Ovarian Insufficiency and Fertility Preservation During and After Childhood Cancer Treatment.

Premature ovarian insufficiency (POI) is one of many potential long-term consequences of childhood cancer treatment in females. Causes of POI in this patient population can include chemotherapy, especially alkylating agents, and radiation therapy. Rarely, ovarian tumors lead to ovarian dysfunction. POI can manifest as delayed pubertal development, irregular menses or amenorrhea, and infertility. This diagnosis often negatively impacts emotional health due to the implications of impaired ovarian function after already enduring treatment for a primary malignancy. The emerging adult may be challenged by the impact on energy level, quality of life, and fertility potential. POI can also lead to low bone density and compromised skeletal strength. This review discusses the health consequences of POI in childhood cancer survivors (CCS). We also explore the role of fertility preservation for CCS, including ovarian tissue cryopreservation and other available options. Lastly, knowledge gaps are identified that will drive a future research agenda.

Impact of ovarian insufficiency on bone health in childhood cancer survivors: Two cases.

PURPOSE: To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI). METHODS: Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician. RESULTS: Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<-2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised. CONCLUSIONS: Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass.

Clinical Assessment of Late Health Outcomes in Survivors of Wilms Tumor.

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

Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.

Neighborhood deprivation index is associated with weight status among long-term survivors of childhood acute lymphoblastic leukemia.

PURPOSE: Area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, has been linked to metabolic outcomes in the general population but has received limited attention in survivors of childhood acute lymphoblastic leukemia (ALL), a population with high rates of overweight and obesity. METHODS: We retrospectively reviewed heights and weights of ≥ 5 year survivors of pediatric ALL (diagnosed 1990-2013). Residential addresses were geocoded using ArcGIS to assign quartiles of ADI, a composite of 17 measures of poverty, housing, employment, and education, with higher quartiles reflecting greater deprivation. Odds ratios (OR) and 95% confidence intervals (CI) for the association between ADI quartiles and overweight/obesity or obesity alone were calculated with logistic regression. RESULTS: On average, participants (n = 454, 50.4% male, 45.2% Hispanic) were age 5.5 years at diagnosis and 17.4 years at follow-up. At follow-up, 26.4% were overweight and 24.4% obese. Compared to the lowest ADI quartile, survivors in the highest quartile were more likely to be overweight/obese at follow-up (OR = 2.33, 95% CI: 1.23-4.44) after adjusting for race/ethnicity, sex, age at diagnosis, and age at follow-up. The highest ADI quartile remained significantly associated with obesity (OR = 5.28, 95% CI: 1.79-15.54) after accounting for weight status at diagnosis. CONCLUSIONS: This study provides novel insights into possible social determinants of health inequalities among survivors of childhood ALL by reporting a significant association between neighborhood deprivation and overweight/obesity. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of childhood ALL residing in neighborhood with greater socioeconomic disadvantage may be at increased risk of overweight and obesity and candidates for targeted interventions.

Weight trends in a multiethnic cohort of pediatric acute lymphoblastic leukemia survivors: A longitudinal analysis.

BACKGROUND: As survival rates for childhood acute lymphoblastic leukemia (ALL) continue to improve, there is growing concern over the chronic health conditions that survivors face. Given that survivors of childhood ALL are at increased risk of cardiovascular complications and obesity, we sought to characterize BMI trends from diagnosis through early survivorship in a multi-ethnic, contemporary cohort of childhood ALL patients and determine if early weight change was predictive of long-term weight status. METHODS: The study population consisted of ALL patients aged 2-15 years at diagnosis who were treated with chemotherapy alone at Texas Children's Hospital. Each patient had BMI z-scores collected at diagnosis, 30-days post-diagnosis, and annually for five years. Linear regression models were estimated to evaluate the association between: 1) BMI z-score change in the first 30 days and BMI z-scores at five-years post-diagnosis; and 2) BMI z-score change in the first year post-diagnosis and BMI z-scores at five-years post-diagnosis. RESULTS: This retrospective cohort study included longitudinal data from 121 eligible patients. The mean BMI z-scores for the population increased significantly (p-value<0.001) from baseline (mean = 0.25) to 30 days post-diagnosis (mean = 1.17) before plateauing after one year post-diagnosis (mean = 0.99). Baseline BMI z-scores were statistically significant predictors to five year BMI z-scores (p <0.001). Independent of baseline BMI z-score and other clinical factors, the BMI z-score at one year post-diagnosis was significantly associated with BMI z-score at five-years post-diagnosis (ß = 0.63, p <0.001), while BMI z-score at 30 days post-diagnosis was not (ß = 0.10, p = 0.23). CONCLUSION: Our results suggest that weight gain within the first year after diagnosis is more strongly associated with long-term BMI than early weight gain (within 30 days). If confirmed, this information may help identify a window of time during therapy when ALL patients would benefit most from weight management directed interventions.

DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors.

BACKGROUND: Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. METHODS: Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. RESULTS: The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P < 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders. CONCLUSIONS: We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.