45 results on '"Robison, Leslie L"'
Search Results
2. Evaluation of Memory Impairment in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Cranial Radiotherapy
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Armstrong, Gregory T., Reddick, Wilburn E., Petersen, Ronald C., Santucci, Aimee, Zhang, Nan, Srivastava, Deokumar, Ogg, Robert J., Hillenbrand, Claudia M., Sabin, Noah, Krasin, Matthew J., Kun, Larry, Pui, Ching-Hon, Hudson, Melissa M., Robison, Leslie L., and Krull, Kevin R.
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- 2013
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3. Renal Carcinoma After Childhood Cancer: A Report From the Childhood Cancer Survivor Study
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Wilson, Carmen L., Ness, Kirsten K., Neglia, Joseph P., Hammond, Sue, Shnorhavorian, Margarett, Leisenring, Wendy L., Stovall, Marilyn, Robison, Leslie L., and Armstrong, Gregory T.
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- 2013
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4. Leveraging Epidemiology and Clinical Studies of Cancer Outcomes: Recommendations and Opportunities for Translational Research
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Elena, Joanne W., Travis, Lois B., Simonds, Naoko I., Ambrosone, Christine B., Ballard-Barbash, Rachel, Bhatia, Smita, Cerhan, James R., Hartge, Patricia, Heist, Rebecca S., Kushi, Lawrence H., Lash, Timothy L., Morton, Lindsay M., Onel, Kenan, Pierce, John P., Robison, Leslie L., Rowland, Julia H., Schrag, Deborah, Sellers, Thomas A., Seminara, Daniela, Shu, Xiao Ou, Thomas, Nancy E., Ulrich, Cornelia M., and Freedman, Andrew N.
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- 2013
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5. Radiation-Related Risk of Basal Cell Carcinoma: A Report From the Childhood Cancer Survivor Study
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Watt, Tanya C., Inskip, Peter D., Stratton, Kayla, Smith, Susan A., Kry, Stephen F., Sigurdson, Alice J., Stovall, Marilyn, Leisenring, Wendy, Robison, Leslie L., and Mertens, Ann C.
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- 2012
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6. Long-term Survivors of Childhood Ewing Sarcoma: Report From the Childhood Cancer Survivor Study
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Ginsberg, Jill P., Goodman, Pamela, Leisenring, Wendy, Ness, Kirsten K., Meyers, Paul A., Wolden, Suzanne L., Smith, Stephanie M., Stovall, Marilyn, Hammond, Sue, Robison, Leslie L., and Oeffinger, Kevin C.
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- 2010
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7. Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study
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Friedman, Debra L., Whitton, John, Leisenring, Wendy, Mertens, Ann C., Hammond, Sue, Stovall, Marilyn, Donaldson, Sarah S., Meadows, Anna T., Robison, Leslie L., and Neglia, Joseph P.
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- 2010
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8. Neurocognitive Functioning in Adult Survivors of Childhood Non-Central Nervous System Cancers
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Kadan-Lottick, Nina S., Zeltzer, Lonnie K., Liu, Qi, Yasui, Yutaka, Ellenberg, Leah, Gioia, Gerard, Robison, Leslie L., and Krull, Kevin R.
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- 2010
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9. Response: Re: Late Recurrence in Pediatric Cancer: A Report From the Childhood Cancer Survivor Study
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Wasilewski-Masker, Karen, Mertens, Ann C., Neglia, Joseph P., Hammond, Sue, and Robison, Leslie L.
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- 2010
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10. Late Recurrence in Pediatric Cancer: A Report From the Childhood Cancer Survivor Study
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Wasilewski-Masker, Karen, Liu, Qi, Yasui, Yutaka, Leisenring, Wendy, Meacham, Lillian R., Hammond, Sue, Meadows, Anna T., Robison, Leslie L., and Mertens, Ann C.
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- 2009
11. Long-term Outcomes in Survivors of Neuroblastoma: A Report From the Childhood Cancer Survivor Study
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Laverdière, Caroline, Liu, Qi, Yasui, Yutaka, Nathan, Paul C., Gurney, James G., Stovall, Marilyn, Diller, Lisa R., Cheung, Nai-Kong, Wolden, Suzanne, Robison, Leslie L., and Sklar, Charles A.
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- 2009
12. Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study
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Armstrong, Gregory T., Liu, Qi, Yasui, Yutaka, Huang, Sujuan, Ness, Kirsten K., Leisenring, Wendy, Hudson, Melissa M., Donaldson, Sarah S., King, Allison A., Stovall, Marilyn, Krull, Kevin R., Robison, Leslie L., and Packer, Roger J.
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- 2009
13. Cause-Specific Late Mortality Among 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study
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Mertens, Ann C., Liu, Qi, Neglia, Joseph P., Wasilewski, Karen, Leisenring, Wendy, Armstrong, Gregory T., Robison, Leslie L., and Yasui, Yutaka
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- 2008
14. New Primary Neoplasms of the Central Nervous System in Survivors of Childhood Cancer: a Report From the Childhood Cancer Survivor Study
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Neglia, Joseph P., Robison, Leslie L., Stovall, Marilyn, Liu, Yan, Packer, Roger J., Hammond, Sue, Yasui, Yutaka, Kasper, Catherine E., Mertens, Ann C., Donaldson, Sarah S., Meadows, Anna T., and Inskip, Peter D.
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- 2006
15. Female Survivors of Childhood Cancer: Preterm Birth and Low Birth Weight Among Their Children
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Signorello, Lisa B., Cohen, Sarah S., Bosetti, Cristina, Stovall, Marilyn, Kasper, Catherine E., Weathers, Rita E., Whitton, John A., Green, Daniel M., Donaldson, Sarah S., Mertens, Ann C., Robison, Leslie L., and Boice, John D., Jr.
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- 2006
16. Premature Menopause in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
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Sklar, Charles A., Mertens, Ann C., Mitby, Pauline, Whitton, John, Stovall, Marilyn, Kasper, Catherine, Mulder, Jean, Green, Daniel, Nicholson, H. Stacy, Yasui, Yutaka, and Robison, Leslie L.
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- 2006
17. Cancer Survivorship—Genetic Susceptibility and Second Primary Cancers: Research Strategies and Recommendations
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Travis, Lois B., Rabkin, Charles S., Brown, Linda Morris, Allan, James M., Alter, Blanche P., Ambrosone, Christine B., Begg, Colin B., Caporaso, Neil, Chanock, Stephen, DeMichele, Angela, Figg, William Douglas, Gospodarowicz, Mary K., Hall, Eric J., Hisada, Michie, Inskip, Peter, Kleinerman, Ruth, Little, John B., Malkin, David, Ng, Andrea K., Offit, Kenneth, Pui, Ching-Hon, Robison, Leslie L., Rothman, Nathaniel, Shields, Peter G., Strong, Louise, Taniguchi, Toshiyasu, Tucker, Margaret A., and Greene, Mark H.
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- 2006
18. Health and Economic Benefits of Well-Designed Evaluations: Some Lessons From Evaluating Neuroblastoma Screening
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Soderstrom, Lee, Woods, William G., Bernstein, Mark, Robison, Leslie L., Tuchman, Mendel, and Lemieux, Bernard
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- 2005
19. Second Malignant Neoplasms in Five-Year Survivors of Childhood Cancer: Childhood Cancer Survivor Study
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Neglia, Joseph P., Friedman, Debra L., Yasui, Yutaka, Mertens, Ann C., Hammond, Sue, Stovall, Marilyn, Donaldson, Sarah S., Meadows, Anna T., and Robison, Leslie L.
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- 2001
20. Breast-Feeding and Risk of Childhood Acute Leukemia
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Shu, Xiao Ou, Linet, Martha S., Steinbuch, Michael, Wen, Wan Qing, Buckley, Jonathan D., Neglia, Joseph P., Potter, John D., Reaman, Gregory H., and Robison, Leslie L.
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- 1999
21. Case-control study of childhood acute lymphoblastic leukemia and residential radon exposure
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Lubin, Jay H., Linet, Martha S., Boice, John D., Jr., Buckley, Jonathan, Conrath, Susan M., Hatch, Elizabeth E., Kleinerman, Ruth A., Tarone, Robert E., Wacholder, Sholom, and Robison, Leslie L.
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Lymphoblastic leukemia in children -- Risk factors ,Radon -- Health aspects ,Health - Abstract
Background. Several ecologic analyses have shown significant positive associations between mean indoor radon concentrations and risk of leukemia at all ages (acute myeloid leukemia and chronic lymphocytic leukemia) and for children (all leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia [ALL]). As part of an age-matched, case--control study of childhood ALL in the United States, we investigated the association between the incidence of ALL in children under age 15 years and indoor radon exposure. Methods: Radon detectors were placed in current and previous homes of subjects where they resided for 6 months or longer. Children were included in analyses if radon measurements covered 70% or more of the 5-year period prior to diagnosis for case subjects (or from birth for case subjects under age 5 years) and the corresponding reference dates for control subjects. Radon levels could be estimated for 97% of the exposure period for the eligible 505 case subjects and 443 control subjects. Results: Mean radon concentration was lower for case subjects (65.4 becquerels; per cubic meter [[Bqm.sup.-3]]) than for control subjects (79.1 [Bqm.sup.-3]). For categories less than 37, 37-73, 74-147, and 148 or more [Bqm.sup.-3] Of radon exposure, relative risks based on matched casecontrol pairs were 1.00, 1.22, 0.82, and 1.02, respectively, and were similar to results from an unmatched analysis. There was no association between ALL and radon exposure within subgroups defined by categories of age, income, birth order, birth weight, sex, type of residence, magnetic field exposure, parental age at the subject's birth, parental occupation, or parental smoking habits. Conclusions: In contrast to prior ecologic studies, the results from this analytic study provide no evidence for an association between indoor radon exposure and childhood ALL. [J Natl Cancer Inst 1998;90:294-300]
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- 1998
22. Smoking in adult survivors of childhood acute lymphoblastic leukemia
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Tao, May L., Guo, Matthew D., Weiss, Robert, Byrne, Julianne, Mills, James L., Robison, Leslie L., and Zeltzer, Lonnie K.
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Cancer survivors ,Lymphocytic leukemia -- Complications ,Health - Abstract
Background: Health-related behaviors are of particular concern in survivors of childhood cancer as they are at increased risk for second cancers and long-term organ dysfunction. The purpose of this study was to compare the smoking behavior and associated factors in young-adult survivors of childhood acute lymphoblastic leukemia (ALL) with those in sibling controls. Methods: A telephone interview that surveyed smoking behavior was conducted with 592 young-adult survivors, treated before age 20 years on Children's Cancer Group ALL protocols, and 409 sibling controls. Using stratified chi-squared analyses and Cox proportional hazards models, we compared the rates of smoking initiation and smoking cessation between survivors and control subjects. Demographic characteristics (age, sex, race, and education) and psychological factors (mood and self-concept) were examined as predictors interacting with survivorship in logistic regression analyses to try to distinguish a subgroup of survivors who may be at greater risk for smoking. Results: Survivors were significantly less likely to have ever smoked (23.0% versus 35.7%; P [is less than] .0001) and thus were less likely to ever be regular, daily smokers than sibling controls (19.1% versus 31.3%; P [is less than] .0001). Survivors were less likely to quit smoking than sibling controls (26.6% versus 35.2%), although this result was not statistically significant. There were no interactions between survivor status and either demographic or psychological features on smoking behavior. Conclusions: Young-adult survivors of childhood ALL are less likely to experiment with smoking but, once having started, are at similar risk for becoming habitual, persistent smokers as sibling controls. [J Natl Cancer Inst 1998;90:219-25]
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- 1998
23. Infant leukemia, topoisomerase II inhibitors, and the MLL gene
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Ross, Julie A., Potter, John D., and Robison, Leslie L.
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Chemotherapy -- Complications ,Leukemia in children -- Causes of ,Acute leukemia, Promyelocytic -- Genetic aspects ,DNA topoisomerase II -- Physiological aspects ,Health - Published
- 1994
24. Chronic Conditions and Utility-Based Health-Related Quality of Life in Adult Childhood Cancer Survivors
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Yeh, Jennifer M., primary, Hanmer, Janel, additional, Ward, Zachary J., additional, Leisenring, Wendy M., additional, Armstrong, Gregory T., additional, Hudson, Melissa M., additional, Stovall, Marilyn, additional, Robison, Leslie L., additional, Oeffinger, Kevin C., additional, and Diller, Lisa, additional
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- 2016
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25. Survivors of childhood cancer and risk of a second tumor
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Robison, Leslie L.
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Tumors in children -- Risk factors ,Cancer survivors -- Health aspects ,Cancer -- Relapse ,Cancer in children -- Research ,Health - Published
- 1993
26. Using Neurocognitive Phenotypes to Inform Interventions for Adult Survivors of Childhood Cancer.
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Banerjee P, Phillips NS, Liu W, Ehrhardt MJ, Bhakta N, Brinkman TM, Williams AM, Yasui Y, Khan RB, Srivastava D, Ness KK, Robison LL, Hudson MM, and Krull KR
- Abstract
Background: Neurocognitive impairments are sequelae of childhood cancer treatment, however little guidance is given to clinicians on common phenotypes of impairment, or modifiable risk factors that could lead to personalized interventions in survivorship., Methods: Standardized clinical testing of neurocognitive function was conducted in 2,958 (74.1%) eligible survivors, who were ≥5 years post-diagnosis and >18 years old, and 477 community controls. Impairment was examined across 20 measures and phenotypes were determined by latent class analysis. Multinomial logistic regression was used to estimate risk for phenotype, predicted by cancer diagnosis and treatment exposures, chronic health conditions, and lifestyle, adjusted for sex and age. Associations between phenotypes and social attainment were examined., Results: Five neurocognitive phenotypes were identified in survivors (global impairment 3.7%, impaired attention 5.0%, memory impairment 7.2%, processing speed/executive function impairment 9.3%, no impairment 74.8%). Risk of global impairment was associated with severe chronic health condition burden (odds ratio [OR]=20.17, 95% confidence interval [95%CI] 11.41-35.63) including cerebrovascular disease (OR = 14.5, 95%CI = 5.47-38.44) and cerebrovascular accident (OR = 14.7, 95%CI = 7.50-26.40). Modifiable risk factors, like quitting smoking reduced risk for global impairment (OR = 0.21, 95%CI 0.06-0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95%CI 2.86-7.21), attention impairment (OR 2.01, 95%CI 1.41-2.87), processing speed/executive function impairment (OR 1.90, 95%CI 1.46-2.48), and memory impairment (OR 2.09, 95%CI 1.54-2.82)., Conclusions: Results support the clinical utility of neurocognitive phenotyping to develop risk profiles and personalized clinical interventions, such as preventing cerebrovascular disease in anthracycline treated survivors by preventing hypercholesterolemia, smoking, and sedentary lifestyle, to reduce the risk for global impairment., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2024
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27. Impact of risk-based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the Childhood Cancer Survivor Study.
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Friedman DN, Goodman PJ, Leisenring WM, Diller LR, Cohn SL, Howell RM, Smith SA, Tonorezos ES, Wolden SL, Neglia JP, Ness KK, Gibson TM, Nathan PC, Turcotte LM, Weil BR, Robison LL, Oeffinger KC, Armstrong GT, Sklar CA, and Henderson TO
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- Humans, Male, Female, Child, Adolescent, Adult, Young Adult, Neoplasms, Second Primary epidemiology, Neoplasms, Second Primary mortality, Risk Factors, United States epidemiology, Proportional Hazards Models, Incidence, Child, Preschool, Neuroblastoma mortality, Neuroblastoma therapy, Cancer Survivors statistics & numerical data
- Abstract
Background: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described., Methods: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings., Results: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1])., Conclusion: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2024
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28. Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report.
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Goldberg JF, Hyun G, Ness KK, Dixon SB, Towbin JA, Rhea IB, Ehrhardt MJ, Srivastava DK, Mulrooney DA, Hudson MM, Robison LL, Jefferies JL, Rohatgi A, and Armstrong GT
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- Male, Humans, Child, Female, Cholesterol, LDL, Cholesterol, HDL, Risk Factors, Cholesterol, Triglycerides, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Cancer Survivors, Neoplasms complications, Neoplasms epidemiology, Dyslipidemias etiology, Dyslipidemias complications, Myocardial Infarction complications, Cardiomyopathies complications
- Abstract
Background: Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors., Methods: Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls., Results: Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non-high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio [HR] = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy., Conclusions: Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2024
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29. Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma.
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Papini C, Mirzaei S S, Xing M, Tonning Olsson I, de Blank PMK, Lange KR, Salloum R, Srivastava D, Leisenring WM, Howell RM, Oeffinger KC, Robison LL, Armstrong GT, Krull KR, and Brinkman TM
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- Adult, Humans, Survivors, Outcome Assessment, Health Care, Employment, Functional Status, Glioma therapy
- Abstract
Background: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown., Methods: Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided., Results: Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory., Conclusion: Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2024
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30. Premature aging as an accumulation of deficits in young adult survivors of pediatric cancer.
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Williams AM, Mandelblatt J, Wang M, Armstrong GT, Bhakta N, Brinkman TM, Chemaitilly W, Ehrhardt MJ, Mulrooney DA, Small BJ, Wang Z, Srivastava D, Robison LL, Hudson MM, Ness KK, and Krull KR
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- Humans, Child, Young Adult, Adult, Middle Aged, Survivors, Ethnicity, Aging, Premature, Neoplasms psychology, Cancer Survivors
- Abstract
Background: We aimed to characterize premature aging as an accumulation of deficits in survivors of pediatric cancer compared with community controls and examine associations with host and treatment factors, neurocognition, and mortality., Methods: Pediatric cancer survivors (n = 4000, median age = 28.6, interquartile range [IQR] = 23-35 years; 20 years postdiagnosis: IQR = 15-27), and community participants without a history of cancer serving as controls (n = 638, median age = 32, IQR = 25-40 years) completed clinical assessments and questionnaires and were followed for mortality through April 30, 2020 (mean [SD] follow-up = 7.0 [3.4] years). A deficit accumulation index (DAI) score was calculated from 44 aging-related items including self-reported daily function, psychosocial symptoms, and health conditions. Items were weighted from 0 (absent) to 1 (present and/or most severe), summed and divided by the total yielding a ratio (higher = more deficits). Scores less than 0.20 are robust, and 0.06 is a clinically meaningful difference. Linear regression compared the DAI in survivors and controls with an age*survivor or control interaction. Logistic regression and Cox-proportional hazards estimated the risk of neurocognitive impairment and death. Models were minimally adjusted for age, sex, and race and ethnicity., Results: The adjusted mean DAI among survivors at age 30 years was 0.16 corresponding to age 63 years in controls (33 years premature aging; β = 0.07, 95% confidence interval [CI] = 0.06 to 0.08; P < .001). Cranial and abdominal radiation, alkylators, platinum, and neurosurgery were associated with worse DAI (P ≤ .001). Higher scores were associated with increased risk of neurocognitive impairment in all domains (P < .001) and increased risk of death (DAI = 0.20-0.35, hazard ratio = 2.80, 95% CI = 1.97 to 3.98; DAI ≥ 0.35, hazard ratio = 5.08, 95% CI = 3.52 to 7.34)., Conclusion: Pediatric cancer survivors experience clinically significant premature aging. The DAI may be used to identify survivors at greatest risk of poor health outcomes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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31. A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.
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Sapkota Y, Ehrhardt MJ, Qin N, Wang Z, Liu Q, Qiu W, Shelton K, Shao Y, Plyler E, Mulder HL, Easton J, Michael JR, Burridge PW, Wang X, Wilson CL, Jefferies JL, Chow EJ, Oeffinger KC, Morton LM, Li C, Yang JJ, Zhang J, Bhatia S, Mulrooney DA, Hudson MM, Robison LL, Armstrong GT, and Yasui Y
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- Adult, Child, Cohort Studies, Doxorubicin, Humans, Cancer Survivors, Heart Diseases chemically induced, Heart Diseases epidemiology, Neoplasms drug therapy, Neoplasms genetics
- Abstract
Background: Adult survivors of childhood cancer are at increased risk of cardiac late effects., Methods: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided., Results: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors., Conclusions: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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32. The Association of Mitochondrial Copy Number With Sarcopenia in Adult Survivors of Childhood Cancer.
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McCastlain K, Howell CR, Welsh CE, Wang Z, Wilson CL, Mulder HL, Easton J, Mertens AC, Zhang J, Yasui Y, Hudson MM, Robison LL, Kundu M, and Ness KK
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- Adolescent, Adult, Child, Child, Preschool, Cross-Sectional Studies, DNA Copy Number Variations, Female, Humans, Male, Mitochondria, Survivors, Cancer Survivors, Neoplasms epidemiology, Sarcopenia etiology, Sarcopenia genetics
- Abstract
Background: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood 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 1762 adult childhood cancer survivors (51.6% male; median age = 29.4 years, interquartile range [IQR] = 23.3-36.8), 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 female than male survivors (31.5% vs 22.9%; P < .001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (P = .01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (odds ratio [OR] = 1.84, 95% confidence interval [CI] = 1.32 to 2.59) and alkylating agents (OR = 1.34, 95% CI = 1.04 to 1.72) increased, whereas glucocorticoids decreased odds (OR = 0.72, 95% CI = 0.56 to 0.93) of sarcopenia. mtDNAcn decreased with age (β = -0.81, P = .002) and was higher among female survivors (β = 9.23, P = .01) and among survivors with a C allele at mt.204 (β = -17.9, P = .02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20, 95% CI = 1.07 to 1.34)., Conclusions: A growing body of evidence supports peripheral blood mtDNAcn as a biomarker for adverse health outcomes; however, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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33. Progression of Frailty in Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Report.
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Delaney A, Howell CR, Krull KR, Brinkman TM, Armstrong GT, Chemaitilly W, Wilson CL, Mulrooney DA, Wang Z, Lanctot JQ, Johnson RE, Krull MR, Partin RE, Shelton KC, Srivastava DK, Robison LL, Hudson MM, and Ness KK
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- Adolescent, Adult, Child, Cohort Studies, Humans, Middle Aged, Survivors, Young Adult, Cancer Survivors, Frailty epidemiology, Frailty etiology, Neoplasms complications, Neoplasms epidemiology
- Abstract
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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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34. Epigenetic Age Acceleration and Chronic Health Conditions Among Adult Survivors of Childhood Cancer.
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Qin N, Li Z, Song N, Wilson CL, Easton J, Mulder H, Plyler E, Neale G, Walker E, Zhou X, Pan H, Hudson MM, Yasui Y, Robison LL, Zhang J, Ness KK, and Wang Z
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- Acceleration, Adult, Child, Cohort Studies, Epigenesis, Genetic, Humans, Survivors, Cancer Survivors, Neoplasms genetics
- Abstract
Background: Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs)., Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine's clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided., Results: EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs -3.61, 95% CI = -4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63)., Conclusions: EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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35. A Comparison of Late Mortality Among Survivors of Childhood Cancer in the United States and United Kingdom.
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Fidler-Benaoudia MM, Oeffinger KC, Yasui Y, Robison LL, Winter DL, Reulen RC, Leisenring WM, Chen Y, Armstrong GT, and Hawkins MM
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- Child, Humans, Risk Factors, Survivors, United Kingdom epidemiology, United States epidemiology, Cancer Survivors, Lymphoma, Neoplasms, Sarcoma
- Abstract
Background: It is unclear whether late-effect risks among childhood cancer survivors vary internationally. We compared late mortality in the North American Childhood Cancer Survivor Study (CCSS) and British Childhood Cancer Survivor Study (BCCSS)., Methods: Late mortality was assessed among 49 822 5-year survivors of childhood cancer diagnosed before 15 years of age from 1970 to 1999 (CCSS, n = 31 596; BCCSS, n = 18 226) using cumulative mortality probabilities (CM%) and adjusted ratios of the standardized mortality ratio., Results: The all-cause CM% at 10 years from diagnosis was statistically significantly lower in the CCSS (4.7%, 95% confidence interval [CI] = 4.5% to 5.0%) compared with the BCCSS (6.9%, 95% CI = 6.5% to 7.2%), attributable to a lower probability of death from recurrence or progression of the primary cancer, with statistically significant differences observed in survivors of leukemia, lymphoma, central nervous system tumors, and sarcoma. However, at 40 years from diagnosis, the CCSS had a greater CM% (22.3% vs 19.3%), attributable to a twofold higher risk of mortality from subsequent malignant neoplasms, cardiac and respiratory diseases, and other health-related causes. Differences increased when assessed by follow-up interval, with the CCSS faring worse as time-since-diagnosis increased. Finally, the gap in all-cause mortality widened more recently, with CCSS survivors diagnosed in 1990-1999 experiencing one-half the excess deaths observed in the BCCSS (ratios of the standardized mortality ratio = 0.5, 95% CI = 0.5 to 0.6)., Conclusions: Our findings suggest that US survivors may have received more intensive regimens to achieve sustainable remission and cure, but the cost of this approach was a higher risk of death from late effects. Although the clinical impact of these differences is unclear, our results provide important evidence to aid the discussion of late effects management., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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36. Sex-Specific Associations Between Chemotherapy, Chronic Conditions, and Neurocognitive Impairment in Acute Lymphoblastic Leukemia Survivors: A Report From the Childhood Cancer Survivor Study.
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van der Plas E, Qiu W, Nieman BJ, Yasui Y, Liu Q, Dixon SB, Kadan-Lottick NS, Weldon CB, Weil BR, Jacola LM, Gibson TM, Leisenring W, Oeffinger K, Hudson MM, Robison LL, Armstrong GT, and Krull KR
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- Adult, Child, Chronic Disease, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Survivors, Cancer Survivors, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology
- Abstract
Background: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only., Methods: This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided., Results: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92)., Conclusion: Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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37. Long-Term Neurocognitive and Psychosocial Outcomes After Acute Myeloid Leukemia: A Childhood Cancer Survivor Study Report.
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Stefanski KJ, Anixt JS, Goodman P, Bowers K, Leisenring W, Scott Baker K, Burns K, Howell R, Davies S, Robison LL, Armstrong GT, Krull KR, and Recklitis C
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- Adolescent, Adult, Age Factors, Bone Marrow Transplantation, Child, Child, Preschool, Confidence Intervals, Educational Status, Female, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute surgery, Male, Marital Status, Middle Aged, Outcome Assessment, Health Care, Psychological Distance, Psychological Distress, Quality of Life, Sex Factors, Siblings, Unemployment, Young Adult, Cancer Survivors psychology, Leukemia, Myeloid, Acute psychology, Neurocognitive Disorders etiology, Socioeconomic Factors
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Background: Survivors of childhood acute myeloid leukemia (AML) are vulnerable to medical late effects of treatment; however, less is known about their psychosocial outcomes. This study evaluated neurocognitive and psychosocial outcomes in long-term AML survivors treated with bone marrow transplantation (BMT) or intensive chemotherapy (IC) without BMT., Methods: AML survivors (N = 482; median age at diagnosis = 8 [range = 0-20] years; median age at evaluation = 30 [range = 18-49] years) treated with BMT (n = 183) or IC (n = 299) and sibling controls (N = 3190; median age at evaluation = 32 [range = 18-58] years) from the Childhood Cancer Survivor Study were compared on emotional distress (Brief Symptom Inventory-18), neurocognitive problems (Childhood Cancer Survivor Study Neurocognitive Questionnaire), health-related quality of life (SF-36), and social attainment. Outcomes were dichotomized (impaired vs nonimpaired) using established criteria, and relative risks (RRs) were estimated with multivariable Poisson regression, adjusted for age at evaluation and sex., Results: AML survivors were more likely than siblings to report impairment in overall emotional (RR = 2.19, 95% confidence interval [CI] = 1.51 to 3.18), neurocognitive (RR = 2.03, 95% CI = 1.47 to 2.79), and physical quality of life (RR = 2.71, 95% CI = 1.61 to 4.56) outcomes. Survivors were at increased risk for lower education (RR = 1.15, 95% CI = 1.03 to 1.30), unemployment (RR = 1.41, 95% CI = 1.16 to 1.71), lower income (RR = 1.39, 95% CI = 1.17 to 1.65), and not being married or having a partner (RR = 1.33, 95% CI = 1.17 to 1.51). BMT-treated survivors did not differ statistically significantly from IC-treated on any outcome measure., Conclusions: AML survivors are at increased risk for psychosocial impairment compared with siblings; however, BMT does not confer additional risk for psychosocial late effects compared with treatment without BMT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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38. Molecular Mechanism of Telomere Length Dynamics and Its Prognostic Value in Pediatric Cancers.
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Wang Z, Rice SV, Chang TC, Liu Y, Liu Q, Qin N, Putnam DK, Shelton K, Lanctot JQ, Wilson CL, Ness KK, Rusch MC, Edmonson MN, Wu G, Easton J, Kesserwan CA, Downing JR, Chen X, Nichols KE, Yasui Y, Robison LL, and Zhang J
- Subjects
- Adolescent, Child, Child, Preschool, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mutation, Telomerase genetics, Whole Genome Sequencing, Neoplasms genetics, Telomere genetics, Telomere Homeostasis, Telomere Shortening
- Abstract
Background: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value., Methods: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor and normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project. Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival., Results: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in alpha thalassemia/mental retardation syndrome X-linked gene, corroborated by a low level of the gene expression in the subset of tumors with RNA sequencing. Telomerase reverse transcriptase gene amplification and/or activation was observed in 10 tumors with telomere lengthening, including two leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggests the implication of a gene ontology process of antigen presentation by Major histocompatibility complex class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46)., Conclusion: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable because they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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39. Radiation Dose and Volume to the Pancreas and Subsequent Risk of Diabetes Mellitus: A Report from the Childhood Cancer Survivor Study.
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Friedman DN, Moskowitz CS, Hilden P, Howell RM, Weathers RE, Smith SA, Wolden SL, Tonorezos ES, Mostoufi-Moab S, Chow EJ, Meacham LR, Chou JF, Whitton JA, Leisenring WM, Robison LL, Armstrong GT, Oeffinger KC, and Sklar CA
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- Adolescent, Adult, Child, Cohort Studies, Diabetes Mellitus etiology, Dose-Response Relationship, Radiation, Female, Humans, Male, Middle Aged, Neoplasms epidemiology, North America epidemiology, Radiation Injuries etiology, Radiotherapy Dosage, Young Adult, Cancer Survivors statistics & numerical data, Diabetes Mellitus epidemiology, Neoplasms radiotherapy, Pancreas radiation effects, Radiation Injuries epidemiology
- Abstract
Background: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear., Methods: Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided., Results: Survivors exposed to abdRT (median age = 31.6 years, range = 10.2-58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RRper 10 years = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RRBMI 30+ = 5.00, 95% CI = 3.19 to 7.83 with referenceBMI 18.5-24.9), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk., Conclusions: Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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40. Traditional Cardiovascular Risk Factors and Individual Prediction of Cardiovascular Events in Childhood Cancer Survivors.
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Chen Y, Chow EJ, Oeffinger KC, Border WL, Leisenring WM, Meacham LR, Mulrooney DA, Sklar CA, Stovall M, Robison LL, Armstrong GT, and Yasui Y
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- Adolescent, Adult, Cardiovascular Diseases etiology, Child, Child, Preschool, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neoplasms therapy, Risk, United States epidemiology, Young Adult, Cancer Survivors statistics & numerical data, Cardiovascular Diseases epidemiology, Neoplasms epidemiology
- Abstract
Background: Childhood cancer survivors have an increased risk of heart failure, ischemic heart disease, and stroke. They may benefit from prediction models that account for cardiotoxic cancer treatment exposures combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes., Methods: Childhood Cancer Survivor Study participants (n = 22 643) were followed through age 50 years for incident heart failure, ischemic heart disease, and stroke. Siblings (n = 5056) served as a comparator. Participants were assessed longitudinally for hypertension, dyslipidemia, and diabetes based on self-reported prescription medication use. Half the cohort was used for discovery; the remainder for replication. Models for each outcome were created for survivors ages 20, 25, 30, and 35 years at the time of prediction (n = 12 models)., Results: For discovery, risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information achieved areas under the receiver operating characteristic curve and concordance statistics 0.70 or greater in 9 and 10 of the 12 models, respectively. For replication, achieved areas under the receiver operating characteristic curve and concordance statistics 0.70 or greater were observed in 7 and 9 of the models, respectively. Across outcomes, the most influential exposures were anthracycline chemotherapy, radiotherapy, diabetes, and hypertension. Survivors were then assigned to statistically distinct risk groups corresponding to cumulative incidences at age 50 years of each target outcome of less than 3% (moderate-risk) or approximately 10% or greater (high-risk). Cumulative incidence of all outcomes was 1% or less among siblings., Conclusions: Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-age survivors of childhood cancer. These prediction models provide a framework on which to base future surveillance strategies and interventions., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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41. Determinants and Consequences of Financial Hardship Among Adult Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study.
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Huang IC, Bhakta N, Brinkman TM, Klosky JL, Krull KR, Srivastava D, Hudson MM, and Robison LL
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- Adolescent, Adult, Cancer Survivors psychology, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Humans, Infant, Male, Neoplasms therapy, Prognosis, Risk Factors, Survival Rate, Young Adult, Cancer Survivors statistics & numerical data, Cost of Illness, Financing, Personal economics, Health Expenditures statistics & numerical data, Neoplasms economics, Quality of Life, Socioeconomic Factors
- Abstract
Background: Financial hardship among survivors of pediatric cancer has been understudied. We investigated determinants and consequences of financial hardship among adult survivors of childhood cancer., Methods: Financial hardship, determinants, and consequences were examined in 2811 long-term survivors (mean age at evaluation = 31.8 years, years postdiagnosis = 23.6) through the baseline survey and clinical evaluation. Financial hardship was measured by material, psychological, and coping/behavioral domains. Outcomes included health and life insurance affordability, retirement planning, symptoms, and health-related quality of life (HRQOL). Odds ratios (ORs) estimated associations of determinants with financial hardship. Odds ratios and regression coefficients estimated associations of hardship with symptom prevalence and HRQOL, respectively. All statistical tests were two-sided., Results: Among participants, 22.4% (95% confidence interval [CI] = 20.8% to 24.0%), 51.1% (95% CI = 49.2% to 52.9%), and 33.0% (95% CI = 31.1% to 34.6%) reported material, psychological, and coping/behavioral hardship, respectively. Risk factors across hardship domains included annual household income of $39 999 or less vs $80 000 or more (material OR = 3.04, 95% CI = 2.08 to 4.46, psychological OR = 3.64, 95% CI = 2.76 to 4.80, and coping/behavioral OR = 4.95, 95% CI = 3.57 to 6.86) and below high school attainment vs college graduate or above (material OR = 2.22, 95% CI = 1.45 to 3.42, psychological OR = 1.75, 95% CI = 1.18 to 2.62, and coping/behavioral OR = 2.05, 95% CI = 1.38 to 3.06). Myocardial infarction, peripheral neuropathy, subsequent neoplasm, seizure, stroke, reproductive disorders, amputation, and upper gastrointestinal disease were associated with higher material hardship (all P < .05). Hardship across three domains was associated with somatization, anxiety and depression (all P < .001), suicidal ideation (all P < .05), and difficulty in retirement planning (all P < .001). Survivors with hardship had statistically significantly lower HRQOL (all P < .001), sensation abnormality (all P < .001), and pulmonary (all P < .05) and cardiac (all P < .05) symptoms., Conclusions: A substantial proportion of adult survivors of childhood cancer experienced financial hardship. Vulnerable sociodemographic status and late effects were associated with hardship. Survivors with financial hardship had an increased risk of symptom prevalence and impaired HRQOL., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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42. Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia.
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Fellah S, Cheung YT, Scoggins MA, Zou P, Sabin ND, Pui CH, Robison LL, Hudson MM, Ogg RJ, and Krull KR
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- Adolescent, Adult, Attention Deficit Disorder with Hyperactivity chemically induced, Attention Deficit Disorder with Hyperactivity psychology, Brain drug effects, Cancer Survivors statistics & numerical data, Child, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma psychology, Prognosis, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Attention Deficit Disorder with Hyperactivity pathology, Brain pathology, Cancer Survivors psychology, Executive Function drug effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Background: The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated., Methods: Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided., Results: Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate., Conclusions: Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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43. A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.
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Brooke RJ, Im C, Wilson CL, Krasin MJ, Liu Q, Li Z, Sapkota Y, Moon W, Morton LM, Wu G, Wang Z, Chen W, Howell RM, Armstrong GT, Bhatia S, Mostoufi-Moab S, Seidel K, Chanock SJ, Zhang J, Green DM, Sklar CA, Hudson MM, Robison LL, Chemaitilly W, and Yasui Y
- Subjects
- Adult, Case-Control Studies, Child, Cohort Studies, Female, Genome-Wide Association Study, Haplotypes, Humans, Menopause, Premature drug effects, Menopause, Premature radiation effects, Ovary drug effects, Ovary radiation effects, Primary Ovarian Insufficiency chemically induced, Primary Ovarian Insufficiency etiology, Primary Ovarian Insufficiency genetics, Radiation Injuries genetics, Risk Factors, Antineoplastic Agents, Alkylating adverse effects, Cancer Survivors statistics & numerical data, Menopause, Premature genetics, Neoplasms drug therapy, Neoplasms radiotherapy, Neoplasms rehabilitation, Polymorphism, Single Nucleotide, Radiotherapy adverse effects
- Abstract
Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown., Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS)., Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways., Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.
- Published
- 2018
- Full Text
- View/download PDF
44. Chronic Health Conditions and Neurocognitive Function in Aging Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.
- Author
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Cheung YT, Brinkman TM, Li C, Mzayek Y, Srivastava D, Ness KK, Patel SK, Howell RM, Oeffinger KC, Robison LL, Armstrong GT, and Krull KR
- Subjects
- Adult, Age Factors, Child, Chronic Disease, Female, Follow-Up Studies, Humans, Male, Neurocognitive Disorders pathology, Prognosis, Survival Rate, Neoplasms complications, Neurocognitive Disorders etiology, Research Report, Survivors statistics & numerical data
- Abstract
Background: Neurocognitive impairment in survivors of childhood cancer may be associated with direct neurotoxicity, as well as indirect effects of systemic health complications. We evaluated associations among treatment exposures, chronic health conditions, and neurocognitive outcomes in adult survivors of childhood cancer., Methods: Participants included 5507 adult survivors of childhood cancer (47.1% male; mean [SD] age = 31.8 [7.6] years at evaluation; 23.1 [4.5] years postdiagnosis) in the Childhood Cancer Survivor Study who completed a self-report measure of neurocognitive function. Cardiac, pulmonary, and endocrine chronic health conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Structural equation modeling was used to examine a priori hypothesized causal pathways among cancer treatment, subsequent chronic health conditions, and neurocognitive outcomes. Multivariable models were used to estimate relative risk for associations of treatments and chronic conditions on neurocognitive function. All statistical tests were two-sided., Results: One-third of survivors with a grade 2 or higher chronic condition reported impairments in task efficiency and memory. In addition to direct effects of cranial radiation, path analyses and multivariable models demonstrated direct effects of cardiopulmonary (β = 0.10, P = .002; relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.12 to 1.44) and endocrine (β = 0.07, P = .04; RR = 1.14, 95% CI = 1.02 to 1.28) conditions on impaired task efficiency. We identified similar effects of cardiopulmonary condition on memory (P = .01) and emotional regulation (P = .01). Thoracic radiation was associated with impaired task efficiency (P = .01) and emotional regulation (P = .01) through endocrine morbidity., Conclusions: Non-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors' neurocognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer.
- Published
- 2018
- Full Text
- View/download PDF
45. Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.
- Author
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Morton LM, Sampson JN, Armstrong GT, Chen TH, Hudson MM, Karlins E, Dagnall CL, Li SA, Wilson CL, Srivastava DK, Liu W, Kang G, Oeffinger KC, Henderson TO, Moskowitz CS, Gibson TM, Merino DM, Wong JR, Hammond S, Neglia JP, Turcotte LM, Miller J, Bowen L, Wheeler WA, Leisenring WM, Whitton JA, Burdette L, Chung C, Hicks BD, Jones K, Machiela MJ, Vogt A, Wang Z, Yeager M, Neale G, Lear M, Strong LC, Yasui Y, Stovall M, Weathers RE, Smith SA, Howell R, Davies SM, Radloff GA, Onel K, Berrington de González A, Inskip PD, Rajaraman P, Fraumeni JF Jr, Bhatia S, Chanock SJ, Tucker MA, and Robison LL
- Subjects
- Adolescent, Adult, Breast radiation effects, Child, Child, Preschool, Cohort Studies, Female, Hodgkin Disease radiotherapy, Humans, Infant, Leukemia radiotherapy, Middle Aged, Proportional Hazards Models, Radiotherapy Dosage, Retrospective Studies, Survivors, Young Adult, raf Kinases genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins genetics, Microfilament Proteins genetics, Muscle Proteins genetics, Neoplasms, Radiation-Induced genetics, Neoplasms, Second Primary genetics, Ribosomal Protein S6 Kinases genetics, Tumor Suppressor Proteins genetics
- Abstract
Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking., Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided., Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts., Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer., (Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2017
- Full Text
- View/download PDF
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