Faculty Bibliography

Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as >/=15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.

Acquired white matter abnormalities in children may be due to a broad spectrum of disorders, with the most significant related to metabolic and toxic etiologies. Recognition of the imaging appearance of neonatal hypoglycemia, nonketotic hyperglycemia, hyperammonemia, hepatic encephalopathy, and central pontine myelinolysis (CPM) is essential because prompt correction of the underlying metabolic abnormality may limit and, in some cases, reverse the cerebral damage. Toxic leukoencephalopathies encompass disorders caused by iatrogenic administration of pharmacologic agents and radiation therapy, poisoning by household substances, and recreational drug use. Although medication-induced leukoencephalopathies often show a propensity for reversibility of clinical and radiologic findings upon discontinuation of the offending substance, recreational drugs may cause white matter toxicity that often portends a poorer prognosis. Our discussion focuses on the clinical aspects, pathophysiological mechanisms, and imaging features of commonly encountered acquired metabolic and toxic leukoencephalopathies in the pediatric population.