Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors

Waas, Marjolein van; Neggers, Sebastian J C M M; Uitterlinden, André G.; Blijdorp, Karin; Geest, Ivana M.M. van der; Pieters, Rob; Heuvel‐Eibrink, Marry M. van den

doi:10.1016/j.ejca.2012.09.007

Cited by 23 publications

(15 citation statements)

References 22 publications

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“…44 reported higher systolic blood pressure values among nonirradiated patients, albeit without performing a statistical analysis of the difference. 42 Finally, one study has shown that blood pressure was significantly higher in non-irradiated patients, which is consistent with our results. 45 Overall, the consequences of CNS irradiation on cardiovascular risk factors seem complex.…”

Section: Number Of Cases (%) 95% CIsupporting

confidence: 82%

“…In the literature however, brain irradiation has been frequently reported as a risk factor for MetS. 18,42,43 This can probably be explained in part by the observation that our irradiated patients displayed a lower risk of elevated blood pressure. We conducted an analysis of the prevalence of each MetS component among patients who had at least one abnormal component ( Figure 3).…”

Section: Number Of Cases (%) 95% CImentioning

confidence: 68%

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Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study

et al. 2016

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C ardiovascular conditions are serious long-term complications of childhood acute leukemia. However, few studies have investigated the risk of metabolic syndrome, a known predictor of cardiovascular disease, in patients treated without hematopoietic stem cell transplantation. We describe the overall and age-specific prevalence, and the risk factors for metabolic syndrome and its components in the L.E.A. (Leucémie de l'Enfant et de l'Adolescent) French cohort of childhood acute leukemia survivors treated without hematopoietic stem cell transplantation. The study included 650 adult patients (mean age at evaluation: 24.2 years; mean follow-up after leukemia diagnosis: 16.0 years). The prevalence of metabolic syndrome was 6.9% (95% CI 5.1-9.2). The age-specific cumulative prevalence at 20, 25, 30 and 35 years of age was 1.3%, 6.1%, 10.8% and 22.4%, respectively. The prevalence of decreased high-density lipoprotein cholesterol, increased triglycerides, increased fasting glucose, increased blood pressure and increased abdominal circumference was 26.8%, 11.7%, 5.8%, 36.7% and 16.7%, respectively. Risk factors significantly associated with metabolic syndrome in the multivariate analysis were male sex (OR 2.64; 95% CI 1.32-5.29), age at last evaluation (OR 1.10; 95% CI 1.04-1.17) and body mass index at diagnosis (OR 1.15; 95% CI 1.01-1.32). The cumulative steroid dose was not a significant risk factor. Irradiated and non-irradiated patients exhibited different patterns of metabolic abnormalities, with more frequent abdominal obesity in irradiated patients and more frequent hypertension in non-irradiated patients. Survivors of childhood acute leukemia are at risk of metabolic syndrome, even when treated without hematopoietic stem cell transplantation or central nervous system irradiation. A preventive approach with regular screening for cardiovascular risk factors is recommended.

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Section: Number Of Cases (%) 95% CIsupporting

confidence: 82%

Section: Number Of Cases (%) 95% CImentioning

confidence: 68%

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study

et al. 2016

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“…With the aim of further characterizing the weight changes, we evaluated the BMI and abdominal circumference, and these two indicators also increased significantly with age in female rats after juvenile brain irradiation. This is in line with the finding in many clinical studies of adult survivors of childhood cancer that radiation exposure induces overweight/obesity in adulthood [18, 25, 26]. Our study has for the first time confirmed in an animal model the impact of juvenile brain irradiation on metabolic dysfunction in adulthood.…”

Section: Discussionsupporting

confidence: 78%

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Sun

Zhou

et al. 2018

Dev Neurosci

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Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients’ quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.

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“…The metabolic syndrome, a known risk factor for cardiovascular disease, 32 has also been associated with subclinical left ventricular myocardial dysfunction in both men and women. 33 An increased risk for developing components of the metabolic syndrome has been frequently reported in childhood cancer survivors.…”

Section: Interventions To Reduce Risk Of Treatment-related Cardiotoximentioning

confidence: 99%

Late cardiotoxicity in aging adult survivors of childhood cancer

Armstrong

Ross

2014

Progress in Pediatric Cardiology

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The survival rate for childhood cancer is steadily improving, and the current estimate for the prevalence of childhood cancer survivors in the United States is 420,000. With this encouraging trend and the aging of this population, there is an ever-increasing responsibility to identify adult survivors of childhood cancer with adverse health outcomes related to cancer treatment across the span of their lives. To accomplish this, large cohort studies have been developed to follow survivors longitudinally. Compared to siblings, survivors have a higher cumulative incidence of morbidity and mortality, and this gap in incidence only widens with age. One of the most significant late toxicities in survivors is late onset cardiotoxicity, largely due to anthracycline and chest-directed radiation exposure. Survivors also have an increased prevalence of traditional cardiovascular risk factors as they age, which potentiates the risk for major cardiac events. Prevention is essential. Minimizing anthracycline dose exposure in pediatric cancer patients is a primary method of cardioprotection. Dexrazoxane and enalapril have also been studied as primary (pre-exposure) and secondary (post-exposure) cardioprotecant agents, respectively. Additionally, the Children’s Oncology Group has published exposure-driven, risk-based screening guidelines for long-term follow-up, which may be a cost-effective way to identify subclinical cardiac disease before progression to clinical presentation. Ongoing research is needed to determine the most effective diagnostic modality for screening (e.g. echocardiography), and the most effective intervention strategies to improve long-term outcomes.

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Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors

Cited by 23 publications

References 22 publications

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study

Metabolic syndrome in long-term survivors of childhood acute leukemia treated without hematopoietic stem cell transplantation: an L.E.A. study

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Late cardiotoxicity in aging adult survivors of childhood cancer

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