (>5; 45.1% vs 40.0%, adjusted prevalence ratio [PR] = 1.20, 95% CI = 1.13 to 1.27), symptoms of insomnia (38.8% vs 32.0%, PR = 1.26, 95% CI = 1.18 to 1.35), snoring (18.0% vs 17.4%, PR = 1.11, 95% CI = 1.01 to 1.23), and sleep medication use (13.2% vs 11.5%, PR = 1.28, 95% CI = 1.12 to 1.45) compared with siblings. Within cancer survivors, PSQI scores were similar across diagnoses. Anthracycline exposure (PR = 1.13, 95% CI = 1.03 to 1.25), abdominal radiation (PR = 1.16, 95% CI = 1.04 to 1.29), and increasing CHC burden were associated with elevated PSQI scores (PRs = 1.21-1.48). Conclusions Among survivors, sleep problems were more closely related to CHC than diagnosis or treatment history, although longitudinal research is needed to determine the direction of this association. Frequent sleep-promoting medication use suggests interest in managing sleep problems; behavioral sleep intervention is advised for long-term management. [ABSTRACT FROM AUTHOR]

Background Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors. Methods Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls. Results Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non–high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio [HR] = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy. Conclusions Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population. [ABSTRACT FROM AUTHOR]

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]

Aims: The aim of this study was to investigate circulating ceramides involved in cardiovascular disease (CVD) in young adult childhood cancer survivors (CCS) and their correlations to previously reported adverse cardiovascular changes in this cohort. Methods and results: Fifty-seven CCS and 53 healthy controls (age 20-30 years) were studied. Plasma long-chain ceramides, known to be cardiotoxic (C16:0, C18:0, C24:0, and C24:1), were analysed by mass spectrometry. The coronary event risk test 2 (CERT2) score was calculated from the ceramide data. Cardiac and carotid artery ultrasound data and lipid data available from previous studies of this cohort were used to study partial correlations with ceramide and CERT2 score data. All four analysed ceramides were elevated in CCS compared with controls (P ≤ 0.012). The greatest difference was noted for C18:0, which was 33% higher in CCS compared with controls adjusted for sex, age, and body mass index (BMI) (P < 0.001). The CERT2 score was higher in CCS compared with controls (P < 0.001). In the CCS group, 35% had a high to very high CERT2 score (7-12) when compared with 9% in the control group (P < 0.001). The CCS subgroup with a CERT2 score ≥ 7 had higher heart rate, systolic blood pressure, and higher levels of apolipoprotein B compared with CCS with a CERT2 score < 6 (P ≤ 0.011). When adjusted for age, sex, and BMI, CERT2 score was significantly correlated with arterial stiffness, growth hormone, and cranial radiotherapy (P < 0.044). Conclusion: Ceramides could be important biomarkers in understanding the pathophysiology of CVD and in predicting CVD disease risk in young adult CCS. [ABSTRACT FROM AUTHOR]

Background Estimating the number of childhood cancer survivors is crucial for cancer control, including clinical guidelines. To compare estimates across countries despite data sharing restrictions, we propose a new method of computing limited-duration prevalence of childhood cancer survivors (POCCS) using aggregated data. Methods We developed a Markov model that simulates, for each calendar year and birth cohort in a population, the proportion of individuals in the following health states: healthy, newly diagnosed with cancer, surviving with cancer, and deceased. Transitions between health states were informed using annual sex- and age-specific incidence rates, conditional 1-year net survival probabilities from the Netherlands Cancer Registry (1989–2011), and annual mortality probability by sex and age group for The Netherlands from the Human Mortality Database. Applying a Markov model, we computed 20-year prevalence of childhood cancer survivors. The resulting POCCS estimates, stratified by sex, were compared with SEER*Stat estimates derived from individual cancer records from the same registry. Results In 2011, POCCS predicted 654 males [95% confidence interval (95% CI): 637–672] and 539 females (95% CI: 523–555) per million persons living in The Netherlands after childhood cancer diagnosed within the previous 20 years. Using SEER*Stat, the 20-year prevalence was 665 males (95% CI: 647–683) and 544 females (95% CI: 529–560) per million persons on 1 July 2011. Conclusions Using the POCCS model and aggregated cancer data, our estimates of childhood cancer survivors limited-duration prevalence were consistent with those computed by a standard method requiring individual cancer records. The POCCS method provides relevant information for planning follow-up and care for childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Overweight and obesity are common challenges among childhood cancer survivors. Overweight may be disguised, as survivors can have normal weight but high fat percentage (fat%) on dual-energy X-ray absorptiometry (DXA). We aimed to assess prevalence, identify determinants and biomarkers, and assess which method captures overweight best, in a nationwide cohort. Methods: The prevalence of overweight and obesity, primarily defined by body mass index (BMI), was assessed in the DCCSS-LATER cohort of adult survivors treated from 1963-2002, with the LifeLines cohort as reference. The associations between risk factors and overweight metrics were investigated using logistic regression. Additional overweight metrics included DXA fat%, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and high-molecular-weight (HMW) adiponectin. Results: A total of 2338 (mean age 35.5 years, follow-up 28.3 years) survivors participated. The overweight prevalence was 46.3% in men and 44.3% in women (obesity 11.2% and 15.9%, morbid obesity 2.4% and 5.4%), with highest rates among brain tumor survivors. Compared to controls, there was no overall increased overweight rate, but this was higher in women > 50 years, morbid obesity in men > 50 years. Overweight at cancer diagnosis (adjusted odds ratio [aOR] = 3.83, 95% CI 2.19-6.69), cranial radiotherapy (aOR = 3.21, 95% CI 1.99-5.18), and growth hormone deficiency (separate model, aOR = 1.61, 95% CI 1.00-2.59) were associated with overweight. Using BMI, WC, WHR, and WHtR, overweight prevalence was similar. Low HMW adiponectin, present in only 4.5% of survivors, was an insensitive overweight marker. Dual-energy X-ray absorptiometry–based classification identified overweight in an additional 30%, particularly after abdominal radiotherapy, total body irradiation, anthracyclines, and platinum. Conclusions: Overweight occurs in almost half of long-term survivors. There was no overall increased incidence of overweight compared to controls. We identified factors associated with overweight, as well as subgroups of survivors in whom DXA can more reliably assess overweight. [ABSTRACT FROM AUTHOR]

Background: Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly. Patients and Methods: This was a cross-sectional study of 132 patients treated with irradiation at Children's Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children's Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data. Results: Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P =.099), with significant savings in patients with CNS tumors (P =.012). Among patients with savings, average savings were $9620 per patient (P =.016) and significantly more likely for females than males (P =.027). Conclusion: Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings. This article compares the projected healthcare costs associated with using volumetric dosimetry versus broad anatomic irradiated regions screening to determine radiation-related late effects screening recommendations for survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Background: Adult survivors of childhood cancer are at increased risk of cardiac late effects.Methods: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided.Results: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors.Conclusions: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association. [ABSTRACT FROM AUTHOR]

Study Question: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors?Summary Answer: We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors.What Is Known Already: Survival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies.Study Design, Size, Duration: Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors.Participants/materials, Setting, Methods: Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression.Main Results and the Role Of Chance: The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046).Limitations, Reasons For Caution: The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls.Wider Implications Of the Findings: Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors.Study Funding/competing Interest(s): This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared.Trial Registration Number: NCT01298388 (clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Study Question: Is the rate of fatherhood among men diagnosed with cancer in childhood and early adulthood different from men without cancer, and, if so, have the differences changed over time?Summary Answer: Men diagnosed with cancer have had significantly reduced rates of fatherhood compared with undiagnosed men; however, the rates of fatherhood among the cancer survivors have increased markedly over time.What Is Known Already: The number of children and young adolescents who survive cancer has steadily increased over recent decades, with a current 5-year survival rate of approximately 80%. Consequently, life circumstances after cancer have gained increasing importance, including the desire among survivors to have children and a family. ARTs to aid reproduction among cancer survivors have been developed, and fertility preservation is increasingly a topic being discussed before undergoing cancer treatment. But the potential for fertility preservation differs dependent on age at diagnosis and type of cancer. Earlier studies have shown a decreased fertility rate among survivors of child and adolescent cancer compared to those diagnosed in early adulthood.Study Design, Size, Duration: This study is a national, register-based cohort study. Men diagnosed with cancer in childhood and early adulthood (<30 years of age) were registered in the Danish Cancer Register in 1978-2016 (n = 9353). According to the time of diagnosis, each cancer-diagnosed man was randomly matched with 150 undiagnosed men from the background population within the same birth year. The men were followed until having their first child, death, migration or the end of the study (31 December 2017) in medical registers and socio-demographic population registers.Participants/materials, Setting, Methods: Fatherhood among the boys and young men diagnosed with cancer were compared with the age-matched comparison group in all statistical analyses. Cancer diagnoses were categorised as central nervous system (CNS) cancers, haematological cancers or solid cancers. Analyses were stratified by age at diagnosis (0-9, 10-19, 20-29 years) and time of diagnosis (1978-1989, 1990-1999, 2000-2009, 2010-2016). Death was incorporated as a competing risk in all analyses.Main Results and the Role Of Chance: The study population consisted of 9353 boys and young men diagnosed with cancer between 1978 and 2016 and 1 386 493 men in the age-matched comparison group. Those surviving CNS cancer as young men had the lowest hazard ratio (HR) of fatherhood compared with the age-matched comparison group (HR 0.67, 95% CI 0.57-0.79), followed by survivors of haematological cancers (HR 0.90, 95% CI 0.81-1.01), while the highest chance of fatherhood was among survivors of solid cancers (HR 1.16, 95% CI 1.12-1.20) with a slightly increased HR compared with undiagnosed males. The HR of becoming a father increased over time. From the first decade to the last decade 30 years later, the HR of becoming a father increased for solid tumours (HR 0.78, 95% CI 0.73-0.83 to HR 1.08, 95% CI 0.95-1.22), haematological cancers (HR 0.64, 95% CI 0.53-0.79 to HR 0.97, 95% CI 0.73-1.30) and CNS cancers (HR 0.44, 95% CI 0.34-0.57 to HR 0.98, 95% CI 0.49-1.95) compared to the age-matched comparison group. Also, when compared with the age-matched comparison group, men diagnosed with cancer when aged 20-29 years were more likely became fathers over the time of the study (HR 0.80, 95% CI 0.74-0.86 to HR 1.08, 95% CI 0.96-1.22).Limitations, Reasons For Caution: The study was based on register data, and information was not available about the men's fertility potential, whether they had a desire to have children and whether it was possible for them to find a partner. Information about fertility preservation, e.g. sperm freezing, could also have provided additional insights. Furthermore, information about diagnosis and ART treatment would have been beneficial.Wider Implications Of the Findings: Information and education of male patients diagnosed with cancer about fertility preservation options and their chances to create their own family is crucial. Reassuringly, time trends showed more men with a previous cancer diagnosis becoming fathers in recent years than in earlier years, reflecting that survival and fertility preservation have improved over time.Study Funding/competing Interest(s): R.S. received a PhD grant from the Rosa Ebba Hansen Foundation and from the Health Foundation (J.nr. 15-B-0095). The funding for the establishment of the DANAC II Cohort was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflicts of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome‐wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time‐to‐event analysis) and prioritized sex‐ and treatment‐stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome‐wide significant (p < 5 × 10−8) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex‐specific effects (psex‐heterogeneity < 7 × 10−6). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10−9; n = 1935 women) at this locus. In treatment‐stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95–1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54–2.28, p = 2.4 × 10−10; >36 Gray only: HR = 3.79, 95% CI 1.95–7.34, p = 8.2 × 10−5). These head/neck RT‐specific HAGHL single‐nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Most childhood cancer survivors who undergo hematopoietic stem cell transplantation subsequently develop impaired glucose tolerance and hypertriglyceridemia. These conditions are presumably associated with total-body irradiation–related acquired lipodystrophy and may lead to cardiovascular disease. Metreleptin (recombinant leptin) may help improve the lipoprotein profile, insulin sensitivity, and quality of life of patients with total-body irradiation-related lipodystrophy. This report describes the safe and effective use of metreleptin supplementation for insulin resistance and dyslipidemia in acquired incomplete lipodystrophy. A 24-year-old Japanese woman with diabetes mellitus and hypertriglyceridemia was admitted to our hospital. She was diagnosed with acute lymphocytic leukemia at 3 years of age and had undergone systemic chemotherapy and total-body irradiation before allogeneic stem cell transplantation. She was also diagnosed with hypertriglyceridemia and diabetes mellitus at 11 years of age. She had a low adiponectin level, low-normal leptin level, and diabetes mellitus with marked insulin resistance. Thus, acquired incomplete lipodystrophy was diagnosed. Her serum triglyceride and lipoprotein profiles improved within 1 month of treatment initiation. Glycemic metabolism and insulin sensitivity in the skeletal muscles improved after 6 months. As previously reported, metreleptin therapy is effective in improving lipid and glycemic profiles in generalized lipodystrophy. In the present case, we considered that metreleptin supplementation could reduce the remnant VLDL cholesterol fraction and improve diabetes mellitus. We conclude that it may be an effective alternative therapy for improving the expected prognosis of patients with acquired incomplete lipodystrophy, including childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Objective To examine the impact of cancer treatment upon neurocognitive and functional impairment; and to explore the relationship between these constructs in pediatric cancer survivors compared to controls. Method A cross-sectional cohort of survivors (n = 26) and controls (n = 53) was included. Survivors were off treatment an average of 6.35 years (SD = 5.38; range 1–15 years) and demonstrated an average "medium" Central Nervous System (CNS) treatment intensity score. Participants completed measures of neurocognitive functions including intellectual assessment (RIST) and executive functions (NIH Examiner), while parents reported on children's functional impairment (BIS). Results Survivors were similar to controls in neurocognitive ability, including intellectual and executive functions, and functional impairment. Regardless of group membership, NIH Examiner performance and functional impairment increased with age. Increased impairment was associated with different neurocognitive variables for survivors versus controls. Conclusions Research regarding functional impairment of cancer survivors and the association between neurocognitive deficits and functional impairment has been limited. Our results demonstrate that, while low treatment intensity may confer relative sparing of neurocognitive and executive functioning among survivors, functional impairment continues to be a potential risk. In conclusion, pediatric cancer survivors should be screened for functional difficulties, particularly in the areas of interpersonal relations and self-care. [ABSTRACT FROM AUTHOR]

Study Question: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)?Summary Answer: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT.What Is Known Already: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited.Study Design, Size, Duration: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study.Participants/materials, Setting, Methods: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology.Main Results and the Role Of Chance: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT.Limitations, Reasons For Caution: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses.Wider Implications Of the Findings: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation.Study Funding/competing Interests: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests.Trial Registration Number: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922. [ABSTRACT FROM AUTHOR]

Study Question: Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer?Summary Answer: Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving.What Is Known Already: Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment.Study Design, Size, Duration: This study is part of the DCOG LATER-VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014.Participants/materials, Setting, Methods: Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire.Main Results and the Role Of Chance: Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2).Limitations, Reasons For Caution: Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment-related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias.Wider Implications Of the Findings: Decisions about parenthood affect all CCSs. It's important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment.Study Funding/competing Interest(s): This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20).Trial Registration Number: NTR2922. [ABSTRACT FROM AUTHOR]

Significant advancements in treatment modalities over the past few decades have significantly improved the survival rates of many types of childhood cancer, directing attention to the psychosocial consequences of successful treatment and subsequent survival. This study assesses quality of life (QoL) among survivors of childhood cancer. Data were collected by means of a survey questionnaire. Participants were assured of confidentiality and of the voluntary nature of participation. Participants ranged in age from 12 to 24 years (mean age = 17.2); 62 percent were male; 45.6 percent were in secondary grades (middle school or high school). Results showed that among the QoL domains, spiritual subscale ranked highest, and physical domain showed the lowest mean score. Self-esteem emerged as an important predictor for social domain of QoL. Cancer-specific worry emerged as a significant predictor for overall QoL. The findings suggest that survivors rated high on positive life changes and sense of purpose, which are associated with positive QoL. However, this was tempered by worries and uncertainty. This study provides seminal information on the psychosocial needs of childhood cancer survivors in an Asian context that can be used by health care professionals and providers to further promote support and health care following treatment. [ABSTRACT FROM AUTHOR]

Abstract: Adult survivors of childhood cancers are more prone to developing poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. Chemotherapy drugs exert cytotoxic effects systemically and therefore can damage the ovaries, leading to infertility, premature ovarian failure, and, to a lesser extent, spontaneous abortions. They have very limited or no deleterious effects on the uterus that can be recognized clinically. By contrast, radiation is detrimental to both the ovaries and the uterus, thereby causing a greater magnitude of adverse effects on the female reproductive function. These include infertility, premature ovarian failure, miscarriage, fetal growth restrictions, perinatal deaths, preterm births, delivery of small‐for‐gestational‐age infants, preeclampsia, and abnormal placentation. Regrettably, the majority of these adverse outcomes arise from radiation‐induced uterine injury and are reported at higher incidence in the adult survivors of childhood cancers who were exposed to uterine radiation during childhood in the form of pelvic, spinal, or total‐body irradiation. Recent findings of long‐term follow‐up studies evaluating reproductive performance of female survivors provided some reassurance to female cancer survivors by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total‐body irradiation. We aimed in this narrative review article to provide an update on the impact of chemotherapy and radiation on the ovarian and uterine function in female survivors of childhood cancer. Implications for Practice: Adult survivors of childhood cancers are more prone to developing a number of poor reproductive and obstetrical outcomes than their siblings and the general population as a result of previous exposure to chemotherapy and radiation during childhood. The impact of radiation therapy on the female genital system is greater than chemotherapy regimens because radiation is detrimental to both the uterus and the ovaries, whereas toxic effects of chemotherapy drugs are confined to the ovaries. Therefore, radiation‐induced uterine damage accounts for most poor obstetrical outcomes in the survivors. These include infertility, miscarriages, stillbirths, fetal growth restrictions, preeclampsia, and preterm deliveries. [ABSTRACT FROM AUTHOR]

Study Question: Is testicular transplantation of in vitro propagated spermatogonial stem cells associated with increased cancer incidence and decreased survival rates in recipient mice?Summary Answer: Cancer incidence was not increased and long-term survival rate was not altered after transplantation of in vitro propagated murine spermatogonial stem cells (SSCs) in busulfan-treated recipients as compared to non-transplanted busulfan-treated controls.What Is Known Already: Spermatogonial stem cell autotransplantation (SSCT) is a promising experimental reproductive technique currently under development to restore fertility in male childhood cancer survivors. Most preclinical studies have focused on the proof-of-principle of the functionality and efficiency of this technique. The long-term health of recipients of SSCT has not been studied systematically.Study Design, Size, Duration: This study was designed as a murine equivalent of a clinical prospective study design. Long-term follow-up was performed for mice who received a busulfan treatment followed by either an intratesticular transplantation of in vitro propagated enhanced green fluorescent protein (eGFP) positive SSCs (cases, n = 34) or no transplantation (control, n = 37). Using a power calculation, we estimated that 36 animals per group would be sufficient to provide an 80% power and with a 5% level of significance to demonstrate a 25% increase in cancer incidence in the transplanted group. The survival rate and cancer incidence was investigated until the age of 18 months.Participants/materials, Setting, Methods: Neonatal male B6D2F1 actin-eGFP transgenic mouse testis were used to initiate eGFP positive germline stem (GS) cell culture, which harbor SSCs. Six-week old male C57BL/6 J mice received a single dose busulfan treatment to deplete the testis from endogenous spermatogenesis. Half of these mice received a testicular transplantation of cultured eGFP positive GS cells, while the remainder of mice served as a control group. Mice were followed up until the age of 18 months (497-517 days post-busulfan) or sacrificed earlier due to severe discomfort or illness. Survival data were collected. To evaluate cancer incidence a necropsy was performed and tissues were collected. eGFP signal in transplanted testis and in benign and malignant lesions was assessed by standard PCR.Main Results and the Role Of Chance: We found 9% (95% CI: 2-25%) malignancies in the transplanted busulfan-treated animals compared to 26% (95% CI: 14-45%) in the busulfan-treated control group, indicating no statistically significant difference in incidence of malignant lesions in transplanted and control mice (OR: 0.3, 95% CI: 0.1-1.1). Furthermore, none of the malignancies that arose in the transplanted animals contained eGFP signal, suggesting that they are not derived from the in vitro propagated transplanted SSCs. Mean survival time after busulfan treatment was found to be equal, with a mean survival time for transplanted animals of 478 days and 437 days for control animals (P = 0.076).Large Scale Data: NA.Limitations, Reasons For Caution: Although we attempted to mimic the future clinical application of SSCT in humans as close as possible, the mouse model that we used might not reflect all aspects of the future clinical setting.Wider Implications Of the Findings: The absence of an increase in cancer incidence and a decrease in survival of mice that received a testicular transplantation of in vitro propagated SSCs is reassuring in light of the future clinical application of SSCT in humans.Study Funding/competing Interest(s): This study was funded by KiKa (Kika86) and ZonMw (TAS 116003002). The authors report no financial or other conflict of interest relevant to the subject of this article. [ABSTRACT FROM AUTHOR]

Study Question: Do young adult survivors of childhood cancer know their fertility status, in the context of their parenthood goals and screening for gonadal functioning?Summary Answer: While 80% of survivors (who were without children) wanted children in the future, most did not know their fertility status, and screening for gonadal functioning was underutilized.What Is Known Already: Survivors of childhood cancer are at risk for infertility, but fertility counseling and assessment are underutilized. Separate studies indicated that survivors' fertility-related knowledge is poor and that they often wanted to have children. Yet, studies have not investigated the intersection of both issues, as well as potential distress if parenthood goals are not met.Study Design, Size, Duration: Young adult male and female survivors of childhood cancer (N = 149) completed cross-sectional surveys, and data for those without children (n = 105, 70.5%) are presented here.Participants/materials, Setting, Methods: Participants were 20-40 years old (M = 26.5), diagnosed 5-33 years prior to study participation, and completed questionnaires online. Knowledge of fertility status, parenthood goals, and potential distress if survivors were unable to have children were assessed. Medical records were reviewed for hormone levels as indicators of screening for gonadal functioning.Main Results and the Role Of Chance: Most survivors (n = 81; 77.1%) did not know their fertility status, while over 80% (n = 89) wanted children (neither aspect varied by socio-demographic/cancer-specific factors). Two-thirds of survivors indicated they would be distressed if parenthood goals remained unfulfilled; especially female (versus male, t = 2.64; P = 0.01) or partnered (versus single, t = -3.45; P < 0.001) survivors. Forty survivors (38.1%) had documented assessments of gonadal functioning, of which 33 (82.5%) reported not knowing their fertility status.Limitations, Reasons For Caution: Relevant risk factors may have not been identified owing to limited sample size and missing treatment information. The underutilization of screening for gonadal functioning needs further exploration in other pediatric centers.Wider Implications Of the Findings: Most adult childhood cancer survivors want to become parents, but do not know their fertility status, which could cause significant psychological distress. Healthcare providers should continuously address fertility among survivors, but more research is needed on how to implement routine fertility counseling and/or testing.Study Funding/competing Interest(s): This study was funded by the Research Institute at Nationwide Children's Hospital (V.L.) and Dutch Cancer Society (RUG2009-4442, M.A.T.). All authors have no conflict of interest to declare. [ABSTRACT FROM AUTHOR]

STUDY QUESTION: What is the effect of different alkylating agents used without pelvic radiation to treat childhood cancer in girls on the ovarian reserve in survivors? SUMMARY ANSWER: Ovarian reserve seems to be particularly reduced in survivors who received procarbazine (in most cases for Hodgkin lymphoma) or high-dose chemotherapy; procarbazine but not cyclophosphamide dose is associated with diminished ovarian reserve. WHAT IS KNOWN ALREADY: A few studies have demonstrated diminished ovarian reserve in survivors after various combination therapies, but the individual role of each treatment is difficult to assess. STUDY DESIGN: Prospective cross-sectional study, involving 105 survivors and 20 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and five survivors aged 17-40years and 20 controls investigated on Days 2-5 of a menstrual cycle or Day 7 of an oral contraceptive pill-free interval. Main outcome measures: ovarian surface area (OS), total number of antral follicles (AFC), serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and anti-Mullerian hormone (AMH). MAIN RESULTS AND THE ROLE of CHANCE: Survivors had a lower OS than controls: 3.5 versus 4.4 cm² per ovary (P = 0.0004), and lower AMH levels: 10.7 versus 22 pmol/l (P = 0.003). Ovarian markers (OS, AMH, AFC) were worse in patients who received high-dose compared with conventional-dose alkylating agents (P = 0.01 for OS, P = 0.002 for AMH, P < 0.0001 for AFC). Hodgkin lymphoma survivors seemed to have a greater reduction in ovarian reserve than survivors of leukaemia (P = 0.04 for AMH, P = 0.01 for AFC), sarcoma (P = 0.04 for AMH, P = 0.04 for AFC) and other lymphomas (P = 0.04 for AFC). A multiple linear regression analysis showed that procarbazine but not cyclophosphamide nor ifosfamide dose was associated with reduced OS (P = 0.0003), AFC (P = 0.0007), AMH (P < 0.0001) and higher FSH levels (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: The small percentage of participating survivors (28%) from the total cohort does not allow conclusion on fertility issues because of possible response bias. The association between procarbazine and HL makes it impossible to dissociate their individual impacts on ovarian reserve. The number of controls is small, but ovarian volume and AMH levels in survivors were compared with published normal values and results were unchanged. WIDER IMPLICATIONS OF THE FINDINGS: Early detection and follow-up of compromised ovarian function after cancer therapy should help physicians to counsel young survivors about their fertility window. However, longitudinal follow-up is required to determine the rate of progression from low ovarian reserve to premature ovarian failure. STUDY FUNDING/COMPETING INTEREST(S): La Ligue contre le Cancer (grant no., PRAYN7497). The authors have no competing interests to disclose. [ABSTRACT FROM AUTHOR]

Smoking among childhood and young adult cancer survivors may increase risk for late effects of treatment, and survivors need assistance in quitting. This paper reports on the prevalence of discussions between childhood cancer survivors and their health care providers about smoking cessation and pharmacotherapy and explores factors that are associated with these discussions. This is a longitudinal study that included 329 smokers who were childhood or young adult cancer survivors, recruited from five cancer centers in the USA and Canada. Fifty-five percent of smokers reported receiving advice to quit smoking from their regular provider during the study period, and only 36 % of smokers reported discussing pharmacotherapy with their provider. Receipt of advice was associated with being female and having a heavier smoking rate. Pharmacotherapy discussions were associated with readiness to quit, heavier smoking rate, and previous provider advice to quit. Health care providers are missing key opportunities to advise cancer survivors about cessation and evidence-based interventions. Systematic efforts are needed to ensure that survivors who smoke get the treatment that they need. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? SUMMARY ANSWER The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. WHAT IS KNOWN ALREADY Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. STUDY DESIGN, SIZE, DURATION We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176). PARTICIPANTS/MATERIALS, SETTING, METHODS We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. MAIN RESULTS AND THE ROLE OF CHANCE The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35–7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. LIMITATIONS, REASONS FOR CAUTION This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. WIDER IMPLICATIONS OF THE FINDINGS Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. STUDY FUNDING AND CONFLICT OF INTEREST W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose. [ABSTRACT FROM PUBLISHER]

Introduction There are over 13 million cancer survivors in the United States, which constitutes 3-4% of the U. S. population. According to the Surveillance Epidemiology and End Results program ( SEER) data the 5-year overall survival rate for children diagnosed with cancer between ages 0-19 is 83.1%, and 2/3 of childhood cancer survivors will experience at least one late effect of treatment. Aim To provide a brief overview of the medical and psychosocial effects of cancer treatments in survivors of childhood cancer with a focus on sexual and reproductive health issues in this population. Methods The development of a manuscript from a presentation at the Annual Society of Sexual Medicine meeting. An overview of long-term and late effects of treatment experienced by young adult cancer survivors was presented. Main Outcome Measure This manuscript is based on a presentation that reviewed the medical and psychosocial literature, consensus statements of professional groups, and clinical observations. Results Cancer and cancer treatments have both direct and indirect effects of physiological, psychological, and interpersonal factors that can negatively impact the health and well-being of cancer survivors including sexual and reproductive function and satisfaction. Conclusions Cancer, its management, and the resulting late effects must be explored and understood by providers caring for childhood cancer survivors so that educational, psychological, pharmacologic, as well as preventive interventions can be implemented with this population. [ABSTRACT FROM AUTHOR]

Aims Subendocardial layer of the ventricle has been shown to be sensitive to anthracycline damage. This study tested the hypothesis that anthracycline therapy for childhood malignancies has differential impact on deformation and rotation of left ventricular (LV) subendocardial and subepicardial layers and hence transmural myocardial strain and rotation gradients. Methods and results Thirty-two anthracycline-treated survivors of childhood malignancies aged 19.3 ± 5.4 years and 28 controls were studied. Apical four-chamber and parasternal LV short-axis acquisitions at base, papillary muscle level, and apex were analysed for layer-specific myocardial strain and apical and basal rotation and rotational velocities using two-dimensional speckle tracking echocardiography. Transmural strain and rotation gradients were calculated as differences between peak systolic strain and rotation between the inner and outer layers, respectively. Compared with controls, patients had significantly lower transmural circumferential, but not radial or longitudinal, strain gradients (P< 0.05), accounted by the reduced subendocardial circumferential strain, at all three ventricular levels (all P< 0.05). No significant difference in basal transmural rotation gradient was found between patients and controls (P= 0.32). On the other hand, apical rotation, systolic twisting velocity, and diastolic untwisting velocity were reduced preferentially at the subendocardial layer in patients (all P< 0.05), hence accounting for their significantly reduced transmural rotation gradient compared with controls (P< 0.001). The LV ejection fraction correlated inversely with apical transmural circumferential strain gradient (r= −0.39, P= 0.002) and rotation gradient (r= 0.33, P= 0.01). Conclusion Preferential impairment of subendocardial circumferential deformation and apical rotation with consequential reduction of transmural circumferential strain and rotation gradients occurs in anthracycline-treated survivors of childhood cancers. [ABSTRACT FROM AUTHOR]

The last four decades have seen tremendous improvements in the survival of children diagnosed with cancer, with 5-year survival rates now at 80%. The burgeoning population of childhood cancer survivors creates an obligation to understand the health and well-being of these individuals. The use of cancer therapy at an early age can produce complications that may not become apparent until years later; it has been demonstrated quite conclusively that approximately two thirds of these survivors will experience at least one late effect and about one third will experience a late effect that is severe or life threatening. Long-term complications in childhood cancer survivors, such as impairment in growth and development, neurocognitive dysfunction, cardiopulmonary compromise, endocrine dysfunction, renal impairment, gastrointestinal dysfunction, musculoskeletal sequelae, and subsequent malignancies, are not only related to the specific therapy employed, but may also be determined by individual host characteristics. This review describes some of the known late effects described in childhood cancer survivors in order to suggest reasonable starting points for evaluation of specific long-term problems in this unique and growing population. [ABSTRACT FROM AUTHOR]

The study’s purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks using a bioassay with γH2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2Gy and 5Gy) and γH2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean γH2AX intensity between cases and controls were compared using Kruskall-Wallis tests. Generalized Linear Models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline γH2AX intensity measured without irradiation was 9.1 (95% confidence interval (95% CI): 8.5–9.7) in the LCLs from cases and 6.4 (95% CI: 6.0–6.8) from controls (P<0.001). Markedly higher γH2AX intensity, particularly at 1 hour post-irradiation, was also found in the LCLs from the cases compared to the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on γH2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by γH2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association. [ABSTRACT FROM AUTHOR]