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.

Diabetes insipidus in pediatric germinomas of the suprasellar region: characteristic features and significance of the pituitary bright spot.

The pituitary bright spot is acknowledged to indicate functional integrity of the posterior pituitary gland, whilst its absence supports a diagnosis of central diabetes insipidus (DI). This feature was evaluated, together with the incidence and clinical characteristics of DI in children with suprasellar/neurohypophyseal germinomas. We performed a review of all suprasellar (SS) or bifocal (BF) germinoma pediatric patients treated in Toronto since 2000. Demographics, symptomatology, treatment outcome and imaging were evaluated. Nineteen patients fulfilled inclusion criteria (10 SS, 9 BF; median age 12.5 years (6.2-16.8 years)). All remained alive at 6.4 years median follow-up (1.2-13.7 years) after receiving chemotherapy and radiotherapy (13 focal/ventricular, four whole brain, two neuraxis), with only one progression. All had symptoms of DI at presentation with a symptom interval above one year in eight cases (42 %). Desmopressin was commenced and maintained in 16 patients (84 %). The pituitary bright spot was lost in most diagnostic interpretable cases, but was appreciated in three patients (18 %) who had normal serum sodium values compared to 'absent' cases (p = 0.013). For two such cases, spots remained visible until last follow-up (range 0.4-3.3 years), with one still receiving desmopressin. No case of bright spot recovery was observed following therapy. Protracted symptom intervals for germinoma-induced central DI may reflect poor clinical awareness. Explanations for persistence of the pituitary bright spot in symptomatic patients remain elusive. Desmopressin seldom reverses the clinical features of germinoma-induced DI to allow discontinuation, nor does treatment cause bright spot recovery.

Medication-induced diabetes during induction treatment for ALL, an early marker for future metabolic risk?

Medication-induced diabetes (MID) is seen in children treated for acute lymphoblastic leukemia (ALL) mostly during induction, due to the use of l-asparaginase and glucocorticoids. Our objective was to assess whether MID during induction, is a risk factor for future impaired glucose tolerance (IGT), diabetes, or metabolic syndrome. Ninety survivors of pediatric ALL, ages 10 yr and older were recruited, 30 with history of MID and 60 controls. Waist/height ratio >0.5 was considered as an increased risk for central adiposity and insulin resistance. Lipid profile and an oral glucose tolerance test (OGTT) were performed. Study patients were older than controls (17.2 vs. 14.9, p < 0.05). The groups had similar sex distribution, body mass index (BMI) z-score, and Tanner staging. A waist/height ratio of >0.5 was seen in 60 and 31.7% of the study and control groups, respectively (p = 0.01). Increased frequency of IGT in the study group compared with the control group was seen (13.3 and 1%, respectively) (p = 0.07). We observed a trend toward higher proportion of patients with multiple features of metabolic syndrome in the study compared with control group (16.7 vs. 5%, p = 0.09). In conclusion, MID during induction may be an early marker for metabolic disturbances later in life. The higher rates of increased waist/height ratio, and subjects with multiple metabolic syndrome features, may predict a metabolic risk in children with history of MID. Rates of IGT were four fold higher in the study group although not statistically significant. MID may be a 'red flag' indicating the need for ongoing metabolic screening and lifestyle modifications to prevent future metabolic disease.

School attendance in childhood cancer survivors and their siblings.

OBJECTIVE: To investigate school absenteeism among childhood cancer survivors and their siblings and examine factors related to absenteeism in survivors. STUDY DESIGN: A cross-sectional study was conducted among consecutive cancer survivors attending a large pediatric cancer survivor clinic. Absenteeism rates were obtained for survivors and their closest in age sibling from school report cards. Absenteeism was compared with a population control group of 167752 students using 1-sample t tests. The Child Vulnerability Scale, Pediatric Quality of Life Inventory, and Behavior Assessment System for Children were administered to survivors. Univariate and multiple regression analyses assessed variables associated with days absent. RESULTS: One hundred thirty-one survivors (median age at assessment: 13.4 years, range 8.0-19.2; median age at diagnosis: 9.4 years, range 4.3-17.3) and 77 siblings (median age at assessment: 13 years, age range 7-18) participated. Survivors and siblings missed significantly more school days than the population control group (mean ± SD: 9.6 ± 9.2 and 9.9 ± 9.8 vs 5.0 ± 5.6 days, respectively, P < .0001). Among matched survivor-sibling pairs (N = 77), there was no difference in absenteeism (9.6 ± 9.2 vs 9.9 ± 9.8 days, P = .85). Absenteeism in survivors was significantly associated with a low Pediatric Quality of Life Inventory Physical Health Summary Score (P = .01). Parents' perception of their child's vulnerability and emotional and social functioning were not associated with absenteeism. CONCLUSIONS: Childhood cancer survivors and siblings miss more school than the general population. The only predictor of absenteeism in survivors is poor physical quality of health. More research should be devoted to school attendance and other outcomes in siblings of childhood cancer survivors.

The search for ectopic ACTH production in a 9-year-old boy.

Ectopic ACTH syndrome (EAS) is rare in children and is challenging to differentiate from Cushing's disease. A 9-year-old boy presented with a history of worsening fatigue, muscle weakness, weight gain and acne, and he appeared cushingoid with central obesity and hyperpigmentation of his palmar creases. Investigations demonstrated an elevated ACTH and an elevated morning cortisol that did not suppress with low or high dose dexamethasone suppression tests. Brain imaging inconsistently showed a small pituitary lesion. Chest and abdomen computed tomography (CT) showed adrenal hyperplasia and a liver hemangioma. [18F]fluorodeoxyglucose positron emission tomography CT was normal. Ultrasound and abdominal magnetic resonance imaging (MRI) also showed a liver hemangioma. Bilateral inferior petrosal sinus sampling, however, was consistent with ectopic ACTH production. An octreotide scan revealed a small focus of increased activity in the liver, which was the likely source of ectopic ACTH production. The patient was managed with metyrapone followed by a wedge liver resection. Pathology showed a well-differentiated neuroendocrine tumor (NET) that stained positive for ACTH. Post-operatively, the signs and symptoms of EAS are resolving and his hypothalamic-pituitary-adrenal axis is recovering. This case describes the first pediatric patient with EAS caused by a liver NET. It illustrates the challenges in localizing the source of ectopic ACTH and treating this rare condition.

Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics.

INTRODUCTION: Medication induced diabetes (MID) during induction therapy (MIDi) in patients with acute lymphoblastic leukemia (ALL) is not well characterized in children, with recent studies yielding conflicting results. PURPOSE: The purpose of the study was to describe the prevalence of MIDi and risk factors for its development. METHODS: We retrospectively gathered demographic, disease course and treatment data on 363 patients aged 1 to 17.9 years diagnosed with ALL at a pediatric tertiary care hospital between 1998 and 2005. MIDi was defined as blood glucose ≥200 mg/dL (11.1 mmol/L) on at least 2 separate days during induction. RESULTS: Fifty-seven subjects (15.7%) developed MIDi during the study period. Patients ≥10 years were more likely to develop MIDi than those <10 years (odds ratio [OR] 9.6, 95% confidence interval [CI] 5.1-17.8). BMI percentile among those with MIDi (mean ± SD 58.2 ± 31.0) did not differ from those without MIDi (52.2 ± 32.0, P = 0.429). The presence of Trisomy 21 (OR 3.6, 95% CI 1.1-11.4, P = 0.030) and CNS involvement at diagnosis (OR 3.8, 95% CI 1.4-10.1, P = 0.009) were associated with an increased risk of MIDi. After adjustment for potential confounding variables, age ≥10 years and the presence of CNS disease at diagnosis remained significantly associated with MIDi. CONCLUSIONS: Older age and CNS involvement at diagnosis increase the risk of MIDi. In contrast to previous studies, higher BMI was not associated with MIDi in our population.

A cross-sectional study of overweight in pediatric survivors of acute lymphoblastic leukemia (ALL).

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for overweight, predisposing them to long-term morbidity. We examined the relationship between body mass index (BMI) and demographic and lifestyle factors in a cohort of ALL survivors. PROCEDURE: We enrolled consecutive ALL survivors who attended the institutional AfterCare Clinic over a 1-year period. BMI (kg/m(2) ) at diagnosis, end-therapy, and current time were calculated. Survivors were classified as overweight/obese (overweight group; BMI for age ≥ 85th percentile) or normal/underweight (normal weight group; BMI for age <85th percentile). We assessed the relationship between current BMI and self-reported current caloric intake, physical activity, and sedentary behavior. RESULTS: 102/157 (65%) eligible survivors consented to enrollment. Median age was 14.3 years (range 8.4-18.6) and time from end of treatment 7 years (2.5-15.6). The proportion of overweight survivors was 21%, 45%, and 35% at diagnosis, end-therapy, and current time, respectively. The overweight group reported less calories (Δ324 kcal, P = 0.018), fat (Δ14.5 g, P = 0.02), and carbohydrates (Δ39 g, P = 0.02) than the normal weight group. These differences disappeared after excluding patients classified as under-reporting their calorie intake according to the Goldberg cut-off method. There were no differences in sedentary behavior or activity between groups. CONCLUSIONS: Many children with ALL gain weight during therapy and fail to return to normal weight after treatment concludes. Subsequent diet, physical activity, and sedentary behavior do not appear to differ between overweight and normal weight survivors. Clinicians should focus on ways to minimize weight gain during therapy rather than waiting for treatment to conclude.

Incidental thyroid abnormalities identified on neck US for non-thyroid disorders.

BACKGROUND: Incidental thyroid abnormalities detected on US examinations in children have not been well documented. OBJECTIVE: To determine prevalence of incidental thyroid abnormalities depicted by US in children and to describe the spectrum of appearances. MATERIALS AND METHODS: Retrospective analysis of clinical and US findings in children who had neck US from January 2006 to December 2007. RESULTS: Of 1,228 neck US exams, thyroid was depicted in 287 children (mean age = 6.2 years). Incidental thyroid abnormalities were detected in 52 (18%) (mean age = 8.1 years). In 35 there were small (<4 mm), well-defined cysts, some with a hyperechoic punctate focus. In nine there were hypoechoic, solid nodules with smooth, straighter margins with echogenicity similar to thymus, suggesting intrathyroid ectopic thymus (mean age = 2.5 years). In three others there were tiny hyperechoic foci without nodules. Other abnormalities included hypoechoic target-like lesions (n = 2), isoechoic nodule (n = 1), multiple hypoechoic foci (n = 1) and non-visualized thyroid lobe resulting from adjacent abscess (n = 1). None of the children developed thyroid dysfunction or malignancy. CONCLUSION: There is a spectrum of incidental thyroid abnormalities in children. These US findings should be interpreted cautiously, avoiding unnecessary referrals and investigations. Intrathyroid ectopic thymus is more common than previously thought, occurs much more frequently in younger boys and should be considered if the lesion has US characteristics of thymus.

Outcome after bariatric surgery in two adolescents with hypothalamic obesity following treatment of craniopharyngioma.

Treatment of craniopharyngioma (CP) in childhood can lead to severe, debilitating obesity with devastating medical and psychological outcomes. Despite sustained nutritional and exercise-oriented interventions, no efficacious medical option is available for hypothalamic obesity. We describe two adolescents who developed morbid obesity and significant comorbidities following diagnosis and treatment of CP, in whom bariatric surgery was achieved, illustrating a novel approach for symptomatic hypothalamic obesity, as well as positive and negative outcomes.