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1.  Central Precocious Puberty following the Diagnosis and Treatment of Pediatric Cancer and Central Nervous System Tumors: Presentation and Long-term Outcomes 
Clinical endocrinology  2015;84(3):361-371.
Objectives
To estimate the prevalence of central precocious puberty (CPP) after treatment for tumors and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes.
Design
Retrospective study of patients with tumors near and/or exposed to radiotherapy to the hypothalamus/pituitary (HPA).
Patients and Measurements
Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa), and last follow-up. Multivariable analysis was used to test associations between tumor location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively.
Results
Eighty patients (47 females) had CPP and were followed for 11.4±5.0 years (mean ± SD). The prevalence of CPP was 15.2% overall, 29.2% following HPA tumors and 6.6% after radiotherapy for non-HPA tumors. Height <-2SDS was more common at the last follow-up than at puberty onset (21.4% vs. 2.4%, p=0.005). Obesity was more prevalent at the last follow-up than at completion of GnRHa or puberty onset (37.7%, 22.6% and 20.8% respectively, p=0.03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR=2.1, 95% CI 1.0–4.3); longer follow-up with obesity (OR=1.3, 95% CI 1.1–1.6). LH/FSHD was diagnosed in 32.6%. There was no independent association between CPP and final height <- 2SDS, LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas.
Conclusions
Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.
doi:10.1111/cen.12964
PMCID: PMC4755813  PMID: 26464129
Puberty; precocious; Primary brain neoplasms
2.  Lifestyle, distress and pregnancy outcomes in the Childhood Cancer Survivor Study cohort 
OBJECTIVE
To evaluate associations between prepregnancy lifestyle factors, psychological distress and adverse pregnancy outcomes among female survivors of childhood cancer.
STUDY DESIGN
We examined pregnancies of 1,192 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, psychological distress and pregnancy outcomes. Interactions between lifestyle factors, psychological 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 1,858 reported pregnancies, there were 1,300 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 to those who had never smoked, survivors with > 5 pack-years smoking history had a higher risk for miscarriage among those treated with > 2.5 Gy uterine radiation (OR: 53.9; 95% CI: 2.2, 1,326.1) 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 (Pinteraction = 0.01).
CONCLUSION
While most lifestyle factors and psychological 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.
doi:10.1016/j.ajog.2014.07.036
PMCID: PMC4275351  PMID: 25068563
pregnancy; childhood cancer survivors; uterine radiation; smoking; lifestyle
3.  Twenty-Five Year Follow-Up of Childhood Wilms Tumor: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;57(7):1210-1216.
Background
Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year Wilms tumor survivors in the Childhood Cancer Survivor Study (CCSS).
Procedure
The CCSS, a multi-institutional retrospective cohort study, assessed Wilms tumor survivors (n=1256), diagnosed 1970 – 1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (n=4023).
Results
The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard Ratios [HR] were 2.0, 95% Confidence Interval [CI], 1.8-2.3 for grades 1 -4 and 4.7, 95% CI, 3.6-6.1 for grade 3-4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (Prevalence Ratio [PR] 1.7; 95% CI, 1.2–2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI, 1.9–4.0%) and of mortality was 6.1% (95%CI, 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin - HR 6.6; 95%CI, 1.6-28.3; doxorubicin ≤ 250 mg/m2 - HR 13.0; 95%CI, 1.9-89.7; doxorubicin > 250 mg/m2 - HR 18.3; 95%CI, 3.8-88.2), SMN (Standardized Incidence Ratio [SIR] 9.0; 95%CI, 3.9-17.7 with and 4.9; 95%CI, 1.8-10.6 without doxorubicin) and death.
Conclusion
Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
doi:10.1002/pbc.23090
PMCID: PMC4634648  PMID: 21384541
Wilms Tumor; late effects; survivorship
4.  Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study 
The Lancet. Oncology  2014;15(11):1215-1223.
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/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 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/m2. 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.
doi:10.1016/S1470-2045(14)70408-5
PMCID: PMC4192599  PMID: 25239573
5.  Infections Among Long-term Survivors of Childhood and Adolescent Cancer: A Report From the Childhood Cancer Survivor Study 
Cancer  2014;120(16):2514-2521.
Purpose
Little is known about infections among adult survivors of childhood cancer. We report the occurrence of and risk factors for infections in a large cohort of survivors of childhood cancer.
Methods
Using the Childhood Cancer Survivor Study (CCSS) cohort, incidence rates of infections among 12,360 five-year survivors of childhood cancer, were compared to those of 4,023 siblings. Infection-related mortality of survivors was compared to the U.S. population. Demographic and treatment variables were analyzed using Poisson regression to determine the rate ratio (RR) and corresponding 95% confidence intervals (CI) for associations with infectious complications.
Results
Compared with the U.S. population, survivors were at an increased risk of death from infectious causes (Standardized Mortality Ratio (SMR)= 4.2; 95% CI, 3.2-5.4), with females (SMR= 3.2; 95% CI, 1.5-6.9) and those exposed to total body irradiation (SMR= 7.8; 95% CI, 1.8-33.0) having the greatest risk. Survivors also reported higher rates than siblings of overall infectious complications (RR=1.3; 95% CI, 1.2-1.4), and higher rates of all categories of infection.
Conclusion
Survivors of childhood cancer remain at elevated risk for developing infectious-related complications, with a higher risk of infection-related mortality years following therapy. Further investigation is needed to provide insight into the mechanisms for the observed excess risks.
doi:10.1002/cncr.28763
PMCID: PMC4159255  PMID: 24824782
Childhood cancer; adolescent cancer; late effects; infections; survivorship
6.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Summary
Background
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
Methods
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
Findings
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Interpretation
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
Funding
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
doi:10.1016/S1470-2045(14)70265-7
PMCID: PMC4142216  PMID: 24954778
7.  Childhood Cancer, Endocrine Disorders, and Cohort Studies 
Lancet  2014;383(9933):1950-1952.
doi:10.1016/S0140-6736(14)60114-8
PMCID: PMC4094362  PMID: 24556021
8.  Aging and Risk of Severe, Disabling, Life-Threatening, and Fatal Events in the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2014;32(12):1218-1227.
Purpose
The first generation of childhood cancer survivors is now aging into their fourth and fifth decades of life, yet health risks across the aging spectrum are not well established.
Methods
Analyses included 14,359 5-year survivors from the Childhood Cancer Survivor Study, who were first diagnosed when they were younger than 21 years old and who received follow-up for a median of 24.5 years after diagnosis (range, 5.0 to 39.3 years) along with 4,301 of their siblings. Among the survivors, 5,604 were at least 35 years old (range, 35 to 62 years) at last follow-up. Severe, disabling, life-threatening, and fatal health conditions more than 5 years from diagnosis were classified using the Common Terminology Criteria for Adverse Events, grades 3 to 5 (National Cancer Institute).
Results
The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6%; 95% CI, 51.5 to 55.6; v 19.8%; 95% CI, 17.0 to 22.7) by age 50 years. When comparing survivors with siblings, hazard ratios (HR) were significantly increased within the age group of 5 to 19 years (HR, 6.8; 95% CI, 5.5 to 8.3), age group of 20 to 34 years (HR, 3.8; 95% CI, 3.2 to 4.5), and the ≥ 35 years group (HR, 5.0; 95% CI, 4.1 to 6.1), with the HR significantly higher among those ≥ 35 years versus those 20 to 34 years old (P = .03). Among survivors who reached age 35 years without a previous grade 3 or 4 condition, 25.9% experienced a subsequent grade 3 to 5 condition within 10 years, compared with 6.0% of siblings (P < .001).
Conclusion
Elevated risk for morbidity and mortality among survivors increases further beyond the fourth decade of life, which affects the future clinical demands of this population relative to ongoing surveillance and interventions.
doi:10.1200/JCO.2013.51.1055
PMCID: PMC3986385  PMID: 24638000
9.  Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(7):647-653.
Purpose
The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed.
Patients and Methods
By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease.
Results
By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10−7). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m2) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09).
Conclusion
Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) –induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.
doi:10.1200/JCO.2013.50.3557
PMCID: PMC3927733  PMID: 24470002
10.  Suicide Ideation and Associated Mortality in Adult Survivors of Childhood Cancer 
Cancer  2013;120(2):271-277.
Background
Adult survivors of childhood cancer are at-risk for suicide ideation, though longitudinal patterns and rates of recurrent suicide ideation are unknown. We investigated the prevalence of late report (i.e. post-initial assessment) and recurrent suicide ideation in adult survivors of childhood cancer, identified predictors of suicide ideation, and examined associations among suicide ideation and mortality.
Methods
Participants included 9,128 adult survivors of childhood cancer and 3,082 sibling controls enrolled in the Childhood Cancer Survivor Study who completed a survey question assessing suicide ideation on one or more occasions between 1994 and 2010. Suicide ideation was assessed using the Brief Symptom Inventory-18. Mortality data was ascertained from the National Death Index.
Results
Survivors were more likely to report late (Odds Ratio (OR) =1.9; 95% Confidence Interval (CI) =1.5–2.5) and recurrent suicide ideation (OR=2.6, 95% CI=1.8–3.8) compared to siblings. Poor physical health status was associated with increased risk of suicide ideation in survivors (late report: OR=1.9, 95% CI=1.3–2.7; recurrent: OR=1.9, 95% CI=1.2–2.9). Suicide ideation was associated with increased risk for all-cause mortality (Hazard Ratio (HR) =1.3, 95% CI=1.03–1.6) and death by external causes (HR=2.4, 95% CI=1.4–4.1).
Conclusion
Adult survivors of childhood cancer are at-risk for late report and recurrent suicide ideation, which is associated with increased risk of mortality. Routine screening for psychological distress in adult survivors appears warranted, especially for survivors who develop chronic physical health conditions.
doi:10.1002/cncr.28385
PMCID: PMC3947253  PMID: 24122148
childhood cancer; survivorship; suicide; mortality; late effects
11.  The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2013;61(1):53-67.
BACKGROUND
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
METHODS
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
RESULTS
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
CONCLUSION
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
doi:10.1002/pbc.24679
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
12.  Abdominal radiation and diabetes: one more piece in the puzzle 
The Lancet. Oncology  2012;13(10):961-962.
doi:10.1016/S1470-2045(12)70340-6
PMCID: PMC4280844  PMID: 22921662
13.  Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(36):4496-4503.
Purpose
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Methods
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
Results
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
Conclusion
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
doi:10.1200/JCO.2013.52.2268
PMCID: PMC3871511  PMID: 24248696
14.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
Purpose
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Results
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Conclusion
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
doi:10.1200/JCO.2013.49.3205
PMCID: PMC3804290  PMID: 24002505
15.  Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort 
The lancet oncology  2013;14(9):10.1016/S1470-2045(13)70251-1.
Background
Prior studies have documented decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. This study investigates infertility and time to pregnancy among female childhood cancer survivors, and analyzes treatment characteristics associated with infertility and subsequent pregnancy.
Methods
The Childhood Cancer Survivor Study (CCSS) is a cohort study including five-year cancer survivors from 26 institutions who were <21 years old at the time of diagnosis between January 1, 1970, and December 31, 1986, and a sibling control group. CCSS females ages 18–39 years reporting they had ever been sexually active (3,531 survivors and 1,366 female controls) were studied. Self-reported infertility, medical treatment for infertility, the time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analyzed.
Findings
Survivors had an increased risk of clinical infertility (>1 year of attempts at conception without success) compared to siblings which was most pronounced at early reproductive ages (≤24 years Relative Risk (RR)=2·92, 95% Confidence Interval (CI) 1·18–7·20; 25–29 years RR=1·61, 95% CI 1·05–2·48; 30–39 years RR=1·37, 95% CI 1·11–1·69). Despite being equally likely to seek treatment for infertility, survivors were less likely to be prescribed medication for treatment of infertility (RR=0·57, 95% CI 0·46–0·70). Increasing doses of uterine radiation and alkylating agent chemotherapy were most strongly associated with infertility. Although survivors had an increased time to pregnancy interval (p=0·032), 64·2% (292/455) with infertility achieved a pregnancy.
Interpretation
A more comprehensive understanding of infertility after cancer is critical for counseling and decision-making regarding future attempts at conception as well as fertility preservation.
doi:10.1016/S1470-2045(13)70251-1
PMCID: PMC3845882  PMID: 23856401
16.  Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study 
Pediatric blood & cancer  2013;61(8):1440-1444.
Background
Individuals with hereditary retinoblastoma (RB) are at very high risk of developing subsequent malignant neoplasms (SMN) of which osteosarcoma (OS) is one of the most common. We hypothesized that annual surveillance using whole-body magnetic resonance imaging (WB-MRI) in asymptomatic survivors of hereditary RB would detect SMN of the bone and soft tissues at an early stage.
Procedure
Retrospective review of the results of a WB-MRI screening program in hereditary RB survivors from February 2008 – August 2012. The primary outcome was to determine the sensitivity and specificity of WB-MRI in detecting SMNs.
Results
Twenty-five patients had at least one WB-MRI performed (range: 1 – 5). First WB- MRI was performed at a median age of 16 years (range: 8 – 25 years). WB-MRI detected new osseous abnormalities suspicious for malignancy in 5 patients: 2 were diagnosed with localized high-grade OS of the extremity and 3 were found to have benign osseous abnormalities after dedicated imaging (n=5/5) and/or biopsy (n=3/5). One patient was diagnosed with secondary OS three months after a normal screening WB- MRI exam. Among a total of 41 WB-MRI screening tests performed in survivors of hereditary RB, the sensitivity of detecting SMN was 66.7% and the specificity was 92.1%.
Conclusions
Preliminary results suggest that annual WB-MRI surveillance detects SMN in survivors of hereditary RB, but with modest sensitivity. Further study is needed to assess the performance of annual surveillance WB-MRIs and whether this modality decreases SMN-related mortality in RB survivors.
doi:10.1002/pbc.24835
PMCID: PMC4007376  PMID: 24402721
Retinoblastoma; survivors; screening; whole-body MRI; pediatric oncology
17.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
Background
The impact of childhood cranial radiation therapy (CRT) on stroke risk in adulthood, and the role of modifiable atherosclerotic risk factors, remains poorly defined. We assessed long-term incidence rates and stroke risk factors in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS).
Patients and Methods
CCSS is a multi-institutional retrospective cohort study of 14,358 five-year survivors of childhood cancer and 4,023 randomly selected sibling controls with longitudinal follow up. Age-adjusted incidence rates of self-reported late-occurring (≥ 5 years after diagnosis) first-stroke were calculated. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors.
Results
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% Confidence Interval [CI] 62–96) compared to 9.3 (95% CI 4–23) for siblings. Treatment with CRT increased stroke risk in a dose dependent manner: hazard ratio (HR) 5.9 (95% CI 3.5–9.9) for 30–49 Gy CRT, and 11.0 (7.4–17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4–1.8) at 10 years post-diagnosis and 12% (95% CI 8.9–15.0) at 30 years. Hypertension (HTN) increased stroke hazard by 4-fold (95% CI 2.8–5.5) and in black survivors by 16-fold (95% CI 6.9–36.6).
Conclusion
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
doi:10.1016/j.ijrobp.2013.03.034
PMCID: PMC3696633  PMID: 23680033
18.  Prevalence of Vitamin D Insufficiency in Survivors of Childhood Cancer 
Pediatric blood & cancer  2012;60(7):1237-1239.
Background
Data on 25-hydroxyvitamin D (25-OH D) status among survivors of childhood cancer are limited. Our aim was to determine the prevalence of and risk factors for 25-OH D insufficiency in a large, diverse population of cancer survivors being followed in a childhood cancer survivor clinic.
Procedure
Retrospective chart review in survivors seen for routine long-term follow-up, who underwent routine screening blood studies including 25-OH D levels. Vitamin D insufficiency was defined as 25-OH D <20 ng/ml.
Results
Four hundred eighty-four subjects (234 males) were evaluable for this analysis. Median age at 25-OH D testing was 12.3 years (2.05–36.4) and median age at cancer diagnosis was 3.9 years (0–18). Diagnoses included brain tumors (23.6%), neuroblastoma (21%), and leukemia (17.6%). Mean 25-OH D level was 25.2 ng/ml (SD = 10.37); 29% of subjects were 25-OH D insufficient. In univariate analysis, race, pubertal status, and age at cancer diagnosis were associated with 25-OH D insufficiency (P < 0.05). In multivariate analysis, a model including race and pubertal status provided a good fit for the data.
Conclusions
The prevalence of 25-OH D insufficiency in these cancer survivors was high but similar to what has been described in the general population. No cancer specific variables were associated with 25-OH D insufficiency. Since cancer survivors are at a higher risk for subsequent malignancies, cardiovascular disease, and low bone mineral density, all of which may be affected by 25-OH D levels, interventions to improve 25-OH D status in this vulnerable population are needed.
doi:10.1002/pbc.24403
PMCID: PMC4006112  PMID: 23192881
cancer survivors; prevalence; vitamin D
19.  Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(10):1324-1328.
Purpose
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Results
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Conclusion
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
doi:10.1200/JCO.2012.43.7038
PMCID: PMC3607671  PMID: 23423746
20.  Differential Effects of Radiotherapy on Growth and Endocrine Function Among Acute Leukemia Survivors: A Childhood Cancer Survivor Study Report 
Pediatric blood & cancer  2012;60(1):110-115.
Background
The differential effects of cranial (CRT), spinal (SRT), and total body irradiation (TBI) on growth and endocrine outcomes have rarely been examined in combination among childhood acute leukemia survivors.
Procedure
Self-reported height/weight, hypothyroidism, and pregnancy/live birth were determined among acute lymphoblastic and myeloid leukemia survivors (n=3,467) participating in the Childhood Cancer Survivor Study, an ongoing cohort study of 5-year survivors of pediatric cancers diagnosed from 1970 to 1986.
Results
Compared with no radiotherapy, risk estimates were consistent across outcomes (adult short stature, hypothyroidism, absence of pregnancy/live birth) with CRT treatment associated with 2–3 fold increased risks, TBI associated with 5–10 fold increased risks, and CRT+TBI associated with >10 fold increased risks. Exposure to any SRT further increased risk of these outcomes 2–3 fold. Changes in body composition were more nuanced as CRT only was associated with an increased risk of being overweight/obese (OR 1.6, 95% CI 1.3–1.9) whereas TBI only was associated with an increased risk of being underweight (OR 6.0, 95% CI 2.4–14.9).
Conclusions
Although patients treated with CRT+TBI were at greatest risk for short stature, hypothyroidism, and a reduced likelihood of pregnancy/live birth, those treated with either modality alone had significantly increased risks as well, including altered body composition. Any SRT exposure further increased risk in an independent fashion.
doi:10.1002/pbc.24198
PMCID: PMC3436954  PMID: 22628201
leukemia; childhood; survivor; growth; hypothyroidism; pregnancy
21.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
Results
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
Conclusion
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
22.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Background
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Methods
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
Results
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Conclusions
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
doi:10.1002/cncr.27626
PMCID: PMC3439597  PMID: 22605509
23.  Clinical Ascertainment of Health Outcomes among Adults Treated for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study 
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 evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions.
Objective
Following systematic exposure-based medical assessments of a large cohort of adult survivors of childhood cancer, determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures.
Design, Setting, and Participants
Presence of health outcomes was ascertained among 1713 adult (median age 32 years, range 18-60) survivors of childhood cancer (median time from diagnosis 25 years, range 10-47) enrolled in the St. Jude Lifetime Cohort Study since 10/1/2007 and followed through 10/31/2012.
Main Outcome Measures
Age-specific cumulative prevalence of adverse outcomes by organ system and sex-adjusted attributable fraction percentages with 95% confidence intervals were calculated.
Results
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary [65.2%(95% CI, 60.4-69.8%)], auditory [62.1%(95% CI, 55.8-68.2%)], endocrine-reproductive [62.0%(95% CI, 59.5-64.6%)], cardiac [56.4(95% CI, 53.5-59.2%)] and neurocognitive [48.0%(95%CI, 44.9-51.0%)] function, whereas abnormalities impacting hepatic [13.0%(95% CI, 10.8-15.3%)], skeletal [9.6%(95% CI, 8.0-11.5%)], renal [5.0%(95% CI, 4.0-6.3%)] and hematopoietic [3.0%(95% CI: 2.1-3.9%)] function were less common. Attributable fractions were highest for endocrine-reproductive disorders [88.4%(95% CI, 80.1-93.3%)] to 100%, but considerably lower for conditions highly prevalent in the general population such as hypertension [9.3%(95%CI, −16.3-29.2%)], dyslipidemia [15.5%(95% CI, 10.2-20.5%)], and obesity [42.1%(95% CI, 34.4-48.9%)]. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at 50 years of age was 21.6%(95% CI, 19.3-23.9%) for cardiomyopathy, 83.5%(95% CI, 80.2-86.8%) for heart valve disorder, 76.8%(95% CI, 73.6-80.0%) for pituitary dysfunction, 81.3%(95% CI, 77.6-85.0%) for pulmonary dysfunction, 86.5%(95% CI, 82.3-90.7%) for hearing loss, 40.9%(95% CI, 32.0-49.8%) for breast cancer, 31.1%(95% CI, 27.3-34.9%) for Leydig cell failure, and 31.9%(95% CI, 28.0-35.8%) for primary ovarian failure. At age 45 years, the estimated cumulative prevalence of any chronic health condition is 95.2% (95% CI 94.8-98.6%) and 80% (95% CI 73.0-86.6%) for a serious, life-threatening or disabling chronic condition.
Conclusion and Relevance
Systematic risk-based medical assessments of adults treated for childhood cancer identified a substantial number of previously undiagnosed problems that are typically prevalent in an older population underscoring the need for ongoing health monitoring and intervention of this population.
doi:10.1001/jama.2013.6296
PMCID: PMC3771083  PMID: 23757085
Childhood cancer; late effects; long-term follow-up; health screening
24.  Impact of Radiation and Chemotherapy on Risk of Dental Abnormalities: A Report from the Childhood Cancer Survivor Study 
Cancer  2009;115(24):5817-5827.
Purpose
Describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors.
Patients and Methods
9308 survivors, diagnosed between 1970–1986, and 2951 siblings from Childhood Cancer Survivor Study completed a survey containing oral-dental health information. We analyzed treatment impact, socioeconomic data and patient demographics on dental outcomes using univariate and multivariate logistic regression models to estimate odds ratios (OR).
Results
In multivariate analysis, survivors more likely reported microdontia (OR 3.0, 95% confidence interval [CI] 2.4–3.8), hypodontia (OR 1.7, 95% CI 1.4–2.0), root abnormalities (OR 3.0, 95% CI 2.2–4.0), abnormal enamel (OR 2.4, 95% CI 2.0–2.9), teeth loss ≥6 (OR 2.6, 95% CI 1.9–3.6), severe gingivitis (OR 1.2, 95% CI 1.0–1.5), xerostomia (OR 9.7, 95% CI 4.8–19.7). Controlling for chemotherapy and socio-economic factors, radiation exposure of ≥20Gy to dentition was significantly associated with increased risk of ≥1 dental abnormality. Dose-dependent alkylating agent therapy significantly increased risk ≥1 anatomic/developmental dental abnormalities in survivors diagnosed <5 years of age (OR 1.7, 2.7, 3.3 for alkylating agent score of 1, 2, 3, respectively).
Conclusion
Radiation and chemotherapy are independent risk factors for adverse oral-dental sequelae among childhood cancer survivors. Patients receiving alkylating agents at < 5 years should be closely monitored.
doi:10.1002/cncr.24670
PMCID: PMC3754878  PMID: 19834960
radiation; chemotherapy; pediatric oncology; dental abnormalities
25.  A Cross-Sectional Study of the Psychosexual Impact of Cancer-Related Infertility in Women: Third-Party Reproductive Assistance 
Introduction
This study empirically assessed emotional and sexual functioning, reproductive concerns, and quality of life (QOL) of cancer-related infertile women in comparison to those without a cancer history and explored awareness of third-party reproduction options in cancer survivors.
Methods
One hundred twenty-two cancer survivors (Gynecologic and Bone Marrow/Stem Cell Transplant) with cancer-related infertility and 50 non-cancer infertile women completed a self-report survey assessing: reproductive concerns(RCS), mood(CES-D), distress(IES), sexual function(FSFI), menopause(SCL), QOL(SF-12), relationships(ADAS), and exploratory (reproductive options) items.
Results
Cancer survivors exhibited greater sexual dysfunction and lower physical QOL than non-cancer infertile women (P<0.001). No significant group differences were identified for mood (CES-D), mental health QOL (SF-12), reproductive concerns (RCS), and relationship satisfaction (ADAS). All groups scored in the FSFI range of sexual dysfunction, and with RCS scores above published means. Multivariate comparisons showed comparable depression and distress levels for all groups, but cancer survivors had poorer physical QOL [F(5,146)=4.22, P<0.01]. A significant effect was also found for knowledge of third-party reproductive options on depression and distress levels [F(3,97)=4.62, P<0.01]. Adjusted means demonstrated higher depression and distress scores for women with perceived unmet informational needs.
Conclusions
Overall, loss of fertility was an emotionally challenging experience for women regardless of its cause. Cancer survivors were found to have lower scores of physical QOL and sexual function than non-cancer infertile women. Unmet informational needs about reproductive options appeared to be associated with negative mood and increased distress in cancer survivors.
Implications for Cancer Survivors
Targeted interventions to increase knowledge about reproductive options could be of great assistance to women pursuing parenthood in cancer survivorship. Additionally, intervention studies to improve sexual functioning and QOL in women with cancer-related infertility should be a priority of future research.
doi:10.1007/s11764-010-0121-2
PMCID: PMC3701949  PMID: 20373042
cancer; infertility; survivorship; quality of life; third-party parenting

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