A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

High prevalence of thrombophilic traits in children with family history of thromboembolism.

OBJECTIVES: To determine a proximate family history of venous thromboembolism (VTE) in (1) the prevalence of thrombophilia; (2) the frequency of recommended changes in management resulting from thrombophilia evaluation; and (3) outcomes in longitudinal follow-up. STUDY DESIGN: Laboratory thrombophilia investigation was performed in 56 children with first- or second-degree family history of thromboembolism before age 55 years, but without personal history of thromboembolism, who were enrolled in a prospective inception cohort. VTE risk factors, family history, thrombophilia findings, and management recommendations were systematically collected, along with thromboembolism risk episodes/exposures, prophylactic anticoagulation, major bleeds, and thromboembolism events during follow-up. RESULTS: The frequencies of all thrombophilia traits were higher than the general population. Among 32 children who underwent complete laboratory evaluation, 34% had >or=2 traits. Thrombophilia testing led to recommendations for risk-based transient antithrombotic prophylaxis in 71% of subjects. No thromboembolism episodes developed during more than 900 patient-months of follow-up, although at-risk exposures were infrequent. CONCLUSION: Risk-stratified approaches to primary prevention of pediatric VTE should be further evaluated in cooperative prospective studies.

Safety considerations in the use of botulinum toxins in children with cerebral palsy.

The use of botulinum toxins to decrease spasticity in children with cerebral palsy has become standard of care during the past decade. In 2008 reports of severe adverse events, including death, were reported in children who received injections of these medications. The following discussion focuses on the background of these reports, the response of the U.S. Food and Drug Administration, as well as the safety profile and pharmacokinetics of botulinum toxins. Finally, the authors will offer their perspective on the safe use of botulinum toxins.