Biomedical subjects

James M Boyett

Publications and source records attributed to James M Boyett.

At least 19 recordsLinked to original sources

PubMed2007

Pseudoscore-based estimation from biased observations.

There are many practical situations where observation of the primary variable Y for individuals in a population is incomplete and depends on some auxiliary variables X that are potentially correlated with Y. We consider parameter estimation for the distribution of Y with the incomplete data, without specifying the underlying association between Y and X. The approach is based on a class of pseudoscore functions using available information of X. We demonstrate the consistency and asymptotic normality of the estimators and study their finite-sample properties in various situations via simulation. The methodology is illustrated by an example involving kindergarten readiness skills in children with sickle cell disease.

Anemia, Sickle Cell↗

PubMed2006

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.

BACKGROUND: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). METHODS: Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. RESULTS: A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr). CONCLUSIONS: Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.

Adolescent↗

PubMed2006

Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma.

BACKGROUND: Children with diffuse brainstem glioma (BSG) commonly undergo novel therapies because their outcome is poor with radiation therapy (RT). Although recent clinical trials using new biologic agents documented intratumoral hemorrhage (IH) among several children with BSG, to the authors' knowledge little is known regarding this phenomenon. In the current study, the authors assessed the characteristics and estimated the cumulative incidence of IH among children with BSG. METHODS: All available brain imaging studies and medical records of 48 consecutive patients with newly diagnosed BSG treated at the study institution over a 10-year interval (1992-2002) were reviewed. Treatment was comprised of RT and various regimens of conventional chemotherapy; none of these patients received biologic agents. At the time of last follow-up, all patients had died of tumor progression. RESULTS: The authors reviewed 319 imaging studies (251 magnetic resonance imaging scans and 68 computed tomography scans). IH was present in 6.25% of patients at the time of diagnosis. The 6-month and 12-month cumulative incidence estimates of IH regardless of the associated symptoms were 15.5% +/- 5.5% and 24.4% +/- 6.5%, respectively. The same estimates for symptomatic cases were 8.9% +/- 4% and 17.8% +/- 6%, respectively. All cases of IH at the time of diagnosis and 78% of symptomatic cases that developed after diagnosis were located in necrotic areas. CONCLUSIONS: Although IH is uncommon at the time of diagnosis, symptomatic IH may occur among nearly 20% of children after the diagnosis of BSG. The uniform occurrence of IH among patients treated with various chemotherapeutic regimens and its association with necrotic areas suggests that tumor biology plays a significant role in this event.

Adolescent↗

PubMed2006

Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

Adolescent↗

PubMed2006

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

BACKGROUND: Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS: After resection, patients were classified as having average-risk medulloblastoma (< or = 1.5 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (> 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. FINDINGS: Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION: Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Adolescent↗

PubMed2005

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Patterns of treatment failure in infants with primitive neuroectodermal tumors who were treated on CCG-921: a phase III combined modality study.

PURPOSE: To analyze patterns of treatment failure in infants with primitive neuroectodermal tumors (PNETs) who were treated primarily with chemotherapy in a large multi-institutional study. MATERIALS AND METHODS: Sixty-five prospectively staged patients with PNET confirmed by central pathology review, who were 18 months or younger were treated on Children's Cancer Group Study 921 (CCG-921) primarily with chemotherapy. Forty-six patients had posterior fossa (PF) primary tumors and 19 patients had supratentorial (ST) primaries. Patterns of sites of initial treatment failure were analyzed and compared to failure patterns of 180 older children who had PF-PNETs, and 44 older children with ST-PNETs who were treated on the same protocol. RESULTS: The entire cohort of younger patients fared much worse than those older than 18 months. Cumulative 5-year relapse incidence (+/-SE) for younger patients with PF-PNETs was 64.5 +/- 8.9% for patients without metastases (M0) compared to 71.4 +/- 13.4% for patients with metastases (M+). The cumulative 5-year relapse incidences for younger patients with ST-PNETs were 64.3 +/- 13.7% for M0 patients compared to 100 +/- 33.3% for M+ patients. Relapses in these patients occurred within 2 years. The overall treatment failure rate was significantly higher for younger compared to older patients with PF-PNET and ST-PNET. There was no statistically significant difference in relapse patterns between patients with PF primary tumors and ST primaries when stratified by stage. There was no statistically significant difference in relapse patterns between M0 and M+ patients. All patients had a high risk of recurrence at primary tumor site. Younger patients who had PF primary tumors without metastasis at presentation were significantly more likely to relapse in PF than older patients. Younger patients were at significant risk of relapse in the spine, but none had it as the sole site of first relapse. CONCLUSIONS: Despite aggressive chemotherapy, younger children with PNETs have high rates of treatment failure and fare worse than high-risk, older patients with PF-PNETs, indicating the need to maximize local, regional, and systemic therapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Statistical significance threshold criteria for analysis of microarray gene expression data.

The methodological advancement in microarray data analysis on the basis of false discovery rate (FDR) control, such as the q-value plots, allows the investigator to examine the FDR from several perspectives. However, when FDR control at the "customary" levels 0.01, 0.05, or 0.1 does not provide fruitful findings, there is little guidance for making the trade off between the significance threshold and the FDR level by sound statistical or biological considerations. Thus, meaningful statistical significance criteria that complement the existing FDR methods for large-scale multiple tests are desirable. Three statistical significance criteria, the profile information criterion, the total error proportion, and the guide-gene driven selection, are developed in this research. The first two are general significance threshold criteria for large-scale multiple tests; the profile information criterion is related to the recent theoretical studies of the connection between FDR control and minimax estimation, and the total error proportion is closely related to the asymptotic properties of FDR control in terms of the total error risk. The guide-gene driven selection is an approach to combining statistical significance and the existing biological knowledge of the study at hand. Error properties of these criteria are investigated theoretically and by simulation. The proposed methods are illustrated and compared using an example of genomic screening for novel Arf gene targets. Operating characteristics of q-value and the proposed significance threshold criteria are investigated and compared in a simulation study that employs a model mimicking a gene regulatory pathway. A guideline for using these criteria is provided. Splus/R code is available from the corresponding author upon request.

Journal Article↗

PubMed2004

Patterns of failure in supratentorial primitive neuroectodermal tumors treated in Children's Cancer Group Study 921, a phase III combined modality study.

PURPOSE: To analyze the patterns of failure in patients with supratentorial primitive neuroectodermal tumors (ST-PNETs) treated with combined modality therapy in a large, randomized, multi-institutional study. METHODS AND MATERIALS: A total of 44 prospectively staged patients with ST-PNET confirmed by central pathology review were treated in the Children's Cancer Group Study 921, which compared two chemoradiotherapy regimens. The patterns of initial sites of failure were analyzed. These were compared with the failure patterns of 188 children with posterior fossa (PF) PNETs treated in the same protocol. RESULTS: The major determinant for progression-free survival was the initial metastatic stage. The 3-year progression-free survival for M0 patients was 53% +/- 8.5% compared with 14% +/- 9.4% for M+ patients. The cumulative 5-year relapse incidence was 71.4% +/- 21% for M+ patients compared with 47.5% +/- 8.6% for M0 patients. The overall failure rate for both M0 and M+ ST-PNETs was greater than that for PF-PNETs (47.5% +/- 8.6% vs. 29.3% +/- 4.7% for M0 and 71.4% +/- 21% vs. 48.4% +/- 5.5% for M+). Failure at the primary site, either as the sole site or as a component of initial failure, was also seen more frequently in ST-PNETs than in PF-PNETs. For M0 patients, the 5-year local failure rate as a component of initial failure was 42.0% +/- 8.5% for ST-PNETs compared with 17.7% +/- 3.9% for PF-PNETs. For patients with primary tumors either in the ST or PF, the 5-year spinal axis failure rate as a component of initial failure was not significantly different statistically when compared by M stage. For M+ patients, the 5-year spinal axis failure rate as a component of initial failure was 42.9% +/- 22.8% for ST-PNETs and 34.6% +/- 5.2% for PF-PNETs. CONCLUSION: Despite aggressive combined modality therapy, ST-PNETs had high rates of failure, with M+ patients faring especially poorly. Both local and spinal failure rates remained high, indicating the need to maximize both local and regional/systemic therapies. Overall, these patients fared worse than those with high-risk PF-PNETs in terms of progression-free survival and failure rates.

Adolescent↗

PubMed2003

Outcome of children with centrally reviewed low-grade gliomas treated with chemotherapy with or without radiotherapy on Children's Cancer Group high-grade glioma study CCG-945.

BACKGROUND: The objectives of the current study were to determine the outcome of children who were treated with chemotherapy and radiotherapy on the Children's Cancer Group (CCG) high-grade glioma protocol (CCG-945) who were diagnosed with low-grade gliomas on post hoc central pathologic review and to identify clinical and biologic features associated with prognosis. METHODS: Between 1985 and 1991, 250 children with institutionally classified high-grade gliomas were enrolled on CCG-945. Patients older than 24 months with intracranial lesions were assigned randomly to receive either lomustine, vincristine, and prednisone (control regimen) or the 8-drugs-in-1-day regimen (experimental regimen); younger patients and those with primary spinal cord tumors were assigned nonrandomly to the experimental regimen. Central independent review by 5 neuropathologists led to a reclassification of low-grade glioma in 70 patients, who were the focus of the current study. RESULTS: The study involved 42 males and 28 females (median age, 7.7 years) with a median follow-up of 10.4 years. At 5 years, the progression-free survival (PFS) rate was 63% +/- 6%, and the overall survival (OS) rate was 79% +/- 5%, compared with a PFS rate of 19% +/- 3% (P < 0.0001) and an OS rate of 22% +/- 3% (P < 0.0001) in the remainder of the cohort. Significantly poorer 5-year PFS was seen in children younger than 24 months, those with fibrillary astrocytoma, and those with posterior fossa tumors. Patients demonstrated a modest improvement in PFS but no improvement in OS compared with children with low-grade gliomas who were treated with contemporary chemotherapy-alone approaches. CONCLUSIONS: The current report calls attention to the importance of central pathologic review in large multiinstitutional trials of children with gliomas and suggests that aggressive front-line combined chemoradiotherapy does not confer a survival advantage in this highly selected population of patients.

Adolescent↗

PubMed2003

Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia.

PURPOSE: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. RESULTS: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for <or= 8 hours daily, were unable to receive all 22 days of etoposide because of toxicity. There was no difference in the AUC at day 1 or day 8 with once- versus twice-daily doses (P =.55 and P =.86, respectively). CONCLUSION: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL.

Administration, Oral↗

PubMed2003

Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment.

Event-free survival for children with acute lymphoblastic leukemia (ALL) now exceeds 80% in the most effective trials. Failures are due to relapse, toxicity, and second cancers such as therapy-related myeloid leukemia or myelodysplasia (t-ML). Topoisomerase II inhibitors and alkylators can induce t-ML; additional risk factors for t-ML remain poorly defined. The occurrence of t-ML among children who had received granulocyte colony-stimulating factor (G-CSF) following ALL remission induction therapy prompted us to examine this and other putative risk factors for t-ML in 412 children treated on 2 consecutive ALL protocols from 1991 to 1998. All children received etoposide and anthracyclines, 99 of whom received G-CSF; 284 also received cyclophosphamide, 58 of whom also received cranial irradiation. There were 20 children who developed t-ML at a median of 2.3 years (range, 1.0-6.0 years), including 16 cases of acute myeloid leukemia, 3 myelodysplasia, and 1 chronic myeloid leukemia. Stratifying by protocol, the cumulative incidence functions differed (P =.017) according to the use of G-CSF and irradiation: 6-year cumulative incidence (standard error) of t-ML of 12.3% (5.3%) among the 44 children who received irradiation without G-CSF, 11.0% (3.5%) among the 85 children who received G-CSF but no irradiation, 7.1% (7.2%) among the 14 children who received irradiation plus G-CSF, and 2.7% (1.3%) among the 269 children who received neither irradiation nor G-CSF. Even when children receiving irradiation were excluded, the incidence was still higher in those receiving G-CSF (P =.019). In the setting of intensive antileukemic therapy, short-term use of G-CSF may increase the risk of t-ML.

Adolescent↗

PubMed2003

A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine.

We investigated the variation in the uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) gene in patients receiving patient-controlled analgesia with morphine. UGT2B7 was sequenced in phenotypic extremes (n = 12) of the distribution of morphine-6-glucuronide/morphine plasma ratios. A new -161C/T promoter variant was in complete linkage disequilibrium with the 802C/T variant and was more frequent in low glucuronidators (P =.039). Both variants were genotyped in all patients (n = 86), and complete linkage disequilibrium was confirmed. Trend analysis showed reduced morphine-6-glucuronide/morphine ratios in patients with T/T, C/T, and C/C genotypes (T/T > C/T > C/C) (P =.031). Morphine levels were lower in T/T patients (median, 18 ng/mL [range, 18-1490 ng/mL]) as compared with C/T and C/C patients combined (median, 66 ng/m; range, 18-3995 ng/mL) (P =.04). Morphine-6-glucuronide and morphine-3-glucuronide concentrations were significantly lower in C/C patients (median, 18 ng/mL; range, 0-66 ng/mL; and median, 152 ng/mL; range, 30-434 ng/mL; respectively) compared with C/T and T/T patients combined (median, 43 ng/mL; range, 0-193 ng/mL; and median, 242 ng/mL; range, 33-1381 ng/mL; respectively) (P =.045 and P =.004, respectively). Interindividual differences in morphine glucuronidation may be the result of genetic variation in UGT2B7, and further studies are indicated.

Adult↗

PubMed2003

Combined modality therapy for poorly differentiated gliomas of the posterior fossa in children: a Children's Cancer Group report.

PURPOSE: To study the effectiveness of combined chemotherapy and radiotherapy for children with high-grade astrocytomas of the posterior fossa. PATIENTS AND METHODS: In the CCG-945 study, 250 patients were treated by members of the Children's Cancer Group (CCG). Sixteen children were randomly assigned to one of two chemotherapy regimens, vincristine, lomustine, and prednisone or '8-in-1', using the same involved-field irradiation in both. Six infants received 8-in-1 chemotherapy before involved-field irradiation. All pathologic specimens had central review. RESULTS: Twenty-two patients with an institutional diagnosis high-grade posterior fossa tumors received chemotherapy and/or irradiation. Fifteen were confirmed by central review to have high-grade gliomas. Overall survival for confirmed high-grade astrocytoma of the posterior fossa was approximately 36 +/- 13% at 5 years for the children (n = 11) and 25 +/- 15% at 5 years for the infants (n = 4). CONCLUSIONS: Involved-field irradiation with chemotherapy appeared to prevent extraneural and subarachnoid metastases. We also confirmed the rarity of the tumor (6% of patients registered). Further Phase III trials are necessary to improve survival in this aggressive tumor.

Adolescent↗

PubMed2003

Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort.

BACKGROUND: Results of recent molecular studies on malignant gliomas in adults showed that deletions within the short arm of chromosome 1 and/or the long arm of chromosome 19 identified a prognostically favorable subgroup of tumors that often respond to conventional chemotherapy. To determine if this association applies to pediatric malignant gliomas, we examined the correlation between 1p and 19q deletions and outcome in the cohort derived from the Children's Cancer Group study 945, the largest randomized trial of such tumors completed to date. METHODS: Archival histopathologic material yielded tissue of sufficient quality and quantity for genotyping in 121 specimens. Sections were examined histologically and targets that contained malignant glioma were isolated by microdissection and subjected to polymerase-chain-reaction-based amplification of microsatellite loci using fluorochrome-labeled primers, followed by capillary electrophoresis, and fluorescent fragment analysis. One hundred and seven specimens had 2 alleles for at least 1 of the 3 1p loci examined, and were therefore informative for determining loss of heterozygosity, defined as at least a twofold difference in fluorescence intensity between the paired allelic bands; 99 were informative at 19q. RESULTS: Thirty-two tumors (29.9%) had loss of heterozygosity involving 1p, 27 (28%) involving 19q, and 13 involving both, an incidence consistent with previous reports involving adult malignant gliomas. However, outcome analyses of the entire cohort found no favorable association between 1p loss, 19q loss, or the combination, and survival. Subset analysis disclosed no association with outcome in either arm of the study (which compared efficacy of 2 chemotherapeutic regimens) or in subgroups stratified by age, tumor location, or tumor histology. CONCLUSION: In contrast to recent observations of adult malignant gliomas, deletions involving chromosomes 1p or 19q did not predict a survival advantage in this series of pediatric high-grade gliomas, which might indicate that frequencies of various histologic and molecular subtypes of malignant gliomas differ between children and adults, and supports further efforts to identify prognostic indicators relevant to pediatric gliomas.

Central Nervous System Neoplasms↗

PubMed2003

The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience.

To examine the influence of the pathology review mechanism on the results of analyses of therapeutic efficacy and biological prognostic correlates for pediatric high-grade gliomas, we evaluated the effects of using single-expert review or consensus review, as alternatives to institutional classification, in determining outcome results of a large randomized trial. The study group was the randomized cohort of Children's Cancer Group study 945, which compared efficacy of 2 chemotherapy regimens adjuvant to surgery and radiation. Trial eligibility required institutional histopathologic diagnosis of high-grade glioma. Sections of study tumors also were centrally reviewed, initially by a study review neuropathologist and subsequently by 5 neuropathologists, including the review pathologist. Reviews were independent, and reviewers were masked to clinical factors and outcomes, and consensus diagnoses of the panel were then established. Among 172 eligible patients, 42 tumors were classified as discordant on single-expert review and 51 on consensus review. Progression-free survival probabilities calculated for patients with tumors classified as high-grade gliomas by either single-expert or consensus review were inferior to those for the overall, institutionally diagnosed cohort. However, conclusions of the study regarding relative efficacy of treatment and clinical and molecular outcome correlates were unaffected by diagnosis method. Resection extent, proliferation index, and p53 expression were associated strongly with outcome, regardless of diagnosis method. However, comparisons between arms in which inclusion was determined by different review criteria for each arm caused spurious conclusions about efficacy differences between treatments. We conclude that the pathology review mechanism had little effect on within-trial comparisons of therapeutic effects or prognostic correlates in this randomized study, but strongly influenced survival distributions that were calculated for each treatment arm. These results support the implementation of expedited central review in therapeutic studies involving childhood malignant gliomas as a way to prospectively identify and exclude cases with discordant diagnoses and indicate the need for additional measures, such as molecular assessments, to increase the reproducibility of neuropathologic classification for these tumors.

Antineoplastic Protocols↗

PubMed2002

De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo.

Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m(2)) or high-dose MTX (HDMTX: intravenous 1 g/m(2)) followed by intravenous MP; or intravenous MP alone (1 g/m(2)), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 +/- 189 vs 250 +/- 38 fmol/nmol/h; P =.001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P <.001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (-50% +/- 4%, -56% +/- 3%, and - 20% +/- 4%, respectively; P <.0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (-63% +/- 4% vs -37% +/- 4%; P <.0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 +/- 298 vs 1075 +/- 114 pmol/10(9) cells; P <.01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P <.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.

Adolescent↗

PubMed2002

Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group.

PURPOSE: This Children's Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Adolescent↗