ABSTRACT
BACKGROUND: High-dose chemotherapy with autologous stem cell rescue (HDC/SCR) has produced responses and prolonged survival for some children with recurrent brain tumors, but is associated with considerable morbidity and mortality. A Phase I trial of two cycles of HDC/SCR for recurrent brain tumors in children was performed to determine the maximum tolerated doses for a novel regimen. PROCEDURES: Two cycles of HDC/SCR were given. Cycle 1 included thiotepa and carmustine given on days -5, -4, and -3. Four to six weeks later, patients received cycle 2 which included thiotepa and carboplatin given on days -5, -4, and -3. Autologous peripheral blood stem cells (PBSC) were infused on day 0 of each cycle. RESULTS: Thirty-two patients were treated and 25 patients received both cycles of HDC/SCR. Common toxicities included mucositis, emesis, diarrhea, anorexia, and pancytopenia. Eight of 32 (25%) assessable children died from regimen-related toxicity. Pulmonary failure occurred in seven patients. Seven patients had grade 3-4 neurotoxicity. The 3-year event-free survival (EFS) was 25%. CONCLUSIONS: We determined the maximum tolerated regimen to be thiotepa 600 mg/m(2) and carmustine 300 mg/m(2) followed by thiotepa 600 mg/m(2) and carboplatin 1,200 mg/m(2) . Pulmonary toxicity was considerable. The toxic death rate was similar to other trials of HDC/SCR for children with recurrent brain tumors performed during the same time period. The regimen resulted in prolonged time to progression for a significant number of patients and long-term survival for some patients with recurrent medulloblastoma and rhabdoid tumor.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/therapy , Peripheral Blood Stem Cell Transplantation/methods , Adolescent , Antineoplastic Combined Chemotherapy Protocols/toxicity , Brain Neoplasms/complications , Brain Neoplasms/mortality , Carboplatin , Carmustine , Child , Child, Preschool , Female , Humans , Infant , Male , Maximum Tolerated Dose , Peripheral Blood Stem Cell Transplantation/mortality , Survival Analysis , Thiotepa , Transplantation, AutologousABSTRACT
With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.
Subject(s)
Cognition Disorders/etiology , Medical Oncology/standards , Neoplasms/complications , Nervous System Diseases/etiology , Pediatrics/standards , Practice Guidelines as Topic , Radiation Oncology/standards , Survivors/psychology , Child , Child Advocacy , Cognition Disorders/diagnosis , Continuity of Patient Care , Humans , Neoplasms/drug therapy , Neoplasms/radiotherapy , Nervous System Diseases/diagnosis , Neuropsychological Tests , Patient Advocacy , United StatesABSTRACT
Development of the vertebrate central nervous system is characterized by significant long distance cell migration. While the radial migration of neuronal precursors to their final location is well established the migration of glial cells and their precursors is less well understood. To define the pathways of migration and dissect the cell and molecular mechanisms mediating such migration requires the development of appropriate models. Here we show that purified neonatal astrocytes injected into organotypic slice cultures of developing cerebral cortex migrate in defined patterns depending on where they are placed within the tissue. Injection into gray matter resulted in radially oriented migration either towards the pial or ventricular surface. By contrast injection into developing white matter resulted in largely longitudinal migration along developing axon tracts. While the cytoarchitecture of the tissue influenced the pattern of migration, the extent of migration appeared to be regulated primarily by the age of the host tissue. Homochronic injections performed prior to postnatal day 4 resulted in extensive migration while after day 7 migration was relatively limited. Heterochronic injections indicated that while astrocytes within the 1st postnatal week retained the capacity to migrate extensively, older tissue failed to support extensive migration of either young or old astrocytes. These data suggest the existence of distinct migrational cues in the CNS and that environmental, not cell intrinsic properties primarily regulate astrocyte migration through the developing cortex.
