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The rationale of this study was to investigate the feasibility of three-dimensional (3D) methods to analyze 18F-fluoro-deoxy-glucose (FDG) uptake in children with anaplastic astrocytoma (AA) in a multi-institutional trial, to compare 3D and two-dimensional (2D) methods and explore data associations with progression-free survival (PFS). 3D tumor volumes from pretreatment MR images (fluid attenuation inversion recovery and postgadolinium) of children with recurrent AA on a phase I trial of imatinib mesylate were coregistered to FDG positron emission tomography (PET) images. PET data were normalized. Four metrics were defined: the maximum ratio (maximum pixel value within the 3D tumor volume, normalized), the total ratio (cumulative pixel values within the tumor volume, normalized) and tumor mean ratio (total pixel value divided by volume, normalized). 2D analysis methods were compared. Cox proportional hazards models were used to estimate the association between these methods and PFS. Strongest correlations between 2D and 3D methods were with analyses using postcontrast T1 images for volume of interest (VOI). The analyses suggest 3D maximum tumor and mean tumor ratios, whether normalized by gray matter or white matter, were associated with PFS. This study of a series of pretreatment AA patients suggests that 3D PET methods using VOIs based on postcontrast T1 correlate with 2D methods and are related to PFS. These methods yield an estimate of metabolically active tumor burden and may add prognostic information after tumor grade is determined. Future rigorous multi-institutional protocols with larger numbers of patients will be required for validation.

Clinical trials and oncology data management have undergone considerable change in the past decade. Imaging has become a key tool for clinical trials management and a biomarker for clinical trial validation as imaging technologies improve and become more precise. Images have become extremely helpful in determining staging/eligibility, treatment response, and outcome determination including disease recurrence and progression. In modern protocols, images are often reviewed in real time to validate these points in order to improve compliance to study requirements and create uniform patient populations for clinical trials analysis. Data acquisition and management systems are currently in use to acquire and display images in electronic digital formats for view by both on site and off site radiology reviewers. As clinical trials become more global in focus, the ability for databases to accommodate diverse imaging acquisition strategies will become increasingly important for information review.

Pretreatment bone marrow cytogenetic studies were included for 1664 patients with acute lymphoblastic leukemia (ALL) accrued to Pediatric Oncology Group (POG) 8035 laboratory classification study from May 1981 through January 1986. There was a significant difference (P = 0.0001) in distribution of stem-line karyotype (normal, hypodiploid, pseudodiploid, or hyperdiploid) among children with early pre-B, pre-B, or T-cell ALL, with early pre-B patients demonstrating a higher proportion of hyperdiploid karyotypes with modal chromosome numbers greater than 51. Cytogenetic classification of 1216 patients with early pre-B or pre-B ALL evaluable for duration of event-free survival (EFS), with median follow-up of 42 months, showed a significant prolongation of five-year EFS associated with hyperdiploidy greater than 51 (75%; standard error [SE] = 5%) compared with hyperdiploidy 47 to 51 (46%; SE = 7%), hypodiploidy (55%; SE = 11%), and pseudodiploidy (45%; SE = 7%) (P = 0.0001). Five-year EFS was intermediate for patients with normal (58%), constitutionally abnormal (66%), or unsuccessful analyses (66%). The breakpoint defining hyperdiploidy associated with better prognosis was best defined as greater than 51 (P = 0.0002). Of 239 children with hyperdiploid karyotypes, analysis of the contribution of each chromosome to EFS duration showed a significant association between improved EFS and additional chromosome(s) six (P = 0.02). Chromosome translocation was associated with shorter EFS (P = 0.0001).

Purpose: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O6-benzylguanine in patients ≤21 years with recurrent brain tumors. Experimental Design: Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.v. administration of O6-benzylguanine at 120 mg/m2 was followed by 48-h continuous infusion at 30 mg/m2/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628, and 835 mg/m2) was given at least 6 h after completion of O6-benzylguanine bolus. Treatment was repeated after recovery from toxicities at least 4 weeks apart for a maximum of 12 courses. Dose escalation followed the modified continual reassessment method. Pharmacokinetic analyses of temozolomide and 5-triazeno imidazole carboxamide (MTIC) were done in 28 patients. Results: A total of 44 and 26 eligible patients were enrolled on Str1 and Str2, respectively. Median age at study entry in each stratum was 8.6 and 11.3 years, respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and Str2 were 562 and 407 mg/m2, respectively, the doses recommended for phase II investigations are 472 and 355 mg/m2, respectively. DLTs were predominantly neutropenia and thrombocytopenia. Three patients with gliomas experienced centrally confirmed partial responses to therapy. Four patients completed all planned therapy. Temozolomide and MTIC exposures were statistically associated with temozolomide dosage. Conclusions: The current schedule of temozolomide and O6-benzylguanine is safe and showed modest activity against recurrent brain tumors in children.

In this paper we propose a stochastic model based on the branching process for estimation and comparison of the mutation rates in proliferation processes of cells or microbes. We assume in this model that cells or microbes (the elements of a population) are reproduced by generations and thus the model is more suitably applicable to situations in which the new elements in a population are produced by older elements from the previous generation rather than by newly created elements from the same current generation. Cells and bacteria proliferate by binary replication, whereas the RNA viruses proliferate by multiple replication. The model is in terms of multiple replications, which includes the special case of binary replication. We propose statistical procedures for estimation and comparison of the mutation rates from data of multiple cultures with divergent culture sizes. The mutation rate is defined as the probability of mutation per replication per genome and thus can be assumed constant in the entire proliferation process. We derive the number of cultures for planning experiments to achieve desired accuracy for estimation or desired statistical power for comparing the mutation rates of two strains of microbes. We establish the efficiency of the proposed method by demonstrating how the estimation of mutation rates would be affected when the culture sizes were assumed similar but actually diverge.

Purpose A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib ( SCH66336 ) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Patients and Methods Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Conclusion Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

10053 Background: We report the results of the dose escalation component of a phase 1/2 trial in children with newly diagnosed DIPG designed to determine the maximum tolerated dose (MTD) and toxici...

10059 Background: Wild type and mutated TP53 are common in pediatric CNS tumors. p28 is a cell penetrating peptide that preferentially enters cancer cells and binds to wild type and mutant p53 prot...

Summary 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 (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 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.

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 μg/mL and declined to 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.

To review interpathologist diagnosis variability and survival of children treated for either anaplastic mixed glioma (AMG) or anaplastic oligodendroglioma (AO) with surgery, irradiation and chemotherapy.Two hundred and fifty patients with an institutional diagnosis of malignant glioma were enrolled on Children's Cancer Group CCG-945 between 1985 and 1991, and administered vincristine during involved field radiotherapy, then six cycles of prednisone, lomustine and, vincristine; or two cycles of "eight-drugs-in-one-day" (8-in-1) chemotherapy then involved-field radiotherapy followed by six cycles of 8-in-1 chemotherapy. Central review of institutional pathology was post hoc by five experienced neuropathologists.Twenty-six children had institutional diagnoses of AMG and four had AO. Complete resection and cerebral tumor location was associated with better overall survival (OS) in patients with institutional diagnoses of AMG. However, central review established that only nine of 26 children had AMG: either mixed oligoastrocytoma (MOA) or anaplastic mixed oligoastrocytoma (AOA) and only one had AO. Central review revealed five more patients with AMG, but none with AO. Institutional and CCG central review diagnoses of AMG or AO had poor Jaccard reliabilities of 0.29 and 0.25 respectively. Five-year EFS and OS for five children with centrally confirmed MOA was 50 +/- 20%, with four centrally confirmed AOA was 37.5 +/- 17%. After central review, small samples made tests for differences in survival between regimes impossible.Diagnosis of these tumors is challenging, with only 35% of institutional diagnoses confirmed for AMG and 25% for AO, and survival among children with these tumors is poor, despite intensive therapy. This suggests reliable diagnostic markers and new therapeutic approaches are needed.

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.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.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.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.

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.

Summary. Sequential conditional probability ratio tests (SCPRTs) provide monitoring procedures with a unique property that a decision reached at early stopping is unlikely to be reversed should the trial continue to the planned end (Xiong, X., 1995, Journal of the American Statistical Association90, 1463–1473; Tan, M., Xiong, X., and Kutner, M. H., 1998, Biometrics54, 682–695). It actually provides a probability statement of a conclusion reversal, should the proposed interim analysis plan be used. To broaden its scope of applications, in this article we develop the SCPRT in terms of Brownian motion, which is applicable to most clinical trials with various endpoints. In addition, we utilize the unique structure of the SCPRT to derive a class of adaptive sequential tests that retain the significance level and power in the presence of a nuisance parameter. We illustrate the proposed methods with examples in clinical trials.

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.

To study the effectiveness of combined chemotherapy and radiotherapy for children with high-grade astrocytomas of the posterior fossa.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.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).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.

Background: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. Methods: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m2 over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m2, or high dose, 1 g/m2 intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. Results: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 ± 14.7 μmol/L versus 23.5 ± 18.0 μmol/L, P < .001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 ± 0.66 pmol/5 × 106 cells versus 7.4 ± 15.2 pmol/5 × 106 cells, P < .001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 ± 13.5 μmol/L versus 3.8 ± 2.5 μmol/L, P = .029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% ± 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% ± 35%) compared with those in patients receiving mercaptopurine alone (P < .0001). Conclusion: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine. Clinical Pharmacology & Therapeutics (2003) 73, 506–516; doi: 10.1016/S0009-9236(03)00063-8

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.

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.

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.

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.

This article examines the impact of four policy changes made to a State children's health insurance program (SCHIP) as it transitioned to Title XXI on program disenrollment and re-enrollment. The changes were: (1) expanded eligibility criteria, (2) reduction in the family share of the premium, (3) expansion of the mental health benefit, and (4) implementation of a 60-day wait period to re-enrollment in the program for children who involuntarily disenrolled due in non-payment of premium. Disenrollment was reduced by 20 percent after the changes were implemented. Disenrollment and re-enrollment rates varied significantly based on the child's health and family income.

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.

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/m2) or high-dose MTX (HDMTX: intravenous 1 g/m2) followed by intravenous MP; or intravenous MP alone (1 g/m2), 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

We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (± 1 day) and 218 on days 22 to 25 (± 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (≥ 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% ± 6%) or on days 22 to 25 (4% ± 3%) as compared to those without lymphoblasts on these dates (78% ± 2% and 76% ± 2%, respectively, P

To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).A prospective, randomized, double-blind, placebo-controlled, multicenter study.Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network.A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group).Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing.The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure-free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo.In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

10065 Background: Pathway activating genetic aberrations of the Ras-MAP kinase signaling pathway have been observed in pediatric low grade glioma (LGG), most commonly a fusion gene, BRAF-KIAA1549 o...

OBJECTIVE: Prognoses of pediatric high-grade gliomas are unpredictable, even when clinical and histological factors are taken into account. In preliminary studies with an institutional cohort of pediatric high-grade gliomas, we observed a strong association between outcome and proliferation index, as assessed by immunolabeling with the MIB-1 antibody. To determine whether this marker could provide prognostically useful information independent of tumor histology, we examined the prognostic usefulness of this marker in the multi-institutional cohort of Children's Cancer Group Study 945, the largest group of childhood high-grade gliomas analyzed to date. METHODS: The study group consisted of tumors within this cohort that were classified as high-grade gliomas on central review according to contemporary World Health Organization guidelines and that had sufficient histopathological material to permit proliferation index assessment. Paraffin-embedded sections were cut and processed, microwave antigen enhancement was used, and MIB-1 indices were calculated by percent labeling in approximately 2000 cells (5-10 high-power fields) in the areas with greatest labeling. To ensure that the review diagnostic classification and proliferation labeling index were assigned independently for each tumor, these analyses were performed by two different neuropathologists at separate institutions, and each was blinded to the results of the other. RESULTS: Ninety-eight tumors met eligibility criteria for this study. Among these high-grade gliomas, there was a strong association between MIB-1 labeling and patient outcome: 5-year progression-free survival was 33 +/- 7% in 43 patients whose tumors had MIB-1 indices of less than 18%, 22 +/- 8% in the 27 patients whose tumors had indices between 18 and 36%, and 11 +/- 6% in the 28 patients whose tumors had indices greater than 36% (P = 0.003). As anticipated, a strong association was also observed between histology and MIB-1 labeling index in these cases. Mean labeling indices were 19.4 +/- 2.66 for tumors classified as anaplastic astrocytoma versus 32.1 +/- 3.08 for those classified as glioblastoma multiforme (P = 0.0024). Notwithstanding this correlation, a significant association was noted between labeling index and progression-free survival, even after the analysis had been stratified by histology (P = 0.001). Although histology had an independent association with outcome, the prognostic value of MIB-1 labeling transcended histological subgrouping and was apparent both in tumors classified as anaplastic astrocytoma (P = 0.02) and in those classified as glioblastoma multiforme (P = 0.046). Multivariate regression modeling confirmed the strong independent association between MIB-1 labeling index and outcome. As a group, tumors with labeling indices higher than 36% had an almost uniformly poor outcome, regardless of histology. CONCLUSION: MIB-1 labeling index and histological categorization are each prognostically relevant in childhood high-grade gliomas. MIB-1 labeling index can help to refine the accuracy of histologically based prognostic assessments.

PURPOSE: To investigate the intellectual outcomes of children with medulloblastomas/primitive neuroectodermal tumors (MB/PNET) treated with reduced-dose craniospinal radiotherapy (RT) plus adjuvant chemotherapy. PATIENTS AND METHODS: Forty-three children with average-risk posterior fossa MB/PNETs underwent longitudinal intelligence testing. All had been treated with a reduced-dose craniospinal RT regimen (23.4 Gy to the neuraxis, 32.4-Gy boost to the posterior fossa) and adjuvant chemotherapy. RESULTS: The estimated rate of change from baseline was significant for Full Scale Intelligence Quotient (FSIQ), Verbal IQ (VIQ), and Nonverbal IQ (NVIQ) (P < .001 for all three outcomes). The rate of change was estimated to be −4.3 FSIQ points per year, −4.2 VIQ points per year, and −4.0 NVIQ points per year. Females were more subject to VIQ decline than were males (P = .008), and young children (< 7 years of age) were more negatively affected than were older children, with a significant decline in NVIQ (P = .016). Finally, patients with higher baseline evaluations suffered greater declines in IQ than did those with lower baseline scores. CONCLUSION: This study represents the largest series of patients with average-risk MB/PNETs treated with a combination of reduced-dose RT and adjuvant chemotherapy whose intellectual development has been followed prospectively. Intellectual loss was substantial but suggestive of some degree of intellectual preservation compared with effects associated with conventional RT doses. However, this conclusion remains provisional, pending further research.

We present the long-term results of three consecutive clinical trials (Total Therapy studies 11, 12 and 13A) conducted for children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1984 and 1994. In study 11 (1984-1988), the overall event-free survival rates (+/-1 s.e.) were 71.8 +/- 2.4% and 69.3 +/- 2.4%, and the cumulative risks of isolated central nervous system (CNS) relapse 5.6 +/- 1.2% and 5.9 +/- 1.3%, at 5 and 10 years, respectively. In study 12 (1988-1991), event-free survival rates were 67.6 +/- 3.4% and 61.5+/- 9.0%, and isolated CNS relapse rates were 10.4 +/- 2.3% and 10.4 +/- 2.3%, respectively. Early intensive intrathecal therapy in study 13A (1991-1994) has yielded a very low 5-year isolated CNS relapse rate of 1.2 +/- 0.9%, boosting the 5-year event-free survival rate to 76.9 +/- 3.3%. Factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 x 10(9)/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

Summary. Sequential monitoring in a clinical trial poses difficulty in hypotheses testing on secondary endpoints after the trial is terminated. The conventional likelihood-based testing procedure that ignores the sequential monitoring inflates Type I error and undermines power. In this article, we show that the power of the conventional testing procedure can be substantially improved while the Type I error is controlled. The method is illustrated with a real clinical trial.

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% ± 4% at 3 years and 79% ± 7% at 5 years. Sites of relapse for the14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS: As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS: The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P = .0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P = .011). Analysis of the subset of patients with embryonal tumors showed similar results (P = .0008). CONCLUSION: Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.

Brain tumours rarely occur in survivors of childhood acute lymphoblastic leukaemia after cranial radiotherapy. An unusually high frequency of brain tumours seen among children enrolled in one of our leukaemia treatment protocols, Total Therapy Study XII, prompted us to identify the potential causes of this complication.We assessed clinical, biological, and pharmacokinetic features in all 52 children who received prophylactic cranial radiotherapy. We compared the cumulative incidence of brain tumours between subgroups, and with that of 421 children who received radiotherapy in previous studies.The incidence of brain tumours among irradiated children (six of 52, 12.8% [SE 5.0]) was high compared with patients in the same study who did not receive radiotherapy (none of 101; p=0.0008) and with other protocols that included cranial radiotherapy (p0.0001). Of the six children, four had erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and three had a genetic defect in thiopurine catabolism. The 8-year cumulative incidence of brain tumour among children with defective versus wild-type thiopurine methyltransferase phenotype was 42.9% (SE 20.6) versus 8.3% (4.7; p=0.0077). This protocol differed from previous protocols, in that more intensive systemic antimetabolite therapy was given before and during radiotherapy.These data support the elimination of prophylactic radiotherapy for acute lymphoblastic leukaemia except in patients at high risk of central-nervous-system relapse. Underlying genetic characteristics and treatment variables may be associated with an increased risk of radiation-associated brain tumours.

PURPOSE: Whether recent improvements in the treatment of childhood acute lymphoblastic leukemia (ALL) have nullified the adverse prognosis associated with male sex remains unclear. Therefore, we analyzed the survival experience and presenting clinical and laboratory features of boys and girls with newly diagnosed ALL who were treated at our institution over the past three decades. PATIENTS AND METHODS: One thousand one hundred fifty-one boys and 904 girls were treated in 13 consecutive Total Therapy studies between 1962 and 1994. An overview analysis was used to investigate the impact of sex on overall and event-free survival, both for the entire cohort and for subgroups defined by treatment era and blast-cell immunophenotype. Stratified analyses were performed to adjust for treatment protocol and known risk factors, and in the modern treatment era, for protocol, immunophenotype, and the DNA content of leukemic cells (ie, DNA index). The pharmacokinetics of methotrexate, teniposide, and cytarabine, as well as the thiopurine methyltransferase activity of erythrocytes, were compared between boys and girls treated on a single protocol. RESULTS: Compared with girls, boys were more likely to have T-cell ALL (20.9% v 10.7%, P CONCLUSION: Although boys and girls alike have benefited from improvements in ALL therapy, these gains have not completely eliminated the sex difference in prognosis that has persisted since the early 1960s. The apparent difference in outcome is partially explained by differences between boys and girls in the distributions of ALL immunophenotype and DNA index.

The fluorescence-activated cell sorter (FACS) was utilized to phenotype lymphocyte compartments in children receiving intensive chemotherapy for acute lymphoblastic leukemia (ALL). Sixteen patients (eight males and eight females) of diverse ages, risks of relapse, and within weeks 7-53 of maintenance/continuation chemotherapy treatment were arbitrarily selected for study. All 16 patients had profound B cell lymphopenia. In contrast, T cell numbers were often normal or marginally low, and accounted for up to 98% of the lymphocyte populations. No abnormality in T cell phenotypes could be demonstrated. Due to the highly skewed B/T lymphocyte ratios in these ALL patients, the absolute white blood cell counts and lymphocyte percentages were not predictive of the underlying B cell lymphopenia. Patients were also tested for serum immunoglobulin levels and most had abnormally low IgG and IgM. None of four patients immunized with the 1996-1997 influenza virus vaccine seroconverted to at least two vaccine antigens as compared to 10 of 10 healthy, age-matched controls. In total, these data highlight for the first time the profound abnormality of the B/T lymphocyte ratio in patients during treatment for ALL, and argue for consideration of B cell-targeted immunotherapy.

The clinical significance of submicroscopic levels of leukaemic cells in bone-marrow aspirates from children with acute lymphoblastic leukaemia (ALL) remains controversial. We prospectively determined the frequency and prognostic importance of minimal residual disease detected by a rapid immunological assay in bone-marrow aspirates of children with ALL.158 children with newly diagnosed ALL received 6 weeks of remission-induction chemotherapy. Once complete clinical remission was attained the patients received 2 weeks of consolidation therapy followed by continuation therapy. Bone-marrow aspirates were collected after induction therapy and during weeks 14, 32, and 56 of continuation therapy, and then at 120 weeks (end of therapy). Cells with leukaemia-associated immunophenotypes were investigated by multiparameter flowcytometry capable of detecting one leukaemic cell among 10,000 normal cells.The proportion of patients with detectable leukaemic cells was 23% at remission induction and 17% at week 14 of continuation therapy, decreasing to 5% and 4% at weeks 32 and 56. None of the 65 samples examined at completion of therapy (week 120) showed evidence of disease. Detectable residual disease at the end of remission induction correlated with adverse genetic abnormalities--the Philadelphia chromosome and MLL gene rearrangements--but not with other presenting features. Detectable leukaemia was associated with subsequent relapse regardless of the time at which bone-marrow samples were examined (p0.002 for all comparisons). For example, 3-year cumulative incidence (SE) of relapse in patients with and without detectable leukaemia at remission induction was 32.5% (10.6) and 7.5% (4.0), respectively (p0.001); for tests done at week 14, it was 42.1% (14.6) and 6.6% (3.5), p0.001. These correlations remained significant after adjusting for adverse presenting features. A higher degree of marrow infiltration by leukaemic cells (or = 0.1%) in week 14 samples identified a subset of patients with an especially poor prognosis.Immunological detection of residual leukaemic cells at any point in the treatment course is a powerful predictor of relapse in children with ALL. Alternative treatment should be considered for cases with persistent disease beyond the first 3 months of continuation therapy.

The rate of clearance of antileukemic agents differs by a factor of 3 to 10 among children with acute lymphoblastic leukemia. We hypothesized that the outcome of treatment would be improved if doses were individualized to prevent low systemic exposure to the drugs in patients with fast drug clearance.We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine. The doses of these drugs were based on body-surface area (in the conventional-therapy group) or the rates of clearance of the three medications in each patient (in the individualized-treatment group). In the individualized-treatment group, doses were increased in patients with rapid clearance and decreased in patients with very slow clearance.Patients who received individualized doses had significantly fewer courses of treatment with systemic exposures below the target range than did patients who received conventional doses (P0.001 for each medication). Among the patients with B-lineage leukemia, those who received individualized therapy had a significantly better outcome than those given conventional therapy (P=0.02); the mean (+/-SE) rates of continuous complete remission at five years were 76+/-6 percent and 66+/-7 percent, respectively. There was no significant difference between treatments for patients with T-lineage leukemia (P=0.54). In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia.Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.

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.

PURPOSE To determine the specificity and prognostic significance of computed tomography (CT) of the chest in pediatric Wilms' tumor. PATIENTS AND METHODS Patients treated for newly diagnosed Wilms' tumor at St Jude Children's Research Hospital between December 1978 and July 1995 were included in the study if an initial chest radiograph and CT were available and if pulmonary involvement (determined by chest radiographs) was absent. For the 202 patients studied, radiographs and CT scans were reviewed blindly and independently by three experienced radiologists for the presence of pulmonary nodules. Outcome variables consisted of intraobserver variability (in a subsample of 40 cases) and concordance between ratings on radiographs and CT scans (both by McNemar's test), interrater variability (by logistic regression), and the cumulative incidence of pulmonary relapse for patients with and without positive CT scans, by reviewer. RESULTS As expected, ratings of pulmonary involvement on radiographs were discordant with CT ratings. There was marked variability among reviewers in CT ratings (P = .0001). Of 202 CT scans, 78 were read as positive by at least one reviewer, 41 were rated positive by only one reviewer, 18 by two reviewers, and 19 by all three. Intrarater variability on repeat reviews was not significant. Patients with nodules identified on CT had a significantly higher pulmonary relapse rate when analyzed separately by reviewer. However, for the 14 patients who had pulmonary relapse, CT scans were rated positive by all three reviewers in only five cases and as negative by all three in another five cases. CONCLUSION The variability in interpretation of chest CT scans in patients with Wilms' tumor limits the predictive utility of these studies. Optimal, standardized techniques and central review are essential if chest CT is to be used for staging in cooperative studies.

✓ The optimum treatment of nonresectable low-grade gliomas of childhood remains undecided. There has been increased interest in the use of chemotherapy for young children, but little information concerning the long-term efficacy of such treatment. Seventy-eight children with a mean age of 3 years (range 3 months—16 years) who had newly diagnosed, progressive low-grade gliomas were treated with combined carboplatin and vincristine chemotherapy. The patients were followed for a median of 30 months from diagnosis, with 31 patients followed for more than 3 years. Fifty-eight children had diencephalic tumors, 12 had brainstem gliomas, and three had diffuse leptomeningeal gliomas. Forty-four (56%) of 78 patients showed an objective response to treatment. Progression-free survival rates were 75 ± 6% at 2 years and 68 ± 7% at 3 years. There was no statistical difference in progression-free survival rates between children with neurofibromatosis Type 1 and those without the disease (2-year, progression-free survival 79 ± 11% vs. 75 ± 6%, respectively). The histological subtype of the tumor, its location, and its maximum response to chemotherapy did not have an impact on the duration of disease control. The only significant prognostic factor was age: children 5 years old or younger at the time of treatment had a 3-year progression-free survival rate of 74 ± 7% compared with a rate of 39 ± 21% in older children (p < 0.01). Treatment with carboplatin and vincristine is effective, especially in younger children, in controlling newly diagnosed progressive low-grade gliomas.

PURPOSE TEL gene rearrangements due to the 12;21 chromosomal translocation are the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL), occurring in approximately 25% of cases with a B-precursor immunophenotype. The limited number of clinically useful genetic markers in this leukemia subtype prompted us to assess TEL status as a predictor of treatment outcome. PATIENTS AND METHODS We determined the status of the TEL gene (rearranged or germline) in 188 cases of B-precursor acute leukemia using Southern blot analysis and related the findings to event-free survival. All comparisons of outcome were stratified by treatment regimen, risk classification, age, and leukocyte count. RESULTS Forty-eight patients (26%) had a rearranged TEL gene. At 5 years of follow-up, an estimated 91% +/- 5% (SE) of this group were event-free survivors, compared with only 65% +/- 5% of the group with germline TEL (stratified log-rank P = .011). For nonhyperdiploid patients, the odds ratio of an adverse event in the germline TEL group to that for the rearranged TEL group was 4.06 (95% confidence interval, 1.86 to 8.84). The relationship of TEL rearrangement to a favorable prognosis was independent of recognized good-risk features in B-precursor leukemia, including age, initial leukocyte count, and hyperdiploidy. CONCLUSION Rearrangement of the TEL gene distinguishes a large subset of children with favorable-prognosis B-precursor leukemia who cannot be identified by standard prognostic features. It may be possible to treat these patients less aggressively without loss of therapeutic efficacy.

Data from St. Jude Total Therapy Study XI were analyzed to identify clinical and biologic features with prognostic significance. Results of this analysis, along with information available in the literature, led us to redefine lower-risk acute lymphoblastic leukemia (ALL) by the following features: DNA index between 1.16 and 1.60, or age 1-9 years plus white blood cell count (WBC)

2036 Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD > 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.

2035 Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enrolled on the study. Immunohistochemistry (IHC) was used to stratify patients to Stratum A (non-SHH group); Stratum B (SHH tumors) and Stratum C (indeterminate). All patients were treated with vismodegib at 150 mg/day PO daily. Tumor response, which had to be maintained for 8 weeks to meet protocol definition of sustained response, was assessed using RECIST criteria and central imaging review. Separate but identical Simon 2-stage MinMax designs (α = 0.10) were used in strata A and B to test for evidence that sustained response rates exceeded 5% with 90% power to detect 25% sustained response rates. Thus, 3/20 sustained responses were needed to declare potential activity of vismodegib. Results: 32 patients with a median age of 30 years (range 22.4-51.9) were enrolled on the study [Stratum A (n = 8); Stratum B (n = 20); Stratum C (n = 4)], including 18 males and 14 females. No responses were observed in Strata A or C and the median duration of treatment was 1.5 months (range 0.66-2.33). Three of 20 patients enrolled on Stratum B had sustained responses. The median duration of therapy for Stratum B patients was 2.76 months (range 0.33- 13.61). Six patients were on treatment for ≥6.44 months and 3 remain on treatment after 5.42, 9.34 and 13.61 months. During course 1, 2 patients experienced grade 3 decrease in lymphocytes; 1 experienced a grade 4 thromboembolic event; and 2 experienced grade 3 toxicities (back pain & syncope). During course 2, 3 patients experienced grade 3 toxicities (decrease in lymphocytes; myalgia & seizure). One other patient experienced grade 3 hypophosphatemia in courses 1 and 2. Conclusions: Vismodegib has activity against recurrent or refractory adult ‘SHH-subtype’ medulloblastoma and should be considered as a therapeutic option for newly diagnosed patients with this disease. Clinical trial information: NCT00939484.

PURPOSE This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.