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Logo of neuroncolAboutAuthor GuidelinesEditorial BoardNeuro-Oncology
 
Neuro-oncol. 2004 October; 6(4): 401–470.
PMCID: PMC1872006

Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology

June 13–16

BIOLOGY

BIO 1. CASPASE-8 LEVELS DETERMINE SIGNALLING PATHWAYS USED IN DEATH LIGAND-INDUCED GLIOMA CELL APOPTOSIS

David M. Ashley, Christopher D. Riffkin, Paul G. Ekert, Melissa J. Knight, and Christine J. Hawkins; Department of Haematology and Oncology, Royal Children’s Hospital, Parkville, Australia

The majority of high-grade glioma patients die within a several years of diagnosis. Elucidating apoptosis signaling pathways may assist in designing better adjuvant therapies. Our earlier work has demonstrated that glioma cells may either employ mitochondrial independent or dependent death receptor-induced apoptotic pathways, characteristic of cells termed type I and type II respectively. In the present study we generated panels of clonal transfectants overexpressing various levels of Bcl-2 in two parental glioma cell lines. These cells were used to explore molecular factors determining the necessity for mitochondrial amplification of death receptor signaling. Our studies have confirmed that Caspase-8 levels can influence the requirement for mitochondrial involvement in death receptor apoptotic signaling in glioma cells. Supporting the significance of these findings are observations that many primary patient glioblastoma samples have low or absent Caspase-8 expression levels.

BIO 2. THE HYPOXIA INDUCIBLE CELL DEATH GENE BNIP3 IS MUTATED IN MALIGNANT ASTROCYTIC TUMORS

Priti Baijal, Teralee Burton, Shunzhen Zhang, Elizabeth Henson, Nicolle Bristow, Mario Fonseca, Spencer Gibson, and David D. Eisenstat; Manitoba Institute of Cell Biology and Departments of Pediatrics and Child Health, Human Anatomy and Cell Science, Physiology and Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada

Astrocytic tumors are the most common brain tumor diagnosed in children and adults. Glioblastoma multiforme (GBM, WHO grade IV) represents the most malignant form of astrocytoma with a time to progression of 12 weeks without intervention and 12–15 months survival with combined modality therapy, including surgery, radiation, and chemotherapy. Response to therapy fails, in part, due to tumor hypoxia facilitating resistance to radiation and chemotherapy. The BCL2 Nineteen Kilodalton Interacting protein, BNIP3, is a Bcl-2 family member that is up-regulated in hypoxic regions in many solid tumors. BNIP3 is directly activated by the transcription factor HIF1α and mediates cell death in a caspase-independent manner through the interaction of the transmembrane (TM) domain of BNIP3 with the mitochondrial membrane. We have determined that BNIP3 is up-regulated in GBM compared to normal brain and is expressed in malignant astrocytes. This increased BNIP3 expression correlates with increased HIF1α and glut-1 that indicate hypoxic regions within these tumors. In glioma cell lines, BNIP3 expression is increased under hypoxia. In 33% of primary (de novo) GBM, we have detected mutations in the PEST and conserved (CD) domains of BNIP3 that result in a truncated protein lacking a functional TM domain. The cDNA mutations have been confirmed by SSCP or by allele-specific PCR and DNA sequencing. Over-expression of BNIP3 into malignant glioma cells induces cell death, whereas treatment with antisense, dominant negative or mutant BNIP3 constructs blocks hypoxia induced cell death. This blockage of cell death is due to failure of BNIP3 to localize to the mitochondria and inhibition of BNIP3-mediated mitochondrial dysfunction. Our discovery suggests that BNIP3 acts as a tumor suppressor and selective pressure within the tumor generates BNIP3 mutations providing a survival advantage. This could explain why treatments for malignant gliomas are often ineffective in hypoxic regions of these tumors.

BIO 3. MICROVESSEL DENSITY PREDICTS BEHAVIOR IN PEDIATRIC OPTIC PATHWAY/HYPOTHALAMIC GLIOMAS

Ute K. Bartels, Cynthia Hawkins, Jing Ma, Amit Ray, Peter Dirks, James Rutka, and Eric Bouffet; The Hospital for Sick Children, Paediatric Brain Tumour Program, Toronto, ON, Canada

Background: Optic pathway/hypothalamic gliomas (OPHG) are predominately low-grade tumors. However, OPHGs show an unpredictable behavior, and there is no recognized histologic or molecular marker anticipating this behavior. This study was performed to investigate angiogenic features as possible independent prognostic factors. Methods: We searched the databases of the Hospital for Sick Children for patients with pathologically diagnosed OPHGs between 1985 and 2002. Tumor specimens were reviewed and reconfirmed as low-grade gliomas. Those with sufficient tissue for staining were included in the study. Sections were immunostained with factor VIII (F8) and counted for microvessel density (MD). A ratio of alpha-smooth muscle actin to F8 immunostaining was calculated to give a vascular maturity index. Vascular endothelial growth factor (VEGF) and VEGF-receptor immunostaining was performed to assess angiogenic features and MIB-1 labeling index (LI) to assess proliferation. These factors were evaluated with respect to progression-free survival (PFS) and outcome of treatment. Results: 60 patients were identified, and 41 had sufficient material for further analysis. All patients underwent surgery. 30 required additional treatment (16 chemotherapy, 8 radiation, 6 chemotherapy + radiation). 8 patients had NF1. 38 are alive. MD showed a wide range of variation between tumors (4.8–73.6, median: 28 vessels/1.2 mm2). The absolute number of F8 stained vessels was significantly higher in infants (p < 0.01). A high MD (>20 vessels/1.2 mm2) was associated with a significantly shorter PFS compared to tumors with a low MD (<20 vessels/1.2 mm2) (p = 0.025). MIB-1 values ranged from 0–10 (median 2.5). Intensity and distribution of VEGF and VEGFR staining and MIB-1 LI were not significantly associated with outcome. Conclusions: Our findings suggest that angiogenesis is important in low-grade glioma and MD rather than MIB-1 has a prognostic value in OPHGs.

BIO 4. P38 MITOGEN-ACTIVATED PROTEIN KINASE IS A NEGATIVE REGULATOR OF RETINOIC ACID RECEPTOR TRANSCRIPTIONAL ACTIVITY IN PRIMITIVE NEUROECTODERMAL TUMOR CELLS

Sandeep Batra, Heather Mears, Stewart Goldman, Jessica Smith, Antonella Sassano, Lakhvir Lal, Yongzhong Li, and Leonidas C. Platanias; Robert H. Lurie Comprehensive Cancer Center and Departments of Pediatrics and Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

13-cis-Retinoic acid (RA), a synthetic retinoid, has recently been shown to inhibit the growth and induce differentiation of central nervous system primitive neuroectodermal tumors of childhood (PNET) cells. The RA-retinoic acid nuclear receptor complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription. Since the p38 mitogen-activated protein kinase (MAPK) is known to play a key role in cell proliferation, apoptosis, and differentiation, we hypothesized that both upstream and downstream effectors of p38 MAPK are activatred by RA, and that p38 MAPK may regulate RA-induced gene transcription. We found that p38 is phosphorylated, accompanied by the induction of its kinase activity (α and γ isoforms), in a time-dependent manner, following RA treatment. Our data also demonstrate that mitogen-activated kinase kinase 3/6 (MKK3/6) is activated by RA and may function as an upstream regulator of p38 activation. Using in vitro kinase assays, we determined that RA also induces activation of MapKapK2 and of mitogen-and stress-activated protein kinase 1 (MSK1) kinase activity in DAOY cells. Luciferase reporter assays were done to measure RARE transcriptional activity in DAOY cells. Pharmacological inhibition of p38 (α and β isoforms) with SB 202190 (5–10 μM), increased RA-dependent gene transcription via RARE elements (P < 0.01). Altogether, our data provide evidence that p38 MAPK is activated by RA and exhibits negative regulatory effects on RA-induced gene transcription in PNET cells.

BIO 5. MEDULLOBLASTOMA NEOPLASTIC MENINGITIS TARGETED RADIOTHERAPY WITH INTRATHECAL α-EMITTER 211AT-LABELED THYMIDINE ANALOGUE

Abraham Boskovitz, Ganesan Vaidyanathan, Gary E. Archer, Hidenobu Ochiai, Tatsunori Okamura, John H. Sampson, Darell D. Bigner, and Michael R. Zalutsky; Brain Tumor Program, Duke University Medical Center, Durham, NC, USA

Medulloblastoma is the most frequent pediatric malignant brain tumor and accounts for up to 25% of all intracranial tumors in children. Because of a strong tendency to disseminate into the CSF and metastasize along the leptomeninges, surgical resection is followed by radiotherapy of the entire neuroaxis. To avoid or reduce radiotoxicity to normal tissues of the CNS, targeted radiotherapy was explored in an animal model of medulloblastoma neoplastic meningitis. Targeted radiotherapy is potentially ideal for disseminated, thin-sheeted tumors if the radioisotope and its specific carrier are carefully selected according to the tumor characteristics. The thymidine analogue iododeoxyuridine (IUdR) is incorporated into the cellular DNA of cells in mitotic S-phase, conferring on it specificity for proliferating tumor cells within the intrathecal space. Astatine-211 211At is an α-emitter with a high linear energy transfer (97 keV/μm), a short range in tissues (73 μm), and a half-life of 7.2 hours. The astatinated analogue of IUdR, 5-[211At] astato-2′-deoxyuridine (AUdR), has demonstrated an exquisite cytotoxicity in vitro to malignant cell populations. We inoculated athymic male rats intrathecally with D341 medulloblastoma cells through a previously surgically implanted intrathecal catheter. In experiment 1, animals were treated intrathecally with 43μCi of AUdR (n = 10), 45 μCi of free [211At] astatide (n = 9), or saline (n = 9). Median survival was improved from 18 days for the saline group to 21.5 days with AUdR (p = 0.02) and 20 days with [211At] astatide (p = 0.56). In experiment 2, groups of animals received on a daily basis three doses of 30 μCi of AUdR (n = 9), 57 μCi of AUdR (n = 7), or saline (n = 9). Median survival was increased from 22 days for the saline group to 27 and 31 days for the low and high AUdR regimens, respectively. These results suggest that targeted radiotherapy with 211At-labeled thymidine analogues may warrant further investigation as a targeted radiotherapeutic for medulloblastoma neoplastic meningitis.

BIO 6. GENE EXPRESSION PROFILING OF PROGRESSIVE AND STABLE CHILDHOOD PILOCYTIC ASTROCYTOMAS

Daniel C. Bowers, Luc Girard, John Minna, Tina Chen, and Gail Tomlinson; University of Texas Southwestern Medical Center, Dallas, TX, USA

Children with Pilocytic Astrocytomas (PAs), the most common CNS tumor in childhood, may have either a quiescent or progressive clinical course. At present, extent of tumor resection and tumor location are the most important prognostic factors; biological prognostic factors are unknown. The identification of new prognostic factors for PAs may have important clinical and therapeutic implications. Ten mcg of purified mRNA was extracted from archival flash frozen tumor tissue from five completely resected recurrent PAs and six incompletely resected quiescent PAs. Samples were hybridized to the Affymetrix GeneChip arrays HG-U133A (22,283 probe sets) and HG-U133B (22,645 probe sets). The two arrays together evaluate the expression of 24,698 unique genes. Images from scanned chips were processed using Affymetrix software GCOS 1.0 to get the raw signals and p-values for each probe set. This data was then analyzed using in-house software (MATRIX): Array data were median-normalized, and replicate genes were combined by averaging their signals. Samples were then grouped according to tumor recurrence or nonrecurrence. Signals were averaged within each group and then compared (by calculating log ratios of recurrent vs. nonrecurrent PAs), and sets of genes showing differential RNA expression in the two groups were derived. Unsupervised hierarchical clustering was performed. 211 genes were found to be overexpressed at least 2-fold in the subset of progressive PAs compared to the subset of quiescent PAs, while 147 genes were found to be underexpressed more than 2-fold. Several of these genes were found to have a neuronal function (e.g., synaptoporin, synaptotagmin IV). Hierarchical clustering did not reveal any association between recurrence and global gene expression. These results demonstrate the ability of gene expression profiling to identify PAs with progressive clinical courses. Children with PAs with such profiling may benefit from closer monitoring and/or earlier adjuvant therapy.

BIO 7. AUTOFLUORESCENT MOUSE MODELS OF HUMAN MEDULLOBLASTOMA

Christopher Calabrese, Waleed Gaber, John Killmar, Christine Fuller, Meredith Allen, and Richard Gilbertson; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

We have developed a new in vivo model of medulloblastoma that recapitulates the behavior of classic and large cell anaplastic (LCA) forms of the disease and allows for serial measurement of tumor growth. To do this, we generated green fluorescent human medulloblastoma cells (Daoy, MEB-MED-8A, and MHH-MED-1) by in vitro infection using an MSCV-Green Fluorescent Protein (GFP) retrovirus. Under stereotactic control, 106 GFP-tagged medulloblastoma cells were inoculated into the superficial cerebral cortex of CD1 nude mice and the cranium sealed with a glass plate. Serial tumor measurements were then made through the cranial window using intravital fluorescence microscopy. By comparing in vivo total fluorescence measurements with 3D tumor reconstruction, we show that the measurement of in vivo fluorescence provides a highly accurate measure of tumor burden. MEB-MED-8A tumors grow very rapidly and result in the death of animals within two weeks: histopathologically these tumors are LCA, invasive, and contain an isochromosome of 17q and amplification of MYCC. In contrast, MHH-MED-1 and Daoy tumors display classic morphology with focal anaplasia and are much less aggressive in behavior, taking more than 7 weeks to become symptomatic. We are now using these models to test a number of molecular targeted therapies for medulloblastoma. We previously reported ERBB2 to be an independent marker of poor prognosis in medulloblastoma. Daoy.2 and MEB-MED-8A tumors express high levels of the ERBB2 receptor, while MHH-MED-1 cells express ERBB4 and low levels of ERBB2. Using our models, we now show that well tolerated doses (50 mg/kg/bd) of the oral ERBB1 and ERBB2 kinase inhibitor Erlotinib (Tarceva, OSI774) abolish ERBB2 signaling, induce cell cycle arrest, and generate marked inhibition of medulloblastoma growth in the CNS. Our model system provides a useful new tool for studying the biology of signal transduction systems in medulloblastomas in the brain and affords an efficient system for preclinical testing of novel therapies for this disease.

BIO 8. TRANSGENIC MOUSE MODEL OF ERBB2 OVEREXPRESSION IN CEREBELLAR GRANULE NEURON PRECURSOR CELLS

Christopher Calabrese, Roberto Hernan, Charles Sherr, Martine Roussel, and Richard Gilbertson; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

ERBB2 is undetectable in developing and adult human cerebellum (Gilbertson et al., Cancer Res., 1998) but is expressed in 40% of medulloblastomas and is associated with a poor clinical outcome (Gajjar et al., JCO, in press). Therefore aberrant expression of ERBB2 in granule neuron precursor cells (GNPC) might play a role in the initiation and/or progression of medulloblastoma. To test this hypothesis, we have generated transgenic mice in which ERBB2, placed under the control of a 1.7 Kb enhancer element of the Math1 promoter, is expressed at high levels in mitotic GNPC. Mice bearing the Math1-ERBB2 transgene display high-level expression of ERBB2 throughout the neural tube from embryonic (E) day 14.5. High levels of membrane associated ERBB2 are also detected in the rhombic lip and throughout the mitotic zone of the cerebellar external germinal layer (EGL) from mid gestation through to postnatal day 20. Western blot analysis of whole postnatal (P) day 5 cerebellum taken from transgenic mice identified high-level expression of phospho-Y1248 ERBB2 and phospho-Ser473 AKT1 relative to transgene negative littermate controls, indicating ERBB2 is actively signaling in mice bearing the transgene. Further, using Affymetrix expression array analysis of P5 cerebellum, we have identified a group of genes that are significantly and differentially expressed in transgene positive compared to transgene negative littermate controls. We are now using this model to study the role of ERBB2 in tumorigenesis in the cerebellum. To do this, we are expanding our colonies of Math1-ERBB2 animals for tumor surveillance studies. Further, we recently reported that the TP53-ARF pathway is disrupted in large cell anaplastic medulloblastoma, a tumor subtype that frequently contains high levels of ERBB2. Therefore, to determine whether ERBB2 expression and TP53-ARF defects are interdependent during medulloblastoma formation, we are breeding Math1-ERBB2 mice with p53 null and Arf null animals. In addition to reporting the characterization of this new mouse model at the meeting, we will also provide a full update on tumor surveillance data.

BIO 9. IDENTIFICATION OF TUMOUR SUPPRESSOR GENES IN CHILDHOOD MEDULLOBLASTOMA BY PROMOTER HYPERMETHYLATION PROFILING

Steven C. Clifford, Janet C. Lindsey, Meryl E. Lusher, Richard J. Gilbertson, Andrew D.J. Pearson, and David W. Ellison; Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne, UK; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Medulloblastoma (MB) is the most common malignant brain tumour of childhood; however, its molecular basis is not well understood. The epigenetic silencing of tumour suppressor gene (TSG) expression by promoter hypermethylation has emerged recently as a major mechanism of TSG inactivation. To assess the role of epigenetic events in MB and identify critical genes in its development, we profiled the promoter methylation status of ten candidate TSGs (p14ARF, p15INK4b, p16INK4a, CASP8, HIC1, TIMP3, TP73, TSLC1, RIZ1, and RASSF1A) in MB and in the normal cerebellum. Extensive hypermethylation of RASSF1A was detected in nearly all MBs, but not in normal cerebellum (41/44 primary tumours vs. 0/5 normal cerebella). In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a background of partial methylation in the normal cerebellum. For all three genes, methylation in MB cell lines was associated with their epigenetic transcriptional silencing and methylation-dependent re-expression following treatment with the DNA methyltransferase inhibitor, 5-aza-2’-deoxycytidine. Further investigation of RASSF1A revealed that complete methylation occurred in the absence of gene deletion or mutation, indicating that its inactivation occurs by bi-allelic promoter hypermethylation alone. The remaining genes showed either low frequency methylation (p14ARF, p16INK4a, RIZ1; <7% of cases) or no evidence of methylation (p15INK4b, TIMP3, TP73, TSLC1), suggesting that their hypermethylation does not play a major role in MB. No evidence was found to support a concordant methylation phenotype affecting multiple genes in this disease. These findings indicate that tumour-specific epigenetic inactivation of RASSF1A, HIC1, and CASP8 are frequent events in MB and identify these as potentially critical TSGs in its pathogenesis. Epigenetic RASSF1A inactivation represents the most common defect detected to date in MB, emphasising the importance of its further investigation. Importantly, our data demonstrate that the comprehensive identification of MB genes will require systematic screening of both the genome and epigenome.

BIO 10. GENE EXPRESSION LEVELS ASSESSED BY MICROARRAY ANALYSIS AND QUANTITATIVE REAL-TIME RT-PCR—HOW WELL DO THEY CORRELATE?

Peter Dallas, Nick Gottardo, Martin Firth, Alex Beesley, Katrin Hoffmann, Philippa Terry, Joseph Freitas, Aaron Cummings, and Ursula Kees; Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, WA, Australia

The use of microarray technology to assess gene expression levels in living cells is now widespread in biological research, and the methodology is likely to receive even broader application as the technology evolves, data analysis procedures improve, and costs decline. The validation of microar-ray results using independent mRNA quantitation techniques including Northern blotting, ribonuclease protection, in-situ hybridisation, or quantitative real-time RT-PCR (qRT-PCR) remains a critical element of any microarray experiment. Despite this, there have been few systematic validation studies of cDNA, or more noticeably, oligonucleotide microarray data using these independent approaches. For researchers to be confident with the interpretation of microarray results, it is important that this issue is addressed. We have undertaken an extensive series of experiments examining gene expression profiles in paediatric cancer specimens and normal tissues using HG-U133A GeneChips (Affymetrix). We processed the microarray data using Affymetrix MAS 5.0 software, or as an alternative, the robust multichip average (RMA) method based on the R statistical package. We selected 34 genes for follow-up verification experiments using qRT-PCR (TaqMan Assays On Demand, Applied-Biosystems). We found that in the majority of cases (29/34; 85%) there was a statistically significant correlation (p < 0.05) between expression levels determined for specific genes by microarray analysis and those determined for the same genes by qRT-PCR. Although our data indicate that generally Affymetrix microarray scores correlate well with qRT-PCR results, we observed a poor correlation (p > 0.05) for 6/34 (18%) of the genes that we examined, emphasising the need for caution when interpreting microarray results and highlighting the importance of independent validation of gene expression levels for any gene of interest selected on the basis of microarray expression scores.

BIO 11. IDENTIFICATION OF PROGNOSTIC MARKERS IN MEDULLOBLASTOMA BY INTEGRATING COMPARATIVE GENOMIC HYBRIDIZATION AND EXPRESSION PROFILES

Jeffrey Deyo, Massimiliano DeBortoli, Tsz-Kwong Man, Pulivarthi H. Rao, John Y. H. Kim, Scott L. Pomeroy, and Ching C. Lau; Texas Children’s Cancer Center, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA

Improving the management of medulloblastoma (MB), the most common malignant brain tumor of childhood, depends upon better understanding of its biology. This requires more comprehensive investigation of the genetic alterations underlying tumorigenesis and progression. Genomic methods present the most efficient means of characterizing these changes. By integrating multiple platforms, we attempt to compensate for intrinsic limitations of each to identify genes associated with outcomes and biological characteristics but would otherwise be overlooked by using any single approach. We describe a more rigorous approach than simply mapping expression profiles with cytogenetic changes to uncover statistically significant alterations in MB that may arise through more complex mechanisms. With comparative genomic hybridization (CGH), we analyzed twenty-seven MB samples that were among 65 previously analyzed with oligonucleotide microarrays [Pomeroy et al. Nature, 2002]. We compared these twenty-seven samples to normal cerebellum samples to generate a “global” list of differentially expressed genes (based on fold change) and then partitioned the dataset for each of the most common chromosomal lesions detected (iso17q, +7q, +2p, −10q, −16q) to identify candidate genes. We selected those that were uniquely identified in the partitioned list and associated with chromosomal lesions but not found in the original “global” list for further analysis. To strengthen outcome prediction, we divided all 65 samples originally analyzed for gene expression into three groups based on the expression level for each candidate gene (unchanged, low, and high). Twenty-five genes identified by partitioning are predictive for survival by Kaplan-Meier analysis (P [neither less-than nor equal to]⃥ 0.01). Our algorithm exploits cytogenetic changes to guide the detection of novel candidate genes from expression profiles. With this strategy, we have identified candidate genes that are strongly associated with survival but have previously eluded detection by either method alone.

BIO 12. TAMOXIFEN ACTIVATED CASPASE PATHWAYS IN ASTROCYTOMA

Andrew M. Donson, Joy Zartman, Julie Fleitz, and Nicholas K. Foreman; Department of Neuro-Oncology, University of Colorado Health Sciences Center, Denver, CO, USA

Introduction: Despite promising preclinical results supporting the use of tamoxifen to treat astrocytoma, clinical studies have proved disappointing. In order to improve the clinical benefit of this drug, it is necessary to better understand the mechanism(s) of its anticancer effects. The object of our study was to address this paucity of data by filling in the missing links in the tamoxifen-induced apoptotic signaling pathways in astrocytoma. Methods: Preclinical trials of novel drugs for the treatment of astrocytoma often use apoptosis as a measure of anti-tumor effect. Presently, there is no single reliable method to determine whether a cell is apoptotic in astrocytoma. Traditional methods for detecting apoptosis, including terminal deoxynucleotidyl transferase nick-end-labeling, nuclear morphology, DNA laddering, Annexin-V binding, and Western blotting for active caspase-3, are subjective, difficult to perform or difficult to quantify in astrocytoma. In this study, we used recently developed cytometric bead array analysis for measurement of active caspase-3 in cell lysates. This technique allowed rapid quantitation of apoptosis in astrocytoma. Results: This study showed that tamoxifen induced apoptosis via caspase-3 activation. The results also revealed a time-and dose-dependent response of tamoxifen induced caspase-3 activity in astrocytoma. Using peptide inhibitors selective to individual caspases, we also demonstrated that both caspase-8 and caspase-9 are involved in activation of caspase-3. Conclusion: The results suggest that tamoxifen induces apoptosis in human astrocytoma cell lines primarily via caspase-3. Further elucidation of these apoptotic pathways will determine whether tamoxifen-triggered caspase-3 activation is occurring via the death receptor pathway or the mitochondrial pathway. Elucidation of these apoptotic pathways will aid the design of novel tamoxifen analogs that retain all of the beneficial effects but are devoid of toxicity.

BIO 13. GENOMIC IMBALANCES IN HIGH- AND LOW-GRADE PAEDIATRIC ASTROCYTOMAS

Sara Dyer,1,2 Emma Prebble,1 Marie-Anne Brundler,3 David Ellison,4 Val Davison,2 and Richard Grundy1; 1Institute of Cancer Studies, University of Birmingham; 2Regional Genetics Lab, Birmingham; 3Department of Pathology, Birmingham Children’s Hospital, Birmingham; 4Department of Neuropathology, Newcastle General Hospital, Newcastle; UK

Astrocytomas are the most common brain tumours observed in adults and children. However, the majority of genetic analyses performed on astrocytomas have used tumours derived from adults, and there are few reports of nonrandom copy number aberrations in their childhood counterparts. To address this, we have analysed 15 high-grade and 15 low-grade paediatric astrocytomas by high-resolution comparative genomic hybridisation (HR-CGH). Only 5 out of 15 (33%) low-grade tumours showed genomic imbalances, and the only consistent abnormality detected was gain of chromosome 5 in 2 cases. However, 12 out of 15 (80%) high-grade tumours had detectable copy number aberrations. The median number of abnormalities detected in the high-grade tumours was 3 (range 0–16). Out of a total of 59 imbalances, 19 involved whole chromosomes and 40 involved chromosomal regions or arms. The most common gains were of 1q in 7 cases (47%) and of 2 or 2q in 4 (27%) cases. The most common losses were of 9 or 9p in 4 (27%) cases, loss of 10 or 10q in 4 (27%) cases, and loss of 13 in 4 (27%) cases. Seven high-level gains were detected: three involved chromosome 7; two were gains of 1q; one high-level gain of chromosome 2 was observed; and one high-level gain was observed on 8q. Gains of chromosome 7 and losses of 9 and 10 have been reported in adult high-grade astrocytomas; however, gains involving chromosomes 1q and 2 have not been commonly reported to date. This study therefore provides evidence of novel chromosomal imbalances in paediatric astrocytomas.

BIO 14. PDGFR INHIBITION IN MEDULLOBLASTOMA CELLS INDUCES APOPTOSIS AND ALTERS GENE EXPRESSION

Meliha Dzirlo, Katia M. Peterson, Rebekah Kushner, Thamara Abouantoun, and Tobey MacDonald; Center for Cancer Research, Children’s Research Institute, Washington, DC, USA

We previously showed that overexpression of platelet-derived growth factor receptor (PDGFR) is associated with metastatic medulloblastoma. PDGFR is a receptor tyrosine kinase (RTK) that undergoes autophosphorylation upon binding to platelet-derived growth factor (PDGF). In other cell types, PDGFR autophosphorylation has been shown to initiate signal transduction through RAS-MAPK and PI3K-AKT, which in turn can promote proliferation, migration, survival, and gene transcription. To determine whether PDGFR plays a similar role in medulloblastoma cells, we inhibited PDGFR expression and activity in the Daoy human medulloblastoma cells using three separate methods: i) small interfering RNA (siRNA) to PDGFR, ii) RTK inhibition of PDGFR (Gleevec ), and iii) anti-PDGF neutralizing antibodies; we then measured the resultant changes in gene expression and survival following PDGF stimulation. These changes were compared to baseline serum-depleted cells, with and without PDGFR inhibition, stimulated with PDGF. PDGFR-active cells stimulated with PDGF demonstrated enhanced proliferation and showed gene expression changes at 24 hours, as measured by Affymetrix microarray profiling, that were specific to the subtype of ligand (PDGFAA or PDGFBB) used for stimulation. PDGFBB, which activates both receptor subtypes (alpha and beta), was more potent than PDGFAA, which only activates the alpha subtype of PDGFR. PDGFBB induced gene expression encoding effectors that primarily regulate signal transduction and cell-cycle control, while PDGFAA induced gene expression encoding effectors that predominantly affect chemotaxis. Inhibition of PDGFR activity, as measured by loss of PDGFR autophosphorylation, resulted in a doubling of baseline apoptosis (8 to 17%) at 24 hours and loss of cell-cell contacts and cell death at 72 hours–96 hours. These cell responses corresponded to alterations in the PDGF-induced gene expression profiles promoting survival. Together, these results suggest that PDGFR is important for medulloblastoma survival and that the mechanism by which this occurs is through signal transduction that promotes prosurvival gene transcription.

BIO 15. COMBINED HISTOPATHOLOGICAL AND MOLECULAR CYTOGENETIC STRATIFICATION DEFINES A HIGH-RISK SUBSET OF PATIENTS WITH MEDULLOBLASTOMA—A UNITED KINGDOM CHILDREN’S CANCER GROUP STUDY

David W. Ellison, Jayne M. Lamont, Charles S. McManamy, Andrew D.J. Pearson, and Steven C. Clifford; Northern Institute for Cancer Research, University of Newcastle Medical School, Newcastle upon Tyne, UK

We examined the utility of stratifying medulloblastomas by a combination of refined histopathological classification and molecular cytogenetic evaluation. Detailed histopathological classification of tumors from a cohort of patients (n = 87) composed mainly of children entered into the International Society of Pediatric Oncology/United Kingdom Children’s Cancer Study Group PNET3 trial (n = 65), included identification of the recently described large cell/anaplastic phenotype. Fluorescence in situ hybridization was used to detect chromosomal abnormalities previously associated with medulloblastoma pathogenesis (chromosome 17 abnormalities, losses of 9q22 and 10q24, and amplification of the MYCC and MYCN oncogenes) in formalin-fixed paraffin wax-embedded tumor biopsies. The large cell/anaplastic phenotype, which was present in 20% of medulloblastomas, emerged as an independent prognostic indicator (P = 0.0005). Loss of 17p13.3 (38% of medulloblastomas) was found across all histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/anaplastic phenotype (P = 0.034). Both loss of 17p13.3 and high-frequency MYCC/MYCN amplification (present in >50% of tumor cells) emerged as prognostic indicators (P = 0.003; P < 0.0001 respectively). Loss of 9q22 was associated with the nodular/desmoplastic medulloblastoma variant, while loss of 10q24 loss was found in all variants. Together with metastatic disease at presentation, the following characteristics: large cell/anaplastic phenotype, 17p13.3 loss, or high-frequency MYC amplification, defined a high-risk group of children whose outcome was significantly (P = 0.0002) poorer than a low-risk group without these tumor characteristics. These data provide a scheme for the stratification of patients with medulloblastoma based on the combined evaluation of novel histopathological features and molecular cytogenetic abnormalities, which is assessable in routinely processed formalin-fixed tumor tissue. Using such schemes, patients likely to be cured could be spared the side effects of maximal therapy, which can be targeted at those with aggressive disease.

BIO 16. SURVIVIN AND SURVIVIN ISOFORMS IN MEDULLOBLASTOMA SHOW UNIQUE PATTERNS OF EXPRESSION AND PROGNOSTIC VALUE

Jason Fangusaro, Yuying Jiang, Vivekanand Singh, Daniel Boué, and Rachel Altura; The Center for Cancer Research, Columbus Children’s Research Institute and Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

Survivin is an inhibitor of apoptosis protein (IAP) that has been identified as a marker for tumor aggression in a variety of pediatric and adult malignancies including lymphoma, neuroblastoma, Wilm’s tumor, breast cancer, colon cancer, gastric cancer, and CNS tumors. Survivin has three known splice variants: Survivin, Survivin-2B, and Survivin Delta-3; and recent literature has suggested that each isoform may have unique functions and subcellular localization. In this study, we investigated the use of Survivin as a prognostic marker in medulloblastoma. We analyzed the levels of Survivin in 40 pediatric medulloblastomas via immunohistochemistry. The percentage of cells positive for Survivin was <5% in 3 samples (7.5%), 5–10% in 5 samples (12.5%), 11–20% in 17 samples (42.5%), and 21–50% in 15 samples (37.5%). Staining patterns were evaluated using two different polyclonal antibodies to Survivin and positivity localized to the nucleus in all tumors. There was a statistically significant association between the percentage of Survivin-positive cells and outcome, suggesting that higher percentages of positivity correlated with a poorer clinical outcome. We also evaluated 20 freshly frozen pediatric medulloblastomas for the presence of the Survivin splice variants by real-time PCR. All of the tumors expressed Survivin and Survivin-2B, but only a fraction of the tumors expressed Survivin Delta-3. Survivin-2B was the highest expressed isoform in all tumors tested. In summary, our study demonstrates a potential role for Survivin as a prognostic marker in medulloblastoma. This is the first report evaluating the expression of Survivin and Survivin isoforms in a series of medulloblastoma tumors.

BIO 17. GENE SPECIFIC ABERRANT METHYLATION IN MEDULLOBLASTOMAS (MB), ANAPLASTIC EPENDYMOMAS (AE), AND STPNET OF CHILDHOOD

Michael C. Frühwald, Jörg Mühlisch, Niels Sörensen, Werner Paulus, Heribert Jürgens, Carsten Hagemann, and Giles Vince; University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, Münster, Germany

Epigenetic modifications of DNA such as promoter methylation and histone deacetylation contribute to oncogenesis by influencing gene transcription. Recent data suggest methylation of a limited number of genes in medulloblastoma, the most common malignant brain tumor of childhood. Discrepant findings derived from screening studies suggest that up to 800 gene loci may become aberrantly methylated in these tumors (Oncogene 2002). Methods: Using methylation-specific PCR (MS-PCR), we screened 6 MB and 2 stPNET cell lines for aberrant methylation of the genes p14ARF, p15INK4B, p16INK4A, DUTT1, DAPK1, SOCS1, TIMP3, CDH1, and MGMT. Results were verified by bisulfite sequencing and COBRA (combined bisulfite restriction analysis). Gene promoters that showed methylation were analyzed in 9 normal cerebella, 6 stPNET, up to 59 MB, and 13 AE. Threshold levels for methylation detected by these methods were quantified using artificially methylated DNA with defined ratios of methylated to unmethylated DNA. Results: We detected tumor type specific and overlapping methylation patterns. Methylation in normal cerebellar tissue was restricted to low-level methylation and tissues from older patients. Promoter methylation was detected for CDH1 (3/6 stPNET, 39/57 MB, 7/12 AE), MGMT (1/6 stPNET, 25/59 MB, 5/11 AE), p16INK4A (17/59 MB, 1/13 AE), p14ARF (9/58 MB), and TIMP3 (1/6 stPNET, 6/59 MB, 1/13 AE). MS-PCR proved a rather sensitive methodology for detecting aberrant methylation, while COBRA and bisulfite sequencing required higher levels of methylation. Conclusion: Aberrant methylation in common CNS malignancies of childhood affects genes with diverse biological functions. Tumor type specific methylation was detected for p14ARF, which was only methylated in MB. CDH1, on the contrary, was methylated in almost 50% of the examined tumors. Methylation may predispose cells for invasion and metastasis. Furthermore, aberrant methylation may, along with other mechanisms, represent a field defect rendering cells susceptible for genomic instability. This work was supported by Deutsche Krebshilfe 10-1699-FR1, DFG FR 1516/1-1, and Karl Bröcker Stiftung.

BIO 18. P53 PATHWAY DYSFUNCTION IN PRIMARY CHILDHOOD EPENDYMOMAS AND XENOGRAFTS

Nathalie Gaspar, Birgit Geoerger, Jacques Grill, Paule Opolon, Marie-José Terrier-Lacombe, Arielle Lellouch-Tubiana, Lysiane Laudani, Alain Pierre-Kahn, and Gilles Vassal; Department of Pediatrics and Pharmacology and New Treatments in Cancer, Institut Gustave-Roussy, Villejuif, France

Childhood ependymoma is a therapeutic challenge. We hypothesized that p53 function might be abrogated in childhood ependymoma and implicated in resistance to anticancer therapy. We analyzed 21 primary ependymomas at diagnosis or relapse from 18 children. Using a functional assay in yeast, p53 gene mutations/deletions were excluded. Neither MDM2 overexpression nor p14ARF deletions were observed in 6 and 5 tumors using Western blot analysis and quantitative RT-PCR, respectively. Pax5 mRNA expression was shown by RT-PCR in 5/13 primary tumors at diagnosis, 2/3 at relapses. We studied two xenografts, IGREP37 and IGREP83, derived from primary childhood ependymomas that presented anaplastic ependymoma features and monosomy 22. The tumor doubling times were 12 and 22 days, respectively. Consistent with our findings in primary tumors, xenografts revealed no p53 mutation/deletion, mdm2 overexpression, or p14 deletion. We accessed the p53 pathway functionality in these xenografts using radiotherapy and found an abrogated p53 pathway in IGREP37. Radiotherapy did not induce p53 stabilization, p21 expression (Western blot), or G1/0 growth arrest (FACS analysis). In addition, IGREP37 was only moderately radiosensitive. In contrast, p53 appeared functional in IGREP83 after radiotherapy with stabilization of p53, induction of p21-mediated G1/0 growth arrest, and apoptotic cell death. This xenograft was highly radiosensitive. Interestingly, Pax5 mRNA was expressed in IGREP37 but not in IGREP83, suggesting its potential role in the abrogation of cellular p53 function. However, using Western blot and immunohistochemistry, pax5 protein was not expressed in both xenografts. To strengthen our findings, we are evaluating pax5 expression in primary tumors using immunohistochemistry. In conclusion, we demonstrated that p53 pathway in ependymoma might be abrogated without p53 mutation, mdm2 overexpression, p14ARF deletion, or increased pax5 protein expression, and needs further investigation. The two xenografts represent valuable in vivo models of ependymomas with aggressive behavior for preclinical studies.

BIO 19. POTENTIAL TARGETS IN PEDIATRIC BRAIN TUMORS FOR THE TYROSINE KINASE INHIBITOR GLIVEC®

Birgit Geoerger, Marie-Jose Terrier-Lacombe, Valerie Velasco, Jean-Francois Emile, Lysiane Laudani, Jacques Grill, Arielle Lellouch-Tubiana, Jean-Christophe Sabourin, Christian Sainte-Rose, Chantal Kalifa, and Gilles Vassal; Department of Pediatrics and Pharmacology and New Treatments in Cancer, Institut Gustave-Roussy, Villejuif, France

Glivec® inhibits specific activations of the platelet-derived growth factor receptor (PDGFR), c-kit, and BCR/Abl tyrosine kinases and has significantly changed the treatment for chronic myeloic leukemia and gastrointestinal stromal tumors. To investigate its potential in the treatment in pediatric brain tumors, we determined expression of c-kit and PDGFRα and β in 39 primary pediatric brain tumors (11 brain stem glioma, 2 medulloblastoma, 4 PNET, 2 atypical teratoid/rhabdoid tumors [AT/RT], 2 ependymoma, 3 low-grade glioma, 2 high-grade glioma, 4 oligodendroglioma, 3 chordoma, and 5 others) and 18 xenograft tumors derived from primary brain tumors (4 malignant oligodendroglioma, 4 glioblastoma multiforme [GBM], 5 medulloblastoma, 4 PNET, and 2 ependymoma). Immunohistochemistry on formalin-fixed paraffin-embedded tissue sections was performed using the polyclonal antibodies anti-CD117 A4520 and anti-PDGFRα AF-307-NA and the monoclonal anti-PDGFRβ P-20. C-kit was expressed in 3 primary tumors, 1 medulloblastoma, 1 pinealoblastoma, and 1 AT/RT. The expression was, however, significantly weaker compared with those observed in GISTs with a positive cytoplasmic staining of 20–30% tumors cells. None of the xenograft models expressed c-kit. PDGFRα was expressed in 7 primary tumors: 1 brain stem glioma, 1 AT/RT, 1 ependymoma with GBM transformation, 1 anaplastic astrocytoma, 2/4 oligodendroglioma, and 1 chordoma. The positivity of tumor cells ranged between 20% and 80%, the latter observed in oligodendroglioma and chordoma. In addition, PDGFRα was expressed in 1 medulloblastoma xenograft, 1 malignant oligodendroglioma xenograft derived from a child, and 2 glioblastoma xenografts. Positivity of the xenograft tumors was confirmed by Western blot analysis. PDGFRα was expressed in 1 brain stem glioma, 1 AT/RT, 2 ependymomas, 1 anaplastic astrocytoma, and 2 chordomas. We are currently evaluating c-kit and PDGFRα mutations in these tumors. Glivec® might play a role in the treatment of some pediatric brain tumors through targeting of the PDGFR; however, c-kit expression is rare. Further investigations are necessary to determine the efficacy of this treatment. This work was supported by the ARC.

BIO 20. CONDITIONALLY REPLICATING ADENOVIRUSES EXPRESSING P53 OR TARGETED TOWARDS EGFR EXHIBIT ENHANCED ONCOLYTIC POTENCY IN MALIGNANT GLIOMAS

Birgit Geoerger, Victor W. van Beusechem, Paule Opolon, Jacques Grill, Martine L.M. Lamfers, Clemens M.F. Dirven, Winald R. Gerritsen, and Gilles Vassal; Department of Pediatrics and Pharmacology and New Treatments in Cancer, Institute Gustave-Roussy, Villejuif, France

Prognosis of malignant glioma is poor and treatment remains a major challenge. Conditionally replicative adenoviruses (CRAds) are novel anti-cancer agents, designed to selectively replicate in and to destroy cancer cells. Critical determinants for the oncolytic potency of CRAds are their capacity to infect tumor cells and to induce cell lysis. Lack of adenovirus receptor CAR expression and dysfunctional cell death pathways, both often observed in malignant glioma, reduce CRAd efficacy. To overcome these limitations, we constructed two new CRAds based on AdΔ24 with specificity for cells dysfunctional in cell-cycle checkpoint control due to a mutated Rb-pathway. AdΔ24-425S11 produces a bispecific scFv adapter molecule to redirect infection via the Epidermal Growth Factor Receptor (EGFR), commonly expressed in malignant gliomas; AdΔ24-p53 expresses p53 in order to restore p53 mediated cell death mechanisms. Compared to the parent AdΔ24, AdΔ24-425S11 exhibited enhanced oncolysis on CAR-deficient cell lines and 7/8 primary glioblastoma multiforme short-term cultures in vitro, as measured by cell viability quantified by WST-1 conversion assay after infection at low MOIs. AdΔ24-p53 killed almost all malignant glioma cell lines and 6/8 primary glioblastoma multiforme short-term cultures more effectively, independent of cellular p53 status as determined by p53-specific transactivation assay. Both viruses caused superior antitumoral effects in subcutaneous human xenografts in nude mice derived from primary tumors in vivo. The effect of targeting was studied in the neuroblastoma IGR-NB8 due to the lack of an adequate CAR-deficient and EGFR-expressing glioma model. Five intratumoral injections of 108 pfu AdΔ24-425S11 yielded significant tumor growth delay of 27 days (p < 0.01) vs. 13 days (n.s.) for AdΔ24 compared to PBS controls. The AdΔ24-p53 caused more frequent regression and more delayed growth of IGRG121 glioblastoma xenografts with 70% tumor regressions and 60% animals surviving more than 120 days tumor-free or with a minimal tumor residual. Thus, CRAds with enhanced oncolytic capacity due to CAR-independent infectivity and/or restoration of p53-dependent cell death are promising agents for treatment of malignant gliomas. This work was supported by La Ligue contre le Cancer.

BIO 21. TRANSCRIPTION FACTORS EXPRESSED BY NEURAL CREST CELLS CORRELATE WITH PHENOTYPE IN DEVELOPMENT AND IN NEUROECTODERMAL TUMORS

Timothy R. Gershon and Steven S. Chin; Children’s Hospital of New York, Columbia University Division of Child Neurology, Columbia Presbyterian Medical Center New York, NY, USA

Embryonic cells derived from the neural crest (NC) have features in common with neuroectodermal tumor cells: both are pluripotent, proliferative cells that migrate from their sites of origin. NC cells and neuroectodermal tumor cells both derive from neuroectoderm and in acquiring proliferative, migratory behavior, neuroectodermal tumor cells resemble their undifferentiated ancestors. We tested the hypothesis that genes that direct NC development are expressed in neuroectodermal tumor cells. Using immunocytochemistry on human embryonic tissue, we developed an array of markers expressed sequentially as neuroectodermal precursors giving rise to migrating NC cells. We then determined the patterns of marker expression in tumors of NC derived tissues and in tumors with primitive neuroectodermal histology. The markers selected were PAX3, AP-2, SOX10, and PAX7. PAX3 was expressed by cells of the dorsal neural tube, migrating NC cells, and mesodermal cells. AP-2 was expressed by NC cells as they exited the neural tube and as they migrated throughout the embryo, as well as by epithelial cells. SOX10, in contrast, was expressed later in NC migration, after cells had exited the neural tube. PAX7 was not detected in extracranial neuroectodermal tissue, but rather served as a mesodermal marker. Analyzing neurofibroma, benign and malignant Schwannoma, neuroblastoma, melanoma, Ewing’s sarcoma, medulloblastoma, and supratentorial PNET, we found these markers were expressed in tumor specific combinations. In a manner that echoed the progression of marker expression by NC-derived cells during embryogenesis, the more malignant, primitive tumors tended to express PAX3, while the less dysregulated tumors, with greater capacity for differentiation, tended to express SOX10. Our findings suggest that patterns of NC transcription factor expression may direct and predict neuroectodermal tumor behavior.

BIO 22. WHAT’S IN A NAME?

Floyd H. Gilles, C. Jane Tavarè, and Ignacio Gonzalez-Gomez, for the Childhood Brain Tumor Consortium; Pediatric Neuropathology, Children’s Hospital Los Angeles, CA; University of Southern California, Los Angeles, CA; USA

Background: Most pediatric neuroglial tumors are histologically heterogeneous. Low intraobserver diagnostic reproducibility, histologic feature recognition reliability, and inadequate diagnostic criteria result in subsets within diagnoses and grades with markedly varying survival expectation. This confounds accurate prognoses and evaluation of treatment regimes of childhood neuroglial tumors. Materials and Methods: 1771 intracranial neuroglial tumors amongst 3291 children in the Childhood Brain Tumor Consortium (CBTC) database. Reliability was measured by Kappa and Jaccard (Dice) statistics. Survival distributions of histologic subsets of frequent WHO diagnoses or Daumas-Duport (DDGS) grades were compared. Results: Only 8 WHO diagnoses had acceptable reproducibility, and only 26 of 57 commonly used histologic features had acceptable reliability. Overall, the WHO classification separated only two prognostically distinct classes of supratentorial astrocytomas. Among infratentorial astrocytomas, there were 2 subsets with five year survival estimates of 0.70 and 0.27, and among supratentorial anaplastic astrocytomas there were 4 subsets with five year survival estimates of 0.57, 0.49, 0.21, and 0.15. The DDGS fared no better. For instance, in DDGS grade 3 (any 2 DDGS criteria), those neuroglial tumors with nuclear atypia and endothelial prominence had a significantly better survival distribution than other possible pairs, and survival was not statistically different from those in DDGS grade 1 or DDGS grade 2 with endothelial prominence only. Thus DDGS grades do not provide unique survival information. WHO classification and DDGS grades are inconsistent: for example, half of infratentorial astrocytomas nos had DDGS grades of 3 and 4. Conclusions: Current classification schemes result in subsets of diagnoses and grades with drastically different survival expectation. To better evaluate tumor survival and treatment regimes, tumors must be separated using complete reliable histology in statistical models that recognize tumor patterns in a reproducible and unbiased manner. This system is available from Pediatric Dev. Pathol. 2000, 3:126–139.

BIO 23. INHIBITION OF RECEPTOR TYROSINE KINASES AND MAMMALIAN TARGET OF RAPAMYCIN OFFERS COMBINATORIAL BENEFIT IN TUMOR CONTROL

Ranjit K. Goudar, Mark D. Hjelmeland, Stephen T. Keir, Charles A. Conrad, Roger E. McLendon, Carol J. Wikstrand, Peter Traxler, Heidi A. Lane, David A. Reardon, Webster K. Cavenee, Xiao-Fan Wang, Darell D. Bigner, Henry S. Friedman, and Jeremy N. Rich; Division of Neurology and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

Pediatric malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a specific molecular target may slow tumor progression, but tumors are likely not dependent on a single gene product. Rather, gliomas exhibit sustained mitogenesis and cell growth mediated, in part, through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the ErbB family members and, at higher doses, the VEGF receptor 2 (KDR). RAD001 [everolimus] is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream ErbB/KDR receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared to single-agent therapy. In vitro experiments with glioma cultures showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 administered orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of the ErbB and mTOR pathways may offer increased benefit in glioma therapy.

BIO 24. BRAIN TUMORS IN CHILDREN WITH TUBEROUS SCLEROSIS COMPLEX—STUDY OF TUBERIN AND HAMARTIN EXPRESSION

Wieslawa.Grajkowska,1 Sergiusz.Jóźwiak,2 Katarzyna.Kotulska,3 Marcin.Roszkowski,4 and Danuta Perek5; 1Pathology Departament, The Children’s Memorial Health Institute, Warsaw; 2Neurology Department, The Children’s Memorial Health Institute, Warsaw; 3Neurology Department, Medical University of Silesia, Katowice; 4Neurosurgery Department, The Children’s Memorial Health Institute, Warsaw; 5Oncology Department, The Children’s Memorial Health Institute, Warsaw; Pathology Department, The Children’s Memorial Health Institute, Warsaw; Poland

Objectives: Subependymal giant cell astrocytomas (SEGAs) are rare, histologically benign brain tumors associated with tuberous sclerosis complex (TSC). Due to the production of hydrocephalus, they have usually poor prognosis. TSC is a neurocutaneus syndrome resulting from mutations in two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. The exact pathway of hamartomas and neoplasms formation in TSC is not known, but recent studies emphasize the common role of tuberin and hamartin in cell-cycle and cell-size regulation control. Aim: To elucidate the tuberin and hamartin expression in SEGAs. Materials and Methods: 10 specimens of SEGAs were analyzed using double-staining with specific anti-tuberin and/or anti-hamartin antibodies under confocal microscopy. The results were attributed to the genotype analysis performed earlier. Results: We found loss of hamartin immunolabeling in all specimens. Three SEGAs were immunolabeled for tuberin.. Interestingly, one of them was obtained from a patient with TSC2 mutation ascertained. Conclusions: These results support a relationship between TSC1 and TSC2 genes products as well as suggest that tuberin and hamartin may somehow reciprocally regulate their expression.

BIO 25. TELOMERE MAINTENANCE IN CHILDHOOD PRIMITIVE NEUROECTODERMAL BRAIN TUMORS

Michael Grotzer, Domenico Didiano, Doris Lang, and Tarek Shalaby; Department of Oncology, University Children’s Hospital of Zurich, Switzerland

Primitive neuroectodermal tumors (PNET), including medulloblastoma (PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain tumors of childhood. The stabilization of telomere lengths by telomerase activation is an important step in carcinogenesis and cell immortalization. Epigallocatechingallate (EGCG), the major polyphenol in green tea, is a telomerase inhibitor with antiproliferative and anticarcinogenic effects against different types of cancer. In this study, we used real time RT-PCR to measure the mRNA expression of the human telomerase reverse transcriptase (hTERT) in 50 primary PNET (43 PNET/MB, 7 sPNET), 14 normal human brain samples and 6 human PNET cell lines. Compared to normal human cerebellum, 38/50 (76%) primary PNET had [not greater-than]5x upregulated hTERT mRNA expression. While a positive correlation between hTERT mRNA expression and telomerase activity was detected in PNET cell lines, no correlation was found between telomerase activity and telomere length. Treatment of PNET cell lines with EGCG resulted in a dose-dependent inhibition of telomerase activity at μM levels. Although EGCG displayed strong proliferation inhibitory effects against TRAP-positive PNET cell lines, it had no significant effect against TRAP-negative D425 cells. In summary, these results provide evidence for a possible role of telomerase in the pathogenesis of most PNET and indicate that subsets of PNET maintain telomere length by alternative mechanisms. Inhibition of telomerase function represents a novel experimental therapeutic strategy in childhood PNET that warrants further investigation.

BIO 26. IGF-II IS A GROWTH FACTOR FOR MEDULLOBLASTOMA CELLS AND CEREBELLAR PROGENITOR CELLS

Wolfgang Hartmann,1 Otmar D. Wiestler,1 Karl Schilling,2 and Torsten Pietsch1; Departmentsof 1Neuropathology and 2Anatomy, University of Bonn, Germany

Medulloblastomas (MB) represent the most frequent malignant brain tumors of childhood. They develop from progenitor cells of the cerebellum. The insulin-like growth factor II (IGF-II) is an important fetal mitogen which is known to be involved in the molecular pathogenesis of various embryonal tumors. Its gene has four developmentally regulated promoter elements P1–P4, of which P2, P3, and P4 are regulated by genomic imprinting. To study the role of IGF-II in the pathogenesis of MB, we analysed the proliferation of murine cerebellar neural progenitor cells (P8) of the external granule cell layer as well as of medulloblastoma cells by 3H-thymidine incorporation assays. In addition, we determined the IGF2 mRNA expression and imprinting status in a series of 16 MB of classic histology and 10 MB of the desmoplastic subtype by quantitative RT-PCR. We identified IGF-II as a potent mitogen of cerebellar neural progenitor cells which acted synergistically with sonic hedgehog which is an essential growth factor of these cells. In human medulloblastoma cells, growth promoting activity of IGF-II was identified in 8 of 10 MB cell lines. This activity could be blocked in most cases by anti IGF-I-receptor antibodies. In both classic and desmoplastic MB IGF2, mRNA expression was detectable. Similar to other embryonal tumors, the IGF2 promoter P3 represented the predominant source of IGF2 transcripts. Interestingly, the activity of the promoters P3 and also P2 was significantly upregulated in MB of the desmoplastic subtype as compared to the classic subtype. This was not a result of alterations of imprinting since these occurred in both subtypes. These data suggest that IGF-II plays an important role in the proliferation control of cerebellar progenitors and medulloblastoma cells. This work was supported by the Deutsche Forschungsgemeinschaft (SFB400) and the BONFOR programme of the Medical Faculty of the University of Bonn.

BIO 27. OLIGOASTROCYTOMA/OLIGODENDROGLIOMA IN ASSOCIATION WITH DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET)

John A. Heath,1 Wai Hoe Ng,1 Wirginia Maixner,2 Chung Wo Chow,3 John Laidlaw,4 Michael Gonzales,5 and David M. Ashley1; Departments of Haematology and Oncology,1 Neurosurgery,2 and Pathology,3 Royal Children’s Hospital, Melbourne; Departments of Neurosurgery4 and Pathology,5 Royal Melbourne Hospital, Melbourne; Australia

Case 1: A young woman presented with right temporal headache and left arm numbness. MR brain imaging demonstrated a left frontal mass lesion. Craniotomy and subtotal excision was performed. Histopathological features were typical of simple DNET. Small oligodendroglia-like cells (synaptophysin positive processes) were seen forming a glioneuronal element and focally enclosing large neurons (NFP positive processes) within microcystic spaces. No glial nodules were identified. Nuclear staining for Ki-67 was not seen. Three years later, she represented with headache and an expressive dysphasia. MRI showed enlargement of the left frontal tumor (4x3x3cm) with areas of contrast enhancement. Sections of the debulked tumor again showed features of simple DNET. In addition a moderately hypercellular (WHO grade 2) oligoastrocytoma (synaptophysin negative) was present in the underlying white matter with infiltration of the DNET and adjacent cortex. Nuclear Ki-67 staining, not apparent in the DNET, was seen in 8% of nuclei. Case 2: A young man presented with a generalised tonic-clonic seizure. An EEG showed epileptiform activity and MRI a focal area of increased signal in the right antero-lateral aspect of the right temporal lobe. He underwent a craniotomy and resection of the anterior 4cm of the temporal lobe. Histopathology showed nodules with typical histological features of the glioneuronal element of DNET. The white matter was expanded by a moderately hypercellular (WHO grade 2) oligodendroglioma (synaptophysin negative). Ki-67 staining, not seen in nuclei in the cortical nodules of DNET, was seen in 6% of nuclei in the oligodendroglioma. LOH analysis (1p and 19q) will be presented. In both cases, the glial tumour was in excess of the nodular glial component frequently seen in complex DNET. These cases challenge present concepts about the biology of DNET. In particular, the occurrence of glioma and DNET together should be considered where complete tumor resection is not possible.

BIO 28. SB-431542, A SMALL MOLECULE TRANSFORMING GROWTH FACTOR-B-RECEPTOR ANTAGONIST, INHIBITS HUMAN GLIOMA CELL LINE PROLIFERATION AND MOTILITY

Mark Hjelmeland, Anita Hjelmeland, Sith Sathornsumetee, Michael H. Herbstreith, Nicholas J. Laping, Darell D. Bigner, Xiao-Fan Wang, and Jeremy N. Rich; Division of Neurology and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

Transforming growth factor-β (TGFβ) is a multifunctional cytokine that promotes tumor invasion, angiogenesis, and immunosuppression expressed in many pediatric central nervous system cancers. Antisense oligonucleotide suppression of TGFβ_ ligand expression has shown promise in preclinical and clinical studies of adult glioblastoma patients, but at least two ligands mediate the effects of TGFβ in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGFβ-receptor, on a panel of human malignant glioma cell lines, including pediatric glioma lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGFβ signaling, with decreased TGFβ-mediated transcription. Further, SB-431542 inhibited the expression of two critical effectors of TGFβ—vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGFβ-mediated morphological changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGFβ receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.

BIO 29. A COMPARISON OF GENOMIC PROFILES OF INFANT AND NONINFANT MEDULLOBLASTOMA BY ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION (CGH)

A. Huang, Ben Behesti, Maria Zielenska, Cynthia Hawkins, Eric Bouffet, Darren Hargrave, and Jeremy Squire; Pediatric Brain Tumor Program, Hospital for Sick Children, Toronto, ON, Canada

Medulloblastoma (MB) in very young children are associated with a higher incidence of metastatic disease and poorer outcome. It is unclear whether distinct genetic features of infant MB underlie these observations. Clearly, a better understanding of the genetic features of these tumours will be important for future advances in infant MB therapy. Genomic changes in MB associated with DNA gain or loss has been well documented by many conventional cytogenetic and comparative genomic hybridization (CGH) studies which have included varying number of infant MB. We undertook a pilot study to compare the genomic profiles of infant MB to MB presenting in older children by array based CGH (A-CGH). 13 tumours were analysed: 5 infant tumours diagnosed at less than or equal to 3 years of age and 7 MB diagnosed at greater than 3 years of age were compared. DNA isolated from frozen and paraffin-embedded tissue were hybridized to commercial genomic arrays (Human BAC array, Spectral Genomics, USA) containing 1000 or 2000 nonoverlapping genomic clones that provide an average 2–4 MB genome wide resolution for detecting DNA copy number imbalances. A-CGH detected copy number gains at chr 5p15: a region encompassing the hTERT gene, at chr 8q24.2 associated with c-myc oncogene amplification, 1p36.33, 7p22.3, 7q31.2, 9q34.3, and 12p13.32. Infant and noninfant tumours generally showed similar changes but differed in the frequency and type of imbalances on chr 10 and 17. Infant MB had a higher frequency of chr 10 loss; a profile consistent with isochromosome 17 was seen in all non-infant and only 2/7 infant MB. Two amplicons at chr 12q21-22 and 14q11.2 were seen in the majority of noninfant MB and were absent in the infant tumours. Validation of these observations in future studies with larger numbers of tumours will be important.

BIO 30. INHIBITION OF PROTEIN KINASE C ACTIVITY AND INSULIN-LIKE GROWTH FACTOR II EXPRESSION ASSOCIATED WITH TAMOXIFEN MODULATION OF ETOPOSIDE CYTOTOXICITY IN BRAIN TUMOR CELLS

Ziad Khatib,1 Cheppail Ramachandran,2 Athena Pefkarou,1 John Fort,1 Hugo B. Fonseca,1 Steven J. Melnick,3 and Enrique Escalon1; 1Division of Hematology/Oncology, 2Research Institute, 3Department of Pathology, Miami Children’s Hospital, Miami, FL, USA

Tamoxifen, a nonsteroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. Tamoxifen (10 μM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), 47.5- and 40-fold in two primary medulloblastoma cell lines (MCH-BT-31 and MCH-BT-39), 6- and 2.7-fold in two primary ependymoma cell lines (MCH-BT-30 and MCH-BT-52) established from pediatric patients. CalcuSyn analysis of cytotoxicity data showed that combination of tamoxifen and etoposide was synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen as a single agent is also cytotoxic at higher concentrations (>20 μM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein, insulin-like growth factor I receptor (IGF-1R), IGF-1, IGF-II, and estrogen receptor (ER) as well as protein kinase C (PKC) activity. While P-glycoprotein, IGF-IR, and IGF-1 were not affected, enhanced inhibition of PKC and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with single agents alone. Tamoxifen at 10 μM when combined with etoposide at 0–100 μM reduced PKC activity 77% compared to only 58% with etoposide alone. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II. This work was supported by seed grant funds from Miami Children’s Hospital Foundation.

BIO 31. FAVORABLE BIOLOGY NEUROBLASTOMA (NB): LEPTOMENINGEAL METASTASES REMAINING STABLE IN A CHILD WITHOUT CHEMORADIOTHERAPY

Kim Kramer,1 Brian H. Kushner,1 Jeffrey C. Allen,2 George Krol,3 and Nai-Kong V. Cheung1; Department of Pediatrics1 and Neuroradiology,3 Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY; Department of Neurology,2 Beth Israel Medical Center, New York, NY; USA

Background: Intrinsic tumor biological features are critical prognosticators of survival of NB. Patients with localized neuroblastoma and favorable biological parameters may be observed without treatment. Conversely, leptomeningeal metastases in patients with primary extracranial neuroblastoma is highly unusual and despite aggressive multi-modality therapies, invariably fatal. Methods: We present the case of a 7-month-old infant who presented with acute paraplegia; MRI revealed an extensive, multi-level epidural mass (T12-L4) causing compression of the conus and cauda equina with intradural, leptomeningeal extension. Results: The patient underwent emergent spinal cord decompression and subsequent surgical resection of the adrenal tumor. The primary tumor revealed favorable biology (favorable Shimada classification, single copy MYCN, low serum lactate dehydrogenase, and favorable VMA/HVA ratio). Metastatic work-up was unrevealing except for MRI evidence of abnormal nodular foci of intradural enhancement coating the conus medullaris and cauda equina suspicious for subarachnoid disease . An 18-fluoro-deoxyglucose (FDG) positron emission tomography scan was compatible with NB in the abdomen; longitudinal linear tracer uptake was also noted in the lower thoracic and lumbar region. Conclusion: Some infants with favorable biology neuroblastoma may be observed without treatment despite the advanced INSS stage.

BIO 32. MONOCLONAL ANTIBODIES (MABS) AGAINST SOMATOSTATIN RECEPTOR 2A (SSTR2A) AS POTENTIAL MEDULLOBLASTOMA THERAPEUTIC REAGENTS

Chien-Tsun Kuan, Carol J. Wikstrand, T. Shelley Davis, Michael R. Zalutsky, and Darell D. Bigner; Department of Pathology, Duke University Medical Center, Durham, NC, USA

SSTR2A, a G protein-coupled molecule, is overexpressed in virtually all medulloblastomas (MED) as investigated by RT-PCR and localization to the cell surface (CS) by FACS analysis. As only low levels of synthetic ligand octreotide uptake via internalization are observed, the use of immune reagents to SSTR2A for therapy has been proposed. Characterized by 7 transmembrane domains, SSTR2A presents an initial extracellular domain (ECD) of 43 amino acids, a 12-mer of which has been shown to be specifically immunogenic in rabbits. We isolated MAbs to the 12-mer 33QTEPYYDLT- SNA43-KLH as well as the SSTR2A amino terminal (amino acids 1–47) (ECD)-GST fusion protein, screened by FMAT analysis on D341 and D283 MED cells, and demonstrated specific binding by Western blot and homogeneous CS binding, indicating 100% of the cells express CS epitope. Following iodination, four MAbs (all IgG2a) were tested for immunoreactive fraction (IRF), KA determination (BIAcore analysis vs. immunizing peptide; Scatchard analysis vs. D341 MED cells), and internalization by MED cells. Four MAbs [IRF values 50–94%], exhibited a range of KAs vs. intact cells (0.32–1.0 x 108 M−1). and similar KAs vs. peptide (1.7–2.4 x 107 M−1Following binding of 125I-MAbs to D341 MED at 4oC, measurement of intracellular, CS, and released 125I at time points after warming to 37°C revealed little or no internalization of the 125I-MAb-receptor, consistent with previous studies performed in the absence of ligand. All MAbs exhibited long-term CS binding (50–90% at 2 hours, 50–62% at 24 hours) indicating stable CS binding over time at 37°C. All four MAbs estimate 1–4 x 105/D341 MED cell CS receptors by Scatchard and QFACs analyses, a level exceeding that required for targeting. Affinity maturation of these MAbs and isolation of higher affinity reagents by MAb generation or phage display are being pursued for development of therapeutic moieties.

BIO 33. NT-3 MEDIATED SIGNALING PATHWAYS IN DAOY MEDULLOBLASTOMA CELLS

Doris Lang, Ratnakar Patti, Johannes Schulte, Alexander Schramm, Tarek Shalaby, Peter C. Phillips, Angelika Eggert, and Michael A. Grotzer; Department of Oncology, University Children’s Hospital of Zurich, Switzerland

High expression of the neurotrophin-receptor TrkC is associated with a favorable survival outcome in childhood medulloblastoma (MB). However, NT-3/TrkC activated signaling pathways in MB are not well understood. To determine the gene expression programs resulting in MB cells overexpressing TrkC, we transfected the human MB cell line DAOY with the TrkC cDNA or an empty vector (EV) control. Gene expression profiles were then obtained from DAOY, DAOY-TrkC, and DAOY-EV treated with the TrkC specific ligand NT-3 in a time course of 0 hours to 24 hours using Affymetrix HGU95Av2 oligonucleotide microarrays screening a total of about 12600 genes. Upon NT-3 activation of DAOY-TrkC cells, a total of 157 genes were dynamically regulated. These results were validated using quantitative RT-PCR. The majority of the NT-3/TrkC regulated genes is involved in signal transduction, cell proliferation, transcription, and cell cycle mechanisms, but also in cell death/apoptosis. Some of the new target genes of TrkC receptors identified, include bradykinin receptor B2 (BDKRB2), prostaglandin-endoperoxide synthase 2 (PTGS2/Cox2), DNA topoisomerase 2A (TOP2A), hyaluronan-mediated motility receptor (HMMR), EZRIN (Villin 2), tumor-suppressing subchromosomal transferable fragment cDNA3 (TSSC3/IPL), solute carrier family 20 member 1 (SLC20A1), and cysteine-rich angiogenic inducer 61 (CYR61). The expression pattern of these genes was also determined in 55 primary MB samples (grouped as MB with high TrkC and high NT-3 vs. MB with low TrkC and/or low NT-3) and mainly correlated with our microarray data. These new findings may contribute to a better understanding of the effects of TrkC signaling in medulloblastoma and may point toward potential therapeutic targets for this common childhood brain tumor.

BIO 34. SPECIES SPECIFIC UROKINASE RECEPTOR LIGANDS REDUCE GLIOMA GROWTH AND INCREASE SURVIVAL PRIMARILY BY AN ANTI-ANGIOGENESIS MECHANISM

Walter E. Laug, Xingyao Bu, Vazgen Khankaldyyan, Ignacio Gonzales-Gomez, Susan Groshen, Wei Ye, Shaoqiu Zhuo, Jaume Pons, Jennifer R. Stratton, and Steven Rosenberg; Department of Hematology-Oncology and Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, CA; Chiron Corporation, Emeryville, CA; USA

The urokinase type plasminogen activator (uPA) system is highly expressed in brain cancers and implicated in tumor progression. We investigated the effect of pegylated mouse (m) and human (h) specific peptides (PEG-uPA 1–48) of the amino-terminal region of uPA on brain tumor growth. Human glioma cells were injected into the forebrains of nude mice, and the peptides were given SC twice weekly after tumor establishment. All control animals died within 70 days. The h peptide showed a slight survival increase (p = 0.019). 70% of the mice receiving the m peptide alone (p = 0.009) and 80% of the mice given both peptides (p = 0.002) survived over 140 days. Similar data were obtained with the PNET cell line DAOY. Tumor sizes were significantly smaller in animals treated with either m or combined peptides (p < 0.001) or h peptide (p = 0.006) than in the control animals (5.3 mm). The mean vascular density and the Ki-67 index were significantly smaller and the apoptotic index higher in all treatment groups when compared to the control animals, and the m and combo treatment groups had large areas of collagen deposition. Vascular tube formation by brain capillary cells in vitro was significantly suppressed in a species-specific manner. While adhesion to vitronectin of tumor and vascular cells was not affected, both peptides inhibited migration of these cells on a vitronectin gradient. Our data demonstrate that these catalytically inactive uPAR ligands suppress glioma growth and increase survival primarily by anti-angiogenic mechanisms and may prove useful as adjuvant treatment for brain tumors.

BIO 35. POSTTRANSCRIPTIONAL SILENCING OF GENES INVOLVED IN THE DEVELOPMENT OF MEDULLOBLASTOMA

Michael J. Lawman , Selena C. Braccili, Cameron K. Tebbi, Blake D. Singletary, Christina M. Lozano, and Joseph Horvath; Division of Pediatric Hematology/Oncology, St. Joseph’s Children’s Hospital of Tampa and Department of Immunology and Medical Microbiology, College of Medicine, University of South Florida, Tampa, FL, USA

Medulloblastoma is the most common malignancy of the cerebellum in children. Published evidence suggests that this condition is the result of deregulation of gene(s) involved in embryonic development. Genes within the hedgehog (Hh) pathway, namely, sonic hedgehog (shh), smoothen (smo), patched (ptch) and the transcription factor family, gli, have all been implicated. The aim of this study was to evaluate RNA interference (RNAi) technology as a method to determine the significance of hh gene(s) in the development of medulloblastoma and ultimately to utilize this technology as a means to control the disease. The RNAi studies reported here involved both small interfering RNA (siRNA) and short hairpin RNA (shRNA). In order to investigate the use of RNAi to disrupt the Hh pathway in the cell lines, DAOY and D283, two potential RNAi targets were chosen, shh and gli1. Actin and GADPH were used as positive controls. In vitro transcription was utilized to synthesize probes for all four genes and the probes nonisotopically labeled, post synthesis, with Psoralen-Biotin. Using Northern blot analysis, these labeled probes were used to measure the levels of mRNA in untreated and siRNA- or shRNA-treated cells. Based upon the predicted sequence, the siRNA and shRNA were designed to contain a 19-nucleotide sequence with a 3’ UU di-nucleotide overhang. Three RNAi sequences per target gene were designed. For each gene in the study, a RNAi containing a “scrambled” sequence was used as a negative control. To analyze the expression of the targeted genes and other neurogenic markers following RNAi treatment, Western blot and/or flow cytometry analysis was used. The alteration of mRNA levels of the RNAi-targeted genes and in protein expression in these cell lines, in conjunction with changes in the growth characteristics, will be discussed relative to the implications that this technology may have as an innovative treatment protocol.

BIO 36. A NOVEL AND RAPID APPROACH TO PROTEIN EXPRESSION PROFILING OF CEREBROSPINAL FLUID (CSF) FROM MEDULLOBLASTOMA PATIENTS USING FUNCTIONALIZIED MAGNETIC BEADS, ANCHORCHIPTM TECHNOLOGY, MALDI-TOF AND MALDI-TOF/TOF MASS SPECTROMETRY

S.-M. Leung,* M. Sheldon,# and C. C. Lau#; *Bruker Daltonics Inc., Billerica, MA; #Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX; USA

Medulloblastoma is the most common malignant brain tumor in children. While the prognosis has improved considerably, leptomeningeal spread of the tumor remains a significantly negative predictor of survival. CSF cytology has been used as part of the routine workup for metastatic disease, but the sensitivity and specificity is suboptimal. Recently we have observed that mitochondrial DNA mutation in cell-free CSF of medulloblastoma patients can be a potential marker for disease monitoring and relapse (1). Here we describe the generation and analysis of protein profiles of CSF from medulloblastoma patients to monitor treatment response and disease progression. Five to ten microliters of CSF taken from patients at various times during their diagnostic workup and treatment was added to magnetic beads with different functionalities (hydrophobic, ionic, metal chelating). After binding and washing, the eluted proteins and peptides were deposited on the AnchorChipTM targets for Matrix Assisted Laser Desorption Ionization Time-Of-Flight (MALDI-TOF) analysis. A comparison map showing the changes in the protein profiles between, before, and after treatment were done using ClinProTools software. The biomarker candidates can then be identified using MALDI-TOF/TOF for MS/MS analysis. Because it only takes 6 to 8 hours from sample preparation to data analysis, this new and rapid approach allows rapid screening and evaluation of protein profiles of CSF, thus aiding in the identification of relevant biomarkers and the subsequent development of diagnostic assays for monitoring disease progression and treatment response.. (1) L-JC Wong, M Lueth, X-N Li, CC Lau, and H Vogel. (2003) Cancer Research 63:3866–71.

BIO 37. ANTI-MEDULLOBLASTOMA EFFECTS OF VALPROIC ACID AS A HISTONE DEACETYLASE INHIBITOR

Xiao-Nan Li, Qin Shu, Jack Men-Feng Su, Laszlo Perlaky, and Ching C. Lau; Laboratory of Molecular Neurooncology, Cancer Genomics Program, Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

The anti-tumor effects of VPA, a well-established anti-epilepsy drug with histone deacetylase (HDAC) inhibiting activity, were investigated in two medulloblastoma cell lines (D283-MED, DAOY) as compared with one supratentorial primitive neuroectodermal (sPNET) cell line (PFSK) by various in vitro and in vivo assays. In all three cell lines, VPA (0.6 mM to 5.1 mM) inhibited cell proliferation in a time- and dose-dependent manner, and produced irreversible suppression of cell growth upon extended treatment with clinically achievable doses (0.6 mM for 28 days). The colony forming ability in soft agar was suppressed by 1.0 mM VPA and almost completely eliminated by 2.7 mM VPA in D283-MED and PFSK cells after 7 days of treatment. In D283-MED and DAOY cells, VPA (1.0 mM and 2.7 mM) arrested cells in G1/G0 phase, promoted apoptosis, and induced expression of glial marker GFAP and neuronal marker synaptophysin (SYN). In PFSK, however, higher dose and/or longer exposure time is required to produce similar effects. The anti-tumor effects of VPA were found to be associated with increased accumulation of hyperacetylated histones H3 and H4, of which the more prominent increase is correlated with the more responsive DAOY and D283-MED cells. Treatment of DAOY cells grown s.c. in SCID mice with VPA (400 mg/kg, daily i.p. for 28 days) resulted in significant growth suppression of the xenografts (P < 0.001), increased expression of GFAP and SYN, and elevated apoptotic cells. In conclusion, our data demonstrated that VPA, through inhibiting HDACs, has potent anti-medulloblastoma effects by inhibiting cell proliferation, promoting apoptosis, and inducing cell differentiation. These results suggest that further preclinical studies to establish the role of VPA as a novel anti-medulloblastoma agent is indicated.

BIO 38. CORRELATION OF ENDOSCOPIC BIOPSY AND TUMOR MARKERS IN PATIENTS WITH PRIMARY INTRACRANIAL GERM CELL TUMORS

Neal Luther, Erika Mark, Ira J. Dunkel, and Mark M. Souweidane; Department of Neurological Surgery, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Primary intracranial germ cell tumors (GCTs) occur most frequently in children and adolescents. Given the predominant midline, intraventricular location of these tumors and the frequent need for concomitantly treating hydrocephalus with endoscopic third ventriculostomy, patients with intracranial GCTs serve as logical candidates for endoscopic tumor biopsy. A minimally invasive technique for tumor sampling is further supported by the high response rates of GCTs using nonsurgical therapy. Numerous studies, including reports from our experience, have established endoscopic biopsy of intra-ventricular brain tumors as an acceptable method for tumor sampling. However, the small sample size obtained using endoscopic techniques coupled with the frequency of mixed tumor histology within a single GCT raises the possibility of misrepresentative tumor sampling. A retrospective analysis was performed of ten patients (eight males, mean age 16) treated for intracranial GCTs to determine the correlation between endoscopic biopsy results and biochemistry of serum and cerebrospinal fluid (CSF). The presence of raised α-fetoprotein (AFP) and human chorionic gonadotropin (β-HCG) has served as a reliable method for determining that GCTs have malignant components. Our criteria for tumor marker measurements diagnostic of a malignant, secreting tumor were a serum or CSF AFP value greater than 9 ng/ml or β-HCG measurement greater than 50 U/L. Nine patients had tumor marker values below our threshold for secreting tumors; six of these patients had endoscopic biopsy results of germinoma, and one showed only gliosis. One sample disintegrated during processing, while another was misinterpreted as astrocytoma (tissue from open resection revealed teratoma). One patient had increased AFP, and in this case endoscopic biopsy diagnosed a yolk sac tumor. In total, all endoscopic biopsies of GCTs correlated with patient tumor marker status. In our series, endoscopic biopsy was highly correlated with biochemical tumor markers, thus supporting the reliability of neuroendoscopic tumor sampling for GCTs.

BIO 39. ENDOTHELIAL APOPTOSIS INDUCED BY ALPHA-V-INTEGRIN INHIBITION REQUIRES GENERATION OF CERAMIDE

Melissa Millard, Linda B. Tran, Orla, T. Cox, and Anat Erdreich-Epstein

Angiogenesis, formation of new capillary blood vessels, is critical for cancer growth. The cell surface receptors, integrins αvβ3 and αvβ5 are critical in angiogenesis. RGDfV (AKA Cilengitide), a function-blocking peptide that blocks integrins αvβ3/αvβ5, has completed phase I trials in adults with recurrent gliomas and is in phase I trial in pediatrics. The molecular mechanism of action of integrin αvβ3/αvβ5 inhibition is poorly understood. We have shown that inhibition of endothelial integrins αvβ3/αvβ5 increases ceramide, a pro-apoptotic lipid second messenger (Erdreich-Epstein et al., Cancer Research 2000). To examine whether this ceramide increase is required for endothelial apoptosis, we seeded human brain microvascular endothelial cells (HBMEC) on vitronectin and induced apoptosis with RGDfV (25 μg/ml). Treatment of [3H] palmiticacid labeled HBMEC with RGDfV with/without myriocin (1–50 nM) or fumonisin B1 (25 μM), inhibitors of de novo ceramide synthesis, or desipramine (10 μM), an inhibitor of acid sphingomyelinase (ASMase), suppressed the ceramide increase. De novo inhibitors suppressed both baseline and RGDfV-induced ceramide but left the difference between ceramide in presence/absence of RGDfV unchanged. Desipramine only suppressed the RGDfV-induced ceramide increase but not baseline ceramide. This suggests presence of at least two pools of intracellular ceramide, only one of which is regulated by integrin binding. Furthermore, sphingomyelin was decreased by RGDfV in [3H] palmitic-acid pretreated HBMEC, supporting the role of SMase(s) in the ceramide increase. And most importantly, desipramine and imipramine (5–20 μM), and another ASMase inhibitor, SR33557 (1–10 μM), but not myriocin or fumonisin, effectively suppressed RGDfV-induced apoptosis (25–90%), suggesting that ASMase activation by RGDfV and the resultant ceramide increase are necessary for endothelial apoptosis. These data suggest for the first time a causal role for ASMase-generated ceramide in mediating endothelial apoptosis induced by inhibition of integrins αvβ3/αvβ5. This will allow rational design of combination therapy using RGDfV in anti-angiogenic treatment of brain tumors.

BIO 40. DETECTION OF JC VIRUS DNA SEQUENCES IN PEDIATRIC BRAIN TUMORS

Toshihiro Mineta, Hiroaki Okamoto, Shigeo Ueda, Yukiko Nakahara, Tetsuya Shiraishi, Takashi Tamiya, and Kazuo Tabuchi; Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan

Object: JC virus (JCV) is a human neurotropic polyomavirus that causes progressive multifocal leukoencephalopathy and is closely related to simian virus 40. Several recent reports have indicated a possible association between JCV and the development of various human brain tumors. We examined the presence of JCV deoxyribonucleic acid (DNA) sequences in primary pediatric brain tumors to elucidate the possibility that certain pediatric brain tumors can arise through infections with JCV. Methods: Genomic DNA sequences were isolated from 62 pediatric brain tumors (32 medulloblastomas, 18 ependymomas, 5 choroid plexus papillomas, and 7 pilocytic astrocytomas) and analyzed for the presence of JCV DNA by Southern blot hybridization and direct sequencing. JCV DNA was detected in 5 ependymomas and one choroid plexus papilloma. Immunohistochemical studies revealed nuclear expression of the large T-antigen in a choroid plexus papilloma. However, none of the medulloblastomas or pilocytic astrocytomas contained JCV DNA. Conclusions: These results provide molecular evidence of the association between JCV and the development of certain ependymomas and choroid plexus papillomas in contrast to medulloblastomas and pilocytic astrocytomas

BIO 41. GLIA MATURATION FACTOR BETA (GMFβ), A MEMBER OF THE COFILIN-ACTIN DEPOLYMERIZING FACTOR SUPERFAMILY, PROMOTES PROCESS OUTGROWTH AND IS DIFFERENTIALLY PHOSPHORYLATED DURING CNS DEVELOPMENT AND GLIOMA PROGRESSION

Christy Murdock, Priti Baijal, Shunzhen Zhang, Tao Fan, and David D. Eisenstat; Manitoba Institute of Cell Biology and Departments of Pediatrics and Child Health, Human Anatomy and Cell Science, and Physiology, University of Manitoba, Winnipeg, MB, Canada

Malignant gliomas respond poorly to combined modality therapy, including surgery, radiation and chemotherapy. Response to therapy fails, in part, due to infiltration of tumor cells into peritumoral white matter. There is considerable interest in unraveling the intrinsic and extrinsic factors affecting glioma invasion, including regulation of the peripheral actin cytoskeleton. Glia maturation factor beta (GMFβ) was initially described as a factor promoting process extension and reduced cell proliferation in primary glioblastoma multiforme (GBM) cultures. GMFβ is a 141 amino acid 17 kD protein with significant homology to actin depolymerizing factors (ADFs) that affect cell shape through direct regulation of actin filament polymerization. ADFs exist in active (dephosphorylated) and inactive (phosphorylated) forms. Adult (differentiated) brain and low-grade gliomas (7/9) express both forms of GMFβ, whereas the active dephosphorylated form is the predominant band found in embryonic brain and high-grade gliomas (16/22 AA and GBM). The upper, phosphorylated band of GMFβ is extinguished following treatment with phosphatases. In primary culture, GMFβ is expressed in astrocytic processes and the axonal compartment of neurons. The cytoplasmic localization of GMFβ is confirmed by the transfection of green fluorescent protein (GFP) constructs. Deletion of the putative C-terminal actin-binding domain of GMFβ does not affect subcellular localization but abrogates process extension in glial and neuronal tumor cell lines. After treatment of U87 malignant glioma cells with cytochalasin D to disrupt the actin cytoskeleton, GMFβ and actin colocalize within the cytoplasmic compartment. Coimmunoprecipitation experiments confirm the GMFβ and actin form protein-protein complexes in vivo. Our results show that GMFβ is an actin-binding protein that promotes process outgrowth through its interaction with the peripheral actin cytoskeleton. Determining the role of GMFβ during CNS development may contribute to our understanding of its role during astrocytoma progression and invasion and towards novel biological approaches directed against these malignancies.

BIO 42. ANALYSIS OF GENOME-WIDE COPY NUMBER PROFILES OF MEDULLOBLASTOMAS USING ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION

Yukiko Nakahara, Tetsuya Shiraishi, Toshihiro Mineta, Hiroaki Okamoto, and Kazuo Tabuchi; Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan

Introduction: Array-based comparative genomic hybridization (array-CGH) is a novel genomic analysis technology that allows high throughput screening for abnormal gene amplifications and deletions with the sensitivity to detect single gene copy change in a tumor genome. We studied genomic changes in medulloblastomas using array-CGH technology and analyzed possible association of genomic changes with the sensitivity of adjuvant therapies. Materials and Methods: DNA was extracted from each frozen medulloblastoma tissues from 8 patients. DNAs of tumor and reference control were labeled with Cy3 and Cy5. We performed hybridization using commercially available genomic DNA microarray slide, GenoSensor ArrayTM 300 (Vysis Inc). It contained 287 clones including telomeres, oncogenes, and tumor suppressor genes. After hybridization, arrays were analyzed by the GenoSensor Reader System (Vysis Inc). Result: The copy number gains were observed on MSH2, CDK6, TIF1, THRA, and TK1 (3/8 cases). The copy number losses were detected on CTSB, FGFR1, MYC, HRAS, HIC1, FLI, and PDGFB (3/8 cases). Our results show that the sensitive group has a tendency to include chromosomal gains or losses. The copy number gains were detected at chromosome 7, 17q, and copy number losses were observed on chromosome 6,8,10q,11,17p in the sensitive group. Conclusion: Array-CGH is a useful tool for the identification of genetic changes of brain tumors and potential genetic markers to correlate with the sensitivity of adjuvant therapy for patients with medulloblastoma.

BIO 43. VARIABILITY OF CONSTITUTIVE HETEROCHROMATIN OF CHROMOSOMES 1, 9 AND 16 IN 57 CHILDREN WITH SOLID TUMORS AND 64 CONTROLS

Melita Nakić, Iskra Petković, Mladen Čepulić, and Ante Čižmić; University Children’s Hospital Zagreb, Zagreb, Croatia

Several studies point to an association of variable heterochromatic segments of chromosomes 1, 9, and 16 and malignant diseases. Investigations carried out so far have mostly dealt with populations of adult patients, whereas studies in children with solid tumours are rare. In this study, variability of constitutive heterochromatin of chromosome 1, 9, and 16 was analysed in 57 children with solid tumors (of those 20 with neuroblastoma and 19 with nephroblastoma) and in 64 healthy controls. The aim of this investigation was to determine the correlations between the quantitative changes and the changes in the distribution of constitutive heterochromatin and the malignant process in children. The analysis was carried out on slides obtained by routine method of peripheral blood culture and stained for C-banding. The quantitative variability of constitutive heterochromatin of chromosome 1, 9, and 16 was determined by objective method of linear measuring. C-segment length was expressed in relative units as a relation of the C-band length and the length of the short arm of chromosome 16. Significant differences between two groups were found in C-band size of chromosome 1, 9, and 16, but no difference in inversion frequency was, however, observed. This data might indicate a possible relationship between the amount of constitutive heterochromatin on chromosome 1, 9, and 16 and malignant transformation in children with solid tumors. This investigation established quantitative differences and difference in frequency of localization variants between specific histologic types of tumor. The analysis revealed significantly higher amount of C-heterochromatin on chromosome 9, and increased frequency of C-segment inversions in the group of 20 children with neuroblastoma as compared to 19 children with nefroblastoma. Additional study are, however, necessary in order to substantiate these preliminary results.

BIO 44. NEUROFIBROMATOSIS 3: A REPORT OF PATIENTS MEETING DIAGNOSTIC CRITERIA FOR BOTH NEUROFIBROMATOSIS 1 AND 2

Bryan C. Oh, Mark D. Krieger, David I. Sandberg, Jonathan Finlay, and J. Gordon McComb; Divisions of Neurosurgery and Neuro-Oncology, Children’s Hospital Los Angeles, Keck School of Medicine/University of Southern California, Los Angeles, CA, USA

Neurofibromatosis (NF) has been classified into two distinct types: NF1 and NF2. Both NF1 and NF2 have well-established diagnostic criteria. However, there have been no reports in the literature of patients meeting diagnostic criteria for both NF1 and NF2. We conducted a retrospective review of patients diagnosed with either NF1 or NF2 from 1993 to 2003. In all, 17 patients were studied. Of these patients, three met diagnostic criteria for both NF1 and NF2. There were 17 patients (9 males and 8 females) in our study population. Eleven patients met diagnostic criteria for NF1 only. Three of these patients had a positive family history of NF1. Three patients met the criteria for a diagnosis of NF2 only. One of these patients had a positive family history for NF2. Of note, 2 of these 3 patients also had peripheral neurofibromas. While they failed to meet strict NF1 diagnostic criteria, they nonetheless had physical findings consistent with NF1. One female and two males met diagnostic criteria for both NF1 and NF2. The female patient and one of the male patients had bilateral vestibular schwannomas, numerous café au lait spots, and peripheral neurofibromas. Her sister also had NF2. The other male patients had bilateral vestibular schwannomas, multiple peripheral neurofibromas, and marked scoliosis. NF is an extremely variable disorder. As it has been well described, NF ranges from extremely mild cases that present in adulthood to severe cases in which serious complications may develop. In our study, we present evidence that the traditional classification scheme of NF1 and NF2 may miss a group of patients who meet diagnostic criteria for both disease processes. We propose that these patients be given the diagnosis of NF3. Performing direct gene testing on these patients may be helpful in better understanding the neurofibromatoses.

BIO 45. GLUTATHIONE S-TRANSFERASE (GST) POLYMORPHISMS AND OUTCOMES IN CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDHOOD AND ADOLESCENTS

M. Fatih Okcu, Qin Shu, Xiao-Nan Li, Bogdan Dinu, Laszlo Perlaky, Melissa Bondy, Dawna L. Armstrong, Adesina Adekunle, Meenakshi B. Bhattacharjee, Robert C. Dauser, Murali Chintagumpala, Susan Blaney, and Ching Lau; Texas Children’s Cancer Center, Departments of Pediatrics, Hematology-Oncology, Neurosurgery, and Pathology, Baylor College of Medicine, Houston, TX, USA

Background: CNS tumors are the most common solid tumors of childhood. With current therapy approximately 50% of children and adolescents with brain tumors are cured. At the time of diagnosis it is impossible to predict in advance which patients will benefit from therapy and which patients will experience significant toxicity. The GST family of enzymes is responsible for clearance of chemotherapy agents including alkylating agents and platinum compounds used in brain tumor treatment. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in response to cancer treatment, hence determining the outcome for survival and toxicity. Methods: We conducted polymerase chain reaction (PCR) for GSTM1 and GSTT1 polymorphisms to investigate the relationship between GST genetic variations and survival in 45 patients with medulloblastoma. Results were analyzed for overall survival (OS) by Kaplan-Meier and Cox-proportional hazard analyses adjusting for age and risk group at diagnosis, and ethnicity. Results: Patients with the GSTM1 null genotype had significantly shorter survival compared to patients with GSTM1 nonnull (3-year OS 52% vs. 87%; p < 0.05). We observed a much higher rate of GSTT1 null genotype (31%) compared with the published frequency of this genotype in normal populations values (15–25%), possibly due to the high frequency of GSTT1 null genotype in the African American patients (83% n = 5/6). Conclusions: These results indicate that GSTM1 polymorphisms may be a potential prognostic factor in children and adolescents with medulloblastoma. The GSTT1 genotype may be a risk factor for development of medulloblastoma in the AA children. GSTM1, GSTT1, and GSTP1 genotyping is still ongoing in the remaining 30 medulloblastoma and 60 glioma patients. Updated results will be presented for survival and toxicity outcome.

BIO 46. CLINICAL AND GENETIC STUDIES OF MEDULLOBLASTOMA WITH EXTENSIVE NODULARITY (NMB) IN PATIENTS WITH AND WITHOUT GORLIN’S SYNDROME

Torsten Pietsch,1 Alessandro Raso,2 Valeria Capra,2 Hendrik Brune,1 Arent Koch,1 Ulrik Milde,1 Armando Cama,3 Claudio Gambini,4 Massimo Brisigotti,5 Paolo Nozza,4 Felice Giangaspero,6 Riccardo Occella,7 Claudia Milanaccio,8 Andra Rossi,9 Gianluca Piatelli,3 Marcello Ravegnani,3 Giorgio Perilongo,7 and Maria Luisa Garrè8; Department of Neuropathology, University of Bonn, Germany1; Department of Pathology, Brescia Hospital, Brescia, Italy5; Neuropathology, Regina Elena, Rome, Italy6; Pediatric Oncology, University of Padua, Italy7; Department of Neuroradiology,9 Department of Neurosurgery,3 Neuro-Oncology,8 and Pathology,4 Giannina Gaslini Children’s Hospital, Genoa, Italy

Genetic characterization of medulloblastomas (MB) has provided evidence of different genetic variants of MB overlapping with well characterized pathological MB entities (NMB, desmoplastic MB [DMB], classic MB [CMB]). NMB has been recently more extensively defined in its clinico-pathological features. In this study we wanted to focus on the involvement of alterations of the Sonic hedgehog/patched pathway in NMB as compared to DMB and CMB. A total of 10 cases of NMB were diagnosed at G. Gaslini Children’s Hospital in the period 1992–2002 (7M, 3F, median age 18 months). All cases are long-term survivors. Two presented with characteristics of Gorlin’s syndrome (GS). All cases reviewed by a pathologists’ panel displayed a similar morphological and immunohistochemical pattern consistent with NMB. In 7/10 cases frozen tissue was available. Genetic study included SSCP analysis of the coding exons of PTCH1 (exons 2– 23). Quantitative RT-PCR for the specific hedgehog target genes GLI-1 and SOX18 was performed both in 7 NMB and in cases of DMB and CMB. SSCP analysis of PTCH1 gene in 7 cases of NMB showed altered migration pattern in 6/7 NMB cases. Sequencing of the fragments uncovered the presence of DNA polymorphisms in exons 2, 22, and 23. In addition, one case of a GS patient with NMB presented a SNP at exon 23 and a 4 bp deletion in exon 2, which was present in the peripheral blood and in the tumor. The second (wt) allele was obviously lost in the NMB, indicating that there was no functional PTCH1 copy present in the tumor (LOH). Quantitative RT-PCR studies showed high GLI-1 mRNA levels as a sign of an activated sonic hedgehog/patched pathway in both, NMB and DMB but not in CMB. We compared the levels of NMB (6 cases) with CMB (12 cases) and DMB (10 cases). Using t-test, 2 sided, p-values were CMB vs. NMB, p = 0.007; DMB vs. NMB p = 0.251 (n.s.). Similarly, the novel SOX18 target gene of SHH was found overexpressed in NMB. This indicates that NMB and DMB are similar in their patched signalling and that they differ from classic MB in their activation status. However, genetic and clinico-pathological features suggest that NMB and DMB could carry different additional genetic alterations and that the patched pathway may be activated at an earlier stage in NMB. This information would be consistent with the high frequency of NMB in early infancy and its peculiar biological features (better prognosis). Our data did not show obvious clinical or genetic differences between NMB associated with GS and sporadic NMB. More data are needed to confirm a possible higher frequency of NMB in Gorlin’s syndrome.

BIO 47. IDENTIFICATION OF GENES FROM CHROMOSOME 1Q THAT ARE UP-REGULATED IN EPENDYMOMA PROGRESSION

Emma Prebble,1 Gregory Riggins,2 Brian Fee,2 and Richard Grundy1; 1Institute of Cancer Studies, University of Birmingham, UK; 2Duke University Medical Center, Durham, NC, USA

The outcome of paediatric ependymoma is difficult to predict based on clinical and histological parameters. To address this issue we previously performed a CGH screen of paediatric ependymomas. Using hierarchical cluster analysis, we described three genetic groups of primary ependymoma, structural, balanced and numerical. The structural group showed few mainly partial imbalances, and multivariate survival analysis showed that this group had a significantly worse outcome when compared with the numerical and balanced tumours. Gains of chromosome 1q were frequently observed in the structural group and in a group of recurrent tumours we analysed. In addition, gain of 1q was observed in three recurrent tumours from patients whose primary tumours showed a balanced profile. Taken together, this data suggests that gain of 1q is involved in the progression of paediatric ependymoma. In order to identify specific genes on chromosome 1q that may be important, we have generated Serial Analysis of Gene Expression (SAGE) libraries from two matched pairs of primary and recurrent paediatric ependymomas. The primary and recurrent tumours from matched pair A had a balanced CGH profile, whereas in matched pair B the primary tumour was balanced and the recurrent tumour had a gain of chromosome 1q. We used a pairwise test based on a Monte Carlo simulation of tag counts from the SAGE 2000 software and Fisher’s exact test to identify 27 SAGE tags from chromosome 1q that were significantly up-regulated in the recurrence of matched pair B, but not matched pair A (p < 0.1). Tag to gene mapping was performed using SAGEGenie (http://cgap.nci.nih.gov/SAGE). Genes identified will be discussed and will include the human cartilage glycoprotein CHI3L1, which has been shown to be highly expressed in the serum of patients with malignant, but not low-grade glioma and the brain-enriched hyaluronan-binding protein Brevican, which has been shown to be up-regulated in a rat model of invasive glioma.

BIO 48. GENOMIC IMBALANCES IN SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOURS (STPNETS)

Emma Prebble,1 Sara Dyer,1,2 Marie-Anne Brundler,3 David Ellison,4 Val Davison,2 and Richard Grundy1; 1Institute of Cancer Studies, University of Birmingham; 2Regional Genetics Lab, Birmingham; 3Department of Pathology, Birmingham Children’s Hospital; 4Department of Neuropathology, Newcastle General Hospital; UK

The current World Health Organisation’s classification of Primitive Neuroectodermal Tumours (PNETs) groups together infratentorial and supra-tentorial tumours; this implies a common origin. However, a recent gene expression study strongly suggests that stPNETS are molecularly distinct from their infratentorial counterparts [Pomeroy et al., Nature 2002: 415, 436–442]. While the outcome for children with medulloblastoma has improved in recent years, the management of PNETs occurring outside the cerebellum remains more difficult, and patients generally have a poor prognosis. Achieving significant advances in the diagnosis, prognosis, and therapy and of stPNETs relies on extensive molecular characterisation of these tumours. To this end, we have analysed 17 primary and 1 recurrent formalin-fixed, Paraffin-embedded stPNET for genomic imbalances by high-resolution Comparative Genomic Hybridisation (hr-CGH). Thirteen out of 18 (72%) of the tumours had genomic imbalances, and the median number of imbalances per tumour was 4 (range 0–18). Out of 68 abnormalities, 43 (63%) were whole chromosome imbalances, while 25 (37%) were partial chromosome imbalances involving a chromosomal region or chromosome arm. Four high-level gains were detected at 12q21, 20q, 1q and 6p. The most common chromosomal gains were of chromosome 2 or 2q in 7 out of 18 (39%) cases and gains of chromosome 17 or 17q in 5 out of 18 cases (28%). The most common losses were losses involving chromosome 9 in 4 out of 18 (22%) cases and loss of 13 or 13q in 3 out of 18 (17%) of cases. Correlation with clinical factors will be discussed. This study represents the largest series of genetic aberrations analysed in stPNETs by CGH to date and reveals characteristic chromosomal imbalances that differ from those observed in medulloblastoma.

BIO 49. GENE EXPRESSION PROFILING OF PEDIATRIC MEDULLOBLASTOMAS BY MICROARRAY HYBRIDIZATION

Cheppail Ramachandran,1 Ziad Khatib,2 Enrique Escalon,2 Sonia Rodriguez,1 P.K. Raveendran Nair,1 Perseus Jhabvala,1 and Steven J. Melnick3; 1Research Institute, 2Division of Hematology/Oncology, 3Department of Pathology, Miami Children’s Hospital, Miami, FL, USA

Medulloblastoma is the most common posterior fossa tumor, representing about 20% of all intracranial tumors in the United States. Microarray hybridization of Clonetech cancer 1.2 arrays was used for expression profiling of pediatric medulloblastomas for identifying upregulated and down-regulated genes that could be used for identifying both diagnostic and prognostic markers. All patients except MCH-BT-38 were under 15 years of age. Medulloblastoma patients with progressive disease (MCH-BT-16, 39, and 76) also had fourth ventricle foraminal extension and larger tumors. Of the 10 patients, three patients showed progressive disease following treatment. One patient died of sepsis/meningitis in the postoperative period and had metastatic lesions. Patients with aneuploid tumors responded better to treatment than patients with diploid tumors. Patients with hyperdiploid and tetraploid tumors had a complete response to therapeutic intervention. Gene expression profiles analyzed by microarray hybridization showed a few upregulated and a large number of downregulated genes among medulloblastoma specimens, as compared to an adult and fetal normal brain RNA samples. Membrane arrays were hybridized with PCR amplified cDNAs of tumor RNAs, and the data was analyzed using EpClust and GeneCluster software. Of the 1176 cancer-associated genes in the array, matrix metalloproteinase-11 and 12, desmoplakin I, moesin-ezrin-radixin-like protein, placental plasminogen activator inhibitor 1 and 2, ephrin -A5 precursor, wnt-5A, A-raf protooncogene serine/threonine-protein kinase, and fibroblast growth factor 6 precursor were upregulated in medulloblastomas as compared to normal brain cells. However, several genes including neurotrophin -3 receptor (TRKC) were downregulated in medulloblastomas. The highly downregulated genes include BRAC-1-associated ring domain protein (BARD1), Calmegin, DNA-binding protein RFX5, placental calcium-binding protein, autoimmunogenic cancer/testis antigen NY-ESO-1, platelet basic protein precursor, STAT-induced STAT inhibitor 3, and bone morphogenetic protein 8. The altered gene expression profiles may provide new targets for diagnosis and treatment of pediatric medulloblastomas. This work was supported by funds from Miami Children’s Hospital Foundation.

BIO 50. ZD6474, A VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 (VEGFR2) INHIBITOR, INHIBITS GROWTH OF MULTIPLE PRIMARY CENTRAL NERVOUS SYSTEM TUMOR TYPES

Jeremy N. Rich, Dragutin Loncar, Sith Sathornsumetee, Stephen Keir, Catherine Wheeler, Isaiah Dimery, Darell D. Bigner, and Henry S. Friedman; Division of Neurology and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

Pediatric primary central nervous system (CNS) tumors remain poorly responsive to most therapies. Although CNS tumors display marked heterogeneity in associated molecular alterations, many tumor types display increased activity of the vascular endothelial growth factor (VEGF) receptor and ErbB family member pathways. Novel therapies targeted at these pathways have been linked to blockade of tumor neoangiogenesis and growth. ZD6474 is a novel orally active inhibitor of the VEGF receptor 2 (KDR) tyrosine kinase and also has activity at higher doses against the tyro-sine kinase associated with epidermal growth factor receptor (EGFR/HER1). Orally administered ZD6474 was well tolerated by athymic nude mice with an LD10 of greater than 200 mg/kg/day when administered for 10 days of a 12-day period. Oral administration of ZD6474 (200 mg/kg/day on 10/12 days) to athymic mice bearing several established, histologically distinct (glioblastoma, medulloblastoma, and ependymoma) pediatric human CNS tumor xenografts produced significant inhibition of tumor growth in all cases (range 10.4–25.4 days of growth delay relative to controls). Most xenografts displayed a high rate of partial regressions with treatment (range 10–100%). Additionally, a glioma cell line selected for resistance to procarbazine (PR), a chemotherapeutic agent frequently used in glioma therapy, displayed near identical sensitivity to the parental cell line. Toxicity was low with rare deaths and only mild weight loss in the treatment group. Examination of tumors revealed decreased vascularity of treated tumors, suggesting an anti-angiogenic effect. Conclusion: ZD6474 is a novel agent with significant activity against a broad range of pediatric CNS tumor xenografts, including chemotherapy-resistant tumors. Further consideration of clinical development is warranted.

BIO 51. CONSEQUENCES OF DELETIONAL AND EPIGENETIC EVENTS AT 17P13.3: TARGETS OF HIC1 MEDIATED TRANSCRIPTIONAL REPRESSION

Brian R. Rood, Sébastien Pinte, Huizhen Zhang, Keri Ramsey, Dietrich Stephan, and Dominique LePrince; Department of Hematology/Oncology, Children’s National Medical Center, The George Washington University School of Medicine, Washington, DC, USA

The short arm of chromosome 17 is the genomic region most frequently affected by deletional events in human neural tumors. The area of minimal deletion has been isolated to 17p13.3 in medulloblastoma, the most common malignant brain tumor of childhood. This region contains a gene cloned from a CpG island that demonstrates frequent hypermethylation in tumors, HIC1 (hypermethylated in cancer 1). HIC1 is a tumor suppressor gene whose transfection into tumor cell lines has been shown to decrease clonogenic survival. In a murine heterozygous knockout model, deletion and epigenetic silencing marked by DNA methylation have been shown to cooperate to inactivate HIC1 and promote tumorigenesis. The protein encoded by HIC1 is a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and an N-terminal BTB/POZ domain. We have identified potential repression targets of HIC1 through the use of microarray expression profiling of U2OS cells infected with an ad-HIC1 construct. In silico analysis has been used to confirm the presence of HIC1 binding motifs proximate to target gene regulatory elements. Electromobility shift assays have been performed to demonstrate binding of HIC1 to target sequence specific DNA probes. Finally, reduction of target gene translation has been assayed using Western blot of ad-HIC1 infected cells. The identification of HIC-1 target genes establishes the first links between the most common chromosomal event in human neural neoplasms and molecular biological alterations.

BIO 52. INTEGRATIVE PROFILING OF CHROMOSOMAL COPY NUMBER ABNORMALITIES AND GENE EXPRESSION IN PEDIATRIC EPENDYMOMAS

Michael Sheldon, Rebecca H. Johnson, Yaojuan Lu, Pulivarthi Rao, Adekunle M. Adesina, Dawna Armstrong, Meenakshi B. Bhattacharjee, Robert C. Dauser, Peter Burger, Jackie Biegel, Charles G. Eberhart, Kenneth D. Aldape, and Ching C. Lau; Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

Ependymomas are gliomas that arise in the ependymal layer of the brain and spinal cord. They account for 3–9% of all neuroepithelial tumors and 6–12% of all intracranial tumors in children. Ependymomas are slow growing tumors with marked variations in histology, with anaplastic features sometimes seen in focal areas. Due to the paucity of histological markers, we endeavor to generate genetic profiles that can be used at the time of diagnosis to facilitate outcome prediction and therapeutic decision-making. The biology research arm of the Children’s Oncology Group (COG) ependymoma trial ACNS-0121 comprises a portion of this study. This trial is the largest investigation ever undertaken of the genetic bases, treatment alternatives, and clinical outcomes for ependymoma. We are using microarray comparative genomic hybridization (aCGH) and gene expression profiling on Affymetrix Human U133 Plus 2.0 arrays to study genetic alterations in childhood ependymoma. Using tumor samples from a variety of institutions, we will identify characteristic patterns of chromosomal copy number aberration (CNA) and classify tumors into clinically relevant subtypes. We will then look for correlations between these CNAs and gene expression profiles from the same tumors. In this way, we will identify new markers as well as generate testable hypotheses that address the etiology and progression of ependymoma. To expand the number of cases that can be included in this and other types of genomic profiling studies, we are refining new techniques for the analysis of cells harvested by laser capture microdissection of tumor samples embedded in paraffin, and also whole genome amplification of nanogram amounts of DNA. Molecular classification by genomic profiling, in conjunction with a prospective clinical trial such as ACNS-0121, will improve risk assessment and outcome prediction for patients with ependymoma and identify new prognostic markers for objective patient stratification in future clinical risk-based therapeutic trials.

BIO 53. SPARC/OSTEONECTIN EXPRESSION INDUCES GLIOMA INVASION AND SURVIVAL UNDER SERUM-FREE CONDITIONS

Qing Shi, Shideng Bao, Mark Hjelmeland, Elisabeth Reese, Xiao-Fan Wang, and Jeremy N. Rich; Division of Neurology and Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

Tumor invasion into normal brain is a major contributor to the failure of pediatric glioma treatment. Osteonectin, also known as secreted protein acidic and rich in cysteine (SPARC), is overexpressed by gliomas at the tumor-brain interface, reactive astrocytes, and neoangiogenic vasculature implying a role in invasion. We have shown that the expression of osteonectin in human malignant glioma cell lines induces an invasive phenotype through extracellular matrix and into normal brain with expression of specific matrix metalloproteinases (MMPs) [Rich JN, et al., J. Biol. Chem. 278: 15951]. Despite gaps in the understanding of invasion process, specific cell signaling pathways have been linked to regulation of MMP expression and invasion. We now show that treatment of malignant glioma cultures with exogenous osteonectin acutely induces phosphorylation of FAK, JNK, and Akt/PKB and increases activity of the small G-protein Rac1. As invading cells may experience relative restriction of nutrients relative to the primary tumor, we examined the survival of polyclonal glioma cultures expressing either vector control or osteonectin under prolonged serum starvation. Cells expressing osteonectin did not differ from vector control in cell cycle fraction under normal serum conditions, but osteonectin expression dramatically lowered the level of apoptosis (4.91 ± 0.01% vs. 0.18 ± 0.02%) and increased G2 cell cycle fraction (4.16 ± 1.70% vs. 51.85 ± 0.36%) with serum starvation. Combination treatment of serum starved glioma cultures serum and osteonectin induced a moderate increase in the phosphorylation of both FAK and Akt, suggesting cooperation between the mechanisms by which osteonectin and serum activate these pathways. Thus, glioma expression of osteonectin may promote tumor invasion through induction of cell motility and survival under stress through the activation of specific intracellular pathways involved in cell movement, protease expression, and cell survival.

BIO 54. C-MYC OVEREXPRESSION RECAPITULATES THE LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA PHENOTYPE IN XENOGRAFTS

Duncan Stearns, Aneeka Chaudhry, Peter C. Burger, and Charles G. Eberhart; Departments of Oncology and Pathology, Johns Hopkins Hospital, Baltimore, MD, USA

Risk assessment in patients with medulloblastoma (MB) has historically rested entirely upon clinical staging criteria. However, histopathologic and molecular features are providing additional insights into progression risk and tumor biology. Tumor anaplasia, defined by increased nuclear size, pleomorphism, increased mitotic and apoptotic rates, has been identified in approximately 25% of MB and has a negative impact on outcome. Amplification of myc oncogenes has been strongly associated with the large cell/anaplastic phenotype (LC/A), but occurs relatively infrequently. More common is elevation of c-myc mRNA levels, which has been shown in several retrospective studies to be a negative prognostic indicator. We show here that c-myc overexpression results in more aggressive MBs that mimic the LC/A phenotype. DAOY medulloblastoma cells, which have low endogenous c-myc expression, were stably transfected with c-myc cDNA. In vitro, c-myc mRNA levels were elevated 10-fold and protein levels 2–3 fold in several sub-cloned lines. Luciferase reporter assays revealed a 1.5–2 fold increase in Myc dependant transcriptional activity. Cell cycle analysis showed an increase in the S and G2/M fractions in the c-myc expressing subclones. When injected subcutaneously into NOD/SCID mice, c-myc expressing DAOY xenografts grew on average 75% larger over 8 weeks than control cell lines (P < 0.01, two-tailed T test). More remarkably, the histopathology of the c-myc expressing xenografts recapitulated that of LC/A medulloblastoma, with increased nuclear size, prominent macro-nucleoli, increased mitotic activity and widespread apoptotic bodies including confluent “apoptotic lakes”. Immunostaining with cleaved caspase 3 and Ki67 confirmed the increases in apoptotic and proliferative activity. We are using this model to identify c-myc targets by examining gene expression profiles in vitro and comparing them to those in primary tumors with low or high c-myc levels.

BIO 55. GENE EXPRESSION PROFILES OF CEREBELLAR TUMORS, EXTERNAL GRANULAR LAYER (EGL) NEURONS, AND HYPERPLASTIC EGL NODULES IN PATCHED-DEFICIENT MICE

Jack M. Su, Charlotte R. Nicholson, Cindy C. Rho, Chris T. Man, Laszlo Perlaky, Xiao-Nan Li, John Y.H. Kim, Barbara A. Antalffy, Dawna A. Armstrong, and Ching C. Lau; Department of Pediatric Hematology-Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

We have studied the cellular origin of medulloblastoma in Patched-deficient mice that have spontaneously developed cerebellar tumors. Gene expression profiles of 13 cerebellar tumors were analyzed in comparison with external granular layer (EGL) neurons, internal granular layer (IGL) neurons, and purkinje cells harvested by density gradient separation or laser capture microdissection at various embryonic and postnatal ages. Hierarchical clustering and Multi-Dimensional Scaling analysis of the expression profiles showed that the majority (9/13) of cerebellar tumors (group 1) most closely resemble the profiles of P0-2 EGL neurons. These data suggest that critical events of tumorigenesis occur in early postnatal periods, coinciding with the period of maximal proliferation of EGL neurons. A second group (4/13) of tumors (group 2), however, resemble the profiles of purkinje cells, and two of these tumors appeared to have originated from the cerebellar vermis, in contrast to the nine tumors in group 1 that were hemispheric in location. EGL-specific genes such as Cxcr4 and purkinjecell specific genes such as Grid2 (glutamate receptor, inotropic, delta 2) were differentially expressed in tumor group 1 and 2, respectively. Our data suggest that, while the majority of cerebellar tumors in Patched-deficient mice arise from EGL neurons, a subgroup of tumors may originate from purkinje cell precursors in the sub-ventricular zone. We also observed inappropriately proliferating EGL layers and nodules in otherwise asymptomatic mice. We hypothesized that these hyperplastic EGL nodules represent premalignant lesions and compared their expression profiles to those of the cerebellar tumors and Patched-deficient EGL neurons. Preliminary analysis showed that dysregulated cell cycle regulation (Cyclin D1, Cdk4) and transcriptional control (Hmga2) may represent early events in tumorigenesis, and impaired DNA-repair and global genomic instability (Rad51, Chk1) appear to be prominent events in subsequent tumor transformation. Further functional characterizations of these candidate genes should elucidate the mechanisms of tumorigenesis.

BIO 56. EPIDERMAL GROWTH FACTOR RECEPTOR GENE AMPLIFICATION IN DISSEMINATED PEDIATRIC LOW-GRADE GLIOMAS

Uri Tabori,1,2 Shlomit Rienstein,1 Yaara Dromi,1 Ayala Aviram,1 Rina Dvir,2 Yoav Burstein,2 Eleonora Trejo,2 Shlomi Constantini,2 Lianna Beni-Adani,2 Amos Toren,1 Shai Izraeli,1 and Gideon Rechavi1; 1Sheba Medical Center, Tel-Hashomer; 2Dana Children’s Hospital, Tel Aviv Medical Center; Israel

Background: Disseminated low-grade gliomas (LGGs) represent 5–10% of pediatric LGGs. The genetic and biological nature of these tumors is poorly understood. Epidermal growth factor receptor (EGFR) gene is located on the short arm of chromosome 7. EGFR amplification is characteristic of primary glioblastomas proliferative and invasive behaviour. We looked for certain molecular abnormalities which may differentiate disseminated LGGs from the other LGGs. Methods: Comparative genomic hybridization (CGH) was applied to 18 pediatric patients with LGG. 6 cases with disseminated LGGs were compared to 12 nonmetastatic LGG controls. FISH analysis and immunohistochemistry were used to further highlight specific genetic targets. Results: CGH revealed multiple chromosomal abnormalities in 5 of 6 disseminated cases and in 5 of 12 controls. There was no correlation between the amount of chromosomal abnormalities and clinical course. Amplification of chromosome 7 was noted in 4/6 cases as opposed to 2/12 controls (P = 0.078). FISH analysis revealed EGFR gene amplification in one case negative for +7 at CGH. Immunohistochemistry for EGFR was positive in 6/6 cases and in 2/9 controls (P = 0.08). At a mean follow-up of 7.2 years all patients are alive with variable but slow disease progression. Conclusions: The high rate of EGFR gene amplification and protein expression in disseminated pediatric LGGs may have implication on our understanding of its role in gliomagenesis. Targeted therapies may be possible for these children. Larger scale studies are needed to further establish these findings.

BIO 57. NEUROTROPHIC FACTORS EXPRESSION IN CHILDHOOD LOW-GRADE ASTROCYTOMAS AND EPENDYMOMAS

Gianpiero Tamburrini, 1Antonio Chiaretti, 1Marco Piastra, 2Alessia Antonelli, 3Antonio Ruggiero, 3Riccardo Riccardi, 1Giancarlo Polidori, and Concezio Di Rocco; Paediatric Neurosurgery, Catholic University of Sacred Heart, Rome; 1Paediatric Intensive Care Unit, Catholic University of Sacred Heart, Rome; 2Department of Neurobiology, CNR, Rome; 3Paediatric Oncology, Catholic University of Sacred Heart, Rome; Italy

Background: Neurotrophic factors ØNerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF)– are growth factors implicated in growth and differentiation of brain nerve cells. An involvement of these factors in biology and progression of some specific tumors has been suggested. According to the role of neurotrophic factors in tumor behaviour, the aim of the present study was to investigate their expression in two childhood brain neoplasm, namely low-grade astrocytomas and ependymomas. Materials and Methods: We investigated the NGF, BDNF, GDNF, and NGF-receptors (TrkA and p75) expression in tumor tissues, cerebrospinal fluid (CSF) and plasma of 10 children affected by low-grade astrocytomas and ependymomas. Control tissue samples (together with CSF and plasma samples) were obtained from patients who underwent surgery for cerebral vascular or epileptogenic lesions. Results: The expression of NGF decreases both in tumor samples and in CSF of affected children, as compared to controls. The expression of GDNF remains unchanged both in tissues and in CSF, whereas BDNF increases in CSF. No differencies were found in neurotrophic factors plasma levels in patients and in controls. Gene expression of NGF and its high-affinity receptor (TrkA) are reduced in tumor tissues, whereas the number of cells immunopositive to the low affinity NGF-receptor (p75) is increased. Conclusion: A reduced expression of NGF and TrkA has been shown in low-grade astrocytomas and ependymomas. These findings might be related to differentiative and apoptotic roles of this neurotrophin. The different expression of NGF, BDNF, and GDNF in low-grade astrocytomas and ependymomas suggests that a different redundancy exists among members of the neurotrophic factors family and that their expression may be correlated with biology and behaviour of these tumors.

BIO 58. GENETIC POLYMORPHISMS IN FOLATE METABOLIZING GENES AS RISK FACTOR FOR CHILDHOOD PRIMITIVE NEUROECTODERMAL, AND ASTROCYTIC TUMORS

Jan M. Van Tornout, Yue-Xian Tu, Stefanie Gilinsky, Jane Kim, Ignacio Gonzalez, and Shahab Asgharzadeh; Children’s Hospital Los Angeles and University of Southern California, Los Angeles, CA, USA

Despite increasing insights into the somatic genetic changes associated with childhood malignant brain tumors, their etiology remains unknown. Various risk factors, including nitrosamine/micronutrient intake, pesticide/fertilizer exposure, and parental occupation in chemical industries have been inconsistently associated with childhood brain tumors. We have previously shown that a polymorphism in methylene-tetrahydrofolate reductase (MTHFRC677T), a gene involved in folate metabolism and neural tube development, was associated with stage and risk of developing neuroblastoma, a childhood cancer derived from neuroepithelial tissue. We hypothesized that polymorphisms among MTHFR and other genes involved in the folate pathway could influence the risk for developing other tumors of neuroepithelial origin, that is, PNET family of tumors (medulloblastoma, supratentorial PNET) and astrocytic tumors. We evaluated the genotype distribution of various polymorphic genes involved in the folate pathway, that is, methionine, MTHFR, methionine synthase (MS), methionine synthase reductase (MTRR), cystathione beta-synthetase (CBS), and reduced folate carrier (RFC1) among 101 pediatric PNETs and 63 astrocytomas. DNA isolated from patients oral swab specimens or whole blood was used for PCR-based genotyping. Genotype distributions of cases at loci of interest were compared with the distributions published in the six largest historical control populations to date. The prevalence of genotypes MTHFR677T was significantly higher (p-value range <0.001–0.026) in the PNET cases compared to 3 out of 5 published control populations (n = 598, 403, 510, 554, 1147, respectively), while the CBS699T genotype was more prevalent (p-value = 0.0386) compared to published control data (n = 364). Similarly, we identified a significant increase (p < 0.0001, control n = 598) in the MTHFR677T genotype among the astrocytoma cases vs. the historic control data, and we found a suggestion of trend (p = 0.058, control n = 371) for increase in CBS1080T genotype among the cases. These data show that polymorphisms among the genes involved in the folate pathway may significantly affect the risk for developing a childhood PNET and/or astrocytic tumors.

BIO 59. IMMUNOTHERAPEUTIC TARGET ANTIGEN PHENOTYPES OF PEDIATRIC VS. ADULT CENTRAL NERVOUS SYSTEM (CNS) TUMOR BIOPSIES, XENOGRAFTS, AND CULTURED CELLS

Carol J. Wikstrand, Chien-Tsun Kuan, Kenji Wakiya, R. Ian Cumming, Katrin Lamszus, Manfred Westphal, and Darell D. Bigner; Department of Pathology, Duke University Medical Center, Durham, NC, USA; University Hospital Eppendorf, Hamburg, Germany

We and others have reported the feasibility of therapeutically targeting the adult glioma-associated, cell surface-expressed epitopes EGFRwt, EGFRvIII, gpnmb, MRP3, and IL-13Rα2. Their relevance for therapy of pediatric CNS malignancies is unknown. We initiated a prospective analysis of the antigenic phenotype of pediatric astrocytic tumor (A; astrocytomas and GBM, glioblastomas multiforme) and ependymoma (EP) biopsies and xenografts and cultured cell lines derived therefrom by Quantitative Fluorescent Cell Sorter Analysis using directly fluoresceinated monoclonal antibodies specific for these target molecules. Adult astrocytic tumor biopsies and xenografts (AA and GBM) exhibit high frequency of EGFRwt expression (21/33, 71%) and moderate frequencies of EGFRvIII (13/33, 39%), gpnmb (12/30, 40%), and MRP3 (11/19, 58%). Only 9/15 (60%) adult GBM biopsies expressed cell surface IL-13Rα2, while 13/15 (87%) exhibited higher IL-13Rα2 densities in the cell cytoplasm; 0/2 adult AA expressed IL-13Rα2. Pediatric A and GBM mimic the adult phenotype for EGFRwt (3/5, 60%) and MRP3 (3/5, 60%) expression but exhibit decreased gpnmb expression (1/5, 20%) and a lack of EGFRvIII (0/5). 2/4 pediatric A and GBM biopsies expressed cell membrane IL-13Rα2 and 3/4, cytosolic receptor. Cultured cell line analysis supports these trends; 5/5 adult and 5/5 pediatric astrocytic tumor biopsy-derived cell lines express EGFRwt; there was modest diminution of MRP3 expression (adult cases 4/6, 67%, pediatric cases 2/5, 40%) and a decrease in gpnmb expression (3/6 in adult cases; 1/5 in pediatric cases). We have studied 3 EP xenografts; 1/3 expressed EGFRwt and gpnmb; all lacked EGFRvIII; 0/3 expressed cell surface IL-13Rα2; 3/3 expressed MRP3. Continuing accrual of cases will allow discrimination of diagnostic subclass antigen phenotypes and determine which therapeutic models defined for adult disease may be applicable to pediatric CNS tumor therapy. As pediatric tumors exhibit lower frequencies of these antigens, it is imperative that new pediatric CNS tumor-associated target epitopes be identified.

BIO 60. MOLECULAR GENOMICS OF MEDULLOBLASTOMA

Hai Yan, Chunhui Di, Daniel Broderick, Roger McLendon, Sridharan Gururangan, Henry Friedman, and Darell Bigner; Department of Pathology, Duke University Medical Center, Durham, NC, USA

Primary brain tumors are the leading cause of cancer deaths in children. The most frequent malignant CNS neoplasm in this age group is the medulloblastoma. Despite advances in therapy, 50% of the children afflicted with medulloblastoma die of the disease, and aggressive treatment of children with radiation and chemotherapy results in impaired neural development, growth deficits, and endocrine dysfunction in the survivors. Research to demonstrate the pathogenic basis of medulloblastoma, and thereby facilitate the development of new approaches to managing this disease, is sorely needed. Genome-wide evaluations of genetic alterations in medulloblastoma will provide unprecedented improvements in molecular classification and novel therapeutic targets. We are applying a recently developed state-of-art genetic approach called digital karyotypying to look at genomic alterations in primary medulloblastoma samples. Digital karyotyping is a genome-wide approach to detect copy number alterations at high resolution. This approach appears uniquely powerful in detecting chromosomal aberrations, homozygous deletions, and amplifications, alterations known to target genes involved in tumorigenesis. We have generated six digital karyotyping libraries from medulloblastoma cell lines and primary tumors. The data have not only confirmed the most common genomic abnormalities which have previously been identified by conventional technologies, but also mapped to several genes that have tumorgenesis potential in medulloblastoma. The results will elucidate medulloblastoma pathogenesis and set the stage for a wealth of future basic scientific and translational research.

BIO 61. NEUROPROTECTION WITH RILUZOLE IN THE IMMATURE RAT CEREBELLUM AFTER RADIATION EXPOSURE

Kaleb Yohay, Sunny Kim, Janice Lee, Grace Kim, and Jeffrey Rothstein; Department of Neurology and Division of Child Neurology, Johns Hopkins University, Baltimore, MD, USA

Ionizing radiation is an essential part of the treatment of many types of central nervous system (CNS) tumors in children. However, severe long-term cognitive effects, especially in younger patients, frequently limit its utility. Modulation of glutamate excitotoxicity has been shown to attenuate CNS injury in neurodegenerative disorders, hypoxia/ischemia, and traumatic injury. Excitotoxicity may also play a role in neuronal injury and death after exposure to ionizing radiation. The aim of our current study is to evaluate the glutamate release inhibitor riluzole in inhibition of neuronal apoptosis in the cerebellum of rat pups exposed to ionizing radiation. Six-day-old rat pups were injected with 8 mg/kg of riluzole or vehicle IP 1 hour prior to irradiation. They were subsequently exposed to a single dose of 0 Gy, 3 Gy or 5 Gy, limited to the head. Six hours after irradiation, the pups were sacrificed and perfused. After brain sectioning, terminal dUTP nick-end labeling (TUNEL) was used to determine the extent and location of apoptosis. Results: The cerebellar granule cell layer showed high levels of radiation dose-dependent apoptosis. Preliminary data shows pups receiving pretreatment with riluzole had a 66% reduction of cells undergoing apoptosis in the granule cell layer when exposed to 3 Gy (n = 4) and a 40% reduction when exposed to 5 Gy (n = 4). Our preliminary data suggests that pretreatment with the glutamate release inhibitor riluzole can significantly decrease neuronal apoptosis in the cerebellum of the immature rat brain exposed to ionizing radiation. Further study needs to be done to determine if riluzole could be an effective means of limiting some of the long-term side effects of therapeutic radiation on the developing brain.

BIO 62. SOMATOSTATIN TARGETED RADIOTHERAPEUICCS FOR MEDULLOBLASTOMA

Ganesan Vaidyanathan, Abraham Boskovitz, Henry S. Friedman, Donna J. Affleck, and Michael R. Zalutsky; Departments of Radiology, Pathology, and Pediatrics, Duke University Medical Center, Durham, NC, USA

Medulloblastoma are relatively radiosensitive malignancies; however, curative doses of radiation often can not be delivered because of dose limiting normal tissue toxicity. This is of particular concern in patients with neoplastic meningitis where radiation induced side effects can be severe. In this disease, targeted radiotherapy is a promising alternative to external beam therapy because of the potential for achieving selective destruction of tumor cells while sparing normal CNS tissues. We have previously shown that radioiodine could be targeted to somatostatin receptors (SSTR) on human medulloblastoma xenografts using the peptide glucosyl-Phe1-[I-Tyr3]octreotate (GluTOCA). The goal of the current study was to develop an SSTR-avid peptide that could be used to treat medulloblastomas with 131I or 211At, a highly cytotoxic α-particle emitting radionuclide with a range in tissue (50–80 μm) well matched to neoplastic meningitis geometry. Octreotate with a Dde-protected lysine was reacted with N-succinimidyl 4-(bis-Boc) guanidinomethyl-3-(trimethylstannyl)benzoate, the Dde group removed, and the resultant stannylated molecule reacted with 131I or 211At and tert-butylhy-droperoxide at 70°C to produce 4-guanidino-3-[131I]iodobenoyl-Phe1-octreotate (GMIBO) or 4-guanidino-3-[211At]astatobenoyl-Phe1-octreotate (AGMBO), respectively. The specific internalization by SSTR-expressing D341 Med medulloblastoma cells of [125I]GMIBO increased from 2.5 ± 0.2% at 30 minutes to 16.9 ± 0.3% at 4 hours, and was significantly higher than that for [131I]GluTOCA; a second study showed that the internalization of AGMBO was not significantly different than that of GMIBO. In addition, retention of radioactivity in D341 Med cells for GMIBO was better than that of Glu-TOCA. The tissue distributions of [131I]GMIBO and [125I]GluTOCA were directly compared in athymic mice with subcutaneous D341 Med xenografts. The tumor uptake of both radioiodine labels was comparable through 8 hours, but at 24 hours, there was about a twofold higher tumor retention for [131I]GMIBO. In summary, our results suggest that GMIBO and its 211At-labeled analogue warrant further investigation as targeted radiotherapeutics for medulloblastoma.

EPIDEMIOLOGY

EPI 1. CNS TUMOR EPIDEMIOLOGY AND OUTCOME IN ADOLESCENTS AND YOUNG ADULTS IN THE UNITED STATES, 1975–1998

Anne Bendel, Lynn Ries, Orren Beaty, Krystal Bottom, and Archie Bleyer; Children’s Hospitals and Clinics, Minneapolis, MN; Children’s Oncology Group, Arcadia, CA; USA

Purpose: Data from the NCI Surveillance, Epidemiology, and End-Results (SEER) were analyzed to determine the incidence and outcome of brain tumors in adolescents and young adults in the United States. Methods: The SEER incidence, U.S. mortality, and SEER 5-year survival of CNS tumors was determined for each 5-year age group from 0 to 44 years of age from 1975 to 1998. Average annual percent change was derived from linear regression of each reported annual rate. Adolescents and young adults were defined as individuals 15–29 years of age. Results: Incidence, 1975–1998 - CNS tumors accounted for 6% of all neoplasms. The nadir in incidence of CNS neoplasms occurred in the 15–29 year age group, at a rate of 22.3 per million. The incidence of CNS tumors increased over time, mainly due to an increased incidence of “other glioma.” Males and White, nonHispanics had a higher incidence of CNS tumors compared to females and other ethnic groups, respectively. Astrocytoma accounted for 64% of CNS neoplasms, “other gliomas” 19%, PNET 8%, and ependymoma 6%. Outcome, 1975–1998 - Mortality rates for individuals 15–29 years of age were similar to the pediatric age group and showed modest improvement over time. Mortality rates were higher for males than females. Survival rates for the 15–29 year age group improved over time, but lagged behind survival rates seen in all other age groups. Among astrocytoma, no improvement in 5-year survival rate was observed in 15–24 year-olds, in contrast to an average annual improvement of 0.5–3% per year in the other age groups. 20-year survival for astrocytoma was 65% for age 15–19 years, 40% for 20–24 years and 25% for 25–29 years. 20-year survival for individuals 15–29 years of age with “other gliomas” was 50% and ependymoma 65%.

EPI 2. OLDER ADOLESCENTS AND YOUNG ADULTS WITH BRAIN TUMORS IN THE UNITED STATES: LACK OF CLINICAL TRIAL PARTICIPATION AND OF SURVIVAL PROLONGATION AND MORTALITY REDUCTION

Archie Bleyer, Maha Hag-Alshiekh, Michael Montello, Troy Budd, Anne Bendel, Orren Beaty, and Maura O’Leary; University of Texas M. D. Anderson Cancer Center, Houston, TX; Children’s Oncology Group, Arcadia, CA; USA

Background: Young adults with cancer have been found to have had less survival improvement than either younger or older patients (Proc. ASCO 21:389a, 2002). We questioned if this observation applied to brain tumors and, if so, why. Method: Annual rates in SEER incidence and 5-year survival from 1975 to 1998 were analyzed for each 5-year age <40 years. Trends were derived from linear regressions of the reported annual rates for 1975–80, 1981–6, 1987–92, and 1993–8 cohorts. National brain tumor trial data were obtained on 2,213 <40 year-olds entered on cooperative group and consortia (PBTC, NABTT, and NABTC) treatment trials during 1997–2001. Results: Above age 10–15, the clinical trial participation and survival rates co-declined precipitously for all malignant brain tumors, and also for gliomas, ependymoma, and primitive neuroectodermal tumors (PNET). In patients with the most common malignant CNS tumors, astrocytomas (including glioblastoma multiforme), the correlation of clinical trial participation and survival rate improvement was statistically significant, with the 15–25 year-olds having the least improvement and the lowest clinical trial participation rate, whether considered as a function of the absolute number of entries (Table) or as a function of the proportion of entries relative to the number of patients diagnosed with the type of tumor.

Correlation of national clinical trial participation and survival prolongation in anaplastic astrocytoma and glioblastoma multiforme (p < .05)

Age (years)0–45–910–1415–1920–2425–2930–3435–39
Clinical trial accruals, 1997–200112712954275497169222
Average annual change in 5-year survival, 1975–19981.3%0.6%1.1%0%0%1.6%3.0%1.9%

Conclusion: The failure in 15–25 year-olds in the U.S. to improve brain tumor survival over the last quarter century appears to be due to their under-representation on clinical trials. Reversing the deficit will require increased clinical trial availability, access, and participation.

EPI 3. INCIDENCE AND PATTERNS OF NEURAXIS METASTASIS (NM) IN PATIENTS (PTS) WITH DIFFUSE PONTINE GLIOMA (DPG)

James Brashears, Sridharan Gururangan, Colleen McLaughlin, Marcello Morgan, James Provenzale, Edward C. Halperin, and Henry S. Friedman; The Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA

Diffuse pontine gliomas comprise 8% of all intracranial tumors in children. Treatment for this tumor is focal radiotherapy, but almost all patients suffer local recurrence and ultimately succumb to the disease. Neuraxis spread of DPG has only rarely been reported in the literature. We therefore estimated the incidence and characterized the patterns of NM in pts with DPG. The radiation oncology database at DUMC was used to identify pts treated for DPG, and a chart review was conducted of those diagnosed with NM (defined as leptomeningeal [LM], parenchymal [PM], and/or subependymal [SE] based on neuroimaging studies). Findings from flurodeoxy glucose positron emission tomography (FDG-PET), magnetic resonance spectroscopy (MRS), and histology were also used to assess NM when available. Between 1986–2000, 86 pts were treated for DPG at our institution. Sixteen pts (18%) [median ages, 9 years, range, 4–17] had NM and were identified at a mean time of 15 months (range, 3–96) from diagnosis. Metastatic patterns included WM in 9 pts, PM in 7, and SE in 6. Five pts showed ≥2 metastatic patterns. The FDG uptake on PET was increased in 5 pts in the sites of NM. Five pts had MRS and showed increase in the choline and decrease in the N-acetyl aspartate peaks characteristic of tumor. Three pts had histologic confirmation of high-grade glioma on biopsy. All pts have died of disease despite salvage therapy. A variety of metastatic patterns occur in a significant proportion of patients with DPG at the time of recurrence Although the outcome is uniformly fatal, identifying NM by noninvasive neuroimaging modalities may help guide palliative treatment and improve quality of life.

EPI 4. SACROCOCCYGEAL MYXOPAPILLARY EPENDYMOMA IN A PATIENT WITH SPINAL DYSRAPHISM AND DWARFISM

Karen W. Braune, Richard S. Tubbs, Keith E. Georgeson, W. Jerry Oakes, David R. Kelly, and Alyssa T. Reddy; Departments of Pediatrics, Neurosurgery, Cell Biology, Pediatric Surgery, and Pathology, The University of Alabama at Birmingham and The Children’s Hospital of Alabama, Birmingham, AL, USA

Myxopapillary ependymoma typically occurs in the distal spinal cord and cauda equina and rarely is diagnosed in pediatric patients. Rare reports also describe subcutaneous sacrococcygeal myxopapillary ependymoma that occurs as a primary lesion. The origin of this tumor outside of the nervous system is unclear, but it has been theorized to arise from an ependymalined cavity that is a remnant of the caudal portion of the neural tube. A 20-month-old female presented to our institution with a chief complaint of inability to walk. Past medical history was significant for mesomelic dwarfism. She had myelopathic neurologic findings with leg weakness and increased lower extremity reflexes. There were no stigmata indicative of occult spinal dysraphism. Her initial evaluation included cervical spine radiographs and MRI of the brain and spine. Findings of these studies included C1–2 instability, osteodysplasia, syringomyelia from T10–T12, tethered cord, and the presence of a 1-centimeter, round cystic lesion in the presacral region. Following recovery from occipitocervical fusion, the patient underwent resection of the presacral mass. Histopathology revealed an epidermoid cyst with a myxopapillary ependymoma present within the adjacent soft tissues without invasion of the coccyx. Although, the follow-up interval is short, the patient is clinically well and will undergo spinal cord detethering soon. To our knowledge, this is the first case in the literature of a subcutaneous myxopapillary ependymoma associated with an epidermoid cyst and also the first in a patient with dwarfism. Rare case reports have noted the coincidence between spinal ependymomas and both split cord malformation and dermal sinus tracts. We theorize that derangement of secondary neurulation may lead to concomitant occult spinal dysraphism in the presence of extraaxial vestiges of ependymal cell rests. This would embryologically unify why our patient had the constellation of an extraaxial epidermoid cyst, myxopapillary ependymoma, and tethered cord.

EPI 5. SYMPTOMS AND SUFFERING AT THE END OF LIFE IN CHILDREN WITH BRAIN TUMORS

Bridget M. Brown and David N. Korones; University of Rochester Medical Center, Rochester, NY, USA

Background: Cancer is the second leading cause of death in children, and brain tumors account for 25 percent of these deaths. However, little is known about the experience of children in the terminal phase of this disease. We hypothesized that children with brain tumors have different signs, symptoms, and needs during the terminal phase of their illness than children with other types of cancer. Methods: We performed a retrospective review of records from all children with cancer treated at Golisano Children’s Hospital who died between the years 1993 and 2003. Records of the last three months of life were examined for demographics, signs and symptoms, hospitalization and treatments, end of life care, and location of death. Information collected about children with brain tumors was compared to that of children with other malignancies. Results: Of 103 records reviewed, 29 patients (28%) had brain tumors and 74 (72%) had other cancers. The most common symptoms were pain and fatigue (>80% in each group). Children with brain tumors were more likely to suffer from a functional loss such as focal motor deficit (p < 0.0001), vision loss (p = 0.005), wheelchair use (p < 0.0001), dysphagia (p < 0.0001), and difficulty speaking (p = 0.0001). They were less likely to suffer from dyspnea (p = 0.006), appetite loss (p = 0.02), and fever (p= 0.0002). Patients who had brain tumors were more likely to die at home (p< 0.0001), had do-not-resuscitate (DNR) orders documented earlier (p = 0.004), and were less likely to receive radiation therapy (p = 0.02), surgery (p = 0.04), or other invasive procedures (p = 0.003) during the last three months. Conclusions: Children with brain tumors have a different experience at the end of life than children with other types of cancer. Healthcare providers should be aware of these differences to better anticipate needs of children with brain tumors. Discussion of end-of-life issues must begin earlier to assure the child’s ability to participate.

EPI 6. MEDULLOBLASTOMA IN CHILDREN. MONOINSTITUCIONAL EXPERIENCE FROM A DEVELOPING COUNTRY

D. Calle; Deparment of Paediatric Haematology and Oncology, Instituto Oncológico Nacional “Dr Juan Tanca Marengo” (SOLCA), Guayaquil, Ecuador

Brain tumors are the second cancer in our center. Objective: To study retrospectively the clinical features, therapeutic reponse, and survival of medulloblastoma in children below 15 years. Methods: Between 1996 and 2003 twenty-one children were diagnosed and treated with surgery, chemotherapy, and craniospinal irradiation. Reponse to treatment was assessed clinically and radiologically. Survival was calculated using percentage values. Results: Of 21 patients with medulloblastoma, median age at diagnosis was 5 years (1 to 15 years). Male:Female radio was 1.6:1. More than 80% of children had headache and vomiting. 12 children had unsteadiness of gait. The majority had the symptoms of 2–3 months’ duration. 16 had midline vermian lesion, three had cerebellar hemisphere lesion, and 2 had CP angle tumor. 7 had obstructive hydrocephalus. One had spinal metastasis. 21 children were evaluated for treatment outcome. All children had surgery (subtotal excision in 20); 9 children received chemotherapy (8 Vp-Cb and 1 M-SFOP) after surgery and before irradiation (55GysFCP-35gy spinal axis); 3 children received only chemotherapy (2 Vp-CB and 1 BB-SFOP) after surgery; 4 children received chemotherapy (Vp-CB) after surgery, before and after craniospinal irradiation; and 5 children had only surgery. Of 21 children, 10 (48%) are alive and free of disease. Estimate response in 15 pts: CR in 10 pts, PR in 5 pts. Median follow-up 12 months (1–39). 11 pts are dead, 6 (progression), 4 (recurrence), and 1 (second cancer). 19% were out of follow-up. Conclusions: 1. The OS is the highest in the group treated with surgery + chemotherapy and radiotherapy. 2. Rate response was 71%. 3. A better optimization in the quality of resection is necessary to offer a better future to these patients.

EPI 7. OUTCOME OF TREATMENT INDUCED HIGH-GRADE GLIOMA (HGG) IN CHILDREN: A STUDY OF THE CANADIAN PEDIATRIC BRAIN TUMOUR CONSORTIUM

Anne-Sophie Carret, Uri Tabori, Bruce Crooks, Juliette Hukin, Isaac Odame, Donna L. Johnston, Daniel L. Keene, Carolyn Freeman, and Eric Bouffet, on behalf of the Canadian Pediatric Brain Tumour Consortium (CPBTC); Pediatric Hematology-Oncology, The Montreal Children’s Hospital/McGill University Health Center, Montreal, PQ, Canada

As cure rates increase, more children treated for cancer are at risk for long-term toxicities including the development of a second malignancy. Reports of treatment related-HGG in survivors of childhood cancers are scarce and data on their evolution and response to therapy are limited. We report treatment related-HGG in 16 children who were treated with irradiation +/− chemotherapy for either acute lymphoblastic leukemia (n = 7) or solid tumour (n = 9). Among the solid tumour patient group, four had an initial diagnosis which can predispose to a second cancer (3 NF1 with optic glioma, 1 bilateral retinoblastoma). Median age at cranial radiation was 4.5 years (range, 0.5–9). Median age at diagnosis of HGG was 14.5 years (range, 7–19) with a median interval between radiation therapy and diagnosis of HGG of 8 years (range, 6–14). All gliomas occurred within the previous radiation fields (unifocal:15; multifocal:1). Fifteen patients had a diagnostic biopsy with histology consistent with glioblastoma multiforme (n = 13), anaplastic astrocytoma (n = 1), gliomatosis cerebri (n = 1), gliosarcoma (n = 1). For one patient the diagnosis was based on imaging only. Twelve patients received chemotherapy and 2 patients palliative treatment only. Surgical resection was part of the treatment for 9 patients including 2 gross complete resections. Six patients were re-irradiated. The overall median survival for all the patients was 8 months (range, 0.1–82 months) with no difference between leukemia and solid tumour patients. Re-irradiation was associated with a better median overall survival (8.5 vs. 13 months). Three patients are still alive with disease. High-grade glioma may occur in children as a consequence of therapy for a prior malignancy. Cranial radiation therapy may affect the multi-step course of tumorigenesis and should be consider as a risk factor. The optimal therapy and particularly the role of surgery and re-irradiation is still not clear and would require a larger epidemiologic study.

EPI 8. INCIDENCE OF BRAIN TUMOR IN CHINESE CHILDREN: A 4 YEAR PROSPECTIVE REVIEW

G.C.F. Chan,1 M.M.K. Shing,2 A.C.W. Lee,3 C.W. Luk,4 C.K. Li,5 H.L.Yuen,4 C.K. Li,2 and S.Y. Ha1; Departments of Paediatrics and Adolescent Medicine of The University of Hong Kong,1 The Chinese University of Hong Kong,2 Tuen Mun Hospital,3 Queen Elizabeth Hospital,4 and Princess Margaret Hospital5; and Hong Kong Pediatric Hematology Oncology Study Group; Hong Kong SAR, China

Objective: We have little information about the incidence and histology types of brain tumors in Chinese children. We analyzed the data from the HKPHOSG surveillance study and compared it with the SEER data. Methods: New cases of childhood (≤15 years) with brain tumors diagnosed in the five major regional hospitals (included nearly all cases of local children with cancer) were registered with predesigned data form at diagnosis from January 1999 to December 2003. The data were double checked with the Hong Kong Cancer Registry database annually. Classification of brain tumors were based on the WHO classification. Data were compared with the published SEER data for children ≤15 years (1975–95). Results: There were 131 new cases of childhood brain tumors diagnosed within this 4-year period, but only 122 were ≤15 years. For these 122 children, median age was 7.81 years (range 0.2–15.6 years) and M:F = 1.4:1. The distribution of tumor histological types ranking from most to least common were: Glioma n = 42/122 (34% vs. 65% in SEER) [astrocytoma n = 30, brainstem glioma n = 9, other glioma n = 3], PNET n = 39/122 (31.9% vs. 22.9% in SEER) (medulloblastoma n = 34, cerebral PNET n = 5); Germ cell tumor n = 19/122 (15.6% vs. <3% in SEER), ependymoma n = 8 (6.5% vs. 9.3% in SEER), craniopharyngioma n = 3, choroids plexus tumor n = 3 and other miscellaneous tumors. Compared to the SEER data, we have a much higher incidence of germ cell tumors and relative high incidence of PNET. Our analyses based on the short term follow-up data relating to their respective treatment outcomes were comparable with the published results. Conclusions: Our preliminary data supported the previous impression that CNS germ cell tumors are more common among oriental. We also found that medulloblastoma is relatively more common in our locality. However, our outcome data did not suggest that any genetic difference in terms of treatment response.

EPI 9. MALE PREDOMINANCE IN CNS GERM CELL TUMORS: ANALYSIS OF SEER DATA

Paul J. Chuba, Richard K. Severson, Kanta Bhambani, D.R. Sharadashree, Ron Thomas, and Merlin R. Hamre; Department of Radiation Oncology, St. John Macomb Hospital, Webber Cancer Center, Warren, MI; Departments of Radiation Oncology, Pediatrics, and Family Medicine, Wayne State University, Detroit, MI; USA

The origin of intracranial germ cell tumors is not known with certainty. Most likely, aberrant migration of germ cells from the wall of the yolk sac (allantois) to the genital ridge takes place during embryogenesis prior to neoplastic transformation. It is also possible that CNS germ cell tumors arise from early gonadal lesions which then migrate to extra-gonadal sites. Male predominance among cases of CNS germ cell tumor was investigated using data from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Program. Fourhundred-eleven cases (M = 312, F = 99) of central nervous system germ cell tumors (ICCC code) were identified in SEER registry data from 1973 to 1999. Cases were grouped by histology as Germinoma (ICD-0-2 code 9064, n = 257), Dysgerminoma (9060, n = 35), Mixed Germ Cell Tumor (9085,9100-2, n = 41) and Malignant Teratoma (9080-4, n = 58). Cases were also grouped as localized and nonlocalized according to the SEER staging system. Contingency table analysis was performed to determine the differences of sex by age, race, localized disease, and histology. Results indicated that both the incidence of CNS germ cell tumors and the male predominance increased about the time of puberty. The peak in incidence (3.8 per million population) occurred in the 15–19 year-old age group, and the greatest male to female ratio (19.5:1) occurred in the 20–24 year old age group. This ratio was markedly reduced after age 30. In females, the peak incidence occurred earlier (10–14 year-old age group). CNS germ cell tumors were rarely detected after age 20 in females, or after age 35 in males. Two possible explanations for sex-ratio imbalance for CNS germ cell tumors seem most likely. Differences in numbers of available male or female germ cells could account for this if transformed germ cells migrate from the gonads to the brain. Alternatively, it is possible that preexisting ectopic germ cells in the CNS are influenced by accelerating endocrine activity at the time of puberty. Gender specific hormonal signals may lead to maturation delay or differentiation arrest, somehow leading to neoplastic transformation. It is possible that germ cells in pineal and/or suprasellar locations (gonadotropin regulatory centers) are particularly susceptible to such influences.

EPI 10. DESMOPLASTIC MEDULOBLASTOMA IN YOUNG CHILDREN: A FEATURE OF GORLIN’S SYNDROME

O. Cruz, J. Mora, J. Vila,1 A. Guillen,2 and J.M. Costa2; Departments of Pediatric Oncology, Pathology,1 and Neurosurgery,2 Hospital St. Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

Introduction: Gorlin syndrome is an inherited condition that confers a high predisposition to cancer, mainly basal cell carcinomas in young adults. We describe an infant with no familial antecedents who presented with desmoplastic medulloblastoma. Case Report: A 12-month-old boy, born to nonconsanguineus parents, consulted for developmental delay and vomiting. On physical examination megacephaly, frontal bossing, and hypertelorism were evident. He had no skeletal or skin abnormalities. MRI revealed a left hemispheric cerebelar tumor with a lamellar pattern. He underwent suboccipital craniectomy with total removal of the tumor. Pathology showed a typical pattern of desmoplastic medulloblastoma. Molecular genetic analysis of his blood showed an heterozygous novel frameshift mutation of the PTCH gene, 385ins, changing the codon 129 from TGG to TTGG resulting in protein truncation. This mutation is a novel disease-causing mutation. The mutation was not detected in the DNA from the parents, suggesting de novo mutation or germline mosaicism. Following surgery, the patient was enrolled in the Spanish Pediatric Oncology Society Baby Protocol for medulloblastoma with the aim of avoiding radiation therapy. Commentary: Nevoid basal cell carcinoma syndrome (NBCCS or Gorlin’s syndrome) is a fully penetrant, autosomal dominantly inherited syndrome with variable expressivity. The disorder is caused by mutations in PTCH. The syndrome comprises multiple basal cell carcinomas, keratocysts of the jaw, spine and rib anomalies, and calcification of the falx cerebri. NBCCS-associated medulloblastomas present earlier than medulloblastomas not associated with the syndrome, and with “desmoplastic” phenotype. Conclusion: This and other similar cases in the literature show the importance of considering Gorlin’s syndrome in the differential diagnosis of any young child who presents with desmoplastic medulloblastoma, especially before the age of 5. Chemotherapy only based protocols should be considered in these patients because radiotherapy has a marked effect on the early development of skin and other cerebral tumors.

EPI 11. PAEDIATRIC SPINAL CORD EPENDYMOMA (SCE) IN THE MRI ERA: A CANADIAN PAEDIATRIC BRAIN TUMOUR CONSORTIUM STUDY

Ugonwa Dag-Ellams, Beverly Wilson, Paul Steinbok, Mariana Silva, Keith Aronyk, Normand Laperriere, and Eric Bouffet; The Canadian Paediatric Brain Tumour Consortium, Paediatric Brain Tumour Program, Hospital for Sick Children, Toronto, ON, Canada

Intramedullary tumours are rare in the paediatric population. It is recognized that the MRI has considerably influenced the management of these tumours. However, the impact of this change has never been evaluated, particularly in terms of postoperative management. A retrospective review of 18 patients (11 males, 7 females), paediatric cases of SCE during the MRI scan era, was conducted in the CPBTC. Median age at diagnosis was 11.6 years (1.5–17.4). Back pain and gait disturbances were the most common presenting symptoms. Median duration of presenting symptoms was 11.5 months (0.75–48). In addition to preoperative MRI, 1 patient had a Myelogram, 2 a CT. 16 MRIs were with Gadolinium enhancement. MRI revealed spinal dissemination in 2 patients. Most tumours were located in the lumbar region (12/18). The median number of segments involved was 4 (2–12). All patients underwent surgery. Resection was total in 10 cases, subtotal in 6, and partial in 1, (unknown in one). Postoperatively, 17 MRIs were performed. 9 showed no residual disease, 4 residual tumour, and 4 equivocal residue. 2 tumours were anaplastic, 3 grade 2, and 12 grade 1/myxopapillary, (no grade in one). Four patients (including two with anaplastic ependymoma) received postoperative radiation for residual tumour. One of these patients received additional chemotherapy. Five patients relapsed, all locally. Four had repeat surgery, followed by radiation in 3. One patient had radiation only. Two patients had a second relapse. At the last follow-up, all patients were alive. 12 of the patients were alive and in remission, 4 patients alive with residual disease, and one alive receiving treatment. Median follow-up was 2.6 years (0.16–10.16). One patient was lost to follow-up. Conclusions: Myxopapillary ependymomas account for the majority of SCE in the paediatric age. The introduction of MRI in follow-up has enabled decreased use of postoperative radiation.

EPI 12. SECOND NEOPLASMS (SN) OF THE CENTRAL NERVOUS SYSTEM (CNS) IN CHILDREN TREATED AT A SINGLE INSTITUTION

Bożenna Dembowska-Bagińska1,1 Iwona Filipek,1 Wiesława Grajkowska,3 Marta Perek-Polnik,1 Marcin Roszkowski,2 and Danuta Perek1; 1Oncology Department, 2Neurosurgery Department, and 3Patomorphology Department, Children’s Memorial Health Institute, Warsaw, Poland

The aim of our study was to analyze SN treated in our center. Between 1997 and 2004, 9 pts (7 boys and 2 girls, aged 5 4/12 years to 21 6/12 years) were treated for second neoplasms in the CNS. Six patients had a primary diagnosis of CNS tumor (PNET, MB, LGG - 3 pts, Meningioma), 1 pt - parameningeal RMS, 1 pt - HD, and 1 pt - ALL. Median time from diagnosis of primary disease to second neoplasm was 6 8/12 years. 7 out of 9 pts underwent radiotherapy for primary tumor. In 4 pts, SN occurred in irradiated field, in 1 - at margins, in 2 - outside of irradiated area. SN was diagnosed within 2 years to 14 11/12 years from radiotherapy. The 2 pts who did not undergo radiotherapy developed a second tumor 3 10/12 years and 5 7/12 years from diagnosis. Onset of the disease was symptomatic in 6 pts. 3 other pts were diagnosed with SN at a routine CNS radiological check up. Second tumors were localised in the brain in 8 pts; 1 pt had a tumor in the spinal cord. In 3 pts with the shortest time of observation from primary diagnosis, relapse was suspected, but pathology confirmed otherwise. 8 pts underwent surgery of their SN. The pt with an intraspinal tumor did not qualify for any kind of surgical intervention. 7 pts had a radical resection of the tumor, 1 - subtotal. Three pts were diagnosed with meningioma, 1 pt with AI, 2 pts with anaplastic Astrocytoma, 1 pt with PNET, and 1 pt with Glioblastoma multiforme. In 1 pt, diagnosis of intraspinal glioma was based on an MRI scan. Surgery was the only treatment in 4 pts (Meningioma and LGG). Five pts had adjuvant chemotherapy; 3 pts had additional radiotherapy. Six pts are alive; 1 pt with intraspinal glioma died of treatment complications. Two pts (PNET, GM) were lost from observation. This work was supported by grant nr C 028/P05/2002.

EPI 13. CHILDHOOD CANCER REGISTRY IN ARGENTINA (REGISTRO ONCOPEDIATRICO HOSPITALARIO ARGENTINO: ROHA). PRIMARY CNS TUMOUR CASES

Blanca Diez, Enrique Schwartman, Marcelo Scopinaro, Mercedes Garcia Lombardi, Maria Davila, Dora Loria, and Florencia Moreno; Roha Buenos Aires, Argentina

ROHA is a not-for-profit institution committed since 2000 to provide a resource for gathering and disseminating epidemiologic data on childhood cancer, describing their incidence and survival patterns, evaluating diagnosis and treatment, and establishing awareness of the disease. It gathers data from 69 sources, 7 registries, and 2 cooperative groups. This report includes 3,368 cancers diagnosed during 2000–02 in children younger than 15 years. Total Argentine population is 36.260.130 (Census 2001); 28% is younger than 15 years. Data are grouped by histologic type and primary site based on the International Classification of Childhood Cancer 1996 (ICCC) and International Classification of Diseases for Oncology, 3rd Edition. In ROHA, 95% of cancers are histologically confirmed. The percentage does vary by ICCC category from 86% for CNS (ICCC III + Xa) to 100% for leukaemia (ICCC I). For epidemiologic purposes, we group CNS tumours into broad histologic categories. For the 3-year period of 2000–02, there were 591 CNS tumours (18% of all malignancies). Embryonal tumours comprised 29.2%, pylocitic astrocitoma 10.6%, low-grade glioma 11.1%, high-grade glioma 8.7%, ependymoma 11.3%, germinal cell 4%, and others 24.7%. Incidence of medulloblastoma (F/M 53/84), ependymomas (F/M 24/43), and germ cell tumors (F/M 9/15) in males is higher than in females. For other types, there is little difference (F/M 175/188). In patients younger than 10 years, localization was brain stem 19.8%, cerebrum 17.8%, and cerebellum 62.3%. In patients older than 10 years, localization was brain stem 21.3%, cerebrum 23.3%, and cerebellum 55.3%. Although survival differs by histology behaviour, size, and location, the survival for all cases was 64%. There were no differences in survival by sex (F 63% vs. M 64%); age was an important factor (older than 3 years 66% vs. younger than 3 years 57%). This data, while not yet rip, are very similar to other published registries.

EPI 15. THE PREDIAGNOSTIC PROBLEMS IN CHILDREN WITH PRIMARY BRAIN TUMORS

Monika Drogosiewicz, Marta Perek-Polnik, Bożenna Dembowska-Bagińska, Danuta Perek, and Iwona Filipek; Department of Oncology, Children’s Memorial Health Institute, Warsaw, Poland

The aim of the study was to assess the prediagnostic period and diagnostic difficulties in patients with primary brain tumors treated in one institution. Material and Method: Prediagnostic period of 172 pts (101 boys, 71 girls, aged 3 months–17 years 3 months, median 8 years 3 months) treated in the oncology department from 01.1997–12.2000 was analyzed based on patients carts. Analysis of tumor location and related symptoms and symptoms interval was performed in correlation with mean diagnostic period and performed diagnostic procedures and involved specialists. Results: In the whole group, 50% of pts were diagnosed within 1 month, 25% in up to 3 months, 16% in 4 to 12 months, and 9% in more than 12 months. According to tumor location, the shortest prediagnostic period was obviously in the brain stem tumors group (mean 2.08 months), while the longest was in the midline tumors (mean 9 months) and hemispheral tumors (mean 7 months). The cause of diagnostic delay in this group was epilepsy treatment without MR check-up. In 47% of cases, the patient was diagnosed by first specialist (mainly neurologists patient was referred to). Only 28% of general pediatritians who saw the patients ordered CT/MR and diagnosed the tumor. The most common misdiagnosis was gastric problems, which was most heavily diagnosed including invasive procedures. Comments: The prediagnostic period in children with primary brain tumors is too long, so more education is needed on the basic level of health care about epidemiology of brain tumors and sign and symptoms of the disease. This work was supported by grant nr C 028/P05/2002.

EPI 16. OPTIMIZING CARE FOR BRAIN TUMOR PATIENTS

Claudia Epelman, Sidnei Epelman, and Alejandro Arancibia; TUCCA-Associação para crianças e adolescentes com tumor cerebra and Santa Marcelina Hospital, São Paulo, Brasil

Malignant brain cancer is a devastating illness. Because of the brain injury caused by the tumor itself and subsequent treatment (surgery, radiation, and chemotherapy), most brain tumor patients develop neurological, emotional, and intellectual difficulties that compromise their ability to live independently, to study, and to work. In Brazil, 1400 new brain tumor patients are diagnosed per year, mainly between 4 and 9 years. Unfortunately, a high incidence of late diagnosis and lack of facilities for adequate approach in public hospitals are still the reality of the country. In order to improve cure rates and decrease sequelae of those patients, the Brain Tumor Association for Children and Adolescents - TUCCA, a charitable organization, was founded in 1998. The association is dedicated to improving the treatment, quality of life, and the long-term outlook for young patients with brain and spinal cord tumors through research, multidisciplinary support, education, and advocacy for families and survivors. TUCCA has joined in a collaborative effort with different institutions in Brazil to fund support programs and quality of life improvements for children and their families that go beyond the budgetary scope of the institutions. The association has already supported 120 patients, distributes a free guide all over the country for parents of children with brain tumors, co-sponsors educational seminars and conferences, and provides online information through www.tucca.org.br. Last year, TUCCA also developed strategies to decrease late diagnosis and improve prognosis in patients with retinoblastoma. An international campaign to bring leucokoria to the attention of pediatricians, ophthalmologists, and the population in general was developed together with International Network for Cancer and Treatment Research. The Brain Tumor Association raises funds through donations and different events such as annual gala dinners and various recitals and other performances.

EPI 17. PRESENTING FEATURES OF BRAIN TUMOURS

Rebecca Ferris, Colin Kennedy, and Ashok Nathwani; Department of Paediatric Neurology, University of Southampton, UK

Objectives: Analysis of patterns of presenting symptoms and signs in children with brain tumour. Methods: Retrospective review of case notes of 200 consecutive children presenting over 14 years at a tertiary referral centre in the UK Results: The most frequent symptoms were headache (56%), vomiting (51%), behavioural and/or educational problems (44%), unsteadiness (40%), and visual problems (38%). 74 of the 112 patients with headache had it as their first symptom, and 14 as their only symptom. Headache was more than 4 months in duration in 36%, including 57% of those in whom it was the only symptom. A diurnal pattern of headache suggestive of raised intracranial pressure was present in two thirds. Headache was commonly associated with vomiting (77%), visual difficulties (57%), unsteadiness (45%), behaviour change (32%), and disturbed sleep (26%). The median duration of symptoms was 3 weeks for visual problems and unsteadiness, 5 weeks for vomiting, and 2 months for headaches and educational and behavioural problems. On examination, cranial nerve abnormalities (49%), cerebellar signs (48%), papilloedema (38%), motor abnormalities (27%) were the commonest findings. 12% had no neurological signs at presentation, including 8.5% with new onset seizures (1 simple partial, 13 complex partial, and 3 generalised). Conclusions: In children with a brain tumour, headache has a recognisable pattern. New onset behavioural/educational problems or unsteadiness are the next commonest presenting symptom after headache and vomiting. Cranial nerve signs, cerebellar signs, and papilloedema are commoner than upper motor neurone signs. Seizures will usually not be associated with abnormal signs. Recognition of this could expedite the diagnosis of brain tumours in childhood.

EPI 18. LENNOX GASTAUT SYNDROME CAUSED BY A PECULIAR CYST: A CASE REPORT OF AN UNEXPECTED TUMOUR

Johanna M. Fock, Eelco W. Hoving, Annet Kingma, and Jan A. Leeuw; Pediatric Neuro-Oncology Workgroup, Departments of Neurology, Neurosurgery, and Pediatric Oncology, University Hospital Groningen, Groningen, The Netherlands

Lennox Gastaut syndrome is one of the malignant child epilepsy syndromes with tonic, atonic, myoclonic seizures, and atypical absences. The pathology of this epilepsy syndrome is not yet solved, although many cases show diffuse brain lesions. Cases resulting from brain tumours are rare. A right-handed boy, aged two, was referred to our hospital with atonic seizures in clusters. He used valproicacid (VPA) resulting in a good control of the attacks. After a flu-like period, the attacks increased and changed into atonic, tonic, and generalized tonic clonic seizures, and atypical absences of 30 seconds. Electroencephalogram confirmed the diagnosis Lennox Gastaut syndrome. Vigabatrin was started with good effect. MRI of the cerebrum was performed, showing an arachnoidal cyst in the left fissura Sylvii. Because of the unsure effect of surgery on amelioration of the epilepsy treatment, a wait and see policy was chosen. 18 Months after the initial seizures another period of severe attacks evolved. Craniotomy for marsupialisation of the cyst was the treatment of choice now. A solid tumour appeared peroperatively and a gross total resection was accomplished. There were no postoperative complications. Histologically the tumour was a low-grade glioma. No adjuvant therapy with radiation or chemotherapy was given. The boy recovered well and did not suffer any more from epileptic seizures. His postoperatively neuropsychological assesment showed a developmental delay for language and visualmotor integration apart from a severe attention-deficit disorder. The parents had never noticed delay or change in mental development; it was therefore assumed that both tumour, Lennox Gastaut epilepsy, and a genetic factor contributed to the cognitive dysfunctioning. 4 Years postoperatively the boy is doing well with significant mental improvement (IQ rise from 50–94), but he still needs special education. Neither the epilepsy syndrome nor the tumour recurred.

EPI 19. NEUROCUTANEOUS MELANOSIS (NCM)—A CHALLENGE FOR THE PEDIATRIC NEUROONCOLOGIST

Michael C. Frühwald, Kathy Keyvani, Hans-Jörg Schulze, Otfried Debus, Heribert Jürgens, and Ronald Sträter; University Children’s Hospital Muenster, Department of Pediatric Hematology and Oncology, Münster, Germany

Tumors of the spinal cord represent between 1 and 6% of all CNS malignancies. Clinical symptoms comprise radiating or localized nerve root pain accompanied by sensory and motor dysfunction. As these neoplasms are rarely amenable to neurosurgical resection or even biopsy, they represent a special diagnostic and therapeutic challenge for the multidisciplinary team. Case Report: Our index case is a 11-month-old boy, who presented at birth with multiple nevus cell nevi on the neck, face, and extremities. At 5 months the boy developed signs of raised intracranial pressure with increased head circumference and irritability. After diagnosis of an internal hydrocephalus by ultrasound and CT, a VP-shunt was placed. At 11 months the patient presented symptoms of incomplete paraplegia. MR-imaging revealed an enhancing mass extending from the medulla oblongata to the cervical spine. Analysis of CSF obtained from the VP-shunt was positive for nests of tumor cells stained by the antimelanosomal antibody HMB-45. The diagnosis of a spinal leptomeningeal melanoma was made. The combination of nevus cell nevi (>3) associated with melanoma of the spine is by definition diagnostic of neurocutaneous melanoma (NCM). Therapy with dexamethasone, temozolomide, and thalidomide brought initial stabilization but could not stop the disease process. The patient succumbed to the neoplasia at 15 months of age. Neurocutaneous melanosis is a rare congenital phacomatosis. Melanomas of the leptomeninges and spinal cord occurring in the course of this syndrome pose a great therapeutic challenge. The outcome is almost inevitably fatal. Herein we discuss current knowledge of the tumor biology and potential therapeutic or at least palliative approaches. This work was supported by the Karl Bröcker Stiftung, Geseke, Germany.

EPI 20. PREDICTORS OF TUMOR PROGRESSION IN PEDIATRIC GANGLOGLIOMAS

Lynn Gargan, Bradley E. Weprin, Linda R. Margraf, and Daniel C. Bowers; The Neuro-Oncology Program, Children’s Medical Center of Dallas and the University of Texas Southwestern Medical Center, Dallas, TX, USA

Few reports describe the outcome and prognostic factors for children with gangliogliomas. The purpose of this study is to identify prognostic factors for tumor progression for children with newly diagnosed ganglioglioma. The medical records of consecutive children <18 years old with a low-grade ganglioglioma were examined. 25 children with ganglioglioma were identified (mean ± SD age, 7.7 years ± 4.9 years; range: 1.3 to 17.6 years). There were 17 (68%) males. The mean duration of follow-up was 5.7 years ± 4 years (median: 6.4 years; range: 0.3–13.9 years). Tumor locations included the cerebral cortex (n = 16), brainstem (n = 4), cerebellum (n = 3), thalamus (n = 1), and suprasellar region (n = 1). 22 children were treated with surgery alone (complete resection = 12, subtotal resection = 10), and 3 were treated with subtotal surgical resection and radiation therapy. Kaplan-Meier 5 year PFS was 91%. Three tumors located in the brainstem progressed at 0.25, 1.2, and 10 years following diagnosis (Brain Stem vs. All other sites, p-value = 0.011). One of these tumors underwent malignant transformation to an anaplastic ganglioglioma, and the child died 10 years following initial diagnosis. The progression-free survival and overall survival of children with ganglioglioma are very good. Tumors located in the brainstem are more likely to progress than in other locations. Malignant transformation is an uncommon event for children with ganglioglioma.

EPI 21. DISSEMINATED JUVENILE PILOCYTIC ASTROCYTOMA IN CHILDHOOD

J. Russell Geyer, Ji Hye Kim, Richard G. Ellenbogen, and Dennis W.W. Shaw; Children’s Hospital and Regional Medical Center, Seattle, WA, USA

Purpose: To evaluate the outcome of the patients with disseminated pilocytic astrocytoma compared to nondisseminated disease. Methods: We identified 12 patients with disseminated pilocytic astrocytoma from our Tumor Registry over a 21 year-period and reviewed medical records and neuroimaging to determine tumor location, pattern of dissemination, clinical characteristics, treatment, and outcome. 24 controls without dissemination, matched for age, histology, and primary location were used for case/control comparison using Kaplan-Meier survival analysis. Results: 12 (12%) out of 99 cases with pilocytic astrocytoma were identified with CSF dissemination. Primary tumor sites were: hypothalamus/chiasm [8], cerebellum [3], medulla/vermis [1], and pineal region [1] (2 sites in one patient). Two cerebellar tumors were gross totally resected, 8 subtotal/partial resected, and 3 biopsied. 10 patients received postop chemotherapy and/or irradiation. Dissemination was present at initial diagnosis in two and from 2 to 99 months after diagnosis in 10. Diagnosis was by MRI [12] and histology [7]. 9 patients had tumor or treatment-related symptoms, and 3 were asymptomatic at time of metastatic detection. 8 patients were treated with single or combinations of resection, irradiation, and chemotherapy for dissemination. On follow-up, 11 of 18 cranial and spinal metastatic lesions improved or remained stable; minimal progression was noted in 7. Four of 12 patients died over a mean follow-up of 78 months since dissemination detection, compared to 2 of 24 controls over a similar period. Mean survival time: disseminated = 161 +/−15 months [CI 130–191], control = 183 +/−11 months [CI 161–205] (p = 0.33). Conclusion: CSF dissemination of pilocytic astrocytoma occurs most commonly in tumors of the chiasm/hypothalamic region. Though the mortality with disseminated tumors appeared greater, the difference did not reach statistical significance in this series. Treatment options should be considered carefully appreciating the potential indolent nature of these tumors even with dissemination.

EPI 22. CYSTIC CENTRAL NEUROCYTOMA OF THE FOURTH VENTRICLE: A CASE REPORT

Hasan Ghaffar, Shan Li, Richard J. Hicks, and Luis A. Moral; Departments of Pathology and Radiology, Baystate Medical Center and Tufts University School of Medicine, Springfield, MA, USA

Central neurocytomas are neuroepithelial neoplasms occurring in young adults that usually arise in the region of the lateral ventricles and/or the third ventricle. They have also been described in atypical locations without any association with the ventricles, and rarely in the posterior fossa. We describe the radiologic, histologic, and immunohistochemical features of a central neurocytoma of the fourth ventricle in a 13-year-old female. Magnetic resonance imaging showed a 3.5x2.0x1.8 cm cystic mass arising in the fourth ventricle and extending superiorly to the tectum. The mass filled the fourth ventricle completely and obstructed the aqueduct of Sylvius. Biopsy revealed a low-grade neoplasm comprised of nests and cords of isomorphous small round cells with perinuclear halos in a gliofibrillary background. Anaplastic features were absent. The neoplastic cells were immunoreactive with synaptophysin and negative with neurofilament, glial fibrillary acidic protein, epithelial membrane antigen, and cytokeratin. The Ki-67 labeling index was less than 1%. Since central neurocytomas occur rarely in the fourth ventricle and can display pronounced cystic changes, they should be considered in the differential diagnosis of cystic lesions within the posterior fossa.

EPI 23. INTRACRANIAL CHILDHOOD EPENDYNOMAS: AN ANALYSIS OF PROGNOSTIC PATTERNS OF FAILURE IN THE GROUP OF 154 CONSECUTIVE PATIENTS

Wieslawa Grajkowska,1 Slawomir Barszcz,2 Marcin Roszkowski,2 Marta Perek,3 Monika Drogosiewicz,3 Danuta Perek,3 Elzbieta Jurkiewicz,4 and Pawel Daszkiewicz2; 1Departments of Pathology, 2Neurosurgery, 3Oncology, and 4Radiology, The Children’s Memorial Health Institute, Warsaw; Poland

From 1981 to 2003, 154 children were treated for intracranial ependynoma at Children’s Memorial Health Institute, Warsaw, Poland. In this study, all cases of ependynoma, were evaluated according to the influence of age of the patients, primary tumor location, histopathological type, mitotic activity, extent of surgical resection, type of radiation therapy, and contemporary chemotherapy (from 1997) on the survival probability. All the recurrences were evaluated according to secondary tumor location and a spinal relapse.

EPI 24. REGISTRY FOR CENTRAL NERVOUS SYSTEM (CNS) ATYPICAL TERATOID TUMOR/RHABDOID TUMOR (AT/RT): TREATMENT AND OUTCOME IN 42 CASES

Joanne M. Hilden, Sharon Meerbaum, Peter Burger, Jonathan Finlay, Anna Janss, Bernd W. Scheithauer, Andrew W. Walter, Lucy B. Rorke, and Jaclyn A. Biegel; Department of Pediatric Hematology/Oncology, The Children’s Hospital, The Cleveland Clinic, Cleveland, OH, USA

The registry was established to collect treatment and outcome information for children with CNS AT/RT, a very rare and aggressive childhood tumor. We report data for 42 registry patients. There were 28 males and 14 females, ranging in age from 1.5 to 118 months (median 24 months) at the time of diagnosis. Twenty (48%) children underwent gross total resection (GTR); twenty-two had a subtotal resection or biopsies. All children received chemotherapy at diagnosis. Thirteen (31%) children received primary radiation therapy (XRT). Sixteen (38%) children received intrathecal (IT) chemotherapy. High-dose chemotherapy and peripheral blood stem cell or marrow rescue (SCR) was given to 13 (31%) children. One child died of toxicity (fungal pneumonia). Twenty-six children (62%) had progression (15) or relapse (11); median time to progression was 12 months (range 3–62 months). Among the 20 children with primary GTR, 10 (50%) are free of disease 9.5–76 months post diagnosis; 10 are dead of disease with a median survival of 15 months (3–76 months). Thirteen children received XRT as initial therapy with a median survival of 48 months (7–96 months post diagnosis), five died of disease 7–62 months, and 8 show no evidence of disease 19–96 months. Children treated with IT had a recurrence rate of 9/13 (69%) with a median survival of 23 months (10–90 months). Of the 13 children treated initially with SCR rescue, 6 (46%) recurred at 10–22 months from diagnosis, 1 died of toxicity, and 6 remain disease-free 9.5 to 90+ months from diagnosis. Fourteen patients (33%) show no evidence of disease (NED) (median survival 42 months; range 9.5–96 months). Median age of the NED children is 30 months (range 5–78 months). Ten (72%) underwent a GTR, 7 (50%) received XRT, 6 (43%) received IT, and 4 (28%) received SCR. Table shows NED patients’ treatment:

Patient #Age (mon)GTRXRTITSCRNED Survival (mon)
629vvv53
928v76
1330vv44
1640vvv90
2278vv72
2319vvvv48
2848v96
2915vvv60
316vv24
322238
4444v21.5
5047v11
5749v9.5
585vvv21

NED = no evidence of disease; GTR = gross total resection; XRT = radiotherapy; IT = intrathecal therapy; SCR = stem cell rescue

Aggressive resection, radiation therapy, and intensive chemotherapy for this rare, often fatal CNS tumor is recommended; stem cell rescue and intrathe-cal chemotherapy should also be considered. Physicians should continue patient enrollment onto the CNS AT/RT registry. Prospective multi-institutional clinical trials should be designed specifically for CNS AT/RT.

EPI 25. REDUCING THE RISKS AND INCREASING THE BENEFITS; AN INTEGRATED CLINICAL PATHWAY FOR CHILDREN WITH CNS TUMOURS

Monica Hopkins, Conor Malluci, Nicki Thorp, Barry Pizer, and Heather McDowell; Royal Liverpool Children’s NHS Trust, Liverpool, UK

Complex interdisciplinary collaboration is becoming the central tenet of effective high-quality care of children with CNS tumours, often across multiple institutions. Meeting the varied needs of these children throughout their cancer journey is challenging. These teams must be co-ordinated, effectively communicate, and be pro-active in their planning of care, always seeking to ensure a sound evidence base. The neuro-oncology team in Liverpool set about constructing a robust framework to facilitate these goals, whilst developing a parallel audit facility to generate data for effective evidenced based care. An integrated care pathway (oncology, surgery, and radiotherapy) for children with CNS tumours was finally launched in September 2004 after extensive consultative work and a pilot strategy. The pathway consists of three sections for the three modalities of therapy plus outpatient documentation for long term follow-up and surveillance. It commences at referral, through treatment and follow-up thereafter, with detailed guidance on the strategy for care and space for the documentation of variance as well as audit questions which generate evidence for and against currently held standards of care. Ten patients have been commenced on this pathway. All of the children have so far completed the surgical section, diagnosis, and initial care. Preliminary analysis has been undertaken to evaluate the pathway and standard surgical care thus far. Themes for analysis were: referral process and timings, presentation status and action, diagnostic imaging efficacy in relation to surgical findings, operative morbidity, and rehabilitation progression. The surgical pathway can now be modified to remove redundant data, rephrase misinterpreted questions, and adapt care for the variances stated.

EPI 26. UNCOMMON PRESENTATION OF CRANIOPHARYNGIOMA WITH ANEMIA AND SCHOOL FAILURE IN AN ADOLESCENT

Khalid Kamal, Bulent Ozgonenel, Sureyya Savasan, and Kanta Bhambhani; Children’s Hospital of Michigan, Division of Hematology/Oncology, Wayne State University, Detroit, MI, USA

A thirteen-year-old girl with a history of decline in academic performance in the last six months was referred for the workup of mild normocytic anemia. Physical examination and review of systems were remarkable for delayed puberty, constipation, and weight gain despite decreased appetite. Initial investigations led to the diagnosis of panhypopituitarism and a suprasellar mass, 2.5 cm in diameter. The patient underwent total resection of the tumor, and histopathologic examination revealed craniopharyngioma. At presentation, the patient did not have any headache, focal neurologic findings, visual field defects, behavioral symptoms, or any clinical or laboratory evidence of diabetes insipidus. Craniopharyngioma can present in children with various symptoms related to endocrine, hypothalamic, visual, and neurologic dysfunction. Although readily explained with an endocrinopathic basis, school failure and anemia in an adolescent are uncommon forms of presentation of craniopharyngioma and the diagnosis may be elusive, requiring careful evaluation of the patient.

EPI 27. CREATION OF A WEBSITE FOR FAMILIES OF CHILDREN WITH BRAIN TUMOURS (BT)

Phyllis McGee, Eric Bouffet, Darren Hargrave, and Ross Hetherington; Pediatric Brain Tumour Program (PBTP) and Family Health Media Group (FHMG), The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

Consumers of online health information are concerned with quality and reliability. In the case of families with a child diagnosed with a paediatric brain tumour (PBT), these concerns are justified. Although over 80% of these parents turn to the Internet as source of information, a review of >4000 websites pertaining to PBT demonstrated that many sites are of poor quality, inconsistent, contain errors, are of poor readability, and not well designed from the user’s perspective. Thus, there is a significant need for high quality websites with comprehensive, reliable, and accessible information to serve families of children with BT. To meet this need, FHMG and the PBTP have collaborated to create a website to serve families of children with BT. The FHMG includes pediatric specialists, medical journalists, a medical illustrator, a Flash animator, a creative director, a user experience consultant, and a team of web developers. Interdisciplinary members of the PBTP provided expert content. Families were consulted both formally and informally throughout the development process. The website will launch in early 2004. There are >200 pages of material on PBT. The Information Architecture follows the natural history of the disease, providing an overview of PBT and specific information on the most common tumour types (including medulloblastoma, ependymoma, brainstem glioma, craniopharyngioma, low-grade glioma), treatment, care at home, and late effects. The material is comprehensive, providing medical information, but also addressing safety, nutrition, psychosocial, educational, and quality of life issues. The website presents current research in an accessible manner. Interactive animations provide parents and children knowledge regarding neuroanatomy, radiation, and MRI. The content scores high using the DISCERN tool. Readability scores using the Flesh-reading system are >50 throughout the document. In the future, secure e-mail and discussion fora will be implemented to facilitate communication between patients/families, community professionals, and members of the PBTP.

EPI 28. END-OF-LIFE CARE OF CHILDREN WITH CENTRAL NERVOUS SYSTEM (CNS) TUMOURS

Phyllis McGee, Eric Bouffet, Ruchi Sinah, Maggie Breen, and Darren Hargrave; Neuro-Oncology Programs, The Hospital for Sick Children (HSC), Toronto, Canada and The Royal Marsden Hospital (RMH), London, UK

The provision of end-of-life care is a crucial element of any paediatric neuro-oncology teams practice, but the clinical course and management interventions have not been well reported. Purpose: The purpose of this study was to retrospectively examine the end-of-life care provided to children dying of a brain tumour in two different oncology programs in two different countries to discern similarities and differences. Methodology: A retrospective analysis was performed to describe each child’s clinical course and the care provided by members of the oncology team in terms of health care professionals involved and symptom assessment and management. Results: There were 102 (RMH 52, HSC 50) cases between 01-01-97(RMH)/01-01-01 (HSC) and 31-12-03. The diagnoses were diffuse pontine glioma 28.4%, PNET/medulloblastoma 23.6%, high-grade glioma 19.6%, ependymoma 10.8%, and other tumours 17.6%. The mean age at diagnosis was 6.9 (range 0.1 to 17) years, and mean age at death 8.1 (0.2 to 18.9) years. The mean times from diagnosis and tumour progression to death were 15.1 (0.1 to 100) and 4.1 (0.1 to 19) months, respectively. Overall 53% of children died at home, whilst 44% died in hospital, and 3% in a hospice. The commonest symptoms managed included pain 60.5%, immobility 57%, seizures 46%, swallow difficulties 36%, and impaired speech 32%. The commonest interventions were dexamethasone 70%, opiate analgesia 55%, palliative chemotherapy 54%, anticonvulsants 48%, and nasogastric tube 28%. The main differences between the two centres included place of death (60% RMH and 46% HSC), dexamethasone usage (55% RMH and 75% HSC), and types of health care professionals involved. Discussion: The end-of-life care of children with a CNS tumour requires close collaboration between the family, the hospital, and community based interdisciplinary teams. This study elucidates the care issues related to end-of-life care for children with CNS tumours and provides direction for future palliative care strategies.

EPI 29. FIRST POLISH CENTRAL NERVOUS SYSTEM (CNS) TUMOR GROUP (PCNST G) INTEGRATED CARE FOR CHILDREN WITH CNS NEOPLASMS IN POLAND

D. Perek,1 B.Dembowska,1 A. Balcerska,2 W. Balwierz,3 A.Chybicka,4 J.Kowalczyk,5 M. Krawczuk-Rybak,6 W. Madziara,7 J.Peregud-Pogorzelski,8 J. Wachowiak,9 M. Wysocki,10 and E. Zielińska11; 1Department of Oncology, Children’s Memorial Health Institute, Warsaw; Department of Hematology and Oncology, Medical Academy, 2Gdańsk, 3Kraków, 4Wrocław, 5Lublin, 6Białystok, 7Katowice, 8Szczecin, 9Poznań, 10Bydgoszcz, and 11Łódź; Poland

Background: In Poland children with CNS tumors have in the recent past been treated mainly with surgery and radiotherapy. They have been operated of their tumors in neither adults or children neurosurgery departments followed by radiotherapy, there was no unified multidisciplinary approach to their diseases, and there was no common chemotherapy protocols. There was also lack of cooperation and integration among specialists in the field of neuroimaging, pathology, surgery, radiotherapy, and chemotherapy. Aim: To change this status and improve diagnosis and treatment results of CNS tumors in children, the PCNSTG was created. PCNSSG focused on organization of child service across the country involving several specialties in 11 centers in Poland. In each region, a pediatric oncologist is a coordinator of the care team. Each specialty has a national coordinator, and the whole program is coordinated by the team from The Children’s Memorial Health Institute. Based on our own experience and utilizing data from literature analysis, a project on diagnosis and combined treatment of CNS tumors in children was launched. The project includes a sequence of multidisciplinary interventions, diagnostic and therapeutic for each tumor type. For MB/PNET, HGG, and children under 3 years of age, a protocol was introduced, and for LGG, GCT - SIOP protocol. A computer database was created; each new patient is registered in the study. Information on treatment methods applied, follow-up, and late effects are collected in the database. By introducing this program, we want to target important issues such as interdisciplinary communication and cooperation and introduction of evidence based medicine. This will result in ruling out anecdotal practices and improvement of treatment results. A pathway for children with CNS tumors should be developed in terms of diagnostic, therapeutic procedures as well as psychosocial support and monitoring of late effects. Organization schema and preliminary results will be presented. This work was supported by grant nr C 028/P05/2002.

EPI 30. INCIDENCE, TIMING, AND OUTCOME OF CENTRAL NERVOUS SYSTEM METASTASIS IN PLEUROPULMONARY BLASTOMA

John Priest and Gretchen Williams; The Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics, St. Paul, MN, USA

PPB is a rare dysembryonic childhood tumor of lung and pleura. Three pathologic Types are: I (cystic), II (cystic and solid), III (solid). The median age at diagnosis in Type I disease is 10 months; II: 34 months; III: 44 months. Incidence: cerebral parenchymal metastases (CM) occur in Types II and III (II–III) PPB: in most complete Registry series, CM occurred in 11/43 cases (26%). In larger Registry series with less follow-up, CM occurred in 17/64 cases (27%). Literature cases with variable follow-up: CM in 10/122 cases (8%). Interval: in Registry and literature cases combined, the interval from PPB diagnosis to CM is 1–60 months, median 11 (n = 24 [literature data incomplete]). In 22 of these, CM developed within 32 months. Registry and literature patients with CM range in age at PPB diagnosis from 24–141 months, median 36 (n = 26), consistent with overall II–III cases. Metastases were not observed in Type I disease. Outcome: 18/24 CM patients died. Of 6 alive: 3 are 12, 24, and 80 months after CM (therapy: surgery, radiation, +/− chemotherapy); 3 are early in therapy after CM. Brain was only site of recurrent PPB in 8/17 Registry patients with CM; the 6 surviving patients were among these 8. Cord compression was noted in 3 cases; mechanism is epidural compression from disease in epidural space or vertebrae. CSF cytology was not positive in any Registry or literature case. Autopsy found leptomeningeal disease in 2 Registry patients with very advanced disease. These data suggest: 1. CM not rare in II–III PPB; 2. surveillance brain MRIs every 3 months in II–III PPB from PPB diagnosis to 36 months after diagnosis; 3. aggressive salvage therapy can succeed in isolated CM. Clinicians should have a high prospective index of suspicion for CM in children with II–III PPB.

EPI 31. EXPRESSION OF SURVIVAL IN MEDULLOBLASTOMA: COLLINS’ LAW REVISITED—TORONTO EXPERIENCE (1986–2003)

M. Ronghe, U. Dag-Ellams, N. Tariq, H. Patel, N. Laperriere, A. Huang, D. Hargrave, J. Rutka, and E. Bouffet; Paediatric Brain Tumour Program, Division of Neurosurgery, Radiation Oncology Department, The Hospital For Sick Children, Toronto, ON, Canada

Background: Collins’ Law (CL), (period of risk of recurrence = age of diagnosis + 9 months), has been described as a reliable scheme for prediction of recurrence or cure of medulloblastoma. Expression of survival if patients remain disease-free with time has not been quantified in the literature. Methods: We tested the applicability of CL to 169 patients with medulloblastoma treated between 1986–2003 inclusive. We also analysed the survival in children treated with upfront craniospinal radiotherapy (CSI) +/− chemotherapy. In disease-free patients we expressed chances of survival at different time points (1, 2, and 3 years from diagnosis). We also studied the relationship between time to relapse and length of survival. Results: 169 patients (115 males, median age 77 months [0.5–185]) were identified. 35 were <3-year-old (infants). Of the remaining 134, 95 were M0 and 39 M+.

+5-Year survival (%) if free of progression at
Number5-Years OS (%)5-Years EFS (%)1-year2-years3-years
All patients1695944
Upfront CSI134+5 Infants6552758991
M09781628898100
M142326375257
Avg-risk7885689098100
High-risk614027466368

77/169 patients had progression or recurrence. Median time to relapse was 11.5 months (1–63). All relapses occurred within CL period. Eighteen patients have survived beyond CL period without relapse. Median follow-up for surviving patients is 4.6 years. Median survival time in patients who relapsed within 1 year of diagnosis was 0.4 years vs. 1.1 years for those relapsing after 1 year. (p = 0.02) Conclusion: CL is a helpful prognostic parameter that provides information about the risk of recurrence. It is possible to predict the chances of long-term survival in disease-free patients with time, with average-risk/M0 patients showing a plateau after 3 years.

EPI 32. PATTERN OF RELAPSE AFTER IRRADIATION ALONE IN LOCALISED INTRACRANIAL GERMINOMA

Frank H Saran and Susanne J Rogers; Department of Radiotherapy, Royal Marsden Hospital NHS Trust, Sutton, UK

Background: Craniospinal radiotherapy (CSRT) is perceived as the gold standard treatment for localised intracranial germinoma and carries an excellent prognosis with 5 year survivals exceeding 90%. As it may carry a risk of severe late morbidity in very young children, there is a trend to reduce the irradiation volume, particularly omitting the spinal component. We performed a literature review to analyse the influence of irradiation volume on the pattern of relapse. Material and Methods: Medline database search for articles published in English after 1988 employing radiotherapy as sole treatment modality, using combinations of key words: germinoma, germ cell tumour, intracranial, central nervous system, radiotherapy, suprasellar, and pineal. Reviews and case reports were excluded. Results: 27 papers were identified. 8 series were excluded because radiotherapy volumes were unspecified, relapse patterns were not described, spinal staging was not reported, or adjuvant chemotherapy was employed. 661 patients were analysed (weighted median age 15.5 years, range 3–64).

RT volumePatients (n)Local relapses (n)Spinal relapses (n)Other relapses (n)Total
CSRT25412710 (3.9%)
WB*/WV**22496419 (8.5%)
Focal only115819729 (25%)
*WB whole brain irradiation and boost
**WV whole ventricular irradiation and boost

Conclusions: Published series are predominantly retrospective and report heterogeneous therapy of small patient numbers with frequently incompletely staged patients. Relapse rates increase with decreasing irradiation volume. Relapse rates after limited volume irradiation and craniospinal radiotherapy for localised intracranial germinoma are similar when the ventricles are included in the treatment volume. These findings would justify a randomised, controlled trial comparing whole ventricular radiotherapy plus boost with craniospinal irradiation and/or combined modality treatment.

EPI 33. BRAIN STEM GLIOMA IN CHINESE CHILDREN IN HONG KONG

M.M.K. Shing, G.C.F. Chan, A.C.W. Lee, C.K. Li, K.W. Chik, H.L. Yuen, C.K. Li, C.W. Luk, and S.Y. Ha; Departments of Paediatrics of Prince of Wales Hospital, Queen Mary Hospital, Queen Elizabeth Hospital, Tuen Mun Hospital, The Chinese University of Hong Kong, and The University of Hong Kong; Hong Kong Pediatric Hematology and Oncology Study Group; Hong Kong SAR, China

Objective: To assess the outcome of the children with brain stem glioma. Method: The new patients of brain tumors from five major hospitals were entered into the central registry conducted by the Hong Kong Paediatric Hematology and Oncology Study Group. The cases with brain stem glioma were reviewed retrospectively. Results: There were 27 patients from 1995–2003. The median age was 6.54 years of age (1.2–17.79). The sex ratio was 2.38:1. Fifteen patients did not receive any biopsy or surgery. Among them, five patients received radiotherapy (RT) and chemotherapy (CT); six patients received RT alone; four patients were observed without any specific treatment. Seven patients received debulking surgery. Among them, 3 received debulking surgery alone, 3 also received RT and CT, while 1 also received RT. Five patients had biopsy. One patient did not receive any specific treatment after biopsy; two received RT and CT; two received RT. Twelve patients (biopsy or surgery) had a pathology of the brain stem glioma (WHO classification grade I: 2, II: 4, III: 1, IV: 1; not specified: 4). Outcome: Twenty patients died because of progressive disease. Seven patients are still alive (complete response: 1, stable disease: 5, progressive disease: 1). The overall survival was 40.5% at 1 year, 11.6% at two years and five years. Patients who had debulking surgery appeared to perform better than those who did not have surgery (28.6% vs. 7.6% at 2 years; p = 0.05). Seven patients who received radiotherapy were alive at 2 years, while none of the patients (n = 8) who did not received radiotherapy was alive (16% vs. 0%; p = 0.64). Chemotherapy did not improve the outcome (chemotherapy: 0%; without chemotherapy: 16.5% at two years). Conclusion: The outcome of the brain stem glioma in this group of patients is poor. Innovative therapy is necessary for improvement.

EPI 34. THE OPTIC TRACT GLIOMA—ARE ALL OPTIC TRACT GLIOMAS THE SAME?

Avinoam Shuper,1 Ian J. Cohen,1 Isaac Yaniv,1 Michael Schwartz,2 Shalom Michowitz,3 and Liora Kornreich2; Departments of Oncology,1 Radiology,2 and Neurosurgery,3 Schneider’s Children Medical Center of Israel, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel

Optic pathway glioma (OPG) is a relatively prevalent tumor of childhood, especially in children with neurofibromatosis (NF). Although it is generally a pilocytic astrocytoma by histology, its clinical behavior is far from being uniform. OPG’s with the same histology, can in some children be aggressive and fatal, while in others, especially in those with NF, can behave in a chronic, very benign manner. We do not have much data on the molecular biology of the benign ones. In the present communication, we intend to look at the imaging presentation of some of the OPG’s, namely those that present as an elongated tumor, growing posteriorly along the optic pathways. This type of presentation is different from that of a central mass arising from the hypothalamus or chiasm. It can be found both in NF and nonNF children, is generally associated with a chronic course and better prognosis, but still can require intervention due to tendency to cyst formation. The characteristic of growing along and inside nervous tracts, rather than as a concentric mass lesion, is probably unique to OPG’s. This characteristic of growing along the optic pathways presumably indicates a different growth mechanism of the tumor. While a “regular” tumor is presumably growing from one nidus and is enlarging more or less concentrically to occupy its environment, the elongated OPG’s require different explanation for their specific way of growing. This different mechanism of growth may have implications on the medical approach in such cases.

EPI 35. MEDULLOBLASTOMA: THE VIENNA EXPERIENCE IN IMPROVEMENT OF OVERALL SURVIVAL RATES BETWEEN 1969 AND 2000

Irene Slavc, Sandra Lechner-Pissenberger, Ingeborg Fischer, Andreas Peyrl, Thomas Czech, Christine Haberler, Wolfgang Dietrich, Karin Dieckmann, and Johannes A. Hainfellner; Departments of Pediatrics, Neurosurgery, and Radiotherapy, and Institute of Neurology, University of Vienna Medical School, Austria

Prognosis of medulloblastoma patients has improved significantly over the past 30 years. The objective of this study was to analyse the evolution of overall survival in the context of continuous improvement in imaging, surgery, and adjuvant radio- and chemotherapy in patients treated at the Vienna University Hospital between 1969–2000. The cohort was divided into 3 groups according to time periods linked to major changes in management of brain tumors, namely introduction of CT in 1980 and MRI in 1987: Group 1: 1969–1979, n = 39; Group 2: 1980–1990, n = 20; Group 3: 1991–2000, n = 25. Total resection was achieved in 47/84 patients; 2 patients each in Groups 1 and 2 underwent biopsy only. In addition to radiotherapy, chemotherapy was introduced in 1974 and was administered to 11/39 patients (28%) in Group 1, 15/20 (75%) in Group 2, and 25/25 (100%) in Group 3 according to a variety of protocols. The 5-year survival rates were 34%, 63%, and 74% for Groups 1, 2, and 3, respectively, and the 10-year survival rates were 19%, 63%, and 65%. On Kaplan-Meier analysis the difference in survival rates between the 1970s and the 1980s (p = 0.0365) was significant, whereas the difference between the 1980s and 1990s was not (p = 0.6519). In summary, our observation indicates a stagnation of overall survival rates over the past 20 years despite ongoing international efforts both in basic and clinical research to improve prognosis of medulloblastomas.

EPI 36. A SINGLE-CENTRE’S MANAGEMENT REVIEW OF MEDULLOBLASTOMAS SPANNING 29 YEARS

Robert Smee, Janet Williams, Graeme Wise, Les White, Ian Andrews, Heather Johnston Anne Bye, Richard Cohn, Warwick Stenning, Bernard Kwok, Marianne Vonau, and Robert Jones; The Prince of Wales and Sydney Children’s Hospital, Randwick, NSW, Australia

Objectives: Presented is a single-institution’s review of the management of these tumours for the paediatric population at the Prince of Wales Hospital. Materials/Methods: Between 1972–2001, 75 patients aged 18 years or younger, diagnosed with medulloblastoma were referred for consideration of treatment (radiotherapy surgery or chemotherapy). Statistical software package for this analysis was SPSS. Total patient population analysed consisted of 50 males and 25 females, the largest age group being 2 years old at presentation (12 patients). Consultation occurred only in 8, 5 presented with recurrence, 53 presented for initial presentation, and 9 patient records were unavailable for research. The study was divided into three time frames: 1972–1984, 1985–2001, and 1990–2001. In series 1, 26 paediatrics presented; series 2 totalled 49 patients; and in series 3, 39 patients presented. Results: 61 patients presented having initial surgery with only one child having surgery twice, and 41 patients had chemotherapy protocol. Median dose and fractions respectively for radiotherapy was 34.06Gy and 21.08. Recurrences occurred in 16 patients, 11 occurring within the posterior fossa (14.7%), spine 4 (5.3%), and 1 patient (1.3%) had extra CNS recurrence. Results for this group of tumours evaluated at our centre are: total paediatric population 5 alive (with disease) 6.7%, 33 alive (disease free) 44%, 2 dead (not due to their disease) 2.7%, 23 dead (due to disease) 30.7%, and 12 records were unavailable to follow up. More recently treated patients have improved outcome (67% 5-year survival). Conclusion: Medulloblastomas are aggressive tumours with a high mortality rate especially in the paediatric population. Early diagnosis, improved imaging capabilities and treatment techniques has produced more favourable results with each time frame.

EPI 37. CRANIOTOMY FOR RESECTION OF PEDIATRIC BRAIN TUMORS IN THE UNITED STATES 1988–2000: PROVIDER VOLUME—OUTCOME RELATIONSHIPS AND EFFECTS OF PROGRESSIVE CENTRALIZATION AND SPECIALIZATION OF CARE

Edward R. Smith, William E. Butler, and Fred G. Barker II; Department of Neurosurgery, Children’s Hospital, Boston, MA; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA; USA

Introduction: This study utilized a national hospital discharge database to ask whether volume of care is related to outcome after pediatric brain tumor resections, and whether there has been centralization and/or specialization of surgical treatment of pediatric brain tumors. Methods: Cross-sectional and longitudinal cohort survey study using the Nationwide Inpatient Sample, 1988–2000. Multivariate logistic regression adjusted for age, sex, geographic region, admission type, tumor location and malignancy, and resection type. Results: 4712 pediatric brain tumor craniotomies were performed at 329 hospitals by 480 surgeons. In-hospital mortality was 1.6%, decreasing from 2.6% (1988–1990) to 1.2% (1997–2000). Mortality was significantly lower at higher-volume hospitals (odds ratio 0.49 for tenfold larger caseload). Mortality rates were 2.1% at low volume hospitals, compared to 1.2% at high volume hospitals. There was a trend toward lower mortality rates by higher-volume surgeons (P = 0.2). About 5% of US hospitals performed pediatric craniotomies for brain tumor during this period. Per-hospital median caseload increased from 1.7 to 3/year and 90th percentile hospital volume increased from 11 to 17/year, accounting for about one-third of the decrease in mortality observed during this period. Care shifted toward teaching hospitals, from 58% of cases in 1988–90 to 85% in 1997–2000 (P < 0.001), and toward surgeons whose practice was predominantly pediatric (median percent of practice age <19 increased from 12% in 1988–90 to 27% in 1997–2000, P = 0.05). Conclusions: Mortality rates for pediatric brain tumor craniotomies were lower at high-volume hospitals in the United States, 1988–2000. There was a trend toward lower mortality over time. For pediatric brain tumor craniotomy in the US, 1988–2000, there were trends toward greater centralization of surgery and more specialization of surgeons. The increased per-hospital caseload explained a substantial fraction of the observed decrease in mortality rates during this period.

EPI 38. A REVIEW OF SPANISH PEDIATRIC MEDULLOBLASTOMAS DURING THE LAST 21 YEARS

A.Urberuaga,1 A. Navajas,1 J. Burgos,1 J.I. Pijoán,1 N. Pardo,2 X. Matias-Guiu,2 M. Melo,3 M. Rey i Ruhí,3 C. Calvo,4 J. Alfaro,4 J.M. Couselo,5 J. Forteza,5 M.J. Antuña,6 P. Ablanedo,6 T. Acha,7 B. Weil,7 A. Muñoz,8 M. García,8 A.M. Alvarez,9 and J.M. Loizaga9; 1Pediatric Oncology Unit and Departments of 2Pathology and 3Clinical Epidemiology, Hospital de Cruces-Barakaldo Vizcaya; Hospital Sant Pau, Barcelona; Hospital de Sabadell, Barcelona; Hospital Miguel Servet, Zaragoza, Hosptial Xeral de Santiago, Lacoruna; Hospital Central de Asturias, Asturias; Hospital Maternal-Inafntil, Malaga; Hospital Ramon y Cajal, madrid; Hospital Virgen del Rocio, Sevilla; Spain Hospital de Cruces-Barakaldo, Vizcaya1; Hospital Sant Pau, Barcelona2; Hospital de Sabadell, Barcelona3; Hospital Miguel Servet, Zaragoza4; Hospital Xeral de Santiago, La Coruña5; Hospital Central de Asturias, Asturias6; Hospital Materno-Infantil, Málaga7; Hospital Ramón y Cajal, Madrid8; and Hospital Virgen del Rocío, Sevilla9; Spain

Introduction: Medulloblastoma is the most common malignant brain tumor in childhood, accounting for 20% of all childhood primary central nervous system neoplasms. Due to the different survival of the affected children, it is understood that there must be a feature related to the biology of these tumors that directs them into a more aggressive behavior. Objective: To find any feature of prognostic significance among the characteristics evaluated at diagnosis to subdivide these patients in different risk groups. Methods: Clinical charts and paraffine blocks of 79 pediatric patients (p) diagnosed as medulloblastoma between 1980 and 2001 were reviewed retrospectively. Nine different hospitals from Spain collaborated in this study. Clinical and histological variables studied were: age, gender, localization, Chang classification, surgical resection, adjuvant treatment, histologic type, desmoplasia, nodularity, fibrilar pattern, nuclear pleomorphism, necrosis, mitotic rate, p53 expression, and vascularity. Overall survival was analyzed in relation to the obtained results using Kaplan-Meier curves. Results: With a mean and median follow-up of 75 and 53 months, (range 1–264 months), respectively, 36 p are alive without disease, 1 p is alive with disease, and 41 p are dead. P values of studied variables were: age, 0.36; gender, 0.75; localization, 0.70; Chang T, 0.06; Chang M, 0.09; surgical resection, 0.00; adjuvant treatment, 0.49; histologic type, 0.33; desmoplasia, 0.17; nodularity, 0.80; fibrilar pattern, 0.45; nuclear pleomorphism, 0.00; necrosis, 0.00; mitotic rate, 0.08; p53 expression, 0.80; and vascularity, 0.00. Comments: Type of surgical resection persists as the only clinical prognostic factor. Among the histological characteristics related to survival, nuclear pleomorphism, necrosis grade, and vascularity showed prognostic significance. A combination of these clinical and histological characteristics evaluated at diagnosis, with the help of molecular biology, could be reliable to subclassify these patients in different risk groups.

EPI 39. PROGNOSTIC FACTORS OF PONTINE GLIOMAS IN CHILDREN

Sabine Wagner,1 Monika Warmuth-Metz,2 Ove Peters,1 Astrid-K Gnekow,3 Norbert Jorch,4 Ronald Sträter,5 Thorsten Pietsch,6 Stefan Rutkowski,7 and Johannes E.A. Wolff1,8; Department of Paediatric Oncology of 1Regensburg, 3Augsburg, 4Bielefeld, 5Münster, and 7Würzburg, Germany; 2Department of Neuroradiology, University of Würzburg, Germany; 6Department of Neuropathology, University of Bonn, Germany; and 8University of Calgary, AB, Canada

Background: The overall prognosis of pontine gliomas remains poor; prognostic factors are uncertain. In the HIT-GBM Database of the GPOH (Society of Paediatric Oncology/Haematology of the German speaking region), children with pontine tumors have been documented in different studies: 1. a documentation study (HIT-DOC), 2. the HIT-GBM Study, a multicenter, prospective cohort comparison study with five consecutive protocols (A–E). Patients and Methods: Children with brainstem gliomas mainly located in the pontine region, registered from 1996 to 2001 in the HIT-GBM Database, were evaluated. using chi-square test and Kaplan Meier curves, log rank test and Cox multivariate regression of the SPSS program. Results: 129 children, 60 males, mean age 8.1 year (1.3–18.6 years) met the eligibility criteria. 30% had low-grade glioma: WHO °I (4/60), WHO °II (14/60), WHO °III (21/60), WHO °IV (21/60), unknown histology (n = 69). 10 tumors were partially resected, 4 tumors subtotally, 108 tumors were nonresected (unknown = 7). The mean overall survival of all patients was 0.87 years, the one year overall survival (1YOS) 40.3% ± 4.8%. No patient survived longer than 2.9 years. Patients younger than 5 years had a significant (p = 0.025) better survival (1YOS = 67% ± 12.3%) than older children (1YOS = 35.6% ± 5.1%). There was no survival advantage for low-grade tumors and for females. In subgroups, defined by radiological criteria, there was no survival advantage for dorsal exophytic gliomas (11/94), for gliomas with contrast enhancement (23/83), or for cystic gliomas (15/95). Focal tumors (13/100: diameter <50% of the pons, sharp borders) had significant better survival than nonfocal tumors (1YOS 66.7% ± 13.6 vs. 32.6% ± 5.7%, p = 0.0281). Typically endophytic gliomas (not cystic, not focal, not dorsal exophytic, 51/85) did not have a survival disadvantage in this data set. Conclusion: Age younger than 5 years and focal growth were favourable prognostic factors. No long-term survival was documented in these patients.

EPI 40. PAEDIATRIC NEURO-ONCOLOGY FROM 2500 BC TO NOW, AN HISTORICAL PERSPECTIVE

David Walker,1 Cliff Bailey,2 Roger Taylor,2 Giorgio Perilongo,3 and Jonathan Punt1; 1Children’s Brain Tumour Research Centre, University of Nottingham, UK; 2Department of Paediatric Oncology, St. James’ Hospital, Leeds, UK; 3University of Padova, Italy

Introduction: Paediatric Neuro-Oncology has evolved as an international subspecialty with the establishment of the ISPNO in 1985. Historically, the scientific body knowledge which forms the basis for modern practice can be traced to 2500 BC. Studying the evolution of this specialty identifies development of combined modality working from the late 19th century to the present day. Methods: Consultation of a wide variety of texts, websites, experienced colleagues, and other historical sources helped create an historical timeline, depicting events, people, institutions, journals, scientific advances, awards, and political events that have shaped the current state of knowledge and practice. This information will be used to stimulate further contributions of important historical events, nationally and internationally, by a request to delegates to identify additional events as part of an on-going chronology of events that will evolve. Suggestions for additional timeline items with images or film would be acknowledged and will be recruited through e-mail referral ( ku.ca.mahgnitton@reklaW.divaD). The first draft has already been incorporated in Brain and Spinal Tumors of Childhood, Editors: D.A. Walker, J.A.G. Punt, R. Taylor, G. Perilongo, Arnold. A DVD version will be developed in July 2004. Results: A summary of the time line will be presented in a lecture format and on a PowerPoint presentation during the exhibition. This presentation will identify the evolution of neuroscience, neurosurgical practice, institutions, diagnostic imaging, radiotherapy, chemotherapy, cancer science, and epidemiology, which have been identified so far as making major contributions to the clinical and scientific practice of neuro-oncology. Conclusion: Further collection and subsequent dissemination of information from this timeline will stimulate international debate of the national and international scientific and clinical developments critical to establishment of effective clinical services for children with brain and spinal tumours in our respective national health systems.

EPI 41. THE ROLE OF THE PAEDIATRIC NEURO-ONCOLOGY CLINICAL NURSE SPECIALIST

Beth Ward and Mandy Reynolds; Paediatric Neuro Oncology, Great Ormond Street Hospital for Children NHS Trust, London, UK

Great Ormond Street Hospital is the largest neuro-oncology centre in the UK, seeing 80–95 newly diagnosed children with Central Nervous System (CNS) tumours per year. In addition to this, a further 40–50 children present with disease progression or recurrence. Our team consists of two neuro–oncology clinical nurse specialists who cover a 50 mile radius around London and provide a 24-hour on call telephone advice service. We work closely with a large multi-disciplinary team and aim to support children and their families from diagnosis to cure, long-term follow-up to palliative care. We link with paediatric community nurses, Gps, and schools to provide a seamless service. The post is both challenging and yet rewarding and enables holistic care to be given from hospital to home.

EPI 42. THE CHALLENGES OF MANAGING PALLIATIVE CARE AT HOME

Beth Ward; Paediatric Neuro-Oncology, Great Ormond Street Hospital for Children NHS Trust, London, UK

When curative treatment is no longer possible, families require support from a trusted professional, enabling them to make informed choices about their child’s palliative care. The Clinical Nurse Specialist is often the most appropriate professional to fulfill this role. In 2003, with the support of the Clinical Nurse Specialists, six children died from progressive Central Nervous System (CNS) disease at home without the need for readmission to hospital. Managing evolving symptoms at home can be challenging, but often these can be anticipated during the palliative phase of a child’s care. The Clinical Nurse Specialists visit families at home, often jointly with the local Paediatrician, Paediatric Community Nurses, and General Practitioners. They offer guidance in managing symptoms, for example progressive disability, pain, agitation, nausea, and vomiting, seizures, hydrocephalus, and bulbar palsy. They also provide psychological support, exploring issues surrounding death and dying with the child, parents, and siblings. A 24-hour telephone support service is available to the families and other professionals.

EPI 43. DESMOPLASTIC VS. NONDESMOPLASTIC MEDULLOBASTOMA: DIFFERENCES IN CLINICAL OUTCOME?

Stergios Zacharoulis, Christopher Turner, Susan Chi, Giannoula Klement, Nicole Ullrich, Scott Pomeroy, Karen Marcus, Liliana Goumnerova, Michael Scott, Mark Proctor, and Mark Kieran; Pediatric Neuro-Oncology, Dana-Farber Cancer Institute and Children’s Hospital Boston, Boston, MA, USA

Background: The prognostic significance of histopathology in medullobastoma is uncertain. We compared the clinical outcome of desmoplastic vs. nondesmoplastic medulloblastoma patients at our institution. Methods: Between June 1985 and November 2002, 96 patients were diagnosed with medulloblastoma based on the WHO criteria and were treated on existing national protocols. A retrospective analysis of the clinical presentation, histopathologic diagnosis, metastatic work-up, and outcome of all medulloblastoma patients was performed. Complete data for analysis were available for 72 patients. Results: There were 40 boys and 32 girls. Median age at diagnosis was seven years (range, 15 months–22 years). The most common presenting symptoms included: headache (82%), vomiting (66%), ataxia (49%), nausea (49%), and diplopia (18%). Gross total resection was achieved in 57/72 (79%) of these patients, subtotal in 13/72 (18%), and partial in 2/72 (3%). Metastatic work-up at diagnosis revealed M1 disease in 12/72 (16%) patients, and M3 disease in 3/72 (4%). No patients with extra-neural disease were identified. There were 41 standard-risk patients (55.5%), and 31 high-risk patients (44.5%) identified. Desmoplastic pathology was identified in 12/72 (16.6%) patients. Median age for this group was 4.5 years (range, 2–11years), whereas the median age of the nondesmoplastic medullobastoma patients was eight years (range, 15 months to 22 years). There were five patients (42%) with high-risk disease in the desmoplastic group solely as a result of age less than three years. The event-free survival (EFS) and overall survival (OS) of the 12 desmoplastic patients was 100% for both, whereas for the nondesmoplastic group the EFS was 80% and the OS 85% (median follow-up time 3.6 years; range, 6 months–16 years). Conclusions: Given the limitations of reviewing retrospectively an institutional experience, it is suggested that desmoplastic pathology is more common in younger patients and in the absence of other risk factors may be associated with a better prognosis, even for patients younger than three years of age.

EPI 44. CLINICAL NURSE CONSULTATION FOR FAMILIES OF CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS

Deborah Shiers and Jill Casellini; Children’s Hospital Boston, Boston, MA, USA

The diagnosis of a central nervous system tumor in a child creates crisis within a family. Families must emotionally cope with the devastating diagnosis of a brain or spinal cord tumor as they attempt to comprehend the complex and alien terminology of multiple services, such as the emergency department, neurosurgery, and oncology. The child must undergo many invasive tests, procedures, surgeries, and treatments in rapid sequence. There is little time for family members to absorb what is happening to them and their child. In order to make sound decisions, families of these children benefit from the professional support of a clinical nurse consultant. Children’s Hospital Boston houses a 24-bed neuroscience/neuro-oncology unit where pediatric patients are treated for CNS tumors. The role of the clinical nurse consultant was created to help families of these patients navigate through the maze of health care providers within the hospital system and the community. The clinical nurse consultant provides professional assistance to the family from the time of admission to the hospital through discharge. Families are also contacted after discharge to reinforce the plan of care, to troubleshoot, and to listen. This role was successfully piloted over two months with eight families and is now a standard of care on our unit. The consultant role includes family and patient education, interdisciplinary case management, and many types of support, including palliative care, if needed. The role is maintained by neuroscience clinical coordinators and educators. This poster will follow the course of a child with CNS tumor and his family along the continuum of care. The instrumental role of the clinical nurse consultant will be highlighted through this example.

EPI 45. BIOLOGIC AND ENVIRONMENTAL RISK FACTORS FOR CHILDHOOD BRAIN TUMORS: THE CALIFORNIA CHILDHOOD BRAIN TUMOR STUDY

P.G. Fisher, S. Preston-Martin, M.R. Wrensch, J.L. Wiemels, J.K. Wiencke, R. McKean-Cowdin, G. Block, C. Metayer, P. Reynolds, J. Von Behren, D.O. Nelson, S. Selvin, D.O. Stram, W.J. Gauderman, M. Tonge, and P.A. Buffler; Stanford University, Palo Alto, CA; University of Southern California, Los Angeles, CA; University of California, Berkeley, CA; University of California, San Francisco, CA; California Department of Health Services, Oakland, CA; USA

Brain tumors are a rare cancer with poor survival, but among children, these neoplasms are the second most frequent malignancy. Etiology for the vast majority of childhood brain tumors (CBT) is unknown. Past epidemiological investigations have used limited samples and addressed largely environmental risk factors, or sometimes genetic predisposition, both in isolation. To understand CBT etiology, one must identify how genes, environment, and lifestyle influence risk and combine to cause CBT. The major goal of this population-based case-control study—The California Childhood Brain Tumor Study—will be to examine biologic and environmental exposures, and their interrelationships that lead to risk of developing a CBT. A single sample of 477 cases and 954 controls will be obtained in a 38-county study area in Northern, Central, and Southern California. This region provides a unique opportunity to investigate CBT, with its 12 pediatric cancer centers and 5.9 million children, of whom nearly 50% are Hispanic. There are systematic differences between Hispanic and nonHispanic White populations in regard to both patterns of environmental exposure and genetic profiles. A network of the 12 pediatric cancer centers, the California Department of Health Services, and 4 major research universities has already been convened for this study. To synergize this network, highly interrelated projects and cores will investigate CBT risk, all efficiently using the same sample of cases and controls. Molecular genetic techniques will be employed rigorously to assess somatic and germline changes, and thus to classify tumors and to examine predisposing biologic changes. Comprehensive epidemiological data will be sought to clarify whether children with CBT experience common environmental or dietary exposures. Subsequent analyses will examine the interrelationships of genetic predispositions and environmental exposures leading to risk of CBT. In general, there will be statistical power of 80% to detect odds ratios of 1.5 to 2.0 for main effects of risk factors with prevalence of 5% to 30%. Furthermore, to overcome limitations of sample size, population attributable fraction analyses will also be employed. This program, assessing biologic and environmental risks and their combined effect in the development of CBT, proposes to be a precise, large, and definitive study not only in CBT, but also in any childhood cancer.

EXPERIMENTAL THERAPIES

EXP 1. SACRAL PLEXOPATHY IN CNS TUMOR PATIENTS RECEIVING INTRATHECAL THIOTEPA

Amy Amundson Smith, Steven Janselewitz, Susan Apkon, Laura Z. Fenton, and Nicholas K. Foreman; The Children’s Hospital, Denver, University of Colorado Health Sciences Center, Denver, CO, USA

At the Children’s Hospital, Denver, 18 patients with intracranial germ cell tumors have been treated from 1995–2002. Among this group, there are 8 pure germinomas and 10 nongerminomatous germ cell tumors. Three of the 7 germinomas presented with disseminated disease, and all of the nongerminomas were localized. Out of this cohort, there have been 5 recurrences and one patient who had rising βHCG after 2 cycles of conventional doses of chemotherapy. These patients were treated with intense chemotherapy as well as craniospinal radiation and intrathecal thiotepa. An unusual yet consistent pattern of sacral plexopathy has been diagnosed in 4 young men, all with high-risk disease, treated similarly. To our knowledge, this complication has not been previously described for these agents and is likely related to IT thiotepa, possibly in combination with another agent or treatment modality.

EXP 2. TOPOTECAN AS A RADIOSENSITIZER IN THE TREATMENT OF CHILDREN WITH MALIGNANT BRAINSTEM GLIOMAS: RESULTS OF A SFOP PHASE II STUDY

Valerie Bernier, Chantal Kalifa, François Doz, Jean-Claude Gentet, Jean-Pierre Vannier, Genevieve Margueritte, Odile Lejar, Veronique Laithier, Frederic Millot, Jean-Louis Habrand, Claire Alapetite, Sylvette Hoffstetter, and Pascal Chastagner, for the Société Française d’Oncologie Pédiatrique

Objectives: To evaluate, in a national prospective study, the efficacy of the concomitant administration of radiotherapy and topotecan used as a radiosensitizer in newly-diagnosed brainstem gliomas. Methods: From August 2000 to October 2002, pts harbouring a diffuse pontine glioma were eligible for the study. Topotecan was administered within one hour prior to radiotherapy (1.8 Gy/day in a single fraction, 5 days/week, for 30 fractions) at the dose of 0.4 mg/kg/day over 30 minutes. Response rate (RR) was assessed by MRI one month after the completion of this treatment, then every 3 months. Survival was the endpoint; the statistical procedure was based on sequential subgroup analysis. The baseline criterion was a survival rate of 50% 9 months from the date of diagnosis. Results: 32 pts, 3 to 16.8 years of age (median: 7), entered onto study. The response rate (partial response) is 30%. The median follow-up and EFS are 27 and 6 months, respectively. The overall survival rate at 9 and 12 months are 56% and 25%, respectively. No thrombocytopenia occurred; 1 death was due to cerebral hemorrhage not related to a progressive disease. Conclusions: These results with a 9-month survival rate of 56% do not compare favourably with those obtained in our three previous SFOP studies evaluating the efficacy of high-dose busulfan/thiotepa (58%), conventional carboplatin (67%), or continuous procarbazine (54%) during and after radiotherapy.

EXP 3. EXPERIENCES WITH INTRAVENTRICULAR ETOPOSIDE IN NEOPLASTIC MENINGITIS OF RELAPSED METASTATIC BRAIN TUMORS

Udo Bode, Chuleekorn Sirisangtragul, Stefan Rutkowski, Carola Hasan, Ulrich Jaehde, and Gudrun Fleischhack; Department of Pediatric Hematology/Oncology, Children’s Medical Hospital, University of Bonn, Bonn, Germany

Therapeutic options are limited in relapsed metastatic brain tumors. As the systemic administration of etoposide is efficacious in these tumor entities, in 1998 a pilot trial was designed to study the feasibility and pharmacokinetics of intraventricularly administered etoposide in these patients. Between February 1998 and December 2003, 48 patients aged 1.9 to 34.6 years with relapsed brain tumors were treated with intraventricular etoposide simultaneously to systemic chemotherapy. Etoposide were administered via an indwelling subcutaneous reservoir for 5 to 10 consecutive days every 2 to 5 weeks over a period of 0.5–16 months in three different dosages: 1) 0.25 mg q 12 hours (4 patients/16 courses), 2) 0.5 mg q 24 hours (28 patients/133 courses) and 3) 1.0 mg q 24 hours (19 patients/112 courses). During 40 courses in 8 patients, serial CSF samples were obtained and etoposide levels were determined by reversed-phase HPLC. Acute side effects included transient headache in five patients, bacterial meningitis in four patients, a CSF pleocytosis without any infection in two patients, and reversible seizures in four other patients with extensive neoplastic meningitis. Longterm side effects were impairment in concentration, verbal fluency, and short-term memory in three patients. Pharmacokinetic analysis was performed by using a two-compartment model. In the different schedules (1/2/3) the following parameters (mean ± SD) were estimated: Cmin 0.21 ± 0.10/0.12 ± 0.07/0.23 ± 0.14 μ g/ml; Vss 0.14 ± 0.05/0.11 ± 0.06/0.12 ± 0.04 L, CL 0.56 ± 0.25/0.37 ± 0.22/0.43 ± 0.15 ml/min and t1/2z 7.20 ± 0.37/7.02±0.64/7.03 ± 0.91 hour. The lumbal CSF concentrations of etoposide 3 to 6 hours following intra-ventricular administration were 0.53 ± 0.19/1.18 ± 0.78 and 1.33 ± 0.39 μg/ml. Intraventricularly administered etoposide is well tolerated. Pharmacokinetic parameters are independent of dose and schedule. With all regimens mean trough levels exceeded the level of 0.1μg/ml assumed to be cytotoxic. Further studies should be focussed on the optimization of dose and schedule. A phase II trial in neoplastic meningitis is warranted.

EXP 4. ROLE OF TEMOZOLOMIDE (TMZ) FOLLOWING RADIATION THERAPY (RT) IN THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE BRAINSTEM GLIOMA (BSG): RESULTS OF A MULTI-INSTITUTIONAL STUDY (SJHG-98)

Alberto Broniscer, Murali Chintagumpala, Daniel Bowers, Maryam Fouladi, Raja Khan, Dana Wallace, Thomas Merchant, Matthew Krasin, Larry Kun, and Amar Gajjar; Division of Neuro-Oncology, Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To determine the efficacy of TMZ following RT in the treatment of children with newly diagnosed BSG in a multi-institutional study. Patients and Methods: Patients (pts) between 3 and 21 years (years) of age with imaging typical BSG received 2 cycles of intravenous irinotecan (IRN) over 6 weeks followed by conventionally fractionated conformal RT. One cycle of IRN (20 mg/m2/day) consisted of two 5 consecutive daily doses separated by 2 days of rest. The 5-day schedule of TMZ started 4 weeks after RT for a total of 6 cycles. TMZ (200 mg/m2/day) was given orally over 5 days with interval between cycles of 21 to 28 days. Results: 33 pts were enrolled onto this study. The median age at diagnosis was 6.4 years (range: 3.1 to 15.2 years). 17 pts refused the IRN therapy. 10 of 16 pts who received IRN completed the planned treatment with stable disease. In 6 pts IRN was discontinued due to clinical progression (n = 5) or toxicity (n = 1). All pts completed RT (median dose = 55.8 Gy). 4 pts did not receive TMZ due to parents’ request (n = 3) or noncompliance (n = 1). 125 cycles of TMZ were given to 29 pts (median number of cycles = 4). Neutropenia, thrombocytopenia, and anemia grades 3 and 4 were documented in 33%, 29%, and 7% of all cycles, respectively. 1 pt had a grade 3 rash and one pt developed neutropenic fever. 45 cycles (36%) of TMZ required dose reduction due to myelosuppression. All pts have died of their disease after a median interval of 12 months. The 1- and 2-year survival rates were 48% ± 8% and 0, respectively. Conclusions: Our poor results are comparable to other studies in children with BSG. TMZ following RT did not impact on the survival of these children.

EXP 5. PHASE II STUDIES OF ANTINEOPLASTONS A10 AND AS2-1 (ANP) IN CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT) OF THE CENTRAL NERVOUS SYSTEM. A PRELIMINARY REPORT

Stanislaw R. Burzynski, Robert A. Weaver, Mark Bestak, Tomasz Janicki, Gabor Jurida, Barbara Szymkowski, Mohammad Khan, and Vsevolod Dolgopolov; Burzynski Clinic, Houston, TX, USA

AT/RT of the CNS is a rare neoplasm affecting children. The disease progresses rapidly regardless of surgery, chemotherapy, and craniospinal radiation. Despite case reports of sustained remissions, the median overall survival is approximately nine months. Large clinical trials are not possible due to low incidence. The anti-tumor activity of ANP was evaluated in the first 11 children treated under study protocol, four of them in the study and seven under Special Exception (SE) due to a low Karnofsky Performance Status. Four patients had widely spread disease in the CNS, and seven patients had single tumors. All patients were previously treated with surgery, nine with chemotherapy, and five with radiation therapy. Except for one nonevaluable case, all patients developed recurrent and progressive disease before ANP. The treatment consisted of intravenous injections of ANP. The average duration of ANP was 5.7 months. The median of average dosages of A10 was 10.6 g/kg/d and AS2-1 was 0.4 g/kg/d. NCI criteria were used for evaluation of responses based on MRI and PET scans. Three SE patients were nonevaluable. The results are as follows: complete response (CR) two patients (25%), partial response one patient (12.5%), stable disease one patient (12.5%), and progressive disease four patients (50%), median survival 17.1 month from diagnosis. One CR patient developed recurrence after premature discontinuation of ANP and obtained a second CR after ANP was restarted. This patient who initially had multiple metastases to the brain and spinal cord died due to aspiration pneumonia and was confirmed by autopsy as disease free. Only one case of serious toxicity was described and consisted of reversible hypernatremia. The study continues, but the accrual is slow due to the rarity of AT/RT.

EXP 6. TREATMENT OF PRIMITIVE NEUROECTODERMAL TUMORS (PNET) WITH ANTINEOPLASTONS A10 AND AS2-1 (ANP). PRELIMINARY RESULTS OF PHASE II STUDIES

Stanislaw R. Burzynski, Robert A. Weaver, Mark Bestak, Tomasz Janicki, Barbara Szymkowski, Gabor Jurida, Mohammad Khan, and Vsevolod Dolgopolov; Burzynski Clinic, Houston, TX, USA

PNET is usually successfully treated with craniospinal radiation and chemotherapy; however, the difficulties with standard treatment can be encountered in very young children, in adult patients at high risk of complication from standard treatment, and in patients with recurrent tumors. Seventeen patients, either with recurrent disease or high-risk, were accrued to Phase II trials with ANP. The patient’s median age was 6 years old (ranging from 12 months to 23 years old). Medulloblastoma was diagnosed in 10 patients, pineoblastoma in 5, and other PNET in 2. The involvement of the spinal cord was found in 1 patient, and multiple metastases in 5. Previous treatment included resection (all patients), chemotherapy (8), and radiation therapy (8). Eight high-risk patients did not receive prior chemotherapy and radiation. The treatment consisted of intravenous infusions of ANP, which was administered for a median of 5.2 months. The median of average dosages of A10 was 9.4 g/kg/d and AS2-1 was 0.4 g/kg/d. MRI and PET scan accessed responses according to NCI criteria. Two patients were nonevaluable due to lack of follow-up scans. Complete response was accomplished in 20%, partial response in 13.4%, stable disease in 33.3%, and progressive disease in 33.3% of evaluable patients. Six patients are alive and well (from over 6 to 10 years) post diagnosis, and five were not treated earlier with radiation therapy and chemotherapy. The median survival is 20.6 months from start of ANP and 41.8 months from diagnosis. The serious side effects included a single occurrence of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients. The percentage of patients’ response is lower than for standard treatment, but reduced toxicity makes ANP promising for very young children, patients at high risk of complication from standard therapy, and patients with recurrent tumors.

EXP 7. AN EXTENSIVE REVIEW OF CHEMOTHERAPY AGENTS SUITABLE FOR INTRATHECAL (IT) THERAPY IN PRIMITIVE NEURO ECTODERMAL TUMOUR (PNET)

Sharon Conroy, Ian Craven, Martin Garnett, Steve Barrett, Jonathan Punt, Terry Parker, and David A. Walker; Children’s Brain Tumour Research Centre, Division of Child Health, School of Human Development, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK

Introduction: PNETs are chemosensitive and potentially metastatic to the CNS in all, justifying, craniospinal radiotherapy (CrSpRT) or prolonged systemic chemotherapy +/− IT therapy, in order to avoid toxicity of CrSpRT. Effective IT therapy could permit further de-escalation of extended field RT doses and systemic chemotherapy. Identification of suitable agents for IT therapy is complex; we report a systematic approach to selection of drugs for IT use that is applicable to new agents as they are developed. Methods: Ideal characteristics with respect to cycle specificity, pharmacological qualities, and toxicity profile were defined. An extensive list of 111 known chemotherapy agents was developed. A literature search strategy on Medline and Embase (1966 to Jan 2001) using drug name plus the terms: medulloblastoma, PNET, leptomeningeal carcinomatosis, and intrathecal administration. The searches were conducted with “explode mode.” 33,033 hits were obtained. Where hits exceeded 50, the drug was reviewed against any specific contraindications via the intrathecal route as a basis for rejection. Subsequent searches were narrowed and physicochemical data were identified and tabulated for comparison. 114 papers were screened. Results: 90 drugs were excluded because of irritant qualities, neurotoxicity, need for enzyme activation, reported adverse reactions to IT administration, and lack of information. 11 drugs were identified: Cytarabine (liposomal), Carboplatin, Diaziquone, Etoposide, Floxuridine, Mafosfamide, Mercaptopurine, Nimustine, Ranimustine, Temozolomide, and Topotecan. Conclusions: Drugs not in reported IT use, yet active against PNET were Carboplatin, Etoposide, Nitrosoureas, and Temozolomide. Drugs with unknown activity against PNET, yet in reported IT use were Cytarabine (liposomal), Floxuridine, Mercaptopurine, and Diaziquone. Drugs with known activity against PNET and in current IT use were Mafosfamide and Topotecan New methods for testing existing drugs and early testing of new drugs is needed.

EXP 8. DO MEDULLOBLASTOMA SAMPLES MEET THE FDA CRITERIA FOR ANTI-ERBB2 THERAPY WITH TRASTUZUMAB?

N. Entz-Werle, V. Velasco, A. Neuville, B. Georger, E. Guerin, and G. Vassal, J. Grill; Pediatric Onco-Hematology, CHRU Hautepierre, Strasbourg; Pediatric Oncology, Gustave Roussy Institute, Villejuif; France

Medulloblastomas represent one of the most common forms of childhood brain tumor. During the last years, several publications have focused on erbB2 expression in these brain tumors and its prognostic correlation. To confirm these data, we experienced the detection of c-erbB2 overexpression at DNA and protein level in medulloblastomas at diagnosis. Tumor samples were obtained at diagnosis from 12 patients and after xenografting in 8 other cases. In this population of 20 pediatric patients, all ages and tumor extension were found. The 12 tumors were fresh-frozen specimens in 6 cases, stored at −20°C, and comprised paraffin-embedded samples for 6 others. A DNA extraction could be done in all 12 samples. At present, a quantitative PCR was only performed on 9 samples using Lightcycler - HER2/neu - quantification kit (Roche, Inc). The erbB2 overexpression was quantified in tumor DNA by comparison to a control gene. An immunohistochemical analysis with NCB11 (Novocastra) and/or DA485 (Dako) antibodies allowed us to study the c-erbB2 protein expression in all samples. On 6 out of 8 xenografted specimens, a FISH analysis was also performed. At DNA level, no overexpression of erbB2 gene was detected with the QPCR in tumor samples and no amplification was obtained with the FISH technique in xenografted tumors. The immnohistochemistry in all specimens confirmed at the protein level the negative results previously obtained by QPCR. Neither overexpression of erbB2 was observed in the 8 xenografted paraffin-embedded tissues as in 9 out of 12 tumor samples. Our results show an absence of erbB2 overexpression in the 20 medulloblastomas, in discordance with previous published data. In any case, such observation allowed us to speculate that erbB2 overexpression could not be the major molecular target in pediatric medulloblastomas. A analysis of c-erbB2 on a larger cohort could confirm or infer these negative results.

EXP 9. ESTIMATING CSF TOPOTECAN EXPOSURE IN CHILDREN WITH HIGH-RISK MEDULOBLASTOMA AND SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR (PNET) USING A PHARMACOKINETIC (PK) MODEL

Burgess B. Freeman III, Lisa C. Iacono, John C. Panetta, Amar Gajjar, Murali Chintagumpala, Stewart J. Kellie, David Ashley, Peter J. Houghton, and Clinton F. Stewart; Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

Embryonal central nervous system (CNS) tumors, such as medulloblastoma, have a high propensity to disseminate throughout the subarachnoid space. The occurrence of metastatic disease throughout the neuraxis suggests the cerebrospinal fluid (CSF) is an important source of drug exposure. Systemic chemotherapy administration is an approach to achieve cytotoxic CSF exposure and avoid the problems associated with intrathecal drug administration. Topotecan (TPT), a topoisomerase I interactive agent, was cytotoxic to medulloblastoma cells in vitro at an exposure duration threshold (EDT) of 1 ng/mL for 8 hours. To ensure patients reach this CSF TPT concentration, CSF sampling is necessary. Unfortunately, such sampling is associated with significant complications, and obtaining CSF solely for pharmacokinetic sampling is often not justified. Therefore, the goal was to develop a population PK model to estimate CSF TPT exposure from plasma PK data. We studied 5 males and 1 female (median age 4.8 years, range 3.6–8.4 years) with high-risk medulloblastoma that received two courses of pharmacokinetically guided TPT to attain a target TPT AUC of 120 to 160 ng/mL-hour. Previous PK simulations suggested that this AUC had a high likelihood of achieving the EDT in the CSF. To assess CSF TPT exposure, serial ventricular CSF samples were obtained in children with an indwelling Ommaya reservoir. Plasma and CSF TPT PK profiles were generated using two and three compartment models, respectively. The population PK parameters and measures of variability were determined using linear mixed effects modeling. Using the population PK parameters and bootstrapping, we simulated numerous plasma TPT AUC values. Of the 18 PK guided TPT studies, 11 met or exceeded the desired plasma target range and 9 of these achieved or surpassed the CSF EDT. Using this population PK model, we demonstrated that the CSF EDT could be attained at tolerable plasma TPT AUC values.

EXP 10. FEASIBILITY OF RADIOSURGERY FOR MALIGNANT BRAIN TUMORS USING ROBOTIC RADIOSURGERY

Cole A. Giller, Brian D. Berger, Joseph P. Gilio, Janice L. Delp, Kenneth P. Gall, Bradley Weprin, and Daniel Bowers; Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

Objectives: The benefits of radiation therapy are generally denied to infants with malignant brain tumors because of the risk of devastating cognitive decline. Although the use of focused radiation might be expected to lessen this morbidity, radiosurgical techniques have not been feasible for these very young children due to the dual requirements of rigid head fixation and high precision. We report here the radiosurgical treatment of five infants using a robotically controlled system without rigid head fixation. Methods: Five infants with malignant brain tumors received radiosurgical treatment with a robotically driven linear accelerator (Cyberknife, Accuray Inc., Sunnyvale, CA). The age at treatment of the five infants was 7, 9, 12, 18 and 30 months, respectively. Immobilization was aided by general anesthesia, form-fitting head supports, face masks and body molds. The average marginal dose was 17 ± 2 Gy and the average treatment volume was 18 ± 22 cc. Results: X-rays obtained during treatment demonstrated acceptable accuracy in all cases. In one case, the lesion did not progress, but a distant recurrence appeared 15 months after radiosurgery and was treated with a second radio-surgery. In another case, tumor in the treated region did not progress, but recurrence elsewhere led to death seven months after treatment. Tumor enlargement occurred in the third patient 3 months following treatment, leading to death 2 months later. Tumor size is smaller in the remaining two patients (9 and 11 months after treatment). There has been no toxicity attributed to treatment. Conclusion: Radiosurgery can be offered to infants with acceptable geometric precision and minimal toxicity using a robotically controlled system without the requirement of rigid fixation. A formal dose-escalation trial is underway to more thoroughly address radiosurgical doses and toxicity for infants.

EXP 11. INTRAOPERATIVE RADIATION THERAPY WITH THE PHOTON RADIOSURGERY SYSTEM IN CHILDREN WITH RECURRENT BRAIN TUMORS: A PRELIMINARY REPORT

John A. Kalapurakal, Stewart Goldman, V. Sathiaseelan, Maryanne H. Marymont, and Tadanori Tomita; Division of Radiation Oncology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

The photon radiosurgery system (PRS) is an intra-operative radiation therapy (IORT) device that is capable of delivering radiation (RT) into the surgical resection cavity of brain tumors. Between 2001 and 2004, 16 children received IORT. Twelve children were enrolled on a phase-I dose escalation protocol. Patients were classified into two groups. One group, GpA, consisted of 8 children with recurrent tumors (5 with supratentorial ependymoma, 1 each with glioma, astroblastoma, and fibrosarcoma) after surgery or chemotherapy but not RT. The other, GpB, comprised of 8 children with recurrent tumors (7 with ependymoma and 1 with a glioma) after surgery, full dose RT (>50 Gy) and chemotherapy. The IORT dose was 10 Gy to 2 mm in ten, 10 Gy to 5 mm in four, and 12 Gy to 2 mm in two patients. The primary study end point was the development of unacceptable (≥grade 3) acute CNS toxicity. The median follow-up was 12 months (4–24). 12 patients (75%) have achieved tumor control after IORT, 6/8 (75%) each in GpA and GpB respectively. Two GpA patients (2/8, 25%) developed radiation necrosis 3–6 months after IORT. One required surgery, and pathology revealed radiation necrosis without tumor recurrence. The second patient is asymptomatic with resolving necrosis on MRI. Both patients were treated with 10 Gy to 5 mm. Among 4 patients treated with 10 Gy to 5 mm, 2/4 developed radiation necrosis. There were no complications noted among GpB patients despite previous RT. Seven patients in GpA (88%) and 5 in GpB (63%) are alive; 6 died of tumor progression. This report describes the feasibility, safety, and early efficacy of IORT (10 Gy to 2 mm) in children with recurrent brain tumors who may or may not have previously received RT. Patients are currently being enrolled at the next dose level (12 Gy to 2 mm) of our study.

EXP 12. INTRATHECAL 131-I-LABELED 3F8 ANTIBODY IN PATIENTS WITH GD2-EXPRESSING CENTRAL NERVOUS SYSTEM AND LEPTOMENINGEAL NEOPLASMS

Kim Kramer, Nai-Kong V.Cheung, John Humm, Samuel Yeh, Ester Dantis, Ira J. Dunkel, Suzanne Wolden, Ron Finn, Brian H. Kushner, Yasmin Khakoo, Mark M. Souweidane, Pat Zanzonico, Keith Pentlow, and Steven M. Larson; Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Objective: To estimate the pharmacokinetics, toxicity, and radiation dose to the cerebrospinal fluid (CSF) following intraventricular injection of 131-I-labeled 3F8 monoclonal antibody in patients (pts) with GD2 antigen-positive central nervous system (CNS) and leptomeningeal (LM) disease. Methods: Fifteen pts with medulloblastoma, melanoma, neuroblastoma, ependymoma, rhabdoid tumor, and retinoblastoma (ages 1–61; 12 with evaluable disease) received an initial tracer (37–74 MBq, 1–2 mCi) of 131-I-3F8 followed by a second, therapeutic injection (370–740 MBq, 10–20 mCi). Whole-body gamma camera scanning was performed at 4, 24, and 48 hours. Serial CSF and blood samples were counted to derive time-activity data for calculating radiation doses. Pre and posttreatment clinical, radiographic, and cytologic status were evaluated. Results: Total absorbed dose to the CSF from both tracer and therapeutic administrations ranged from 120–1300 cGy (CSF samples). Using region-of-interest analysis of the gamma camera images, the dose to the CSF in the ventricles was 320–4150 Gy and 100–1370 Gy in the spinal column. Average 131-I-3F8 clearance half-life was 12.5 hours (3.5 – 44 hours). Average ratio of the therapy/tracer administration (Gy/MBq), was 0.88 (±0.58) and 1.08 (±0.66) by CSF counting and ROI analysis, respectively. Side effects included self-limited headache, fever, vomiting. At the higher dose levels, transient elevations in intracranial pressure (n = 1) and asymptomatic bradycardia (n = 2) were observed. Of 12 evaluable patients, clinical improvement (n = 2), radiographic improvement (n = 2), and cytology clearing of malignant cells (n = 2) were observed at both dose levels. No long-term toxicities have been observed 19 months postinjection. Conclusions: Intrathecal 131-I-3F8 can be safely administered to pts with GD2-expressing CNS malignancies. A high CSF:blood ratio is observed. Tracer studies reliably predict the therapeutic dose to the CSF. Ongoing dose escalation will further define the role of targeted radioconjugates in the treatment of CNS tumors.

EXP 13. POTENTIAL ROLE OF THYMOSIN-α1 ADJUVANT THERAPY FOR GLIOBLASTOMA

Peter E. Manley, Arno Sungarian, Sohini Sanyal, Jack R. Wands, and Suzanne M. de la Monte; Pediatric Hematology/Oncology and Departments of Medicine, Pathology, and Neurosurgery, Hasbro Children’s Hospital, Rhode Island Hospital, and Brown Medical School, Providence, RI, USA

Glioblastomas are high-grade, malignant central nervous system (CNS) neoplasms that are nearly always fatal within 12 months of diagnosis. Recent studies showed that immunotherapy using pro-inflammatory cytokines such as IL-2 or IL-12 may prolong survival with glioblastomas. Thymosin-α-1 (Talpha1) is a thymic hormone that acts as an immune-modulator, increasing IL-2 production and T-cell proliferation. The present work examines the potential in vivo therapeutic effects of Talpha1 in relation to glioblastomas and utilizes an in vitro model to determine the mechanisms by which Talpha1 exerts its anti-tumor effects. For in vivo experiments, 9L cells (104) were implanted into the right frontal lobes of Long Evans rats that were subsequently treated with vehicle, BCNU, Talpha1, or Talpha1 + BCNU beginning on day 6 after tumor cell implantation. Rats treated with Talpha1 + BCNU had significantly lower tumor burdens and increased cure rates. In vitro experiments demonstrated that Talpha1 had no direct effect on viability or mitochondrial function in cultured 9L cells. Instead, Talpha treatment resulted in increased levels of pro-apoptosis gene expression, including FasL, FasR, and TNFα-R1 (65.89%, 44.08%, and 22.18%, respectively), and increased sensitivity to H202 induced oxidative stress. Furthermore, Talpha1 enhanced 9L cell sensitivity to both Granzyme B and BCNU-mediated killing. These results suggest that Talpha1 can enhance BCNU-mediated eradication of glioblastoma in vivo and that Talpha1 mediates its effects by activating pro-apoptosis mechanisms, thereby rendering the neoplastic cells more sensitive to oxidative stress and killing by Granzyme B (CTL and NK cells) and chemotherapeutic agents.

EXP 14. A LONG-TERM VENTRICULAR DRAINAGE FOR THE PATIENTS WITH GERM CELL TUMORS OR MEDULLOBLASTOMA: EFFECTIVENESS OF PERCUTANEOUS LONG-TUNNELED VENTRICULAR DRAINAGE

Jun Matsumoto,1 Masato Kochi,1 Hideo Nakamura,1 Keishi Makino,1 Naoki Shinojima,1 Motohiro Morioka,1 Yukitaka Ushio,2 and Junichi Kuratsu1; Department of Neurosurgery, 1Kumamoto University School of Medicine, Kumamoto; 2Otemae Hospital, Osaka; Japan

Hydrocephalus associated with intracranial germ cell tumors or medulloblastoma has been treated with ventriculo-peritoneal shunt (VPS). However, this procedure has a potential risk of intraperitoneal metastasis of these brain tumors. In order to prevent this potential risk, we developed a percutaneous long-tunneled ventricular drainage (PLTVD). In this study, we retrospectively evaluated the effect of this procedure on extra-neural metastasis and infection. From 1979 to 2003, we have treated 103 patients with germ cell tumors or medulloblastoma in our hospital. Of 103 patients, 65 had hydrocephalus and 13 of them required the long-term CSF drainage to manage the obstructive hydrocephalus due to long-lasting tumor, or communicating hydrocephalus due to dissemination. We performed PLTVD for these cases using flow-controlled shunt devise and percutaneous long-tunneled shunt tube (peritoneal catheter) exiting at upper abdomen, connecting to drainage system. The average duration to keep the drainage was 74 days (range 34–115 days). All of 13 cases could receive full dose chemotherapy and radiotherapy without extra-neural metastasis and infectious complication. In addition, 10 cases of 13 patients became free from permanent CSF divergence. In conclusion, PLTVD was effective method to manage long-lasting obstructive or communicating hydrocephalus with germ cell tumors and medulloblastoma.

EXP 15. PHASE I STUDY OF CONCURRENT CEREPORT AND CARBOPLATIN WITH RADIATION THERAPY FOR CHILDREN WITH NEWLY-DIAGNOSED BRAIN STEM GLIOMAS (BSG)

Roger Packer, Mark Krailo, Minesh Mehta, Jeffrey Allen, and Gregory Reaman; Children’s National Medical Center, Washington, DC, USA; Children’s Oncology Group, Arcadia, CA, USA

Radiotherapy remains the only, albeit transient, effective therapy for BSG. Carboplatin has some efficacy against gliomas and radiosensitization properties, but its effectiveness is limited by the blood-brain barrier. Cereport (RMP-7), a bradykinin analog, is a bradykinin B2 receptor agonist that causes selective permeability of the blood-brain-tumor interface. A phase I study in children with diffuse intrinsic BSG was undertaken to determine the duration of concurrent therapy possible, and the toxicity of Cereport/Carboplatin given daily, 5 days in succession during radiotherapy. Cereport was given at 300ng/Kg of IBW/D over 10 minutes beginning 5 minutes before the end of carboplatin (35 mg/m2) infusion. Local radiotherapy (5940 cGy) was given within 4 hours of completion of drug delivery. Patients were treated with a fixed dose of Cereport/Carboplatin. The duration of treatment was escalated in a step-wise, weekly fashion in cohorts of three until there was treatment-limiting toxicity or until radiotherapy was completed. Between 2/2001 and 10/2003, 13 patients, median age 7 years (range 3–14), began treatment. One child died early in treatment due to progressive disease and was not evaluable for toxicity assessment. Treatment for 3, 4, or 5 weeks was well tolerated, with mild flushing. Grade I or II tachycardia, nausea, vomiting, dizziness, and abdominal pain were seen occasionally at all durations of treatment. One of 3 children treated at the full duration of therapy (33 doses/7 weeks) developed dose-limiting hepatotoxicity and neutropenia. Due to lack of Cereport availability, this cohort could not be expanded. 9 of 12 evaluable patients have developed progressive disease. The estimated median survival is 327 days from initiation of treatment. The results of this study confirm the feasibility of giving Cereport/Carboplatin daily during RT. Difficulties with drug availability and preliminary efficacy results question the rationale for further development of this approach.

EXP 16. MRI-GUIDED STEREOTACTIC INTERSTITIAL BRACHYTHERAPY OF NEWLY DIAGNOSED THALAMIC MALIGNANT GLIOMAS OUTCOME CORRELATED TO IMAGING PATTERNS

Jinlin Wang, Xiangsheng Xiao, Xuehua Ding, Yicheng Lu, and Yaofan Zhang; Department of Radiology, Changzheng Hospital, Second Military Medical University, Shanghai, China

The long-term prognosis for survival of patients with inoperable deeply located malignant glioma (MG) is very poor. In spite of increasing experience with stereotactic interstitial brachytherapy (SIBT) for brain tumors, many issues remained unresolved. The authors studied outcomes and tumor response in patients who had undergone MRI-guided fractionated high-dose-rate SIBT for MG in thalamus and basal ganglion correlated to imaging characteristics. SIBT was used for 17 GMs in thalamus and basal ganglion, aged 6 to 67 years with average of 31 years. The tumors were sub-categorized into 3 groups based on enhanced MR imaging: Group including 8 patients of densely enhanced 8 MGs; Group consisting of 4 patients with cystic ring enhanced MGs; Group including 5 patients with nonenhancing anaplastic astrocytomas. The quick shrinkage of tumor volume took place in enhancing MGs; the reduction rate was from 9% to 84% (average, 43%). The nonenhanced astrocytoma had undergone no apparent shrinkage during or immediately after SIBT. Of 8 patients with MG in Group, 4 patients were disease free with 5 to 7 years. Four patients died of radionecrosis or edema with a median survival time of 12.5 months (range, 10 to 17 months). The median survival time was 9 months (range 3 to 15 months) in Group and 11 months (range, 5 to 19 months) in Group. The outcome of MG treated by SIBT was highly correlated to imaging patterns. Local control of homogeneously enhanced MG may be obtained using SIBT exclusively, whereas SIBT may bear a high risk or even be life threatening in nonenhanced MG.

EXP 17. STEREOTACTIC FRACTIONATED CONFORMAL DYNAMIC INTERSTITIAL BRACHYTHERAPY OF INTRACRANIAL GERM CELL TUMORS

Jinlin Wang, Xiansheng Xiao, Xuehua Ding, Yicheng Lu , and Yaofan Zhang; Department of Radiology, Departments of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China

Little is known about the underlying mechanism and process involved in germinoma response to irradiation therapy. This study is to evaluate the process of intracranial germ cell tumors response during and immediately after stereotactic fractionated conformal dynamic interstitial brachytherapy (SFCDIB) using single afterloading catheter in protracted fractionations as first line therapy of intracranial germ cell tumor. SFCDIB using iridium-192 was used in 9 patients for the first line therapy, with a median age at diagnosis of 14.3 years (range, 5–27 years). Stereotactic trajectory, biopsy target, as well as entry point on the scalp were determined using MRI. SFCDIB was performed under MRI guidance within 20 days. The tumor response was assessed by means of volume reduction. The occurrence as well as evolution of intratumor hemmorrage was analyzed. The average tumor volume reduction 85.3% could be obtained in 9 pineal tumors just at the end of therapy. Intratumoral hemorrhage that is to be absorbed quickly accompanying tumor remission was demonstrated in all patients. A complete response was seen in all 9 patients at follow-up 2 month (5 patients) and 3 to 4 months (4 patients) after SFCDIB. We suggest that SFCDIB could be given as an alternative strategy for intracranial germ cell tumor. The histological diagnosis of germ cell tumor can be verified at one operation. Germinoma responded quickly to brachytherapy, so that it appears that extensive surgical resection and a bypass shunt might be not usually necessary.

EXP 18. SURGERY AND ADJUVANT DENDRITIC CELL-BASED TUMOR VACCINATION FOR PATIENTS WITH RELAPSED MALIGNANT GLIOMA

Stefan Rutkowski,1 Steven De Vleeschouwer,2 Eckhart Kaempgen,3 Johannes E.A. Wolff,4 Niels Soerensen,5 Frank Van Calenbergh,6 and Stefaan W. Van Gool7; 1Pediatric Oncology and 5Neurosurgery, University of Wuerzburg, Germany; 3Dermatology, University of Erlangen, Germany; 4Pediatric Oncology, University of Regensburg, Germany; 2,6Neurosurgery and 7Pediatric Oncology, University Hospital Gasthuisberg, Leuven, Belgium

Introduction: In patients with relapsed malignant glioma, an immuno-therapeutic strategy was developed using autologous mature dendritic cells loaded with autologous tumor homogenate. Methods. 22 patients (median age 31.5 years, range: 8–78) with malignant glioma histology and one or more prior relapse were included. All patients received new surgery to obtain tumor tissue. Vaccination started about 4 weeks after surgery, consisting of intradermal injections of mature loaded DC at week 1, 3, and further each 4 weeks. Results: Complete (n = 11), subtotal (n = 7) and partial (n = 4) resection could be performed prior to vaccination. A median of 5 (range: 1–7) vaccines was given. In the patient group with total resection, 5 patients are in continuous complete remission for 33, 32, 17, 13 and 7 months. In this group, both progression-free survival (PFS) and overall survival (OS) at 33 months was 40% (median survivals of 16 respectively 23 months). In the 11 patients with residual tumor load after surgery, vaccination induced 1 stable disease during 8 weeks, and 1 partial response. All these patients were again progressive within 5 months (OS 17% at 10 months, median survivals of 3 respectively 7 months). PFS after 12 months was better for patients <20 years compared to patients >20 years of age (55% and 7%, p < 0.02); however, most patients with complete/subtotal resection belonged to the lower age-group. There were no adverse events except in one patient with gross tumoral disease prior to vaccination, who developed repetitive vaccine-related peritumoral edema. Conclusion: Immunotherapy with autologous mature dendritic cells loaded with autologous tumor homogenate for patients with relapsed malignant glioma is feasible without major adverse events. The beneficial effect for improving PFS and OS by adjuvant tumor vaccination became obvious especially for patients with minimal residual tumor burden.

IMAGING

IMAG 1. SURVEILLANCE SPINAL MRI IN THE FOLLOW-UP OF CHILDREN TREATED WITH MEDULLOBLASTOMA

Ute K. Bartels, Manohar Shroff, Ugo Dag-Ellams, Normand Laperierre, and James Rutka, and Eric Bouffet; The Hospital for Sick Children, Paediatric Brain Tumour Program, Toronto, ON, Canada

Background: Standard follow-up of children treated for medulloblastoma/PNET includes regular cranial and spinal MRI. There has been extensive debate on the clinical value of follow-up cranial MRI. The role of surveillance spinal MRI has not yet been established. Purpose: To study the predictive value of postoperative follow-up cranial MRI in determining the relevance of surveillance spinal MRI. Methods: A search was performed within the neuro-oncology database of the Hospital for Sick Children for patients diagnosed with medulloblastoma and subsequently followed in the institution between 1985 and 2003. Only children treated with craniospinal irradiation as part of their initial treatment were considered. Contrast-enhanced spinal MRIs, which were done concomitant with cranial MRIs (doublets) were reviewed by two investigators. Recurrence was defined as any new abnormal lesion (in the brain or the spine) in a symptomatic or asymptomatic patient. Results: Out of 122 patients, 63 patients (18F: 45M, median age: 6.6 years, median follow-up time: 4.3 years) had at least 1 evaluable doublet in the follow-up period. 275 doublets were available (median per patient: 3, range: 1–13). Of 244 doublets with negative (no signs of recurrence) cranial MRI, no new lesion was identified on spinal MRI (negative predicitive value: 100%). Of 31 cranial MRIs (23 patients) showing signs of recurrence/progression, 20 spinal MRIs showed nodular or leptomeningeal lesions (positive predictive value: 65%). Conclusions: Postoperative follow-up cranial MRI has a very useful value in predicting disease in the spine. Absence of progression on cranial MRI is highly predictive of a negative spinal MRI. The relevance of surveillance spinal MRI is questionable (in children who underwent craniospinal radiation as part of their initial treatment) when cranial MRI showed no recurrence.

IMAG 2. WHITE MATTER LESIONS (WML) DETECTED BY MAGNETIC RESONANCE IMAGING (MRI) FOLLOWING RADIATION THERAPY (RT) AND HIGH-DOSE CHEMOTHERAPY (HDC) IN CHILDREN WITH MEDULLOBLASTOMA (MB) AND SUPRATENTORIAL PNET (SPNET)

Maryam Fouladi, Murali Chintagumpala, Fred Laningham, David Ashley, Stewart Kellie, James Langston, C. McCluggage, Mehmet Kocak, Larry Kun, Valerie Ahem, Marie Sexton, Raymond Mulhern, and Amar Gajjar; Division of Neuro-Oncology, Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: WML have been described as a “delayed effect” of cranial irradiation in children with brain tumors, or a transient “subacute effect” characterized by an intralesional or perilesional reaction in patients following therapy. Here we report the occurrence of WML detected by MRI in children prospectively evaluated during and after therapy for MB/PNET. We document the clinical, imaging, and neuropsychological findings associated with these lesions. Methods: Study group included 134 eligible SJMB 96 patients (pts) with MB/SPNET treated prospectively with risk-adjusted craniospinal irradiation (CSI) and conformal boost to the primary tumor bed, followed by 4 cycles of HDC with stem cell rescue. MR sequences included at least T1 with and without contrast and T2-weighted imaging. Patients had at least 12 months of follow-up since diagnosis. Neurocognitive assessments included IQ tests and tests of academic achievement. Results: WML developed in 22 pts at a median time of 7.8 months after the start of therapy (1.9–13.0 months). Cumulative incidence of WML at 1 year was 15 ± 3%. Lesions were predominantly in the pons (8) and cerebellum (6). In sixteen patients (73%) WML resolved at a median of 6.4 months (range: 1.6–23.5 months) after initial appearance. Two pts subsequently developed atrophy and necrosis and 4 patients had persistent WML at the time of their last scan. Three patients developed persistent neurological symptoms. Compared to an age-and treatment-matched control group, patients with WML had a significant decline in EIQ (−2.5 per year; p = 0.03) and math (−4.5 per year; p = 0.003) scores. Conclusion: WML in MB/PNET patients treated with RT and HDC are typically transient and asymptomatic but may mimic early tumor recurrence. A minority of patients with WML develop permanent neurological deficits and imaging changes. Overall, the presence of WML is associated with greater neurocognitive decline.

IMAG 3. RESULTS OF CENTRAL IMAGING REVIEW FOR PATIENTS ENROLLED ON AVERAGE RISK MEDULLOBLASTOMA (MB) PROTOCOL A9961

Amar Gajjar, Gilbert Vezina, James Langston, Karin Muraszko, Mark Dias, Sandy Kessels, Richard Sposto, and Roger Packer; Division of Neuro-Oncology, Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Memphis, TN; Department of Neurology, Children’s National Medical Center, Washington, DC; and for the Children’s Oncology Group, Arcadia, CA; USA

Purpose: To centrally verify the eligibility of patients enrolled on the COG A 9961 protocol by a multidisciplinary review mechanism that included 2 neuroradiologists (JL, GV); 2 neurosurgeons (KM, MD); 2 neuro-oncologists (AG; RP). Patients and Methods: Between December, 1996 and December 2000, 421 children between 3 and 21 years of age, with nondis-seminated MB having less than 1.5 cm2 of residual disease after surgery, were entered on a prospective randomized study receiving one of two chemotherapeutic regimens and radiotherapy with “reduced”-dose craniospinal irradiation (CSRT, 2340 cGy) plus local RT (cumulative dose 5480 cGy). For the purposes of central imaging review, the following films were sent to the Quality Assurance Review Center (QARC): Cranial (CT or MRI) with and without contrast obtained preop and within 72 hours of surgical resection; MRI with gadolinium of the entire spine with contrast in at least 2 planes obtained within 5 days prior to surgery, or within 28 days after surgery; patients with inadequate imaging studies were considered inevaluable on the protocol but were still eligible for protocol. Patients with M+ disease or >1.5 cm2 of evaluable disease were considered ineligible for the protocol. Results: Of the 421 patients enrolled on the study, we have reviewed the films on 410 pts. Of the 410 pts centrally reviewed, 321 pts (79%) were confirmed to meet eligibility criteria as defined in the protocol; 30 pts (7%) were ineligible (M+ = 16; > 1.5cm2 = 12; other = 2); 59 pts (14%) were inevaluable because of inadequate spinal imaging (n = 31); inadequate imaging technique (n = 22) and films not available for review (n = 6). Conclusions: 21% of the patients enrolled on this protocol were either ineligible or inevaluable from an imaging perspective. Central imaging review serves as an excellent quality control mechanism for neuroimaging studies obtained at participating centers. Adequate spinal imaging to exclude subarachnoid metastatic disease can be difficult in pediatric patients. Imaging protocols defined by the Children’s Oncology Group for evaluation of pediatric patients with CNS tumors need to be applied nationwide to meet expected standards.

IMAG 5. UNSPECIFIC INTRADURAL EXTRAMEDULLARY LESIONS IN EARLY FOLLOW-UP MR EXAMINATIONS AFTER NEUROSURGICAL TREATMENT OF POSTERIOR FOSSA TUMORS IN CHILDREN

Elżbieta Jurkiewicz, Iwona Pakuła-Kościesza, Katarzyna Malczyk, Katarzyna Nowak, Andrzej Kościesza, Marta Perek-Polnik, Monika Drogosiewicz, Bożenna Dembowska-Bagińska, Sławomir Barszcz, Marcin Roszkowski, and Roman Kaźmirczuk; The Children’s Memorial Health Institute, Warsaw, Poland

Background: The children with posterior fossa tumors are usually operated in sitting position. It causes the possibility of moderate hemorrhage into the spinal canal. Early control MR examinations are performed to detect metastases in spinal canal. In some cases we can observe different intradural extramedullar findings, which are probably connected with the sitting position of the child during the operation. Purpose: Presentation of unspecific changes in spinal canal in early follow-up MR examinations of children after neurosurgical treatment of posterior fossa tumors. Material and Methods: We show results of MR examinations of 5 children (two girls and three boys) aged 8–12 y. MR examinations of spinal canal were performed 2–3 weeks after the operation. All examinations were performed using a 1.5T unit with FSE sequences in T1- and T2-weighted images in two planes. Thickness of slices: 3 mm. Gadolinium was used in all cases in the standard dose. Results: In all patients we observed intradural, extramedullary, linear lesions isointensive in T1-weighted and hyperintensive in T2-weighted images with contrast enhancement after Gadolinium administration. In further follow-up examinations after 2–3 weeks we found complete regression of these lesions in all cases. Conclusions: A small number of patients enables to draw final conclusions but we suggest that lesions found on early MR examinations are probably connected with postoperative changes and position of the child during the operation and they are not metastases. To confirm the diagnosis in such cases we suggest next early follow-up (after 2–3 weeks). This work was supported by grant nr C 028/P05/2002

IMAG 6. USEFULNESS OF PROTON MAGNETIC RESONANCE SPECTROSCOPY (MRS) IN DIFFERENTIATION OF PATHOLOGIC LESIONS IN NEUROFIBROMATOSIS TYPE 1 (NF 1) IN CHILDREN

Elżbieta Jurkiewicz,1 Iwona Pakuła-Kościesza,1 Katarzyna Malczyk,1 Marta Perek-Polnik,2 Monika Drogosiewicz,2 and Bożenna Dembowska-Bagińska2; 1Department of Radiology, MR Unit, 2Department of Paediatric Oncology, The Children’s Memorial Health Institute Warsaw, Poland

Background: Neurofibromatosis type 1 is the most common phakomatosis, especially in childhood. It is an autosomal dominant genetic disorder. Typical brain lesions are focal benign brain changes and glial tumors. The presence of the benign changes is a potential mechanism that underlies learning disability in NF-1 children. The pathogenesis and histology of them remains still unclear. They are frequently visualized as noncontrast-enhancing areas of increased signal intensity on PD- and T2-weighted images. They are found in the cerebellar white matter, basal ganglia, thalamus, brain stem and optic radiations. In many cases their size decreases over time. About 15% children with benign changes will develop cerebral low-grade astrocytomas. Typical nonneoplastic lesions may be occasionally difficult to differentiate from low-grade gliomas. Purpose: To estimate metabolic spectra of glial tumors and benign changes and possibility to differentiate these lesions. Materials and Methods: 31 boys and girls with NF1, aged 3–18 years, were examined. MRI was performed with a 1.5T using FLAIR, SE, FSE sequences, T1, PD, T2-weighted images. Gd-DTPA was administered in standard dose. Single voxel MRS was obtained using PRESS sequence with TE – 35ms. Results: HMRS indicated in all cases differences of spectrum in glial tumors (elevated level of Cho, reduced level of NAA) and in high signal-intensity foci on T2-weighted images (elevated level of Cho, almost normal level of NAA). HMRS of benign lesions showed no major abnormalities. We found slight reduction of NAA/Cr and NAA/Cho, almost normal Cho/Cr, normal mI/Cr, and lack of lactates. In all gliomas we observed reduction of NAA/Cr and NAA/Cho, elevated Cho/Cr, and moderate higher mI/Cr. Low or moderate peak of lactates was found in some cases. Conclusion: HMRS allows to distinguish astrocytomas from focal benign lesions. It is a useful part of MRI examination. In some cases the role of MRS can be diagnostic and prognostic as well. This work was supported by grant nr C 028/P05/2002.

IMAG 7. PNET HISTOLOGY CAN BE NONINVASIVELY PREDICTED BY ELEVATED TAURINE LEVELS DETECTED BY PROTON MAGNETIC RESONANCE SPECTROSCOPY

Mark D. Krieger, Ashok Panigrahy, J. Gordon McComb, Marvin D. Nelson, Ignacio Gonzales-Gomez, and Stefan Bluml

Introduction: Primitive neuroectodermal tumors (PNETs) of the posterior fossa, or medulloblastomas, are malignant tumors which typically occur in children. To date, clinical, radiological, and histological criteria have proven to be poor predictors of disease activity. Novel noninvasive diagnostic tools that provide characterization of tumors in vivo may provide additional information to guide therapeutic decisions and elucidate prognosis in individual patients. The present study utilizes proton magnetic resonance spectroscopy (MRS) to elucidate identifying features of PNETs in vivo which may lead to improved diagnosis and treatment. Materials and Methods: Under an IRB approved protocol, 34 children with newly diagnosed brain tumors and 14 normal age-matched controls were studied on a 1.5T GE clinical scanner. Upon retrospective review, 13 of these children had PNETs, whereas the other 21 had other tumors of the posterior fossa, including astrocytomas, pilocytic astrocytomas, and ependymomas. Single voxel 1H MRS spectra of the tumors were acquired using a single voxel PRESS sequence. The regions of interest (ROIs) were placed in the center of solid lesions and did not include any partial volume with surrounding normal appearing tissue in all cases. Single voxel 1H MRS quantification included determination of the fractions of tissue and of necrotic/cystic fluid. Spectra were processed using the LCModel V6.0 software, and absolute concentrations in institutional units (i.u.) of biochemical peaks were determined. Processing of MRS data was completely automated and did not require user interaction. Results: Peaks attributed to taurine (Tau) were readily observed in all PNET patients, and Tau was quantified with a high degree of reliability (Cramer-Rao bounds <20%). [Tau] was significantly higher in “PNET” than in “Control” (3.94 ± 1.45 vs. 0.96 ± 0.50, p <1e-7) or “Other Tumor” (0.47 ± 0.57, p < 1e-10) and separated all “other tumor” patients from PNET. Discussion: In PNETs, although clinical variables permit broad distinctions between patient risk groups, when used alone, they have proved an unreliable basis for assigning therapy. 1H MRS is a standard MR technique available on most clinical MR systems and readily incorporated into the presurgical MR examination of children with brain tumors. Results are immediately available after an MR examination and can thus be used for treatment decisions. In particular, this study identifies taurine as a biochemical constituent which uniquely identifies PNETs and can be used as a noninvasive means of diagnosis and disease follow-up. Other studies have identified elevated taurine levels in neonatal brains but not in children or adults, pointing to its presence in primitive neural tissue. Future work examines the correlation of taurine levels with malignancy in individual tumors.

IMAG 8. MRI ENHANCEMENT PATTERNS IN FOLLOW-UP IMAGING OF CHILDHOOD BRAIN TUMOURS

Stephen J. Laughton,1 John K. Pereira,2 Elizabeth A. Bland,1 and Richard J. Cohn1; 1Centre for Children’s Cancer and Blood Disorders and 2Department of Medical Imaging, Sydney Children’s Hospital, Randwick, NSW, Australia

MRI technology has continued to evolve and is now well established as the standard of care in defining and following brain tumours. Aim: To correlate post therapeutic, follow-up MRI enhancement patterns with clinical and histological outcome. Methods: A retrospective audit of all children, aged <16 years at diagnosis with intracranial brain tumour, treated at the Sydney Children’s Hospital from January 1994 to December 2003 was conducted. MRI scans and the monthly Paediatric Neuro-Oncology Tumour Board meeting minutes were reviewed and correlated with clinical management and outcome data (n = 225). Results: Spontaneous resolution of linear enhancement following surgery was not associated with recurrence or residual tumour. Post surgical enhancement almost always resolved or improved by 12 weeks. Increasing enhancing tissue at the surgical site correlated with local recurrence. Persistence of enhancing tissue beyond 12 weeks was usually due to residual tumour. Development of enhancing foci in the previously nonenhancing tumour was due to radionecrosis or histological change in the grade of the original tumour. Nodular postsurgical enhancement was nonspecific and secondary to post surgical changes, residual tumour or occasionally choroid plexus. Conclusions: Enhancement on follow-up post therapy MRI scans does not always equate with recurrence or residual tumour. The MRI enhancement pattern changes need to be interpreted in the light of recent therapeutic interventions and with knowledge of the current clinical status of the child.

IMAG 9. MOBILE LIPIDS DETECTED BY SHORT ECHO TIME 1H MAGNETIC RESONANCE SPECTROSCOPY CORRELATE WITH MALIGNANCY IN CHILHOOD BRAIN TUMORS

Andrew Peet, Patti Garala, Lesley MacPherson, Kal Natarajan, Spyros Sgouros, and Richard Grundy; Department of Oncology, Birmingham Children’s Hospital and Institute of Child Health, University of Birmingham, UK

Aims: To investigate the importance of the mobile lipid profile (MLP) in characterising childhood brain tumors using short echo time (TE) 1H magnetic resonance spectroscopy (MRS). Background: A number of MRS studies have been successfully conducted in children with brain tumors. The choline/creatine ratio, an indirect measure of cellular turnover, is generally increased in tumors compared with normal brain but does not always reflect the histological grade. Recent in vitro studies have shown a correlation between MLPs measured by MRS and cellular apoptosis and necrosis. Recent clinical MRS studies in adult brain tumors have shown MLPs to be an important indicator of tumour activity and response to therapy. To date most pediatric MRS studies have been carried out at long echo times where lipid signals are attenuated. We have therefore used short echo time MRS to investigate the importance of MLPs in characterising childhood brain tumors. Methods: Single Voxel MRS (TE 30ms) was performed on 60 children with brain tumors at Birmingham Children’s Hospital on a Siemens Symphony 1.5T Magnetom. Absolute concentrations of metabolites and lipids were determined by fitting a linear combination of metabolite basis functions (LCModel). In vivo water was used as an internal concentration standard. Lipid levels are quoted in terms of the concentration of lipid H atoms present. Results: Absolute mobile lipid levels were found to be significantly lower in noninvolved brain [4.8 mmol/l], compared with low-grade gliomas [11.9 mmol/l] (p = 0.01), and these were significantly lower than in malignant brain tumors [20.1 mmol/l] (p = 0.03). Importantly, there was no significant difference in the choline/creatine ratios between the low-grade gliomas and malignant tumors. Amongst the low-grade gliomas, the highest levels of MLPs were seen in tumors which showed rapid clinical progression. Conclusion: We have demonstrated that significant differences in MLPs exist between ‘normal’ brain and childhood brain tumors. Moreover, the absolute level of mobile lipid correlates with malignant potential and predicts clinical behaviour independent of histology.

IMAG 10. COMBINED STEREOTACTIC POSITRON EMISSION TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING FOR IMAGE-GUIDED SURGICAL RESECTION OF BRAIN TUMORS IN CHILDREN

Benoit Pirotte, Serge Goldman, David Wikler, Alphonse Lubansu, Alec Aeby, Patrick Van Bogaert, Philippe David, Jacques Brotchi, and Marc Levivier; Department of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Background: Because brain tumors are histologically heterogeneous, we developed a technique allowing integration of positron emission tomography (PET) data into the planning of stereotactic biopsies and showed it increased the technique’s diagnostic yield in adults and children by selecting targets in areas of highest tracer uptake. We integrated PET images into the stereotactic image-guided navigation planning of ill-defined but accessible brain tumors to help defining tumor limits and of tumors infiltrating functional structures to target partial resection on portions presenting the highest tracer uptake. Aim: We analysed the interest of this technique in children. Material and Methods: Since 1998, we integrated PET in the navigation planning of 16 children (10M/6F, aged 1–14y) with brain tumors (11 supratentorial-hemispheric, 2 cerebellum, 2 brainstem, 1 pineal) when MRI did not individualise clear limits for partial (tumors infiltrating functional areas*) or total (ill-defined but accessible tumors**) resection. Tracer uptake (18Ffluorodeoxyglucose 2, 11Cmethionine 11, both 3) level, heterogeneity/extension helped to define contours for image-guided partial/total resection. Results: This technique allowed to define clear limits of resection in all cases. In 5*, PET allowed to delineate foci of increased tracer uptake (18Ffluorodeoxyglucose 1, 11Cmethionine 4) taken as contours for partial resection. In 11**, PET tracer uptake boundaries (18Ffluorodeoxyglucose 2, 11Cmethionine 9) provided clear tumor delineation taken as contour for total resection (achieved in all but 2 cases: tumor residue left in place to avoid morbidity). Conclusion: This preliminary series suggests that combining PET to image-guided surgical tumor resection in children: 1) provides contour to achieve total resection of ill-defined tumors estimated accessible, 2) could increase the accuracy of partial resection in tumors infiltrating functional structures.

IMAG 11. IMPACT ON THE SURGICAL STRATEGY OF INTEGRATING POSITRON EMISSION TOMOGRAPHY IN THE DIAGNOSTIC IMAGING OF PEDIATRIC BRAIN LESIONS

Benoit Pirotte, Alphonse Lubansu, Serge Goldman, Eléna Dain, Patrick Van Bogaert, Philippe David, Dominique Detemmerman, Marc Levivier, and Jacques Brotchi; Department Of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Introduction: The accurate surgical management of pediatric brain lesions (PBL) is a real challenge when some clinical/radiological characteristics suggest a nonevolving/nontumoral nature or a difficult choice between biopsy and resection. Positron Emission tomography (PET) provides independent and complementary information on brain tumor metabolism. Aim: We analyzed the interest of integrating PET in the diagnostic imaging of such PBL. Material and Methods: Since 1991, 73 children (29F/44M) with a newly-diagnosed brain lesion were selected for a PET study (n = 104) because the clinical presentation (52 nonepileptic children with no/few symptoms or 21 chronic epileptic with MRI suspecting tumor) and/or the CT/MRI characteristics (no contrast/gadolimium-enhancement, no oedema, ill-defined boundaries, infiltrative along highly functional structures) suggested to surgeons that the lesion could be nontumoral/nonevolving or inacessible to resection. PET (18Ffluorodeoxyglucose in 18 children, 11Cmethionine in 24, both tracers in 62) was performed to sustain surgical option (tumor suspicion) or to help to decide biopsy/resection in some cases (n = 22). We analyzed each case according to the PET tracer used, tumor type/grading, and clinical expectations. Results: 11Cmethionine-PET appeared accurate to detect tumor tissue and sustained surgical option (n = 39) when it suggested a tumor (diagnosis confirmed in 39). No 11Cmethionine uptake motivated conservative option. PET images were integrated in stereotactic surgical procedures whenever possible (n = 15). The accuracy of 18Ffluorodeoxyglucose-PET to represent anaplastic tissue remains under evaluation. Conclusion: This preliminary series suggests that integrating PET in the diagnostic imaging of PBL helps the surgical strategy when clinical/radiological characteristics suggest a nonevolving/nontumoral lesion or a difficult choice between biopsy and resection. PET should be limited to selected cases and the choice of tracer related to specific clinical questions.

IMAG 12. POSTOPERATIVE POSITRON EMISSION TOMOGRAPHY IMAGING FOR THE EVALUATION OF SURGICAL RESECTION IN PEDIATRIC BRAIN TUMORS

Benoit Pirotte, Alphonse Lubansu, Marc Levivier, Eléna Dain, Patrick Van Bogaert, Philippe David, Christophe Fricx, Jacques Brotchi, and Serge Goldman; Department of Neurosurgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Introduction: Total resection improves the outcome in some pediatric brain tumors (PBT) and second-look surgery can benefit to survival. To evaluate tumor resection, early MR imaging may present limitations in delineating abnormal residual signals, in differentiating between signals from tumor residue and inflammation. Therefore, it cannot be used as a basis for complementary surgical decision. Aim: We studied the interest of postoperative positron emission tomography (PET) to evaluate PBT resection. Material and Methods: Since 1997, 16 children (4F/12M) operated for total resection of a PBT (5 ependymomas, 4 oligodendrogliomas, 4 pilocytic astrocytomas, 1 hemangiopericytoma, 1 neurocytoma, 1 pituitary adenoma) presented a signal suspected of residue on postoperative MRI (inconclusive imaging). Either tumor resection was supposed total peroperatively (n = 9) or surgery left in place tissue fragment(s) too risky to remove and assumed to be nontumoral (n = 7). Early postoperative PET was performed to confirm/infirm the tumoral nature of this signal and to consider second-look surgery. Results: One PET study used 18Ffluorodeoxyglucose, 12 used 11Cmethionine, 6 used both tracers. 11Cmethionine was used in 15/16 children (13/15 were low-grade tumors): increased tracer uptake in 10 children lead to reoperate 7/10 (tumor tissue found in all). No tracer uptake in 5 children lead to choose conservative option (MRI follow-up [22–40 months] showed no tumor progression). Conclusion: This short series illustrates the interest and accuracy of postoperative PET to detect tumor tissue (neither false negative nor false positive), to evaluate tumor resection and to take appropriate therapeutic option including consideration of a second-look surgery. This could be particularily useful in glial tumors for which radical surgery is a key factor of prognosis.

IMAG 13. IMAGING STRATEGIES IN CHILDREN FOLLOWING INITIAL SURGERY FOR CEREBELLAR ASTROCYTOMA

Dawn E. Saunders, Kim P. Phipps, Angela M. Wade, and Richard D. Hayward; Departments of Radiology and Neurosurgery, Great Ormond Street Hospital; Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health; London, UK

The purpose of this paper is to evaluate surveillance strategies for the detection of residual and recurrent disease and subsequent regression or progression of the disease. Children are divided into 3 groups: (1) those that have had a complete resection and (2) those who have residual disease who are not felt to require immediate adjunctive therapy, and (3) those that received adjuvant radiotherapy. Imaging studies and clinical data obtained in children with posterior fossa pilocytic astrocytomas (PCA), who presented between, January 1988 to September 1998, were retrospectively reviewed. 84 children (99%) survived a median follow-up period of 5 years 3 months (mean 6 years 10 months, range 2 years–13 years 3 months). One child within the cohort died. Seventy of the 84 children had a complete resection; 9 children developed a recurrence (13%). The mean time to a recurrence was 22.4 months (range 7 months–3 years 11 months). Fourteen children had a subtotal resection, 3 required immediate adjunctive treatment, and 11 had surveillance imaging. Of these 11, tumour progression was seen in 5 at 7, 9, 12, 13, and 20 months (mean of 12.2 months from initial surgery), and tumour regression was seen in 5 children at 7, 16, 29, 42, and 66 months (mean 32 months). One child had stable disease at 14 months. Only one child developed a recurrence at 4 years and 9 months after radiotherapy for residual disease. There was no significant difference between the scanning schedules following a complete recurrence compared to those with residual disease. We conclude that surveillance imaging before 6 months was not advantageous. Following both a complete and partial resection, a period of surveillance of 5 years was more than sufficient for the detection of tumour recurrence. Regular surveillance imaging occurred more frequently than yearly in all groups, and a surveillance schedule of 6 months, 1 year, 2 years, 3.5 years, and 5 years is proposed following either a complete or incomplete recurrence.

IMAG 14. A PILOT STUDY OF PROTON MAGNETIC RESONANCE SPECTROSCOPIC IMAGING IN THE EVALUATION OF NEUROTOXICITY IN CANCER PATIENTS: NEUROPSYCHOLOGICAL FUNCTIONING

Kim C. Shimoda, Pamela Wolters, and Kathy Warren; National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA

Cranial irradiation, intrathecal methotrexate, and high-dose systemic chemotherapy have been associated with neurocognitive deficiencies, including an increased incidence of learning disabilities, impaired academic achievement, and lower scores on intelligence tests. Some patients have manifestions on neuroimaging, but the clinical implications of these radiographic findings are unclear. The correlation of MRI changes with clinical symptoms and neuropsychological findings has been inconsistent. New techniques in brain imaging may provide better tools for detecting and characterizing changes associated with the later development of clinical neurotoxicity. In a pilot study of 1H-NMRS imaging in the evaluation of neurotoxicity in cancer patients, 37 patients underwent neuropsychological evaluation within one week of brain imaging. Of these, 28 patients reported complaints of neurotoxicity from tumor or previous treatment (i.e., headache, learning problems, memory loss), 9 patients did not report neurotoxicity as the primary concern when enrolled on the study. The two groups did not differ significantly on Verbal, Performance, or Full Scale IQ scores or selected tests of memory functions. Intellectual and memory functioning fell within the average range. On the Connors Behavior Rating Scale, completed by the parents, the children in the neurotoxicity group had significantly higher scores on the learning problems subdomain (p < .05) and hyperactivity index (p < .05). Of these significant differences, the learning problems scale was the only score that approached the clinically significant level (T-score mean = 69.3). Despite reports of neurotoxicity from parents and by patient’s self-report, these patients were within normal limits on most measures of cognitive and behavioral functioning and were not significantly different from patients without symptoms of neurotoxicity except for parental report of learning problems and hyperactivity.

IMAG 15. SURVEILLANCE IMAGING FOLLOWING ATTEMPTED CURATIVE TREATMENT FOR CHILDHOOD CRANIOPHARYNGIOMA: HOW OFTEN AND HOW LONG?

Guirish A. Solanki, Kim Phipps, Dawn Saunders, William Harkness, Dominic Thompson, and Richard Hayward; Departments of Paediatric Neurosurgery, Neuroradiology, and Neuro-Oncology, Great Ormond Street Hospital for Children, London, UK

Aims: Determine optimum-surveillance-imaging regime for cranio-pharyngioma in order to detect presymptomatic stage recurrences while using overstretched scanning resources in the most cost-effective way. Patients and Methods: Children with histologically proven craniopharyngioma diagnosed between 1987–1997 were reviewed. They were divided into two groups: GroupAñcurative treatment was surgery (the surgeon thought the tumour had been completely removed). GroupB–those-includes failures from GroupA-that had Radiotherapy(DXT). Treatment groups were further subdivided into those that had initial treatment (A1/B1) or following failure of initial treatment be it surgery or radiotherapy (A2/B2). Results: There were 56 patients, 21 females, 35 males. Mean age of boys/girls was 7.6/6.8 years, range = 1.3–15 years. M:F ratio = 1.6. Mean follow-up = 10 years (range = 6–16 years). In GroupA1, 47 patients had primary curative surgery. These patients were scanned at 3 monthly intervals for the first 6 months, 6 monthly in the subsequent 12 months and then yearly. 3 patients were lost to follow-up. 18 patients had recurrences. 2 were symptomatic, 16 were asymptomatic. Mean time to detection was 27.5 months. 10 (55.5%) recurred within 2 years, mean of 12.5 months. Only 2 recurred after a 4-year follow-up. In GroupA2, there were 10 attempts at secondary curative resection. Half the patients had asymptomatic recurrences all occurring within 2 years mean of 11.6 months. In GroupB1, 13 patients underwent DXT. Surveillance was similar to GroupA1. No recurrences in the first 12 months, 3 patients had asymptomatic recurrences at average 26 months. In GroupB2, there were 15 attempts at secondary radiotherapy treatment. 1/3 recurred at mean time of 24 months. One recurrence was symptomatic. Discussion: This preliminary study suggests that for those patients who had an apparently curative removal, surveillance scanning continued for at least 5 years at 3-3-6-9-12-12-18-month intervals, will identify 95% (17/18) of recurrences. 100% identification (all recurrences occurred within 10 years) would require two 24 monthly or one 48 monthly scan. For those patients for whom DXT has been the ‘curative’ treatment, we conclude that patients should be followed up for 5 years at the following interval: 6-12-12-12-18 months. In this way all the recurrences in this series would have been detected, and if applied it would have resulted in a savings of 235 scans–in the surgery group and an additional 104 scans in the radiotherapy group per mean 10-year follow-up period.

IMAG 16. BRAIN MAGNETIC RESONANCE IMAGING (MRI) FINDINGS AFTER HIGH-DOSE CHEMOTHERAPY AND RADIOTHERAPY (RT) FOR CHILDHOOD CNS TUMORS: A DEVELOPING WORLD

Filippo Spreafico, Davide Scaramuzza, Lorenza Gandola, Graziella Cefalo, Roberto Luksch, Terenziani Monica, Michela Casanova, Andrea Ferrari, Daniela Polastri, Marta Podda, Cristina Meazza, Franca Fossati-Bellani, Renato Musumeci, and Maura Massimino; Pediatric Oncology Unit, Radiotherapy Unit, Department of Radiology, Istituto Nazionale Tumori, Milan, Italy

The RT-related iatrogenic Magnetic Resonance Imaging (MRI) changes are known, while a possible synergistic effect of HDCT and RT is underestimated. The authors reviewed their experience on imaging studies following RT and high-dose CT and autologous stem cell rescue (HDCT/ASCR) in 35 children. Diagnosis was as follows: 18 high-grade gliomas, 11 medulloblastomas, 6 PNETs. There were 14 males and 21 females; median age at diagnosis 7.1 years (range 1.4–20.8 years). Conditioning regimen consisted of thiotepa (900 mg/m2); carboplatin (1 g/m2) was added in 5 pts. Among medulloblastoma/PNETs, the treatment plan included 2 HD-thiotepa courses in 13 cases, and 3 courses in 2 cases. Irradiation was given pre HDCT in 18 cases or post in 17 cases. Children with gliomas received local RT at a median dose of 60 Gy, while medulloblastoma/PNETs had median 39 Gy craniospinal hyperfractionated-accelerated RT (range 20.8–39 Gy) plus posterior fossa boost (60 Gy). Median follow-up is 22 months from diagnosis. Twelve children (34%) (5/18 high-grade gliomas; 7/17 medulloblastoma/PNETs) had abnormal brain MRI findings, after median 7 months from RT (range 2-21 months). The particular pattern of lesions was rapresented by multiple pseudonodular, irregular-shaped, millimeter-sized, T1-weigthted disomogeneously enhancing foci; the T2-weighted images demonstrated surrounding edema. The lesions gradually decreased in size over several months, often living a colliquative central nucleus. In 4 medulloblastoma/PNET pts we observed subdural fluid leaks too, with hyperintense T2-weighted and isointense T1-weighted signal. Typically, meningeal enhancement and thickening over the leaks were observed. The low compressive effect meant a subacute origin of the effusions, rather than an acute event. The higher incidence of pathological MRI in medulloblastoma/PNET pts could be explained by the use of craniospinal irradiation (vs. tumor bed only) and a higher number of lumbar punctures (which can be the cause of intracranial hypotension and subdural effusions). Multiple enhancing cerebral lesions on brain MRI early post HDCT/ASCR are frequently seen and may be a consequence of the treatment, to be distinguished from metastatic disease.

IMAG 17. METHIONINE POSITRON EMISSION TOMOGRAPHY FOR BRAIN TUMOR IN CHILDREN

Naohiro Tsuyuguchi, Ichiro Sunada, and Mitsuhiro Hara; Osaka City University Graduate School of Medicine, Department of Neurosurgery, Saiseikai Ibaragi Hospital, Department of Neurosurgery, Osaka, Japan

Introduction: Methionine (Met) - Positron Emission Tomography (PET) provides good contrast with tumor uptake, so background uptake of amino acids in normal brain tissue is low. Met-PET images can identify the existence of tumor cells as a hot lesion, even in a small tumor lesion, the lesions being characterized by a marked uptake of Met. However, there are a few reports of brain tumors in children. We discussed the usefulness Met-PET for those tumors. Clinical Materials and Methods: This study included 11 cases (2 cases: medulloblastoma, 2 cases: pontine glioma, 1 case: anaplastic astrocytoma, 1 case: anaplastic ependymoma, 2 cases: low-grade glioma, 1 case: DNT, 2 cases: germinoma). Mean age was 8.1 years old (from 1 to 14). The diagnosis in 8 out of 11 cases (except 2 pontine gliomas and one glioma) was based on surgical resection or biopsy within 6 weeks after PET. Two pontine glioma cases died within a half year. On glioma case, there was no change for two years. We calculated T/N defined as the ratio of radioisotope count of tumor tissue to that of the homologous contralateral gray matter. Results: In malignant tumors, T/N values were more than 1.35. PET showed an infiltrated lesion of a tumor precisely. Especially, in anaplastic ependymoma, PET could detect small tumor recurrence. On the other hand, there was low accumulation in benign lesions. Conclusion: Met-PET matched the clinical diagnoses and was usefulness for differentiating benign from malignant tumor. Numerous reports have shown Met-PET to exhibit high sensitivity for brain tumors, in a fact, supported by the results of the present study of pediatric brain tumors. In any case, if methionine accumulation is observed, subsequent treatment must be given full consideration.

IMAG 18. EVALUATING NEUROTOXICITY IN CANCER PATIENTS

Kathy Warren, Rene Hill, Jeannette Black, Alberta Aikin, Pam Wolters, Kim Shimoda, and Frank Balis; National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, USA

Neurotoxicity is a significant complication for a number of cancer survivors. The relationship between treatment and development of neuropsychological or structural manifestations has been difficult to define. We performed a pilot study to determine if Proton Magnetic Resonance Spectroscopic Imaging (1H-MRSI) can be used to detect, define and characterize CNS toxicities in patients with cancer. Patients with brain tumors, patients receiving high-dose systemic chemotherapy, intrathecal chemotherapy, or cranial radiation were eligible, as were those with presumed/documented neurotoxicity from prior cancer treatment. MRI and 1H-MRSI were performed on a 1.5 T magnet on 50 patients, ages 2 years–53 years (median 11 years, mean 15.3 years). An age-appropriate neuropsychological battery of testing was performed within 1 week of imaging. 31 patients reported symptoms of neurotoxicity primarily associated with prior therapy; 18 patients were receiving anticancer therapy, and 4 had received no antitumor therapy. The diagnoses included CNS tumor (n = 34), acute lymphoblastic leukemia (n = 12), and sarcoma (n = 4). 21 patients had abnormal MRI findings outside the tumor bed or operative field, including 15 with white matter changes. 1H-MRSI was abnormal in 40/48 patients, including 22 that were abnormal outside the known tumor area. 1H-MRSI results did not always correlate with abnormalities on MRI. Areas of white matter changes on MRI did not yield consistent 1H-MRSI results. The median full-scale IQ score (n = 36) was 90 (mean 90, range 46–138), median verbal IQ was 91 (52–141), and median performance IQ was 95 (50–127). An abnormal peak was identified in the area of lipid and lipid breakdown products in 9 patients. The median full-scale IQ was significantly lower in this subgroup of patients, compared to those patients who did not demonstrate this peak (70 vs. 94, p <.05). Additional study using 1H-MRSI in a more homogeneous population is warranted.

IMAG 19. ESTABLISHING A MULTI-INSTITUTIONAL PEDIATRIC BRAIN TUMOR NEUROIMAGING CENTER (NIC)

Tina Young-Poussaint,1 Uma Ramamurthy,3 James Boyett,3 Mark Kieran,1,2 and Larry Kun,3 for the Pediatric Brain Tumor Consortium (PBTC); 1Children’s Hospital Boston, Boston, MA; 2Dana-Farber Cancer Institute, Boston, MA; 3St. Jude Children’s Research Hospital, Memphis, TN; USA

Purpose: The development of novel treatment programs for children with central nervous system (CNS) tumors requires a multi-institutional effort given the small and diverse nature of this population. As new biologic, anti-angiogenic, infusional, and novel chemotherapeutic agents are tested, neuroimaging will become an important component of the evaluation of these modalities with regard to activity and toxicity. We report on the development and implementation of a multi-institutional completely digital Neuroimaging Center for the Pediatric Brain Tumor Consortium (PBTC) which provides leadership for the diagnostic imaging component of PBTC protocols and incorporates imaging endpoints into the PBTC research program. Materials and Methods: A multi-institutional neuroimaging center was established from the 10 programs within the PBTC. A dedicated digital imaging transport system was created by the PBTC Operations and Biostatistics Center (OBC) where MR and PET imaging studies are sent from each member institution scanners via a dedicated PBTC laptop and are subsequently uploaded via a secure tunnel on the internet (HIPPAA compliant) to the PBTC imaging server at the OBC. These images are then uploaded to the Neuro-Imaging Center (NIC) via the internet to a dedicated workstation. Subsequent quality assurance (QA) measures are applied as the information is processed and data analysis is then performed. In order to allow for uniformity of data and a direct comparison between images obtained across all sites, the quality assurance program was developed for both MR and PET scans using a set of standard phantoms applied to the different scanners used by the member institutions. Formation of a Neuro-Imaging Committee consisting of neuro-radiologists from each participating member site to provide consensus on imaging protocols and QA procedures was also created. Results: Digital imaging transfer has been accomplished with 675 different MR studies currently uploaded at the NIC. Analysis of different data sets from the MR scans is now underway. The methodology for PET study transfer has been completed and validated, and uploading of these scans for formal central analysis will begin soon. Conclusion: A multi-institutional Neuro-Imaging Center has been created for a national brain tumor consortium with the appropriate infrastructure. We are now evaluating the quality and usability of the data obtained as additional protocols are opened.

IMAG 20. ANALYSIS OF CORRELATIVE MRI PERFUSION AND DIFFUSION IN A PHASE I TRIAL OF THE ANTI-ANGIOGENESIS AGENT SU5416 IN CHILDREN WITH REFRACTORY OR PROGRESSIVE BRAIN TUMORS: A REPORT FROM THE PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC)

Tina Young-Poussaint,1 Uma Ramamurthy,3 James Boyett,3 Larry Kun,3 and Mark Kieran,1,2 for the Pediatric Brain Tumor Consortium; 1Children’s Hospital Boston, Boston, MA; 2Dana-Farber Cancer Institute, Boston, MA; 3St. Jude Children’s Research Hospital, Memphis, TN; USA

Purpose: To review novel radiographic techniques including serial MRI diffusion, perfusion and spectroscopy imaging in an exploratory and investigational evaluation of the phase I anti-angiogenesis agent SU5416 in pediatric brain tumor patients. Materials and Methods: A multi-institutional Pediatric Brain Tumor Consortium (PBTC #002) study of SU5416, a novel small molecule inhibitor of Vascular Endothelial Growth Factor (VEGF) signaling in recurrent or progressive poor prognosis brain tumors, was completed. A total of 33 patients were treated, 23 were accrued at 3 different dose levels in stratum 1 (off anticonvulsants), and 10 were accrued at 2 dose levels in stratum 2 (on anticonvulsants). Given the small number of patients, a descriptive analysis was performed to assess for trends in MR volumes, MR diffusion, MR perfusion, and MR spectroscopy. The time on therapy for each patient was calculated. Patients were divided into a long survivors group (more than 5 months on treatment) and a short survivors group (less than 5 months on treatment) for whom at least two serial scans were available, including a baseline pretherapy evaluation. Regions of interest were calculated on diffusion and perfusion images over the tumor and compared to the contralateral white matter. Results: There were studies available for 19 boys and 13 girls. The majority of lesions were supratentorial tumors (66%) and were comprised of a mix of glial and neural histologies. The long survivors group had a mean duration of 335 days of therapy (the minimum was 161 days). The mean duration for the short survivors group was 36 days (the longest was 98 days). In the long survivors group, the diffusion values within the tumor were increased over time on therapy. By contrast, in the short survivors group, the diffusion values decreased over time. A similar difference was observed for tumor perfusion, with higher values for the long survivors group when compared to the short survivors group. Conclusion: Treatment of refractory or progressive brain tumors in children with SU5416 led to increased diffusion values over time likely reflecting decreased cellularity of the tumor with treatment. Perfusion values were increased in the tumors of patients on therapy for an extended time which may provide for a surrogate marker of drug activity. Validation of such results will require larger series with different agents to be combined from future PBTC anti-angiogenic agent trials.

IMAG 21. SINGLE PHOTON EMISSION TOMOGRAPHY (SPECT) FINDINGS IN CHILDREN WITH AND WITHOUT POSTERIOR FOSSA SYNDROME AFTER CEREBELLAR TUMOR RESECTION

M. Zwienenberg-Lee,1 M. Van Veelen-Vincent,2 and C.E. Catsman-Berrevoets3; Department of Neurological Surgery, University of California Davis, CA, USA1; Department of Pediatric Neurosurgery2 and Department of Child Neurology,3 Erasmus MC/Sophia Children Hospital Rotterdam, The Netherlands

Introduction: Posterior Fossa Syndrome (PFS) or its subtype, Mutism with Subsequent Dysarthria (MSD) are fairly common in children after posterior fossa surgery, occurring in approximately 13 to 29% of cases. The etiology of PFS is largely unknown. Previous studies have suggested it may be related to transient perturbation of the cerebello-thalamocortical pathways. Specific changes in 99mHMPAO SPECT-cerebral perfusion patterns, have been associated with PFS, although this could not be confirmed in a recent prospective study. We have studied 11 children with 99mHMPAO-SPECT after posterior fossa cerebellar tumor resection surgery and found distinct differences in supratentorial perfusion in those with and without PFS. Results: Eleven children (mean age 9 years, range 3–17) with posterior fossa cerebellar tumors, who were admitted to the Sophia Children Hospital in Rotterdam were included in this study. Seven children had medulloblastomas, three had pilocytic astrocytomas, and one child had an ependymoma. Eight children presented with hydrocephalus (Bicaudate index (BI) 0.19–0.29). Six patients underwent ventriculo-peritoneal shunting. Tumor resection was complete in 4, near total in 5, and subtotal in 2 cases. MSD syndrome was observed in 7 patients and another form of PFS in two. The duration varied from 17 days to 4 months. There was no relation with hydrocephalus. No specific radiological abnormalities were seen on pre and postoperative MRI, except for the postoperative lesion in the cerebellum. 99mHMPAO-SPECT scans were obtained in all patients during the mutistic phase. In three patients, scans were obtained after resolution of mutism. In the two children without PFS, scans were made on the 14th and 21st postoperative day respectively. A consistent pattern of bilateral basal fronto-temporo-occipital cerebral hypoper-fusion with relative sparing of the high fronto-parietal cortex was seen in all children with PFS, but not in those without. The hypoperfusion became less intense with resolution of the PFS. There was no association with the presence of hydrocephalus. Conclusion: PFS appears to be associated with a distinct pattern of supratentorial hypoperfusion. A prospective study is presently under design to determine if the duration and severity of PFS can be more accurately predicted with the use of SPECT.

LATE EFFECTS

LE 1. NEUROENDOCRINE SEQUELAE IN SURVIVORS OF PEDIATRIC BRAIN TUMORS IN SASKATCHEWAN, CANADA: 1984–2000

Kaiser Ali, Angela Jones, Betty Riddell, Tom Best, and Christopher Mpofu; Saskatoon Cancer Centre and Colleges of Medicine (Pediatrics) and Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

Permanent neuroendocrine sequelae (NES) are increasingly diagnosed in survivors of childhood cancer, especially those with brain tumors (BT). We undertook to review our experience with BT patients in a Pediatric Oncology Database derived from the Saskatchewan Cancer Registry, the oldest Cancer Registry in North America. Between 1984–2000, a total of 1,124 children 19 years of age and under were diagnosed with cancer in the province of Saskatchewan; of these, 204 (18.1%) had brain tumors. Mean age at diagnosis was 8.4 years. There were 34 (16.7%) survivors with NES (26 long-term survivors (LTS) and 8 survivors (S), of whom 6 had craniopharyngiomas). Supratentorial tumors comprised 23 (67.6%) cases, 11 located in the suprasellar/pituitary area and 12 in other sites; the remaining 11 (32.3%) were infratentorial. BT survivors were divided into 2 groups: those who were <5 years posttreatment (S, n = 8) and those surviving >5 years off all therapy (LTS, n = 26). Survivors with NES fell into two main treatment groups: 15 (44.1%) received a combination of surgery, radiation therapy, and chemotherapy, while 7 (20.6%) underwent surgery and radiation therapy. Mean time from diagnosis of BT to detection of NES was 2.2 years. From 1–5 NES were present in each patient. Sequelae included 29 (85.3%) cases of hypothyroidism (7 primary, 22 secondary), 25 (73.5%) with proven/probable growth hormone deficiency, 15 (44.1%) cases of adrenal insufficiency, 13 (38.2%) with hypogonadism, 11 (34%) of diabetes insipidus, and 3 (8.8%) with precocious puberty. Eleven of the 34 (32.4%) patients with NES had panhypopituitarism. Long-term survivors of pediatric brain tumors are at risk for multiple neuroendocrine axis abnormalities, especially those who undergo pituitary ablation or tumoricidal doses of cranial irradiation. Close monitoring and early intervention in affected patients will facilitate their growth, sexual maturation, and progression to adulthood.

LE 2. LONGITUDINAL NEUROPSYCHOLOGICAL STUDY OF CHILDREN WITH MEDULLOBLASTOMA

Joann Ater, Donna Copeland, and Bartlett Moore, III; Division of Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

The neuropsychological (NP) consequences of cranial-spinal radiation in older children are not well defined. Children and adolescents with medulloblastoma were evaluated with an age appropriate complete battery of NP tests performed annually as part of a longitudinal NP study of children with cancer. The test battery included evaluations of intellectual function, academic achievement, fine motor function, executive function, memory, and attention. For medical and social reasons, not all tests were performed at all time points. Forty children with medulloblastoma were identified who had average of 4.2 test batteries each (range 2 to 11). This group included 13 girls and 27 boys ranging in age from 31 to 228 months at time of cranial radiation. Six children less than 3 years at diagnosis had no cranial radiation. The time intervals between the first and last test batteries averaged 55.2 (range11 to 174) months. Mean Full Score IQ (FSIQ), Performance IQ (PIQ), Verbal IQ (VIQ), and change in each comparing first (F) to last (L) tests are shown by age group in those with complete IQ testing (n = 34):

AGE YrsNVIQ FVIQ LVIQ L−FPIQ FPIQLPIQ L−FFSIQ FFSIQ LFSIQ L−F
<7 no
CRT693.494.5+ 2.4108108.8+ 4.0100101+ 3.4
< 71093.083.3−14.587.977.2−14.089.776.7−14.5
7–1011101.494−6.897.992.7−5.099.793.0− 6.0
>107109.3112.0+ 2.7106.3106.7+0.4107.4108.1+2.4

Declines in PIQ, VIQ, and FSIQ were found in the children less than 10 who received cranial radiation. Young children treated without radiation and children over 10 years had stable IQ. Age related results of other domains of NP function will also be presented to elucidate the impairments in all age groups as related to clinical factors.

LE 3. SECOND NEOPLASMS (SN) IN PEDIATRIC PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: THE ST. JUDE CHILDREN’S RESEARCH HOSPITAL EXPERIENCE

Alberto Broniscer, Weiming Ke, Christine E. Fuller, Jianrong Wu, Amar Gajjar, and Larry E. Kun; Division of Neuro-Oncology, Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To define the incidence, clinical characteristics, risk factors, and outcome of SN following pediatric CNS tumors. Methods: All patients (pts) <22 years with a primary CNS tumor referred to our institution between 1984 and 2002 were identified. We reviewed clinical and treatment data for pts who developed any SN. Pts with neurofibromatosis type 1 were excluded. Cumulative incidences of SN were estimated among 1046 newly diagnosed pts evaluated during the study period. Results: 24 pts with SN were identified. SN included 10 gliomas (42%), 5 meningiomas (21%), 2 desmoid tumors, 2 myelodysplastic syndromes, 2 basal-cell carcinomas, 1 leukemia, 1 malignant fibrous histiocytoma, and 1 thyroid carcinoma. Twenty-one pts had previously received radiation therapy (RT); twelve had been given chemotherapy. The SN was related to a genetic syndrome in 7 pts (29%; e.g Gorlin syndrome, Gardner syndrome). The median latency between the first diagnosis and SN was 7.9 years. Eleven pts died of their SN, including 8 with a glioma and 2 with myelodysplastic syndromes. The estimated 15-year cumulative incidence of SN and second malignant neoplasms was 5.3% and 4%, respectively. Among subgroups of primary CNS diagnoses, children with choroid plexus tumors had an estimated 10-year cumulative incidence of SN of 20.2%; two of these pts had germline TP53 mutations. Age <2 years was a significant risk factor (P = 0.016) only when pts with genetic conditions were included. No significant difference in estimated cumulative incidence of SN was found among 4 different therapy approaches (RT only vs. chemotherapy only vs. both vs. neither). Conclusions: The risk of lethal SN after pediatric CNS tumors is small. Young pts and those with choroid plexus tumors seem to have increased risks of SN associated with genetic predispositions. The analysis of treatment effect was limited by the small number of events.

LE 4. LONG-TERM SEQUELAE IN CHILDREN WITH CEREBELLAR ASTROCYTOMA IN NEUROLOGIC, NEUROPSYCHOLOGICAL AND BEHAVIORAL PERSPECTIVE

Coriene E. Catsman-Berrevoets., Femke K. Aarsen, Hugo R. Van Dongen, Philippe F. Paquier, and Marijke Van Mourik; Department of Child Neurology, Erasmus MC/Sophia Children Hospital, Rotterdam, The Netherlands

In children a few days after resection of a cerebellar tumor Mutism and Subsequent Dysarthria or Posterior Fossa Syndrome can occur. Also cognitive disturbances such as impairments of lexicon, receptive syntax, auditory memory, expressive language (mean length of utterances), visual and visual-spatial functions may occur shortly after resection of a Cerebellar Pylocytic Astrocytoma (CPA). As long-term effects have not been systematically investigated, we studied these effects on neurologic, neuropsychological and behavioral functioning in children after CPA resection without additional therapy. We assessed speech, language, nonverbal intelligence, attention, memory, executive skills, and visual (-spatial) functions in a consecutive series of 21 children. Neurologic and neuropsychological follow-up ranged from one year and one month to eight years and ten months after resection. Long-term sequelae in the investigated domains were found in all children with CPA surgical lesions. Apraxia, motor neglect, dysarthric features, language disturbances, disorder of sustained attention, visual-spatial impairments, executive difficulties, as well as behavioral problems were observed in various combinations and to different degrees. No clear pattern of neurocognitive disturbances could be discerned in this group. The high percentage of children who needed special education reflects the relevance of the disturbances. Despite the current opinion of a good quality of life after CPA surgery, we conclude that careful long-term neurocognitive follow-up is needed in order to inform parents and teachers on behavioral and cognitive sequelae and to contribute to timely social and educational intervention.

LE 5. RADIATION ENHANCES LEUCOENCEPHALOPATHY AFTER METHOTREXATE (MTX): DELINIATION AND PREVENTION

Ian J. Cohen; Department of Paediatric Hematology/Oncology, Schneider’s Children Medical Center of Israel, Petah-Tiqva; Sachler Medical School, Tel Aviv University; Israel

High-dose radiotherapy causes radionecrosis but not leucoencephalopathy. Post radiation MTX has been avoided by some centers because of leucoencephalopathy but not by others. The cause has been considered a mysterious multifactorial interaction. An in depth literature search was performed to investigate this phenomenon. Pollack and Kaufman in 1978 showed that dihydrofolate reductase is present in the brain and is inhibited in the brain and liver by 3x10−8mol MTX. Small reductions in MTX doses have prevented leucoencephalopathy after radiotherapy. Inadequate folinic acid rescues after MTX has been associated with various expressions of neurotoxicity, including leucoencephalopathy. Radiation has been shown to increase the CSF MTX levels achieved. 3gm/m2post radiation was found to give 24-hour CSF levels equivalent to those achieved after 7.5gm/m2 alone. CSF levels of MTX and folinic acid are similar for equivalent doses. The level of folinic acid needed to restart cell growth after MTX increases out of proportion to a similar increase in MTX level. Although a hundred times excess of folinic acid is sufficient to negate a MTX level of 10−7 mol, with 10−6 mol there is only partial reversal. Radiotherapy will result in a equivalent increase in MTX and folinic acid CSF levels since permeability of the blood brain barrier to both is similar, but the folinic acid level may now be inadequate for rescue if the folinic acid level was previously borderline. Neurotoxicity has been prevented after high-dose MTX by increasing folinic acid doses. Blood Brain Barrier Disruption resulted in no neurotoxicity after MTX when high doses of folinic acid were used. Treatment protocols have shown reduced neurotoxicity with increased folinic acid doses (but no reduction in efficacy). Thus, raising the post MTX dose of folinic acid after Radiotherapy will tend to prevent leucoencephalopathy without compromising efficacy.

LE 6. RISK OF GASTROSTOMY FEEDING TUBES INSERTION ON VENTRICULOPERITONEAL SHUNTS INFECTIONS IN PEDIATRIC BRAIN TUMORS

A. Gassas, J. Kennedy, G. Green, B.L. Connolly, U. Dag-Ellams, A. Kulkarni, and E. Bouffet; Hospital for Sick Children, Toronto, Ontario, Canada

Children with brain tumors often require gastrostomy tubes (GT) as a modality nutritional management during treatment. Such patients may have a coexisting hydrocephalus requiring ventriculoperitoneal (VP) shunt. Identification of risk factors for VP shunts infections and predictors of infectious pathogen may improve the current methods to prevent and treat shunt infections. Objectives: Primary, to determine whether insertion of GT post VP shunt will increase the risk of shunt infection in children with brain tumors. Secondary, to determine the safest time for GT insertion in such patient population. Patients and Methods: All children (Age 0–18 years) with brain tumors diagnosed and treated at the Hospital for Sick Children, Toronto, Canada, were subjected to a retrospective analysis. Two groups were identified; Study group included children with VP shunt and GT; Control group included children with VP shunt only. Each study patient was matched with 4 controls to compare rate of infections. Results: There were 1167 children diagnosed and treated with primary brain tumors during the study period (1988–2003), 151 (12.5%) had a VP shunt and 23 (2%) children had both GT and VP shunt. In the study group, 21 patients (91%) had a GT inserted at a median time of 105 days (range 6–546 days) post VP shunt insertion. Two (9%) patients had late onset hydrocephalus with their VP shunt inserted after the GT. VP shunt infection rate in the study group was 26% (6/23 patients). Three of the six patients (50%) had an ascending VP shunt infection directly related to their GT insertion. These GTs were inserted at 13, 47, and 58 days post VP shunt insertion. One patient had a previous abdominal surgery for Wilm’s tumor removal 5 years prior to his brain tumor. Conclusion: Placement of GTs in the acute phase in children with brain tumors and VP shunts may lead to a significant risk of ascending meningitis.

LE 7. FUNCTIONAL OUTCOME OF CHILDREN ≤ 4 YEARS OF AGE WITH CNS MALIGNANCIES

Elizabeth Gilger, Maryam Fouladi, Mehmet Kocak, Dana Wallace, Gray Buchanan, Cara Reeves, Nicole Robbins, Leslie Musick, Amar Gajjar, and Raymond Mulhern; Division of Neuro-Oncology, Department of Hematology Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive outcome in children ≤ 4 years of age who survived for at least 2 years after the diagnosis of an intracranial CNS malignancy. Methods: Records were reviewed for 195 children ≤ 4 years of age with intracranial CNS malignancies who survived at least 2 years after diagnosis from 1984–2000. 126 patients (pts) who had at least one neurocognitive evaluation (NE) are included. Results: There were 69 males and 57 females. The median age at diagnosis was 1.9 (0.1–3.5 years). Median follow-up was 8.4 (2.1–18.4 years). Tumors were infratentorial in 72 (57%), midline in 30 (24%) and supratentorial in 24 (19%). Fifty-four pts had a shunt (43%), 33 (26%) had a seizure disorder. 39 pts (34%) of 115 with an audiology exam had Grade III/IV ototoxicity. Therapy included no radiation therapy (RT) in 47 pts (37%), local RT in 54 (43%), craniospinal irradiation (CSI) RT in 25 (20%). A longitudinal analysis estimated that the rate of IQ decline for pts who received CSI (mean, −1.18 points/year) and local RT (mean, −0.56) was significantly different from IQ gain in the no RT group (mean, 0.89 points/year; p = 0.01 and p = 0.035, respectively). Pts with supratentorial tumors had the largest decline in IQ compared with infratentorial and midline tumor locations (−1.52 points/year, −0.38 points/year, 0.46 points/year, respectively). A cross-sectional analysis on a subgroup of 96 patients with their last NE at least 2 years after diagnosis revealed a median IQ of 82 (46–130). Supratentorial tumor location (p = 0.06), RT type (p < 0.0001) and shunt (p = 0.0004) were all significant predictors of decreased IQ. Conclusion: In young children treated for intracranial CNS tumors, CSI, presence of shunts, and supratentorial location of tumors are associated with significant declines in IQ scores.

LE 8. EVALUATION AND TREATMENT OF DYSPHAGIA IN A CASE OF CNS TUMOR

Maria Ines Rebelo Goncalves, Henrique Manoel Lederman, Fernanda Menezes, Nasjla Saba da Silva, and Sergio Cavalheiro; Instituto de Oncologia Pediatrica, Department of Speech Pathology, Department of Diagnostic Imaging, Department of Neurology and Neurosurgery, Universidade Federal de Sao Paulo, Brazil and Universidade Tuiuti do Paraná, Brazil

Our goal is to describe swallowing alterations in a 16-year-old male after surgery for neurofibromatosis type II and his rehabilitation. Patient presented clinical diagnosis of neurofibromatosis type II with bulbar ependimoma and was submitted to resection. After surgery the patient presented severe difficulties swallowing saliva, liquids, and solid foods, and severe choking. At the videofluoroscopic dynamic swallowing evaluation, the following were observed: traqueal aspiration before and after the swallow, assistematic and nonefficient cough reflex, reduced laryngeal elevation during swallowing, a great amount of residue in pyriform sinus, and poor response in facilitating swallowing maneuvers. Due to this severe dysphagia, the following were recommended: feeding by a nasogastric tube and swallowing therapy, which included exercises to improve laryngeal elevation, strengthen glottic closure, and clean the residue in pyriform sinus. The patient was submitted to another videofluroscopic dynamic swallow evaluation after 18 days of therapy and presented mild residue, better laryngeal elevation during swallowing, and mild aspiration only for thick liquids, showing efficacy of the rehabilitation. The patient was allowed to eat orally thin liquids, paste consistencies, and solids; after 1 month he was eating all consistencies without aspiration. This case shows the importance of the evaluation and rehabilitation of swallowing in patients with tumors of the central nervous system. This intervention associated with a videofluoroscopic dynamic swallowing evaluation can detect and/or prevent pulmonar aspiration, reducing the risk for pneumonias and contributing to a better quality of life for the patients.

LE 9. LONGITUDINAL NEUROPSYCHOLOGICAL FOLLOW-UP OF CHILDREN TREATED WITH HYPERFRACTIONATED AND REDUCED BOOST RADIOTHERAPY FOR STANDARD RISK MEDULLOBLASTOMA IN THE M-SFOP 98 PROTOCOL

Jacques Grill, Virginie Kieffer, Delphine Viguier, Georges Dellatolas, Jean-Louis Habrand, Xavier Muracciole, Chantal Kalifa, Christian Carrie, and the French Neuropsychology Group for Brain Tumors; Institut Gustave Roussy, Villejuif, France

Craniospinal irradiation (CSI) with a boost to the whole posterior fossa are part of the standard treatment for medulloblastoma. However, due to the high risk of cognitive sequelae after irradiation, dose and volume reduction are studied in patients with good prognostic features. Hyperfractinated radiotherapy (HFRT) is supposed to increase the biologic equivalent dose to the tumor without increasing biologic equivalent dose to the normal tissue. Reduced boost volume is supposed to decrease the mean total dose to the brain. Between 12/98 and 10/01, 55 patients with standard risk medulloblastoma less than 19 years were treated. All patients received hyperfractionated radiotherapy (36 Gy [36 fractions]) on craniospinal axis, boost with conformal therapy restricted to the tumor bed (68 Gy [68 fractions]), and no chemotherapy. Serial neuropsychological evaluations were done before and after radiotherapy using a common protocol nationwide. Preliminary results (16 patients) did not show the expected decline in IQ that has been reported with monofractionated radiation techniques (ie a yearly decline of 2.5 IQ points). Here, mean full scale IQ was 92 +/− 19, 90 +/− 11, and 95 +/− 18 prior HFRT at one and two years after HFRT, respectively. Similarily, verbal IQ, usually the most sensitive to radiotherapy, remained normal during follow-up (mean VIQ at 100). For performance IQ, there was a gradual improvement of the score after HFRT compared to the results obtained immediately after surgery: 86 +/− 19 prior RT vs. 88 +/− 16 and 89 +/− 16 at one and two years after RT, respectively. The encouraging results in terms of radio-induced neuropsychological sequelae obtained in this pilot study will now be explored in the French part of the coming SIOP PNET 4 trial that will compare standard monofractionated irradiation with HFRT together with a postirradiation maintenace chemotherapy.

LE 10. OUTCOME OF CRANIOPHARYNGIOMA IN CHILDREN: LONG-TERM COMPLICATIONS AND QUALITY OF LIFE

Michael A. Grotzer, Andrea Poretti, and Eugen Boltshauser; Department of Oncology, University Children’s Hospital of Zurich, Switzerland

There is considerable controversy about the optimum management of childhood craniopharyngiomas. The two common treatment approaches are primary total resection or limited resection followed by radiotherapy. Endocrine, visual, neurological, and cognitive impairments are well documented sequelae of craniopharyngioma treatment, but information on subsequent behaviour and quality of life (QoL) is scant. To study the outcome after a primary surgical approach, we followed 25 consecutive patients under 16 years of age who were treated in a single institution with a management policy of radical tumour excision. The mean follow-up time after primary surgery was 11 years 3 months. Tumour control, and neurological, endocrine, and hypothalamic complications and their impact on health-related quality of life (HRQoL) were comprehensively assessed using qualitative and quantitative measures (conventional medical follow-up, semi-structured interview, and various questionnaires). Despite excellent results in terms of tumour control, local failure (defined as recurrence after complete resection or tumour progression of residual tumour) was observed only in 6 of 25 patients, and severe late-treatment complications decreased quality of life for many long-time survivors. Endocrine deficiency occurred in 96%, visual complications in 67%, neurological complications in 33%, obesity in 61%, increased daytime sleepiness in 29%, and significant school problems in 50%. Craniopharyngioma patients rated their HRQoL considerably lower than healthy controls, the domains of social and emotional functioning being particularly affected. The parents’ ratings were considerably lower than those of the patients. Poor functional outcome was associated with large tumours infiltrating or displacing the hypothalamus, the occurrence of hydrocephalus, and young age at diagnosis, but also with multiple operations due to tumour recurrence. Especially in very young patients with large tumours, alternative treatment strategies with potentially lower risks of posttreatment complications should be considered on an individual basis.

LE 11. VISUAL OUTCOME IN LOW-GRADE OPTIC PATHWAY GLIOMAS (OPG)

Darren Hargrave, Joanne Dondey, Nauman Tariq, Ray Buncic, and Eric Bouffet; Neuro-Oncology and Ophthalmology Programs, Hospital for Sick Children, Toronto, ON, Canada

Methods: Retrospective chart review of children diagnosed with OPG between 1986–2001. Baseline visual acuity (VA) and subsequent VA’s related to treatment intervals were collected. All visions were measured with age-appropriate tests and converted to logMAR (minimum angle of resolution) VA. VA’s were assessed at baseline, throughout Rx, at completion of treatment, and, where possible, 1 year after Rx. Baseline VA categorised as: good, (0–0.4 logMAR); moderate, (0.5–1 logMAR); poor, (>1.0 logMAR); hand movements, (HM); light perception only, (LP); and no light perception, (NPL). Results: Total of 66/81 (36F, 30M) cases were evaluable, mean diagnostic age was 66 (6–178) months, and follow-up was 6–183 months. Neurofibromatosis-1 (NF-1) was present in 34 cases. The site of OPG was: optic-chiasm, 23 (35%); unilateral optic-nerve, 18 (27%); bilateral optic-nerves, 5 (8%); opto-hypothalamic, 16 (24%), and extensive optic pathway, 4 (6%). Management was as follows: 23 observation only (96% NF-1), 12 surgery only, 12 chemotherapy only, 10 surgery and chemotherapy, 4 surgery and radiotherapy, and 5 cases with surgery, chemotherapy, and radiotherapy. Of the 132 eyes evaluable at baseline, VA was: good, 78%; moderate, 13%; poor, 10%; HM, 1%; LP, 18%; and NPL, 0%. The baseline VA was greater in the observation group compared to the treatment group (good VA 91% vs. 52%). The visual outcome was available in 176 eyes, as some patients underwent several therapy modalities. The visual outcome on completing therapy was categorised as follows: VA stable: observation, 96%; surgery, 73%; chemotherapy, 60%; radiotherapy, 89%. VA improved: observation, 0%; surgery, 10%; chemotherapy, 17%; radiotherapy, 0%. VA deteriorated, (with NPL): observation, 4% (2%); surgery, 17% (8%); chemotherapy, 23% (8%); radiotherapy, 11% (0%). The visual outcome 1 year after treatment: improved, 7%; stable, 63%; and deteriorated, 20% (14% went blind). Children with NF 1 had a better visual outcome than those with sporadic tumours. Conclusion: Observation was a safe strategy in children with NF-1. The majority of children studied demonstrated a stable VA during and up to 1 year after treatment. A fifth of eyes deteriorated with 14% becoming blind. Only 7% of eyes improved overall with therapy.

LE 12. INCIDENCE AND TRENDS OF OVERWEIGHT AND AT RISK FOR OVERWEIGHT AMONG PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMOR PATIENTS

Della L. Howell, Anna J. Janss, and Lillian R Meacham; Pediatrics, Emory University and AFLAC Cancer Center, Atlanta, GA, USA

The incidence of overweight and at risk for overweight is increasing significantly in the pediatric population. Obesity is also of concern in pediatric CNS tumor patients, but the incidence, trends, and etiologies are not known. We conducted a single institution, retrospective chart review of pediatric CNS tumor patients, followed in the AFLAC Cancer Center Brain Tumor Clinics. Body Mass Index (BMI) kg/m2 was calculated from heights and weights from clinic visits. BMI percentiles were determined using the Centers for Disease Control (CDC) BMI charts. Patients with BMI >95th percentile were considered overweight (OW), and BMI between 85th–95th percentile were considered at risk for overweight (AROW). All patients were stratified by age, diagnosis, location of tumor, and radiation therapy. Population-based norms from the 2000 National Health and Nutrition Examination Survey, CDC, and Georgia Public Health Department were used for comparison. A total of 292 CNS tumor patients were analyzed. 31.5% were OW (CDC 15%, p < 0.001), and 18.5% were AROW (CDC 15%). All histologies and tumor locations were at or above the CDC rates of AROW and OW (Table 1).

Table 1
Incidence of overweight and at risk for overweight by histology, location, and radiation.

In summary, the overall percentages of patients who were AROW were very similar to population norms. However, CNS tumor patients were much more likely to be OW >95th percentile than population norms. Certain tumors and tumor regions were associated with higher (craniopharyngioma/hypothalamic area tumors) or lower (medulloblastoma/posterior fossa tumors) rates of OW and AROW. Surprisingly, radiation to the hypothalamic-pituitary axis and/or whole brain radiation had little effect on the incidence of OW and AROW.

LE 13. NEUROPSYCHOLOGICAL OUTCOME AFTER LOCAL POSTERIOR FOSSA RADIATION FOR EPENDYMOMA

Katja Ittner, Virginie Kieffer Renaux, Christine Levy-Piebois, Karim Morsli, Jean-Louis Habrand, Chantal Kalifa, and Jacques Grill; Department of Paediatrics, Gustave Roussy Institute, Villejuif, France

Purpose: To investigate the neuropsychological outcome of children treated with posterior fossa (PF) radiation for a localized ependymoma. Patients and Methods: 21 patients who were treated with local PF radiation since 1985 where evaluated in this retrospective study. Age at radiation ranged between 1 and 14 years with 9 patients under the age of five. Neuropsychologic evaluation was performed one to four times with the last testing at a median of 3.5 years after radiotherapy and included an age-appropriate version of the Wechsler Intelligence Scale for Children and evaluation of manual performance with the purdue pegboard. Results: Mean full scale intellectual quotient (FSIQ) was reduced (88.4; SD = 13). 10 children had normal IQ at last evaluation (median interval since RT of 2.5 years). There was a significant difference between results for verbal IQ (VIQ) and performance IQ (PIQ), with mean VIQ and PIQ of 94 and 85, respectively. In a longitudinal analysis of 16 patients who had two or more neuropsychological evaluations, there was no trend for loss or gain in intellectual outcome measured with the FSIQ. The comparison of IQ scores between young children (<5 years) and older children at time of radiation showed no significant difference; however, all five children with PIQ scores <70 were under the age of seven at radiation. There was a significant association between the presence of cerebellar syndrome at the time of neuropsychological examination and poorer PIQ outcome (p < 0.001). Results of the examination of manual skills with the purdue pegboard were strongly correlated with poorer neuropsychological outcome. Conclusions: Cognition after PF irradiation for ependymoma is preserved in most of the children and postoperative neurological deficits have a strong impact on intellectual outcome. Age below 5 years at irradiation was not a significant risk factor for long term intellectual deficits; however, reduced IQ scores were seen only in children with early disease manifestation and treatment.

LE 14. PROSPECTIVE NEUROPSYCHOLOGICAL AND NEUROENDOCRINE EVALUATION IN CHILDREN WITH BENIGN/LOW-GRADE BRAIN TUMOURS TREATED WITH STEROTACTIC CONFORMAL RADIOTHERAPY (SCRT) AND CONVENTIONAL RADIOTHERAPY: EARLY RESULTS OF A RANDOMISED TRIAL

Rakesh Jalali, Rajiv Sarin, Nitin More, Rashmi Kamble, Savita Goswami, Nalini Shah, and Sachin Parab; Departments of Radiation Oncology and Clinical Psychology, Tata Memorial Hospital; Department of Clinical Endocrinology, KEM Hospital; Brain Tumour Foundation of India; Mumbai, India

Prospective data of 35 accrued patients (target 200) participating in an ongoing randomised trial of SCRT (18 patients) vs. conventional radiotherapy (17 patients) is presented. Tumours included optic-pathway glioma (13), craniopharyngioma (11), supratentorial low-grade astrocytoma (6), cerebellar astrocytoma (5), and 2 others. Eleven patients, each in SCRT and Con-vRT arms, had hypopituitarism at baseline with no additional deficits at 6 months. Mean baseline global IQ (normal 90–109) of patients in SCRT and ConvRT arms were 84 and 91, respectively, with 10/16 patients assessed in SCRT and 6/13 in ConvRT, having below normal IQ’s even before starting radiotherapy, the corresponding values at 6-month evaluation being 95 and 91. VITHOBA battery (normal 100) for blind revealed preRT values of 97 in SCRT and 56 in ConvRT arms. Memory remained maintained in SCRT (mean 101 baseline and 114 at follow-up) but worsened in ConvRT (107 preRT and 57 postRT). LOTCA battery used for patients aged >6 revealed respective average baseline and 6-month follow-up values of 95 and 100 for SCRT and 98 and 90 for ConvRT. Anxiety assessments with C1, C2 (no anxiety <35) and HARS (normal < 17) showed mean baseline values of 48, 40, and 20 in SCRT reducing to 31, 25, and 20, respectively, at follow-up but worsened in ConvRT (mean respective baseline of 42, 32, 18 vs. 37, 30, and 24 at follow-up). Mean depression values using Hamilton scale (normal < 17) was 19 before and 10 after SCRT, which was better than seen in ConvRT (13 and 19, respectively). For QOL in children, HUI values (mean 10 and 9) and Barthel’s ADL were maintained in both arms before and after RT. Our early analysis in a small cohort reveals considerable neuroendocrine and neuropsychological deficits in children with brain tumours before starting radiotherapy. SCRT at short follow-up seems to show nonsignificant improvement in levels of anxiety, depression, and memory compared to conventional radiotherapy, which, however, clearly needs mature data in larger number of patients for firm conclusions.

LE 15. FUSIFORM ANEURYSM AS A COMPLICATION OF THERAPY FOR MEDULLOBLASTOMA

Donna Johnston, Daniel Keene, Laval Grimard, and Jean Michaud; Departments of Pediatrics and Pathology, Children’s Hospital of Eastern Ontario; Department of Radiation Oncology, Ottawa Regional Cancer Centre; Ottawa, ON, Canada

High-risk medulloblastoma patients are treated with radiation therapy and chemotherapy following surgery. These treatments are often associated with significant side effects. We report one case of high risk medulloblastoma who had many complications, and eventually died from an intracranial hemorrhage secondary to a ruptured fusiform aneurysm. A seven-year-old male was treated for high-risk medulloblastoma following POG protocol 6931. He received radiation therapy to a dose of 36 Gy in 20 fractions to the craniospinal axis and a 3D conformal boost of 19.9 Gy in 11 fractions to the tumorectomy site with margins in the posterior fossa. Chemotherapy consisted of oral etoposide, cisplatin, cyclophosphamide, and vincristine. He suffered multiple complications during chemotherapy including typhlitis, bacteremia, gastrointestinal hemorrhage, hemorrhagic cystitis, herpes zoster infection, grade peripheral neuropathy, and fungal pneumonia. Following completion of therapy he presented with sudden right leg weakness. MRI demonstrated an infarct of the left paramedial branch of the basilar artery. One month later he developed a second ischemic event in the right side of the pons. Three months later he collapsed at home and died. Autopsy demonstrated a recent massive subarachnoid hemorrhage. The distal vertebral and basilar arteries were thickened and fibrotic. A ruptured fusiform aneurysm of the left anterior inferior cerebral artery and a small nonruptured aneurysm of the opposite artery were found. Histologically, the intima was thickened and fibrotic with variable stenosis of the lumen. The internal elastic lamina was frequently disrupted with segments persisting in the wall of the aneurysm. The media was severely fibrotic, and inflammation was scarce. There was no evidence of residual tumor present. Pathological findings were consistent with radiation-induced vasculopathy causing fusiform aneurysm formation. In summary, this patient developed a rare complication of radiation therapy, fusiform aneurysm, as a result of his therapy for high-risk medulloblastoma.

LE 16. CHANGES IN ATTENTIONAL PERFORMANCE IN CHILDREN AND YOUNG ADULTS WITH LOCALIZED PRIMARY BRAIN TUMORS REQUIRING RADIATION THERAPY

Erin N. Kiehna, Raymond K. Mulhern, Chenghong Li, Xiaoping Xiong, and Thomas E. Merchant; Division of Radiation Oncology, Division of Behavioral Medicine, Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To prospectively assess the impact of conformal radiation therapy (CRT) and demographic and clinical variables on four measures of attention in pediatric and young adult patients with localized primary brain tumors. Patients and Methods: One hundred twenty patients ranging in age from 2.0 to 24.4 years at CRT (median age 9.2 years) with primary brain tumors were evaluated prospectively using the computerized Conners’ continuous performance test (CCPT) of attention before CRT, weekly during CRT, and at 6, 12, 24, 36, 48, and 60 months following the initiation of CRT. Analyses were conducted on Errors of Omission (failure to respond to a target stimulus), Errors of Commission (responding to a nontarget stimulus), Reaction Time, and an Overall Index of performance from the CCPT. Results: PreCRT, mean Errors of Omission were significantly elevated. During CRT, there was significant improvement in the mean Errors of Commission (p = 0.02). Following CRT, patients exhibited a significant increase in Errors of Omission (p = 0.03) and an increasing Overall Index of attention problems (p = n.s.). Increased Errors of Omission were associated with craniopharyngioma (p < 0.0001), supratentorial tumors (P = 0.008), optic pathway and diencephalic tumors (p = 0.012), and patients who underwent subtotal resection of their disease (p = 0.010). Conclusion: Children with brain tumors have problems with sustained attention and reaction time resulting from the tumor and treatment. The decline in impulsivity (Errors of Commission) and the relative stability of the other CCPT scores over the course of radiation therapy demonstrate the absence of any early radiation related side effects. During the first five years after RT, increasing inattentiveness (Errors of Omission), was noted for patients with optic pathway and diencephalic tumors. Local tumoral effects, surgical extent, or focal irradiation to the central structures contribute to long-lasting attention problems.

LE 17. NEURO-COGNITIVE FUNCTION IN SAME-SEX TWINS FOLLOWING FOCAL RADIATION FOR MEDULLOBLASTOMA

Donald J. Mabbott, Marcia Barnes, and Eric Bouffet; Department of Psychology and Division of Haematology, Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, ON, Canada

Treatment with cranial-spinal radiation for medulloblastoma has an adverse impact on cognitive outcome for young children. Consequently, protocols have been developed that combine chemotherapy, second-look surgery, and focal posterior fossa radiation therapy with the goal of maintaining treatment efficacy while reducing adverse late effects. As these protocols are relatively new, little data exist regarding cognitive outcome. We conducted a twin control case study to investigate neuro-cognitive outcome in a preschool patient treated with focal posterior fossa radiation for medulloblastoma. Changes in intelligence, language, and visual-motor ability over time were compared for the patient and her nonaffected twin. The patient was 16 months old at diangosis and was treated with surgery, chemotherapy, autologous bone marrow transplant, and focal radiation therapy to the posterior fossa. Her nonaffected twin had a history of speech-language delay. The twins were assessed on 2 occasions: (a) 21 months following diagnosis and 12 months following the completion of radiation for patient and (b) 12 months later. Verbal and performance IQ for both twins fell within borderline to low average range at the first assessment. The IQ scores for the patient improved to within the low-average to average range at the second assessment, while the scores for the nonaffected remained relatively stable. Although both twins’ demonstrated poor language expression, the patient’s language comprehension improved from low average to average across assessments, while the nonaffected twin demonstrated stable low-average performance. Visual-motor integration improved for both twins across assessments from low average to average ability, and the patient demonstrated higher tests scores compared to the nonaffected twin. We observed improvement in neuro-cognitive functioning of a preschool patient treated with focal radiation from approximately 12 months to 24 months after treatment. These findings are notable and among the first to document the relative benefit of focal radiation.

LE 18. SERIAL EVALUATION OF ACADEMIC AND BEHAVIORAL OUCTOME FOLLOWING TREATMENT WITH CRANIAL RADIATION IN CHILDHOOD

Donald Mabbott, Brenda Spiegler, Mark Greenberg, James Rutka, Douglas Hyder, and Eric Bouffet; Department of Psychology and the Divisions of Hematology/Oncology and Neurosurgery, The Hospital for Sick Hospital, Departments of Pediatrics and Surgery, University of Toronto, Toronto, ON, Canada

Treatment with cranial-spinal radiation for pediatric brain tumours is consistently associated with a progressive decline in intelligence. The impact of cranial radiation on academic and behavioral functioning has received considerably less attention. The goal of the present study is to examine patterns of change over time in academic and behavioral functioning in children treated with cranial-spinal radiation for malignant posterior fossa (PF) tumors. Thirty-one children (23 males) were followed with serial evaluation of academics and/or behavioral functioning. Twenty-seven patients were treated for medulloblastoma and 4 for ependymoma. Twelve patients were treated with reduced dose (2340–3020 cGy), and 18 with standard dose (3400–3600 cGy) cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized achievement tests and behavioral questionnaires were administered at different times following diagnosis. The rate of change in scores was determined using a mixed model regression. Children’s spelling and mathematics declined over time (slopes = −1.21 and −1.72, ps < .01). The pattern of change for reading was different; scores were affected early and remained a stable deficit over time. Significant declines were also evident in parent’s and teacher’s ratings of academic ability (slopes = −1.18 and −.93, ps < .01). Parent’s and teacher’s ratings indicated few clinically significant problems in internalizing and externalizing behavior problems. Increases in parent’s rating of social difficulties (slope = 1.06, p = .01) and teachers ratings of social withdrawal, social difficulties, and attention problems (slopes = 1.08, 1.16, and 1.43, ps < .05) were observed over the modeled time period, however. Cranial radiation is associated with declines in academic ability and increases in social and attention problems. However, neither psychological distress nor behavior problems were evident, highlighting the resiliency of children and families in the context of severe medical stressors.

LE 19. A REPORT OF THREE CASES OF SECONDARY TUMORS AFTER TREATMENT OF GERM CELL TUMORS

1Keishi Makino, 1Masato Kochi, 1Hideo Nakamura, 2Yukitaka Ushio, and 1Junichi Kuratsu; 1Department of Neurosurgery, Kumamoto University School of Medicine, Kumamoto; 2Otemae Hospital, Osaka; Japan

Radiation therapy is commonly used for treatment of germ cell tumors and effective for the primary tumors. However, secondary tumors were sometimes seen in or close to the radiation fields several years later after radiation. At that time, it is necessary to distinguish these tumors from recurrent tumors. Here three cases of postradiation tumors are described. Two patients were irradiated for suprasellar germ cell tumors, and one was for pineal tumor. These patients were 5, 16, and 20 years old at the first treatments. The dose ranged from 44 to 67 Gy, and the latency period was 2 to 9 years after the radiation. Two cases arose in the fields of irradiation, and another one arose close to the fields. All secondary tumors were verified histologically (meningioma, hemangiopericytoma, and glioblastoma), and no evidence of persistence of the primary tumors was found. As the secondary tumors occur after the treatment of germ cell tumors, we should carefully follow up these patients.

LE 20. PROTECTION BY HYPOTHYROIDISM DUE TO CRANIOSPINAL IRRADIATION IN MEDULLOBLASTOMA PATIENTS

Maura Massimino, Lorenza Gandola, Annalisa Serra, Emanuele Pignoli, Filippo Spreafico, Ettore Seregni, Federica Pallotti, Monica Terenziani, and Franca Fossati-Bellani; Pediatric Oncology Unit, Radiotherapy Department, Medical Physics and Nuclear Medicine Unit, Istituto Nazionale Tumori, Milano, Italy

More and more papers deal with the consequences of irradiation in medulloblastoma, both from the neuro-psychological and the endocrinological point-of-view. Hypothyroidism has always been one of the earliest and more frequently described late effects. In 1998, therefore, we launched a study to evaluate the protective activity of TSH-suppression during RT. From January 1998 to February 2001, 38 euthyroid children who had to receive cranio-spinal irradiation (CSI) for medulloblastoma-PNET were submitted to thyroid ultrasound and evaluation of fT3, fT4, TSH, thyroglobulin at the beginning and at the end of CSI; thereafter blood exams were done every six months and ultrasound after one year: if normal thereafter every other year. From day –7 before RT up to the end, patients were administered l-thyroxin at suppressive doses; every other day TSH-suppression had to be checked as a value < 0.3 μM/ml. During subsequent follow-up hypothyroidism was diagnosed as an elevation of TSH. CSI was made through HART; doses were in the range of 20–39 Gy; models were done to evaluate doses received by thyroid bed included in the CSI. Of the 38 pts, 32 were alive with a median interval of 36 months from CSI: while 22 children were adequately TSH-suppressed during CSI, 10 were not. Fourteen/32 children suffered iatrogenic hypoparathyroidism at a median interval of 16 months after CSI. Hypothroidism-free survival at three years was 90% for the “TSH-suppressed” group and 41% for the “TSH-nonsuppressed group” (p 0.042). TSH-suppression through l-thyroxin medication had a protective activity on thyroid function at three years. Longer follow-up is needed to confirm data, but the feasibility, low costs, and absence of side effects of this experience prompt us to organize a randomized trial to verify this suggestive preliminary data.

LE 21. SPEECH AND LANGUAGE FUNCTIONING FOLLOWING SURGERY FOR POSTERIOR FOSSA TUMORS

Talar Misakyan, Deryk Beal, Peter Dirks, James Rutka, Eric Bouffet, and Donald Mabbott; Departments of Psychology and Communication Disorders and the Divisions of Hematology/Oncology and Neurosurgery, The Hospital for Sick Children; Departments of Pediatrics and Surgery, University of Toronto; Toronto, ON, Canada

The most widely documented speech and language deficit following surgery for posterior fossa (PF) tumors is transient mutism. Speech outcomes likely occur on a continuum, however, and few studies have examined the extent of other speech and language deficits. A novel contribution of our study was the use of a detailed speech language assessment to evaluate the pattern of functioning following surgery. Twenty-four of 60 patients diagnosed with PF tumors between July 2000 and October 2003 and older than 3 years were seen for speech and language assessment postoperatively or at recovery of speech if applicable: mean time from surgery to assessment was 11.09 weeks. Seventeen patients were treated for medulloblastoma, 3 for ependymoma, and 4 for astrocytoma. Surgery resulted in gross total (42%), near-complete (37%), or subtotal (25%) resections. Mean ages at diagnosis and assessment were 6.98 and 7.22 years, respectively. Mutism was evident in 38% of patients assessed (mean duration = 3.9 weeks). These patients continued to demonstrate impairments following speech recovery, including deficits in oral motor control (100%), reduced rates of conversational speech and producing alternating speech sounds (78% and 67% respectively), as well as reduced intelligibility of speech (56%). Children who did not experience mutism also demonstrated impairments, including deficits in oral motor control (73%), reduced rates of conversational speech and producing alternating speech sounds (33% and 73%, respectively), and reduced intelligibility of speech (26%). All patients demonstrated average basic language skills (mean receptive vocabulary standard score = 98; mean expressive vocabulary standard score = 98). We identified more pervasive speech deficits than have been reported previously. Our findings provide further evidence of the role the cerebellum may play in modulating communication and support the need for prospective speech-language evaluation in all patients with posterior fossa tumors.

LE 22. THE EFFECT OF RADIATION DOSIMETRY ON IQ AFTER CONFORMAL RADIATION THERAPY IN PEDIATRIC PATIENTS WITH LOCALIZED EPENDYMOMA

Thomas E. Merchant, Erin N. Kiehna, Chenghong Li, Xiaoping Xiong, and Raymond K Mulhern; Division of Radiation Oncology, Department of Biostatistics and Division of Behavioral Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To assess the effect of radiation dose-volume distribution on the longitudinal trend of IQ scores for ependymoma patients after conformal radiation therapy. Patients and Methods: The study included 86 patients (median age 2.8 years ± 4.5 years) with localized ependymoma who received conformal radiation therapy (CRT) (54–59.4 Gy) using a 1cm clinical target volume between July 1997 and January 2003. Patients were evaluated with psychometric testing including IQ measures at baseline, 6, 12, 24, 36, 48, and 60 months following CRT. Dose-volume histograms (DVH) were acquired for five normal tissue structures for each patient (brain, supratentorial brain, infratentorial brain, right and left temporal lobes). DVH data were partitioned into three intervals (V0–20Gy, V20–40Gy, V40–60Gy), representing the fractional volume receiving dose over the specified interval, and combined with clinical data to form a regression model to estimate IQ as a function of time after CRT. Results: With a median follow-up of 29.4 months, a total of 327 IQ tests have been performed in 66 infratentorial and 20 supratentorial patients. When all patients were included, IQ could be estimated by age (years) at CRT, dose to the supratentorial brain and time (months) after CRT using the equation:

equation image

where Age (p < 0.0001), V0–20Gy (p = 0.01), V20–40Gy (p = 0.001), and V40–60Gy (p = 0.04) contributed significantly to the model. A model with significant dose-volume terms was also derived for the total brain. When patients were stratified according to infratentorial and supratentorial tumor location, models with significant dose-volume terms was developed for the total brain, supratentorial brain, infratentorial brain, and left temporal lobe. A dose-volume model could not be developed to estimate IQ for supratentorial patients. Conclusion: Radiation dosimetry can be used to estimate IQ after CRT in patients with localized ependymoma. The significance of models developed to estimate radiation dose-volume effects may be enhanced by grouping patients according to tumor location.

LE 23. AGE AT DIAGNOSIS A PROMINENT RISK FACTOR WHEN EVALUATING COGNITIVE PERFORMANCE FOLLOWING RISK ADAPTED TREATMENT FOR MEDULLOBLASTOMA (MB)

Raymond Mulhern, Shawna L. Palmer, Thomas Merchant, Dana Wallace, Mehmet Kocak, Pim Brouwers, Murali Chintagumpala, David Ashley, Larry Kun, and Amar Gajjar; Division of Behavioral Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: We conducted a longitudinal study to examine the effects of age, radiation dose, gender, and time from diagnosis on intellectual quotient (IQ) and academic achievement (Reading, Spelling, Math) among patients treated for MB. Patients and Methods: Patients received serial neurocognitive testing spanning from 0.25 to 6.75 years after diagnosis (median follow-up = 3.07 years). The study included 111 patients 3 to 20 years of age at diagnosis (median = 7.4 years) treated for medulloblastoma with postsurgical risk-adapted craniospinal irradiation (CSI) followed by 4 cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, vincristine) with stem cell support: High-risk (HR, n = 37) patients received CSI to 36–39.6 Gy and conformal boost treatment of the primary site to 55.8–59.4 Gy. Average-risk (AR, n = 74) patients received CSI to 23.4 Gy, conformal boost treatment of the posterior fossa to 36 Gy and primary site to 55.8 Gy. Results: Multivariate modeling revealed statistically significant declines in Estimated IQ (P= 0.046), Full Scale IQ (P = 0.04), Reading (P = 0.0001), Spelling (P = 0.0001), and Math (P = 0.028) scores for the entire group. The effects of risk classification were mediated by age with statistically significant (p < 0.05, two-tailed) rates of decline observed for young (age < 7 years) HR patients for EIQ, Reading, Spelling, and Math, while young AR patients also demonstrated significant declines in Reading and Spelling. There were no significant declines for older patients on any of the outcome variables. Conclusions: Young age at diagnosis is the most prominent risk factor for neurocognitive deficits among survivors of MB despite reductions in CSI dosing and efforts to limit the boost volume. Both younger AR and HR patients exhibit substantial problems with the development of reading (phonological analysis) skills. This study represents the largest comparison of neurocognitive performance among patients treated for medulloblastoma with conventional or reduced dose RT and adjuvant chemotherapy.

LE 24. OSTEOPENIA AND HEALTH-RELATED QUALITY OF LIFE IN SURVIVORS OF BRAIN TUMORS TREATED IN CHILDHOOD

Isaac Odame, JoAnn Duckworth, Lesley Beaumont, Danielle Talsma, William Furlong, Colin Webber, and Ronald Barrl; McMaster University Health Sciences Centre, Hamilton, ON, Canada

Objectives: To examine the relationships between bone density and health-related quality of life (HRQL) among survivors of brain tumors treated in childhood. Design/Methods: Subjects were survivors of cerebellar astrocytoma, medulloblastoma, or optic glioma, < 18 years of age at diagnosis and >1 year posttreatment. Bone mineral density of the lumbar spine (BMD-LS) and whole body (BMD-WB) were measured by dual energy x-ray absorptiometry (DXA). DXA measurements were expressed as z-scores using normative Canadian data. Severe osteopenia was defined as z-score <-2. Health status and HRQL were assessed using the Health Utilities Index Mark 3 (HUI3) system. Standard 15-item HUI questionnaires completed by parents collected information about eight attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. HRQL and single-attribute morbidity scores were calculated using established algorithms. The relationships between DXA measurements and HUI scores were assessed using linear regression. Differences in mean scores between severely osteopenic patients and others were assessed by t-test. Results: Of 40 eligible survivors, 24 (60%) had both HUI assessment and DXA measurements. Mean age at time of study was 16.5 years. (SD = 4.93) for the population and 15.4 years. (SD = 4.83) for the sample (p = 0.38). The prevalence rate of severe osteopenia was 20.8% using BMD-LS and 16.7% using BMD-WB. A statistically significant correlation was observed between HRQL and BMD-LS (r = 0.59, p = 0.003) and HRQL and BMD-WB (r = 0.43, p = 0.036). Correlation of single-attribute utility scores and BMD-WB was statistically significant for pain (r = 0.49, p = 0.015). Mean HRQL was significantly lower (p = 0.010) for severely osteopenic patients (mean = 0.468) than for the other patients (mean = 0.814). Conclusions: This pilot study demonstrates that, among survivors of childhood brain tumors, HRQL is less and pain more severe in those with low BMD scores. Furthermore, patients classified as severely osteopenic have lower HRQL. A larger multi-centre study is needed to confirm these results.

LE 25. SUPRATENTORIAL OLIGODENDROGLIOMA OCCURRING AS SECONDARY NEOPLASM TEN YEARS AFTER SUCCESSFUL TREATMENT OF POSTERIOR FOSSA EPENDYMOMA WITH SURGERY AND INTENSIVE CHEMOTHERAPY ONLY

Andreas Peyrl, Thomas Czech, Wolfgang Dietrich, Christine Haberler, Peter Ambros, Martina Kronberger, Daniela Prayer, and Irene Slavc; Departments of Pediatric, Neurosurgery, and Radiology, and Institute of Neurology, University of Vienna Medical School; Children’s Cancer Research Institute, Vienna; Austria

In March 1993, a 16-month-old patient presented with a posterior fossa ependymoma WHO grade II–III. Gross total resection was followed by HIT-91 sandwich chemotherapy supplemented by intraventricular MTX because of the persistence of tumor cells in the CSF over a 4-month period and continued with HIT-SKK-87 baby protocol maintenance therapy to postpone radiotherapy. Subsequent examinations with MRI revealed no recurrence, but in August 1994 leukoencephalopathy was described for the first time. Therefore, radiotherapy was considered too risky and high-dose chemotherapy with thiotepa, etoposide, and carboplatin according to the Finlay protocol followed by autologous peripheral stem cell rescue was performed. The patient is mildly mentally retarded and attends a special education program. In May 2000, the patient developed complex focal seizures with secondary generalization. However, follow-up MRI-scans performed every six months showed no signs of recurrence. In July 2003, the patient presented with right sided hemiparesis and facial palsy. MRI showed a tumor of 4 cm in diameter in the left parietal region with perifocal oedema causing a mid-line-shift which was not present 6 months earlier. A neuronavigated frameless biopsy of the tumor was taken, and histological examination revealed oligodendroglioma grade II. Molecular cytogenetics showed imbalance of chromosomal region 1p36.3, but no sign of deletion of 19q. Additionally, molecular cytogenetics of the original ependymoma was performed, and this examination showed neither deletion of 1p nor 19q. Chemotherapy with temozolomide 200 mg/m2 x 5 every four weeks was initiated and led to rapid clinical improvement, diminished facial palsy and hemiparesis, and decreased frequency of seizures. After three courses of temozolomide MRI showed partial remission and reduced contrast enhancement. Temozolomide appears to be an effective treatment option in this heavily pretreated patient with secondary oligodendroglioma.

LE 26. SECOND MALIGNANT NEOPLASMS IN LONG-TERM SURVIVORS OF PEDIATRIC BRAIN CANCER: AN ANALYSIS OF SEER DATA

Katia M. Peterson, Cheng Shao, Tobey MacDonald, and Julianne Byrne; Children’s National Medical Center Center for Cancer Research, Washington, DC, USA

Advances made in treatment of a childhood brain cancer have extended the lives of many children and adolescents. Treatment success, however, brings the opportunity to assess late effects; most worrying among these are secondary malignant neoplasms (SMN). Even though the cumulative incidence is quite small, long-term follow-up is required because treatment-induced cancers can occur years after initial treatment. The increased relative risk of developing a SMN after a primary brain tumor in childhood has been attributed to the type and strength of radiation treatment and chemotherapuetic agents. The purpose of this project was to determine what treatments and what host characteristics of children treated for a primary brain cancer can increase the risk of a SMN. We analyzed data from 2,057 five-year survivors, of primary brain cancer in the SEER (define) database between 1973–1998. Forty patients developed a SMN. We used Cox regression models and standardized incidence ratios (SIRs) to evaluate the independent contribution of a number of risk factors. For five year survivors the most important risk factor for developing a SMN was the era in which the primary cancer was treated. Compared to treatment prior to 1979, those patients treated between 1979–1984 had a 4.7 fold increase in risk (p= .001), while those treated after 1984 had a 7.0 fold increase in risk. (p = .002). In these long-term survivors, radiation was an independent risk factor for SMN (hazard ratio = 2.0, p = 0.06). We conclude that patients treated most recently carry the greatest risk of SMN development even after controlling for radiation. This could be due to the increase in treatment aggressiveness compared to earlier years. Although the absolute excess risk of SMN remains quite low, continued surveillance is needed to evaluate long-term effects of new therapies.

LE 27. HYPERFRACTIONATED RADIOTHERAPY (HFRT) FOR POSTERIOR FOSSA EPENDYMOMA: NEURO-PSYCHOLOGICAL OUTCOME

Geraldina Poggi,1 Maura Massimino,2 Lorenza Gandola,2 Mariarosaria Liscio,1 Susanna Galbiati,1 Anna Adduci,1 Filippo Spreafico,2 Felice Giangaspero,2 Franca Fossati-Bellani,2 and Enrico Castelli1; 1Istituto di Ricovero e Cura a Carattere Scientifico E. Medea Bosisio Parini, Lecco; 2Istituto Nazionale dei Tumori, Milano; Italy

A postsurgical “stage-based” protocol for ependymoma (EPD) was designed in 1994. Children received 1) focal hyperfractionated radiotherapy (HFRT) if there was no evidence of disease (NED) or 2) four courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction bid) on tumor bed plus a 2-cm margin; VEC consisted of VCR (1.5 mg/m2 1/w), VP16 (100 mg/m2/d x 3), CTX (3 g/m2 d x 1). When feasible, second-look surgery was recommended. Sixty-three consecutive children were enrolled between 1993 and 2001: 46 NEDs and 17 EDs; the tumor was infratentorial in 47 and supratentorial in 16 patients, with spinal metastasis in one. Of the 47 children with posterior fossa tumor, 34 were NED and 12/34 were treated and followed at our Institutions. Six out of 12 patients were studied with an age-appropriate neuropsychological protocol at diagnosis, that is at a median time of 8 weeks after surgery, and again one time at a median interval of 15 months after. The mean age of the patients at the two assessments was 8.2 and 9.3 years, respectively; the inter-assessment interval was 1 year. Three children were evaluated also after 4, 6.3 and 6.4 years. At assessment 1, the mean VIQ was 108.2, with PIQ = 111 and FIQ = 108.4. At assessment 2, the VIQ was 107.4, PIQ = 96.4 and FIQ = 102.2. In the three children with a longer interval of evaluation after surgery and HFRT, the VIQ, PIQ, and FIQ were, respectively, 129, 136, 137 (after 3 years); 96, 93, 93 (after 6.3 years); and 95, 81, 86 (after 6.4 years). A clinically significant drop in performance was observed, in particular on tasks requiring attention and planning skills as well as organization of information. During the inter-assessment period, an overall impairment—however, always with abilities preserved in the normality range—of the intellectual level became evident, especially affecting neuropsychological skills which may impact on learning. These effects are the sum of surgery and HFRT effects and deserve an appropriate follow-up.

LE 28. INFLUENCE OF POSTOPERATIVE ACTIVE FEEDING IN BODY WEIGHT OF CHILDREN WITH POSTERIOR FOSSA TUMOURS

Laura Powell, Michelle Snipe, and Spiros Sgouros; Dietetic Department, Birmingham Children’s Hospital, Birmingham, UK

Introduction: Malnutrition is a common complication of cancer treatment, as it can affect calorie intake and tolerance of treatment. Aim: To investigate the effect of active feeding during the early postoperative months on the nutritional status of children with posterior fossa tumours that require adjuvant treatment. Patients and Methods: Retrospective review was carried out of 29 children that were treated for posterior fossa tumours between 1997–2003. Children who received postoperative chemotherapy and radio-therapy were grouped as ‘fed’ (enteral feeding for six months); ‘partially fed’ (enteral feeding for less than six months); ‘not fed’ (no tube feeding). Patients who did not receive adjuvant treatment or enteral feeding constituted the control group. For each patient, actual and ideal body weight were recorded preoperatively, and at 6 months postoperatively. A body weight ratio (BWR) was calculated by dividing actual to ideal weight. Results: Median age at presentation was 6 years 9 months (range: 1 year 3 months–16 years 8 months).

Fed n = 4Partially Fed n = 2Not Fed n = 13Control n = 10
Median BWR at diagnosis0.900.910.961.04
Median BWR at 6 months postoperatively0.990.840.931.21
Median difference in BWR0.09–0.07–0.030.17

There was no difference for preoperative body ratios for the feeding groups. The results appear to show that enteral feeding improves BWR, although larger numbers are required. Conclusion: It appears that active feeding following surgical excision of a posterior fossa tumour is beneficial to children’s nutritional status while they are receiving adjuvant therapy. It is, however, clear that further work is required in this area.

LE 29. NEUROPSYCHOLOGICAL LONG-TERM SEQUALE OF POSTERIOR FOSSA TUMORS IN CHILDHOOD

Michelle Sadeh,1,2 Andrea Berger,3 Gabriel Zur,3 Liora Kornreich,5 Avinoam Shuper,4 Shlomi Constantini,6 Orna Friedman,6 Shalom Michovitz,7 Ian Cohen,4 Dov Inbar,1 and Isaac Yaniv4; 1Child Development and Rehabilitation Center, 4Hematology and Oncology Department, 5Imaging Department, and 7Pediatric Neurosurgery Department of Schneider Children’s Medical Center of Israel, Petah-Tikva; 2Israel Cancer Association; 3Behavioral Sciences Department at Ben Gurion University of the Negev; 6Department of Pediatric Neurosurgery at Dana Children’s Hospital, Tel Aviv Medical Center; Israel

The cerebellum is currently the focus of neuropsychological research around the world. Numerous studies find the cerebellum an important part of the complex cognitive processes, once thought to be solely related to the cerebral hemispheres. Our study assessed the damage to the cerebellum, following neurosurgery (without chemotherapy or radiotherapy), on the development of general cognitive abilities, language, and memory in children. Eleven children (posterior fossa tumor group-PFT) who arrived at the clinic during 1999–2001 were assessed using a wide range of cognitive tests. Histopathological diagnosis included: ependymoma (4 children), astrocytoma (6 children), and an undefined cystic tumor (1 child). Age range at testing was 7.3–16.7 years, at surgery 1.0–10.8 years. All children had MR scans within a year postoperatively. Children were tested at least 3 years post surgery and native Hebrew speakers. Matching to controls was done based on age (PFT group: average age 12.6, Control: 13.2 years), intellectual abilities (PFT group: VIQ = 110; PIQ = 119, Control group: VIQ = 116; PIQ = 121), sex (both groups: 5 boys, 3 girls); and Social Economic Status. Our findings show that the PFT group had similar function to the Control group, and their cognitive difficulties were related to verbal memory processes. No significant difference was found between PFT group and Control group on Verbal Fluency Tasks (NEPSY naming and picture speeded naming, FAS semantic and phonemic; writing and dictating stories), on NonVerbal memory tasks (Rey Osterrieth Complex figure, immediate and delayed recall), Working memory (Digit span vs. Corsi Blocks), Visual Spatial Organizational Abilities (Hooper, ROCF copy and VMI), and Stratigical Planning task (Tower of Hanoi). On Verbal Memory tasks—memory for stories and words, both immediate and delayed—a significant difference was found. The results will be discussed in relation to the MRI findings and the similarities and discrepancies with other studies.

LE 30. MEDICAL SEQUELAE OF PEDIATRIC LOW-GRADE GLIOMA

Antoinette Y.N. Schoutenvan Meeteren,1 Weiling L. Lee,1 Ellen Mandl,2 and W. Peter Vandertop2; Department of Pediatrics1 and Neurosurgery,2 VU University Medical Center, Amsterdam, The Netherlands

Introduction: Compared to other brain tumors low-grade gliomas during childhood are considered to be a rather benign tumor. Since most children survive this disease, it is important to focus on the medical consequences for survivors of low-grade glioma. Patients and Methods: Charts of low-grade glioma patients treated in our hospital during the past 15 years were analysed. The location, histologic subtype, degree of resection, therapy, and survival data were documented. Late sequelae regarding vision, hearing, neurology, and endocrinology were gathered from dossiers of medical specialists consulted in our hospital. Results: A total of 86 children (42 male, 44 female) with low-grade glioma (located 33% cerebellar, 24% optic pathway or (hypo)thalamic, 15% brainstem, 24% other, 3 multiple sites) were included in the study with a mean age at diagnosis of 7.3 years (range 0.6–17.4), including 5 patients with neurofibromatosis I. Histology varied from 72% pilocytic astrocytoma, 9% oligodendroglioma, 10% diffuse low-grade glioma and a remaining subgroup. Neurosurgery was performed in 72 patients (7 biopsy only) and 12 patients had a wait and see strategy, 1 radiotherapy, and 1 chemotherapy. 38 patients received a ventriculo peritoneal shunt. Overall survival was 91% (median follow-up 5.9 years). Progression occurred in 23 patients after 0.13–11 years (median 1.6 years) mainly in optic pathway, thalamic, or brainstem tumors. In surviving patients, 35 had ophthalmologic consequences like blindness (4), severe low vision (5), any eye movement disorder (23), visual field loss (9), while 10 had hearing loss and one loss of smell. Neurological sequelae were present in 47 patients, varying from epilepsy in 14, ataxia and coördination disturbance in 21, facial nerve palsy in 19, and other cranial nerve palsy in 4 patients. Endocrinopathies were present in 12 patients (4 panhypopituitarism, 4 pubertas praecox, 4 other). Only three patients had none of these sequelae. Each patients consulted 1–7 medical specialists with a median number of 3.6 per patient. Since our study certainly harbours the disadvantage of a retrospective analysis, these data might underestimate reality. Conclusion: Patients with low-grade glioma are entitled to medical care within several fields of medicine since most of them have sequelae of disease and/or treatment. Adequate diagnosis of these and, if possible, intervention should minimize the impact of these sequelae.

LE 31. CEREBELLAR INJURY AND NEUROCOGNITIVE OUTCOMES AFTER TUMOUR THERAPY—A PILOT CASE-CONTROL STUDY

Zoe Wang,1 Louise Braithwaite,1 Terry Parker,3 Tim Jaspan,4 Paul Morgan,4 Steve Barrett,2 Nicola Pitchford,5 and David Walker2; 1Medical Students, 2Children’s Brain Tumour Research Centre, School of Human Development, University of Nottingham; 3School of Biomedical Sciences, 4Division of Diagnostic Imaging, University Hospital Nottingham; 5Department of Psychology, University of Nottingham; UK

Introduction: Two-thirds of paediatric intracranial tumours occur in the posterior fossa. Cerebellar injury consequent to tumour and its treatment can cause mutism post operatively and impaired motor coordination, which can be disabling. Recently nonmotor cerebellar functions affecting learning, language, and visuo-spatial skills have been identified. Improvements in survival rates and an expanding range of treatments with diverse neurotoxicities means that enhanced knowledge of neuropsychological effects of cerebellar tumour injury may influence treatment selection aimed at optimising neuro-cognitive outcome. We aimed to test the hypothesis that neuropsychological outcome correlates with the site and size of tumour and patient age at the time of tumour resection. Methods: 4 cases with cerebellar tumours and 4 controls with supratentorial tumours matched for sex and radiotherapy dose were identified. All patients had previously undergone neuro-cognitive testing with the WISC-III. Tumour volume and location were measured from MRI scans using the MRIcro programme. WISC-III results from neuropsychological reports were correlated with the patients’ age at the time of tumour resection and tumour size and site. Results: Tumour sizes ranged from 19–49 mm2. Cases had lower performance IQ (46–91) and processing speed scores (50–74), and a larger discrepancy between Verbal IQ and Performance IQ (20–35) than controls. Neuropsychological outcome correlated adversely with greater size in the cases (r = −0.63 for PIQ), all of which were vermian based, whilst it correlated positively with size in the controls (r = 0.7 for PIQ). Conclusions: This is a small pilot study from which limited conclusions can be drawn. Tumour volume as measured by MRIcro was feasible and reproducible. Selection of controls for this study is problematic. Estimates of anatomical extent postoperative cerebellar injury would be valuable additional data for the full study. There was a trend for greater cerebellar tumour volume to be associated with poorer cognitive performance, supporting the cerebellum’s cognitive role.

LE 32. ESOPHAGEAL STRICTURES IN PATIENTS WITH SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR TREATED WITH CRANIOSPINAL IRRADIATION FOLLOWED BY HIGH-DOSE CHEMOTHERAPY

Stergios Zacharoulis, Susan Chi, Christopher Turner, Giannoula Klement, Leslie Lehmann, Victor Fox, Gath Semri, and Mark Kieran; Pediatric Neuro-Oncology, Bone Marrow Transplant Program and Gastroenterology, Dana-Farber Cancer Institute and Children’s Hospital Boston, Boston, MA, USA

Background: Esophageal stricture formation in children resulting from cancer related treatment is an exceedingly rare, but serious complication. We report the presence of esophageal strictures in two pediatric patients with supratentorial primitive neuroectodermal tumor (sPNET) who underwent high-dose chemotherapy and autologous peripheral blood stem cell rescue (PBSCR). Methods: Retrospective review of the clinical course and the endoscopic studies of these patients are reported. Results: Both patients were diagnosed with nonmetastatic sPNET. Postsurgical therapy included induction chemotherapy with cyclophosphamide and vincristine, followed by craniospinal irradiation (CSI 3600 cGy, primary boost 5480 cGy). Patients then underwent a single consolidation regimen of carboplatin, thiotepa, and etoposide with autologous PBSCR. Patient 1 is an eight-year-old girl who developed significant nausea and vomiting during RT, which persisted throughout the PBSCR period. Symptoms continued for two months post-PBSCR requiring parenteral nutrition. Attempts at oral feedings were unsuccessful. Endoscopy revealed multiple exudative ulcers in the lower half of the esophagus and an esophageal stricture for which a balloon dilatation procedure with steroid injection was required. Due to continued progression of the stricture, a second dilatation was required, followed by gastrostomy tube placement. Patient 2 is a ten-year-old boy who developed severe mucositis and hematemesis during the PBSCR period. One month postrecovery, he developed dysphagia, nausea, and vomiting, which, despite antacid therapy, persisted with variable intensity for several months. An upper GI series revealed a moderate to severe stricture in the middle and distal third of the thoracic esophagus, requiring balloon dilatation. Conclusion: We report these two occurrences of an unusual but severe complication in patients treated with CSI, followed by high-dose chemotherapy with carboplatin, thiotepa, and etoposide. A number of chemotherapeutic agents have been reported to exacerbate the radiation effect. Prompt investigation and aggressive treatment of suspected esophagitis in pediatric brain tumor patients undergoing multi-modality treatment is recommended. Whether the sequence of the treatment modalities is responsible for this severe toxicity needs to be investigated further in the era of high-dose chemotherapy with PBSCR protocols.

LE 33. RISK FACTORS FOR POOR SEIZURE CONTROL AND CHOICE OF ANTI-EPILEPTIC DRUG IN CHILDREN WITH BRAIN TUMORS

Raja Khan, Daniel Hunt, Frederick Boop, Robert Sanford, Thomas Merchant, Amar Gajjar, and Larry Kun; St. Jude Children’s Research Hospital, Memphis, TN, USA

Background: Predictors of seizure outcome are unknown in brain tumor children. Standard anti-epilepsy drugs (AED) enhance hepatic clearance of chemotherapy drugs and may adversely affect survival. Methods: Retrospective chart review of 157 brain tumor children with seizures treated from January 1985–2003. Seizure control was defined for the 6-month period prior to last follow-up: controlled (C) if no seizure; partially controlled (PC) if seizures were less than seizure a month; and intractable (IN) if seizure occurred each month. Since 1999, we treat new onset seizures with gabapentin monotherapy. Fisher Exact and multiple regression analysis was performed to assess risk factors related to uncontrolled seizures (C vs. PC + IN) and IN (C + PC vs. IN). Results: Median age at tumor diagnosis and first seizure was 6.6 and 7.5 years. Median follow-up from 1st seizure is 3.3 years. Tumors involved cerebral cortex in 48%, paramedian structures in 33%, and posterior fossa in 19%. First AED included phenytoin (n = 52), carbamazepine (n = 38), phenobarbital (n = 14), gabapentin (n = 31), and others (n = 22). Of the 157 children, 65% are C, 18% are PC, and 17% are IN. Gabapentin showed a trend toward better seizure control (p = 0.06). On univariate analysis, radiation, leucoencephalopathy, T-2 peri-cavity hyperintensity, ≥3 breakthrough seizures and focal slow waves predicted IN. Residual tumor, shunt, and focal neurologic deficits were additional risk factors for uncontrolled seizures. On regression analysis, neurologic deficits, T-2 peri-cavity hyperintensity and EEG slow waves were risk factors for uncontrolled seizures and only T-2 peri-cavity hyperintensity for IN. There was a higher presence of risk factors in the gabapentin treated children. Conclusion: We have identified T-2 peri-cavity hyperintensity, focal neurologic deficits, and slow waves on EEG as predictors of poor seizure control in brain tumor children. Seizures can be controlled in the majority of brain tumor children, and gabapentin has comparable efficacy to standard first line AED.

OUTCOMES

OUT 1. SURVEY OF CAREGIVER CONCERNS IN RAISING A CHILD WITH A BRAIN TUMOR

Heather M. Austin, Avi Madan-Swain, Alyssa Reddy, Jan Wallander, Alok Madan, Richard Brown, and Karen Braune; University of Alabama at Birmingham Division of Pediatric Hematology/Oncology at Children’s Hospital, Birmingham, AL, USA

The impact of the brain tumor (BT) diagnosis is challenging and stressful for all family members, but particularly the primary caregivers. Varni and colleagues (2002) noted that youth diagnosed with a BT scored significantly lower across all quality of life domains relative to other cancer diagnoses. Yet there is a paucity of objective data documenting the nature and severity of specific concerns experienced by caregivers. Such epidemiological data is necessary to proactively design effective interventions for the family. The purpose of this study was to examine the nature and severity of stressors encountered by caregivers of a child with a BT. Respondents were 63 consecutive families of children diagnosed with BT between the ages of 1 and 21 years, ranging from newly diagnosed to off-treatment. Families were recruited during their Neuro-oncology clinic appointments at a large medical center. Survey completed by participants included high-frequency items from the Parents of Children with Disability Inventory, general pediatric psychology literature, Dr. Varni’s research, as well as our clinical experience. The major categories included: parental distress, parent-child relationships, psychosocial support, medical adjustment, and school difficulties. Parents were asked to rate each of the 42 items on a 4-point likert type scale. Findings based on nonparametric analysis indicate that, regardless of treatment stage, the majority of caregivers remain concerned about their child’s prognosis. Specific concerns were expressed regarding neurcognitive and social difficulties, negotiating the school system, as well as difficulties engaging their children in age appropriate leisure activities. Differences also were found between maternal and paternal responses. Identification of these common stressors will enable the medical team to more effectively design behavioral interventions such as problem-solving and advocacy training to target potential concerns.

OUT 2. A GROUP SOCIAL SKILLS INTERVENTION PROGRAM FOR SURVIVORS OF CHILDHOOD BRAIN TUMOURS

Maru E. Barrera, Carly F. Fleming, Norma M. D’Agostino, and Brenda J. Spiegler; Department of Psychology, Haematology/Oncology Program, Hospital for Sick Children, Toronto, ON, Canada

Purpose: Survivors of childhood brain tumours are at risk for several adverse late effects including social isolation. The purpose of this study was to identify survivors whose social skills were below average, invite them to attend a social skills intervention group, and pilot test the program. We present the manualized social skills intervention and preliminary data on its efficacy. Methods: Fifty-eight survivors of childhood brain tumours, age 8 to 19 years (M = 13.7 years) were assessed at baseline. Survivors completed standardized measures of social skills, depressive symptoms, and behaviour. Parents completed measures of social skills and behaviour. Survivors scoring below the 25th percentile on social skills measures were invited to attend the intervention and participants completed pre and postintervention assessments. The intervention involved 8 2-hour sessions focusing on a specific social skill (i.e., initiating conversation, handling teasing, assertiveness). Results: Twenty-nine survivors (50%) were identified as having social skills difficulties. Of these, 18 (62%) have agreed to participate in the intervention group (13 have participated or are currently participating, 5 are on a waiting list). Of the nonparticipants, 3 were lost to follow-up, 2 reported no current social skills difficulties, and 6 no interest. To date, we have completed one group of 7 participants (males, age 14 to 18 years) and are currently running a second group of 6 participants (2 boys and 4 girls, age 10 to 14 years). Data will be presented regarding changes in social skills, depressive symptoms, and behaviour problems from baseline to postintervention. Conclusions: As a group, survivors of childhood brain tumours may not be at increased risk of social skills difficulties. However, a subgroup of this population may benefit from social skills intervention. A manualized social skills group intervention was developed to meet the needs of this subgroup and is currently being pilot tested.

OUT 3. ANALYSIS OF WISC-R SUBTESTS ACROSS DIFFERENT CHILD BRAIN DISEASES

Jordi Bernabeu, Adela Cañete, Concepción Fournier, and Jesus Suárez; Pediatric Oncology Unit, La Fe Hospital, Valencia; Psychiatry and Psychology Unit, Niño Jesus Hospital, Madrid; Universitat de València, Valencia; Spain

Introduction: Wechsler IQ scales have been routinely used as standard measure for evaluation of neurocognitive functions in different diseases. Being able to predict the nature and deepness of damage by analyzing the subtests results could give the professionals tools to evaluate and advise our patients and their families. Objectives: To find out differences among clinical variables in order to analyse the implication of brain structures in cognitive functioning in different types of diseases: neurological, oncological, and learning difficulties. Besides, we tried to find out the relationship among different clinical variables and damage location (posterior or anterior), and the effect of different treatments (surgery, chemotherapy, radiotherapy, megatherapy) in brain and leukemia groups. Patients and Methods: Patients diagnosed and treated in our Units were evaluated. Wechsler scales were applied according to age: WPPSI, WISC-R, WAIS-III. We divided patients in 5 disease groups: leukemias, brain tumors, epilepsy, traumatisms, degenerative disorders, and learning difficulties, although for the purpose of the study only brain tumors and leukemias were considered. Clinical variables were disease group, gender, neurofibromatosis, location, imaging sequelae, hydrocephalus, type of treatment, age at diagnosis and evaluation, and time between end of treatment and evaluation date. Statistical analysis was carried out by using SPSS package. Discriminate analysis. Results: 107 patients were studied. Median age was 11 (range: 3–24). There were 61 malign tumors, 36 benign ones, and 10 leukemias. Discriminate analysis identify 69% of malign tumors, benign tumors, and leukemias; 80% of left and right hemisphere; 79.7% of chemotherapy and nonchemotherapy groups; 80% of holocranial and nonholocranial Rt; and 60% of anterior, posterior, cerebellum, and other localization. Conclusions: Although the discriminate analysis could help us in designing this predictive model, we need further data to determine more accurately the influence of disease and clinical variables in Wechsler IQ subtests.

OUT 4. THE TORONTO EXPERIENCE: INTEGRATION OF SOCIAL WORK INTERVENTION WITH MEDICAL TREATMENT AS A MEANS TO MAXIMIZE THE QUALITY OF LIFE OF CHILDREN WITH CNS TUMOUR

David Brownstone, Eric Bouffet, Annie Huang, Douglas Hyder, and Cindy van Halderen; Paediatric Brain Tumour Program, Hospital for Sick Children, Toronto, ON, Canada

The Paediatric Brain Tumour Program (PBTP) at the Hospital for Sick Children (HSC), Toronto, has developed a unique partnership between social work and the medical team. In a highly comprehensive manner, this close partnership model integrates the family’s characteristics and interpretations of the disease experience with the implementation of medical decisions and treatment required for that disease. Psychosocial care is incorporated as an integral part of medical care in every aspect from diagnosis to posttreatment follow-up or palliative and bereavement care. Optimal psychosocial care for this population is both hospital and community focused, with recognition that the majority of care for CNS tumour occurs as an outpatient. Two social workers dedicated to the PBTP are involved with over 120 children with CNS tumour each year. Social work provides a holistic focus in the team’s provision of care to patients and families through various levels of intervention. Trends demonstrated by hours of social work intervention by diagnosis, prognosis, and demographic factors will be presented. The transition to palliative care provides a clear indication of heightened involvement with families and colleagues in order to provide meaningful and co-ordinated service. It is evident that a comprehensive repertoire of flexible psychosocial supports and strategies can provide a vital foundation for a child and family’s adaptation to the diagnosis of CNS tumour and its lifelong implications. The model of care provided by the PBTP has facilitated a unique responsiveness to, and integration of, psychosocial issues across the continuum of care. Through discussion of the social work experience, the PBTP model of care, and analysis of trends, this presentation will explore the implications and benefits for the integration of psychosocial intervention at key treatment junctures.

OUT 5. SEARCHING FOR A TOOL TO ASSESS QUALITY OF LIFE (QOL) IN BRAIN TUMOUR SURVIVORS —RESULTS OF THE PEDQOL IN A COHORT OF ITALIAN CHILDREN AND ADOLESCENTS

Cinzia Cereda, Gabriel Calaminus, Stefania Varotto, Lucia Masiero, Giovanni Scarzello, Giovanni Bisogno Roberto Faggin, and Giorgio Perilongo; Division of Haematology-Oncology, Department of Paediatrics, University-Hospital of Padova, Italy; Düsseldorf, Germany

Objectives: Searching for an effective instrument to test QoL in Italian children, we decided to validate the PEDQOL—a self-rating QoL questionnaire for children aged between 8 and 18 years, specifically developed for paediatric oncology. Methods: The PEDQOL developed in Germany was first translated in Italian and then back translated to verify consistency. The PEDQOL was then administered (upon consent form signing by the children or legal guardians) to 271 healthy children attending public schools. The age distribution was: 8–10 years: 41 children; 11–14 years: 88; and 15–18 years: 142. Additionally the PEDQOL was administered to 126 cancer patients off treatment: Leukaemia/lymphoma: 65; solid tumours: 29; and brain tumours: 32. The age distribution at evaluation was: 8–10 years: 44; 11–14 years: 47; and 15–18 years: 35. The mean interval between diagnosis and the time of evaluation was 4.87 years. The PEDQOL evaluated QoL in seven domains: autonomy (SE), emotion (EV), body image (KB), cognition (LV), physical functioning (KV), social functioning friends (Fr), and family (Fam). QoL was rated as the percentage of negative answers (mean and standard deviation) according to the evaluated domains, Results in school children were compared (Mann-Whitney-Test) to cancer survivors. The influence of age was additionally analysed. Results: The percentage of negative answers in healthy children was about 50% (48–69%) similar to the cancer survivors (41–72%). Age at evaluation seems to influence QoL, as children 8 to 10 years rated their QOL more negative in SE, LV, Fr than older children. Children with brain tumours rated their QoL more negative than patients with other tumour entities, this was specifically related to EV, LV, KV, and Fr (p < 0.05). Conclusion: The PEDQOL questionnaire is a reliable tool to measure QoL in Italian children and adolescents. It is also possible to differentiate between disease groups.

OUT 6. EARLY CHILDHOOD BRAIN TUMOURS LEADING TO IMPAIRED COMMUNICATION, SYMBOLIC PLAY, AND SOCIALISATION

Carlos de Sousa, Dianne Gumley, and Kim Phipps; Great Ormond Street Hospital for Children, London, UK

We have identified a group of children who present at a young age with brain tumours and are subsequently found to have distinctive impairments in their communication, symbolic play, and social interaction. The disorder is characterised by a delay in the acquisition of language. Expressive language is disordered, with all children using many inappropriate learnt phrases, which are not in context. All show a lack of flexibility in social interactions and have encountered problems with reciprocal communication. All have phases of obsessive and ritualistic behaviour. Episodic aggressive behaviour has been common. Between 1995 and 2002, 123 children under 3 years of age were diagnosed at our hospital as having brain tumours. Of these 34 died. Of the remaining 89, we have identified 4 patients with this disorder. All four children had normal development prior to presentation. None have subsequently shown severe global developmental delays and most have some developmental skills within the normal range. None fulfil the DSM-IV criteria for autism. No child with a posterior fossa tumour and no child presenting after 3 years of age developed the same disorder. All four tumours were located centrally: two also involved the right temporal lobe and three the hypothalamus. Three tumours were low-grade supratentorial gliomas and one was a choroid plexus carcinoma. Two children had hydrocephalus (one required placement of a shunt). Two children underwent surgical resection (in both cases there was postoperative infection). Three children underwent chemotherapy, one radiotherapy, and one has had no treatments. Two children have experienced epileptic seizures, but neither has had frequent seizures or required long-term anti-epileptic drug treatment. All four have moderately severe visual impairments. We believe that children presenting at less than three years of age with midline supratentorial tumours are at risk of developing this distinctive disorder. No single factor predisposes to this, but the additive effects of visual impairment, epilepsy, and hydrocephalus may contribute to its evolution. Early identification and educational rehabilitation can help these children to integrate more fully with their peers.

OUT 7. USE OF A VERBAL LANGUAGE SCREENING TOOL PRIOR TO PEDIATRIC QUALITY OF LIFE (QOL) QUESTIONNAIRE ADMINISTRATION

Patricia A. Garvie, May Lin Tao, Lisa N. Schum, Celiane M. Rey-Casserly, Raymond K. Mulhern, and Susan K. Parsons; Behavioral Medicine Division, St. Jude Children’s Research Hospital, Memphis, TN, USA

To assure adequate language processing abilities prior to QOL questionnaire administration, the Woodcock-Johnson Revised, Tests of Cognitive Ability, Verbal Analogies (WJR-VA) subtest was administered as a screener to pediatric cancer patients at risk for cognitive impairment. Method: The WJR-VA was administered to 290 pediatric brain tumor and leukemia patients (ages 8–18). Eight correct responses (2.1 grade equivalent) were required to proceed to the QOL administration. Available IQ data were abstracted from medical records to assess relationship with WJR-VA score. Results: WJR-VA administration time to obtain 8 items was 60–90 seconds (n = 60); 75% completed the screener in ≤6 minutes. 93.1% passed (270/290). Mean WJR-VA Summary Score (SS) was 1.68 SD lower for those who failed vs. passed, and mean IQ score was 1 SD lower (p < .001). For those who failed the screener, age equivalent and grade equivalent, as derived from the WJR-VA, were significantly different from current age and grade, respectively (p < .001). For those who passed the screener, 34.5% (73/210) had an age equivalent >2 years below their current age (mean = 4.98 below), and 33.5% (69/206) had a grade equivalent >2 grades below current grade (mean = 4.32 below). The SS predicted functioning for Full Scale IQ (B= .719), prorated IQ (B= .686), and Verbal IQ (B= .640; all p < .001) when controlling for race and age at diagnosis in a regression model. Conclusion: The WJR-VA successfully identified children who, despite meeting study eligibility for current age/grade, were unable to demonstrate adequate verbal competency. The screener additionally identified children who had significant cognitive impairment below expectation for age and grade. The implications of this on the validity of certain children’s self-report and the novel use of this brief screener prior to QOL questionnaire administration will be discussed.

OUT 8. SPEECH PATHOLOGY IN PEDIATRIC ONCOLOGY

Maria Ines Rebelo Goncalves, Silvia Rovath Cesar, Tatiana Radzinski, Brasilia Maria Chiari, and Nasjla Saba da Silva; Instituto de Oncologia Pediatrica and Department of Speech Pathology, Universidade Federal de Sao Paulo; Universidade Tuiuti do Paraná; Brazil

Malignant neoplasies in children include systemic affections and solid tumors. Improvement of the survival rates observed in the last years was obtained due to the evolution of treatment methods and follow-up of the rehabilitation team. Usually children with tumors of the central nervous system present more sequelaes which can impair speech, swallowing, voice, hearing and/or language functions, requiring speech rehabilitation. It is important to remember that chemotherapy can lead to hearing loss and consequent decay in school performance. Speech therapy can occur at bedside and/or at the clinic during pre and/or postcancer treatment and includes counseling, specific exercises and maneuvers, and development of adaptations or compensations related to communication and/or feeding. The duration of rehabilitation varies according to the patient’s alterations, and it is very important to point out that better results are obtained only if there is a team concerned about how to contribute to the best quality of life for each child.

OUT 9. EXPLAINING DIAGNOSTIC PROCEDURES AND THERAPEUTIC MODALITIES TO THE CHILD WITH A BRAIN TUMOR

Michael A. Grotzer and Anna Sommer; Department of Oncology, University Children’s Hospital of Zurich, Switzerland

Explaining diagnostic procedures and therapeutic modalities to the child with a newly diagnosed brain tumor and their family is a difficult task. Consequently, many children and their families do not fully comprehend the procedures performed in the hospital. In response to this, we developed a booklet for children age 4 and higher. On 72 pages with 34 illustrations, the book tells the story of Eugen, who has surgery and radiotherapy for his brain tumor. In the hospital, he meets Julie who has chemotherapy. In Zurich and other Swiss hospitals, the booklet gets distributed for free to our patients. So far, the responses of patient families, doctors, nurses, teachers, and psychotherapists are extremely positive. For example, the booklet was judged to be of great value not only for the patients but also for their siblings. Moreover, the booklet was judged to be important for the information of foreign language speaking families. In addition, the booklet was the topic of newspaper articles and radio interviews, and it may therefore promote awareness for the disease “brain tumor” among people not directly affected. Translated editions are in preparation.

OUT 10. NORMAL IQ—SO WHAT!—PROBLEMS FACED BY CHILDREN WITH AN IQ IN THE NORMAL RANGE FOLLOWING TREATMENT FOR A BRAIN TUMOUR

Dianne Gumley, Kim Phipps, Matt Bruce, and Anthony Michalski; Great Ormond Street Hospital for Children, London, UK

We fully assessed the intellectual and academic functioning of 21 children treated for Medulloblastoma and Astrocytoma tumours in the posterior fossa. All children were over three years at diagnosis and over 6 years at time of most recent assessments. All children underwent surgery, and the Medulloblastoma group had adjuvant radiotherapy. The results suggest that a full scale IQ within the normal range can mask the range of specific difficulties and disabilities that these children have. Disabilities such as visual impairment and motor problems, together with the child’s individual neuropsychological profile, will impact on their ability to access learning and cope with the tasks of daily life. The results are important because we recognise that in order to plan future long-term intervention and follow-up of these children, it is essential to take a holistic view of the child.

OUT 11. PRELIMINARY EVIDENCE OF NONVERBAL LEARNING DISABILITY IN SURVIVORS OF PEDIATRIC BRAIN TUMORS

Kristina K. Hardy, Melanie J. Bonner, Lea Bromell, and Sri Gururangan; Departments of Psychiatry, Pediatrics, and Surgery, Duke University Medical Center, Durham, NC, USA

Objective: To examine the pattern of cognitive, academic, visual-motor, and psychosocial late effects among children and adolescents previously treated for tumors of the central nervous system for consistency with Non-Verbal Learning Disability (NLD). Method: Subjects included 65 child and adolescent survivors of pediatric brain tumors who had been off treatment for at least one year at the time of assessment. Thirty-four males and 31 females aged 6–17 years were included. Diagnosis type included 26.2% (n = 17) medulloblastoma, 10.8% (n = 7) ependymoma, 15.4% (n = 10) pilocytic astrocytoma, and 47.6% (n = 31) other tumors of the central nervous system. Twenty-eight percent of the sample received surgery or chemotherapy only, whereas 70.8% received whole-brain radiation in addition to other treatments. To assess late effects associated with NLD, data was extracted from a database of patients who had received neuropsychological evaluations as part of their routine follow-up care at DUMC. Data from the following measures were used: Wechsler Intelligence Scale for Children (WISC-III), Woodcock-Johnson Tests of Achievement–Revised (WJ-R), Test of Visual Motor Integration (VMI), and Child Behavior Checklist (CBCL). Results: The survivors in this sample evidenced cognitive skills significantly below that of the standardization sample. Moreover, consistent with NLD theory, scores associated with nonverbal abilities were significantly lower than verbal IQ scores. Performance on measures of visual-motor integration and processing speed also were significantly lower than normative means. Also consistent with the NLD model, survivors in this sample evidenced math achievement scores that were significantly below measures of basic reading ability. Finally, as would be predicted by the NLD model, parent-reported social problems for this group were significantly higher than normative means. Conclusions: Data were interpreted as providing preliminary evidence for NLD syndrome in survivors of pediatric brain tumors. Prospective investigation of NLD in this population (particularly with regard to loss of white-matter volume) is warranted.

OUT 12. PAEDIATRIC ONCOLOGY HEALTH INFORMATION ON THE INTERNET: A SURVEY OF USAGE BY FAMILIES

Darren Hargrave, Doina Lupea, Phyllis McGee, Alex Jadad, Albert Pappo, Sheila Weitzman, and Eric Bouffet; Neuro-Oncology Program and Division of Haemato-Oncology, Hospital for Sick Children, Toronto; Program for e-Health Innovation, University of Toronto; Canada

The Internet is increasingly becoming a source of health information, but little is known about the usage amongst families of children with oncological conditions. Methods: Trained interviewers surveyed the carers of children attending the paediatric oncology outpatients of the HSC. Data Surveyed: Demographics of patient and carer and questions regarding the use of the Internet specifically for gaining health information. Results: 306/319 (95%) carers agreed to the survey (mother 69%, father 28%). The child’s age was divided equally between < 6.6–12 and >12 years. Diagnoses included: leukaemia, (44%); lymphoma, (12%); CNS tumours, (12%); other solid tumours, (20%). Age of carers was 21–40, (55%) or 41–60, (43%) years. 72% had English as a first language with 71% educated to college or higher level. 85% of carers had used the Internet, of whom 72% had looked for health information (but only 15% of children). Internet access was: home, (92%); work, (45%); hospital, (15%); public library, (9%). Websites were identified by link pages, (74%) and search engines, (37%). Health information sought included: tumour type, (60%); treatments, (60%); prognosis, (59%); cancer research, (55%); aetiology, (47%); family support, (27%); alternative therapies, (24%): and schooling issues, (11%). Types of sites included: cancer associations, (67%); hospital/university, (52%); government, (29%); commercial sponsored, (21%); and message boards, (13%). Carers had used e-mail: to contact their child’s health care professionals, (16%) and 6% for a second opinion. 30% of carers shared information with their child’s doctor, but only 14% had a website recommended by the doctor. The majority found the Internet trustworthy and easy to use. The carers of a child with a CNS tumour spent more time searching for information on the Internet and were more likely to look for information on school issues. Conclusion: Most carers use the Internet as a source of health information about their child’s cancer. They believe it to be reliable and wish for further opportunities to use the Internet for communication with their child’s oncology team.

OUT 13. STUDY ON FAMILIES WITH CHILDREN DIAGNOSED AS BRAIN TUMOR—A SURVEY OF MEMBERS

Akiko Higuchi,1 Aya Inazuka,1 Fumiko Ikeda,1 Hiroko Kondo,1 Keiko Oumi,1 Yoshikatsu Suitsu,2 and Ryota Hosoya3; 1Children’s Cancer Association of Japan; 2Tokyo Gakugei University; 3St. Luke’s International Hospital, Tokyo; Japan

Children’s Cancer Association of Japan (CCAJ) was established in 1968 by parents who had lost children to cancer for the purpose of supporting children with cancer and their families. CCAJ has been and is the only nonprofit organization in Japan whose mission is to improve the quality of life for those children with cancer and their families by providing emotional and financial support. Long-term medical treatment of childhood cancer causes psychosocial problems. Specifically the children with brain tumor have many problems such as troubles with school-life and daily life, their late-effects, and so on. We analyzed 100 patients with brain tumor, focusing on their quality of life. The first stage of the study was to identify, within the 3,071 CCAJ members (as of March 1, 2002), families with children diagnosed with childhood cancer. Of the 1,131 respondents of the first stage study, a survey was conducted in July 2002. The survey questionnaire is divided into five stages of care: diagnosis, hospitalization, out-patient treatment, recovery, and late-stage to after-death. The 732 responses received by December 31, 2002 were deemed to be effective. (51.11% response rate.) Out of these responses, patients diagnosed as brain tumor was 13.6% (n = 100: 68 patients are survivors and 32 patients are dead), second only to leukemia. Problems that were indicated included large financial burden and difficulties in attending school from late-effects of treatment. The data suggest that, even after treatment, children diagnosed with brain tumor and their families face numerous difficulties.

OUT 14. EXPLORING THE EXPERIENCES OF PEDIATRIC CANCER PATIENTS, INCLUDING THOSE WITH BRAIN TUMORS, IN THE YOUTH AND PET SURVIVORS PROGRAM

Anne Ingalls, Kim A. Gorgens, and Colleen Chambers; The Children’s Hospital, Denver, CO; Graduate School of Professional Psychology, University of Denver, CO; Animal Care Foundation, Veterinary Referral Center of Colorado, Englewood, CO; USA

Background: The Youth and Pet Survivors Program (YAPS) is a unique pen-pal program created to connect children undergoing chemotherapy with dogs who have survived treatment for cancer. Rationale: Pediatric cancer patients, even those in isolation, can have a meaningful and supportive relationship with a dog that has gone through similar experiences. Dog owners can enhance their own quality of life by being a pen-pal for a child with cancer. Sample: Twelve children, dogs, and their owners are part of YAPS, with more being added. Four of these children have brain tumors. Methods: Children, aged 8 to 18, are in YAPS based on their interest and ability to participate. The child selects a pen-pal from a portfolio of dogs who have submitted photos and biographies. Dog owners are interviewed and carefully selected for ability to be creative, fun, and emotionally manage a relationship with a child with cancer. The owners assume the personality of the dog when corresponding with a child. Pen-pals meet in person at events hosted by the Animal Care Foundation, as well as get together on their own. Implications: Child participants report enhanced well-being while corresponding with “a dog who understands them in ways people don’t.” Parents report that YAPS is a healing and fun distraction for their child. Some parents and dog owners become close friends. Dog owners report a sense of contribution knowing that their dog’s illness can make a difference in a child’s life. Friendships among the families of child and dog are formed and most last long after the death of either pen pal. Future: Two formal research projects are underway gathering qualitative and quantitative data to support the unique benefits and importance of the YAPS program. The intention is to make YAPS programs available to Children’s Hospitals and Veterinary Centers around the globe.

OUT 15. CREATIVE ARTS THERAPY FOR PEDIATRIC BRAIN TUMOR PATIENTS DURING OUTPATIENT CHEMOTHERAPY

Jennifer R. Madden, Patricia Mowry-Rutter, Robin Strecker, and Nicholas Foreman; The Children’s Hospital, Denver, CO; University of Colorado Health Sciences Center, Denver, CO; USA

Purpose: The Creative Arts Therapy (CAT) Project is a pilot-sized randomized trial to study the effects of movement, music, and art therapy on the quality of life (QOL) of children with brain tumors receiving chemotherapy. Rationale: Children with brain tumors primarily receive all chemotherapy infusions in the outpatient setting. Currently there are no therapeutic interventions available to improve and maintain quality of life during chemotherapy. Psychological trauma during chemotherapy may adversely affect the QOL, both during the infusions and subsequently. Sample: To be included in the study, patients must be between 2 and 18 years of age. They must also be newly diagnosed with a brain tumor and plan to receive treatment. Treatment must be planned to continue for at least three continuous months after entering the study. A total of 24 patients will be enrolled. Study completion is anticipated by at least 20 of the patients. Methods: The CAT Project randomizes appropriate brain tumor patients to two groups. The experimental group will receive 6 infusions with an hour of CAT while the control group receives 6 infusions playing with a volunteer. All subjects will be tested using the patient and parental report PedsQL at study entrance, after 3 infusions of chemotherapy, and after 6 infusions (after CAT is completed). Also, six month and one year follow-up points are completed. Six children are currently enrolled on study; 4 on the CAT arm and 2 on the volunteer arm. Implications: The hypothesis of the study is that children who receive CAT will have an improvement in their QOL. The trial is presented in the current atmosphere of increasing interest in supportive care and complementary therapy trials for children with cancer. Rigorous experimental research is needed to show the importance of incorporating art into the healing process.

OUT 16. CARING FOR SURVIVORS OF CHILDHOOD BRAIN TUMORS: CLINICAL SERVICE NEEDS FROM THE PARENTS’ PERSPECTIVE

Eugene A. Meyer, Susan K. Parsons, Brian L. Delaney, Christine A. Chordas, Mark W. Kieran, and Christopher D. Turner; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, MA, USA

The organization and content of long-term follow-up care for survivors of childhood brain tumors varies greatly across clinics from multidisciplinary specialty clinics to a single oncologist or nurse practitioner providing follow-up care and referring to specialists in the community on an “as needed” basis. Currently there are no reports in the literature of the parents’ perspective regarding the clinical service needs of survivors. We conducted a focus group with 15 parents of childhood brain tumor survivors who were receiving care in a large pediatric neuro-oncology clinic. Feedback was elicited from parents on a preliminary survey measure designed by staff to assess clinical service needs for survivors. The survey was then revised and administered to 50 consecutive, eligible families. Results provide the parents’ perspective regarding the life issues and clinical services perceived as “important” for the survivor, as well as the degree of impairment experienced by the survivor across areas of functioning. Since concluding treatment, 68% of parents in this sample have accessed three or more healthcare subspecialists to meet the life needs of their child. The top four specialty clinical services, not including core treatment disciplines, depicted as important for the survivor included neuropsychological testing, educational consultation, endocrinology, and psychological consultation. The top four life-issues identified as important for the survivor were emotional/psychological functioning, learning issues, social relationship issues, and medical late effects. Parents reported at least moderate morbidity for survivors in the areas of school performance (54%), social relationships (48%), general physical health (46%), cognitive abilities (38%), and emotional well-being (36%). These results indicate that parents perceive survivors to be in need of a wide variety of medical and nonmedical follow-up services. We conclude that the follow-up of this survivor group is enhanced by the participation of a range of professionals.

OUT 17. HEALTH-RELATED QUALITY OF LIFE OF CHILDREN WITH BRAIN TUMORS: PARENT REPORT USING THE HUI2/3

Eugene A. Meyer, May Lin Tao, Leanne Streja, Patricia A. Garvie, and Susan K. Parsons; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, MA, USA

Studies on the health-related quality of life (HRQOL) of children treated for brain tumors have reported significant morbidity across domains of functioning although sample sizes have been relatively small. As part of a large study designed to test the measurement properties of a child-reported brain-specific HRQOL measure, the Health Utilities Index 2/3 (HUI2/3) was used to examine HRQOL based on parent report. The HUI2/3 is a 15-item, multi-attribute, preference-linked general health status instrument, with previous applications in adult and pediatric brain tumor populations. Data on the HUI2 is presented in this abstract. Parents of 51 on-treatment and 172 off-treatment children at three academic centers completed the HUI2 after 9 with discrepant/missing data were excluded. 66% of those on-treatment and 60% of those off-treatment were reported to be experiencing morbidity (score of ≥2 on an attribute) in two or more attributes. 17% of those off-treatment and 14% of those on-treatment were reported to have no morbidity.

HUI2: Proportion experiencing morbidity

AttributeOn-treatment sampleOff-treatment sample
Pain57%34%
Emotion43%46%
Cognition33%52%
Sensation (vision, hearing, speech)34%49%
Mobility22%12%
Self-care14%6%

With an HUI2 global utility score of 1.0 representing perfect health, previous studies have reported mean scores of .95 for healthy children and a range of .78–.94 for survivors of brain tumor in childhood (Furlong, 2001). In our study, the mean on-treatment score was .84 (SD .15, range .43–1.0), while the off-treatment score was .85 (SD .14, range .31–1.0). 30 unique health states for children on-treatment and 64 unique health states for children off-treatment were reported. Results from the HUI3 and analysis by subgroups will be discussed. The range and degree of morbidity noted in this study highlight the heterogeneity of this population. Findings suggest that the primary areas of functioning affected are consistent on and off treatment. Implications for using a generic utility measure to assess HRQOL in this population will be discussed.

OUT 18. SUBTESTS PROFILE OF WECHSLER INTELLIGENCE SCALES IN PATIENTS WITH PINEAL GERM CELL TUMORS

Ryo Nishikawa and Masao Matsutani; Department of Neurosurgery, Saitama Medical School, Saitama, Japan

Objectives: To investigate the intellectual characteristics of patients with pineal germ cell tumors (GCTs). Patients and Methods: Nine patients with pineal GCTs underwent Wechsler intelligence tests (WAIS-R for patients 17 years old or older and WISC-III for those younger than 17). Six of them had been treated with surgery + radiotherapy (24–30Gy to ventricles +/− 20Gy to tumor) + chemotherapy, one patient was tested before and just after a surgery, one patient was tested before a surgery, and one patient was tested just after neoadjuvant radiotherapy. Years from end of radiotherapy to intelligence testings were 0.5–15 years (median = 4.5). We tested thirteen control cases of similar age including two neurohypophyseal GCTs, three basal ganglia GCTs, four posterior fossa and third ventricular gliomas, a central neurocytoma, a right parietal arteriovenous malformation with hematoma, and two cases of head injury. Results: Four out of nine pineal GCT patients showed a more than 25 points lower performance IQ than verbal IQ. The performance subtests profile of those four patients were similar; relatively low scores in coding, picture arrangement, object assembly and symbol search in WISC-III, or in picture completion and object assembly in WAIS-R; block design was uniformly higher than the other performance subtests scores. Control patients including two patients with neurohypophyseal GCTs showed balanced VIQ and PIQ with relatively flat subtests profile patterns, except for a case with right parietal AVM who showed similar pattern of performance subtests profile to pineal GCT patients. Conclusions: Pineal GCT patients showed lower PIQ, especially in subtests estimating visual perception and attention. As patients with neurohypophyseal GCTs who had been treated with similar regimen of radio- and chemotherapies did not show deterioration in PIQ, the affected subtests scores observed in pineal GCT patients were not likely due to radio- and chemotherapies.

OUT 19. QUALITY OF LIFE ASSESSMENT (QUOLA) IN PEDIATRIC BRAIN TUMOR POPULATION: FEASIBILITY AND MEASUREMENT PROPERTIES OF A NEW BRAIN-SPECIFIC INSTRUMENT

May Lin Tao, Michael Masterman-Smith, Patricia A. Garvie, Rita Engelhardt, and Susan K. Parsons; Division of Cancer Prevention and Control Research, Departments of Radiation Oncology and Pediatrics, University of California, Los Angeles, CA, USA

We present the feasibility and preliminary measurement properties of a health-related quality of life (HRQL), self-report tool designed for the pediatric brain tumor population. After iterative pilot testing, we conducted a validation study at 3 academic centers. Of 290 subjects, ages 8–18, screened for adequate verbal competency, 269 completed the QUOLA with interviewer assistance as needed: 167 brain tumor off treatment, 49 brain tumor on treatment, 53 acute lymphoblastic leukemics off treatment who did not receive cranial irradiation. Median time to complete the 57-item QUOLA was 8 minutes (range 3–37, 13 = 90th percentile); 94% had no missing items. Full range of the 3-point response was used for 56/57 items. Principal components analysis was used to investigate the QUOLA structure in 50% of the sample (derived sample), randomly selected within disease and age groups (< 13 and ≥13 years), resulting in selection of an eight-component solution which accounted for 50% of the variance. Items with poor loadings (< 0.4) on any of the components, poor item-scale correlations (< 0.4), and/or poor conceptual fit were eliminated, leaving 7 components and two single items. The structure was validated on the second half of the sample (replication sample) using structural equation modeling (goodness of fit = 0.75). Internal consistency reliability (ICR) revealed: Schooling (Cronbach’s alpha = 0.96), Treatment Tolerance (0.75), Cognition (0.73), Worry/Upset (0.59), Social Integration (0.73), Esteem (0.61), and Body Image (0.58). Internal consistency reliability was similar for both the derived and replication samples and for the 2 age groups. Instrument performance and scores for those with and without cognitive impairment and for the disease/age groups will be discussed. We have developed a brief HRQL tool for the pediatric brain tumor population with acceptable structure and reliability. Cross validation of this tool with other generic tools is underway.

OUT 20. A SCHOOL INTERVENTION PROGRAM TO ADDRESS THE LEARNING AND SCHOOL ADJUSTMENT NEEDS OF CHILDREN TREATED FOR BRAIN TUMORS

Maria Luisa Victoria, Julianne Doyle, Rupa Gambhir, Cori Cieurzo, Samantha Barry, and Barbara Gannon; Dana-Farber Cancer Institute, Division of Psychosocial Services, Boston, MA, USA

The School Liaison Program (SLP) at Dana-Farber began as a demonstration project in 1994 in response to the clinical and research findings that pediatric cancer patients who received central nervous system treatment often experience cognitive and learning difficulties. The SLP thus began providing consultation to patients, families, teachers, and medical staff regarding curriculum modifications and requisite academic and social supports for students treated for brain tumors. With the growing recognition of the need for such intervention, the SLP has experienced tremendous growth, from consulting to 24 families at its inception to the current caseload of 405 families. Although consultation may consist of a single session, most often the SLP is requested by families, schools, or staff to provide additional consultation during critical points in the child’s primary and secondary education. Consultation is also offered to help parents adjust their expectations of patients who have experienced a significant change in cognitive functioning. In addition, community outreach is provided through parent seminars and school workshops. In this manner, the SLP endeavors to educate about the application of special education regulations for this population as well as encourage self-advocacy among patients and families. For the past four years we have surveyed parents and teachers who have, on average, reported that: SLP interventions have increased their understanding of the impact of cancer treatment on learning and social functioning; that SLP recommendations were relevant and helpful; and that SLP consultation has increased their understanding of needed curriculum modifications and educational supports to match patients’ learning needs. In light of this and the increasing utilization of the program, school consultation has become an integral component of a survivor’s interdisciplinary treatment at the authors’ hospital and may serve as a model for other programs at cancer centers.

OUT 21. NEUROPSYCHOLOGICAL BASES OF EVERYDAY COGNITIVE PROBLEMS IN ADOLESCENTS TREATED FOR CRANIOPHARYNGIOMA

Deborah P. Waber, Abigail Chiverton, Mark Kieran, Scott L. Pomeroy, and Michael J. Rivkin; Departments of Psychiatry and Neurology, Children’s Hospital, Boston, MA; Department of Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA; USA

We evaluated self-reported everyday cognitive problems in relation to laboratory measures of declarative memory (California Verbal Learning Test, CVLT), working memory (CANTAB Spatial Working Memory Test, SWM) and speed of processing (Wechsler Coding/Digit Symbol, C/DS) in 10 patients with a history of treated craniopharyngioma (6F/4M; median age 17, range 13–34; median IQ 97, range 84–130). All were treated surgically; 7/10 also had stereotactic radiotherapy. The Cognitive Failures Questionnaire (CFQ, Broadbent, Cooper, Fitzgerald, and Parkes, 1982) was used to assess everyday cognitive difficulties. The mean (S.D.) CFQ score of 49 (11.7) for these patients is well above the reported mean (19) for American college students (Pollina, Greene, Tunick and Puckett, 1992), indicating significantly increased prevalence of cognitive difficulties. Mean scores on the 8-item SWM and C/DS were somewhat below expectation (both −0.9 S.D.), and the CVLT (+0.8 S.D.) was somewhat above. Age (r2 = .31, p < 0.1) and the Beck Depression Inventory (BDI) (r2 = .32, p < 0.1) predicted CFQ, but IQ was unrelated (r2 = .02, p < 0.7). After adjusting for the effects of age and BDI, we found that both spatial working memory (r2 = .47, p < 0.03) and declarative memory (r2 = .50, p < 0.03) predicted everyday cognitive problems, but processing speed (r2 = .02, p < 0.7) did not. Patients with a history of craniopharyngioma experience an elevated level of everyday cognitive problems that may not be easily corroborated by standard neuropsychological testing. These problems may reflect in part the integrity of both declarative memory and working memory but involve other cognitive processes associated with neurological compromise as well. This work was supported in part by the Stop and Shop Family Pediatric Brain Tumor Program.

OUT 22. NEUROPSYCHOLOGICAL EFFECTS IN PEDIATRIC MEDULLOBLASTOMA

Brenda Wagner, Alcuin Johnson, Claire Mazewski, and Howard Goldfischer; AFLAC Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta, Atlanta, GA, USA

Eighteen patients between the ages of 6 and 16 years were administered neuropsychological evaluations. Participants ranged in age at time of diagnosis from 18 months to 14 years. The range of time between initial diagnosis and the time of testing was 1/2-month to 84 months. Eleven patients underwent gross total resection and 7 underwent subtotal resection. Sixteen subjects received cranial irradiation to the tumor and/or cranial-spinal axis. Fourteen of the participants exhibited hydrocephalus at the time of diagnosis. Results indicated that lower doses of radiation appear to decrease the neurocognitive decline and memory difficulties when compared to earlier studies. Slow processing speed and visual-coordination deficits typically seen in prior studies are replicated. Even with lower radiation doses patients with medulloblastoma typically require special education modifications following treatment.

OUT 23. DEVELOPMENT OF A QUALITY OF LIFE SCALE FOR CHILDREN WITH CHRONIC ILLNESS WITH CNS INVOLVEMENT: PRELIMINARY DATA

Pamela Wolters, Staci Martin, Mary Anne Tamula, Lori Wiener, Lori Perez, Alberta Aikin, Frank Balis, Kim Shimoda, and Kathy Warren; Medical Illness Counseling Center and HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, USA

Children with chronic illness are at risk for central nervous system (CNS) manifestations due to the effects of the disease and associated treatment. There is a need to measure quality of life (QOL) in addition to medical outcome data in clinical trials, yet few existing QOL scales include both parent and child self-report forms and assess CNS effects. We developed the Impact of Pediatric Illness (IPI) Scale to assess the QOL of children from 6 to 18 years. It yields raw scores for four theoretical subdomains (Adaptive Behavior, Psychological Functioning, Medical/Physical Status, CNS) and the overall scale. Twenty-nine patients with brain tumors (age range = 11.1–18.8; mean age = 14.8) and their parents completed the IPI Scale at their baseline evaluation. Preliminary results found no significant differences between the parents and adolescents on any subdomain scores or the total score. However, differences were found between the subdomain scores within each group (p < .0001). Adaptive behavior scores were significantly higher (more impaired) than scores on the Psychological Functioning and Medical/Physical Status (parent and adolescent) as well as the CNS (parent) subdomains (p’s range from < .0001 to .01). Coefficient alpha reliability estimates ranged from .66 (adolescent Medical/Physical Status) to .84 (parent CNS) for the subdomains and .89 (adolescent) to .92 (parent) for the total scales. Pearson product-moment correlation coefficients comparing the parent and child responses for the total scale and the four subdomains ranged from .62 to .82 (p’s < .001 to .0001). These preliminary findings suggest that the IPI Scale has adequate internal consistency and interrater reliability. In these adolescents with brain tumors, adaptive functioning appears to be among the most impaired areas affecting their quality of life. Further analyses will examine the factor structure, concurrent and discriminant validity, and IPI Scale data from other pediatric populations.

OUT 24. COGNITIVE FUNCTION IN LONG- TERM SURVIVORS OF CHILDHOOD BRAIN TUMORS—PREDICTION OF INTELLECTUAL DEFICITS

Justyna Korzeniewska, Bozena Dembowski-Baginska, Marta Perek-Polnik, Monika Drogosiewicz, and Danuta Perek; The Children’s Memorial Health Institute, Oncology Department, Warsaw, Poland

Purpose: Aim of this study was to assess cognitive status after anticancer treatment and identify factors associated with IQ scores in long-term survivors of childhood brain tumors. Patients and Methods: 114 survivors of childhood brain tumors, treated with surgery, with or without radiotherapy, and with or without chemotherapy were studied. Patients were divided into subgroups according to: gender, tumor location (posterior fossa, hemisphere, intracerebral), age at diagnosis, age at irradiation, field of irradiation (local/whole brain) and type of surgery (biopsy, total, subtotal resections), and other type of treatment. Children with posterior fossa tumors consisted the largest group. The patients were examined using a battery of psychological methods. For statistical comparison, IQ (FSIQ Full–Scale IQ score), measured by L. Terman, M. Merrill Intelligence Scale, WISC-R, WAIS-R (depend on age of child), were used. IQ is not the best characteristic of function of these children but is representative and can be used in statistical analyses. Qualitative analyses of cognitive development and emotional function are also provided. Results: The most significant predictor of IQ decrease was age at cranial (whole-brain) irradiation. Children under 3 years of age at time of irradiation showed profound decrease in IQ (mean IQ 55, median 55). There is a tendency of IQ increase with older age at whole-brain irradiation. With local radiotherapy we did not find any differences in IQ in different age subgroups. Children who had total resections of their tumors had a higher IQ than the ones with subtotal surgery. Detailed data will be presented. Conclusion: Young age at the time of irradiation is an adverse factor associated with IQ decrease, and these patients need early rehabilitation. More studies are needed on risk factors influencing psychosocial status in survivors of brain tumors. This work was supported by grant number C028/P05/2002.

THERAPEUTICS

THER 1. RADIOLOGICAL RESPONSE OF OPTIC NERVE GLIOMAS TO CHEMOTHERAPY

Samina Afzal, Roxana S. Gunny, Kim Phipps, Dawn E. Saunders, and Anthony Michalski; Great Ormond Hospital, Departments of Oncology and Radiology, London, UK

Optic nerve gliomas in childhood are typically low-grade astrocytomas but have a wide range of biological activity. Chemotherapy is usually reserved for those children with visual disturbance, neurological deterioration, or tumour progression as assessed radiologically. We have observed an early transient increase in tumour size following chemotherapy that could be interpreted as treatment failure and result in withdrawal of chemotherapy. Imaging studies and clinical data in children with optic nerve pathway gliomas (ONG) who presented between January 1995 and March 2003 were retrospectively reviewed. All patients were treated on the low-grade glioma protocol, carboplatin and vincristine for 49 weeks. Those that did not tolerate carboplatin or progressed later after completion of carboplatin had a change of chemotherapy to either vincristine and actinomycin D or Tpcv (thioguanine, procarbazine, lomustine and vincristine). Twenty-one children (mean age 3 years 2 months, range 2 months–9 years, 1 with type 1 neurofibromatosis) received chemotherapy. 7 received radiotherapy, one had surgery, and another had both. 6 required a VP shunt. Nineteen children survived a mean follow-up period of 5 years 8 months (range 1 year 10 months to 13 years 6 months). Two within the cohort died at 1 year 3 months and 2 years eight months from diagnosis. Nine children had radiological evidence of tumour progression following chemotherapy. Of these, 3 initially regressed at 1, 14, and 15 months following diagnosis and subsequently progressed. Six children had progressive disease at 3, 3, 3, 8, 20, and 27 months following diagnosis. Four had stable disease and 8 had tumour regression in response to treatment. Two children with tumour progression on the 10-week post chemotherapy scan went on to have tumour regression. In this cohort, six children had tumour progression following chemotherapy, but some subsequently responded to continuation of the same therapy. We conclude that transient tumour ‘progression’ can occur as a response to treatment and should not result in treatment withdrawal.

THER 2. COMBINED APPROACH WITH VENTRICULAR IRRADIATION FOR CNS GERMINOMA: THE SIOP EUROPEAN CONSENSUS

Claire Alapetite,1 Umberto Ricardi,2 Frank Saran,3 Rolf Kortman,4 Maria-Louisa Garre,5 Didier Frappaz,6 James Nicholson,7 Catherine Patte,8 Hervé Brisse,1 Geneviève Gaboriaud,1 and Gabriele Calaminus,9 on behalf of the International Society of Paediatric Oncology (SIOP) CNS GCT Study Group; 1Institut-Curie Paris, 6Lyon, and 8Villejuif, France; 2Turin and 5Genova, Italy; 3Sutton and 7Cambridge, UK; 4Tübingen and 9Düsseldorf, Germany

CNS Germinoma develops in 3d-ventricle recesses in adolescents, is radiocurable, chemosensitive, and associated with good long-term survival. The optimal therapeutic index of localised ICG is controversial. To reduce potential late effects of standard treatment with cranio-spinal irradiation, SFOP90 and SIOP96 arm-B studies have applied a combined approach with primary carboplatin based chemotherapy followed by focal-RT. The relapse rate is 16.4% and 14.6%, respectively; ventricular dissemination, at margins of or outside RT-field, is the predominant mode of relapse in both series (8/10 and 4/6 cases) but was not reported after craniospinal-RT (SIOP96 arm-A). This pattern of relapse suggests that the chemotherapy used might be less effective than RT in controlling subclinical ventricular disease. A high rate of incomplete initial work up (markers and/or dissemination) was observed in those multicentre studies and was recognised as a prognostic factor for relapse when RT is applied to limited volume. This highlights the need for large, properly staged, homogeneously treated series of histologically proven CNS Germinoma to further define risk subgroups and minimal necessary RT. For the next prospective multicentre SIOP study, the CNS-GCT group therefore proposes widening RT-volume in combined modality treatment to include, at prophylactic doses, the ventricular system (WV-RT) while improving the quality of the diagnostic workup. The next SIOP trial will be described with special emphasis on RT recommendations. Ventricles plus tumour bed represent a large complex volume. Adequate delineation of the ventricles (best obtained with preRT T2-weighted 3D magnetic resonance [MR] fusion with planning CT) and of the tumour bed (best obtained by fusion with preRT T1-weighted 3D MR with contrast) is prerequisite to good conformity index of dose distribution. Optimised 3D conformal-RT and theoretical benefit of proton and IM-RT will be presented. Conformal, 3D-planned-RT delivery should allow for documented evaluation of both disease control and late effects.

THER 3. INTENSIVE THERAPY FOR CHILDHOOD ATYPICAL TERATOID RHABDOID TUMOR OF THE CENTRAL NERVOUS SYSTEM: A SINGLE INSTITUTION’S EXPERIENCE WITH FOUR CASES AND A REVIEW OF THE LITERATURE

Uma Athale, JoAnn Duckworth, Isaac Odame, and Ronald Barr; Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, ON; Hamilton Health Sciences, Hamilton, ON; Canada

Purpose: The epidemiology of atypical teratoid rhabdoid tumor (ATRT) of the central nervous system (CNS) is still evolving. It is an uncommon aggressive tumor with very poor prognosis. Few investigators have reported successful treatment of CNS ATRT with sarcoma-like therapy. We report our experience with such therapy in four patients and review the literature. Methods: Therapy included surgery, intensive multiagent induction chemotherapy [3 courses of vincristine (VCR) (1.5 mg/m2), cisplatin (90 mg/m2), VP-16 (150 mg/m2 X 2) to alternate with 2 courses of vincristine, cyclophosphamide (CTX) (2.2 g/m2), doxorubicicn (45 mg/m2 X 2)], and involved-field radiation therapy (6 weeks) with concomitant weekly VCR and 3-weekly CTX (2.2 g/m2).1 Maintenance chemotherapy consisted of VCR, CTX, and actinomycin-D (1.5 mg/m2) for 28 weeks. Case-reports published after 1995 were analyzed to evaluate the effect of intensive therapy on survival and disease recurrence. Results: Of four patients (3 males) with CNS-ATRT, one had congenital disseminated disease. This patient died after the first course of chemotherapy. Three patients (age 1, 4, and 8 years) with localized disease (2 had gross total resection; 1 partial) received the planned therapy. After an initial good response, all 3 patients had progressive disease. The average survival was 9 months (range 6 weeks–12 months) compared to 15 months in historic patients (n = 20). Patients (n = 7) treated with upfront prophylactic intrathecal chemotherapy, with or without spinal radiation, had an average survival of 23 months (4 alive) compared to 11 months in those without any spinal prophylaxis. Overall 42% patients had craniospinal recurrence consistent with CSF dissemination. Conclusions: Multimodal intensive therapy can induce remission even in patients with partial resection of CNS-ATRT. Survival, however, is still dismal. With a high rate of relapse in the spinal/CSF area, intensification of therapy with prophylactic spinal radiation and intrathecal chemotherapy may be considered. J Ped Hematol/Oncol; 1995:17:71-5

THER 4. LONG-TERM OUTCOME FOR CHILDREN LESS THAN SIX YEARS OF AGE WITH DIAGNOSIS OF CONSENSUS REVIEWED HIGH-GRADE GLIOMAS: A REPORT OF THE CCG-945 STUDY

Vandana Batra, Richard Sposto, J. Russell Geyer, Jeffrey Allen, Ian Pollack, and Jonathan Finlay; The Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, CA, for the Children’s Oncology Group, Arcadia, CA; USA

Between 1985 and 1992, 250 children were enrolled upon the CCG-945 trial for high-grade gliomas (HGG) of the brain and spinal cord. The trial randomized children <3 years old to either the ‘standard’ pCV or ‘experimental’ “8-in-1” chemotherapy regimens, with local field irradiation. Children <3 years old at diagnosis were nonrandomly assigned to the “8-in-1” regimen, with delay or avoidance of irradiation. Eighty-seven children less than 6 years old (34.8% of all patients) were enrolled with institutional diagnoses of high-grade gliomas, of whom 51 were less than 3 years old. 43.1% of children <3 years old and 38.8% aged 3–6 years old underwent >90% tumor resection. Irradiation was delivered to 100% of 3–6 years old children at diagnosis, while 21.6% <3 years old received irradiation at some time-point. Upon centralized review by five expert neuropathologists, 41.1% aged <3 years old and 41.7% aged 3–6 years old had diagnoses other than HGG. For patients aged <3 years old, the 10-year event-free (EFS) and overall survival (OS) are 27 +/− 6% and 37 +/− 7%. For patients 3–6 years old, the 10 year EFS and OS are 33 +/− 8% and 42 +/− 8%. For patients with eligible reviewed HGG pathology, those aged <3 years old had 10-year EFS and OS of 17 +/− 8% and 26 +/− 8%, while those 3–6 years old had 10-year EFS and OS of 24 +/− 9% and 24 +/− 9%. There was no survival advantage in children <3 years old who received irradiation, either in the total patient group or those with reviewed eligible HGG pathology. There is a high discordance rate in institutional diagnoses of HGG amongst children <6 years old. The long term (10-year) EFS and OS for children <3 years old with reviewed diagnoses of HGG treated with avoidance of irradiation is not different from that of children aged 3–6 years old at diagnosis treated with irradiation and chemotherapy. A radical change in diagnostic and treatment strategies for young children with HGG is indicated by these findings.

THER 5. RESULTS OF THE HIT-REZ-97 STUDY: TREATMENT OF RELAPSED PRIMITIVE NEUROECTODERMAL BRAIN TUMORS (PNET) IN CHILDHOOD AND ADOLESCENTS

Udo Bode, Martina Zimmermann, Angela Emser, Monika Warmuth-Metz, Stefan Rutkowski, Carola Hasan, and Gudrun Fleischhack; Department of Pediatric Hematology/Oncology, Children’s Medical Hospital, University of Bonn, Bonn, Germany

HIT-REZ-97 study, a phase III trial in children and adolescents with relapsed PNETs, was initiated in 1997. In the curative arm (CA), the recommendation was to apply high-dose chemotherapy (HDCT, thiotepa, carboplatin, VP16 600/2000/1000 mg/m2) with autologous stem cell support in patients who achieved a CR/PR (good-responders) following a conventional chemotherapy with continuous iv infusion of carboplatin and VP16 (800/400 mg/m2/96 hours, 3 to 4 courses). In the palliative arm (PA), an oral chemotherapy with VP16 and trofosfamide (25/100 mg/m2/d for 21 days, every 4 weeks) was given until progression. In both arms, the opportunities of local therapy had to be utilized. Between 1997 and 2003 71 and 29 patients entered the curative and palliative arm, respectively. 32 of 69 (46%) and 6 of 24 (25%) evaluable patients achieved a CR/PR following iv carboplatin/VP16 and orally VP16/trofosfamide, respectively. 27 of 71 (38%) patients got HDCT, 22 in CR/PR. The time of OS (median ± SE) in both arms was significantly prolonged in the good-responders (CR, PR) (CA: OS 24.8 ± 13.5 m, PA: OS 36.0 ± 5.2 m) compared to the poor-responders (MR, SD, PD) (CA: OS 14.1 ± 7.2 m, PA: OS 8.0 ± 1.8 m). PFS and OS were not influenced by administration of HDCT or age at diagnosis. They were increased, however, comparing the curative with the palliative arm. Main toxicity of the curative arm was severe myelosuppression associated with febrile episodes in one-half of patients. Following the HDCT main toxicities were infections with two therapy-related deaths (mortality rate of 7.4%), severe mucositis, and ototoxicity. The side effects of the palliative arm were generally mild. The intensive relapse regimen of this study induced a high response rate in poor prognosis PNETs. However, the duration of response is short in the majority of patients independently of the treatment arm.

THER 6. PILOT STUDY OF VINBLASTINE IN PATIENTS WITH RECURRENT AND REFRACTORY LOW-GRADE GLIOMA

E. Bouffet, S. Goldman, R. Jakacki, M.L. Garre, N. Foreman, E. Cairney, M. Etzl, N. Tariq, D. Hargrave; Department of Paediatric Neuro-Oncology, Toronto, ON, Canada; Chicago, IL, USA; Pittsburgh, PA, USA; Genoa, Italy; Denver, CO, USA; London, ON, Canada; London, UK

Background: For low-grade glioma (LGG) patients who show progression during or after a first line of chemotherapy, there is increasing interest in trying to delay radiation further by using second-line chemotherapy, particularly in younger children. Methods: Weekly vinblastine (6 mg/m2/once a week) was given for 52 weeks in patients with recurrent/refractory LGG. Response was assessed at 10 weeks, 6, 9, and 12 months. Results: 20 patients (9 males 11 females, median age 7 years–range 1.4 to 16) were included in the pilot study. Tumour site was chiasmatic/hypothalamic (15), spinal or cervicomedullary region (3), hemispheric (2). On Histology, there were 8 pilocytic astrocytomas, 8 low-grade gliomas NOS, 3 gangliogliomas, 1 pilomyxoid tumour. 19 patients had received prior chemotherapy: 1 regimen (6), 2 regimen (10), 3 regimen (1), 4 regimen (2). 5 patients had previous radiotherapy. Toxicity was tolerable: 8 patients experienced grade 3–4 ANC toxicity, 1 patient required platelet transfusions, 4 patients RBC transfusion. There were 3 admissions for fever and neutropenia. Three patients developed symptoms of peripheral neuropathy, and 4 had significant or complete alopecia. Six patients required dose reductions. All patients are evaluable for response. There were 4 partial responses and 3 minor responses; 9 patients had stable disease, and 5 showed progression (at 1, 1, 1, 6, and 9 months). The overall response rate was 35% with 75% patients remaining at least stable during the 52 weeks of treatment. Conclusion: Vinblastine shows promising activity in recurrent LGG with a olerable toxicity profile. The optimal duration of treatment remains unknown. However, prolonged administration (12 months or more) in responders, particularly in younger children, appears to allow further delay in the need for radiation.

THER 7. OUTCOME FOR CHILDREN WITH CONCENSUS REVIEWED PATHOLOGY OF HIGH-GRADE GLIOMAOF THE SPINAL CORD; A REPORT ON THE CCG-945 STUDY

E. Bouffet, R. Sposto, J. Allen, A.Yates, I. Pollack, and J.L. Finlay

In the CCG 945 randomized study (1985–1992) for pediatric high-grade glioma, children with spinal cord tumor were nonrandomly assigned to the experimental “8/1” regimen, along with spinal irradiation. 18 children were enrolled (12 males, 6 females, median age 5.9 years, range 1–17.7). The purpose of this report is to update the results in this subgroup after centralized review of pathology. Methods: CCG 945 data were re-analyzed after central independent review by 5 neuropathologists. A final consensus diagnosis was issued from this central pathology review. Follow-up on all patients has been extended by 7 years since the initial report. Results: Institutional diagnoses were anaplastic astrocytoma, AA (13 pts), glioblastoma multiforme, GBM (4 pts), and anaplastic mixed glioma (1 pt). Consensus diagnoses were AA (6), GBM (3), low-grade glioma, LGG (6), other eligible (2), insufficient material (1). There was full agreement between reviewers in 5 cases (1 GBM, 2 AA, 1 LGG, 1 insufficient material). 9/18 registered patients were deemed discordant. Event-free (EFS) and overall survival (OS) for all 18 patients is 38% and 50% (at a median follow-up of 12 years). After central review, EFS and OS for confirmed HGG and discordant diagnoses was 33% vs. 44% (NS) and 33% vs. 66% (NS), respectively. OS and EFS between confirmed HGG and discordant diagnoses were not significantly different for each individual pathologist. Age <5 years and shorter duration of presenting symptoms were the only factors associated with poorer outcome (p = 0.05 and p = 0.01, respectively). Specimen for biological studies were available for 8 patients, including 6 with confirmed HGG. Only one showed p53 overexpression. Conclusion: The incidence of discordant diagnoses in spinal cord astrocytoma is high. However, the revision of the histological diagnosis did not have a statistically significant effect on outcome. The lack of significance between HGG and discordant diagnoses probably reflects small patient numbers.

THER 8. REDUCTION OF COCHLEAR DOSE USING PROTON BOOST FOR PEDIATRIC MEDULLOBLASTOMA

Yen-Lin Chen, Torunn Yock, William Butler, Judy Adams, Barbara Fullerton, and Nancy Tarbell; Department of Radiation Oncology and Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

Purpose: The current standard of care for children with medulloblastoma involves craniospinal irradiation followed by a posterior fossa boost and cisplatin-based chemotherapy. Both cisplatin and radiation (RT) are potentially ototoxic. Hearing loss is a significant long-term sequelae of medulloblastoma treatment and can lead to impaired language, social, and cognitive development. The rate of hearing loss from conventional RT and cisplatin-based chemotherapy is dose dependent and ranges from 25% to as high as 100%. As a result, efforts have been made to reduce the cochlear dose with conformal radiation techniques. With conventional RT, the cochlea receives 100% or greater of the prescribed total dose, whereas 3D conformal RT and IMRT have been reported to reduce cochlear dose to 65–68% of total dose. Proton RT offers dosimetric advantages over photon RT with high conformal dose distribution, lower entrance dose, lower integral dose, and absence of exit dose. The purpose of this study is to analyze the reduction in cochlear dose using proton boost. Methods: 24 pediatric medulloblastoma patients were treated from 1998 to 2002 with photon craniospinal irradiation followed by proton boost to the posterior fossa (n = 16) or involved field (n = 8). All patients received cisplatin-based chemotherapy in addition to RT. Median craniospinal irradiation dose was 23.4 Gy in standard risk patients and 36 Gy in high-risk patients. Posterior fossa or involved field boost dose ranged from 18 to 36 CGE, bringing the posterior fossa or tumor bed dose to a median of 54 Gy. All critical structures were confirmed by a neuroanatomist to ensure consistency. Dose volume histograms were generated for both cochlea. The cochlear doses were calculated as a percentage of the total prescribed dose. Results: Radiation treatment with photon craniospinal irradiation plus a proton posterior fossa or involved boost delivered average cochclear dose ranging from 15 to 45 Gy with a median of 30 Gy +/− 5.8 Gy (or 58% +/− 11% of prescribed dose). In patients treated with proton involved field boost, the average cochlear dose ranged from 15 to 34 Gy with a median of 29 Gy (55% of prescribed dose). For patients treated with proton posterior fossa boost, the average cochlear dose ranged from 23.9 to 45 Gy with a median of 32 Gy (60% of prescribed dose). The average cochlear dose was lower in patients receiving CSI dose of 23.4 Gy vs. 36 Gy: 29 Gy vs. 43 Gy (56.5% vs. 78% of prescribed dose). Cochlear dose decreased with increasing proportion of dose from proton. Conclusion: Proton boost resulted in average cochlear dose of 58% of the total prescribed dose, which compares favorably with the reduction seen with IMRT and 3-D conventional techniques in the literature. Cochlear dose decreased with increasing proportion of proton, involved field rather than posterior fossa boost, and lower CSI dose. Audiogram analysis on these patients will provide clinical correlation on the magnitude of reduction in hearing loss from reduced radiation dose to the cochlea using proton boost.

THER 9. NEWLY DIAGNOSED HIGH-RISK MALIGNANT BRAIN TUMORS WITH LEPTOMENINGEAL DISSEMINATION IN YOUNG CHILDREN: RESPONSE TO “HEAD START” INDUCTION CHEMOTHERAPY INTENSIFIED WITH HIGH-DOSE METHOTREXATE

Susan N. Chi, Sharon Gardner, Adam S. Levy, Edmond A. Knopp, Douglas C. Miller, Jeffrey H. Wisoff, Howard L. Weiner, and Jonathan L. Finlay; Divisions of Pediatric Oncology, Neuroradiology, Neuropathology, and Pediatric Neurosurgery, New York University Medical Center, NY, USA, and participating institutions in the USA, Argentina, Australia, and Canada

The prognosis for young children with newly diagnosed malignant brain tumors remains poor, particularly for those with leptomeningeal dissemination. From January 1997 to March 2003, eligible children were enrolled on the prospective multi-center protocol, “Head Start II” chemotherapy regimen A2, intensified with high-dose methotrexate. Following diagnosis, maximal surgical resection and clinical staging, patients were treated with five cycles of vincristine (0.05 mg/kg/week x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/day x two days per cycle), cyclophosphamide (65 mg/kg/day x two days per cycle) with MESNA, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Children without disease progression by the completion of induction chemotherapy underwent a single myeloablative chemotherapy cycle (carboplatin, etoposide, and thiotepa) with autologous hematopoeitic stem cell rescue. Thirty-seven patients were enrolled (medulloblastoma, 21; other primitive neuroectodermal tumor, 6; ependymoma, 5; atypical teratoid/rhabdoid tumor AT/RT, 4; choroid plexus carcinoma, 1), with mean age at diagnosis 44 months, range 5 to 119 months. Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, occurred. There were two toxic deaths. There were 25 complete responses (CR), five partial responses (PR), one with stable disease and four with progressive disease (two toxic deaths), for a CR + PR response rate of 81%. For patients with disseminated medulloblastoma, the CR rate is even higher (81%). The 4-year EFS and OS for all patients are 20% (95% CI, 31% to 52%) and 28% (95% CI, 39% to 63%), respectively. EFS and OS for patients with disseminated medulloblastoma are 51% (95% CI, 28% to 75%) and 55% (95% CI, 29% to 81%), respectively. Of note, there are two patients with AT/RT surviving, 12 and 30 months postdiagnosis. This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients having disseminated medulloblastoma (M2 or M3 disease) or other highly malignant brain tumors at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored for future studies.

THER 10. INTENSITY MODULATED RADIATION THERAPY(IMRT) INDUCES CHANGES THAT MIMIC NEW LEPTOMENINGEAL DISEASE IN PATIENTS WITH MEDULLOBLASTOMA

Murali Chintagumpala, Michael Morriss, Joseph Chiu, Jeremy Jones, Jack Su, Alison Bertuch, Adekunle Adesina, Robert Dauser, and Shiao Woo; Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

IMRT is a relatively new technology for administering conformal radiation therapy. We describe changes in the posterior fossa following IMRT in 4 children with medulloblastoma which mimic new leptomeningeal disease. These changes resolved without additional intervention. From 2000 to 2003, 11 patients with medulloblastoma were treated with IMRT to the posterior fossa as part of craniospinal radiation therapy followed by either conventional chemotherapy (10 patients) or high-dose chemotherapy and autologous bone marrow transplant (ABMT-1 patient). Craniospinal irradiation was delivered using standard technique with 23.4 Gy for standard-risk patients and 36 Gy for high-risk patients. An additional 12.6 Gy was given to the posterior fossa in standard-risk patients only. All patients received a tumor bed boost (resection cavity ± residual tumor with a 2 cm margin) of 19.8 Gy. The isodose was 80–85%. 4/11 (3/10 who received conventional chemotherapy and 1/1 who received ABMT) developed increased T2 signal in the cerebellar folia and white matter on FLAIR imaging at a mean of 6 months from completion of radiation therapy. Contrast images demonstrated patchy, multifocal, nodular, and plaque-like areas of enhancement within the areas of abnormal FLAIR signal. 4–6 weeks later there was evidence of progression indistinguishable from new leptomeningeal dissemination of tumor. Follow-up studies showed dramatic resolution of the abnormal enhancement and progressive decrease in abnormal FLAIR signal. There was no evidence of supratentorial abnormalities during this period. To our knowledge this is one of the first reports describing the effects of IMRT which strongly mimic recurrent disease in the posterior fossa. These changes may be the result of radiation dose inhomogeneity within the target area.

THER 11. IS THERE JUSTIFICATION FOR THE CONTINUED USE OF VINCRISTINE IN PEDIATRIC BRAIN TUMOR TREATMENT?

Kenneth J. Cohen and Leslie Aronson; Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Vincristine is routinely administered in the treatment of pediatric brain tumors. There is negligible data supporting its use. The Phase II study of vincristine was published in 1976, prior to the CT era, and reported 8/17 responders. Issues are raised regarding the interpretation of the data including the response of two pontine gliomas (presumed pilocytic astrocytomas), the characterization of a “cystic” anaplastic astrocytoma which may well represent a low-grade tumor, and the concomitant use of steroids and radiation therapy in some patients. A variety of findings suggest that vincristine does not penetrate the CNS including the absence of measurable cerebrospinal fluid (CSF) levels of vincristine when administered systemically and the failure of radiolabelled vincristine to penetrate the CNS. High CSF concentrations of vincristine are fatal when inadvertently administered intrathecally. Vincristine could not be placed in polymer and applied directly to the CNS without killing all experimental animals (J. Weingart, personal communication). While peripheral neuropathies abound when vincristine is administered, there is only modest evidence of central neurotoxicity. This appears to be most pronounced when efforts are made to disrupt the blood-brain barrier presumably allowing for improved vincristine penetration in the CNS and has been manifested in some patients by seizures. In addition, apparent associations between vincristine administration and cortical blindness have been reported although the mechanism for this toxicity is poorly understood. Recently, there has been some data suggesting an antiangiogenic activity for vincristine. However, data is preliminary and probably does not justify routine use on that basis. Vincristine appears to be utilized, despite the lack of supporting data, because of noncompeting toxicities (e.g., the absence of hematologic toxicity) when utilized with other agents. However, the therapy can be quite morbid for many patients and requires improved evidence to justify its continued use in pediatric patients with brain tumors (As previously published in Neuro-Oncol. 2003; 5:358).

THER 12. MENINGIOMA IN CHILDREN: A SINGLE CENTRE STUDY

O. Cruz, P. Teixidor,1 A. Guillen,1 J.M. Costa,1 J. Vila2; Departments of Pediatric Oncology, Neurosurgery1 Pathology,2 Hospital St. Joan de Déu Esplugues de Llobregat, Barcelona, Spain

Meningiomas in children are uncommon, infrequently described in the literature, and the most important factor influencing outcome is neurofibromatosis. Aim Of The Study: We report a series of 10 children treated between 1981 and 2003 for an intracranial meningioma in our hospital. Results: There were 5 boys and 5 girls. The age at diagnosis ranged between infancy and 13 years (mean age 8 years +/− 5.2). The two infants presented with a congenital tumor. Only two patients had remarkable antecedents: one patient diagnosed with NF, and another who had cranial radiation for medulloblastoma 6 years before. The most common neurological symptoms were seizures (60%) and a focal neurological deficit (40%). Supratentorial location was present in 9 patients, 4 of them in frontal convexity. Five patients had their tumor in an elocuent area. Size of the tumors showed a mean diameter of 41.9 mm (+/−21.7) vs. 35.1 mm (+/− 16.2 ). A gross total resection was performed in 60%. Histologically, the majority (90%) of the tumors were meningothelial or mixed, only one had atypical features, but none of the tumors was classified as a Grade III (anaplastic) meningioma. Four patients with incomplete resection relapsed, and all were treated with re-excision. Radiotherapy was used in three of these relapsed patients. All patients are alive, with a mean follow-up of 23.7 months (between 4 and 60 months). Commentary: Childhood meningiomas are infrequent, but no exceptional tumors. Complete resection is not always possible and should be performed as an image-guided operation. This study confirms the rarity of meningiomas in children and the absence of the female predominance associated with meningiomas in adults.

THER 13. ATYPICAL TERATOID/RHABDOID TUMORS OF THE CNS EXPERIENCE IN FOUR CHILDREN

Thomas Czech, Georg Widhalm, Andreas Peyrl, Wolfgang Dietrich, Karin Dieckmann, Christine Haberler, and Irene Slavc; Departments of Neurosurgery, Pediatrics, Radiotherapy, and Institute of Neurology, University of Vienna Medical School, Austria

Atypical teratoid/rhabdoid tumors (AT/RT) of the CNS are malignant embryonal tumors manifesting mainly in infancy and early childhood. Radiological and histological features are similar to primitive neuroectodermal tumor-medulloblastoma, but in contrast to these tumours AT/RT are characterized by a more aggressive tumor growth with a poorer prognosis. We report about our experience in four primarily diagnosed AT/RT. From 1997 to 2002 four patients 11 months to 7 years old, 3 male, 1 female, with AT/RT were treated at the Vienna University Hospital. Tumor localization was left frontal (1), fourth ventricle (2), and spinal cord (1). Three patients presented with signs of increased intracranial pressure, and the patient with the spinal cord tumor had torticollis and neck pain. Primary dissemination was ruled out by MRI of the craniospinal axis in all four patients. Gross total resection was performed in the three patients with intracranial tumor localization, biopsy only in the patient with the high cervical ventrally located intra-/extramedullary tumor. Postoperative treatment included an intensive chemotherapy consisting of cyclophosphamide, vincristine, methotrexate, etoposide, cisplatin, ifosfamide, and doxorubicin followed by high-dose chemotherapy with autologous stem cell rescue. Two patients were additionally treated with intraventricular chemotherapy (mafosfamide and methotrexate). All patients recieved local radiotherapy. Three patients are still alive without evidence of disease at 83, 19, and 14 months of follow- up. In patient two, near total regression of the spinal tumor was documented after chemo-/radiotherapy. He died 23 months after diagnosis because of symptomatic, leptomeningeal dissemination without radiological evidence of recurrence at the initial tumor site. Although the prognosis for this tumor entity as reported in the literature is dismal, rare patients may become long-term survivors. The respective role of the extent of tumor resection and of adjuvant therapy is still uncertain. A standardized treatment protocol is warranted.

THER 14. SURGICAL TREATMENT OF TUMORS OF CENTRAL REGION OF BRAIN IN CHILDREN—AN ANALYSIS OF OWN MATERIAL

Paweł Daszkiewicz and Marcin Roszkowski; Department of Neurosurgery, Children’s Memorial Health Institute, Warsaw, Poland

Background. Until recently, central region tumors were considered inoperable. Progress in neurosurgery has lead to increasingly frequent surgical attacks on these tumors, and results obtained are promising. Aim of this paper was to present our results of surgical treatment of central region tumors in children and to determine prognostic factors for patients’ survival. Material and Method: Medical records, radiographies, and histopathological specimens of patients treated at the Department of Neurosurgery with the diagnosis of central region tumor were retrospectively reviewed. Questionnaires were mailed to patients’ parents asking them to define present condition of their child. Since January 1980 till March 2003, we treated 114 children with the diagnosis of central region tumor. This group included 54 girls and 60 boys, whose mean age at the time of diagnosis was 8.05 years. In this group of patients the following procedures were performed: 61 shunting procedures (placement or revision), 54 biopsies, 10 placements of a Rickham reservoir, and 35 tumor resections of variable extent. Total tumor resection has been obtained in 9 cases, subtotal in 9, partial in 15, and open biopsy in 2. In the whole group of patients analysed, the mean follow-up time is 38.4 months. In the subgroup of children with benign tumors (n = 70), 70% are still alive, and 21.4% are dead. No data are available for the remaining 8.5%. The mean survival time in this group was 23 months. In the subgroup with malignant tumors (n = 12), 33.3% of children are still alive, and 66,6% are dead. The mean survival time in this group was 14.2 months. In the group of children who had their tumor bulk reduced (total or partial resection) (n = 35), 71.4% are still alive, 17.1% are dead, and no data are available for the remaining 11.4%. The mean survival time in this group was 24 months. In the group of children who underwent palliative procedures, only 59.5% (n = 47) are still alive, 27% are dead, and no data are available for the remaining 12,7%. In this group, the mean survival time was 18.3 months. Statistical analysis revealed highly significant differences in the survival of children dependent on tumor grade (p = 0.00059) and extent of resection (p = 0.00825). Conclusions: Tumors of the central region of brain in children are a heterogenous group of tumors of variable malignancy, so in every case histopathological diagnosis should be obtained in order to define optimal treatment regimen and prognosis. Prognostic factors are: degree of histologic malignancy and extent of surgical resection, so in each case the feasibility of surgical resection should be contemplated.

THER 15. TREATMENT RESULTS IN CHILDREN WITH OPTIC NERVE GLIOMA. ONE INSTITUTION EXPERIENCE

Bożenna Dembowska-Bagińska,1 Monika Drogosiewicz,1 Marta Perek-Polnik,1 Iwona Filipek,1 Ewa Długołȩcka,1 Marcin Roszkowski,2 and Danuta Perek1; 1Department of Oncology and 2Department of Neurosurgery, Children’s Memorial Health Institute, Warsaw, Poland

Aim: Analysis of treatment effectiveness in children with optic nerve glioma in our institution. Material and Method: From 1987 to 2002 52 pts with optic nerve glioma were treated. There were 29 girls and 23 boys aged from 4 months to 17 years 11 months, median 5 years 11 months. 17 pts had NF1. In case of single nerve involvement and blind eye, complete surgery was performed. Partial resections were recommended in egzofitic lesions of the chiasm in symptomatic patients. 29 pts underwent surgery and 24 received chemotherapy as primary treatment. Chemotherapy SIOP protocol (VCR, CBDCA) was implemented in case of unresectable progressing tumors and/or vision loss. PFS and time to progression was estimated for surgery and chemotherapy group. In chemotherapy group response to treatment was assessed. Comparison of PFS in NF1 and nonNF1 pts was done. Vision status and hypersensitivity to carboplatin was assessed. Results: 5 years PFS was 63% in the surgery group, and 79% in chemotherapy group. In the surgery group, median time to progression was 43 months, while in the chemotherapy group median was 3 months. In chemotherapy group, 9 out of 24 patients had good clinical response to treatment, with 8 partial remissions on CT/MR. Children under one year of age had a much better response to chemotherapy than older patients. PFS for NF 1 patients was 84% and for nonNF 70% regardless of treatment methods. Vision improved in 4 pts receiving chemotherapy, 6 pts had stabilization, 5 pts’ vision deteriorated. Hypersensitivity to carboplatin occurred in 6 pts (25%). Comments: A small number of patients enables definite conclusions, but from our observations we can state that chemotherapy is a good option for young children. Short mean time to progression in chemotherapy group indicates no response and new chemotherapy protocol for these patients is needed. Patients with NFI fared better. This work was supported by grant nr C 028/P05/2002.

THER 16. HIGH-GRADE GLIOMAS (HGG) IN CHILDREN BELOW 5 YEARS OF AGE: RESULTS OF A CHEMOTHERAPY ONLY APPROACH WITH THE BBSFOP PROTOCOL. A MULTICENTER TRIAL OF THE FRENCH SOCIETY OF PEDIATRIC ONCOLOGY

Christelle Dufour, Jacques Grill, Arielle Lellouch-Tubiana, Christian Sainte-Rose, Pascal Chastagner, Didier Frappaz, François Doz, Fabienne Pichon, Marie-Anne Raquin, and Chantal Kalifa; Pediatric Hemato-Oncology, American Memorial Hospital, France

Purpose: To evaluate a strategy that avoids radiotherapy in first-line treatment in children less than 5 years of age with HGG, by exclusively administering 16 months of adjuvant multiagent chemotherapy after surgery. Patients and Methods: Between October 1990 and June 2002, 21 children received adjuvant chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine-carboplatin, etoposide-cisplatin, vincristine-cyclophosphamide). Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment was not standardized. Results: Out of 21 children, 11 were infants under 24 months old. The mean age at diagnosis was 23 months (range: 1 to 47 months). Tumor was supra tentorial in 17 and in the posterior fossa in 4. The centrally reviewed diagnoses were anaplastic oligodendroglioma in 8, anaplastic oligoastrocytoma in 1, anaplastic astro-cytoma in 4, and glioblastoma in 8. Surgical resection was complete with 7 patients, subtotal with 2, partial in 9, and only a biopsy in 3. The 5-year PFS in this series was 31% (16% to 52%) and the 5-year OS was 54% (34% to 73%). At last update, 13 children were alive: 7 in complete remission (median interval since diagnosis of 66 months), 4 with a stable residue and 2 with progressive disease. Six children were alive without recourse to radiotherapy 5 years after initiating chemotherapy. In this series, age below 2 and complete resection were associated with a better prognosis. Conclusions: HGG seems to have a better prognosis in young children compared to the same histologies in older children, despite a schedule where irradiation was avoided as first-line treatment. Radiotherapy may even be avoided in selected cases. We hypothesize that biological correlates could explain this difference in outcome.

THER 17. HIGH-DOSE CARBOPLATIN, THIOTEPA, AND ETOPOSIDE WITH AUTOLOGOUS STEM CELL RESCUE (ASCR) FOR RECURRENT MEDULLOBLASTOMA

Ira Dunkel, Sharon Gardner, James Garvin, Stewart Goldman, Weiji Shi, and Jonathan Finlay; Memorial Sloan-Kettering Cancer Center, New York, NY; New York University Medical Center, New York, NY; Columbia University College of Physicians and Surgeons, New York, NY; Children’s Memorial Hospital, Chicago, IL; Children’s Hospital of Los Angeles, CA; Children’s Oncology Group; USA

Recurrent medulloblastoma is highly lethal, with very few patients surviving following conventional retrieval treatments. We have previously reported promising results using high-dose carboplatin, thiotepa, and etoposide with ASCR (J Clin Oncol 1998;16:222) as the core of our retrieval strategy, and now report an expanded series with long-term follow-up. Patients were brought to a minimal disease state via surgery, radiation therapy (RT), and/or conventional chemotherapy prior to enrollment on the protocol. Protocol-prescribed chemotherapy consisted of carboplatin (Calvert formula with AUC = 7 mg/ml·min, maximum 500 mg/m2/day) on days −8, −7, and −6, and thiotepa (300 mg/m2/day), and etoposide (250 mg/m2/day) on days −5, −4, and −3, followed by ASCR on day 0. Seventeen patients received RT as part of the retrieval therapy (9 preASCR, 8 postASCR). Forty patients with recurrent medulloblastoma, aged 2.9 to 44.7 years (median 11.5 years) at ASCR, were treated. Four patients (10%) died of treatment-related toxicities within 30 days of ASCR due to multiorgan system failure (n = 3) and Aspergillus infection with veno-occlusive disease (n = 1). Twelve patients (30%) are event-free survivors at a median of 95.6 months postASCR (range 62.5 to 147.9 months). Kaplan-Meier estimates of event-free and overall survival are both 30% (95% confidence interval, 16%–44%) at 8 years postASCR. M-0 recurrence prior to protocol (vs. M-1+), documented chemosensitivity after preprotocol recurrence, and lack of tissue confirmation of relapse were not associated with better EFS. A strong trend towards better EFS was noted in patients whose original treatment was chemotherapy only (p = 0.06), but a more powerful association was better EFS in patients who received RT as part of their retrieval therapy (p = 0.006). This retrieval strategy using high-dose carboplatin, thiotepa, and etoposide with ASCR provides long-term EFS for some patients with recurrent medulloblastoma. The use of RT as part of the retrieval regimen is associated with better outcome.

THER 18. PHASE II STUDY OF TEMOZOLOMIDE IN CHILDREN AND ADOLESCENTS WITH BRAIN TUMOR

Sidnei Epelman, Renato Melaragno, and Alejandro Arancibia; Pediatric Oncology Department, Santa Marcelina Hospital, Sao Paulo, Brazil

Despite aggressive treatment, recurrent brain tumors and brain-stem gliomas have a poor prognosis with current methods. New treatments strategies that address symptom control and quality of life as well as progression-free and overall survival are urgently needed. Temozolomide has shown efficacy against brain tumors with a safety profile while maintaining and improving quality of life. A phase II trial of temozolomide 200 mg/m2/day for 5 days monthly in 14 recurrent brain tumors and 8 brain-stem tumors received 75 mg/m2/daily during local radiotherapy and 200 mg/m2/day for 5 days monthly for 10 cycles. Objective responses were seen in 10, which in 5 complete and partial responses (2 ependimomas after 6 and 10 cycles, 2 brain-stem gliomas and 1 medulloblastoma). Temozolomide was well tolerated. A total of 97 cycles were analyzed: myelotoxicity grade III/IV was seen in 19 cycles, fever and neutropenia which required antibiotics in 3 cycles. These encouraging results with temozolomide suggest the potential for its use as first-line therapy in medulloblastoma and ependimoma patients. This work was supported in part by TUCCA-Children’s Brain Tumor Association.

THER 19. PERIPHERAL HEMATOPOIETIC PROGENITOR CELL HARVESTS IN PEDIATRIC BRAIN TUMOR PATIENTS UNDERGOING HIGH-DOSE CHEMOTHERAPY: EXPERIENCE WITH PATIENTS WEIGHING LESS THAN 15 KG

Nicholas Foreman, Tuan Le, Edmund Orsini, Deborah Noonan, Roger Giller, and Janice Gurley; Neuro-Oncology/BMT Division-Pediatrics, Blood Donor Center, Pathology, The Children’s Hospital, Denver, CO, USA

The therapy of young children is complicated by the need to limit radiation. Protocols using high-dose chemotherapy with PBSC rescue have been piloted. It is assumed that age (often less than 6 months) and/or weight restrictions (less than 10 kg) limit the ability to peripherally harvest stem cells. However, technical advances may have been made in venous access, citrate toxicity, and volume shifts. Apheresis was performed with the Auto PBSC Spectra with red cell priming. Using G-CSF, a WBC >2,000 and a mononuclear fraction >25% initiated harvesting. ACDA anticoagulant and prophylactic intravenous calcium supplement were used. The goal was a minimum yield of 9 *106 CD34/kg. Eight patients (ages 3.8–36 months), mean weight of 8.6 kg, underwent outpatient harvesting. There were 5 children <10 kg and 3 between 10–15 kg. 3 were <6 months of age and the other 5 ≤ 36 months. Dual-lumen apheresis catheters were used in 5. In the 3 < 6 months, harvesting was with two single lumen PICCs or Broviacs (n = 2) or a single lumen PICC and a single lumen Broviac (n = 1). The minimum flow for the Auto PBSC (≥10 mL/min.) was achieved (range: 10–29.4). A median 5.5 total blood volumes (range: 5–11) were processed over a median of 320 minutes (range: 226–474). In patients <10 kg, a median product yield of 18.4*106 CD34/kg was obtained and in those 10–15 kg 22.5*106 CD34/kg. No leukapheresis-related complications were noted. Five patients underwent a total of 13 PBSC rescues with a median ANC engraftment of 10 days (range: 10–12) and a median platelet engraftment of 19.5 days (range: 14–32).

PatientAge (months)Weight (kg.)Mean Flow Rates (max/min in mL/min)# of Harvest (sessions)Mean Duration of Harvest (minutes)Mean TBV ProcessedCumulative Product Yield (10°6CD34/kg)
14.575.815.3/4.813911148.8
24.75.810/101266531.8
33.8610/101421816.2
4117.511.9/10.51280518.4
5248.816.2/16.21358817.6
6361015.8/11.342825157.9
7261112.8/121474622.5
8361429.4/19.43226522.2

Conclusion: The use of dual-lumen apheresis catheters or 2 single-lumen catheters, red cell prime, and intravenous calcium supplement allow for leukaphereses in the very young. Age and/or weight restrictions need reevaluating given technical advances.

THER 20. INTRAMEDULLARY SPINAL CORD ASTROCYTOMAS IN CHILDREN

Nicholas Foreman, Nicole Townsend, Michael Handler, and Julie Fleitz; University of Colorado Health Sciences Center, Denver, CO; The Children’s Hospital, Denver, CO; USA

Background: Intramedullary spinal cord astrocytomas are uncommon tumors in childhood. There is little information on therapy and outcome of astrocytomas in this location. Procedure: Ten children were treated between 1996 and 2003 for spinal cord astrocytomas. Only one had metastatic disease. Those presenting with pain and decreased motor skills tended to have tumors in the cervical spine region, whereas patients presenting with scoliosis tended to have tumors in the thoracic spine. All ten patients underwent surgical resection, 9 partial and 1 total. Eight had low-grade tumors, and two high-grade tumors. Two had surgery only, 4 had chemotherapy only, 2 had radiation only, and 2 had both radiation and chemotherapy. Results: Progression-free survival was 58% and survival was 68% at 4 years. Four patients had disease progression, of which three died. Both children with high-grade astrocytomas died. Two out of 8 of the children with low-grade astrocytomas of the cord recurred, one having received radiation as initial therapy and the other chemotherapy. The child, who relapsed after radiation, had a spastic quadriplegia from radiation myelitis, and no salvage therapy was attempted. The four patients who treated with chemotherapy alone, all with low-grade astrocytomas, received carboplatin and vincristine. Of these 4, 3 are in continuous remission, and one relapsed but was salvaged with radiation. Conclusions: Chemotherapy and radiation did not benefit those with high-grade astrocytomas of the spinal cord. Carboplatin and vincristine appeared to be effective, safe therapy for those with low-grade astrocytomas of the cord.

THER 21. A STUDY OF SEQUENTIAL HIGH-DOSE CYCLOPHOSPHAMIDE AND HIGH-DOSE CARBOPLATIN WITH PERIPHERAL STEM CELL RESCUE IN RESISTANT OR RECURRENT PEDIATRIC BRAIN TUMORS

Nick Foreman, Michael Handler, Deb Schissel, Tuan Le, John Strain, Julie Fleitz, Ralph Quinones, and Roger Giller; University of Colorado Health Sciences Center, Denver, CO; The Children’s Hospital, Denver, CO; USA

Purpose: To determine the maximum tolerated dose (MTD) of carboplatin with autologous hematopoietic stem cell rescue in children with poor-prognosis brain tumors. Patients and Methods: A previously determined dose of cyclophosphamide with stem cell rescue was used as a first course. In a second course, Carboplatin was given for 3 days with stem cell rescue to 20 children. The starting dose of Carboplatin was 400 mg/m2/day with increments of 75 mg/m2/day in subsequent cohorts. Toxicity and tumor response were recorded. Results: There were 2 grade IV toxicities at the dose level of 775 mg/m2/day. There were no toxic deaths. Thus, the MTD of carboplatin was 700 mg/m2/day for 3 days. There were 6 complete responses (33%; 95% confidence interval [CI], 13% to 59%), 2 partial responses (11%; 95% CI, 1% to 35%), 4 with stable diseases (22%; 95% CI, 6% to 48%) and 6 progressed (33%; 95% CI, 13% to 59%) out of 18 assessable. Seven of the 8 responses were in primitive neuroectodermal tumors (PNETs) or Germinomas. One child with a metastatic anaplastic astrocytoma had a CR. The median duration of tumor response was 10 months (range, 1.5 to 87 months) with 2 children disease free at 66 and 87 months. Actuarial survival is 21%, at a median follow-up of 35 months in survivors (range 15 to 87 months). Conclusion: The MTD of Carboplatin with stem cell rescue is 700 mg/m2/day for 3 days. Sequential stem cell supported Cyclophosphamide and Carboplatin was tolerable in children with brain tumors and produced responses in PNETs and Germinomas.

THER 22. OUTCOME AFTER FIRST RELAPSE OF 4th VENTRICULAR EPENDYMOMAS IN CHILDREN UNDER 5 YEARS OF AGE AT INITIAL DIAGNOSIS

Nick Foreman, Amy Smith, Mark Matthews, and Elaine Weng; University of Colorado Health Sciences Center, Denver, CO; The Children’s Hospital, Denver, CO; USA

Outcome after first relapse of an intracranial ependymoma is poor. We report outcome after first relapse of 4th ventricle ependymomas in 6 consecutive children. Age at initial presentation ranged from 11 to 51 months. All 6 had complete resections at initial presentation, 3 at first and 3 at second surgery. Chemotherapy was variable ranging from short course Carboplatin/VP16 to extended cisplatin/cytoxan/VP16. Only one was radiated in first remission using conformational techniques. 5 relapsed within 24 months from diagnosis with one late at 52 months. Relapses were local without metastases. 3 tumors were still WHO grade II; one had upgraded from Grade II to III; and 2 remained grade III. The MIB-1 had increased in 4 and ranged from 2 to 40% (median of 25%). At relapse, 3 children had complete resections and received conventional radiation. One who had previous radiation had a complete resection and radiosurgery. Two had incomplete resections at relapse and received conventional fractionated radiation followed by radiosurgery to the residual. None received chemotherapy. 3 children had subsequent relapses at 15,16, and 23 months after their first relapse. 3 children are in continuous complete remission (CCR) with no evidence of tumor at 36, 55, 60 months. 2 in CCR were those who had residual disease after surgery at relapse and received conventional radiation with a radiosurgery boost. %. The other child in CCR was one of those not previously irradiated who had a complete resection and conventional fractionated radiation. 2/3 of these in CCR had grade III tumors at relapse, and 2/3 had raised MIB-1s of 30 and 40 Grade III histology; increased proliferation index and even residual tumor did not necessarily result in a poor outcome. Young children, not previously radiated, may be salvaged at first relapse with radiation therapy, including radiosurgery for those with residual disease.

THER 23. HYPERFRACTIONNATED POSTOPERATIVE FOCAL RADIOTHERAPY (BIDRT) IN INTRACRANIAL EPENDYMOMAS: UPDATE OF THE S.F.O.P. EXPERIENCE

D. Frappaz,* V. Bernier, P. Thiesse, D. Plantaz, J.C. Gentet, F. Gomez, and C. Carrie; Centre Léon Bérard, Lyon, France, for the SFOP

Rationale: To prospectively investigate the role of BifRT in the optimal treatment of intracranial ependymoma. Material and Methods: Post operative focal BidRT was proposed to every child (more than 5 years at diagnosis) with localised intracranial ependymoma. The dose (delivered in two daily fractions of 1 Gy) was tailored according to post operative MRI: 60 Gy in case of complete removal (CompRem), and 66 Gy in case of less than complete removal (IncompRem). Results: From 11/1996 to 12/2003, 24 children with infratentorial (20 pts) or supratentorial (4 pts) ependymomas were included. Median age was 9 years [5; 17]. Removal was reported by local physician as complete in 19 pts (3 doubtful and 1 IncompRem at central review) and incomplete in 5 pts (1 CompRem and 1 doubtful at central review). Pathology was centrally reviewed as WHO grade II: 12 pts, III: 9 pts, nonassessable: 3 pts. The 3 year overall survival is 73% and EFS 53%. Eleven patients had a relapse: 7 were local, 3 were local and regional, 1 was only regional. Four/12 grade II, 5/9 grade III, 2/3 grade not assessed relapsed. According to assessment by local physician: 8/19 CompRem and 3/5 Incom-pRem relapsed. Conclusion: BidRT is a safe procedure after optimal removal of intracranial ependymoma. Further follow-up is warranted to demonstrate that the rate of sequellae is decreased by this type of radiation. This work was supported by grants from Comité du Rhône Ligue Nationale Contre le Cancer and Association Sébastien à Boston.

THER 24. EPENDYMOMA: CURRENT CONTROVERSIES

D. Frappaz,1 T. Merchant, M. Massimino, R. Kortmann, and R Grundy, on behalf of the SIOP Working Group; 1Centre Léon Bérard, Lyon, France

A consensus meeting was held in Paris (13–14/O2/03), to review the current status and controversies in management of ependymoma for infants and children. Histology and Biology: There were discrepancies concerning grading (II: classical vs. III: anaplastic) in different countries. Tumors with focal areas of anaplasia have been classified as grade II or III. Standardisation efforts and biological investigations are required especially in the latter subgroup. Investigation of new biological tools is warranted such as CGH and ErbB determination. Imaging: Response continues to be defined by size determination and to a lesser extent by changes in the pattern of enhancement. The addition of MR spectroscopy and other tools has been suggested as a means to increase the specificity of response evaluation.disparition. Surgery: Gross-total resection, defined as macroscopic tumor resection confirmed by postoperative neuroimaging was a widely recognised as a significant prognostic factor. Second surgery was encouraged for patients with residual tumor after initial resection with referral to specialty centers if required. Radiation therapy: Fractionation (daily, bid), total dose (54 or 59.4 Gy) and treatment margins (clinical target volume = 1cm) were reviewed. Optimisation of target definition, immobilization, and the use of general anesthesia were discussed. Chemotherapy: The application of chemotherapy was reviewed including its use in very young children (French, UK, Italian, and German experiences), ability to delay irradiation, and prior to second surgery. No current proof of efficacy has been demonstrated although its future role prior to second surgery and in the setting of treatment failure was discussed. With all current data available, a proposal for common protocol was initiated.

THER 25. EXCELLENT EVENT-FREE SURVIVAL (EFS) IN NEWLY DIAGNOSED HIGH-RISK (HR) MEDULLO-BLASTOMA (MB) TREATED WITH CRANIOSPINAL RADIATION (CSI) THERAPY FOLLOWED BY 4 CYCLES OF HIGH-DOSE CHEMOTHERAPY AND STEM CELL RESCUE: RESULTS OF A PROSPECTIVE MULTICENTER TRIAL (SJMB 96)

Amar Gajjar, Murali Chintagumpala, Stewart Kellie, David Ashley, Tim Hassall, Dana Wallace, Greg Hale, Alberto Broniscer, Maryam Fouladi, Thomas Merchant, Matthew Krasin, Shaio Woo, Marie Sexton, Valerie Ahem, Robyn Cheuk, Ching Lau, Richard Gilbertson, and Larry Kun; Division of Neuro-Oncology, Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To estimate the EFS of HR MB treated with CSI with a boost to the primary tumor site delivered by 3-dimensional conformal radiation therapy followed by 4 cycles of high-dose chemotherapy supported by stem cell rescue. Patients and Methods: Between Sept 1996 and Dec 2003, 47 children with MB between the ages of 3–21 years were enrolled on the HR arm of the SJMB 96 protocol. Patients with HR disease had either residual tumor (≥1.5 cm2) or disseminated disease in the neuraxis (M1–3) as defined by the Chang staging system. All patients had pre and postoperative MRI to determine extent of resection and presence of disseminated disease. Lumbar CSF cytology was obtained 14 days postop to document presence of tumor cells. All patients received stage adapted CSI (M0–1 -36 Gy; M2 - 36–39.6 Gy Cr; 36 Gy Sp; M3- 39.6 Sp); the tumor bed received 55.8 Gy. Six weeks after completion of RT, all patients received adjuvant chemotherapy consisting of 4 cycles of high-dose cyclophosphamide (4000 mg/m2 per cycle); with cisplatin (75 mg/m2) and vincristine (two 1.5 mg/m2 doses per cycle). EFS was calculated from the start of radiation therapy to the date of last follow-up. Results: The median age of the patients was 6.5 years (range 3.1–16.10 years); the cohort consisted of 36 males and 11 females. Of the 47 patients, 6 patients had residual disease and the rest of the 41 patients had metastatic disease (9 M1; 6 M2: 26 M3). All patients received their planned chemotherapy. There were no toxic deaths on the study. The EFS for the entire cohort is 71 ± 10 with a median F/U of 4 years. Conclusions: 4 cycles of high-dose cyclophosphamide based chemotherapy with stem cell support following CSI in patients with HR MB has resulted in excellent EFS with no toxic mortality.

THER 26. PHASE I DOSE ESCALATION OF TEMOZOLOMIDE WITH THIOTEPA AND CARBOPLATIN WITH AUTOLOGOUS STEM CELL RESCUE (ASCR) IN PATAIENTS WITH RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Sharon Gardner, David Baker, Jean Belasco, Peter Phillips, Nancy Bunin, Stephan Grupp, Robert Iannone, Edmond Knopp, Douglas Miller, Kelly Cervone, Hanh Ngo, and Jonathan Finlay; New York University, New York, NY, USA

Temozolomide is an oral alkylating agent with myelosuppression as its primary dose limiting toxicity. The maximum tolerated dose of temozolomide without ASCR is 180 mg/m2/d x 5 days and 215 mg/m2/d x 5 days in patients with and without prior craniospinal irradiation, respectively. In the present study temozolomide was given in a dose escalating fashion with thiotepa and carboplatin with ASCR to patients with recurrent/refractory CNS tumors. The dose of temozolomide ranged from 100 mg/m2/d to 400 mg/m2/d on days −10 to −6. Thiotepa 300 mg/m2/d and carboplatin AUC = 7 using the Calvert formula (maximum 500 mg/m2/d) were given on days −5 to −3. ASCR occurred on day 0. Twenty-three patients ranged in age from 3.2–49.75 years (median 29.5 years). Diagnoses included glioma (n = 11), medulloblastoma/supratentorial PNET (n = 7), CNS germ cell tumors (n = 3), ependymoma (n = 1), and paraspinal PNET (n = 1). One patient had dose limiting toxicity (veno-occlusive disease) at dose level 3 (200 mg/m2/d). One patient had dose limiting toxicity (severe mucositis) at dose level 7 (400 mg/m2/d). The primary toxicities seen in all patients included pancytopenia and mucositis requiring parenteral nutrition and intravenous narcotics. Additional grade III/IV toxicities included hyperbilirubinemia (grade 3: 4 patients; grade 4: 1 patient); elevated transaminases (grade 3: 5 patients; grade 4: 1 patient); grade 3 skin toxicity: 2 patients; grade 3 hearing, pulmonary, renal, and fever in one patient each. There were no toxic deaths. Eighteen patients are alive 0.1–3.1 years (median 1 year) from study enrollment. Twelve patients are event-free survivors 0.1–3.1 years (median 1 year) from study entry with the diagnoses of medulloblastoma/supratentorial PNET (n = 6), glioma (n = 4), paraspinal PNET (n = 1) and CNS germ cell tumor (n = 1). Four patients are alive following relapse 1.4–3 years from study entry. Two patients are too early to evaluate. Conclusion: The use of ASCR has permitted significant increase in the dose of temozolomide. Phase II studies are needed to see if the combination of temozolomide, thiotepa, and carboplatin will result in increased survival.

THER 27. INTENSIVE INDUCTION CHEMOTHERAPY FOLLOWED BY HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE (ASCR) IN YOUNG CHILDREN NEWLY DIAGNOSED WITH CENTRAL NERVOUS SYSTEM (CNS) ATYPICAL TERATOID RHABDOID TUMORS (ATT/RT)—THE “HEAD START” REGIMENS

Sharon Gardner, Blanca Diez, Adam Green, Biljana Horn, Stewart Kellie, Edmond Knopp, Geoffrey McCowage, Douglas Miller, Susan Chi, and Jonathan Finlay; New York University, New York, NY, USA

CNS ATT/RT are rare tumors of childhood with a dismal prognosis. Historically surgery and standard dose chemotherapy have resulted in median survival of 8.5 months from diagnosis. Between 1992 and 2002, 12 children newly diagnosed with CNS ATT/RT were treated with the “Head Start” regimen. Six children (3 males) median age at diagnosis of 36 months (range 4–45 months) were treated on “Head Start I” from 1992–1997. Six children (4 males) median age at diagnosis of 34 months (range 4–45 months) were treated on “Head Start II” from 1997–2002. Therapy included resection followed by 5 cycles of cisplatin, vincristine, cyclophosphamide, and etoposide. High-dose methotrexate was added to each of the 5 induction courses in “Head Start II”. Consolidation for both regimens included carboplatin, thiotepa, and etoposide with ASCR. Five patients had gross total resections and 2 had near total (>90%) resections at diagnosis. One patient received irradiation (RT) following ASCR but prior to recurrence; 3 patients received RT at recurrence (2 craniospinal; 1 focal). There are presently 3 event-free survivors 12, 34, and 46 months following diagnosis. None received RT. One child is in second complete response 16 months from diagnosis. All 4 survivors were enrolled on “Head Start II” although one did not receive methotrexate. Two had gross total resections and two had near total resections at diagnosis. Seven patients died of disease (6 on Headstart I); one patient died from infection. Toxicity consisted primarily of pancytopenia, infection, and mucositis. Conclusion: Surgery and intensive induction chemotherapy including high-dose methotrexate followed by high-dose chemotherapy with ASCR have resulted in long term survivors of CNS ATT/RT.

THER 28. MYEOLOABLATIVE CHEMOTHERAPY WITH PERIPHERAL BLOOD STEM CELLS RESCUE BEFORE CRANIOSPINAL RADIOTHERAPY, IN PATIENTS WITH MEDULLOBLASTOMA WITH POSTOPERATIVE RESIDUAL OR METASTATIC DISEASE. RESULTS OF A MONO-INSTITUTIONAL STUDY IN ITALY

Maria Luisa Garrè,1 Sandro Dallorso,2 Claudia Milanaccio,1 Barbara Cappelli,2 Lucia Rivabella,3 Salvina Barra,4 Paola Franzone,4 Paolo Tortori-Donati,5 Maura Faraci,2 Marcello Ravegnani,6 Marco Pavanello,6 Gianluca Piatelli,6 Miriam Tumolo,7 Paolo Nozza,8 Valeria Capra,9 Alessandro Raso,9 and Armando Cama6; Radiotherapy Istituto Scientifico per La Ricerca sul Cancro, Genoa4; Neuro-Oncology,1 Bone Marrow Transplant Unit,2 Neurosurgery6, Neurosurgery Lab,9 Neuroradiology,5 Anestaesiology,7 Pathology,8 and Transfusion Centre3 of Giannina Gaslini Children’s Hospital, Genoa; Italy

Adjuvant chemotherapy (CT) increases the cure rate for patients with high- or average-risk MB and it’s now a standard part of contemporary management in association with cranio-spinal irradiation (CSI). Radiotherapy (RT) remains irreplaceable in the care of MB despite its risk of permanent side effects. More effective CT modalities in sequence with RT are under investigation in order to improve control of disease and reduce risk of sequelae. The prognostic significance of residual tumor greater of 1.5 cm3 is a matter of debate. At our institution we included patients with residual tumor in the high-risk protocol. Treatment (Tx) consisted of sequential induction chemotherapy: CR 1.5 mg/m2/MTX 8 gr/m2; HDVP16 2.4 gr/m2; R 1.5 mg/m2/CTX 4 gr/m2; VCR 1.5 mgr/m2/CARBO 800 mg/m2 followed by 2 courses of myeloablative CT (CARBO 1.5 gr/m2/VP16 1.5 gr/m2 and THIOTHEPA 900 mgr/m2/MPH 120 mgr/m2) with re-infusion of PBSCs; CSI was planned within 30–60 days from re-infusion for a total of 24 Gy CSI and 54 on the posterior fossa and boost on metastasis sites. In the period 1997–2003 28 cases with MB were admitted at IGG, 12 (42.8%) were standard-risk, 16 presented high-risk features (57%): 9 T+/M0 having >1.5 cm3 of residual tumor; 7 were M+: 3M3, 3M2 and 1 M1; (2 of M+ were relapsed cases). Interval from surgery and start of CT ranged from 20 and 41 day (median 27); duration of chemotherapy was 65–117days (media 100 days; interval from end of CT and start of RT ranged from 30–84 days (median 60); median duration of full Tx: 7.2 months. Median duration of follow-up 9 months. PBSCs collection ranged from 5–56 CD34x10/Kg (median 15.2); cells were subdivided in 3 parts for each case: 2 reinfuse after myeloablative CT courses in all, 1 post RT if needed. Toxicity was unremarkable after 1st course CT (median duration of hospital admission 22 days); a longer duration of hospital admission due to GI toxicity >grade 2 or infection was reported after 2 course of myeloablative CT; no toxic deaths were observed. Five Years OS and EFS was of 79%; failures were registered in the metastatic group only (1 PD during induction, patient treated at relapse; 1 with massive metastatic disease preoperatively). In 8/9 cases with residual tumor CT obtained a CR; in one PR was obtained after CT and CR after RT. In this group no relapses have been observed although follow-up is still short; in 5 long-term-survivors (45, 50, 55, 60, 70 months), endocrine and neuro-cognitive outcomes were better compared with standard-risk group (12 pts) receiving full standard-dose CSI plus standard CT. Myeloablative CT is feasible with an acceptable toxicity not precluding irradiation and may allow “safe” reduced CSI doses in cases with no metastasis.

THER 29. CHILDHOOD EPENDYMOMA: IMPROVED SURVIVAL FOR PATIENTS WITH INCOMPLETELY RESECTED TUMORS WITH THE USE OF PREIRRADIATION CHEMOTHERAPY

James Garvin, Richard Sposto, Philip Stanley, Lucy Rorke, and Roger Packer; Columbia University, New York, NY; Children’s Oncology Group, Arcadia, CA; USA

Ependymomas are among the most common childhood brain tumors. Survival for children with incompletely resected ependymoma is approximately 35% after surgery and radiotherapy (RT), consistently inferior to the outcome with total resection and RT. Between February 1995 and October 1999, 84 consecutive children over 3 years of age (median age 6.7 years, range 3 to 21 years) with ependymomas were prospectively entered on Children’s Cancer Group Protocol 9942. The tumor was infratentorial in 58%. Those without postoperative residual disease (N = 43) were treated with local RT alone; while those with residual disease (N = 41) received 4 cycles of preirradiation cisplatin, vincristine, cyclophosphamide, and etoposide. Of 33 fully evaluated patients receiving chemotherapy (CT), 14 (42%) had a complete response (CR), 6 (18%) a partial response (PR), 9 (27%) a minor response or stable disease (MR/SD), and 5 (15%) progressive disease prior to RT. The three-year event-free survival (EFS) for the fully evaluated chemotherapy patients was 58 6%. The 3-year EFS was 86% for patients with CR, 83% for PR, and 44% for MR/SD. For the entire study population, EFS did not differ between patients assigned to RT alone because of no postoperative residual disease (62 8%) and patients assigned to CT plus RT because of residual disease (55 9%). Tumor histology did not significantly impact outcome. The results of this study demonstrate a relatively high rate of response to CT in childhood ependymoma, and better EFS than previously reported for patients with postoperative residual disease. These results suggest that preRT CT should be incorporated into the management of childhood ependymomas.

THER 30. ATYPICAL TERATOID/RHABDOID TUMOR: 3 CASES BEYOND INFANCY

Corrie Gidding, Pieter Wesseling, Erik van Lindert, Geert Janssens, and Corrie Erasmus; Pediatric Oncology and Departments of Pathology, Neurosurgery, Radiotherapy, and Pediatirc Neurology, University Medical Center Nijmegen, Radboud, Nijmegen, The Netherlands

Atypical teroid/rhabdoid tumor (AT/RT) of the central nervous system is a rarely described malignancy, which has been first recognized as a separate entity during the nineteen-eighties. It concerns a very aggressive tumor and survival is usually less than 12 months. Treatment strategies have been resection, irradiation, and different chemotherapy regimens including PNET-like, sarcoma-like, and high-dose regimens with autologeous stem cell rescue. AT/RT is mostly diagnosed in the posterior fossa during infancy. We describe 3 patients with supratentorial localisation and presentation beyond infancy. All 3 were boys, between 5 and 10 years old. All presented with a short history of symptoms of increased intracranial pressure. MRI revealed supratentorial hemispheral tumors. Resection was macroscopically total in two, partial in one. Pathological diagnosis was AT/RT on morphological criteria. There were no metastases detected. We treated all 3 patients after surgery with a sarcoma-like chemotherapy regimen with 9 courses of: ifosfamide, vincristine, dactinomycin, epirubincin, and etoposide plus intraventricular triple therapy and craniospinal irradiation during the 4th and 5th chemotherapy course. Follow-up during treatment showed no progressive disease and in the one patient with residual tumor: response on MRI. Follow-up after treatment revealed local or distant relapse within 3 months in all 3 patients. The first showed a symptomatic, massive, multifocal relapse and died 12 months after diagnosis. The second child developed a symptomatic metastasis in the cervical spinal cord. He was treated with second irradiation and is still alive 24 months after diagnosis. The third child developed an asymptomatic small local relapse. He underwent second irradiation and high-dose chemo followed by autologeous stem cell rescue. He is alive 14 months after diagnosis. In summary AT/RT is recognized more often beyond infancy. A sarcoma-like treatment seems not to be sufficient. Relapse therapy is not by definition unsuccessful.

THER 31. THALIDOMIDE AND CARBOPLATIN FOR THE TREATMENT OF BRAIN STEM GLIOMA

Stewart Goldman, Tadanori Tomita, Maryanne Marymont, John Kalapurakal, SandeepBatra, Theresa Gleason, Monica Newmark, Joanna Weinstien, Anne Bendel, Douglas Hyder, Michael Etzl, Gessina Keating, and Kenneth Cohen; Division of Hematology/Oncology, Children’s Memorial Hospital, Northwestern University Fienberg School of Medicine, Chicago, IL, USA

Brain stem gliomas account for approximately 10% of pediatric CNS tumors. Multiple clinical trials of radiation with standard cytotoxic regimens have failed to increase survival. This protocol incorporates an antiangiogenic agent (thalidomide) with carboplatin and radiation therapy to increase PFS. Materials and Methods: Twenty six patients with pontine glioma age 3.2–19.8 years (Mean/Medain 8.2/7.1 years) were treated on a protocol, which included Thalidomide and Carboplatin. 20 patients were enrolled on study at the time of diagnosis with 6 entered after 1st progression. The newly diagnosed patients received 54–60 Gy, irradiation concurrent with the start of this protocol. 14 females, 12 males (18 Caucasian, 5 Hispanic, 1 Native American, 2 other) have been enrolled. The lesions were intrinsic in 24 with 2 having partially extrinsic tumors. Carboplatin was administered at a dose of 560 mg/m2; thalidomide dosed at 300 mg/m2 escalating to 700 mg/m2 daily. Results: Best response data is available for 22/26 patients. Of the 16 treated at diagnosis 0 CR, 7 PR, 8 SD, and 1 PD. Best response for those treated with progression, 4 SD, 2PD. Four newly diagnosed pts. remain progression free at 59+, 339+, 460+, and 1069+ days. Mean TTP (newly Dx) was 315 days (Median 283 days); 1 and 2 years projected PFS is approximately 30% and 15%, respectively. Of the 6 with recurrent tumor, mean TTP was 118 days. Two patients progressed with disseminated disease with local control. 1 pt. was ineligible, 3 patients were removed from study without PD per family wishes, 3 were off study with toxicity. Toxicities included P.E. (1), Stevens-Johnson syndrome (1), TIA/CVA (1), colitis (1). Rash, constipation, and somnolence was seen in most patients but easily controlled with prophylactic regimens and titration of dose. Conclusion: This outpatient regimen is feasible and generally well tolerated. This regimen compares favorably with historical controls and could be incorporated into future trials.

THER 32. THERAPEUTIC STRATEGY FOR ATYPICAL TERATOID/RHABDOID TUMOR: A REPORT OF TWO CASES AND REVIEW OF THE LITERATURE

Akira Gomi,1 Hisashi Suzuki,1 Takahiro Miyata,1 Eiji Matsumoto,1 Yuiko Koizumi,1 Hiriko Fujii,1 Yuuichi Tanaka,1 and Shinji Sakurai2; Departments of Surgical Neurology1 and Pathology,2 Jichi Medical School, Tochigi, Japan

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a highly malignant neoplasm that primarily affects children less than 5 years of age. Despite aggressive multimodality therapy including surgical resection, chemotherapy, and irradiation, prognosis is dismal. Here we report two young AT/RT patients with extended survival. The first patient was a male, 11 months of age at presentation. The tumor was located in the right cerebellar hemisphere without radiographic metastatic disease. Initial therapy consisted of gross total surgical resection followed by 7 cycles of mild chemotherapy (cisplatin and etoposide). No relapse occurred within 25 months of initial treatment. The second patient was a female, 24 months of age at presentation. The tumor was located in the fourth ventricle without radiographic metastatic disease. Initial therapy consisted of gross total surgical resection followed by 3 cycles of mild chemotherapy (cisplatin and etoposide). Relapse occurred within 3 months of initial treatment. Postrecurrence treatment consisted of surgical resection and extended local irradiation to a dose of 5600 cGy. After 17 months of continued remission, cerebrospinal dissemination occurred. Following extended chemotherapy (cisplatin/etoposide and ifosfamide), the size of the tumor was reduced. It is important to consider the therapeutic strategy best suited to each individual AT/RT patient. For children less than 3 years of age, we hesitate to use radiotherapy because it impairs physical and mental development; therefore, extended surgical resection and chemotherapy should be selected as initial therapies. Some cases of AT/RT may not be sensitive to chemotherapy, and once we have determined that chemotherapy is ineffective, we should not hesitate to induce radiotherapy even if the child is less than 3 years old. Previous reports have indicated that most AT/RT are radiosensitive. In the event of recurrence, we recommend surgical resection and intensive chemotherapy.

THER 33. LOCALIZED MEDULLOBLASTOMAS CAN BE CURED WITHOUT RECOURSE TO CRANIOSPINAL IRRADIATION PROVIDED COMPLETE SURGERY CAN BE CARRIED OUT: FINAL RESULTS OF THE FIRST FRENCH PROSPECTIVE STUDY IN CHILDREN BELOW FIVE YEARS OF AGE (BBSFOP)

Jacques Grill, Christian Sainte-Rose, Anne Jouvet, Fabienne Pichon, Jean-Claude Gentet, Odile Lejars, Didier Frappaz, François Doz, Anne-Isabelle Bertozzi, Pascal Chastagner, Marie-Anne Raquin, Marie-Cécile Le Deley, and Chantal Kalifa, on behalf of the SFOP; Institut Gustave Roussy, Villejuif, France

Young children with medulloblastoma have a dismal prognosis and a high morbidity with standard therapy including craniospinal irradiation (CSI). Current clinical trials are aiming at delaying or avoiding craniospinal irradiation in these children. In this study, patients were treated with a 16-months polychemotherapy named BBSFOP (carboplatin-procarbazine, cisplatin-etoposide, and cyclophosphamide-vincristine) whatever the extent of the disease. Irradiation was not planed in the absence of relapse. In case of local relapse, salvage treatment consisted in single high-dose chemotherapy (HDCT) + stem cell transplantation (SCT) and reoperation followed by posterior fossa radiotherapy (PFRT) (see presentation of Vita Ridola at this meeting). In case of metastatic relapse, various strategies have been experimented over this decade based either on sequential HDCT or CSI. Based on treatment results, three risk groups were identified. Thirteen of 15 patients with metastatic medulloblastoma relapsed; there were only two long-term survivors. Sixteen of the 18 patients with postoperative macroscopic residue relapsed; however, 5-year OS was 50% after salvage treatment. The larger group of 47 patients for whom the study remained open until 2002 were those without metastasis nor radiological postoperative residue. 5-year OS and PFS were 76% and 32%, respectively. Absence of relapse was associated with complete surgical removal as mentioned on the operative report and absence of adherence to the brainstem. 5-year PFS of children with complete resection was 50% vs. 0% in children with subtotal resection (p < 0.01). In conclusion, BBSFOP chemotherapy was not sufficient in children with metastatic or partialy resected medulloblastomas. However, half of the children with completely resected medulloblastoma as described by the neurosurgeon in the operative report could be cured with conventional chemotherapy only. In case of local relapse, salvage treatment with HDCT plus PBSCT followed by PFRT was very efficient. Analysis of the operative report should be incorporated in risk group definition for medulloblastoma.

THER 34. INFANTS WITH EPENDYMOMA: OUTCOME FOLLOWING SURGERY AND BABY BRAIN CHEMOTHERAPY

Dianne Gumley, Kim Phipps, Juliet Reynolds, and Anthony Michalski; Great Ormond Street Hospital for Children, London, UK

We treated 21 children with the Baby Brain Chemotherapy (UKCCSG CNS 9204 study) between April 1993 and February 2002. 14 children are currently alive, 5 of these children have been treated for recurrent Ependymoma. The remaining 9 children have had an event-free survival (range 3 years 7 months–10 years 9 months, mean: 6 years 4 months). All 9 of this group have posterior fossa tumours. Eight of them had CR following surgery, the other child had subtotal removal of tumour, and the other child achieved CR in the post chemotherapy period. We have fully evaluated the 9 children with event-free survival and report on their physical status, emotional well-being, and neuropsychological profile (including memory, executive functioning, literacy, and numeracy skills). The results suggest that this cohort is doing well. These results are important, as they define a treatment strategy that results in a good chance of cure and good long-term functional outcome. A comparison with other strategies that include focal radiotherapy will allow the assessment of the relative contributions of various therapeutic modalities on neuropsychological performance.

THER 35. SPONTANEOUS REGRESSION OF RESIDUAL OR RECURRENT CEREBELLAR PILOCYTIC ASTROCYTOMA IN CHILDREN

Roxanna Gunny, Dawn E. Saunders, Kim P. Phipps, and Richard D. Hayward; Departments of Radiology and Neurosurgery, Great Ormond Street Hospital, London, UK

Cerebellar pilocytic astrocytomas (PCA) of childhood are the second most common tumour of the posterior fossa in childhood and are benign tumours, which are frequently cured by surgery alone or together with adjuvant radiotherapy. Recent reports have demonstrated spontaneous regression of residual PCA which raises the question as to whether children with residual disease should be subjected to radiotherapy and its associated complications. We reviewed our cohort of children with PCA to establish the incidence of spontaneous regression of residual tumour. Imaging studies and clinical data obtained in children with posterior fossa PCA who presented between January 1988 to September 1998 were retrospectively reviewed. 84 children (99%) survived a median follow-up period of 5 years 3 months (mean of 6 years 10 months, range 2 years–13 years 3 months). One child within the cohort died. Fourteen children had an incomplete recurrence and MRI visible residual disease of which 11 underwent surveillance imaging. In these 11 children, spontaneous tumour regression was seen in 5 children at 7, 16, 29, 42, and 66 months (mean 32 months) at which point surveillance imaging was stopped in 2 and continued for a maximum period of 5 years 11 months in the remaining 3. We conclude that the observation of spontaneous tumour resolution in children with residual PCA requires a period of surveillance imaging to establish tumour biological activity before the advent of further surgery or radiotherapy.

THER 36. PHASE II STUDY OF ORAL TEMOZOLOMIDE (TMZ) IN CHILDREN WITH PROGRESSIVE LOW-GRADE GLIOMAS (LGG)

Sri Gururangan, Jeffery C. Allen, Peter C. Phillips, Erih Dillard, and Henry. S. Friedman; The Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA

We are currently conducting a phase II study of TMZ in children with progressive LGG. Eligible patients (pts) received TMZ 200 mg/m2/day by mouth for 5 days every 4 weeks until tumor progression, unacceptable toxicity, or a maximum of 12 cycles of treatment. Dose reduction of 50 mg/m2/day was allowed for platelet nadir of <50, 000/cu.mm, absolute neutrophil count of <1000/cu.mm, or any grade III-IV nonhematologic toxicity during any cycle. Between June 1999 and Dec 2003, 32 pts have been enrolled on study. Median age at study entry is 10 years (range, 4–17). Eighteen of the 32 pts (56%) had optic or hypothalamic LGG. Thirty-one pts have received a median of 9 cycles (range, 2–12) of treatment. Thirty pts have been assessed for response to TMZ. Maximum responses include partial response (PR) in 3 pts (10%), minor response (MR) in 1 (3%), stable disease (SD) in 12 (40%), and progressive disease (PD) in 14 (47%). The over-all disease stabilization rate (PR + MR + SD) is 53%. One pt has died of disease. The one-year progression-free and overall survivals are 51% [95% confidence interval (CI), 39–70] and 96% [95% CI, 89–99], respectively. Worst toxicity related to TMZ include grade II-IV thrombocytopenia in 7 pts, grade II-IV neutropenia in 7, grade II skin rash 1, and intra-tumor hemorrhage in 1. TMZ given in this schedule has been successful in stabilizing disease in a significant proportion of pts with LGG with manageable toxicity.

THER 37. EXTRAOSSEOUS EWINGS SARCOMA (EES) OF THE CENTRAL NERVOUS SYSTEM (CNS)—CASE REPORTS AND MOLECULAR DIAGNOSIS

Sri Gururangan, Julia A. Bridge, Thomas J. Cummings, Edward C. Halperin, and Henry S. Friedman; The Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC, USA

The occurrence of primary EES of the CNS has only been rarely reported in the literature. It is important to distinguish this entity from the more common primitive neuroectodermal tumor (PNET) of brain since the management of these tumors is completely different from that of EES. We present the clinical, radiologic, and pathologic features of two cases of EES occurring in the brain and spinal cord, respectively. The diagnosis was further confirmed in the patient with EES of the brain by molecular analysis using fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) to identify the t(11;22) (q24;q12) chromosomal translocation. The patient with EES of the spinal cord (intradural but extramedullary) initially underwent surgery, chemotherapy, and focal radiotherapy but suffered recurrence in the posterior fossa in the region of the IV ventricle. He subsequently died despite salvage therapy. The other patient with localized EES of the brain underwent initial surgical debulking followed by 6 cycles of chemotherapy (vincristine, cyclophosphamide, and doxorubicin alternating with ifosfamide and etoposide) and focal radiotherapy. She had an almost complete response to chemotherapy and is currently alive without evidence of disease 13 months following diagnosis. Although rare, the possibility of EES should be considered when tumors that arise near the meningeal surface of the brain or spinal cord and have the pathologic appearance of a PNET. Molecular analysis would help to confirm the diagnosis and enable appropriate therapy.

THER 38. UNIQUE OCCURRENCE OF ATYPICAL TERATOID/RHABDOID TUMORS IN THREE SIBLINGS

Christine Haberler, Thomas Ströbel, Gabriele Amann, Irene Slavc, Johannes Andreas Hainfellner, and Herbert Budka; Institute of Neurology, Departments of Clinical Pathology and Pediatrics, University of Vienna, Austria

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant CNS tumors associated with deletion or mutation of the hSNF/INI1 gene. So far the occurrence of familial AT/RT has been reported only once in two siblings. We present clinical, histological, immunohistochemical, and genetic data of AT/RTs in 3 brothers. In the first child a tumor in the skull base invading neck, fronto-basal brain areas and orbit was diagnosed at the age of 3 months. The boy had multiple lung metastases and died at the age of 5 months. One year later, dizygotic twins were born. The first twin had a tumor in the vermis and died 3 days after birth. The second twin displayed at the age of 6 months a tumor in the third ventricle with tumor seeding in neck and spinal cord and died at the age of 7 months. Biopsy and autopsy material of the first child and the second twin showed characteristic morphological and immunohistochemical features of AT/RT. Autopsy material of the first twin showed a primitive small cell tumor without rhabdoid features and with immunohistochemical expression of vimentin. In all three tumors immunohistochemical nuclear expression of the INI gene was absent. PCR analysis of paraffin embedded tissue did not detect LOH on short arm of chromosome 22 or a mutation in the INI gene in any of the tumors. In the first child and the first twin a germline TP53 mutation (CGT273AGT) was found. We conclude that the tumors in all three siblings are AT/RTs. The absence of immunohistochemical expression of INI gene indicates an alteration of the INI gene product. To our knowledge this is the first family presenting with infantile AT/RT associated with a germline TP53 mutation.

THER 39. LACK OF MORBIDITY FOR “SECOND” OPERATIONS IN EPENDYMOMAS

Michael H. Handler, Patti Batchelder, and Nicholas Foreman; Departments of Neurosurgery and Neuro-Oncology, The Children’s Hospital, Denver, CO, USA

Second-look operations after short courses of chemotherapy have been advocated as a way to reduce morbidity while increasing the potential for gross total resection in ependymoma. We have reviewed our series to understand whether second operations, performed after a short waiting period, carry the same risk as the first operations. Over a 6 year period, 9 patients underwent craniotomies for tumors, which proved to be ependymomas without gross total resections. The reasons for failure to achieve gross total resections at initial operation varied, but in most cases involved a judgment that unacceptable morbidity would have resulted from proceeding. In all cases the attention was to do a second surgery usually after a short course of chemotherapy (Carboplatin/VP16). Eight patients underwent the second operation, all within three months of the initial procedure. The length of hospital stay after the initial procedure was a median of 15.5 days vs. a median of 5 days after the second operation. After the first procedure, three patients developed cerebellar mutism, two developed hydrocephalus, two developed cranial nerve deficits transiently, and one transient lower extremity weakness. There were substantially fewer complications after the second procedure: none developed cerebellar mutism, none developed hydrocephalus, and three developed transient lower cranial nerve weakness related to more extensive dissection of tumor from among lower cranial nerves. We conclude that “second-look” operations have considerably less morbidity than the initial procedures, result in short hospitalizations, and are safe.

THER 40. PILOT STUDY OF REDUCED-DOSE CRANIOSPINAL RADIOTHERAPY FOLLOWED BY HIGH-DOSE CHEMOTHERAPY CONSISTING OF THIOTEPA AND MELPHALAN IN CHILDREN WITH M1/2/3 MEDULLOBLASTOMA

Junichi Hara, on behalf of Japanese Consortium of Pediatric Brain Tumor; Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Osaka, Japan

To avoid late sequelae induced by radiotherapy, reduction of dose of radiotherapy is needed. This pilot study was undertaken to determine the feasibility and efficacy of treating children with M1/2/3 medulloblastoma with reduced-dose craniospinal radiotherapy (18 Gy) plus chemotherapy including high-dose chemotherapy consisting of thiotepa and melphalan with stem cell rescue. Between 2000 and 2002, eight children (M1: 2, M2/3: 6) between 4 and 13 years of age were treated with postoperative craniospinal radiation therapy (18 Gy) and 50 Gy of local radiation therapy to the primary site. Four cycles of chemotherapy consisting of cyclophosphamide, etoposide, cisplatin, and vincristine were administered. After administration of a single course of chemotherapy, peripheral stem cells were collected and radiation therapy was started concomitantly with the second course of chemotherapy. During radiation therapy, administration of etoposide was skipped. After chemotherapy of four cycles, high-dose thiotepa (200 mg/m2) and melphalan (70 mg/m2) were given on day -11, -10, -4, and –3 followed by peripheral stem cell rescue on day 0. Although five patients experienced sepsis during chemotherapy and/or high-dose chemotherapy, there was no severe adverse effect by which chemotherapy or radiotherapy should be postponed or omitted. Grade III stomatitis after high-dose thiotepa and melphalan was the most severe adverse effect. Thus, all eight patients were given four cycles of chemotherapy, high-dose chemotherapy, and radiotherapy according to the plan, and they remain in progression-free survival (14–46 months, median: 20 months). Reduced-dose craniospinal radiotherapy followed by high-dose chemotherapy consisting of thiotepa and melphalan was feasible in children with M1/2/3 medulloblastoma. The early outcome results of this strategy were very encouraging. A nationwide phase II study is in preparation.

THER 41. ANZCCSG BABY B99: SYSTEMIC CHEMOTHERAPY, SECOND-LOOK SURGERY AND INVOLVED FIELD RADIATION FOR CHILDREN LESS THAN FOUR YEARS OF AGE WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMOURS

Timothy Hassall,1 Maree Sexton,2 Jennifer Houlihan,3 Lesley Chow,3 Yvonne Hastings,1 and David Ashley3; Departments of Haematology and Oncology, Royal Children’s Hospital Brisbane, 1 Royal Children’s Hospital Melbourne,3 and Peter MacCallum Cancer Institute Melbourne,2 Australia

Postoperative patients aged less than 4 years with a newly diagnosed malignant CNS tumour are eligible to be enrolled in this study. Courses 1 and 2 consist of Etoposide Phosphate 2 mg/kg/day nasogastric for 21 days and Cisplatin 4 mg/kg intravenously (IV). Course 3 consists of Cyclophosphamide 40 mg/kg IV daily D1-3, Etoposide phosphate 7.5 mg/kg IV, and Vincristine 0.05 mg/kg IV. Course 4 has Cyclophosphamide increased to 70 mg/kg IV daily D1-3, followed by stem cell rescue. Second-look surgery is then considered. Course 5 consists of Carboplatin AUC 12 mg/ml.min and Melphalan 4.6 mg/kg followed by stem cell rescue. Treatment is to be completed with involved field radiation to 54 Gy. Between November 1999 and January 2004, 24 patients (13 males and 11 females, average age 26.6 months) with medulloblastoma (8), ependymoma (4), atypical teratoid/rhabdoid tumour (4), glioblastoma multiforme (4), PNET/embryonal (2), others (2) have been treated on study. Two patients had positive CSF cytology at presentation (no patients with disseminated neuraxis disease on MRI). Postoperative MRI confirmed 6 total resections only. The 13 patients with definite residual disease were evaluated after Course 2: 4 complete responses, 2 partial responses, 5 stable disease, and 2 progressions. Overall, 15 patients have progressed: 7 during treatment and 8 following treatment. Twelve patients have died (median time to death 9 months) with 12 current survivors (median 26.4 months from diagnosis). The courses and the associated toxicities were as follows: Courses 1 and 2 (48): Anaemia grade 3 (5), Thrombocytopenia grades 3 (3) and 4 (1), Neutropenia grades 3 (12) and 4 (7), febrile neutropenia grade 3 (5); Course 3 (21): Anaemia grades 3 (8) and 4 (3), Thrombocytopenia grades 3 (8) and 4 (2), Neutropenia grade 4 (17), Febrile neutropenia grade 3 (11); Course 4 (20): Anaemia grades 3 (12) and 4 (1), Thrombocytopenia grades 3 (10) and 4 (7), Neutropenia grade 4 (15), Febrile neutropenia grade 3 (17), Seizures grade 4 (1); Course 5 (12): Anaemia grade 3 (7), Thrombocytopenia grades 3 (4) and 4 (6), Neutropenia grades 3 (1) and 4 (9), Febrile neutropenia grade 3 (4). Three patients have had second-look surgery (complete resections: 2). Involved field radiation (50.4–60 Gy) has been completed in 7 patients with no significant toxicity noted. In summary, the treatment was well tolerated. Despite the evidence of good early response, there was no overall improvement in the poor early progression-free survival rates seen in similar studies. Novel approaches must therefore be investigated in these patients.

THER 42. COMBINED MODALITY THERAPY IN THE MANAGEMENT OF PEDIATRIC DISSEMINATED PRIMARY ANAPLASTIC EPENDYMOMA OF THE SPINAL CORD

Theodore S. Hong, Diane Puccetti, Kristin A. Bradley, Bermans Iskandar, M. Shahriar Salamat, and Minesh P. Mehta; University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA

Primary anaplastic ependymoma of the spinal cord is a very rare tumor, comprising approximately 3% of primary spinal ependymomas. Subarachnoid spread is an occasional feature of this disease. Because of the rarity of this clinical presentation, management remains undefined. Historically, this has consisted of resection of the dominant lesions and craniospinal irradiation. We reviewed institutional clinical records from 1990 to present. 2 pediatric patients with disseminated anaplastic ependymoma were identified. The first patient is an eighteen-year-old girl who presented with lower back pain. MRI revealed an enhancing lesion at T8-10 with spinal cord deviation and a second mass at the level of L1-4. Gross nodular subarachnoid seeding was noted. The patient underwent subtotal resection of the thoracic mass confirming a diagnosis anaplastic ependymoma. She received craniospinal irradiation delivered 1 Gy BID to a dose of 40 Gy followed by an additional 10 Gy boost to gross disease. She also received chemotherapy with etoposide, cisplatin, cyclophosphamide, vincristine, and carboplatin. She remains fully functional and disease free at 13 years, without adverse neurocognitive deficits. The second patient presented at age 11 with severe low back pain. MRI revealed an enhancing intramedullary mass at L2-3 and diffuse leptomeningeal enhancement of the entire spine and brain. Gross total resection of the dominant spinal mass was performed. He received chemotherapy with cyclophosphamide and vincristine with stem cell collection. He then received craniospinal irradiation delivered 1 Gy BID to a dose of 40 Gy followed by an 8 Gy boost to gross disease with weekly vincristine. He remains clinically, functionally, and radiographically stable at 27 months. Disseminated anaplastic ependymoma of the spinal cord is a rare disease. In spite of the presence of gross disease, long disease-free remission was achieved with chemotherapy and radiation therapy in this limited experience.

THER 43. INTRACYSTIC BLEOMYCIN THERAPY FOR CRANIOPHARYNGIOMA IN CHILDREN: CANADIAN EXPERIENCE

Juliette Hukin, Paul Steinbok, Lucie Lafay-Cousin, Yvan Samson, William Howes, Eric Bouffet, on behalf of the Canadian Pediatric Brain Tumor Consortium (CPBTC); Division of Neurology, Oncology, and Neurosurgery, British Columbia’s Children’s Hospital, Vancouver, Canada

Introduction: Surgical removal and radiation therapy is associated with significant morbidity in the pediatric population with craniopharyngioma. The aim of this study was to review the Canadian experience with a less invasive technique, intracystic bleomycin therapy. Method: All centers in the Canadian Pediatric Brain Tumor Consortium were invited to participate in a retrospective review of this treatment. A standardized data form was sent to each center. The data was analyzed in Vancouver. Results: Four centers have participated to date. Bleomycin was considered at each center from 1995, 2000, 2001. Bleomycin was not recommended at diagnosis in 25 patients, as they were older, the risk of surgical resection was considered low, or the tumor was mainly solid. 15/17 patients with intention to treat, received bleomycin. Two had leakage of contrast on CT, therefore did not receive bleomycin. 10/15 patients had a single cyst. The median size of the largest cyst was 5.8cm (2–8.4). 8/15 had a calcified cyst wall. Eleven were treated at diagnosis, four at progression. Median total dose of bleomycin: 55 mg (15–115 mg). Minor side-effects included: nausea, headache, vomiting. Post bleomycin: vision improved in four; two deteriorated in function due to cyst reaccumulation; one had transient symptomatic peritumoral edema; and one developed morbid obesity and precocious puberty in spite of cyst shrinkage. Five patients had a complete response, three a partial response, five a minor response, and two did not respond to bleomycin. Nine progressed; eight received additional treatment. Median progression-free survival was 8 months (4–60), overall survival 6–108 months. One patient died of a massive infarct secondary to radiation induced moyamoya. Conclusion: Intracystic bleomycin is well tolerated in children. Bleomycin may at least delay the need for aggressive surgery or radiation therapy. Bleomycin is a useful option in the treatment of cystic craniopharyngioma in children.

THER 44. SKULL BASE PRIMITIVE NEUROECTODERMAL TUMOR IN INFANT: A CASE REPORT AND REVIEW OF LITERATURE

Takayuki Inagaki, Takahide Nakano, Takumi Imahori, Yasuo Yamaonouchi, and Keiji Kawamoto; Departments of Neurosurgery and Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan

We reported a case of a primitive neuroectodermal tumor (PNET) involving the frontal and temporal skull base in a 12-month-old female infant. She presented with vomiting which lasted approximately one month and progressing exophthalmos on the right side. Preoperative magnetic resonance imaging revealed an enhanced mass which extended from the right orbit to the left middle fossa. The tumor biopsy was performed. Pathological findings were consistent with a primitive neuroectodermal tumor. We treated her with high-dose chemotherapy consisting of vincristine, dactinomycin, etoposide, pirarubicin, and ifosfamide with peripheral blood stem cell transplant. She is free from disease after chemotherapy for approximately two years. Because skull base PNET in infant is rare, we presented a case and reviewed the literatures.

THER 45. A PHASE I TRIAL OF TEMOZOLOMIDE AND CCNU IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED INCOMPLETELY RESECTED NONBRAINSTEM HIGH-GRADE GLIOMAS (HGG): A CHILDREN’S ONCOLOGY GROUP STUDY

Regina Jakacki, Michael Prados, Allan Yates, Robert Timmerman, Mark Krailo, Wenchun Qu, Peter Adamson, and Ian Pollack; Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

Background: The nitrosoureas and temozolomide are among the most commonly used agents for patients with high-grade gliomas but have not been studied as a combination in pediatrics. Methods: Newly diagnosed patients with measurable residual disease were eligible. Two courses of CCNU/temozolomide were given 4 weeks apart prior to radiation therapy. Up to six additional courses were administered after radiation therapy. All patients received 90 mg/m2 of CCNU on day 1 and temozolomide days 1–5 (starting dose 100 mg/m2/d) using a standard Phase I design. Results: Thirty-two patients (age 4–21 years, median 12 years) were enrolled between May 2001 and March 2003, and 28 were evaluable for toxicity. Grade 4 neutropenia and thrombocytopenia were seen at the 200 mg/m2/d dose level, and a temozolomide dose of 160 mg/m2 with 90 mg/m2 of CCNU was determined to be the MTD. One of 15 patients accrued to the MTD experienced a DLT (thrombocytopenia). Twenty-six patients were evaluable for response. Diagnoses included glioblastoma (GBM) (n = 14), anaplastic astrocytoma (n = 11), and other (n = 1). Twelve patients had thalamic or bithalamic primaries. Following the first two courses, there was one complete response (CR), two partial responses (PR), three minor/objective responses, one mixed response (PR at the primary site with concomitant development of metastases), and 11 patients had stable disease. Five patients with GBM progressed during the first course of therapy, while three patients had progressive disease after two courses. Of note, 9 patients developed metastatic disease within several months of diagnosis, including 6 of 12 patients with thalamic or bithalamic primaries. One year overall survival was 62.6% (95% CI 40, 79%). Conclusions: The combination of 90 mg/m2 CCNU and 160 mg/m2/day x 5 days of temozolomide is feasible with encouraging results in this poor-prognosis group of patients. Patients with thalamic primaries may be at increased risk for metastases.

THER 46. ATYPICAL TERATOID RHABDOID TUMORS (AT/RT) OF THE CENTRAL NERVOUS SYSTEM (CNS): SURVIAL AND TREATMENT RESPONSE IN 35 PATIENTS DIAGNOSED AT CHILDREN’S HOSPITAL OF PHILADELPHIA

Anna J. Janss, Changhu Chen, Huikuo Shu, Michael Fisher, Jean Belasco, Lucy B. Rorke, Jaclyn Biegel, and Peter C. Phillips; Children’s Hospital of Philadelphia, Philadelphia, PA, USA

AT/RT of the CNS, described first by Rorke et. al.1 represent a highly malignant embryonal tumor of infants and young adults. While initial reports suggested this is a terminal diagnosis, Olson et. al.2 found that using sarcoma-like therapy (IRS-III) there were treatment responses and survivors. Between 1/1985 and 7/2003 thirty-five children were diagnosed with CNS AT/RT at CHOP. This report is a retrospective review of their treatment and outcome. Methods: Charts, radiology reports, and neuro-images of 35 children with CNS AT/RT diagnosed at CHOP were reviewed for details of staging, treatment, response, and outcome. Children were grouped according to treatment: supportive care alone (1), IRS-III like therapy (2) as described by Olson et al.2, or chemotherapy and/or radiation therapy per other protocols (3). Results: Demographic and Survival Data of 35 patients with AT/RT:

Treatment Group1. Palliation2. IRS-III3. Other
Number91214
Male/Female6/38/69/5
Age in months
Median (range)5.7 (0.2–9)47.5 (6–156)16.5 (3–78)
Surgery (GTR/<GTR)3/67/56/8
Stage
M0/M > 0/ND4/4/17/59/4/1
Survival in months
 Median (range)2.7 (3d–5mo)37.5 (12–67)8.5 (1–29)
Children still alive071
Follow-up in survivors
 Median (range)44 mo (4–78)11mo

M0 = negative spine MRI or myelogram, and negative CSF cytology

M>1 = positive spine imaging or CSF cytology

ND = not done

Although tumor volume and enhancement decreased in groups 2 and 3 following induction chemotherapy, 2-year overall survival was significantly greater in the IRS-III group. (0, 50, and 14%; p < 0.05). Conclusion: These retrospective data demonstrate efficacy of sarcoma therapy (IRS-III) for CNS AT/RT and support the ongoing prospective trial for children with newly diagnosed CNS AT/RT using similar chemotherapy and radiation. References: 1. J. Neurosurgery (1996) 85:56–65; 2. Am. J. Pediatr. Hemaltol. Oncol. (1995) 17:71–75.

THER 47. HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD STEM CELL TRANSPLANTATION IN PATIENTS WITH PEDIATRIC MALIGNANT BRAIN TUMORS

Kyozo Kato, Suguru Inao, Hiroshi Ikeda, Toshihisa Nishizawa, Shigeyuki Hayashi, Takehiro Naito, Takaharu Matsuyama,1 and Koji Kato1; Department of Neurosurgery, *Department of Pediatrics, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

Objective: Despite considerable advances in the treatment of children with malignant brain tumors, patients with medulloblastoma who suffer recurrences are rarely cured. On the contrary, efficacy of high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) for pediatric malignant tumor, especially in leukemia and neuroblastoma, has been reported. We have undertaken trials of high-dose chemotherapy with PBSCT in patients with high-risk pediatric malignant brain tumors since 2001. Material and Method: Four children with medulloblastoma and one with york sac tumor were treated with high-dose chemotherapy with PBSCT. Three patients with medulloblastoma were recurrent cases. The case with yolk sac tumor suffered from dissemination. Three patients received combination of TEPA and L-PAME and two received Topotecan, TEPA and CBDCA. Results: The toxicity of this chemotherapy was tolerable. All four patients of medulloblastoma are still alive at least 2 years after this therapy. Three patients have achieved complete remission and the other patient has achieved partial response. One patient of yolk sac tumor died 13 months after treatment. Conclusion: Despite a limited number of patients, it appears that high-dose chemotherapy with PBSCT may be effective in improving survival for even recurrent cases of medulloblastoma. Key Word: high dose chemotherapy, PBSCT, malignant pediatric brain tumor.

THER 48. EFFECT OF NEO-ADJUVANT CHEMOTHERAPY ON LONG-TERM HEALTH STATE AND BEHAVIOUR IN THE PNET3 RCT OF TREATMENT FOR PRIMITIVE NEURO-ECTODERMAL TUMOUR (PNET)

Colin Kennedy and Kim Bull, on behalf of the United Kingdom Children’s Cancer Study Group; Department of Child Health, University of Southampton, Southampton General Hospital, UK

The addition of chemotherapy to craniospinal irradiation (CSI) for treatment of PNET is currently considered ‘the standard of care’ to improve both rate and quality of survival (QoS), but its effect on QoS has not been systematically assessed. We assessed QoS in UK children previously enrolled in the SIOP PNET3 RCT of CSI (35 Gy plus 20 Gy boost to posterior fossa) vs. CSI plus neo-adjuvant chemotherapy (Vincristine, Carboplatin, Etoposide, and Cyclophosphamide) using a cross-sectional multi-informant questionnaire design. Total scores on the two core measures, the Health Utilities Index mark 3 (HUI3) and the Strengths and Difficulties Questionnaire (SDQ), were compared between the two treatment arms using the Mann-Whitney U test. Information was obtained from patients, parents, and health professionals on 103/169 (61%) of survivors at a mean (SD) of 15.4 (4.0) years of age and 7.0 (2.25) years from diagnosis. Median {interquartile range} HUI scores and mean (SD) SDQ total difficulties scores were:

HUI3SDQ
RespondentParentSelf*ParentSelf**
n44 vs. 5538 vs. 4433 vs. 4327 vs. 35
CSI0.71 {0.52}0.92 {0.37}11.4 (5.21)10.6 (4.59)
CSI + Chemo0.72 {0.48}0.65 {0.45}13.7 (5.90)11.4 (5.90)
*aged over 11 years;
***aged 11–17 years

Self-complete HUI3 scores were lower (Z = −2.263, p = 0.024, two-tailed) and parent-complete SDQ scores tended to be higher (Z = −1.559, p = 0.119, two-tailed) in the ‘CSI plus chemotherapy’ group. Parent-/child-complete SDQ scores were abnormally high in 14.0/2.9% and 33.3/7.4% of children in the ‘CSI’ and the ‘CSI plus chemotherapy’ arms, respectively. Patients in the two treatment arms will also be compared with respect to subscale scores on these measures, responses to quality of life questionnaires, and information from health professionals. These findings suggest that differences between self- and proxy-assessment are important and that the addition of chemotherapy to ‘standard dose’ CSI may adversely affect health status and behaviour. The effect on these measures of reducing the dose of CSI and simultaneously adding chemotherapy requires further investigation.

THER 49. PURE GERMINOMA IN PINEAL REGION AND BRAIN PARENCHYMA AROUND LATERAL VENTRICLES (IN AND OUTSIDE LATERAL VENTRICLES): A REPORT OF TWO CASES

Tomoyuki Koga, Takeshi Ogura, Kazuhiko Mishima, Ryo Nishikawa, and Masao Matsutani; Department of Neurosurgery, Saitama Medical School, Irumagun, Saitama, Japan

Pure germinoma affecting both pineal region and bilateral frontal lobes is rare. Review of literature found no such case. We report two cases of young males with pure germinoma, in whom the lesion was observed in pineal region and frontal lobe parenchyma surrounding lateral ventricles. Frontal parenchyma tumors in these two cases were protruded from ventricular wall and were pathologically diagnosed as pure germinoma by surgical specimens. Chemotherapy and radiation therapy were performed on these patients, and complete or partial remission has been achieved. Case 1 was 17-year-old male presenting polydypsia, polyuria, and epilepsy attack. MRI revealed enhanced mass lesion in pineal region, pituitary stalk, and white matter beneath the wall of lateral ventricles. The lesion in the left frontal lobe contained cystic component. Obstructive hydrocephalus caused by the pineal mass could also be seen. Hydrocephalus was improved by endoscopic third ventiriculostomy performed simultaneously with open biopsy of the left frontal lesion. The lesion was diagnosed as pure germinoma, and complete remission was obtained by performing chemotherapy (carboplatin and etoposide) and limited field irradiation to a dose of 24 Gy. Case 2 was 15-year-old male presenting headache and vomiting. MRI showed enhanced lesion in pineal region and bilateral frontal lobe without enlargement of ventricular system. Lesions in the frontal lobes contained cysts as seen in the previous case. Open biopsy of the left frontal lesion was done, and this case was also diagnosed as pure germinoma. Chemotherapy and irradiation yielded partial remission in this case.

THER 50. CENTRAL NERVOUS SYSTEM ATYPICAL TERATOID/RHABDOID TUMOR MOLECULAR DIAGNOSIS AND RESPONSES TO CHEMOTHERAPY

U. Kordes,1 K. Michael,1 K. Ittner,1 T. Kammler,2 M. Westphal,2 C. Hagel,3 R. Siebert,4 and R. Schneppenheim1l; Pediatric Hematology Oncology,1 Neurosurgery,2 and Neuropathology,3 University Hospital Hamburg, Germany; Human Genetics, University Kiel,4 Kiel, Germany

We report tumor responses in four patients with central nervous system ATRT treated on a baby-brain tumor/sarcoma protocol hybrid. No patient was irradiated. One Chemotherapy cycle consisted of Carboplatin 3 x 200 mg/sqm d1–3, VP16 3 x 150 mg/sqm d1–3; VCR 1 x 1.5 mg/sqm d21, ADR 2 x 40 mg/sqm d21–22, IFO 2 x 3 gm/sqm d21–22; VCR 1 x 1.5 mg/sqm d42, Acto-D 1 x 1.5 mg/sqm d42, IFO 2 x 3 gm/sqm d42–43; triple i.th. therapy was given on d1, 21, 42. Pt 1 (post.fossa T2M0) CCR x 48 months. He had a GTR at age 13 months followed by 2.5 cycles of the above therapy, then by 3 cycles of low-dose oral Trofosfamide/VP16 x 21 d. DOD with menigeal dissemination 54 months after diagnosis. Pt 2 (post.fossa T3M3, constitutional heterozygous SNF5 mutation) SD x 8 months. She had a STR at age 6 months followed by 3 cycles. DOD 15 months after diagnosis. Pt 3 (renal T2 and post.fossa T4M2: biallelic loss of SNF5, constitut. heteroz del) PR x 4 months. He had a complete tumor-nephrectomy at age 1 month, followed by 6 weeks of ACT-D and VCR, then presented with a metastatic post fossa tumor, and diagnosis was revised. He had a very good PR after 1 cycle, but progressed after cycle 2. DOD 6 months after diagnosis. Pt 4 (supratentorial) SD x 3 months. She had a STR at age 10 months followed by 1 cycle. She then progressed, with an unsuccessful attempt at salvage with Irinotecan. DOD 7 months after diagnosis. In single cases prolonged tumor control in central nervous system ATRT is possible with conventional combination therapy such as the above protocol, even without radiation. Myelotoxicity reached grade 2–3, infectious toxicity grade 3. SNF5 gene analysis was helpful in diagnosing ATRT in histologically equivocal cases. By using FISH with two probes flanking the SNF5 locus as well as PCR of all 9 exons on available tumor specimen and PBL, both large chromosomal losses as well as small mutation were found. Identifying constitutional SNF5 mutation is of prognostic importance.

THER 51. TEMOZOLOMIDE AND ORAL VP-16 FOR CHILDREN AND YOUNG ADULTS WITH RECURRENT OR SECONDARY MALIGNANT BRAIN TUMORS

David N. Korones, Amy A. Smith, Eric Bouffet, and Nicholas Foreman; University of Rochester Medical Center, Rochester, NY, USA

Children and young adults with recurrent or secondary malignant brain tumors have limited and/or short-lived responses to temozolomide or oral VP-16 when either is administered as a single agent. A combination of these two agents was administered to 11 children and young adults with recurrent brain tumors in hopes of achieving better responses. The eleven patients were treated at Golisano Children’s Hospital in Rochester, NY, The Children’s Hospital in Denver, CO, and Hospital for Sick Children in Toronto, Canada with varying combinations of temozolomide (150–210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4 to 12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record. The median age of the 11 patients was 10 years (range 5–23 years). Their diagnoses included 6 glioblastoma (including 3 that were second malignancies following an initial diagnosis of medulloblastoma, 1 following ALL, and 1 a malignant transformation of an oligoastrocytoma), 2 brainstem glioma, 2 anaplastic astrocytoma, and one medulloblastoma. All 11 patients had received radiotherapy (including 5 who received craniospinal radiation), and 8 had had prior chemotherapy. Eight patients were treated at first recurrence, two at second recurrence, and one at sixth recurrence. One patient had a complete response, 7 had a partial response, and 3 had progressive disease. The median progression-free survival was 8 months (range 1– 15+months), and the duration of responses was 4, 4, 5, 5+, 6, 8, 10+, and 15+months. Other than one patient with grade 3 thrombocytopenia, there were no grade 3 or 4 hematologic or other toxicities. These data suggest there is activity of the combination of temozolomide and oral VP-16 for children and young adults with recurrent malignant brain tumors, and that the combination is well-tolerated, even in heavily-treated patients.

THER 52. INFANT MEDULLOBLASTOMA: REVIEW OF AN INSTITUTONAL EXPERIENCE

Lucie Lafay-Cousin, Eric Bouffet, Donald Mabbott, Ugonwa Dag-Ellams, Darren Hargrave, Douglas Hyder, and Annie Huang; Pediatric Brain Tumor Program, Hospital for Sick Children, Toronto, ON, Canada

Infant medulloblastoma are thought to be biologically distinct and have poorer prognosis than medulloblastoma in older children. In order to assess for potential prognosticators in this age group, we conducted a retrospective review of 33 children diagnosed with medulloblastoma ≤36 months, over an 18-year period in our institution. Median age at diagnosis was 1.8 years; 55% had metastatic disease at diagnosis. 28/33 children received adjuvant therapy after surgical resection with intent to cure. 21/28 patients received chemotherapy as part of their initial treatment, with the aim of deferring or eliminating radiation. 76% (16/21) of these patients had disease progression at a median of 9.9 months from diagnosis; only 33% (2/6) were salvaged with radiation therapy. 3/21 patients achieved prolonged remission with chemotherapy alone. Chemotherapy with early radiotherapy were given to 7/21 patients. 71% (5/7) were alive at a median follow-up of 116 months. Overall survival for all treated infants was 35%, with projected 5 year EFS and OS of 23.4% and 23.7%, respectively. Outcome did not correlate with metastatic status while extent of surgical resection was correlated with better outcome in patients without metastases at diagnosis (p = 0.043). Of the 10 survivors, 50% (5/10) had received early radiation, 20% (2/10) had radiation salvage, while 30% (3/10) were cured with chemotherapy alone. Neurocognitive assessment with median 2.9 years follow-up was available for 6/10 survivors. 2 patients who received craniospinal irradiation (CSI) had IQ scores 2SD below normative mean. In contrast, 4 patients, 2 treated with chemotherapy alone and 2 with reduced CSI/focal posterior fossa radiation, had IQ scores within the average range. In summary, infant medulloblastoma are curable with radiation but with substantial neurocognitive sequelae. Significantly, some infant medulloblastoma are curable without radiotherapy. Future biologic studies of homogenously treated infants should lend valuable insights into this unique subgroup.

THER 53. CHEMOTHERAPY FOR CHILDREN WITH HYPOTHALAMIC OPTIC PATHWAY GLIOMA (HOPG) AND DIENCEPHALIC CACHEXIA (DC): A SFOP PROSPECTIVE STUDY

Véronique Laithier, Marie-Anne Raquin, François Doz, Eric Sariban, Dominique Plantaz, Hervé Rubie, Dominique Couanet, Arielle Lellouch-Tubiana, Jacques Grill, and Chantal Kalifa, for the Société Française d’Oncologie Pédiatrique; Hemato-Oncology Unit, University Hospital of Besançon, France

Objective : To evaluate the efficacy of the “BB SFOP” regimen in infants with HOPG and DC. Methods: Between 1990 and 2003, children with HOPG and DC received a combination of carboplatin, procarbazine, etoposide, cisplatinum, cyclophosphamide, and vincristine over a 16-month period. Results: 18 patients (10 males and 8 females), from 3 to 25 months of age (median: 9 months) entered the study; 1 pt had a NF1. In 3 cases, l eptomeningeal dissemination was present at diagnosis. All had failure to thrive as their presenting symptom. 9 pts had biopsy or partial resection; histology was pilocytic astrocytoma in 5, fibrillary astrocytoma in 2, low-grade astrocytoma NOS in 2. 9/18 pts completed BBSFOP chemotherapy. The radiographical best response was: GPR in 1, PR in 2, OR in 3, SD in 6, and PD in 6 pts. A weight gain was observed under chemotherapy in 11. Disease progression occurred in 17/18 patients within a median time of 14 months [2–86]. One patient without progression is still undergoing BBSFOP chemotherapy. Second-line chemotherapy was the vincristine-carboplatin regimen. 9/18 pts have received irradiation. The need for radiation was delayed for a median time of 33 months [21–114]. 14/18 pts are alive with a median follow-up of 88 months [8–154]. 4 pts died, of progressive disease in 2 (3 months, 8 months), sepsis in 1 (4 months), and seizures in 1 (86 months). Conclusions: These patients with HOPG and DC have a worse response to chemotherapy compared to patients with HOPG and without DC. The objective response rate to chemotherapy was 17% in these patients compared to 42% in the whole population of children with progressive HOPG. Nevertheless, chemotherapy is an effective treatment for children with HOPG and DC in terms of weight gain and in deferring irradiation.

THER 54. FAILURE PATTERNS AND LONG-TERM OUTCOME IN PEDIATRIC PATIENTS TREATED FOR CRANIOPHARYNGIOMA

Lilie Lin, David Mansur, Jeffrey Leonard, Mary Ann Lockett, and Jeff Michalski; Departments of Radiation Oncology and Neurosurgery, Washington University in St. Louis and St. Louis Children’s Hospital, St. Louis, MO, USA

Purpose: The aim of our study was to assess the long-term results and failure patterns of pediatric patients treated with surgery and/or radiotherapy for craniopharyngioma. Methods: We reviewed the records of 31 patients treated at our institution between 1970 and 2002 for craniopharyngioma. Median age at diagnosis was 8.1 year (range 1.1–21 years). Fourteen patients underwent gross total resection with observation, and 6 patients underwent limited resection with observation. Ten patients had a limited resection followed by external beam radiotherapy (EBRT), and one patient underwent cyst aspiration followed by P32 intracystic instillation. Mean dose of EBRT delivered was 4600 cGy (range 3932–5400 cGy). Median follow-up for all living patients was 5.5 years (range 0.8–25 years). Overall (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. Results: OS and RFS at 8 years was 96% and 54%, respectively. One patient died of disease. Twelve patients had a subsequent recurrence. Of those patients, 6 had initial limited resection with observation, and 6 had gross total resection (GTR) with observation. Mean time to recurrence was 18.5 months for patients who underwent limited resection, and 68.7 months for patients who underwent GTR. At the time of recurrence, 3/12 patients underwent limited resection and observation, 3/12 patients underwent limited resection and EBRT, and 6/12 patients underwent EBRT without resection. The three patients who had surgery followed by observation had a second recurrence. No patient who underwent radiotherapy at initial diagnosis had a subsequent recurrence. 8-years RFS for the 11 patients who received initial RT was 100%. 8-years RFS for the 20 patients who did not receive initial RT was 28%. Conclusion: Overall survival for pediatric patients with craniopharyngioma is excellent. Radiotherapy continues to play a key role in the management of craniopharyngioma both following subtotal resection and at the time of recurrence.

THER 55. TEMOZOLOMIDE (TMZ) AND RADIATION (XRT) FOR AGGRESSIVE PEDIATRIC MALIGNANCIES

Kenneth C. Loh, Jennifer Willert, Hal Meltzer, William Roberts, Bryce Kerlin, Richard Kadota, Michael Levy, Amy Geddis, Deborah Schiff, Laura Martin, Alice Yu, Faith Kung, and Matthew A. Spear; Radiation Oncology, University of California at San Diego Cancer Center, San Diego, CA, USA

TMZ combined with XRT has gained widespread use in CNS tumors secondary to low toxicity, good CSF penetration, and possible synergy. Prior reports have focused on adult patients. Thus, the outcomes of several uncommon and therapeutically challenging pediatric diagnoses treated with regimens combining TMZ and XRT are presented. Toxicity, survival, and response rate (CR, PR, SD, PD) were determined by chart review. Diagnoses were pathologically confirmed. Patient 1 (P1) (9 year) had pilocytic astrocytoma (PA) exhibiting rapid local recurrences in spite of multiple resections. P2 (6 year) presented with PA having both rapid local regrowth and CSF dissemination. P3 (15 year) had glioblastoma. P4 (2 year) presented with rapidly progressing recurrence and CSF dissemination of medulloblastoma. Patients with focal disease were treated with concomitant TMZ (daily 75 mg/m2) and 3D-conformal XRT (54–60 Gy) followed by TMZ (200 mg/m2 5 days/month). Those with disseminated disease were also treated with craniospinal XRT (39.6 Gy) prior to conformal boost, followed by TMZ (200 mg/m2 5 days/month). P4 was further treated with TMZ (90 mg/m2) concomitant to XRT. P1 had grade 3 lymphopenia during treatment, initially demonstrated a PR with marked improvement of neurologic deficits, but died at 0.5 years from CSF dissemination. P2 suffered grade 3 neutropenia, thrombocytopenia, and lymphopenia, but is alive with an ECOG PS of 1 at 1.8 years post-diagnosis with a PR at all sites. P3 had increased neurologic symptomology during XRT, initially with SD, but died at 0.8 years from PD. P4 exhibited grade 1 lymphopenia with a PR, then died at 0.5 years from PD. No XRT related dermatologic toxicity beyond the expected was seen. TMZ combined with XRT is well tolerated in aggressive pediatric malignancies, even when full dose craniospinal radiation is utilized. Patient numbers are small, but outcomes appear to be at least as good as expected with frequent PR.

THER 56. SALVAGE TREATMENT FOR EPENDYMOMA (EPD) AFTER SURGERY ONLY: PITFALLS OF OMITTING “AT ONCE” ADJUVANT TREATMENT

Maura Massimino, Lorenza Gandola, Felice Giangaspero, Alessandro Sandri, Giorgio Perilongo, Maria Luisa Garrè, Umberto Ricardi, Lorenzo Genitori, Giovanni Scarzello, Filippo Spreafico, Salvina Barra, Maurizio Mascarin, Armando Cama, Paola Collini, Giuseppe M. Milano, and Enrico Madon, for the AIEOP Pediatric Neuro-Oncology Group; Pediatric Oncology Unit, Istituto Nazionale Tumori, Milano, Italy

From 1993 to 2002, while 63 children were electively treated with the Italian postsurgical protocol for EPD (hyperfractionated radiotherapy –HFRT VCR/CTX/VP16), 12 other patients were referred for adjuvant treatment after 2 (n = 10) or 3 (n = 2) excisions of the tumor whose treatment had been considered surgery only by the referral neurosurgeon. Mean time to local progression had been 14 months; mean age at diagnosis 5 years. Tumor originated in posterior fossa (PF) in 8 children and was supratentorial (ST) in the other 4; 9 tumors had been completely excised at both surgical report and radiological evaluation; 3 had macroscopic residues. Histological diagnosis was classic EPD in 10 pts and anaplastic in 2. Seven children were referred NED and 5 ED after second or further surgery, 4 had low cranial nerves palsy (1 requiring tracheostomy), 1 recurrent surgery-related meningitis, and 1 persistent hydrocephalus. All children were treated with RT to tumor bed (6 HFRT: 70.4 Gy, 6 standard RT: 54 Gy) and 5 also with preRT CT. Four of 12 pts (4/8 with PF tumors) had a further relapse at a mean of 6 months after last surgery; all have died, thus obtaining a PFS of 63% and a OS of 71% at a mean follow-up of 3 years after referral. Considering only pts with PF tumors, PFS and OS were 45% and 57%, respectively. Pts with relapsing EPD after surgery only, especially if originating in PF, have a more severe prognosis despite surgery completeness and nonanaplastic subtype than pts receiving adjuvant treatment after first diagnosis (PF tumors 3-years OS: 57% vs. 80% p = 0.07); moreover subsequent surgical acts for tumor re-growth are followed by severe neurological sequelae.

THER 57. HIGH-DOSE CHEMOTHERAPY IS NOT ENOUGH TO CURE SUPRATENTORIAL PNET(S-PNET)

Maura Massimino, Lorenza Gandola, Filippo Spreafico, Roberto Luksch, Paola Collini, Fabio Bozzi, Graziella Cefalo, Marta Podda, Michela Casanova, Emanulee Pignoli, Andrea Ferrari, Monica Terenziani, Daniela Polastri, Davide Scaramuzza, Fernando Ravagnani, and Franca Fossati-Bellani; Pediatric Oncology, Radiotherapy, Transfusional Unit, and Pathology Department, Istituto Nazionale Tumori, Milano

S-PNET have notoriously a worse prognosis with respect to medulloblastoma: they tend to locally relapse and spread in CNS. From 1997 to 2003, we enrolled 12/15 consecutive pts (3 excluded because [neither less-than nor equal to]⃥3 years of age at diagnosis) into the adjuvant treatment in use for metastatic medulloblastoma, adopting preRT CT with VCR+ hdMTX, hdVP16, hdEDX, hdCB-DCA followed by HART (31.2-39 Gy CSI, focal dose 60 Gy) hdthiotepa. Median age was 9 years, M/F ratio 1. Site of disease was pineal in 2 (1 ED/1 NED) and nonpineal in 10 (6 ED with M+ in 2 cases, 4 NED). Of the 7 ED pts, 2 showed objective response after CT (1 CR, 1 PR), 4 had SD, and 1 PD; of the 6 ED before RT, 1 had CR, 3 PR, 2 MR with clinical improvement. Due to rapid progression after RT of the first 3/5 treated pts, Hdthiotepa was systematically adopted after HART in 7/12. Five of 12 pts relapsed (5 locally, plus dissemination in 2, and only dissemination in 1) at a mean interval of 6.5 months from CT start, and two had second tumors (acute myeloid leukemia at 23 months and glioblastoma at 34 months after CT beginning); the 5 relapsers died at median of 13 months. Three year-PFS, EFS, and OS were 51%, 26%, and 51%, respectively at a mean follow-up of 32 months. Radiotherapy needs to be anticipated in those patients without satisfying early response to CT. The introduction of the myeloablative phase was not enough to improve prognosis (3/7 vs. 3/5 relapses), and outcome remained grim despite the adoption of the same intensive treatment that has allowed to ameliorate the prognosis of metastatic medulloblastoma (MPO 2002; 39:248, O115).

THER 58. MULTI-INSTITUTIONAL COOPERATIVE CLINICAL STUDY FOR INTRACRANIAL GERM CELL TUMORS IN JAPAN

Masao Matsutani; Japanese Pediatric Brain Tumor Study Group, Department of Neurosurgery, Saitama Medical School, Japan

We induced a new treatment protocol appropriate for histological subgroups. After histological verification by surgery, two kinds of chemotherapy (3 courses) were delivered prior to irradiation. They were carboplatin-etoposide combination (CARE) and IFOS-cisplatin-etoposide combination (ICE). (1) Patients with germinoma were treated by CARE (carboplatin 450 mg/sqm in day 1, etoposide 150 mg/sqm in days 1–3) followed by local irradiation (24 Gy). (2) Patients with moderately malignant tumors were treated by CARE followed by local irradiation (50 Gy). They received additional chemotherapy for 5 times. (3) Patients with highly malignant tumors were treated by ICE (IFOS 900 mg/sqm, cisplatin 20 mg/sqm, and etoposide 60 mg/sqm in days 1–5) followed by whole neuroaxis irradiation. They received additional chemotherapy for 5 times. Large or multiple tumors with germinoma or moderately malignant tumors were treated by ICE instead of CARE. Results: Two hundred twenty-four cases were evaluated without serious complications. In germinoma (n = 130), a 5-year overall survival rate and disease-free survival rate were 97.8% and 90.8%, respectively. Seventy-eight patients treated by generous local field irradiation showed a better local control rate of 97.4%. In moderately malignant group (n = 71), 8 recurrences with 2 death were noted with a median follow-up of 4.9 years. The 3-year survival rate of highly malignant group (n = 23) was 65.5%. These results in moderately and highly malignant groups are better than those by postoperative radiation therapy alone.

THER 59. ATYPICAL TERATOID/RHABDOID TUMORS: RESISTANCE TO MULTIPLE CHEMOTHERAPEUTIC AGENTS

Michael J. McManus, Diane M. Puccetti, and Monica A. Koehn; Pediatric Oncology and Neurology, Marshfield Clinic, Marshfield, WI, USA

Atypical teratoid/rhabdoid tumor of the central nervous system is an aggressive pediatric brain tumor that is generally resistant to chemotherapy. Two different approaches to the chemotherapeutic treatment of this tumor have been advocated. One approach is to use sarcoma-directed treatment including vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. A second approach is to use medulloblastoma-directed treatment including cisplatin with the addition of methotrexate. We report three cases of rhabdoid tumor that did not respond to these chemotherapeutic approaches. Two of the patients were 17-month-old girls, both treated with vincristine-doxorubicine-cyclophosphamide-ifosfamide and etoposide. One of these children had a gross total resection of a 7 x 7 cm right cerebral, contrast-enhancing mass with cystic elements. She had localized, progressive disease within 2 months of starting chemotherapy. The second child presented with a lumbar dural sac tumor that encompassed nerve roots and could only be partially resected. Within 2 months she had local recurrence and leptomeningeal spread of tumor onto the cervical cord, the brain stem, cerebellum, and inferior frontal lobes. A third patient was an 18-year-old girl who underwent a gross total resection of a 4 x 5 cm right temporal lobe, contrast-enhancing mass with cystic components. This patient was treated with vincristine, methotrexate, etoposide, cisplatin, and cyclophosphamide, but had localized and disseminated relapse within 3 months. The tumors in all three patients had widespread, rhabdoid histologic features. Upfront radiation therapy was not used in these three patients but may need to be considered in future treatment protocols. Considering the very young age of most patients with rhabdoid tumors, the use of radiation would be problematic. Novel chemotherapeutic agents are needed to treat this aggressive pediatric central nervous system tumor that can present in a brain or spinal location in infants, children, and young adults.

THER 60. RELAPSED EPENDYMOMA IN CHILDREN: A UKCCSG STUDY

Boo Messahel,1 Kath Robinson,2 Claire Weston,2 Kim Phipps,3 Darren Hargrave,1 Frank Saran,1 Sue Picton,4 Ross Pinkerton,1 and Richard Grundy5; 1. Department of Paediatric Oncology, Royal Marsden Hospital, Surrey; 2. United Kingdom Children’s Cancer Study Group Data Centre, Leicester; 3. Department of Neuro-Oncology, Great Ormond Street Hospital for Children, London; 4. Department of Paediatric Oncology, St. Jame’s, Leeds; 5. Institute of Cancer Studies, University of Birmingham; UK

Introduction: The management of relapsed ependymoma in children remains a difficult dilemma. Currently there is limited information available on how best to treat these patients and their outcome is still largely unknown. We therefore reviewed the clinico-pathological data and treatment given to 108 children with relapsed ependymoma in the UK over the last 17 years. Methods: A retrospective study was carried out over the last 17 years. Data on children 16 years and under with relapsed ependymoma was retrieved from the UKCCSG data centre and from anonymised questionnaire returned from UKCCSG centres. Results: Prerelapse data: Of 108 patients, 50% were infants (3 years or younger) treated on the UKCCSG ‘Baby Brain’ protocol. Overall the posterior fossa was the most common site of initial presentation in 77% of cases. Spinal metastasis was present in 6% with 91% having had spinal imaging at diagnosis. The majority of patients had an incomplete resection at initial diagnosis (56% in infants, 52% in older children). Most infants were treated with chemotherapy alone (81%) compared with older children where treatment was mainly by irradiation (74%). Relapse data: The primary site was the most common site of first relapse and involved in 83% of all relapses. Spinal metastasis alone accounted for 5%. Interestingly, in only half of children there was an attempt at surgical resection at relapse. Radiotherapy was used as salvage therapy in most infants (65%) compared to older children (50%), and the use of chemotherapy was limited at relapse in both groups, with Etoposide containing regimens used in most cases. Older children tended to have multiple relapses and multiple treatments. The overall survival for infants was 24% (mean follow up = 3 years) and older children 26% (mean follow up = 5 years). Conclusions: Relapse is associated with a poor outcome for the majority of patients in both age groups. More favourable outcome was noted in infants who had received radiotherapy at the time of relapse. A uniform policy for the management of relapsed ependymoma is recommended.

THER 61. PRELIMINARY REPORT OF A9961: A PHASE III RANDOMIZED STUDY OF CRANIOSPINAL RADIOTHERAPY (CSRT) FOLLOWED BY ONE OF TWO ADJUVANT CHEMOTHERAPY REGIMENS (CCNU, CPDD, VCR OR CPM, CPDD, VCR) IN CHILDREN WITH NEWLY DIAGNOSED AVERAGE-RISK MEDULLOBLASTOMA (MB)

Roger Packer, Amar Gajjar, Gilbert Vezina, David Langston, Lucy Rorke, Peter Burger, Patricia Robertson, Karin Murasko, Daniel Armstrong, Douglas Ris, Deborah LaFond, Lisa Boyer, and Richard Sposto; Children’s National Medical Center, Washington, DC; Children’s Oncology Group, Arcadia, CA; USA

Over four years (1996–2000), 421 children between 3 and 21 years of age with nondisseminated MB having less than 1.5 cm2 of postsurgical residual disease were entered on a prospective randomized study receiving one of two chemotherapeutic regimens (CCNU, CPDD and VCR-Reg A, or CYCLO, CPDD, VCR-Reg B) during (VCR) and after radiotherapy with “reduced”-dose (2340 cGy) of CSRT plus local RT (5480 cGy). Over 90% of patients have been radiographically centrally reviewed, and 3–5% of patients are likely to be considered ineligible due to neuroimaging evidence of dissemination. Another 10% of patients had “inadequate” neuroimaging studies submitted. Few patients have been excluded on central neuropathologic review. In preliminary analysis of 400 treated patients, at a median follow-up of 44 months, 3-year progression-free survival was statistically similar for Reg A (85 ± 3%) and Reg B (83 ± 3%). Postoperative posterior-fossa mutism was identified in 22%. Hematologic toxicity (96%) was common, but infection was relatively infrequent. Severe infection was more common in Reg B (18% vs. 29%, P < .005) than Reg A. Hearing loss affected 25% of patients. The majority of treatment failures were due to tumor, but there were two toxic deaths (1 hemorrhage during RT and one sepsis), and 4 possible secondary tumors (1 T-ALL, 2 cerebellar gliomas, and 1 basal cell carcinoma). In summary, these preliminary results, pending final review of eligibility, are reassuring that 2340 cGy of CSRT, plus chemotherapy during and after RT, is a reasonable approach for children with nondisseminated MB. Issues which need to be addressed, after completion of central reviews, include the excessive incidence of surgical “postfossa” mutism; relatively high incidence of ototoxicity; relative safety of the regimens; quality and interpretation of staging neuroimaging; and compliance with study required neurocognitive and biologic components.

THER 62. TREATMENT RESULTS OF POOR RISK MEDULLOBLASTOMA AND PNET ACCORDING TO OWN PROTOCOL

Marta Perek-Polnik,1 Bożenna Dembowska-Bagińska,1 Monika Drogosiewicz,1 Wiesława Grajkowska,2 Anna Skowrońska-Gardas,3 and Danuta Perek1; 1Department of Oncology, 2Department of Pathology, the Children’s Memorial Health Institute, Warsaw; 3Department of Radiotherapy, the Oncology Institute, Warsaw; Poland

The aim of the study was to asses the results of treatment of medulloblastoma/PNET with poor prognosis according to own protocol. Material and Method: Since 1997, we treated 37 pts with supratentorial PNET’s (12 pts) and medulloblastoma with visible disease after surgery (M2 M3 and/or partially resected tumors) defined as poor risk. There were 25 boys and 12 girls aged from 3 years 3 months to 14 years 8 months, mean 8 years 9 months, median 9 years. All were operated on and received 4 courses of chemotherapy consisting of alternating courses of VCR, VP-16, CBDCA and VP-16, IF, CDDP followed by irradiation. They received 35 Gy to the brain and spine with dose escalation up to 40 Gy to the metastases. After irradiation, adjuvant chemotherapy (8 courses of VCR, CDDP, CCNU) was given. 3- and 5-years EFS and OS in the whole group was evaluated, and EFS and OS in supratentorial PNET group and MB group were compared. Results: 3-years and 5-years EFS in the whole group was 65%, OS 70% and 65% subsequently. 5-years EFS in PNET’s was 50%, in MB 72%, p = 0.05. Comments: Patients with metastatic medulloblastoma have significantly better prognosis than patients with supratentorial PNET’s. This work was supported by grant nr C 028/P05/2002.

THER 63. AGE LESS THAN ONE YEAR AS PROGNOSTIC FACTOR FOR PROGRESSION-FREE SURVIVAL (PFS) IN CHILDREN AFFECTED BY LOW-GRADE GLIOMA (LGG), INITIALLY TREATED WITH CHEMOTHERAPY (CT); A REPORT FROM THE SIOP-LGG 1993 STUDY

Giorgio Perilongo,1 Astrid Gnekow,2 Rolf Kortmann,3 Giovanni Scarzello,4 Roger Taylor,5 Maria Luisa Garrè,6 Gian Luca De Salvo,7 Tore Stokland,8 Aurora Navajas,9 and David A. Walker10; 1Department of Paediatrics, Padua, Italy; 2Klinik fu r Kinder, Augsbrug, Germany; 3Department of Radiotherapy, Tu bingen, Germany; 4Padua, Italy; 5Leeds, UK; 6G. Gaslini Children’s Hospital, Genoa, Italy; 7Clinical Epidemiology Unit, Padua, Italy; 8Department of Pediatrics, Tromso, Norway; 9Unit of Pediatric Oncology, Baracaldo, Spain; 10Department of Oncology, Nottingham, UK, on behalf of the International Research Consortium on Childhood LGG

Objective: To investigate prognostic factors for PFS in the 210 children treated with CT entered into the SIOP LGG study (1993/2000). Method: A forward variable selection procedure was used to identify clinical variables that contributed additional prognostic information to the multivariate model for PFS. The proportional hazards assuming for each covariate included in the models was checked by plotting the estimate log cumulative hazards vs. time and was tested for each potential factor using the method based on weighted residuals. Results were reported using the p-value of the Wald statistic and the estimated hazard ratio (HR) with their 95% confidence intervals. Results: The 3- and 5-years PFS of the 210 study patients were 57.5% (95%CI 49.7–65.3%) and 45.2% (95%CI 35.8–54.7%), respectively. The following clinical variables were investigated for their impact on PFS: sex; age category (≤1 years, >1 age ≤5, >5 age ≤10, >10 years); neurofibromatosis 1 (NF1); type of initial surgery (biopsy vs. surgical debulking vs. only neuroradiological diagnosis); leptomeningeal metastases; and response to CT (complete and partial response vs. stable disease). At the univariate analysis, age (p =0.001), NF1 status (p = 0.03), leptomeningeal metastases (p = 0.004), and type of initial surgery (p = 0.001) predicted forPFS. At the multivariate analysis, age and type of initial surgery remained independent variables; children aged ≤1 year were more likely to have a poorer PFS than children aged <1 age ≤5, <5 age ≤10, >10 years, HR 0.44, 0.49, 0.92, respectively. Children who had a biopsy or some form of debulking surgery had a higher risk of having a lower PFS than the others who entered the trial based on clinical diagnosis (debulking surgery and biopsy, HR 1.28 and 2.27, respectively). Conclusions: Hypotheses accounting for adverse outcomes in children <1 years and after surgery at diagnosis will be generated and tested.

THER 64. ATYPICAL TERATOID/RHABDOID TUMOR OF THE CENTRAL NERVOUS SYSTEM IN A CHILD: COMPLETE RESPONSE TO CHEMOTHERAPY

Ove Peters,1 Peter Stadler,2 Monika Friedrich,3 Odo W. Ullrich,3 and Johannes E.A. Wolff 1; 1Department of Pediatric Oncology and Hematology, 2Department of Radiotherapy, and 3Department of Neurosurgery, Regensburg, Germany

Background: The atypical teratoid/rhabdoid tumor (AT/RT) is a very rare tumor of the central nervous system (CNS). Usually newborns and infants are affected. The overall survival is exceptionally poor (median survival 6–11 months). A successful multimodal therapy does not exist. Patient and History: 18-month-old white boy with a 4-week history of balance disturbance, vomiting, and headache. On admission he presented a right hemiparesis and a right central seventh nerve palsy. Magnetic resonance imaging revealed a contrast enhancing tumor of the left basal ganglia (diameter 4.5cm) without seedings (M0), which was resected subtotally (SR). Histological diagnosis of ATRT was confirmed by two German Tumor Reference Centers (University of Bonn and Kiel). Therapy and Outcome: Only 20 days after SR a local tumor progression (diameter 2.5 cm) was observed. Without any further tumor resection a Rickham reservoir was implanted and a novel chemotherapy strategy was started immediately. Partial response was seen after the first chemotherapy course (doxorubicin: 25 mg/m2/d, 12 h i.v., d 1, 2, 3; actinomycin D: 45 μg/kg/d, i.v. push, d 1; cisplatin: 70 mg/m2/d, 6 h i.v., d 4; vincristine: 1.5 mg/m2/d, i.v. push, d 8, 15; methotrexate: 2.0 mg single dose, intrathecal, d 1, 2, 3, 4). A complete response was seen after a second chemotherapy course (same as first course), which was applied within 3 weeks. Conventional local 3D radiotherapy (tumor region + 1cm safety margin: 54 Gy, 5 x 1.8 Gy/week, 6 MeV photons) with simultaneous chemotherapy (carboplatin: 80 mg/m /d, 6 h i.v., d 1–4) was given next, followed by a third chemotherapy course (same as first course). After that a continuous chemotherapy (6 cycles/9 months: CCNU, cisplatin, vincristine; methotrexate i.th.) was started. Toxicity following the 1.–3. chemotherapy course included: hematological/stomatitis grade 4, general condition grade 3, infection/skin grade 2. No toxicity was observed after or within the time of radiotherapy and continuous chemotherapy. The initial neurological deficits resolved almost complete and the boy is still in a continuous complete remission 20 months after diagnosis. Conclusion: Based upon this case we suggest this anthracyclin based treatment for a larger clinical study.

THER 65. A UKCCSG STUDY OF THE TREATMENT OF RELAPSED CNS PRIMITIVE NEUROECTODERMAL TUMOURS USING HIGH-DOSE CHEMOTHERAPY

Susan Picton, Kath Robinson, Claire Weston, Antony Michalski, Roger Taylor, David Ellison, and Barry Pizer, on behalf of the UKCCSG Brain Tumour Group

Background: The outcome following a relapse of CNS primitive neuroectodermal tumour (PNET) remains extremely poor. The UKCCSG has developed a protocol based on myeloablative chemotherapy for this patient group. Methods: The strategy consists of an initial cytoreductive phase using 2–4 courses of high–dose cyclophosphamide (4 mg/m2 over 2 days) in conjunction with local therapy (surgery or local radiotherapy) if possible. Harvest of peripheral blood stem cells (PBSC) takes place during this cytoreductive phase. If complete or near complete remission is achieved, the patient proceeds to treatment with 2 courses of myeloablative chemotherapy followed by PBSC rescue. The first course consists of thiotepa (300 mg/m2/day for 3 days) with PBSC reinfusion on day 5 and G-CSF from day 10 until neutrophil recovery. The second course consists of carboplatin dosed to a total AUC of 21 m again with PBSC and G-CSF support. Results: Data is available on 28 patients who have completed the treatment so far; 19 trial patients and 9 pilot patients. 15 patients had a local relapse and 12 a metastatic relapse (1 patient, data unknown). Eleven of 21 evaluable patients demonstrated a radiological response to cyclophosphamide chemotherapy (5 CR, 6 PR). At the end of cytoreductive therapy, 9 patients were in CR and 6 in PR. 16 patients received high-dose thiotepa, but only 10 went on to complete the high-dose carboplatin. 19 patients have died (18 from disease progression and 1 toxic death). The 1-year overall survival = 76% (95% CI: 6091) and 1-year event-free survival = 59% (95% CI: 40–77). Median survival = 3.1 years (range: 4 months–4.3 years). At present 20% of patients are alive and disease free. Conclusions: This treatment prolongs survival following relapsed PNET. Overall survival remains poor, but the results presented here are comparable with those reported by other national groups.

THER 66. CHILDHOOD CRANIOPHARYNGIOMA: CLASSIFICATION AND TREATMENT ACCORDING TO THE DEGREE OF HYPOTHALAMUS INVOLVEMENT

S. Puget, C. Sainte-Rose, D. Renier, M. Zerah, and A.P. Kahn; Service de Neurochirurgie Pédiatrique Hôpital Necker Enfants Malades, Paris, France

Objective: Identification of factors correlated with the outcome in childhood craniopharyngioma. Material and Methods: Retrospective study of a series of 66 children treated at Necker’s Hospital in the past 20 years. Neurological status, visual and endocrine function, Functional Health Utility Index (HUI) and Body mass index (BMI) have been studied pre and postoperatively and compared with the degree of hypothalamic involvement scored on pre and postoperative MRI, by a third party, as 0 (no visible involvement/damage), 1 (intermediate), or 2 (severe). Results: The preoperative hypothalamic involvement (0, 1, 2) was 21%, 37%, and 42%, respectively. Surgery alone was performed in 68% of the cases; in 32% of the cases radiation therapy was used in association with surgery. The vast majority of the patients (90%) required postoperative hormonal therapy. The postoperative hypothalamic damage (0, 1, 2) were 32%, 30%, and 38%, respectively. The hypothalamic involvement/damage score was correlated, pre and postoperatively, both with the BMI at the last follow-up (p = 0,007 and p = 0,001, respectively), and HUI (p = 0,000 and p = 0,003 respectively). The surgeon skill (more than 3 cases/year) was correlated with the postoperative BMI and HUI. Conclusion: Outcome of children having a craniopharyngiomas is correlated with the degree of hypothalamic damage scored postoperatively on the MRI which can be predicted on the preop image and is influenced by the surgeon skill. We propose that the treatment has to be adapted to each group of patient according to the degree of preoperative hypothalamic involvement (MRI scores 0, 1, 2) to minimize the morbidity. A tumor, away from the hypothalamus (score 0), can be removed safely. For a tumor deforming the hypothalamus (score 1), the outcome depends on the surgeon skill. For a tumor involving the hypothalamus (score 2), subtotal surgery + local radiation therapy allows to reduce morbidity without impairing mortality.

THER 67. MULTI-MODALITY APPROACH IN PEDIATRIC NEURO-ONCOLOGY IN EMERGING COUNTRIES: THE JORDAN-KING HUSSEIN CANCER CENTER (KHCC) EXPERIENCE

Ibrahim Qaddoumi, Abdelatif Almousa, Nasri Khoury, Ziad Mahadeen, Asem Mansour Maher Sughayer, Awni Musharbash, Ala’ Addasi, Dara Mardan, and Dian Udeh; King Hussein Cancer Center, Amman, Jordan

Background: Multidisciplinary team based approach and strict therapy guidelines have contributed significantly to improving survival and quality of life in the oncology field. Pediatric neuro-oncology is a very demanding field where an integrated multi-modality approach is needed most to deliver the best optimal care. Our aim was to implement such a multidisciplinary team at KHCC since the inception of our brain tumor program in December 2002. Methods: After careful review of our needs and available resources, we took the following steps towards establishing the first integrated pediatric neuro-oncology multidisciplinary team in Jordan. First, we identified a core team composed of a radiation oncologist, a neurosurgeon, a neurologist, and a pediatric oncologist. Other specialties such as endocrinology, social worker, and physical therapy were consulted on a regular basis depending on patients needs. Second, we established therapy guidelines based on standard of care and results of published phase III studies. Third, we established regular crosstalk among team members. This was done through the weekly multidisciplinary neuro-oncology clinic, regular group meetings, and hospital tumor boards. Fourth, we established connections with leading teams around the world for consultation, teleconference, and collaboration. Results: Over a period of 14 months KHCC neuro-oncology team followed 61 pediatric neuro-oncology cases. Through comprehensive review and team discussion for each case, we have been able to revise the planned therapy on numerous occasions with great positive impact (like reducing treatment delay, proposing second surgery, offering chemotherapy or simply just observation). Conclusion: Multidisciplinary approach for pediatric neuro-oncology is feasible in an emerging country like Jordan, and it helps improve the level of care delivered for patients. This model can be adopted by other emerging countries and modified to be used for other fields in pediatric oncology. Ongoing studies will document the impact of this approach on the outcome and quality of life of our patients.

THER 68. MONTHLY CARBOPLATIN AND VINCRISTINE: A PRACTICAL AND EFFECTIVE TREATMENT FOR LOW-GRADE GLIOMAS

Ibrahim Qaddoumi, Asem Mansour, Abdelatif Almousa, Nasri Khoury, Ziad Mahadeen, Maher Sughayer, Awni Musharbash, Ala’ Addasi, Dara Mardan, and Dian Udeh; Departments of Pediatrics, Radiology, Radiation Oncology, Surgery, Pathology, and Internal Medicine, King Hussein Cancer Center, Amman, Jordan

Background: Total resection is not feasible for many low-grade gliomas, and many patients are treated with radiation therapy following surgery. Recently, researchers have demonstrated efficacy of adjuvant chemotherapy in the management of low-grade gliomas. Weekly carboplatin and vincristine in particular have been shown to be very effective. In Jordan where resources are limited and patients’ compliance is suboptimal, weekly therapy is not practical. Therefore, we treated eight patients with monthly carboplatin and vincristine. We here report our preliminary experience. Methods: All eligible patients received carboplatin (18.5 mg/Kg for less than 10 Kg and 560 mg/m2 for older children) and vincristine (0.05 mg/Kg for less than 10 Kg and 1.5 mg/m2 for older children) every three weeks for 3 cycles. Evaluation of response was done at week 10. Patients who had a response (including those with stable disease) were then given monthly doses for additional 12 cycles (total of 15 cycles). Follow-up of patients ranged from 2 months to 13 months. Results: Eight patients were eligible for the protocol. One patient however, had significant morbidity following surgery and was given only weekly vinblastine. Out of the seven evaluable patients, one progressed and underwent second surgery. This particular patient expired within four weeks postOP due to aspiration pneumonia. None of the 7 patients developed allergic reaction, and only one had prolonged thrombocytopenia that prompted carboplatin dose reduction (by 50%). One patient needed inpatient chemotherapy administration because of transportation. Conclusion: Monthly carboplatin and vincristine appears to be a feasible, practical, and effective protocol with limited toxicity for low-grade gliomas. The number of patients and follow-up period in this series is small to allow making any firm conclusions regarding the long-term survival of patients treated. Further accrual and follow-up is needed.

THER 69. HIGH-DOSE CHEMOTHERAPY AND POSTERIOR FOSSA RADIOTHERAPY FOR CHILDREN LESS THAN 3 – 5 YEARS WITH LOCALIZED HIGH-RISK MEDULLOBLASTOMA AT DIAGNOSIS OR AT RELAPSE. THE SFOP EXPERIENCE

Vita Ridola, Francois Doz, Didier Frappaz, Jean Claude Gentet, Xavier Rialland, Genevieve Marguerite, Christian Saint-Rose, Jacques Grill, Olivier Hartmann, and Chantal Kalifa; Pediatric Oncology Department, Gustave Roussy Institute, Paris, France

This study was designed to determine the outcome of children with high-risk localized medulloblastoma treated with high-dose chemotherapy and posterior fossa irradiation as salvage treatment. Treatment plan consisted in one cycle of high-dose busulfan 600 mg/m2 and thiotepa 900 mg/m2, followed by autologous stem cells transplantation and radiotherapy of the posterior fossa at 50–55 Gy. In case of residue, surgery was performed before radiotherapy. Forty children were included in this study. Twenty-two patients had a local relapse of an initially completely resected medulloblastoma treated with conventional chemotherapy (BBSFOP protocol). Eighteen patients had a local residue after surgery; 6 were treated immediately after the operation, and 12 at the time of progression under conventional chemotherapy. The median age at the inclusion in this protocol was 38 months (range: 6–81 months). The median delay between diagnosis and relapse or progression was 10 months (range: 2–31 months). Acute toxicity consisted mainly in bone marrow aplasia with neutropenia <500 neutrophils/mm3 for a median of 9 days (range: 5–30), thrombocytopenia <50.000 platelets/mm3 for a median of 30 days (range: 4–120). Grade III-IV veno-occlusive disease was observed in 8 cases, and grade III-IV mucositis in 19. One child died of toxicity because of an invasive aspergillosis. Delayed toxicity was observed in 25% of patients. It consisted of abnormal gadolinium enhancement on MRI, localized in the radiation fields and appearing a few months after irradiation. Overall survival (OS) at 5 years is 69.4%. In the group treated for local relapse with this protocol, OS at 5 years is 78.6%. Patients with local residue have an OS at 5 years of 100% when treated initially with HD-CT, but an OS at 5 years of only 46.2% when treated at progression. This strategy has a manageable immediate toxicity and offers a high overall survival rate in the setting of localized high-risk medulloblastoma. However, additional toxicity of busulfan and posterior fossa irradiation is a special concern and will be correlated with long-term neuropsychological outcome.

THER 70. MULTIMODALITY THERAPY FOR CNS NONGERMINOMA GERM CELL TUMORS (NGGCT): RESULTS OF A PHASE II CONSORTIUM

Patricia Robertson,1 Joao Siffert,2 Regina Jakacki,3 Juliette Hukin,4 Linda.Velasquez,2 and Jeffrey Allen2; University of Michigan Medical Center, Ann Arbor, MI, USA1; Beth Israel Medical Center, NY, USA2; Children’s Hospital of Pittsburgh, PA, USA3; Children’s and Women’s Hospital, Vancouver, BC, Canada4

CNS nongerminoma germ cell tumors (NGGCT) are more refractory to treatment than germinomas. Recent protocols employing chemotherapy (CHT) followed by radiation therapy (RT) have produced better outcome than either modality alone. Patients who are rendered free of disease prior to RT, either by surgery or chemotherapy, have the most favorable prognosis, as supported by a recent pilot study. The 5-year PFS was 100% in the 5/12 pts who achieved a complete response (CR) to preRT CHT (Robertson et al, 1997). A sequel study was devised with the goal of increasing the CR rate prior to RT by intensifying CHT and second-look surgery, where feasible. Following surgical or tumor marker confirmation of NGGCT and complete CNS staging, 4 cycles of multi-agent CHT1 is given. In pts not achieving CR, a second-look surgery is encouraged, followed by tandem cycles of submyeloablative CHT2 with PBSC support. Methods: Eligible pts had a CNS NGGCT confirmed histologically, or by elevated serum/CSF markers for AFP or β-HCG (>100 IU/dl). Pts received neoadjuvant CHT1: cisplatin (20 mg/m2/day X 5), etoposide (75 mg/m2/day X 5), ifosfamide (1.2 g/m2/day X 5) X 4 cycles. Pts who achieved less than CR underwent second-look surgery and/or received 2 additional cycles of DI-CHT2: carboplatin (400 mg/m2/day X 3), cyclophosphamide (2 g/m2/day X 2), with PBSC support). All pts received 36 Gy craniospinal RT, (except pts with local disease and a CR to CHT, who received 36 Gy whole ventricular RT), with a boost to the primary site(s) (50.4–55.8 Gy). Results: Between October 1998 and March 2003, 27 pts were enrolled: M/F - 20/7; ages - 1.5–26 years; suprasellar -10, pineal -13; pineal/suprasellar - 3, posterior fossa - 1; M0 - 20, M+ - 7. Responses to CHT1: CR - 9/27 (2 confirmed CR at second-look surgery); probable CR - 3/15 (min. residual, unconfirmed surgically); CR rendered by initial surgery - 4/27; partial response (PR) to CHT1 - 10/27; progressive disease (PD) - 1/27. Of the 10 pts with PR to initial CHT, 4 pts underwent second-look surgery, of whom 2 were rendered surgically CR, and 5 pts received CHT2, converting 3 to a CR. In total, 21/27 pts were rendered CR prior to receiving RT (12 with CHT1, 3 with CHT2and 6 with surgery). The 3-year PFS in the 15 pts achieving CR before RT was 71% vs. 50% in 6 pts not achieving a CR before RT. At a median follow-up of 33 months, 18/27 pts (66%) are without disease-progression (17 NED and 1 toxic death without progression), and 20/27 (74%) pts remain alive. 9/27 pts experienced a relapse, which was outside the RT field in 3/5 pts who had disease progression after RT. Conclusions: This sequel pilot study achieved its goal of inducing a higher CR rate prior to RT than our earlier study (78% vs. 61%), with an encouraging 66% 3-year PFS. The attainment of a CR prior to RT may improve progression-free survival. The pattern of relapse outside the radiation field in 3/5 pts who progressed after RT reinforces the need for craniospinal RT volume in these patients.

THER 71. TEMOZOLOMIDE IN THE TREATMENT OF PROGRESSIVE LOW-GRADE GLIOMA

Nasjla Saba, Valesca Paes, Jesus Galeana, Ana Paula Pascalicchio, and Sergio Cavalheiro; Instituto de Oncologia Pediátrica, GRAACC/Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, SP, Brasil

Temozolomide has been shown to be active in gliomas. The goals of this study were to determine the efficacy and side-effects profile of this agent. We report on the results of Temozolomide for the treatment of patients with progressive low-grade glioma in our institution during the time-period of March 2001–January 2004. Fourteen patients with low-grade glioma have been treated to date, three of whom previously received chemotherapy. Age ranged from 3-years to 12-years with a median age of 7.5-years. Twelve patients had diencephalic astrocytoma; two had thalamic oligodendroglioma. Temozolomide was administered orally, in a fasting state, once a day for 5 consecutive days at a starting dose of 200 mg/m2/day. Cycles were repeated every 28 days. Response was assessed by MRI every 4 cycles. Two patients demonstrated stable disease, four partial responses were observed, three patients demonstrated progressive disease, and five are too early in treatment for evaluation. Vision improvement was observed in two patients. Observed toxicity during the study was limited to four patients. Three patients experienced grade 3 and 2 thrombocytopenia. Grade 2 thrombocytopenia was observed in 2 cycles and grade 3 in 1 cycle. Nonhematological toxicity included grade 2 nausea/vomiting in 1 patient. One patient experienced grade 3 hepatic toxicity shown by a reversible increase of liver transaminases. Extended, low-dose Temolozomide was well tolerated and showed activity with low toxicity in progressive low-grade gliomas. Survival and quality of life data will be presented.

THER 72. EFFICACY OF CHEMOTHERAPY CONSISTING OF CARBOPLATIN AND VINCRISTINE TO AN INFANT WITH OPTICO-HAYPOTHALAMIC PILOCYTIC ASTROCYTOMA

Taiichi Saito, Kazuhiko Sugiyama, Kuniki Eguchi, Fumiyuki Yamasaki, Yoshinori Kaziwara, Yasuharu Kurokawa, Kazunori Arita, and Kaoru Kurisu; Department of Neurosurgery, Hiroshima University Medical and Dental Hospital, Hiroshima, Japan

We present a 14-month-old boy with epilepsy due to an optico-hypothalamic pilocytic astrocytoma, treated with chemotherapy alone. After biopsy, he received 8 courses chemotherapy consisting of Carboplatine and Vincristine. This treatment produced gradually remarkable reduction in size of the tumor with partial cystic change and improvement of symptom in 30 months after surgery. Severe complications were not seen. Packer et.al. reported seventy-eight children with mean age of 3 years who had newly diagnosed, progressive low-grade gliomas and treated with combined carbolatin and vincristine chemotherapy. The fifty-eight children (74%) of all patients had diencephalic tumors. Forty-four (56%) of 78 patients showed an objective response to treatment. The response to treatment in 58 patients with diencephalic tumors were only 3 patients of progeressive disease (CR 2, PR 17, MR 14, SD 22, PD 3). Silva et. al. reported 14 patients of optico-hypothalamic pilocytic astrocytoma under 3 years old who treated mainly carbplatine chemotherapy. Eight (57%) of 14 patients had a sustained reduction of tumor during the follow-up time. These tumor reductions were often accompanied by clinical improvements. Chemotherapy to optico-hypothalamic pilocytic astrocytoma of infants may preserve more functions of central nervous system than radiation therapy. Furthermore long-term follow-up of many cases will reveal the efficacy and complications of chemotherapy to infants before irradiation.

THER 73. FRACTIONATED STEREOTACTIC RADIATION THERAPY FOLLOWING LIMITED SURGERY IN CHILDHOOD CRANIOPHARYNGIOMA

Giovanni Scarzello, Maria S. Buzzaccarini, Giorgio Perilongo,1 Carla Carollo,2 Maria L. Garrè,3 Roberto Faggin,1 Massimo E. Abate,4 and Guido Sotti; Radiation Therapy Department, 1Paediatrics Department, and 2Neuroradiology Department, University Hospital of Padua; 3Neurosurgical Department, G. Gaslini Institute Genoa; 4Paediatrics Department, Casa Sollievo della Sofferenza, San Giovanni Rotondo; Italy

Aggressive surgery for craniopharyngioma can be associated with severe morbidity, mainly visual deficits and hypothalamic and pituitary disfunctions. Because of that many authors recommend a less radical surgical approach followed by radiation therapy. A 70 to 83% local tumor control rate at 10 years has been associated with this combined approach. Fifteen children with a median age of 9 years (range: 6–18 years) affected by an histologically proven craniopharyngioma were initially treated with limited surgery and fractionated stereotactic radiation therapy (FSRT) between October 1997 and June 2003. Eight patients received FSRT after surgery and 4 after neuroendoscopic cyst drainage and biopsy. Three were treated at the time of tumor recurrence; they were previously treated with surgery and conventional external beam radiotherapy (2) and 89Y intracavitary irradiation (1) 43, 60, and 76 months before FSRT, respectively. Median tumor volume at the time of RT was 8 ml (range: 2.3–15 ml). Treatment planning was carried out with the Radionics X knife 3 and X knife 4 systems. The collimators size ranged from 25 to 50 mm, median 37.5. Three to 7 noncoplanar arcs (median 4) were given daily up to a total dose of 54 Gy in 27 fractions using a nondedicated 6 MV Siemens MX2 Linac equipped for stereotactic treatments. Follow-up included MR imaging and ophthalmologic, endocrinologic, and neurologic examinations. After a median follow-up of 58 months (range: 14–150 months), the actuarial local control and survival rates at 5 years are 100%. Two patients showed a complete and 10 a partial response. In 3 patients the disease remained stable. In 3 patients vision improved after radiation therapy and no visual deterioration was documented. All patients did not show impairment in their endocrinologic neither neuropsychologic outcome after therapy. FSRT seems to be effective and safe in the treatment of paediatric craniopharyngiomas.

THER 74. COMPARISON OF 3D-CONFORMAL RADIATION THERAPY (3D-CRT) AND INTENSITY MODULATED RADIATION THERAPY (IMRT) FOR THE TREATMENT OF PEDIATRIC POSTERIOR FOSSA BRAIN TUMORS

Hui-Kuo G. Shu, Abhirup Sarkar, Roberto J. Santiago, Paul M. James, and Alireza Kassaee; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA

Pediatric brain tumors such as primitive neuroectodermal tumors and ependymomas commonly present in the posterior fossa. 3D-CRT has been widely adopted for the treatment of these tumors and can significantly lower doses to the cochleas and temporal lobes compared with traditional techniques. IMRT should be able to further reduce doses to these critical structures while maintaining tumor coverage although the extent of this improvement is not well characterized. Furthermore, we hypothesize that, for IMRT at this site, noncoplanar techniques (NCPTs) would be superior to coplanar techniques (CPTs). For this study, five patients with posterior fossa tumors were planned using these techniques. For IMRT, seven beams were used for both the CPT (all equally spaced) and the NCPT (four along CPT plane, three along vertex plane). Inverse planning was performed using the same constraints for the two techniques with bilateral cochleas, and temporal lobes included as structures at risk. For 3D-CRT, forward plans were optimized using the above NCPT beams. In all plans, tumor coverage was achieved although IMRT did increase dose heterogeneity. Overall, tumor volumes were better covered in four of five cases with the NCPT compared with the CPT. The average median dose to the cochleas with 3D-CRT was 55% of the prescription dose. IMRT was able to further reduce this dose an additional 40%. The median dose to the temporal lobes could also be reduced an average of 50% with IMRT. Depending on tumor location, the NCPT was also able to reduce dose to critical structures compared with the CPT. We conclude that while optimal beams for IMRT are likely to be dependent on tumor configuration, our NCPT appears somewhat better than the CPT. However, IMRT clearly has superior dosing profiles compared to 3D-CRT and should be considered, when possible, for the treatment of pediatric posterior fossa tumors.

THER 75. OUTCOME OF THERAPY FOR ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) ON PEDIATRIC ONCOLOGY GROUP STUDY (POG) 9233/34

Douglas Strother, Stephen Linda, Peter Burger, Patricia Aronin, Louis Constine, James Langston, Patricia Duffner, Henry Friedman, Mary Jo Kupst, Larry Kun, and Marc Horowitz; Southern Alberta Children’s Cancer Program, University of Calgary, Calgary, AB, Canada

Between March 23, 1992 and December 14, 2000, 36 patients (pts) <3 years of age (18 male) with centrally reviewed diagnoses of ATRT were enrolled on POG study 9233/34. Institutional diagnoses were ATRT (12 pts), medulloblastoma (13), supratentorial primitive neuroectodermal tumor (6), choroid plexus carcinoma (2), and other malignant tumors (3). Metastases were present in CSF only (3 pts) or in CSF and spine (4). Four pts had complete resection of primary disease and no metastases. All pts were randomized to standard or dose-intensive chemotherapy outlined below.

AgentStandard Dose: six 12-week cyclesIntensive Dose: eight 9-week cycles
Cyclophosphamide65 mg/kg, weeks 1, 52 × 65 mg/kg, weeks 1, 4
Vincristine.065 mg/kg, weeks 1–6.065 mg/kg, weeks 1–6
Cisplatin4 mg/kg, week 95 mg/kg, week 7
Etoposide2 × 6.5 mg/kg, week 92 × 7.5 mg/kg, week 7

Chemotherapy responses, evaluable in 28 pts, were designated by the institutions as complete (6 pts), partial (6), stable or none (7), and progressive disease (PD; 9). Thirty-one pts had recurrent or progressive disease, noted at the local site in 25 and in distant sites in 10. Of these 31 pts, 5 then received radiation therapy (RT) and 6 received alternative chemotherapy. For all 36 pts, median event-free survival was 4.7 months and median survival was 6.6 months. All patients died, 31 of disease and 5 of therapy related complications. We conclude that: 1) the chemotherapy regimens on this trial were ineffective treatment for ATRT, particularly in controlling local disease; 2) RT was uncommonly used but was ineffective after PD; and 3) most diagnoses of ATRT came through central review. Molecular diagnostic techniques may identify more pts with ATRT. Earlier use of RT may increase local tumor control rates, but new chemotherapy approaches are also needed.

THER 76. VOLUME-REDUCED RADIATION FOLLOWING PLATMUN-BASED CHEMOTHERAPY CAN IMPROVE ANTERIOR PITUITARY FUNCTIONS AND PRESERVE HIGH QUALITY OF LIFE IN THE PATIENTS WITH NEUROHYPOPHYSEAL GERMINOMA

Kazuhiko Sugiyama, Kazunori Arita, Kaoru Kurisu, Fumiyuki Yamasaki, Yoshinori Kajiwara, and Taiichi Saitoh; Department of Neurosurgery, Hiroshima University Medical Center, Hiroshima, Japan

Purpose: The aim of this prospective study is to assess the efficacy of volume-reduced radiotherapy following chemotherapy to improve anterior pituitary functions of the patients with germinoma involving neurohypophyseal region. Methods: From 1996 to 2003, nine patients (6 males, 6 children: 12–38 (median 14.2 years old) were enrolled who received 3 cycles of PE or ICE chemotherapy followed by 24 Gy extended-local irradiation after surgery. All patients achieved a CR during chemotherapy. They were evaluated with dynamic hormonal examination simultaneously enhanced by CRF, GRF, LH-RH, and TRH on admission and 1 year after radiotherapy. Serum titers of cortisol, GH, LH, FSH, TSH, and PRL were measured at 0, 30, 60, and 90 minutes after stimulations, respectively. The hormonal impairment was judged according to the Merchant’s criteria (Int. J. Radiat. Oncol. Bio. Phys. 54: 45–50, 2002). Results: Median follow-up time was 39 months. All patients have been in full performance status without recurrence. The numbers of hormonally normalized patients were 2 before and 5 after this treatment (2/6) in ACTH, 0/3 in GH, 1/4 in LH, 2/5 in FSH, 4/6 in TSH, and 2/8 in PRL. The numbers of the patients with posttherapeutic progressive hormonal function were only 2 in TSH, and none in others. After this treatment, 23-year-old man recovered from ED, 38-year-old woman from secondary amenorrhea, and 14-year-old girl from primary amenorrhea. Conclusions: Our treatment consisting of chemotherapy and volume-reduced radiation can always preserve and occasionally improve anterior pituitary functions of the patients with germinoma involving neurohypophyseal region. Their outcome is also satisfactory.

THER 77. MEDULLOBLASTOMA IN THE SECOND DECADE OF LIFE: A SPECIFIC GROUP WITH RESPECT TO TOXICITY AND MANAGEMENT. A CANADIAN PAEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

Uri Tabori, Juliette Hukin, Bruce Crooks, Normand Laperriere, Anne-Sophie Carret, Doug Strother, Maria Silva, David Eisenstat, Beverly Wilson, Isaac Odame, Chris Mpofu, Yvan Samson, Lillian Sung, and Eric Bouffet, on behalf of the Canadian Paediatric Brain Tumor Consortium (CPBTC)

Background: 25% of patients diagnosed with medulloblastoma are ≥10 years old at presentation. Chemo-radiotherapy protocols have been shown to be exceedingly toxic in adults. The management of teenagers with chemotherapy is frequently challenging, but the magnitude of the problem is not known. Methods: We retrospectively studied the toxicity profile, compliance, and outcome of children aged 10 to 20 years with medulloblastoma, treated at centers of the CPBTC between 1986–2003. Detailed toxicity data from 2 chemotherapy protocols (ICE-Ifosfamide-Carboplatin-Etoposide on 14 patients/113 courses and CCV-CCNU-Cisplatin-Vincristine on 16 patients/106 courses) were collected for teenagers and compared to controls aged 5 to 10 years. Results: A total of 63 patients were analyzed. Median age at diagnosis was 12.9 years. Chemotherapy was given to 75% of patients. Grade ≥2 ototoxicity and neurotoxicity occurred in 46% and 78% of chemotherapy treated patients, respectively. Grade 3-4 hematotoxicty occurred in 95% of cases. Toxicity resulted in delay of treatment in 68% and dose modification in 74% of cases, including protocol discontinuation in 19% of patients. Weight loss of more than 10% was encountered in 80% patients requiring interventions such as g-tubes and TPN in 44% of patients. Teenagers on ICE and CCV protocols had significantly more hematotoxicity (P < 0.0001) and neurotoxicity (P = 0.0017) than controls. Ototoxicity was similar in both age groups. In both protocols, toxicity resulted in more treatment delays (P < 0.0001) and dose modifications (P = 0.0073) in teenagers than controls. 5 year overall and event-free survival were 79 + -6% and 70+ -6%, respectively with a median time to relapse of 2.9 (0–8.4) years. Conclusions: Teenagers with medulloblastoma have considerable toxicity from the current chemotherapy protocols. Most patients cannot tolerate current standard chemo-radiotherapy strategies. Time to relapse was longer than reported in most pediatric series, suggesting a possible different biology. This age group deserves special attention and may necessitate different approaches than younger children.

THER 78. OUTCOME FOR PATIENTS WITH CHANG STAGE M2-3 MEDULLOBLASTOMA (MB) TREATED WITH SIOP/UKCCSG PNET-3 CHEMOTHERAPY (CT)

Roger Taylor, Clifford Bailey, Kathryn Robinson, Claire Weston, David Ellison, James Ironside, Barry Pizer, David Walker, and Linda Lashford; United Kingdom Children’s Cancer Study Group, University of Leicester, UK

Between 1992 and 2000, patients with M0-1 MB were randomised to CT followed by RT, or RT alone in the PNET-3 study. During this time M2-3 patients were recommended to receive CT and RT. This study is an analysis of outcome for these patients. In total 77 patients were treated, 9 with RT alone and 68 with CT comprising vincristine, etoposide, carboplatin, and cyclophosphamide. For 61 patients CT was followed by craniospinal RT 35 Gy/21 fractions with a posterior fossa (PF) boost, 20 Gy/12 fractions. 27/70 (38.6%) irradiated patients received a RT boost to metastases (total RT dose to metastases 37.3–55.1 Gy, mean 46.4 Gy). Median follow-up was 5.8 years. For all 77 patients, 3- and 5-year OS were 49.2% and 43.4%, respectively, and 3- and 5-year EFS were 40.1% and 38.7%, respectively. For patients treated by CT, 3- and 5-year EFS were 39.5% and 37.9%, respectively. Univariate analysis did not demonstrate a statistically significant impact of gender, age, extent of resection, M stage, RT duration, use of CT, or metastatic boost. Response to CT was assessable from institutional reports for 44 (64.7%) patients. 17 (38.6%) had CR, 15 (34.1%) PR, 4 (9.1%) stable disease, and 8 (18.2%) progression. Three-year OS was 12.5% for those with progression compared with 51.4% for those with response or stable disease (p = 0.002). Three-year EFS was 12.5% for those with progression compared with 42.9% for those with response or stable disease (p = 0.003). Although CT improved EFS for M0-1 patients in the randomised study and resulted in a high response rate in this study, there has been no apparent improvement in outcome for M2-3 patients when compared with earlier or contemporaneous multi-institutional series. Newer approaches such as more intensive CT and RT need to be explored.

THER 79. ATYPICAL TERATOID RHABDOID TUMORS (ATRT): IMPROVED SURVIVAL IN CHILDREN ≥ 3 YEARS OF AGE TREATED WITH RADIATION THERAPY (RT) AND HIGH-DOSE ALKYLATOR BASED CHEMOTHERAPY

Tanya Tekautz, Christine Fuller, Maryam Fouladi, Alberto Broniscer, Thomas E. Merchant, Matthew Krasin, Gregory Hale, Larry E. Kun, Dana Wallace, and Amar Gajjar; Division of Neuro-Oncology, Department of Hematology Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: Evaluation of the clinical features, therapy, and survival correlates in pediatric patients (pts) with ATRT at a single institution. Patients and Methods: We reviewed the clinical records and pathology samples from pts with ATRT treated at our institution between July 1984 and June 2003. Initially all pts underwent maximal surgical resection. Pts < 3years of age received cisplatin and alkylator based therapy. The majority of pts ≥ 3-years received craniospinal radiation followed by high-dose alkylator based therapy with stem cell support. Results: Thirty-one newly diagnosed pts with ATRT were accrued during the study interval; 22 pts were <3-years at diagnosis (median = 1.0-years; range = 0.2–2.7-years; group A), 9 were ≥3-years (median = 3.9 years; range = 3.3–7.4 years; group B). In groupA, 16 pts presented with localized disease, and 6 with metastatic (M+) disease. No pt in group B presented with M+ disease. Results at 3 years show EFS of 11 + 6% for Gp A vs. 58 + 19% Gp B (p = 0.009, fig. 1) and overall survival of 17 + 9% Gp A vs. 89 + 13% Gp B (p = 0.0005). As age was significantly associated with EFS and OS, further analyses were stratified for age at diagnosis. Tumor location was equally distributed between the posterior fossa and supratentorial region and was not prognostic of EFS (p = 0.41). EFS was not significantly different for M+ disease at diagnosis (p = 0.95) or gross total/near total resection (n = 21) vs. subtotal resection (n = 10, p = 0.096). Eighteen pts in group A developed disease recurrence; none have survived >13-months beyond relapse. In group B, recurrent disease developed in 4 pts; 3 are alive (median 1.2 years from recurrence) after therapy with ifosfamide, carboplatin, and etoposide (ICE).

Figure 1
Event-free Survival by Age at Diagnosis

Conclusions: ATRT in infants and young children has a dismal prognosis. EFS in older children is significantly better with irradiation and high-dose alkylating therapy. Further, salvage therapy with ICE is an effective treatment in older patients with relapsed disease.

THER 80. HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MEDULLOBLASTOMA IN CHILDREN

Mizuhiko Terasaki,1 Haruhiko Eguchi,2 Shintaro Nakagawa,2 Naohisa Miyagi,1 Etsuyo Ogo,3 and Minoru Shigemori1; The Department of Neurosurgery,1 Pediatrics,2 and Radiology,3 Kurume University School of Medicine, Fukuoka, Japan

Purpose: This study aims to assess the effect of high-dose chemotherapy (HDT) with peripheral blood stem cell transplantation (PBSCT) for medulloblastoma in children. Materials and Methods: Between 1987 and 2004, 19 patients with 13 newly diagnosed or 6 recurrent medulloblastoma were enrolled. Thirteen newly diagnosed patients received surgical excision and carboplatin-based chemotherapy and patients except whose age was under 3 years old received irradiation prior to HDT. Six patients with recurrent medulloblastoma priory treated with surgery, chemotherapy, and radiation therapy were also received HDT with PBSCT at progression. Fifty percent of recurred patients received the additional boost irradiation. Results: Forty-six percent of newly diagnosed patients had complete surgical excision. All of these cases responded completely to HDT. Eighty-three percent of remaining patients with residual disease achieved complete remission after HDT with PBSCT. One patient has died because of toxicity. In recurrent medulloblastomas, all patients had disseminated disease at progression. After the HDT with PBSCT, one of six (16.7%) patients showed complete response and four of six (66.7%) had partial response. With a median follow-up time of 48.2 months in newly diagnosed medulloblastomas, disease-free, stable disease, and died patients were 53.8%, 15.4% and 31%, respectively. Conclusion: HDT with PBSCT was well tolerated for newly diagnosed medulloblastomas; however, recurrent cases still may require more aggressive treatment.

THER 81. TREATMENT OF HIGH-RISK MEDULLOBLASTOMAS IN CHILDREN ABOVE THE AGE OF 3 YEARS: THE SFOP TC 04/94 STUDY

Joris Verlooy, Chantal Kalifa, Jean-Claude Gentet, Didier Frappaz, Christine Edan, Pascal Chastagner, Eric Sariban, Anne Pagnier, Annie Babin, Sylvia Neuenschwander, Danielle Bours, Veronique Mosseri, Christian Carrie, and Doz F; Institut Curie, Paris, France

Aim: improvement of disease-free survival of children with high-risk medulloblastoma. Patients: Between 1993 and 1999, 114 patients (3–18 years, mean 8 years) with diagnosis of high-risk medulloblastoma were included. Mean follow-up was 56 months (9–95). After surgery treatment consisted of 4 courses of postoperative (“sandwich”) chemotherapy (2x ‘8in1’ and 2x etoposide/carboplatin) followed by craniospinal radiotherapy (FP 55 Gy, Brain 30.6 Gy, axis 36 Gy), and 4 cycles of postradiotherapy chemotherapy (alternation of ‘8in1’ and etoposide/carboplatin). Results: Patients were staged according to Chang-criteria: solitary FP residue: 27, M1: 20, M1 and FP residue: 5, M2/M3 (without consideration of FP or M1): 62. Sandwich chemotherapy was well tolerated and administered completely in 93 patients; one chemotherapy course was omitted in 21 patients. Median delay between surgery and radiotherapy was 98 days with a median radiotherapy duration of 44 days. Postradiotherapy chemotherapy was completed in 74 patients, incomplete in 23, and 15 did not receive any. Toxicity was mainly haematological: grade 3 and 4 anaemia and thrombocytopenia. Grade 3 and 4 infections during chemotherapy were more important during sandwich chemotherapy. There were no toxic deaths. Intermediate evaluation before radiotherapy was available for 113 patients: CR was observed in 38, PR (>50%) in 28, and PR (<50%) in 16 patients. Seventeen patients had stable disease, whereas 10 showed progression. Kaplan Meier analysis showed Disease-Free Interval at 3 years of 54% ± 9% and OS 68% ± 9%. In detail according to subgroups, DFI was 65% for PF residue only, 50% for M1 disease, and 52% for M2/M3. Conclusion: The proposed treatment protocol is well tolerated. DFS of metastatic medulloblastoma patients is 54% at 3 years.

THER 82. PRIMARY CENTRAL NERVOUS SYSTEM DISSEMINATION OF CHILDHOOD HIGH-GRADE GLIOMAS

1Sabine Wagner, 2Martin Benesch, 3Frank Berthold, 4Astrid Gnekow, and Johannes E.A. Wolff; Department of Pediatric Oncology of 1Regensburg, Germany; 2Graz, Austria; 3Köhn, Germany; 4Augsburg, Germany; Calgary, Canada

Primary central nervous system (CNS) dissemination of high-grade gliomas (HGG) is rare. To assess incidence, clinical characteristics, and outcome, a retrospective chart review of all HGG patients (n = 353) enrolled into four consecutive high-grade glioma protocols (HIT-GBM) of the German Society for Pediatric Hematology and Oncology (GPOH) from 1995 until January 2003 was conducted. A total of ten patients with high-grade gliomas presented with CNS dissemination (3.5%). Median age at diagnosis was 9.3 years (range, 0.3–21.3 years). No significant differences were found between the group with primary CNS dissemination and the group without dissemination, with regard to gender, age, and histological grading. Three patients had anaplastic astrocytoma (AA), six glioblastoma multiforme (GBM), and one patient diffuse intrinsic pons glioma. The most frequent primary tumor sites were the cortex (n = 4), followed by the ventricles (n = 2), cerebellum (n = 1), spinal cord (n = 1), and pons (n = 1). One patient had diffuse gliomatosis cerebri. Following initial surgery (biopsy: n = 5, partial resection: n = 2, subtotal/total resection: n = 2), seven patients received local radiotherapy and eight additional chemotherapy (HIT-GBM-A: n = 1, HIT-GBM-B: n = 1, HIT-GBM-C: n = 2, HIT-GBM-D: n = 2, HIT-SKK: n = 2). At a median follow-up of 10 months (range, 0.05–3 years), four patients are alive. Median progression-free (PFS) and overall survival (OS) was 0.8 years (95% CI 0.2–1.4) and 1.5 years (95% CI 0.67–2.29), respectively. No statistically significant differences were observed with regard to OS and PFS between the two groups. We conclude that prognosis of patients with high-grade gliomas and primary CNS dissemination is not inferior to patients without CNS dissemination.

THER 83. CPT-SIOP-2000 STUDY: AN INTERIMS ANALYSIS

Sabine Wagner,1 Tezer Kutluk,2 Ute Bartels,3 Albert Moghrabi,4 Tim Hassall,5 Jonathan Finlay,6 Werner Paulus,7 and Johannes E.A. Wolff1,8; 1Pediatric Oncology, Regensburg, Germany; 2Haematology/Oncology, Ankara, Turkey; 3Pediatric Oncology, Mainz, Germany; 4Haematology/Oncology, Victoria, Australia; 5Haematology/Oncology, Montreal, Canada; 6Children’s Hospital, Los Angeles, USA; 7Department of Neuropathology, University of Münster, Germany; 8Children’s Hospital, University of Calagary, Canada

Background: The CPT-SIOP-2000 study is a world wide study for children and adults with choroid plexus carcinomas. Choroid plexus tumors are rare with an incidence of 0.4–0.8% of all brain tumors. There is little evidence available for the best treatment. Patients and Methods: Children and adults with choroid plexus tumors are enrolled in this study. Surgery is followed by a wait and see approach for patients with choroid plexus papillomas (CPP) without metastases and for patients with anaplastic plexus papillomas (APP) without residual tumor and without metastases. For patients with choroid plexus carcinomas (CPC), APP with residual tumor or metastases and CPP with metastases, a total number of six chemotherapy cycles is given by randomization into either a carboplatin-etoposide-vincristine arm or a cyclophosphamide-etoposide-vincristine arm. After the first two cycles of chemotherapy, irradiation and resurgery have to be considered. Results: From October 2000 to January 2004, 36 patients (23 males) were documented with an median age of 2.2 years (range 0.2–45.6 years), 18 patients are 2 years or older. Patients were registered from Germany, Australia, Canada, Belgium, Turkey, U.S.A, Chile, New Zealand, Russia, Netherlands. 14 CPP, 7 APP, and 14 CPC (1 unknown) were mainly localized and in the right lateral ventricle (12/32) and in the left lateral ventricle (8/32). 9 patients were treated according to the cyclophosphamidearm, 8 patients according to the carboplatin–arm (14 CPP untreated, 5 not documented). Response data of 11 patients after the first two cycles of chemotherapy are: CCR n = 3 (1 cyclo-arm, 2 carbo-arm), CR 1/8 (cyclo-arm), PR 3/8 (1 cyclo -arm, 2 carbo-arm), SD 4/11(2 cyclo-arm, 2 carbo-arm), PD 0/11. The median time-to-progression between CPP (no event) and CPC (0.87 years) is significantly different (p = 0.0295). Conclusion: There are more adult patients than expected. The preliminary treatment results are encouraging.

THER 84. THE IMPACT OF EXTENT OF SURGICAL RESECTION OF CONSENSUS-REVIEWED PEDIATRIC INTRACRANIAL HIGH-GRADE GLIOMA ON OUTCOME: A REPORT OF THE CHILDREN’S CANCER GROUP TRIAL NO. CCG-945

James D. Weisfeld-Adams., Dermot M. Murphy, Jeffrey H. Wisoff, Richard Sposto, David Young, and Jonathan L. Finlay; Department of Paediatric Oncology, Schiehallion Unit, Royal Hospital for Sick Children, Glasgow, UK, on behalf of the Children’s Oncology Group, Arcadia, CA, USA

Objectives. We sought to evaluate the influence of extent of neurosurgical resection on outcome in 219 pediatric patients enrolled on the CCG-945 trial between 1985 and 1992 with intracranial high-grade glioma (excluding brainstem glioma). One hundred and sixty-seven patients in whom diagnoses of high-grade glioma were confirmed at consensus panel review by five independent neuropathologists are the subject of this report. Of the remaining 52 cases, 40 were diagnosed as low-grade glioma at consensus panel review. Methods. Patients were stratified into groups according to extent of tumor resection, tumor location, and histopathology. After consensus review, tumors were classified as anaplastic astrocytoma (n = 93), glioblastoma multiforme (n = 60), and ‘other’ high-grade glioma (n = 14). Statistical analysis was performed using Minitab (version 13). A radical resection (defined as resection of >90% of tumor mass) was performed in 39.5% patients in the group as a whole, but only accomplished in 6.8% of patients with primary tumors of the deep cerebrum or midline structures. Results. Univariate and multivariate analysis revealed that radical resection was associated with significantly improved five-year event-free survival (p < 0.0001) and overall survival (p = 0.0026) rates, independent of tumor location. A highly significant association (p < 0.0001) was detected between primary location and extent of resection. For patients with confirmed diagnoses of high-grade glioma, radical resections were associated with superior survival outcomes compared to lesser resections in terms of both five-year overall survival (42 ± 4% vs. 25 ± 4%; p = 0.0183) and five-year event-free survival (36 ± 5% vs. 18 ± 3%; p = 0.0056); the effect of radical resection was greatest in children with glioblastoma multiforme (overall survival: 29 ± 4% vs. 3 ± 1.5%, p = 0.0091; event-free survival: 25 ± 4% vs. 3 ± 1.5%, p = 0.0201). Conclusions. This large multi-institutional study demonstrates that extent of surgical resection and tumor location significantly and independently influence long-term outcome in children with consensus panel diagnoses of high-grade glioma.

THER 85. PROLONGED LOW-DOSE ORAL ETOPOSIDE IN CHILDREN WITH RELAPSED AND REFRACTORY BRAIN TUMOURS

T. Yanagisawa, N. Akiyama, K. Yokoi, Y. Yuza, Y. Katoh, K. Fujisawa, Y. Hoshi, T. Johki,1 T. Takahashi,1 H. Nakasaki,1 S. Ohi,1 T. Abe,1 J. Fujigasaki,2 and Y. Etoh; Department of Paediatric Oncology, 1Department of Neurosurgery, and Department of Neuropathology, Jikei University School of Medicine, Tokyo, Japan

Background: Prolonged low-dose oral etoposide, which exploits the schedule dependency of the agent, has sometimes demonstrated increased activity in both haematological and solid malignancies in children compared with bolus administration. Purpose: A prospective Phase II study has been conducted in our institute to evaluate the efficacy and toxicity of prolonged schedule second- or third-line oral etoposide in children with relapsed or refractory malignancies in a palliative treatment setting. Methods: Patients were treated with oral etoposide (50 mg/m2/day given daily for 21 consecutive days every 4 to 5 weeks) after failing in medical, radiological, and/or surgical treatments. Endpoint for follow-up was disease progression or death. Three patients with brain tumors were entered. Patient 1: 6-year-old boy with suprasellar mature teratoma with malignant component. Two years after the initial treatment with repeated surgeries, radiotherapy, and chemotherapy, he had local relapse. Failing in ICE and BEP regimen chemotherapy and gamma-knife treatment, oral etoposide was initiated for progressive tumor. Stable disease duration was 28 months only with oral etoposide. Patient 2: 4-year-old girl with suprasellar immature teratoma. 6 months after high-dose chemotherapy with thiotepa and etoposide regimen for the first local relapse, tumor regrowth was noticed. Oral etoposide was initiated for progressive tumor after failing in ICE regimen chemotherapy. Progression-free survival was 11 months. Patient 3: 1-year-old girl with pontine low-grade astrocytoma. Oral etoposide was begun after failing in initial chemotherapy with vincristine and carboplatin. She is alive at home for 21 months with stable disease. Conclusion: Chronic oral etoposide appeared to be well tolerated, had modest toxicity, and showed excellent palliative effect in the children with recurrent and refractory brain tumors, including heavily pretreated children who progressed during conventional chemotherapy. Further large-scale investigation seems justified particularly in poor-risk intracranial germ cell tumors to determine the indication and the optimal use of oral etoposide.

THER 86. EFFICACY OF HIGH-DOSE CYCLOPHOSPHAMIDE WITH ETOPOSIDE AND VINCRISTINE (“VETOPEC”) IN VERY HIGH-RISK PAEDIATRIC BRAIN TUMOURS

David S. Ziegler, Richard J. Cohn, Geoffrey McCowage, Frank Alvaro, Cecilia Oswald, Robert Mrongovius, and Les White, for the Australian and New Zealand Children’s Cancer Study Group; Sydney Children’s Hospital, Randwick, NSW, Australia

Objective: To assess the efficacy of the “VETOPEC” combination with escalating doses of cyclophosphamide (CPA) in paediatric patients with high-risk brain tumours. Method: Since 1991 the ANZCCSG has conducted three studies utilising high-dose CPA in high-risk paediatric solid tumours. Children <4 years of age with newly diagnosed malignant brain tumours were treated in the “Baby Brain í91” study with CPA 120 mg/kg/cycle plus etoposide (VP) and vincristine (VCR). Patients with high-risk solid tumours (with an expectation of <25% 2-year survival), including relapsed or progressive brain tumours, were treated in the “VETOPEC I” study with VP, VCR, and CPA at 90 mg/kg/cycle escalating to 165 mg/kg/cycle in successive cycles. The “VETOPEC II” study treated similar high-risk patients with VP, VCR, and CPA at doses ranging from 180 mg/kg/cycle to 270 mg/kg/cycle, supported by peripheral blood stem cell rescue. The maximum tolerated dose of CPA was not reached. We assess the response to these intensive therapies of the subset of patients with high-risk brain tumours treated with these protocols. Results: A total of 69 brain tumour patients were treated with “VETOPEC” based protocols. Of the 52 evaluable patients, 17 had a complete response (CR) and 19 a partial response (PR) to treatment, resulting in an overall response rate of 69%, (medulloblastoma 19/23; PNET 5/9; grade 3 and 4 astrocytomas 5/10 and ependymomas 6/8). Escalating doses of CPA did not appear to be associated with improving response. At a median follow-up of 40 months, OS was 36% with EFS 13%. There were no toxic deaths in the PBSC supported “VETOPEC II” cohort, despite higher CPA doses, compared with 11% in the nonrescued patients. Conclusion: This construct produces high response rates in paediatric patients with very poor-risk brain tumours. Long-term survival remains poor. With PBSC rescue in “VETOPEC II” study, haematologic toxicity was no longer a limiting factor and toxicity was manageable. The response rates observed warrant further development of treatment regimens.

THER 87. CURE OF CHILDREN LESS THAN THREE YEARS OF AGE WITH MEDULLOBLASTOMA (M0/M1-STAGE) BY POSTOPERATIVE CHEMOTHERAPY ONLY: FINAL RESULTS OF THE HIT-SKK’92 STUDY

Stefan Rutkowski, Udo Bode, Frank Deinlein, Holger Ottensmeier, Monika Warmuth-Metz, Niels Sörensen, Norbert Graf, Angela Emser, Torsten Pietsch, Johannes E.A. Wolff, Christian Urban, Rolf-D. Kortmann, and Joachim Kuehl, for the German Pediatric Brain Tumor Study Group; Pediatric Oncology, Children’s Hospital, University of Wuerzburg, Wuerzburg, Germany

Design: HIT-SKK’92 was designed to improve poor outcome and quality of life of children younger than 3 years with medulloblastoma by intense postoperative chemotherapy only. Patients received 3 cycles of chemotherapy with 800 mg/m2 cyclophosphamide (d1,2,3), 5 g/m2 MTX (d15,29), 1.5 mg/m2 vincristin (d1,15,29), 200 mg/m2 carboplatin (d43,44,45), 150 mg/m2 VP-16 (d43,44,45), and 2 mg MTX intraventricular (d1,2,3,4, 15,16,29,30,43,44,45,46). Radiotherapy was not recommended for children in CR. Results: Between April ’92 and December ’97, 45 of 62 eligible patients were treated according to protocol. 5-year PFS and OS were 55.5 ± 7.7% and 63.3 ± 7.4%, respectively. PFS was better in 19 patients with desmoplastic medulloblastoma (84.2 ± 8.4%) as compared to classical medulloblastoma (34.2 ± 9.4%; p < 0.0005). 14 of 18 patients without postoperative residual tumor and without metastasis remained in CCR (5-year PFS 77.8 ± 9.8%) without radiotherapy. In 14 children with postoperative residual tumor, but without metastasis, the 5-year-PFS and OS were 50.0 ± 13.4% and 56.3 ± 13.5%. PFS and OS were lower in 13 patients with M2/M3-stage (30.7 ± 12.8%, and 34.6 ± 14.4%, p = 0.001). Classic histology of medulloblastoma, macroscopic metastasis, M1-stage, and age <2 years were identified as unfavourable prognostic factors by multivariate analysis. No major unexpected toxicity was reported from systemic and intraventricular chemotherapy. A significant correlation was found between cumulative doses of intraventricular methotrexate and grade of leukencephalopathy (r = 0.53; p < 0.01). Full-scale IQ of nonirradiated children (n = 14) was significantly higher (p < 0.005, CPM 92 vs. 79, md 4.7 years after treatment) as compared to irradiated patients from the former trial HIT-SKK-87 (n = 14), who did not receive intraventricular MTX. Conclusion: HIT-SKK’92 chemotherapy was highly effective in infants with medulloblastoma, especially for the subgroup without metastasis and without postoperative residual tumor. Omission of radiotherapy appears to contribute to a better quality of life in children cured from medulloblastoma. For patients with initial metastases, high-dose chemotherapy and other strategies are currently evaluated. This work was supported by German Cancer Aid.

THER 88. THE ROLE OF CHEMOTHERAPY IN THE MULTIDISCIPLINARY MANAGEMENT OF LOW-GRADE GLIOMAS IN THE BRAINSTEM: A PROSPECTIVE MULTICENTRIC STUDY OF THE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY (SFOP)

A. Pagnier,1 J. Grill,2 A. Lellouch-Tubiana,3 C. Durand,4 F. Nugues,4 J.G. Passagia,5 M.A. Raquin,2 E. Sariban,6 X. Rialland,7 P. Lutz,8 A. Pierre Kahn,3 C. Kalifa,2 and D. Plantaz1; Departments of Paediatric Hematology/Oncology,1 Radiology,4 and Neurosurgery,5 University Hospital, Grenoble; Departments of Paediatrics, Institut Gustave Roussy, Villejuif2; Departments of Pathology, Necker Hospital, Paris3; Departments of Paediatric Haematology/Oncology, Children’s Hospital, Bruxelles6; Departments of Paediatrics, General Hospital, Angers7; Departments of Paediatrics, University Hospital, Strasbourg8; France

Background: Brain stem gliomas represent a therapeutic challenge when complete surgery is not achievable. In order to postpone or avoid RT in young children that cannot be cured by surgery only, we used chemotherapy in low-grade brain stem gliomas since 1990. Patients and Methods: Eligible patients were children with newly diagnosed or recurrent low-grade astrocytoma as confirmed by central review. The BBSFOP regimen consists in 7 cycles of 3 combinations (procarbazine-carboplatine, etoposide-cisplatinum, and vincristine-cyclophosphamide), with a duration of 15 months. Results: 19 children (median age 36.5 months) were treated in 8 institutions (1990–2001). 12 children were treated initially, and 6 at the time of relapse or progression of a residue. Initial surgery was biopsy in 7, partial resection in 9, and subtotal resection in 2. The diagnosis of low-grade was retrospectively confirmed by histopathological review in 16/19 patients, of which 11 pilocytic astrocytomas. 12 patients had an objective response to BBSFOP regimen (2 CR, 6 GPR, 3 PR, 1OE), and 2 showed stable disease in the 14/16 patients with correct imaging workout. PFS of patients with confirmed LGG histology, after BBSFOP chemotherapy, at 5 years was 60,94% +/− 13%, including 3 patients who received RT at the end of the CT. Overall Survival is 93,3% +/− 6,4% at 5 years with a median follow-up of 81 months. 11 children are alive progression free without recourse to RT. Conclusion: Given the response rate to CT of these tumors, this treatment should take place in the global management of low-grade gliomas in the brain stem. The benefits in term of survival and long-term side effects will have to be evaluated in further studies. Key words: astrocytoma, low grade, brain stem, chemotherapy, child.

THER 89. EXPERIENCE OF MIDAZOLAM WITH CHILDREN DYING FROM BRAIN TUMORS

Joanne Pearson, Nicholas Foreman, and Karen Tilley; Department of Neuro-Oncology, The Children’s Hospital, Denver, CO, USA

Background/Purpose: Children dying from brain tumors have been difficult to manage at home and have required hospitalization for breakthrough symptoms and family respite. Sudden pain, vomiting, seizures, and other distressing neurologic symptoms made it difficult to manage with oral/rectal medications in the home. Parents would exhaust giving medications that often failed to provide relief and were increasingly more difficult to administer as function was lost in the dying process. The hypothesis was intravenous Midazolam would improve the quality of life of the child and simplify care by parents. This would enhance the quality of life and prevent unnecessary hospitalization. Intervention: A protocol was developed by our neuro-oncology team for the use of continuous infusion Midazolam, based on experience from England. The initial starting dose was 100mcg/hour with a plan for dose escalation based on assessment of the child. Parents and care providers required education about the benefits of iv Midazolam, administration, dosing, and seizure risk if medication suddenly stopped. Management was a collaborative effort between hospice, parents, and neuro-oncology. Outcome: Midazolam by continuous infusion was administered to children dying from brain tumors after 1997. Seizures, vomiting, anxiety, and restlessness were controlled. It was useful to relieve pain and tightness from muscle spasticity. Surprisingly, patients were less lethargic and more interactive. Families felt like they had more quality time with their child and were empowered with more control over comfort and symptom management. Continuous Midazolam increased the confidence of neuro-oncology staff in their management of dying children. This approach also prompted earlier discussion of terminal care with the family, facilitated referral to hospice, and earlier initiation of Midazolam at home. Education and staff availability guided the use and established the role of Midazolam in terminal care in the home. Chart review is underway to look at dose range and complications.

THER 90. CHEMOTHERAPY IN CHILDREN WITH SUPRATENTORIAL PNET AGED 3 TO 18 YEARS: RESULTS OF THE HIT′91 TRIAL

Stefan Rutkowski, Bernward Hinkes, Frank Deinlein, Julia Becker, Monika Warmuth-Metz, Niels Sörensen, Udo Bode, Norbert Graf, Frank Berthold, Johannes Wolff, Peter Kaatsch, Torsten Pietsch, Rolf-D. Kortmann, Uwe Mittler, Christian Urban, and Joachim Kuehl, for the German Pediatric Brain Tumor Study Group; Pediatric Oncology, Children’s Hospital, University of Wuerzburg, Wuerzburg, Germany

Aim: To assess efficacy and timing of chemotherapy in children with supratentorial primitive neuroectodermal tumors (stPNET) aged 3 to 18 years. Design: The HIT’91-trial was designed for children with medulloblastoma, stPNET, anaplastic ependymoma, and high-grade glioma. Patients received either PRERT-CTH consisting of 8 courses of DDP, CCNU, VCR and if response after RT was poor additional 8 cycles of CARBO, CCNU, VCR, or POSTRT-CTH consisting of PROC followed by 2 cycles of IFO/VP16, hdMTX, and DDP/ARAC. RT consisted of 35.2 Gy to the neuraxis, followed by a local boost of 20 Gy for all patients. Patients: 34 patients with stPNET from 73 institutions were eligible for analysis. Twenty-nine patients were considered standard risk (SR, M0/M1). Five patients with macroscopic metastases were classified as high risk (HR, M2-/M3-stage), four of them received PRERT-CTH. Four patients with SR had pineoblastoma. Results: 5-year PFS and OS of all 34 patients were 39.0 ± 8.6% and 43.2 ± 8.6%, respectively. No significant difference was observed between the 20 patients receiving PRERT-CTH (5-year PFS and OS 40 ± 11.0%) and 14 patients treated with POSTRT-CTH (5-year PFS 32.7 ± 13.1%, OS 38.5 ± 13.5%). In SR patients, there was no difference of PFS between PRERT-CTH and POSTRT-CTH (43.8 ± 12.4% and 41.7 ± 14.2%, respectively). Four of the five HR patients died of PD within two years; one patient remains in CR after 94 months. All four patients with pineoblastoma are remaining in CR 60 to 109 months after diagnosis. Conclusion: In contrast to medulloblastoma, no advantage of pre vs. postradiation chemotherapy was found in stPNET. The HIT’91 trial confirms the need of further modification and intensification of therapy in patients with stPNET, especially in the HR-group. It also indicates a better prognosis for patients with pineoblastoma within the group of stPNET. This work was supported by the German Cancer Aid and the German Childhood Cancer Foundation.


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