Publications by authors named "Gregory T Armstrong"

285 Publications

Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences.

Cancer 2021 Oct 13. Epub 2021 Oct 13.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes.

Methods: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored.

Results: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12).

Conclusions: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.
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http://dx.doi.org/10.1002/cncr.33969DOI Listing
October 2021

Functional Outcomes and Social Attainment in Asian/Pacific Islander Childhood Cancer Survivors in the United States: A Report from the Childhood Cancer Survivor Study.

Cancer Epidemiol Biomarkers Prev 2021 Oct 4. Epub 2021 Oct 4.

School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong

Background: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors.

Methods: This study included 203 API five-year survivors (age at follow-up: 29.2 [SD=6.3] years) and 12,186 NHW survivors (age at follow-up 31.5[SD=7.3] years) from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment.

Results: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors (mean 54.11 [SD=8.98] vs. 51.32 [SD=10.12]; P<.001). NHW survivors were less likely to have attained at least a college degree than API survivors (odds ratio[OR]=0.50; 95% confidence interval[CI]=0.34, 0.73). API survivors were more likely than NHW survivors to be never-married (OR=2.83, 95% CI=1.93, 4.13) and to live dependently (OR=3.10; 95% CI=2.02, 4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P's<0.05).

Conclusion: We observed differences in social attainment between API and NHW survivors, though statistically significant differences in neurocognitive and emotional outcomes were not identified.

Impact: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0628DOI Listing
October 2021

Subsequent malignant neoplasms in the childhood cancer survivor study: Occurrence of cancer types in which human papillomavirus is an established etiologic risk factor.

Cancer 2021 Oct 4. Epub 2021 Oct 4.

Pediatric Infectious Diseases, Nemours Children's Hospital, Orlando, Florida.

Background: Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMN ) in childhood cancer survivors are poorly understood.

Methods: The cumulative risk of SMN was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMN risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs).

Results: In total, 46 survivors developed an SMN (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMN sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMN (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMN (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMN SIRs in multivariable analysis.

Conclusions: Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMN in cancer survivors is warranted.
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http://dx.doi.org/10.1002/cncr.33922DOI Listing
October 2021

Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma.

Nat Commun 2021 09 20;12(1):5531. Epub 2021 Sep 20.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.
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http://dx.doi.org/10.1038/s41467-021-25709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452624PMC
September 2021

Lung Cancer as a Subsequent Malignant Neoplasm in Survivors of Childhood Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Sep 14. Epub 2021 Sep 14.

Department of Pediatrics, University of Minnesota.

Background: Lung cancer, the most common cancer cause of death in adults, has not been well studied as a subsequent malignant neoplasm (SMN) in childhood cancer survivors. We assessed prevalence, risk factors, and outcomes for lung SMN in the Childhood Cancer Survivor Study (CCSS) cohort.

Methods: Among 25,654 five-year survivors, diagnosed with childhood cancer (<21 years), lung cancer was self-reported and confirmed by pathology record review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, comparing survivors to the general population, and hazard ratios (HR) were estimated using Cox regression for diagnosis and treatment exposures.

Results: Forty-two survivors developed a lung SMN (SIR 4.0, 95% CI 2.9-5.4) with a cumulative incidence of 0.16% at 30 years from diagnosis (95% CI 0.09%-0.23%). In a treatment model, chest radiation doses of 10-30 Gy (HR 3.4, 95% CI 1.05-11.0), >30-40 Gy (HR 4.6, 95% CI 1.5-14.3) and >40 Gy (HR 9.1, 95% CI 3.1-27.0) were associated with lung SMN, with a monotone dose trend (p-trend<0.001). Survivors of Hodgkin lymphoma (SIR 9.3, 95% CI 6.2-13.4) and bone cancer (SIR 4.4, 95% CI 1.8-9.1) were at greatest risk for lung SMN.

Conclusions: Survivors of childhood cancer are at increased risk for lung cancer compared to the general population. Greatest risk was observed among survivors who received chest radiotherapy or with primary diagnoses of Hodgkin lymphoma or bone cancer.

Impact: This study describes the largest number of observed lung cancers in childhood cancer survivors and elucidates need for further study in this aging and growing population.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0250DOI Listing
September 2021

Impact of COVID-19 pandemic on a large cohort of adult survivors of childhood cancer.

Pediatr Blood Cancer 2021 11 31;68(11):e29324. Epub 2021 Aug 31.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Childhood cancersurvivors may be differentially impacted by coronavirus disease 2019 (COVID-19). From April to June of 2020, we examined psychosocial/health concerns in 4148 adult survivors and 571 siblings. Although more survivors reported concerns about getting sick (p = .002) and needing hospitalization (p = .003) in general, survivors and siblings were comparably concerned about being infected with and the consequences of COVID-19. Cranial radiation was associated with social isolation (relative risk [RR] = 1.3, CI = 1.1-1.7), and central nervous system (CNS) tumors were associated with unemployment due to COVID-19 (RR = 1.7, CI = 1.2-2.2). Some survivors appear more vulnerable and may require more support to meet health care and vocational needs during COVID-19, though siblings also perceive substantial risk.
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http://dx.doi.org/10.1002/pbc.29324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463488PMC
November 2021

Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Aug 31. Epub 2021 Aug 31.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction.

Methods: A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS.

Results: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE ( = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS ( = 0.010, AUC = 72.9% vs. 70.6%).

Conclusions: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest.

Impact: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0448DOI Listing
August 2021

Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the Childhood Cancer Survivor Study.

Radiother Oncol 2021 Aug 26;163:199-208. Epub 2021 Aug 26.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, United States; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, United States. Electronic address:

Background And Purpose: We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (H). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (H). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort.

Methods: We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with H and mean heart dose (D), percent volume receiving ≥ 20 Gy (V) and ≥ 5 Gy with V = 0 ( [Formula: see text] ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with D, V, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, D was also considered as a continuous variable.

Results: Consistent with previous findings with H, reevaluation using H dosimetry found that, D ≥ 10 Gy, V ≥ 0.1%, and [Formula: see text]  ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for D in the category of 20 to 29.9 Gy and V in the category of 30% to 79.9%. When changes in the linear dose-response relationship for D were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy.

Conclusion: These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.
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http://dx.doi.org/10.1016/j.radonc.2021.08.012DOI Listing
August 2021

[C]-Methionine PET for Identification of Pediatric High-Grade Glioma Recurrence.

J Nucl Med 2021 Aug 26. Epub 2021 Aug 26.

St. Jude Children's Research Hospital, United States.

Differentiating tumor recurrence or progression from pseudoprogression during surveillance of pediatric high-grade gliomas (PHGGs) using magnetic resonance imaging (MRI), the primary imaging modality for evaluation of brain tumors, can be challenging. The aim of this study was to evaluate whether C-methionine positron emission tomography ([C]MET -PET), a molecular imaging technique that detects functionally active tumors, is useful for further evaluating MRI changes concerning for tumor recurrence during routine surveillance. We evaluated 27 lesions in 26 patients with new or worsening MRI abnormalities, where PHGG tumor recurrence was of concern during follow-up visits with [C]MET -PET. We performed quantitative and qualitative assessments of both [C]MET-PET and MRI data to predict the presence of tumor recurrence. Further, to assess for an association with overall survival we plotted the time from development of the imaging changes against survival. Qualitative evaluation of [C]MET-PET achieved 100% sensitivity, 60% specificity, and 93% accuracy to correctly predict the presence of tumors in 27 new or worsening MRI abnormalities. Qualitative MRI evaluation achieved sensitivity ranging from 86% to 95%, specificity ranging from 40% to 60%, and accuracy ranging from 85% to 89%. The interobserver agreement for [C]MET-PET assessment was 100%, whereas the interobserver agreement was only 50% for MRI ( = <0.01). Quantitative MRI and [C]MET-PET evaluation using receiver operating characteristics demonstrated higher specificity (80%) than qualitative evaluations (40-60%). Postcontrast enhancement volume, metabolic tumor volume, tumor-to-brain ratio and presence of tumor as determined by consensus MRI assessment were inversely associated with overall survival. [C]MET-PET has slightly higher sensitivity, and accuracy for correctly predicting presence of tumor recurrence, with excellent interobserver agreement, than does MRI. Quantitative [C]MET-PET can also predict overall survival. These findings suggest [C]MET-PET can be useful for further evaluation of MRI changes during surveillance of previously treated PHGG.
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http://dx.doi.org/10.2967/jnumed.120.261891DOI Listing
August 2021

Cardiac remodeling after anthracycline and radiotherapy exposure in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study.

Cancer 2021 Aug 19. Epub 2021 Aug 19.

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.

Background: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy.

Methods: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed.

Results: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15-2.68).

Conclusions: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance.
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http://dx.doi.org/10.1002/cncr.33860DOI Listing
August 2021

Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

Eur J Cancer 2021 Sep 11;155:216-226. Epub 2021 Aug 11.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied.

Materials And Methods: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure.

Results: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure.

Conclusions: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study.
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http://dx.doi.org/10.1016/j.ejca.2021.06.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429192PMC
September 2021

Breast Cancer Screening Among Childhood Cancer Survivors Treated Without Chest Radiation: Clinical Benefits and Cost-Effectiveness.

J Natl Cancer Inst 2021 Jul 29. Epub 2021 Jul 29.

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA.

Background: Early initiation of breast cancer screening is recommended for high-risk women, including survivors of childhood cancer treated with chest radiation. Recent studies suggest that female survivors of childhood leukemia or sarcoma treated without chest radiation are also at elevated early onset breast cancer risk. However, the potential clinical benefits and cost-effectiveness of early breast cancer screening among these women are uncertain.

Methods: Using data from the Childhood Cancer Survivor Study, we adapted two Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation models to reflect the elevated risks of breast cancer and competing mortality among leukemia and sarcoma survivors. Costs and utility weights were based on published studies and databases. Outcomes included breast cancer deaths averted, false-positive-screening results, benign biopsies, and incremental cost-effectiveness ratios (ICERs).

Results: In the absence of screening, the lifetime risk of dying from breast cancer among survivors was 6.8% to 7.0% across models. Early initiation of annual mammography with MRI screening between ages 25 and 40 would avert 52.6% to 64.3% of breast cancer deaths. When costs and quality of life impacts were considered, screening starting at age 40 was the only strategy with an ICER below the $100,000 per quality-adjusted life-year (QALY) gained cost-effectiveness threshold ($27,680 to $44,380 per QALY gained across models).

Conclusions: Among survivors of childhood leukemia or sarcoma, early initiation of breast cancer screening at age 40 may reduce breast cancer deaths by half and is cost-effective. These findings could help inform screening guidelines for survivors treated without chest radiation.
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http://dx.doi.org/10.1093/jnci/djab149DOI Listing
July 2021

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

JNCI Cancer Spectr 2021 Apr 23;5(2):pkab007. Epub 2021 Jan 23.

Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.

Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.

Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided  = 3 × 10). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including , , , , and . A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (, , , ), Wilms tumor (, ), non-Hodgkin lymphoma (), and soft tissue sarcomas (, , , , ) compared with other pediatric cancers.

Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
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http://dx.doi.org/10.1093/jncics/pkab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023430PMC
April 2021

Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Cancer 2021 Nov 19;127(21):4091-4102. Epub 2021 Jul 19.

Department of Medicine, University of Chicago, Chicago, Illinois.

Background: Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT.

Methods: Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT-treated survivors in the Childhood Cancer Survivor Study. Genome-wide association studies (GWASs) of CRT-related tinnitus and hearing loss were also performed.

Results: Males were more likely to report CRT-related tinnitus (9.4% vs 5.4%; P = 5.1 × 10 ) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10 ; hearing loss: P = 6.4 × 10 ), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10 ; hearing loss: P = 1.7 × 10 ) in comparison with controls. GWAS of CRT-related tinnitus revealed a genome-wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10 ), whereas GWAS of CRT-related hearing loss identified rs332013 (P = 5.8 × 10 ) in chromosome 8 and rs67522722 (P = 7.8 × 10 ) in chromosome 6 as nearly genome-wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT-related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10 ).

Conclusions: CRT-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use, and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722, which was supported in an independent cohort of survivors.

Lay Summary: Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long-term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.
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http://dx.doi.org/10.1002/cncr.33775DOI Listing
November 2021

Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort.

J Clin Oncol 2021 Jul 20:JCO2100194. Epub 2021 Jul 20.

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer.

Methods: Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS-directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance.

Results: Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, -0.93 to -0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (β = .22; difference of βs = -.76; 95% CI, -1.19 to -0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (β = -.40; 95% CI, -0.67 to -0.12), cognitive flexibility (β = -.62; 95% CI, -1.02 to -0.22), and verbal fluency (β = -.23; 95% CI, -0.41 to -0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail β = -.35; 95% CI, -0.53 to -0.17; frail β = -.48; 95% CI, -0.83 to -0.12) compared with nonfrail survivors.

Conclusion: Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.
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http://dx.doi.org/10.1200/JCO.21.00194DOI Listing
July 2021

Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Cancer Epidemiol Biomarkers Prev 2021 Aug 7;30(8):1536-1545. Epub 2021 Jun 7.

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut.

Background: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact.

Methods: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes.

Results: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9-12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1-34.6) and sarcomas (PR, 11.5; 95% CI, 9.1-14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8-24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5-2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1-1.2), anxiety (PR, 2.5; 95% CI, 2.2-2.9), depression (PR, 2.1; 95% CI, 1.9-2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90-0.94) and employment (PR, 0.8; 95% CI, 0.8-0.9).

Conclusions: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes.

Impact: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0154DOI Listing
August 2021

Health-related and cancer risk concerns among siblings of childhood cancer survivors: a report from the Childhood Cancer Survivor Study (CCSS).

J Cancer Surviv 2021 Jun 1. Epub 2021 Jun 1.

Department of Pediatrics, University of California at Irvine, Irvine, CA, USA.

Objective: To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors.

Methods: This study reports longitudinal data (baseline and follow-up) from 3969 adult siblings (median age = 29 [range 18-56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6-33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression.

Results: Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors' diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), and 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12-2.20; grades 3-4 OR=1.86, 95% CI: 1.18-2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05-1.94; grades 3-4 OR=1.64, 95% CI: 1.09-2.47; compared to less than grade 2).

Conclusions: Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns.

Implications For Cancer Survivors: Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings.
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http://dx.doi.org/10.1007/s11764-021-01056-0DOI Listing
June 2021

Material, behavioral, and psychological financial hardship among survivors of childhood cancer in the Childhood Cancer Survivor Study.

Cancer 2021 Sep 1;127(17):3214-3222. Epub 2021 Jun 1.

University of Utah, Salt Lake City, Utah.

Background: Medical financial burden includes material, behavioral, and psychological hardship and has been underinvestigated among adult survivors of childhood cancer.

Methods: A survey from 698 survivors and 210 siblings from the Childhood Cancer Survivor Study was analyzed. The intensity of financial hardship was estimated across 3 domains: 1) material, including conditions that arise from medical expenses; 2) behavioral, including coping behaviors to manage medical expenses; and 3) psychological hardship resulting from worries about medical expenses and insurance, as measured by the number of instances of each type of financial hardship (0, 1-2, and ≥3 instances). Multivariable logistic regressions were conducted to examine the clinical and sociodemographic predictors of experiencing financial hardship (0-2 vs ≥3 instances).

Results: The intensity of financial hardship did not significantly differ between survivors and siblings. Survivors reported more instances of material hardship than siblings (1-2 instances: 27.2% of survivors vs 22.6% of siblings; ≥3 instances: 15.9% of survivors vs 11.4% siblings; overall P = .03). In multivariable regressions, insurance was protective against all domains of financial hardship (behavioral odds ratio [OR], 0.12; 95% confidence interval [CI], 0.06-0.22; material OR, 0.37; 95% CI, 0.19-0.71; psychological OR, 0.10; 95% CI, 0.05-0.21). Survivors who were older at diagnosis, female, and with chronic health conditions generally had higher levels of hardship. Brain radiation and alkylating agents were associated with higher levels of hardship.

Conclusions: Material, behavioral, and psychological financial burden among survivors of childhood cancer is common.
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http://dx.doi.org/10.1002/cncr.33613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489494PMC
September 2021

Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch Hodgkin Late Effects and LATER Cohorts.

J Clin Oncol 2021 Sep 28;39(27):3012-3021. Epub 2021 May 28.

Duke University Medical Center, Durham, NC.

Purpose: Women treated with chest radiation for childhood cancer have one of the highest risks of breast cancer. Models producing personalized breast cancer risk estimates applicable to this population do not exist. We sought to develop and validate a breast cancer risk prediction model for childhood cancer survivors treated with chest radiation incorporating treatment-related factors, family history, and reproductive factors.

Methods: Analyses were based on multinational cohorts of female 5-year survivors of cancer diagnosed younger than age 21 years and treated with chest radiation. Model derivation was based on 1,120 participants in the Childhood Cancer Survivor Study diagnosed between 1970 and 1986, with median attained age 42 years (range 20-64) and 242 with breast cancer. Model validation included 1,027 participants from three cohorts, with median age 32 years (range 20-66) and 105 with breast cancer.

Results: The model included current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age at menopause, and history of a first-degree relative with breast cancer. Ten-year risk estimates ranged from 2% to 23% for 30-year-old women (area under the curve, 0.63; 95% CI, 0.50 to 0.73) and from 5% to 34% for 40-year-old women (area under the curve, 0.67; 95% CI, 0.54 to 0.84). The highest risks were among premenopausal women older than age 40 years treated with mantle field radiation within a year of menarche who had a first-degree relative with breast cancer. It showed good calibration with an expected-to-observed ratio of the number of breast cancers of 0.92 (95% CI, 0.74 to 1.16).

Conclusion: Breast cancer risk varies among childhood cancer survivors treated with chest radiation. Accurate risk prediction may aid in refining surveillance, counseling, and preventive strategies in this population.
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http://dx.doi.org/10.1200/JCO.20.02244DOI Listing
September 2021

Artificial Intelligence-Assisted Prediction of Late-Onset Cardiomyopathy Among Childhood Cancer Survivors.

JCO Clin Cancer Inform 2021 04;5:459-468

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Early identification of childhood cancer survivors at high risk for treatment-related cardiomyopathy may improve outcomes by enabling intervention before development of heart failure. We implemented artificial intelligence (AI) methods using the Children's Oncology Group guideline-recommended baseline ECG to predict cardiomyopathy.

Material And Methods: Seven AI and signal processing methods were applied to 10-second 12-lead ECGs obtained on 1,217 adult survivors of childhood cancer prospectively followed in the St Jude Lifetime Cohort (SJLIFE) study. Clinical and echocardiographic assessment of cardiac function was performed at initial and follow-up SJLIFE visits. Cardiomyopathy was defined as an ejection fraction < 50% or an absolute drop from baseline ≥ 10%. Genetic algorithm was used for feature selection, and extreme gradient boosting was applied to predict cardiomyopathy during the follow-up period. Model performance was evaluated by five-fold stratified cross-validation.

Results: The median age at baseline SJLIFE evaluation was 31.7 years (range 18.4-66.4), and the time between baseline and follow-up evaluations was 5.2 years (0.5-9.5). Two thirds (67.1%) of patients were exposed to chest radiation, and 76.6% to anthracycline chemotherapy. One hundred seventeen (9.6%) patients developed cardiomyopathy during follow-up. In the model based solely on ECG features, the cross-validation area under the curve (AUC) was 0.87 (95% CI, 0.83 to 0.90), whereas the model based on clinical features had an AUC of 0.69 (95% CI, 0.64 to 0.74). In the model based on ECG and clinical features, the cross-validation AUC was 0.89 (95% CI, 0.86 to 0.91), with a sensitivity of 78% and a specificity of 81%.

Conclusion: AI using ECG data may assist in the identification of childhood cancer survivors at increased risk for developing future cardiomyopathy.
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http://dx.doi.org/10.1200/CCI.20.00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462657PMC
April 2021

Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Lancet Oncol 2021 05 9;22(5):e196-e206. Epub 2021 Apr 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.
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http://dx.doi.org/10.1016/S1470-2045(20)30688-4DOI Listing
May 2021

Esophageal disease among childhood cancer survivors-A report from the Childhood Cancer Survivors Study.

Pediatr Blood Cancer 2021 Aug 12;68(8):e29043. Epub 2021 Apr 12.

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

There is limited information addressing the occurrence of esophageal strictures among the growing population of survivors of childhood cancer. Using the Childhood Cancer Survivor Study, we analyzed data from 17,121 5-year survivors and 3400 siblings to determine the prevalence and risk factors for esophageal strictures. Prevalence among survivors was 2.0% (95% confidence interval [CI]: 1.8-2.2%), representing a 7.6-fold increased risk compared to siblings. Factors significantly associated with risk of esophageal stricture included diagnosis of Hodgkin lymphoma, greater chest radiation dose, younger age at cancer diagnosis, platinum chemotherapy, and hematopoietic stem cell transplantation. While uncommon, survivors are at risk for therapy-related esophageal strictures.
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http://dx.doi.org/10.1002/pbc.29043DOI Listing
August 2021

Contribution of Polygenic Risk to Hypertension Among Long-Term Survivors of Childhood Cancer.

JACC CardioOncol 2021 Mar 16;3(1):76-84. Epub 2021 Mar 16.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: Childhood cancer survivors experience significantly higher rates of hypertension which potentiates cardiovascular disease, but the contribution and relationship of genetic and treatment factors to hypertension risk are unknown.

Objectives: To determine the contribution of a blood pressure polygenic risk score (PRS) from the general population and its interplay with cancer therapies to hypertension in childhood cancer survivors.

Methods: Using 895 established blood pressure loci from the general population, we calculated a PRS for 3572 childhood cancer survivors of European ancestry from Childhood Cancer Survivor Study (CCSS) original cohort, 1889 from CCSS expansion cohort, and 2534 from the St. Jude Lifetime Cohort (SJLIFE). Hypertension was assessed using National Cancer Institute criteria based on self-report of a physician diagnosis in CCSS and by blood pressure measurement in SJLIFE.

Results: In the combined sample of 7995 survivors, those in the top decile of the PRS had an odds ratio (OR) of 2.66 (95% CI=2.03-3.48) for hypertension compared to survivors in the bottom decile. The PRS-hypertension association was modified by being overweight/obese (per SD interaction OR=1.13; 95% CI=1.01-1.27) and exposure to hypothalamic-pituitary axis radiation (per SD interaction OR=1.18; 95% CI=1.05-1.33). Attributable fractions for hypertension to the PRS and cancer therapies were 21.0% and 15.7%, respectively, they jointly accounted for 40.2% of hypertension among survivors.

Conclusions: A blood pressure PRS from the general population is significantly associated with hypertension among childhood cancer survivors and contributes to approximately one quarter of hypertension risk among survivors. These findings highlight the importance of screening for hypertension in all childhood cancer survivors, and identify higher risk subgroups.
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http://dx.doi.org/10.1016/j.jaccao.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026142PMC
March 2021

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

Clin Cancer Res 2021 May 18;27(10):2879-2889. Epub 2021 Mar 18.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.

Materials And Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; = 52) and children (SJMB03: age 3-21 years; = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.

Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR ( = 21), SHH ( = 30), and MYC ( = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. GLAs were not associated with PFS.

Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127412PMC
May 2021

Progression of Frailty in Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Report.

J Natl Cancer Inst 2021 Oct;113(10):1415-1421

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail.

Methods: Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates.

Results: Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32).

Conclusions: Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors.
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http://dx.doi.org/10.1093/jnci/djab033DOI Listing
October 2021

Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of Long-Term Morbidity: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2021 Jul 25;39(20):2266-2275. Epub 2021 Feb 25.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy.

Methods: Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures.

Results: HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition ( trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8).

Conclusion: This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.
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http://dx.doi.org/10.1200/JCO.20.01186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260906PMC
July 2021

St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem.

Cancer Discov 2021 05 6;11(5):1082-1099. Epub 2021 Jan 6.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102307PMC
May 2021

Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors.

J Bone Miner Res 2021 04 30;36(4):685-695. Epub 2020 Dec 30.

School of Public Health, University of Alberta, Edmonton, Canada.

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 ) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex-specific effects (p  < 7 × 10 ). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10 ; 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 ; >36 Gray only: HR = 3.79, 95% CI 1.95-7.34, p = 8.2 × 10 ). 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).
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http://dx.doi.org/10.1002/jbmr.4234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044050PMC
April 2021

Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry.

Cancer Res 2021 05 7;81(9):2556-2565. Epub 2020 Dec 7.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; = 246) were compared with cardiotoxic-exposed survivors of European ancestry ( = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; = 2.8 × 10) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137513PMC
May 2021
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