Clinical Importance of Free Thyroxine Concentration Decline After Radiotherapy for Pediatric and Adolescent Brain Tumors.

CONTEXT: Clinical significance of a decline in free T4 (FT4) concentrations across the reference range in children with brain tumors treated with radiation therapy (RT) is uncertain. OBJECTIVES: To study trends in FT4 in children after RT and risk factors and health outcomes associated with plasma FT4 concentrations. DESIGN AND SETTING: Longitudinal, single-center retrospective cohort study. PATIENTS: Low-grade glioma or ependymoma patients (n = 267; age ≤25 years) who received RT (50.4 to 59.4 Gy) at a single institution (1996 to 2016) and followed with serial FT4 measurements. MAIN OUTCOME MEASURE: A linear mixed-effects model with a random intercept was used to investigate risk factors for longitudinal changes in FT4 concentrations. A two-stage mixed-effects model examined associations between clinical outcomes and plasma FT4 concentrations. RESULTS: FT4 concentrations declined over time after RT (P < 0.001). Females (P < 0.001) and younger patients (P < 0.001) demonstrated greater declines in FT4 concentrations over time. The rate of weight gain, but not of height loss, increased with a higher FT4 decline rate (P < 0.001). At last follow-up, patients with lower baseline FT4 concentrations had increased risk of glucose disorder (OR, 19.73; P = 0.002) or dyslipidemia (OR, 19.40; P = 0.003) but not high fat mass (P = 0.18). Lower baseline FT4 concentrations were not associated with impaired scores for intelligence, attention, memory, or psychosocial functioning. CONCLUSIONS: FT4 concentrations significantly decline in children with brain tumor after RT. Variation and trends in FT4 concentration are associated with physical health outcomes. Future studies should assess whether continuous FT4 concentrations and trends, rather than population-based cut-off values, can distinguish between euthyroid and hypothyroid states.

Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost.

BACKGROUND: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. METHODS: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). RESULTS: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042). CONCLUSIONS: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors.

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short-term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2-3, dentate gyrus (DG)-CA4, stratum radiatum-lacunosum-moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short-term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale-third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG-CA4, CA1, CA2-3, and stratum radiatum-lacunosum-moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG-CA4, CA1, and stratum radiatum-lacunosum-moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.

Improved patient quality of life following intradural extramedullary spinal tumor resection.

OBJECTIVE Resection significantly improves the clinical symptoms and functional outcomes of patients with intradural extramedullary tumors. However, patient quality of life following resection has not been adequately investigated. The aim in this retrospective analysis of prospectively collected quality of life outcomes is to analyze the efficacy of resection of intradural extramedullary spinal tumors in terms of quality of life markers. METHODS A retrospective review of a single institutional neurosurgical administrative database was conducted to analyze clinical data. The Oswestry Disability Index (ODI), visual analog scale (VAS) for pain, and the EQ-5D-3 L descriptive system were used to analyze quality of life preoperatively, less than 1 month postoperatively, 1-3 months postoperatively, 3-12 months postoperatively, and more than 12 months postoperatively. RESULTS The ODI scores increased perioperatively at the < 1-month follow-up from 36 preoperatively to 47. Relative to preoperative values, the ODI score decreased significantly at 1-3, 3-12, and > 12 months to 23, 17, and 20, respectively. VAS scores significantly decreased from 6.1 to 3.5, 2.4, 2.0, and 2.9 at the < 1-month, 1- to 3-, 3- to 12-, and > 12-month follow-ups, respectively. EQ-5D mobility significantly worsened at the < 1-month follow-up but improved at the 3- to 12-and > 12-month follow-ups. EQ-5D self-care significantly worsened at the < 1-month follow-up but significantly improved by the 3- to 12-month follow-up. EQ-5D usual activities improved at the 1- to 3-, 3- to 12-, and > 12-month follow-ups. EQ-5D pain and discomfort significantly improved at all follow-up points. EQ-5D anxiety and depression significantly improved at 1- to 3-month and 3- to 12-month follow-ups. CONCLUSIONS Resection of intradural extramedullary spine tumors appears to significantly improve patient quality of life by decreasing patient disability and pain and by improving each of the EQ-5D domains.

Long-term quality of life in children treated for posterior fossa brain tumors.

OBJECT: In the face of increasing survival, quality of life (QOL) has become an important indicator of treatment success in children with posterior fossa brain tumors (PFBTs). The authors' objective was to assess the long-term QOL in survivors of PFBT. METHODS: The authors conducted a cross-sectional study of children who, between birth and age 18 years at diagnosis, had previously been treated at their institution for a PFBT. At the time of assessment for this study, children were between 5 and 19 years old and had received standard treatment for PFBT ending at least 6 months before the assessment. The QOL was measured with the Pediatric Quality of Life Inventory (PedsQL) generic score scales and the Health Utilities Index Mark 3 (HUI3). Multivariate analyses were used to assess several variables (patient related, treatment related, and socioeconomic) for association with QOL. RESULTS: A total of 62 children participated in the study (median age at assessment 11.9 years, interquartile range [IQR] 7.8-14.8, and median age at tumor diagnosis of 4.9 years, IQR 2.5-6.9). Median time since active treatment for their PFBT was 5.2 years (IQR 2.4-10.1). Tumor types included cerebellar pilocytic astrocytoma (45.2%), medulloblastoma (30.6%), ependymoma (11.3%), and brainstem astrocytoma (11.3%). Adjuvant therapy included chemotherapy (40.3%) or radiotherapy (14.5% focal and 21.0% craniospinal radiotherapy). Permanent treatment for hydrocephalus was required in 38.7% of the patients. Tumors recurred in 11.3%, requiring repeat treatment in these patients. The median HUI3 utility score was 0.91 (IQR 0.71-1.00) and the median PedsQL total score was 78.3 (IQR 64.1-92.4). Only the following variables were significantly associated with decreased QOL in multivariable model testing (all p < 0.05): need for permanent hydrocephalus treatment, large ventricle size, decreased family functioning, and lower family income. CONCLUSIONS: As a group, long-term survivors of pediatric PFBT appear to have QOL indicators that are similar to those of the general population, although a reasonable minority of patients experience poor outcomes. Although several confounding variables likely remain in this retrospective study, important associations with QOL include the presence of hydrocephalus and socioeconomic factors. The study sample size, however, was limited and the presence of other important factors cannot be excluded.

Differential language trajectories following treatment for pediatric posterior fossa tumor: an investigation of four cases.

Up to 85% of children treated for brain tumor survive beyond five years; hence optimizing quality of life in survivorship has become a priority. As multiple factors contribute to the heterogeneity of neurocognitive and language outcomes for individual children following treatment, a means of monitoring subsequent development is needed for the individual child, particularly when pre-morbid performance indices are not available. The current study investigated the use of developmental language trajectories as a means of monitoring language development subsequent to treatment for tumors located within the posterior fossa. The language skills of four children treated for posterior fossa tumor (PFT) were monitored over time (range of monitoring: 2-6 years) and the resultant trajectories were plotted against the trajectories based on tests' normative data as well as the trajectories of control children drawn from each child's local community. Each child's trajectory was considered in terms of age-appropriate developmental gains and discussed regarding the need for ongoing clinical monitoring of emerging, developing or established language skills. The study's findings highlight the heterogeneity of language outcomes following PFT. The utility of the application of developmental trajectories for the provision of individualized post-treatment support is discussed.

A 5-year investigation of children's adaptive functioning following conformal radiation therapy for localized ependymoma.

PURPOSE: Conformal and intensity modulated radiation therapies have the potential to preserve cognitive outcomes in children with ependymoma; however, functional behavior remains uninvestigated. This longitudinal investigation prospectively examined intelligence quotient (IQ) and adaptive functioning during the first 5 years after irradiation in children diagnosed with ependymoma. METHODS AND MATERIALS: The study cohort consisted of 123 children with intracranial ependymoma. Mean age at irradiation was 4.60 years (95% confidence interval [CI], 3.85-5.35). Serial neurocognitive evaluations, including an age-appropriate IQ measure and the Vineland Adaptive Behavior Scales (VABS), were completed before irradiation, 6 months after treatment, and annually for 5 years. A total of 579 neurocognitive evaluations were included in these analyses. RESULTS: Baseline IQ and VABS were below normative means (P<.05), although within the average range. Linear mixed models revealed stable IQ and VABS across the follow-up period, except for the VABS Communication Index, which declined significantly (P=.015). Annual change in IQ (-.04 points) did not correlate with annual change in VABS (-.90 to +.44 points). Clinical factors associated with poorer baseline performance (P<.05) included preirradiation chemotherapy, cerebrospinal fluid shunt placement, number and extent of surgical resections, and younger age at treatment. No clinical factors significantly affected the rate of change in scores. CONCLUSIONS: Conformal and intensity modulated radiation therapies provided relative sparing of functional outcomes including IQ and adaptive behaviors, even in very young children. Communication skills remained vulnerable and should be the target of preventive and rehabilitative interventions.

Psychological intervention in young brain tumor survivors: the efficacy of the cognitive behavioural approach.

PURPOSE: Cognitive and behavioural therapy (CBT) is often used to treat behavioural and emotional disorders in children, and its efficacy has been described in several studies. As behavioural and emotional disorders are frequent sequelae in brain tumor survivors, the goal of this work is to describe the efficacy of a CBT intervention in the treatment of young brain tumor survivors. METHODS: Forty young patients, aged 4-18 years, were included in the study. The treatment group, composed of 17 patients, received sessions of CBT. The Child Behaviour Checklist 4-18 (CBCL/4-18) and the Vineland Adaptive Behavioural Scales (VABS) were administered to parents at the beginning and at the end of the hospitalisation. The statistical significance of changes for clinical subjects during the CBT administration was estimated. RESULTS: With regard to the CBCL/4-18, the clinical group showed a significant advantage on the withdrawn, somatic complaints, social problems, attention problems, internalising and total problem scales. On the VABS, the treatment group improved to a significantly greater extent in the social skills domain. CONCLUSIONS: These results substantiate our assumption that CBT is an effective intervention for young patients surviving brain tumors and may be particularly helpful to younger individuals in managing cancer-related limitations.

Neuropsychological sequelae and quality of life following treatment of posterior fossa ependymomas in children.

INTRODUCTION: Modern treatment of posterior fossa ependymomas in children has improved the overall survival, but as more children live longer, the neuropsychological problems that they endure as result of the disease and its treatment become more the focus of attention. MATERIAL: Early problems such as cerebellar mutism appear to be related to surgery and do not seem to be influenced in their incidence or outcome by the otherwise beneficial effect of oncological treatment. Indeed, the cause of cerebellar mutism is still elusive. While it was originally believed to be totally reversible, it is increasingly realized that it may be related to more complex delayed neuropsychological problems. Late problems such as the cerebellar cognitive affective syndrome are increasingly being recognized. The deleterious effect of both surgery and radiotherapy that is commonly administered afterwards is now well appreciated. CONCLUSION: Careful neuropsychological assessment of these children and early intervention will maximize chances for recovery and improvement of academic functions and quality of life issues.

Gender differences in facial expression recognition in survivors of pediatric brain tumors.

OBJECTIVE: To examine the relation between gender, history of cranial radiation therapy (CRT) and facial expression recognition (FER) skill in survivors of pediatric brain tumors. METHODS: Fifty-three survivors (27 females) completed a measure of FER and an intelligence test. RESULTS: There was a significant interaction between gender and CRT on ability to interpret low-intensity facial expressions, such that females who had not had CRT made fewer errors than either females who had CRT or males. CONCLUSION: A history of CRT has a notable effect on FER skill in females: girls who received CRT performed significantly more poorly than girls who did not.

Social functioning and facial expression recognition in survivors of pediatric brain tumors.

OBJECTIVE: To assess social functioning and facial expression recognition skill in survivors of pediatric brain tumors (BT) as compared to children with juvenile rheumatoid arthritis (JRA). METHODS: The social functioning of 51 survivors of BT and 31 children with JRA was assessed using a facial expression recognition task, questionnaire ratings of social functioning, and an IQ screener. RESULTS: After controlling for estimated IQ, survivors of BT made significantly more errors interpreting adult facial expressions as compared to children with JRA. Additionally, history of therapy and diagnosis age predicted performance on the child portion of the facial recognition task. Finally, survivors of BT demonstrated significantly impaired social functioning across multiple measures when compared to children with JRA. CONCLUSIONS: Survivors of pediatric BT showed significant deficits in social functioning as compared to an illness comparison group. Errors in facial expression recognition represent another method for evaluating deficits that contribute to social outcomes.

Impairment of intellectual functions after surgery and posterior fossa irradiation in children with ependymoma is related to age and neurologic complications.

BACKGROUND: To investigate the neuropsychological outcome of children treated with surgery and posterior fossa irradiation for localized infratentorial ependymoma. METHODS: 23 patients (age 0.3 - 14 years at diagnosis) who were treated with local posterior fossa irradiation (54 Gy) underwent one (4 patients) or sequential (19 patients) neuropsychologic evaluation. The last evaluation was performed at a median of 4.5 (1 to 15.5) years after RT. RESULTS: Mean last full scale IQ (FSIQ), verbal IQ (VIQ) and PIQ were 89.1, 94.0, and 86.2 respectively. All patients had difficulties with reading, and individual patients showed deficits in visuospatial, memory and attentional tasks. There was no trend for deterioration of intellectual outcome over time. All 5 children with IQ scores < or = 75 were under the age of four at diagnosis. There was a significant association between the presence of cerebellar deficits and impaired IQ (72.0 vs 95.2, p < 0,001). The absence of hydrocephalus was an indicator of better neuropsychologic outcome (mean FSIQ of 102.6 vs 83.9, p = 0.025). CONCLUSION: Within the evaluated cohort, intellectual functions were moderately impaired. Markedly reduced IQ scores were only seen with early disease manifestation and treatment, and postoperative neurological deficits had a strong impact on intellectual outcome.

Radiation dosimetry predicts IQ after conformal radiation therapy in pediatric patients with localized ependymoma.

PURPOSE: To assess the effects of radiation dose-volume distribution on the trajectory of IQ development after conformal radiation therapy (CRT) in pediatric patients with ependymoma. METHODS AND MATERIALS: The study included 88 patients (median age, 2.8 years +/- 4.5 years) with localized ependymoma who received CRT (54-59.4 Gy) that used a 1-cm margin on the postoperative tumor bed. Patients were evaluated with tests that included IQ measures at baseline (before CRT) and at 6, 12, 24, 36, 48, and 60 months. Differential dose-volume histograms (DVH) were derived for total-brain, supratentorial-brain, and right and left temporal-lobe volumes. The data were partitioned into three dose intervals and integrated to create variables that represent the fractional volume that received dose over the specified intervals (e.g., V(0-20 Gy), V(20-40 Gy), V(40-65 Gy)) and modeled with clinical variables to develop a regression equation to estimate IQ after CRT. RESULTS: A total of 327 IQ tests were performed in 66 patients with infratentorial tumors and 20 with supratentorial tumors. The median follow-up was 29.4 months. For all patients, IQ was best estimated by age (years) at CRT; percent volume of the supratentorial brain that received doses between 0 and 20 Gy, 20 and 40 Gy, and 40 and 65 Gy; and time (months) after CRT. Age contributed significantly to the intercept (p > 0.0001), and the dose-volume coefficients were statistically significant (V(0-20 Gy), p = 0.01; V(20-40 Gy), p < 0.001; V(40-65 Gy), p = 0.04). A similar model was developed exclusively for patients with infratentorial tumors but not supratentorial tumors. CONCLUSION: Radiation dosimetry can be used to predict IQ after CRT in patients with localized ependymoma. The specificity of models may be enhanced by grouping according to tumor location.