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Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis Krueger DA; Care MM; Holland K; Agricola K; Tudor C; Mangeshkar P; Wilson KA; Byars A; Sahmoud T; Franz DNN Engl J Med 2010[Nov]; 363 (19): 1801-11BACKGROUND: Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex. METHODS: Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter. RESULTS: We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (+/-SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4+/-12.4) and 6 months (62.1+/-14.2) over the baseline score (57.8+/-14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported. CONCLUSIONS: Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).|Administration, Oral[MESH]|Adolescent[MESH]|Adult[MESH]|Angiofibroma/drug therapy[MESH]|Anticonvulsants/therapeutic use[MESH]|Astrocytoma/*drug therapy/etiology/pathology[MESH]|Brain Neoplasms/*drug therapy/etiology/pathology[MESH]|Child[MESH]|Child, Preschool[MESH]|Cognition/drug effects[MESH]|Drug Therapy, Combination[MESH]|Everolimus[MESH]|Facial Neoplasms/drug therapy[MESH]|Female[MESH]|Humans[MESH]|Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors[MESH]|Male[MESH]|Prospective Studies[MESH]|Protein Serine-Threonine Kinases/*antagonists & inhibitors[MESH]|Quality of Life[MESH]|Seizures/*drug therapy/etiology[MESH]|Sirolimus/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics[MESH]|TOR Serine-Threonine Kinases[MESH]|Tuberous Sclerosis/complications/*drug therapy[MESH]|Young Adult[MESH] |
