Introduction. Childhood brain tumors survivors are at increased risk of developing cardiovascular disease, which contributes substantially to premature mortality. This increased risk arises from the primary disease itself and/or from its treatment.
This doctoral thesis outlines the underlying causes of endocrine and metabolic disorders that may develop following treatment for a childhood brain tumor. It describes the incidence of these complications in our patient cohort, based on tumor location and treatment modality. To assess cardiovascular health in the selected population, we used carotid intima-media thickness (cIMT), a well-established non-invasive biological marker of atherosclerosis. CIMT was measured using a semi-automated radiofrequency ultrasound method suitable for clinical practice among specialists outside the fields of radiology and cardiology. As an additional marker of cardiovascular health, glycemic variability was assessed in a subgroup of the population by continous interstitial glucose monitoring.
Despite increasing recognition of the susceptibility to metabolic disorders among survivors of childhood brain tumors, important gaps remain in understanding their prevalence, underlying mechanisms, and clinical course. A more precise characterization of metabolic outcomes and cardiovascular health is essential for the development of effective follow-up strategies, early detection, and targeted prevention of complications, thereby helping to reduce premature mortality in this population. Data on cIMT are currently available only for small groups of survivors of various childhood tumors, and no data on glycemic variability in this population have yet been reported.
Objectives. To determine the frequency of endocrine and metabolic disorders following completion of oncological treatment for childhood brain tumors. To assess cardiovascular risk after completion of oncological treatment for childhood brain tumors by measuring carotid intima-media thickness and glycemic variability. An additional objective was to investigate the associations between the studied complications and tumor type, tumor location, and treatment modality.
Methods and participants. The study included individuals diagnosed with a brain tumor at or before 18 years of age at the University Children’s Hospital, University Medical Centre Ljubljana, between 2008 and 2018. Demographic data, tumor location, histological findings, treatment modalities (surgery, radiotherapy, chemotherapy), and medication use were collected from medical records. Participants were invited for a comprehensive outpatient evaluation to determine the presence of metabolic disorders. Anthropometric measurements, blood pressure measurements, and fasting blood sampling for the assessment of endocrine axes and metabolic parameters were performed. Body composition was assessed by dual-energy X-ray absorptiometry (Hologic). CIMT was measured using a radiofrequency ultrasound system (RF-quality intima-media thickness, Esaote), and the obtained values were compared with normative values from a healthy population. Glycemic variability was assessed by at least 10 days of continuous interstitial glucose monitoring using the Freestyle Libre 2 system (Abbott Diabetes Care). Standard deviation scores (SDs) were calculated for comparison of the studied variables. Statistical analyses were performed using R project software and Orange.
Hypotheses. The frequency of endocrine complications after completion of oncological treatment for childhood brain tumors in the studied national cohort is similar to that reported in the literature. The frequency of metabolic disorders after completion of oncological treatment for childhood brain tumors in the studied national cohort is higher than in the general healthy population and depends on tumor type, tumor location, and treatment modality. Carotid intima-media thickness in childhood brain tumor survivors is increased compared to the healthy population. Glycemic variability in metabolically at-risk individuals is higher and depends on tumor type, tumor location, and treatment modality.
Results. The study included 94 participants (mean age 14.9 ± 5.5 years, mean follow-up 8.1 ± 3.0 years, 48 males). Most participants had a primary tumor located in the posterior fossa (45), followed by supratentorial tumors (37) and tumors in the suprasellar region (12). At the most recent evaluation, a disorder of at least one hormonal axis was identified in 23% of the cohort, most commonly growth hormone deficiency. Endocrine axis dysfunction was more frequent among survivors with tumors in the suprasellar region, in those with hydrocephalus, and in those who had received radiotherapy. At the last follow-up, survivors showed a significant decline in height SD compared with height SD at the start of treatment. This decline was more pronounced in those who had undergone craniospinal irradiation. Body composition analysis, based on percentage body fat, identified obesity in 46% of participants. Dyslipidemia was present in 54%. No hypertension was recorded in the studied cohort. Type 2 diabetes was identified in two participants. CIMT above the 95th percentile for age and sex was measured in 21 of 81 patients (26%) and was more frequent among survivors with tumors in the suprasellar region, in those with higher BMI SD, and in those who had received radiotherapy as part of their treatment. No differences in glycemic variability markers were identified between specific subgroups defined by tumor location and tumor type or presence of endocrine or metabolic disorders. In four individuals treated for medulloblastoma, dysglycemia was identified, with a proportion of time above the target glucose range of ≥10 mmol/L.
Conclusions. The incidence of endocrine and metabolic disorders among survivors of childhood brain tumor treatment is high, particularly in those with suprasellar tumors. Among survivors treated for brain tumors in other locations, the prevalence of metabolic disorders is higher than in the general population. BMI SD underestimates the frequency of obesity in this population; therefore, body composition analysis is necessary for an accurate assessment. Increased early cardiovascular risk, determined by cIMT measurement, was detected in more than one quarter of survivors of childhood brain tumor treatment within the first decade after completion of oncological therapy. Higher SD BMI, radiation therapy, and tumor location in the suprasellar region were identified as factors associated with elevated cIMT.
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