Publications by authors named "Melissa M Hudson"

493 Publications

Genetic factors in treatment-related cardiovascular complications in survivors of childhood acute lymphoblastic leukemia.

Pharmacogenomics 2021 Sep 10. Epub 2021 Sep 10.

Immune Diseases and Cancer Research Axis, Sainte-Justine University Health Center (SJUHC), Montreal, QC H3T 1C5, Canada.

Cardiovascular disease represents one of the main causes of secondary morbidity and mortality in patients with childhood cancer. To further address this issue, we analyzed cardiovascular complications in relation to common and rare genetic variants derived through whole-exome sequencing from childhood acute lymphoblastic leukemia survivors (PETALE cohort). Significant associations were detected among common variants in the gene, left ventricular ejection fraction (p ≤ 0.0005), and fractional shortening (p ≤ 0.001). Rare variants enrichment in the , and was observed in relation to left ventricular ejection fraction, and in and genes in relation to fractional shortening. Following stratification according to risk groups, the modulatory effect of rare variants was additionally found in the , and genes. None of the associations was replicated in St-Jude Lifetime Cohort Study. Further studies are needed to confirm whether the described genetic markers may be useful in identifying patients at increased risk of these complications.
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http://dx.doi.org/10.2217/pgs-2021-0067DOI Listing
September 2021

Seizures' impact on cognition and quality of life in childhood cancer survivors.

Cancer 2021 Sep 1. Epub 2021 Sep 1.

Division of Neurology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: The objective of this study was to determine the impact of seizure-related factors on neurocognitive, health-related quality of life (HRQOL), and social outcomes in survivors of childhood cancer.

Methods: Survivors of childhood cancer treated at St. Jude Children's Hospital (n = 2022; 48.3% female; median age, 31.5 years; median time since diagnosis, 23.6 years) completed neurocognitive testing and questionnaires. The presence, severity, resolution, and treatment history of seizures were abstracted from medical records. Adjusting for the age at diagnosis, sex, and prior cancer therapy, multivariable models examined the impact of seizures on neurocognitive and HRQOL outcomes. Mediation analyses were conducted for social outcomes.

Results: Seizures were identified in 232 survivors (11.5%; 29.9% of survivors with central nervous system [CNS] tumors and 9.0% of those without CNS tumors). In CNS tumor survivors, seizures were associated with poorer executive function and processing speed (P < .02); in non-CNS tumor survivors, seizures were associated with worse function in every domain (P < .05). Among non-CNS survivors, seizure severity was associated with worse processing speed (P = .023), and resolution was associated with better executive function (P = .028) and attention (P = .044). In CNS survivors, seizure resolution was associated with improved attention (P = .047) and memory (P < .02). Mediation analysis revealed that the impact of seizures on social outcomes was mediated by neurocognitive function.

Conclusions: Seizures in cancer survivors adversely affect long-term functional and psychosocial outcomes independently of cancer therapy. The resolution of seizure occurrence is associated with better outcomes. Seizure severity is associated with poorer outcomes and should be a focus of clinical management and patient education.
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http://dx.doi.org/10.1002/cncr.33879DOI Listing
September 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

Long-term Follow-up Care for Childhood, Adolescent, and Young Adult Cancer Survivors.

Pediatrics 2021 Sep;148(3)

Department of Pediatrics, University of California, Los Angeles, Los Angeles, California.

Progress in therapy has made survival into adulthood a reality for most children, adolescents, and young adults with a cancer diagnosis today. Notably, this growing population remains vulnerable to a variety of long-term therapy-related sequelae. Systematic ongoing follow-up of these patients is, therefore, important to provide for early detection of and intervention for potentially serious late-onset complications. In addition, health counseling and promotion of healthy lifestyles are important aspects of long-term follow-up care to promote risk reduction for physical and emotional health problems that commonly present during adulthood. Both general and subspecialty health care providers are playing an increasingly important role in the ongoing care of childhood cancer survivors, beyond the routine preventive care, health supervision, and anticipatory guidance provided to all patients. This report is based on the guidelines that have been developed by the Children's Oncology Group to facilitate comprehensive long-term follow-up of childhood, adolescent, and young adult cancer survivors (www.survivorshipguidelines.org).
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http://dx.doi.org/10.1542/peds.2021-053127DOI Listing
September 2021

Coronary artery disease surveillance among childhood, adolescent and young adult cancer survivors: A systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Eur J Cancer 2021 Oct 24;156:127-137. Epub 2021 Aug 24.

St. Jude Children's Research Hospital, Memphis, USA. Electronic address:

Background: Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking.

Aim: To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers.

Methods: A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations.

Results: 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations.

Conclusion: These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.
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http://dx.doi.org/10.1016/j.ejca.2021.06.021DOI Listing
October 2021

Concordance between self-reported sleep and actigraphy-assessed sleep in adult survivors of childhood cancer: the impact of psychological and neurocognitive late effects.

Support Care Cancer 2021 Aug 26. Epub 2021 Aug 26.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA.

Purpose: To examine self-reported (30-day) sleep versus nightly actigraphy-assessed sleep concordance in long-term survivors of childhood cancer.

Methods: Four hundred seventy-seven participants enrolled in the St. Jude Lifetime Cohort (53.5% female, median (range) age 34.3 (19.3-61.6) years, 25.4 (10.9-49.3) years from diagnosis) completed the Pittsburgh Sleep Quality Index and ≥ 3 nights of actigraphy. Participants had neurocognitive impairment and/or a self-reported prolonged sleep onset latency (SOL). Self-reported 30-day sleep and nightly actigraphic sleep measures for sleep duration, SOL, and sleep efficiency (SE) were converted into ordinal categories for calculation of weighted kappa coefficients. General linear models estimated associations between measurement concordance and late effects.

Results: Agreements between self-reported and actigraphic measures were slight to fair for sleep duration and SOL measures (k = 0.20 and k = 0.22, respectively; p < 0.0001) and poor for SE measures (k = 0.00, p = 0.79). In multivariable models, severe fatigue and poor sleep quality were significantly associated with greater absolute differences between self-reported and actigraphy-assessed sleep durations (B = 26.6 [p < 0.001] and B = 26.8 [p = 0.01], respectively). Survivors with (versus without) memory impairment had a 44-min higher absolute difference in sleep duration (B = 44.4, p < 0.001). Survivors with, versus without, depression and poor sleep quality had higher absolute discrepancies of SOL (B = 24.5 [p = 0.01] and B = 16.4 [p < 0.0001], respectively). Poor sleep quality was associated with a 12% higher absolute difference in SE (B = 12.32, p < 0.0001).

Conclusions: Self-reported sleep and actigraphic sleep demonstrated discordance in our sample. Several prevalent late effects were statistically significantly associated with increased measurement discrepancy. Future studies should consider the impacts of late effects on sleep assessment in adult survivors of childhood cancer.
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http://dx.doi.org/10.1007/s00520-021-06498-xDOI Listing
August 2021

Online Platform to Assess Complex Social Relationships and Patient-Reported Outcomes Among Adolescent and Young Adult Cancer Survivors.

JCO Clin Cancer Inform 2021 Aug;5:859-871

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

Purpose: Social integration and relationship issues have been understudied among adolescent and young adult (AYA) cancer survivors. This study compared social relationships (social networks, support, and isolation) between AYA cancer survivors and noncancer controls, and identified social integration mechanisms through which the cancer experience influences patient-reported outcomes (PROs).

Materials And Methods: One hundred two AYA cancer survivors and 102 age, sex, and race-matched noncancer controls from a national Internet panel completed an online survey to identify up to 25 of closest friends and relatives whom they have contacted within the past 2 years. Participants' interpersonal connections were used to create a social network index. The Duke-UNC Functional Social Support Questionnaire, UCLA Loneliness Scale, and PROMIS-29 Profile were used to measure social support, perceived isolation or loneliness, and PROs (physical functioning, pain interference, fatigue, anxiety, and depression domains), respectively. Path analysis tested effects of cancer experience on PROs using serial social relationship variables as mediators.

Results: Compared with controls, survivors of lymphoma, leukemia, and solid tumor had better social networks; however, survivors of solid tumor and central nervous system malignancies had higher perceived loneliness (all values < .05). Cancer experience was directly associated with poor PROs ( values < .05 for all domains except fatigue) and indirectly associated through the social network-support-loneliness pathway (all values < .05). Survivors with higher loneliness had lower physical functioning and higher pain interference, fatigue, anxiety, and depression versus controls with lower loneliness (all values < .05).

Conclusion: Compared with controls, survivors were more socially connected but experienced greater loneliness, which was associated with poorer PROs. Screening social integration issues during follow-up care and providing appropriate interventions are warranted.
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http://dx.doi.org/10.1200/CCI.21.00044DOI 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

Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Lancet Diabetes Endocrinol 2021 09 30;9(9):622-637. Epub 2021 Jul 30.

Department for Pediatric Hematology and Oncology CHU Nord, University Hospital Saint-Etienne, Saint-Priest en Jarez, France; 28U1059 Sainbiose, University Jean Monnet, Saint-Etienne, France.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.
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http://dx.doi.org/10.1016/S2213-8587(21)00173-XDOI Listing
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

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 Jul 19. 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
July 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

A relationship between the incremental values of area under the ROC curve and of area under the precision-recall curve.

Diagn Progn Res 2021 Jul 14;5(1):13. Epub 2021 Jul 14.

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

Background: Incremental value (IncV) evaluates the performance change between an existing risk model and a new model. Different IncV metrics do not always agree with each other. For example, compared with a prescribed-dose model, an ovarian-dose model for predicting acute ovarian failure has a slightly lower area under the receiver operating characteristic curve (AUC) but increases the area under the precision-recall curve (AP) by 48%. This phenomenon of disagreement is not uncommon, and can create confusion when assessing whether the added information improves the model prediction accuracy.

Methods: In this article, we examine the analytical connections and differences between the AUC IncV (ΔAUC) and AP IncV (ΔAP). We also compare the true values of these two IncV metrics in a numerical study. Additionally, as both are semi-proper scoring rules, we compare them with a strictly proper scoring rule: the IncV of the scaled Brier score (ΔsBrS) in the numerical study.

Results: We demonstrate that ΔAUC and ΔAP are both weighted averages of the changes (from the existing model to the new one) in separating the risk score distributions between events and non-events. However, ΔAP assigns heavier weights to the changes in higher-risk regions, whereas ΔAUC weights the changes equally. Due to this difference, the two IncV metrics can disagree, and the numerical study shows that their disagreement becomes more pronounced as the event rate decreases. In the numerical study, we also find that ΔAP has a wide range, from negative to positive, but the range of ΔAUC is much smaller. In addition, ΔAP and ΔsBrS are highly consistent, but ΔAUC is negatively correlated with ΔsBrS and ΔAP when the event rate is low.

Conclusions: ΔAUC treats the wins and losses of a new risk model equally across different risk regions. When neither the existing or new model is the true model, this equality could attenuate a superior performance of the new model for a sub-region. In contrast, ΔAP accentuates the change in the prediction accuracy for higher-risk regions.
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http://dx.doi.org/10.1186/s41512-021-00102-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278775PMC
July 2021

Integration of Pediatric Hodgkin Lymphoma Treatment and Late Effects Guidelines: Seeing the Forest Beyond the Trees.

J Natl Compr Canc Netw 2021 06 30;19(6):755-764. Epub 2021 Jun 30.

1Department of Oncology, and.

The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that >95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.
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http://dx.doi.org/10.6004/jnccn.2021.7042DOI Listing
June 2021

Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia.

Lancet Haematol 2021 Jul;8(7):e513-e523

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address:

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.
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http://dx.doi.org/10.1016/S2352-3026(21)00136-8DOI Listing
July 2021

Forgoing needed medical care among long-term survivors of childhood cancer: racial/ethnic-insurance disparities.

J Cancer Surviv 2021 May 27. Epub 2021 May 27.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Mailstop 735, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

Purpose: To investigate racial/ethnic-related disparities by insurance status in "forgoing needed medical care in the last year due to finances" in childhood cancer survivors.

Methods: Our study included 3310 non-Hispanic/Latinx White, 562 non-Hispanic/Latinx Black, and 92 Hispanic/Latinx survivors from the St. Jude Lifetime Cohort Study. Logistic regression analyses, guided by Andersen's Healthcare Utilization Model, were adjusted for "predisposing" (survey age, sex, childhood cancer diagnosis and treatment, and treatment era) and "need" (perceived health status) factors. Additional adjustment for household income/education and chronic health conditions was considered.

Results: Risk of forgoing care was highest among non-Hispanic/Latinx Blacks and lowest among Hispanics/Latinxs for each insurance status. Among privately insured survivors, relative to non-Hispanic/Latinx Whites, non-Hispanic/Latinx Blacks were more likely to forgo care (adjusted OR: 1.82, 95% CI: 1.30-2.54): this disparity remained despite additional adjustment for household income/education (adjusted OR: 1.43, 95% CI: 1.01-2.01). In contrast, publicly insured survivors, regardless of race/ethnicity, had similar risk of forgoing care as privately insured non-Hispanic/Latinx Whites. All uninsured survivors had high risk of forgoing care. Additional chronic health condition adjustment did not alter these results.

Conclusions: Provision of public insurance to all childhood cancer survivors may diminish racial/ethnic disparities in forgoing care that exist among the privately insured and reduce the risk of forgoing care among uninsured survivors to that of privately insured non-Hispanic/Latinx Whites.

Implications For Cancer Survivors: Under public insurance, childhood cancer survivors had low risk of forgoing care, at the similar level to privately insured non-Hispanic/Latinx Whites, regardless of race/ethnicity.
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http://dx.doi.org/10.1007/s11764-021-01061-3DOI Listing
May 2021

Association between obesity and neurocognitive function in survivors of childhood acute lymphoblastic leukemia treated only with chemotherapy.

Cancer 2021 Sep 29;127(17):3202-3213. Epub 2021 Apr 29.

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

Background: Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated.

Methods: Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross-sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement.

Results: For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross-sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P < .05), attention (attention span and risk taking; all P < .05), and processing speed (visual motor coordination, visual speed, and motor speed; all P < .05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P = .01) and slower motor speed (P = .02), which persisted throughout the treatment.

Conclusions: Overweight/obesity was significantly associated with neurocognitive impairment during long-term follow-up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk.
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http://dx.doi.org/10.1002/cncr.33624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355093PMC
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
April 2021

Assessment and Monitoring of Neurocognitive Function in Pediatric Cancer.

J Clin Oncol 2021 Jun 22;39(16):1696-1704. Epub 2021 Apr 22.

Nottingham Children's Hospital, Nottingham, United Kingdom.

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http://dx.doi.org/10.1200/JCO.20.02444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260911PMC
June 2021

Aging in Adult Survivors of Childhood Cancer: Implications for Future Care.

J Clin Oncol 2021 Jun 22;39(16):1741-1751. Epub 2021 Apr 22.

Department of Supportive Care, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1200/JCO.20.02534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260926PMC
June 2021

Life-Altering Consequences of Neurocognitive Impairment in Survivors of Pediatric Cancer.

J Clin Oncol 2021 Jun 22;39(16):1693-1695. Epub 2021 Apr 22.

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

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http://dx.doi.org/10.1200/JCO.21.00211DOI Listing
June 2021

The Association of Mitochondrial Copy Number with Sarcopenia in Adult Survivors of Childhood Cancer.

J Natl Cancer Inst 2021 Apr 19. Epub 2021 Apr 19.

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

Background: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood (PB) mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors.

Methods: Among 1,762 adult childhood cancer survivors (51.6% male; median age = 29.4 [IQR = 23.3-36.8] years), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided.

Results: The prevalence of sarcopenia was 27.0%, higher among females than males (31.5% vs. 22.9%; P < 0.001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (p = 0.01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (OR = 1.84; 95% CI = 1.32-2.59) and alkylating agents (OR = 1.34; 95% CI = 1.04-1.72) increased, while glucocorticoids decreased odds (OR = 0.72; 95% CI = 0.56-0.93) of sarcopenia. mtDNAcn decreased with age (β=-0.81; P = 0.002), was higher among females (β = 9.23; P = 0.01) and among survivors with a C allele at mt.204 (β=-17.9; P = 0.02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20; 95% CI = 1.07-1.34).

Conclusions: While a growing body of evidence supports PB mtDNAcn as a biomarker for adverse health outcomes, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors.
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http://dx.doi.org/10.1093/jnci/djab084DOI Listing
April 2021

A global approach to long-term follow-up of targeted and immune-based therapy in childhood and adolescence.

Pediatr Blood Cancer 2021 Jul 16;68(7):e29047. Epub 2021 Apr 16.

ACCELERATE Platform LTFU Working Group Co-Chair, ACCELERATE, Brussels, Belgium.

While considerable efforts and progress in our understanding of the long-term toxicities of surgery, radiation and chemotherapy in children with cancer have been made over the last 5 decades, there continues to be a wide gap in our knowledge of the long-term health impact of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE, a multi-stakeholder collaboration of clinical and translational academics, regulators from the EMA and FDA, patient/family advocates and members spanning small biotechnology through to large pharmaceutical companies have initiated the development of an international long-term follow-up data registry to collect this important information prospectively. Providing critical safety data on the long-term use of these approved and investigational therapies in children will support the regulatory requirements and labeling information. It will also provide the necessary insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning.
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http://dx.doi.org/10.1002/pbc.29047DOI Listing
July 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

Prevalence and predictors of cancer-related worry and associations with health behaviors in adult survivors of childhood cancer.

Cancer 2021 Aug 12;127(15):2743-2751. Epub 2021 Apr 12.

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

Background: Cancer-related worry (CRW) is common among cancer survivors; however, little is known about factors associated with CRW or its impact on health behaviors in adult survivors of childhood cancer.

Methods: Survivors in the St. Jude Lifetime Cohort Study (n = 3211; 51% male; mean age, 31.2 years [SD, 8.4 years]; mean time after diagnosis, 22.8 years [SD, 8.3 years]) underwent medical evaluations and completed ratings of CRW, psychological symptoms, and health behaviors. Multivariable modified Poisson regression models examined associations between CRW and treatment exposures, chronic health conditions, psychological symptoms, and health behaviors.

Results: Sixty-four percent of survivors (95% confidence interval [CI], 62.6-65.9) reported worry about subsequent malignancy, 45% (95% CI, 43.5-46.9) reported worry about physical problems related to cancer, and 33% (95% CI, 31.2-34.4) reported worry about relapse. Multiple psychological symptoms, treatment exposures, and chronic conditions significantly increased the risk of CRW. Survivors reporting CRW were at increased risk for substance use, inadequate physical activity, and increased health care utilization after adjustments for chronic conditions. For example, with adjustments for chronic conditions, those who endorsed CRW were more likely to have ≥5 cancer-related physician visits, ≥5 physician visits related to cancer, and ≥5 calls to a physician's office in the previous 2 years in comparison with survivors who were not worried. CRW was also associated with an increased risk of current tobacco use, past marijuana use, and current marijuana use.

Conclusions: A substantial proportion of adult survivors of childhood cancer reported CRW associated with increased health care utilization. CRW may serve as an intervention target to promote well-being and adaptive health behaviors.
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http://dx.doi.org/10.1002/cncr.33563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323824PMC
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

Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation.

J Clin Oncol 2021 Jul 7;39(20):2276-2283. Epub 2021 Apr 7.

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

Purpose: Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL.

Methods: Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov (identifier: NCT01920932).

Results: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy.

Conclusion: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.
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http://dx.doi.org/10.1200/JCO.20.03286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260923PMC
July 2021

Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.

Genome Med 2021 04 6;13(1):53. Epub 2021 Apr 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA.

Background: It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.

Methods: We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.

Results: By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).

Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.
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http://dx.doi.org/10.1186/s13073-021-00875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025387PMC
April 2021

Short sleep duration and physical and psychological health outcomes among adult survivors of childhood cancer.

Pediatr Blood Cancer 2021 Jul 6;68(7):e28988. Epub 2021 Apr 6.

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

Background: To examine associations between phenotypes of short sleep duration and clinically assessed health conditions in long-term survivors of childhood cancer.

Methods: Survivors recruited from the St. Jude Lifetime Cohort (n = 911; 52% female; mean age 34 years; 26 years postdiagnosis) completed behavioral health surveys and underwent comprehensive physical examinations. Sleep was assessed with the Pittsburgh Sleep Quality Index. Short sleep was defined as ≤6 h per night with phenotypes of short sleep including poor sleep efficiency (<85%), prolonged sleep onset latency (SOL; ≥30 min), and wake after sleep onset (≥3 times per week). Covariates included childhood cancer treatment exposures, demographics, body mass index, and physical inactivity. Separate modified Poisson regression models were computed for each health category to estimate relative risks (RR) and 95% confidence intervals (CI). Multinomial logistic regression models examined associations between sleep and an aggregated burden of chronic health conditions.

Results: Short sleep duration was reported among 44% (95% CI 41%-47%) of survivors. In multivariable models, short sleep duration alone was associated with pulmonary (RR = 1.35, 95% CI 1.08-1.69), endocrine (RR = 1.22, 95% CI 1.06-1.39) and gastrointestinal/hepatic conditions (RR = 1.46, 95% CI 1.18-1.79), and anxiety (RR 3.24, 95% CI 1.64-6.41) and depression (RR = 2.33, 95% CI 1.27-4.27). Short sleep with prolonged SOL was associated with a high/severe burden of health conditions (OR = 2.35, 95% CI 1.12-4.94).

Conclusions: Short sleep duration was associated with multiple clinically ascertained adverse health conditions. Although the temporality of these associations cannot be determined in this cross-sectional study, sleep is modifiable and improving sleep may improve long-term health in survivors.
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http://dx.doi.org/10.1002/pbc.28988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165003PMC
July 2021
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