Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma.

AIMS: A few case series in adults have described the characteristics of epithelioid glioblastoma (e-GB), one of the rarest variants of this cancer. We evaluated clinical, radiological, histological and molecular characteristics in the largest series to date of paediatric e-GB. METHODS: Review of clinical characteristics and therapy, imaging studies and histology was performed in patients younger than 22 years with e-GB seen at our institution over 15 years. Sequencing of hotspot mutations and fluorescence in situ hybridization of relevant genes were undertaken. RESULTS: Median age at diagnosis of six patients was 7.6 years. Tumours originated in the cerebral cortex (n = 2) or diencephalon (n = 4). Three patients presented with acute, massive haemorrhage and three had leptomeningeal dissemination at diagnosis. Paediatric e-GB had the typical histological characteristics seen in adult tumours. Universal immunoreactivity for INI1 and lack of diverse protein expression were seen in all cases. One tumour had a chromosome 22q loss. Three tumours (50%) harboured a BRAF: p.V600E. One thalamic tumour had an H3F3A p.K27M. All patients received radiation therapy with (n = 3) or without chemotherapy (n = 3). All patients experienced tumour progression with a median survival of 169 days. One patient with nonmetastatic disease had early leptomeningeal progression. Two patients had symptomatic tumour spread outside the central nervous system (CNS) through a ventriculoperitoneal shunt. One additional patient had widespread metastases outside the CNS identified at autopsy. CONCLUSIONS: Paediatric e-GBs are rare cancers with an aggressive behaviour that share histological and genetic characteristics with their adult counterparts. BRAF inhibition is a potential treatment for these tumours.

Pretreatment Normal WM Magnetization Transfer Ratio Predicts Risk of Radiation Necrosis in Patients with Medulloblastoma.

BACKGROUND AND PURPOSE: Radiation necrosis, for which abnormal WM enhancement is a hallmark, is an uncommon complication of craniospinal irradiation in children with medulloblastoma. The magnetization transfer ratio measures macromolecular content, dominated by myelin in the WM. We investigated whether the pretreatment supratentorial (nonsurgical) WM magnetization transfer ratio could predict patients at risk for radiation necrosis after radiation therapy for medulloblastoma. MATERIALS AND METHODS: Ninety-five eligible patients with medulloblastoma (41% female; mean age, 11.0 [SD, 5.4] years) had baseline balanced steady-state free precession MR imaging before proton or photon radiation therapy. Associations among baseline supratentorial magnetization transfer ratio, radiation necrosis (spontaneously resolving/improving parenchymal enhancement within the radiation field)3, age, and the presence of visible brain metastases were explored by logistic regression and parametric/nonparametric techniques as appropriate. RESULTS: Twenty-three of 95 (24.2%) children (44% female; mean age, 10.7 [SD, 6.7] years) developed radiation necrosis after radiation therapy (19 infratentorial, 1 supratentorial, 3 both). The mean pretreatment supratentorial WM magnetization transfer ratio was significantly lower in these children (43.18 versus 43.50, P = .03). There was no association between the supratentorial WM magnetization transfer ratio and age, sex, risk/treatment stratum, or the presence of visible brain metastases. CONCLUSIONS: A lower baseline supratentorial WM magnetization transfer ratio may indicate underlying structural WM susceptibility to radiation necrosis and may identify children at risk for developing radiation necrosis after craniospinal irradiation for medulloblastoma.

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma.

AIM: To examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma. METHODS: Patients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records. RESULTS: Patients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P < 0.001), attention (Estimate = -0.10, P < .001) and processing speed (Estimate = -0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P < 0.001). CONCLUSION: Greater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Anatomic Neuroimaging Characteristics of Posterior Fossa Type A Ependymoma Subgroups.

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.

Neuroimaging Findings in Children with Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Constitutional mismatch repair deficiency is a hereditary childhood cancer predisposition syndrome characterized by brain tumors and colorectal and hematologic malignancies. Our objective was to describe the neuroimaging findings in patients with constitutional mismatch repair deficiency. MATERIALS AND METHODS: This retrospective study included 14 children with genetically confirmed constitutional mismatch repair deficiency who were referred to 2 tertiary pediatric oncology centers. RESULTS: Fourteen patients from 11 different families had diagnosed constitutional mismatch repair deficiency. The mean age at presentation was 9.3 years (range, 5-14 years). The most common clinical presentation was brain malignancy, diagnosed in 13 of the 14 patients. The most common brain tumors were glioblastoma (n = 7 patients), anaplastic astrocytoma (n = 3 patients), and diffuse astrocytoma (n = 3 patients). Nonspecific subcortical white matter T2 hyperintensities were noted in 10 patients (71%). Subcortical hyperintensities transformed into overt brain tumors on follow-up imaging in 3 patients. Additional non-neoplastic brain MR imaging findings included developmental venous anomalies in 12 patients (85%) and nontherapy-induced cavernous hemangiomas in 3 patients (21%). CONCLUSIONS: On brain MR imaging, these patients have both highly characteristic intra-axial tumors (typically multifocal high-grade gliomas) and nonspecific findings, some of which might represent early stages of neoplastic transformation. The incidence of developmental venous anomalies is high in these patients for unclear reasons. Awareness of these imaging findings, especially in combination, is important to raise the suspicion of constitutional mismatch repair deficiency in routine diagnostic imaging evaluation or surveillance imaging studies of asymptomatic carriers because early identification of the phenotypic "gestalt" might improve outcomes.

MRI Patterns of Extrapontine Lesion Extension in Diffuse Intrinsic Pontine Gliomas.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a devastating childhood cancer that despite being primarily diagnosed by MR imaging alone, lacks robust prognostic imaging features. This study investigated patterns and quantification of extrapontine lesion extensions as potential prognostic imaging biomarkers for survival in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Volumetric analysis of baseline MR imaging studies was completed in 131 patients with radiographically defined typical diffuse intrinsic pontine gliomas. Extrapontine tumor extension was classified according to the direction of extension: midbrain, medulla oblongata, and right and left middle cerebellar peduncles; various extrapontine lesion extension patterns were evaluated. The Kaplan-Meier method was used to estimate survival differences; linear regression was used to evaluate clinical-radiographic variables prognostic of survival. RESULTS: At least 1 extrapontine lesion extension was observed in 125 patients (95.4%). Of the 11 different extrapontine lesion extension patterns encountered in our cohort, 2 were statistically significant predictors of survival. Any extension into the middle cerebellar peduncles was prognostic of shorter overall survival (P = .01), but extension into both the midbrain and medulla oblongata but without extension into either middle cerebellar peduncle was prognostic of longer overall survival compared with those having no extension (P = .04) or those having any other pattern of extension (P < .001). CONCLUSIONS: Within this large cohort of patients with typical diffuse intrinsic pontine gliomas, 2 specific extrapontine lesion extension patterns were associated with a significant overall survival advantage or disadvantage. Our findings may be valuable for risk stratification and radiation therapy planning in future clinical trials.

Mechanisms of resistance: useful tool to design antibacterial agents for drug - resistant bacteria.

Drug-resistant bacteria are now a global health threat. In the last 5 years the WHO, The House of Lords (UK), the Centre for Disease Control (USA) and many more agencies have presented reports on the scale of this problem. Microorganisms multiply very rapidly and have adapted to fill almost every available environmental niche (Rapidly growing species of bacteria under ideal conditions of growth can multiply in about 20 minutes). All members of the chemically related beta-lactam class act at the same phase in cell wall synthesis; as a result, a bacterial cell resistant to one agent is often resistant to all other analogues. The beta-peptide has two promising characteristics that distinguish it from traditional antibiotics. Firstly, bacteria may have trouble developing resistance to the beta-peptide since bacterial defenses may not recognize its unnatural amino acids. Secondly, the magainins that the beta-peptides mimic have been around for millions of years, yet bacteria have not become resistant to them. All classes of antibiotics are subject to resistance by an efflux mechanism mediated by more than one type of pump within the same organism. The bacterial cell may have a membrane pump capable of pumping a class or several classes of antibacterial agents back out of the cell. Other mechanisms of drug resistance include destruction of beta-lactam ring by beta-lactamases, impermeability of the drug into the bacterial cell wall, alteration of targets within the bacterial cells and the by-pass mechanism (bacterial cell may have acquired an alternative mechanism for achieving the essential function).

Novel MYC-driven medulloblastoma models from multiple embryonic cerebellar cells.

Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma.

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.

Silent lacunar lesions detected by magnetic resonance imaging of children with brain tumors: a late sequela of therapy.

BACKGROUND: Cerebral lacunes, which generally appear on magnetic resonance imaging as foci of white matter loss, usually occur in adults after ischemic infarcts. We report the development of lacunes in children after therapy for brain tumors. PATIENTS AND METHODS: We reviewed the clinical characteristics and radiologic studies of 524 consecutive children with brain tumors treated over a 10-year period. We documented the neuropsychologic findings associated with lacunes and the factors predictive of lacunar development. RESULTS: Lacunes developed in none of the 103 patients observed or treated with surgery alone. Twenty-five of the 421 patients treated with chemotherapy or radiation therapy or both had lacunes. Patients were a median of 4.5 years old at the time of both diagnosis (range, 0.3 to 19.8 years) and radiotherapy (range, 1.5 to 20 years). Fourteen patients were treated with craniospinal irradiation, and 11 were treated with local radiotherapy. The median time from radiotherapy to the appearance of lacunes was 2.01 years (range, 0.26 to 5.7 years). For all patients, lacunes were an incidental finding with no corresponding clinical deficits. The factor most predictive of lacunar development was age less than 5 years at the time of radiotherapy (P =.010). There was no significant difference in estimated decline in intelligence quotient scores between patients with lacunes and age and diagnosis-matched controls. CONCLUSION: Lacunes may be caused by therapy-induced vasculopathy in children with brain tumors, with the most significant predictor being age less than 5 years at the time of radiotherapy.

Low-grade astrocytoma: a decade of experience at St. Jude Children's Research Hospital.

PURPOSE: To evaluate the impact of primary tumor site, age at diagnosis, extent of resection, and histology on progression-free survival (PFS) in pediatric low-grade astrocytoma. PATIENTS AND METHODS: Medical, pathologic, and imaging information were reviewed for 142 children (ages 2 months to 19 years) with low-grade astrocytoma treated between January 1984 and July 1994. Gross total resection (GTR) was attempted for cerebellar and cerebral hemisphere tumors, with biopsy or less aggressive resection used predominantly for tumors in other sites. Surgery was followed by observation in 107 cases, radiation therapy in 31, and chemotherapy in four. RESULTS: The overall survival rate was 90% +/- 3% (SE) at 4 years. PFS was significantly better for patients with cerebellar and cerebral hemisphere tumors (n = 75) than those with tumors in all other sites (P = .0006). Within the former group, there was no significant difference in PFS for patients in whom GTR was achieved versus those with incomplete resections (4-year estimates, 89% and 77%, respectively). Histology (juvenile pilocytic v astrocytoma not otherwise specified [NOS]) was not related to PFS in an analysis that controlled for tumor site and patient age. Patients younger than 5 years at diagnosis had a significantly poorer PFS than older children, regardless of histology (P < .03) or tumor site (P < .002). Treatment for progressive/recurrent disease was effective in a majority of patients, but appeared more successful in patients with hemispheric than thalamic or hypothalamic tumors. CONCLUSION: The overall survival in this series of pediatric low-grade astrocytomas is excellent. Age at diagnosis and tumor location, but not histology, had a significant impact on PFS. Efforts to improve treatment outcome should focus on young patients (< 5 years) and on those with central midline tumors. The majority of patients with completely resected hemispheric tumors were monitored without further therapy, which supports attempted GTR of cerebral and cerebellar hemisphere low-grade astrocytoma.

Medulloblastoma in very young children: outcome of definitive craniospinal irradiation following incomplete response to chemotherapy.

PURPOSE: To evaluate survival and neurodevelopmental outcomes following radiation therapy in infants and young children with residual or progressive medulloblastoma after primary chemotherapy. PATIENTS AND METHODS: Thirteen young patients (< or = 36 months old) with medulloblastoma were treated with preirradiation multiagent chemotherapy and maximal surgical resection. Patients were scheduled to receive radiation therapy at the time of documented disease progression or upon completion of chemotherapy with residual disease. All patients underwent neurodevelopmental evaluation at the time of diagnosis, before receiving radiation therapy, and at yearly intervals posttreatment. RESULTS: Two patients completed the scheduled chemotherapy with residual disease and received delayed radiation therapy. The remaining 11 patients had either local or leptomeningeal progression during chemotherapy (median time to progression, 5 months). Six patients had a complete response (CR) to radiation therapy, and three of these children are alive 48 to 104 months postdiagnosis. Of the five patients who had progressive disease (PD) during radiation therapy or residual imaging abnormalities after treatment, only one is alive (with stable enhancing leptomeningeal abnormalities) 48 months postirradiation. Two additional survivors were rendered disease-free by surgical resection before radiation therapy and are without evidence of disease at 91 and 107 months after diagnosis. Thus, six of 13 patients are alive at 48 to 107 months postdiagnosis. Neurodevelopmental scores tended to be below age norms at diagnosis; scores improved during chemotherapy, but then decreased during posttreatment follow-up evaluation. CONCLUSION: Radiation therapy appears to produce long-term disease-free survival in a proportion of very young patients who have progressive or residual medulloblastoma during or after primary chemotherapy. However, neurodevelopmental deficits are frequent among long-term survivors.

Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis.

PURPOSE: To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers. PATIENTS AND METHODS: Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence SCALES: These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed. RESULTS: At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P =.0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores. CONCLUSION: These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.

Risks of young age for selected neurocognitive deficits in medulloblastoma are associated with white matter loss.

PURPOSE: To test the hypothesis that inadequate development of normal-appearing white matter (NAWM) is associated with the relationship between young age at the time of craniospinal irradiation (CRT) and deficient neurocognitive performance in survivors of childhood medulloblastoma. PATIENTS AND METHODS: Forty-two patients treated since 1985 participated in this cross-sectional study. All had been treated with CRT with or without chemotherapy and had survived 1 or more years after treatment. Neurocognitive evaluations were conducted with tests of intellect (intelligent quotient; IQ), verbal memory, and sustained attention. Quantitative magnetic resonance imaging, using a hybrid neural network, assessed the volume of NAWM. RESULTS: Neurocognitive test results were below normal expectations for age at the time of testing. A young age at CRT was significantly associated with worse performance on all neurocognitive tests except that of verbal memory. An increased time from completion of CRT was significantly associated with worse performance on all neurocognitive tests except that of sustained attention. After statistically controlling for the effects of time from CRT, we examined the association of NAWM with neurocognitive test results. These analyses revealed that NAWM accounted for a significant amount of the association between age at CRT and IQ, factual knowledge, and verbal and nonverbal thinking, but not sustained attention or verbal memory. CONCLUSION: The present results suggest that, at least for some cognitive functions, deficient development and/or loss of NAWM after CRT may provide a neuroanatomical substrate for the adverse impact of a young age at the time of CRT.

Response of recurrent medulloblastoma to low-dose oral etoposide.

PURPOSE: The outcome for patients with recurrent medulloblastoma has historically been poor, with most patients dying of disseminated disease. Here, we report on seven patients with recurrent medulloblastoma, most heavily pretreated with a variety of chemotherapeutic agents, including parenteral etoposide (VP-16), who showed responses to the administration of repeated courses of low-dose oral VP-16. PATIENTS AND METHODS: Seven patients age 4 to 16 years were treated with VP-16 after neuroradiographic and clinical evidence of tumor progression. Six had received prior irradiation. All seven had been pretreated with a variety of chemotherapeutic agents and schedules, including parenteral VP-16. VP-16 was administered orally as repeated 21-day courses at 50 mg/m2/d with a 7-day interval between courses. Evaluation consisted of neuroradiographic and clinical examination after completion of every two courses of therapy. Complete blood cell counts were performed weekly. RESULTS: The major toxicity of oral VP-16 was hematologic, with two patients requiring platelet transfusions due to thrombocytopenia and two requiring RBC transfusions. All seven patients developed treatment-related neutropenia. Two patients were supported with granulocyte colony-stimulating factor (G-CSF) between courses. One patient developed infectious epididymitis after course 2 and required intravenous antibiotics; this illness was complicated by Clostridium difficile colitis. There was one episode of fever associated with neutropenia. There were no treatment-related deaths. Of seven patients assessed, six have demonstrated partial responses (PRs) and the remaining patient had stable disease (SD). CONCLUSION: This report demonstrates the activity of oral VP-16 in the treatment of a small cohort of pretreated patients with recurrent medulloblastoma. This form of administration of oral VP-16 was well tolerated and produced modest toxicity.

Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study.

PURPOSE: This study was designed to determine the feasibility and safety of delivering four consecutive cycles of high-dose cyclophosphamide, cisplatin, and vincristine, each followed by stem-cell rescue, every 4 weeks, after completion of risk-adapted craniospinal irradiation to children with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: Fifty-three patients, 19 with high-risk disease and 34 with average-risk disease, were enrolled onto this study. After surgical resection, high-risk patients were treated with topotecan in a 6-week phase II window followed by craniospinal radiation therapy and four cycles of high-dose cyclophosphamide (4,000 mg/m2 per cycle), with cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5-mg/m2 doses per cycle). Support with peripheral blood stem cells or bone marrow and with granulocyte colony-stimulating factor was administered after each cycle of high-dose chemotherapy. Treatment of average-risk patients consisted of surgical resection and craniospinal irradiation, followed by the same chemotherapy given to patients with high-risk disease. The expected duration of the chemotherapy was 16 weeks, with a cumulative cyclophosphamide dose of 16,000 mg/m2 and a planned dose-intensity of 1,000 mg/m2/wk. RESULTS: Fifty of the 53 patients commenced high-dose chemotherapy, and 49 patients completed all four cycles. The median length of chemotherapy cycles one through four was 28, 27, 29, and 28 days, respectively. Engraftment occurred at a median of 14 to 15 days after infusion of stem cells or autologous bone marrow. The intended dose-intensity of cyclophosphamide was 1,000 mg/m2/wk; the median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m2/wk for cycles 1 through 4, respectively; associated median relative dose-intensity was 101%, 102%, 97%, and 99%. No deaths were attributable to the toxic effects of high-dose chemotherapy. Early outcome analysis indicates a 2-year progression-free survival of 93.6% +/- 4.7% for the average-risk patients. For the high-risk patients, the 2-year progression-free survival is 73.7% +/- 10.5% from the start of therapy and 84.2% +/- 8.6% from the start of radiation therapy. CONCLUSION: Administering four consecutive cycles of high-dose chemotherapy with stem-cell support after surgical resection and craniospinal irradiation is feasible in newly diagnosed patients with medulloblastoma/supratentorial PNET with aggressive supportive care. The early outcome results of this approach are very encouraging.

Relation of tumor-cell ploidy to survival in children with medulloblastoma.

PURPOSE: To assess the value of tumor-cell ploidy as a predictor of survival in medulloblastoma. PATIENTS AND METHODS: Ploidy determinations were based on the flow-cytometric analysis of cellular DNA content in fresh tumor specimens taken from 34 consecutively treated children with newly diagnosed medulloblastoma. Patients were assigned a high or low risk of failure depending on tumor size and invasiveness, and the presence or absence of metastatic disease. Treatment consisted of radiotherapy, with or without chemotherapy, according to institutional or cooperative group protocols. RESULTS: Univariate analysis of candidate prognostic factors showed that only tumor-cell ploidy and clinical risk group had a statistically significant influence on survival. Patients with hyperdiploid stem lines (n = 9) had significantly longer survival times (P = .04) than did those with diploid lines (n = 20). The estimated 5-year survival probabilities (+/- SE) for these two subgroups were 89% +/- 11% and 48% +/- 13%, respectively. Although clinical risk status (high v low) showed essentially the same predictive strength as ploidy, the two features identified largely nonoverlapping subgroups. Thus, within the clinical high-risk group, it was possible to distinguish hyperdiploid patients whose 5-year survival rate (83% +/- 15%) was comparable to that of patients with localized, low-risk tumors. CONCLUSION: This prospective study indicates that both ploidy and clinical risk group are important prognostic factors in medulloblastoma. Their combined use at diagnosis would distinguish patients who require more aggressive therapeutic intervention (diploid, clinical high-risk group) from those who could be expected to benefit most from standard treatment.

Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia.

PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase. PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing. RESULTS: The percentage of patients with undetectable (< 0.04 micromol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 micromol/L before, less than 0.04 micromol/L during, and less than 0.04 micromol/L at 1 to 5 days, 1.63 micromol/L at 6 to 10 days, 1.70 micromol/L at 11 to 30 days, and 5.70 micromol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003). CONCLUSION: CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.