Oral Presentations 01 Medulloblastoma/Cns-Pnet—Biology

Neuro-Oncology 12(6):ii1–ii134, 2010. doi:10.1093/neuonc/noq043

show that a previously unidentiﬁed molecular subgroup, characterized NEURO-ONCOLOGY genetically by high-level c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-96 182 183 expression, is associated with signiﬁcantly lower rates of event free and overall survival. CONCLUSION: Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized Abstracts molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.

MED.03. DNA METHYLOMICS IDENTIFIES CLINICALLY ORAL PRESENTATIONS SIGNIFICANT EPIGENETIC SUBGROUPS OF 01 MEDULLOBLASTOMA/CNS-PNET—BIOLOGY MEDULLOBLASTOMA E. C. Schwalbe1, J. C. Lindsey1, M. E. Lusher1, K. O’Toole1, S. L. Nicholson1, R. J. Gilbertson2, R. Taylor3, P. Hauser4, D. W. Ellison2,

5 5 1 1 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 MED.01. MEDULLOBLASTOMA COMPRISES FOUR DISTINCT B. Dembowska-Bagin´ ska , D. Perek , S. Bailey , and S. C. Clifford ; 1 2 DISEASES Newcastle University, Newcastle upon Tyne, United Kingdom; St Jude 3 P. A. Northcott1, A. Korshunov2, H. Witt2, T. Hielscher2, C. Eberhart3, Children’s Research Hospital, Memphis, TN, United States; South Wales 4 S. Mack1, E. Bouffet1, S. Clifford4, C. Hawkins1, P. French5, J. Rutka1, Cancer Institute, Swansea, United Kingdom; Semmelweis University, 5 S. Pfister2, and M. D. Taylor1; 1The Hospital for Sick Children, Toronto, Budapest, Hungary; The Children’s Memorial Health Institute, Warsaw, ON, Canada; 2German Cancer Research Center, Heidelberg, Germany; Poland 3Johns Hopkins University, Baltimore, MD, United States; 4Newcastle University, Newcastle, United Kingdom; 5Erasmus University Medical We undertook a genome-wide screen to assess DNA methylation patterns Center, Rotterdam, Netherlands in a cohort of 101 medulloblastomas to investigate their utility for disease sub-classification. For the first time, we demonstrate that medulloblastomas Recent genomic approaches have suggested the existence of multiple dis- cluster into four distinct methylomic subgroups. We observed significant tinct subtypes of medulloblastoma. We performed an integrative analysis relationships between specific subgroups and aberrations of the Wnt and on a cohort of 103 primary medulloblastomas using a combination of Sonic Hedgehog (Shh) embryonal signalling pathways. One subgroup (desig- Affymetrix expression and SNP genotyping arrays to determine how many nated 2) was highly enriched for Wnt-subtype medulloblastomas (character- subgroups of the disease exist, how they differ, and the extent of overlap ised by Wnt pathway activation, chromosome 6 loss and CTNNB1 between subgroups. Multiple unsupervised analyses of transcriptional pro- mutation). This subgroup was associated with a favourable prognosis, files identified four distinct, non-overlapping molecular subgroups: WNT, classic histology and did not include infant cases. Shh pathway-activated SHH, Group C, and Group D. Supervised analysis of these four subgroups tumours were associated with subgroups 3 and 4. These closely related sub- revealed significant subgroup-specific demographics, histology, metastatic groups were significantly enriched for tumours of nodular/desmoplastic his- status, and DNA copy number aberrations. Immunohistochemical staining tology, but differed in their age distribution. Subgroup 1 was associated with for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group expression signatures of the previously postulated non-Shh/non-Wnt tran- D) performed on two separate medulloblastoma tissue microarrays contain- scriptomic subgroups C and D/E (Kool et al. 2008), but the existence of dis- ing 294 non-overlapping tumors demonstrated that 98% (288/294) of cases crete sub-clusters within subgroup 1 could not be identified confidently. All stained positive for only a single marker. Leptomeningeal dissemination was four methylomic subgroups identified validated successfully in an indepen- highly over-represented in Group C (47%) followed by Group D (30%) dent medulloblastoma cohort (n ¼ 50). We subsequently identified the patients. Importantly, Group C patients exhibited a significantly diminished most discriminatory DNA methylation events that defined each of the four progression-free and overall survival irrespective of their metastatic status. subgroups, including events specifically associated with subgroup 1, repre- Our integrative genomics approach to a large cohort of medulloblastomas senting the first description of gene-specific molecular defects in non-Wnt/ has identified four non-overlapping subgroups with distinct demographics, non-Shh medulloblastomas. These distinct epigenetic subtypes, which clinical presentation, transcriptional profiles, genetic abnormalities, and clini- display strong associations with underlying molecular events, transcriptomic cal outcome. While these four entities fall under the histological diagnosis of profiles and clinical features, provide further evidence for the existence of dis- medulloblastoma, they likely represent separate and distinct diseases. crete disease subtypes of medulloblastoma. DNA methylomics offers signifi- Medulloblastomas can be reliably assigned to subgroups through immunohis- cant potential for medulloblastoma sub-classification, risk-assessment and tochemistry, thereby making medulloblastoma sub-classification widely avail- the identification of novel molecular events. able. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. MED.04. MICRO-RNA EXPRESSION SIGNATURES DISCRIMINATE MOLECULAR RISK GROUPS IN MED.02. INTEGRATIVE GENOMIC ANALYSIS OF MEDULLOBLASTOMA 1,2 1,2 3 4,5 1 MEDULLOBLASTOMA IDENTIFIES A MOLECULAR SUBGROUP A. H. Bai , M. Remke , P. Northcott , A. Korshunov , G. Toedt , 6 2,7 8 1 THAT DRIVES POOR CLINICAL OUTCOME A. Benner , M. Castoldi , W. Scheurlen , A. Pscherer , 2,7 2 1 3 Y. Cho1,2, P. Tamayo3, A. Tsherniak3, H. Greulich3,J.Lu4, M. Kool5, M. U. Muckenthaler , A. E. Kulozik , P. Lichter , M. D. Taylor , and 1,2 1 T. Zhou6, C. G. Eberhart7, J. M. Olson8, C. C. Lau9, M. Meyerson2,3, S. M. Pfister ; Division Molecular Genetics, German Cancer Research 2 J. P. Mesirov3, and S. L. Pomeroy1; 1Children’s Hospital Boston, Boston, Center (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, MA, United States; 2Dana-Farber Cancer Institute, Boston, MA, United Hematology & Immunology, University of Heidelberg, Heidelberg, 3 States; 3Broad Institute of MIT and Harvard, Cambridge, MA, United States; Germany; Division of Neurosurgery, Arthur and Sonia Labatt Brain 4Yale University Medical Center, New Haven, CT, United States; 5Academic Tumour Research Centre, Program in Developmental and Stem Cell Biology, Medical Center, Amsterdam, Netherlands; 6Children’s Oncology Group, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 4 Acadia, CA, United States; 7Johns Hopkins Medical Center, Baltimore, MD, Department of Neuropathology, University of Heidelberg, Heidelberg, 5 United States; 8Fred Hutchinson Cancer Research Center, Seattle, WA, Germany; Clinical Cooperation Unit Neuropathology, German Cancer 6 United States; 9Texas Children’s Hospital, Houston, TX, United States Research Center (DKFZ), Heidelberg, Germany; Division Biostatistics, German Cancer Research Center (DKFZ), Heldelberg, Germany; 7 PURPOSE: Medulloblastomas are heterogeneous tumors that collectively Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany; 8 represent the most common malignant brain tumor in children. To better Cnopf’sche Kinderklinik, Nu¨ rnberg Children’s Hospital, Nu¨ rnberg, understand the molecular characteristics underlying their heterogeneity Germany and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis on a large Medulloblastoma (MB) is the most frequent malignant brain tumor in series of primary tumors. PATIENTS AND METHODS: We profiled the children. To gain a better insight into the molecular biology of MB, we mRNA transcriptome of 194 medulloblastomas and performed high-density aimed to determine a microRNA signature distinguishing between high SNP array and miRNA analysis on 115 and 98 of these, respectively. and low molecular risk groups. This signature was used to select putative Non-negative matrix factorization-based clustering of mRNA expression candidate microRNAs for further functional studies. Based on genomic data was used to identify molecular subgroups of medulloblastoma and imbalances, patients were separated into a high molecular risk group (17q DNA copy number, miRNA profiles, and clinical outcomes were analyzed gain, 6q gain and/or MYC/MYCN amplification) and a standard molecular for each. RESULTS: Identified are 6 distinct molecular subgroups of medul- risk group (6q deletion, balanced copy-number status for MYC/MYCN, 6q loblastoma, each with a unique combination of DNA copy number altera- and 17q). Samples were analyzed by microRNA expression profiling (737 tions that globally influence mRNA and miRNA expression. We reveal the microRNAs). Unsupervised hierarchical clustering and SAM was applied relative contribution of each subgroup to clinical outcome as a whole and to determine microRNA signatures discriminating between molecular risk

Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2010. Abstracts

groups. MicroRNA signatures were validated in an independent set of MB microscopical pictures of a given lesion; moreover it permits to analyze intra- (n ¼ 90). Expression of candidate microRNAs was further confirmed by tumoural variability. Medulloblastomas have been classified according to the using QRT-PCR. Unsupervised hierachical clustering based on the WHO 2007 classification. Twelve MDB (five classic, three anaplastic, two microRNA expression profiles of 33 MB samples revealed two groups clearly after radiotherapy, one nodular, one melanotic) were studied by 2- congruent with molecular risk groups. SAM analysis delineated 43 dimensional electrophoresis. Proteins were identified by peptide mass finger- microRNAs best distinguishing between high and standard risk groups in the printing. Following protein identification, quantitative gene expression pro- screening and the validation set. Strikingly, we found miR-96, miR-182 and filing was performed for all different proteins identified in every group. The miR-183 to be highly expressed in patients with higher molecular risk. combination of proteomic identification coupled with quantitative gene Functional studies showed that stable over-expression of these miRNAs signifi- expression techniques allowed simultaneous study of a large number of pro- cantly increased the migratory and invasive properties of the MB cell line teins. In every tumour about one hundred proteins have been studied as D458Med. Taken together, our data suggest a functional role of these retina typical of medulloblastomas. Proteins most consistently expressed in specific microRNAs in the pathogenesis of high-risk MB. Further studies are tumours with “classical” histology belong to many categories, such as required to elucidate the potential of these miRNAs for target therapies includ- “stress response proteins (HPS)” and proteins involved in neoplastic trans- ing antagomirs. formation. The results of this combined approach are shown. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021

MED.07. MYC GENE FAMILY AMPLIFICATION AND MED.05. CLINICAL, PATHOLOGICAL, AND MOLECULAR EXPRESSION IN CHILDHOOD MEDULLOBLASTOMA: VARIABLES DEFINE RISK-STRATIFICATION GROUPS IN BIOLOGICAL SIGNIFICANCE AND UTILITY FOR HIGH-RISK CHILDHOOD MEDULLOBLASTOMA DISEASE STRATIFICATION D. W. Ellison1, H. Megahed2, M. Kocak1, J. Dalton1, S. L. Ryan2, S. C. Clifford1, S. L. Ryan1, M. Cole1,Y.Lu1, M. E. Lusher1, K. o’Toole1, M. Lusher2, C. Fraga1,W.Zhao1, S. L. Nicholson2, K. Robinson3, S. Nicholson1, P. Hauser2, R. E. Taylor3, S. Bailey1, and D. W. Ellison4; R. E. Taylor4, S. Bailey2, and S. C. Clifford2; 1St. Jude Children’s Research 1Northern Institute for Cancer Research, Newcastle University, Newcastle Hospital, Memphis, TN, United States; 2University of Newcastle, Newcastle, upon Tyne, United Kingdom; 2Semmelweis University, Budapest, Hungary; United Kingdom; 3University of Leicester, Leicester, United Kingdom; 3South Wales Cancer Institute, Swansea, United Kingdom; 4Department of 4University of Swansea, Swansea, United Kingdom Pathology, St. Jude Children’s Research Hospital, Memphis, TN, United States Medulloblastomas are heterogeneous and include good prognosis tumors characterized by Wnt-pathway activation. Developing a therapeutic stratifi- INTRODUCTION: Refined disease-risk assessment and therapeutic stra- cation that includes accurate identification of patients with low-risk disease tification is a major goal in medulloblastoma. The MYC gene family rep- offers the potential to reduce adjuvant therapy and minimize long-term resent the most commonly amplified disease loci, but their biological and adverse effects in a subgroup of survivors, while the identification of high- clinical significance require comprehensive assessment and validation. risk cases offers opportunities for treatment intensification to optimize METHODS: We examined MYC family copy number status in 292 medullo- chances of a cure. Using immunohistochemistry, iFISH, direct sequencing blastomas derived predominantly from the SIOP/UKCCSG PNET3 clinical and qPCR to identify tumors with a Wnt-pathway signature and those har- trial. MYC family gene transcript levels, alongside clinical, pathological boring copy number abnormalities (CNAs) of potential prognostic impor- and biological disease characteristics were also assessed, to establish their tance (MYC, MYCN, and chromosomes 6 and 17), we evaluated clinical, biological significance and potential application for disease-risk stratifica- pathological and molecular outcome indicators and stratification models in tion. RESULTS: Elevated copy numbers were detected for MYCC (6% a large (n ¼ 207) cohort of medulloblastoma patients with median age 8.4 (17/292)), MYCN (6% (18/292)) and, more rarely, MYCL (1% (3/292)). years (range, 3–16 years) and enrolled on the SIOP PNET3 trial. Heterogeneous intra-cellular patterns of gene amplification were consistently Metastatic disease and the large cell / anaplastic (LC/A) phenotype were observed, which always occurred against a background of copy number gain. the clinicopathological variables associated with poor progression-free survi- In multivariate analysis, MYCC or MYCN amplification, large cell/anaplas- val. Nuclear immunoreactivity for b-catenin, CTNNB1 mutation, and tic pathology, metastatic disease (M2–4) and male gender, were each inde- monosomy 6 all identified a group of good prognosis patients. MYC ampli- pendent hazards to survival in patients aged ≥3to,16 years at diagnosis. fication detected by iFISH was associated with poor outcome, but other A linear relationship was observed between increased MYCC and MYCN CNAs were not. Low-risk medulloblastomas were defined as b-catenin copy number and diminished survival, and all deaths in amplified cases nucleopositive tumors without LC/A phenotype or metastasis at presen- occurred within 38 months of diagnosis. Elevated transcript levels of tation. High-risk medulloblastomas were defined as tumors with LC/A MYCC and MYCN were associated with increased copy number, but also phenotype, MYC amplification, or metastatic disease. Low-risk, with the activation of developmental signalling pathways (e.g. Sonic hedge- standard-risk, and high-risk categories of medulloblastoma had significantly hog, Wnt). CONCLUSIONS: Our findings establish MYCC or MYCN (p , 0.0001) different progression-free and overall survivals. Integrating amplification as independent high-risk markers, and strongly support their molecular assays into stratification schemes for medulloblastoma alongside incorporation into combined schema, to define high-risk cases for assessment clinical and pathological outcome indicators can refine the current definition in future clinical trials. Regulation of MYCC and MYCN expression appears of disease risk and guide the use of adjuvant therapy. to be multifactorial and requires further investigation to establish its significance.

MED.06. SUBTYPES OF MEDULLOBLASTOMA ARE DIFFERENT DISEASES MED.08. THE PROTO-ONCOGENE LASP1 ON 17Q PROMOTES P. Gibson1, Y. Tong1, G. Robinson1, M. C. Thompson2, D. S. Currle1, METASTATIC DISEASE IN MEDULLOBLASTOMA C. Eden1, T. L. Hogg1, D. Finkelstein1, S. Pounds1,Y.Pei3, S. Brun3,Y.Lee1, M. Remke1,2, C. Traenka3, A. Korshunov4, S. Bender2, H. Witt1,2, F. Zindy1, J. C. Lindsey4, D. H. Gutmann5, F. A. Boop1, R. A. Sanford1, P. A. Northcott5, W. Scheurlen6, G. Reifenberger7, M. D. Taylor5, A. Gajjar1, S. C. Clifford4, M. F. Roussel1, P. J. McKinnon1, D. W. Ellison1, A. E. Kulozik1, P. Lichter2, E. Butt3, and S. M. Pfister1,2; 1Department of R. Wechsler-Reya3, and R. J. Gilbertson1; 1St Jude Children’s Research Pediatric Oncology, Hematology and Immunology, University Hospital Hospital, Memphis, TN, United States; 2The Cleveland Clinic, Cleveland, Heidelberg, Heidelberg, Germany; 2Division Molecular Genetics, German OH, United States; 3Duke University Medical Center, Durham, NC, United Cancer Research Center, Heidelberg, Germany; 3Institute of Clinical States; 4Northern Institute For Cancer Research, Newcastle upon Tyne, Biochemistry and Pathobiochemistry, University of Wurzburg, Wurzburg, United Kingdom; 5Washington University School Of Medicine, St Louis, Germany; 4Department of Neuropathology, University Hospital Heidelberg, MO, United States Heidelberg, Germany; 5Division of Neurosurgery, and Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Medulloblastoma (MDB) is an aggressive usually paediatric tumour ON, Canada; 6Cnopf’sche Kinderklinik, Nu¨ rnberg Children’s Hospital, located in the posterior fossa, and is considered an embryonal tumour. It is Nu¨ rnberg, Germany; 7Department of Neuropathology, the most frequent malignant paediatric tumour of the CNS; great improve- Heinrich-Heine-University, Du¨ sseldorf, Germany ments in survival have been achieved in recent years by multimodal therapeutic approaches, but cognitive and neuropsychological damages on Medulloblastoma is the most common malignant brain tumor and one of developing brain are still often relevant. A proteomic approach to the the leading causes of cancer-related mortality in children. Treatment failure study of these tumours may allow the identification of biomarkers which mainly occurs in metastatic tumors. These aggressive malignancies typically might be useful to subdivide patients in groups according to different carry an isochromosome 17 or 17q gain, a common cytogenetic hallmark of degrees of malignancy, thus allowing more effective therapeutic strategies. intermediate and high-risk medulloblastoma. To pinpoint the oncogene(s) The study has been performed on neoplastic tissue snap frozen at the time targeted by 17q gain, mRNA expression profiling was performed in of surgery. This allows a precise correlation between macro- and primary tumors with and without this imbalance. This comparison identified ii2 NEURO-ONCOLOGY † JUNE 2010 Abstracts

LIM and SH3 protein 1 (LASP1) as one of the most up-regulated genes on medulloblastoma cell lines and primary samples were treated with Shh and chromosome 17q in tumors with 17q gain. Strong association of LASP1 KAAD-cyclopamine (Shh antagonist). Preliminary data indicates that Bmi1 abundance with 17q gain and metastatic disease at diagnosis was revealed expression positively correlates with increasing Shh ligand concentrations. using quantitative real-time PCR (QRT-PCR) analysis in an independent Moreover, we observed that Shh pathway genes, such as Gli1 and Gli2, cor- cohort of 101 primary medulloblastoma patients. We then analyzed relate strongly with Bmi1 expression, suggesting a regulatory mechanism. protein expression by immunohistochemistry in a larger medulloblastoma Interestingly, it appears that KAAD-cyclopamine preferentially targets the cohort (n ¼ 207). High LASP1 protein expression was significantly associ- CD133+ population. Lastly, we performed knockdown experiments to ated with 17q gain, metastatic dissemination, and unfavorable outcome con- further delineate the regulatory mechanism between Shh and Bmi1. It firming our QRT-PCR data. Notably, multivariate analysis identified LASP1 appears that Hedgehog signaling not only drives Bmi1 expression, but expression as an independent novel prognostic marker for overall survival there may be a feedback mechanism where downstream effectors of Bmi1 and disease progression. In vitro experiments in three established medullo- may regulate Hedgehog signaling. blastoma cell lines showed a strong reduction of cell migration and proliferation upon LASP1 knockdown via siRNA, further indicating a functional role for LASP1 in high-risk medulloblastoma. Altogether, LASP1 constitutes a key regulator in the metastatic dissemination of medulloblastoma. LASP1 MED.11. INTERFERON SIGNALING: A DRIVING FORCE FOR expression additionally has a high potential to serve as a prognostic marker NEURAL PROGENITOR PROLIFERATION AND A NOVEL Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 in future prospective studies. In conclusion, LASP1 comprises a promising TARGET FOR MEDULLOBLASTOMA novel candidate gene for future targeted therapy approaches in high-risk T. R. Gershon and M. Deshmukh; University of North Carolina at Chapel medulloblastoma. Hill, Chapel Hill, NC, United States

Medulloblastoma is the most common malignant brain tumor in children. Established treatment is excessively morbid and fails to cure many patients. MED.09. PROGNOSTIC VALUE OF TP53 MUTATIONS IN Understanding the dynamics of medulloblastoma formation may lead to CHILDHOOD MEDULLOBLASTOMA more effective, less toxic therapies. Many lines of evidence indicate that E. Pfaff1, M. Remke1,2, D. Sturm1, H. Witt1,2, A. O. von Bueren3, medulloblastomas derive from excessive mitogenic activation of neural pro- A. Wittmann1, A. Scho¨ ttler1, W. Scheurlen4, A. E. Kulozik2, O. Witt2,5, genitors and current animal models draw on hyper-stimulation of Sonic A. von Deimling6,7, S. Rutkowski3, C. Hawkins8, U. Tabori8, P. Lichter1, Hedgehog (Shh) signaling in order to drive cerebellar progenitors to form A. Korshunov7, and S. M. Pfister1,2; 1Division Molecular Genetics, German tumors. Shh-pathway activation, however, is only seen in a subset of Cancer Research Center, Heidelberg, Germany; 2Department of Pediatric human medulloblastoma. We present evidence that the interferon-response Oncology, Hematology and Immunology, University Hospital Heidelberg, pathway is a novel mechanism that operates in parallel with Shh signaling Heidelberg, Germany; 3Department of Pediatric Hematology and Oncology, to promote proliferation of neural progenitors and medulloblastoma cells. University Medical Center Hamburg-Eppendorf, Hamburg, Germany; We found interferon-induced genes to be specifically expressed by proliferat- 4Cnopf’sche Kinderklinik, Nu¨ rnberg Children’s Hospital, Nu¨ rnberg, ing progenitors in the postnatal cerebellum and by medulloblastoma cells. Germany; 5Clinical Cooperation Unit Pediatric Oncology, German Cancer Stimulation of cerebellar progenitors with Shh caused up-regulation of Research Center, Heidelberg, Germany; 6Department of Neuropathology, interferon-related genes and phosphorylation of interferon substrates Stat1 University of Heidelberg, Heidelberg, Germany; 7Clinical Cooperation Unit and Stat3. Moreover, direct application of interferon-gamma caused pro- Neuropathology, German Cancer Research Center, Heidelberg, Germany; genitors to proliferate as effectively as Shh. Interferon substrates were also 8The Hospital for Sick Children, Brain Tumor Research Center, Toronto, activated in medulloblastoma, and inhibition of Jak2-mediated interferon ON, Canada signaling inhibited the growth of both cerebellar progenitors and medulloblastoma cells. We therefore propose a model in which canonical interferon Medulloblastoma (MB) is one of the leading causes of cancer related mor- signaling, activated in neural progenitors by either Shh or interferon-gamma, tality in childhood. Since 17p allelic loss (chromosomal locus of TP53)isa drives proliferation and tumorigenesis. Our findings reveal a previously hallmark cytogenetic lesion in sporadic MB and MB occur in patients with unknown connection between neural development, inflammation and Li-Fraumeni Syndrome (TP53 germline mutation), it is important to further cancer, and provide a rational basis and for considering elements of the cano- elucidate the role of TP53 mutations in MB. In the present study, we investi- nical interferon pathway, including Stat1, Stat3 and Jak2, as potential thera- gate the relationship between TP53 mutations, p53 immunostaining and cyto- peutic targets for medulloblastoma. genetic as well as clinical variables. Mutation analysis of all coding exons of TP53 by direct sequencing in a total of 321 primary MB revealed TP53 mutations in 5.9% of tumor samples. A strong positive correlation between TP53 mutation and p53 immunopositivity was observed rendering immunos- MED.12. TARGETING RESISTANCE TO SMOOTHENED taining an excellent surrogate marker for TP53 mutation. Surprisingly, TP53 ANTAGONISTS IN MEDULLOBLASTOMA BY INHIBITING THE mutations were not associated with 17p allelic loss and were even overrepre- PI3K PATHWAY sented in the prognostically favorable WNT-subgroup characterized by M. Dorsch1, S. Buonamici1, A. Wang1, R. Guo1, A. Vattay1, K. Hsiao1, CTNNB1 mutations (n ¼ 35). Survival probability was not worse for patients J. Yuan1, L. Ostrom1, P. Fordjour1, D. Anderson1, M. Morrissey1, who´s tumors carried both mutations (n ¼ 8). Since TP53 mutations, although J. Monahan1, J. Kelleher1, S. Peukert1, S. Pan2,X.Wu2, S. Maira1, quite infrequent in MB, were detected in all molecular and clinical subgroups C. Garcia-Echeverria1, N. Watkins3,Y.Yao1, C. Lengauer1, M. Warmuth1, and were not associated with patient outcome in our large cohort mostly D. Amakye1, and W. Sellers1; 1Novartis Institutes for Biomedical Research, treated with postoperative radiotherapy plus vincristine, cisplatin and lomus- Cambridge, MA, United States; 2Genomics Institute of the Novartis tine - in contrast to a recent report in a study population receiving a different Research Foundation, San Diego, CA, United States; 3Monash Institute of treatment (e.g., higher cumulative doses of alkylating agents) - we concluded Medical Research, Clayton, Australia (i) that TP53 mutations constitute a late event in medulloblastoma tumorigenesis and (ii) that the prognostic value of TP53 mutation status seems to be Smoothened (Smo) is a G-protein coupled receptor-like molecule that acti- dependent on the therapy regimen applied. vates the Hedgehog (Hh) signal transduction pathway. Mutations in Hh pathway genes, leading to constitutive activation of Smo, occur in sporadic medulloblastoma. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for treating this MED.10. REGULATION OF BMI1 BY THE SHH PATHWAY IN disease. However, acquired resistance has emerged as a challenge to targeted HUMAN MEDULLOBLASTOMA BRAIN TUMOUR INITIATING therapeutics and may limit their anti-cancer efficacy. Here, we describe novel CELLS mechanisms of acquired resistance to Smo antagonists in medulloblastoma. X. Wang, C. Venugopal, M. Lenkiewicz, and S. K. Singh; McMaster NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling University, Hamilton, ON, Canada and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched, a tumor suppressor in the Hh Overexpression of Bmi1 promotes cell proliferation and is required for pathway. However, after long-term treatment, evidence of acquired resist- Hedgehog (Hh) pathway-driven tumourigenesis. The objective of this ance was observed. Molecular analysis of resistant tumors revealed distinct study was to determine the role of Sonic Hedgehog (Shh) and Bmi1 in child- resistance mechanisms. Chromosomal amplification of Gli2, a downstream hood medulloblastomas sorted for neural stem cell marker, CD133. effector of Hh signaling, led to reactivated Hh signaling and restored Although current literature suggests that there is a correlation between Shh tumor growth. Unexpectedly, analysis of pathway gene-expression signa- pathway genes and Bmi1 expression, it is unclear whether downstream effec- tures selectively deregulated in resistant tumors identified increased phos- tors of Shh, such as Gli1 and Gli2, bind to and activate the Bmi1 promoter. phoinositide 3-kinase (PI3K) signaling as another potential resistance Our previous data have shown that Bmi1 is upregulated in the CD133- popu- mechanism. Probing the functional relevance of increased PI3K signaling, lation. We confirmed these findings with qRT-PCR by demonstrating that we demonstrated that the combination of NVP-LDE225 with the dual Shh and Bmi1 are both upregulated in the CD133- population in medullo- PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development blastomas. To address whether Shh induces expression of Bmi1, of resistance. Our findings have important clinical implications for future

NEURO-ONCOLOGY † JUNE 2010 ii3 Abstracts

treatment strategies in medulloblastoma. NVP-LDE225 is currently under- therapies targeting tumors in a specific manner are urgently warranted. going clinical evaluation in a first-in-human study in adult patients with This study investigated the possible roles of human histone deacetylase advanced solid cancers (including medulloblastoma), primarily to determine (HDAC) family members in medulloblastoma prognosis and tumor cell the maximum tolerated dose, with additional assessments of its pharmacoki- growth. We used gene expression arrays, quantitative real-time RT-PCR netics, pharmacodynamics and potential efficacy. and immunohistochemistry to study the expression of all classical HDACs in primary medulloblastoma samples, and validated the findings on gene expression-level in an independent cohort. We additionally conducted functional studies using siRNA-mediated knockdown of the relevant HDACs in a MED.13. COMMON GENE EXPRESSION SIGNATURES OF cell culture model. In prognostically poor subgroups, HDAC5 and HDAC9 C19MC AMPLIFIED CNS-PNET ARISING FROM VARIOUS SITES showed the highest expression, and a significant association of high HDAC5 SUGGEST C19MC IDENTIFIES A UNIQUE HISTIOGENETIC and HDAC9 expression with poor overall survival of patients (p ¼ 0.00004, SUB-GROUP OF BRAIN TUMOURS log-rank) was shown. A strong staining for HDAC5 and HDAC9 proteins in M. Li1, D. Shih1, L. M. Zhou1, E. Bouffet2, L. L. Cousin3, C. Eberhart4, medulloblastoma cells was revealed by immunohistochemistry. V. P. Collins5, P. Modeno6, C. C. Lau,7, S. Pomeroy8, T. Van Meter9, siRNA-mediated knockdown of HDAC5 or 9 in medulloblastoma cells A. Gajjar10, C. E. Hawkins1,10, and A. Huang1,11; 1Labatts Brain Tumour reduced cell growth and resulted in increased cell death. Taken together, HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblas- Research Centre, Hospital for Sick Children, Toronto, ON, Canada; Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 2Division of Hematology-Oncology, Hospital for Sick Children, Toronto, toma and their expression is associated with poor survival. Our functional ON, Canada; 3Division of Hematology-Oncology, Alberta Childrens studies point towards a role in medulloblastoma cell growth. Therefore, we Hospital, Calgary, AB, Canada; 4Division of Pathology, John Hopkins reason that both HDAC5 and HDAC9 are not only valuable markers for risk University School of Medicine, Baltimore, MD, United States; 5Division of stratification, but may also be potential novel drug targets. Pathology, University of Cambridge, Cambridge, United Kingdom; 6Unit of Experimental Oncology, CRO, Aviano National Cancer Institute, Aviano, Italy; 7Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, United States; 8Department of Neurology, Children’s Hospital MED.15. CHROMOSOME 17 AND PEDIATRIC Boston, Boston, MA, United States; 9Department of Neurosurgery, Virginia MEDULLOBLASTOMA Commonwealth University, Richmond, VA, United States; C. Haberler1,2, S. Fattet3,2, M. Benetkiewicz2, G. Rigaill2, D. Williamson2, 10Neuro-oncology Division, St. Jude Children’s Research Hospital, P. Varlet4, F. Doz5, S. Puget6, J. Grill7, M. Kool8, and O. Delattre2; 1Institute Memphis, TN, United States; 11Division of Hematology-Oncology, Hospital of Neurology, Vienna, Austria; 2Institut Curie, Centre de Recherche, Paris, for Sick Children, Toronzo, ON, Canada France; 3Centre Hospitalier Universitaire Vaudois, Unite´ d’He´matologie et Oncologie Pe´diatrique, Lausanne, Switzerland; 4Department of Central nervous system primitive neuroectodermal tumours (CNS-PNET) Pathology-Neuro-Oncology, Sainte-Anne Hospital, Paris, France; 5Institut have poorly defined clinical and biological features and remain significant Curie, De´partement d’Oncologie Pe´diatrique, Paris, France; 6Hoˆ pital Necker diagnostic challenges. The current WHO classification system identifies Enfants Malades, Service de Neurochirurgie Pe´diatrique, Paris, France; several distinct histologic CNS-PNET sub-types; however, it remains 7Institut Gustave-Roussy, De´partement d’Oncologie Pe´diatrique, Villejuif, unknown if these represent biologically distinct tumours. Recently, we ident- France; 8Department of Human Genetics, Academic Medical Center, ified and correlated amplification of a novel oncogenic miRNA cluster, Amsterdam, Netherlands C19MC, on chr19q13.42, with aggressive hemispheric CNS-PNET. In this study we evaluated C19MC genomic and gene expression status Alterations of chromosome 17 are the most frequent genetic aberrations in (miR-520g, 517c, 517a, 519a2 and 520c-3p) by FISH and/or PCR analysis medulloblastoma and isochromosome 17q is detectable in 40–60% of all in various pediatric brain tumors including CNS-PNET, medulloblastoma, tumours. However, so far it is not clear if a disruption of a gene/s in the choriod plexus tumors, ependymoma and malignant gliomas, in order to recurrent breakpoint region at chr17p11.2 and/or the resulting gene characterize histopathologic and clinical features of C19MC associated dosage effect contribute to tumorigenesis. We analyzed a series of 90 medul- tumours. 3% (15/500) of tumours had C19MC amplification, most arose loblastomas by array CGH and detected isochromosome 17q in 40 tumours. in young children (,4 years) and originated in the cerebrum (10/15) but a In 32/40 tumours the breakpoint was found in the recurrent breakpoint region proportion (5/15) arose in various locations (posterior fossa, brain stem, on chromosome 17p11.2. To further investigate this region we performed a ventricles). All tumours stained for synaptophysin/nestin and IN11, but high-density oligonucleotide CGH array in 14 tumours. These analyses had variable GFAP expression; 9/15 tumours exhibited rosette formation. detected the breakpoint in a region with low copy repeats. Quantitative Histopathologic diagnosis of C19MC amplified tumours ranged from supra- PCR of candidate genes within the region confirmed the breakpoint region tentorial (SPNET - 4) with or without ependymal differentiation (3), ependy- between the genes GRAP and EPN2. Additionally, we analyzed the gene moblastoma (3), anaplastic ependymoma (1), medullo-epithelioma (2) and expression profiles in a subset of 53/90 tumours including 23 tumours with ENATR (embryonal neoplasm with excess neuropil and true rosettes-2). isochromosome 17q. Unsupervised hierarchical clustering detected the Significantly, despite anatomic and apparent histologic heterogeneity, majority of isochromosome 17q tumours in one subgroup. However, not all C19MC-associated tumours exhibit unique gene expression signatures indi- tumours clustering in this subgroup had an isochromosome 17q and after cating they represent a molecularly distinct tumour group, likely derived exclusion of all probe sets on chromosome 17 the same subgroups were from common cell of origin. Thus, we propose that C19MC represents a retained. These data were projected by meta-analysis techniques across an promising biological marker that should be evaluated as a diagnostic/prog- independent series of 62 medulloblastomas and confirmed. These findings nostic tool in the management of brain tumours arising in younger children. show that medulloblastomas with isochromosome 17q constitute a subgroup of medulloblastomas. Yet, isochromosome 17 might be only a surrogate marker, whereas other genetic events or a different cell of origin might represent the genetic background. MED.14. HISTONE DEACETYLASES 5 AND 9 IN MEDULLOBLASTOMA ARE NOVEL MARKERS FOR MEDULLOBLASTOMA RISK STRATIFICATION AND PLAY A ROLE IN MEDULLOBLASTOMA CELL GROWTH MED.16. DEREGULATION OF MIR106B-25 CLUSTER T. Milde1, I. Oehme1, A. Korshunov2,3, A. Kopp-Schneider4, M. Remke5,6, EXPRESSION IN MEDULLOBLASTOMA P. Northcott7, H. E. Deubzer1,6, M. Lodrini1,6, M. D. Taylor7, A. von K. Lau, W. Ng, Q. Chan, J. Pang, A. Hui, C. Lam, and H. Ng; The Chinese Deimling2,3, S. Pfister5,6, and O. Witt1,6; 1CCU Pediatric Oncology (G340), University of Hong Kong, New Territories, Hong Kong, Hong Kong German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Department of Neuropathology, University Hospital Heidelberg, Germany; Medulloblastoma (MB) is the most common childhood brain cancer. 3CCU Neuropathology (G380), German Cancer Research Center (DKFZ), Emerging evidences pointed towards deregulations of small non-coding Heidelberg, Germany; 4Department of Biostatistics (C060), German Cancer RNAs (miRNAs) as critical events driving cancer development. To investi- Research Center (DKFZ), Heidelberg, Germany; 5Division Molecular gate the involvements of miRNAs in MB, we employed miRMAX microar- Genetics (B060), German Cancer Research Center (DKFZ), Heidelberg, ray analysis to quantitatively profile 182 miRNAs in MB cell lines and Germany; 6Department of Pediatric Oncology, Hematology and clinical samples and compare the profiles with normal cerebellum. Class Immunology, University Hospital Heidelberg, Germany; 7Division of comparison analysis with random permutation test for p-value correction Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, indicated upregulation of 17 miRNAs and downregulation of 9 miRNAs Program in Developmental and Stem Cell Biology, Hospital for Sick expression in MB. Hierarchical clustering analysis on these differentially Children, University of Toronto, Toronto, ON, Canada expressed miRNAs demonstrated associations of the clustered miRNAs expression. Similar upregulated expression of miR-93 and miR-25 at Medulloblastomas are the most common malignant brain tumors in child- 7q22.1 among the samples were observed and there is a trend of increased hood and 5-year survival rates of large-cell/anaplastic medulloblastoma or expression of miR106b. The upregulations were confirmed in formalin-fixed metastasized disease are as low as 30–40%. Furthermore, surviving children and paraffin-embedded MB samples by stem-loop RT-PCR. Array-CGH suffer from high morbidity due to therapy-related side effects. Thus, analysis revealed frequent 7q22.1 genomic gain in MB, suggesting a potential ii4 NEURO-ONCOLOGY † JUNE 2010 Abstracts

mechanism for these miRNA upregulations. Using 7 computational target (EFS) at 3 and 5 years FU is 0.82 + 0.02 and 0.79 + 0.03 with no significant prediction programs, we identified 10 common predicted targets for difference between the two arms. Patients with residual tumor .1.5 cm2 had miR-106b and 7 for miR-93. Among them, ZNFX1 is a common predicted a significantly increased risk for relapse. The pattern of relapse will be dis- target for both miRNAs. With luciferase reporter assay, miRNA inhibitors cussed. Survival 3 years after relapse was 0.08 + 0.05. Complete analysis targeting miR-106b or miR-93 but not miR-25 blocked the repressive of the whole set of biological markers planned was achieved in 50% of the activity of endogenous miRNAs on 3’UTR of ZNFX1 in MB cells. patients. CONCLUSION: There was no significant difference in EFS Site-directed mutations or deletion of the predicted recognition sites pre- between the two radiotherapy arms. Longer follow-up may reveal a benefit vented the blockades of the miRNA inhibitors, demonstrating the specificity of either RT arm for late effects. The patients can be stratified according of the miR-106b and miR-93-mediated repressions on ZNFX1 expression in to clinical and biological data (reported elsewhere) into three risk groups MB cells. In conclusion, deregulation of miR106b-25 cluster may restrain for future studies. ZNFX1 expression contributing to MB tumorigenesis.

MED.19. TREATMENT OF CHILDREN AND ADOLESCENTS 02 MEDULLOBLASTOMA/CNS-PNET - CLINICAL WITH METASTATIC MEDULLOBLASTOMA BY

CONVENTIONAL CHEMOTHERAPY AND Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 HYPERFRACTIONATED RADIOTHERAPY. PRELIMINARY MED.17. AIEOP (ASSOCIAZIONE ITALIANA DI RESULTS OF THE PROSPECTIVE GPOH-TRIAL HIT 2000 (MET EMATOLOGIA-ONCOLOGIA PEDIATRICA) SNC99 HIT 2000 AB4) TREATMENT PROTOCOL FOR STANDARD RISK CHILDHOOD S. Rutkowski1, A. O. von Bueren1, M. Warmuth-Metz2, N. Soerensen3, MEDULLOBLASTOMA: RESULTS OF AN ITALIAN F. Deinlein4, P. G. Schlegel4, J. Kuehl4, M. Benesch5, I. Zwiener6, MULTICENTER COOPERATIVE STUDY A. Faldum6, T. Pietsch7, and R. D. Kortmann8; 1Department of Pediatric D. Bertin1,2, S. Vallero3, M. E. Basso3, E. Romano3, I. Bini3, A. Mussano4, Hematology and Oncology, University Medical Center P. Peretta5, P. Ragazzi5, P. Gaglini5, I. Morra6, M. Forni7, M. L. Garre`8, Hamburg-Eppendorf, Hamburg, Germany; 2Department of A. Sandri9, and L. Cordero di Montezemolo3; 1Pediatric Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; Hematology-Oncology, A.O. OIRM-S.Anna, Turin, Italy; 2Ph.D. Program 3Department of Pediatric Neurosurgery, University of Wuerzburg, in Biomedical Sciences and Human Oncology, University of Turin, Turin, Wuerzburg, Germany; 4Department of Pediatric Hematology and Oncology, Italy; 3Pediatric Hematology-Oncology, University of Turin, Turin, Italy; University of Wuerzburg, Wuerzburg, Germany; 5Division of Pediatric 4Radiotherapy Unit, A.O. OIRM-S.Anna, Turin, Italy; 5Neurosurgery Unit, Hematology and Oncology, Department of Pediatrics and Adolescent A.O. OIRM-S.Anna, Turin, Italy; 6Pathology Unit, A.O. OIRM-S.Anna, Medicine, Medical University of Graz, Graz, Austria; 6Institute for Medical Turin, Italy; 7Molecular Biology Center, University of Turin, Turin, Italy; Statistics, Epidemiology and Informatics, University of Mainz, Mainz, 8Pediatric Neuro-Oncology, Gaslini Hospital, Genoa, Italy; 9Department of Germany; 7Department of Neuropathology, University of Bonn, Bonn, Clinical and Biological Science, University of Turin, Orbassano, Turin, Italy Germany; 8Department of Radiation Oncology, University of Leipzig, Leipzig, Germany From 1998 to 2003, patients diagnosed as standard risk medulloblastoma (total/subtotal resection and M0/M1) have been treated according to the PURPOSE: To assess the survival rates of patients with metastatic medul- AIEOP protocol “SNC99”. Treatment consisted of three phases: 1) pre- loblastoma (MB) between 4–21 years treated according to the prospective irradiation chemotherapy (preRT-CT): high dose methotrexate (8 g/sqm), vin- multicenter trial HIT 2000 (conventional arm) between January 2001 and cristine (1.5 mg/sqm) and intrathecal methotrexate (12 mg) on day 1 followed December 2007. PATIENTS AND METHODS: Children received 2 cycles by CBCDA (600 mg/sqm), vincristine (1.5 mg/sqm), intrathecal methotrexate of HIT-SKK systemic multiagent chemotherapy and intraventricular metho- (12 mg) on day 8 and etoposide (150 mg/sqm) on days 8–9; this block was trexate, followed by hyperfractionated radiotherapy (2 x 1 Gy/d, 40 Gy cra- repeated after 3 weeks; 2) hyperfractionated cranio-spinal radiotherapy niospinal, 60 Gy posterior fossa, 68 Gy tumor bed, 50–60 Gy boost to (HFRT) 1 Gy bid up to 36 Gy CSI plus 30 Gy posterior fossa boost; 3) post- metastatic deposits) and 4 cycles of maintenance chemotherapy. irradiation chemotherapy: vincristine (1.5 mg/sqm), CCNU (80 mg/sqm) RESULTS: In 128 so far eligible patients, median age was 7.97 years and CDDP (75 mg/sqm) repeated every 6 weeks for 4 cycles. We enrolled 58 (median follow-up, 4.1 years). Four-year event-free survival (EFS) and patients (23 females and 35 males), between 3 and 20 years of age (median overall survival (OS) rates were 65 + 5 % and 80 + 4%. EFS were not differ- age, 8 years 3 months). Forty-two patients underwent total resection, 16 sub- ent between 35 patients with isolated M1-stage (62 + 8%) and 93 patients total; 4 patients were M1. Fifty-seven patients ended the treatment: 43 are with M2/M3-stage + M1-stage (65 + 5%). Pattern of relapse was local now in CCR at a median follow-up time of 49 months (range, 12–134); 15 (n ¼ 7) distant (n ¼ 27) and combined (n ¼ 7). There was no significant patients relapsed: 1 during the treatment and 14 at a median time of 17 difference in survival rates of children with classic (n ¼ 107), desmoplastic months (range, 5–35) from off-therapy. Disease-free survival was 71.5% at (n ¼ 15), and large-cell/anaplastic MB (n ¼ 6). Multivariate analyses for 3 and 5 years (SE 6.3%) and overall survival at 3 and 5 years was 81.1% (SE EFS and OS identified age, histology, response to first HIT-SKK cycle, and 5.4%) and 77.1% (SE 6.1%), respectively. In this multicenter trial HFRT number of intraventricular methotrexate applications during the first was safely administered without relevant side effects. Indeed, despite very HIT-SKK cycle as independent risk factors. No major unexpected toxicities favourable survival rates, sandwich treatment doesn’t seem to be superior if and no treatment-related deaths were reported. CONCLUSION: These pre- compared to postoperative CSI followed by adjuvant chemotherapy. liminary survival rates are significantly higher than results from the previous study HIT 91. Improved survival rates, in the range of results obtained by other strategies including high-dose chemotherapy or hyperfractionated accelerated radiotherapy, can be obtained by conventional chemotherapy MED.18. HIT-SIOP PNET4 - A RANDOMISED MULTICENTRE and hyperfractionated radiotherapy with acceptable acute toxicities. STUDY OF HYPERFRACTIONATED (HFRT) VERSUS Neurocognitive outcome needs to be assessed. STANDARD RADIOTHERAPY (STRT) IN CHILDREN WITH STANDARD RISK MEDULLOBLASTOMA B. Lannering1, S. Rutkowski2, F. Doz3, B. Pizer4, G. Gustafsson5, 6 7 8 9 10 MED.20. RISK-ADAPTED CRANIOSPINAL RADIOTHERAPY A. Navajas , M. Massimino , A. Faldum , S. Clifford , T. Pietsch , and FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH R. Kortmann11; 1University of Gothenburg, Gothenburg, Sweden; 2 3 4 AUTOLOGOUS STEM CELL RESCUE IN CHILDREN WITH Hamburg, Germany; Paris, France; Liverpool, United Kingdom; LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA: RESULTS 5Stockholm, Sweden; 6Bilbao, Spain; 7Milan, Italy; 8Mainz, Germany; 9 10 11 FROM ST. JUDE MEDULLOBLASTOMA 96 (SJMB96) AND Newcastle, United Kingdom; Bonn, Germany; Leipzig, Germany ST. JUDE MEDULLOBLASTOMA 03 (SJMB03) K. D. Wright1, M. Chintagumpala2, T. Hassall3, D. M. Ashley4, E. Bouffet5, BACKGROUND: The aim of this study was to compare whether HFRT is S. J. Kellie6, S. Gururangan7, R. Cohn8, M. Fisher9, A. Broniscer1, superior to StRT for survival and late effects. Tumor material was collected I. Qaddoumi1, E. B. Morris1, G. Armstrong1, T. E. Merchant1, to study biological markers for future risk grouping. MATERIAL AND A. Pai Panandiker1, D. W. Ellison1, S. Lesh1, D. Wallace1, and A. Gajjar1; METHODS: Patients 3–21 years with standard risk medulloblastoma 1St. Jude Children’s Research Hospital, Memphis, TN, United States; 2Texas (M0) were randomised to craniospinal HFRT 1.0 Gy twice daily (36 Gy cra- Children’s Hospital, Baylor College of Medicine, TX, United States; 3Royal niospinal, 60 Gy posterior fossa, 68 Gy residual tumor) or StRT 1.8 Gy daily Children’s Hospital in Brisbane, Queensland, Australia; 4Royal Children’s (23.4 Gy craniospinal, 54 Gy posterior fossa). Thereafter chemotherapy with Hospital, University of Melbourne, Melbourne, Australia; 5Hospital for Sick cisplatin, CCNU and vincristine was given in 8 courses. RESULTS: Between Children, University of Toronto, Toronto, ON, Canada; 6Children’s 2001 and 2006 339 patients were included (211 M, 128 F) from ten Hospital at Westmead, University of Sydney, Sydney, Australia; 7Duke countries. Randomisation assigned 170 patients to HFRT and 169 to University Medical Center, Durham, NC, United States; 8Sydney Children’s StRT. Central review of pathology was performed in 97%. Sixty-three Hospital, Sydney, Australia; 9Children’s Hospital of Philadelphia, patients (19%) have relapsed. One child died in remission. Mean/Median Philadelphia, PA, United States follow-up (FU) for children in remission is 52/48 months. Event-free survival

NEURO-ONCOLOGY † JUNE 2010 ii5 Abstracts

BACKGROUND: The large cell/anaplastic medulloblastoma (LCA MB) MED.22. SYSTEMIC CHEMOTHERAPY, SECOND LOOK phenotype has been associated with aggressive behavior and inferior survival SURGERY AND CONFORMAL RADIATION THERAPY LIMITED rates. Additionally, studies have identified poor outcomes for children with TO THE POSTERIOR FOSSA AND PRIMARY SITE FOR LCA phenotype and amplified myc status. METHODS: To evaluate the CHILDREN > 8MONTHSAND< 3 YEARS WITH prognostic impact of LCA histology, M stage and myc amplification in a NONMETASTATIC MEDULLOBLASTOMA: A CHILDREN’S cohort of pediatric patients treated with risk-adapted craniospinal radiother- ONCOLOGY GROUP PHASE III STUDY, FOLLOW UP REPORT apy (average risk 23.4 Gy; high risk 36–39.6 Gy) and cyclophosphamide- D. M. Ashley1, T. E. Merchant2, T. Zhou3, R. Geyer4, I. E. Pollack5, based high dose chemotherapy (HDC), two consecutive institutional MB P. K. Duffner6, P. Burger7, M. C. Miller8, L. Coleman1, L. Kun2, and trials, SJMB96 (n ¼ 22/134; 16.4%) and SJMB03 (n ¼ 34/190; 17.9%), D. Strother9; 1Royal Childrens Hospital, Parkville, Australia; 2St. Jude were screened for patients with LCA histology and at least one year Children’s Research Hospital, Memphis, TN, United States; 3Childrens follow-up (n ¼ 56/324; 17.3%). DNA myc amplification was evaluated in Oncology Group, Arcadia, CA, United States; 4Seattle Children’s Hospital, SJMB03 patient tumor samples. RESULTS: Three-year overall survival Seattle, WA, United States; 5Children’s Hospital of Pittsburgh, Pittsburgh, (OS) for patients separated by M stage (M0 or M + ) and LCA status differed PA, United States; 6Women and Children’s Hospital, Buffalo, NY, United significantly. In particular, of the 198 evaluable patients with non-LCA his- States; 7Johns Hopkins Hospital, Baltimore, MD, United States; 8University tology and M0 disease at 3-year follow-up, OS was 93.6% + 1.6%. of Missouri - Columbia, Columbia, MO, United States; 9Calgary Health, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Three-year OS for 70 evaluable patients with non-LCA medulloblastoma Calgary, AB, Canada and M + stage was 84.9% + 5%. In comparison, 3-year OS for 33 evaluable patients with LCA and M0 status was 81.8% + 7.6%. The 3-year OS for 23 BACKGROUND: P9934 was a trial of systemic chemotherapy, second evaluable patients with LCA and M+ status, however, was significantly look surgery and conformal radiation therapy limited to the posterior worse at 58.7% + 11.4%. Among the 34 patients with LCA histology fossa and primary site for children .8 months and ,3 years with non meta- enrolled on SJMB03, 7 of the 9 patients who died of disease possessed static medulloblastoma. METHODS: After initial surgery children received myc amplification (78%; c-myc: n ¼ 2; n-myc: n ¼ 5). CONCLUSIONS: induction chemotherapy, consisting of cyclophosphamide, vincristine, cis- Standard risk radiation and HDC should be considered for patients with platin, and etoposide. This was followed by assessment for second surgical LCA histology and M0 stage. Further study should be directed to myc ampli- resection. Next patients received an age and response adjusted course of con- fication as a potential prognostic factor. formally planned radiation therapy to the tumour bed and posterior fossa. Finally, a maintenance course of chemotherapy was given consisting of cyclophosphamide and vincristine and oral VP-16. RESULTS: Eighty-two patients were registered from October, 2000 until June, 2006: 74 met eligi- MED.21. STRATIFICATION OF CHILDREN AND bility criteria. With a median follow-up of 4.8 years (range 0.9–8.1), the ADOLESCENTS WITH MEDULLOBLASTOMA BY 4-year EFS was 50% + 6%, which compares favorably to the results from HISTOLOGICAL AND BIOLOGICAL PARAMETERS IN the historical POG9233 cohort (25% + 6%, p ¼ 0.01). Multivariate analy- SIOP-EUROPE PNET CLINICAL TRIALS sis showed that the presence of desmoplasia was a prognostic factor in pre- S. C. Clifford1, S. Rutkowski2, G. Gustafsson3, D. Figarella–Branger4, dicting survival. Whereas 7 of 10 patients who had disease progression R. D. Kortmann5, F. Doz6, D. W. Ellison7, and T. Pietsch8; 1Northern prior to irradiation had failure at the primary site, 15 of 19 who progressed Institute for Cancer Research, University of Newcastle, Newcastle upon after radiation had distant site failure involving the anterior cranial fossa or Tyne, United Kingdom; 2Department of Pediatric Haemotology and the spinal thecal space below C2/3. CONCLUSIONS: The addition of CRT Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, to postoperative chemotherapy in young children with non-metastatic Germany; 3Department Pediatric Haematology and Oncology, University of medulloblastoma results in a statistically significant increase in event-free Go¨ teborg, Go¨ teborg, Sweden; 4Faculte´ Me´decine Timone, Marseille, France; survival compared to the use of post-operative chemotherapy alone. Future 5Department of Radiation Oncology, University of Leipzig, Leipzig, studies will use the presence of desmoplasia to stratify patient’s therapy by Germany; 6Institut Curie, Paris, France; 7Department of Pathology, St. Jude risk of relapse. Children’s Research Hospital, Memphis, TN, United States; 8Department of Neuropathology, University of Bonn, Bonn, Germany

INTRODUCTION: Treatment selection for medulloblastoma, the most common malignant brain tumor of childhood, has historically been based MED.23. TREATMENT OF INFANTS MEDULLOBLASTOMA on clinical risk factors including age at diagnosis, M-stage, and extent of (MB): FINAL RESULTS OF THE FIRST COOPERATIVE STUDY OF tumor resection. METHODS: The recent prospective randomised PNET4 ITALIAN ASSOCIATION OF PEDIATRIC HAEMATOLOGY AND ONCOLOGY - AIEOP clinical trial, conducted by the SIOP-Europe PNET group, aimed to identify 1 1 1 1 1 and validate histological and biological parameters of prognostic impor- M. L. Garre` , M. L. Casciana , G. Morreale , C. Milanaccio , A. Cama , A. Pession1, A. Pession2, E. Basso3, S. La Dogana4, M. La Spina5, tance. Forthcoming trials are planned to investigate the utility of validated 6 7 8 9 10 markers for improved treatment stratification. RESULTS: In PNET4, medul- G. Perilongo , V. Biassoni , L. Gandola , G. Cinalli , P. Bertolini ,C.Di Rocco11, E. Viscardi6, P. Pierani12, D. Bertin3, P. Fidani13, D. Bertin3, loblastoma patients between 3 and 21 years without metastases were treated 14 8 1 by radiotherapy (conventional or hyperfractionated) and chemotherapy S. Barra , and M. Massimino ; Giannina Gaslini Children’s Hospital, 2 3 between 2001–2006. Complete analysis of a full set of biological parameters Genoa, Italy; Sant’Orsola Hospital, Bolgna, Italy; Regina Margherita 4 was achieved in 179/339 cases. In preliminary analyses, three risk groups Hospital, Torino, Italy; Casa Sollievo della Sofferenza, San Giovanni 5 6 were identified; 1) Favourable-risk: Patients with b-catenin nuclear accumu- Rotondo, Italy; University of Catania, Catania, Italy; University of Padua, Padua, Italy; 7Istituto Nazionale dei Tumori - INT, Milan, Italy; 8Istituto lation, absence of significant postoperative residual tumor, and without 9 / Nazionale dei Tumori-INT, Milan, Italy; Santobono Hospital, Naples, large-cell anaplastic histology, MYC or MYCN gene amplification, 2) 10 11 Intermediate-risk: Patients without ß-catenin accumulation but fitting all Italy; Univrsity of Parma, Parma, Italy; Policlinico Gemelli, Rome, Italy; 12Salesi Hospital, Ancona, Italy; 13Bambin Gesu` Hospital, Rome, Italy; other criteria described in (1), and 3) High-risk: Patients with significant 14 post-operative residuum, large-cell / anaplastic histology or MYC or Istituto Scientifico dei Tumori-IST, Genoa, Italy MYCN amplification. The next SIOP-Europe medulloblastoma trials (PNET5, PNET6), will use combined biological, pathological and clinical Treatment of very young children with MB aims to improve survival in factors for treatment stratification. Feasibility studies are currently underway cases with metastasis (M) and to avoid irradiation in selected patients. across SIOP-E partner countries, to establish systems for rapid, quality con- From 1995 to 2007, the first Italian cooperative study for infants MB used trolled, centralised pathology review and molecular diagnostics, to support two regimens: A): protocol AIEOP SNC9501: conventional chemotherapy these trials. CONCLUSION: Histological and biological risk factors of prog- (CT) including systemic Methotrexate; B): high dose (HD) sequential and nostic value have been identified and will be applied prospectively in forth- myeloablative chemotherapy-MAT which consisted of an induction phase (VCR 1.5 mg/m2/ MTX 8 g/m2; HD VP16 2.4 g/m2; VCR 1.5 mg/m2/ coming SIOP-E PNET trials, aiming to improve risk-adapted treatment 2 2 2 stratification, survival rates and quality of survival. CTX 4g/m ; VCR 1.5 mg/m / CARBO 800 mg/m ) followed by 2 courses of MAT (CARBO 1.5 g/m2/ VP16 1.5 g/m2 and THIOTHEPA 900mg/m2 / MPH 120 mg/m2). For both regimens irradiation was planned if residual tumour (T) or metastases were present. A total of 65 cases were included (33 in regimen A, 32 in regimen B); 39 males, 26 females; median age was 21 months; median duration of follow-up 4.29 yrs. Thirty-two percent of cases were M0/T0; 38% T + /M0, 19% M+ /T+ or T-; histological variants were: 36 cases Classic-CMB, 14 Desmoplastic-DMB, 12 MB with extensive nodularity-MBEN; 3 anaplastic. Tree out of 13 and 12/14 irradiated cases in regimen A and B respectively underwent elective irradiation at the end of CT; the others were irradiated at relapse. Ten cases in regimen A and 14 cases in regimen B are long-term ii6 NEURO-ONCOLOGY † JUNE 2010 Abstracts

survivors without irradiation. Five years OS was significantly higher in was disseminated in 17 cases. Surgical resection was considered as complete regimen B comparing with regimen A (72.3% vs. 44.8% p ¼ 0.02). in 12 patients, subtotal in 7 and partial in 13. Only a biopsy was performed Favorable histology (DMB and MBEN) impacted significantly on OS and in 10 children. Radiotherapy was performed in 31 children, using a craniosp- EFS in regimen A comparing with regimen B. CONCLUSIONS: The intro- inal irradiation in 14 cases. Chemosensitivity after the two first courses was duction of HDCT produced a significantly better disease control and influ- observed in 16 out of 30 with residual tumor after surgery. Twelve patients enced the role of histology as prognostic factor. are in complete remission with a median follow-up of 48 months (range, 12 to 83 months). The EFS and OS at 3 years was 37% and 40%, respectively, at 3 and 5 years. The toxicity was manageable. CONCLUSION: This therapeutic strategy is well tolerated and produced survival even if a high rate of progressive disease was observed during chemotherapy. MED.24. TREATMENT OF YOUNG CHILDREN (<4 YEARS) WITH MEDULLOBLASTOMA BY CHEMOTHERAPY ALONE. INTERIM RESULTS OF THE PROSPECTIVE MULTICENTER GPOH-TRIAL HIT 2000 (HIT 2000 BIS4) CONFIRMING THE PROGNOSTIC IMPACT OF HISTOLOGY MED.26. PROGNOSTIC FEATURES OF CHILDHOOD A. O. von Bueren1, T. Pietsch2, M. Warmuth-Metz3, N. Soerensen4, MEDULLOBLASTOMA BY MAGNETIC RESONANCE IMAGING Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 F. Deinlein5, P. G. Schlegel5, J. Kuehl5, M. Benesch6, I. Zwiener7, K. Yeom, J. B. Andre, J. K. Rosenburg, B. C. Mobley, H. Vogel, P. G. Fisher, A. Faldum7, R. D. Kortmann8, and S. Rutkowski1; 1Department of Pediatric M. S. B. Edwards, P. D. Barnes, and S. Partap; Stanford University, Stanford, Hematology and Oncology, University Medical Center CA, United States Hamburg-Eppendorf, Hamburg, Germany; 2Department of Neuropathology, University of Bonn, Bonn, Germany; 3Department of PURPOSE: To investigate distinctive magnetic resonance imaging (MRI) Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; features of medulloblastoma (MB), as defined by the World Health 4Department of Pediatric Neurosurgery, University of Wuerzburg, Organization’s Tumours of the Central Nervous System (4th edition) classi- Wuerzburg, Germany; 5Department of Pediatric Hematology and Oncology, fication, and correlate with clinical outcome. METHODS: A retrospective University of Wuerzburg, Wuerzburg, Germany; 6Division of Pediatric review of 89 patients (ages 2–21 years; median 8 years) with MB since Hematology and Oncology, Department of Pediatrics and Adolescent 1998 was performed. Thirty-one had pre-surgical MRI and original pathol- Medicine, Medical University of Graz, Graz, Austria; 7Institute for Medical ogy slides and 5 of those had studies with recurrent tumor. Thirty-six radi- Statistics, Epidemiology and Informatics, University of Mainz, Mainz, ologic/pathologic correlates were evaluated, by 2 neuroradiologists and Germany; 8Department of Radiation Oncology, University of Leipzig, neuropathologists. MRI images obtained included T1, T2, diffusion Leipzig, Germany weighted imaging, T2*, and post-gadolinium enhancement. Imaging was correlated with MB pathologic subtypes [classic, desmoplastic/nodular, PURPOSE: To confirm the favorable survival rates and the prognostic sig- extensive nodularity, and large-cell/diffuse anaplasia], initial clinical risk- nificance of histology in young children with non-metastatic medulloblas- stratification (average-risk versus high-risk), and overall survival (OS). toma (MB) treated from January 2001 to December 2005 by postoperative RESULTS: Two MRI features correlated with tumor aggressiveness. The chemotherapy alone as in the previous trial HIT-SKK 92. presence of a characteristic honeycomb enhancement (HE) pattern predicted EXPERIMENTAL DESIGN: After surgery, patients received three cycles anaplasia (p ¼ 0.004) as did tumors with T2 heterogeneity (T2H) (p ¼ of HIT-SKK systemic multiagent chemotherapy and intraventricular metho- 0.011). HE and T2H detected anaplasia with 100% sensitivity (both 95% trexate. Treatment was terminated with two additional cycles of chemother- CI: 63–100%) but were not specific (57%; 95% CI: 37–76% and 50%; apy, if a complete remission was achieved. Otherwise second surgery, 95% CI: 30–70%, respectively). The occurrence of HE correlated with craniospinal radiotherapy and consolidation chemotherapy were rec- T2H as well (p ¼ 0.024). By log-rank testing, anaplasia was associated ommended. RESULTS: The five-year EFS and OS (+SE) rates of 45 eligible with poor OS (p ¼ 0.048) as was HE (p ¼ 0.032). The presence of small patients were 62 + 7% and 80 + 6% (median follow-up: 4.4 years, median focal cysts or mineralization was inversely correlated with anaplasia (p ¼ age: 2.5 years). Twenty patients with desmoplastic / nodular MB variants 0.013 and p ¼ 0.030) and was not predictive of poor OS. CONCLUSION: had significantly better five-year EFS and OS rates (90 + 7% and 100 + The presence of HE and T2H is predictive of aggressive MB behavior and 0%) than did 23 patients with classic MB (37.5 + 10% and 64 + 10%). anaplasia and may indicate a less favorable prognosis. Treatment strategies One of two patients with anaplastic MB died after relapsing. Following for high-risk subtypes should be considered in these patients. three cycles of chemotherapy, 29 of 30 (97%) patients without postoperative residual tumor were in continuous complete remission. The response rate in 15 patients with postoperative residual tumor was 73%. CONCLUSIONS: These interim results confirm that postoperative chemotherapy alone MED.27. AGE AT DIAGNOSIS AND CRANIOSPINAL appears to be a promising treatment in young children with non-metastatic RADIATION DOSE EFFECTS ON INTELLECTUAL OUTCOME IN desmoplastic / nodular MB variants. Local radiotherapy has been intro- CHILDREN/ADOLESCENTS TREATED FOR duced since January 2006 - after confirmation of lower survival rates - for MEDULLOBLASTOMA all children older than 18 months with non-desmoplastic / nodular MB T. Diver,1,2, P. Manley,2,3, M. W. Kieran,2,3, S. Chi,2,3, L. Goumnerova,4,2, variants. R. Scott,4,2, K. J. Marcus,5,6, N. Ullrich,7,2, C. Liptak,8, C. Chordas,2, M. Zimmerman,2, B. Delaney,8, and C. Rey-Casserly,1,2; 1Department of Psychiatry, Children’s Hospital Boston, Boston, MA, United States; 2Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; 3Hematology/Oncology, Children’s Hospital Boston, Boston, MED.25. SEQUENTIAL HIGH-DOSE CHEMOTHERAPY MA, United States; 4Neurosurgery, Children’s Hospital Boston, Boston, FOLLOWED BY IRRADIATION IN CHILDREN WITH MA, United States; 5Radiation Oncology, Children’s Hospital Boston, SUPRA-TENTORIAL PRIMITIVE NEUROECTODERMAL Boston, MA, United States; 6Radiation Oncology, Dana-Farber Cancer TUMORS Institute, Boston, MA, United States; 7Neurology, Children’s Hospital 1 2 3 1 4 5 F. Fouyssac , M. Raquin , A. Jouvet , P. Chastagner ,F.Doz , D. Frappaz , Boston, Boston, MA, United States; 8Pediatric Psychosocial Oncology, 6 7 8 9 2 2 J. Gentet , P. Leblond , A. Bertozzi , J. Grill , J. Grill , and C. Dufour ; Dana-Farber Cancer Institute, Boston, MA, United States 1CHU NANCY, Vandoeuvre les nancy, France; 2Institut Gustave Roussy, 3 4 Villejuif, France; Hoˆ pital neurologique, Lyon, France; Institut Curie, Paris, PURPOSE: To examine effects of age at diagnosis and treatment intensity 5 6 France; Centre León Be´rard, Lyon, France; CHU Marseille, Marseille, on neurocognitive outcomes in patients treated for medulloblastoma. 7 8 France; Centre Oscar Lambret, Lille, France; CHU Toulouse, Toulouse, PATIENTS AND METHODS: Cognitive outcomes of children/adolescents 9 France; Institut Gustave Roussy, Pari, France diagnosed with medulloblastoma between 1986 and 2008 followed clinically at DFCI/CHB were examined. Neuropsychological data were available for PURPOSE: To evaluate the outcome of children with supratentorial primi- 83 patients; 57 had more than one evaluation. 64% were ≤ age 7 at diagno- tive neuroectodermal tumors (sPNET) treated on a phase II study based on sis (median age at diagnosis 6.6 years); 54% were male. Patients were sequential high-dose chemotherapy followed by irradiation. PATIENTS grouped into three categories: no CSI (7); Standard Dose CSI , 30 Gy AND METHODS: Patients with sPNET younger than 10 years of age (46); High Dose CSI . 30 Gy (30). Mean follow-up from radiation was were eligible. After initial surgery, children received two courses of carbopla- 4.9 years; median age at most recent neuropsychological evaluation was tin - etoposide. In absence of disease progression, five sequential courses of 13.6. RESULTS: IQ score range: 40 to 132; mean ¼ 87. IQ score distribution 2 high dose chemotherapy were performed: melphalan (100 mg/m ), cisplatin was significantly different from expectations: 16% of scores were ≤ 70, 2 2 (100 mg/m ), melphalan, cisplatin and thiotepa (720 mg/m ). Irradiation 41% , 85, and only 4% ≥ 115. Mean IQ for no CSI was 84; Standard was planned 6 weeks later, with a primary tumor site irradiation (45 to 58 Dose 90; and High Dose 84. For patients with repeated evaluations (n ¼ Gy) and an age-adapted craniospinal irradiation only in case of metastatic 57), change in IQ from initial evaluation to most recent ranged from -40 disease (18 to 36 Gy). RESULTS: Forty-two children were enrolled with a to +17 points (mean ¼ -5). Change in IQ over time correlated significantly median age of 4.2 years (range, 0.4 to 9.2 years). At diagnosis, the disease with younger age at diagnosis. Mean change in IQ also varied by group:

NEURO-ONCOLOGY † JUNE 2010 ii7 Abstracts no CSI (n ¼ 5) ¼ +2; Standard Dose (n ¼ 38) ¼ -5; and High Dose (N ¼ 03 DIFFUSE INTRINSIC PONTINE GLIOMA 14) ¼ -8. CONCLUSIONS: Cognitive outcomes for children treated for medulloblastoma vary widely but lower IQ scores are more frequent than DIPG.01. PROSPECTIVE COLLECTION OF TISSUE SAMPLES expected. Younger age at diagnosis and more intensive radiation treatment OBTAINEDATAUTOPSYINCHILDRENWITHDIFFUSE are associated with greater decline in IQ over time. INTRINSIC PONTINE GLIOMA A. Broniscer1, J. N. Baker1, S. J. Baker1, S. N. Chi2, J. R. Geyer3, E. B. Morris1, and A. Gajjar1; 1St Jude Children’s Research Hospital, Memphis, TN, United States; 2Children’s Hospital of Boston, Boston, MA, MED.28. DEVELOPMENTAL AND FUNCTIONAL OUTCOME United States; 3Seattle Children’s Hospital, Seattle, WA, United States FOLLOWING POST-OPERATIVE CHEMOTHERAPY AND BACKGROUND: Autopsy remains a valuable tool for investigational LOCAL CONFORMAL RADIATION IN INFANTS WITH studies in children. We conducted a prospective, multicenter study to MEDULLOBLASTOMA USING A CENTRALLY ADMINISTERED assess feasibility of tissue collection by autopsy and suitability of the tissue PHONE BASED INTERVIEW TECHNIQUE, FOLLOW UP for genome-wide molecular analyses in children with diffuse intrinsic REPORT: A CHILDREN´ S ONCOLOGY GROUP STUDY pontine glioma. Methods Tumor tissue was collected at diagnosis, if clini- D. M. Ashley1, N. Lyon2, M. Bonner3, M. Msall4, Z. Tianni5, D. Strother6, 7 8 9 7 2 1 cally indicated, or at autopsy. Normal brain tissue was also collected at

T. Merchant , R. Geyer , I. E. Pollack , L. Kun , and P. Duffner ; Royal Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 autopsy. The integrity of DNA and RNA was evaluated in all samples. Childrens Hospital, Parkville, Australia; 2Women and Children’s Hospital, Logistical data about autopsies were recorded. The feasibility of tissue collec- Buffalo, NY, United States; 3Duke University Medical Center, Durham, NC, tion by autopsy was assessed for patients treated at a single institution over a United States; 4University of Chicago, Chicago, IL, United States; 5Childrens 41-month period. Parental regret for participation was assessed. Findings Oncology Group, Arcadia, CA, United States; 6Calgary Health, Calgary, AB, Tumor samples were collected at diagnosis (n ¼ 3) or at autopsy (n ¼ 35) at 26 Canada; 7St. Jude Children’s Research Hospital, Memphis, TN, United centers across the US. Samples were obtained at both diagnosis and autopsy in States; 8Seattle Children’s Hospital, Seattle, WA, United States; 9Children’s two cases. Normal brain samples were obtained in 86% of autopsies. The Hospital of Pittsburgh, Pittsburgh, PA, United States median interval from death to autopsy was 7.5 hours. DNA and RNA with minimal or partial degradation, which were suitable for genome-wide analysis, BACKGROUND: P9934, used multi-agent chemotherapy and conformal were obtained from 100% and 68.5% of tumor samples, respectively. At the irradiation (RT) limited to the posterior fossa and post-operative tumor bed coordinating institution, 39.5% of parents consented to autopsy and 37.5% early in the treatment course. We report here the developmental and func- declined. During the same period, 11 autopsies were obtained from patients tional outcomes. METHODS: Developmental questionnaires about skills who never received therapy at the coordinating center; in ten of these cases the in gross and fine motor, communication, problem solving, and personal- process of tissue donation was initiated by the parents or the child’s oncologist. social skills were administered at baseline, pre-chemotherapy, pre-radiation, No parents regretted participating in the trial. Interpretation Multicenter biologi- and at 12, 24, 36 and 48 months following diagnosis. Formal neuropsycho- cal studies of tissue obtained at autopsy are feasible in children with brain tumors. logical testing was administered pre-RT and at 2 and 4 years following diagnosis. RESULTS: After 4 years there continues to be 100% compliance with the phone based interview system in contrast to that achieved with neurop- sychologic testing (58% pre-RT and 46% at 2 years). The majority of DIPG.02. GENETIC COMPARISON OF PEDIATRIC DIFFUSE infants had mild to moderate delays in WeeFIM functional quotients at base- INTRINSIC PONTINE GLIOMAS (DIPG) TO HIGH AND LOW line. (Mobility: Mean 77; Self-care Mean 84; Cognition Mean 84 range) GRADE ASTROCYTOMAS These delays were more profound in all domains; mobility, selfcare and cog- C. Hawkins, P. Buczkowicz, U. Bartels, U. Tabori, I. Fried, M. Zarghooni, nition (p , 0.0002) by the time of the “Pre-chemotherapy” assessments, and E. Bouffet; The Hospital for Sick Children, Toronto, ON, Canada indicating injury from the intervening effects of either the tumor or surgery. In the case of mobility there was some recovery of functioning at DIPG is one of the most devastating of pediatric malignancies. No effective later time points (p , 0.05 at 24 months and 36 months). However, this therapy exists and little is known of DIPG biology. We have already shown could not be established for cognition or self-care where recovery did not potential novel therapeutic targets for DIPG using high-resolution reach statistical significance. CONCLUSIONS: After 4 years no significant SNP-based analysis. Here we extend our initial study to include expression or consistent decline in developmental functioning could be demonstrated array analysis, amalgamating the datasets to generate a more complete after the delivery of chemotherapy and local conformal RT. Significant understanding of the genetic alterations underlying this devastating declines in skills compared to the pre-morbid “baseline” suggests that disease. DIPG (n ¼ 13) copy number was compared to that of pediatric surgery and/or the tumor may have a profound impact on development. high grade (HGA, n¼ 20) and low grade (LGA, n¼ 30) astrocytomas. Unsupervised Pearson’s Dissimilarity clustering resulted in 3 distinct groups (DIPGs only, LGA + few HGA, HGA + few DIPGs). Venn analysis of regions found in .30% of each tumor type revealed regions overlapping all three, as well as regions specific to each tumor type. Four genes were MED.29. SECONDARY MALIGNANT NEOPLASMS (SMNS) deleted in .30% of all tumors including RB1 and PCDH17. Nine genes FOLLOWING “SUCCESSFUL” TREATMENT OF were exclusively gained in .30% of DIPG including PDGFRA, LNX1 NON-DISSEMINATED MEDULLOBLASTOMA (MB): A 10-YEAR and CHIC2. Nineteen genes were associated with both HGA and DIPG (9 FOLLOW-UP OF PATIENTS TREATED ON A COG STUDY gained, 10 deleted) including AKT3, CREB5, DDX60 and PGBD5 gains 1,2 2 2 3,2 1,2 R. J. Packer , E. Holmes , T. Zhou , A. Gajjar , and G. Vezina ; and UPB1, RCBTB2 and P2RY5 deletions. CREB5 was also altered on 1 Children’s National Medical Center, Washington, DC, United States; expression-array analysis and immunohistochemical staining in a subset of 2 3 Childrens Oncology Group, Arcadia, FL, United States; St. Jude Research DIPG patients. PARP1 was expressed in .50% of DIPGs. These data high- Hospital, Memphis, TN, United States light the genetic distinctiveness of DIPGs and further our understanding of their biology. This is needed in order to develop agents targeted more specifi- Between December 1996 and December 2000, 379 eligible patients with cally towards this disease particularly given the dismal prognosis and unre- non-disseminated MB were treated on a randomized trial of radiotherapy sponsive nature of these tumors to conventional treatment. (2340 cGy CSRT, 5580 local), with vincristine (VCR) during radiotherapy and either VCR, cis-platin and CCNU or VCR, cis-platin and cyclophosphamide post-radiotherapy. At 8 years, event-free survival was 77 + 2% and overall survival was 82 + 2%. Fourteen patients have developed SMNs a DIPG.03. MOLECULAR PROFILING OF PEDIATRIC DIFFUSE median of 5.75 years (range, 3.2–10.1) from diagnosis, 10 of which occurred INTRINSIC PONTINE GLIOMAS AT DIAGNOSIS IDENTIFIES greater than 5 years from diagnosis. Tumors included high-grade gliomas (5), TWO BIOLOGICALLY DISTINCT ENTITIES 1 2 3 4 5 1 carcinoma (3), leukemia (1), sarcomas (1), myelodysplastic syndromes (2), S. Puget , C. Philippe , B. Job , P. Varlet , F. Andreuiolo , T. Roujeau , 3 5 6 7 1 5 pilocytic astrocytoma (1), and basal cell carcinoma (1). Seven have died of P. Dessen , C. Richon , V. Lazar ,F.Doz , C. Sainte Rose , G. Vassal , and 5 1 SMNs. Three of 5 malignant gliomas and 5 of the 7 deaths (3 malignant J. Grill ; Neurosurgical Unit, Hopital Necker, Universite´ Rene´ Descartes, 2 gliomas, 1 osteosarcoma, and 1 myelodysplastic syndrome) occurred on Paris, France; University Paris-Sud, CNRS UMR 8302 “Vectorology and the CCNU arm. Two patients on the cyclophosphamide arm were recently Anticancer Treatments”, Institut Gustave Roussy, Villejuif, France; 3 diagnosed with glioblastoma multiforme and remain alive with disease. Laboratory of translational research, Institut Gustave Roussy, Villejuif, 4 More than 5 years from entry, SMNs were a more common cause of “late France; Anatomopathological Unit, Hopital Sainte Anne, Universite´ Rene´ 5 disease” occurrence than relapse (9 late relapses). This rate of SMNs is extre- Descartes, Paris, France; University Paris-Sud, CNRS UMR 8302 mely worrisome and SMNs are a common cause of late tumor-related mor- “Vectorology and Anticancer Treatments”, Gustave Roussy Institute, 6 bidity and mortality. Villejuif, France; Genomic plateforme, Institut Gustave Roussy, Villejuif, France; 7Pediatric oncology unit, Institut curie, Paris, France

BACKGROUND: The mechanisms that drive the oncogenesis of Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) are unknown because of a lack of ii8 NEURO-ONCOLOGY † JUNE 2010 Abstracts

tissue samples at diagnosis. METHODS: We performed stereotactic biopsy were enrolled in the study. All patients received induction therapy; consolida- at diagnosis in 60 children with typical MRI appearance of BSIG. Among tion therapy I and II were administered in 31 and 15 patients, respectively. 38 patients with frozen samples, we could carry out arrayCGH and / or Ten patients received nimotuzumab after week 36 (up to 169 weeks). Best gene expression profiles for 35 of them. RESULTS: Median age was 7.3 y responses were PR in 4 patients (9.8%) and SD in 27 patients (65.8%). and median OS was 10.5 months. After histopathological review, one case Median PFS and OS were 5.5 + 0.2 months and 9.6+ 1.0 months, respect- was diagnosed as DIPG but could not be graded, 10, 14 and 10 were ively, with significant longer OS in radiological responders than in non- grade II, III and IV respectively. The grade and the MRI features of the responders (p ¼ 0.004). QL analysis showed a trend of amelioration from diag- tumours were not associated with survival. The most frequent aCGH imbal- nosis to week 24 in terms of subjective rating. Adverse events were mostly mild. ances were gains of chromosome 1q(34%), Xq(25%), 2p and 7p(22%) and Repeated applications of nimotuzumab concomitantly to radiotherapy were losses of chromosomes 14q(31%), 10q(28%) and 17p(25%). Amplifications safe. This combination therapy had transient cytotoxic efficacy in the majority were found for numerous genes including PDGFRa locus, RNH1, LRP1 and of patients. The survival data being comparable to other combination therapies, MET. We confirmed amplification of PDGFRa by FISH analyses in 4 but without antibody related toxicity, suggest that nimotuzumab may have a samples. Deletions were seldomly found, eg PTEN, CDKN2A/B, AKT1 role in multidrug regimens for children with PG. and CEBPB. Gene-Expression analyses identified 2 patterns. One was characterized by enrichment for neural patterning genes and the other one was characterized by angiogenic and adhesion genes. This clusterisation Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 did not correlate with tumour grades or histological subtypes. The first group comprised all gains / amplifications of PDGFRa and showed a DIPG.06. A PHASE II STUDY OF PEGYLATED INTERFERON shorter survival compared to second group (71% versus 12% of patients ALFA-2B (PEG-INTRONTM)INCHILDRENWITHDIFFUSE with OS , medianOS, respectively; P ¼ 0.008, chi2 test). CONCLUSION: INTRINSIC PONTINE GLIOMAS (DIPG) We identified two molecular subgroups of DPIG characterized by chromoso- K. Warren, R. Bent, P. Wolters, J. Shih, A. Prager, and K. Camphausen; mal regions and potential therapeutic targets. National Cancer Institute, Bethesda, MD, United States

BACKGROUND: Continuous low-dose exposure of interferon has demonstrated superior antitumor activity in prior in vitro studies compared to inter- DIPG.04. PREDICTING OUTCOME OF CHILDREN WITH DIPG mittent high-dose exposure. A Phase II study of low-dose PEG-Intron was USING MULTIPARAMETRIC IMAGING performed on an IRB- approved protocol in children with DIPG who completed S. J. Hipp1,2, E. Steffen-Smith1, D. Hammoud3, J. H. Shih1, R. Bent1, and radiation therapy. The endpoint was 2-year survival compared to historical K. E. Warren1; 1National Cancer Institute, Bethesda, MD, United States; controls who received radiation therapy alone. METHODS: Eligible patients 2Walter Reed Army Medical Center, Washington, DC, United States; had an infiltrative mass on MRI with the epicenter within the pons, involving 3National Institute of Health, Bethesda, MD, United States .50% of the pons, and without a primary exophytic component. Patients received weekly subcutaneous injections of PEG-Intron at a dose of 0.3 mg/ BACKGROUND: Studies have separately evaluated perfusion, multi-voxel kg beginning 2–10 weeks after completion of adequate radiation therapy and spectroscopy, single-voxel spectroscopy and tumor enhancement to determine continued until disease progression. Patients were evaluated clinically and DIPG tumor progression and survival, but no single imaging parameter has radiographically using multiparametric imaging. Serum and urine were been prognostic. Multiparametric analysis entails combining multiple assayed for bFGF and VEGF prior to each cycle. Parents of patients, ages 6– imaging techniques at one time point to create a predictive model for survival. 18 years (n ¼ 11), completed quality of life (QOL) evaluations at baseline METHODS: Eligible patients had a mass consistent with a DIPG based on MRI and every other cycle. RESULTS: Thirty-two patients (median age 5.3 years; findings and clinical findings. Spectroscopic data were acquired longitudinally range, 1.8–14.8) were enrolled and received a median of 7 cycles of therapy + on a 1.5T MRI. Spectroscopic and perfusion data and were analyzed using (range, 1–53 ). Estimated 2-year survival was 14%, median survival time G.E. proprietary software while multi-voxel data were analyzed using a was 351 days, and median time to progression was 235 days. PEG-Intron custom software package. RESULTS: 98 studies were performed on 34 patients, therapy was well tolerated. Total mean QOL scores improved significantly mean age of 6.7 years. Median survival from diagnosis was 468 days (range 51 from baseline to pre-cycle 3 (n ¼ 7; 3.59–3.89; p ¼ 0.0434) suggesting an to 3,716 days). Univariate analysis showed at the first imaging only perfusion improvement in QOL in a subset of children over the first 2 months of the was able to predict shorter survival with a hazard ratio (HR) of 4.91 (p ¼ 0. study. CONCLUSIONS: Although low dose PEG-Intron therapy is well toler- 0.00042). When analyzing all time points increased lipid lactate levels (HR ¼ ated, it does not significantly improve 2-year survival in children with DIPG. 2.15, p ¼ 0.031), increased perfusion (HR ¼ 4.01, p ¼ 0.035) and enhancement (HR ¼ 3.39, p ¼ 0.012) each predicted shorter survival. When combining perfusion and enhancement there was a significant association (p ¼ 0.046) showing decreased survival from imaging. CONCLUSION: This data shows that increased perfusion at either the initial imaging or at any time DIPG.07. ANTIANGIOGENIC COMBINATION THERAPY AFTER point predicts a shorter survival. In combination with increasing enhancement LOCAL RADIOTHERAPY WITH TOPOTECAN it can be useful to predict survival. Although proton spectroscopy may describe RADIOSENSITIZER: HOPE FOR CHILDREN WITH INOPERABLE metabolic features of tumors, it does not predict survival in patients with DIPG BRAINSTEM GLIOMAS? 1 2 3 4 when combined in this data set. S. M. Kivivuori , P. Riikonen , L. Valanne ,T.Lo¨ nnqvist , and U. Saarinen-Pihkala1; 1Division Hem Onc and SCT, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; 2Department of Pediatrics, Kuopio University Hospital, University of Kuopio, Kuopio, Finland; 3Helsinki Medical Imaging Center, University of Helsinki, Helsinki, DIPG.05. CONCOMITANT THERAPY OF NIMOTUZUMAB AND Finland; 4Division of Neurology, Hospital for Children and Adolescents, STANDARD RADIOTHERAPY FOR THE TREATMENT OF University of Helsinki, Helsinki, Finland NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMAS IN CHILDREN AND ADOLESCENTS BACKGROUND: Outcome of children with brainstem tumors remains G. Fleischhack1, N. Siegler1, M. Zimmermann1, M. Warmuth-Metz2, dismal with no curative therapy available. We present a novel approach by R. Kortmann3, M. Massimino4, E. Khuhlaeva5, G. Calaminus6, F. Bach7, using a radiosensitizer with conventional radiotherapy, followed by antian- and U. Bode1; 1Dept. of Pediatric Hematology/Oncology, Medical Center, giogenic combination therapy. METHODS: Eight consequtive patients University of Bonn, Bonn, Germany; 2Dept. of Neuroradiology, University of with brainstem tumor have been enrolled. Initially patients received local Wuerzburg, Wuerzburg, Germany; 3Dept. of Radiooncology, University of irradiation combined with topotecan. Thereafter three antiangiogenic Leipzig, Leipzig, Germany; 4Division of Pediatric, Istituto Nazionale drugs (thalidomide, celecoxib, etoposide) were started. The historical Tumori, Milano, Italy; 5Pediatric Neurosurgical Dept., Burdenko control group consisted of 13 patients with brainstem tumor. RESULTS: Neurosurgical Institute, Moscow, Russian Federation; 6Dept. of Pediatric After RT, the study patients had improvement both clinically and in MRI. Hematology and Oncology, Childrens Hospital, University of Muenster, First signs of decreased QoL appeared at a median of 11 and 6,8 months Muenster, Germany; 7Oncoscience AG, Wedel, Germany (p ¼ 0.04) after diagnosis and median survival was 12.5 vs 8.5mo (p ¼ 0.8) in the study and control patients, respectively. However, the terminal This phase III trial was designed to explore the safety and efficacy of the phase was shorter in study patients than in the control patients. monoclonal anti-EGFR antibody nimotuzumab in combination with a stan- CONCLUSIONS: This preliminary data suggests that topotecan is a poten- dard radiotherapy in the treatment of patients with a newly diagnosed diffuse tially effficient radiosensitizer, that our antiangiogenic combination therapy intrinsic pontine glioma (PG). Patients with radiologically proven PG were does not have any nonhematological toxicities, and that the symptom-free eligible for the study. The treatment consisted of an induction therapy time with good QOL seems to be prolonged while the terminal period (weekly infusion of 150 mg/m2 nimotuzumab for 12 weeks, concomitantly with poor QoL is short. More patients and longer follow-up are needed radiotherapy at weeks 3–8, TD 54 Gy). In case of non-PD a consolidation for documentation of survival benefit. Development of antiangiogenic thera- therapy of nimotuzumab biweekly followed until disease progression. The pies may give new hope for this challenging group of patients. quality of life (QL) assessment and radiological responses were documented every 12 weeks. From 2006 to 2007 forty-one eligible patients aged 3–16 years

NEURO-ONCOLOGY † JUNE 2010 ii9 Abstracts

DIPG.08. MULTIMODAL THERAPY FOR DIFFUSE INTRINSIC 04 HIGH GRADE GLIOMA PONTINE GLIOMAS INCLUDING NIMOTUZUMAB AND BEVACIZUMAB HGG.01. INTEGRATED MOLECULAR GENETIC PROFILING OF O. Cruz1, C. de Torres1,M.Sunõl1, H. Salvador1, E. Lopez1, T. Cardesa1, PEDIATRIC HIGH-GRADE GLIOMAS AND DIFFUSE INTRINSIC A. Parareda1, E. Rodriguez1, J. Vinent1, M. Alamar1, M. Ramos2, PONTINE GLIOMAS REVEALS KEY DIFFERENCES WITH J. Muchart1, S. Candela1, N. Rodriguez1, J. Giralt2, G. Pedrals1, A. Cuerva1, ADULT GLIOMAS A. Negre1, C. Llanos1, and J. Mora1; 1Hospital St Joan de Deu/University of B. S. Paugh1, C. Jones2,C.Qu1, Z. Liu1, M. Adamowicz-Brice3, J. Zhang1, Barcelona, Esplugues de Llobregat, Barcelona, Spain; 2Hospital Vall D. A. Bax2, B. Coyle3, J. Barrow3, D. Hargrave4, J. Lowe3, W. Zhao1, d’Hebron, Radiation Therapy, Barcelona, Spain J. R. Geyer5,S.Chi6, N. Saba da Silva7, J. Baker1, A. Gajjar1, R. Grundy3, D. W. Ellison1, A. Broniscer1, and S. J. Baker1; 1St. Jude Children’s Research BACKGROUND: The prognosis for DIPG is dismal; new therapeutic Hospital, Memphis, TN, United States; 2Institute for Cancer Research, options are needed. Our previous experience showed Irinotecan/Cisplatin Surrey, United Kingdom; 3University of Nottingham, Nottingham, United to be active in Astrocytomas. Nimotuzumab has shown to be safe and Kingdom; 4Royal Marsden NHS Foundation Trust, Surrey, United active in DIPG. Adult trials have demonstrated responses with bevacizumab Kingdom; 5University of Washington, Seattle, WA, United States; 6Dana in GBM. PROCEDURE: A prospective multimodal ambulatory treatment in Farber Cancer Institute, Boston, MA, United States; 7Universidade Federal 11 DIPG patients was performed, including a pre-radiation-window-phase-2 de Sao Paulo, Sao Paulo, Brazil Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 with Cisplatin/Irinotecan, followed with radio-chemotherapy (temozolomide-75mg/m2/d x42d), and a maintenance-phase using nimotu- To improve understanding of the molecular defects driving childhood zumab (130mg/m2/dose), Bevacizumab (10-15 mg/K/m2) and valproate. high-grade glioma (HGG), we conducted a high-resolution unbiased analysis At progression, symptomatic care included short pulses of corticoids if of genomic imbalances and gene expression signatures in 78 pediatric HGG, needed. The best response achieved, time to progression (TTP), and associ- including 7 diffuse intrinsic pontine gliomas (DIPG). We compared our ated toxicities were recorded and compared with a previous cohort of 9 results with publicly available data from adult tumors and found that pedi- patients treated with radiotherapy and chemotherapy at progression. atric HGG represent a related spectrum of disease when compared to adult RESULTS: 11 patients received this regimen, 4 remaining on treatment. HGG, but with notable differences in underlying genetic defects. Pediatric The window phase was well tolerated, although all patients progressed. and adult glioblastoma were clearly distinguished by frequent gain of Best clinical/radiological responses were achieved after radiotherapy. A chromosome 1q (30% compared to 9%) and lower frequency of chromo- non significant trend to improvement in TTP was noted compared with some 7 gain (13% compared to 74%). The most common focal amplifica- the former cohort. Avoidance of Cushing-syndrome and thus better QoL tions also differed, with PDGFRA and EGFR predominant in childhood was accomplished during all treatment. Most severe adverse events were and adult populations respectively. Moreover, focal copy number changes related to Temozolomide, with 2 patients suffering grade-4 thrombopenic in a number of additional glioma- and cancer-associated genes were ident- hemorrhages (one life-threatening digestive hemorrhage and one intratu- ified. No IDH1 hotspot mutations were found in the 78 pediatric HGG pro- moral hemorrhage). No grade 3–4 toxicities were noted with bevacizumab, filed, highlighting differences in the molecular pathogenesis between or nimotuzumab. Only one grade-2 skin toxicodermy related to childhood HGG and adult secondary glioblastoma. Pediatric and adult Nimotuzumab was documented. Autopsy was performed in 6/7 dead HGG share gene expression signatures associated with the Proneural, patients, all showing grade-4-astrocytoma. CONCLUSIONS: For DIPG Proliferative and Mesenchymal subclasses, but also show differences in patients an improvement in QoL was achieved using this regimen. A trend expression patterns. Integrated copy number and gene expression data indi- to TTP was shown. In this small series Bevacizumab and Nimotuzumab cated that deregulated PDGFRa signaling plays a major role in pediatric were well-tolerated. HGG, implicating this receptor tyrosine kinase as an important therapeutic target for pediatric HGG, including DIPG. To further determine similarities and differences between supratentorial HGG and DIPG, we analyzed genomic imbalances in an additional 44 DIPG, 7 diagnostic and 37 autopsy samples. The results of this comparison will be presented. DIPG.09. PHASE I STUDY OF VANDETANIB DURING AND AFTER RADIATION THERAPY (RT) IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) A. Broniscer1, J. N. Baker1, M. Tagen1, A. Onar1, T. K. Chin2, R. J. Gilbertson1, A. Pai-Panandiker1, A. Davidoff1, M. Kocak1, HGG.02. MICROSATELLITE INSTABILITY IN PAEDIATRIC T. E. Merchant1, W. Leung1, S. Kaste1, A. Gajjar1, and C. F. Stewart1; HIGH GRADE GLIOMA IS ASSOCIATED WITH GENOMIC 1St. Jude Children’s Research Hospital, Memphis, TN, United States; PROFILE AND DIFFERENTIAL TARGET GENE INACTIVATION 2University of Tennesee Health Sciences Center, Memphis, TN, United States M. Viana-Pereira1,2, A. Lee2, S. Popov2,3, D. A. Bax2, S. Al-Sarraj4, L. Bridges5, J. N. Sta´vale6, D. Hargrave3, C. Jones2,3, and R. M. Reis1; 1Life PURPOSE: To evaluate the safety, maximum tolerated dose (MTD), phar- and Health Sciences Research Institute (ICVS), School of Health Sciences, macokinetics, and pharmacodynamics of vandetanib, an oral VEGFR-2 and University of Minho, Braga, Portugal; 2Section of Paediatric Oncology, EGFR inhibitor, administered daily during and after RT in children with Institute of Cancer Research, Sutton, United Kingdom; 3Paediatric newly diagnosed DIPG PATIENTS AND METHODS: RT dose was 54Gy Oncology, Royal Marsden Hospital, Sutton, United Kingdom; 4Department (1.8 Gy fractions). Five dose levels of vandetanib were tested. Vandetanib of Clinical Neuropathology, Kings College Hospital, London, United started on the same day as RT for a maximum treatment duration of 2 Kingdom; 5Neuropathology, St George’s Hospital, London, United years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 Kingdom; 6Department of Pathology, Universidade Federal de Sao Paulo, weeks of therapy. Pharmacokinetic studies were performed in all patients ˜ Saõ Paulo, Brazil and pharmacodynamic studies were obtained in consenting patients. RESULTS: Twenty-one patients were enrolled on study at 50 (n ¼ 3), 65 High grade gliomas (HGG) are one of the leading causes of cancer-related (n ¼ 3), 80 (n ¼ 3), 110 (n ¼ 6), and 145 mg/m2 (n ¼ 6) per day. Only deaths in children, and there is increasing evidence that paediatric HGG may one patient experienced DLT (grade 3 diarrhea at 145 mg/m2). We then harbour distinct molecular characteristics compared to adult tumours. We treated an expanded cohort of 14 patients (110 [n ¼ 10] and 145 mg/m2 have sought to clarify the role of microsatellite instability (MSI) in paediatric [n ¼ 4]); one patient in each dose level developed grade 4 posterior reversible versus adult HGG. MSI status was determined in 144 patients (71 paediatric encephalopathy syndrome. There was a direct correlation of AUC after 0–24 and 73 adults) using a well established panel of five quasimonomorphic first dose and C at steady state with increasing doses of vandetanib. trough markers by pentaplex PCR. Expression of MLH1, MSH2, MSH6 and Results of pharmacodynamic studies will be presented. Twenty-seven PMS2 was determined by immunohistochemistry, mutation analysis by patients have already experienced disease progression. Eight patients direct sequencing and MLH1 promoter methylation using MS-PCR. DNA remain progression-free, including 3 patients who are . 20 months from copy number profiles were derived using array CGH, and mutations in eigh- diagnosis. CONCLUSIONS: The MTD of vandetanib administered during teen MSI target genes studied by multiplex PCR and genotyping. MSI was and after RT in children was not reached. Although treatment was mostly found in 11/71 (15.5%) paediatric cases, significantly more than observed safe at the highest dose levels, we recommend close monitoring of hyperten- in adults (4/73, 5.5%; p , 0.05, Chi-square test). MLH1 expression was sion. We are further testing the combination of RT and vandetanib with downregulated in 8/11 cases, however no MLH1 mutations or promoter other biologic agents in children with DIPG. methylation were found. MSH6 was absent in one paediatric MSI-H tumour, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and was associated with a remarkably stable genomic profile, a feature absent in adult HGG. We identified mutations in two genes, MSH6 and DNAPKcs; however for the majority of cases it appears that the classical target genes for MSI in other tumour types are not frequently mutated in gliomas. This study thus provides evidence for a potential novel molecular pathway in a fraction of brain tumours associated with the presence of MSI. ii10 NEURO-ONCOLOGY † JUNE 2010 Abstracts

HGG.03. INTEGRATED GENOMICS IDENTIFIES THREE ages, the paediatric disease harbours a distinctspectrumof copy numberaberra- HIGH-GRADE GLIOMA SUBTYPES WITH DISTINCT GENETIC tions compared to adults. PROFILES, PATHWAY SIGNATURES AND CLINICOPATHOLOGICAL FEATURES S. Puget1, C. Philippe2, E. DeCarli2, R. Grundy3, M. Adamovicz-Brice3, B. Job4, P. Varlet5, C. Miquel5, L. lacroix6, P. Dessen4, C. Richon4, V. Scott2, V. Lazar4, C. Sainte Rose1, G. Vassal2, and J. Grill2; 1Neurosurgical Unit, HGG.05. CPG ISLANDS METHYLATION ANALYSIS OF Hopital Necker, Universite´ Rene´ Descartes, Paris, France; 2University PAEDIATRIC HIGH GRADE GLIOMA SAMPLES IDENTIFIES A Paris-Sud, CNRS UMR 8302 “Vectorology and Anticancer Treatments”, SUBGROUP OF PATIENTS WITH DIFFERENTIALLY Gustave Roussy Institute, Villejuif, France; 3Children’s Brain Tumour METHYLATED DNA PATTERNS IN VERY YOUNG PATIENTS Research Centre, University of Nottingham, Nottingham, United Kingdom; M. J. Adamowicz-Brice1, S. Puget2, J. Lowe1, E. De Carli2, E. Schwalbe3, 4Genomic plateforme, Institut Gustave Roussy, Villejuif, France; B. Coyle1, J. Grill4, and R. G. Grundy1; 1Children Brain Tumour Research 5Anatomopathological Unit, Hopital Sainte Anne, Universite´ Rene´ Centre, University of Nottingham, UK, Nottingham, United Kingdom; Descartes, Paris, France; 6University Paris-Sud, CNRS UMR 8302 2Department of Paediatric and Adolescent Oncology, Institute Gustave “Vectorology and Anticancer Treatments”, Institut Gustave Roussy, Roussy, Paris, France; 3Northern Institute for Cancer Research, Newcastle Villejuif, France University, Sir James Spence Institute, Newcastle upon Tyne, United Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Kingdom; 4Department of Paediatric and Adolescent Oncology, Institute Molecular pathogenesis of pediatric malignant glioma (pMG)is poorly Gustave Roussy, Paris, France described and the histo-prognostic classifications used for their adult counterparts may not apply completely. Our study aimed to identify specific Tumours of the Central Nervous System are the leading cause of cancer- genomic abnormalities to generate a biological classifier. After histopatholo- related death in Children, notably the case for High Grade Glioma. A gical review, aCGH profiles and gene expression (GE) signature of 45 pMG better outcome has been reported for children under 5 years of age. were analysed by oligonucleotide microarrays (Agilent 44K); 36 samples Advances in understanding brain tumours have led to improved survival from an independent group were used to validate the aCGH classifier. for some children. A number of pediatric high-grade gliomas have limited Candidate genes were validated using RT-PCR and immunohistochemistry copy number changes and other mechanisms of gene regulation need to be (IHC). The aCGH unsupervised hierarchical clustering identified 3 patterns investigated. The presence of epigenetic changes, like hypermethylation of that were associated with survival. The addition of the 36 external samples con- known tumour suppressor genes such as MGMT and PDCD4 have been firmed the prognostic implication of the new aCGH-based classification. The widely described in glioblastoma multiforme, but a genome-wide profile of poor prognosis group consisting in the oldest patients (p ¼ 0.007) with adult aberrant DNA methylation patterns in paediatric high grade gliomas high-grade gliomassimilarities: gain of 7 and loss of 10q and adult glioma GE (pHGG) is not available. In the present analysis, we have quantified the pattern with proliferative profile on Gene Set Enrichment Analysis. However, DNA methylation level of 1,505 CpG dinucleotides (807 genes) in 28 EGFR amplification was rare and no PTEN mutation were found in tumors paraffin-embedded pHGG samples without copy number changes using uni- with 10q loss. Another group was characterized by a gain of 1q and 17q. Its versal Illumina Bead Arrays. Unsupervised cluster analyses identified a sub- GE profile showed an enrichment for proliferation and neural patterning group of 10 samples which clustered separately. Clinical data analysis genes. The last group consisting in the youngest patients with balanced showed that these samples belonged to patients diagnosed at the age of aCGH profile and a significantly better prognosis than others. It showed less than five years old. Supervised cluster analyses identified five and 28 an overexpression of CDKN1A. Potential prognostic markers on IHC genes which were respectively hypomethylated and hypermethylated in (p53, PTEN, EGFR and nuclear betacatenin) were distributed among the 3 35% of the 28 studied cases. The most frequently hypermethylated genes groups. We identified 3 molecular subgroups of pMG with survival correlates. in young children were NOTCH4, CD86, NAT2, FRK, PPARG, PDGFB, Their molecular profiling did fit neither with the histopathological classification PI3. An additional set of 72 frozen samples of paediatric high grade nor with the genomic signature of their adult counterparts. glioma have now been analysed to confirm these methylation patterns which, together with clinical information, will provide more insight to the development of pHGG.

HGG.04. A DISTINCT SPECTRUM OF COPY NUMBER ABERRATIONS IN FORMALIN-FIXED, PARAFFIN-EMBEDDED HGG.06. CLINICAL AND MOLECULAR CHARACTERISTICS OF CONGENITAL GLIOBLASTOMA MULTIFORME PAEDIATRIC HIGH GRADE GLIOMA 1,2 1,2 1,2 1 2 1 1,3,4 1,3 M. E. Macy , D. K. Birks , V. N. Barton , D. A. Bax , A. Mackay , S. E. Little , D. Carvalho , M. Viana-Pereira , 1,3 1,2 1,2 2 5 2 3 6 B. K. Kleinschmidt-DeMasters , A. M. Donson , and N. K. Foreman ; N. Tamber , A. Grigoriadis , A. Ashworth , R. M. Reis , D. W. Ellison , 1 2 7 8 1 1 University of Colorado Denver, Aurora, CO, United States; The Children’s S. Al-Sarraj , D. Hargrave , and C. Jones ; Section of Paediatric Oncology, 3 Institute of Cancer Research, Sutton (Surrey), United Kingdom; Hospital, Aurora, CO, United States; University of Colorado Hospital, 2Breakthrough Breast Cancer Research Centre, London, United Kingdom; Aurora, CO, United States 3Life and Health Sciences Research Institute, University do Minho, Braga, Portugal; 4Center for Neuroscience and Cell Biology, University of Coimbra, BACKGROUND: Congenital glioblastoma multiforme (cGBM) histori- Coimbra, Portugal; 5Breakthrough Breast Cancer Unit, Kings College cally has been considered an aggressive tumor of infancy requiring extensive London, London, United Kingdom; 6St Jude Childrens Research Hospital, chemotherapy to achieve cure. We report on 5 patients at our institution with Memphis, TN, United States; 7Clinical Neuropathology, Kings College cGBMs who were treated with surgery and chemotherapy (carboplatin and Hospital, London, United Kingdom; 8Paediatric Oncology, Royal Marsden etoposide every 21 days for 2–6 cycles). At the time of publication, all 5 Hospital, Sutton (Surrey), United Kingdom patients are progression free at a median time of 11 months (4 - 84 months). To characterize the molecular biology of cGBM, we compared As genome-scale technologies begin to unravel the complexity of the equival- the gene expression profiles of 3 cGBMs to 14 pediatric, 5 radiation-induced ent tumours in adults, detailed characterisation of high grade gliomas in chil- and 7 adult high grade gliomas (HGG). This analysis included hierarchical dren have until recently been lacking. In order to validate and extend clustering and gene ontology analyses. Selected gene expression findings investigations of the differences between paediatric and adult tumours, we were validated using immunohistochemistry. RESULTS: In a clustering carried out copy number profiling by array CGH using a 32K BAC platform analysis of gene expression profiles, cGBMs formed a distinct subgroup on 63 formalin-fixed paraffin-embedded (FFPE) cases of high grade glioma within the HGGs suggesting gene expression of these tumors differs from arising in children and young people (,23 yrs). The genomic profiles of these HGGs in older children and adults. Unique molecular features of congenital tumours could be subclassified into four categories - those with stable GBMs identified included over-expression of multiple genes involved in genomes, which conferred a better prognosis on these patients; those with aneu- central nervous system development. CONCLUSIONS: To our knowledge, ploid or highly rearranged genomes; and those with an amplifier genotype, this is the first study to report that cGBMs are treatable with surgery and which had a significantly worse clinical outcome. Independent of this was a moderate chemotherapy. Moreover, this is the first report examining the clear segregation of cases with 1q gain (more common in children) from molecular signature of cGBM by gene expression microarray. In addition those with concurrent 7 gain / 10q loss (a defining feature of adults). A detailed to defining genes which are up and down regulated in cGBMs, our analysis mapping of all the amplification and deletion events revealed numerous low fre- suggests reasons for their excellent outcome. The altered expression of quency amplifications which have not been observed previously in paediatric genes in development may imply that the aggressive course of these tumors high grade glioma including IGF1R, PDGFRB, PIK3CA, CDK6, CCND1, is attenuated by recapitulation of normal developmental pathways. CCNE1; and novel homozygous deletions encompassing unknown genes including those at 5q35, 10q25, and 22q13. Despite this, aberrations targeting the “core signalling pathways” in adult glioblastomas are significantly under- represented in the paediatric setting. Taken together, these data highlight that whilst there are overlaps in the genomic events driving gliomagenesis of all

NEURO-ONCOLOGY † JUNE 2010 ii11 Abstracts

HGG.07. SELECTIVE TARGETING OF PEDIATRIC NEURAL HGG.09. MGMT-INDEPENDENT TEMOZOLOMIDE CANCER STEM CELLS BY TELOMERASE INHIBITION RESISTANCE IN PAEDIATRIC GLIOBLASTOMA CELLS P. Castelo-Branco1, C. Zhang1, T. Lipman2,1, M. Fujitani1, L. Hansford1, ASSOCIATED WITH A PI3-KINASE-MEDIATED HOX / STEM I. Clarke1, C. B. Harley3, R. Tressler3, D. Malkin1,2, E. Walker1, CELL GENE SIGNATURE D. Kaplan1,2, P. Dirks1,2, and U. Tabori1,2; 1The Hospital for Sick Children, N. Gaspar1,2, L. V. Marshall1,3, L. Perryman1, D. A. Bax1, S. E. Little1, Toronto, ON, Canada; 2University of Toronto, Toronto, ON, Canada; M. Viana-Pereira1,4, S. Y. Sharp1, G. Vassal2, A. D. J. Pearson1,3, 3Geron Corporation, Menlo Park, CA, United States R. M. Reis4, D. Hargrave3, P. Workman1, and C. Jones1; 1The Institute of Cancer Research, Sutton, United Kingdom; 2Institut de Cancerologie Gustav Pediatric neural tumors comprise the largest group of pediatric solid Roussy, Villejuif, France; 3The Royal Marsden NHS Foundation Trust, tumors and are responsible for most morbidity and mortality from childhood Sutton, United Kingdom; 4Life and Health Science Research Institute (ICVS), cancer. The ability of these tumors to recur after maximal therapy is thought Universidade do Minho, Braga, Portugal to be related to limitless replicative potential of cancer stem cells (CSC) and telomerase activation. Although expression of telomerase is observed in most Sensitivity to temozolomide (TMZ) is restricted to a subset of glioblastoma malignant tumors, its activation in tumor cell subpopulations or normal patients, with the major determinant of resistance being a lack of promoter tissue stem cells is still unknown. In order to address safety and viability of methylation of the gene encoding the repair protein DNA methyltransferase telomerase inhibition in neural tumors we used our ability to separate MGMT, although other mechanisms are thought to be active. Due to limited Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 tumor cells into subpopulations and grow long term glioma, neuroblastoma preclinical information in model systems derived from paediatric glioma and corresponding normal tissue stem cell lines. Tumor subpopulations iso- patients, we have screened a series of cell lines for TMZ efficacy in vitro, and lated from fresh resected human gliomas revealed that only the CSC sub- have investigated the differential mechanisms of resistance involved. In the population displayed high levels of telomerase activity while the bulk of majority of cell lines, a lack of MGMT promoter methylation, and subsequent tumor cells lacked telomerase and showed a mature and senescent pheno- protein overexpression, was linked to TMZ resistance. An exception was the type. Strikingly, normal neural and neural crest stem cell lines had undetect- paediatric glioblastoma line KNS42. Expression profiling data revealed a able telomerase activity and much longer telomeres suggesting lack of co-ordinated upregulation of HOX gene expression in resistant lines, especially “addiction” to telomerase for their self renewal. The telomerase antagonist KNS42, which was reversed by PI3-kinase pathway inhibition. A high level of imetelstat had no effect on normal stem cells but caused proliferation HOXA9/HOXA10 gene expression was associated with a shorter survival in arrest and irreversible loss of self-renewal capabilities in both glioblastoma paediatric high grade glioma patient samples. Combination treatment in vitro and neuroblastoma CSC. In vivo telomerase inhibition led to significant of pathway inhibition and TMZ resulted in a highly synergistic interaction in reduction in tumor growth and survival in mouse xenograft model. Our find- KNS42 cells. The resistance gene signature further included contiguous genes ings suggest that telomerase is active only in CSC and not in normal stem within the 12q13-q14 amplicon including the Akt enhancer PIKE, significantly cells. Therefore, targeting CSC with telomerase inhibitors may represent a overexpressed in the KNS42 line. These cells were also highly enriched for specific and safe therapeutic approach for pediatric neural tumors. CD133 and other stem cell markers, demonstrating an in vitro link between PI3-kinase-mediated HOXA9/HOXA10 expression, and a drug- resistant, progenitor cell phenotype in MGMT-independent paediatric glioblastoma.

HGG.08. SORTING NEXIN 3 DISRUPTS EGFR AND MET ENDOSOMAL TRAFFICKING PROMOTING CELL PROLIFERATION AND TUMORIGENICITY IN HIGH GRADE HGG.10. A PHASE II STUDY OF CONCURRENT RADIATION GLIOMAS AND TEMOZOLOMIDE (TMZ) FOLLOWED BY D. Khuong Quang1, T. Haque1, D. Faury1, B. Meehan2, J. Rak2, TEMOZOLOMIDE AND LOMUSTINE (CCNU) IN THE S. Albrecht2, and N. Jabado1,2; 1Research Institute of the McGill University TREATMENT OF CHILDREN WITH HIGH GRADE GLIOMA Health Centre, Montreal, QC, Canada; 2Montreal Children’s Hospital, (HGG): RESULTS OF COG ACNS0423 Montreal, QC, Canada R. I. Jakacki1, P. Burger2, T. Zhou3, A. Buxton3, K. Cohen2, M. Rosenblum4, D. Brat5, R. Lavey6, and I. Pollack1; 1Children’s Hospital of Pittsburgh, INTRODUCTION: Amplification/mutation of receptors-tyrosine-kinases Pittsburgh, PA, United States; 2Johns Hopkins, Baltimore, MD, United (RTK) plays a major role in gliomagenesis. Using microarray data we gener- States; 3Children’s Oncology Group, Arcadia, CA, United States; 4Memorial ated, we identified overexpression of Sorting Nexin 3 (SNX3), a protein Sloan Kettering, New York, NY, United States; 5Emory University, Atlanta, involved in the endosomal trafficking of RTK including EGFR. Our hypoth- GA, United States; 6Children’s Hospital of Los Angeles, Los Angeles, CA, esis is that dysregulated expression of SNX3 may delay RTK degradation and United States promote sustained intracellular activation through these receptors, mimicking RTK amplification seen in adult-GBM events in a subset of PURPOSE: To determine whether the combination of CCNU and TMZ pediatric-GBM(pGBM). METHODS: We stably overexpressed given as adjuvant therapy following radiation therapy (RT) and concurrent cMyc-tagged-SNX3 in pGBM (SF188 and SJG2) and aGBM (U87) cell TMZ results in an improvement in event-free survival (EFS) compared to his- lines. Parallel SNX3 knock-down experiments were performed in cell lines. torical controls treated with RT/TMZ and adjuvant TMZ. PATIENTS AND Effects of overexpression/silencing of SNX3 were investigated on EGFR METHODS: Following maximal surgical debulking, newly diagnosed chil- and MET activation, cell signaling and cell proliferation in vitro and in dren with non-metastatic, non-brainstem HGG underwent involved field vivo (xenograft model NOD/SCID mice). We also investigated effects of RT with concurrent TMZ. All patients received adjuvant chemotherapy selective MET and EGFR inhibitors on cell growth. RESULTS: SNX3 over- with up to 6 cycles of 90 mg/m2 of CCNU on day 1 and TMZ 160 mg/ expression delayed EGFR and MET degradation following RTK engage- m2/d x 5 administered every 6 weeks depending on count recovery. ment. This increased and sustained activation of Ras and JNK pathways RESULTS: 118 patients were enrolled between March, 2005 and August, and cell proliferation in vitro Importantly, it promoted tumour formation 2007. 12 patients were deemed ineligible, 8 for ineligible histology on in NOD-SCID mice. The use of both RTK inhibitors was needed to inhibit central review. Of the 106 eligible patients (mean age, 12.5 years; range, growth of SNX3 transfectant-cells. Experiments done on SNX3-knocked 3- 21), there were 44 patients with anaplastic astrocytoma (AA) and 62 down cell lines led to increased RTK degradation, decreased intracellular sig- patients with glioblastoma (GBM). Median follow up is 27.4 months nalling and cell growth. CONCLUSION: Our results indicate that (range, 3.0–46.9 months). Non-hematologic toxicity was minimal. SNX3-overexpression disrupts physiological trafficking of multiple mem- Cumulative myelosuppression was seen as expected. Only approximately brane receptors including EGFR and MET. They potentially shed light as 30% of patients who completed therapy received all 6 courses of full-dose to how in pGBM EGFR is overexpressed in the absence of the genetic CCNU. Two-year EFS is 29% + 4.5% compared to 19% + 4% in a abnormalities seen in adult-HGA, and further indicate that simultaneous tar- similar cohort of 99 patients treated on ACNS0126 with adjuvant TMZ geting of multiple RTK is needed to affect cell growth. alone (p ¼ 0.04). Two-year overall survival (OS) is 45% + 5% versus 36% + 5% on ACNS0126 (p . 0.1). CONCLUSIONS: The combination of CCNU and temozolomide as adjuvant therapy resulted in a significant short term improvement in EFS compared to historical controls treated with adjuvant temozolomide alone, although OS was not significantly different.

ii12 NEURO-ONCOLOGY † JUNE 2010 Abstracts

HGG.11. IMMUNOTHERAPY INTEGRATED IN and HIT2000, , 4 years) and of children with ependymoma (ED) treated RADIOCHEMOTHERAPY AND MAINTENANCE by systemic chemotherapy and local RT (LRT; HIT2000, , 4 years). TEMOZOLOMIDE: FINAL RESULTS OF THE HGG-2006 STUDY METHODS: Based on CHC-theory 60 children (SKK′87/′92, n ¼ 19; S. W. Van Gool, H. Ardon, F. Van Calenbergh, R. Sciot, P. Demaerel, HIT2000, n ¼ 41) treated according to protocol remaining without relapse J. Goffin, and S. De Vleeschouwer; Catholic University of Leuven, Leuven, have been examined at a median interval of 15.3 (11.5–22.9) and 5.2 Belgium (4.2–7.0) years after diagnosis, respectively, using 3 main intelligence tests. RESULTS: MB (SKK′87/′92): Six children after CRT, but no Glioblastoma multiforme (GBM) is the most malignant diffuse high grade ivcMTX showed severe outcome (CPM 63 + 16, VMI 63 + 16, KABCII-K glioma with a dismal prognosis in spite of multimodal treatment. Dendritic IF 70 + 11) 15 years after diagnosis. Thirteen children with ivcMTX, but cell-based immunotherapy is a novel treatment approach to improve control no CRT had moderate mental decrease (CPM 83 + 23, VMI 81 + 14, over disease progression in patients with relapsing disease. Based upon our KABCII-K IF 80 + 13). MB (HIT2000-SKK; M0/1): Fifteen children after large experience in treatment for relapsed patients and data from pilot ivcMTX, but no CRT had less severe mental outcomes (CPM 93 + 14, patients (J Neurooncol, in press), we initiated the integration of immunother- VMI 86 + 16, KABC-IF 90 + 14) within -1 standard deviation (SD) below apy within the “Stupp-based” treatment for adults (18–70 years) with average. ED (HIT2000-SKK; M0): Twenty-six children having received sys- primary diagnosis of reference-histology proven GBM in whom tumor resec- temic chemotherapy and LRT had almost normal mental outcomes (CPM tion was (sub)total and tissue was conserved sterile, dry and frozen for pre- 96 + 18, VMI 91 + 14, KABC-IF 94 + 13). CONCLUSION: At long term Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 paring lysate. Seventy-eight patients were included as intent-to-treat (ITT), follow-up, mean IQ scores of children with medulloblastoma after craniosp- 58 patients were treated as per protocol (due to early relapse, toxicity inal RT (HIT-SKK′87) have further decreased to more than 2 SD below upon chemotherapy, restart of corticosteroids). Median age of ITT patients average. Children treated by chemotherapy alone (HIT-SKK′92 and was 57 years, median PFS was 9.5 months, 6-month PFS was 70.5%, median SKK-2000) have IQ levels within 1 SD of the norm population without sig- OS was 20.7 months and 2-year OS was 42.8%. All ITT patients belonged to nificant further decrease. Children with ependymoma have only marginally prognostic RPA classes III, IV and V which reflect integrated (pre)treatment decreased main IQ scores. risk factors. The median PFS rates were respectively 31.3 months, 9.7 months and 4.9 months, while the median OS rates were undefined, 20.7 months and 11.5 months. These median survivals were significantly improved as compared to the RPA-stratified patients reported in the trial by Stupp et al. Toxicity was minimal, and the treatment was given in out- PSY.03. PREOPERATIVE LANGUAGE IMPAIRMENT: CAN IT patient setting. These data are of importance in designing future clinical PREDICT CEREBELLAR MUTISM AFTER POSTERIOR FOSSA trials for children with GBM in which immunotherapy will be integrated TUMORS RESECTION? in multimodal temozolomide-based standard treatment. D. Chieffo, G. Tamburrini, P. Frassanito, B. L. Pettorini, L. Massimi, M. Caldarelli, and C. Di Rocco; Catholic University Medical School, Rome, Italy

05 NEUROPSYCHOLOGY Cerebellar Mutism Syndrome (CMS) is a well-know complication of posterior fossa tumor surgery in children, usually presenting in the first 24–48 postoperative hours after resection of a posterior fossa tumor. Symptoms PSY.01. NEUROPSYCHOLOGICAL OUTCOME IN A STUDY OF include mutism and emotional lability. The duration is variable. Surgical CRANIOSPINAL RADIATION THERAPY FOLLOWED BY trauma, cerebrospinal fluid circulation disorders, psychic factors and menin- ADJUVANT CHEMOTHERAPY FOR NEWLY DIAGNOSED gitis are mechanism involved in the pathogenesis. Proximal portions of den- AVERAGE-RISK MEDULLOBLASTOMA (MB): A CHILDREN’S tatothalamocortical pathways, including dentate nuclei, cerebellar ONCOLOGY GROUP (COG) STUDY peduncles, and brainstem, are considered as probably more damaged M. Ris1,2, K. Walsh3,2, D. Armstrong4,2, E. Holmes2, and R. J. Packer3; areas. Between January 2005 and September 2009, 41 patients affected by 1Texas Children’s Hospital, Houston, TX, United States; 2Children’s posterior fossa tumors were submitted to a pre- and post-operative neurop- Oncology Group, CA, United States; 3The Children’s National Medical sychological assessment. Children less than 2 years of age were excluded for Center, Washington, DC, United States; 4Mailman Center for Child the difficult language assessment and mutism surveillance. For all patients Development, Miami, FL, United States demographic information was recorded. There was no gender preponder- ance. The age ranged from 2 to 16 years. The most frequent location of Neurobehavioral studies were conducted on children with MB assigned the lesion was the midline (64.8%). Preoperative hydrocephalus was to one of two arms of this Phase III COG randomized trial differing in present in 27 patients. Preoperative language disorders were found in 11 chil- post-RT chemotherapy; lomustine, cisplatin, and vincristine versus lomus- dren (26.8%). After tumor removal, two of them showed spontaneous resol- tine, vincristine, and cyclophosphamide. All patients received 23.4 Gy of ution. Two had stabilized language disorders. Seven patients developed a CSRT with a posterior fossa boost of 32.4 Gy for a total dose of 55 CMS. The factor more significantly related with the development of post- Gy. Four hundred and twenty patients between 3 and 21 years of age operative mutism was the presence of severe hydrocephalus at diagnosis were treated group-wide under the parent study, while this sample of up (7/7 patients developing a CMS). Preoperative neuropsychological evalu- to 117 patients comprised a subset evaluated at institutions capable of ation pointed out that a speech disorder can be present at diagnosis in chil- conducting the prescribed battery of tests. Neuropsychological testing dren affected by posterior fossa tumours and represents a risk factor for the was conducted serially at 1 year, 2 years, and 3–5 years post-RT. development of a CMS. Outcome measures included intelligence, achievement, visual-motor integration, adaptive behavior, and emotional-behavioral adjustment. Preliminary analyses indicate normal-range neuropsychological functioning one year post-RT, followed by declines across most measures (except PSY.04. INTELLECTUAL OUTCOME IN BILINGUAL AND emotional-behavioral adjustment) up to 5 years post-RT. These results MONOLINGUAL CHILDREN WITH MEDULLOBLASTOMA confirm other reports that children with MB treated with reduced dose M. Di Pinto, V. Shen, L. McDonald, G. Mucci, J. Schenk, T. Templeman, RT still suffer significant neuropsychological late-effect. More detailed J. Pathare, and K. Hawking; Children’s Hospital of Orange County, Orange, results will be presented. CA, United States OBJECTIVE: Children diagnosed with medulloblastoma are at risk for intellectual decline following treatment. To our knowledge, no prior studies have investigated whether bilingualism imparts risk or resiliency PSY.02. LONG TERM NEUROPSYCHOLOGICAL FOLLOW UP OF with respect to cognitive late effects. METHODS: Seventeen children with YOUNG CHILDREN WITH MEDULLOBLASTOMA AND average risk medulloblastoma underwent intellectual testing 1 and 2 years EPENDYMOMA TREATED IN THE TRIALS HIT-SKK′87/′92 AND post-treatment. Nine children were monolingual English speakers and 8 chil- HIT 2000 dren were bilingual English and Spanish speakers. Intellectual functioning H. Ottensmeier1, S. Frahsek1, A. Faldum2, and S. Rutkowski3; 1University was assessed using the age specific English version of the Wechsler scales. Children’s Hospital, Wu¨ rzburg, Germany; 2Institute of Medical Biostatistics, RESULTS: Average age at diagnosis was 5.94 years, with no significant Epidemiology and Informatics, University Medical Center of Mainz, difference between the monolingual and bilingual subgroups. Gender was Germany; 3Department of Pediatric Hematology and Oncology, University equally distributed across subgroups. Monolingual children had significantly ¼ ¼ Medical Center Hamburg-Eppendorf, Germany higher verbal IQ (p .006) and nonverbal IQ scores (p .008) than bilingual children 1 year post-treatment (monolingual: VIQ ¼ 98, PIQ ¼ 97; ¼ ¼ OBJECTIVE: To compare neuropsychological outcomes of children with bilingual: VIQ 79, PIQ 76). Monolingual children also had significantly ¼ medulloblastoma (MB) treated within the GPOH-HIT studies with systemic higher VIQ scores 2 years post-treatment (p .009), with bilingual children ′ ¼ chemotherapy and craniospinal irradiation (CRT; SKK 87 , 3 years), sys- experiencing further VIQ decline over time (monolingual: VIQ 96; bilin- ′ ¼ temic and intraventricular methotrexate (ivcMTX; HIT-SKK 92 , 3 years, gual: VIQ 71). In contrast, PIQ scores increased over time in the bilingual

NEURO-ONCOLOGY † JUNE 2010 ii13 Abstracts

subgroup, with no significant difference between subgroups 2 years post- PSY.07. ASSESSMENT OF ATTENTION IN CHILDREN WITH treatment (monolingual: PIQ ¼ 98; bilingual: PIQ ¼ 84). CONCLUSION: BRAIN TUMORS: WHAT SHOULD WE LOOK AT? Overall, bilingual children with medulloblastoma were at greater risk of L. Weiler1, T. Pletschko2, A. Schabmann1, I. Slavc2, and U. Leiss2; 1Faculty adverse intellectual outcome versus monolingual children, with verbal intel- of Psychology, University of Vienna, Vienna, Austria; 2Department of lectual outcome most susceptible to decline. These findings underscore the Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, importance of considering multicultural factors, particularly early exposure Austria to multiple languages and bilingualism, in the identification of subgroups at increased risk of adverse neurocognitive outcome. PURPOSE: Previous studies give clear evidence of problems in attentional performance in children with brain tumors. Due primarily to methodological problems, however, there is still no conclusive consent about which dimension of attention is most affected. Therefore, the aim of the study was to describe PSY.05. DEFICITS IN PLANNING, ATTENTION AND attentional performance in a very detailed manner, in order to learn about INFORMATION PROCESSING IN PEDIATRIC POSTERIOR the predominant problems and then to develop specific intervention strategies. FOSSA TUMOR SURVIVORS PATIENTS/METHODS: Summarizing the results of theoretical and empirical 1 1 1 2 E. Koustenis , P. Hernaíz Driever , G. Henze , L. de Sonneville , and research, the following six attention constructs were chosen for further analy- 1 1 S. Rueckriegel ; Pediatric Neuro-oncology Program, Department of sis: alertness, sustained attention, ability of distraction, divided attention, pro- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Pediatric Oncology and Hematology, Charite´-Universita¨tsmedizin Berlin, cessing speed and focused attention. Fifty four children with different types of 2 Berlin, Germany; Clinical Child and Adolescent Studies, Leiden University, brain tumors were compared with 102 children from a healthy control group Leiden, Netherlands regarding their attention performance, as assessed with appropriate neuropsychological measurements. Furthermore, child-, treatment- and tumor-related BACKGROUND AND PURPOSE: Besides motor function the cerebellum factors were considered in the analysis. RESULTS: The results indicate that controls complex supratentorial functions. Thus, we investigated executive children with brain tumors show significantly lower attention performance functions in pediatric posterior fossa tumor patients. PATIENTS AND than the control group concerning alertness and ability of distraction. METHODS: We tested information processing, planning and aspects of Moreover, a significantly slower processing speed was found in the brain problem solving as well as intelligence in 40 pediatric patients with posterior tumor group. On the contrary, no significant difference arose with regard to fossa brain tumors (mean age 14.63 yrs, SD 5.03). Patients had either slowly focused attention. In order to interpret the results on sustained and divided growing tumors (LGCT) treated with surgery only (n ¼ 17) or malignant attention, the sample size will be increased. CONCLUSION: The results tumors (HGCT) requiring in addition adjuvant treatment (n ¼ 23). The emphasize the importance of detailed assessment of attention to cover the Amsterdam Neuropsychological task program (ANT) evaluated divided range of possible problems in attentional performance and to decide on the attention, information speed and attention flexibility whereas the Tower of appropriate intervention strategies. London-test (TOL) discerned forward thinking abilities. IQ was determined using the Wechsler Intelligence Scale. RESULTS: In the TOL, both patient groups showed equal forward thinking regardless of task difficulty, albeit both groups exhibit a significantly greater risk to score below average when compared to the norm, i.e. 8 and 3.5 times higher for LGCT and PSY.08. NEUROCOGNITIVE DEVELOPMENT OF CHILDREN HGCT, respectively. No correlation between fluid intelligence and TOL per- WITH BRAIN TUMORS DIAGNOSED AT AGE ≤ 3 YEARS formance was detected. The ANT revealed deficits in accuracy and reaction U. Leiss1, C. Dorfer2, T. Pletschko1, A. Schwarzinger1, A. Peyrl1, A. Azizi1, speed as task difficulty increased for both patient groups. HGCT patients M. Heinrich1, T. Czech1, and I. Slavc1; 1Department of Pediatrics and were significantly slower and committed more errors. CONCLUSION: Adolescent Medicine, Medical University of Vienna, Vienna, Austria; Pediatric posterior fossa tumor survivors exhibit impairments in forward 2Department of Neurosurgery, Medical University of Vienna, Vienna, thinking, information processing and aspects of attention regardless of Austria form of treatment that are increased by chemo- and radiotherapy-associated toxicity. The pattern of function loss active in both groups is due to lesions to PURPOSE: Previous studies point out that young age at time of diagnosis is cerebro-cerebellar circuits modulating critical executive functions. a significant risk factor for neuropsychological outcome in childhood brain tumor survivors. We documented neurocognitive development in children treated for a brain tumor at age ≤ 3 years and analysed influencing factors. PATIENTS/METHOD: We followed 105 patients with infant PSY.06. RELATIONSHIP OF CHILD-PERCEIVED COGNITIVE brain tumors treated at the Medical University of Vienna from 1992– FUNCTION, FATIGUE AND DEPRESSION 2009. 23 patients died, 9 were lost to follow-up and 4 children could not J. Lai1, Z. Butt1, and S. Goldman2; 1Northwestern University, Chicago, IL, be assessed due to too young age. 67 children aged 2,5 to 15 years were United States; 2Children’s Memorial Hospital, Chicago, Chicago, IL, United tested with a follow-up time of 1 to 11 years. Neuropsychological assessment States included age appropriate standardized developmental scales (ET 6–6) or IQ-tests (Wechsler-scales). Furthermore attentional performance, learning, OBJECTIVE: Cognitive function is a major concern for childhood brain memory and processing speed were tested. Quality of life and behavior tumor survivors. Although changes in perceived cognitive function (PCF) was rated by the parents. RESULTS: 63% of the tested children scored often prompt referral for neuropsychological testing, there remains concern within the normal range regarding their overall intellectual abilities. For that PCF may reflect non-specific concerns of depression or fatigue. This 31% of the children we found results below age norm, 6% showed major study reports the association between PCF, fatigue, and depression. developmental delay. The findings indicated a wide variability of outcome, METHODS: The sample included 140 adolescents and 179 children with epi- most likely caused by tumor- and treatment related factors as well as socio- lepsy, traumatic brain injury, cerebral palsy, or brain tumor. PCF, depression, economic status and language difficulties. Despite normal range IQ-scores and fatigue were measured by the pedsFACIT-PCF, the Neuro-QOL pediatric 52% of the patients showed specific learning disorders or specific neuropsy- depression scale, and pedsFACIT-fatigue. Parents completed the Child chological deficits, which require either special education programs in school Behavior Check List (CBCL). RESULTS: Compared to the US pediatric popu- or special trainings. CONCLUSION: Although 63% of this group of chil- lation norms, adolescents reported more severe (.1 SD) PCF (M ¼ 30.74), dren showed good outcomes in terms of IQ, 70% of them have difficulties fatigue (M ¼ 21.1); and depression (M ¼ 17.9). Among children, PCF and 1 ¼ in special areas, which makes appropriate support essential. depression were 2 SD more severe than norms, M 26.22 and 16.8, respectively. Fatigue (M ¼ 12.4) was 1SD more severe than norm. PCF was moderately correlated with depression and fatigue, r ¼ .44 and .47 for adolescents and r ¼ .67 and .67 for children. Stronger correlations were found between fatigue and depression, r ¼ 0.93 and 0.76 for adolescents and children, PSY.09. DIFFUSION TENSOR IMAGING (DTI) FOLLOWING respectively. PCF scores significantly differentiated normal vs. abnormal TREATMENT FOR PEDIATRIC EMBRYONAL TUMORS: CBCL attention, social and thought (p , .0001). CONCLUSIONS: As CORRELATION WITH SPEED OF PROCESSING expected, this patient sample was more depressed, fatigued, and had poorer S. L. Palmer, W. E. Reddick, J. O. Glass, R. Ogg, A. Broniscer, I. Qaddoumi, PCF than normal comparators. Fatigue and depression were highly correlated, G. T. Armstrong, B. Morris, and A. Gajjar; St. Jude Children’s Research yet explained , 50% of the variance in PCF. PCF scores also discriminated the Hospital, Memphis, TN, United States sample within and outside of CBCL normal ranges. Further study comparing PCF to other objective data is warranted. PURPOSE: Processing speed is a critical cognitive function related to working memory as well as general intellect. Children treated for embryonal tumors demonstrate reduced cognitive processing speed with increasing time from treatment, as well as damage to white matter within the brain. The present study examines whether reduced white matter integrity is related to decreased speed of cognitive processing. PATIENTS AND METHODS: At 36 months post-treatment with radiotherapy (CSI 23.4–39.6 Gy, 3-D ii14 NEURO-ONCOLOGY † JUNE 2010 Abstracts

conformal boost to the primary site 55.8–59.4 Gy) and chemotherapy, 38 support and distress through MRI (r ¼ 1.00). All parents judged the patients (median age at diagnosis ¼ 9.06 years) enrolled at our institution MRI-training as helpful and beneficial. It was decided during the program completed an MRI examination including DTI imaging sequences and neu- that three children would require anesthesia during the MRI. Their parents ropsychological evaluation including assessment of processing speed showed lower supporting educational behavior (f(x)¼ -23.86) but also (Woodcock Johnson Tests of Cognitive Abilities). White matter fractional high parental distress through MRI (f(x) ¼ 17.27). CONCLUSION: The anisotropy (WMFA) values were calculated for 6 specific regions of interest training allowed the majority of the children to successfully complete the (ROI) and correlated with speed of processing. RESULTS: Age at evaluation MRI without anesthesia. The sample size available so far was small but was significantly related to WMFA within 5 ROI (p , .05) as well as proces- the program and its evaluation are still in the process of collecting more sing speed (r ¼ .43, p ¼ .007). Therefore the remaining analyses were com- data in order to improve the program. pleted controlling for age. Results indicated reduced WMFA within the splenium of the corpus callosum was associated with slower visual matching (r ¼ .407, p ¼ .013), decision speed (r ¼ .396, p ¼ .015) and processing speed (r ¼ .442, p ¼ .006). CONCLUSIONS: The corpus callosum is the largest white matter tract in the brain. It’s posterior aspect, the splenium, MULTI.03. “TALK WITH ME”: COMMUNICATING WITH is in close proximity to the posterior fossa. Therefore it is also an area that DYING CHILDREN WHO HAVE TROUBLE SPEAKING receives a potentially high dose of irradiation. Efforts to protect this vulner- C. Kaise, C. Eaton Russell, D. Brownstone, T. Chau, and E. Bouffet; The Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 able area may be needed to preserve critical cognitive functions. Hospital for Sick Children, Toronto, ON, Canada

Little is known about communication with children who have limited or no speech when they are dying because of a brain tumour. A qualitative 06 MULTIDISCIPLINARY APPROACH TO THE research was conducted that involve parents of children undergoing pallia- PATIENT AND FAMILY tive care for CNS tumour. Interviews elicited parents’perspectives of: com- municative needs and abilities of dying children; creative strategies used to facilitate meaningful communication; issues that were most important for families to discuss; and strategies to support their own and their children’s MULTI.01. EXPERIENCES OF FAMILIES AND EDUCATORS complex needs. Overall, parents stressed the critical role of communication ENGAGED IN A NEW SCHOOL LIAISON PROGRAM FOR in maintaining relationships and intimate connections during the end of CHILDREN WITH CNS TUMORS 1 2 3 1 their children’s lives. Following this study, a handbook was developed to sum- A. Chapman , J. Newcombe , and A. MacDonald ; IWK Health Centre, marise these findings. It contains information, experience and wisdom collected Halifax, NS, Canada; 2Chignecto-Central Regional School Board, Truro, 3 from the parents of these 14 children and can be used as valuable resource for NS, Canada; b.r.a.i.n Child Maritimes, Halifax, NS, Canada families whose children struggle to communicate. It includes practical strategies and concrete tools as well as parents’ suggestions about how to discuss and BACKGROUND: Families and children often report challenges at school support their children through complex emotional, spiritual and end-of-life after undergoing treatment for a brain tumor. A school liaison program issues. Although this study focused on families of children with brain tumors, familiarized teachers with the implications each child’s treatment with lessons learned are transferrable to a range of pediatric and adult populations. respect to learning, behavior and socialization. The purpose of this study By walking participants through the handbook chapter by chapter, and high- was to explore the experiences of ten families and their teachers who partici- lighting parents’ messages through the stories they shared, this presentation pated in the program. METHODS: The successes and challenges of the will: explore the experience of family members trying to communicate when program were captured through 21 individual interviews with parents, tea- a dying child struggles to express him/herself; consider families’priorities chers and health professionals. The inquiry was grounded in a constructivist towards the end of their children’s lives; share concrete tools to enhance com- paradigm and transcribed interviews were examined using thematic analysis. munication without speech and have an opportunity to practice using these FINDINGS: Through the program, individualized programs were nego- tools. tiated between families and education staff to address behavorial, academic and social needs of each child. This provided an opportunity for the child to learn to their ability rather than be judged on the achievements of their respective grade levels. Parents reported the program strengthened their advocacy skills and improved the children’s social and MULTI.04. SPEECH PATHOLOGICAL ALTERATIONS IN learning achievements. Teachers reported an improved ability to provide PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM more comprehensive educational programming suited to the child’s TUMORS needs. Overall, most children in the program achieved or exceeded their M. I. R. Gonçalves1, R. Popriaga1, R. Ramalho1, F. T. Menezes1, initial academic, social and behavioural expectations that were envisioned T. Radzinsky1, N. Bortolatto1, S. Cavalheiro1, B. M. Chiari2, for the two year period. CONCLUSIONS: Providing consistent support A. Cappellano1, D. F. Curcio1, and N. S. Silva1; 1Pediatric Oncology Institute strengthened parents’ ability to be stronger advocates and assisted in devel- Federal University of Saõ Paulo, Saõ Paulo, Brazil; 2Speech Pathology oping mutually shared realistic expectations between parents and teachers. Department Federal University of Saõ Paulo, Saõ Paulo, Brazil Early education intervention with anticipatory planning for each child’s learning and social needs through a school liaison program has demon- PURPOSE: To verify the most frequent alterations regarding speech path- strated significant potential to enhance the learning experience for children ology in pediatric patients with central nervous system. METHOD: analysis with brain tumors. of data of speech pathology screening protocols from March 2002 to December 2007. Data from 201 patients were analyzed, both sexes, with an age ranging from 0 to 18 years, diagnosed with central nervous system tumors. Statistical analysis was performed using the chi-square test; significance level was 0.05 (5%). CONCLUSIONS: We observed high prevalence MULTI.02. EVALUATION OF A PSYCHOLOGICAL TRAINING of speech pathological alterations in this population; the most frequent TO PREPARE CHILDREN AGED FROM 4 TO 7 YEARS FOR MRI alterations were related to orofacial myology (22.4%), speech (17.1%), WITHOUT ANESTHESIA 1 2 2 2 1 hearing (10.5%), voice (10.5%), dysphagia (9.4%) and language (8.4%); A. Schwarzinger , D. Leitner , P. Deimann , U. Kastner-Koller , I. Slavc , medulloblastoma and astrocytoma were more frequently related to the and U. Leiss1; 1Medical University of Vienna, University Clinic for Pediatric 2 observed alterations, and tumors located in brain stem, posterior fossae and Adolescent Medicine, Vienna, Austria; University of Vienna, Faculty of and diencephalus presented higher correlation with the observed alterations. Psychology, Vienna, Austria

PURPOSE: Keeping still during MRI is a demanding challenge. Therefore preschoolers usually undergo MRI while under anesthesia. To prepare children aged from 4 to 7 years for undergoing MRI without anesthesia, a MULTI.05. EMPLOYMENT STATUS AND SOCIAL COGNITION psychological training was developed. The goal of this study was the evalu- IN ADULTS FOLLOWING PEDIATRIC BRAIN TUMOR ation of the effectiveness of this program. The first step was to evaluate the TREATMENT experiences of the parents and their reported impact of the program. T. T. Vlagsma1, A. Kingma1, R. B. Huitema2, and J. A. Leeuw1; 1Pediatric METHODS: A standardized psychological test-battery, which includes ques- Oncology, University Hospital Groningen, Groningen, Netherlands; tionnaires to assess anxiety, distress, mental state, educational behavior and 2Neuropsychology, University Hospital Groningen, Groningen, Netherlands social support of the children and their parents, was used before the training and before the MRI without anesthesia was performed. RESULTS: Between BACKGROUND: Treatment of childhood brain tumor often results in March and September 2009, nine children with different brain tumors were permanent cognitive deficits with potential consequences for employment registered in the sample. Six completed the program and successfully under- in adulthood. Aim of this study was to investigate the possible relation went the MRI without anesthesia. The results indicated that the parents of between deficits in social cognition and rate of regular employment. those six children showed significantly higher scores regarding parental

NEURO-ONCOLOGY † JUNE 2010 ii15 Abstracts

PATIENTS AND METHODS: 18 Patients (78% participation) were caregiver demand. Multiple regression analyses were used to predict care- included in the study with the following criteria: tumor localization in the giver demand from the mother’s mental and physical health, the survivor’s posterior fossa, follow-up since diagnosis .10 years, current age between quality of life, and family functioning. Based on research with other popu- 18 and 40 yrs., IQ . 60. 10 Patients treated with surgical resection (astrocy- lations of caregivers, it was hypothesized that poorer caregiver, survivor, toma) only were compared to 8 patients treated with surgical resection, and household functioning would be related to increased caregiving whole brain radiation therapy and chemotherapy (medulloblastoma). demands. RESULTS: Higher caregiver state anxiety (p , .05) and worse sur- Education and employment status were determined by a semi-structured vivor physical quality of life (p , .05) significantly predicted greater care- interview; general cognitive functioning and social cognition were evaluated giver demands, explaining approximately 18% of the variance (adjusted 2 with neuropsychological tests. Patients were compared to healthy controls. R :¼ 0.18; F(8,104)- ¼ 3,74, p , 0.001). The remaining variables were non- RESULTS: Thirty eight percent of the medulloblastoma group and 60% of significant. CONCLUSIONS: Both caregiver and survivor functioning influ- the astrocytoma group had regular employment. In comparison to healthy enced the level of demands on the caregiver, highlighting potential targets for controls, the combined patient group showed significantly lower scores on intervention. Continued research with larger sample sizes is needed to ade- all tests of general cognitive functioning and social cognition. No significant quately test this caregiving model as well as longitudinal work to measure differences were found between both patient groups. We hypothesize that both changes in caregiver demand over-time and factors influencing risk loss of employment is most likely caused by general poor mental functioning and resilience. and additionally, possibly by poor social cognition, i.e. recognition of Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 emotions. CONCLUSIONS: Treatment for childhood brain tumor affects patient’s employment status in adulthood. Both a general decline in cognitive functioning and poor social cognition has effect on employment later in life. More support for pediatric brain patients should be given to improve their MULTI.08. ASSESSING BEREAVED PARENTS’ PERCEIVED education and chances for employment. PURPOSE, HOPES AND REGRETS FOR PARTICIPATING IN A PROSPECTIVE AUTOPSY SPECIMEN STUDY FOR THEIR CHILD WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) J. N. Baker, J. Windham, P. S. Hinds, J. Gattuso, P. Gajjar, N. West, and A. Broniscer; St Jude Children’s Research Hospital, Memphis, TN, United MULTI.06. HOW DO PARENTS COPE WITH THEIR CHILD’S States DIAGNOSIS AND TREATMENT OF AN EMBRYONAL TUMOR? RESULTS OF A PROSPECTIVE AND LONGITUDINAL STUDY BACKGROUND: How bereaved parents perceive participating in S. L. Palmer1, S. Lesh1, D. Wallace1, M. J. Bonner2, M. Swain3, autopsy-related research is unknown. We conducted a study to document L. Chapieski4, D. J. Mabbott5, S. Knight6, R. Boyle7, C. Armstrong8, and parents’ hopes, reasons and regrets about participating in a prospective A. Gajjar1; 1St. Jude Children’s Research Hospital, Memphis, TN, United autopsy study of children with DIPG. METHODS: Twenty-six parents States; 2Duke University Medical Center, Durham, NC, United States; who consented to the autopsy study completed a questionnaire after their 3Royal Children’s Hospital, Brisbane, Australia; 4Texas Children’s Hospital, child’s death regarding their reasons and hopes for study participation. Houston, TX, United States; 5The Hospital for Sick Children, Toronto, ON, Parents also provided suggestions about ways clinicians could discuss autop- United States; 6Royal Children’s Hospital, Melbourne, Australia; 7Sydney sies, and completed the Decisional Regret Instrument. RESULTS: Purposes Children’s Hospital, Sydney, Australia; 8Children’s Hospital of Philadelphia, most frequently for participation included wanting to advance knowledge/ Philadelphia, PA, United States find a cure, to protect future patients/families, being frustrated at how little information exists, and choosing as their child would have wanted. PURPOSE: Parent response serves a critical role in a child’s adjustment to Obtaining closure was an additional hope for participation. The most fre- critical illness. The current study reports coping responses among parents of quent suggestions for discussing autopsy included providing education/ children diagnosed with an embryonal tumor. PATIENTS AND anticipatory guidance, having a trusted professional sensitively approach METHODS: Patients (n ¼ 219) were enrolled on a treatment protocol for families and providing results in a timely manner. All parents reported that a pediatric embryonal tumor. Their parents (n ¼ 251) completed the participating in the study was the ‘right decision’ for them, 88% did not Coping Response Inventory at time of their child’s diagnosis and yearly regret it, 92% would make the choice again, 88% did not think participating thereafter, resulting in 502 observations. Outcomes were examined with did ‘a lot of harm’, and all felt it was a wise decision. CONCLUSION: patient and parent age at diagnosis, patient risk, parent gender and education Participation in autopsy-related research for parents of children who were as covariates. RESULTS: At the time of diagnosis, the highest observed treated for a brain tumor is motivated by parental desires to improve knowl- coping method was seeking guidance with well above average scores (T ¼ edge about their child’s disease and wanting to help others. Importantly, par- 61.6). Over time, younger parents were found to seek guidance at a signifi- ticipation did not result in harm for the parent. Parents suggested providing cantly higher rate than older parents (p ¼ .01) and the use of acceptance res- anticipatory guidance, being approached in a sensitive manner by a trusted ignation and seeking alternative results by all parents significantly increased professional and timely provision of results as ways to better discuss autopsy. (p ¼ .01 and p , .0001 respectively). The use of emotional discharge was also above average (T¼ 56.2) with younger fathers being more likely to exhibit emotional discharge (p ¼ .002). Differences in coping according to age of the patient and parent education level were also found and will be presented. CONCLUSIONS: Results show a high need for guidance, MULTI.09. EDUCATIONAL NEEDS OF PEDIATRIC and above average emotional discharge, especially among younger parents. NEURO-ONCOLOGY FAMILIES CAN BE ADDRESSED IN A It is imperative for the healthcare team to lead with accurate information SUPPORT GROUP SETTING so that these parents may make informed decisions about the care of their D. M. Spoljaric1, C. Sandvoss2, and J. Isenberg2; 1Washington University child. This need remains high years after diagnosis. Therefore it is critical School of Medicine, St Louis, MO, United States; 2St Louis Children’s to continue a consistent level of effective communication and support, Hospital, St Louis, MO, United States even following treatment. BACKGROUND: Families of children with brain tumors desire increased knowledge about tumors, their treatment, and long-term effects of therapy. Further, they seek contact with other families affected by these tumors. HYPOTHESIS: Families of children with brain tumors would benefit from MULTI.07. CAREGIVING DEMANDS: SURVIVORS OF participation in an educational/support group in which relevant information CHILDHOOD BRAIN TUMORS is presented to the group and families have the opportunity to share their J. A. Deatrick1, M. Fisher2, J. P. Ginsberg2, W. Hobbie2, L. Barakat2, own experiences and provide support. APPROACH: We surveyed 238 J. Hicks1, P. Paik1, M. Hocking2, E. M. Palma1, and T. Hardie3; 1University families to assess interest in an education/support group, motivation/will- of Pennsylvania, Philadelphia, PA, United States; 2The Children’s Hospital of ingness to attend, potential educational topics, and best times to meet. Philadelphia, Philadelphia, PA, United States; 3Widener University, Chester, Funding was obtained through local organization to cover lunch, supplies PA, United States and attendance prizes for the group at no cost to families. RESULTS: Fourteen percent of families responded to the questionnaire. Eleven sessions AIM: Many childhood brain tumor survivors will struggle for indepen- were held with an average attendance of 6.7 families. Discussion topics dence from their families of origin. Subsequently, mothers of these survivors included: Navigating the Emotional Terrain; School: Pathway to the bear disproportionate demands of the caregiving after their child Future; Nutritional Tips; Horizons in Pediatric Brain Tumor Research; transitions into survivorship. The aim was to explore predictors of the care- Seizures: what are the options? Headaches; Helping siblings adjust/cope givers’ demands related to caring for their children who had survived a brain and a Resource Fair. CONCLUSION: Educational/support groups can tumor. METHODS: Telephone interviews were conducted in this cross- foster knowledge, support, and comfort for families affected by pediatric sectional study using structured questionnaires with a sample of 104 care- brain tumors. Families traveled an average of 46 miles to attend the sessions, givers whose survivors were still living at home. Self-report questionnaires which suggests strong motivation to participate. Surveys collected after each measured functioning of themselves, their survivor, and their family and session indicate that 100% of families find the educational sessions helpful. ii16 NEURO-ONCOLOGY † JUNE 2010 Abstracts

On-going surveys of families’ needs led to implementing a teen support is approaching 60%. Cancer therapy given at a young age produces compli- group. To date, six teen patient support group sessions have been held. In cations that may appear or persist years later. 2/3 of childhood cancer survi- the future, we will examine barriers to participation and initiate a teen edu- vors will experience at least one late effect. 1/3 will have a severe or cation session. life-threatening late effect. Survivors of pediatric CNS tumors are likely to have multiple late effects, including: endocrine, musculoskeletal, neurologic, sensory, pulmonary, and integumentary issues. They frequently experience neurocognitive deficits and face educational, psychosocial, financial and legal obstacles. In addition to following-up with their neuro-oncology MULTI.10. SURVIVORS’ AND PARENTS’ EVALUATION OF team, this high-risk population is also seen in primary care practices and FOLLOW-UP HEALTH CARE NEEDS AFTER CHILDHOOD CNS by multiple pediatric subspecialists. Providing comprehensive care to these TUMOUR TREATMENT survivors is difficult, especially in the midst of a busy neuro-oncology E. I. Hoveń and K. K. Boman; Karolinska Institutet, Stockholm, Sweden clinic where active therapy patients are being seen concurrently. The emerging challenge: to provide survivors of childhood brain tumors with appro- OBJECTIVE: To comprehensively describe health care needs of adult sur- priate medical care while empowering them with the knowledge they need vivors of childhood CNS tumours. METHODS: In this population-based to advocate for themselves and live happy, successful lives. We developed cohort study, 526 of 679 eligible survivors and 550 parents (82.4%) pro- an innovative model of care for long-term survivors of CNS tumors at our Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 vided data. Health care needs were assessed by a questionnaire covering 4 institution. The establishment of a multidisciplinary, nurse practitioner areas: medical care, care coordination, illness education, and psychosocial driven, neuro-oncology late effects clinic will be described including needs services. Health care needs were categorized as no need, met need, and assessment, staffing, care delivery model, patient and staff satisfaction, and unmet need. Outcomes were analysed in relation to survivors’ health status research opportunities. assessed with the Health Utilities IndexTM. RESULTS: Overall, 39% of survivors experienced their need of health care to exceed population average. 90% of survivors had some kind of health care need in adult life, and 1/2 reported having a health care need that was unmet. Survivors’ perceived needs were highest for illness education, followed by care coordination, MULTI.14. THE IMPACT OF A CONSULT-BASED PALLIATIVE medical care, and psychosocial counselling. The most frequent type of CARE TEAM ON PEDIATRIC NEURO-ONCOLOGY PATIENTS unmet needs concerned psychosocial services and illness education. WHO DIED Survivors with impaired health status had greater health care needs, but J. N. Baker, S. Singhal, J. Yang, C. Wang, and J. R. Kane; St Jude Children’s also more unmet such needs. Parents rated their child’s need of health care Research Hospital, Memphis, TN, United States and extent of unmet needs greater than did the survivors themselves. CONCLUSIONS: The use of multiple informants adds reliability to the BACKGROUND: Children dying a cancer-related death and their families evaluation of survivors’ health care needs. Identification of the extent of experience a great deal of suffering, but little is known about how to best health care needs is a precondition for the development of effective indivi- integrate palliative care into the continuum of their care. We aimed to deter- dualised surveillance of childhood CNS tumour survivors. Our findings mine the impact of a consult-based pediatric palliative care team on show that a considerable proportion of survivors experience unmet health end-of-life issues in children with brain tumors and their families. care needs. By addressing these unmet needs properly, quality of comprehen- METHODS: We conducted a retrospective chart review of end-of-life care sive health care can be increased. characteristics of pediatric neuro-oncology patients who died while being followed by our institutional palliative care team. These patients were compared with an earlier cohort of neuro-oncology patients who died prior to the creation of the team. RESULTS: Twenty-four patients were included in the palliative care cohort and 143 in the historical cohort. The groups differed MULTI.11. LATE EFFECTS IN CHILDHOOD BRAIN TUMORS in their religious affiliation and place of death. There were significant differ- SURVIVORS: DEVELOPING A SCREENING TOOL FOR ences between the time from first end-of-life (EoL) discussion to DNR order, IDENTIFYING TREATMENT TARGETS number of documented EoL discussions and proportion of patients enrolled N. Greenberg1, S. Freedman1, R. Eshel1, N. Zverling1, R. Elhasid1, R. Dvir1, in hospice. There were also increases in the documentation of sibling counsel- M. Yalon2, A. V. Kulkarni3, and S. Constantini1; 1DANA Children’s ing (38.3 vs. 15.7%) and bereavement services (95.3 vs. 49.7%) when the Hospital, Tel Aviv Medical Center, Tel Aviv, Israel; 2Sheba Medical Center, entirety of the cohorts was compared. No other differences between the Ramat Gan, Israel; 3Hospital of Sick Children, Toronto, ON, Canada two groups were observed. CONCLUSIONS: Children with brain tumors receiving palliative care through a consult-based team are medically Following treatment for pediatric brain tumors, survivors can develop late complex and frequently die on the inpatient ward. An approach that does effects due to the primary disease and the treatment side-effects. It is time not exclusively rely on consult-based palliative care services must be consuming and expensive to subject all children to detailed specialist assess- applied in order to optimize the integration of palliative care into the conti- ments for every potential late effect. It may, therefore, be beneficial to nuum of care for all pediatric neuro-oncology patients. produce a simple, efficient screening tool that will identify the potential needs of the individual, so that specific, targeted interventions can be offered quickly (e.g. physiotherapy, pain clinic, psychology etc.). We, therefore, designed an easy-to-use screening questionnaire, which is a tool for identifying specific deficits and needs. The questionnaire is mailed to the MULTI.15. THE CANADIAN PAEDIATRIC BRAIN TUMOUR patient and family, to be filled at home. It may be supplemented with a tele- CONSORTIUM (CPBTC): A NATIONAL NETWORK USING phone conversation. The questionnaire is designed to be treatment oriented TELECONFERENCING according to specific fields, such as: general health, pain, neuro-cognition, be- E. Bouffet1, A. Carret2, B. Crooks3, J. Hukin4, D. Eisenstat5, B. Wilson6, havior, motor-skills, and social relationships. Each potential late-effect is K. Scheinemann7, S. Zelcer8, D. Johnston9, M. Silva10, V. Larouche11, typically covered by two types of questions: the degree of severity of the N. Jabado12, M. Christopher13, D. Keene9, and D. Strother14; 1the Hospital effect (from non-existing to very severe) and its influence on the patient’s for Sick Children, Toronto, ON, Canada; 2Hopital Sainte Justine, Montreal, quality of life. Positive responses to a given set of questions then initiate a QC, Canada; 3IWK, Hallifax, NB, Canada; 4BC Children Hospital, more detailed specialist assessment for the given field of concern.The Vancouver, BC, Canada; 5Cancer Care Mannitoba, Winnipeg, MB, Canada; responses to the screening questionnaire items can be scored to provide a 6Stollery Children Hospital, Edmonton, AB, Canada; 7MacMaster quantitative, objective assessment of the patient’s deficits and the influence University, Hamilton, ON, Canada; 8CHWO, London, ON, Canada; on the patient’s quality of life. The validity and reliability of the question- 9CHEO, Ottawa, ON, Canada; 10Kingston General Hospital, Kingston, naire is now being evaluated. ON, Canada; 11Centre Hospitalier Laval, Quebec, QC, Canada; 12Montreal Children’s Hospital, Montreal, QC, Canada; 13Saskatoon Cancer Centre, Saskatoon, SK, Canada; 14Alberta Chilren’s Hospital, Calgary, AB, Canada

BACKGROUND: Cooperation requires communication between insti- MULTI.13. INTEGRATING A LATE EFFECTS CLINIC INTO A tutions, which is limited by ﬁnancial resources (travel expenses) and avail- NEURO-ONCOLOGY PROGRAM ability (travel time). Teleconferencing can overcome these limitations. D. A. Lafond and H. DeLuca; Children’s National Medical Center, METHODS: the CPBTC is a group of 16 tertiary care Canadian centres Washington, DC, United States involved in the conduct of studies related to pediatric brain tumors. Members of this group instituted in 2002 a bimonthly brain tumour round Over the past several decades, treatment for pediatric malignancies has using teleconferencing. RESULTS: Between December 2002 and December progressed resulting in higher cure rates. In the US, 1 in 570 young adults 2009, 61 conferences took place. Conferences were held bimonthly initially is a survivor of childhood cancer. Tumors of the central nervous system and then monthly since 2004. Each conference lasts one hour and is held at are the most common solid tumor of childhood and the cure rate of these 2:00 PM Eastern time in order to accommodate the time difference between

NEURO-ONCOLOGY † JUNE 2010 ii17 Abstracts

institutions in Canada (4:30 time difference coast to coast). All institutions HR and SR eases the drug schema, accepts variations in radiotherapy plan- chair the conference in turn. Five institutions joined the initial conferences. ning and adapts the proper guidelines for imaging according to existing The number of participating institutions increased overtime and ranged resources. CONCLUSION: This experience provides the opportunity to between 11 and 15 during the period 2004 to 2009. Ten institutions attended offer standard treatment adapted to the technical realities of our institutions .75% of the conferences. More than 40 proposals were discussed during in Central America. this period, including retrospective and prospective studies and clinical trials. The CPBTC successfully completed 4 clinical trials (phase I/II of metronomic temozolomide, phase II of imatinib, brainstem glioma study and one Low-grade glioma study) and holds several peer review grants. The consortium has so far published 11 peer review articles and presented EMERG.03. NEURO-ONCOLOGY EXPERIENCE IN CCHE (2008– numerous abstracts at national/international meetings. CONCLUSIONS: 2009) Despite the large availability of teleconferencing services, such experiences M. A. El Beltagy, H. Moustafa, H. Taha, M. S. Zaghlool, M. Awaad, remain limited in paediatric neuro-oncology. Teleconferencing facilitates M. Aggag, O. Afifi, M. EL Shami, S. Ezat, M. Kamal, and N. EL Khateeb; communication and could be used by national groups to facilitate communi- Cacer children’sHospital Egypt, Cairo, Egypt cation and increase cooperation, allowing the development of cooperative studies. 347 cases of paediatric brain and spinal cord tumors were treated in the Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Children’s Cancer Hospital of Egypt (CCHE) between January 2008 and December 2009. Pediatric brain tumors were more common in male than females. Surgical resection was performed in almost all cases aiming at gross 07 EMERGING PROGRAMS IN DEVELOPING total resection, CSF diversion was needed in certain cases with hydrocephalus, COUNTRIES ETV and VP shunt were performed. ETV showed a higher rate of success in certain pathologies of the posterior fossa tumor. 310 tumor tissue samples were received for histopathologic diagnosis through Hx and E stains and immunohistochemical stains including GFAP, Synaptophysin, EMA, CK, Vimentin, EMERG.01. IDENTIFYING OBSTACLES IN TREATING INI-1,PLAP,OCT3/4 and MIb-1index with cut off 4%. Intra-operative diagno- CHILDREN WITH PRIMARY CENTRAL NERVOUS SYSTEM sis by Frozen section and smears were routinely performed since June 2008 (160 (CNS) TUMORS IN DEVELOPING COUNTRIES 1 2 2 3 1 cases) with success rate of 97%. Low grade gliomas were the commonest pre- S. Partap ,T.V.Hoc,T.T.Ha, and D. Ashley ; Stanford University, senting tumor followed by medulloblastomas. All patients underwent post- Stanford, CA, United States; 2National Hospital of Pediatrics, Hanoi, Viet 3 operative MRI within the first 48 hours of surgery provided their clinical Nam; Royal Children’s Hospital, Melbourne, Australia condition permits. CSF cytology was performed to all cases 15 days postoperatively to asses Tumor seedling. After which patients were submitted to the pro- PURPOSE: To use international efforts to create a multi-disciplinary team tocols of adjuvant treatment according to our hospital policy. Patients were (MDT) to diagnose, treat, and manage primary pediatric CNS tumors in the followed-up by clinical examination on regular monthly basis after discharge developing society of Hanoi, Vietnam at the National Hospital of Pediatrics and MRI scans every 3 months. Impact of degree of tumor resection on (NHP). METHODS: With the resources from 5 institutions (Royal Overall & Progression free Survival was studied. The overall survival of each Children’s Hospital Melbourne, Nossal Institute for Global Health, individual tumor was calculated. The overall survival of brain tumors was University of Melbourne, Australia; Stanford University, USA; and NHP), over 80% until May 2009. a MDT consisting of pediatric neurologists, neurosurgeons, oncologists, pathologists, radiologists, nursing, and social work was created at NHP in 2008. Visits from collaborators from Australia and USA were at regular 4–6 month intervals with a permanent project manager stationed at NHP. These visits consisted of intense formalized teaching sessions, patient EMERG.04. AN INTERNATIONAL AND LOCAL ALLIANCE TO rounds, tailored chemotherapy protocols, and review of cases. Attention PROMOTE PEDIATRIC NEUROONCOLOGY IN MOROCCO was placed on visiting each specialty and addressing avenues of improve- I. Qaddoumi1, L. Hessissen2, T. Tihan3, M. Karkouri4, F. Saran5, S. Zafad6, ment. RESULTS: Over the 18 month interval, the greatest obstacles to J. Baker1, M. Harif7, F. Boop1, M. Nachef8, J. Finlay9, A. El Khamlichi10, patient care were clinical diagnosis (exam), surgical expertise, and critical M. Bloomer3, M. Al-Hussaini11, M. Al-Qudimat11, A. Madani12, care management thereafter. Morbidity and mortality was greatest either S. Cherkaoui12, S. Sahraoui13, A. Benider12, and E. Bouffet14; 1St. Jude pre- or post-operation. Thus, improvements in neurosurgery, neurology, Children’s Research Hospital, Memphis, TN, United States; 2Rabat pathology, and radiology services were implemented with further physician Children’s Hospital, RABAT, Morocco; 3University of California at training in Australia and India. Other areas identified were nursing and edu- San Francisco, CA, United States; 4Ibn Rochd Hospital, CASABLNCA, cational needs (diagnosis and exam) and reference materials (libraries, online Morocco; 5Royal Marsden Hospital, United Kingdom; 6Clinique Al Madina, information) with continued support from NHP to further these depart- Casablanca, Morocco; 7CHU Mohammed VI, Marrakech; 8Rabat ments. Weekly MDT meetings (tumor board) have evolved and a computer- Children’s Hospital; 9Children’s Hospital of Los Angels, CA, United States; based CNS tumor registry was created. CONCLUSIONS: Treating CNS 10Hoˆ spital des Spećialite´s; 11King Hussein Cancer Center, Amman, Jordan; tumor patients in resource-poor countries is possible with consistent atten- 1220 Aouˆ t 1953 Hospital, Casablanca, Morocco; 13Ibn Rochd Hospital, tion to MDT needs. Neurosurgical and high-acuity skills are rate-limiting Casablanca, Casablanca, Morocco; 14Hospital for Sickkids, Toronto, ON, and further avenues of training are warranted. Canada

BACKGROUND: There is an urgent need in the care of pediatric brain tumors in countries with limited resources and growing interest to promote care for children with brain tumors by the international outreach EMERG.02. NEUROONCOLOGY AS A REASON FOR HOPE IN program (IOP) at St. Jude and the society of neurooncology (SNO). CENTRAL AMERICA Morocco was chosen as a pilot country due to well established neurosurgical M. S. Ah Chu1,2; 1Panama Children’s Hospital, Panama´, Panama; 2 services and pediatric oncology units with ongoing twinning initiatives in Association of Central America Pediatric Hematology and Oncology, major cities. METHODS: IOP, SNO, and other international experts with Panama the support of three pediatric oncology (including all disciplines) units in Casablanca, Rabat, and Marrakech, started an initiative aiming at improving INTRODUCTION: In February 2009 the Association of Central America care for children with brain tumors. Core teams of different disciplines were Pediatric Hematology and Oncology (AHOPCA) started a collaborative identiﬁed in each city. Regular online meetings via cure4kids (free of charge) project involving the elaboration of two treatment protocols: low-grade were held on monthly basis to discuss difﬁcult cases from Morocco. glioma (LGG AHOPCA) and standard and high-risk Medulloblastoma RESULTS: Between April 2009 and February 2010, 10 conferences took (MB AHOPCA). We present the principal changes proposed during this place. One to 3 patients were discussed at each conference. These conferences experience that may cause real impact on the region. METHODS: LGG helped to identify issues in the management of children with CNS tumour in AHOPCA consists of an induction using Carboplatin 500 mg/m2 and 2 Morocco. As a consequence, the partners of this initiative decided to Vincristine (VCR) 1.5 mg/m every 3 weeks for 3 cycles, followed by a main- organize a workshop to address these challenges and optimize the delivery tenance using the same drugs every 4 weeks for a total of 9 cycles. MB of care. A summery of the online meetings will be presented in addition AHOPCA consist on surgery followed by radiotherapy (36 Gy for CS and the recommendations of the workshop. CONCLUSIONS: It is important 54 Gy for boost in HR and 23.4 Gy for CS and 54 Gy for boost in SR) fol- + for international societies and brain tumor experts to coordinate their lowed by 6 cycles of chemotherapy (3 CDDP/VP16 3 cyclophosphamide/ effort in supporting colleagues working in countries with limited resources Vcr every 28 days for both HR and SR). We describe the main changes intro- in order to speed the process of improving care for children with CNS duced on these protocols. RESULTS: The LGG protocol, applied on a tumors in these countries. monthly base and reducing carboplatinum from 540 mg/m2 to 500 mg/m2 avoids myelosupressive effects and reduces cost in a range of 420–500$/ cycle/patient in comparison with a weekly schema. The MB protocol for ii18 NEURO-ONCOLOGY † JUNE 2010 Abstracts

EMERG.05. THE KING HUSSEIN CANCER CENTRE (KHCC) - 08 LOW GRADE GLIOMA - CLINICAL HOSPITAL FOR SICK CHILDREN (SICKKIDS) TELEMEDICINE EXPERIENCE IN PEDIATRIC NEUROONCOLOGY: AN UPDATE N. N. Abuirmeileh1, A. Musharbash1, M. Swaidan1, M. AlHussaini1, U. Aljumaily1, S. Hashem1, I. Qaddoumi2, U. Tabori3, U. Bartels3, J. Drake3, LGG.01. CLINICAL RISK FACTOR ANALYSIS IN THE GERMAN and E. Bouffet3; 1King Hussein Cancer Center, Amman, Jordan; 2St Jude HIT-LGG 1996 TRIAL FOR CHILDREN AND ADOLESCENTS Children’s Research Hospital, Memphis, TN, United States; 3Hospital for WITH LOW GRADE GLIOMA (LGG) - DEFINITION OF Sick Children, Toronto, ON, Canada PROGNOSTIC SUBGROUPS FOR FUTURE TRIALS A. K. Gnekow1, S. von Hornstein1, B. Thieme1, C. Mirow1, A. Emser2, 2 3 4 5 BACKGROUND: A videoconferencing program was initiated in 2003 I. Zwiener , T. Pietsch , M. Warmuth-Metz , R. Kortmann , and A. Faldum2; 1Children’s Hospital, Klinikum Augsburg, Germany; 2IMBEI, between KHCC and Sickkids. Preliminary results have been reported (PBC 3 2007;48:39–43). However, the sustainability and evolution of such initiat- University Mainz, Germany; Institute of Neuropathology, University Bonn, Germany; 4Neuroradiology, University Wuerzburg, Germany; ives is unknown. METHODS: We retrospectively reviewed the agendas 5 and minutes of all meetings since 2007. RESULTS: Between January 2007 Radiooncology, University Leipzig, Germany and December 2009, 33 telemedicine sessions were held and minuted. In total, 160 cases were discussed, some more often than once. Diagnoses To identify consistent risk factors we analysed 1044 prospectively regis- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 included 47 low-grade glioma, 23 medulloblastomas, 16 high-grade tered patients of the HIT-LGG 1996 trial for survival and defined relevant glioma, 12 ependymomas, 8 sPNET and 54 others. Discussion led to therapeutic subgroups. Following the trial strategy children were observed change in decision in 31 patients and detailed discussions with suggestions after complete tumour resection or, after incomplete resection/radiological in 48 cases. This led to treatment changes in 28 cases (including observation diagnosis, if their tumour was asymptomatic and/or non-progressive. in 7) and change in diagnosis in 2 patients. Educational material including Non-surgical treatment upon defined clinical/radiological indications was che- , powerpoint slides and articles were distributed with the minutes providing motherapy (Vincristin/single-dose Carboplatin) for children 5 years and . teaching in addition to input for management of cases discussed. radiotherapy for those 5 years of age. Brachytherapy for suitable tumours Technically, the connection evolved from a six-channel ISDN telephone had no age-restriction. Multivariate risk-factor analysis was performed at line($360/h) to an internet based connection, allowing other institutions medium follow-up of 5.0 years, including age, sex, NF1-status, presence of (St Jude’s Research hospital, 57357 in Cairo) to join intermittently. diencephalicsyndrome(DS) or dissemination(DLGG), tumour localization, his- , ≥ However, technical problems relating to security bridging, affecting quality tology (including Ki67-index), and extent of resection. For OS age 1 and 11 of sound and image have been an obstacle for the past 6 months. years, non-pilocytic histology, diencephalic localization and presentation with CONCLUSION: Twinning programs using telemedicine are sustainable. DS were unfavourable prognosticfactors, while complete resectionproved to be The type of interaction changes over time, and so are the changes in decision favourable. For EFS, all locations within the supratentorial midline, less than (with a reduction in diagnosis changes for example). Continued education complete resection and the presence of DS heralded subsequent events. For with potential to expand the benefit further geographically is possible in PFS following chemo-/radiotherapy, non-pilocytichistologyanddissemination the long term. Commitment of medical colleagues and technical IT were prognostically unfavourable, and within the chemotherapy cohort, , ≥ support are essential for continuity. additionally, age 1 and 11 years, the presence of DS, and female sex. NF1 status was not prognostic. This analysis defines three prognostic subgroups. “Standard”: all children with completely resected tumours irrespective of location, “high risk”: all children ,1 year of age, especially with DS, and those ≥11 years with non-pilocytic histology, and/or dissemination, and EMERG.06. GLOBAL PERSPECTIVES ON PEDIATRIC “medium risk”: 1–10 year olds with incompletely resected tumours, especially ONCOLOGY & NEURO-ONCOLOGY TRAINING: CAREER if within the supratentorial midline. The relevance of such risk grouping has to DEVELOPMENT OF INTERNATIONAL PEDIATRIC ONCOLOGY be investigated in future trials. FELLOWS TRAINED IN SYDNEY S. J. Kellie1,2,M.Li2, and J. Hall3; 1The Children’s Hospital at Westmead, Sydney, Australia; 2School of Public Health, University of Sydney, Sydney, Australia; 3School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia LGG.02. NEUROFIBROMATOSIS TYPE 1 ASSOCIATED OPTIC GLIOMA VISUAL OUTCOMES FOLLOWING CHEMOTHERAPY: The career development of Pediatric Oncology fellows from low or middle AN INTERNATIONAL MULTI-CENTER RETROSPECTIVE income countries (LMIC) training in high income countries has not been ANALYSIS M. J. Fisher1,2, L. Balcer2, D. Gutmann3, R. Listernick4, R. Ferner5, examined previously. This study examines their expectations, career devel- 6 7 8 9 10 opment and the extent to which their fellowship influenced or equipped R. Packer , R. Hoffman , U. Tabori , N. Ullrich , S. Ardern-Holmes , D. Hargrave11, E. Bouffet8, M. Loguidice2, and G. Liu1,2; 1Children’s them to contribute to the development of pediatric cancer medicine in 2 LMIC. Fifteen international fellows from LMIC trained in Pediatric Hospital of Philadelphia, Philadelphia, PA, United States; University of Pennsylvania School of Medicine, Philadelphia, PA, United States; Oncology and Neuro-Oncology at Children’s Hospital at Westmead, 3 (CHW) between 1990 and 2009. Thirteen fellows consented to participate Washington University School of Medicine, St Louis, MO, United States; 4Northwestern University, Chicago, IL, United States; 5Guy’s and Thomas’ in semi-structured interviews exploring their personal and family back- 6 grounds, educational history, fellowship experience at CHW and subsequent Hospital, London, United Kingdom; Children’s National Medical Center, Washington, DC, United States; 7University of Utah, Salt Lake City, UT, career pathway after leaving CHW. The study was approved by the USyd 8 Ethics Committee. All interviews were audiotaped with consent and tran- United States; The Hospital for Sick Children, Toronto, ON, Canada; 9Children’s Hospital, Boston, MA, United States; 10The Children’s Hospital scribed for analysis. All subjects completed early schooling and their 11 primary medical qualification in their country of birth: India - 6, at Westmead, Sydney, Australia; Royal Marsden Hospital, London, United Philippines - 3, Malaysia - 2, other - 2. Subjects commenced at CHW 6 to Kingdom 15 years (median, 11yrs) after medical graduation. Ages ranged from 27.7yrs to 39.9yrs (median, 35.9yrs) and duration ranged from 9months INTRODUCTION: Optic gliomas (OPGs) arise in 15–20% of children to 36 months, (median, 15mo). Several factors emerged as significant in with neurofibromatosis type 1 (NF1); nearly half become symptomatic. fellows’ decisions to return to their country of origin including extended There is little information regarding ophthalmologic outcomes after che- ¼ family networks, fellowship funding from country of origin, and interval motherapy. METHODS: A retrospective multi-center (n 9) study was between graduation and fellowship. CHW prepares international fellows undertaken to evaluate visual outcomes following chemotherapy for for a range of subsequent appointments including practice in LMIC settings. NF1-associated OPG, to identify risks for visual loss, and to ascertain indi- Fellows would benefit from an expanded knowledge by their host of their cations for treatment. Subjects included children undergoing initial treat- specific needs and career goals, particularly where future practice in LMIC ment for OPGs with chemotherapy between January 1997 and December is envisaged. 2007. RESULTS: Of 110 subjects, 1/3 had tumors of the anterior visual pathway (nerves and/or chiasm). Visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment; however, for most subjects, more than one factor spurred treatment (mean ¼ 2.48), including tumor size/extent, visual field loss, and tumor location. Eighty-six subjects and 162 eyes were evaluable for VA outcomes. At completion of chemotherapy, VA improved (31% of subjects), remained stable (40%), or declined (29%). Tumor involvement of the tracts/radiations was associated with poor VA outcome (p ¼ 0.02). Notably, no subjects treated at age ,2 years had improved vision by the end of therapy (p ¼ 0.03); there was a trend towards VA worsening in those .5 years old. Gender and NF1 type (familial vs. sporadic) did not appear to be risk factors for visual progression. CONCLUSIONS: Although most patients with OPG have improvement or

NEURO-ONCOLOGY † JUNE 2010 ii19 Abstracts

stabilization of vision after treatment with chemotherapy, VA worsens in 1/3 LGG.05. PHASE I/II STUDY OF TARCEVA/RAPAMYCIN FOR of subjects despite treatment. In particular, tumor location in the optic RECURRENT PEDIATRIC LOW-GRADE GLIOMAS (LGG) tracts/radiations and older age appear to be risk factors for progressive R. J. Packer1, M. Yalon2, B. R. Rood1, M. Chao1, M. M. Miller1, visual loss. G. McCowage3, and G. Vezina1; 1Children’s National Medical Center, Washington, DC, United States; 2Dana Children’s Hospital, Tel-Aviv, Israel; 3Children’s Hospital at Westmead, Sydney, Australia

In September 2007, a prospective, international, multi-center Phase I/II LGG.03. SIOP HIT LGG 2004: RADIOTHERAPY FOR CHILDREN study of Tarceva and rapamycin for recurrent pediatric LGG was undertaken. WITH LOW GRADE GLIOMA. AN INTERNATIONAL Tarceva was given at 65 mg/m2/d for 28 days, and then, if tolerated, rapamy- MULTICENTRE TRIAL, INTERIM ANALYSIS FOR GERMAN cin was added at 0.8 mg/m2/dose twice daily in 28-day cycles. Both medi- PATIENTS cations were given on 28-day cycles without break. Sixteen patients, a R. Kortmann1, T. Pietsch2, M. Warmuth-Metz3, and A. Gnekow4; 1Clinic median of 4.6 yrs (range 9 mos to 10.1 yrs) were treated. Seven had NF1. for Radiation Therapy and Radiooncology, Leipzig, Germany; 2University of Tumors were located in the thalamus (3); hypothalamus (5); chiasm (5); and Bonn, Neuropathology, Bonn, Germany; 3University of Wuerzburg, brainstem (3). Two had disseminated disease. Histologies in the 9 non-NF Neuroradiology, Wuerzburg, Germany; 4Children’s hospital Augsburg, patients were pilocytic (3) and Grade 2 (6). No patient was removed from Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Augsburg, Germany study due to toxicity, although one patient had therapy temporarily interrupted due to cellulitis. Non-dose-limiting toxicities included: rash (6); BACKGROUND: Evaluation of toxicity, tumour control and visual func- hypercholesteremia (2); oral ulcers/mucositis (5); neutropenia/lymphopenia tion for children with low grade glioma (LGG) after conformal radiotherapy (2); and vomiting (1). Objective responses two months after initiation of and brachytherapy MATERIAL/METHODS: Children, age of 1 - 18 years therapy were: PR (1); MR (1); SD (10); and PD (3). Six patients discontinued with LGG were evaluated, external radiotherapy 54.0 Gy; 1.8Gy/day, therapy due to progression at a median of four months (range: 2 to 8 mos), and Brachytherapy (median dose 60 Gy) patients with complete data were eval- 2 were removed with stable disease either due to poor compliance or parental uated (78 / 105 patients; 24/78 brachytherapy, 54/78 ext. RT) included discretion. Eight have remained in remission from 1 to 18 mos. All patients between 2004 and October 2009. RESULTS: Primary radiotherapy 68 with NF1 had either stable disease or response and 2 have remained cases, after chx failure 10 patients. Only WHO grade I and II toxicities progression-free for greater than one year. We conclude that the Tarceva/ were observed. Children with primary radiotherapy showed less toxicities Rapamycin regimen is well-tolerated and has demonstrated efficacy in children (28 % for headache) compared to patients with initial chemotherapy with recurrent low-grade gliomas, especially in those with NF1. (63% for headache). Visual acuity (25 children) improved in 27 %, stable in 66 % and worse in 5.5 % pat. At a median follow up of 7.7 month 22 children showed progressive disease ( 0.04–3.89 years for ext. RT, 0.36–4.65 years for brachytherapie), 17/54 (31.5%) children after external RT and 5/24 (20.8%) children after brachytherapy. 12 pat. showed progression on LGG.06. VINORELBINE IN PROGRESSIVE UNRESECTABLE imaging within 12 month after RT (19/ 68 pat. with primary RT, 28%, LOW GRADE GLIOMA: EXPERIENCE OF A SINGLE and 3/10, in RT after CHX 30%). 6 pat. are DOD. 5 of them had non pilo- INSTITUTION zytic histology. CONCLUSION: Radiation therapy (external RT and bra- A. M. Cappellano1, S. Cavalheiro2, M. Bergamo1, P. Carmona1, chytherapy) was tolerated well. The positive impact on visual function M. F. F. Soares3, V. S. Tostes3, M. T. Seixas4, and N. S. da Silva1; 1IOP/ could prospectively be confirmed. The high rate of early progression indi- GRAACC/Saõ Paulo Federal University, Saõ Paulo, Brazil; 2Department of cates possible uncertainties in response assesment on imaging (pseudo pro- Neurology and Neurosurgery, IOP/GRAACC/Saõ Paulo Federal University, gression) and warrants further analysis. Study is still ongoing. Saõ Paulo, Brazil; 3Department of Radiology, IOP/GRAACC/ Saõ Paulo Federal University, Saõ Paulo, Brazil; 4Department of Pathology, IOP/ GRAACC/Saõ Paulo Federal University, Saõ Paulo, Brazil

BACKGROUND: The management of progressive unresectable low-grade LGG.04. A CHILDREN’S ONCOLOGY GROUP (COG) PILOT glioma (PULGG) remains controversial. Some series suggests that che- STUDY USING CARBOPLATIN, VINCRISTINE AND motherapy may delay or even avoid radiotherapy and/or surgery in a pro- TEMOZOLOMIDE IN CHILDREN WITH PROGRESSIVE/ portion of children. Within this context, we introduce vinorelbine, a SYMPTOMATIC LOW-GRADE GLIOMA semi-synthetic vinca alkaloid that shown activity against glioma. M. M. Chintagumpala1, A. Adesina1, M. Morriss2, T. Zhou3, E. Holmes4, PATIENTS AND METHODS: From July 2007 to February 2010, 25 C. C. Lau1, and A. Gajjar5; 1Baylor College of Medicine, Houston, TX, patients with recurrent (8) and newly diagnosed (17) PULGG have been United States; 2University of Texas Southwestern Medical School, Dallas, treat with vinorelbine 30 mg/m2 on days 0, 8 and 22 for 18 cycles. TX, United States; 3Children’s Oncology Group, Arcadia, CA, United States; Response criteria used a combination of magnetic resonance imaging, phys- 4Baylor College of Medicine, Arcadia, CA, United States; 5St Jude Children’s ical and visual evaluation. RESULTS: Median age 7,1y. Tumor sites: 14 optic Rsrch Hosp, Memphis, TN, United States pathways, 2 spines, 2 hemispheric, 2 brainstem, 2 gliomatosis cerebri and 3 disseminated. Eighteen patients had neurosurgical intervention and the his- Chemotherapy is the initial treatment of choice in young children with tology revealed 12 grade I and 6 grade II astrocytoma. One child has neuroﬁ- midline progressive/symptomatic low-grade glioma. COG initiated a pilot bromatosis type 1. Twenty-three patients were assessable after 8 cycles of study to evaluate the timely delivery of a combination of carboplatin, vincris- vinorelbine with objective response (OR) in 9 patients, stable disease (SD) tine and temozolomide. METHODS: Eligible children ≤10 years, without in 13 and progressive disease (PD) in 1. After 18 cycles, 18 patients were NF-1, received cycles of weekly carboplatin, vincristine alternating with assessable for response, 3 OR, 12 SD and 3 PD, alive in different protocols. temozolomide. Short-term feasibility endpoint: ability to complete induction Two patients died of other causes (1 SD and 1 OR). Five patients did not and one maintenance cycle in 24 weeks without more than 25% reduction in reach the evaluation at this point. Grade II/IV hematologic toxicity was either carboplatin or temozolomide in ≥ 80% of patients. Long-term feasi- observed in 3 patients, grade I/II gastrointestinal toxicity in 5 and grade I/ bility: ability to deliver induction and 4 maintenance cycles within 60 II neurotoxicity in 2. CONCLUSION: The preliminary results suggest that weeks in ≥ 70% of patients. RESULTS: 66 patients were enrolled with 37 vinorelbine may be an option for PULGG, showing some activity with low males. The median age was 4.6 years (range 0.4 to 9.8). 50 patients were eva- toxicity and excellent quality of life. luable for both endpoints. Of the remaining 16 patients, 10 progressed early, 2 were lost to follow up, 1 had meningitis and 3 had incomplete data. There were 12 episodes of febrile neutropenia. 7 developed allergic reactions to carboplatin. No serious adverse events or deaths occurred. 44/50 (88%, 95% CI, 76%-95%) evaluable patients met the criteria for short term feasibility. LGG.07. PHASE I STUDY OF VINBLASTINE IN COMBINATION 39/50 (78%, 95% CI, 65%-87%) met the criteria for long-term feasibility. WITH CARBOPLATIN FOR CHILDREN WITH NEWLY The 2 year EFS was 80 + 5.1% and the 2-year OS was 97 + 2.2%. DIAGNOSED AND RECURRENT LOW-GRADE GLIOMAS: CONCLUSION: It is feasible to deliver cycles of vincristine and carboplatin RESULTS OF COG ADVL0515 alternating with temozolomide over a prolonged period of time with toler- R. I. Jakacki1, E. Bouffet2, A. M. Ingle3, M. Krailo3, S. Voss4, able side effects. Preliminary data suggests that this combination is effective. P. C. Adamson5, and S. M. Blaney6; 1Children’s Hospital of Pittsburgh, Further follow up is necessary to assess the efﬁcacy of this regimen. Pittsburgh, PA, United States; 2Hospital for Sick Children, Toronto, ON, Canada; 3Children’s Oncology Group, Arcadia, CA, United States; 4Children’s Hospital of Boston, Boston, MA, United States; 5Children’s Hospital of Philadelphia, Philadelphia, PA, United States; 6Texas Children’s Cancer Center, Houston, TX, United States

PURPOSE: Carboplatin and vinblastine have single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating two different ii20 NEURO-ONCOLOGY † JUNE 2010 Abstracts

schedules of the combination of these agents was performed. PATIENTS treatment; large, exophytic lesions may benefit from surgical debulking. AND METHODS: Using the standard 3 + 3 phase 1 design, two schedules Oncological treatment includes chemotherapy (vincristin + carboplatin) in were studied: (1) carboplatin 140 mg/m2 weekly x 3 + vinblastine, 4.5 or children younger than 8 years, in whom radiotherapy is contemplated only 3.5 mg/m2, weekly x 6, every 6 weeks (2) carboplatin, 300, 400 or in case of proven progression; conversely, radiotherapy (conformal .3cm, 500 mg/m2 on day 1 + vinblastine 4.0 mg/m2 weekly x 3 every 4 weeks. stereotactic fractionated ,3 cm) is the main treatment for children older RESULTS: Twenty-six patients, median (range) age 4.8 (1.2–14.4) years than 8 years. Despite extensive resection is burdened with surgical morbidity were enrolled. Five of 9 pts enrolled on the initial schedule had recurrent neu- regarding functional disturbances, neurosurgery is indicated for histological tropenia, suggesting that this schedule was not feasible. Seventeen patients verification and to perform primary partial resection in case with sympto- were enrolled on the second schedule. At the 500 mg/m2 carboplatin dose matic exophytic portion, huge cystic component, mass effect and hydro- level, 2 of 3 pts developed DLT (elevated alkaline phosphatase, neutropenia). cephalus, and to perform secondary partial resection upon progression At the 400 mg/m2 carboplatin dose level, none of the 6 pts had DLT. Of the during/following chemotherapy or before radiotherapy. 21 patients evaluable for response, central review confirmed 2 partial responses, 5 minor responses, 11 with stable disease (. 3 months) and 3 with progressive disease. Six of 13 patients with visual pathway tumors had significant ophthalmologic improvement. 10 of 16 patients who received LGG.10. THE ROLE OF SURGERY FOR treatment on the second schedule completed the prescribed twelve courses. CHIASMATIC-HYPOTHALAMIC GLIOMAS IN CHILDREN - THE ALDER HEY HOSPITAL EXPERIENCE Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 CONCLUSIONS: The recommended dose and schedule is carboplatin 1 1 2 1 1 2 2 C. L. Mallucci , J. Goodden , N. Thorp , and B. Pizer ; Alder Hey 400 mg/m /dose on day 1 and vinblastine 4 mg/m /dose weekly x 3, 2 repeated every 4 weeks. Further study of this combination in patients with Children’s Hospital, Liverpool, United Kingdom; Clatterbridge Centre for low-grade glioma is warranted. Oncology, Bebington, United Kingdom BACKGROUND: Chiasmatic-hypothalamic gliomas (CHG) are rare low- grade tumours often requiring combination therapy to achieve disease control. We present our institutional experience of these tumours. LGG.08. PREMATURE DEATHS AND SEVERE MORBIDITY IN METHODS & PATIENTS: Casenotes of patients identified from the 192 LONG-TERM SURVIVORS OF PEDIATRIC OPTIC PATHWAY neuro-oncology database were retrospectively reviewed. Data collected TUMORS (OPT): A 50 YEARS STUDY included: symptomatology, visual and endocrine function, NF1 genotype, E. De Carli1, C. Kalifa2, M. Raquin2, J. Lemerle2, J. Habrand3, D. Couanet4, tumour size and location, treatment and control/relapse rates. RESULTS: C. Sainte-Rose5, X. Rialland1, D. Valteau-Couanet2, and J. Grill2; 1Pediatric Forty-three patients were treated between 1997 and 2009. Median age at diag- Oncology, University Hospital, Angers, France; 2Pediatric and Adolescent nosis was 5y 9m (range 1yr 1m to 16yr 8m). Median follow-up was 5 years. Oncology, Gustave Roussy Institute, Universite Paris-Sud, Villejuif, France; The 19 NF1 patients had a benign course, rarely needing treatment. We have a 3Institute Gustave Roussy, Department of Radiation Oncology, Villejuif, low threshold for offering limited surgical debulking in the case of carefully France; 4Institute Gustave Roussy, Department of Radiology, Villejuif, selected patients at progression or with tumours causing obstructive hydro- France; 5Neurosurgery Department, Necker Hospital, Universite cephalus. 26 debulking procedures, 13 via a transcallosal route, were under- Paris-Descartes, Paris, France taken in 18 patients. Significant (.50%) tumour debulking was achieved in 69% patients. Surgical morbidity was low, with no incidence of visual deterio- The natural history of OPT remains unpredictible and optimal therapeutic ration, 1 cases of permanent diabetes insipidus, and 1 transient hemiparesis. management is still controversial. The study describes the outcome of a Chemotherapy with SIOP LGG protocols was given to 13 patients and radio- large single institution cohort treated for an OPT between 1952 and 2004. therapy to only 5 patients, usually after failure of either chemotherapy and/or Five, 10, 20 and 30 years overall survival (OS) were 90%, 83%, 70% and surgery. During therapy, stability of visual status was noted in 70% patients. 56%, respectively. Mortality was higher in children younger than 1 year at Endocrinopathy was recorded in 37% patients. Thirteen patients (30%) diagnosis but was not influenced by treatment. Among children receiving che- remain asymptomatic. Two patients have died, both unrelated to surgery. motherapy, survival was better in case of radiological response to treatment; CONCLUSIONS: We recommend an individualised approach to treatment. 10y OS was 90% vs 66% (p ¼ 0.017). Main causes of the 57 deaths were pro- Transcallosal surgery can safely debulk exophytic third ventricular tumours gression of the tumor (27) and second tumors (11), both ocurring eventually whilst preserving function. Surgery has roles for diagnosis, tumour control, late during follow-up. Second tumors were more frequent in children receiving relief of mass effect, and avoidance of shunts. irradiation (p ¼ 0.008), especially before the age of 7 (p ¼ 0.008) and/or in the context of NF1 (p ¼ 0.003). Visual outcome was poor, especially in younger children (p ¼ 0.05) with 35 (20%) complete and 73 (40%) monocu- LGG.11. INFARCTION FOLLOWING SURGICAL RESECTION IN lar blindness. Vascular complications (p ¼ 0.08), epilepsy (p ¼ 0.002), neuro- CHIASMATIC LOW GRADE GLIOMAS (LGG) cognitive impairement (p , 10e4), and GH deficiency (p , 10e4) were more M. Warmuth-Metz1, M. Hupp1, B. Bison1, C. Mirow2, J. Krauß3, and frequent in children receiving irradiation. Early puberty (51 patients (26%)) A. K. Gnekow2; 1Dept. Neuroradiology University of Wu¨ rzburg, Wu¨ rzburg, was more frequent in children younger at diagnosis (32% vs 21%, p ¼ Germany; 2SIOP/LGG study center, Augsburg, Germany; 3Dept. Pediatric 0.008). Diabetus insipidus was more frequent after surgery (p ¼ 0.01). Neurosurgery University of Wu¨ rzburg, Wu¨ rzburg, Germany Obesity was noted in 46 (34%) patients. Young children and NF1 patients had more frequently school delays than the others (p ¼ 0.04 and p ¼ 0.005, Currently, within the SIOP-LGG study chiasmatic tumours identified as respectively). In children with OPT, morbidity is severe, especially after LGG on the basis of neuroradiological characteristics may be treated irradiation. Long-term multidisciplinary surveillance is mandatory and refine- without histological verification. As some tumours especially in very young ment of therapeutic strategies is definitively needed. children do not respond well to treatment the search for histopathological and molecular genetic markers from tumour tissue is gaining importance. However, reviewing postoperative scans we noticed an increased frequency of infarctions following resections in the chiasmatic area. Our patient cohort consisted of 88 children registered in the data pool of the national LGG.09. NEUROSURGICAL AND NEUROONCOLOGICAL reference centre for Neuroradiology. Histology was obtained during 104 sur- ASSESSMENT OF OPTIC PATHWAY GLIOMAS geries, 29 biopsies (18 stereotactic, 9 open 2 endoscopic), 65 partial/subtotal A. Cama, M. Garre`, A. Rossi, and P. Nozza; G. Gaslini Children’s Hospital, resections (10 patients without information on the mode of surgery). At the Genoa, Italy time of operation median age was 5y 2m. Infarctions were identified following 15 (14.9%) surgical procedures (all resections). Biopsies of whatever OBJECTIVES: To illustrate the most efficacious strategy for multidisci- modality were not complicated by infarctions. The age of children with plinary decision-making for low-grade optic pathway gliomas (OPG) in chil- infarctions (2y 4m) was considerably younger than the age of the whole dren. METHODS: We evaluated 65 children with OPG treated in the past 20 group. As a control group served 51 consecutive patients with an LGG of years. RESULTS: 49% of cases occurred in neurofibromatosis 1 (NF1) the cerebellum with 66 surgical procedures (2 biopsy, 22 partial/subtotal patients, whereas the remainder were isolated. Visual impairment was resections, 42 total resections). Median age at the time of surgery was 7y more frequent in NF1, while severe endocrine impairment was rare in both 4m. Only one resection was followed by an infarction (1.5%). groups. All patients underwent MRI as well as clinical, endocrinological, CONCLUSION: There is a high risk of infarction linked to resections for and tumor marker evaluation. Biopsy was not performed in NF1 cases. In chiasmatic LGG especially in the younger children. Since usually complete case of huge isolated tumors, surgical debulking was performed following resection is not feasible in tumours of chiasmatic localization, retrieval of hydrocephalus treatment. Outcome at 5 years was favorable, with 80% material for histological diagnosis and scientific investigation should be per- alive without evidence of progression or with stable regressive disease. formed by biopsy only. CONCLUSIONS: Treatment strategies include biopsy, surgery, chemo/ radiotherapy, and observation. NF1 cases require no histological verification; follow-up is the first option, whereas oncological treatment is reserved to progressive cases. Isolated OPG require biopsy followed by oncological

NEURO-ONCOLOGY † JUNE 2010 ii21 Abstracts

LGG.12. DOES SURVEILLANCE NEUROIMAGING CHANGE We retrospectively analyzed outcome of BSLGG patients undergoing MANAGEMENT OF OPTIC PATHWAY GLIOMAS IN upfront partial resection only. We than compared treatment results of NEUROFIBROMATOSIS TYPE 1? patients requiring additional radiotherapy or chemotherapy as single N. J. Ullrich1,2, C. McGowan3, A. Porter4, D. Miller3, M. Kieran5,2, medical agent. RESULTS: Of 191 children with brainstem tumors, 71 had B. Korf6, and M. B. Irons3; 1Department of Neurology, Children’s Hospital biopsy proven low grade glioma with consistent radiographic findings. Boston, Boston, MA, United States; 2Pediatric NeuroOncology, Dana-Farber Thirty nine children underwent upfront partial resections without further Cancer Institute, Boston, MA, United States; 3Department of Genetics, medical treatment. Five and ten years progression free survival (PFS) was Children’s Hospital Boston, Boston, MA, United States; 4Department of 53% and 41% respectively. None of these children died during follow up. Genetics Children’s Hospital Boston, Boston, MA, United States; Of the patients who required further medical therapy initially or at pro- 5Department of Hematology/Oncology, Children’s Hospital Boston, gression 16 received radiotherapy (group 1) and 15 received chemotherapy Boston, MA, United States; 6Department of Genetics, University of Alabama (group 2). Average age was 11.19 years and 5 years in group1 and 2 respect- at Birmingham, Birmingham, AL, United States ively. Five year PFS and overall survival were 72% and 100% in group 1, and 46.4% and 94% in group 2 (p ¼ 0.21 and 0.55 respectively). On long term PURPOSE: Optic pathway gliomas (OPG) are the most common intracra- morbidity assessment 3/13 (23%) children with known outcome on group 1 nial tumors in patients with NF1 and may account for significant morbidity had mild or no long term morbidities compared to 7/14 (50%) in group 2. in some patients. Although the majority is asymptomatic, some OPGs may CONCLUSION: Children undergoing partial resection for BSLGG will often Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 become symptomatic, leading to vision loss and/or endocrine disturbance. require no further therapy. There was a trend toward improved PFS in the PATIENTS AND METHODS: We conducted a retrospective review of all group of patients treated by irradiation but long term morbidities where patients with Neurofibromatosis and MRI evidence of an OPG between seen more often in that group also. 1997–2008. Clinical data reviewed included imaging, visual assessments, criteria for treatment, monitoring and follow-up. RESULTS: Patient cohort included 1450 individuals with NF1. 88 patients were identified by MRI with an OPG; of these 68 were asymptomatic and 20 were symptomatic, requiring treatment with chemotherapy and/or radiation. Indications for LGG.15. LONG TERM FOLLOW UP OF PEDIATRIC BENIGN MRI included: growth disturbance, precocious puberty, headaches, torticollis, CEREBELLAR ASTROCYTOMAS craniofacial plexiform neurofibroma, optic nerve asymmetry/pallor, visual H. Ogiwara and T. Tomita; Children’s Memorial Hospital, Chicago, IL, disturbance, or screening. Visual deterioration determined need for treatment, United States except for one patient with unreliable visual assessments and a change in size and enhancement in the OPG and expanding brainstem lesion. A total of 409 OBJECT. The aim of this study is to elucidate the roles of clinical, radio- MRIs were performed during the follow-up period. Imaging alone did not logical, and therapeutic factors in the survival of the patient with cerebellar identify an OPG that became symptomatic and required therapy. astrocytioma and tumor recurrence with more than 10 years follow up. CONCLUSIONS: These results support the recommendation that patients METHODS. Retrospective review was conducted of 102 children who with radiographic evidence for NF1-associated OPG can be monitored with were surgically treated for a cerebellar astrocytoma. RESULTS. Primary careful ophthalmological screening. Despite the frequency of repeat MRIs, locations were in the cerebellar hemisphere in 35 patients (34.3%), in the visual evaluation determined the need for treatment. 23% of OPGs required vermis in 29 (28.4%), in the fourth ventricle in 27 (26.5%), and in the cer- tumor-directed therapy, which approximates prior estimates of symptomatic ebellar peduncle in 11 (10.8%). Tumors extended to the brainstem in 22 OPGs. MRI did not direct treatment or management, indicating that “base- patients (21.6%) and cerebellar peduncle in 21 patients (20.6%). Total line” or routine MRI screening has no additive advantage to close clinical/ resection was performed in 52 patients (51.0%). Thirty-two percent (16/ ophthalmologic screening and follow-up. 50) of the residual tumors showed spontaneous involution and sixteen percent (8/50) showed arrested growth after incomplete resection. Radiographic recurrence was noted in 30 patients. Factors that affect the higher recurrence rate discovered by multivariate analysis include the extent of surgical resection. No factors were significantly prognostic in LGG.13. POOR OUTCOMES WITH RADIATION THERAPY IN relation to patient survival. Surgical resection was performed for most of PATIENTS WITH OPTIC PATHWAY GLIOMAS the recurrence (25/30, 83.3%). Seventeen (17/20, 85.0%) of those who A. C. Dietz, S. Shaw, T. R. Dahlheimer, J. L. Torkelson, J. P. Neglia, and were treated surgery alone for recurrent tumor showed no evidence of recur- C. L. Moertel; University of Minnesota, Minneapolis, MN, United States rence afterwards (mean follow up; 15.8 years). CONCLUSIONS. Considering that almost half of residual tumors show spontaneous regression This retrospective study examined outcomes in optic pathway glioma or arrested growth in the long term, and overall prognosis of cerebellar astro- patients treated with and without radiation through a medical record cytoma is relatively good, we advocate that invasive potion of the tumor into review of 70 patients seen at the University of Minnesota from 1982 to the brainstem should not be resected in order to avoid neurological deficits. 2009. The cohort included patients aged 0.75 to 45 years (mean 7.3, median 4.1). Presentation included: screening MRI for NF1 (31%), decline in visual acuity (17%), proptosis (16%), headache (9%), wandering eye (2%), and seizures (1%). Ophthalmologic examination at presentation 09 LOW GRADE GLIOMA – BIOLOGY revealed visual deficits (30%) and optic pallor (23%). NF1 was identified in 70%. Group A treatment included observation (41%), chemotherapy (29%) and surgery (16%). Group B included radiation (16%) and combination radiation/chemotherapy (6%). Visual acuity of the good eye immedi- LGG.16. NOVEL BRAF FUSION GENE AND ately after treatment worsened by 1.23 lines of Snellen acuity in Group B CHARACTERIZATION OF BRAF AND RAF1 BREAKPOINTS IN PILOCYTIC ASTROCYTOMA compared to an improvement of 1 line in Group A (p ¼ 0.22). Visual 1 2 1,3 1,3 4,5 5 acuity worsened for the bad eye in Group B by 1.46 lines but did not H. Cin , C. Meyer , H. Witt , M. Remke , W. Janzarik , T. Van Anh , H. Olbrich5,6, A. von Deimling7,8, A. E. Kulozik3, R. Marschalek2, O. Witt9, change in Group A (p ¼ 0.42). In follow-up of 10 years or greater, visual 5,6 1 8 1,3 1 acuity of the good eye worsened by an average of 1.63 lines in Group B com- H. Omran , P. Lichter , A. Korshunov , and S. M. Pfister ; Division pared to an improvement of 2 lines in Group A (p ¼ 0.16). The bad eye wor- Molecular Genetics, German Cancer Research Center Heidelberg, Germany; 2Institute of Pharmaceutical Biology, Diagnostic Center of Acute Leukemia sened in the Group B by 2.56 lines but improved in Group A by 1.8 lines (p ¼ 3 0.13). Radiation-attributed complications include: death (2), cerebral vascu- (DCAL), University of Frankfurt, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, litis (3), secondary malignancy (2), seizures (2), and endocrinopathies (5). 4 These data suggest that radiation should not be recommended in the treat- Germany; Department of Neurology, University Hospital Freiburg, Germany; 5Department of Pediatric Neurology and Muscle Disorders, ment of optic pathway glioma given poor visual outcomes and frequency 6 of complications. University Hospital Freiburg, Germany; Clinic and Policlinic for Pediatrics, Department of General Pediatrics, University Hospital Muenster, Germany; 7Department of Neuropathology, University Hospital Heidelberg, Germany; 8Clinical Cooperation Unit Neuropathology, German Cancer Research Center Heidelberg, Germany; 9Clinical Cooperation Unit Pediatric LGG.14. PEDIATRIC LOW GRADE GLIOMA OF THE Oncology, German Cancer Research Center Heidelberg, Germany BRAINSTEM - COMPARATIVE STUDY OF DIFFERENT TREATMENT MODALITIES Deregulation of MAPK signaling, especially the RAF genes emerges as a I. Fried, E. Bouffet, U. Bartels, A. Huang, A. Kulkarni, C. Hawkins, common finding in pilocytic astrocytoma (PA). In particular, we and E. Tsangaris, and U. Tabori; Hospital for Sick Children, Toronto, ON, others have recently demonstrated that tandem duplications at chromosome Canada 7q34 targeting the BRAF locus define a hallmark genetic lesion in PA development, resulting in BRAF fusion genes and constitutive activation of MAPK Brainstem low grade glioma (BSLGG) is rarely amenable to total resection. signaling. NF1, KRAS,andBRAF mutations, and occasionally RAF1 gene Data regarding treatment options and outcomes are limited. METHODS: fusions occur mostly in a mutually exclusive manner with BRAF gene ii22 NEURO-ONCOLOGY † JUNE 2010 Abstracts

fusions, except a single case in our series which concomitantly harbors NF1 OncoMap. Samples were also assayed for BRAF mutational status and pres- and BRAF mutations in conjunction with a BRAF fusion. In the present ence of the BRAF duplication. Patients were divided into 0–3, 4–9 and 10– study, we screened 62 PA for BRAF and RAF1 fusion genes using multiplex 20 years old for this analysis. RESULTS: Gene expression array analysis of and long-distance inverse PCR and direct genomic sequencing for detailed classic pilocytic astrocytomas (n ¼ 29) and non-classic pilocytic astrocytoma breakpoint mapping. Fusions targeting RAF kinases were identified in (n ¼ 18) were compared. 100% of all classic pilocytic astrocytomas versus 71% (44/62) of cases. Sequencing confirmed all previously reported intronic 33% of the non-classic lesions were BRAF duplication positive. One of the variants of KIAA1549-BRAF fusion genes. We here report the first non- classic tumors was BRAF V600E mutated. More over, gene expression pat- intronic breakpoint in exon 8 of BRAF. Most interestingly, we identified terns differed significantly within the three age groups. DISCUSSION: two novel SRGAP3-RAF1 breakpoints and the novel BRAF fusion partner Pilocytic astrocytomas can be defined in part by the presence of BRAF dupli- FAM131B. This finding strongly argues for the existence of additional but cation. In spite of this, significant molecular expression heterogeneity was yet unknown fusion genes targeting RAF genes. Notably, all fusion events identified between the morphologically identical lesions based on the age occur in close proximity to the C-terminal domain but still retain the of the patient. The identification of non-overlapping developmentally regu- intact kinase domain enabling constitutive activation of the RAF kinase lated genes identified in the three groups will be discussed in detail. protein. Taken together, our findings implicate a fundamental role of RAF kinase fusion products as a specific marker for PA and strengthen the role of BRAF fusion genes as an ideal tumor-specific therapeutic target. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021

LGG.19. SPECIFIC GENE EXPRESSION SIGNATURES OF LOW-GRADE GLIOMAS (LGG) S. Mascelli1, A. Raso1, P. Nozza2, S. Pignatelli3, R. Biassoni4, A. Barla5, LGG.17. BREAKPOINT ANALYSIS OF RAF GENE FUSIONS IN S. Mosci5, L. Rosasco5, A. Verri5, G. Wittenberg6, K. Noy6, C. Mircean6, PAEDIATRIC LOW-GRADE ASTROCYTOMAS D. Fasulo6, G. Morana7, C. Milanaccio3, A. Cama1, V. Capra1,and T. Forshew1, A. R. J. Lawson1, G. F. L. Hindley1, R. G. Tatevossian1,2, M. L. Garre`3; 1Neurosurgery Unit, Giannina Gaslini Research Institute, G. Jamie1, D. W. Ellison2, and D. Sheer1; 1Queen Mary University of Genoa, Italy; 2Pathology Unit, Giannina Gaslini Research Institute, Genoa, London, Blizard Institute of Cell and Molecular Science, London, United Italy; 3Neuro-Oncology Unit, Giannina Gaslini Research Institute, Genoa, Kingdom; 2Department of Pathology, St Jude Children’s Research Centre Italy; 4Molecular Medicine Unit, Giannina Gaslini Research Institute, Hospital, Memphis, TN, United States Genoa, Italy; 5University of Genoa (DISI), Genoa, Italy; 6Siemens AG, USA, Genoa, Italy; 7Neuroradiology, Department, Giannina Gaslini Research Several recent studies, including our own, have identified KIAA1549- Institute, Genoa, Italy BRAF gene fusions in the majority of sporadic pilocytic astrocytomas (PAs) tested and, less frequently, in other low-grade astrocytomas. These Low-Grade Gliomas (LGGs) are a heterogeneous group of slowly growing gene fusions are created by tandem duplication of the 1.9Mb region glial tumors histologically corresponding to WHO grade I or II. Their prog- between KIAA1549 and BRAF. A total of five different exon pairings have nosis is mainly influenced by histology and site of lesion. Pilocytic been discovered, creating in-frame fusion proteins which include the Astrocytoma (PA) (WHO grade I) is the most common LGG in children N-terminus of KIAA1549 and the C-terminal kinase domain of BRAF. and is well known to be a benign, circumscribed tumor with a 5-year survival The autoinhibitory domain of BRAF is excluded from the fusion protein, rate of 85–100% after complete resection, although sporadic examples may resulting in constitutive activation of BRAF and thus the MAPK pathway. disseminate or tend to relapse. In order to perform a biological characteriz- In addition to these BRAF fusions, SRGAP3-RAF1 fusions have been ation of LGG and particularly of PA, we performed gene expression analysis reported in two cases of PA. These are also formed by tandem duplications, by using Affymetrix Platform on 60 pediatric LGG comprising 47 PA from with the region of gain at 3p25 rather than 7q34. We have sequenced the different brain regions (cerebellum, hemispheres and midline) and 13 DNA breakpoints of these RAF fusions, including examples of all known Gangliogliomas almost localized in hemispheres. The analyses of the micro- KIAA1549-BRAF variants and one SRGAP3-RAF1 fusion, in 39 PAs, one array data were performed using two different statistical methods. One is a pilomyxoid astrocytoma and one pilomyxoid glioma. This has allowed us filtering technique following conventional statistics, while the other is a to map the fusion breakpoints within the relevant introns and identify the multivariate statistical learning selection procedure based on regularization presence of insertions and regions of microhomology. Additionally, we and nested in a bias-free model selection framework. A specific genetic signa- have analysed the neighbouring sequence for recurrent motifs, regions of ture related to tumor site emerged regarding genes codifying for cell cycle homology and non-B DNA conformations. These DNA fusions show strik- communication, focal adhesion, cell differentiation and development. In ing similarity to those described in the first large-scale breast cancer order to confirm and validate such results we performed Q-PCR that paired-end sequencing project. Our findings throw light on the possible allowed us to assess the differential expression level of the genes. Our analy- mechanisms by which these aberrations are created and may help explain sis showed a distinctive subset of gene expression profiles between PAs and the relative frequencies of different RAF gene fusions and variants in paedia- Gangliogliomas that could represent possible genetic markers for these two tric brain tumours. entities. Moreover, we highlighted a specific gene expression pattern for PAs which is peculiarly related to their brain site.

LGG.18. MOLECULAR CHARACTERIZATION BY AGE OF PEDIATRIC PILOCYTIC ASTROCYTOMAS IN THE PRESENCE LGG.20. INTEGRATIVE MOLECULAR PROFILING OF OR ABSENCE OF BRAF MUTATION OR DUPLICATION PEDIATRIC LOW-GRADE ASTROCYTOMAS M. W. Kieran1,2, B. E. Rich3,4, L. MacConaill5,6, J. A. Chan6,7, M. W. Kieran1,2, L. MacConaill3,4, J. A. Chan5,4, S. Santagata6,4, D. Goff5, S. Santagata6,4, D. Goff3, C. Stiles3, T. Golub8,6, L. Garraway5,6, and C. Stiles5, L. Garraway3,4, and K. L. Ligon5,6; 1Pediatric Neuro-Oncology, K. L. Ligon3,4; 1Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Dana-Farber Cancer Institute, Boston, MA, United States; 2Pediatric Boston, MA, United States; 2Pediatric Hematology/Oncology, Children’s Hematology/Oncology, Children’s Hospital Boston, Boston, MA, United Hospital Boston, Boston, MA, United States; 3Cancer Biology, Dana-Farber States; 3Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, United Cancer Institute, Boston, MA, United States; 4Department of Pathology, States; 4The Broad Institute of MIT and Harvard, Cambridge, MA, United Brigham and Women’s Hospital, Boston, MA, United States; 5Medical States; 5Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; 6The States; 6Department of Pathology, Brigham and Women’s Hospital, Boston, Broad Institute of MIT and Harvard, Cambridge, MA, United States; MA, United States 7Department of Pathology, Brigham and Woman’s Hospital, Boston, MA, United States; 8Pediatric Oncology, Dana-Farber Cancer Institute, Boston, BACKGROUND: Analysis of pediatric low-grade astrocytomas has been MA, United States hampered by the rarity of the disease limiting the availability of high quality fresh tumor material, as well as the long time-frame over which the BACKGROUND: Pilocytic astrocytomas are classified as WHO grade I true biologic nature of these tumors will become evident. METHODS: tumors and comprise the largest group of pediatric brain tumors. They Here we describe an integrated series of molecular tests which can identify occur throughout childhood. Based on smear preparations, H&Es and in paraffin embedded tissue all of the currently known key genetic lesions immunohistochemistry, tumors that possess all of the necessary features of in pediatric gliomas. These tests have been developed at the DFCI Center pilocytic astrocytomas are easily categorized and were previously thought for Cancer Genome Discovery and Center for Molecular Oncologic to represent a single entity. METHODS: Pediatric patients with classic pilo- Pathology and the Broad Institute to evaluate the molecular profile of pedi- cytic astrocytoma, (as well as those with non-classic features, such as missing atric low-grade astrocytomas. RESULTS: Results to be reported include the one or more elements for the WHO criteria) were evaluated with gene array following methods. 1) Gene array expression profiling methods using and mutational analysis using formalin fixed paraffin embedded (FFPE) Illumina DASL platform on FFPE tumor tissue have been developed so tissue after IRB approval was obtained. Gene array analysis was performed that large numbers of samples can be evaluated in which the outcome for on the Illumina DASL platform while mutational status was performed with the patients is already known and will be reported for the over 250 LGA

NEURO-ONCOLOGY † JUNE 2010 ii23 Abstracts

samples analyzed. 2) Mutation detection methods to identify and map “stemness” which has been noted in multiple other stem cell studies. mutations in kinases using archived tumor samples have been developed Reported at Asilomar Germany 2010 and will be reported for over 150 LGA samples analyzed. 3) The development of CLIA certiﬁed methodologies for BRAF gene duplications or gene mutation (V600E) in pediatric LGA have been developed and validated and these results will be presented. DISCUSSION: A series of novel molecular techniques have been developed to allow large scale analysis of parafﬁn LGG.23. MOLECULAR CHARACTERIZATION AND embedded tumor material. Details of these techniques will be presented TARGETING OF PEDIATRIC LOW GRADE GLIOMAS using results derived from pediatric low-grade glioma samples. A. J. Sievert, N. Choudhari, K. Boucher, S. Sharma, A. R. Judkins, J. A. Biegel, P. C. Phillips, P. B. Storm, and A. C. Resnick; The Children’s Hospital of Philadelphia, Philadelphia, PA, United States

LGG.21. TUMOR VASCULATURE AND ANGIOGENIC PROFILE Low-grade gliomas are the most common type of central nervous OF PEDIATRIC PILOCYTIC ASTROCYTOMA; IS IT MUCH system tumor in children. At the Children’s Hospital of Philadelphia, DIFFERENT FROM GLIOBLASTOMA? there were more than 75 children with newly diagnosed or recurrent glioma treated in 2008. Effective, targeted therapies directed against the M. Sie, E. S. J. M. de Bont, F. J. G. Scherpen, E. W. Hoving, and W. F. A. den Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Dunnen; University Medical Center Groningen, Groningen, Netherlands specific biochemical or cellular abnormalities found in pediatric gliomas have not been developed due in large part to the absence of information INTRODUCTION: Pilocytic astrocytomas are the most frequent brain regarding the genetic and molecular changes that drive pediatric glioma tumors in children. Despite a 5-year survival of 90%, outcome is not formation. Children with unresectable or recurrent/disseminated low- always favourable. So this study aimed to characterize tumor vasculature grade gliomas have been left with few treatment options. Their event and angiogenic profile of 59 pediatric pilocytic astrocytomas to obtain free and overall survival rates have been dismal. Our discovery of an acti- insights into potential angiogenic related therapeutic targets in these vated, novel KIAA1549-BRAF fusion oncogene in the majority of pedi- tumors. MATERIAL AND METHODS: Microvessel density, vessel maturity atric low-grade gliomas along with additional BRAF alteration in terms of basement membrane and pericytes coverage, turnover of endo- characterizing a number of of other low grade CNS tumors offers the thelial and tumor cells, and vascular endothelial growth factor (VEGF) potential for developing targeted treatment options. Our investigation expression were evaluated in tumor tissue, immunohistochemically stained of the oncogenic addiction of the RAS/RAF/ERK mitogen activated with respectively CD34, collagen IV, Smooth Muscle Actin (SMA), Ki67/ protein kinase (MAPK) pathway, and specifically of the CD34, caspase-3/CD34, and VEGF(-A-D). Collagen IV and SMA slides KIAA1549-BRAF fusion, has provided a better understanding of the mol- were quantified using morphometry software. As indicator for vessel stab- ecular events that drive low-grade gliomas. Using cell-based assays we ility, angiopoietin-1/angiopoietin-2 balance was calculated using Real compared the mechanisms of action and pharmacological targeting of Time RT-PCR. These data were compared with previously described 62 the KIAA1549-BRAF fusion and the more canonical BRAF V600E adult glioblastomas as prototype of tumor angiogenesis.(Sie, J Neurosurg mutant prevalent in melanomas. Our preclinical in vitro testing using 2009) RESULTS: Pilocytic astrocytoma and glioblastoma showed similar selected BRAF and MEK inhibitors shows promise that targeted inhi- fractions of vessels covered with basement membrane and pericytes. bition of the KIAA1549-BRAF fusion may be an effective treatment for Overlapping angiopoietin-1/angiopoietin-2 balance and VEGF-A low-grade gliomas. expression was seen. Pilocytic astrocytoma had fewer but wider vessels compared with glioblastoma. Turnover of endothelial and tumor cells were relatively lower (p , 0.001). Within pilocytic astrocytoma, lower numbers of vessels were correlated with higher VEGF-A expression (r: -0.434, p ¼ 0.001). CONCLUSION: Despite the fact that pilocytic astrocytoma LGG.24. BRAF INDUCES CELLULAR TRANSFORMATION AND showed a different vessel architecture compared with glioblastoma, a critical SENESCENCE IN HUMAN NEURAL STEM CELLS: A MODEL OF overlap in vessel immaturity/instability and angiogenic profile was seen PILOCYTIC ASTROCYTOMA 1 2 2 2 3 4 between both tumors. These findings suggest encouraging possibilities for E. H. Raabe , K. Lim , E. Bar , X. Mao , J. Maciaczyk , U. Kahlert , 4 2 1 targeting angiogenesis (for instance with anti-VEGF) as therapeutic strategy G. Nikkhah , and C. Eberhart ; Johns Hopkins Division of Pediatric 2 in pilocytic astrocytoma. Oncology, Baltimore, MD, United States; Johns Hopkins Division of Neuropathology, Baltimore, MD, United States; 3Division of Neurosurgery, University of Freiburg, Freiburg, Germany; 4Division of Stereotactic Neurosurgery, University of Freiburg, Freiburg, Germany LGG.22. REMISSION AND RELAPSE IN PEDIATRIC LOW GRADE BRAF activation via gene duplication/fusion or V600E point mutation ASTROCYTOMA: AN OPPOSITIONAL RELATIONSHIP has recently been identified as the primary molecular alteration in pilocy- BETWEEN STEMNESS AND P53? tic astrocytoma. To investigate the mechanisms by which BRAF acti- M. W. Kieran1,2, S. Mehta3, E. Huillard4, D. H. Rowitch4, A. Saad5, vation leads to transformation, BRAF V600E was introduced into C. D. Stiles3, and K. L. Ligon3,5; 1Pediatric Neuro-Oncology, Dana-Farber cortical and cerebellar human fetal neural stem and progenitor cells. Cancer Institute, Boston, MA, United States; 2Hematology/Oncology, Overexpression of BRAF V600E did not lead to increases in cellular pro- Children’s Hospital Boston, Boston, MA, United States; 3Cancer Biology, liferation compared to controls, but did initially promote colony forming Dana-Farber Cancer Institute, Boston, MA, United States; 4Pediatric ability in soft agar. However, after initially growing well, BRAF V600E Neurosurgery, UCSF, San Francisco, CA, United States; 5Department of expressing cells subsequently showed decreased proliferation as compared Pathology, Brigham and Women’s Hospital, Boston, MA, United States to control cells, though they remained viable visually. Because constitutive BRAF activation in melanocytes usually leads to cellular senescence, INTRODUCTION: Central tenets of the cancer stem cell hypothesis with only rare lesions progressing to melanoma, we examined if senescent remain contentious for adult brain cancers. However pediatric low-grade markers were induced in our system. Overexpression of BRAF V600E led astrocytomas (PLGAs) conform very well to one facet of the stem cell to an increase in multiple markers of oncogene-induced senescence, model. Specifically, PLGAs recurrant after treatment can respond to the iden- including acidic beta-galactosidase, p16, and PAI-1. The pattern of tical regimen. Repetitive cycles of chemotherapy-induced remission and initial clonogenic transformation followed by senescence is similar to relapse are predicted by the cancer stem cell hypothesis but difficult to recon- the frequently indolent course of pilocytic astrocytoma, suggesting that cile with the fact that the majority of PLGAs are p53-positive. METHODS: overexpressing constitutively active BRAF in human neural stem and pro- Archival samples of pilocytic and fibrillary astrocytomas were analyzed for genitor cells phenocopies the behavior of this tumor. A tissue microarray Olig2 expression. Gene targeting methods were used to disrupt Olig2 and/ containing 60 pilocytic astrocytomas showed heterogenous p16 immunor- or p53 in murine neural progenitors. Hairpin RNAi was used to knockdown eactivity in the majority of cases, suggesting that senescence may occur in Olig2 expression in p53-positive and p53 mutant neurosphere cultures from primary tumors as well. Our data thus support the concept that BRAF adult gliomas. RESULTS: All PLGA are positive for Olig2 expression. oncogene-induced senescence plays a role in the pathobiology of pilocytic Murine neural progenitors that express both Olig2 and p53 are resistant to astrocytoma. ionizing radiation or to genotoxic drug treatment (Temozolomide). Ablation of Olig2 unmasks p53-dependent responses (growth arrest/apoptosis) to radiation or drug treatment. Neurosphere cultures from p53 positive adult gliomas are resistant to radiation unless endogenous Olig2 expression is knocked down by hairpin RNAi. By contrast p53-null human glioma cells are resistant to radiation irrespective of Olig2 expression. CONCLUSIONS: PLGAs may be more properly described as tumors comprised of developmentally stalled, Olig2-positive neural progenitors. Recurrence of these p53 positive pediatric tumors following an initial response to chemotherapy may reflect an intrinsic oppositional relationship between p53 and ii24 NEURO-ONCOLOGY † JUNE 2010 Abstracts

10 EPENDYMOMA EPEN.03. NUCLEOLIN AND HUMAN TELOMERASE REVERSE TRANSCRIPTASE (HTERT) EXPRESSION AS INDEPENDENT PROGNOSTIC FACTOR IN CHILDHOOD EPENDYMOMAS F. Giangaspero1,2, F. R. Buttarelli1, P. Modena3, M. Antonelli1, I. Morra4, EPEN.01. CROSS-SPECIES GENOMICS MATCHES MUTATIONS L. Lauriola5, C. Di Rocco5, R. Miceli6, M. Garre`7, I. Sardi8, L. Genitori8, AND CELL COMPARTMENTS TO MODEL EPENDYMOMA 6 6 1 1 1 1 1 L. Gandola , and M. Massimino ; University Sapienza, Rome, Italy; K. D. Wright , R. Johnson , H. Poppleton , K. M. Mohankumar , 2 3 1 2 3 1 1 4 IRCCS Neuromed, Pozzilli (isernia), Italy; Centro Riferimento D. Finkelstein , V. Rand , S. Leary , E. White , S. Pounds , P. Northcott , 4 4 1 5 1 1 Oncologico, Aviano, Italy; Ospedale Regina Margherita, Turin, Italy; S. Mack , G. Neale , B. Coyle , J. Atkinson , M. Dewire , 5 6 1 6 7 1 1 Policlinico Gemelli, Catholic University, Rome, Italy; Istituto Nazionale T. A. Kranenburg , Y. Gillespie , J. Allen , T. Merchant , F. A. Boop , 7 8 1 1 4 5 Tumori, Milan, Italy; Gaslini Hospital, Genoa, Italy; Meyer Hospital, A. Gajjar , D. W. Ellison , M. D. Taylor , R. G. Grundy , and Florence, Italy R. J. Gilbertson1; 1St. Jude Children’s Research Hospital, Memphis, TN, United States; 2Sir James Spence Institute, Royal Victoria Infirmary, 3 BACKGROUND: Recently some biomolecular markers have been indi- Newcastle, United Kingdom; Seattle Children’s Hospital, Seattle, WA, cated as predictors of outcome in pediatric ependymoma. Among these, United States; 4Hospital for Sick Children, Toronto, ON, Canada; 5 1q25 gain, expression of nucleolin and EGFR have been identified as the Children’s Brain Tumor Research Centre, University of Nottingham, most promising. MATERIAL AND METHODS: We constructed, from 41 Nottingham, United Kingdom; 6University of Birmingham, Birmingham, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 7 out of 60 non-metastatic ependymomas prospectively treated, a tissue micro- AL, United States; New York University Langone Medical Center, array (TMA). We used immunohistochemistry to analyze nucleolin and New York, NY, United States EGFR, and FISH for 1q gain. For 29 tumors with frozen material, the mRNA expression of EGFR, prominin1/CD133 and telomerase catalytic BACKGROUND: Understanding the biology that underlies histologically subunit (hTERT) was evaluated by quantitative RT-PCR RESULTS: similar, but molecularly distinct subgroups of cancer has proven difficult Among clinical variables, at multivariable analysis by Cox model, only since their defining genetic alterations are often numerous, and the cellular grading III vs II affected both EFS (p ¼ 0.05) and OS (p ¼ 0.07). origins of most cancers remain unknown. We sought to decipher this hetero- Multivariable analyses of each biological marker separately accounting for geneity by integrating matched genetic alterations and candidate cells of penalty-weighted estimates were performed with adjustment for clinical vari- origin to generate accurate disease models. METHODS: We identified sub- ables. Relatively high hazard ratios (HRs) for EFS were achieved by nucleolin groups of human ependymoma among 56 supratentorial, 110 posterior (HR high vs. low: 1.88; p ¼ 0.110) and EGFR (HR low vs. strong: 1.76; p ¼ fossa and 38 spinal ependymomas using 500k SNP, U133Plus2 Affymetrix 0.140), and by EGFR (HR 32.7 vs. 5.1: 1.76; p ¼ 0.396) and hTERT (HR gene and microRNA expression microarrays. Real-time polymerase chain 33.5 vs. 1.2: 2.04; p ¼ 0.337); the 5-year EFS was 46% vs. 20% (p ¼ reaction and fluorescence in situ hybridization were used to validate selected 0.004) in the subgroup with low (,50%) versus high nucleolin expression, genetic alterations. To select cellular compartments most likely to give rise to respectively. The strongest association with OS emerged for hTERT mRNA subgroups of ependymoma, we matched the transcriptomes of human expression (HR: 9.9; p ¼ 0.011), while EGFR (HR: 3.12; p ¼ 0.444) was not tumors to those of 177 individual mouse neural stem cell (NSC) cultures iso- significant. The 5-year OS was 84% vs. 48% (p ¼ 0.005) in the subgroup lated from different regions of the CNS at different developmental stages, with hTERT,6 median value versus . ¼ 6, respectively. with an intact or deleted Ink4a/Arf locus. Viral transduction was used to CONCLUSIONS: ultivariable analyses show that nucleolin was the strongest introduce subgroup-specific mutations into matched NSCs. RESULTS: The biological marker for EFS while hTERT emerged as the strongest predictor transcriptome of human cerebral ependymomas with amplified EPHB2 for OS. and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/ Arf -/- radial glia (RG). Remarkably, activation of Ephb2 signaling in these RG, but not other NSCs, generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human cerebral tumor. EPEN.04. AN INTERSPECIES GENOMICS BASED CONCLUSIONS: Our data demonstrate the power of interspecies genomics HIGH-THROUGHPUT SCREEN FOR NOVEL TREATMENTS OF to meticulously match subgroup specific driver mutations with cellular com- EPENDYMOMA partments to model and interrogate cancer subgroups. J. M. Atkinson1, A. Shelat2, R. Johnson1, H. Poppleton1, T. Kranenburg1, K. Wright3, K. M. Mohankumar1, E. White1, R. K. Guy2,and R. J. Gilbertson1; 1St Jude Childrens Research Hospital, Department of Developmental Neurobiology, Memphis, TN, United States; 2St Jude Childrens Research Hospital, Department of Chemical Biology and EPEN.02. EPIGENOMIC ANALYSIS OF ALU REPEATS IN Therapeutics, Memphis, TN, United States; 3St Jude Childrens Research HUMAN EPENDYMOMAS Hospital, Department of Oncology, Memphis, TN, United States H. Xie1, M. Wang1, M. d. F. Bonaldo1, V. Rajaram2, W. Stellpflug2, 1 1 2 2 1 C. Smith , K. Arndt , S. Goldman , T. Tomita , and M. B. Soares ; Utilizing interspecies genomics we meticulously matched specific driver 1Children’s Memorial Research Center, Chicago, IL, United States; 2 mutations with distinct types of mouse neural stem cell (NSC) to accurately Children’s Memorial Hospital, Chicago, IL, United States model human ependymoma subgroups in mice for drug screening. Stem-like tumor cells (TSCs) and control transduced NSCs were cultured in neuro- Global loss of DNA methylation has been known for decades as an epige- sphere conditions adapted for use in an automated high-throughput small nomic aberration associated with carcinogenesis. Loss of DNA methylation molecule screening system. We first performed replicate primary screens of was frequently observed within repetitive elements, which contribute more a ‘bioactive library’ including natural products, bioactive alkaloids and mar- than 50% of CpG dinucleotides to the human genome. Due to the lack of keted drugs (5760 agents) in a single concentration format (10 mM). Active an effective approach, no studies have been conducted to reveal such compound hit rate varied from 0.9% to 4.8% in TSCs and 3.1% in control genome wide methylation changes at a single base resolution. To precisely NSCs. The primary screen was highly reproducible (263 and 261 hits in repli- determine the CpG sites with methylation loss during tumor progression, we cate assays, of which 226 of were common). Receiver operating character- exploited a high-throughput bisulfite sequencing approach which generates istic (ROC) analysis of primary screen data was used to assess predictive methylation profiles for thousands of Alu elements and flanking sequences power of the screen (ROC AUC . 0.89 (0.85–0.92 95% CI)). We next per- in ependymomas at different disease stages. Comparison of the methylation formed secondary screens of all primary screen hits. These included full profiles between normal and tumor tissues revealed that the methylation 10-point dose response assays that identified a total of 292 agents with status of the majority of CpG sites adjacent to or within Alu repeats remained activity in at least one cell population. Additionally, we screened a collection unaltered; while a small set of CpG sites gain or lose methylation in ependy- of 320 FDA approved active pharmaceutical ingredients representing all drug momas. Compared to the CpG sites with stable methylation level between classes and all approved chemotherapy agents in a 10-point dose response normal control and ependymomas, the differentially methylated CpG sites format. The hit rate of this drug collection was 10.36% to 15.4% and hit are enriched in the sequences with low CpG ratio and the flanking regions compounds represented a variety of drug classes. Seven agents were selected of Alu repeats rather than within the Alu sequences. In addition, the CpG for assessment of in vivo activity against the originating ependymoma mouse sites hypermethylated in ependymomas are closer to the most adjacent CpG models after displaying a potency in TSCs which was equal or greater than islands, while the CpG sites hypomethylated are overrepresented in the inter- that in control NSCs. genic regions. Lastly, with pyrosequencing verification, the methylation aberrations of several genomic loci were identified to be associated with the aggressive and relapsed ependymomas.

NEURO-ONCOLOGY † JUNE 2010 ii25 Abstracts

EPEN.05. TENASCIN-C IS AN INDEPENDENT PROGNOSTIC EPEN.07. INTRACRANIAL EPENDYMOMA EXHIBIT A MARKER IN PEDIATRIC EPENDYMOMA: AN INTERNATIONAL TREMENDOUS CLINICAL HETEROGENEITY WHICH MIGHT COLLABORATIVE STUDY BE EXPLAINED BY SUBGROUP-SPECIFIC MOLECULAR F. Andreiuolo1, A. Mauguen1, J. Kilday2, P. Modena3, M. Massimino4, ALTERATIONS P. Varlet5, F. Giangaspero6, D. Figarella-Branger7, D. Frappaz8, R. Grundy2, H. Witt1,2, S. Bender1, T. Milde3, T. Hielscher4, A. Benner4, S. Riester1, and J. Grill1; 1Institut Gustave Roussy, Villejuif, France; 2University of M. Remke1,2, A. von Deimling5, A. E. Kulozik2, O. Witt3, P. Lichter1, Nottingham, Nottingham, United Kingdom; 3Centro di Riferimento A. Korshunov6,7, and S. Pfister1,2; 1German Cancer Research Center, Oncologico, Aviano, Italy; 4Istituto Nazionale dei Tumori, Milan, Italy; Molecular Genetics, Heidelberg, Germany; 2Department of Pediatric 5Hoˆ pital Sainte-Anne, Paris, France; 6Universita` La Sapienza, Rome, Italy; Oncology, Hematology and Immunology, University Hospital Heidelberg, 7Hopital de la Timone, Marseille, France; 8Institut d’He´mato-Oncologie Heidelberg, Germany; 3Clinical Cooperation Unit Pediatric Oncology, Pe´diatrique, Lyon, France German Cancer Research Center, Heidelberg, Germany, Heidelberg, Germany; 4Division Biostatistics, German Cancer Research Center, BACKGROUND: The prognosis of pediatric ependymoma is not consist- Heidelberg, Germany, Heidelberg, Germany; 5Department of ently predictable based on histopathological grading or known biological Neuropathology, University of Heidelberg, Germany, Heidelberg, Germany; markers, the only well established factor influencing outcome being complete 6Department of Neuropathology, University of Heidelberg, Germany, surgery. METHODS: Potential prognostic markers for ependymoma (metal- Heidelberg, Germany; 7Clinical Cooperation Unit Neuropathology, German Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 lothioneins 1–2 and 3, YAP1, nucleolin, ASPM, EGFR, KI-67, tenascin-C Cancer Research Center, Heidelberg, Germany, Heidelberg, Germany (TNC)) were tested by immunohistochemistry in tumors from patients treated prospectively in three countries (United Kingdom, n ¼ 105; Italy, Prognosis of intracranial ependymomas remains relatively poor and its n ¼ 62; France, n ¼ 93). Paraffin embedded tissue-microarray (TMA) blocks biological behavior is unpredictable based on current staging approaches. from patients with well documented clinical history and treatment were con- We studied in total 292 samples from patients with intracranial ependy- structed nationally. Based on preliminary national studies, the three most moma by genome-wide assessment of DNA-copy-number aberrations promising immunohistochemical markers (nucleolin, YAP1 and TNC) were using array-CGH (10K-BAC-array), for validation procedures we performed tested on TMA slides for the entire three cohorts. Prognostic value of FISH on tissue-microarrays (n ¼ 170) in an independent cohort. markers on overall survival and recurrence-free survival were assessed Consecutively, we investigated genome-wide mRNA expression-profiles through a Cox model stratified on country. RESULTS: Median age at diagnosis (Agilent-44K) of 65 primary ependymomas and performed unsupervised was 2.8 years (4 months-16.7 years) and median follow-up was 7 years (1 clustering separately for supratentorial (n ¼ 26) and infratentorial (n ¼ 39) day19.8 years). Strong expression of TNC was the only unfavorable prognostic ependymomas. Gene-signatures and potential biomarkers were validated biological marker. In multivariate analysis, factors associated with a higher by QRT-PCR and by immunohistochemistry on TMAs. Based on our risk of death were a strong expression of TNC (HR ¼ 2.32, 95% CI ¼ [1.38 array-CGH results (n ¼ 122), we proposed a novel molecular staging - 3.91], p ¼ 0.002) and incomplete surgery (HR ¼ 1.93 [1.22 - 3.05], p ¼ system comprised of three genetically distinct subgroups: i) low-risk group 0.005). Factors associated with a higher risk of recurrence were a strong (34%; n ¼ 41) including tumors with gain of chromosomes 9, 15q, 18, or expression of TNC (HR ¼ 1.53 [1.03 - 2.41], p ¼ 0.01), incomplete surgery loss of chromosome 6, or combination thereof (5-year OS ¼ 100%); ii) (HR ¼ 1.65 [1.13 - 2.41], p ¼ 0.01) and initial adjuvant treatment other intermediate-risk group (41%; n ¼ 51) characterized by balanced cytoge- than radiotherapy (chemotherapy + radiotherapy: HR ¼ 3.17 [1.47 - 6.83]; netic profiles especially for chromosomes 1q, 9, 15q, 18, 6 and the chemotherapy alone: HR ¼ 1.55 [0.84 - 2.84]; no other treatment: HR ¼ CDKN2A-locus (5-year OS ¼ 77%); iii) high-risk group (25%; n ¼ 30) 1.63 [0.44 - 5.96]; p ¼ 0.02). When adjusted on TNC expression, tumor defined by tumors harbouring a gain of 1q and/or a homozygous deletion location was no more prognostic. CONCLUSION: Strong expression of of CDKN2A (5-year OS ¼ 33%). Interestingly, for infratentorial tumors TNC is associated with a poor outcome in pediatric ependymoma. low-risk and high-risk tumors were identified by unsupervised clustering indicating substantial biological differences. For supratentorial localization we were able to identify a low-risk group comprised of tumors with balanced profiles in adult patients and a high-risk group predominantly of children. In conclusion, we developed a novel stratification model for intracranial epen- EPEN.06. HIGH-RISK EPENDYMOMAS ARE DISTINGUISHABLE dymomas, based on cytogenetic aberrations, which show a localization- BY ELEVATED EXPRESSION OF THE EPIDERMAL GROWTH specific overlap with subgroups identified by transcriptome analysis. FACTOR AND THE Y-BOX BINDING PROTEIN-1 Integration of both datasets allows us to identify novel biomarkers which J. Hukin1, J. H. Law1, S. Yip1, J. Maguire1, T. Yamashita2, C. Fryer1, might be useful for stratifying patients in future clinical trials. A. Singhal1, T. Ailon1, G. Hendson1, C. Hawkins3, and S. E. Dunn1; 1University of British Columbia, Vancouver, BC, Canada; 2University of Western Ontario, London, ON, Canada; 3Hospital for Sick Children, Toronto, ON, Canada EPEN.08. INFANT EPENDYMOMA IN 10-YEAR AIEOP (ASSOCIAZIONE ITALIANA EMATOLOGIA ONCOLOGIA INTRODUCTION: The overall survival (OS) rate of childhood ependy- PEDIATRICA) EXPERIENCE WITH OMITTED OR DEFERRED RADIOTHERAPY moma is 30–70% and at this time there are limited molecular biomarkers 1 1 2 3,4 5 to stratify patients into high versus low risk groups. Furthermore there is dis- M. Massimino , L. Gandola , S. Barra , F. Giangaspero , C. Casali , P. Potepan1, C. Di Rocco6, P. Nozza7, P. Collini1, E. Viscardi8, d. Bertin9, cordance with the current stratification system used to define risk based on 1 10 11 12 13 World Health Organization (WHO) tumour grading. We hypothesised V. Biassoni , A. Cama , C. Milanaccio , P. Modena , R. Balter , G. Tamburrini14, P. Peretta15, M. Mascarin16, G. Scarzello17, S. Pignatelli18, that signalling components of the epidermal growth factor receptor 19 20 21 18 1 (EGFR) and Y-box binding protein-1 (YB-1) signalling pathway will P. Fidani , G. M. Milano , I. Sardi , and M. L. Garre` ; Fond. IRCCS Istituto Nazionale Tumori, Milano, Italy; 2Istituto Nazionale per la Ricerca sul improve risk stratification given that they lead to uncontrolled tumour cell 3 4 growth and drug resistance. METHODS: We performed a pilot retrospective Cancro, Genova, Italy; Universita` La Sapienza, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy; 5Fond. IRCCS Istituto Neurologico Carlo Besta, review of all children under 18 years old diagnosed with ependymoma in 6 British Columbia between 1982 and 2004. Tissue microarray slides were Milano, Italy; Pediatric Neurosurgery; Univesrita` Cattolica, Roma, Italy; 7IRCCS Giannina Gaslini, Genova, Italy; 8Pediatrin Oncology, University, constructed and immunostained for EGFR and YB-1. Patient 5 year 9 10 overall survival was assessed. RESULTS: 48 children were eligible for the Padova, Italy; Pediatric Oncology, OIRM, Torino, Italy; Neurosurgery, IRCCS Giannina Gaslini, Genova, Italy; 11IRCCS Giannina Gaslini, Genova, study. Reviewer discrepancy between WHO Grade II and III was evident, 12 13 highlighting the need for independent risk assessment. High EGFR staining Italy; Experimental Oncology 1, CRO, Aviano, Italy; Pediatric Oncology, Ospedale Borgo Roma, Verona, Italy; 14Pediatric Neurosurgery; Universita` was associated with poor (OS) (45% vs 84%, p ¼ 0.004). We also evaluated 15 16 the EGFR downstream molecule YB-1 to address whether risk could be Cattolica, Roma, Italy; Neurosurgery, OIRM, Torino, Italy; Radiotherapy Unit, CRO, Aviano, Italy; 17Radiotherapy Unit, Padova, Italy; 18Neurosurgery further stratified. Patients with tumours expressing high levels of EGFR 19 and YB-1 had far worse survival (17% vs 85% OS, p ¼ 0.00001) than if Unit, IRCCS Giannina Gaslini, Genova, Italy; Pediatric Oncology, Ospedale Bambino Gesu` , Roma, Italy; 20Pediatric Oncology, Ospedale S. Maria della the levels were both low. CONCLUSION: This is the first pilot study on a 21 population-based cohort to demonstrate that EGFR and YB-1 are features Misericordia, Perugia, Italy; Pediatric Oncology, Firenze, Italy of high-risk childhood ependymoma suggesting that inhibitors to this pathway may be beneficial in the management of this tumor. PURPOSE: Nineties’ protocols omitted or delayed irradiation utilizing up-front chemotherapy (CT), thus saving youngest survivors from radiotherapy (RT) sequelae. Accordingly, we treated 41 younger than 3 with intracranial ependymoma. PATIENTS AND METHODS: After surgery, CT consisted of regimen 1 including 4 blocks of vincristine, high-dose methotrexate 5 g/m2 and cyclophosphamide 1.5 g/m2 alternated with CDDP 90 mg/m2 plus VP16 450 mg/m2 for a duration of one year, and regimen 2, that was VEC: VCR, VP16 300 mg/m2 and CTX 3 g/m2 for a duration of 6 months. RT was planned only for residual tumour at CT end or if progression occurred. RESULTS: Between 1994 and 2003, we treated 41 ii26 NEURO-ONCOLOGY † JUNE 2010 Abstracts

patients, 23 were males, 18 females; median age was 22 months. Fourteen years: 85.7% + 9.4%. In patients with completely resected tumours the were treated with regimen 1 and 27 with regimen 2; 22 were completely 5-year EFS (infratentorial tumours) was 74.3%, and 84% for supratentorial operated and 19 had residues. Ependymoma was grade 2 in 25 and grade sites. The 5-year EFS for grade II tumours was 84.4% and for grade III 3 in 16, tumor localization was infratentorial in 37 and supratentorial in 79.2%, for doses less than 68 Gy: 73.3% and for dose ¼ 68 Gy: 79.2 %. 4. One child had intracranial metastases. Twenty nine children progressed The 5-year EFS for ¼/, 46 days duration of radiotherapy was 83.3%, locally at a median of 9 months. EFS at 3/5 years were 26%, and 23% at and 76.3% for . 46 days (p ¼ n.s.). CONCLUSION: HFRT was tolerated 8 years. One child died for sepsis, another developed a glioblastoma 72 well. The extent of resection was an important prognostic factor, leading months after RT. PFS at 3, 5, 8 years were 27%. OS at 3, 5, 8 years were to a new treatment stratification after 2005. After complete resection there 48%, 37% and 28%, respectively. Of the 13 survivors, 6 were never irra- was a trend towards better tumour control for supratentorial tumours, diated. Intellectual outcome was not significantly different according to grade II histology, correct treatment time and correct dose prescription. irradiation. CONCLUSIONS: Our results confirm low EFS/OS for upfront CT in infant ependymoma without showing a better neuro-cognitive outcome in those few never irradiated survivors.

EPEN.11. SURVIVAL BENEFIT WITH RE-IRRADIATION FOR RECURRENT INTRACRANIAL EPENDYMOMA IN CHILDREN Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 W. H. Ballourah, N. Lapperierre, D. Mabbott, A. Kulkarni, C. Hawkins, EPEN.09. PROTON THERAPY FOR CHILDHOOD CNS E. Tsagaris, U. Bartels, A. Huang, E. Bouffet, and U. Tabori; The Hospital EPENDYMOMA: CLINICAL OUTCOMES IN A COHORT OF 49 for Sick Children, Toronto, ON, Canada PATIENTS S. M. MacDonald1, B. Lavally1, B. Y. Yeap1, K. Marcus2, D. Ebb1, The outcome of recurrent ependymoma in children is dismal. T. I. Yock1, and N. J. Tarbell1; 1Massachusetts General Hospital, Boston, Re-irradiation has been proposed as an effective modality for ependymoma MA, United States; 2Children’s Hospital, Boston, MA, United States relapse. However, the short and long term benefits of this approach have not been well established. We conducted a retrospective population based study BACKGROUND: Protons allow for highly conformal radiation with of all patients with recurrent ependymoma treated between 1986 and 2010 improved sparing of normal tissues. Previously, we reported outcomes for at the Hospital for Sick Children in Toronto (catchment population of 5 17 patients treated with proton radiation for ependymoma. We now million people). Demographic, treatment and outcome data were analyzed update and expand our previously published experience to include 49 for the entire cohort. Out of 102 patients with intracranial ependymoma, patients. METHODS: All children with intracranial ependymoma treated 43 relapsed. At the time of relapse, 28 patients were treated with either sur- at the Massachusetts General Hospital between November, 2000 and gical resection and/or chemotherapy (group 1). Four patients underwent sur- November, 2009 were included. Forty-nine patients were treated with IF gical resection and focal modified radiation not to exceed combined total proton radiation. RESULTS: Median age at the time of treatment was 41 dose of 54 Gy (group 2) and 11 patients received full dose re-irradiation months (range, 12 months-20 years). Thirteen (27%) patients had supraten- with or without surgery at recurrence (group 3). Re-irradiation was tolerated torial ependymoma and 36 (73%) had infratentorial ependymoma. well. No radionecrosis or other acute complications were noticed. The 3-year Thirty-three (67%) had a gross total resection (GTR) while 16 (33%) had overall survival rates were 18% +/- 7%, 0%, and 80% +/- 17% for group a non-GTR (NGTR). Twenty (41%) had anaplastic histology; the remainder 1, 2 and 3 respectively (p ¼ 0.0008). For re-irradiated patients the 3-year had WHO grade II ependymoma. At median follow-up of 17 months from progression free survival was 67% +/- 5%. At a mean follow-up of 5.82 the start date of therapy, local control, progression-free, and overall survival years only 2/11 patients had endocrine dysfunction. 6/11 patients are at 2/3 years was 84%/71%, 78%/65%, and 96%/83%, respectively. attending regular class, 4/11 are attending regular class with support and NGTR was significantly associated with poorer local control (57%/38% only 1 requires special school. Re-irradiation is a safe and effective treatment vs. 96%/85%, p ¼ 0.006) and with lower progression-free survival (45%/ and may change the natural history of recurrent ependymoma in children. 30% vs. 92%/81%, p ¼ 0.007). Anaplastic histology was significantly Additional follow-up is needed to determine the risk of late recurrence and associated with lower progression-free survival (59%/40% vs. 90%/79%, functional outcome of these children. p ¼ 0.035). Local control was 75%/57% among patients with anaplastic histology and was 90%/79% among those with WHO grade II ependymoma, though the difference was not significant (p ¼ 0.266). CONCLUSIONS: Preliminary disease control with proton therapy compares favorably to the literature. NGTR correlated with inferior outcome. The EPEN.12. EVALUATING THE UTILITY OF LUMBAR early age at diagnosis and the proximity of critical structures makes the CEREBRO-SPINAL FLUID (CSF) SAMPLES IN CHILDREN WITH use of proton radiation an ideal method of radiotherapy delivery for child- NEWLY DIAGNOSED INTRACRANIAL EPENDYMOMA: THE hood ependymoma. CHICAGO CHILDREN’S MEMORIAL HOSPITAL EXPERIENCE J. Fangusaro1, C. Van Den Berghe2, T. Tomita1, V. Rajaram1, D. Aguilera1, and S. Goldman1; 1Children’s Memorial Hospital, Chicago, Chicago, IL, United States; 2Northwestern Feinberg School of Medicine, Chicago, IL, United States EPEN.10. HIT 2000: HYPERFRACTIONATED RADIOTHERAPY FOR CHILDREN WITH NONMETASTATIC EPENDYMOMA. Ependymomas are the third most common CNS tumor in childhood. At PRELIMINARY REPORT OF A PROSPECTIVE MULTICENTRE diagnosis, the standard evaluations of intracranial ependymomas include a TRIAL spine MRI and lumbar CSF to evaluate for metastasis, however, there may R. Kortmann1, A. O. von Bueren2, N. U. Gerber3, S. Klagges1, T. Pietsch4, be minimal diagnostic or prognostic value in a lumbar CSF sample when M. Warmuth-Metz5, B. Timmermann6, and S. Rutkowski7; 1Clinic for the post-contrast spine MRI is positive. Some question the value of a Radiation Therapy and Radiooncology, Leipzig, Germany; 2University of lumbar CSF sample when the spine MRI is negative. We retrospectively eval- Hamburg, Children’s Hospital, Hamburg, Germany; 3University of Zurich, uated all patients at our institution with intracranial ependymoma treated Children’s Hospital, Zurich, Switzerland; 4University of Bonn, between 1–91 and 6–08. Approximately 61 patients were identified: 46% Neuropathology, Bonn, Germany; 5University of Wuerzburg, were male, and the mean age at diagnosis was 63 months. The most Neuroradiology, Wuerzburg, Germany; 6University of Essen, Centre of common tumor location was the posterior fossa, and approximately 60% Protonentherapy, Essen, Germany; 7University of Hamburg, Children´ s underwent a gross total resection at diagnosis. Five-year overall survival of Hospital, Hamburg, Germany the entire cohort was 66%. Approximately 10% presented with bulky metastatic disease as seen on post-contrast spine MRI, and the remaining evalu- BACKGROUND: Evaluation of hyperfractionated radiotherapy (HFRT) able patients had negative spine MRIs at diagnosis. Interestingly, no for children 4–21 years with ependymoma. MATERIAL AND patient with a negative spine MRI had positive lumbar CSF cytology. METHODS: 68 patients with ependymoma (M0, complete documentation These data put into question the necessity of lumbar CSF samples as part only) received HFRT to tumour site (1 Gy bid/68–72 Gy total dose) of the routine evaluation in newly diagnosed ependymoma. The implications between 2000 and 2005. 19 patients had grade II and 49 patients grade III of this are significant as a change in practice would not only reduce health tumours. Tumour histology was reviewed by the reference centre for neuro- care costs, but it would also eliminate unnecessary procedures. However, pathology. In grade III tumours 5 cycles of modified HIT SKK chemotherapy there is also a risk of providing inferior therapy to true M1 patients who were given after radiotherapy . RESULTS: Biopsy (1 patient), partial resec- may be undiagnosed without performing this procedure. Prospective, multi- tion (4 patients), subtotal resection (9 patients), total resection (54 patients). institutional studies are necessary to confirm these results before safely elim- Acute maximal toxicity (CTC score): no grade IV toxicity, grade III 1.4% for inating this procedure in the evaluation of ependymoma patients. headache, 2.8% for nausea. EFS after total resection at 3 and 5 years: 87% + 4.6% and 77.9% + 6.0%; after a partial resection: 50% + 13.4% and 25% + 18.9% (p ¼ 0.001). OS after total resection at 3 and 5 years: 92.6% + 3.6% and 90.7% + 4.0%. OS after partial resection at 3 and 5

NEURO-ONCOLOGY † JUNE 2010 ii27 Abstracts

11 GERM CELL TUMOR (50 Gy). They received additional chemotherapy for 5 times. The 10 year overall and progression-free survival rates (OS; PFS) were 89.3% and 81.5%, respectively. The 10 year PFS was significantly different between disease-free patients (94.7%) and those with residual tumors after the GCT.01. PRIMARY INTRACRANIAL GERM CELL TUMORS IN initial treatment (62.2%). There was no indicative correlation between radi- CHILDREN AND THEIR MOLECULAR CORRELATION ation volumes, histology, and recurrence rate. These results suggest that T. Wong, H. Wang, D. Ho, and K. Chang; Pediatric Neuro-Oncology adjuvant chemotherapy would be unnecessary for CR patients after the Group, Taipei, Taiwan initial treatment. Patients within the poor prognostis group (n ¼ 27) were treated by ICE (IFOS 900 mg/m2, cisplatin 20 mg/m2, and etoposide BACKGROUND: For intracranial GCTs, germinomas are clinically classi- 60 mg/m2 in days 1–5) and concurrent whole neuroaxis irradiation. They fied as good prognostic group and NGMGCs are recognized as poor prog- received additional chemotherapy for 5 times. The 10 year OS and PFS nostic ones which required more extensive drug and irradiation treatment. rates were 58.8% and 62.7%, respectively. The underlying mechanisms are not clear yet. We applied genomics molecular approaches to unmask the transcriptome compositions of pediatric intracranial GCTs and correlate with clinical behavior. MATERIAL AND METHOD: We reviewed the clinical database of 176 cases of pediatric intra- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 cranial GCTs in children. The overall survivals of germinomas and GCT.04. OUTCOME OF LOCALIZED AND METASTATIC NGMGCTs of this series were studied to support the difference of malig- GERMINOMA TREATED ACCORDING TO SIOP CNS GCT 96 nancy and outcome these GCTs. Among 22 cases GCTs with array G. Calaminus1, C. Alapetite2, R. Kortmann3, J. Nicholson4, M. Garre´5, studies, transcriptome (13 mRNA, 12 miRNA) analysis were performed in 6 7 8 1 U. Ricardi , F. Saran , and D. Frappaz ; University Hospital Mu¨ nster, 13 cases. RESULTS: In this series, 58.5% were germinoma and 35.2% 2 dep.of pediatric Hematology and Oncology, Mu¨ nster, Germany; Institute were NGMGCTs. The outcome study revealed that germinoma patients Curie, Paris, France; 3University Hospital Leipzig, Dept. of Radiotherapy, ¼ had better overall survival than NGMGCT ones (p 0.0005). In transcrip- Leipzig, Germany; 4Dept. of Pediatric Oncology, Cambridge, United tome analysis, we identified a distinct mRNA profile correlating with GCT Kingdom; 5Neuro-Oncology, Dept. of Pediatric Hematology/Oncology, histological differentiation and prognosis. Most of the differentially Genova, Italy; 6Dept. of Medical and Surgical Sciences, Radiation Oncology expressed miRNAs were downregulated in germinomas, but miR-142-5p Unit, Turin, Italy; 7Dept. of Radiotherapy, Royal Marsden Hospital, Sutton, and miR-146a were up. Genes responsible for self-renewing (Oct4, Nanog United Kingdom; 8Centre León Be´rard, Lyon, France and KLF4) and immune response were abundant in germinomas, while genes associated with differentiation, Wnt/b-catenin pathway, invasiveness OBJECTIVE: SIOP CNS GCT 96 aimed to standardize diagnostic/treat- and epithelial-mesenchymal transition (including Slug and Twist2) in ment for Germinoma. In localized disease: patients (PTs) received 2 NGMGCTs. In cytogenetic analysis, chromosomal copy number variations courses of carboplatin/etoposide alternating with 2 of etoposide/ifosfamide, between germinomas and NGMGCTs were at cytobands 4q21.1 4q25 followed by focal irradiation with 40 Gy (RT), or RT alone with 24 Gy to the and 4q26 4q28.2. CONCLUSION: Our data integrate molecular profiles craniospinal axis (CSI) and 16 Gy tumor boost. In metastatic disease, PTs with clinical observations and provide the underlying mechanisms. Genes, received 24 Gy CSI with 16 Gy boost to primary/metastases. The trial was pathways and microRNAs identified hold the potential of being novel thera- closed internationally on July 1, 2008. PATIENTS: 396 protocol PTs were peutic targets. registered (median age 13 years). 294 were boys. 317 were localized (153 pineal, 94 suprasellar, 46 bifocal, 24 other sites) and 72 metastatic. RESULTS: Event-free survival of patients (pEFS) with chemo + focal RT (n¼ 76) was 0.76 + 0.11 (median follow-up 45 months), and overall survival (OS) 0.89 + 0.05. Nine relapses occurred: 4 local, 4 combined (ventricu- GCT.02. LONG-TERM FOLLOW-UP OF GERMINOMAS lar area). One girl died 4 years after treatment due to meningitis. pEFS of TREATED BY VENTRICULAR IRRADIATION WITH 24GY AND patients with localized disease and CSI (n ¼ 128) was 0.97 + 0.02, and OS CONCURRENTLY ADMINISTERED CARBOPLATIN & 0.97 + 0.01: 4 relapses occurred at primary site, one death 5 years after diag- ETOPOSIDE CHEMOTHERAPY nosis following a neurosurgical intervention, one 2nd malignancy. pEFS in 49 M. Matsutani; Saitama International Medical Center, Hidaka, Japan metastatic PTs was 0.98 + 0.02 (median follow-up 52 months); one patient died following metabolic decompensation CONCLUSION: SIOP CNS GCT We conducted a phase II study for intracranial germ cell tumors from 1995 96 has shown that CSI controls metastatic disease and spinal radiotherapy to 2003, and evaluated 10 years OS and PFS of 228 patients with the median can be omitted in localized germinoma with chemo. Focal RT after chemo follow-up period of 8.2 years. Patients with germinoma (n ¼ 123) were 2 2 does not prevent ventricular recurrences. Based on this experience the con- treated by CARE (carboplatin 450mg/m in day 1, etoposide 150mg/m current SIOP CNS GCT II is on its way with the participation of more in days 1–3) followed by ventricular irradiation (24 Gy). The 10 year than 12 countries. Supported in part by Deutsche Krebshilfe overall and progression-free survival rates (OS; PFS) were 97.5% and 84.7%, respectively. Analysis of 17 recurrent patients indicated a critical factor of the radiation volume. In 107 patients with tumors around the third ventricle, 7 of 13 recurrences developed in the ventricle, and all 3 recurrences of 7 tumors in the basal ganglia were remote sites from the primary GCT.05. LOCALISED AND METASTATIC NON-GERMINOMA sites. These results suggest that combination of CARE and 24 Gy irradiation (NGGCT) TREATED ACCORDING TO THE SIOP CNS GCT 96 would be enough for control germinomas, and that the irradiation volume PROTOCOL. UPDATE ON RISK PROFILES AND OUTCOME would be the whole ventricle for germinoma patients around the third ven- G. Calaminus1, J. Nicholson2, D. Frappaz3, M. Garre´4, C. Alapetite5, tricle and the whole brain to those in the basal ganglia. Patients with HCG 6 7 8 1 U. Ricardi , F. Saran , and R. Kortmann ; University Hospital Mu¨ nster, or bHCG secreting germinomas (n ¼ 38) were treated by CARE followed 2 dep.of pediatric Hematology and Oncology, Mu¨ nster, Germany; Dept. of by local irradiation (50 Gy). They received additional chemotherapy for 5 Pediatric Oncology, Cambridge, United Kingdom; 3Centre León Be´rard, times. The 10 year OS and PFS rates were 97.3% and 88.3%, respectively. Lyon, France; 4Neuro-Oncology, Dept. of Ped. Hematol/Oncol., Genova, There were no statistical differences in serum HCG or titers between recur- Italy; 5Institute Curie, Paris, France; 6Department of Medical and Surgical rent and non-recurrent patients. The radiation volume was a critical factor Sciences, Radiation Oncology Unit, Turin, Italy; 7Dept. of Radiotherapy, for recurrence as in pure germinomas. These results suggest that bHCG Royal Marsden Hospital, Sutton, United Kingdom; 8University Hospital secreting germinomas could be successfully treated by the same regimen to Leipzig, Dept. of Radiotherapy, Leipzig, Germany pure germinomas. OBJECTIVE: The SIOP CNS GCT 96 protocol aimed to standardise diagnostic and treatment of intracranial NGGCT. Diagnosis was made by imaging and markers in serum/ CSF (AFP / ß-HCG) if possible. The trial was closed internationally on 1.07.2008 PATIENTS AND TREATMENT: GCT.03. EXCELLENT 10-YEAR’S OS & PFS OF PATIENTS WITH One hundred and seventy two protocol patients (PT) with NGGCT were NON-GERMINOMATOUS GERM CELL TUMORS (NGGCT) registered. Median age was 12 years, 133 were boys. 135 were localized TREATED BY SURGERY, RADIATION & CHEMOTHERAPY (75 pineal, 37 suprasellar, 10 bifocal, 13 other), and 37 metastatic. PT M. Matsutani; Saitama International Medical Center, Hidaka, Japan with localized disease received 4 courses of PEI followed by 54 Gy focal RT. PT with metastases received after chemo 30 Gy craniospinal RT (CSI) In the phase II study for intracranial germ cell tumors from 1995 to 2003 and 24 Gy boost (tumor/metastatases). RESULTS: Progression-free survival in Japan treating 228 patients, we divided non-germinomatous germinomas (PFS) of PT with chemo + local RT was 0.69 + 0.05 (median follow-up 45 into 2 subtypes, the intermediate prognosis group including malignant tera- months), and with chemo + CSI 0.64 + 0.09 (median follow-up 47 tomas, and mixed tumors mainly composed of germinoma or teratoma, and months). Twelve relapses were observed after CSI (n ¼ 36): 6 local, 1 the poor prognosis group including choriocarcinoma, yolk sac tumor, distant, 5 combined and 33 relapses after chemo + focal RT (n ¼ 127): 18 embryonal carcinoma, and their mixed tumors. Forty patients in the inter- local, 12 combined, 3 distant. Two PT progressed, one patient in CR mediate prognosis group were treated by CARE followed by local irradiation ii28 NEURO-ONCOLOGY † JUNE 2010 Abstracts

committed suicide. Twenty one PT had an AFP . 1000 ng/ml (serum and/ elevated CSF with normal serum bHCG in 22, elevated CSF and serum or CSF), 12 relapsed (PFS 0.35 + 0.12; median follow-up 11 months). After levels in 3 and elevated serum and normal CSF in 0 patients. In the 25 pts RT residual tumor was found in 68 of 144 PT. Twenty five relapsed. with measurable bHCG levels in either CSF or serum, CSF levels were CONCLUSION: SIOP CNS GCT 96 has proven that 2/3 of the PTs with higher than serum levels in 23 (92%) and the mean CSF bHCG was 6.8 malignant NGGCT treated accordingly are cured. Based on the collected (1.6-18.7). CONCLUSIONS: Serum bHCG is not a reliable screen for experience, the concurrent SIOP CNS GCT II trial is on its way and will CNS germinoma since only 5%(3/60) of pts had abnormal values. be opened in more than 12 participating countries. Lumbar CSF bHCG was elevated in only 42%(25/60). Until a more sensitive and specific serum and/or CSF marker for pure germinoma is discovered, histologic confirmation is recommended.

GCT.06. A PHASE II TRIAL OF NEOADJUVANT CHEMOTHERAPY 1/- SECOND-LOOK SURGERY PRIOR TO RADIOTHERAPY FOR NON-GERMINOMATOUS GERM CELL GCT.08. EVALUATION OF PATIENTS WITH PITUITARY STALK TUMORS (NGGCT): CHILDREN’S ONCOLOGY GROUP ENLARGEMENT ACNS0122 N. J. Robison1,2, S. N. Chi1,2, M. W. Kieran1,2, P. Manley1,2, L. E. Cohen3, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 S. Goldman1, E. Bouffet2, p. G. Fisher3, M. D. Wharam4, D. Shaw5, L. Goumnerova1,4, E. Smith1,4, M. Scott1,4, and N. J. Ullrich1,5; 1Pediatric P. J. Chuba6, L. A. Heier7, P. Robertson8, J. C. Allen9, C. S. Kretschmar10, Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; M. K. Rosenblum11, T. Zhou12, and I. F. Pollack13; 1Children’s Memorial 2Dept. of Hematology/Oncology, Children’s Hospital Boston, Boston, MA, Hospital,Northwestern University, Chicago, IL, United States; 2Hospital for United States; 3Div. of Endocrinology, Children’s Hospital Boston, Boston, Sick Children, Toronto, ON, Canada; 3Stanford University Medical and MA, United States; 4Dept. of Neurosurgery, Children’s Hospital Boston, Lucile Packard Children’s Hospital, Palo Alto, CA, United States; 4Sidney Boston, MA, United States; 5Dept. of Neurology, Children’s Hospital Kimmel Comprehensive Cancer at Johns Hopkins, Baltimore, MD, United Boston, Boston, MA, United States States; 5Seattle Children’s Hospital, Seattle, WA, United States; 6St. John Webber Cancer Center/ St. John Health Systems, Warren, MI, United States; PURPOSE: The significance of pituitary stalk enlargement .2-3mm is 7Weill Medical College of Cornell University, New York, NY, United States; often unclear, and appropriate evaluation remains controversial. Our goal 8University of Michigan Medical School, Ann Arbor, MI, United States; was to define the etiology, necessary workup, and risk factors for neoplastic 9New York University Medical Center, New York, NY, United States; involvement of the infundibulum in children. Methods: We conducted an 10Boston Floating Hospital, Boston, MA, United States; 11Memorial IRB-approved retrospective review to identify patients with enlargement Sloan-Kettering Cancer Center, New York, NY, United States; 12Children’s of the pituitary stalk from 1995–2008. Presenting features, imaging, Oncology Group, Arcadia, CA, United States; 13Children’s Hospital of further workup, pathology and outcome were evaluated. RESULTS: 83 Pittsburgh, Pittsburgh, PA, United States patients with suprasellar lesions were identified; of these, 42 had lesions isolated to the infundibulum. 23/42 were female. Median age at detection INTRODUCTION: ACNS 0122 aimed to improve event-free survival by imaging was 12.0 years (range 2–20); mean length of follow-up, 3.8 (EFS) and OS (overall survival) for intracranial NGGCT, by increasing years. Most frequent reasons for imaging included diabetes insipidus response rate (complete [CR] and partial [PR]) with neoadjuvant carbopla- (DI, 40%), hyperprolactinemia (17%), precocious puberty (12%), and tin/VP-16, alternating with ifosfamide/VP-16, followed by craniospinal growth failure (12%). Tumor markers were normal in cerebrospinal irradiation (CSI) plus involved field boost. In patients not obtaining CR/PR fluid in 22/23 and serum in 23/23 patients. No consistent criteria gov- by neuro-imaging and tumor marker response after neoadjuvant chemother- erned decision to biopsy. 4/11 infundibular biopsies were diagnostic, 5 apy, second-look surgery was recommended. Patients with persistent radio- showed non-specific inflammation, and 2 showed normal tissue. 6/16 graphic disease or positive markers underwent myeloablative chemotherapy patients with DI were ultimately diagnosed with either germ cell tumor (thiotepa/VP-16) prior to CSI. OBJECTIVES: 1) To determine response (4 patients) or Langerhans cell histiocytosis (2; both with characteristic rate following three cycles of neoadjuvant chemotherapy; 2) to determine bone lesions). One asymptomatic patient with incidental imaging had cra- EFS and OS; and 3) To determine whether additional CR can be achieved niopharyngioma. No definitive diagnosis was obtained in the remaining 35 with high-dose thiotepa/VP-16 for patients not achieving CR/PR. patients, who had no clinical or radiographic evidence of progression. RESULTS: 104 patients enrolled from 1/04–7/08. Median age was 12 CONCLUSIONS: We review a large cohort of pediatric patients with (range 3–23) years. 76% were male,. No toxic deaths occurred. Among 84 infundibular thickening. Most (81%) were idiopathic. Bone imaging and evaluable patients, response rate was reported as 70% (33 CR, 26 PR). assessment of tumor markers had screening utility only in the setting of With central imaging review (58/84 patients reviewed to date) response rate DI. Observation alone may be appropriate in most other cases. was 90%. Nineteen patients underwent second-look surgery, 2 secondary to progression; reviewed pathology in 11 was malignant teratoma or mature teratoma (8), fibrosis (1), and NGGCT (2). Median follow-up for patients without events is 1.9 years (range 0.06–4.9). Fifteen patients have experi- 12 QUALITY OF LIFE enced recurrence or progression to date with 6 subsequent deaths. Two-year EFS and OS are 84.4% + /- 4% and 93% +/- 3%, respectively. Further stratification of responses will be presented. CONCLUSION: Neoadjuvant che- QOL.01. FATIGUE SYMPTOMS IN SURVIVORS OF CHILDHOOD motherapy for NGGCT demonstrates a very high response rate and when CANCER: A COMPARISON OF PATIENT AND PARENT REPORT administered before CSI may increase survival. M. C. McCarthy, C. R. DeLuca, D. Papachristos, V. A. Anderson, and D. M. Ashley; Royal Children’s Hosptial, Melbourne, Australia

BACKGROUND: Persisting cancer-related fatigue is an understudied area in childhood cancer survivorship research. This study examined fatigue GCT.07. CAN SERUM AND/OR LUMBAR CSF BHCG BE USED symptoms in childhood cancer survivors, correlations between patient and TO DIAGNOSE A CNS GERMINOMA? parent report and relationships with cancer type and treatment intensity. 1 1,2 1 3 4 J. C. Allen , B. Donahue , J. Mathew , C. Kretschmar , and I. Pollack ; METHOD: One hundred and twenty-seven parents and 107 children/ado- 1 NYU Langone Medical Center, New York, NY, United States; lescents completed a fatigue scale. Children were 2–6 years post-treatment 2 3 Maimonides Medical Center, Brooklyn, NY, United States; Tufts New for cancer, aged less than 19 years and treated at the Royal Children’s 4 England Medical Center, Boston, MA, United States; University of Hospital (Melbourne, Australia). Parent, child and adolescent fatigue Pittsburgh School of Medicine, Pittsburgh, PA, United States forms were completed, assessing the frequency of fatigue symptoms over the previous week and the causes of this fatigue. RESULTS: Moderate corre- INTRODUCTION: Histologic conﬁrmation of a CNS germ cell lations were found between parent and child/adolescent report. Children tumor(GCT) is challenging due to tumor location and small tissue samples with brain tumours reported greater fatigue symptoms when compared to delivered by either an endoscopic or open biopsy. Currently elevated those with blood-related cancers. Treatment intensity did not predict differ- serum and/or lumbar CSF AFP and bHCG values are accepted as surrogate ences for either adolescent or parent reports, however there was a trend for diagnostic markers for non-germinoma GCT in lieu of biopsy. The use of children who had received higher intensity treatment to report more fatigue bHCG alone for diagnosis of a pure germinoma is not well studied. symptoms. Parents and adolescents mainly reported symptoms relating to METHODS: Paired serum and lumbar CSF bHCG assays were measured lack of energy, with parents also endorsing items suggesting altered sleep at diagnosis for 23 patients(pts) from a COG phase III germinoma study to be an issue. In contrast, symptoms were not reported to be interrupting (ACNS0232) and 37 pts from a NYU/Beth Israel phase II germinoma con- daily activities. CONCLUSIONS: Fatigue issues persist in a proportion of sortium. Eligibility for both studies included histological documentation of survivors of childhood cancer 2–6 years following treatment. Younger chil- a pure germinoma, normal CSF and serum AFP and CSF and serum dren with brain tumours may be at greatest risk for ongoing fatigue symp- ≤ bHCG 50 mIU/ml. RESULTS: The combined bHCG data on 60 pts toms. Despite moderate correlations between patient and parent report, from theses 2 cohorts revealed: normal CSF and serum values in 36 pts,

NEURO-ONCOLOGY † JUNE 2010 ii29 Abstracts

the findings suggest that both should be asked about the persistence of fatigue the central nervous system (CNS), have increased risks of educational and symptoms as part of their routine late effects follow up. social difficulties. It is therefore hypothesized they are more likely to encounter legal problems, which may negatively affect their quality of life (QoL). METHODS: A survey was developed to collect information on patients’ legal needs. QoL was measured with the Functional Assessment of Cancer Therapy (FACT). Fisher’s exact and t-tests assessed differences in categorical QOL.02. SELF-REPORT QUALITY OF LIFE (QOL) IN CHILDREN and continuous variables, respectively. Propensity score analysis with linear TREATED FOR POSTERIOR FOSSA TUMOURS 16, 27 AND 39 regression modeling assessed the relationship between QoL and legal difficul- MONTHS POST DIAGNOSIS COMPARED WITH A ‘NON ties, accounting for potential confounding variables. RESULTS: TUMOUR’ GROUP Seventy-seven adult survivors were approached, 98.7% of whom completed K. S. Bull and C. R. Kennedy; Clinical Neurosciences, University of the survey. The mean age of respondents was 7.5 at diagnosis and 31.8 at Southampton, United Kingdom survey completion. CNS tumours were the most common malignancy (34.2%), followed by leukemia (31.6%), sarcoma (15.8%), and lymphoma OBJECTIVE: To describe QoL in children treated for medulloblastoma (11.8%). Legal problems were common overall (38.1%), though more (SRM, n ¼ 37), cerebellar astrocytoma (LGCA, n ¼ 35) and a non-tumour prevalent in those with CNS versus non-CNS tumours (59.1% vs. 26.8%; group (CG, n ¼ 38) at a mean of 16 (T1), 27 (T2) and 39 (T3) months post p ¼ 0.016). In addition, individuals with legal difficulties had lower QoL Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 diagnosis. To identify factors that may predict QoL. METHODS: 110 children scores than those who did not (76.7 vs. 93.2; p ¼ 0.003). Furthermore, aged 8–14 years. Child-, parent- and teacher- report of the child’s QoL, health this relationship remained significant after adjusting for diagnosis, che- status (HS), IQ, behaviour, attributional style, and executive function; parents’ motherapy use, presence of relapse, age (current and at diagnosis), and reports of their own general health and attributional style. RESULTS: A mixed gender (p ¼ 0.029). 93.3% of individuals with legal problems found it diffi- ANOVA showed significant main effects of time and group in QoL scores p , cult to find legal help. CONCLUSIONS: Legal difficulties are common in .001 (T1 means (SD) - SRM 56.2 (18.1), LGCA 69.9 (19.8), CG 82.4 (11.7); survivors of pediatric malignancies, especially those with CNS disease. T2 - SRM 60.6 (14.2), LGCA 74.3 (19.1), CG 85.0 (11.4); T3 - SRM 66.4 Furthermore, individuals with legal difficulties have worse quality of life. (17.5), LGCA 77.4 (16.7), CG 86.8 (10.9)). Multiple regression showed that Further research is needed to improve legal resource programs and access. at T1 HS, behaviour and SRM group accounted for 63%, 6% and 6% of the variance in QoL scores respectively (p , .001). At T2 HS, behaviour, SRM group, LGCA group and IQ accounted for 48%, 14%, 7%, 4% and 1% of the variance (p , .001 to p ¼ .036). At T3 HS, behaviour, IQ and 13 OUTCOME STUDIES SRM group accounted for 57%, 13%, 6% and 2% of the variance (p , .001 to p ¼ .007). CONCLUSIONS: Children treated for SRM had a poorer outcome. HS was the main predictor of QoL over time followed by behaviour. OUT.01. LONG-TERM SURVIVAL & HEALTH OUTCOMES Behaviour and IQ increased in importance as predictors of QoL. These data AFTER DIAGNOSIS OF LOW GRADE GLIOMA highlight the importance of monitoring children’s progress following treatment G. T. Armstrong, H. Conklin, S. Huang, A. Gajjar, T. E. Merchant, for brain tumors to implement timely interventions when necessary. M. Hudson, R. A. Sanford, D. Srivastava, L. L. Robison, and E. B. Morris; St. Jude Children’s Research Hospital, Memphis, TN, United States

Objective Report long-term survival and cumulative incidence of adverse health/cognitive outcomes in children with low grade glioma (LGG). QOL.03. MOBILITY RELATED SOCIAL ISOLATION AND Methods Analysis of overall survival (OS) and progression free survival QUALITY OF LIFE AMONG ADULT SURVIVORS OF (PFS) included 361 patients diagnosed with LGG between 1985–2007 at CHILDHOOD BRAIN TUMORS St. Jude. Cumulative incidence of adverse health outcomes at 15 years 1 1 1 1 2 1 K. K. Ness , R. Allgood ,Z.Li , C. R. Howell , and J. P. Neglia ; St. Jude from diagnosis was estimated among 240 5-yr survivors (mean 10 years 2 Children’s Research Hospital, Memphis, TN, United States; University of from diagnosis, range 5–22). Cox proportional hazards models assessing Minnesota, Minneapolis, MN, United States risks associated with tumor location and therapeutic exposure were constructed. Results Among the 361 cases, OS at 15 years from diagnosis was BACKGROUND: Adult survivors of childhood brain tumors (BT) may be 86% (95% confidence interval [CI] 82–90%) and PFS 55% (95% CI 51– at increased risk for mobility related social isolation when compared to 58%). Cumulative incidence of adverse outcomes at 15 years from diagnosis peers. Social isolation may decrease Quality of Life (QOL) and Life was: blindness (acuity ≥20/200) 17% (95% CI 10–25%), associated with Satisfaction. METHODS: Scores on the Environmental Access Mobility diencephalic tumor location (HR 21.2, 95% CI 2.6–173.8); hearing loss Questionnaire (EAMQ), Medical Outcomes Short-Form 36 (SF-36) and 22% (95% CI 13–30%) with no association with platinum chemotherapy Satisfaction With Life Scale (SWLS) were compared between 78 young (HR 1.6, 95% CI 0.8–3.2); obesity/overweight 53% (95% CI 43–64%), adult (median age 22 years, 54% male) BT survivors and age, sex and zip hyperinsulinism 24% (95% CI 13–35%). Deficiencies in growth hormone code matched controls. The associations between scores on the EAMQ (cumulative incidence 29%, 95% CI 22–36%), thyroid hormone 33% and the SF-36 and SWLS, and between diagnoses and treatment factors (95% CI 25–41%) and ACTH (26%, 95% CI 19–33%) were associated and scores on the EAMQ were evaluated among survivors in multiple vari- with diencephalic location and RT exposure. 182 5-year survivors (75%) able models. RESULTS: BT survivors were 2.9 (95% Confidence Interval were assessed for intellectual functioning (IQ). 34% scored below average (CI): 1.4–5.9) times more likely to report poor mobility related community (, 85), associated with extent of resection (p ¼ .05), treatment type (p ¼ access and 6.1 (95% CI: 1.7–22.1) times more likely to report poor physical .003), placement of VP shunt (p ¼ .02) and epilepsy (p ¼ .01). Conclusion QOL than controls. Low EAMQ scores were highly correlated with low Despite high OS, survivors of childhood LGG experience substantial long- scores on the SF-36 physical component summary, physical function, role term adverse effects. The cumulative incidence of adverse outcomes con- physical, bodily pain, general health, and social function subscales, and tinues to increase well-beyond the 5-year survival time point. with a low score on the SWLS (all p-values , 0.05). A tumor location in the posterior fossa was the only diagnosis/treatment factor associated with a lower score on the EAMQ (0.41 posterior fossa tumor vs. 0.65 other tumor location, p ¼ 0.04). DISCUSSION: Adult survivors of childhood BT report more mobility related social isolation than their peers. This partici- OUT.02. SECONDARY NEOPLASMS (SN) IN 54 CHILDHOOD pation restriction is associated with poor QOL and lower Life Satisfaction. BRAIN TUMOR SURVIVORS TREATED WITHIN THE Interventions to restore or accommodate mobility limitations may improve PROSPECTIVE GPOH-HIT TRIALS outcomes for these survivors. U. R. Kordes1, N. U. Gerber2,3, R. Streib4, I. Zwiener5, I. Jung6, A. O. von Bueren1, F. Deinlein7, M. Benesch8, T. Pietsch9, M. Warmuth-Metz10, R. D. Kortmann11, and S. Rutkowski1; 1Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Oncology, QOL.04. COMPARISON OF LEGAL NEEDS IN ADULT University Children’s Hospital, Kinderspital Zu¨ rich, Zu¨ rich, Switzerland; SURVIVORS OF PEDIATRIC CENTRAL NERVOUS SYSTEM 3Department of Pediatrics, Children’s Hospital, University of Wu¨ rzburg, (CNS) AND NON-CNS MALIGNANCIES Wurzburg, Germany; 4Department of Pediatric Oncology, Childrens’s 1,2,3 1 4 1,3 1 ¨ R. A. Olson , G. Hung , M. Bobinski , and K. Goddard ; University of Hospital, University of Wurzburg, Wurzburg, Germany; 5Institut fur 2 ¨ ¨ ¨ British Columbia, Vancouver, BC, Canada; Harvard School of Public Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Mainz, 3 Health, Boston, MA, United States; BC Cancer Agency Vancouver Centre, Germany; 6German Childhood Cancer Registry (GCCR), Mainz, Germany; 4 Vancouver, BC, Canada; University of British Columbia, Faculty of Law, 7Department of Pediatric Oncology, Children’s Hospital, University of Vancouver, BC, Canada Wu¨ rzburg, Wu¨ rzburg, Germany; 8Divison of Pediatric Hematology and Oncology, Medical University of Graz, Graz, Austria; 9Institute of BACKGROUND: Survivors of childhood malignancies, especially those of Neuropathology, University of Bonn, Bonn, Germany; 10Department of ii30 NEURO-ONCOLOGY † JUNE 2010 Abstracts

Neuroradiology, Wu¨ rzburg, Germany; 11Department of Radiation II breasts by palpation. Patients excluded; deceased prior to onset of puberty Oncology, University of Leipzig, Leipzig, Germany (n ¼ 4), diagnosed after pubertal onset (n ¼ 12) or incomplete records (n ¼ 10). BMI determined at onset of treatment, nadir weight during treatment, OBJECTIVE: To report secondary neoplasms (SN) in 54 childhood brain and at pubertal onset. RESULTS: Seventeen/22 had entered puberty spon- tumor survivors treated within the prospective GPOH-HIT trials. taneously. All had received radiation, craniospinal or focal. Higher pituitary METHODS: Between 03/87–02/97 a total of 748 patients were registered dose was associated with later onset of puberty and lower dose with earlier to the trials HIT-SKK87, HIT-SKK92, HIT88 and HIT91. Until 01/08, SN onset of puberty (p ¼ 0.02). Seven/17 (41%) had pubertal onset at a bone were reported in 33 study patients. SN were also reported in 14 non-study age younger than expected (,8years 10 months); in this subset, there was patients as well as 7 patients from the ongoing HIT2000 trial. RESULTS: a significant relationship between nadir BMI and earlier pubertal onset 54 patients (29 male, 25 female; 11 syndromal) developed SN (high-grade (p ¼ 0.01). CONCLUSIONS: Patients with significant weight loss during glioma (11), meningioma (6), hematopoietic malignancies (13), sarcoma treatment have early pubertal onset with younger than expected bone age. (10), teratoma (3), skin tumors (7), thyroid cancer (4)). Initial diagnoses This may be due to growth delay during treatment. Increased BMI post- were medulloblastoma (32), ependymoma (10), CNS PNET (5), high-grade treatment may additionally impact early onset of puberty, along with radi- glioma (3), ATRT (1), atypical papilloma (1) and carcinoma (1) of choroid ation, and should be explored further. plexus, anaplastic meningioma (1). Median ages at primary and secondary diagnosis were 5.9 and 13.4 years, respectively. 48/54 patients were in com- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 plete remission at the end of primary therapy, 53/54 received chemotherapy, 49/54 received radiotherapy as part of their primary treatment (43 craniospinal, 6 focal). In 32 patients SN localization was within the radiation field. OUT.05. HEARING IMPAIRMENT IN CHILDREN TREATED FOR The median time between diagnoses was 6.6 years (8.9 for secondary CNS MALIGNANCIES brain tumors, 6.7 for other solid tumors, 4.9 for hematological malignan- A. A. Azizi1, V. Brink1, M. Heinrich1, C. Arnoldner2, K. Dieckmann3, and cies). The cumulative incidences of 33 SN for all 748 study patients at five, I. Slavc1; 1Department of Pediatrics and Adolescent Medicine, Medical ten and 15 years were 1.4, 7.5 and 14.2 %, respectively. The 5-year University of Vienna, Vienna, Austria; 2Department of Dpmt. of Ear, Nose and overall survival rate for all 54 patients after diagnosis of SNs was 35%. Throat Diseases, Medical University of Vienna, Vienna, Austria; 3Department CONCLUSION: Long-term follow-up demonstrates a substantial risk for of Radiation Oncology, Medical University of Vienna, Vienna, Austria malignant secondary neoplasm in survivors of malignant childhood brain tumors. BACKGROUND: Tumours of the CNS represent the most common solid malignancies in childhood. Treatment includes maximum safe resection and frequently chemo- (CTX) and radiotherapy (RTX). The ototoxic drugs cisplatin and carboplatin are widely used and the inner ear may be exposed to scattered radiation during RTX. The present study evaluates the effects OUT.03. SECONDARY TUMORS AFTER TREATMENT OF of treatment on the hearing of children with CNS malignancies. BRAIN TUMORS IN CHILDHOOD METHODS: Retrospective analysis of 108 patients (median age 8.8 years, L. Zadravec Zaletel and B. Jereb; Institute of Oncology, Ljubljana, Slovenia 1–277 months). Evaluation according to Munster classification and statistical analysis. RESULTS: 87 evaluable patients, median follow-up 42.9 BACKGROUND: In patients (pts) treated for childhood cancer in Slovenia months (2–195). 74/87 received RTX, 77/87 CTX with platinum agents. the cumulative risk for secondary tumors (ST) was 12.6% 25 years after So far, 42/87 patients (48.3%) suffered a hearing impairment. Nearly diagnosis of first cancer and 13,4% after diagnosis of primary brain 60% showed impairment 5 years after starting therapy. Factors correlated tumors (BT). AIM: We studied the frequency and survival of secondary with a higher risk of hearing impairment are: posterior fossa localisation, tumors in pts treated for BT in Slovenia between 1960 to 2006. combined RTX and CTX, young age at start of CTX (higher-grade PATIENTS AND METHODS: 416 pts (185 alive, 231 dead) treated for hearing impairment), RTX before or parallel to CTX. In case of posterior BT, aged 16 years or less (average 7.5) were included until January 31, fossa radiation the grade of hearing loss was dose dependent and the 2010. Follow-up time was 3–42 years (average 19). RESULTS: 18 patients overall risk increased significantly above a dose of 48 Gy. More than 75% developed ST, 2 to 36 (average 22.6) years after diagnosis of BT. One of patients receiving both cisplatin and carboplatin suffered a hearing patient with neurofibromatosis type 2 had several intra- and extracranial impairment. Cisplatin showed stronger ototoxicity than carboplatin, con- meningiomas and schwanomas. Ten out of the 17 pts developed secondary cerning frequency and grade of hearing loss. ED50 of cisplatin was brain tumors (8 meningiomas), 4 papillary thyroid carcinoma, 3 basalioma 370 mg/m2, that of carboplatin 4000 mg/m2. CONCLUSION: Multiple (inside the RT field), and one hypopharingeal cancer, laryngeal cancer and risk factors for hearing impairment in children treated for CNS malignancies AML, respectively.Fourteen pts had one ST, two had 3 different ST, one were identified. This may help to adapt therapy protocols in order to reduce had 2 different STs. All 17 pts received radiotherapy of the brain, including the risk of hearing impairments in these children. central nervous axis in 8 pts. Six pts died of ST (all malignant), 12 are alive, 5 of these with multiple meningeomas with evidence of disease. CONCLUSIONS: After treatment of BT in childhood, BT are the most frequent secondary tumors, and the majority (9 out of 11) are meningeomas. Survival of the whole group is favorable, depending on the histology of ST. OUT.06. DE NOVO PAEDIATRIC BRAIN TUMOURS PRESENTING WITH HAEMORRHAGE: DOES IT WORSEN SURVIVAL? G. A. Solanki, M. K. Hossain-Ibrahim, and M. English; Birmingham Children’s Hospital, Birmingham, United Kingdom OUT.04. ABNORMAL TIMING OF PUBERTAL ONSET IN FEMALE SURVIVORS OF MEDULLOBLASTOMA OBJECTIVE: The frequency of intracranial haemorrhage (ICH) in chil- P. E. Manley1,2, I. Jones3, C. Chordas1, M. Zimmerman1, M. W. Kieran1,2, dren with de novo brain tumours is unknown. This study reports on fre- S. N. Chi1,2, M. Lee1,2, N. Robison1,2, N. Stratton1, L. Goumnerova1,4, quency of haemorrhage as presenting feature, survival period and N. J. Ullrich1,5, K. J. Marcus6,7, and L. E. Cohen3; 1Pediatric outcomes in these children. PATIENTS AND METHODS: Prospectively col- Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; lected data (April 2003 - May 2008) for the Regional Tumour Registry data- 2Hematology/Oncology, Children’s Hospital Boston, Boston, MA, United base was reviewed to analyse tissue diagnosis, age at diagnosis, gender, States; 3Endocrinology, Children’s Hospital Boston, Boston, MA, United symptomatology, tumour morphology, radiological features, recurrence States; 4Neurosurgery, Children’s Hospital Boston, Boston, MA, United and survival information. 212 (135 boys and 77 girls, M:F ratio:1.75:1) con- States; 5Neurology, Children’s Hospital Boston, Boston, MA, United States; secutive children presenting with de novo tumours were studied. Statistically 6Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, United significant conclusions regarding frequency of haemorrhage in different States; 7Radiation Oncology, Children’s Hospital Boston, Boston, MA, intracranial tumour groups were analysed using measures of central ten- United States dency, variance, correlation and survival curves. RESULTS: Just under 10% of paediatric de novo brain tumours presented with ICH (20/212). PURPOSE: Medulloblastoma treatment includes cranial radiation at doses Of the 20 that presented with ICH, 10 (11%) were supratentorial, 3 (4%) that cause both precocious puberty and hypogonadotropic hypogonadism. were infratentorial, 4 (18%) pineal. 3/6 (50%) of supratentorial PNETs, Patients lose significant amounts of weight followed by rebound once treat- 4/23 (17%) of pineal region, 40% (4/10) of GBMs and 8.4% (8/95) of ment is completed. In the general population, thinness in early life followed LGG presented with ICH. Medulloblastomas, ependymomas and DNETs by rapid increase in body weight is associated with early pubertal onset. We did not present with ICH. Median survival for children presenting with examined whether females treated for medulloblastoma have early puberty, ICH was 18 months, but 30 months without ICH (p ¼ 0.001). Mortality with relation to radiation dose, body mass index (BMI) at nadir weight and rates were highest in PNETs. Median survival times for PNET and GBM BMI at onset of puberty. PATIENTS AND METHODS: After IRB approval, were significantly decreased. Age, sex and tumour size did not affect ICH chart review on all females diagnosed with medulloblastoma or followed at risk. Only half the children presenting with ICH survived while survival DFCI from 1998–2007 (n ¼ 48). Pubertal onset was defined as Tanner stage without ICH was 78%. CONCLUSION: Brain tumours presenting with

NEURO-ONCOLOGY † JUNE 2010 ii31 Abstracts

ICH are associated with a worsened median survival. Children presenting PNET or glial tumour and 76 had a WHO grade. Overall accuracy rates with ICH in PNETs had a higher mortality. were 84% for classifier 1 and 85% for classifier 2, with only slightly higher rates achieved for lead centre test cases (90% and 87% respectively). CONCLUSIONS: Prospective evaluation of multivariate MRS classifiers shows high non-invasive diagnostic accuracy for childhood brain tumours that is consistent across scanner platforms and centres. OUT.07. TREATMENT RESULTS IN 28 PATIENTS WITH PINEOBLASTOMA O. G. Geludkova1, E. V. Kumirova1, A. G. Melikian2, Y. V. Kushel2, O. I. Scherbenko3, V. I. Oserova2, R. Z. Shammasov4, M. V. Mushinskaya5,1, L. P. Privalova6, I. D. Borodina1, S. V. Gorbatyh7, IMAG.02. METABOLIC, PERFUSION AND DIFFUSION MR E. V. Pavlova7, V. E. Popov7, and M. I. Livshits7; 1Federal Research Clinical CORRELATES OF PEDIATRIC ASTROCYTOMAS: PREDICTION Center of Pediatric Hematology, Oncology and Immunology, Moscow, OF CLINICAL COURSE Russian Federation; 2Research Institute of Neuroseurgery N.N.Burdenk, A. Panigrahy1, G. Dhall2, J. Finlay3, M. D. Nelson3, and S. Bluml3; Moscow, Russian Federation; 3Russian Research Centre of Radiology, 1Childrens Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States; Moscow, Russian Federation; 4Children’s Clinical Hospital, Kazan, Russian 2Childrens Hospital Los Angeles, Los Angeles, CA, United States; 3Childrens Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Federation; 5Children’s Clinical Hospital, Perm, Russian Federation; Hospital of Los Angeles, Los Angeles, CA, United States 6Children’s Clinical Hospital, Nizhni-Novgorod, Russian Federation; 7Children’s Clinical Hospital ~1, Moscow, Russian Federation PURPOSE: To determine whether low-grade (WHO II) astrocytoma with malignant progression have metabolic, diffusion or perfusion MR We evaluated the treatment results of 28 patients (pts) with pineoblas- features that distinguishes them from grade II astrocytoma with stable toma, treated from 1997 to 2009, with different protocols of chemother- disease. METHODS: Medical records and MRS studies of pediatric patients apy (CHT) and radiotherapy (RT). There were 12 girls and 16 boys. 13 with astrocytomas were retrospectively reviewed. Five patients were ident- pts were under 6 years of age. Median age was 8 years (range, 10 ified with low-grade astrocytomas (WHO II) and no clinical or radiological months-19 years). 13 pts had M0 stage, 1 Mx, 2 M1, 5 M2, 7 M3. progression over at least two years of follow-up (indolent-LGA). Six patients Three pts received total resection, 10 subtotal resection, 7 partial resec- were identified with low-grade astrocytomas with progression within two tion, and 8 stereotactic biopsy. 7 pts did not receive RT (6 because of years after diagnosis (aggressive-LGA). Twelve patients with high-grade the age less than 3 years and 1 pt due to wrong diagnosis). 17 pts received (WHO III) astrocytomas and poor outcome (HGA) were also included in weekly vincristine during RT. 25 pts received CHT: 9 (less than 3 years) this analysis. All indolent-LGA subjects were alive whereas all according to HIT-SKK, 16 (older than 3 years) according to the aggressive-LGA and HGA subjects have succumbed to their disease at the “Philadelphia” protocol. Median time of follow up was 20 months. For time of the completion of this study. MR spectra were acquired with single- all pts the OS and PFS were 0,40 and 0,32, respectively. 3 pts were lost voxel PRESS (TE ¼ 35ms) on a 1.5T MR scanner. Fully automated to follow up. 13 pts are still alive, 12 pts died. 15 pts relapsed. Initial dis- LC-Model software was used to determine absolute concentrations semination of disease had an impact on outcome, but this was not signifi- (mmol/kg) of metabolites. Perfusion (CBV) and diffusion (ADC)MR data cant (PFS M0: 45%, M: 26%; OS 52/41%; p ¼ 0,35). Also neither sex, was also obtained. RESULTS: Citrate (Cit) was significantly higher in nor complete resection, CHT during RT were found to have an impact aggressive-LGA than in indolent-LGA and NAA was lower in on outcome. Age older than 3 years was a significant positive predictive aggressive-LGA (p , 0.001). There was no significant difference in choline factor for OS (62%) compared to younger age (,3 years) (0%; p ¼ levels between these two groups. Mean CBV was not statistically different 0,002) and for PFS (45% and 0%; p ¼ 0.022), respectively. The OS of between the three groups. The mean minimum ADC was significantly children treated with RT was 59%, without RT 0% (p ¼ 0,0598). higher in the stable grade II vs malignant grade II (p , 0.01). Advantage for irradiated children was also observed in PFS rates: 49%, CONCLUSION: Elevated citrate and reduced NAA differentiate and in contrast for non irradiated 0% (p ¼ 0,002). aggressive-LGA from indolent-LGA. MR perfusion does not predict clinical couse of pediatric gliomas in individual patients. Minimum ADC can distinguish between stable and malignant grade II astrocytomas. 14 NEUROIMAGING

IMAG.01. MULTICENTRE PROSPECTIVE CLASSIFICATION OF IMAG.03. POSTOPERATIVE POSTERIOR FOSSA SYNDROME: CHILDHOOD BRAIN TUMOURS BASED ON 1HMRS MAGNETIC RESONANCE IMAGING INVESTIGATIONS TO METABOLITE PROFILES UNRAVEL THE UNDERLYING PATHOPHYSIOLOGY N. P. Davies1,2, T. N. Arvanitis3,4, D. Auer5, A. French5, R. Grazier4, Z. Patay, N. Miller, U. Lo¨ bel, B. Morris, A. Sablauer, M. Kocak, Y. Li, and R. Grundy5,6,F.A.Howe7, D. Hargrave8, T. Jaspan6, S. Lateef4, A. Gajjar; St. Jude Children’s Research Hospital, Memphis, TN, United M. O. Leach8,9, L. MacPherson4, K. Natarajan2,4, G. Payne8,9, States E. Orphanidou-Vlachou1,4, D. Saunders10,Y.Sun1,4, M. Wilson1,4, and A. C. Peet1,4; 1Cancer Sciences, University of Birmingham, Birmingham, PURPOSE: Posterior fossa syndrome (PFS) is an early postoperative com- United Kingdom; 2Medical Physics, UHB NHS Foundation Trust, plication recognized in up to 25% of pediatric patients undergoing posterior Birmingham, United Kingdom; 3Department of Electrical, Electronic and fossa surgery. We sought to obtain evidence to support that PFS follows Computer Engineering, University of Birmingham, Birmingham, United bilateral surgical damage to the proximal efferent cerebellar pathways Kingdom; 4Birmingham Children’s Hospital NHS Foundation Trust, (pECPs), disrupting dentato-thalamo-cortical and dentato-olivary projec- Birmingham, United Kingdom; 5University of Nottingham, Nottingham, tions. Therefore, we set out to: (1) assess the post-surgical structural United Kingdom; 6University Hospital Nottingham, Nottingham, United damage patterns of the pECPs and their relationship with the development Kingdom; 7St. George’s University of London, London, United Kingdom; of PFS, (2) investigate remote effects of pECP disruption on cerebral 8Royal Marsden Hospital, London, United Kingdom; 9The Institute of cortex and inferior olivary nuclei (ION). MATERIALS AND METHODS: Cancer Research, London, United Kingdom; 10Great Ormond Street To test our hypotheses we used anatomical and dynamic susceptibility- Hospital, London, United Kingdom weighted contrast-enhanced (DSC) perfusion MRI in 13 patients with PFS and age/gender matched controls without PFS (age-range:3–11y), all PURPOSE: The aim was to prospectively evaluate MRS as a diagnostic treated on IRB-approved therapeutic trials after surgery for posterior fossa tool for paediatric brain tumours on a multi-centre basis. METHODS: An tumors (12 medulloblastomas, 1 ATRT in each subgroup). RESULTS: MRS training dataset was acquired using PRESS (TR/TE 1500/30ms) on Logistic regression analysis showed positive correlation between bilateral Siemens Symphony and GE 1.5 T scanners at the lead centre between pECP damage and the development of PFS (odds ratio: 12, 95% CI:1.12, March 2003 and April 2008 (N ¼ 83) and used to build classifiers for 1) 129, p ¼ 0.04). All patients with bilateral ION degeneration had PFS clini- PNET vs glial tumours and 2) low vs high grade tumours based on histo- cally. Perfusion data showed significant decrease of cerebral blood volume pathological diagnosis. The classifiers were based on LCModelTM metabolite and flow within frontal lobes (p , 0.05) and a trend toward global cortical profiles employing principal components analysis (PCA) for dimension hypoperfusion. CONCLUSION: Bilateral surgical damage to the pECP is the reduction and linear discriminant analysis (LDA) for classification. The likely cause of PFS. Resultant depression of cerebral cortical perfusion may test dataset consisted of 105 cases with MRS acquired at the lead centre represent cerebello-cerebral diaschisis. Since hypoperfusion was most promi- between May 2008 and December 2009 (N ¼ 49) and at 3 other centres: nent in frontal regions, cerebellar mutism (the central manifestation of PFS) Centre 2 (Philips 1.5 T and 3 T, N ¼ 35), Centre 3 (Siemens 1.5T, N ¼ 8) may correspond to speech apraxia. Bilateral ION degeneration may be a sen- and Centre 4 (Philips 1.5 T, N ¼ 13). Some external test cases were acquired sitive, and in appropriate clinical settings, specific, although delayed, surro- at 3 T and with TE between 23ms and 40ms. RESULTS: In the test dataset, gate imaging indicator of PFS. 87 cases passed quality control (SNR . 4, water linewidth , 10 Hz) and artifact screening and 73 of these had a histopathological diagnosis of ii32 NEURO-ONCOLOGY † JUNE 2010 Abstracts

IMAG.04. FRONTO-CEREBELLAR FIBER TRACTOGRAPHY IMAG.06. DIFFUSION TENSOR IMAGING (DTI) IN CHILDREN AFTER CEREBELLAR TUMOR REMOVAL - CORRELATION WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) WITH CLINICAL OUTCOME E. A. Steffen-Smith1, J. E. Sarlls2, C. Pierpaoli2, and K. E. Warren1; 1NCI, V. Soelva1, A. Abbushi1, S. Rueckriegel2, H. Bruhn3, P. Hernaiz2, Pediatric Oncology Branch, Bethesda, MD, United States; 2NICHD, E. J. Haberl4, W. Eisner5, and U. W. Thomale4; 1Neurosurgery, Charite´ Program on Pediatric Imaging and Tissue Sciences, Bethesda, MD, United Campus Virchow Klinikum, Berlin, Germany; 2Pediatric Oncology, Charite´ States Campus Virchow Klinikum, Berlin, Germany; 3Radiology, Charite´ Campus Virchow Klinikum, Berlin, Germany; 4Pediatric Neurosurgery, Charite´ BACKGROUND: DTI provides quantitative, non-invasive analysis of Campus Virchow Klinikum, Berlin, Germany; 5Neurosurgery, tissue microstructure. DTI metrics including apparent diffusion coefficient Universita¨tsklinik, Innsbruck, Austria (ADC) and fractional anisotropy (FA) are associated with tumor progression and treatment response in supratentorial tumors. This study uses DTI to OBJECTIVE: Cerebellar mutism (CMS) is a dreaded complication follow- evaluate white matter tracts in the pons of DIPG patients. METHODS: ing fossa posterior tumor removal in children and is characterized by inhi- Diffusion weighted images (DWI) were acquired using a single-shot bition of neuropsychological impulsion. Similar symptoms can also be spin-echo EPI sequence on a 1.5T scanner with 8-channel coil. DWIs under- observed after extensive bifrontal lobe disturbances. We hypothesize that dis- went motion and distortion correction before tensor calculation. FA and ruption of fronto-cerebellar association fibers (FCF) are involved in manifes- ADC (units 1023mm2/s) were calculated in cortico-spinal tracts (CST), Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 tation of this syndrome. METHODS: In 29 patients (mean age: 8.9 + 4.4 transverse pontine (TPF) and sensory fibers from the region of the pons years), who cerebellar tumor removal as well as in 10 healthy children with the largest diameter. We identified displacement and tumor infiltra- (12.9 + 3.8 years), diffusion weighted imaging (3Tesla MRI, Signa, GE) tion/edema using FA and direction encoded color (DEC) maps. Results was performed to generate tractography of FCF using a fiber tracking algor- were compared to tracts in normal-appearing pons. RESULTS: DTI was col- ithm software (BrainLab2.5). The volume of these fiber tracts were lected longitudinally in 20 DIPG patients (total 44 scans). Of identifiable measured. On reconstructed slices the anatomical course were determined tracts, displacement (Right CST ¼ 1, Left CST ¼ 2, TPF ¼ 2, Right and measured in a semiquantitatively. Postoperative clinical symptoms sensory ¼ 11, Left sensory ¼ 12) was observed infrequently without associ- were recorded. RESULTS: In volume measurements of FCF a significant ated tumor infiltration/edema. Tumor infiltration/edema was regularly difference between children with symptoms of CMS (19.3 + 11.7cm3) observed without displacement (Right CST ¼ 23, Left CST ¼ 15, TPF ¼ could be observed compared to neurological unaffected children (26.9 + 18, Right sensory ¼ 11, Left sensory ¼ 14). Mean FA was decreased 11.9cm3) and to control group (36.5 + 13.8cm3). In the analysis of anatom- (Right CST ¼ 0.30, Left CST ¼0.29, TPF ¼ 0.30, Right Sensory ¼ 0.44, ical structures significant differences of the fiber tracts were observed in the Left Sensory ¼ 0.46). Mean ADC was increased similarly in all regions superior cerebellar peduncle and the midline cerebellar structures in CMS (Right CST ¼ 0.98, Left CST ¼ 0.93, TPF ¼ 0.92, Right Sensory ¼ 0.98, with less distinct tracts compared to unaffected children and to controls. Left Sensory ¼ 0.97). CONCLUSIONS: DTI is feasible in the brainstem of CONCLUSION: DTI is a feasible method for visualizing fronto-cerebellar DIPG patients and may be used to characterize tumor involvement. fibers. Our data identifies postoperative disturbed FCF tracts at the location Results indicated the majority of displaced tracts also showed signs of of the superior cerebellar peduncle and midline cerebellar structures which tumor infiltration/edema. Additional patients are being evaluated to investi- may contribute to CMS. gate association of DTI results with patient status.

IMAG.05. DECREASE OF FRACTIONAL ANISOTROPY (FA) OF IMAG.08. NOVEL SEMI-AUTOMATIC VOLUMETRIC WATER DIFFUSION IN SUPRATENTORIAL TRACTS GOES MEASUREMENTS OF OPTIC PATHWAY GLIOMAS PARALLEL WITH IMPAIRED COGNITIVE AND MOTOR L. Ben-Sira1, B. Shofty2, R. Precel1, D. Ben-Bashat1, S. Freedman2, FUNCTION IN POSTERIOR FOSSA TUMOR SURVIVORS L. Weizman3, A. Kesler1, and S. Constantini2; 1Tel Aviv Medical Center, Tel S. M. Rueckriegel1,2, H. Bruhn1, and P. Hernaíz Driever1; Aviv, Israel; 2DANA Children’s Hospital, Tel Aviv Medical Center, Tel Aviv, 1Charite-Universita¨tsmedizin Berlin, 13353 Berlin, Germany; Israel; 3Hebrew university, Jerusalem, Israel 2Universita¨tsklinikum Wu¨ rzburg, Wu¨ rzburg, Germany Volumetric assessment of progressive optic pathway gliomas (OPGs) is OBJECTIVES: Tumor and therapy-associated neurotoxic effects cause important in identifying growing tumors prior to clinical deterioration. brain damage in pediatric patients with posterior fossa tumors. When using the accepted methods (Dodge, modified Dodge) precise esti- Therapy-related toxicity includes resection in pilocytic astrocytoma (PA) mation and follow-up of the lesions is imperative, hence the need to and additionally combined irradiation and chemotherapy in medulloblas- develop an appropriate quantification method. An ideal method for quanti- toma (MB). We examined whether MR Diffusion Tensor Imaging (DTI) fying these irregular lesions should ideally be fast, objective, specific, sensi- derived fractional anisotropy of white matter tracts correlates with func- tive, and accurate. Our study assesses a novel method of volumetric tional results of ataxia assessment, IQ, and kinematic parameters of hand- measurement of OPGs, specifically in NF-1 patients. We compared two semi- writing in these patient groups. PATIENTS AND METHODS: 23 MB and automatic volumetric measurement methods; the first using T1 + Gad in the 17 PA survivors (mean age, 14.3 years, SD: 4.8) were subjected to MR axial plane, the second included co-registered and normalized, combined imaging and DTI (b ¼ 1000, 25 directions) on a 3T-MR system equipped T1 + Gad & T2 (CRCM) in the axial plane. Co registration was performed with an 8-channel headcoill (GE Healthcare). Mean FA of the tracts were using the SPM package. Semi-automated measurements were all performed calculated and skeletonized FA maps, excluding the cerebellum, were gener- using the ANALYZE 9.0 software. Four NF patients with diagnosed OPG ated using the FMRIB Software Library. Ataxia was quantified using the were included in the study, each with 3–6 consecutive MRs, with a total International Cooperative Ataxia Rating Scale (ICARS). The Wechsler of 20 exams. Measurements were performed twice in each method by a radi- Intelligence Scale for Children was applied to determine IQ. Movements of ology resident, and once in the CRCM by a senior pediatric handwriting were analyzed using a digitizing graphic tablet that allowed ana- neuro-radiologist. One-way repeated measures ANOVA showed no signifi- lyzing speed and automation through CSWIN software. RESULTS: Mean FA cant difference between OPG volumes in recurrent measurements. Pearson correlated significantly (Spearman correlation) with movement parameters correlation demonstrated a significant correlation between measurements of handwriting (speed: r ¼ 0.48, p ¼ 0.012, automation: r ¼-0.4, p ¼ performed by the resident to the measurements performed by the senior, 0.038) and IQ (r ¼ 0.39, p ¼ 0.038). No correlation between mean FA revealing a stronger correlation between CRCM and the senior measure- and ICARS scores were found. All significant correlations indicated func- ments (r ¼ 0.991, p , 0.0001) then the correlation between senior measure- tional loss when mean FA WM was decreased. CONCLUSION: DTI is a ments and the single axial T1 + Gad method (r ¼ 0.954, p , 0.0001). We powerful tool to quantify brain damage in posterior fossa tumor patients. suggest two novel volume assessment methods that may provide efficient Mean FA of supratentorial tracts is a representative marker for cognitive and reliable follow-up for OPGs in NF patients. and motor deterioration of this patient group. Support of this study by the “Kind-Philipp” foundation is gratefully acknowledged.

NEURO-ONCOLOGY † JUNE 2010 ii33 Abstracts

IMAG.09. INCREASED TRYPTOPHAN METABOLISM IN fatal. We aimed at assessing these presumptions in a large cohort. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS: A PET METHODS: all coding exons of hSNF5/INI1 were sequenced and deletions STUDY were searched for by MLPA. Clinical data for all patients were collected. C. Juhasz1,2, O. Muzik1,2, H. T. Chugani1,2, P. K. Chakraborty1,S.Sood2, RESULTS: 77 constitutional DNAs from 122 INI1-deficient rhabdoid and D. C. Chugani1,2; 1PET Center, Children’s Hospital of Michigan, tumours were prospectively analysed: germline mutations were found in Detroit, MI, United States; 2Department of Pediatrics, Wayne State 29/77 (37%). Six additional familial cases were studied. Altogether, data University, Detroit, MI, United States from 35 mutated patients were collected. Median age at tumour onset was 6mo, compared to 18mo in the absence of predisposition. 28/58 patients BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are younger than 2years and 7/25 older than 2years harboured a germline low-grade, epileptogenic glioneuronal tumors. Recent tissue studies demon- mutation. The 2years survival was 7% in mutated and 20% in wild-type strated presence of microglia and activation of the immuno-modulatory patients (p ¼ 0.04); 1 mutated patient survived longer than 2years. 21/21 kynurenine pathway of tryptophan metabolism in these lesions. In this explored fathers and 20/21 mothers showed wild-type sequences. study we used PET scanning with alpha[C-11]methyl-L-tryptophan (AMT) Therefore, apart from one hereditary mutation (G . A exon 5 donor splice to evaluate tryptophan metabolism in DNETs in vivo. METHODS: site), germline mutations result from de novo events or germinal mosaicism; Twelve children (mean age: 10 years) with an epileptogenic temporal lobe consistently, 1/11 prenatal diagnosis was positive. No mutation was found DNET underwent MRI, interictal glucose and AMT PET scanning before in exon 1 nor exon 8. Six constitutional 22q11.2 deletions were found; Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 resective surgery. The standard uptake value (SUV) for AMT in tumor and one of these patients with bladder exstrophy developed a tumour at contralateral temporal cortex, and tumor/cortex SUV ratios were calculated. 22years. CONCLUSION: Our results allow correlating age at tumour diag- AMT kinetic analysis was also performed in 8 patients with blood input nosis and risk of predisposition, but germline mutations should be searched function available. RESULTS: All DNETs showed decreased glucose metab- for at any age. Large deletions may predispose to later disease. Long-term olism, and 9/12 tumors showed no contrast enhancement on MRI. Higher survival is rare. Prenatal diagnosis is justified by the low but actual risk of AMT SUV was seen in 10/12 tumors compared to cortex, with a mean familial recurrence. SUV tumor/cortex ratio of 1.39 (range: 1.15–1.67). Two hippocampal DNETs showed normal (,1.05) SUV ratios; however, one of these patients had an increased AMT SUV in adjacent epileptic cortex. Kinetic analysis of 8 DNETs with abnormally high AMT SUV ratios showed high unidirectional uptake rates in 3 and high transport rates in 7 cases. CONCLUSIONS: While CPS.02. HIGH-DENSITY SNP ARRAY IDENTIFIES A POTENTIAL low SUV has been reported for other amino acid PET tracers in most GLIOMA SUSCEPTIBILITY GENOTYPE INVOLVING CAMP DNETS, high AMT SUV was measured in 83% of DNETs in this study. REGULATION IN PATIENTS WITH NF1 This suggests tryptophan-specific mechanisms involving both increased S. Ganzhorn1, T. E. Druley1, N. M. Warrington1, A. C. Albers1, transport and metabolism in DNETs or adjacent epileptic cortex. These D. Spoljaric1, U. Tabori2, P. Parkin2, S. Lewis2, R. McKinstry1, S. Crosby1, increases may indicate activation of the kynurenine pathway, a potential J. Luo1, D. H. Gutmann1, and J. B. Rubin1; 1Washington University School therapeutic target in these tumors. of Medicine, St Louis, MO, United States; 2University of Toronto, Toronto, ON, Canada

Oncogenesis involves critical reciprocal relationships between tumor progenitors and the surrounding microenvironment (stroma). We previously IMAG.10. MR IMAGING OF INTRACEREBRAL LANGERHANS used genetically-engineered mouse (GEM) optic glioma models to identify CELL HISTIOCYTOSIS CXCL12 and its downstream target, cAMP, as one of the critical stromal H. Prosch1, N. Grois2, B. Fahrner2, M. Minkov1, and D. Prayer1; 1Medical signals that drive gliomagenesis in the cancer predisposition syndrome, University of Vienna, Dept. of Radiology, Vienna, Austria; 2St. Anna Neurofibromatosis-1 (NF1). Here, we employ high density SNP array analy- Childrens Hospital, Vienna, Austria sis of DNA from NF1 patients with and without glioma to confirm the importance of this pathway, and discover a potentially novel glioma risk gen- PURPOSE: Langerhans Cell Histiocytosis (LCH) is a rare systemic granulo- otype that includes multiple cAMP regulatory genes. We obtained DNA matous disease that affects the central nervous system in up to 20% of the cases. specimens from 50 patients with NF1 and glioma and 39 patients with The purpose of this exhibit is to review the imaging presentation of intracranial NF1 and no evidence of glioma on MRI obtained after 10 years of age. All LCH and to provide a guideline how to perform and evaluate MR studies in DNA was subject to Affymetrix 6.0 high density SNP array analysis. LCH patients. MATERIALS & METHODS: The authors report on the Genotype calls were made through Bayesian Robust Linear Modeling imaging findings of more than 900 MR studies from 295 patients registered using the Mahalanobis Distance algorithm in Bird Seed. Potential SNPs in the LCH CNS study center in Vienna, Austria. RESULTS: Intracranial were ranked according to p-value in a dominant model of effect. Among LCH lesions may present as: a) enhancing granulomatous lesions of the cranio- the top loci associated with glioma in NF1 were three cAMP regulatory facial bone and skull base with or without soft-tissue extension b) enhancing genes, including: Adenylyl Cyclase 8, Phosphodiesterase 4D (PDE4D), and intracerebral granulomatous lesions (most frequently in the hypothalamic pitu- Ga14. The significance of these polymorphisms in cAMP regulatory genes itary regio) c) neurodegenerative changes d) cerebral atrophy. To evaluate was underscored by proof-of-principle studies in which forced expression patients with suspected intracranial LCH we suggest thin coronal and axial of PDE4A (a closely related homologue of PDE4D) in the cortex of Nf1 T1-weighted sequences, axial T2-weighted sequences and contrast enhanced GEM resulted in the genesis of ectopic, cortical gliomas. Together, these coronal T1 weighted sequence with magnetization transfer contrast. If enhan- data confirm the importance of the cAMP pathway to gliomagenesis in cing lesions are detected, additional planes with or without fat saturation are NF1, and suggest that a glioma risk assessment in children with NF1 suggested as indicated. CONCLUSION: Intracranial LCH has a broad spec- might be possible through SNP analysis. trum of manifestations. To assess patients with intracranial LCH, one should follow a standardized MR study protocol and systematically evaluate potential intra- and extracerebral sites of inolvement.

CPS.03. BRAIN TUMORS IN CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME: FOUR NEW FAMILIES WITH 15 CANCER PREDISPOSITION SYNDROMES BIALLELIC PMS2 MUTATIONS K. Wimmer1, I. Slavc2, Y. Goldberg3, M. Chmara4, A. Attarbashi5, M. Heinrich2, A. Peyrl2, A. Wernstedt1, U. Strasser6, and E. Legius7; 1 CPS.01. HIGH PROPORTION AND POOR PROGNOSIS OF Division Human Genetics, Medical University Innsbruck, Innsbruck, 2 / GERMLINE MUTATIONS Austria; Department of Pediatrics and Adolescent Medicine, Medical HSNF5 INI1 3 F. Bourdeaut1, S. Reynaud1, L. Brugiere2, D. Lequin1, C. Dufour2,F.Doz1, University Vienna, Vienna, Austria; Sharett Institute of Oncology, N. Andre3, Y. Perel4, C. Sainte-Rose5, C. Bergeron6, X. Rialland7, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4 J. Stephan8, D. Figarella-Branger3, P. Varlet9, P. Freneaux1, D. Ranchere10, Department of human genetics, University Hospital Gasthuisberg, 5 I. Coupier11, M. Gauthier-Villars1, G. Pierron1, and O. Delattre1; 1Institut Innsbruck, Belgium; St Anna Children’s Hospital, Vienna, Austria; 6 Curie, Paris, France; 2Institut Gustave Roussy, Villejuif, France; 3APHM, la Department of Pathology, Medical University Innsbruck, Innsbruck, 7 Timone, Marseille, France; 4CHU Bordeaux, Bordeaux, France; 5APHP, Austria; Department of human genetics, University Hospital Gasthuisberg, Hopital Necker, Paris, France; 6Centre Le´on Be´rard, Lyon, France; 7CHU Innsbruck, Austria Angers, Angers, France; 8CHU St Etienne, St Etienne, France; 9APHP, Hoˆ pital Sainte Anne, Paris, France; 10Centre Leon Berard, Lyon, France; Constitutional mismatch repair-deﬁciency (CMMR-D) due to biallelic 11CHU Montpellier, Montpellier, France germline mutations in one of the mismatch repair genes, MLH1, MSH2, MSH6 or PMS2, causes an early onset cancer predisposition syndrome. Rhabdoid tumours may develop in a context of hSNF5/INI1 germline The tumor spectrum of this syndrome overlaps with Turcot syndrome, but mutations. The predisposition is reputed highly penetrant and rapidly includes also hematological and embryonic malignancies. Moreover, the ii34 NEURO-ONCOLOGY † JUNE 2010 Abstracts

vast majority of CMMR-D patients show neurofibromatosis type 1 (NF1) palmar and plantar pits, falx cerebri calcifications, skeletal malformations, like features. Here we report seven new CMMR-D patients from four macrocephaly) and tumors (basal cell carcinoma, MB, meningiomas). families. In each of the families at least one of the affected developed a Mutations in the PTCH1 gene are responsible for the development of brain tumor, i.e. one anaplastic astrocytoma, one anaplastic oligodendro- GS; recently another gene, SUFU, which encodes for another component glioma, and three glioblatomas. Other tumors in these patients included of the Hedgehog pathway, has been found to be germline mutated in T-cell non-Hogdkin lymphoma and adenoma and carcinoma of the colon. patients with MB and GS. To date we have analyzed PTCH1 and SUFU All but one patient showed multiple cafe´ au lait spots (CLS). The notion in 20 MB patients, 16 of which had GS. Seven of the GS patients that PMS2 mutations are overrepresented especially in CMMR-D carried mutations in PTCH1, 2 in SUFU. No mutations were found in patients/families with brain and/or LS-associated tumors is corroborated the 4 cases with MB alone. All of the patients had DMB. We now aim by our newly identified cases, since in the affected of three families we to analyze a pool of 65 children affected by all variants of MB and found three different homozygous truncating PMS2 point-mutations. One enrolled between 1995 and 2007 in the protocols of the Italian patient was compound heterozygous for two intragenic copy number vari- Association of Pediatric Hemato-Oncology for children diagnosed with ations. Proper diagnosis usually including immunohistochemistry and/or malignant brain tumors under 3 years of age. Patients with GS will be microsatellite-instability as well as subsequent mutation analysis in individ- identified by means of a cooperative approach involving oncologists, ual cases is desirable since identification of CMMR-D patients has larger human geneticists and neuropathologists. Molecular testing of the implications for the entire family, i.e. a 25% recurrence risk and an increased PTCH1 and SUFU genes will identify the patients who are most likely Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 risk of LS-associated tumors in heterozygous MMR-gene mutation carriers. to benefit from therapies with Hedgehog pathway inhibitors and who To provide the basis for recommendations on how to manage patients with need long-term follow-up for GS. CMMR-D, systematically evaluated data related to cancer screening, treatment and outcome in a larger cohort of patients are needed.

CPS.06. MEDULLOBLASTOMA (MB) IN PATIENTS WITH HETEROZYGOUS GERM-LINE MUTATIONS IN THE NBN CPS.04. DISTINCTIVE CLINICAL, GENETIC AND CANCER GENE - CLINICAL FEATURES FEATURES OF CHILDREN WITH MISMATCH REPAIR CANCER M. Perek-Polnik, B. Dembowska-Baginska, M. Drogosiewicz, E. Ciara, SUSCEPTIBILITY AND RAS/MAPK SYNDROMES D. Piekutowska-Abramczuk, K. Chrzanowska, and D. Perek; The Children’s C. Durno1, c. Hawkins1, M. Aronson2, S. Holter2, S. Waltho2, S. Gallinger2, Memorial Health Institute, Warsaw, Poland P. Parkin1, R. Farah3, H. Chan1, E. Bouffet1, U. Bartels1, A. Huang1, H. Druker1, D. Malkin1, and U. Tabori1; 1The Hospital for Sick Children, INTRODUCTION: The NBN gene is a double-strand break repair gene. Toronto, ON, Canada; 2Familial GI Cancer Registry, Mount Sinai Hospital, Biallelic mutations in the NBN gene cause Nijmegen Breakage syndrome Toronto, ON, Canada; 3St Georges University Hospital, Beirut, Lebanon with increased tumor risk and increased toxicity of anti-cancer treatment. NBN heterozygotes may have increased susceptibility for developing medul- Mutations in the RAS/MAPK pathway result in neurofibromatosis type-1 loblastoma. Aim of our study was to describe clinical features, toxicity (NF1) and related syndromes. The hallmarks of these patients are Cafe´-au profile and treatment outcome of MB patients heterozygous for NBN germ- lait spots (CAL), mental and growth retardation and cardiovascular line mutation. PATIENTS AND METHODS: Ninety-eight MB patients (7 anomalies. Although the risk of cancer is increased in such individuals, heterozygous for NBN mutations) were analyzed for age at diagnosis, dur- malignant brain neoplasms are extremely rare. Biallelic mismatch repair ation of symptoms, disease stage, histology, extent of resection, treatment (bMMR) gene carriers present with malignant brain tumors and lymphomas complications (grade 3, 4; CTC 3.0), chemotherapy compliance, 5-years during childhood but exhibit CAL and therefore mislabeled as NF1/RAS/ EFS and OS. Results were analyzed and compared in patients with and MAPK syndromes. In order to differentiate these syndromes clinically and without mutation in the NBN gene. RESULTS: Median age at diagnosis biologically, we screened patients referred to our Neurofibromatosis and was 5 years 2 months in heterozygotes and 8 years 10 months in others. Neurooncology clinics for evidence of CAL and malignant brain tumor. There were no differences in symptoms duration (10.9 vs 10.4 weeks). Molecular and genetic analyses were performed on all tumors and germline Dissemination and tumor residual was present in 43% of heterozygotes when available. Twelve patients fulfilled these criteria. Only 3 fulfilled the and in 29 % and 30 % of other patients, respectively. Histology revealed full criteria for NF1. All patients had normal growth, normal developmental classic MB in all heterozygotes. Chemotherapy doses were reduced to 77 status and 9/12 had consanguinity distinguishing them from RAS/MAPK % in heterozygotes and to 86% in others. Heterozygotes presented with syndromes. Brain tumors included 8 high grade gliomas, 2 brain sarcomas more grade 3 and 4 non-hematological toxicities compared to rest of and 2 PNET. Two children developed additional T-cell lymphoma. patients. Five-year EFS was 57.1% for heterozygotes and 72.4% for Surprisingly, only one family had GI malignancies suggestive of Lynch syn- others, 5-year OS was 71% and 83%, respectively. CONCLUSIONS: drome. Immunohistochemical analysis revealed bMMR dysfunction in all Younger age, advanced disease at diagnosis, considerable chemotherapy tumors. Genetic analysis is ongoing. A surveillance protocol developed for dose reductions in NBN heterozygotes suggest that NBN heterozygous these families uncovered one patient with glioblastoma which was comple- mutation has an impact on clinical course and outcome of MB. tely resected and the patient is alive and NED 15 months from diagnosis. bMMR patients have distinct clinical phenotype and cancer spectrum and should not be misdiagnosed as NF1 patients. High index of suspicion and genetic testing must be applied for such children. Surveillance protocol may improve survival for these devastating syndromes. CPS.07. STRIKING SURVIVAL BENEFIT WITH EARLY DETECTION OF BRAIN TUMORS FOR CHILDREN WITH LI-FRAUMENI SYNDROME A. Villani1, U. Tabori1, J. Schiffman Huntsmann Cancer Institute, Onc2, A. Shlien1, H. Druker1, A. Novokmet1, F. Jonathan3, and D. Malkin1; 1The CPS.05. MUTATIONS IN PTCH1 AND SUFU IN Hospital for Sick Children, Toronto, ON, Canada; 2Huntsmann Cancer MEDULLOBLASTOMA (MB): THE EXPERIENCE OF AN Institute, Salt Lake City, UT, United States; 3Children’s Hospital of Los ITALIAN SERIES Angeles, Los Angeles, CA, United States L. Pastorino1, P. Ghiorzo1, W. Bruno1, V. Capra2, P. Fidani3, A. Raso2, G. Perilongo4, C. Marzocchi5, M. Clementi5, G. Bianchi Scarra` 1, and BACKGROUND: Li-Fraumeni syndrome (LFS) carries a staggering life- M. L. Garre`6; 1Department of Oncology, Biology and Genetics, University of time risk of developing cancer. However, to date, routine biochemical and Genoa, Genoa, Italy; 2Department of Neurosurgery, Giannina Gaslini radiographic surveillance has been discouraged due to the lack of evidence Children’s Research Hospital (IRCSS), Genoa, Italy; 3Department of supporting its effectiveness. METHODS: A clinical surveillance protocol Paediatric Oncology, Bambin Gesu` Paediatric Hospital (IRCSS), Roma, for LFS has been implemented at The Hospital for Sick Children in Italy; 4Division of Hematology-Oncology, Department of Pediatrics, Toronto and and several institutions in the United States. TP53 mutation University Hospital of Padua, Padua, Italy; 5Clinical Genetics Unit, analysis and complete family histories, including site and age at diagnosis Department of Pediatrics, Universita di Padoa, Padoa, Italy; 6Department of of neoplasms, were prospectively collected for LFS families who have Haemato-Oncology, Giannina Gaslini Children’s Research Hospital members participating in this protocol. RESULTS: Among the eight families, (IRCSS), Genoa, Italy 49 TP53 mutation carriers were identified. In 16 TP53 mutation carriers who were screened, the surveillance protocol detected 9 cancers, including Medulloblastoma (MB) is the most frequent brain tumor among chil- 6 pediatric brain tumors. All 16 are alive after a mean follow-up time of dren. The classic variant (CMB) accounts for 65% of cases; the other var- 38 months. All mutation carriers (100%) who developed cancers identified iants are: desmoplastic (DMB), with extensive nodularity (MBEN), and by the surveillance protocol are alive with no evidence of disease, compared anaplastic medulloblastoma (AMB). Gorlin syndrome (GS) predisposes with only 5/27 (18.5%) TP53 mutation carriers who developed cancers and to MB, particularly DMB or MBEN. GS is an autosomal dominant dis- who did not undergo surveillance (p ¼ 2.12 x 10–5). Specific brain tumor order characterized by developmental anomalies (odontogenic keratocysts, analysis revealed that 6/6 screened brain tumor patients (including

NEURO-ONCOLOGY † JUNE 2010 ii35 Abstracts

choroid plexus carcinomas and high grade gliomas) are alive while 2/11 non prognostic factors. PATIENTS AND METHODS: A national retrospective screened patients are alive but with disease (p ¼ 0.002) CONCLUSION: We study of children ,18 years with ATRT between 1995 and 2007 was under- demonstrate that a clinical surveillance protocol can detect asymptomatic taken including central pathology review. RESULTS: There were 48 patients neoplasms including brain tumors in carriers of a germline TP53 mutation, (32 males; median age at diagnosis of 18.5 months, range 0–188). Fourteen and can significantly reduce cancer mortality among these patients. Specific patients (29.1%) were . 36 months. Infratentorial location accounted for guidelines for genetic screening, surveillance and risk stratification of child- 52% of tumours. Twenty one (43.5%) were metastatic; 11(23%) patients hood LFS will be discussed. had a gross total resection (GTR). Eleven patients (23%) underwent palliation. Among the 37 remaining patients, 24 received conventional chemotherapy and 13 high dose chemotherapy (HDC); 9 patients received intrathecal chemotherapy. Fifteen patients (40.5%) underwent upfront radiation. 30/ 16 ATYPICAL TERATOID RHABDOID TUMOR 37 treated patient have relapsed/progressed at a median time of 6.5 months(0.2–32.4). Median survival time was 12.5 months (5.7–19.2)., 9 patients were alive with a median follow-up of 40.8 months. Age, tumour location and metastatic status were not prognostic factors. Patient with ATRT.01. THE EUROPEAN RHABDOID REGISTRY (EU-RHAB) - GTR had a better survival (2y OS 54%+ 15 versus 20.8%+ 8.2 p A COMPREHENSIVE APPROACH TOWARDS BIOLOGY AND ¼0.013). Patients who received HDC regimen had better outcome (2 y Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 CLINICAL MANAGEMENT OS:51.9%+ 14 versus 20.8%+ 8.3 p ¼0.027). Upfront radiation did not M. C. Fru¨ hwald1, B. Krefeld1, M. Benesch2,J.Bu¨ chner3, J. Boos1, provide survival benefit (p ¼ 0.587). CONCLUSION: The outcome of G. Ebetsberger4, N. Graf5, R. Kortmann6, K. Nysom7, S. Rutkowski8, ATRT remains poor. However, the use of HDC provide encouraging R. Schneppenheim8, R. Siebert9, B. Timmermann10, M. Warmuth-Metz11, results. Gross total resection is a significant prognostic factor. The role of and M. Hasselblatt12; 1University Children’s Hospital, Mu¨ nster, Germany; upfront radiation is still unknown. 2University Graz Pediatric Hematology and Oncology, Graz, Austria; 3University Hospitals North Norway, Department of Pediatric Hematology and Oncology, Tromso, Norway; 4Community Children’s Hospital, Linz, Austria; 5University Children’s Hospital, Homburg (Saar), Germany; 6University Hospital, Department of Radiooncology, Leipzig, Germany; ATRT.03. EXPLORING THE FEASIBILITY OF EPIGENETIC 7University Hospital Coepenhagen, Department of Pediatric Hematology THERAPIES FOR RHABDOID TUMOR and Oncology, Coepenhagen, Denmark; 8University Hospital, UKE D. M. Ashley1, A. Muscat2, L. Rigby2, and E. Algar3; 1Royal Childrens Department of Pediatric Hematology and Oncology, Hamburg, Germany; Hospital, Parkville, Australia; 2Murdoch Childrens Research Institute, 9Institute of Human Genetics, Christian-Albrechts-University and University Parkville, Australia; 3University of Melbourne, Parkville, Australia Hospital, Kiel, Germany; 10University Hospital Essen, Departemnt of Radiooncology, Essen, Germany; 11University Hospital Wu¨ rzburg, We have previously shown that the rhabdoid tumor suppressor gene and Department of Neuroradiology, Wu¨ rzburg, Germany; 12Institute of chromatin remodeller, SMARCB1 is an epigenetic regulator of the imprinted Neuropathology, University Hospital, MU¨ NSTER, Germany cyclin dependent kinase inhibitor gene, CDKN1C. Both histone H3 and H4 acetylation in the CDKN1C promoter, and CDKN1C expression, is Rhabdoid tumors mainly affect very young children; below 6 months of increased in response to histone deacetylase inhibitor (HDACi) exposure, age they may be the most common intracranial malignancies. In 2007 we leading us to hypothesize that HDACi may restore cell cycle and cell death initiated the European Rhabdoid Registry (EU-RHAB) in cooperation with pathways otherwise disrupted by the absence of SMARCB1. Several the SIOP subcommittee on brain tumors to increase our knowledge of rhab- HDACi are effective at inducing cell death in rhabdoid tumor cell lines doid tumors and to ultimately improve outcome. EU-RHAB has collected that are resistant to conventional chemotherapies. Using an inducible data on epidemiology, molecular genetics, pathology and treatment of expression system, we have extended our previous studies to further 35 patients with atypical teratoid rhabdoid tumors (AT/RT). Median explore the role of SMARCB1 in cell death and epigenetic regulation and age at diagnosis was 22 months. All cases were confirmed by reference his- obtain further evidence supporting our hypothesis. We show that topathology (in general by INI1 staining). Only one case showed no SMARCB1 expression sensitizes G401 cells to death and increases their sen- INI1-loss. Molecular genetic analyses of SMARCB1/hSNF5/INI1 were sitivity to HDACi by at least ten-fold suggesting that SMARCB1 plays a performed in 24 cases (germ line mutations n¼ 3). In only 11 of 29 direct role in cell death and its absence contributes to chemoresistance. patients initial pathology revealed the correct diagnosis. 2/35 received Our preliminary data suggests increased nuclear and cytoplasmic histone no therapy, 32 were treated according to a consensus therapy. acetylation in cells induced to express SMARCB1, consistent with our Follow-up is short (0 to 29 months). Patients treated according to the con- hypothesis that SMARCB1 promotes histone acetylation. Using Illumina sensus demonstrate a 1-year-OS of 71.4%. 11 received some form of 27K CpG arrays we have examined the promoter methylation status of radiotherapy, all of these are alive. 10 patients are free of disease .12 14,495 genes pre and post the induction of SMARCB1 expression in rhab- months. The median age at diagnosis of the 9 patients who died within doid tumor. We did not observe differences in gene promoter methylation 0.5–12 months was 9 months. Patients with a germ line mutation and linked to SMARCB1 however several genes including RASSF1, TP73, those who did not receive any therapy were among these. SMARCA3, RB1 and WT1 were consistently hypermethylated. Our data CONCLUSION: We present first data from the European Rhabdoid suggest that combinations of demethylating agents and HDACi may have Registry (EU-RHAB). The prospective registration of children with rhab- potential as rhabdoid tumor therapy. doid tumors is a prerequisite for the development of innovative strategies that will then be implemented into phase I/II clinical trials. Supported by Horizont/Weseke and the Deutsche Kinderkrebsstiftung

ATRT.04. INHIBITION OF AURORA KINASE A RADIOSENSITIZES AT/RT CELLS AND INCREASES CELL DEATH ATRT.02. CNS ATYPICAL RHABDOID TUMOUR: THE T. L. Tello, S. Venkataraman, P. Harris, A. Donson, N. Foreman, A. Liu, and CANADIAN PEDIATRIC BRAIN TUMOR CONSORTIUM R. Vibhakar; Department of Pediatrics, University of Colorado, Denver, CO, EXPERIENCE United States L. Lafay-Cousin1, F. Rizzuti1, A. S. Carret2, D. L. Johnston3, S. Zelcer4, B. Wilson5, N. Jabado6, K. Scheinemann7, C. Fryer8, D. Eisenstat9, BACKGROUND: Atypical Teratoid/Rabdoid Tumors (AT/RT) are B. Crooks10, A. Huang11, D. Strother1, C. Hawkins11, and E. Bouffet11; aggressive, malignant, neoplasms of the central nervous system with poor 1Alberta Children’s Hospital, Calgary, AB, Canada; 2Hopital Sainte Justine, outcomes. Thus we sought to identify potential targets that maybe amenable Montreal, QC, Canada; 3Children’s Hospital of Eastern Ontario, Ottawa, to targeted therapy. Microarray based analysis demonstrated an increased ON, Canada; 4Children’s Hospital of Western Ontario, London, ON, expression of Aurora Kinase A (AKA) in AT/RT compared to normal Canada; 5Stollery Children’s Hospital, Edmonton, AB, Canada; 6Montreal brain and a panel of other brain tumors. Aurora Kinase A is important for Children’s Hospital, Montreal, QC, Canada; 7McMaster Children’s genomic stability and over-expression is associated with tumor formation. Hospital, Hamilton, ON, Canada; 8British Columbia’s Children’s Hospital, We hypothesized that inhibition of Aurora Kinase A would inhibit the pro- Vancouver, BC, Canada; 9Manitoba Institute of Child Health, Winnipeg, liferation and radiosensitize AT/RT cells. METHODS AND RESULTS: MB, Canada; 10IWK Health Centre, Halifax, NS, Canada; 11Hospital for We performed microarray based gene expression analysis of AT/RT Sick Children, Toronto, ON, Canada samples using the Affymetrix U133 array. AT/RT cells (BT16 and BT12) were cultured under standard conditions, treated with a AKA inhibitor BACKGROUND: ATRTs are aggressive tumours, mostly seen in early (C1368) and irradiated with 0.3Gy. Treatment of BT-16 with C1368 and childhood. Most of the information come from one registry and retrospective radiation signiﬁcantly decreased cell proliferation as measured by the institutional experiences. Our aim was to provide a population-based trypan blue exclusion method. Furthermore treatment of BT-12 with approach of this entity to further characterize ATRT and delineate C1368 decreased colony formation and this effect was potentiated by ii36 NEURO-ONCOLOGY † JUNE 2010 Abstracts radiation. Flow cytometric analysis of annexin staining showed increased cell 17 NEUROSURGERY death in BT-16 cells treated with C1368 and radiation as compared to individual treatments alone. Inhibition of Aurora Kinase A promoted induction of p21 in response to irradiation as well. CONCLUSIONS AND SIGNIFICANCE: We found that treatment of AT/RT cells with low dose radiation and Aurora Kinase inhibitor can synergistically 1) decrease NSX.01. INTRAOPERATIVE NEUROPHYSIOLOGICAL tumor cell survival; 2) decrease cell proliferation and; 3) increase cell MONITORING AND MAPPING OF THE CORTICOSPINAL death. Our data suggest that Aurora Kinase A is a promising therapeutic TRACT IN PEDIATRIC SUPRATENTORIAL TUMOR SURGERY target in the treatment of AT/RT. A. Korn and S. Constantini; DANA Children’s Hospital, Tel Aviv Medical Center, Aviv, Israel

OBJECTIVES: In adults, intraoperative motor evoked potentials (MEPs) are used in supratentorial tumor surgery in order to assess function and ATRT.05. THE CYTOTOXICITY OF NOVEL AND STANDARD map components of the corticospinal tract (CST). Few reports are available ANTI-CANCER AGENTS IN RHABDOID TUMOR CELL LINES in the pediatric context, where the underlying physiology and anatomy is H. Lu¨ nenbu¨ rger, C. Lanvers-Kaminsky, and M. C. Fru¨ hwald; University more challenging. Herein we describe our experience with intraoperative Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Children’s Hospital Mu¨ nster, Mu¨ nster, Germany MEPs in 12 children under the age of 9 years. METHODS: Data were analyzed from 12 pediatric patients (avg 4.7 years old) who were operated on for INTRODUCTION: Improvement of 2-year-survival rates for children a variety of supratentorial lesions. MEP data were collected following direct with AT/RT and other rhabdoid tumors in recent years has been reported. 60 Hz cortical stimulation, and short, fast-train methodology for both Unfortunately cure still seems unachievable as relapse is common and long- primary motor cortex (PMC) mapping and continuous CST monitoring. term disability as a consequence of tumor location and aggressive therapy is Phase-reversal methodology was used as an indirect motor mapping the rule rather than exception. We sought to explore the activity of standard method. In 3 procedures subcortical stimulation was undertaken to approxi- and novel anticancer agents against rhabdoid tumors in vitro to prioritise mate the distance from the subcortical pyramidal fibers. Data analysis them for future preclinical and clinical studies. METHODS: includes MEP success/failure, MEP stimulation threshold values, and inci- Antitproliferative activity was assessed by a modified dence of MEP alarms. RESULTS: Fast-train MEP mapping was successful 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) in 92% of the procedures, compared with 17% with the 60Hz method. proliferation assay on rhabdoid tumor cell lines A204 (liver), G401 The average stimulation intensity needed to evoke MEP was 12.7mA, and (kidney) and BT16 (brain). RESULTS: As expected from clinical observations, multiple electrode trajectories (.4) often were necessary. Phase-reversal anthracyclines inhibited proliferation by 50% (GI50) in the nanomolar range. was successful in 66% of the procedures. In 2 procedures, subcortical stimu- The antimetabolite actinomycin-D was most effective with GI50 values lation showed significantly higher distance-to-CST/stimulation threshold ranging from 2.8 × 1026nM for G401 to 3.8nM for A204. The only alkylating values. CONCLUSIONS: Intraoperative collection of MEP data can help agent, which inhibited cell growth at clinically relevant concentrations was to delineate the limits of tumor resection vis-a`-vis the CST. The limitations thiotepa. Target specific drugs such as sorafenib, roscovitine and rapamycin of the neurophysiologic information as well as potential modifications of showed promising effects. Furthermore we demonstrate for the first time that the neurophysiological protocol must be recognized for the pediatric setting. the herb derivatives apigenin and curcumin effectively inhibit rhabdoid tumor growth. CONCLUSIONS: In support of previous reports our data indicate that cyclin D1 one of the downstream targets of compounds such as rapamycin and sorafenib is an excellent target in rhabdoid tumor cells. Idarubicin and mitoxantrone are potent alternatives to doxorubicin and vinorelbine NSX.02. ENDOSCOPIC RHINO-NEUROSURGICAL APPROACH may substitute vincristine in future trials. We thus demonstrate a series of FOR PEDIATRIC SKULL BASE LESIONS novel and well characterized anticancer agents for consideration in clinical S. Kurschel, H. G. Eder, V. Gellner, E. Holl, G. Clarici, H. Stammberger, and trials for rhabdoid tumors. M. Mokry; Neurosurgery, Graz, Austria

PURPOSE: To evaluate the surgical results of endoscopic endonasal trans- sphenoidal approaches for skull base lesions in children. METHODS: From 2003 to 2009, 16 children with sellar and skull base lesions were treated by ATRT.06. PAIRED OVER-EXPRESSION OF NR2E1 AND HMGA2 21 endoscopic approaches. The mean age was 13.5 years (range 4–18), 56% DRIVES GROWTH IN ATYPICAL TERATOID / RHABDOID were female. Visual disturbances were present in 5 children. The surgical TUMORS goal varied from case to case and included total removal, partial removal, D. K. Birks1, R. Vibhakar1,2, A. M. Donson1, V. N. Barton1, biopsy, odontoidectomy, and optic nerve decompression RESULTS: Mean N. K. Foreman1,2, and M. H. Handler1,2; 1University of Colorado Denver, follow-up was 32.3 months (range 5–63). Pathological entities comprised Aurora, CO, United States; 2The Children’s Hospital, Aurora, CO, United pituitary adenoma in 6 children, craniopharyngioma in 4, and PNET, States Rathke cleft cyst, fibrillary astrocytoma, schwannoma, odondoit invagina- tion, and osteoblastoma in 1, respectively. The surgical goal was achieved Atypical teratoid / rhabdoid tumors (AT/RTs) are highly aggressive CNS in 81% (13/16). Postoperative transient complications included cerebrosp- tumors. While loss of INI-1 protein expression and expression of Claudin-6 inal fluid leakage in 3 and diabetes insipidus (DI) in 5 children, three children are known markers of AT/RTs, their biology remains poorly understood. To showed persistent DI. Further treatment consisted of five endoscopic reinter- gain further insight into this, we performed gene expression profiling on a ventions, one craniotomiy, and four radiosurgical procedures due to residual wide panel of pediatric CNS tumor samples, including 12 AT/RT patient or recurrent tumors. Vision normalized in four children, in one patient it samples and three AT/RT cell lines. The top two up-regulated genes in remained stable. CONCLUSIONS: The endoscopic rhino-neurosurgical AT/RTs were NR2E1 and HMGA2; each showed a greater than 20-fold approach has shown to be applicable for a wide variety of sellar and skull average increase in AT/RTs compared to other tumors. Additionally, AT/ base lesions. As our data prove, this procedure can be performed with satisfy- RTs showed higher co-expression of these genes than any other tumor ing results even in children. types (which most often expressed only one or the other). We also found within AT/RTs that higher expression of NR2E1 and HMGA2 was associated with a higher rate of proliferation, as judged by MIB1 immunohistochemistry. Both of these genes are important in normal development. NR2E1 is known to promote proliferation in neural stem cells. HMGA2 is NSX.03. SIMULTANEOUS ENDOSCOPIC THIRD highly expressed in both embryonic and neural stem cells, but is not normally VENTRICULOSTOMY AND PINEAL REGION TUMOR found in differentiated cells. HMGA2 is over-expressed in many cancer MANAGEMENT: A TAILORED SURGICAL APPROACH 1 1 1 2 1 types. Therefore, we investigated the functionality of these two genes in P. F. Morgenstern , N. Osbun , J. Tsiouris , and M. M. Souweidane ; Weill 2 AT/RTs. Knockdown of either NR2E1 or HMGA2 in AT/RT cells signifi- Cornell Medical College, New York, NY, United States; Weill Cornell cantly slowed cell growth, and simultaneous knockdown of both genes pro- Medical College and Memorial Sloan Kettering Cancer Center, New York, duced a synergistic effect. Re-expression of INI-1 in AT/RT cells resulted in NY, United States lower levels of both NR2E1 and HMGA2, as well as reduced growth. These data suggest that paired over-expression of NR2E1 and HMGA2 strongly INTRODUCTION: Simultaneous endoscopic third ventriculostomy contribute to the malignant phenotype of AT/RTs. (ETV) and tumor biopsy is a widely accepted therapeutic and diagnostic procedure for patients with non-communicating hydrocephalus secondary to a pineal region tumor. Advocated approaches include using a steerable fiberop- tic scope or rigid lens scope with one or two trajectories. However, the optimal approach has never been established based on the anatomical characteristics of individual patients. METHODS: A review was conducted of patients

NEURO-ONCOLOGY † JUNE 2010 ii37 Abstracts who underwent simultaneous ETV and tumor management. Pre-operative 18 CRANIOPHARYNGIOMA MR images were examined to measure degree of hydrocephalus, tumor size and distance from the massa intermedia, and the interval between the mesen- cephalon and massa intermedia. RESULTS: Over a 7-year period, 24 patients were managed for a newly diagnosed pineal region tumor. Twelve underwent simultaneous ETV and tumor management. These patients were 6–71 years CRANIO.01. LONG-TERM CLINICAL OUTCOMES FOLLOWING of age (mean 34.6 years) with five under 18 years of age. Five underwent a TREATMENT OF CHILDHOOD CRANIOPHARYNGIOMA 1,2 1,2 3 3 4 dual trajectory and seven a single trajectory approach. All cases were com- K. M. Winkfield , H. K. Tsai , X. Yao , D. Neuberg , E. Larson , 5 5 6 7,8 9 pleted without complications or the need for a future CSF diversionary pro- S. L. Pomeroy , N. Ullrich , L. E. Cohen , M. W. Kieran , R. M. Scott , 9 2 1 cedure. Mean measurements did not vary significantly between single and L. L. Goumnerova , and K. S. Marcus ; Harvard Radiation Oncology 2 dual trajectory groups; there was a trend toward treating patients with Program, Boston, MA, United States; Department of Radiation Oncology, 3 larger tumors using a single trajectory. CONCLUSIONS: This case series Children’s Hospital, Boston, MA, United States; Department of Biostatistics suggests that anatomical measurements may aid in selecting a single or dual and Computational Biology, Dana Farber Cancer Institute, Boston, MA, 4 trajectory approach to simultaneous ETV and pineal region tumor biopsy. United States; Department of Radiation Oncology, Brigham & Women’s 5 However, there are no clear-cut criteria. Each patient must be evaluated indi- Hospital, Boston, MA, United States; Department of Neurology, Children’s 6 vidually. Using this approach, the surgical morbidity of this procedure is low Hospital, Boston, MA, United States; Division of Endocrinology, Children’s 7 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 and the diagnostic yield is high. Hospital, Boston, MA, United States; Division of Pediatric Hematology/ Oncology, Children’s Hospital, Boston, MA, United States; 8Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; 9Department of Neurosurgery, Children’s Hospital, Boston, MA, United States NSX.04. ANTERIOR TENTORIUM-BASED EPIDERMOID TUMOURS: RESULTS OF RADICAL SURGICAL TREATMENT IN PURPOSE: To review our institution’s experience with treatment of cra- 14 CASES niopharyngioma in children, and to report long-term treatment outcomes. D. Muzumdar and A. Goel; Seth Gordhandas Sunderdas Medical College MATERIALS AND METHODS: We reviewed the records of one hundred and King Edward VII Memorial Hospital, Mumbai, India, Mumbai, India children who underwent surgery for craniopharygioma at The Children’s Hospital, Boston (CHB) from August 1976 to March 2003. Of these, A retrospective analysis of 14 surgically treated tentorium and anterior seventy-nine children (median age 8.5 years) had initial treatment at CHB tentorial hiatus-based epidermoid tumors from 1997–2008 are presented. and sufficient follow-up data to be included in this analysis. We report The most prominent symptoms were headache (50.3%) and ataxia their treatment course, recurrence rates, and treatment-related morbidity. (34.8%). The average tumour size was 4.1 cm. Surgical approaches included We compared the results in two different treatment eras based on changes the posterior cranial fossa route (9 cases), the basal subtemporal middle fossa in surgical approach at CHB. RESULTS: Thirty-six patients underwent route (4 cases), and combined posterior fossa and subtemporal routes in one initial treatment with surgery alone; 63% treated prior to 1988 recurred case. Total tumor resection was performed in 12 patients. Three and 2 and 36% treated after 1988 recurred. Recurrence rates following combined patients developed transient and sustained postoperative neurological defi- modality therapy (CMT) with limited surgery followed by radiation were cits, respectively. There was no mortality. There was non-symptomatic recur- 21% and 5% in the pre- and post-1988 eras, respectively. Accounting for rence of the tumor in two cases. Twelve patients are leading active functional treatment era, patients treated with surgery alone were 7.7 times as likely lives. Radical and safe resection of anterior tentorium-based epidermoid to recur as those treated with CMT (95% CI: 2.0, 28.7). Four patients receiv- tumors is associated with symptomatic relief and lasting cure. Extensive dril- ing CMT developed second tumors, resulting in 2 deaths. One patient in the ling of the petrous bone can be avoided. Gentle dissection of the tumor and surgery cohort and 4 in the radiation cohort developed moyamoya vasculo- capsule from the critical neurovascular structures can limit post-operative pathy. Treatment-related morbidity was otherwise similar between groups. morbidity. CONCLUSIONS: Improvements in surgical techniques for craniopharyngioma have improved the local control rates both in patients treated with surgery alone and in those undergoing CMT. The excellent survival rates of children with craniopharyngioma necessitate long-term patient follow-up to identify and manage any treatment-related effects, including second NSX.05. TREATMENT CONCEPTS FOR PEDIATRIC tumors, vascular abnormalities, and endocrinopathies. LOW-GRADE GLIOMAS IN CRITICAL LOCATIONS A. Peraud, J. C. Tonn, and F. W. Kreth; Department of Neurosurgery, Klinikum Großhadern, Ludwig-Maximilians-University Munich, Munich, Germany CRANIO.02. LIMITING HYPOTHALAMUS DAMAGE IN OBJECTIVE: In search for optimized treatment conditions for children CRANIOPHARYNGIOMAS: RESULTS OF A PROSPECTIVE with WHO grade I and II gliomas not accessible to complete resection, bra- SERIES 1 2 3 1 1 1 chytherapy (BT) has been proven to be beneficial. BT with temporary S. Puget , C. Alapetite , N. Boddaert , H. Piana , T. Roujeau , F. DiRocco , 4 5 1 1 Iodine-125-seeds provides precise radiosurgical planning sparing surround- S. Gaillard , V. Couloignier , M. Zerah , and C. Sainte Rose ; 1 ing normal tissue. The results in 29 pediatric cases treated with BT after Neurosurgical Unit, Hopital Necker, Universite´ Rene´ Descartes, Paris, 2 partial tumour resection or with BT alone, are presented. METHODS: 15 France; Pediatric oncology unit, Institut curie, Paris, France; 3 boys and 14 girls were included in the present study. Mean age at the time Neuroradiological Unit, Hopital Necker, Universite´ Rene´ Descartes, Paris, 4 5 of BT was 9 years. Tumour location was hypothalamic/suprasellar in 9, France; Neurosurgical Unit, Hopital Foch, Suresnes, France; ENT Unit, lobar in 8, deep in 6, within the brainstem in 4, and in the cerebellum in 2 Hopital Necker, Universite´ Rene´ Descartes, Paris, France children. Histology revealed 18 pilocytic astrocytomas, 9 fibrillary astrocytomas, one ependymoma and one ganglioglioma. Partial resection with sub- BACKGROUND: Craniopharyngiomas remain a therapeutic challenge in sequent BT was performed in 12 cases, 17 tumours were stereotactically terms of treatment related morbidity. We aimed to assessthe results of a prospec- biopsied and implanted with Iodine-125-seeds. RESULTS: Mean follow-up tive series of children treated according to a risk-based treatment algorithm pre- time was 33 months. Ten tumours showed complete regression 6 to 40 serving hypothalamus. MATERIAL AND METHODS: The records of 56 months after seed implantation, tumours decreased in size in 18 children 2 children (mean age 8.9 y) operated on in our unit since 2002 were prospectively to 16 months after BT. Two children developed space occupying radionecro- analysed. RESULTS: Onpre-op MRI, patients were staged as grades 0, 1 and 2 in sis which had then to be resected leading to neurological improvement. One 19%, 28% and 53% of cases respectively according to hypothalamus involve- boy died due to tumour progression of his WHO grade II astrocytoma. ment. Total removal was achieved in half of cases (10 by endoscopic endonasal Twelve children even experienced an improvement of their previous neuro- approach) and a subtotal resection followed by radiotherapy in remaining cases logical deficits. CONCLUSIONS: Brachytherapy is a safe and effective (proton beam in 23 cases). After a mean follow-up period of 3.2 y (3 m-6.5 y), method even in the younger patient group under 3 years of age. visual function and endocrine status were consistent with those reported in Microsurgery in combination with BT or BT as single treatment provides our retrospective study. We remarked an increased appetite in 25% of cases pre- excellent surgical outcome, good tumour control and low morbidity. operatively (21% being obese), whose prevalence reached 32% post operatively. Importantly, 27% of thepatients were obese at last follow-up against 60% inour previous study. Moreover, none of the children had behavioural disorders or compulsive eating. CONCLUSION: This novel strategy has clearly decreased the number of patients suffering from hypothalamic disturbances without 1 impairing tumoral control. There is still 4 of the patients showing increased weight post operatively, most of them being already obese preoperatively. However, compared to the retrospective study, the impact of the hypothalamic disturbances in these obese patients on the quality of life is dramatically reduced.

ii38 NEURO-ONCOLOGY † JUNE 2010 Abstracts

CRANIO.03. VERBAL AND VISUAL LEARNING IN CHILDREN surgical management alone in such tumors in paediatric age group. WITH LOW-GRADE GLIOMA AND CRANIOPHARYNGIOMA METHODS: Between January 2008 and January 2010, 24 children (14 AFTER CONFORMAL RADIATION THERAPY males, 10 females) aged between 6 months and 14 years (mean age 8 years) M. Di Pinto, H. M. Conklin, C. Li, X. Xiong, and T. E. Merchant; St. Jude were diagnosed with craniopharyngioma. All patients underwent surgical Children’s Research Hospital, Memphis, TN, United States excision few days after their first presentation. Data were retrospectively collected for all 24 patients to assess the efficacy and outcome of surgical treat- OBJECTIVE: This prospective, longitudinal study examined the effects of ment. RESULTS: 17 (70%) out of 24 patients underwent gross-total conformal radiation therapy (CRT) on verbal and visual learning in children resection (GTR), confirmed by intra-operative impression and postoperative diagnosed with low-grade glioma (LGG) and craniopharyngioma. The MRI studies. There was no operative death. Diabetes insipidus was observed impact of clinical and demographic risk factors were investigated. in 11 cases postoperative. 12 cases required cortisol replacement postopera- METHODS: The sample consisted of 101 patients with LGG (n ¼ 57) and tively. Two patients (8%) had tumor recurrences within the first 6 months craniopharyngioma (n ¼ 44). Measures included the California Verbal and were reoperated. Disease control was achieved surgically in 17 (70 %) Learning Test - Children’s Version (CVLT-C) and the Visual-Auditory patients and with surgery and Radiotherapy in 3 patient during the first 2 Learning Test (VAL). Patients were tested prior to CRT, at six months and years follow-up. Visual affection occurred postoperatively in one patient on then yearly for 5 years after CRT. RESULTS: Linear mixed models revealed the ipsilateral side of the surgery,otherwise vision was preserved in all other verbal and visual learning were stable over time in both tumor groups after patients as preoperatively. There was no other long-term neurological mor- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 CRT. For the CVLT-C, cerebrospinal fluid (CSF) shunting (p ¼ 0.042) pre- bidity. CONCLUSIONS: Gross total resection remains the first choice for pae- dicted lower scores at 5 years in patients with craniopharyngioma; younger diatric patients harbouring Craniopharyngiomas, with the least morbidity age (p ¼ 0.050), CSF shunting (p ¼ 0.022), and pre-CRT chemotherapy and complications when aiming at preservation of the existing hypothalamic (p ¼ 0.041) predicted lower scores at 5 years in patients with LGG. For function and vision. Surgery alone could provide long term tumor control, and the VAL, CSF shunting (p ¼ 0.001) and female gender (p ¼ 0.004) predicted minimize neurotoxic effects from other treatment options. lower scores at 5 years in patients with craniopharyngioma; younger age (p ¼ 0.050), CSF shunting (p ¼ 0.022) and pre-CRT chemotherapy (p ¼ 0.041) predicted lower scores at 5 years in patients with LGG. CONCLUSION: Aggregate learning scores after CRT remained stable with no evidence of global decline; however, specific variables predicted worse CRANIO.06. SURGERY FOR RECURRENT outcome. CSF shunting had the greatest impact on the CVLT-C and VAL CRANIOPHARYNGIOMA IN CHILDREN for both tumor groups. These findings should assist with identification of R. Shirane1, T. Hayashi2, and T. Tominaga3; 1Miyagi children’s Hospital, children at greatest risk for learning impairment after CRT and provides a Tohoku University, Sendai, Japan; 2Miyagi children’s Hospital, Sendai, comparative dataset with which to compare newer treatment approaches. Japan; 3Tohoku University, Sendai, Japan

INTRODUCTION: Craniopharyngioma has a tendency of high rate of recurrence in childhood. The aim of the present study was to establish the usefulness of reoperation as a safety treatment modality for children with CRANIO.04. SLEEP DYSFUNCTION IN LONG TERM recurrent craniopharyngioma. METHOD: From 1995 to 2010, we per- SURVIVORS OF CRANIOPHARYNGIOMA formed reoperations in 22 pediatric patients presenting with recurrent cra- P. E. Manley1,2, K. McKendrick1, S. N. Chi1,2, M. W. Kieran1,2, niopharyngiomas. Age ranged 5 to 20 at reoperation. RESULTS: The total K. J. Marcus3,4, L. E. Cohen5, L. Goumnerova1,6, M. Lee1,2, N. Robison1,2, number of reoperations was 23. Gross total resection of the lesion was S. Pomeroy1,7, and N. J. Ullrich1,7; 1Pediatric Neuro-Oncology, Dana-Farber achieved in 15 cases, sub-total in 4 cases, and partial in 3 cases due to fibrosis Cancer Institute, Boston, MA, United States; 2Hematology/Oncology, after previous surgery or radiotherapy. In addition, 3 patients underwent Children’s Hospital Boston, Boston, MA, United States; 3Radiation external irradiation and 6 patients underwent radiosurgical procedure. In Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; the immediate postoperative period, complications, including impairment 4Radiation Oncology, Children’s Hospital Boston, Boston, MA, United of visual field, were observed in two cases. No patient died after surgery or States; 5Endocrinology, Children’s Hospital Boston, Boston, MA, United because of tumor progression; one patient died of subarachnoid hemorrhage States; 6Neurosurgery, Children’s Hospital Boston, Boston, MA, United due to aneurysm rupture during follow up. CONCLUSION: In our experi- States; 7Neurology, Children’s Hospital Boston, Boston, MA, United States ence, resection for recurrent craniopharyngioma is an efficient method for tumor control and offers a good quality of patient’s life. BACKGROUND: Craniopharyngiomas are slow growing intracranial tumors of the sellar and parasellar region and may also involve the hypothalamus. Treatment is maximal surgical excision or subtotal resection followed by focal radiation therapy. Late effects of treatment include endocrinopathies, cognitive deficits, behavioral changes, obesity, and sleep CRANIO.07. A PRELIMINARY RESEARCH ON THE POTENTIAL dysfunction. METHOD: We conducted a retrospective review of all patients CORRELATION BETWEEN THE SPLICING FACTOR-2 OF with craniopharyngioma more than 2 years off treatment and who were seen STROMAL CELL DERIVED FACTOR-1 (SF-2 OF SDF-1) AND THE in the neuro-oncology survivorship clinic between 2003 and 2007. Clinical RECURRENCE OF THE ADAMANTINOMATOUS data, extent of resection, treatment modalities, patient symptom report CRANIOPHARYNGIOMA IN CHILDREN and sleep study results were collected. RESULTS: 28 patients were identified J. Gong; Beijing Tiantan Hospital, Beijing, China (25% female). 15/28 received radiation. 19/28 self-reported daytime fatigue or sleep disturbance. Of these 4/6 patients had gross total resection, 15/22 OBJECTIVE: The close correlation between the invasion and recurrence of subtotal resection and 8/13 no radiation, 11/15 with radiation. All but one craniopharyngioma and SDF-1 play an important role in the invasion of patient had pituitary dysfunction requiring hormonal replacement. Patients many malignant tumors. This is an original study to explore the correlation with more than one sleep related complaint had a higher BMI (44.3 versus between the SF-2 of SDF-1 and the recurrence of adamantinomatous cranio- 32.5). 8 patients had formal sleep evaluation. 3 patients had documented pharyngioma (ACP). METHODS: Totally, there were 20 fresh frozen speci- central or obstructive sleep apnea. Mean number of arousals ranged from mens of ACP which were picked up from Beijing Tiantan Hospital over a 2–160, with an arousal index 11.0 (normal ,5). Two patients were period of one year (Group A including 10 primary ACP and Group B includ- treated with melatonin and 3 were treated with stimulants for excessive ing 10 recurred ACP). Two samples from each group, which were selected daytime sleepiness. CONCLUSION: A majority of patients with craniophar- randomly, were analyzed by micro-array (gene chip analysis) and all the yngioma have self-reported daytime fatigue and/or sleep dysfunction after samples were tested by RT-PCR. RESULTS: The gene chip analysis treatment. Neither extent of resection or prior treatment with radiation showed the significantly higher expression of SF-2 of SDF-1 in the recurrent increased likelihood of patient report. Patients with a higher BMI were group (Group B) compared to the primary group (Group A) (p ,0.01) and more likely to experience sleep disturbance. Formal sleep evaluation this result was confirmed by RT-PCR in a larger number of samples. should be initiated in all patients with craniopharyngioma. DISCUSSION: This preliminary research suggested that the expression levels of SF-2 of SDF-1 were associated with the recurrence of ACP and SF-2 of SDF-1 may become a potential marker for the risk assessment of tumor recurrence.The underlying mechanism should be further explored. CRANIO.05. SURGICAL MANAGEMENT OF CRANIOPHARYNGIOMAS IN CHILDREN: CHILDREN’S CANCER HOSPITAL EGYPT (2 YEARS EXPERIENCE) M. A. El Beltagy, H. M. Kamal, S. Ezat, M. Kamal, and N. EL Khateeb; Cancer Children’s Hospital Egypt, Cairo, Egypt

OBJECT: Craniopharyngioma constitutes up to 6–10% of childhood brain tumors. Craniopharyngioma is the third most common intracranial tumor of childhood. The aim of this retrospective study is to evaluate the efﬁcacy of

NEURO-ONCOLOGY † JUNE 2010 ii39 Abstracts

19 RADIOTHERAPY RTX.03. DEVELOPMENT AND EVALUATION OF MULTIPLE ISOCENTRIC VMAT TECHNIQUE FOR CRANIOSPINAL AXIS RADIOTHERAPY PLANNING Y. K. Lee1, C. Brooks1, J. L. Bedford1, A. P. Warrington1, and F. H. Saran2; 1Joint Department of Physics, Royal Marsden NHS Foundation Trust, RTX.01. INTENSITY MODULATED RADIOTHERAPY WITH Sutton, United Kingdom; 2Radiotherapy Department, Royal Marsden NHS DAILY INTRA-FRACTIONALLY MODULATED JUNCTION(S) Foundation Trust, Sutton, United Kingdom FOR CRANIO-SPINAL AXIS IRRADIATION J. M. A. M. Kusters, P. G. M. van Kollenburg, M. C. Kunze-Busch, Patients receiving craniospinal irradiation(CSA RT) are at a significant risk R. J. W. Louwe, C. E. M. Gidding, E. J. van Lindert, J. H. A. M. Kaanders, to develop late sequaelae due to the close proximity of radiosensitive organs and G. O. R. J. Janssens; Radboud University Nijmegen Medical Center, to the target volume. The feasibility of using Volumetric-Modulated- Nijmegen, Netherlands Arc-Therapy(VMAT) to reduce the organs-at-risk(OAR) dose was compared to a conventional supine method for varying lengths of the spinal axis. Three PURPOSE: To develop a treatment technique for cranio-spinal irradiation conventional plans (lateral brain and posterior spine fields) were acquired. using intensity-modulated radiotherapy (IMRT) with improved dose hom- The lengths of the planning target volumes(PTV) were 21, 58 and 79cm ogeneity at the field junction(s), increased target volume conformity and respectively. The Elekta 6MV VMAT plans were inversely-planned using Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 minimized dose to the organs at risk (OARs). Material and methods: Five Philips SmartArc v9.0. One isocentre at the base of brain and the patients with high-risk medulloblastoma, underwent CT simulation in minimum number of isocentres required for the specified lengths of spine supine position. For each patient, an IMRT plan with daily intra-fractionally were used to create VMAT plans. The plans were optimised with high modulated junction(s) was generated as well as a treatment plan based on weighting for PTV coverage and low weighting for OAR sparing. Dose stat- conventional 3D planning (3DCRT). A dose of 39.6 Gy in 22 daily fractions istics from the two plans (prescription dose 23.4Gy/13fractions) were com- of 1.8 Gy was prescribed. Dose-volume parameters for target volumes and pared. Initial planning results have shown that the mean conformity and OARs were compared for the two techniques. RESULTS: The maximum heterogeneity indices for VMAT were 1.28 and 1.06 respectively compared dose with IMRT was ,107% in all patients. V,95 and V.107 were to 1.90 and 1.10 respectively for conventional plans. The mean dose to the 3 3 ,1cm for IMRT compared to 1–8 cm for the cranio-spinal and 9– heart, thyroid, oesophagus, and left and right lenses was reduced by 3 21 cm for the spinal-spinal junction with 3DCRT. IMRT provided con- 5.8Gy, 2.2Gy, 4.1Gy, 5.7Gy and 4.9Gy respectively with VMAT, when siderable sparing of acute and late reacting tissues. V75 for the esophagus, compared to conventional plans. Body V15Gy and V10Gy reductions were gastro-esophageal junction and intestine was 80%, 74% and 22% with observed but V5Gy and V2Gy were increased with VMAT, compared to con- 3DCRT versus 5%, 0% and 1% with IMRT respectively. With IMRT ventional plans. A novel VMAT CSA RT technique was devised, which sig- dose reduction to the larynx and proximal esophagus was independent of nificantly reduces OAR dose, potentially leading to lower late organ toxicity. the shoulder position. V75 for the heart and thyroid was 31% and 35% However, low dose volumes are increased carrying a potentially increased versus 0% with IMRT. CONCLUSION: IMRT with daily intra-fractionally risk of secondary malignancies. modulated junction results in a superior target coverage and junction homogeneity compared to 3DCRT. The technique is applicable for junctions between conventional and IMRT fields as well as junctions between IMRT and IMRT fields. A significant dose reduction can be obtained on acute and late reacting tissues. RTX.04. CLINICAL OUTCOMES USING INTENSITY MODULATED RADIATION THERAPY (IMRT) TUMOR BED BOOST FOR MEDULLOBLASTOMA S. Wolden, W. Polkinghorn, M. Souweidane, Y. Khakoo, S. Gilheeney, D. Lyden, O. Becher, and I. Dunkel; Memorial Sloan-Kettering Cancer RTX.02. WHOLE VENTRICULAR IRRADIATION FOR Center, New York, NY, United States CHILDREN WITH LOCALISED INTRACRANIAL GERMINOMA: ARGUMENTS FOR PROTON THERAPY IN COMPARISON TO PURPOSE: In order to decrease toxicity in survivors of medulloblastoma, IMRT AND TOMOTHERAPY we began using intensity modulated radiation therapy (IMRT) to boost the 1,2 2 1 1 1 C. Alapetite , L. De Marzi , S. Zefkili , C. Dauphinot , M. Amessis , tumor bed in 1999. METHODS: Thirty-three patients with newly diagnosed 1 3 1,2 2 2 H. Brisse , D. Frappaz , S. Bolle , F. Lacroix , R. Ferrand , and medulloblastoma were treated with an IMRT boost to the tumor bed plus a 1,2 1 2 A. Mazal ; Institut Curie, Paris, France; Institut Curie - Centre de 1 cm margin following craniospinal irradiation (CSI). Six standard-risk 3 Protontherapie, Orsay, France; Centre León Be´rard, Lyon, France patients were treated on a protocol with 18Gy CSI with a boost to 54Gy plus intrathecal iodine-131-labeled monoclonal antibody. Nineteen Intracranial germinoma demonstrates an excellent long-term survival after standard-risk patients received 23.4Gy CSI and 8 high-risk patients received craniospinal-irradiation plus tumor-bed boost. Recent studies examined a 36–39.6Gy CSI, all with a boost to 55.8Gy. Standard concurrent and adju- combined approach with reduced dose/volume radiation. The vant chemotherapy was used. Pure-tone audiograms were graded using the SFOP-90-study delivered primary chemotherapy plus tumor-bed boost. At National Cancer Institute’s Criteria (CTCAE, v3.0). RESULTS: Median a median follow-up of 8.6 yrs [2.4–15], OS is 95%, and EFS is 84% + age was 9 (4–46) years. Median follow up was 63 months. Kaplan-Meier 10. Relapse pattern identified the ventricles as the area at risk of dissemina- estimates of progression free survival (PFS) and overall survival (OS) for tion (8/10) marginal or outside radiation-fields. The SIOP-96 study prelimi- all patients were 76% and 83% at 5 years, respectively. PFS and OS differ- nary analysis shows a similar pattern. Proposing for next SIOP-protocol, ences between the risk groups were not statistically significant. Two patients whole-ventricular irradiation (WV) at a prophylactic dose of 24Gy, with experienced isolated posterior fossa failures within the boost field, 3 failed 16 Gy boost at the primary site should be applied when response after che- both within the posterior fossa and distantly, and 2 failed only distantly. motherapy was not complete. WV plus 5mm margin is a large/complex clini- There were no isolated posterior fossa failures outside of the boost cal target volume justifying evaluation which RT-technique is best to volume. Pre- and post-treatment audiograms were available for 24 patients improve the radio therapeutic index. Optimised 3Dconformal (3 fields), of whom 13% at a median follow up of 18 months developed hearing loss Linac-based IMRT(5 fields), and helical-IMRT (Tomotherapy) plans were warranting therapeutic intervention. CONCLUSION: An IMRT tumor-bed compared to Proton Therapy (PT; 4 fields). Mean dose to supratentorial boost results in excellent local control while delivering a reduced dose to the brain-PTV is 15.5 Gy; 14 Gy; 13.6 Gy and 9.8 CGE, respectively. While cochlea resulting in a low rate of ototoxicity. Linac-IMRT plans improved conformity and spares additional amount of normal-brain at higher doses in comparison to 3DCRT, this gain is obtained at the expense of an increased normal-brain volume exposed to a lower radiation-dose. Both characteristics are amplified using tomotherapy. In comparison, proton-beam delivery offers high conformity and homogeneity RTX.05. LATE NEUROVASCULAR EVENTS IN PEDIATRIC and reduces supratentorial and infratentorial brain exposure at higher and BRAIN TUMOR PATIENTS lower dose-levels (volume of the 8 Gy isodose is 1451 cc, 1596 cc, 1751 C. J. Campen1, S. M. Kranick2, S. E. Kasner3, S. Kessler4, R. Ichord4, cc, and 957 cc, respectively). The forthcoming SIOP intracranial germinoma L. A. Beslow4, S. E. Smith4, D. J. Licht4, and M. J. Fisher4; 1Stanford study will be opened to the use of proton beams. In the context of an increas- University, Stanford, CA, United States; 2National Institutes of Health, ing number of proton therapy facilities around the world, developing this Washington D.C., DC, United States; 3University of Pennsylvania, sophisticated radiation-treatment modality is of particular relevance consid- Philadelphia, PA, United States; 4Children’s Hospital of Philadelphia, ering the high percentage of long-term survivors, in order to preserve these Philadelphia, PA, United States children from adverse late-effects including risk of secondary tumors. BACKGROUND: With improved survival in pediatric brain tumors, late treatment effects including stroke are becoming more evident. Radiation- associated stroke is well documented in adults, but little has been written concerning this late effect in children. OBJECTIVES: To determine the ii40 NEURO-ONCOLOGY † JUNE 2010 Abstracts

incidence of late neurovascular events in pediatric brain tumor patients at european experience with more than 150 brain tumour patients treated one tertiary care center and to evaluate radiation as a risk factor. will be shared during the meeting. In conclusion, the capacity to study new METHODS: Retrospective cohort study of primary brain tumor patients anticancer compounds for children with brain tumours has been significantly at a pediatric center. Inclusion criteria: diagnosis of a primary brain increased and strengthened in Europe during the last 5 years, through the tumor, aged birth to 21 years at diagnosis and treatment between 1/1/ ITCC SIOPE Brain collaboration. However, there is still a dramatically 93–12/31/02. Exclusion criteria: diseases associated with vascular abnorm- limited and difficult access to new compounds that has not been improved alities (e.g. neurofibromatosis type 1), and perioperative stroke. The outcome so far by the European Paediatric Regulation. was stroke or transient ischemic attack (TIA). RESULTS: A cohort of 432 subjects with a median age of 7.7 (IQR 3.9–13) years was followed for 6.5 (2.2–9.2) years. Radiation was administered to 62%. Nineteen neurovascular events occurred in 14 subjects (8 stroke, 11 TIA) a median of 4.9 (1.7–5.5) years after diagnosis. The incidence rate of stroke or TIA was DRUG.02. THE KIDS CANCER KINOME PROJECT: 5.2/1000 person-years, compared to 6/100,000 person-years in the IDENTIFICATION AND VALIDATION OF KINASES AS general pediatric population. Risk was associated with radiation treatment POTENTIAL DRUG TARGETS IN PEDIATRIC CANCER (OR 8.3, 95%CI: 1.1–64; p ¼ 0.043). Radiation to the circle of Willis M. Kool1, E. Westerhout1, J. Molenaar1, M. den Boer2, S. Segers2, increased risk of cerebrovascular events (OR 9.2, 95%CI: 1.2–71; p ¼ R. Pieters2, O. Delattre3, M. Benetkiewicz3,F.Doz3, C. Lanvers4, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 0.034). CONCLUSIONS: The incidence of neurovascular events in the pedi- J. Renshaw5, J. Shipley5, M. Serra6, K. Scotlandi6, B. Geoerger7, G. Vassal7, atric brain tumor population is 100 fold higher than in the general pediatric O. Degrand8, M. Allen9, S. Clifford9, M. Holst10, T. Pietsch10, R. Versteeg1, population, with intracranial radiation being a prominent risk factor. Close and H. Caron1; 1Academic Medical Center, Amsterdam, Netherlands; monitoring is warranted, and future studies should target primary stroke pre- 2Erasmus Medical Center, Rotterdam, Netherlands; 3Institut Curie, Paris, vention in this population. France; 4University Childrens Hospital, Muenster, Germany; 5Institute of Cancer Research, Sutton, United Kingdom; 6Istituti Ortopedici Rizzoli, Bologna, Italy; 7Institut Gustave-Roussy, Villejuif, France; 8FEI, Le Vesinet, France; 9Northern Institute for Cancer Research, Newcastle, United Kingdom; 10University of Bonn, Bonn, Germany RTX.06. RADIO-INDUCED TUMORS AFTER BRAIN IRRADIATION IN CHILDREN: A SINGLE-INSTITUTION STUDY Kids Cancer Kinome (KCK) is a translational research effort connecting 9 M. Vinchon1, P. Leblond2, and I. Delestret1; 1Lille university hospital, Lille, European research laboratories aimed at the systematic investigation of the France; 2centre Oscar Lambret, Lille, France human protein kinase family in pediatric cancers to validate novel drug targets and develop targeted therapies. KCK focuses on six aggressive child- BACKGROUND AND PURPOSE: Radioinduced tumors (RIT) are hood tumors, killing 2000 children in Europe annually, i.e medulloblas- increasingly recognized as late-onset complications of brain irradiation toma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, during childhood. However their incidence is poorly documented and few and ALL. Gene expression profiles (Affymetrix U133plus2) have been gener- guidelines exist regarding the long-term follow-up of patients irradiated ated for .500 clinical tumor samples and cell lines of those six tumor types. during childhood. MATERIAL AND METHODS: In order to evaluate the Tissue microarrays with .800 tumor samples have been analysed for incidence of RIT after brain irradiation in children, we performed a retro- various kinases and for phosphorylation status of downstream proteins. spective analysis of patient irradiated for brain tumor before the age of 18 Clustering analyses on the combined expression data of all tumor types years. RESULTS: We studied 552 children irradiated for brain tumor since revealed a cluster containing many G2/M kinases that showed significantly 1974, at a mean age of 8.3 years, with a mean maximal dose of 52.8 Gy. higher expression patterns than in the reference tissues. Most of these kinases We identified 41 patients with RIT, diagnosed 26 months to 29 years after are also overexpressed in adult tumors, but generally at lower levels than in irradiation (mean, 13.0 years). 75.6% of the patients were adult at the pediatric tumors. The G2/M checkpoint is a potential target for therapy. time of diagnosis of RIT, but 75% were diagnosed within 17.9 years after Examples of interesting expression patterns of the human kinome will be irradiation. The actuarial incidence of RIT was 3.3% at 10 years and presented with a focus on medulloblastoma. Based on the expression 9.2% at 20 years. We found no correlation with the age at the time of patterns KCK has selected several kinases (i.e. PI3K, IGF1R, CDK2, irradiation nor with the maximal dose of irradiation; on the contrary, AURKA, AURKB) for further evaluation of their role in pediatric cancer. lesions appeared to grow preferentially from the borders of the zone of Selected genes are being silenced in cell lines using lentiviral shRNAs, maximal irradiation. We identified 43 cavernomas, 19 meningiomas, 1 sequenced for mutations, and targeted with specific drugs in in vitro and meningosarcoma, 1 malignant glioma, five thyroid tumors and 1 juvenile in vivo models. breast cancer. 25 lesions were operated in 19 patients. CONCLUSION: A significant number of children undergoing irradiation for brain tumor present with RIT, often during adulthood. We think that follow-up MRI should be performed every year until 18 years after irradiation, then every five years. DRUG.03. ITCC BIOLOGICAL AND PHARMACOKINETIC STUDY OF ERLOTINIB IN CHILDREN WITH REFRACTORY BRAIN TUMORS AND NEWLY DIAGNOSED PONTINE GLIOMAS 20 CLINICAL TRIALS AND DRUG DEVELOPMENT B. Geoerger1, D. Hargrave2, F. Andreiuolo1, E. Chatelut3, P. Varlet4, C. Jones5, D. Frappaz6,F.Doz7, R. Riccardi8, T. Jaspan9, M. Le Deley1, and G. Vassal1; 1Institut Gustave Roussy, Villejuif, France; 2Royal Marsden 3 DRUG.01. NEW DRUG DEVELOPMENT FOR CHILDREN WITH Hospital, London, United Kingdom; Institut Claudius Regaud, Toulouse, 4 5 BRAIN TUMOURS: THE EXPERIENCE OF THE EUROPEAN France; Centre Hospitalier Sainte-Anne, Paris, France; The Institute of 6 CONSORTIUM FOR INNOVATIVE THERAPIES FOR CHILDREN Cancer Research, Sutton, United Kingdom; Institut 7 WITH CANCER (ITCC) d’He´matologie-Oncologie Pe´diatrique, Lyon, France; Institut Curie, Paris, 8 9 G. Vassal1,2; 1Institut Gustave Roussy, Villejuif, France; 2On behalf of the France; Universita` Cattolica del Sacro Cuore, Rome, Italy; Nottingham ITCC executive committee, France University Hospital, Nottingham, United Kingdom

BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitor ITCC was created in 2003 to conduct a comprehensive preclinical and w early clinical new drug development program taking into account the Erlotinib (Tarceva ) has shown activity in adult gliomas. This multicenter ≤ unique ethical dimension of investigating new treatments in children with phase I study determined its recommended dose (RD) in patients 21 life-threatening disease. The biology program aims at identifying and validat- years alone or in combination with radiation, pharmacokinetics and tumor ing relevant therapeutic targets along with the preclinical evaluation of new biology. METHODS: Patients with refractory/relapsed brain tumors anticancer drugs. The clinical program is run through a network of 34 inves- received erlotinib alone (group 1), newly diagnosed pontine gliomas 54 Gy + tigating centres across Europe. They take care of 3400 new patients yearly, of irradiation and erlotinib (group 2). Conventional 3 3 and continual reas- which 25% have a brain tumour. A successful collaboration has been estab- sessment method dose escalation were used respectively. RESULTS: lished with the SIOPE Brain Tumour Committee in order to run a biology- Twenty-nine patients in group 1 and 21 in group 2 were treated. Median guided strategy for new drug development from phase I to phase III and age was 10 and 6 years, respectively. Dermatologic and neurologic symptoms their introduction into standard care. Brain tumours represent an important were most common; intratumoral hemorrhage was noted in 4 patients. In part of ITCC activity. Among the 20 ITCC studies (6 closed, 7 ongoing, 7 in group 1, 8 patients (27.6%) had stable disease, 2 malignant glioma preparation; 8 phase I, 12 phase II), 9 accrue brain tumour patients, of which showed 45% tumor regression. In group 2, median OS was 12 months. 5 are for brain tumours only. Drugs are targeted compounds (imatinib, erlo- Mean erlotinib clearance in 46 patients was 143.7 mL/h/kg (+ 66.3 SD), tinib, bevacizumab, nilotinib, anti-IGF1R MoAB) or cytotoxic compounds volume of distribution of 3.5 L/kg (+ 3.0), and mean half-life of 20.4 + (plitidepsin, gemcitabine, oxaliplatin, irinotecan, topotecan), frequently hours. Immunohistochemical analyses showed 18/37 tumors EGFR , + + + combined with temozolomide. Lessons from this clinical multicentric 3/37 EGFRvIII ,16/37 pAKT and 23/36 pMAPK . High EGFR

NEURO-ONCOLOGY † JUNE 2010 ii41 Abstracts

expression was more common in supratentorial gliomas; PTEN loss was DRUG.06. PHASE I TRIAL OF SORAFENIB IN CHILDREN WITH most common in pontine glioma (15/19) and not observed in ependymomas. NEUROFIBROMATOSIS TYPE I (NF1) AND INOPERABLE FISH showed a gain for EGFR in one supratentorial glioma but no amplifica- PLEXIFORM NEUROFIBROMAS (PN) tions. CONCLUSION: The RD of erlotinib was 125 mg/m2/day in both A. Kim1, E. Dombi1, K. Tepas1, E. Fox2, F. M. Balis2, B. Korf3, and strata with acceptable toxicity profile, although intratumoral hemorrhage B. C. Widemann1; 1National Cancer Institute, Bethesda, MD, United States; may occur. Further studies are required to define its efficacy and to establish 2Children’s Hospital of Philadelphia, Philadelphia, PA, United States; the impact of biomarkers on outcomes in pediatric glial tumors. 3University of Alabama, Birmingham, AL, United States

BACKGROUND: Sorafenib may inhibit PN growth in NF1 by blocking RAF, c-KIT, and VEGFR. At the recommended adult dose (400mg BID ¼ 222 mg/m2/dose), drug exposure after the initial dose (AUC0–12h) was DRUG.04. PHASE I STUDY OF PERIFOSINE (AKT INHIBITOR) 22 mg†h/mL and at steady state (AUCss) was 48 mg†h/mL. In children FOR RECURRENT PEDIATRIC SOLID TUMORS with malignant solid tumors, the maximum tolerated dose is 200 mg/m2/ O. J. Becher1, T. Trippett1, S. Gilheeney1, Y. Khakoo1, D. Lyden1, dose twice daily. We are conducting a phase 1 trial of sorafenib in children S. Haque1, M. Petriccione1, S. Camelia1, A. Lassman1, C. Fischer1, with NF1 and PN. METHODS: Sorafenib is administered orally twice J. Kolesar2, Z. Jiang1, S. Modak1, E. Holland1, and I. Dunkel1; 1Memorial daily, continuously. Dose limiting toxicity (DLT) is determined during the Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Sloan-Kettering Cancer Center, New York, NY, United States; 2University of initial 3 months of therapy. Optional pharmacokinetic samples are obtained Wisconsin, Madison, WI, United States at day 1 or steady state. RESULTS: Six children, median (range) age 9.5 (5– 12) years have enrolled. At the starting 115 mg/m2/dose (n ¼ 5), 2 experi- BACKGROUND: Perifosine is a synthetic alkylphospholipid which inhi- enced grade 3 pain in the PN (DLT) within 2 weeks of initiating treatment. bits Akt activity and also has been reported to affect the JNK and MAPK sig- Grade 2 toxicities were edema (n ¼ 1), pain at the PN (n ¼ 1), and hyperten- naling pathways. Single agent trials of perifosine in adults have demonstrated sion (n ¼ 1). One child enrolled at the de-escalated 80 mg/m2/dose experi- responses in patients with renal cell carcinoma, advanced brain tumors, soft- enced grade 3 rash (DLT). At 115 mg/m2/dose, estimated AUC0–12h was tissue sarcomas, hepatocellular carcinoma, and in hematologic malignancies 46 mg†h/mL (n ¼ 1); at 80 mg/m2/dose, AUCss was 44 mg†h/mL for twice including multiple myeloma and Waldenstrom’s macroglobulinemia. We daily dosing (n ¼ 1) and 30 mg†h/mL for once daily dosing (n ¼ 1). sought to determine the safety of perifosine in children with recurrent solid CONCLUSION: The dose of sorafenib tolerated by children with NF1 and tumors. METHODS: Pediatric patients with recurrent solid tumors were PN is lower than the recommended dose in children with malignant solid enrolled in a phase I, open-label, dose-escalating study to assess pharmaco- tumors. Sorafenib associated tumor pain, a toxicity not previously described, kinetics (PK), and to identify the maximally tolerated dose (MTD). occurred frequently in children with NF1. The trial is enrolling at 80 mg/ Cohorts of 3 patients were treated at three dose levels: 25 mg/m2/day, m2/dose, and will expand at the MTD to gain additional pharmacokinetic 50 mg/m2/day and 75 mg/m2/day after a load on D#1. RESULTS: 9 and toxicity data. patients (4 male, 5 female) with high-grade glioma (n ¼ 5), medulloblastoma (n ¼ 2) or neuroblastoma (n ¼ 2) have been treated to date. Their median age was 13 years (range, 5–18), most were heavily pretreated, with a median of 3 prior treatment regimens (range, 1–10). No dose-limiting toxicities (DLTs) were observed. No ≥ grade 3 toxicities or adverse events have DRUG.07. INTRAVENTRICULAR THERAPY WITH ETOPOSIDE been encountered. Grade 2 toxicities that were possibly related to perifosine IN RECURRENT CNS-PNETS AND EPENDYMOMAS - INTERIM include asthenia (22%), asymptomatic transaminase elevation (22%), neu- RESULTS OF A PHASE II STUDY tropenia (33%), leukopenia (11%), hyperglycemia (22%), hypomagnesemia G. Fleischhack1, S. Reichling1, C. Weber1, M. Zimmermann1, (22%), hypophosphatemia (11%), and colitis which resolved despite drug M. Warmuth-Metz2, T. Pietsch3, I. Zwiener4, A. Faldum4, and U. Bode1; continuation (11%). Preliminary PK data resulted in the following steady 1Dept. of Pediatric Hematology/Oncology, Medical Center, University of state serum levels: 14.1 + 4 mM for dose level 1, 32.8 + 8.1 mM for dose Bonn, Bonn, Germany; 2Dept. of Neuroradiology, University of Wuerzburg, level 2, and 31.6 + 7.8 mM for dose level 3. CONCLUSIONS: Perifosine is Wuerzburg, Germany; 3Dept.of Neuropathology, Medical Center, well tolerated in children with advanced solid tumors. University of Bonn, Bonn, Germany; 4Institute of Biostatistics, IMBEI, University of Mainz, Mainz, Germany

In 2006 a phase II study was initiated to evaluate the efficacy and safety of intraventricularly (ivc) administered etoposide in recurrent CNS-PNETs and DRUG.05. PHASE I TRIAL OF ARSENIC TRIOXIDE ependymomas with subarachnoid disease manifestation. Between 2006 and CHEMORADIOTHERAPY IN THE TREATMENT OF 2009 thirty-two patients (24 medulloblastomas, 1 supratentorial PNET, 2 INFILTRATING ASTROCYTOMAS OF CHILDHOOD pineoblastomas, 5 ependymomas) aged in median 10.9 years (range, 1.9 - K. Cohen1, L. Gore2, P. G. Fisher3, and R. Hayashi4; 1Johns Hopkins 30.7 years) were enrolled into the study. 24 patients suffered from their University School of Medicine, Baltimore, MD, United States; 2University of first relapse, one patient each from their second and third relapse, and 6 Colorado, Denver, CO, United States; 3Stanford University, Palo Alto, CA, patients had progressive disease following the primary treatment. The treat- United States; 4Washington University at St Louis, St Louis, MO, United ment consisted of three 5-day cycles of etoposide (daily age-dependent dose States of 0.7–1.0 mg) for 5 weeks. The tumor response and safety were documented clinically, by CSF cytology and MRI between days 40 to 45 after start of The prognosis for children with high-grade gliomas (HGG) and diffuse therapy. So far 31 patients are evaluable for response and showed one partial intrinsic pontine gliomas (DIPG) remains poor. A Phase I trial utilizing remission (medulloblastoma), 12 stable diseases (9 medulloblastomas, 3 arsenic trioxide (ATO) in combination with external beam radiotherapy ependymomas) and 18 progressive diseases. Nine patients discontinued the (XRT) was undertaken stemming from a variety of preclinical studies treatment early: before (n ¼ 1) or after/during the first or second cycle of demonstrating synergy between ATO and XRT in xenograft models. New treatment (n ¼ 8) due to rapid progressive disease (n ¼ 6) or for toxicity patients with a diagnosis of HGG or DIPG were eligible. ATO was given reasons (CSF leak, disturbance of memory and infection in one patient at a fixed dose of 0.15 mg/kg/day IV over one hour followed by XRT. each). The adverse events were mostly mild in form of transient headache, Daily dose was constant. Doses/week were escalated. 21 children were nausea, fever or fatigue. Infectious complications (one ventriculitis) were enrolled (12 DIPG, 9 HGG). There was one dose limiting toxicity (DLT) seen in 7 patients. Our data suggest that the repeated intraventricular etopo- at dose level 4 of grade 4 neutropenia which resolved spontaneously. This side application is well tolerated. It has cytotoxic efficacy in recurrent brain cohort accrued an additional 3 subjects without a subsequent DLT. tumors, especially in medulloblastomas. The continuation of the phase II Pending the completion of treatment for the final subject on dose level 5, it trial is warranted. appears that the expanded cohort of 6 subjects at this dose level will be without a DLT. Response to the use of ATO/XRT was difficult to determine because of the concomitant use of XRT during arsenic administration and varying adjuvant regimens. ATO is well tolerated given at a dose of 0.15 mg/kg/day given daily during focal XRT in children diagnosed with infiltrating astrocytomas. No MTD was identified, but the dose was not escalated above 0.15 mg/kg/day because of the known toxicity of higher doses in children receiving ATO for the treatment of leukemia in the absence of XRT. ATO/XRT will be one of the arms of the upcoming Children’s Oncology Group (COG) trial for children with HGG.

ii42 NEURO-ONCOLOGY † JUNE 2010 Abstracts

DRUG.08. PHASE II STUDY OF THE MTOR INHIBITOR patients ages 3–63 years (neuroblastoma ¼ 7, medulloblastoma ¼ 18, SIROLIMUS FOR NON-PROGRESSIVE NF1-ASSOCIATED retinoblastoma ¼ 3, anaplastic ependymoma ¼ 1, melanoma ¼ 2) received PLEXIFORM NEUROFIBROMAS: A NEUROFIBROMATOSIS 2 mCi 131I, or more recently 124I- 3F8, for pharmacokinetics, biodistribu- CONSORTIUM STUDY tion (SPECT or PET) and dosimetry followed by 4 serial injections of 10 mCi B. Weiss1, M. J. Fisher2, E. Dombi3, A. Cantor4, A. Vinks1, B. Korf4, 131I-3F8, (therapeutic goal .2 injections, dosimetry permitting). RESULTS: E. Schorry1, D. Gutmann5, R. Packer6, and B. C. Widemann3; 1Cincinnati Of the 31 patients, 23 patients received .2 therapeutic injections (8 patients Children’s Hospital Medical Center, Cincinnati, OH, United States; removed: 3 for disease progression, 3 for dosimetry limitations, and 2 for 2Children’s Hospital of Philadelphia, Philadelphia, PA, United States; toxicity). 18 of 23 patients were treated in a state of minimal disease. 14 3National Institutes of Health, Bethesda, MD, United States; 4University of of 18 exceeded survival . 6 months, 10 remain in cytologic and radio- Alabama at Birmingham School of Medicine, Birmingham, AL, United graphic remission (6 - 48 months since treatment). 2 of 5 patients treated States; 5Washington University School of Medicine, St Louis, MO, United with more than minimal disease remain alive with disease .2 years; the States; 6Children’s National Medical Center, Washington, DC, United States other 3 progressed and died 8, 9 and 13 months after treatment. Mean absorbed cerebrospinal fluid (CSF) dose was 1440 cGy; mean dose to CSF BACKGROUND: Plexiform neurofibromas (PN) are a common and 62 cGy/mCi; blood 1.3 cGy/mCi. Common acute toxicities included self- potentially debilitating complication of neurofibromatosis type 1 (NF1). limited headache, fever, and vomiting. No long-term side effects directly NF1 gene loss results in mTOR pathway activation. We performed a multi- attributable to 124I/131I-3F8 have been observed although 1 patient has Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 center Department of Defense-funded phase 2 trial to determine if sirolimus received treatment for CNS vasculitis. CONCLUSIONS: Weekly therapeutic can induce objective radiographic response (PN volume decrease ≥20%) of intra-Ommaya injections of 10 mCi 131I-3F8 are feasible. Prolonged remis- PN. METHODS: Subjects with NF1 and ≥ 1 inoperable PN without radio- sions have been observed, particularly when treating minimal residual graphic progression within one year prior to trial entry were eligible. disease. Radioimmunotherapy with 131I-3F8 as consolidation for high-risk Sirolimus (0.8 mg/m2/dose po q12 h continuous dosing, 1 course ¼28 patients with recurrent GD2-expressing CNS malignancies should be days) trough levels were maintained between 10–15 ng/ml. Subjects considered. received a maximum of 6 courses of sirolimus unless there was evidence of response, in which case treatment could continue. Volumetric MRI analysis was performed at baseline and after every 3 courses. Using a two-stage Simon Optimal design (target response rate 20%, rule out 5%), enrollment would be expanded if ≥1 of the initial 12 enrolled subjects had a response. In the DRUG.12. ARE THE METHYLATION OF MGMT absence of response in the first 12 subjects, the stratum would close. (O6-METHYLGUANINE-DNA METHYLTRANSFERASE) AND RESULTS: Seven females and 5 males, median age 11 yrs (range, 3–35 THE DNA MISMATCH REPAIR (MMR) MECHANISM yrs) and median PN volume 847 mL (range, 23–2476 mL), enrolled. All sub- FREQUENTLY INVOLVED IN PEDIATRIC BRAIN TUMORS? jects were removed from sirolimus after 6 courses: one for PN progression, N. Entz-Werle, A. Nguyen, M. Legrain, E. Pencreach, E. Guerin, M. Gaub, 11 for lack of response. CONCLUSIONS: Sirolimus was well tolerated but P. Lutz, and D. Guenot; CHRU Strasbourg, Strasbourg, France not effective in shrinking non-progressive NF1 PN. Evaluation of whether sirolimus can prolong the time to progression in subjects with NF1 and pro- In pediatric neuro-oncology, protocols are including now temozolomide gressive PN at trial entry is ongoing in another stratum of this trial. (TMZ) as a major drug in high grade gliomas (HGG) or in medulloblastomas (MB). Increased MGMT activity and the defect of MMR mechanism are usually involved in the cancer cell resistance to this drug. Only few studies have been already performed in the pediatric field around these markers of TMZ resistance. Based on the therapeutic indications of this drug in pediatric DRUG.09. PHASE II CLINICAL TRIAL OF LAPATINIB IN brain tumors, we performed a study in 43 malignant brain tumors including: CHILDREN AND ADULTS WITH NF2-RELATED TUMORS 5 brain stem gliomas, 15 medulloblastomas (MB), 13 high grade gliomas M. A. Karajannis, M. Ballas, I. Ayanru, A. Orrico, A. Nusbaum, (HGG) and 35 low grade gliomas (LGG) to evaluate comparitively M. Hagiwara, T. Roland, J. Golfinos, and J. Allen; New York University MGMT methylation and MMR mechanism. MATERIAL/METHODS: School of Medicine, New York, NY, United States DNA was extracted from tumors at diagnosis. The methylated status of MGMT was analyzed by methylation specific PCR. Its expression was PURPOSE: Lapatinib is an orally active receptor tyrosine kinase inhibitor studied by immunohistochemistry. An allelotyping method was performed that reversibly inhibits EGFR and ErbB2. We have recently shown that in these tumors, using the NIH reference microsatellites, to analyze the EGFR and ErbB2 are consistently expressed and activated in vestibular MMR status in each tumor RESULTS: 2 HGGs and 1 MB were presenting schwannomas (VS) in patients with NF2 and that lapatinib is active in a pre- MSI (microsatellite instability), witness of a MMR deficiency. Only 2 clinical VS model. This study aims to determine the response rate to lapatinib HGGs and 1 LGG had a methylated MGMT. One HGG was presenting at in children and adults with VS and other NF2-related tumors. the same time both abnormalities. For the tumors treated with TMZ (all EXPERIMENTAL DESIGN: A 2-stage clinical trial design was used and HGGs and 4 MBs), there were no significant differences on survival NF2 patients . 3 years of age with progressive NF2-related tumors including between the unmethylated and methylated tumors. DISCUSSION: VS, meningiomas and ependymomas were eligible. Lapatinib was adminis- Methylation of MGMT and MMR deficiency seem not to be the major tered continuously for 28-day courses. MRIs of the brain and spine, includ- mechanisms involved in the TMZ sensitivity. These results are suggesting ing volumetric tumor analysis, as well as audiograms were performed at that additional mechanisms of TMZ sensitivity and resistance are probably baseline and after every 3rd course. Primary endpoint was defined as a involved. decrease of at least 15% in tumor volume. RESULTS: At the time of submission, enrollment on the first trial stage has been completed with 9 eligible patients. Two patients discontinued protocol therapy after 3 courses due to progression. One of 3 evaluable patients to date had a 16.6% reduction in tumor volume of his VS after 3 courses. The remaining 6 patients continue DRUG.13. INHIBITION OF AURORA KINASES WITH THE on trial. CONCLUSION: A full report of tolerance and activity will be SMALL MOLECULE INHIBITORS ZM44739, VX680 AND reported on the first 9 patients, but preliminary response data suggests that SH-RNA REVEALED ANTI-PROLIFERATIVE EFFECTS IN lapatinib may have anti-tumor activity against VS in NF2 patients. MEDULLOBLASTOMA CELLS Predefined study response criteria on stage 1 were met to allow enrollment M. I. Holst1, E. Westerhout2, M. Kool2, J. Molenaar2, H. Caron2, of 8 additional patients on stage 2 of this trial. R. Versteeg2, S. Clifford3, M. Allen3, A. von Bueren4, S. Rutkowski4, and T. Pietsch1; 1University of Bonn, Bonn, Germany; 2Academic Medical Center, Amsterdam, Netherlands; 3Northern Institute for Cancer Research, Newcastle, United Kingdom; 4University Medical Center Hamburg-Eppendorf, Hamburg, Germany DRUG.10. RADIOIMMUNOTHERAPY FOR HIGH-RISK AND RECURRENT CENTRAL NERVOUS SYSTEM (CNS) CANCERS: Kids Cancer Kinome (KCK, http://www.kidscancerkinome.org)isa RESULTS OF A PHASE II STUDY WITH INTRA-OMMAYA European research project investigating aggressive childhood cancers. 131I-3F8 Focusing on the human protein kinase family nine research centers explore K. Kramer, P. M. Smith-Jones, J. L. Humm, P. B. Zanzonico, different pediatric tumors (medulloblastoma, Ewing sarcoma, osteosarcoma, N. Pandit-Taskar, J. A. Carrasquillo, S. Modak, S. Tickoo, W. L. Gerald, rhabdomyosarcoma, neuroblastoma, ALL) to validate novel drug targets I. J. Dunkel, Y. Khakoo, S. W. Gilheeney, M. M. Souweidane, S. M. Larson, and develop new therapeutic options. Medulloblastomas of the cerebellum and N. V. Cheung; Memorial Sloan-Kettering Cancer Center, New York, represent the most frequent malignant brain tumors of childhood. We investi- NY, United States gated the mRNA expression (AffymetrixU133plus2) of the protein kinase family in 62 medulloblastoma tumor samples and 14 cell lines compared PURPOSE: High-risk metastatic CNS malignancies are difficult to cure. with normal cerebellar tissue and an extensive expression-dataset of various We report results of a near-completed phase II trial using intra-Ommaya other tumor types. We discovered several kinases including the Aurora 131I-3F8 for GD2-expressing tumors. PATIENTS AND METHODS: 31 kinases, that are significantly overexpressed in primary medulloblastomas

NEURO-ONCOLOGY † JUNE 2010 ii43 Abstracts

and medulloblastoma cell lines compared to non-neoplastic tissues. Aurora available pre-clinical and human data. Here we report clinical data for a kinases play a crucial role in cellular division by controlling chromatid segre- cohort of 35 children with brain tumors treated with metronomic protocol gation. Kaplan-Meier scans revealed an inverse association between overall COMBAT in 3 European institutions. Eighteen of them with relapsed/ pro- survival and the mRNA expression levels of Aurora kinases. A panel of differ- gressive disease, 29/35 had measurable disease at the beginning of metro- ent small molecule kinase inhibitors was applied to test for growth inhibition nomic chemotherapy. Seventeen children (59%) experienced improvement in medulloblastoma cell lines. The Aurora kinase inhibitors ZM447439 and during COMBAT treatment with 2-year EFS 33% and OS 53%. VX680 exhibited an anti-proliferative effect on the medulloblastoma cells. Metronomic chemotherapy in children with relapsed CNS tumors is feasible, In a second approach, we transduced cell lines with lentiviral particles carrying associated with minimal toxicity; patients in palliative setting can maintain a shRNA targeting Aurora A and B kinase. The specific down regulation of good quality of life. In some children we have observed prolonged remissions Aurora kinases with lentiviral shRNA was confirmed by Western blotting or at least some window of opportunity for further therapies. Further inves- and had a negative effect on the viability of medulloblastoma cells. In con- tigation of this strategy in children with CNS tumors is warranted, despite clusion, our data suggest that the inhibition of Aurora kinases may represent several important challenges, like identification of proper drugs/combi- a promising approach for novel targeted strategies in the treatment of medul- nations, validation of surrogate markers and long-term safety or proper loblastoma patients. design of metronomic trial. Contract grant number 9873–3 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021

DRUG.14. ENHANCED EFFICACY OF IGF1R INHIBITION IN DRUG.16. ANTIANGIOGENIC METRONOMIC PAEDIATRIC GLIOBLASTOMA BY COMBINATORIAL CHEMOTHERAPY FOR PATIENTS WITH RECURRENT TARGETING OF PDGFRALPHA/BETA EMBRYONAL AND EPENDYMAL BRAIN TUMORS A. B. Bielen1, L. Perryman1, G. Box2, M. Valenti2, A. de Haven Brandon2, A. Peyrl1, A. A. Azizi1, B. Reismueller1, M. W. Kieran2, M. Heinrich1, S. Popov1, F. Hofmann3, D. Hargrave4, S. Eccles2, and C. Jones1; 1Paediatric T. Czech3, K. Dieckmann4, and I. Slavc1; 1Medical University of Vienna, Oncology, The Institute of Cancer Research, Sutton, United Kingdom; Department of Pediatrics, Vienna, Austria; 2Department of Pediatric 2Cancer Research UK Centre for Cancer Therapeutics, The Institute of Oncology, Dana-Farber Cancer Institute and Childrens Hospital Boston, Cancer Research, Sutton, United Kingdom; 3Novartis Pharma AG, Basel, Boston, MA, United States; 3Medical University of Vienna, Department of Switzerland; 4Paediatric Oncology, Royal Marsden Hospital, Sutton, United Neurosurgery, Vienna, Austria; 4Medical University of Vienna, Department Kingdom of Radiotherapy, Vienna, Austria

Paediatric glioblastoma (pGBM), although rare, is one of the leading BACKGROUND: Patients with relapsed malignant brain tumors have a causes of cancer-related deaths in children, with tumours essentially refrac- poor prognosis despite intensive treatment including high-dose chemotherapy tory to existing treatments. We have identified the receptor tyrosine kinase with stem cell rescue. We report on our experience with an antiangiogenic (RTK) IGF1R to be a potential therapeutic target in pGBM due to IGF1R metronomic chemotherapy for patients with recurrent embryonal and ependy- amplification and high levels of IGF2 expression in tumour samples, as mal tumors. PATIENTS: Thirteen patients (median age: 8 years, range: 2–24) well as constitutive receptor activation in pGBM cell lines SF188 and with recurrent (6 first, 7 multiple) brain tumors (medulloblastoma n ¼ 6, supra- KNS42. In order to evaluate the therapeutic potential of strategies targeting tentorial primitive neuroectodermal tumor n ¼ 3, pineoblastoma n ¼ 1, atypi- the receptor, we have carried out in vitro and in vivo preclinical studies using cal teratoid rhabdoid tumor n ¼ 1, ependymoma WHO Grade III n ¼ 2) the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was received daily oral thalidomide 3–10mg/kg, twice daily oral celecoxib seen in vitro, with GI50 values of 5–6 mM, and concurrent inhibition of 100mg, daily oral fenofibrate 70mg/m2, and alternating 21–day cycles of receptor phosphorylation. Specific targeting of IGF1R with siRNA decreased daily oral etoposide 10–50mg/m2 and cyclophosphamide 0.5–2.5mg/kg, cell viability, diminished downstream signalling through PI3-kinase and augmented with biweekly intravenous bevacizumab 10mg/kg plus/minus induced G1 arrest, effects mimicked by NVP-AEW541, both in the absence intrathecal chemotherapy. At recurrence, 4 patients were reoperated on their and presence of IGF2. Hallmarks of PI3-kinase inhibition were observed tumor and/or received conventional chemotherapy, and 2 local radiotherapy after treatment with NVP-AEW541 by expression profiling and Western prior to antiangiogenic metronomic chemotherapy. RESULTS: OS at 6 blot analysis. Phospho-RTK arrays demonstrated phosphorylation of months was 100% and PFS 69.2 + 12.8%, OS at 12 and 24 months was PDGFRa/b in pGBM cells suggesting co-activation of an alternative RTK 80.0 + 12.6% and PFS 53.8 + 13.8%. Overall, therapy was well tolerated. pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed No intratumoral hemorrhage occurred in any of the patients. Side effects additional effects targeting the MAP-kinase pathway, and co-treatment of included lymphopenia in 13/13 patients, severe pneumonia in 2/13 patients, the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly syner- proteinuria in 1/13 patient, peripheral neuropathy requiring dose reduction gistic interaction in vitro, and increased efficacy after 14 days therapy in vivo of thalidomide in 5/13 patients, and new onset hypothyreoidism in 6/13 compared with either agent alone. These data provide evidence that inhi- patients. Quality of life was considered better by all patients compared to bition of IGF1R, possibly in combination with other targeted agents, may prior conventional chemotherapy. CONCLUSION: Antiangiogenic metro- be a useful and novel therapeutic strategy in pGBM. nomic chemotherapy has clinical activity in recurrent malignant brain tumors and may present a promising therapeutic option for heavily pretreated patients.

DRUG.15. METRONOMIC CHEMOTHERAPY IN RECURRENT AND HIGH RISK PEDIATRIC BRAIN TUMORS. EXPERIENCE DRUG.17. HIGH DOSE CHEMOTHERAPY (HDC) WITH FROM 3 EUROPEAN INSTITUTIONS AUTOLOGOUS STEM CELL REINFUSION (ASCR) FOLLOWED J. Sterba1, N. Andre2, L. Deak3, J. Ventruba4, Z. Pavelka1, K. Zitterbart1, BY 13-CIS-RETINOIC ACID (13-CRA) IN CHILDREN WITH D. Bronisova1, T. Kepak1, P. Mudry1, J. Skotakova5, H. Oslejskova6, RECURRENT MALIGNANT BRAIN TUMORS - A PEDIATRIC L. Kren7, V. Bajciova1, L. Dubska8, M. Kyr1, and D. Valik8; 1University BLOOD AND MARROW TRANSPLANT CONSORTIUM STUDY Hospital Brno, Pediatric Oncology Department, Brno, Czech Republic; S. Gardner1, M. Atlas2, G. Veal2, J. Belasco2, A. Termuhlen2, L. Worth2, 2Pediatric Oncology Department, Pediatric Hospital, Marseille, France; V. Aquino2, R. Duerst2, H. Frangoul2, H. Grodman2, A. Haight2, A. Khan2, 3University Hospital Kosice, Pediatric Oncology Department, Kosice, M. Radhi2, A. Chen2, and A. Bendel2; 1New York University, New York, Slovakia; 4University Hospital Brno, Pediatric Surgery Department, Brno, NY, United States; 2Pediatric Blood and Marrow Transplant Consortium, Czech Republic; 5University Hospital Brno, Pediatric Radiology Salt Lake City, UT, United States Department, Brno, Czech Republic; 6University Hospital Brno, Pediatric Neurology Department, Brno, Czech Republic; 7University Hospital Brno, BACKGROUND: The prognosis for children with recurrent malignant Department of Pathology, Brno, Czech Republic; 8Masaryk Memorial brain tumors is dismal. AIM: The aims of this study are to determine the Cancer Institute, Brno, Czech Republic feasibility and efficacy of a novel HDC regimen followed by 13-CRA for children with recurrent malignant brain tumors and pharmacokinetic and phar- The outcome of children with relapsed and high risk brain tumors remains macogenetic evaluation of 13-CRA following ASCR. METHODS: poor, despite the introduction of dose intensified chemotherapy (CHT), high- Patients , 21 years of age with recurrent malignant brain tumors with dose CHT and several novel therapies, e.g. monoclonal antibodies and minimal residual disease were eligible. Patients (pts) received temozolomide kinase inhibitors. Despite an initially impressive tumor regression or remis- 175 mg/m2/dose twice daily for 5 days followed by carboplatin dosed using sion, re-growth or recurrence is quite common. Therefore, treatment strat- the Calvert formula with AUC ¼ 7 (maximum 500 mg/m2/day) and thio- egies which act on multiple levels including tumor cells and stromal milieu tepa 300 mg/m2/day on days -5 through -3 with ASCR day 0. Patients may be of benefit. One such strategy is metronomic CHT, which is adminis- were permitted to receive irradiation following ASCR. 13-CRA was given tration of CHT at doses below the maximal tolerated dose on a frequent no sooner than 42 days following ASCR twice daily for 2 weeks each schedule, with no prolonged drug-free breaks. Wish list of such drugs month for 6 months. RESULTS: Between 10/1/2005 and 12/31/09, 26 includes oral drugs with non-overlapping mechanism of action and toxicity, pts were enrolled. Diagnoses included medulloblastoma (MB)/ ii44 NEURO-ONCOLOGY † JUNE 2010 Abstracts

supratentorial primitive neuroectodermal tumor (SPNET) ¼ 16; high grade metastatic tumor, a long delay was associated with a more advanced glioma (HGG) ¼ 3; choroid plexus carcinoma ¼ 2; ATRT ¼ 2; local extension (tumor size, T stage, inﬁltration of the 4th ventricle) germinoma ¼ 1; ependymoma ¼ 1; other ¼ 1. Ages ranged from 2–20.5 and incomplete tumor resection. A short duration of symptoms before years (median ¼ 11.5 years). Four of 12 evaluable pts with MB/SPNET, 1 diagnosis was signiﬁcantly associated with a more severe disease: meta- pt with HGG and 1 pt with germinoma are progression- free survivors at static tumor (median delay 31 vs. 91 days), non desmoplastic histology least 1 year following ASCR. All 4 pts with MB/SPNET received full dose (61 vs. 112 days), decreased 10 years survival (47 vs. 60%, RR ¼ 1,8 RT as part of their initial therapy. There was 1 toxic death. Peak 13-CRA [1,2 - 2,8]). CONCLUSION: Time interval between initial symptoms concentrations ranged from 0.6–4 micromolar. CONCLUSION: HDC and diagnosis of medulloblastoma in children is still long and possibly with ASCR followed by 13-CRA is feasible in pts with recurrent malignant related to the aggressive behaviour of the tumor itself. brain tumors. This regimen resulted in long term survival for patients with MB/PNET, germinoma and HGG.

EPI.02. EPIDEMIOLOGY OF MALIGNANT, HIGH-GRADE PEDIATRIC CNS TUMORS: A POPULATION-BASED STUDY BY DRUG.18. PEG FUNCTIONALIZED NANOPARTICLES AS THE AUSTRIAN BRAIN TUMOR REGISTRY, 1996–2006 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 DELIVERY SYSTEMS FOR TARGETING BRAIN TUMORS A. Woehrer1,2, I. Slavc3, T. Waldhoer4, H. Heinzl5, N. Zielonke6, T. Czech7, A. B. Etame1, S. D. Perrault2, C. A. Smith1, W. C. W. Chan2, and A. A. Azizi3, M. Benesch8, M. Scarpatetti9, G. Ebetsberger10, S. Weis11, J. T. Rutka1; 1Labatt Brain Tumour Research Centre - The Hospital for Sick N. Jones12, A. Klein-Franke13, W. Sterlacci14, B. Jauk15, A. Kiefer16, Children, Toronto, ON, Canada; 2Institute of Biomaterials and Biomedical G. Mueller17, U. Gruber-Moesenbacher18, A. Reiner-Concin19, Engineering - University of Toronto, Toronto, ON, Canada H. Feichtinger20, J. A. Hainfellner1,2, and C. Haberler1; 1Institute of Neurology, Medical University of Vienna, Vienna, Austria; 2On behalf of the Systemic delivery of chemotherapeutic agents against malignant brain Austrian Brain Tumor Registry, Austria; 3Department of Pediatrics, Medical tumors can be confounded by blood-brain barrier (BBB) limitations. The University of Vienna; 4Center of Public Health, Department of intimate anatomical and biochemical relationship between brain endothelial Epidemiology, Medical University of Vienna; 5Center for Medical Statistics, cells and astrocytes provides a very formidable selective physical and bio- Informatics, and Intelligent Systems, Medical University of Vienna; chemical barrier. Strategies that exploit endothelial transcytosis mechanisms 6Austrian National Cancer Registry, Statistics Austria; 7Department of such as nano-particle mediated delivery have the potential to increase the Neurosurgery, Medical University of Vienna; 8Division of Pediatric bioavailability and efficacy of tumor-targeted therapies. The small size and Hematology/Oncology, Department of Pediatrics, Medical University of potential biocompatibility of nanoparticles in conjunction with their Graz; 9Institute of Pathology, Medical University of Graz; 10Department of ability to permeate biological membranes makes them ideal delivery Pediatrics, Children´ s and Maternity Hospital Linz; 11Department of systems. We therefore sought to design a nanoparticle based delivery Pathology and Neuropathology, State Neuropsychiatric Hospital system for targeting malignant brain tumors. As a preliminary step, we syn- Wagner-Jauregg, Linz; 12Department of Pediatrics, Paracelsus Private thesized and characterized polyethylene glycol (PEG) functionalized nano- Medical University Salzburg; 13Department of Pediatrics, Medical University particles using UV-VIS spectrophotometry, dynamic light scattering as well of Innsbruck; 14Institute of Pathology, Medical University of Innsbruck; as transmission electron micrograph (TEM). The effect of PEG size on nano- 15Department of Pediatrics, State Hospital Klagenfurt; 16Institute of particle hydrodynamic diameter was assessed and correlated. The transcyto- Pathology, State Hospital Klagenfurt; 17Department of Pediatrics, State sis ability of PEG functionalized nanoparticles was assessed in an in-vitro Hospital Feldkirch; 18Institute of Pathology, State Hospital Feldkirch; BBB model using rat brain endothelial cells. We observed a size-dependent 19Institute of Pathology, Danube Hospital, Vienna; 20Department of favorable endothelial transcytosis of PEG functionalized nanoparticles. Pathology, Krankenanstalt Rudolfstiftung, Vienna Transmission electron micrograph (TEM) was confirmatory for endothelial transcytosis. We anticipate that these preliminary studies will establish the CNS tumors represent 20% of all childhood cancer in developed framework for optimizing this nanoparticle-mediated delivery system for countries. They constitute the second most common group of neoplasms subsequent targeting of malignant brain tumors. after leukemias, and the most common cause of cancer-related death in children. In the present study we analyzed the incidence and survival of malignant, high-grade CNS tumors in Austria. A nation-wide survey on malignant, high-grade CNS tumors (WHO grade III/IV), diagnosed in 21 EPIDEMIOLOGY children (0–14 years) from 1996–2006 was conducted by the Austrian Brain Tumor Registry. Case ascertainment was based on multiple sources and included a central histopathology review. A total of 311 EPI.01. DIAGNOSIS DELAY OF MEDULLOBLASTOMA IN newly diagnosed, malignant CNS tumors were reported. 72.3 % of CHILDREN: DISTRIBUTION, DETERMINANTS AND tumors were microscopically verified. The M/F ratio of the total CONSEQUENCES IN A POPULATION-BASED STUDY cohort was 1.25. Histology groupings according to the WHO classifi- J. F. Brasme1,2, J. Grill1,2, F. Doz3,4, D. Valteau-Couanet1,2, S. Gaillard5,6, cation showed that embryonal brain tumors constituted the largest O. Delalande7, N. Aghakhani8,2, C. Sainte-Rose9,4, G. Breárt10, S. Puget9,4, group (45.7 %), followed by astrocytic (27.7 %) and ependymal and M. Chalumeau11,4; 1Department of Pediatric and Adolescent Oncology, tumors (7.7 %). The most common tumor entity was medulloblastoma Institut Gustave Roussy, Villejuif, France; 2Universite´ Paris Sud, Le Kremlin (ASR 5.77/1,000,000 person-years), followed by glioblastoma (ASR Biceˆtre, France; 3Department of Pediatric and Adolescent Oncology, Institut 3.11/1,000,000 person-years) and CNS PNET (ASR 2.14/1,000,000 Curie, Paris, France; 4Universite´ Paris Descartes, Paris, France; 5Department of person-years). 5-year overall survival was favorable for medulloblastoma Neurosurgery, Hoˆpital Foch, Suresnes, France; 6Universite´ Paris Ile-de-France and CNS PNET (76.6 %, 72.7 %), and particularly poor for malignant Ouest, Guyancourt, France; 7Department of Pediatric Neurosurgery, gliomas and AT/RT (31.0 %, 37.4 %), respectively. This is the first Fondation Rothschild, Paris, France; 8Department of Neurosurgery, Centre population-based and histologically-verified study on malignant pediatric Hospitalier de Biceˆtre, AP-HP, Le Kremlin Bicetre, France; 9Department of brain tumors. These data provide important insights into the burden of Pediatric Neurosurgery, Hoˆpital Necker-Enfants Malades, AP-HP, Paris, disease and may contribute to improved patient management and care. France; 10INSERM U953, Epidemiological research unit on perinatal health and women’s and children’s health, Paris, France; 11Department of Pediatrics, Hoˆpital Saint-Vincent-de-Paul, AP-HP, Paris, France

OBJECTIVE: To study the distribution, determinants and consequences of EPI.03. NATIONAL PEDIATRIC BRAIN TUMOR REGISTRY IN diagnosis delays of medulloblastoma in children. METHODS: A retrospec- THAILAND: REPORT FROM THAI PEDIATRIC ONCOLOGY tive cohort study included all cases of pediatric medulloblastoma in a GROUP (2003–2005) 1 2 2 3 4 region of France between 1990 and 2005. The relationships between diagno- S. Hongeng , I. Nuchprayoon , P. Seksarn , S. Wiangnon , G. Veerakul , 5 1 sis delay, clinical features, disease stage and survival were studied using uni- and T. Krutvecho ; Faculty of Medicine, Ramathibodi Hospital, Mahidol 2 and multivariate analyses. FINDINGS: The median diagnosis delay of the University, Bangkok, Thailand; Faculty of Medicine, Chulalongkorn 3 166 cases was 65 days (IQR 31 - 121, range, 3 - 457), without any Memorial Hospital, Chulalongkorn University, Bangkok, Thailand; Faculty decrease during the study period. For 32% of the children under 3 of Medicine, Srinakarin Hospital, Khon Kaen University, Khon Kaen, 4 years, the diagnosis was made at the time of life-threatening signs of Thailand; Faculty of Medicine, Siriraj Hospital, Mahidol University, 5 intracranial hypertension. Children showing “psychological” symptoms Bangkok, Thailand; Pramongkutklao College of Medicine, Bangkok, (27%) had a signiﬁcantly longer delay (median 90 vs. 58 days, p ¼ Thailand 0,02). The causes of diagnosis delay were multiple: inconsistent or late association of vomiting and headache, spontaneous remission of symp- OBJECTIVE: Brian tumor is the 2nd commonest cancer in childhood and toms, absent or late neurological signs, “psychological” symptoms, there was no population-based study on its incidence in Thai children. normal neurological or ocular fundus examination. For patients with a Therefore, we would like to study the incidence and the survival of childhood

NEURO-ONCOLOGY † JUNE 2010 ii45 Abstracts

brain tumors in Thailand based on the national registry. MATERIALS AND 36 with non-chromosomal defects, with an overall elevated risk estimate METHODS: Prospective collection of pediatric brain tumor data from the of 1.70 (95% CI 1.24–2.34). Risks for astrocytoma (HR 1.54, 95% CI 20 major hospitals. These 20 hospitals are the only institutions with pediatric 0.92–2.58), medulloblastoma (HR 1.65, 95% CI 0.68–4.04), PNET (HR oncology service in our locality. A standard data entry sheet was used and the 3.01, 95% CI 1.40–6.46), and germ cell tumor (HR 4.43, 95% CI 1.77– data collection and entry was performed by designated data managers. The 11.13) were all elevated in children with birth defects. CONCLUSIONS: data were further crosschecked. RESULTS: From January 2003 to December Children with non-chromosomal birth defects exhibit increased risk for 2005 (3 years), a total of 302 cases of childhood (≤15 years) brain tumors brain tumors. Speciﬁc defects and their association to brain tumor subtypes were diagnosed. Astrocytoma was the most common (33.77%), followed should be explored to understand genetic abnormalities that predispose to by PNET (29.51%), germ cell tumor (16.72%), ependymoma (8.2%), teratogenesis and carcinogenesis. choroid plexus tumor (0.66%), and the other types of tumor (11.15%). The 7-year overall survival (OS) of all patients was 45.5% (95%CI: 39.43–51.35), astrocytoma 39.52% (95%CI: 29.44–49.42), PNET 45.11% (95%CI: 33.82–55.74), germ cell tumor 72.76% (95%CI: 64.1– 86.73), and ependymoma 32.0% (95%CI: 13.13–52.52). A high incidence EPI.06. INCIDENTALOMAS: SIGNIFICANCE OF A GROWING of intracranial germ cell tumors has been noted in our study and in other PROBLEM AND THERAPEUTIC OPTIONS oriental countries such as Japan, Taiwan, and Hong Kong. R. F. Keating1, J. S. Myseros1, A. L. Yaun2, S. N. Magge2, J. Roth3, and Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 CONCLUSION: We noted a different distribution pattern of brain tumors S. Constantini4; 1Children’s National Medical Center, Washington, DC, types in our Thai children (high incidence of germ cell tumors) as compared United States; 2Children’s national medical center, washington, DC, United to the SEER data (1975–1995) and our germ cell tumor patients had the best States; 3Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 4Dana OS compared to the other types. Children’s Hospital, tel aviv, Israel

The increasing utilization of sophisticated radiographic evaluation for a multitude of neurological disorders in children, has led to a significant escalation of incidentally found brain tumors. Records from Children’s National EPI.04. INCIDENCE AND SURVIVAL OF FIRST PEDIATRIC Medical Center (Washington) as well as Dana Children’s Hospital(Tel PRIMARY MALIGNANT CENTRAL NERVOUS SYSTEM Aviv) were reviewed for incidentally found tumors and evaluated with TUMORS IN ISRAEL, 1998–2007 respect to treatment paradigms and clinical outcomes for both surgical as M. Ben Arush1,2, R. Rabinowicz3, N. Ramu4, and M. Barchana5; 1Rambam well as non-surgical patients. Over the past five years 24 children(18 M/ 6 Medical Center, Haifa, Israel; 2The Bruce Rappaport Faculty of Medicine, F), avg age 7.62y(0.25–21y) were found to have incidental brain tumors Technion, Israel; 3The Bruce Rappaport Faculty of Medicine, Technion, on CT/MRI studies done for a variety of reasons: head trauma(9), head- Haifa, Israel; 4Hadassah Hospital, Jerusalem, Israel; 5Israel National Cancer ache(2), seizures(2), genetic work-up(1), developmental disorders(1), endo- Registry, Ministry of Health, Jerusalem, Israel crine abnormalities(1), Lyme disease(1). Incidental findings were characterized by two groups: completely unexpected(12 pts) vs evaluation This study used data from the Israel Cancer registry to examine pediatric for neurological issues but demonstrating unrelated radiographic findings(12 brain tumors with the international classification of childhood cancer. pts). Seventeen patients underwent surgery & seven were treated conservati- Incidence rates for central nervous system (CNS) tumors in children aged vely(observation). Surgical patients(17) demonstrated benign pathology in 0–19 years in Israel, between 1998–2007, were examined. CNS malignant 82% whereas three patients(18%) had malignant disease. The pathology tumors were classified according to gender, topography, age distribution, ranged from low-grade astrocytomas(9), pleomorphic xanthocytoma(2), origin, and histological diagnosis. Survival probability updated in craniopharyngioma(1), chordoma(1), choroid plexus papilloma(1), as well December 2009 was estimated. There were 815 children and teens, with a as ependymoma(1), ATRT(1) and anaplastic astrocytoma(1). The were no mean age of 9.37 years (10 days-19.98 years); 351 girls, 464 boys; 595 surgical mortalities and the complication rate was low. Follow-up for surgi- Jewish children (73%), 186 Arabic children (23%), 34 Christian children cal patients was 26.2m(1m-57m) and 24.2 m(6–60m) for patients treated (4%). Overall survival (OS) at 5 years was 73.2%, 64.7% for the Arabic conservatively. Clinicians are increasingly being challenged by the discovery population, and 75.9% for the Jewish population (p ¼ 0.004). 5-year OS of incidental findings on routine radiographic studies. While the true inci- was 64.1% for children less than 1 year, 70.5% for the 1–4 year, 69.6% dence of incidental brain tumors remains unclear in the pediatric population, for the 4–9 year, 75.4% for the 9–14 year, and 80% for the 14–19 year this is unquestionably becoming a universal dilemma around the world. age groups. The most frequent tumors were pilocytic astrocytoma (n ¼ Future studies need to ascertain the true significance of this problem as 157) (OS 95.5%), astrocytoma grade I-II (n ¼ 94) (OS 81.6%), astrocytoma well as optimum management strategies. grade III (n ¼ 74) (OS 54.6%), medulloblastoma (n ¼ 96) (OS 69%), ependymoma (n ¼ 61) (OS 81.6%), and glioblastoma multiforme (n ¼ 34) (OS 15%). The histological type of the tumor was the most powerful independent predictor of survival. According to diagnosis and origin, OS was inferior in 22 RARE TUMORS the Arabic population with ependymoma (p ¼ 0.007) and glioma grade III (p ¼ 0.052). Children in Israel with CNS tumors had a good survival experience compatible with the high quality of care. A larger study implicating RARE.01. MENINGIOMAS IN CHILDREN: REVIEW OF 49 CASES genetic factors needs to be performed, including comparisons with other H. Chen1, N. Travers2, C. Sainte-Rose3,4, M. Bourgeois3,4, M. Zerah3,4, countries of the Middle East. T. Roujeau3,4, N. Boddaert5, and S. Puget3,4; 1Taipei Veterans General Hospital, Taipei, Taiwan; 2Hopital Clocheville, Tours, France; 3Hopital Necker-Enfants Malades, Paris, France; 4Universite Paris-Descartes, Paris, France; 5Neuroradiological department, Paris, France

EPI.05. BIRTH DEFECTS AS A RISK FACTOR FOR CHILDHOOD The occurrence of meningiomas in children younger than 18 years of age is BRAIN TUMORS AND OTHER CANCERS rare. The authors of this study thought to add to the limited available infor- 1 2 3 2 P. G. Fisher , J. Von Behren , S. Carmichael , P. Reynolds , and mation regarding clinicopathological factors that influence outcome, disease 1 1 2 G. M. Shaw ; Stanford University, Palo Alto, CA, United States; Northern progression, and survival in children with meningiomas according to the 3 California Cancer Center, Fremont, CA, United States; California Research experiences of single centers. Forty-nine children under 17 years of age Division, March of Dimes Foundation, Oakland, CA, United States with meningiomas were treated during the period 1974–2008 in Necker’s Hospital. We operated on 45 intracranial and 4 spinal meningiomas with BACKGROUND: Children with birth defects have been postulated to a male predominance (2:1). Median age at diagnosis was 9.8 and 10.4 harbor an increased risk of cancer. METHODS: We examined cancer risk years for male and female, respectively (range, 6 months-17 years). Six in children with and without birth defects, using three data sources: the cases were associated with NF2. Presenting symptoms were related to the California Birth Defects Monitoring Program (CBDMP), the California tumor location. Skull base was the most common location (31%) followed Cancer Registry (CCR), and the live birth files from the State Office of by convexity (20%) and parasagittal with dural attachment 18%. All the Vital Records. Using probabilistic record linkage, we matched children tumors were operated on and total removal was achieved in 37 patients in with newly diagnosed cancer to California live birth certificates. We linked one or two steps (75%). During follow-up, 15 patients recurred and were those cancer cases to the CBDMP. RESULTS: We identified a cohort of treated by surgery and/or irradiation. Histological types and locations will 3,246,444 live births from 1988 to 2004, and 66,372 infants from the be discussed according to the outcome. The absence of large series of child- CBDMP with a structural birth defect. We linked 4,871 cancer cases to chil- hood meningiomas with long follow-up precludes any definite conclusions dren in the birth cohort; 227 of these had a birth defect. Cancer risk was on the clinical course and outcome. Uniform observations made in different increased in children with chromosomal anomalies (hazard ratio [HR] series including ours, include its male predominance, large size, distinctive 12.98, 95% confidence interval [CI] 10.57–15.94) and those with non- radiological features, and high rate of atypical/malignant histological sub- chromosomal birth defects (HR 1.48, 95% CI 1.26–1.76). Brain tumors types. Location and extent of excision appear to be more important than his- were identified in 39 children with birth defects, 3 with chromosomal and topathology grade in predicting outcome. ii46 NEURO-ONCOLOGY † JUNE 2010 Abstracts

RARE.02. TRIGEMINAL NEURINOMAS IN CHILDREN: underwent surgery, there were significant differences. The younger patients ANALYSIS OF SURGICAL TREATMENT IN 22 CASES more frequently presented with an incidental finding (78% vs. 14%, p ¼ D. Muzumdar and A. Goel; Seth Gordhandas Sunderdas Medical College 0.0081), less commonly had hydrocephalus (33% vs. 85%, p ¼ 0.2237), and King Edward VII Memorial Hospital, Mumbai, India, MUMBAI, India and had smaller cysts (mean maximal diameter 7.99 vs. 11.18 mm, p ¼ 0.0421). There were no differences in patient outcome, degree of removal, The surgical management issues of 22 cases of trigeminal neurinoma treated and recurrence rates. CONCLUSIONS: While differences exist between over an 18-year period were analyzed. The case records and radiologic material young patients compared with adults regarding colloid cyst presentation, of 15 patients with trigeminal neurinoma between the year 1990 and 2008 there appears to be no difference in outcome following endoscopic were retrospectively analyzed. The appropriateness of the selected surgical removal. These results may impact the decision making process for young route is studied. None presented with pathologic laughter. Three approaches asymptomatic patients given their expected life expectancy and projected were found appropriate to treat these tumors: the infratemporal fossa inter- rates of progression. dural approach, the lateral basal subtemporal approach, and the retrosigmoid approach. In 19 cases (83.3%), total tumor excision was achieved. There was no mortality. During an average follow-up of 60 months, there has been a recurrence in 2 cases and 17 patients are leading an independent and active life. Radical surgery is associated with an excellent clinical outcome and long- RARE.05. PRIMARY DIFFUSE LEPTOMENINGEAL Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 term tumor control. A majority of tumors, even those that are large and multi- GLIOMATOSIS (PDLG): A MULTI-INSTITUTIONAL STUDY OF compartmental, can be removed in a single surgical stage and exposure. A RARE ENTITY C. Milanaccio1, A. Rossi2, P. Nozza3, G. Piatelli4, J. Grill5, G. Perilongo6, E. Viscardi6, M. Massimino7, V. Biassoni7, F. Giangaspero8,and M. L. Garre`1; 1Neuro-Oncology Unit, Department of Pediatric Haemato-Oncology, Giannina Gaslini Children’s Research Hospital RARE.03. PRIMARY CNS LYMPHOMA IN CHILDREN AND (IRCSS), Genova, Italy; 2Neuroradiology, Giannina Gaslini Children’s ADOLESCENTS: A DESCRIPTIVE ANALYSIS FROM THE Research Hospital (IRCSS), Genova, Italy; 3Pathology, Giannina Gaslini INTERNATIONAL PRIMARY CNS LYMPHOMA Children’s Research Hospital (IRCSS), Genova, Italy; 4Neurosurgery, COLLABORATIVE GROUP IPCG) Giannina Gaslini Children’s Research Hospital (IRCSS), Genova, Italy; O. Abla1, S. Weitzman1, J. Y. Blay2, B. P. O’Neill3, L. Abrey4, E. Neuwelt5, 5Department of Pediatric, Istitut Gustave-Roussy, Paris, France; N. D. Doolittle6, J. Baehring7, K. Pradhan8, S. E. Martin9, M. Guerrera10, 6Department of Pediatrics, Division of Haematology-Oncology, University S. Shah11, M. Silver12, R. A. Betensky12, and T. Batchelor12; 1The Hospital Hospital of Padua, Padua, Italy; 7Unit of Paediatric Oncology, IRCCS for Sick Children, Toronto, ON, Canada; 2Centre Leon Berard, Lyon, Foundation, National Cancer Institute, Milan, Italy; 8Department of France; 3Mayo Clinic Cancer Center, Rochester, MN, United States; Experimental Medicine, University of Rome La Sapienza & IRCCS 4Sloan-Kettering Cancer Center, New York, NY, United States; 5Oregon Neuromed, Pozzilli, Rome, Italy Health & Science, Portland, OR, United States; 6Oregon Health & Science University, Portland, OR, United States; 7Yale University, New Haven, CT, PDLG is a rare entity characterized by widespread leptomeningeal infiltra- United States; 8Indiana University Medical Center, Indianapolis, IN, United tion without evidence of CNS intraparenchymal primary tumor. Since 1980 States; 9Helen F. Graham Cancer Center, Newark, DE, United States; less than 50 cases have been reported: only one third occurred in childhood. 10Children’s National Medical Center, Washington, DC, United States; Objectives of this study were to describe clinical and radiological features, 11Christus Santa Rosa Children’s Hospital, San Antonio, TX, United States; diagnostic work up, treatment and outcome of a four-institutional series. 12Harvard Medical School, Boston, MA, United States Between 1995 and 2008, 11 cases of PDLG were diagnosed. Age at diagnosis ranged between 2 and 15 years. Symptoms duration was highly variable (5 An international retrospective study was conducted to describe the demo- days-10 years). Early signs were often unspecific; neurological symptoms graphic and clinical features and outcomes of children and adolescents with were mainly related to intracranial hypertension, followed by behavioural primary CNS lymphoma (PCNSL). 29 patients with a median age of 14 years disturbances, back pain, gait abnormalities, cranial nerves palsy. were identified from ten cancer centers. All had disease confined to the brain Cerebrospinal fluid studies revealed elevated protein, moderate pleocytosis, or meninges. Sixteen (55%) had an ECOG PS ≥ 1. Most patients were no evidence of infection; in only 2 cases atypical cells were evident. immunocompetent; the most common pathological subtype was DLBCL Craniospinal MRI showed diffuse or nodular leptomeningeal enhancement (69%). CSF cytology was positive in 8/26 patients, 3 of them had primary predominant in cerebral sulci, cerebellum, basal cisterns, spinal cord. leptomeningeal lymphoma. Nineteen patients (66%) were treated with che- Ventriculomegaly was present in 8 cases. In all patients diagnosis was poss- motherapy (CT) only, while 10 (34%) had CT plus cranial radiotherapy ible after a meningeal biopsy (6/11 at clinical onset, 5/11 after a previous (CRT). Most patients received methotrexate (MTX)-based regimens. treatment for tuberculous meningitis). All patients were treated with che- Overall response rate was 86% (CR 69%, PR 17%). The 2 year PFS and motherapy, using different regimens; 8 children progressed during follow OS rates were 61% and 86%, respectively; the 3 year OS was 82%. up and none achieved CR: 3 died of disease, 4 are alive with progressive Univariate analyses were conducted for age (≤ 14 vs . 14 years), PS (0 or disease, 4 with stable disease. Our study confirmed the difficulties of early 1vs.1), deep brain lesions, MTX dose, front-line treatment with CT diagnosis due to the variability of clinical presentation, and to the lack of alone vs CT + CRT, intrathecal chemotherapy and high-dose therapy. CSF and neuroradiological specificity. Meningeal biopsy is the best approach Only CT alone was associated with better overall response rates with an for establishing a definitive diagnosis. Optimal treatment needs to be defined. OR of 0.125 (p ¼ 0.02). There was a marginally significant relationship between higher doses of MTX and response. ECOG-PS of 0 or 1 was the only factor associated with better outcome with hazard ratios of 0.136 and 0.073 for PFS and OS, respectively. The outcome of children and adolescents appears to be better than in adults. ECOG-PS of 0–1 is associated with better RARE.06. PRIMARY PERIPHERAL PRIMITIVE survival. International prospective studies are warranted. NEUROECTODERMAL TUMORS (PPNET) OF THE SPINAL CORD WITH T(11;22): REPORT OF THREE CASES AND REVIEW OF LITERATURE G. Dhall1, E. Adam1, R. J. Brown1, K. K. Wong1, S. Khatua1, J. L. Finlay1, and L. H. Wexler2; 1Childrens Hospital Los Angeles, Los Angeles, CA, RARE.04. COLLOID CYSTS OF THE THIRD VENTRICLE IN United States; 2Memorial Sloan-Kettering Cancer Center, New York, NY, CHILDREN AND YOUNG ADULTS United States M. M. Souweidane; Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, New York, NY, United States INTRODUCTION: pPNET is a small blue round cell tumor arising in bone and soft tissue that consistently demonstrates t(11;22). Only 4 cases of INTRODUCTION: The rarity of colloid cysts of the third ventricle in chil- primary spinal pPNET with t(11;22) have been reported. METHODS: We dren and young adults has delayed a comprehensive assessment in this popu- reviewed the medical records of 3 patients diagnosed with primary spinal lation. Further, most published series have not focused on any meaningful pPNET with t(11;22). RESULTS: Patient 1: A 16-year old female who pre- comparison as related to age. METHODS: From a prospective data base sented with an intradural mass from L2-S1 on spine MRI, underwent subtotal (inclusion dates 1995–2010), all endoscopic colloid cyst removals were resection, focal irradiation (XRT) from T12-S3 and vincristine, doxorubicin, assessed with emphasis on the age of the patient at the time of surgery. cyclophosphamide (CAV) and ifosfamide/etoposide (IE) chemotherapy. She Surgical indications, ventricular size, colloid cyst dimension, and surgical relapsed 20 months from diagnosis with leptomeningeal disease. She was outcome were compared (2 tail Fisher exact test) between patients aged 20 treated with cyclophosphamide/topotecan alternating with irinotecan/temo- years or less with those greater than 20 years old. RESULTS: From a total zolomide for 1 year, followed by craniospinal irradiation (CSI) and boost to of 61 endoscopic colloid cyst resections, 9 (15%) were performed on patients bulky disease. She progressed 3 months after completing XRT and died 37 20 years of age or younger (mean 15.8, range 9–20 years). When compared months after diagnosis. Patient 2: A 15-year old female presented with an with the 51 patients . 20 years of age (mean 45.7, range 23–80 years) who intradural mass at C3 on spine MRI. She underwent a complete excision, 7

NEURO-ONCOLOGY † JUNE 2010 ii47 Abstracts

cycles of CAV/IE, focal XRT (from C1 to C5), followed by 7 more cycles of Medicine until March 2008 was reviewed. Of the 906 patients with CPTs, CAV/IE. She is currently alive with no evidence of disease (NED) 14 months 190 patients had non-metastatic choroid plexus carcinoma. All non- from diagnosis. Patient 3: A 35-year old male presented with an intradural metastatic patients who underwent complete resection with or without radi- mass from T2-T3 and bulky leptomeningeal disease on spine MRI. He under- ation therapy were compared for effect of chemotherapy on survival. In non- went an incomplete resection followed by craniospinal irradiation and CAV/ irradiated patients, the overall survival of those receiving chemotherapy was IE chemotherapy. He is currently alive with NED 12 months from diagnosis. 76% compared to 38% in patients not receiving chemotherapy (p ¼ 0.024). CONCLUSION: Primary spinal pPNET with t(11;22) is an extremely rare In patients who received radiation therapy, the overall survival was 88% neoplasm. We present a series of 3 patients to better understand the presen- with the addition of chemotherapy and 76% in those who did not receive tation, treatment and outcome of this disease. chemotherapy (p ¼ 0.52). This literature database review supports the use of chemotherapy in patients with completely resected, non-metastatic choroid plexus carcinoma who do not receive radiation therapy as part of their treatment.

RARE.07. FOCAL GENOMIC AMPLIFICATION AT 19Q13.42 COMPRISES A DIAGNOSTIC MARKER FOR EMBRYONAL TUMORS WITH EPENDYMOBLASTIC ROSETTES Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 A. Korshunov1, M. Remke2,3, M. Gessi4, M. Ryzhova5, H. Witt2,3, CPT.02. MULTI-MODALITY TREATMENT OF CHOROID V. Tobias6, A. M. Buccoliero7, M. P. Gardiman8, J. Bonnin9, PLEXUS PAPILLOMAS IN INFANTS B. Scheithauer10, A. E. Kulozik2, O. Witt2,11, S. Mork12, A. von J. S. Myseros, J. J. Wind, R. F. Keating, and W. O. Bank; Children’s National Deimling13,1, F. Giangaspero14, M. Rosenblum15, T. Pietsch4, P. Lichter3, Medical Center, Washington, DC, United States and S. M. Pfister2,3; 1Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany; 2Department of Pediatric INTRODUCTION: Choroid plexus papillomas (CPP) of infancy represent Oncology, Hematology & Immunology, University of Heidelberg, a challenging group of tumors for the pediatric neurosurgeon despite their Heidelberg, Germany; 3Division Molecular Genetics, German Cancer benign nature. Because of their vigorous vascular supply, the young age Research Center, Heidelberg, Germany; 4Department of Neuropathology, and small blood volume of the children, morbidity and mortality can be sig- University of Bonn, Bonn, Germany; 5NN Burdenko Neurosurgical Institute, nificant. We present the current treatment algorithm used in our institution Moscow, Russian Federation; 6Department of Pathology, South Eastern for these formidable lesions. METHODS: Infants less than 12 months of Area Laboratory Service (SEALS) at Sydney Childrens Hospital, Sydney, age with CPPs of the lateral, third, and fourth ventricles, with presenting Australia; 7Department of Pathology, Careggi Hospital, Florence, Italy; signs and symptoms will be presented. Treatment strategies for CPPs of 8Pathology Unit, Azienda Ospedaliera, Padova, Italy; 9Division of various sizes and location, as well as the management of accompanying Neuropathology, Indiana University School of Medicine, Indianapolis, IN, hydrocephalus will also be addressed and discussed. RESULTS: All tumors United States; 10Department of Pathology, Mayo Clinic, Rochester, MN, were successfully treated by the following: surgery alone, feeding vessel United States; 11Clinical Cooperation Unit Pediatric Oncology, German embolization followed by surgery, or embolization alone. In addition, preo- Cancer Research Center, Heidelberg, Germany; 12Department of Pathology, perative hydrocephalus in this young group seldom resolved post-tumor The Gates Institute, Bergen, Norway; 13Department of Neuropathology, treatment and required subsequent diversionary shunting. DISCUSSION: University of Heidelberg, Heidelberg, Germany; 14Department of Pathology, The best long-term survival for CPPs is based on complete surgical resection. University La Sapienza, Rome, Italy; 15Department of Pathology, Memorial Although smaller tumors, particularly in the lateral and fourth ventricles, are Sloan-Kettering Cancer Center, New York, NY, United States amenable to upfront resection, the recent advances in interventional embolization techniques, even in small infants, have assisted in minimizing intrao- Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil perative bleeding, decreasing complications, and allowing for more and true rosettes (ETANTR) are very aggressive embryonal neoplasms controlled and safer surgery, particularly for larger lesions and those in the characterized by the presence of true or “ependymoblastic” rosettes typically less-accessible third ventricle. Specifically, we present one case of definitive occurring in children below six years of age. It has not been established radiographic resolution of a third ventricular CPP treated with embolization whether these two tumors really comprise distinct entities. Using aCGH alone. we identified a unique focal amplification at 19q13.42 in a case of ETANTR, which we had never identified in any of 150 medulloblastomas or stPNETs, and 120 intracranial ependymomas on the same platform. Consecutively, we investigated this locus by FISH in 39 tumors which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH CPT.03. CHOROID PLEXUS TUMORS IN CHLIDREN. ONE analysis revealed 19q13.42 amplifications in 35/37 samples with appropri- INSTITUTION EXPERIENCE ate hybridization signals (95%). Among tumors harboring the amplification, I. Filipek, B. Dembowska-Baginska, M. Drogosiewicz, M. Perek-Polnik, 17 samples were identified as ETANTR and 18 as EBL. The two remaining E. Swieszkowska, M. Roszkowski, and D. Perek; The Children’s Memorial tumors (both diagnosed as EBL) only showed a polysomy of chromosome 19. Health Institute, Warsaw, Poland The amplification was present in 30–80% of nuclei in primary tumors and was evenly distributed in neuropil-like and cell-rich areas. Analysis of recur- The aim of our study was to analyze clinical data and treatment outcome rent/metastatic tumors (n ¼ 7) showed that the proportion of nuclei carrying in children with CPT treated in our department. Seventeen patients (pts) the amplification was further increased (up to 80–100% of nuclei) in com- treated between 1996 and 2009, 8 girls and 9 boys aged 3 months to 17 parison to their primaries. In conclusion we have identified a hallmark cyto- years (median 21 months), were evaluated. Nine pts were under 3 years of genetic aberration occurring in virtually all embryonal brain tumors with age at diagnosis. Sixteen pts had choroid plexus carcinoma, one atypical ependymoblastic rosettes indicating that ETANTR and EBL may comprise papilloma. Nine patients had localized disease, 3 had multifocal tumors, 5 a single biological entity. FISH analysis of the 19q13.42 locus is a very prom- showed dissemination. Six pts had complete tumor resection, 1 gross total ising diagnostic tool to identify a subset of primitive neuroectodermal tumors resection, 9 partial resection and 1 biopsy. In all patients chemotherapy with distinct morphology, biology, and clinical behavior. was administered (14 pts- CPT-SIOP-2000 protocol, pts treated before 2000- other protocols). Eleven pts were irradiated (9 pts in first line treatment, 2 in second line). Twelve out of 17 pts are alive 8 months to 8.5 years from diagnosis (median 3.3 years): 9 pts after surgery, chemotherapy 23 CHOROID PLEXUS TUMOR and radiotherapy, 3 pts after tumor resection (total or gross total) and chemotherapy. All pts alive were treated according to CPT-SIOP-2000 protocol. Four pts relapsed locally from 5m to 2yrs7m from diagnosis. None of them CPT.01. CHEMOTHERAPY IMPROVES SURVIVAL IN received radiotherapy in first line treatment. All relapsed patients died 9 NON-IRRADIATED NON-METASTATIC CHOROID PLEXUS months to 11.4 years from diagnosis (3 pts of disease, 1 of second malig- CARCINOMA nancy). Three pts progressed: 1 pt died, 2 pts are still treated. Five year B. G. Hemker1, J. E. Wolff2, S. G. Berrak3, and S. S. Jogal1; 1Medical College overall survival is 75%. In our series extent of surgical resection and radio- of Wisconsin, Milwaukee, WI, United States; 2M.D. Anderson Cancer therapy had prognostic relevance; in case of residual disease and dissemina- Center, Houston, TX, United States; 3Marmara University Medical Center, tion response to chemotherapy and complete remissions were observed. Altunizade, Istanbul, Turkey Study supported by grant R130011 06/2009 from Ministry of Science, Poland Choroid plexus tumors are rare brain tumors in children. Choroid plexus carcinomas in general have a poor prognosis. There is role for aggressive surgical resection in non-metastatic choroid plexus carcinoma. However, there is little data regarding the role of chemotherapy in patients with completely resected, non-metastatic choroid plexus carcinoma. To evaluate this question, the CPT database containing all CPTs registered at the Library of ii48 NEURO-ONCOLOGY † JUNE 2010 Abstracts

CPT.04. RESECTION NOT SO IMPORTANT AFTER ALL? - differentiating glial cells. Studies in mouse glioma models point to ANALYSIS OF THE CHOROID PLEXUS TUMOR SIOP STUDY neural and glial progenitors as a potential cellular origin of human J. E. Wolff1, B. Wrede2, J. Weinberg1, O. Peters2, A. Mahajan1, P. Thall1, gliomas. It is unclear, however, whether the ability to undergo asym- O. Witt3, T. Kutluk4, B. Diez5, S. Rutkowski6, A. S. Carret7, P. Hauser8, and metric cell division (ACD) is somehow linked to the neoplastic transform- M. Hasselblatt9; 1MDAnderson Cancer Center, Houston, TX, United States; ation of mammalian glial progenitors. Understanding the steps that turn 2Pediatric Oncology, Regensburg, Germany; 3DKFZ, Heidelberg, Germany; normal progenitors to glioma cells is however important as it may yield 4Hachettepe University, Istanbul, Turkey; 5Pediatric Oncology, Buenos novel therapeutic targets. For mechanistic insights into progenitor trans- Aires, Argentina; 6University Hospital, Hamburg, Germany; 7St Justine, formation, we deviced novel cell culture based and in vivo assays to visu- Montreal, QC, Canada; 8Semmelweis, Budapest, Hungary; alize and quantify ACD of normal and malignant mammalian glial 9Neuropathology, Muenster, Germany progenitors. Using these assays, we show in a mouse glioma model that glial progenitors switch from asymmetric to symmetric divisions at QUESTION: For choroid plexus tumors, meta-analyses have shown com- premalignant stages in response to upregulated epidermal growth factor plete resection to be of prognostic relevance (Br J Cancer 87:1086). Here we receptor. Upon loss of p53, glial progenitors become malignant, comple- analyzed prospectively collected data in the context of the CPT-SIOP-2000 tely loose ACD, fail to differentiate and rather expand through symmetric study for the same question. DATA: 173 patients were registered from 26 divisions. These data suggest that loosing the ability to divide asymmetri- nations. Among those 57 had choroid plexus papilloma (CPP), 49 atypical cally is directly linked to malignant transformation of glial progenitors. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 choroid plexus papilloma (APP), and 57 choroid plexus carcinoma (CPC). In support of such a direct link, we found that expression levels of 10 had other tumors and were excluded from further analysis. Gross total ACD regulator proteins are frequently altered in human glioblastoma. resections were achieved in 79%, 92%, and 61% of the CPP, APP, and We present how we use our novel assays to determine whether loss of CPC, respectively. The 5 year overall survival (OS) was 83% (+0.5), and cellular asymmetry directly causes defects frequently found in human the event free survival (EFS) 63 (+0.6). When comparing prognostic glioma cells. Lastly, we will discuss how understanding the function of factors, the histologic grading has the same relevance as in the meta-analysis ACD regulators in gliomagenesis may lead to novel therapeutic (CPP best, CPC worst). However, the relevance of surgery has changed: For approaches for pediatric brain tumors. Kaplan-Meier curves and log rank tests, the survival curves crossed for patients with complete resection versus incomplete resection regardless if this was done with EFS or OS. In some subgroup analyses, the result was even opposite with incomplete resection linked to a better outcome. For instance, the 2 year OS for completely resected CPC was 67% (+0.93) P-BIO.02. RNA EDITING IN PEDIATRIC ASTROCYTOMAS AND and for CPC after partial resection 83% (+0.93). The same results were OTHER TUMORS true when using COX-regression analysis regardless which endpoint was A. Gallo1, L. Massimi2, F. Galeano1, S. Tomaselli1, L. D’angelo2, and C. Di used. INTERPRETATION: We do not think this should call for leaving Rocco2; 1OPBG, Rome, Italy; 2Catholic University Medical School, Rome, tumor behind unnecessary. Instead, we hypothesize that it is caused by Italy more chemotherapy given to the patients with residual tumors. RNA editing is a mechanism to create new proteins through the adenosine (A) to inosine (I) conversion in pre-mRNA. The A-to-I editing is realized by the ADAR enzymes (ADAR1, ADAR2 and ADAR3). A reduction of RNA editing has been found in adulthood malignant gliomas. Here, we report a CPT.05. DOES THE P53 STATUS JUSTIFY TREATMENT study concerning the RNA editing activity in pediatric astrocytomas and DECISIONS IN CHOROID PLEXUS TUMORS (CPTS)? the effects of the reintroduction of ADAR2 in astrocytoma cell lines. For J. E. Wolff1, S. Van Gool2, A. Kruse3, O. Peters4, B. Wrede4, T. Pietsch5, this purpose: 1) The samples of 14 children (10 astrocytomas and 4 R. Kebudi6, D. Malkin7, T. Hassel8, I. Slavc9, W. Paulus3, and control tissues) were analyzed and, 2) Human astrocytoma cell lines M. Hasselblatt3; 1MDAnderson Cancer Center, Houston, TX, United States; (U118, A172, U87) were transfected by ADAR2 to evaluate possible 2Pediatric Oncology, Leuven, Belgium; 3Neuropathology Institute, changes. A decreased editing activity was found in astrocytoma samples, Muenster, Germany; 4Pediatric Oncology, Muenster, Germany; with an inverse relationship between the tumor grade and the ADAR2 5Neuropathology, Bonn, Germany; 6Pediatric Oncology, Istanbul, Turkey; editing activity. After the re-introduction of ADAR2, astrocytoma cells 7Genetics, Sick Kids Hospital, Toronto, ON, Canada; 8Pediatric Oncology, showed a significant reduction of their proliferation and migration. To Brisbane, Australia; 9Pediatric Oncology, Vienna, Austria study whether RNA editing is decreased in other human tumors rather than in the brain ones, we identified a new ADAR substrate, the Choroid plexus tumors are frequent in Li-Fraumeni families with bladder cancer-associated protein (BLCAP), which is ubiquitously mutated p53. We analyzed the existing data of the CPT-SIOP-2000 expressed and edited by both ADAR1 and ADAR2 at different sites. study, for the question, if the p53 status should be taken into account We found a down-regulation of the BLCAP editing in all the sites, in the treatment algorithm. The question, if the patient had p53 mutation mainly edited by ADAR2 in different tumor tissues when compared in tumor or in germ line was not a prospectively planned question. Data with their related normal tissues. These identified down-regulated were available in some patients through the consultation service of the editing events can be useful to distinguish malignancies or epigenetic study center. In three patients p53 germ line mutations were confirmed. changes in different tumors. One of these three patients had unexpected high treatment toxicity, the other two did well on treatment. In 69 tumors, p53 expression could be analyzed by immunohistochemistry. It was stabilized (¼not functioning) in 10 and normal in 59. As a univariate parameter, the p53 status of CPTs appeared to be of prognostic significance (p ¼ 0.002) for event-free P-BIO.03. DEVELOPMENT AND CHARACTERISATION OF IN survival. However, in a Cox regression analysis using age, histological VIVO MODELS OF PAEDIATRIC HIGH-GRADE GLIOMA type, metastatic status, and completeness of resection as covariates, the L. A. Perryman1, G. Box2, J. K. R. Boult3, L. Marshall1, S. Popov1, A. Jury1, statistical relevance was lost (p ¼ 0.3), as the available data were too A. D. J. Pearson4, P. Workman2, D. Hargrave4, S. P. Robinson3, C. Jones1, few. These data do not allow making a treatment decision based on and S. A. Eccles2; 1Paediatric Oncology, The Institute of Cancer Research, the p53 status. For the next protocol CPT-SIOP-2009, the p53 status Sutton, Surrey, United Kingdom; 2Cancer Research UK Centre for Cancer will be evaluated prospectively through a new collaboration with the Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United genetic laboratory in Toronto. Kingdom; 3Cancer Research UK and EPSRC Cancer Imaging Centre, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom; 4Paediatric Oncology, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom POSTER PRESENTATIONS P01 BIOLOGY Glioma is the most common form of brain cancer in children, and despite advances in cancer therapy the prognosis of high grade (HGG) lesions remains poor. Progress in the treatment of these tumours is hampered in part by a lack of well-characterised in vivo models of paediatric P-BIO.01. POLARITY AND ASYMMETRIC DIVISION OF BRAIN HGG that accurately reflect the clinical disease. As well as representing PROGENITORS AS NOVEL MECHANISMS OF TUMOR the specific genomic alterations present in childhood tumour samples, SUPPRESSION IN GLIOMAGENESIS models need to mimic the infiltrative phenotype often absent in currently C. Petritsch, S. Sugiarto, E. Gonzalez Munoz, J. Philips, C. James, and available adult HGG xenografts. We have utilised serial xenografting of a M. Berger; University of California San Francisco, San Francisco, CA, United panel of previously profiled paediatric glioma cell lines in order to estab- States lish tumours in vivo, both subcutaneously as well as orthotopically via intracranial injection. Tumours were imaged by both bioluminescence Normal mouse glial progenitor cells divide asymmetrically to maintain using incorporation of a luciferase construct (luc) and magnetic resonance a stable balance of proliferative, glial progenitors and post-mitotic,

NEURO-ONCOLOGY † JUNE 2010 ii49 Abstracts

imaging. Neither of the low grade cell lines (Res259 and Res186) were non-stem-like serum-cultured counterpart. NF-kB inhibitors sulphasala- found to be tumorigenic at either site, whilst by combined use of zine and parthenolide induced growth inhibition in primary patient and MatrigelTM and growth factors, all HGG cells generated sublines with established medulloblastoma, ependymoma and anaplastic astrocytoma 100% take rate both subcutaneously and intracranially. Orthotopic xeno- cell lines, in a dose dependent fashion (IC50 parthenolide: 4 mM, 2– grafts derived from SF188luc, KNS42A1.1luc, and UW479B1.1luc cells 12 mM, 6 mM and IC50 sulphasalazine: ≈ 300 mM). Likewise, dose- were established in 20, 31 and 42 days respectively. These tumours dis- dependent reduction of transcriptional activation of NF-kB-p65 using a played a prominent invasion into the surrounding brain, varying degrees NF-kB Gaussia luciferase reporter system was detected in these cells. of necrosis and vasculature, and less atypical nuclear pleomorphism Combining irradiation with sulphasalazine and parthenolide, no radiosen- than their subcutaneous counterparts. The development of such models sitization was observed in medulloblastoma cells. This might be due to derived from childhood tumour samples in the appropriate brain micro- their low NF-kB expression and relatively high radiosensitivity. environment may help to fulﬁl a currently unmet need for the preclinical Whether sulphasalazine and parthenolide sensitize the more radioresistant and mechanistic assessment of novel therapeutic strategies in paediatric ependymoma and HGG cells to radiation is currently under investigation. HGG. CONCLUSION: NF-kB is constitutively activated in childhood HGG and ependymoma and inhibition of NF-kB induces growth inhibition in these cells. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021

P-BIO.04. COMPARISON OF INTRATUMORAL BIODISTRIBUTION OF A PEGYLATED AND A NON-PEGYLATED FORM OF LIPOSOMAL DOXORUBICIN IN P-BIO.06. SILENCING OF TRANSCRIPTIONAL FACTORS YB1 ORTHOTOPIC HIGH GRADE GLIOMA XENOGRAFTS AND NFKB REGULATES DISSIMILAR ABC PROTEINS AND P. Chastagner1, H. Sudour1, S. Pinel1, and M. Barberi-Heyob2; 1EA 4421, ENHANCES APOPTOSIS IN PEDIATRIC BRAIN TUMOR CELL Nancy University, France, Vandoeuvre, France; 2UMR 7039 CNRS, Centre LINES EXPOSED TO VINBLASTINE A. Vautrin, Nancy University, Vandoeuvre, France E. T. Valera1, M. A. A. F. Cortez2, M. S. Brassesco1, V. S. Silveira1, R. G. P. Queiroz1, A. G. Morales2, J. C. Oliveira2, J. A. Pezuk2, N. Jabado3, BACKGROUND: Biodistribution studies showed that liposomal forms D. Faury3, M. S. Bobola4, C. A. Scrideli1, and L. G. Tone1; 1Department of of doxorubicin (DXR) reduce DXR concentrations in sensitive organs, Pediatrics, University of Saõ Paulo, Ribeiraõ Preto, Brazil; 2Department of but increase it in tumors. Liposomal entrapped DXR (L-DXR) improves Genetics, University of Saõ Paulo, Ribeiraõ Preto, Brazil; 3Department of penetration through the blood-brain barrier. Using a heterotopic model of Pediatrics, Montreal Children’s Hospital Research Institute/McGill human malignant gliomas xenografts, we demonstrated a synergistic anti- University Health Center, Montreal, QC, Canada; 4Department of tumor effect of non pegylated L-DXR concurrently associated with radio- Neurological Surgery, University of Washington, Seattle, WA, United States therapy. We aim to determine the maximal tolerable dose (MTD) of 2 L-DXR forms (pegylated or not) with 2 injection schedules and to BACKGROUND: information on regulation of ABC proteins, a potent evaluate which L- DXR form and schedule allow to obtain the highest transmembrane inducer of cell resistance, may unravel potential targets for and more prolonged tumor concentration in order to design a radiosensi- adjuvant treatment in brain cancer. OBJECTIVES: to evaluate the influence tizing treatment. METHODS: DXR concentrations in normal and of siRNA of Yb1 and NFkB on the expression of ABCB1, ABCC1 and tumoral brain hemispheres were assessed by HPLC in an orthotopic ABCG2 in pediatric cell-lines SF188 (glioblastoma) and UW3/UW473 model of malignant glioma xenografts (U87). Each L-DXR form was (medulloblastoma), prior and following exposure to vinblastine, a potent administered at these MTD in 4 or 6 injections over 2 weeks. ABC inducer. To compare the dynamics of cell proliferation and apoptosis RESULTS: MTD were 30 and 12 mg/kg, respectively for the non- in this setting. METHODS: SF188, UW3 and UW473 cell-lines were cul- pegylated and the pegylated L-DXR forms, whatever the schedule. tured at 378C, 5%CO2, in Opti-MEM media. Experiments were performed Using these equi-toxic doses, average DXR concentrations were always in unmodified cells and following subculture with vinblastine sulphate higher in the tumor/normal cerebral tissue. The best tumoral/normal (10nM). SiRNA of Yb1 and NFkB were achieved by specific pre-designed oli- AUC ratio was 5.9 for the non-pegylated form versus 3.6. The best gomers, and reversely transfected using lipofectamine. Efficiency of silencing AUC observed in the tumoral hemisphere was obtained with the non- was verified through QPCR and Western Blotting. Cell proliferation was pegylated form administered in 4 injections. CONCLUSION: Multiple evaluated by XTT method; apoptosis by caspase-3 activation. Statistical injections of L- DXR forms lead to good and prolonged DXR brain analysis: non-parametric Dunn test, Kruskal-Wallis post-test (proliferation); tumor impregnation with a very favorable tumoral/normal brain ratio Fisher exact-test (apoptosis). RESULTS: SiRNA for both NFkB and Yb1 which promotes the treatment of malignant gliomas using L-DXR lowered ABCC1 expression in unmodified SF188 and of ABCG2 in resistant forms concurrently with radiotherapy. SF188. Medulloblastoma cell-lines over-expressed ABCB1 following vinblastine and SiRNA for Yb1 reduced ABCB1. SiRNA of both Yb1 and NFkB promote apoptosis only in the presence of vinblastine (p , 0.001). Cell proliferation was unaffected. DISCUSSION: NFkB and Yb1 seem to regulate dissimilar ABC transporters in different brain tumor cells. P-BIO.05. DEREGULATION AND POTENTIAL THERAPEUTIC Silencing of these transcriptional factors adjuvant to chemotherapy enhances TARGETING OF THE NF-kB PATHWAY IN HIGH-GRADE apoptosis. New compounds that repress expression of either NFkB or Yb1 CHILDHOOD BRAIN TUMORS might be an interesting model to be tested in association to chemotherapy. D. G. Van Vuurden1,2, E. Hulleman2,3, P. M. Van der Stoop2,3, R. Gupta2, Supported by FAPESP: grant 2007/04065–9. L. E. Wedekind2,3, C. E. Badr2,4, D. H. Meijer2, D. P. Noske2,3, T. Wu¨ rdinger2,4, G. J. L. Kaspers1, and J. Cloos1,5; 1Department of Pediatrics, Pediatric Oncology / Hematology, VU University Medical Center, Amsterdam, Netherlands; 2Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, P-BIO.07. AMPLIFICATION OF MYCN AND MYCC IN Netherlands; 3Department of Neurosurgery, VU University Medical Center, PEDIATRIC BRAIN TUMORS Amsterdam, Netherlands; 4Molecular Neurogenetics Unit, Departments of A. Vicha1, M. Zapotocky´ 1, M. Tichy2, J. Zamecnik3, J. Malis1, and Neurology and Radiology, Massachusetts General Hospital and Harvard D. Sumerauer1; 1Dep. Of Pediatric Hematology and Oncology, 2nd Medical Medical School, Boston, MA, United States; 5Department of Hematology, faculty and Faculty hospital Motol, Prague, Czech Republic; 2Departament VU University Medical Center, Amsterdam, Netherlands of Neurosurgery, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic, Prague, Czech Republic; The nuclear factor kappa B (NF-kB) family of transcription factors is 3Departament of Pathology and molecular medicine, 2nd Medical School, constitutively active in multiple cancers, promoting the transcription of Charles University and University Hospital Motol, Prague, Czech Republic, genes involved in apoptosis resistance, tumor development and pro- Prague, Czech Republic gression, angiogenesis and invasion. Aim of this study is to investigate the role of aberrant NF-kB-p65 activation in high-grade childhood Brain tumors are the most common malignant tumors in children. Current brain tumors, thought to arise from defective normal development and treatment decisions are based on clinical variables. Novel tumor-derived bio- maturation pathways. Since NF-kB activation is described to convey markers may improve the risk stratification of these patients. I-FISH analysis radioresistance, this research will focus on the radioresistance found in for the detection of MYCN and MYCC amplification was performed. these tumors. Immunohistochemistry of (phospho-)NF-kB revealed consti- Amplification of MYCN/MYCC is defined as a greater than 4-fold increase tutive expression / activation in ependymoma and high-grade glioma in the MYCN/MYCC signal number as compared to a reference signal (HGG), but weak to negative expression in medulloblastoma samples. probe. We investigated 354 tissues from 292 patients (Astrocytoma 132, Interestingly, immunofluorescence microscopy showed very strong glioblastoma 9, Medulloblastoma 57, PNET 15, Ependymoma 39, other expression of phosphorylated NF-kB-p65 in stem-like anaplastic astrocy- 31). High-level amplification of MYCN or MYC was detected in ten toma cells growing in neurobasal medium as compared to their tumors (3,4%) and eight tumors (2,7%), respectively, without ii50 NEURO-ONCOLOGY † JUNE 2010 Abstracts

co-amplification. In the medulloblastoma/PNET group we found amplifica- P-BIO.10. DO b-ADRENERGIC RECEPTORS PLAY A ROLE IN tion of MYCN or MYC in five tumors (3,6%) and 6 tumors (4,3%), in the PEDIATRIC BRAIN TUMOR NEOANGIOGENESIS? A group of glial tumors only an astrocytoma grade 3, a sample of gliomatosis MOLECULAR ANALYSIS cerebri and two glioblastoma showed amplification(3x MYCN; 1x MYCC), I. Sardi1, L. Giunti1, L. Filippi2, A. M. Buccoliero3, E. Sieni1, D. Rossi and in the ependymoma group one ependymoma grade 2 and two ependy- Degl’Innocenti3, M. Massimino4, L. Genitori5, and M. Arico` 1; 1Department moma grade 3 (1x MYCN; 2x MYCC). In the group of those 18 patients of Pediatric Hematology Oncology, Anna Meyer Children’s Hospital, with amplification 13 patients (72%) died, 12 for progressive disease and Florence, Italy; 2Department of Neonatology, Anna Meyer Children’s one from treatment complication. We confirm CR in four cases, two patients Hospital, Florence, Italy; 3Department of Human Pathology and Oncology, are still under treatment, one only 8 month from end of therapy. Only one University, Florence, Italy; 4Department of of Pediatrics, IRCCS Foundation, patient with medulloblastoma is a long term survivor (8.25 years). In a National Cancer Institute, Milan, Italy; 5Department of Neurosciences, patient with metastatic ependymoma grade 3 progressive disease was Anna Meyer Children’s Hospital, Florence, Italy detected. Mean survival from diagnosis was 17,34 month (median 13 month). We confirm that amplification of MYCC or MYCN can be detected Microvessels b-adrenergic receptors have been well characterized in in all types of childhood brain tumors. Amplification is associated with high human and animal brain. They seem to subserve the regulation of capillary grade tumors and with bad prognosis. Supported by VZFNM 0064203 function in both physiological and pathological conditions. Three subtypes have been distinguished: b1, b2 and b3- adrenergic receptors. Brain Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 tumors are supplied by vessels that differ from those supplying normal cerebral tissue in various structural and functional parameters. In order to study the characteristics of brain tumor microcirculation, we investigated P-BIO.08. INTRACELLULAR LOCALIZATION OF TAP73 AND the presence of b-adrenergic receptors in different types of pediatric DNP73 PROTEIN ISOFORMS IN MEDULLOBLASTOMA CELL tumors highly vascularized (3 anaplastic ependimoma; 6 Medulloblastoma LINES and 3 high grade glioma, HGG) using qRT-PCR and immunohistochemistry K. Zitterbart1, M. Nekulova2, J. Sterba1, and R. Veselska2; 1Department of of b-adrenergic receptors (b1, 2 and 3). The preliminary expression data Pediatric Oncology, University Hospital Brno and Masaryk University, Brno, indicate the presence of b1andb2 receptors and the absence of expression Czech Republic; 2Department of Experimental Biology, School of Science, of b3 receptor in all types of pediatric tumors in our study versus our Masaryk University, Brno, Czech Republic control (Universal Human Reference RNA, Stratagene). Our study showed the feedback of b1 and b2 receptors expression in microvascolarization p73, the protein homologous to the tumor suppressor p53, has been shown could represent a main mechanism in regulation of tumor vascolarization. to play essential roles during development and tumorigenesis. We have pre- Thus, beta blockers alone or in combination with chemiotherapeutic viously documented that p73 immunohistochemical positivity may be a agents could play a relevant role in blocking neoangiogenesis of pediatric marker of unfavorable outcomes in medulloblastoma [Zitterbart et al., brain tumors. Acta Neuropathol 2007]. However, there are virtually no detailed morphological studies analyzing endogenous expression of p73 isoforms at cellular level in cancer cells. In this study, we investigated the expression and subcel- lular distribution of two N-terminal isoforms, TAp73 and DNp73, in five medulloblastoma cells using immunofluorescence microscopy. Both proteins P-BIO.11. CYTOPLASMIC LIPID DROPLETS - A NOVEL were observed in all cell lines used, but some differences in intracellular local- INDICATOR OF TUMOUR GROWTH AND POTENTIAL ization between Daoy cell line and newly established medulloblastoma cell THERAPEUTIC TARGET IN CHILDHOOD BRAIN AND lines (MBL) were noted. TAp73 as well as DNp73 were located predomi- NERVOUS SYSTEM TUMOURS nantly in cell nuclei, however, there was a heterogeneity in TAp73 distri- X. Pan1,2, M. Wilson1,2, C. M. McConville1, M. Brundler2, bution in MBL cells, with protein located also in the limited non-random T. N. Arvanitis1,2, J. L. Griffin3, R. A. Kauppinen4, and A. C. Peet1,2; area in the cytoplasm. In small percentage of cells, there was cytoplasmic 1University of Birmingham, Birmingham, United Kingdom; 2Birmingham localization of TAp73 only, i.e. nuclear exclusion was observed. Our Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom; results provide a basis for future studies of the causes and functions of dis- 3University of Cambridge, Cambridge, United Kingdom; 4Dartmouth tinct intracellular localization of p73 protein isoforms in medulloblastoma College, Hanover, NH, United States cells with respect to different protein-protein interactions. This study was supported by grant IGA MZCR NS10218–3/2009 BACKGROUND: Tumour lipid signals detected by 1H Magnetic Resonance Spectroscopy are correlated with grade, treatment response and outcome. The signals are thought to arise from cytoplasmic lipid droplets (LDs), dynamic organelles containing proteins, polar and non-polar lipids. The close association of LDs with tumour growth makes them a potential P-BIO.09. ABCB1 EXPRESSING CANCER STEM CELLS SURVIVE target for novel therapy. METHODS: Sucrose-gradient ultracentrifugation DRUG TREATMENT IN EPENDYMOMA AND PNET CELL LINES was performed to isolate LDs from four human tumour cell lines, DAOY W. Punjaruk, D. Hussein, D. Carrier, L. C. D. Storer, P. Braker, (medulloblastoma), PFSK (ST-PNET),U87-MG (glioblastoma) and R. G. Grundy, I. D. Kerr, and B. Coyle; University of Nottingham, BE(2)M17 (neuroblastoma). Nile red staining was applied to assess the Nottingham, United Kingdom size of the LDs. 1H NMR spectroscopy was performed on the whole cells, the isolated LDs and a chloroform/methanol extract of both the LDs and An understanding of the mechanism of drug resistance in hard-to-cure, whole cells. A detailed chemical analysis of LDs was performed by Mass high-risk PNETs and ependymomas will allow the targeting of the cells Spectrometry. RESULTS: 1H NMR lipid-signals showed a close correspon- that subsequently promote tumour re-growth. These cells may initially be dence between whole cells and isolated fractions supporting the assertion refractive to therapy, or able to up-regulate drug resistance pathways in that the lipid signals arise from intracellular LDs. A positive correlation response to therapy. We tested the hypothesis that cancer stem cells expres- was observed between the size and amount of Nile red stained LDs and sing ATP binding cassette (ABC) multidrug transporters lie at the root of this the visibility of the 1H NMR signals. 1H NMR and mass spectroscopic analy- resistance. We investigated the clonogenic survival of five patient derived cell sis revealed that the LDs contain protein as well as phosphatidylcholine, tri- lines in response to etoposide, irinotecan, cisplatin and methotrexate, all glycerides, cholesterol and cholesterol ester with fatty acid chains being clinically applied ABC transporter substrates. Immunofluorescence and saturated, mono-unsaturated and polyunsaturated. The composition differed western blotting analysis demonstrated that ABCB1 was predominantly from that of whole cell extracts. CONCLUSIONS: Cytoplasmic LDs are an co-expressed with the stem cell marker CD133 in drug-selected clones. important component of childhood brain and nervous system tumour cells Flow cytometric comparison to the parental cell lines demonstrated that, which can be imaged using MRS. Their composition is different from the for a recurrent ependymoma cell line, drug-selected clones comprised a lipid pool of the whole cell and may provide a novel therapeutic target. similar proportion of cells expressing functional ABCB1. This proportion remained remarkably stable and did not increase after multiple rounds of drug treatment. In contrast, drug selected clones from the other lines (a primary ependymoma, a primary CNS PNET and primary and recurrent medulloblastomas) comprised a higher proportion of extruding cells. Finally, we have demonstrated that inhibition of ABCB1 function re-sensitizes our cells to these drugs. In summary, we have demonstrated using a panel of cell lines representative of 3 different tumour types, that the presence of ABCB1 expressing cancer stem cells can explain both tumour recurrence and progression. Importantly, we have also shown that inhibition of ABCB1 can re-sensitize cells to chemotherapy, even after multiple rounds of drug-selection.

NEURO-ONCOLOGY † JUNE 2010 ii51 Abstracts

P-BIO.12. IDENTIFICATION OF PEDIATRIC BRAIN P-MED.02. GENOME-WIDE MOLECULAR NEOPLASMS USING RAMAN SPECTROSCOPY CHARACTERISATION OF CENTRAL NERVOUS SYSTEM D. Leslie1, J. Poulik2, R. Kast3, R. Rabah4, L. Reisner3, A. Pandya3, S. Sood5, PRIMITIVE NEUROECTODERMAL TUMOUR AND G. Auner3, and M. Klein1; 1Department of Surgery Children’s Hospital of PINEOBLASTOMA Michigan/Wayne State University, Detroit, MI, United States; 2Department S. M. Miller1, H. A. Rogers1, V. Rand1, M. Adamowicz1, S. Dyer2, of Pathology Children’s Hospital of Michigan/Wayne State University, M. Brundler3, J. Lowe4, B. Coyle1, and R. G. Grundy1; 1Children’s Brain Detroit, MI, United States; 3Smart Sensors and Integrated Microsystems/ Tumour Research Centre, University of Nottingham, Nottingham, United Wayne State University, Detroit, MI, United States; 4Department of Kingdom; 2West Midlands Regional Genetics Laboratory, Birmingham Pathology University of Michigan Health System, Ann Arbor, MI, United Women’s Hospital, Birmingham, United Kingdom; 3Department of States; 5Department of Neurosurgery Children’s Hospital of Michigan/ Pathology, Birmingham Children’s Hospital, Birmingham, United Kingdom; Wayne State University, Detroit, MI, United States 4Department of Neuropathology, Nottingham University Hospital, Nottingham, United Kingdom PURPOSE: Raman spectroscopy can quickly and accurately diagnose tissue in near-real-time. This study evaluated Raman spectroscopy’s diagnos- Central nervous system primitive neuroectodermal tumours (CNS PNET) tic ability with pediatric brain tumors. METHODS: Samples of untreated and pineoblastoma are highly malignant embryonal brain tumours of poor pediatric medulloblastoma (n ¼ 4 samples from 4 patients) and glioma prognosis. Improved therapies based on an understanding of the underlying Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 (astrocytoma, oligodendroglioma, ependymoma; n ¼ 27 samples from 19 biology are urgently needed. 36 paediatric CNS PNETs and 8 pineoblasto- patients) were collected fresh from the operating room or from our frozen mas were analysed using Affymetrix SNP arrays to identify genome-wide tumor bank. Normal brain samples (n ¼ 33 samples from 5 patients) were copy number alterations. Gene copy number alterations were validated also collected. Half of each sample was tested using routine pathology. using qPCR. Loss of CDKN2B/p15INK4b was further investigated at the The other half was tested using Raman spectroscopy. At least 12 Raman protein level using immunohistochemistry. Overall, frequent gains of 1q spectra were collected from each sample. Principal component analysis (22.7%), 2p (15.9%), 21q (15.9%) and loss of 16q (11.4%) were identified. was used to compress the data, and leave-one-out support vector machine Patterns of broad copy number changes were associated with patient age and analysis was used to classify spectra using the pathology diagnosis as the anatomical location of the tumour. Unsupervised hierarchical clustering of gold standard. RESULTS: Normal spectra (n ¼ 321) were correctly distin- cytoband copy number imbalance revealed the pineoblastomas clustered sep- guished from medulloblastoma spectra (n ¼ 82) with 100% sensitivity and arately to the majority of CNS PNETs. Novel gene copy number alterations 98.8% specificity, from ependymoma spectra (n ¼ 66) with 93.9% sensi- were found, including gain of PCDHGA3, 5q31.3 (68.2%) and FAM129A, tivity and 99.7% specificity, and from glioma spectra (n ¼ 246) with 1q25 (63.6%) and losses of OR4C12, 11p11.12 (40.9%), CADPS, 3p14.2 95.5% sensitivity and 96.0% specificity. Anaplastic ependymomas (n ¼ (27.3%), and SALL1, 16q12.1 (18.2%). Two novel clinical associations 41) were differentiated from low-grade ependymomas (n ¼ 25) with 100% were linked to gene copy number imbalance; gain of PCDHGA3 was associ- sensitivity and 96.0% specificity. Medulloblastomas were correctly distin- ated with metastatic disease at diagnosis (p ¼ 0.018) and pineoblastoma guished from astrocytomas (n ¼ 59) with 98.8% sensitivity and 81.4% (p ¼ 0.079). On comparison of 5 primary and recurrent CNS PNET pairs, specificity and from high-grade gliomas (n ¼ 128) with 96.3% sensitivity gain of 2p21 was the most common alteration maintained in 80% of and 96.1% specificity. Normal tissue was distinguished from low-grade cases. This high resolution, genome-wide analysis has revealed the marked gliomas (n ¼ 118) with 91.5% sensitivity and 97.8% specificity and from molecular heterogeneity of CNS PNET and pineoblastoma and has low-grade ependymomas with 92.0% sensitivity and 99.7% specificity. enabled the identification of putative novel genes and clinical associations CONCLUSION: These results suggest that Raman spectroscopy can accu- potentially involved in the pathogenesis of these tumours. rately distinguish pediatric brain neoplasms from normal brain tissue and also show promise for distinguishing high- from low-grade tumors.

P-MED.03. GENE EXPRESSION IN LATERALIZING P02 MEDULLOBLASTOMA/CNS-PNET MEDULLOBLASTOMAS IN ADOLESCENTS AND YOUNG ADULTS SHOWS MORE SIMILARITY TO ASTROCYTOMAS P-MED.01. MOLECULAR MECHANISMS IN SUPRATENTORIAL J. R. Madden, S. Z. Rush, A. M. Donson, B. K. Kleinschmidt-DeMasters, CNS-PNET DEVELOPMENT R. Vibhakar, and N. K. Foreman; The Children’s Hospital, University of J. T. Hayden1, M. Allen1, S. L. Ryan1, S. L. Nicholson1, E. C. Schwalbe1, Colorado, Aurora, CO, United States M. E. Lusher1, J. C. Lindsey1, P. Hauser2, M. Hasselblatt3, M. C. Fruhwald4, S. Bailey1, and S. C. Clifford1; 1Northern Institute Cancer Research, Lateralizing medulloblastomas in adolescents and young adults (AYA) are Newcastle University, Newcastle Upon Tyne, United Kingdom; thought to have a poor prognosis compared to average risk pediatric medullo- 2Semmelweis University, Budapest, Hungary; 3Institute of Neuropathology, blastoma patients. Lateralization of medulloblastoma is a known poor prog- University Hospital Munster, Munster, Germany; 4Department of Pediatric nostic indicator in the adult literature, but little has been published Hematology & Oncology, University Children’s Hospital Munster, regarding the AYA population. Different gene expression patterns have been Munster, Germany noted for tumors in different locations of the same pathologic type. Fore example, large-cell medulloblastomas are known to over-express c-myc, BACKGROUND: Supratentorial PNETs of the central nervous system which can be used for risk stratification. We present three cases of AYA (CNS-PNET) predominantly affect young children. CNS-PNET show histo- patients with lateralizing medulloblastomas. As compared with classical, logical similarities to infratentorial PNET (medulloblastomas), however midline medulloblastomas, the gene-expression profiles for these 3 cases their overall prognosis is worse and any relationships at the molecular grouped with astrocytomas rather than classic medulloblastoma by hierarch- level require investigation. Insights into the molecular pathogenesis of ical clustering analysis. The most overexpressed genes in lateralizing versus CNS-PNET may enable improved treatments through identification of (i) midline medulloblastoma included astrocytoma associated markers ERBB3, biomarkers for disease stratification and (ii) targets for therapeutic exploita- SOX10 and OLIG2. These 3 patients have all had poor outcomes with early tion; however their biological basis is not well understood. METHODS: We local recurrence (median time to recurrence 14 months). Because these latera- investigated the involvement of a series of clinically and/or biologically sig- lizing medulloblastomas are genetically more similar to astrocytomas, their nificant medulloblastoma defects, in a panel of 25 pathologically reviewed tendency to relapse locally and at earlier time points is better understood. primary CNS-PNET. These investigations focussed on commonly amplified Aggressive treatment is warranted in these very high risk patients. (MYC and MYCN), deleted (p-arm of chromosome 17) and hypermethylated (RASSF1A) medulloblastoma loci, alongside critical pathways in medulloblastoma development (P53 and Wnt). RESULTS: RASSF1A epigenetic inactivation (74% (17/23)), MYCN (but not MYC) amplification (12% (3/25)), and Wnt pathway activation (b-catenin nuclear accumulation P-MED.04. T-CELL-RECEPTOR-ALPHA GENE IS EXPRESSED IN in 9% (2/23), associated with CTNNB1 mutation in 1/2 cases) were recur- MEDULLOBLASTOMA TUMOR CELLS - HIGH EXPRESSION rent events in our CNS-PNET cohort. P53 pathway defects (P53 nuclear CONFERS A GOOD PROGNOSIS W. Teo1,2, L. Song3, D. Liu3,A.Yu1, J. Shen1, C. Davis1, X. Zhao1, Z. Liu1, accumulation (91% (20/22), associated with gene mutations in 4/22 1 1 3 1 1 cases) and 17p-arm loss (0/23) occurred at significantly different frequencies T. Man ,X.Li , L. Metelitsa , and C. C. Lau ; Cancer Genomics Program, than in medulloblastoma. P53 and WNT pathway disruption were mutually Department of Pediatric Hematology-Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, United States; 2KK exclusive (p ¼ 0.004), suggesting the existence of distinct CNS-PNET mol- 3 ecular disease subgroups. CONCLUSIONS: We have identified a series of Women’s & Children’s Hospital, Singhealth Services, Singapore; Cell & novel molecular pathways in CNS-PNET development, which now merit Gene Therapy, Texas Children’s Cancer Center, Baylor College of Medicine, further investigation of their therapeutic relevance. Our data support the Houston, TX, United States hypothesis that, whilst similarities exist, medulloblastomas and CNS-PNET display a distinct molecular pathogenesis, which may underlie BACKGROUND: Gene profiling identified medulloblastomas (MBs) with their divergent clinical behaviours. good prognosis to have high T-Cell-Receptor-alpha (TRA@) gene ii52 NEURO-ONCOLOGY † JUNE 2010 Abstracts

expression. OBJECTIVE: To investigate the role of TRA@ expression in cases showed that desmoplastic histology is associated with type B (p ¼ MBs. METHODS & MATERIALS: Gene profiling of 56 primary MBs, 6 0.0089), and most metastatic cases are found among type C, D, or E normal brain tissues using Affymetrix U133plus2.0, qRT-PCR of 4 MB tumours (p ¼ 0.0026), which confirmed previous results. All 26 infants in cell lines were performed. Tumor cells from 4 TRA@lo and 5 TRA@hi these series were classified as either type B (n ¼ 15) or DE (n ¼ 11) (p ¼ fresh MB surgical specimens were injected into cerebellum of 72 NOD/ 0.000005). Importantly, all infants with metastasis (n ¼ 7) were classified SCID mice. Kaplan Meier method was used for survival analysis. as type D or E (p ¼ 0.00044). All these data provided much more insight RESULTS: While normal brain tissues have invariably low TRA@ in the biology and genetics of medulloblastoma, but further evaluation is expression, TRA@ is differentially expressed in MBs. Five-year EFS and needed to identify tumour-driving genes, potential drug targets and the OS of patients with TRA@hi MBs were 77.8% and 45.1% (p ¼ 0.012), best diagnostic and prognostic markers for each of these subtypes. and TRA@lo MBs, 80.6% and 52.5% (p ¼ 0.009). Functional Therefore, we are currently collecting a large series of medulloblastoma TCR-ab-heterodimer is expressed on tumor-infiltrating T-cells, not MB patients treated in European therapy trials. The tumours will be analyzed tumor cells, demonstrated by FACs of a primary MB. However, qRT-PCR by various high-throughput genomic techniques. All data including clinical of 4 MB cell lines identified presence of TRA@ transcript with both variable data will be integrated into the database R2. R2 is a highly sophisticated and constant regions. All mice injected with TRA@lo MBs formed tumors bioinformatic toolbox that allows users to do all kind of analyses and visu- with 100% tumorigenicity while TRA@hi MBs formed tumors with 67– alizations of the data and helps to identify genes, pathways, etc. that correlate 100% tumorigenicity. Median survival time of mice bearing TRA@lo intra- with any annotated parameter of a tumour series. The use of R2 will be Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 cerebellar MBs was shorter compared to TRA@hi tumors (131 vs 163 days, demonstrated. log rank p ¼ 0.001). In-vitro, neurosphere formation of TRA@hi MBs was observed to be slower. We hypothesize that TRA@ expression possibly play a role in regulating tumor proliferation in MBs. Knockdown experiments are on-going in-vitro and in-vivo. CONCLUSION: TCR@ gene expression appeared to be a unique event in MB tumor cells and is likely P-MED.07. EXPRESSION ANALYSIS OF PRECURSOR CELL to play a non-immune role. MARKERS IN CHILDHOOD MEDULLOBLASTOMA M. Zakrzewska1, K. Zakrzewski2, S. M. Gresˇner1, B. Zalewska-Szewczyk3, T. Fiks4, and P. P. Liberski1; 1Department of Molecular Pathology and Neuropathology, Chair of Oncology, Medical University of Ło´ dz´, Ło´ dz´, Poland; 2Department of Neurosurgery Polish Mother Memorial Hospital P-MED.05. IDENTIFICATION OF RHO GUANINE NUCLEOTIDE Research Institute, Ło´ dz´, Poland; 3Department of Pediatrics Oncology, EXCHANGE FACTORS AS NOVEL THERAPEUTIC TARGETS Hematology and Diabetology, 1st Chair of Pediatrics, Medical University of FOR MEDULLOBLASTOMA INVASION Ło´ dz´, Ło´ dz´, Poland; 4Department of Pathology Polish Mother Memorial S. M. Zavarella1,2,3, M. Mittler2,3, M. Symons1, and S. J. Schneider1,2,3; Hospital Research Institute, Ło´ dz´, Poland 1Center for Oncology and Cellular Biology, The Feinstein Institute for Medical Research Of North Shore-LIJ Healthcare System, Manhasset, NY, Medulloblastoma (MB) is the most frequent type of embryonal tumor United States; 2Department of Neurosurgery, Harvery Cushing Institute of in the pediatric population. The pathogenesis of this tumor is still Neurosciences of North Shore-LIJ Healthcare System, Manhasset, NY, unclear, but two sources of potential tumor precursor cells, the external United States; 3Division of Pediatric Neurosurgery, Schneider Children’s granule layer (EGL) and cerebellar ventricular zone (CVZ), are con- Hospital, New Hyde Park, NY, United States sidered. The presence of specific precursor cell markers for each region is suggested, but their expression profile and potential links with progno- Medulloblastoma, accounting for 25% of pediatric brain tumors, is the sis have not been analyzed yet. In this work we analyze mRNA most common solid primary tumor of childhood. These tumors display inva- expression of precursor cell markers (SOX2, PROM1, FUT4, ATOH1, sion of individual cells into adjacent parenchyma, and subsequently the CSF, OTX1, OTX2, NGFR), their associations with demographic and clinical causing metastasis and poor prognosis. We recently demonstrated that Rac1, data, and their usefulness in predicting outcomes. Forty children with a member of the Rho family of GTPases, is essential for the invasive behavior medulloblastoma (22 males and 18 females, aged from 5 months to 17 of medulloblastoma and that Rac1 is hyperactive in medulloblastoma years) undergoing surgery at the Department of Neurosurgery, Polish tumors. Here, we report on the identification of guanine nucleotide exchange Mothers Memorial Hospital Research Institute, were included in this factors (GEFs), activators of Rho family GTPases mediating medulloblas- study. The expression level of genes was measured by quantitative real- toma invasion. Specific depletion of proteins was achieved by small interfer- time PCR with commercially available cerebellar RNA. Statistical analysis ing RNA (siRNA). Invasive cellular behavior was studied by quantifying revealed no significant differences in the expression level of any of the invasion through reconstituted extracellular matrix (Matrigel) in response genes studied between the two age groups (under 3 years vs. over 3 to serum. siRNA-based screening revealed that three GEFs, Trio, DOCK9, years) or between two clinical risk stratification groups (high risk vs. and Vav2 play critical roles in Daoy invasion. In addition to Rac1, Trio acti- standard risk). The survival analysis based on the median expression level vates RhoG and RhoA, whereas DOCK9 is specific for Cdc42. Interestingly, of each gene revealed an association between higher expression levels of we found that siRNA-mediated depletion of either RhoG or Cdc42 inhibits PROM1 and SOX2 and decreased patient survival. In summary, our analysis invasion, whereas RhoA depletion stimulates invasion. Depletion of Trio has indicates that selected precursor cell markers are associated with the aggres- a relatively small effect on glioblastoma cell invasion, whereas depletion of siveness of disease and could be used as molecular factors helpful in the pre- DOCK9 has no effect, indicating specificity of these GEFs for medulloblas- diction of outcomes for children with medulloblastoma. Work supported by toma. Vav2, which activates multiple GEFs, had a greater contribution to MNiSW Grant N401 180 32/3580. glioblastoma invasion, thus slightly less specific for medulloblastoma. Our results indicate that Trio and DOCK9 are specific for medulloblastoma invasion and metastasis. The invasive role of Trio is likely mediated by Rac1 and RhoG. We propose targeting Trio, DOCK9 or Vav2 signaling elements present novel therapeutic avenues for advanced medulloblastoma. P-MED.08. OTX2 REGULATES CELL CYCLE GENES IN MEDULLOBLASTOMA J. Bunt, N. Hasselt, J. Koster, D. Zwijnenburg, R. Versteeg, and M. Kool; Academic Medical Centre, Amsterdam, Netherlands

P-MED.06. EXPRESSION PROFILES, GENETIC ABERRATIONS OTX2 is a homeobox containing transcription factor, which is essen- AND CLINICAL DATA OF MOLECULAR SUBTYPES IN tial for normal brain development. It is expressed in brain progenitor MEDULLOBLASTOMA: ANALYSIS AND VISUALIZATION OF cells, but expression is switched off in differentiated neurons. However, DATA WITH THE BIOINFORMATIC TOOLBOX R2 the majority of medulloblastoma highly overexpress OTX2, occasionally M. Kool1, J. Koster1, N. Schouten-van Meeteren1, S. Clifford2, T. Pietsch3, via amplification. Little is known about the precise function of OTX2 S. Rutkowski4, H. Caron1, R. Versteeg1,F.Doz5, C. Haberler6, and in medulloblastoma or its downstream targets. Therefore, we generated O. Delattre5; 1Academic Medical Center, Amsterdam, Netherlands; doxycycline-inducible cell line models in which we can either overexpress 2Northern Institute for Cancer Research, Newcastle, United Kingdom; ectopic OTX2 or silence endogenous OTX2. Overexpression of OTX2 3University of Bonn, Bonn, Germany; 4University Medical Center, induced an oncogene-induced senescence-like phenotype in both Hamburg-Eppendorf, Germany; 5Institut Curie, Paris, France; 6Institute MED8A and DAOY cells, which we attributed to a differential regulation Neurology, Medical University, Vienna, Austria of cell cycle genes followed by P53 activation. Silencing of OTX2 in the D425 cells strongly inhibited cell proliferation and induced differen- Medulloblastoma are the most frequent malignant brain tumours in child- tiation. Expression profiling of time series after OTX2 induction or silen- hood. Recently, we and others have shown that medulloblastoma exists of at cing in the different cell lines identified a large repertoire of potential least five distinct subtypes, characterized by WNT signalling (type A), SHH target genes of which the expression is controlled by OTX2. signalling (type B), expression of neuronal differentiation genes (type C and Subsequent chromatin immunoprecipitation assays combined with D), or photoreceptor genes (type D and E). Clinicopathological data of 120 chip-analyses (ChIP-on-chip) to identify genome-wide the regions where

NEURO-ONCOLOGY † JUNE 2010 ii53 Abstracts

OTX2 binds revealed G2/M cell cycle genes as one of the major gene DNA damaging agents, we could not find evidence for this effect on postopera- categories that are under direct control of OTX2. Interestingly, these tive residual tumors when analyzed by imaging. genes also correlated with OTX2 in tumors. Our results give a first glance at the OTX2 transcriptional network. Both the overexpression and the silencing models suggest direct regulation of cell cycle genes by OTX2. Therefore OTX2 may act as an oncogene in medulloblastoma by directly driving and maintaining proliferation in P-MED.11. MICRO-RNA 128A INCREASES INTRACELLULAR medulloblastoma. ROS LEVEL AND PROMOTES TUMOR CELL SENESCENCE IN MEDULLOBLASTOMA BY TARGETING THE ONCOGENE BMI-1 S. Venkataraman1, I. Alimova1, J. Pierson2, R. Fan2, P. Harris1, N. Foreman1, and R. Vibhakar1,2; 1University of Colorado, Denver, CO, P-MED.09. MYC MEDIATES MEDULLOBLASTOMA United States; 2University of Iowa Childrens hospital, Iowa city, IA, United METASTASIS BY DIRECT REGULATION OF GENES INVOLVED States IN CELL MIGRATION AND ADHESION L. Zhou1,2,Y.S.Ra3, D. Picard4,M.Li1,2, and A. Huang1,2; 1Labatts Brain BACKGROUND: MicroRNAs (miRNAs) are a class of short non-coding Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Tumour Research Centre, Hospital for Sick Children, Toronto, ON, RNAs that regulate cell homeostasis by inhibiting translation or degrading Canada; 2Division of Hematology-Oncology and Hospital for Sick Children, mRNA of target genes and thereby can act as tumor suppressor genes or Toronto, ON, Canada; 3Department of Neurosurgery, College of Medicine, oncogenes. The role of microRNAs in medulloblastoma has only recently Yonsei University, Seoul, Republic of Korea; 4Department of Laboratory been addressed. We hypothesized that miRNAs differentially expressed Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada during normal CNS development might be abnormally regulated in medulloblastoma and be functionally important for medulloblastoma cell growth. Myc gene amplification is known to be associated with unfavorable METHODS AND RESULTS: We examined the expression of microRNAs medulloblastoma, however, molecular mechanisms underlying these obser- in medulloblastoma and then investigated the functional role of one specific vations remain poorly understood. We established high Myc expression in one, miR-128a in regulating medulloblastoma cell growth. We found that 2 medulloblastoma cell lines and demonstrate that Myc confers two potent many microRNAs associated with normal neuronal differentiation are sig- oncogenic traits, increased cell migration and invasion and recapitulates nificantly down regulated in medulloblastoma. We found that one of clinico-pathological features of aggressive Myc-amplified human medullo- these, miR-128a, inhibits growth of medulloblastoma cells by targeting the blastoma. We observed that high constitutive or induced Myc expression Bmi-1 oncogene. In addition re-expression of miR-128a increased the intra- strikingly increased cell invasion and migration as measured by trans-well cellular redox state of tumor cells and promoted cellular senescence in and wound healing assays in UW228 and UW426 cells, and also had medulloblastoma. We also noticed alteration in the levels of proteins potent oncogenic effects in vivo. While orthotopically injected UW228 or involved in reactive oxygen species (ROS) signaling pathways, such as P16, UW426 cells exhibited limited tumor growth, mice injected with P14 and E2F1 that lead to cellular senescence with re-expression of UW228-Myc (8/10) or UW426-Myc (9/10) had rapidly growing cerebellar microRNA128a in medulloblastoma cells. CONCLUSIONS AND tumors and significantly shortened survival (p , 0.05). UW228 and UW426 SIGNIFICANCE: Here we report the novel regulation of ROS by Myc induced xenografts had histological features resembling primary large microRNA 128a via the specific inhibition of the Bmi-1 oncogene. We cell anaplastic medulloblastoma, invaded adjacent normal cerebellum, con- demonstrate that miR-128a has growth suppressive activity in medulloblas- tiguous leptomeninges and exhibited distant spinal cord metastasis (4/8 toma and that this activity is partially mediated by Bmi-1. These data have UW228-Myc and 4/9 UW426-Myc tumor bearing mice). To identify Myc implications for modulation of redox states in cancer stem cells, which are effector pathways underlying these highly aggressive medulloblastoma phe- thought to be resistant to therapy due to low ROS states. notypes, we performed ChIP-chip analyses on UW228-Myc cells using the Agilent 244K genomic array. In addition to protein coding genes (including Tsp-1/THBS1, ING4, CDH13, TGFBR3 and BAI2), our study revealed 14 miRNA coding loci as Myc direct targets in medulloblastoma. Notably, gene function enrichment analysis of Myc target identified by ChIP-chip P-MED.12. P53-DEPENDENT MI-RNA TRANSCRIPTION revealed significant overrepresentation of loci with functions in cell moti- DETERMINES MEDULLOBLASTOMA CELL SENSITIVITY TO lity/adhesion and cellular differentiation and provides novel insights into CHEMOTHERAPEUTIC INTERVENTION how the Myc regulatory network may be targeted for treatment of metastatic Y. N. Fan1, D. Meley1, D. Spiller1, M. White1, B. L. Pizer2, and V. See1; medulloblastoma. 1University of Liverpool, Liverpool, United Kingdom; 2Alder Hey Children’s Hospital, Liverpool, United Kingdom

INTRODUCTION: Neuronal proliferation, differentiation and migration P-MED.10. HIGH C-MYC EXPRESSION SENSITIZES are coordinated during cerebellar development. Disruption of these processes MEDULLOBLASTOMA CELLS TO DNA DAMAGING AGENTS can lead to Medulloblastoma (MB), the most common malignant paediatric A. O. von Bueren1,2, C. Oehler-Ja¨nne3, T. Shalaby2, M. Pruschy3, B. Seifert4, 5 1 2 1 brain tumour. Etoposide inhibits the DNA repair mechanism thus activating M. Warmuth-Metz , S. Rutkowski , and M. A. Grotzer ; Department of the p53 apoptotic pathway. However, some MB cells are resistant to etopo- Pediatric Hematology and Oncology, University Medical Center side, and we have previously shown a correlation between p53 activity in MB Hamburg-Eppendorf, Hamburg, Germany; 2Neuro-Oncology Program, 3 and glioblastoma cells and cell sensitivity to chemotherapeutic intervention. University Children’s Hospital Zurich, Zurich, Switzerland; Department of Here we show that the p53-dependent microRNA, miR-34a, is induced upon Radiation Oncology, University Hospital Zurich, Zurich, Switzerland; etoposide treatment in p53 WT cells and in cell death. METHODS AND 4Biostatistics Unit, Institute of Social and Preventive Medicine, University of 5 RESULTS: We used two medulloblastoma cells lines, D-283 cells (p53 Zurich, Zurich, Switzerland; Department of Neuroradiology, University of WT) and MEB-Med-8A cells (p53 mutated). We performed time-lapse con- Wuerzburg, Wuerzburg, Germany focal microscopy in single living cells using p53 and mdm-2 fluorescent fusion proteins in presence of etoposide. We observed mdm-2 activation sub- PURPOSE: To study whether and how c-MYC expression determines sequent to p53 nuclear accumulation in D-283 cells and have further shown response to radio- and chemotherapy in childhood medulloblastoma (MB). by qPCR a correlation between p53 transcriptional activity and miR-34a EXPERIMENTAL DESIGN: We used DAOY and UW228 human MB cell transcription. We then demonstrated decreasing levels of the sirtuin-1 deace- lines engineered to stably express different levels of c-MYC, and tested tylase (SIRT-1), which is a potential miR-34a target, concomitant with whether c-MYC expression has an effect on radio- and chemosensitivity miR-34a increase and that the loss of SIRT-1 activity is mediating using MTS, clonogenic survival, apoptosis assays, cell cycle analysis, and etoposide-induced cell death. We are currently investigating the possibility western blot assessment. In an effort to validate our results, we analyzed of by-passing p53 activity by directly targeting SIRT-1 in p53 deficient c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor cells. CONCLUSION: We have demonstrated that etoposide-induced p53 samples from well-documented patients with postoperative residual tumor transcriptional activity is necessary for miR-34a transcription and SIRT-1 and compared c-MYC mRNA expression with response to radio- and che- degradation and that the loss of SIRT-1 activity is contributing to motherapy as examined by neuroradiological imaging. RESULTS: In DAOY etoposide-induced cell death. Our data suggest that miR-34a or SIRT-1 - and to a lesser extent UW228 - cells expressing high levels of c-MYC, cytotox- could constitute new targets to enhance medulloblastoma treatment. icity of cisplatin, etoposide, and doxorubicin was higher when compared with control cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. Response of residual tumors to postoperative radio- or chemotherapy was similar in MB with high or low c-MYC mRNA expression (Mann-Whitney U test, p ¼ 0.50 and p ¼ 0.67, respectively). CONCLUSION: Although high c-MYC expression sensitizes MB cells to

ii54 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-MED.13. GENE EXPRESSION ANALYSIS SEGREGATES Unlike GBM, MAPK activation remained unaltered by prolonged treatment TUMORS ON WNT PATHWAY AND LOCATION of medulloblastoma cells with rapamycin and MAPK suppression by U0126 H. A. Rogers1, S. Miller1, J. Lowe1, G. Ball2, B. Coyle1, and R. G. Grundy1; did not affect pS6K. Also, p27 levels and localization were influenced by PI3/ 1University of Nottingham, Nottingham, United Kingdom; 2Nottingham AKT/mTOR suppression in a time dependent manner. Migration of medul- Trent University, Nottingham, United Kingdom loblastoma cells toward fibronectin was significantly suppressed by PI3K/ mTORC-complexes inhibition. Therefore, these results suggest that Central nervous system primitive neuroectodermal tumors (CNS PNET) another oncogene, ALK (or other), may participate in tumorigenesis of and medulloblastoma are embryonal tumors that occur predominantly in medulloblastoma, and the PI3K/AKT/mTOR pathways may influence the children. Previously the two tumor types have been grouped together due maintenance as well as cancer cell stromal interaction in tumorigenesis. to their histological similarities. However recent research has suggested mol- (Supported by Children’s Hospital Foundation). ecular and genetic differences. We undertook a study investigating gene expression using Affymetrix U133 plus 2.0 arrays in a cohort of 23 embryonal tumors including 13 CNS PNETS, 8 medulloblastomas, 1 pineoblastoma and 1 atypical teratoid/rhabdoid tumor (ATRT). Hierarchical P-MED.16. A PROTEOMIC APPROACH TO PAEDIATRIC clustering and principal component analysis segregated the tumors into dis- MEDULLOBLASTOMA: METHODS AND PRELIMINARY tinct subgroups. The medulloblastomas grouped separately from the rest of RESULTS Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 the tumors. Higher expression of the proto-oncogene ETS1 was seen in the I. Morra1, M. Leone2, P. Peretta3, P. Ragazzi3, P. Gaglini3, M. Forni4, CNS PNETs compared to the medulloblastomas. Genes involved in cerebel- G. Mandili5, E. Basso2, D. Bertin2, L. Cordero di Montezemolo2, and lar development were identified in medulloblastoma supporting the hypoth- C. Zanini4; 1Pathology Department ASO OIRM-S.Anna, Torino, Italy; esis that these tumors arise from cerebellar progenitor cells. The CNS PNETs 2Paediatric Onco-Haematology University of Torino, Torino, Italy; segregated into two subgroups which demonstrated an association with 3Neurosurgery Department ASO OIRM-S.Anna, Torino, Italy; 4Molecular WNT pathway status, determined by the intra-cellular location of beta- Biology Centre University of Torino, Torino, Italy; 5C.E.R.M.S., Torino, Italy catenin. Genes significantly up-regulated in the CNS PNET subgroup associated with WNT pathway activation included FZD7, YAP1 and COL5A1. Medulloblastomais an aggressive usuallypaediatric tumour locatedinthe pos- Genes up-regulated in the other subgroup included OMG, OLIG2 and terior fossa, and is considered an embryonal tumour. It is the more frequent SNAP91. Protein expression of YAP1 demonstrated a significant association malignant paediatric tumour of CNS; great improvements in survival have ¼ with WNT pathway status (n 31) and over-expression of the WNT been achieved in recent years by multimodal therapeutic approach, but cognitive ¼ pathway target cyclin D1 (n 21). Although not significant, 75% of and neuropsycological damages on developing brain are still often relevant. ¼ tumours with high OLIG2 protein expression (n 8) did not demonstrate Proteomic approach to the study of these tumours may allow the identification WNT pathway activation. Our findings support the occurrence of distinct of biomarkers which might be useful to subdivide patients in groups according CNS PNET subgroups associated with WNT pathway status as seen in to different degrees of malignancy, thus allowing more effective therapeutic strat- medulloblastoma. egies. The study has been performed on neoplastic tissue snap frozen at the time of surgery. This allows a precise correlation between macro- and microscopical pictures of a given lesion; moreover it permits to analize intra-tumoural variability. Medulloblastomas have been classified according to WHO 2007 classification. P-MED.14. AN INVESTIGATION OF WNT PATHWAY Twelve MDB (five classic, three anaplastic, two after radiotherapy, one ACTIVATION OF MEDULLOBLASTOMA PATIENTS nodular, one melanotic) were studied by 2-Dimensional Electrophoresis. N. Ohe, H. Yano, M. Okada, N. Nakayama, and T. Iwama; Department of Proteins were identified by peptide mass fingerprinting. Following protein identi- Neurosurgery, Gifu University Graduate School of Medicine, Gifu city, Japan fication, quantitative gene expression profiling was performed for all different proteins identified in every group. The combination of proteomic identification BACKGROUND: The WNT pathway has been implicated in many tumor coupled with quantitative gene expression techniques allowed simultaneous types, and its activation is one of favorable prognostic factors in medulloblas- study of a large number of proteins. In every tumour about one hundred proteins toma patients. We aimed to investigate the WNT pathway activation by beta- have been studied as typical of medulloblastomas. Proteins most consistently catenin location in children with medulloblastoma. MATERIALS: 13 expressed in tumours with “classical” histology belong to many categories, formalin-fixed, paraffin-wax-embedded tumor samples of medulloblastoma such as “stress response proteins (HPS)” and proteins involved in neoplastic patients (8 boys and 5 girls ) with a median age of 8.5 years (range, 4–16 transformation. The results of this combined approach are shown. years ) who received initial treatment in our institute were investigated. METHODS: 13 samples were investigated using immunohistochemical analysis by primary antibodies against beta-catenin (CTNNB1) and secreted frizzled-related protein (SFRP) 1. The cellular location of CTNNB1 was analyzed. RESULTS: 3 samples (23%) displayed CTNNB1 nuclear and cyto- P-MED.17. LABEL FREE MASS SPECTROMETRIC ANALYSIS OF plasmic / cell membranous staining and 10 samples (77%) displayed no THE MEDULLOBLASTOMA CEREBROSPINAL FLUID CTNNB1 nuclear staining but cytoplasmic / cell membranous staining. In PROTEOME three samples with CTNNB1-positive nuclei, one case displayed high M. U. Rajagopal1, Y. Hathout1, T. J. MacDonald2, H. Gordish-Dressman1, CTNNB1 nuclear staining of more than 10% of positive nuclei and two and B. R. Rood1,3; 1Children’s National Medical Center, Washington, DC, cases displayed low CTNNB1 nuclear staining of less than 10%. All three United States; 2Emory University, Atlanta, GA, United States; 3Pediatric cases with CTNNB1-positive nuclei are alive relapse-free to date. Brain Tumor Consortium, TN, United States CONCLUSION: The WNT / beta-catenin pathway has been found to be active in 23% of medulloblastoma patients. Our results confirm that the acti- Investigation of the changes that occur in the cerebrospinal fluid (CSF) pro- vation of WNT pathway is one of the good prognostic factors. It will be necess- teome of children with medulloblastoma can identify tumor-specific protein ary to examine the mechanism of WNT pathway activation in detail in future. biomarkers that correlate with the presence of tumor. CSF biomarkers could be used to monitor a tumor’s response to therapy and, if sensitive enough, could also be used to detect minimal residual disease and disease recurrence. The CSF is especially an attractive source of such markers because of its P-MED.15. SIGNALING PATHWAYS OF MEDULLOBLASTOMA proximity to the tumor and the potential for serial sampling during A. L. Mohan, P. Gulati, E. McKenna, A. Braun, R. Murali, and therapy and post-treatment monitoring. As a first step towards the identifi- M. Jhanwar-Uniyal; New York Medical College, Valhalla, NY, United States cation of markers that are tumor-specific, we have used mass spectroscopy label-free protein quantitation (LFPQ) to survey disease-specific proteins in Medulloblastoma is the most common primary CNS tumor in children, the CSF of children with newly diagnosed medulloblastoma compared to representing about 20% of all cancers, which arises in the fourth ventricle, controls. We identified a total of 196 proteins of which 6 were significantly but may spread to other sites. Studies have shown that Gli1-transformed (p , 0.05) altered in MB. These proteins include apolipoprotein B, comp- epithelioid cells require mTOR activity for their survival. The modulation lement factors C6 and C8, monocyte differentiation antigen and 14–3–3. of mTOR is an important signaling pathway in medulloblastoma, promoting All of these were increased by at least 3 fold in the tumor samples. 14–3– the status of the CDK inhibitor, p27. The Hedgehog-Patch-Gli pathway acti- 3 is an anti-apoptotic protein that has been detected by immunohistochem- vates the oncogene N-myc, which is often upregulated in medulloblastoma, istry in the majority of primary human brain tumors. Interestingly, the brain- and carries a poorer prognosis. In this study, we examined the status of the specific zeta/delta isoforms of protein 14–3–3 were present only in the N-myc oncogene in addition to anaplastic lymphoma kinase (ALK; the result tumor samples but absent in the controls making it a good candidate bio- of a chromosomal translocation at 2p23 is in close proximity to N-myc) and marker. In conclusion, our work demonstrates the novel use of LFPQ tech- investigated the mTOR pathway as it relates to motility of medulloblastoma nology to survey quantitative changes in medulloblastoma associated CSF cells. For the first time, we observed additional clones of ALK in medullo- proteins which may serve as biomarkers for the presence of disease. blastoma, where N-myc was not amplified. Inhibiting mTOR with rapamycin resulted in a time-dependent suppression of mTORC1 substrate, pS6K, and rapamycin-treated cells remained unresponsive to PDGF treatment.

NEURO-ONCOLOGY † JUNE 2010 ii55 Abstracts

P-MED.18. CHARACTERISING METABOLITE PROFILES OF genetically engineered mouse (GEM) models die rapidly after exposure to MEDULLOBLASTOMAS IN TRANSGENIC SMO MICE USING 1H a low dose of radiation. We have therefore developed an animal model MAGNETIC RESONANCE SPECTROSCOPY that is useful for studying the radiation response of this tumor. This model M. Wilson1,2, S. K. Hekmatyar3, N. Jerome3, J. L. Griffin4, A. C. Peet1,2, and involves the orthotopic transplant of freshly harvested primary tumor cells R. A. Kauppinen3; 1Cancer Sciences, University of Birmingham, from a GEM model of medulloblastoma. The hosts were monitored for Birmingham, United Kingdom; 2Birmingham Children’s Hospital NHS early tumor formation by MRI or bioluminescence imaging. Foundation Trust, Birmingham, United Kingdom; 3Department of Tumor-bearing mice survived exposure to 2–4 Gy ionizing radiation (IR), Radiology, Dartmouth College, Hanover, NH, United States; 4Department a dose which is lethal to GEM mice with tumors. The implanted tumors dis- of Biochemistry, University of Cambridge, Cambridge, United Kingdom played a perivascular niche architecture resembling that of the spontaneous tumors, with radiation-resistant nestin-positive stem-like cells residing near Aberrant hedgehog signaling is implicated in the generation of human blood vessels, and a tumor bulk of radiation-sensitive nestin-negative cells. medulloblastomas occurring in 25% of these tumours. The Shh-Patched sig- Administration of 4 Gy IR resulted in a significant survival advantage to naling pathway plays a crucial role in mitogenic regulation of granule cell mice with implanted tumors, as compared to mock-irradiated control progenitors (GCP). Recently, a genetically modified mouse line has been gen- animals. Tumor regression and subsequent relapse were readily evident by erated overexpressing smoothened receptor (SMO) in GCPs and found to MRI. The relapsed tumors displayed a cellular composition of mixed nestin- have a very high incidence of medulloblastomas. Previous studies using 1H positive and nestin-negative cells that strongly resembled the initial tumor. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 magnetic resonance spectroscopy (MRS) have shown metabolite profiles of This transplanted model bypasses many of the difficulties in using xenografts medulloblastomas in children to be strongly characteristic for this tumour, or GEMs in studying the response of medulloblastoma to radiation. These providing promising biomarkers for metastatic potential and treatment mice survive radiation while carrying tumors that recapitulate the radiation monitoring. We have determined metabolite profiles of SMO transgenic response seen in GEM and human tumors, allowing for long term follow-up both in-vivo and ex-vivo using MRS and high-resolution magic angle spin- and characterization of medulloblastoma after radiotherapy. ning (HRMAS) to validate this new model. SMO mice of 118 + 42 days were scanned with C57Bl/6 as wild type (WT) controls. Single voxel MRS were acquired at 7T using the LASER sequence. Voxel dimensions were set according to the T2-hyperintensity in medulloblastomas and in the basal cerebellum in WT (2 x 2 x 3 mm3). Tissue specimens from SMO and P-MED.21. A CASE-BASED INTERACTIVE E-LEARNING WT mice were analysed using 1H HRMAS at 11.7T. Medulloblastomas PROGRAM FOR PEDIATRIC NEURO-ONCOLOGY: showed very low N-acetyl-aspartate, low GABA and myo-inositol and RATIONALE, DEVELOPMENT AND USER EVALUATION high taurine, total choline, and glycine both in-vivo and ex-vivo, in agree- RESULTS ment with studies of pediatric medulloblastoma, confirming the validity of V. Ma1, R. A. Olson1,2, J. Hukin1,3, D. Johnson4, A. Singhal1,3,and the model. This work indicates a strong link between SMO and the metabolic K. Goddard1,2; 1University of British Columbia, Vancouver, BC, Canada; pathways that are key to medulloblastoma making the MRS investigation of 2BC Cancer Agency, Vancouver, BC, Canada; 3BC Children’s Hospital, SMO mice a potentially important tool for evaluating novel drugs for medul- Vancouver, BC, Canada; 4Children’s Hospital of Eastern Ontario, Ottawa, loblastoma. [SMO mice were a gift from FHCRC, Seattle, WA.] ON, Canada

INTRODUCTION: Pediatric brain tumors (BT), though relatively unusual, are responsible for a significant proportion of childhood illnesses and death. Diagnosis is often delayed due to lack of knowledge regarding P-MED.19. ESTABLISHING AN ORTHOTOPIC early symptoms and signs of pediatric posterior fossa BT. Knowledge MEDULLOBLASTOMA MODEL IN MICE FOR TESTING NOVEL about BT presentation among medical students and health care practitioners THERAPEUTICS (HCPs) is critically important and can be addressed using e-learning pro- T. Shalaby1, G. Tabatabai2, Z. Hovacs1, G. Noe-vonkuerthy2, grams. PURPOSE: We designed a unique interactive case of a pediatric M. Bernasconi1, C. Eberhart3, and M. Grotzer1; 1Oncology Department medulloblastoma in order to meet the educational needs of medical students University Children’s Hospital, Zurich, Switzerland; 2Neurology and HCPs as part of the website http://www.pedsoncologyeducation.com, Department, University Hospital, Zurich, Switzerland; 3Division of outlining the presentation, diagnosis and initial investigation of a pediatric Neuropathology, Johns Hopkins University School of Medicine, Baltimore, BT. METHODS: Flash animation was used for case construction. Content MD, United States was developed using feedback from medical students and HCPs. All respondents completed the case, and subsequently an internet based survey to RATIONALE: Medulloblastomas MBs are the most common malignant collect user characteristics, perceived case efficacy, and user satisfaction. paediatric brain tumours that account for around 10% of all childhood RESULTS: There were 28 respondents, three quarters of whom were cancer deaths. The microenvironment surrounding brain tumour cells medical students. On a 5 point scale, the mean rating for case graphic exerts a significant influence on the tumour’s growth and its response to design, ease of use, quality of content, and teaching efficacy were 4.14 (SD treatment. Orthotopic tumour models have shown similar tumour architec- 1.04), 4.25 (0.70), 4.36 (0.91) and 4.44 (0.51), respectively. The majority ture, cell morphology and molecular characteristics as clinical cancer. This of written feedback regarding the case was positive and indicated that study was undertaken to establish an orthotopic MB model in mice useful teaching points had been relayed to respondents. CONCLUSIONS: induced by MB cell lines expressing different levels of c-Myc. METHODS: Overall the interactive case was well received and viewed as effective by par- Three MB cell lines expressing different levels of c-Myc were injected into ticipants. Further research is needed in order to explore whether perceived the cerebellum of female nude mice using a stereotaxic instrument. Mice effectiveness translates into improved knowledge of posterior fossa brain were examined twice weekly to detect the presence of symptoms indicative tumour diagnosis and initial investigation. of tumour formation and were sacrificed to prevent suffering caused by late- stage disease. Brains were removed and stained with H/E to detect the presence of tumour cells. RESULTS: All mice injected with human MB cells successfully developed tumours in their cerebellum between 6–9 weeks. Macroscopic and histological analysis demonstrated that the injected P-MED.22. SGK1 IS A PROGNOSTIC MARKER AND NOVEL human MB cells in mice cerebellum have grown at the primary site similar THERAPEUTIC TARGET IN MEDULLOBLASTOMA to MB in patients. Mice injected with human MB cells expressing high D. Sturm1, S. Pleier1, M. Remke1,2, H. Witt1,2, G. Reifenberger3, J. Felsberg3, c-Myc showed early tumour development, more aggressive tumours and A. E. Kulozik2, O. Witt4, A. Korshunov5, P. Lichter1, and S. Pfister1,2; demonstrated anaplastic changes. CONCLUSIONS: The developed orthoto- 1Division Molecular Genetics, German Cancer Research Center, Heidelberg, pic mouse model is an efficient MB model that will enable a better under- Germany; 2Department of Pediatric Oncology, Hematology and standing of the role of c-Myc in MB progression and provide a clinically Immunology, University Hospital Heidelberg, Heidelberg, Germany; relevant system for novel drug testing and evaluation. 3Department of Neuropathology, Heinrich-Heine-University of Duesseldorf, Duesseldorf, Germany; 4Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany; 5Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany P-MED.20. MOUSE MODEL TO STUDY THE RADIATION RESPONSE OF MEDULLOBLASTOMA IN VIVO We have recently demonstrated that genomic aberrations of chromosome R. A. Bish and E. C. Holland; Memorial Sloan Kettering Cancer Center, arm 6q provide a powerful marker for outcome prediction in medulloblas- New York, NY, United States toma (MB). However, the genes targeted by copy-number losses and gains on chromosome 6q remain to be identified. 47 MB samples were included Radiation therapy is a key component of the treatment of medulloblas- in a genome-wide transcriptome study. Results were validated by quantitat- toma. Existing mouse models are unsuitable for the study of the response ive real-time PCR (QRT-PCR) and correlated to 6q copy-number status as of medulloblastoma to radiation, as most tumor-bearing animals from assessed by array-CGH. SGK1 protein expression was examined by ii56 NEURO-ONCOLOGY † JUNE 2010 Abstracts

immunohistochemistry on a tissue microarray representing a large cohort of pediatric MBs in order to elucidate age-dependent differences in tumor uniformly treated patients (n ¼ 260). Inhibition of SGK1 was investigated in biology and to define age-specific risk stratification models. Array-based com- vitro by administration of SGK1 antagonist GSK650394 to established MB parative genomic hybridization (array-CGH) was performed in a cohort of 34 cell lines. QRT-PCR revealed a strikingly close correlation of SGK1 adult MBs. Several genomic imbalances were identified as markers for unfa- expression levels with chromosome 6q DNA copy-number status. Tumors vorable outcome. These findings were validated by fluorescence in situ hybrid- with 6q gain showed a significant up-regulation of SGK1 mRNA levels, ization in an independent validation cohort of 112 MBs. The results were whereas down-regulation was observed in tumors carrying a 6q deletion. compared with the data obtained from 404 pediatric MBs. Consecutively, Furthermore, high SGK1 protein expression was associated with poor we performed genome-wide transcriptome analysis (Agilent-44K) in 65 MBs overall survival in a large independent patient cohort. Finally, inhibition of and compared our findings with an independent expression profiling study SGK1 impressively reduced the growth of MB cell lines in a dose- and time- (n ¼ 103). Gene signatures were validated by QRT-PCR and by immunohis- dependent manner. We identified the AKT-homologue SGK1 as a novel can- tochemistry on tissue microarrays. CDK6 amplification, 10q loss and 17q didate gene in MB, partially explaining the particularly poor or especially gain constitute the most powerful molecular markers for poor prognosis in good prognosis of cases with chromosome 6q gain or loss, respectively. In adults. Although MYC/MYCN oncogene amplifications have a high prognos- vitro experiments in MB cell lines showed effective suppression of cell tic value in pediatric MB, they rarely occur in adult tumors. Surprisingly, adult growth upon SGK1 inhibition. Taken together, our studies established a tumors showing 6q deletion and consecutive WNT pathway activation do not role for SGK1 in MB pathogenesis and we propose SGK1 as a novel prognos- share the excellent prognosis with their pediatric counterparts. In an integra- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 tic biomarker and potential therapeutic target in MB. tive analysis DNA copy-number changes are currently correlated with matching mRNA expression data to fine-map genes targeted by these genomic imbalances. Adult MBs are distinct from pediatric tumors in terms of molecular background and its impact on clinical outcomes. Consequently, age- specific risk stratification models are required. P-MED.23. DEVELOPMENTAL CNS VARIATIONS IN MEDULLOBLASTOMA PATIENTS: A MRI-BASED VOLUMETRIC STUDY R. R. G. Knops1, A. Klomp2, C. B. Majoie2, H. N. Caron1,and A. Y. N. Schouten-van Meeteren1; 1Emma Children’s Hospital AMC, P-MED.25. MEDULLOBLASTOMA HISTOLOGICAL VARIANTS Amsterdam, Netherlands; 2Academic Medical Centre, Amsterdam, AS THE MOST POWERFUL PROGNOSTIC INDICATOR: A Netherlands 10-YEAR MONO-INSTITUTIONAL EXPERIENCE M. Massimino1, L. Gandola1, V. Biassoni1, P. Collini1, B. Pollo2, and INTRODUCTION AND BACKGROUND: Medulloblastoma is the most F. Giangaspero3,4; 1Fond. IRCCS Istituto Nazionale Tumori, Milano, Italy; common malignant brain tumor in childhood. Several molecular genetic 2Fond. IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; 3Universita` pathways are involved in the development of medulloblastoma which are La Sapienza, Roma, Italy; 4Fond IRCCS Neuromed, Pozzilli, Italy also crucial in early CNS development. This suggests a relationship between neurogenesis and oncogenesis in medulloblastoma patients. The BACKGROUND: Histological classification in medulloblastoma has purpose of this study is to detect developmental CNS variations in medullo- aroused in importance and newer protocols will include histology as risk blastoma patients by means of MRI. MATERIAL AND METHODS: We factor. We centrally revised all our medulloblastoma cases of the last ten measured MRI-based volumes of 14 brain structures in medulloblastoma years and highlighted their histology to identify its prognostic importance. patients. From our retrospective cohort of 66 medulloblastoma patients MATERIAL AND METHODS: Patients’ samples were reviewed according only 8 met the technical criteria for precise MRI 3D volume measurement. to the two subsequent WHO classifications 2000 and 2007. Consecutive To establish normal CNS morphometry we performed a literature search patients were 127. RESULTS: Male were 91, M0 were 88, primary tumor to identify age and gender specific MRI-based volumes of these brain struc- was completely resected in 99, 11 patients were under 3 years of age. tures in healthy children. We compared these MRI-based brain volumetric Median follow-up was 54 months. Treatment applied was institutional data of healthy children with volumes of brain structures in our cohort of driven, hyperfractionated accelerated radiotherapy (HART) based, for 38 medulloblastoma patients. Additionally we revised the MRIs of our cohort cases before 2003; applied European PNET IV protocol in 30; was insti- of medulloblastoma patients for other brain abnormalities. RESULTS: tutional, HART based, for 40 high risk; infants tailored in 11 (mostly with Measured brain volumes of our cohort of 8 medulloblastoma patients HDCT), patient condition tailored in 7. Six-year PFS/EFS/OS were 75, 72 were all within the normal range described in literature. However, the and 79.5%, respectively. Histology was classic in 93 cases, desmoplastic in corpus callosum showed a slight increase in volume compared to normal 21, anaplastic/large cell in 6/4 and with extensive nodularity (MBEN) in the values; this might be due to early radiation effects. Furthermore, no remark- last three. PFS was 76.4% for M0 cases and 72.6% for M+ ones; 78% for able structural anomalies were found in the medulloblastoma patient cohort NED cases and 66.4% for those with residual tumor; further stratification after revision of the MRIs. CONCLUSION: We found no significant vari- according to both presence of residual disease and metastases was not prognos- ations in brain structure volumes of medulloblastoma patients. No develop- tic either, as were not the main different protocols adopted. Histology showed mental CNS variations or abnormalities in medulloblastoma patients could 83.5% PFS for desmoplastic variant, 79% for classic, 50% for MBEN and 0% be identified by MRI. for anaplastic/large cell one (p , 0.0001). CONCLUSIONS: “Tailored” treatment to recognized risk factors has flattened prognostic differences while histologic variants, that were not considered when designing previous trials, remained the most powerful prognostic factors.

P-MED.24. TUMOR BIOLOGY OF ADULT AND PEDIATRIC MEDULLOBLASTOMAS REQUIRES DISTINCT APPROACHES P-MED.26. CLINICOPATHOLOGICAL CHARACTERISTICS AND FOR MOLECULAR RISK STRATIFICATION LONG-TERM SURVIVAL OUTCOMES OF ADULT M. Remke1,2, A. Korshunov3, P. A. Northcott4, W. Werft5, A. Benner5, MEDULLOBLASTOMA M. Ryzhova6, H. Witt1,2, D. Sturm1, D. Haag1, A. Wittmann1, A. Scho¨ ttler1, S. SahebjamMD1, C. AngMD1, H. Al-HalabiMD1, M. GuiotMD2, A. von Bueren7, F. Westermann8, S. Rutkowski7, A. von Deimling9, G. KasymjanovaMD1, D. RobergeMD1, T. MuanzaMSc,MD1,and W. Scheurlen10, A. E. Kulozik2, M. D. Taylor4, P. Lichter1, and P. KavanMD, PhD1; 1Department of Oncology, McGill University, S. M. Pﬁster1,2; 1Division Molecular Genetics, German Cancer Research Montreal, QC, Canada; 2Department of Pathology, McGill University, Center, Heidelberg, Germany; 2Department of Pediatric Oncology, Montreal, QC, Canada Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany; 3Clinical Cooperation Unit Neuropathology, German Cancer Adult medulloblastoma is a challenging diagnosis. Due to the rarity of this Research Center, Heidelberg, Germany; 4The Hospital for Sick Children, disease in adult patients, there has been little known about the tumor charac- Brain Tumour Research Centre, Toronto, ON, Canada; 5Division teristics, prognostic factors and optimal management. METHODS: We Biostatistics, German Cancer Research Center, Heidelberg, Germany; 6NN reviewed the medical records of adult patients (≥ 18 years old) with histo- Burdenko Neurosurgical Institute, Moscow, Russian Federation; logically proven medulloblastoma who received their treatment at the 7Department of Pediatric Haematology and Oncology, University Medical McGill University teaching hospitals. RESULTS: Between 1989 and Center Hamburg-Eppendorf, Hamburg, Germany; 8Department of Tumor January 2010, thirty-one patients (15 women and 16 men) were treated. Genetics, German Cancer Research Center, Heidelberg, Germany; Median age at diagnosis was 30 years (range, 18–53). Desmoplastic 9Department of Neuropathology, University of Heidelberg, Heidelberg, variant was present in 7 patients (22%). Lateral cerebellar lesions were Germany; 10Cnopf’sche Kinderklinik, Nu¨ rnberg Children’s Hospital, more common than midline tumors (72% vs. 28%). Metastatic disease Nu¨ rnberg, Germany was present in 6 patients (2 with M1, 2 with M2, and 2 with M3). Patients were treated with tumor resection (gross total, subtotal, or Medulloblastoma (MB) is the most common malignant brain tumor in partial), adjuvant craniospinal plus posterior fossa irradiation, and che- childhood, whereas it rarely occurs in adults. Genetic aberrations were inves- motherapy (CCG 921, POG 9031, or house protocol). Individuals with tigated in 146 adult MBs and ﬁndings were compared with data obtained in recurrence/disease progression (7 patients) were treated with salvage

NEURO-ONCOLOGY † JUNE 2010 ii57 Abstracts

regimens. The median follow up was 49 months (range, 5 - 217).The median P-MED.29. MEDULLOBLASTOMA: BIOPSY AS AN INITIAL overall survival was 10 years with the 5- and 10-year overall survival rates of APPROACH TO THIS DISEASE 66 % and 30%, respectively. The 5- and 10-year event-free survival rates A. A. Smith, J. Bennett, and D. W. Pincus; University of Florida, Gainesville, were 50% and 23%, respectively. CONCLUSION: Adult medulloblastoma FL, United States has distinct characteristics from pediatric type. This warrants further study of the clinical and biologic prognostic factors. Prognostic significance of Maximal resection of medulloblastoma is the standard of care. Degree of patient characteristics, tumor pathology (including expression of bio- resection is positively correlated with outcome. However, this is less clear in markers), different treatment modalities/regimens (including salvage patients with disseminated disease. Surgical morbidities from posterior fossa therapy) as well as long term sequelae of treatment will be presented. tumor resections are not insignificant. We present 2 cases of children with M3 medulloblastoma who underwent biopsy of their initial disease in an attempt to decrease morbidity. PATIENT #1: A 6-year-old female with M3 disease underwent T 12 laminectomy and biopsy of a large metastatic P-MED.27. ESTABLISHMENT OF REAL-TIME CENTRALISED lesion which revealed medulloblastoma. Treatment was similar to CCG PATHOLOGY REVIEW (CPR) AND MOLECULAR DIAGNOSTICS 99701 with craniospinal radiation (CSI), concurrent carboplatin followed FOR MEDULLOBLASTOMA IN THE UNITED KINGDOM by maintenance chemotherapy. The patient is now 4 years from diagnosis S. L. Nicholson1, K. Robson2, T. Jaques3, S. B. Wharton4, A. Michalski3, 5 6 6 1 without evidence of disease. PATIENT #2: A 6-year-old male presented B. Pizer , N. Bown , and S. C. Clifford ; Royal Victoria Infirmary, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 with a very large 4th ventricular primary lesion. He underwent a third ven- Newcastle upon-Tyne, United Kingdom; 2Queens Medical Centre, triculostomy and tumor biopsy as well as placement of an Ommaya reser- Nottingham, United Kingdom; 3Great Ormond Street Hospital, London, voir. Treatment was similar to #1 except he underwent second surgery United Kingdom; 4Royal Hallamshire Hospital, Sheffield, United Kingdom; prior to maintenance due to a small residual tumor at the primary site. He 5Alder Hey Children’s Hospital, Liverpool, United Kingdom; 6Newcastle experienced cerebellar mutism though is without any evidence of disease University, Newcastle upon-Tyne, United Kingdom now near completion therapy. No conclusions can be drawn from our two patients; however it is interesting and encouraging that patient#1 was able INTRODUCTION: The Children’s Cancer and Leukaemia Group to avoid a craniotomy altogether and is doing well from a disease standpoint (CCLG) has commenced a study to establish the feasibility of rapid collec- for over 4 years. Unfortunately we were not able to avoid mutism in patient tion, consent, transportation, centralised molecular diagnostic analysis and #2 even with substantial reduction in tumor size prior to resection. We think CPR, for patients diagnosed with medulloblastoma. The aim is to establish this approach should be considered and examined on a larger scale. systems for participation in the forthcoming SIOP PNET 5 and PNET 6 trials, which will (i) stratify therapy according to risk defined by clinical, pathological and biological disease features, and (ii) mandate submission of frozen tumour material for biological assessment. MATERIALS AND METHODS: CCLG local centres inform the national coordinator of newly P-MED.30. RESECTION ALONE IN LIEU OF ADJUVANT diagnosed cases, obtain consent and submit tissue. CPR and molecular diag- THERAPY IN THE TREATMENT OF MEDULLOBLASTOMA IN nostics are coordinated by the national reference centre, including the assess- GORLIN SYNDROME ment of high-risk (MYC/MYCN amplification status) and favourable-risk L. Rasmussen, J. Hukin, S. R. Rassekh, A. Singhal, and G. Hendson; BC (b-catenin status) biomarkers. A time-frame of 30 days post-surgery has Children’s Hospital, University of British Columbia, Vancouver, BC, Canada been set for return of results to local centres, to allow treatment selection prior to commencement of adjuvant therapy. RESULTS: 22 patients have BACKGROUND: Patched gene (PTCH) is implicated in desmoplastic been registered from 9 CCLG centres since February 2009. CPR was achiev- medulloblastoma. Germline mutations in PTCH are associated with Gorlin able for all, and assessment of all biomarkers in 21/22 cases. Results were syndrome (GS). GS is a hereditary condition characterized by multiple devel- reported to local centres within 30 days in 21/22 cases. MYCN amplification opmental abnormalities and a predisposition to developing neoplasms, was observed in 2 cases, which would have elevated these to ‘high-risk’ status specifically medulloblastoma. A predilection to the desmoplastic/medullo- under risk group classifications planned for the PNET trials. Further, the his- blastoma with extensive nodularity (MBEN) variant has been noted in topathological sub-classification of 2 cases was modified, indicating CPR these patients. Although MBEN variants are thought to have better progno- will influence patient risk stratification in the trials setting. sis, the gold standard therapy resulting in the best survival in medulloblas- CONCLUSIONS: A centralised system for CPR and molecular diagnostics toma is gross total resection followed by adjunctive radiotherapy and has been established, which will be incorporated into forthcoming SIOP chemotherapy. Some patients have been cured with surgery and intensive clinical trial protocols. chemotherapy. Avoiding radiation is of particular importance in children with GS given their predisposition to developmental delay and radiation induced tumors. METHODS: This is a case report of a child with MBEN and GS treated with resection alone. RESULTS: A 4-month-old male had a gross total resection of a posterior fossa MBEN. Aggressive chemotherapy P-MED.28. MRI CHARACTERISTICS OF ANAPLASTIC VERSUS was not given in view of his extensive medical issues and severe developmen- NON-ANAPLASTIC MEDULLOBLASTOMA IN CHILDREN tal delay. Given his age, he was not a candidate for radiation. The diagnosis A. Lignelli, K. Surapaneni, R. J. Hanisch, J. H. Garvin, and W. S. Millar; of GS was confirmed by phenotypic diagnosis. Two years post-operatively he Columbia University Medical Center, New York, NY, United States remains in remission with remarkable developmental gains. CONCLUSION: This is the first report of MBEN progression-free survival following resection The WHO 2007 classification of medulloblastoma (MB) recognizes ana- alone. Given that MBEN has a better prognosis it is possible that surgery plastic subtype which has been associated with unfavorable outcome. No alone may be curative, especially in the context of GS. studies have addressed whether anaplastic MB can be suspected preoperatively. We retrospectively evaluated MRI characteristics of MB in 25 patients (age 1 to 16 years; 8 anaplastic, 17 non-anaplastic) newly diagnosed between 2000 and 2009. MRIs were performed on a 1.5 T magnet. FLAIR, FSET2, GRE, DWI, ADC maps and postcontrast T1 sequences were P-MED.32. TREATMENT OF ADULT MEDULLOBLASTOMA reviewed. Signal intensity ratios of tumor to normal tissue were performed ACCORDING TO THE MULTICENTER PROSPECTIVE HIT for T2, FLAIR and contrast enhancement. ADC maps were calculated on a TRIALS: A SINGLE CENTER EXPERIENCE 4.2 aw GE workstation. Tumor size was measured using 2 orthogonal P. Sovinz1, M. Benesch1, H. Lackner1, W. Schwinger1, A. Nebl1, H. Eder2, dimensions in the axial plane. There was no significant difference between K. Kapp3, and C. Urban1; 1Division of Pediatric Hematology and Oncology, MB subtypes on T2, FLAIR, DWI, ADC maps, nor in average tumor size, Department of Pediatrics and Adolescent Medicine, Medical University of cystic characteristics, or contrast enhancement. All cases demonstrated Graz, Graz, Austria; 2Department of Neurosurgery; Medical University of decreased ADC values, with no difference between anaplastic and non- Graz, Graz, Austria; 3Department of Therapeutic Radiology and Oncology, anaplastic subtypes. Low GRE signal was observed in a majority of both sub- Medical University of Graz, Graz, Austria types, without significant difference. Five of 8 (63%) of anaplastic MB, versus 7 of 17 (40%) of non-anaplastic MB, were classified as partly periph- PURPOSE: Five-year overall survival rates of 64–72% have recently been eral in location. Of the anaplastic peripheral cases, 4/5 demonstrated non- reported in adult medulloblastoma (MB). The aim of this retrospective study contiguous bulky tumor without evidence of leptomeningeal spread. While was to analyze the outcome of adults with MB treated according to the pedi- no significant difference was seen in size, signal intensity, enhancement atric HIT protocols at a single institution. PATIENTS AND METHODS: and diffusion characteristics between the two subtypes, peripheral location Eight adult patients with MB (male, n ¼ 4; median age: 30 years) were and multifocal, bulky morphology were more commonly seen in anaplastic treated according to the German/Austrian brain tumor trials HIT 91 (n ¼ than non-anaplastic MB. These pre-operative MRI findings should raise sus- 4) and HIT 2000 (n ¼ 4) between 1995 and 2009. The most common pre- picion for the presence of histologic anaplasia. senting symptoms were headache, dizziness, gait instability, nausea/vomiting and ocular symptoms. Gross total resection was performed in 2, subtotal in 2 and partial resection in 4 patients. Cytological analysis of ii58 NEURO-ONCOLOGY † JUNE 2010 Abstracts

cerebrospinal fluid was negative in 7 patients and positive in one. Seven P-MED.35. DELAYED METHOTREXATE EXCRETION IN patients received craniospinal irradiation (craniospinal axis dose: 35.2 Gy, INFANTS AND YOUNG CHILDREN WITH POSTOPERATIVE n ¼ 4; 23.4 Gy, n ¼ 3) with concomitant weekly vincristine followed by 8 CENTRAL NERVOUS SYSTEM (CNS) FLUID COLLECTIONS: cycles of maintenance chemotherapy (Packer protocol). The patient with PHARMACOKINETIC ANALYSIS AND IMPLICATIONS FOR M1 disease underwent partial resection followed by 2 cycles of HIT-SKK BRAIN TUMOR TREATMENT chemotherapy, hyperfractionated craniospinal radiotherapy and 4 cycles of K. D. Wright1, M. Tagen1,R.P.Sanders2, D. A. Ward1, C. Haidar1, maintenance chemotherapy. RESULTS: With a median follow-up of 85.5 T. McKibbin1, M. Williams-Griffin1,Z.Patay1,M.Dewire1, I. Qaddoumi1, (range, 59–120) months seven patients are alive with one of them still receiv- B. Morris1,A.Broniscer1,F.A.Boop1,A.Gajjar1, and C. F. Stewart1; 1St. Jude ing therapy. Two patients relapsed 5 and 2 months after the end of therapy; Children’s Research Hospital, Memphis, TN, United States; 2Robert K Johnson one of them died of progressive disease. In the other one local recurrence was Md Pa & Associates Pediatrics Clinic, San Antonio, TX, United States successfully retreated by stereotactic radiosurgery and chemotherapy. Six survivors suffer from neurological late effects. CONCLUSIONS: BACKGROUND: High dose methotrexate (HD MTX) has been Craniospinal irradiation followed by maintenance chemotherapy is feasible included in several clinical trials for the treatment of young children in adult patients with MB and may yield promising survival rates. with CNS tumors. Studies involving other tumor types have revealed accumulation of methotrexate within pathological fluid collections may lead to delayed excretion and consequently, increased risk of systemic tox- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 icity. To date, the potential effect of intracranial fluid collections on MTX pharmacokinetics has not been formally reviewed. METHODS: The P-MED.33. REDUCED BOOST VOLUME IRRADIATION IN THE plasma MTX levels and brain MRIs of 61 patients, ages 8 days to 3 POSTERIOR FOSSA FOR AVERAGE-RISK MEDULLOBLASTOMA years, following first course of induction therapy with HD MTX (dose IN CHILDHOOD: PATTERNS OF RELAPSE 5000 mg/m2;n¼ 57/61) were reviewed for delayed clearance and intra- G. O. R. J. Janssens1, A. Baeten2, P. Meijnders3, C. E. M. Gidding1,J.H.A. cranial fluid collections, respectively. MTX levels were drawn prior to M. Kaanders1, and J. Menten2; 1Radboud University Nijmegen Medical and at 6, 23, 42 and 66 hours after the infusion start. Delayed plasma Center, Nijmegen, Netherlands; 2Leuvens Kanker Instituut, Leuven, clearance was defined as a MTX level . 0.1 mM at 66 hours. Belgium; 3Academic Radiotherapy Antwerp, Antwerp, Belgium Leucovorin was administered starting at 42 hrs and dosed every 6 h until the serum MTX concentration was , 0.1 mM, in addition to an PURPOSE: The irradiated boost volume for average-risk medulloblastoma increase in hydration. RESULTS: Of the 27 patients (44.3%) with patients remains controversial. We reviewed the patterns of failure with delayed plasma clearance of MTX, all but one possessed CNS fluid collec- reduced boost volume rather than a boost to the whole posterior fossa. tions (96.3%). Twenty-three of 34 patients (67.6%) without delayed MTX MATERIAL AND METHODS: Between September 1993 and July 2009, clearance lacked significant CNS fluid collections. The average 66 hour 39 patients (age 3-21 years) with newly diagnosed average-risk medulloblas- MTX level for patients with delayed MTX excretion was 0.23 mM com- toma received a postoperative 2D or 3D conformal boost to the tumor bed in pared to 0.03 mM for patients with normal clearance. CONCLUSIONS: conjunction with craniospinal irradiation at the university hospitals of Careful monitoring, aggressive hydration and leucovorin rescue can Leuven (n ¼ 19), Nijmegen (n ¼ 15) and Antwerp (n ¼ 4). Twenty-four prevent significant toxicity in patients with intracranial fluid collections, patients also received chemotherapy. Craniospinal and cumulative tumor allowing for safe administration of this agent. bed doses ranged from 18.0-36.0 Gy and 51.2-56.0 Gy, respectively. The planning target volume for the primary site included the postoperative tumor bed surrounded by an anatomically confined margin of 1-2 cm, expanded with a geometric margin of 0.5 cm. RESULTS: At a median P-MED.36. FEASIBILITY OF USING CONCURRENT follow-up of 65 months, seven patients relapsed; the site of first relapse CARBOPLATIN AND REDUCED DOSE CRANIOSPINAL was leptomeningeal outside the posterior fossa in 4 patients (supratentorial, RADIATION (24 GY) FOR METASTATIC MEDULLOBLASTOMA n ¼ 3; spinal n ¼ 1) and at the tumor bed in combination with elsewhere in AND HIGH-RISK SUPRATENTORIAL PNET the posterior fossa (n ¼ 3). No isolated posterior fossa recurrence occurred J. R. Madden, A. K. Liu, and N. K. Foreman; The Children’s Hospital, outside the high-dose boost region. Five year actuarial event-free and University of Colorado, Aurora, CO, United States overall survival rates were 91.1% and 94.6%, respectively. Freedom from posterior fossa failure was 96.2% and 92.3% at 5 and 10 years, respectively. Pilot data from Children’s Oncology Group (COG) study 99701 show CONCLUSION: Because isolated recurrences in the posterior fossa outside the excellent results (89% 3-year event-free survival (EFS)) with daily carbo- high-dose boost area did not occur, strong arguments to limit the boost to the platin combined with radiation for high-risk brain tumors. However, 36 tumor beddo exist. Further investigation isneeded once boost volume reduction Gy of radiation is associated with extremely poor quality of life including with intensity-modulated radiotherapy or protontherapy is introduced. poor cognitive function, hormonal, and growth problems. The current IRB-approved ongoing study evaluates the efficacy of reducing the dose of craniospinal radiation to limit adverse effects, while adding concurrent carboplatin with weekly vincristine administration during radiation in P-MED.34. CHEMOTHERAPY DOSE-INTENSITY AND metastatic medulloblastoma or supratentorial primitive neuro-ectodermal SURVIVAL FOR CHILDHOOD MEDULLOBLASTOMA tumor (PNET) patients. Patients must be newly diagnosed and age 3 to R. Smith1, I. Kamaly-Asl1, H. Gattamaneni2, and E. Estlin1; 1Royal 25 years. Anaplastic pathology and tumors with FISH evidence of c-myc Manchester Childrens Hospital, Manchester, United Kingdom; 2Christie expression are excluded. After maximum tumor resection, informed Hospital, Manchester, United Kingdom consent is obtained. Radiation (23.4 Gy craniospinal; 54 Gy boost to tumor bed) is given concurrently with carboplatin (35 mg/m2). Post-radiotherapy chemotherapy based on cisplatin, CCNU and vincristine Radiation is followed by standard adjuvant chemotherapy (cisplatin, has become a standard for the therapy of childhood medulloblastoma, but sig- lomustine, vincristine alternating with cyclophosphamide, vincristine) for nificant between-patient variability for dose-intensity achieved exists with con- 12 months. The primary objective is to obtain preliminary estimates of temporary treatment protocols. Chemotherapy dose-intensity is an important EFS in preparation for a future phase III randomized trial. To assess effi- determinant for prognosis for many childhood cancers, and the aim of this cacy we will accept equivalency of 90% EFS at 3 years. One failure within study was to relate prescribed chemotherapy dose intensity, patient risk 10 patients will close the study. Current enrollment includes 6 patients (3 factors and outcome for the thirty eligible articles identified from 1970 to metastatic medulloblastoma, 3 supratentorial PNET). All 6 patients are 2009. 2434 patients were identified, and of these 1017 were classified as “stan- without recurrence (4 off therapy, 2 near to completion of therapy). dard risk” and 671 as “high risk” patients, with a 5-year overall survival (OS) of Progression free survival is at a median of 21 months (range, 12-30 67.2% and 47.6%, respectively. Overall, a protective effect for chemotherapy months). Neuropsychological data is currently being gathered to assess versus radiotherapy alone (5-year OS of 58.2% vs 51.6%) was found. for cognitive outcomes. Chemotherapy administered during and after radiotherapy was more effective than pre-radiotherapy treatment. Individually, the four most commonly used chemotherapy agents vincristine, cisplatin, CCNU and cyclophosphamide appear to be the most beneficial relative to radiotherapy alone, particularly for "high risk" patients. With respect to the dose-intensity for these agents, all except CCNU show a positive relationship between OS and dose-intensity, and this was statistically significant for cyclophosphamide. Furthermore, when compared to radiotherapy alone a minimum dose-intensity is required to provide benefit, except for CCNU, which appears to have a protective effect even at lower doses. Chemotherapy is now an important and established modality of treatment for childhood medulloblastoma, and considerations of chemotherapy dose-intensity may help to further optimize this treatment for future patients with this disease.

NEURO-ONCOLOGY † JUNE 2010 ii59 Abstracts

P-MED.37. PRELIMINARY RESULTS OF TANDEM HIGH-DOSE P-MED.39. A TRIAL OF INTRA-OMMAYA (IO) CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE RADIOIMMUNOTHERAPY (RIT), REDUCED-DOSE EXTERNAL AND REDUCED DOSE OF CRANIOSPINAL IRRADIATION FOR BEAM CRANIOSPINAL RADIOTHERAPY (RT) WITH YOUNGER CHILDREN WITH MEDULLOBLASTOMA/PNET INTENSITY-MODULATED RADIOTHERAPY (IMRT) BOOST, M. Lee1, K. Sung2, D. Lim2, H. Shin2, H. Back3, J. Park4, H. Park5,H.Im6, AND CHEMOTHERAPY FOR PATIENTS WITH H. Kim7, H. Shin8, and C. Suh9; 1Dankook University Hospital, Cheonan, STANDARD-RISK MEDULLOBLASTOMA Republic of Korea; 2Samsung Medical Center, Seoul, Republic of Korea; I. J. Dunkel, S. L. Wolden, M. M. Souweidane, C. A. Sklar, Y. Khakoo, 3Chonnam National University Hospital, Hwasoon, Republic of Korea; S. M. Larson, O. J. Becher, T. R. Gershon, S. W. Gilheeney, D. C. Lyden, 4Ajou University Hospital, Suwon, Republic of Korea; 5National Cancer S. Haque, E. Lis, M. K. Rosenblum, H. T. Thaler, and K. Kramer; Memorial Center, Ilsan, Republic of Korea; 6Asan Medical Center, Seoul, Republic of Sloan-Kettering Cancer Center, New York, NY, United States Korea; 7Kyemyung University Dongsan Medical Center, Daegu, Republic of Korea; 8Seoul National University Hospital, Seoul, Republic of Korea; BACKGROUND: Most standard-risk medulloblastoma patients achieve 9Yonsei University Hospital, Seoul, Republic of Korea long-term EFS, but chronic morbidities can compromise their quality of life. METHODS: We aimed to maintain the good EFS and to reduce the The survival rate of children with medulloblastoma (MB) or supratentorial risk of chronic morbidities by modifying the RT. We (1) added IO RIT primitive neuroectodermal tumor (PNET) less than 3-year old age is very (131-I-3F8, 2 mCi test dose and 10 mCi therapeutic dose), (2) decreased cra- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 poor, and the life quality of the survivors is suboptimal. A prospective niospinal RT to 1800 cGy, and (3) decreased the IMRT boost volume to nationwide study of high-dose chemotherapy with autologous stem cell tumor bed + 1 cm margin. Patients received conventional chemotherapy. rescue (HDCT/ASCR) was conducted in younger children with newly diag- Dosimetry was assessed post-test dose. RESULTS: We treated 6 patients nosed MB/PNET in order to improve survival as well as to reduce late com- aged 49 to 119 months with classic (n ¼ 4), desmoplastic (n ¼ 1), or large plications. Patients with MB/PNET under 3-year age who were diagnosed cell/anaplastic (n ¼ 1) standard-risk medulloblastoma. IO RIT began a between March 2005 and August 2007 were registered. Tandem HDCT/ median of 36.5 days post-surgery (range, 26-40 days) and external beam ASCR was given after receiving 6 cycles of conventional chemotherapy. RT a median of 12 days (range, 7-18) later. No unexpected SAE’s occurred. Local radiotherapy to primary site or reduced dose of craniospinal Three patients suffered tumor recurrences at 8, 18, and 26 months post-start irradiation was given pending on the response of the tumor from the of therapy (1 within the boost volume, 2 non-marginal distant). Three tandem HDCT/ASCR. The study consisted of 11 patients (4 males and 7 patients are EFS at 54, 71, and 75 months post-start of therapy. Median females) with a median age of 17 months (range, 10-34) from 5 hospitals. CSF and blood doses were 24 cGy/mCi (range, 18-92.8) and 1.6 cGy/mCi Nine patients achieved complete remission, one had partial response, and (range, 0.77-5.7). CONCLUSION: Adding IO RIT was feasible and not the remaining one died of HDCT/ASCR toxicity. Other complications associated with unexpected toxicity. Slow accrual and possible increased were manageable. Of the two who had tumor relapse, one died of disease failure rate led to early termination of the trial. Future trial development progression. The median follow up duration was 48 months (range, plans include (1) decreasing the interval from surgery to RT start, (2) increas- 28-57). The 3-year overall and progression free survival (PFS) rate for all ing total dose delivered by RIT (40 mCi in the current phase II study), and (3) 11 patients was 80.8 + 12.2 % and 70.1 + 14.7 %, respectively. Using exclusion of large cell/anaplastic subtype. tandem HDCT/ASCR, we were successful either in eliminating or delaying the radiotherapy without jeopardizing the PFS in these young children with newly diagnosed MB/PNET. A long-term follow-up study with a larger cohort is needed to conﬁrm the beneﬁt of tandem HDCT/ASCR. P-MED.40. INTRATHECAL LIPOSOMAL CYTARABINE IN COMBINATION WITH SYSTEMIC CHEMOTHERAPY IN CHILDREN WITH DISSEMINATED LEPTOMENINGEAL MEDULLOBLASTOMA P-MED.38. MODIFYING THE PHYSICAL AND BIOLOGICAL C. D. Turner1,2, S. N. Chi1,2, C. A. Chordas1, M. A. Zimmerman1, PARAMETERS OF RADIOTHERAPY TO OPTIMIZE OUTCOMES N. Ullrich1,3, L. Goumnerova1,4, and M. W. Kieran1,2; 1Pediatric IN CHILDREN WITH AVERAGE-RISK MEDULLOBLASTOMA Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; T. Gupta1, R. Jalali2, S. Goswami2, R. Sarin1, V. Nair1, and N. Merchant2; 2Hematology/Oncology, Children’s Hospital Boston, Boston, MA, United 1ACTREC, Tata Memorial Centre, Navi Mumbai, India; 2Tata Memorial States; 3Neurology, Children’s Hospital Boston, Boston, MA, United States; Hospital, Mumbai, India 4Neurosurgery, Children’s Hospital Boston, Boston, MA, United States

PURPOSE: To optimize the physical and biological parameters of radio- PURPOSE: The prognosis of children with leptomeningeal medulloblas- therapy in average-risk medulloblastoma. METHODS: Nineteen children toma is poor. A retrospective review of four children with recurrent or refrac- with average-risk medulloblastoma were accrued on an ongoing prospective tory medulloblastoma with leptomeningeal dissemination treated with protocol of hyperfractionated radiotherapy (HFRT). Radiotherapy consisted intrathecal (IT) liposomal cytarabine (LC) and systemic chemotherapy was of 2 fractions daily of 1 Gy each, 6 hours apart, 36 Gy/36 fractions of cra- performed after obtaining IRB waiver. PATIENTS/METHODS: niospinal irradiation (CSI), followed by conformal tumor bed boost (32 Gy/ Intrathecal LC was administered at a fixed dose of 35mg every 2 weeks 32 fractions) for a total tumor bed dose of 68 Gy/68 fractions over 6.5 during induction, every 4 weeks during consolidation and then every 8 weeks. Chemotherapy was not given upfront, but reserved for relapse. weeks (maximum 10 doses) over 1 year via lumbar puncture or ommaya Apart from neuro-imaging, pre and post-radiation evaluation included peri- reservoir. Dexamethasone was administered prior to LC to minimize ara- odic assessments of neuro-cognitive, endocrine, and audiometric function chnoiditis. All received concomitant etoposide (35mg/m2/day PO days and growth monitoring. RESULTS: The median age of the cohort was 8 1-21) and temozolomide 150mg/m2/day PO days 1-5) and additionally 2 years (range, 5-14 years). Acute hematologic toxicity was mild and self- patients received alternate cycles of cyclophosphamide (2.1g/m2/day IV limiting. Four (21%) patients developed grade III neutropenia (of whom for 2 days). RESULTS: Patients aged 3 to 11 years received 4 to 10 doses one needed growth factors). Two (10.5%) patients developed grade II throm- of LC. Therapy was generally well tolerated. Three patients experienced bocytopenia, while no one developed grade III-IV thrombocytopenia. Seven signs of arachnoiditis that was managed with corticosteroids and all contin- of 19 (37%) children had suboptimal Intelligence Quotient (IQ) scores even ued treatment. Three patients demonstrated decreased leptomeningeal before radiotherapy. At a median follow-up of 24 months (range, 7-43 disease after 6 weeks. One patient had stable disease at 6 weeks, but evidence months), 3 patients had died (2 of relapse and 1 of accidental burns). The of progression after 12 weeks. Two patients had ongoing radiographic 3-year relapse-free-survival and overall survival was 83% and 70%, respect- improvement of their leptomeningeal disease, but discontinued after 2 or 9 ively. The mean IQ scores for all tested domains were preserved in 16 chil- months due to increased intracranial parenchymal disease. A 3 year old dren evaluable at 1-year and 10 children evaluable at 2-year follow-up. patient had significant improvement in leptomeningeal enhancement by CONCLUSION: HFRT for average-risk medulloblastoma has an acceptable MRI with clearing of CSF cytology. She received treatment for 1 year (10 acute toxicity profile, without an unduly increased risk of relapse. Early doses) and is currently disease-free 3 years off therapy. CONCLUSION: IT interim analysis suggests that it is not associated with any significant LC in combination with chemotherapy shows evidence of anti-tumor activity decline in neuro-cognitive function over time. in leptomeningeal dissemination of medulloblastoma.

ii60 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-MED.41. TEMOZOLOMIDE IN CHILDREN AND the good outcome. Siriraj Pediatric Brain Tumor Network was founded and ADOLESCENTS WITH RECURRENT/PROGRESSIVE set a guideline for childhood medulloblastoma management. The treatment MEDULLOBLASTOMAS plan was stratified into average and high risk according to a modified Chang R. Kebudi1,2, F. Y. Agaoglu3, O. Gorgun4, H. Emiroglu4, N. Dagoglu3, staging. METHODS: Forty-one patients between 2 years to 15 years old (15 Y. Dizdar3, and E. Darendeliler3; 1Istanbul University, Cerrahpasa Medical boys, 26 girls) were enrolled in our study from 1999 to 2009. Twenty one Faculty & Oncology Institute, Division of Pediatric Hematology-Oncology, and 20 patients were in average and high risk, respectively. The mean age Istanbul, Turkey; 2VKF American Hospital, Istanbul, Turkey; 3Istanbul was 8.8 years. The treatment plan consisted of tumor removal, followed by cra- University, Oncology Institute, Division of Radiation Oncology, Istanbul, niospinal irradiation and adjunctive chemotherapy including vincristine, cyclo- Turkey; 4Istanbul University, Oncology Institute, Division of Pediatric phosphamide, cisplatinum and oral etoposide. RESULTS: The event-free Hematology-Oncology, Istanbul, Turkey survival for average and high risk patients were 71.41% and 30%. Four patients in average risk and 7 patients in high risk relapsed. The median Temozolomide is an alkylating agent which penetrates the blood brain time of relapse was 17.24 months. Ten patients died of relapse and only barrier. Temozolomide is now considered as standard treatment in combi- one relapsed patient survived after surgery and adjuvant chemotherapy. nation with radiotherapy for management of high grade gliomas in adults. Five patients died of toxicity. Overall survival for average and high risk However, studies with temozolomide in children with CNS tumors are patients were 78.61% and 40.63% respectively. One patient in high risk limited. In this study, the effect of temozolomide as second line chemother- developed acute myeloid leukemia 11 months after completed adjunctive Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 apy in 8 children (3-15 years) with recurrent / progressive medulloblasto- chemotherapy and died. The median follow up time was 34.95 months. mas, treated in the Istanbul University, Oncology Institute, was assessed. CONCLUSION: Outcome of average risk childhood medulloblastoma in All patients, diagnosed with high-risk medulloblastoma (positive CSF / our institute can achieve favorable result. However, high risk patients still residual tumor / spinal axis involvement), had been treated with craniospinal have a poor outcome, this group of patients may need stem cell rescue radiotherapy and chemotherapy. After recurrent/progressive disease (1 after high dose chemotherapy to improve survival rate. tumor progression / 1 local recurrence / 6 spinal axis, or CSF involvement), temozolomide (150 mg/m2/day x 5 days every 28 days) was administered orally. Two patients who were treated for 15 courses each (1 complete response, 1 stable after partial response) are on follow-up for 4.5 years after the completion of treatment, continue regular school and have a P-MED.44. TREATMENT-RELATED OPTIC NEUROPATHY IN A good quality of life. Six patients received a median of 8 courses of chemother- PATIENT WITH MEDULLOBLASTOMA apy, 2 are still under treatment, four have had disease stabilization but later D. M. Pucccetti1, N. J. Patel1, K. A. Bradley2, M. C. Struck2, B. Mathew2, died with progressive disease. No major adverse effect necessitating to stop T. J. Daley2, T. A. Kennedy2, K. T. Casey1, D. C. Delgado1, and treatment was detected. Thrombocytopenia was the most common toxicity. B. C. Gadbaw1; 1American Family Children’s Hospital, Madison, WI, In conclusion, temozolomide is an effective and tolerable agent for recurrent United States; 2University of Wisconsin Hospital and Clinics, Madison, WI, / progressive medulloblastomas. Its oral use and not requiring hospitaliz- United States ation are also important factors in terms of quality of life. It may also lead to long term survival in some patients. Standard treatment for children with medulloblastoma includes surgery, radiation therapy, and chemotherapy. Much has been reported regarding the acute and long term side effects of this combination therapy. Toxicity involving the visual system is quite rare. We report the case of a 15-year-old boy who P-MED.42. MEDULLOBLASTOMA OVER THREE DECADES IN A developed optic neuropathy while undergoing treatment for medulloblastoma. SINGLE INSTITUTION - WHAT HAVE WE ACHIEVED After surgical resection he received craniospinal irradiation plus a boost to the T. Al-Asaad, J. Duckworth, N. Barr, S. Singh, and K. Scheinemann; posterior fossa. Six doses of vincristine were given weekly during the radiation McMaster Children’s Hospital, Hamilton, ON, Canada therapy. He then began maintenance chemotherapy with lomustine, cisplatin and three doses of vincristine each at one week interval. At the time of his Medulloblastoma (MB) is the most frequent brain tumor in children. Over second maintenance course he reported blurry vision of the right eye. the past several decades, the survival of children has improved significantly. Retrospectively this had been present since completion of the chemoradiother- From 1981 to 2009, 33 children were diagnosed with MB at our institution apy. An ophthalmologic exam revealed an afferent papillary defect, central and their medical records and pathological reports were reviewed. Median scotoma on the right side. He was diagnosed with optic neuropathy with the age at diagnosis was 8 years (range, 15 months to 17 years), the majority right eye more involved than the left. MRI scans including dedicated views of were males (75 %). Seven patients (21 %) presented with metastatic the optic nerves did not reveal any pathology. Though rare, vincristine and cis- disease. Surgical reports revealed gross total resection (GTR) in 20 patients platin have been associated with optic neuropathy. Vincristine seemed the most (61 %). Five patients had anaplastic histology and 3 of them died of early likely culprit since reportedly the patient was aware of his vision changes even relapse. Thirty-one children underwent craniospinal radiation with no prior to receiving cisplatin. Vincristine was eliminated in the subsequent cycles lower age limit. Twenty-four patients survived and 9 patients died due to of chemotherapy and no further decline has occurred with his vision. A review relapse or progressive disease. Relapse occurred between 6 months and 3 of the literature will be included. years after diagnosis, although 80 % of relapses happened within the first year of treatment completion. Analyzing morbidity in the survivor population revealed hearing loss in 20 % as the most frequent complication. Endocrinopathies were seen in 10 patients: 4 with hypothyroidism, 3 with growth hormone deficiency and 3 with panhypopituitarism. Severe motor P-MED.45. FUNCTIONAL EVALUATION IN METASTATIC and intellectual deficiencies occurred only in 2 survivors, while 20 % of MEDULLOBLASTOMA G. Poggi1, A. Adduci1, L. Gandola2, and M. Massimino2; 1IRCCS E. Medea, them had learning difficulties. In our single institution experience anaplastic 2 histology was identified as a negative prognostic factor, whereas GTR and Bosisio Parini-LECCO, Italy; National Tumor Institute, Milano, Italy metastatic stage did not alter the prognosis - suggesting a new, more biologically based, risk stratification needs to be discussed. Long term morbidity PURPOSE: To compare the cognitive outcome in metastatic medulloblas- was high, which must be considered for future study designs. toma (MMp) vs. non-metastatic medulloblastoma (NMMp) patients treated with an identical post-surgery pre-radiant chemotherapy schedule but with a median higher CSI-(hyperfractionated accelerated radiotherapy) HART (range, 31-39 Gy vs. 19.2-39 Gy) and with post-HART high-dose che- P-MED.43. OUTCOME OF CHILDHOOD MEDULLOBLASTOMA motherapy in selected cases (JCO 27(4):566-71). METHODS AND IN THAILAND MATERIALS: 19 MMp and 25 NMMp underwent age-appropriate cogni- B. Pongtanakul1, T. Sangruchi2, S. Nunta-aree3, O. Chawalparit4, tive/neuropsychological testing, at 1.6 and 1.9 years from diagnosis for N. Suntornpong5, and G. Veerakul1; 1Division of Hematology and the first evaluation, respectively; the second evaluation was done 3 and 2 Oncology, Department of Pediatrics, Faculty of Medicine,Siriraj Hospital, years after the 1st one, respectively. Cognitive tests included the Wechsler Mahidol University, Bangkok, Thailand; 2Department of Pathology, Faculty Scales, the Continuous Performance Test (CPT) for attention, the Rey Test of Medicine,Siriraj Hospital, Mahidol University, Bangkok, Thailand; for memory and praxic abilities, the Wisconsin Card Sorting Test (WCST) 3Division of Neurosurgery, Department of Surgery, Faculty of for executive functions, the Benton Test for spatial organization. Medicine,Siriraj Hospital, Mahidol University, Bangkok, Thailand; RESULTS: Age at diagnosis, at radiotherapy and at first evaluation were sig- 4Department of Radiology, Faculty of Medicine,Siriraj Hospital, Mahidol nificantly higher in MMp; basal IQ testing showed lower performances in University, Bangkok, Thailand; 5Division of Radiation Oncology, MMp (mean FIQ: 86.21 in MMp vs. 92.28 in NMMp). Significant differ- Department of Radiology, Faculty of Medicine,Siriraj Hospital, Mahidol ences at diagnosis were found in the mean scores of the two groups for the University, Bangkok, Thailand neuropsychological evaluation: the group of MMp showed a greater incidence of impairments in multiple domains (attention, memory, executive BACKGROUND: Medulloblastoma is the most common malignant brain functions and praxic abilities). At follow-up MMp showed a tendency to tumor in children. The treatment requires a multidisciplinary team to achieve deterioration vs. a tendency to improvement in NMMp, without statistical

NEURO-ONCOLOGY † JUNE 2010 ii61 Abstracts

significance. CONCLUSIONS: At baseline cognitive-neuropsychological 2Department of Pediatric Hematology and Oncology, University Medical testing MMp are globally more impaired than NMMp; tendency to deterio- Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Pediatric ration is not significantly higher in this more heavily treated subgroup of Hematology/Oncology, Dr von Haunersches Kinderspital, Ludwig patients, even if later evaluated than NMMp. Maximilians University, Munich, Germany; 4Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 5Department of Radiation Oncology, University of Leipzig, Leipzig, Germany; 6Institute of Neuropathology, University of Bonn, Bonn, Germany P-MED.46. TREATMENT STRATEGIES FOR RECURRENT MEDULLOBLASTOMA - REPORT OF A SINGLE INSTITUTION The aim of this retrospective study was to evaluate the outcome of children EXPERIENCE with primary primitive neuroectodermal tumors (PNETs) of the spinal cord S. W. Gilheeney1, S. McLaren1, H. Dreyfus1, O. J. Becher1, Y. Khakoo1, registered in the database of the German/Austrian brain tumor trials HIT 91 K. Kramer1, D. C. Lyden1,2, M. Souweidane1,2, S. Wolden1, and and HIT 2000. Four patients (female, n ¼ 2; age at diagnosis: 10, 16, 23, 174 I. J. Dunkel1; 1Memorial Sloan-Kettering Cancer Center, New York, NY, months) were identified. Duration of symptoms ranged from 1-8 weeks. United States; 2Weill Cornell Medical Center/New York-Presbyterian Location of primary tumors was cervical, medulla oblongata-Th1, Th7-10 Hospital, New York, NY, United States and Th10-L2. Two patients had metastatic disease at diagnosis. A complete and incomplete resection was performed in one patient each, whereas two Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 BACKGROUND: Despite advances in the treatment of patients with newly patients underwent biopsy only. Two patients received chemotherapy only diagnosed medulloblastoma, patients who develop recurrence fare poorly. according to the HIT 91 trial, but no radiotherapy because of their young 1 Analysis of treatment for this population of patients could help identify more age. They developed disease progression and died 5 and 6 2 months after diag- effective regimens for recurrent medulloblastoma. METHODS: We identified nosis. One patient was given chemotherapy according to the HIT 2000 trial fol- all patients from 1993 to 2009 who were treated at our center, had a diagnosis lowed by craniospinal radiotherapy and 4 courses of maintenance of medulloblastoma, and who had experienced at least one recurrence. Medical chemotherapy (“Packer” protocol). The patient is in complete remission records were reviewed for treatment history, response to treatment, and survi- almost 4 years after diagnosis. The fourth patient developed disease progression val data. RESULTS: From July 1993 to July 2009, 64 patients with the diagno- while receiving carboplatin and etoposide. Hence, chemotherapy was switched sis of recurrent medulloblastoma were treated at our institution. At recurrence, to a modified Head Start protocol. After three cycles he underwent double auto- 24 patients (37.5%) underwent surgical resection of their disease. Twenty-two logous stem cell transplantation and craniospinal irradiation. Twenty-nine (34.4%) underwent some form of irradiation post recurrence, with 12 of those months after diagnosis the patient is alive and well, but surveillance MRI still patients having received radiation at initial diagnosis. 6/10 patients who shows nodular enhancing lesions in the area of the primary tumor and intracra- received radiation at recurrence only are alive, versus 6/12 patients who nial meningeal enhancement. Primary PNETs of the spinal cord carry a grave received radiation at both times. Median progression free survival was noted prognosis and seem to require multimodality treatment including radiotherapy to be greater in those who received radiation at recurrence only. 23/64 patients to achieve long-term survival. (36%) are currently survivors. Treatment for 18/23 survivors included conventionally dosed chemotherapy. Most common chemotherapy regimens included an alkylator and/or a platinum agent combined with topoisomerase inhibitor. P-MED.49. A PILOT STUDY OF LESS-EXTENSIVE Fourteen of 23 survivors received high dose chemotherapy with autologous RADIOTHERAPY AND CHEMOTHERAPY IN PATIENTS WITH stem cell rescue. Twenty-one of 23 survivors received multi-modality treatment STAGE M0/1 SUPRATENTORIAL PNET versus only 17/41 patients who died of disease. DISCUSSION: Surgical resec- C. K. Tseng1 and T. H. Jaing2; 1Department of Radiation Oncology, Chang tion, radiation, and multi-agent chemotherapy are important components of Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2Department of treatment post first recurrence/progression. Combination of these modalities Pediatric Hemato-Oncology, Chang Gung Memorial Hospital at Linkou, may offer a survival advantage for recurrent/progressive medulloblastoma. Taoyuan, Taiwan

We undertook this study to evaluate the feasibility of withholding the spinal irradiation in patients with newly diagnosed non-metastatic supratentorial P-MED.47. PRIMITIVE NEUROECTODERMAL TUMOR OF THE primitive neuroectodermal tumor (sPNET), the treatment consisted of whole FRONTAL LOBE IN CHILDHOOD: A CASE REPORT brain irradiation with additional radiation to the primary tumor site and 6 S. Usui, K. Sugiyama, F. Yamasaki, Y. Kajiwara, T. Saito, T. Mitsuhara, and courses post-radiation chemotherapy in older aged patients and pre-radiation K. Kurisu; Department of Neurosurgery, University of Hiroshima, chemotherapy in young children (age , 3 years). Between 2004 and 2007, 7 Hiroshima, Japan patients with sPNET were enrolled. All patients were staged as M0/1 after negative findings of whole spinal MRI study but without cerebrospinal fluid OBJECTIVE AND IMPORTANCE: Central nervous system primitive neu- cytological examinations. Patients received whole brain radiotherapy 23.4 Gy roectodermal tumors (CNS PNETs) are a rare type of tumors. CLINICAL first and the tumor bed received a total of 54-59.4 Gy. Six patients received PRESENTATION: A 7-year-old girl presented with general convulsion. six cycles of cisplatin and VP-16, and the other one received carboplatin and Physical examination revealed decreased deep tendon reflexes in the left upper VP-16. The median age at diagnosis was 9.2 years (range, 2.5-16.4); three limb. Preoperative computed tomography revealed a low density mass with cal- patients were male and 4 female. Five patients are alive at a median follow-up cification in the right frontal lobe. Magnetic resonance imaging revealed an of 34 months (range, 15-52). Three patients experienced tumor relapse at the approximately 3.5-cm intraaxial lesion without perifocal edema. Anterior primary tumor sites, but no spinal relapse was encountered. The 3-year event- portion of the lesions was enhanced with gadolinium injection, and posterior free and overall survival estimates for all patients were 57% + 19% and portion was not enhanced. INTERVENTION: The patient underwent a 64% + 21%. The lack of spinal relapse during follow-up in these patients partial resection of the tumor through a right frontal craniotomy. On light may help to start a larger study to exploit the strategy of exclusion of whole microscopy, the tumor cells were closely packed with uniform, small, and spinal irradiation in patients with newly diagnosed non-metastatic sPNET. round cells containing hyperchromatic nuclei. In addition, mitotic figures were commonly observed. Focally, small numbers of Homer-Wright rosettes were identified within the primitive component. Immunohistochemical studies showed that the tumor cells were positive for vimentin, synaptophysin, and neuron-specific enolase, and negative for glial fibrillary acidic protein and P-MED.50. SIOP PNET4: ACUTE TOXICITY AND IMPACT OF MIC2. The MIB-1 labeling index was 20-30%. These findings confirmed the RADIOTHERAPY PARAMETERS ON OUTCOME diagnosis of CNS PNET. Following surgery, the patient was administered R. Kortmann1, S. Rutkowski2, G. Gustafsson3, L. Gandola4, C. Carrie5, cranio-spinal radiation therapy followed by chemotherapy consisting of ifosfa- R. Taylor6, J. Giralt7, F. Oldenburger8, A. Faldum9, T. Pietsch10, and mide, etoposide and cisplatin for the residual tumors. The tumors have comple- B. Lannering11; 1Clinic for Radiation Therapy and Radiooncology, Leipzig, telydisappeared after 3 courses of chemotherapy. CONCLUSION: CNS PNETs Germany; 2University of Hamburg, Children´ s Hospital, Hamburg, are rare, small, malignant, blue-cell, cerebral neoplasms with a poor prognosis. Germany; 3University of Stockholm, Karolinska Institute, Stockholm, The treatment of cranio-spinal radiation followed by ifosfamide, etoposide and Sweden; 4Radiotherapy, Instituto nazionale tumori, Milano, Italy; 5Centre cisplatin chemotherapy is effective for CNS PNETs. We review the literature. Leon Berard, Radiooncology, Lyon, France; 6South West Wales Cancer Institute, Swansea, United Kingdom; 7University of Barcelona, Radiooncology, Barcelona, Spain; 8University of Amsterdam, Department of Radiooncology, Amsterdam, Netherlands; 9University of Mainz, Institute of P-MED.48. PRIMARY PRIMITIVE NEUROECTODERMAL medical biometrics, Mainz, Germany; 10University of Bonn, TUMORS (PNETS) OF THE SPINAL CORD: A RARE SUBTYPE OF Neuropathology, Bonn, Germany; 11University of Gothenburg, Pediatric CENTRAL NERVOUS SYSTEM (CNS) PNETS Oncology, Gothenburg, Sweden M. Benesch1, D. Weber-Mzell1, A. O. von Bueren2, U. B. Graubner3, M. Warmuth-Metz4, R. D. Kortmann5, T. Pietsch6, and S. Rutkowski2; BACKGROUND: The aim of this analysis was to evaluate acute toxicity 1Division of Pediatric Hematology and Oncology, Department of Pediatrics and radiotherapy parameters. MATERIAL AND METHODS: Patients and Adolescent Medicine, Medical University of Graz, Graz, Austria; 3-21 years with standard-risk (SR) medulloblastoma were investigated. ii62 NEURO-ONCOLOGY † JUNE 2010 Abstracts

170 patients received hyperfractionated radiotherapy (HFRT) (36 Gy CSI, effective treatment strategy for recurrent sPNET. A phase I/II trial is now 60 Gy PF / 8 Gy boost 1 Gy bid) and 169 patients standard radiotherapy underway at our institution. (StRT) (23.4 Gy CSI, 54 Gy PF, 1.8 Gy fraction dose). RESULTS: No grade IV toxicity occurred. Grade I and II toxicity (StRT): skin (62.2 % and 7.2 %), mucosa (23.2 % and 6.6 %), CNS (14.6 % and 2.6 %), grade III toxicity (StRT): skin (1.3 %), mucosa (0.7 %), CNS 0.7 %); P03 ATYPICAL TERATOID RHABDOID TUMOR grade I and II toxicity (HFRT): skin (56.4 % and 15.5 %), mucosa (27.8 % and 9.3 %), CNS (18 % and 4 %), grade III toxicity (HFRT): skin (2 %), mucosa (3.3 %) and CNS (0.7 %). 5-year EFS: start of RT , 28 days: P-ATRT.01. RHABDOID TUMOR PREDISPOSITION SYNDROME + 83 %; 29- , 40 days: 80% 4%; . 40 days: 73 %, (p ¼ n.s.). DUE TO MUTATION OF BRG1/SMARCA4 Radiotherapy was interrupted in 29.6% in StRT and in 27.6% in HFRT. M. C. Fru¨ hwald1, R. Schneppenheim2,S.Gesk3, M. Hasselblatt4, I. Vater3, 5-year EFS: RT duration (StRT/40 days) for , 42 days: 83.6 %; 43-, 49 U. Kordes2, I. Leuschner5, M. Subero3, T. Obser2, F. Oyen2, and R. Siebert3; days: 76.6%. RT duration (HFRT/46 days) for 43- , 49 days: 83.5% and 1University Children’s Hospital, Mu¨ nster, Germany; 2University Medical 50- , 56 days: 81.4 % (p ¼ n.s.). CONCLUSION: RT was tolerated well Center Hamburg-Eppendorf, Department of Pediatric Hematology and with higher acute toxicity after HFRT, without signiﬁcance. A rising risk Oncology, Hamburg, Germany; 3Institute of Human Genetics, for relapse was observed with respect to time interval surgery - start of RT Christian-Albrechts-University Kiel & University Hospital Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 and protraction of overall treatment time. A time interval between surgery Schleswig-Holstein, Campus, Kiel, Germany; 4Institute of Neuropathology, and start of RT up to 40 days seems to be uncritical. University Hospital, Mu¨ nster, Germany; 5Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrechts-University Kiel and University Schleswig-Holstein, Campus, Kiel, Germany

The rhabdoid tumor predisposition syndrome (RTPS) has in all previously P-MED.51. THE ROLE OF GAMMA-KNIFE RADIOSURGERY IN reported cases been associated with heterozygous germline mutations THE TREATMENT OF PRIMITIVE NEURO-ECTODERMAL and subsequent inactivation of the tumor suppressor SMARCB1/INI1/ TUMORS IN CHILDREN hSNF5. We have previously reported on a pedigree of two affected siblings, K. Pistracher, S. Kurschel, E. Holl, and H. G. Eder; Neurosurgery, Graz, (one with rhabdoid tumor of the kidney, the other with an AT/RT). Both Austria patients showed the typical clinical and histophathologic features of RT, however were positive for SMARCB1. FISH analysis, conventional immuno- PURPOSE: To investigate the effects of GKRS as a boost therapy in the histochemistry (IHC), comparative genome hybridization (CGH) and array treatment of PNETs. METHODS: Between 1993 and 2009, 16 children CGH were employed. Exons and exon-intron boundaries of four candidate with PNET ranging in age from 18 months and 18 years were treated radio- genes were sequenced (SMARCA4, SMARCA2, SMARCC1 and surgically. In one child GKRS was performed as part of initial management SMARCC2). SNP array was used to delineate homozygosity between after stereotactic biopsy, in 15 patients for residual or recurrent disease. tumor and constitutional DNA. cDNA expression was analyzed by These 15 children postoperatively underwent chemotherapy, 13 children of RT-PCR. IHC revealed absent SMARCA4 protein in both tumors. them in combination with conventional radiation therapy. The mean target Sequencing revealed a nonsense mutation c.3565C . T in the DNA of volume was 2.1ccm. A mean marginal radiation dose of 17.4Gy (range both tumors and the paternal blood DNA of the healthy father. 8-25Gy) was delivered to a mean peripheral isodose of 50% (range Expression analyses indicated nonsense mediated decay of the cDNA. 40-70%). RESULTS: Mean follow-up after GKRS was 49 months (range Array CGH demonstrated copy neutral LOH encompassing the gene locus 2-180 months) in 14 children. 2 children were lost to follow up. Full response in 19p13. On screening of sporadic AT/RT, one additional case with with no evidence of residual tumor was present in 7 children (50%). Five have absent SMARCA4 expression and retained SMARCB1 expression was ident- shown a progression-free survival of mean 64 months, one is severely disabled ified. CONCLUSION: Rhabdoid tumors lacking SMARCB1 mutations may due to radionecrosis and another one died in an immunocompromised state. 2. be associated with inactivation of SMARCA4. Germline mutations suggest No change in tumor size was observed in 25% (n ¼ 4), all of them died with a SMARCA4 as a second locus for RTPS. An additional case suggests that mean survival time of 9 months. 3. Tumor-progression occurred in 25% (n ¼ SMARCA4 may be involved in sporadic as well as inherited RT and may 4) leading to reoperation in all three children after a mean of 4 months. Two of thus play an important role in pathogenesis. them died of further progression. CONCLUSIONS: GKRS may extend survival times of children with PNET and represents a possible complementary treatment option as a boost therapy. GKRS may be favored to conventional radiotherapy in children under the age of 5. P-ATRT.02. THE ROLE OF MTOR PATHWAY IN PATHOGENESIS OF ATYPICAL TERATOID/RHABDOID TUMOR IN CHILDREN W. A. Grajkowska1, J. Jozwiak2, M. Roszkowski3, D. Perek4, P-MED.52. MULTIPLY RECURRENT SUPRATENTORIAL PNET B. Dembowska-Baginska4, and M. Perek4; 1Department of Pathology,The TREATED WITH INTRA-ARTERIAL CHEMOTHERAPY Children’s Memorial Health Institute, Warsaw, Poland; 2Department of FOLLOWING BLOOD BRAIN BARRIER DISRUPTION Histology and Embryology, Centre for Biostructure Research, Medical R. M. Loret de Mola, E. A. Neuwelt, and K. J. Nazemi; Oregon Health and University of Warsaw, Warsaw, Poland; 3Department of Neurosurgery,The Science University, Portland, OR, United States Children’s Memorial Health Institute, Warsaw, Poland; 4Department of Oncology,The Children’s Memorial Health Institute, Warsaw, Poland INTRODUCTION: Supratentorial PNETs (sPNET) carry a poor prognosis. Treatments for patients with sPNET are based on strategies used in Childhood brain tumors are becoming an increasing problem in a modern medulloblastoma. However, outcomes in sPNET are inferior to those in society. Atypical teratoid/rhabdoid tumor (AT/RT) is one of highly malig- medulloblastoma. Patients with relapsed or progressive sPNET have a nant childhood brain tumors with well-known chromosome 22 mutation dismal prognosis. We present a 19-year-old patient with multiply recurrent in the region of hSNF5/INI1 gene, whose protein product participates in sPNET who is being treated with intra-arterial chemotherapy following chromatin remodeling. Unfortunately, although the presence of this blood brain barrier disruption (IA/BBBD) who has experienced a dramatic mutation is well described, molecular pathways underlying AT/RT develop- decrease in tumor after four cycles of therapy. METHODS: The patient ment are poorly understood. In our current research we evaluated a case of was initially diagnosed at age 12 with sPNET. She underwent gross total AT/RT with special consideration of two pathways often implicated in resection, craniospinal and focal radiation, and chemotherapy per protocol tumor development: protein kinase B (PKB or Akt) and extracellular signal- CCG 9961. Four years after completion of therapy, a local recurrence was regulated kinase (Erk). We found increased activation of insulin receptor in histologically confirmed and a remote focus concerning for metastasis was the tumor. This phenomenon was accompanied by marked upregulation of identified. She was treated with incomplete resection, focal radiation, and 3-phosphoinositide-dependent kinase 1 (PDK1), Akt and effector of this chemotherapy. There was no evidence of disease at completion of therapy. pathway, glycogen synthase kinase-3 (GSK-3). Based on significance of Routine MRI one year after the first recurrence showed a new metastatic Akt kinase, we postulate that this pathway is necessary for neoplastic devel- lesion. After rapid progression of the new lesion, the patient began treatment opment of ATRT. with blood brain barrier disruption and intra-arterial carboplatin (150 mg/ m2/dose) and melphalan (4 mg/m2/dose), given on 2 consecutive days every 4 weeks. RESULTS: Our patient has undergone 4 cycles of IA chemotherapy with BBBD. There has been an almost complete response, with dramatic decrease in tumor size. The treatment has been well-tolerated. CONCLUSION: Intra-arterial chemotherapy with carboplatin and melphalan following blood brain barrier disruption with mannitol may be an

NEURO-ONCOLOGY † JUNE 2010 ii63 Abstracts

P-ATRT.03. IS CLAUDIN6 A USEFUL DIAGNOSTIC MARKER Haberler et al. (2006) described INI-1 negative tumours that are essentially FOR ATYPICAL TERATOID/RHABDOID TUMOR? ATRTs, yet have a paucity of rhabdoid cells on histology. An overexpression F. Giangaspero1,2, M. Antonelli1, V. Donofrio3, L. Lauriola4, P. Nozza5, and of claudin 6 in ATRT cells has been demonstrated (Birks et al., 2009), which M. Garre`6; 1Dept. of Experimental Medicine, University Sapienza, Rome, suggests a role for CLDN6 IHC as a confirmatory stain for tumours lacking Italy; 2IRCCS Neuromed, Pozzilli (Is), Italy; 3Dept. of Pathology, Ospedale classic features. DESIGN: Fifteen pediatric cases of INI-1 negative tumours Pausillipon, Naples, Italy; 4Dept. of Pathology, Catholic University, Rome, were studied. Five had classic features and been initially diagnosed as Italy; 5Dept. of Pathology, Ospedale Gaslini, Genoa, Italy; 6Ospedale ATRTs. Ten were originally diagnosed prior to the use of INI-1 staining, Gaslini, Genua, Italy and were interpreted to be other tumours (i.e. supratentorial PNET, medulloblastoma, gliosarcoma). Of the 15 patients, 75% had only survived 2 years Immunostain for INI1 is used for the diagnosis of atypical teratoid/rhab- or less; 25% were long term survivors (. 3 years). These samples were doid (ATRT). A microarray study of gene expression in ATRT has identified studied for claudin-6 expression via immunohistochemistry. RESULTS: claudin6 (CLDN6) mRNA as highly and specifically express in ATRT Out of the 5 cases originally diagnosed as AT/RTs, all had positive immu- (Brain Pathol 20:140-150,2010). In this study we sought the expression of noreactivity for claudin-6. Of the 10 originally diagnosed as other high CLDN6 in a series of 15 cases of ATRT. Moreover CLDN6 expression was grade tumours, 6 were found to be positive, and 4 were negative. Three of evaluated in 52 paediatric primary brain tumors: 20 high grade gliomas the four samples with negative claudin-6 and INI-1 immunostaining are (HGG), 2 coroid plexus papilloma (CPP), 3 pilocytic astrocytoma (PA), 5 from long-term survivors (EFS greater than 3 years). CONCLUSION: Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 supratentorial PNET, 1 oligodendroglioma, 1 desmoplastic infantile ganglio- INI-1 negative tumours that lack classic ATRT features present a diagnostic glioma. The following antibodies were used: rabbit polyclonal anti-claudin 6 challenge, supporting the need for more confirmatory tests. Claudin-6 IHC (American Research Products, Belmont, MA, USA) and mouse monoclonal may add further information in these cases. Interestingly, none of the long anti-BAF47 (INI1) (BD Transduction Laboratories, San Jose, CA, USA). term survivor samples showed positive CLDN-6 staining; this test may Fourteen of the 15 cases of ATRT showed no INI1 nuclear staining. One also have prognostic implications in patients with presumed ATRT. case was INI1 positive. CLDN6 was detected in 8 out 15 cases. In one case positivity was detected in more than 50% of neoplastic cells, in 5 cases positivity was in 20-50% of cells and in two positivity was present in less than 10% of cells. Moreover CLDN6 immunoreactivity was detected in five out 25 pediatric HGG and in 2 out 2 CPP and 1 out of 3 PA. These results indicate that P-ATRT.06. MIR-221 IS OVER-EXPRESSED IN ATYPICAL CLDN6 is frequently but not constantly expressed in ATRT. Moreover TERATOID / RHABDOID TUMORS, BUT NOT IN PEDIATRIC CLDN6 is not a specific for ATRT. However in rare cases of INI1 positive GLIOBLASTOMAS ATRT, CLDN6 may be helpful to support such diagnosis. D. K. Birks1, R. Vibhakar1,2, A. M. Donson1, V. N. Barton1, N. K. Foreman1,2, and M. H. Handler1,2; 1University of Colorado Denver, Aurora, CO, United States; 2The Children’s Hospital, Aurora, CO, United States P-ATRT.04. PROGNOSTIC SIGNIFICANCE OF P53, GLUT-1, CLAUDIN6, BETACATENIN AND MIB-1 IMMUNOLABELING MicroRNAs are short non-protein coding RNAs which post- INDEX IN ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) transcriptionally regulate gene expression by down-regulating protein IN CHILDREN expression of targeted genes. They play important roles in both normal P. Varlet1, D. Figarella-Branger2, A. Jouvet3, C. A. Maurage4, M. B. Delisle5, development and cancer. Multiple studies have found miR-221 to be F. Legall6, I. Quintin-Roue7, J. M. Vignaud8, M. Polivka9, P. Levillain10, up-regulated in adult high-grade astrocytomas and glioma cell lines. In I. Salmon11, and C. Dufour12; 1Hopital Sainte Anne, Paris, France; 2Hopital these studies, knockdown of miR-221 resulted in decreased tumor growth de la Timone, Marseille, France; 3Hopital Neurologique, Lyon, France; and decreased resistance to chemotherapeutic drugs. Therefore, based on 4CHRU Lille, Lille, France; 5CHU Toulouse Rangueil, Toulouse, France; its role in adult gliomas, we examined the expression of miR-221 in pediatric 6Hopital Pontchaillou, Rennes, France; 7Hopital de Brest, Brest, France; glioblastoma multiforme (GBM) and atypical teratoid / rhabdoid tumors 8CHU de Nancy, Nancy, France; 9Hopital Lariboisiere, Paris, France; (AT/RT). To measure miR-221 expression, total RNA was collected from 10CHU de Poitiers, Poitiers, France; 11Hopital Erasme, Bruxelles, Belgium; 7AT/RT, 12 pediatric GBM, and 9 adult GBM tumors, as well as 6 pediatric 12Institut Gustave Roussy, Villejuif, France non-tumor brain samples. Quantitative RT-PCR was performed using Taqman microRNA assay probes. Results showed significant over- PURPOSE: To determine prognostic relevance of histological and immunoexpression of mir-221 in AT/RTs, comparable to that seen in adult histochemical risk factors in children with ATRT. METHOD: A central patho- GBMs, but no over-expression in most pediatric GBMs. Similar results logical review of 64 patients with newly diagnosed ATRT treated in France over were found using microRNA microarrays (Agilent Human, V1): miR-221 a period of 10 years (1998-2008) was performed. Fifty-five cases (86%) were was highly expressed in AT/RTs (n ¼ 4), but not in pediatric GBMs, pilocy- confirmed as ATRT based on morphological and immunophenotypical profiles tic astrocytomas, medulloblastomas, or ependymomas (n ¼ 20). Since including INI-1 loss. Nine cases were excluded: 3 for technical considerations cyclin-dependent kinase inhibitor 1B (p27, Kip1) is a known target of and 6 INI-1 positive tumors classified as PNET (1), malignant gliomas (4) or miR-221, we also examined protein expression of p27. Analysis by malignant tumor of unknown origin. In all cases, immunolabellings of P53, western blot showed lower levels of p27 in AT/RTs compared to other pedi- Glut-1(Glucose transporter-1 protein), Claudin-6 (CLDN6), betacatenin and atric tumors. These results indicate that miR-221 may be a potential thera- Ki-67 was realized and could be correlated with patient outcome for a subset peutic target for AT/RTs, but not for pediatric GBMs, and illustrate that of 46 cases (median follow-up: 58 months). RESULTS: No histological criteria there are differences between pediatric and adult GBMs at the biological such as extensive necrosis, presence of microcalcifications, abundant lymphoid level. infiltrates, hemorrhagic features or absence of rhabdoid phenotype was associated with overall survival. A strong cytoplasmic Glut-1 immunoreactivity was observed in 97% of cases associated with an intense vascular expression in 59% of the cases. Claudin-6 was expressed by 89 % of ATRT and a significant betacatenin nuclear accumulation was noted in 57%. Overexpression of P53 P-ATRT.07. ATYPICAL TERATOID/RHABDOID TUMOR was observed in 69% of ATRT. MIB-1 labelling index, P53 overexpression, MIMICKING A BETACATENIN IMMUNOPOSITIVE NODULAR Glut-1, Claudin-6 and betacatenin immunostatus do not allow for stratification MEDULLOBLASTOMA: A CASE REPORT into distinct prognostically subgroups. CONCLUSIONS: We confirmed that P. Varlet; Hopital Sainte Anne, Paris, France Glut-1 and Claudin-6 represent strong positive markers of ATRT. No histological criteria or biomarkers including MIB-1, P53, Glut-1, Claudin-6 or betacate- CASE REPORT: A previously healthy 18-month-old girl presented with nin were associated with patient outcome. an axial hypotonia with increasing cranial perimeter. A MRI revealed a large enhancing mass in the fourth ventricle with an upward extension into the third ventricle. A partial surgical resection was performed. Histological examination demonstrated a highly cellular malignant neo- P-ATRT.05. CLAUDIN-6 AND INI-1 IMMUNOHISTOCHEMICAL plasm with multiple “pale islands” nodules morphologically consistent EXPRESSION IN ATYPICAL TERATOID RHABDOID TUMOURS with the diagnosis of a nodular medulloblastoma. Immunohistochemical OF THE CNS characteristics confirmed the diagnostic of medulloblastoma with nodules A. J. Fleming1, D. K. Birks2, S. Yip3, M. H. Handler2, of neurocytic maturation. Intranodular cells were strongly immunoreactive B. K. Kleinschmidt-DeMasters2, and C. Dunham1; 1British Columbia for synaptophysin and NeuN with a very low Ki-67 labeling index. Children’s Hospital, Vancouver, BC, Canada; 2University of Colorado at Reticulin staining failed to delimit the intranodular from the internodular Denver, Denver, CO, United States; 3British Columbia Cancer Agency, components. INI-1immunoexpression was negative in all tumoral cells Vancouver, BC, Canada with an appropriate internal vascular positive control. ß-catenin staining showed nuclear immunoreactivity focally in more than 10 % of tumoral BACKGROUND: INI-1 immunohistochemistry (IHC) has been accepted cells. No rhabdoid cells were identified. The diagnosis of non rhabdoid as a diagnostic test for Atypical Teratoid Rhabdoid Tumours (ATRTs). ATRT was confirmed by a punctual mutation at R53X (C157T) exon 2 of ii64 NEURO-ONCOLOGY † JUNE 2010 Abstracts

hSNF5/INI1 gene in the tumor. No germ line alteration of SMARCB1/INI1 P-ATRT.10. NEOADJUVANT CHEMOTHERAPY FOR ATYPICAL was found. In addition, CTNNB1 was wild type in the tumor. The girl was TERATOID RHABDOID TUMORS treated with a chemotherapy regimen consisting of vincristine, cyclopho- T. Annou1, H. Oguma1, E. Watanabe1, and A. Gomi2; 1Department of sphamide, doxorubicin, etoposide, methotrexate, cisplatinum, ifosfamide. Neurosurgery, Jichi Medical University, Shimotuke, Tochigi, Japan; A complete surgical resection of the residual tumor was performed and 2Department of Pediatric Neurosurgery, Jichi Children’s Medical Center tumor bed was irradiated at 40,5 Gy. The child is alive in complete remission Tochigi, Shimotuke, Tochigi, Japan 15 months after the diagnosis. CONCLUSION: We recommend screening routinely for INI-1 expression all non rhabdoid malignant pediatric CNS INTRODUCTION: Atypical teratoid rhabdoid tumors (ATRT) are refrac- tumors including nodular medulloblastoma subtype, particularly in children tory neoplasms of the central nervous system that mainly occur during early less than 3 years. childhood, and are resistant to chemotherapy. We describe total resection of an ATRT after neoadjuvant chemotherapy that resulted in an excellent outcome. CASE: A 3-year-old girl was admitted to our emergency department with obstructive hydrocephalus. Magnetic resonance imaging (MRI) revealed a large tumor located in the fourth ventricle involving the dorsal midbrain that P-ATRT.08. CEREBROSPINAL FLUID CYTOLOGY IN extended to the quadrigeminal cistern. Initial emergency surgical resection of CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMOR the tumor in the fourth ventricle was followed by chemotherapy with cisplatin Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 (AT/RT) OF THE CNS and etoposide for the residual tumor after histological verification of ATRT. N. U. Gerber1,2, H. J. Girschick2, K. von Hoff2,3, K. Petrasch2, R. Schmid2, The tumor size was reduced, the tumor margin became apparent, and the M. A. Grotzer1, P. G. Schlegel2, and S. Rutkowski2,3; 1Department of residual tumor was then totally resected without neurological complications. Oncology, University Children’s Hospital, Zu¨ rich, Switzerland; DISCUSSION: Recent literature indicates that the prognosis of patients with 2Department of Pediatrics, University of Wu¨ rzburg, Wu¨ rzburg, Germany; ATRT after gross total resection is better than after partial removal or biopsy. 3University Medical Center Hamburg-Eppendorf, Department of Pediatric However, extensive surgical resection of a large tumor in the fourth ventricle Hematology and Oncology, Hamburg, Germany might be associated with the risk of damage to the brainstem and the cerebellar vermis. Neoadjuvant chemotherapy should help to increase the rate of resec- BACKGROUND: AT/RT are highly malignant CNS tumors of early tion and decrease that of surgical complications. Chemotherapy for ATRT has childhood with the capacity of metastatic spreading within the cerebrospinal not been established, although some agents that exert a temporary cytoreduc- fluid (CSF) space. Diagnosis of metastatic disease, including accurate CSF tive effect against this tumor can function as neoadjuvant therapeutic agents. analysis, is important for prognosis, treatment decisions and therapeutic CONCLUSION: Our experience suggests that neoadjuvant chemotherapy advances. However, little is known about cytologic and immunohistochemic supports the safe and successful gross total resection of extensive ATRT. features of AT/RT cells in CSF. METHODS: Positive CSF cytospin samples of 10 children with intracranial (n ¼ 9) or spinal (n ¼ 1) AT/RT were examined at the GPOH (Gesellschaft fu¨ r Paediatrische Haematologie und Onkologie) central reference center for CSF diagnostics in childhood brain tumors. Positive CSF samples were collected at initial diagnosis in 8 and at P-ATRT.11. THE COMBINED THERAPY OF 3 AT/RT CASES relapse in 2 cases through ventricular shunt in 5, lumbar puncture in 4, UNDER 3-YEAR-OLD IN HYOGO PREFECTURAL KOBE and both routes in 2 patients. Tumor cells were morphologically assessed CHILDREN’S HOSPITAL after Pap staining. In patients with supplementary cytological material avail- A. Kawamura, T. Hori, K. Yamamoto, and T. Nagashima; Department of able, selected immunohistochemical stains (NSE, GFAP, Vimentin, S-100, Neurosurgery,Hyogo Prefectural Kobe Children’s Hospital, Kobe, Hyogo, PAS) were performed. RESULTS: Tumor cells showed a marked inter-patient Japan variability in nuclear-cytoplasmic ratio, presence of mitoses, polynuclear cells, nuclear and cytoplasmic vacuolisation, other nuclear atypia, and pres- INTRODUCTION: Atypical teratoid / rhabdoid tumors (AT/RT) of the ence of cell aggregates. Some, but not all of the samples were positive for central nervous system are rare, highly malignant pediatric brain tumors and NSE, vimentin, and S-100, two samples were positive for GFAP or PAS. no effective therapy has been established. Median survival with surgical and CONCLUSION: Morphologically, AT/RT cells spread into the CSF show standard chemotherapy is less than 12 months. This report reflects our signs of malignancy with marked inter-individual variability. No consistent experience at the Hyogo Prefectural Kobe Children’s Hospital (Japan) with pattern of immunohistochemical staining could be detected. We believe that aggressive treatment of three AT/RT cases aged less than 3 years from standardized CSF analysis contributes to improving management and under- 2007 to 2009. METHODS: Three cases underwent microsurgical resection standing of this disease. and were treated with a regimen of multi-agent chemotherapy (CDDP + VP16 + VCR + CY), followed by high dose chemotherapy with peripheral blood stemcell transplantation (PBCST). Diagnosis was confirmed with rhabdoid cells and negative nuclei stain of BAF47. RESULTS: In two cases whole brain irradiation had to be added to control tumor progression P-ATRT.09. REDEFINING THE INCIDENCE, OUTCOMES, AND during multi-agent chemotherapy. One of these two cases is a long-term sur- PROGNOSTIC FACTORS FOR CNS ATYPICAL TERATOID vivor that has indicated CR to the tumor and meningeal dissemination in RHABDOID TUMOURS AT BC CHILDREN’S HOSPITAL MRI studies for 31 months. The other case remained NC for a few months A. J. Fleming1, J. Hukin1, S. R. Rassekh1, C. J. H. Fryer1, S. Yip2, and and obtained quality of life (QOL) before PBCST. The last patient had CR C. Dunham1; 1British Columbia Children’s Hospital, Vancouver, BC, with only multi-agent chemotherapy for 8 months from diagnosis before Canada; 2British Columbia Cancer Agency, Vancouver, BC, Canada high dose chemotherapy. CONCLUSION: In order to improve outcome and preserve QOL despite the poor prognosis, radiotherapy would be BACKGROUND: Atypical Teratoid Rhabdoid Tumour (ATRT)) is a useful in AT/RT patients less than 3 years old. highly malignant embryonal neoplasm. Prognosis is poor, and little is known about factors that influence survival. The “INI-1” antibody test has been used to diagnose ATRT at BC Children’s Hospital (BCCH) since 2007. HYPOTHESES: 1) Prior to the use of the INI-1 test at BCCH, some ATRT cases may have been diagnosed as other tumours, which would P-ATRT.12. GERMAN PEDIATRIC ATYPICAL TERATOID / alter the true incidence and outcome. 2) Epigenetic factors such as promoter RHABDOID TUMORS: ANALYSIS OF THE ATRT CNS PILOT methylation may differentiate the rare long-term survivors of ATRT. STUDY DESIGN: The INI-1 test was applied retrospectively to all archived embryo- O. Peters1, T. Pietsch2, M. Warmuth-Metz3, R. Kortmann4, L. Kitanovski5, nal tumour samples (1986 - 2009) at BCCH. Samples with negative INI-1 and J. Wolff6; 1Dept. of Oncology, St. Hedwig Children’s Hospital, staining and positive internal controls were considered to be ATRTs. University of Regensburg, Germany; 2Neuropathology Reference Center, Promoter methylation analyses was performed using Methylation Specific University of Bonn, Germany; 3Neuroradiology Reference Center, University PCR (MSP). RESULTS: INI-1 staining was negative in 15 samples (5 orig- of Wu¨ rzburg, Germany; 4Radiotherapy Reference Center, University of inally diagnosed as ATRT, 10 as others). Median survival was ,2 years, Leipzig, Germany; 5Dept. of Oncology, Children’s Hospital, University of yet we found three ATRT long-term survivors (.3 years). Preliminary pro- Ljubljana, Slovenia; 6Section Neurooncology, MD Anderson Cancer Center, moter methylation analysis of MGMT, RASSF1A, MLH3, RUNC3,and TX, United States HIC1 has not been able to reveal differentiating features in the long-term survivors. DISCUSSION: This study increases our incidence of ATRT by a BACKGROUND: ATRT account for ,1% of all CNS tumors. Usually factor of 3 (from 5 to 15). Using the INI-1 test to find 3 previously unrecog- newborns and infants are affected. Recently, the outcome was dismal nized ATRT long-term survivors changes the survival rate from 0% to 20%. (median OS 6-11 months). Thus, in 2004 we conducted a novel multimod- Capturing ATRT as a separate entity will allow improved reporting of survi- ality multicenter phase-II pilot study for pediatric ATRT. The therapy val rates for other CNS embryonal tumours. Epigenetic changes need to be concept was based on the retrospective analysis of German and published further explored for differences that may offer prognostic value. pediatric ATRT patients (1985-2004) and 7 pediatric ATRT-patients, pre- phase treated with the designated ATRT-CNS regimen. METHODS:

NEURO-ONCOLOGY † JUNE 2010 ii65 Abstracts

Twenty children were enrolled with newly diagnosed and reviewed CNS 11/11, EMA: 9/11, Synaptophysin: 6/10, p53: 2/9, GLUT-1: 7/9 and ATRT. ATRT-CNS-2004: I) induction: 2 cycles (doxorubicin 25mg/m2, INI-1: 0/11. Ki67 was between 5-80%. CONCLUSIONS: - AT/RTs show 12h iv, d1-3; dactinomycin 45 mg/kg, iv, d1; cisplatin 70mg/m2, 6h i.v., overlapping histological features with other embryonal tumors, but their d4; VCR 1,5mg/m2, iv, d8 + 15; MTX 2 mg iventr, d1-4); II) conventional prognosis is usually worse. - Cellular discohesivity is a common finding in local 3DXRT (54Gy) + radiochemotherapy (carboplatin 80mg/m2, 6h iv, AT/RT and it is not a histological feature observed in other embryonal d1-4); III) reinduction: 1 cycle (same as induction); IV) consolidation: 6 tumours. - Rhabdoid cells are not found in every biopsy, making the diagnosis cycles (CCNU 75mg/m2, p.o., d1; cisplatin 70mg/m2, 6h iv, d1; VCR difficult. - As AT/RT shows divergent differentiation, only the loss of INI-1 1,5 mg/m2, iv, d1 + 8 + 15; MTX 2mg iventr, d1-4). RESULTS: 20 patients expression is useful in the diagnosis. - INI-1 should be performed in every pedi- (16 male; median age 28,3 months) have been treated. Tumor site: 10 hemi- atric embryonal tumour to disclose AT/RT. spheric, 4 cerebellum, 1 pineal, 3 cerebellopontine angle, 2 basal ganglia (25% dissemination). Primary surgery: 4 complete, 4 subtotal, 9 partial resections, 3 biopsies.Objective response to the induction was 64%. Three-year EFS/OS: 65% +12% / 71% + 11%. Five-year EFS/OS: 58% +13% / 71% +11%. Grade III-IV infection/mucositis in 13% / 60% P-ATRT.15. OUTCOME OF ATYPICAL TERATOID / RHABDOID (48 induction / reinduction cycles). Neurotoxicity / complications: 1 toxic TUMOR: A SINGLE INSTITUTE EXPERIENCE death / 1 death after VP-shunt implantation / 1 transient transverse myelitis Y. Y. Lee1,2, Y. W. Chen3,2, K. P. Chang4,D.M.T.Ho5, P. I. Huang3,2, and Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 / 1 transient seizures after radiochemotherapy / 1 encephalopathy. M. L. Liang1,2; 1Division of Pediatric Neurosurgery, The Neurological CONCLUSION: This anthracycline-based induction regimen appears effec- Institute, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of tive but has significant toxicity. The outcome is significantly improved com- Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 3Cancer pared to the historic German pediatric ATRT-patients, treated with the center, Taipei Veterans General Hospital, Taipei, Taiwan; 4Department of HIT-protocol. Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; 5Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan; 6Faculty of Medicine,National Yang-Ming University, Taipei, Taiwan

PURPOSE: To assess the outcome in patients with atypical teratoid / rhab- P-ATRT.13. ATYPICAL TERATOID/RHABDOID TUMORS (AT/ doid tumors (ATRT) who had been treated at the Taipei Veterans General RT) IN CHILDREN: THE FRENCH EXPERIENCE SINCE 1998 Hospital in Taiwan. PATIENTS AND METHODS: The authors reviewed A. Beaugrand1, M. Quidot1, P. Varlet2, F. Bourdeaut3, N. Andre4, the records of 27 patients (0.5 months to 26 years old) diagnosed with G. Palenzuela3, D. Frappaz5, P. Leblond6, F. Fouyssac7, A. Bertozzi8, ATRT at Taipei VGH between Jan 1982 and April 2007. Kaplan-Meier sur- J. Kanold9, C. Edan10, J. Grill1, M. Le Deley1, and C. Dufour1; 1Institut vival analyses were used to analyze the impact of clinical features, prognostic Gustave Roussy, Villejuif, France; 2CHU St Anne, Paris, France; 3Institut factors and therapeutic approaches on overall survival (OS). RESULTS: Curie, Paris, France; 4CHU La Timone, Marseille, France; 5Centre León Twenty-seven patients were diagnosed with ATRT at Taipei VGH during Berard, Lyon, France; 6Centre Oscar Lambret, Lille, France; 7CHU Nancy, the 25-year study interval. All patients underwent surgical resection. 3 Nancy, France; 8CHU Toulouse, Toulouse, France; 9CHU Clermont patients that had not received radiotherapy were excluded. Of the remaining Ferrand, Clermont Ferrand, France; 10CHU Rennes, Rennes, France 24 patients, 15 received subsequent chemotherapy. The mean age of patients treated with platinum-based chemotherapy (n ¼ 15) and radiation alone were PURPOSE: To describe clinical features and therapeutic approaches and to 6.9 and 9.4 years. Overall mortality was 67%. Disease progression was the identify prognostic factors in children with AT/RT. METHOD: Patients major cause of death. The median overall survival (OS) and progression-free younger than 18 years of age with AT/RT treated in France between survival (PFS) were 18.2 and 13.3 months, respectively. The 1-year PFS and January 1998 and July 2008 were identified from hospital files and French OS rates (+ standard error) are 51% + 11% and 74% + 9%, respectively, Pediatric Cancer registry. The diagnosis of AT/RT was confirmed by and the 2-year PFS and OS rates (+ standard error) are 44% + 11% and central pathological review and/or molecular investigation. RESULTS: 88 45%+ 10%, respectively. The overall survival was unrelated to sex, tumor patients were diagnosed with AT/RT in France during 10 years. 30 patients site, and extent of resection. CONCLUSIONS: ATRT have a dismal prognosis were excluded from this clinical review based on pathologic or clinical cri- especially in younger age. Although there is still no proper chemotherapeutic teria. Median age was 1.4 years (range, 15 days - 8.5 years). Primary regimen for ATRT, a platinum-based regimen combined with radiation is tumor site was supratentorial (ST) in 28, posterior fossa (PF) in 26, mixed instrumental in making long-term survival possible. (ST + PF) or medullar in 4 patients. The disease was disseminated at diagnosis in 17 patients. Initial surgical resection was complete in 36 patients. Adjuvant therapy included chemotherapy in 47 cases and radiotherapy in 16 patients. Chemotherapy regimens were not standardized more than the P-ATRT.16. TREATMENT RESULTS IN PATIENTS WITH ATRT - study period: ATRT04, PNET High Risk and BB SFOP protocols were SINGLE INSTITUTION STUDY most frequently used. Median follow-up was 58 months (range, 9 months M. Perek-Polnik1, B. Dembowska-Baginska1, W. Grajkowska1, - 10.4 years). Disease progression or relapse occurred in 54 children. M. Drogosiewicz1, I. Filipek1, E. Swieszkowska1, A. Skowronska-Gardas2, Median time to progression/relapse was 4.4 months. Median survival time M. Roszkowski1, and D. Perek1; 1The Children’s Memorial Health Institute, was 9 months. One-year progression-free survival and OS were 19% and Warsaw, Poland; 2The Maria Sklodowska-Curie Institute of Oncology, 41%, respectively. Metastatic status at diagnosis was the only prognostic Warsaw, Poland factor (HR for death: 2.25, 95%CI: 1.14 - 4.5, p ¼ 0.02). CONCLUSIONS: Children with ATRT have a dismal prognosis. The pres- Aim of the study was to evaluate clinical status and treatment results of ence of metastasis at diagnosis seems to be the only prognostic factor of patients with ATRT treated in our institution. Eleven patients, 6 boys and outcome. 5 girls aged from 16 months to 24 years 7 months (median 3 years 7 months) treated between 1998 and 2009 were evaluated. Tumor location, extent of surgery, type of treatment and treatment results were analyzed. Results; Tumor was localized in posterior fossa in 3 patients, cerebral hemi- P-ATRT.14. ATYPICAL TERATOID/RHABDOID TUMOURS. spheres in 5, III ventricle in 1, spine in 1, multifocal in 1. One total, 4 subtotal CLINICO-PATHOLOGICAL FEATURES OF 11 CASES. and 4 partial resections were performed; 2 had biopsy only. Three patients M. Sun˜ ol, C. Rovira, C. Jou, E. Rodriguez, O. Cruz, and V. Cusi; Hospital under 3 years of age and 2 patients older than 3 were treated according to Universitari Sant Joan de Deu, Barcelona, Spain HR MB/PNET protocols; 2 patients were treated individually and 4 according to ERR. In 4 children younger than 3 treated with chemotherapy only INTRODUCTION: Atypical Teratoid/Rhabdoid Tumor (AT/RT) of tumor relapsed/progressed. All received second line chemotherapy; one CNS is an aggressive embryonal tumour, affecting children almost exclu- responded and was irradiated with favorable outcome. Two of 5 older sively. Its characteristical feature are rhabdoid cells, but an embryonal com- patients treated with chemo and radiotherapy relapsed/progressed and ponent is most commonly encountered. AT/RT is often misdiagnosed as didn’t respond to second line chemotherapy. Three out of 11 patients (1 medulloblastoma, ependymoma or supratentorial PNET due to its overlap- after total, 2 partial resection) are alive in CR 1.5, 3, 7 years from diagnosis, ping histological features with other embryonal tumors, METHODS: We 2 are still treated. Six patients died 5 of disease, 1 in CR of AML diagnosed 4 studied 11 patients diagnosed of AT/RT; seven had been previously diag- years from the ATRT diagnosis. In most patients we observed good response nosed as medulloblastoma, ependymoma or supratentorial PNET. to different types of first line chemotherapy. Radiotherapy improved Histopathological and clinical data were reviewed in all cases. RESULTS: outcome while extent of resection did not. Study supported by grant The patients were 4 boys and 7 girls. The average age at diagnosis was 2.9 R130011 06/2009 from Ministry of Science, Poland years with a range from 6 months to 6.5 years. Nine patients died from their disease with a follow-up range among 20 days to 20 months; 2 were alive after a follow-up period of 3 and 4 years respectively. Histologically AT/RTs showed a marked cellular discohesivity, but rhabdoid cells were encountered in only 3 cases. Immunohistochemistry showed: Vimentin: ii66 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-ATRT.17. RAPIDLY PROGRESSIVE PRIMARY LEPTOMENINGEAL ATYPICAL TERATOID/RHABOID BACKGROUND: Inactivation of SMARCB1/INI1, a core member of the TUMOR: A REPORT OF TWO CASES ATP dependent SWI/SNF chromatin remodeling complex, is thought to be K. M. Gauvain, A. Nayak, M. McHugh, S. Burton, and T. J. Geller; St Louis characteristic for malignant rhabdoid tumors such as atypical teratoid/rhab- University, St Louis, MO, United States doid tumor (AT/RT). The role of INI1 in the biology of other pediatric brain tumors, however, remains ill-defined. METHODS: A total of 94 pediatric Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor in brain tumors that had been diagnosed as choroid plexus neoplasms were cen- young children that may present with metastatic leptomeningeal disease. We trally reviewed and screened for INI1-protein loss using immunohistochem- describe two cases of rapidly progressive, diffuse leptomeningeal AT/RT istry. RESULTS: All tumors in which the initial diagnosis of a choroid plexus without a solid primary mass. CASE 1: A 16-month-old presented to an tumor was confirmed, showed retained INI1-staining. One tumor with lost outside hospital with right ptosis, gait instability, and nausea. He was INI1 expression was re-classified as AT/RT. Interestingly, we also encoun- treated with steroids and antibiotics for acute demyelinating encephalomye- tered three young children (aged 10 months, 12 months and 26 months) litis. He presented to us several weeks after with progressive right CN III with unusual non-rhabdoid cribriform neuroepithelial tumors within and palsy, torticollis, opisthotonis, irritability and fevers. CSF revealed leukocy- around the third or fourth ventricle showing well-defined EMA positive sur- tosis and elevated protein. MRI of the brain revealed increased T2 signal faces and loss of nuclear INI1 expression of the tumor cells. Histological fea- intensity in an expanded medulla, enhancement of CN III, a small nodule tures and immunohistochemical staining profile did not correspond to Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 extending from the medulla, and enhancement in the basilar regions and choroid plexus tumors as well as other established tumor types, including spinal canal. He rapidly developed a flaccid quadriplegia, absent corneal AT/RT, medulloepithelioma and ependymoma. FISH and sequencing ana- reflexes, ventilator dependence and support was withdrawn. An autopsy lyses confirmed chromosomal alterations of the SMARCB1/INI1 locus in revealed AT/RT with diffuse involvement of the brain and spinal cord. 2/3 of these non-rhabdoid tumors. Of note, the children responded well to CASE 2: A 28-month-old presented with a two week history of new onset conventional adjuvant therapy protocols: all of them are alive and in com- tonic seizures, language regression, ataxia, dysphagia, and dysconjugate plete remission, two for more than five years postoperatively. gaze. On exam, he had right CN VI and VII palsies. CSF showed a mild leu- CONCLUSION: Cribriform neuroepithelial tumor (CRINET) is a non- kocytosis. Brain MRI revealed thickening of the quadrigeminal plate and pial rhabdoid ventricular tumor showing loss of tumoral INI1 protein that may enhancement of the brain, brainstem, 3rd ventricle, and vermis. Two weeks have a relatively favorable prognosis, thereby extending the histological following he developed dysphagia, vomiting, weight loss, lethargy, ataxia, and clinical spectrum of INI1-deficient tumors. with progressive CN findings, opisthotonis and fevers. CSF showed leukocy- tosis and elevated protein. Repeat MRI at showed diffuse bulky meningeal enhancement brain and spinal cord. Biopsy of the spinal cord and nerve root lesion revealed AT/RT. P04 DIFFUSE INTRINSIC PONTINE GLIOMA

P-ATRT.18. ATYPICA TERATOID/RHABDOID TUMOR CASE P-DIPG.01. MULTIPLE CATHETERS LINKED LOCAL DELIVERY REPORT: A SURVIVOR AFTER RELAPSE TREATED WITH BY DARCARBAZINE PROLONGS SURVIVAL IN THE BRAINSTEM GLIOMA MODEL IN RATS AGRESSIVE SURGERY AND MULTI-AGENT CHEMOTHERAPY 1 1 2 3 4 5 1 2 2 1 P. Casalis , A. Kombaka , B. Tyler , P. Hernaiz , M. Synowitz , G. I. Jallo , M. Hishii , M. Miyajima , and H. Arai ; Juntendo University Nerima 1 1 Hospital, Tokyo, Japan; 2Juntendo University Hospital, Tokyo, Japan and U. W. Thomale ; Pediatric Neurosurgery, Charite´ Campus Virchow Klinikum, Berlin, Germany; 2Neurosurgery, Johns Hopkins Medical 3 INTRODUCTION: Central nervous system atypical teratoid/ Institutions, Baltimore, MD, United States; Pediatric Oncology, Charite´ Campus Virchow Klinikum, Berlin, Germany; 4Neurosurgery, Charite´ rhabdoid(AT/RT) tumors are highly malignant neoplasms that occurs in 5 infants and young children. In spite of multiple treatments consisting of sur- Campus Virchow Klinikum, Berlin, Germany; Pediatric Neurosurgery, The gical resection, radiation therapy and chemotherapy, the prognosis has been Johns Hopkins Hospital, Baltimore, MD, United States extremely poor. We would like to report a case of a boy who is surviving more than 66 months after the recurrence of AT/RT. PATIENT: This 3 OBJECTIVE: Diffuse intrinsic brainstem gliomas are associated with a month old boy developed lethargy and downward deviation of the eyeballs. dismal outcome. New possible therapeutical options include local che- Computed tomography(CT) images and magnetic resonance(MR) images motherapy. The present study investigates multiple cannulae linked local revealed a large inhomegeneous enhanced mass in the right cerebellopontine darcarbazine infusion in the rat brainstem glioma model. MATERIALS ¼ angle with resultant hydrocephalus. A gross-total surgical resection was per- AND METHODS: Fisher rats (n 8) were locally infused with 0,5% or formed. The pathological diagnosis was AT/RT. Immunohistochemical 0.167% evans blue (EB) dye for 48 hours to evaluate dye tissue distribution staining showed tumor cells negative for INI1. He underwent 6 cycles of sys- in the brainstem using one or three cannulae connected to osmotic pumps (pump rate: 1 ml/h), respectively. In addition Fisher rats (n ¼ 34) received temic intravenous administration of IFO, CBDCA, VP16 and intrathecal 5 administration of MTX. After 13 months, the MR image revealed local implantation of 10 F98cells/3 ml into the brainstem. At five days after tumor recurrence. The second surgery achieved gross total resection and tumor implantation in 18 animals one cannula was implanted for local treat- the pathology was again, AT/RT. Another 4 cycles of systemic intravenous ment with either placebo or 10 mg/ml darcabazine (1 ml/h over 7days), chemotherapy with CPM, VCR, THP-ADR and CDDP was administrated while 7 animals received three cannulae with 6,66 mg/ml (3 ml/h, 7d). following the second surgery. The patient remained stable except mild devel- Weight loss and neurological grading was measured on a daily basis. Days opmental delay. Serial MR images revealed no residual or recurrent tumors of survival were recorded to evaluate potential beneficial effect. RESULTS: for 66 months after the second surgery. Radiation therapy has not been EB distribution in the three versus one cannulas group showed a more administrated since the onset of AT/RT. CONCLUSION: Radiation balanced dye distribution in the brainstem. Neurological impairment due therapy for AT/RT is a controversial issue because most of the onset starts to local delivery was less exaggerated in the three cannulae group. Using dar- prior to the age 3 years. We report a survivor after relapse treated with carbazine for local delivery a better outcome of survival was observed in the aggressive surgery and multi-agent intravenous and intrathecal chemother- three cannulae group (25 + 9days, p , 0.05) compared to one cannula dar- apy, without radiation therapy. carbazine (19 + 2), placebo treatment (18 + 4) or tumor implantation alone (19 + 2). CONCLUSION: Local delivery of drugs in the brainstem tumor model is feasible. Continuous infusion of darcarbazine via three cannulas has beneficial effect on survival. Enzymatic activation of daracrbazine by intact tissue may be necessary for therapeutical effect. P-ATRT.19. CRIBRIFORM NEUROEPITHELIAL TUMOR (CRINET): EXTENDING THE HISTOLOGICAL AND CLINICAL SPECTRUM OF INI1 DEFICIENT TUMORS M. Hasselblatt1, U. Kordes2, S. Gesk3, H. Schmid4, M. C. Fru¨ hwald5, R. Schneppenheim6, R. Siebert3, J. E. A. Wolff7, and W. Paulus1; 1Institute of P-DIPG.02. UNUSUAL EARLY DIAGNOSIS OF A PATIENT WITH Neuropathology, University Hospital Mu¨ nster, Mu¨ nster, Germany; A DIFFUSE INTRINSIC PONTINE GLIOMA 2Department of Pediatric Hematology and Oncology, University Medical M. H. A. Jansen, D. G. van Vuurden, R. J. Vermeulen, P. Vandertop, and Center Hamburg-Eppendorf, Hamburg, Germany; 3Institute of Human G. J. L. Kaspers; VU University Medical Center, Amsterdam, Netherlands Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 4Department of Pediatric Patients with diffuse intrinsic pontine gliomas (DIPG) usually present with Hematology and Oncology, University of Hannover, Hannover, Germany; symptoms of progressive brain nerve deficits and ataxia. We present a 6-year 5Department of Pediatric Hematology and Oncology, University Children’s old boy with a history of awkward locomotion since he started walking. No Hospital Mu¨ nster, Mu¨ nster, Germany; 6of Pediatric Hematology and abnormalities were observed during physical examination. An MRI brain Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, was performed mainly because of very concerned parents, but surprisingly Germany; 7Department of Pediatrics, University of Texas M. D. Anderson revealed a focal pontine glioma, involving less than 50% of the pons. Cancer Center, Houston, TX, United States Because the patient had no clinical symptoms or complaints, it was

NEURO-ONCOLOGY † JUNE 2010 ii67 Abstracts

decided not to start treatment, but to monitor the patient frequently. Twelve to pre-irradiation chemotherapy statistically influenced outcome. Low, inter- months after diagnosis, the patient progressed with symptoms of abducens mediate and high risk groups were identified with 5 years OS - 76%, 14.4% nerve paresis, facial nerve paresis and ataxia. MRI was repeated and and 0 % respectively. Detailed description of proposed treatment strategies showed a diffuse expanding mass with basilary artery encasement. Because will be presented. of the unusual history of a focal pontine tumor, the patient was biopsied. The tumor concerned an anaplastic WHO grade III astrocytoma. Radiotherapy in combination with gemcitabine as radiosensitizer was started and the patient clinically improved and radiologically experiences stable disease for 6 months at time of writing. A few questions raised in P-DIPG.05. PROGNOSTICATION OF CHILDHOOD DIFFUSE this particular case: At first presentation; did this concern a typical case of INTRINSIC BRAINSTEM GLIOMAS (DIPGS) WITH CLINICAL a DIPG, discovered by coincidence in an unusual early stage? And when AND BIOLOGICAL IMAGING PARAMETERS: RESULTS FROM A should treatment have been initiated: at time of primary diagnosis or at PROSPECTIVE TRIAL time of symptoms? This case suggests that if a diagnosis is made very early R. Jalali, D. Datta, T. Gupta, B. Arora, N. Merchant, V. Rangarajan, in the course of the disease, the natural course itself may explain stable B. Zade, and P. Kurkure; Tata Memorial Hospital, Mumbai, India disease for at least one year, rather than an effect of treatment. PURPOSE: Prognostication of DIPGs with clinical, radiological and bio- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 logical imaging parameters. Materials and methods: Between March 2005-November 2006, 20 patients (3-21 years) with DIPGs were accrued in a phase-II prospective study of concomitant chemo-radiotherapy P-DIPG.03. INCIDENTAL DIAGNOSIS OF DIFFUSE INTRINSIC (CTRT) (54 Gy and Temozolomide (TMZ), D1-42 and 12 adjuvant PONTINE GLIOMA IN CHILDREN cycles). Patients underwent MRI, MR spectroscopy (MRS) and MR per- A. Broniscer1, D. K. Cheuk1, N. D. Sabin1, R. Y. McNall-Knapp2, fusion and PET scans at baseline and follow up. Clinical and imaging find- Z. A. Khatib3, and A. Gajjar1; 1St. Jude Children’s Research Hospital, ings were co-related with survival. RESULTS: At baseline MRI, 6 (30%) Memphis, TN, United States; 2University of Oklahoma Health Sciences patients showed no enhancement, 11 (55%) patchy enhancement and 3 Center, Oklahoma City, OK, United States; 3Miami Children’s Hospital, (15%) diffuse contrast enhancement. MRI features (contrast enhancement, Miami, FL, United States MRS and hyperperfusion) of high-grade glioma (HGG) and low-grade gliomas (LGG) were seen in 12 (60%) and 8 (40%) patients respectively. BACKGROUND: Children with diffuse intrinsic pontine glioma (DIPG) FDG-PET-scan increased uptake was seen in 55% and no uptake in rest. present with progressive neurologic deficits within short intervals. Among 8 patients with histology, 6 patients had LGG and 2 had HGG. METHODS: We reviewed the medical records of all patients with inciden- Age, gender, symptom-duration, tumour volume and histopathological tally diagnosed DIPG evaluated at our institution. Incidental diagnosis was grade did not have significant impact on survival. MRI features (HGG vs defined as the unexpected discovery of DIPG by imaging which was unre- LGG, OS 8.8 versus 15.1 months; p ¼ 0.043) and MR perfusion lated to the purpose of the examination. Magnetic resonance (MR) (Hyperperfusion versus hypoperfusion, 8.9 versus 15.1 months; p ¼ 0.043) imaging characteristics of DIPG consisted of infiltrative tumors involving . showed significant correlation with survival. FDG-PET scan had no survival 50% of the pons. MR imaging and spectroscopy were obtained in all function correlation (p ¼ 0.966). Patients with post-RT neurological patients. RESULTS: Five patients were identified (median age at diagnosis, improvement had significant survival (minimal versus good clinical response; 4.5 years). None of the patients had symptoms attributable to brainstem OS 8.23 and 13.31 months; p ¼ 0.048). Sensitivity and specificity of MRI involvement at diagnosis. Two patients presented acutely ill because of and PET to detect LGGs were low (33-66%), however, they were high to head trauma (n ¼ 1) and meningococcal septicemia (n ¼ 1); once recovered detect HGG (50-100%). CONCLUSIONS: Biological imaging appear prom- from those unrelated events, both patients had normal neurologic exam ising in prognosticating DIPG and further research is needed to improve except for subtle deficits in one patient. Brain imaging was also obtained management of these tumours. in three other patients because of developmental delay (n ¼ 1), language disorder (n ¼ 1), and migraine (n ¼ 1); only one of these patients had subtle neurologic deficits at diagnosis. MR spectroscopy suggested the diagnosis of DIPG in all patients. One patient underwent tumor biopsy which revealed a pilocytic astrocytoma. Remarkably, four patients were observed only P-DIPG.06. EVALUATION OF BRAINSTEM GLIOMA (median interval, 14.5 months; range, 9-31 months) until tumor progression. METABOLISM USING 11C-METHIONINE PET All patients received radiation therapy. Three patients died of tumor pro- T. Aki1, S. Takenaka1, K. Miwa1, M. Yamada1, T. Ito1, Y. Asano1, gression (median survival, 30 months). Two patients remain alive at +28 K. Yokoyama1, J. Shinoda1, H. Yano2, T. Iwama2, and J. Yamada1; 1Chubu and +30 months from diagnosis. CONCLUSIONS: This is the first series Medical Center for Prolonged Traumatic Brain Dysfunction, Kizawa reporting incidentally diagnosed DIPG. Although some children experienced Memorial Hospital, Minokamo City, Japan; 2Department of Neurosurgery, prolonged survival, their prognoses remained poor. Gifu University Graduate School of Medicine, Gifu City, Japan

OBJECTIVE: Brainstem gliomas vary in their biological characteristics and malignancy, and their classification for establishing appropriate treatments remains controversial and challenging. 11C-methionine positron P-DIPG.04. CHILDHOOD DIFFUSE BRAIN STEM TUMORS. RISK emission tomography (MET-PET) has provided clinically useful infor- FACTORS OTHER THAN HISTOLOGY mation for evaluating the metabolism and biological activity of cerebral M. Drogosiewicz1, B. Dembowska-Baginska1, E. Jurkiewicz2, and D. Perek1; gliomas. In this study, we attempted to classify brainstem gliomas neuror- 1Department of Oncology Children’s Memorial Health Institute, Warsaw, adiologically based on their morphological and metabolic activity using Poland; 2Department of Radiology Children’s Memorial Health Institute, MRI and MET-PET. CLINICAL MATERIALS AND METHODS: Warsaw, Poland Thirty-two patients with brainstem gliomas (mean 22 years old), including 10 pediatric patients, underwent MRI and MET-PET. The tumors were classi- INTRODUCTION: Despite progress in pediatric neurooncology treat- fied into four types according to the report by Choux et al. as follows: Type I ment results of brainstem tumors remain poor, with diffuse tumors having (intrinsic diffuse) in 18 cases, Type II (intrinsic focal) in 6 cases, Type III (exo- the worst prognosis. The most common tumors in this site are gliomas. phytic) in 1 case, and Type IV (cervico medullary) in 7 cases. Symptoms, ana- Localization and infiltrating character of these tumors often enable to tomical localization of tumor, extension pattern (diffuse or focal), growth perform biopsy without risk of complications so as a result more than half direction (intrinsic or exophytic), Gadolinium (Gd) enhancement (yes or no), of these patients are treated without pathological diagnosis. The aim of tumor volume, and MET up_take were assessed. RESULTS: MET up take our study was to: define prognostic factors other than tumor histology in was significantly decreased in tumors localized in the tectum and also in diffuse brainstem tumors, characterize risk groups and establish risk based tumors with symptom-free, focal extension and no Gd enhancement. treatment. Patients and methods: Retrospective analysis of 107 medical Moreover, Type II brainstem gliomas have a tendency for low MET up_take records of children with brainstem tumors treated with radiotherapy alone and small size. CONCLUSIONS: In addition to existing morphological infor- or pre-irradiation chemotherapy, radiotherapy and maintenance chemother- mation obtained from CT or MRI, information regarding tumor metabolic apy was performed. Statistical analysis of: gender, age, symptoms and it’s activity obtained from MET-PET, which is an important factor in predicting duration, MRI tumor images ( size, contrast enhancement, intra or peritu- biological malignancy and efficacy of treatment, may be useful to determine moral cysts), chemotherapy, radiotherapy, response to treatment and it’s the appropriate treatment strategies for brainstem gliomas. influence on 1 and 5 year overall survival (OS) was performed. Risk groups were defined based on prognostic factors identified with Cox multivariate analysis. Treatment based on risk groups is proposed. RESULTS: 1 and 5 yrs OS of patients with brainstem tumors was 54 and 16.7% respectively. Multivariate analysis showed that duration of symptoms, fully expressed brainstem syndrome, type of contrast enhancement and response ii68 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-DIPG.07. ADDITION OF CHEMOTHERAPY TO RADIATION of Pediatrics, Sungkyunkwan University Kangbuk Samsung Hospital, Seoul, CONFERS BETTER RADIOLOGICAL RESPONSE IN Republic of Korea; 6Department of Pediatrics, Dankook University College CHILDHOOD DIFFUSE INTRINSIC PONTINE GLIOMA: MD of Medicine, Cheonan-shi, Republic of Korea ANDERSON CHILDRENS CANCER CENTER EXPERIENCE V. Subbiah, K. Sawale, T. Vats, M. Rytting, R. Bingham, R. Epps, M. Nagel, OBJECTIVE: This prospective study was performed to determine the effi- A. Mahajan, L. Ketonen, and J. Wolff; UT MD Anderson Cancer Center, cacy and safety of temozolomide (TMZ) plus thalidomide during and after Houston, TX, United States radiation therapy in pediatric patients with newly diagnosed diffuse pontine glioma (DPG). MATERIALS AND METHODS: Between BACKGROUND: Despite multi-institutional trials and multi-modality November 2004 and March 2008, 17 patients with pediatric DPG were treatment the prognosis for childhood diffuse intrinsic pontine glioma enrolled. The median age was 8 years (range, 3-16 years); seven patients (DIPG) is poor. Radiation is the primary modality with chemotherapy were male, and ten were female. The authors used the Korean Society for added in an attempt to improve outcomes. Clearly novel therapies are war- Pediatric Neuro-Oncology (KSPNO)-A053 protocol. The mean follow-up ranted. We sought to compare the radiological improvement in the tumors period was 12 months (range, 8.5-25 months). Rates of response to treat- following radiotherapy with combined chemotherapy and radiotherapy ment and survival were analyzed for 12 patients. RESULTS: Ten out of alone. METHODS: Out of a database of 200 patients with DIPG, 25 patients twelve patients showed a partial response (PR), while one exhibited stable matched our criteria of radiologically confirmed diagnosis of DIPG, treat- disease (SD) and another experienced progression (PD). The tumor control Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 ment with radiotherapy and chemotherapy, radiotherapy alone, availability rate was 92% (11/12), and the response rate was 83% (10/12). The of pre and post treatment MRI for comparison. 17 patients received radio- median progression-free survival (PFS) of 12 patients was 7.2 months therapy (intensity modulated radio therapy or external beam radiotherapy) (range, 3.6-10.7). The six-month and 12-month PFS rates were 58.3% and with adjuvant chemotherapy (any one of HIT-GBM protocol, temozola- 16.7%, respectively. The overall survival was 12.7 months (range, mide, etoposide, or gefitinib) and 8 were treated with radiotherapy alone. 10.4-15.1). The one- and two-year survival rates were 58.3% and 25%, Medio-lateral diameter, antero-posterior diameter, cranio-caudal diameter respectively. The main adverse effect was hematologic toxicity, with four were assessed. RESULTS: We found a difference in the product of transverse patients exhibiting grade 3 or 4 toxicity. All patients tolerated the regimen diameter and the antero-posterior diameter and the decrease in cranio-caudal well enough to continue with adjuvant chemotherapy. No Pneumocystis jir- diameter of the tumor in two groups to be statistically significant. Mann oveci pneumonia was noted. CONCLUSION: The TMZ plus thalidomide Whitney U test showed that “p values” for mediolateral diameter, anteropos- regimen was safe and tolerated well enough to be given on an out-patient terior diameter, craniocaudal diameter, McDonald’s number were 0.11, basis. This regimen significantly improved initial response rate, overall survi- 0.21, 0.023 and 0.027 respectively. CONCLUSION: Adding chemotherapy val, and two-year survival over standard therapy. to radiation improves the quantitative response in patients with DIPG. The cranio-caudal diameter of the tumor proved to be most useful. The endpoint might prove superior in future clinical studies.

P-DIPG.10. REIRRADIATION FOR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA H. J. Patel, C. C. Pinnix, J. E. Wolff, L. M. Ketonen, and A. Mahajan; M D P-DIPG.08. RADIOTHERAPY WITH CONCURRENT AND Anderson Cancer Center, Houston, TX, United States ADJUVANT TEMOZOLOMIDE IN CHILDREN WITH DIFFUSE BRAINSTEM GLIOMA OBJECTIVE: The goal is to report the first series of patients with diffuse A. Chassot1, P. Varlet2, S. Puget3, L. Negretti1, F. Dhermain1, J. Grill1, and intrinsic pontine glioma (DIPG) treated with a second course of radiation C. Dufour1; 1Institute Gustave Roussy, Villejuif, France; 2Hoˆ pital therapy (RT). METHODS: Six patients were treated with reirradiation for Sainte-Anne, Paris, France; 3Hoˆ pital Necker Enfants Malades, Paris, France progressive DIPG at our institution from 2007 to 2009. Progression was confirmed by clinical course and MRI. Clinical records were reviewed. Each case PURPOSE: To evaluate the overall survival in newly diagnosed pediatric was discussed at a multidisciplinary conference prior to reirradiation. diffuse brainstem glioma (DBG) treated with radiotherapy (RT) plus conco- RESULTS: Time from the first course of RT was 8 to 28 months. Initial mitant and adjuvant temozolomide (TMZ). METHODS: Pediatric patients RT was 54 to 55.8 Gy with concurrent chemotherapy. Time to initial pro- with newly diagnosed DBG were treated at Institute Gustave Roussy with gression was between 3 and 16 months. All patients progressed on salvage focal radiotherapy up to 54 Gy in 30 fractions along with concurrent daily chemotherapy. Reirradiation was with concurrent chemotherapy and was temozolomide (75 mg/m2, Days 1-42). Four weeks after completed the as follows: 20 Gy in 10 fractions (n ¼ 4), 18 Gy in 10 fractions (n ¼ 1), TMZ - RT schedule, adjuvant TMZ (200mg/m2/daily for 5 days) was one patient withdrew care after a single 2 Gy fraction. Four patients had con- given every 28 days for a maximum of 6 cycles. All patients underwent a siderable clinical improvement in symptoms with improvement in speech biopsy to confirm the histology. Response was evaluated clinically and radi- (n ¼ 3), ataxia (n ¼ 3), and swallowing (n ¼ 2). Three patients were not ologically with magnetic resonance imaging. RESULTS: Between September ambulating prior to radiation but did so after treatment. Four patients had 2005 and September 2009, 18 patients (median age, 6.3 years) were treated decrease in tumor size on post-treatment MRI. Acute toxicity reported was according to this approach. Pathological diagnosis was glioblastoma multi- fatigue (n ¼ 2), alopecia (n ¼ 2), decreased appetite (n ¼ 1). There were no forme (3), WHO grade III oligodendroglioma (1), WHO grade III oligoastro- grade 3 or 4 toxicities. CONCLUSIONS: Progression after definitive treat- cytoma (3), WHO grade III astrocytoma (2), WHO grade II astrocytoma (3), ment of DIPG is accompanied by severe neurologic deficits and morbidity. and unclassified high-grade glioma (5). For 1 patient, no material was Reirradiation might be a feasible option to improve symptoms and further obtained for histological diagnosis. One month after the end of concurrent delay progression. This may be considered in select patients, particularly radiotherapy, 13 patients presented partial response, 3 stable disease and 2 those with favorable prognostic factors such as prolonged response to progressive disease. The median survival was 8.8 months (range, 11 days - initial therapy and long interval since initial radiation. 17,6 months). Four children presented metastatic relapse. Grade IV throm- bopenia occurred in 9 patients and led to dose reduction in 7. Febrile neutropenia occurred in 6 patients. Three patients presented pseudoprogression on imaging early after RT. CONCLUSIONS: TMZ with RT has not improved the outcome of the DBG and is associated with higher toxicity compared P-DIPG.11. A RETROSPECTIVE REVIEW OF CHILDREN with radiotherapy alone. TREATED AT THE SYDNEY CHILDREN’S HOSPITAL / PRINCE OF WALES HOSPITAL R. I. Smee1, R. Cohn2, D. Ziegler2, B. Kwok3, H. Johnston2, A. Bye2, I. Andrews2, and W. Stening2; 1The Prince of Wales Cancer Centre, Sydney, Australia; 2The Sydney Children’s Hospital, Sydney, Australia; 3The Prince P-DIPG.09. A PROSPECTIVE STUDY OF TEMOZOLOMIDE PLUS of Wales Cancer Centre / The Sydney Children’s Hospital, Sydney, Australia THALIDOMIDE DURING AND AFTER RADIATION THERAPY FOR PEDIATRIC DIFFUSE PONTINE GLIOMAS: PRELIMINARY PURPOSE: To evaluate a single centre’s experience of children treated by RESULTS OF THE KOREAN SOCIETY FOR PEDIATRIC radiotherapy for their brain stem glioma. MATERIALS AND METHODS: NEURO-ONCOLOGY (KSPNO) STUDY The brain stem glioma data base at Prince of Wales Hospital (SCH) was B. K. Cho1,C.Y.Kim2, S. K. Kim1, J. H. Phi1, M. M. Lee2, I. A. Kim3, audited for all paediatric patients aged less than 18 years in which clinical I. H. Kim4, K. C. Wang1, H. L. Jung5, and M. J. Lee6; 1Division of Pediatric presentation and imaging was consistent with a brain stem glioma and Neurosurgery, Seoul National University Children’s Hospital, Seoul, received radiotherapy. Clinical, imaging and treatment details were Republic of Korea; 2Department of Neurosurgery, Seoul National University extracted. The primary end point was median survival with the secondary Bundang Hospital, Seongnam-shi, Republic of Korea; 3Department of end point of neurological function at time of last follow-up for survivors. Radiattion Oncology, Seoul National University Bundang Hospital, RESULTS: In this Ethics approved study between 1990 and 2007 39 patients Seongnam-shi, Republic of Korea; 4Department of Radiation Oncology, were referred of whom 23 received radiotherapy, 19 at diagnosis and 4 at Seoul National University Hospital, Seoul, Republic of Korea; 5Department time of progression. There were 10 boys and 13 girls, with median age of

NEURO-ONCOLOGY † JUNE 2010 ii69 Abstracts

7 years. Symptom duration was less than 1 month in 5, 1-3 months in 11 and novel prognostic markers for GBM, my laboratory has employed unbiased greater than 3 months in 7. Some form of surgery was performed in 12. The genome-wide microarray analysis of archived pediatric and adult GBM diag- median radiotherapy dose was 53.7Gy in 30 fractions with all children now nostic surgical specimens (n ¼ 21) with known clinical outcomes (median treated by Stereotactic IMRT. Chemotherapy was initially used in 11 chil- survival 11 months; range 0-82). Unexpectedly, this approach revealed dren. At last follow-up 10 patients (44%) who received radiotherapy are that a signiﬁcant overexpression of immune genes is the predominant alive and functioning well with only minor deﬁcit. Mean follow-up is feature that distinguishes long term survival in GBM (p ¼ 2.5 x 10216). 41months. CONCLUSION: Close to 50% of these patients are functioning Survival-associated genes include CD3 delta, epsilon, gamma and zeta sub- well many months following treatment. The outcome in this population is units; CD8 alpha and beta chains; T-cell receptor beta and gamma chains; better than that quoted in the literature, this will be discussed. and granzymes A, B, H and K. The presence of these immune genes is strongly indicative of a cytotoxic T-cell response. Other notable immune related genes include numerous cytokines and chemokines, in particular interleukin 15 ligand and receptor, that can enhance anti-tumor CD8 T-cell activity. This association of immune factors with longer survival in P-DIPG.12. TWENTY YEARS OF PEDIATRIC PONTINE TUMORS GBM is consistent with our group’s recent discovery that immune gene IN VU UNIVERSITY MEDICAL CENTER: A RETROSPECTIVE and T-cell enrichment is the predominant factor associated with a good prog- ANALYSIS nosis in ependymoma, a common pediatric brain tumor. Based on these data, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 M. H. A. Jansen, E. J. Schaafsma, D. G. Vuurden, R. J. Vermeulen, we hypothesize that the host immune system is involved with controlling P. Vandertop, and G. J. L. Kaspers; VU University Medical Center, tumor growth in long-term survivors of GBM. Amsterdam, Netherlands

BACKGROUND: Pontine tumors can be diffuse (DIPG) and focal, based on their MRI-presentation. Only limited data are available with regard to symp- P-HGG.02. INFLUX OF NON-IMMUNOSUPPRESSIVE MYELOID toms and outcome separately for focal pontine tumors. Taken together, the CELLS UPON REGULATORY T CELL DEPLETION IN THE 3-year survival varies in studies between 2.7-18%. METHODS: A retrospective BRAIN OF GLIOMA-BEARING MICE analysis was performed on children with pontine tumors diagnosed at the VU M. Wim, T. Verschuere, A. Van Hoylandt, J. Ceuppens, S. De Vleeschouwer, University Medical Center in the past 20 years. Aim of this analysis was to elu- and S. W. Van Gool; Catholic University of Leuven, Leuven, Belgium cidate patient characteristics and compare outcome of focal pontine tumors and DIPG. RESULTS: Thirteen DIPG-patients and seven with focal tumors were Background. We performed in-depth characterization of brain-infiltrating diagnosed. All DIPG-patients versus 86% with focal tumors presented with immune cells in the context of immunotherapy for experimental glioma. abducens nerve paresis. 70% of both groups experienced ataxia. Headache Prophylactic depletion of regulatory T cells (Treg) led to complete protection and vomiting was presented in respectively 54% and 38% of DIPG and against primary glioma challenge (but not re-challenge) and unexpectedly also 14% of focal pontine tumors. All focal tumors were biopsied: five high resulted in a pronounced infiltration of CD11b+ myeloid cells in the brain. grade gliomas, one pilocytic astrocytoma and one medulloepithelioma. Hypothesis. Temporal downregulation of Treg activity skews functionality DIPG was not biopsied. Total resection was impossible in all of brain-infiltrating myeloid cells towards a non-immunosuppressive macro- focal tumors and 43% received radiotherapy. DIPG-patients were irradiated phage phenotype. Methodology. All experiments were performed in the syn- in 54% and 46% received temozolomide. Median survival was 5 months geneic GL261 orthotopic glioma model in C57BL/6 mice. Treg depletion was for DIPG and 7 for focal pontine tumors. There were no long term survi- achieved by administration of anti-CD25 monoclonal antibody (mAb) clone vors. CONCLUSION: Symptoms of focal pontine tumors and DIPG were PC61 three weeks prior to tumor challenge. Two weeks after tumor challenge, in general comparable, although signs of increased pressure were more fre- brain-infiltrating cells were isolated for phenotyping and functional analysis. quently seen in DIPG. Prognosis of both patient groups was very poor; the Results. Treatment with anti-CD25 mAb resulted in a massive increase of dismal outcome of focal pontine tumors can be explained by the unfavour- brain-infiltrating CD11b+ myeloid cells (9.14 + 2.88x106) compared to able histology and inability to obtain a complete resection. Innovative untreated animals (1.26 + 0.36x10 p ,0.05). Virtually all CD11b+ cells dis- therapy is needed for patients with both focal and diffuse pontine tumors. played high expression of the F4/80 surface marker and were considered macrophages based on cell morphology. No expression of the Ly6G marker was found but we could clearly distinguish a Ly6C+ and Ly6C- subpopu- lation. Neither the latter two CD11b+ subpopulations nor the entire CD11b+ parent population displayed suppressive activity in vitro. P-DIPG.13. TREATMENT AND OUTCOMES OF DIFFUSE Conclusion. Elimination of Treg is protective against subsequent glioma chal- PONTINE GLIOMAS AT THE STOLLERY CHILDREN’S lenge and allows infiltration of the brain with large numbers of myeloid cells. HOSPITAL, CANADA These cells lack immunosuppressive activity in vitro and hence do not corre- W. Beaudoin, C. McDonald, V. Mehta, J. Pugh, and B. Wilson; Stollery spond with myeloid derived suppressor cells or tumor-associated macro- Children Hospital, Edmonton, AB, Canada phages that are found in primary glioma challenge without Treg depletion. Diffuse pontine gliomas are a highly aggressive and deadly brain tumor seen in the pediatric population. Children often present with significant and rapidly progressing morbidity, including significant cranial nerve deficits and ataxia. With the mean survival rate of less than a year and surgical P-HGG.03. DOES IMMUNOHISTOCHEMISTRY CORRELATE removal not an option, Pediatric Neuro-Oncology teams are forced to act WITH GENETIC AND CLINICAL FACTORS IN PAEDIATRIC quickly and to consider aggressive forms of treatment to try to prolong the HIGH GRADE GLIOMA? imminent demise of these children. In 2009, we have had 5 new tumors of S. J. Smith, M. Adamowicz-Brice, D. C. Macarthur, B. Coyle, and this type diagnosed at the Stollery Children’s Hospital. This has lead us to R. G. Grundy; Children’s Brain Tumour Research Centre, University of complete a review of the diffuse pontine gliomas diagnosed at our institute Nottingham, Nottingham, United Kingdom over the past 10 years. We have examined presenting symptoms, diagnosis, treatment, and survival rates of these high risk patients in order to better INTRODUCTION: Paediatric high grade glioma (pHGG) has poor survival guide treatment considerations in the future. rates with median survival for older children in the order of 14 to 18 months, but a somewhat better life expectancy in younger infants. In adult studies, mitotic index as assessed by Ki67 labelling has been correlated with survival, as has microvessel density within the sample. We investigated whether P05 HIGH GRADE GLIOMA similar correlations can be drawn in the paediatric population. METHODS: We have undertaken immunohistochemical staining on tissue microarrays from a large cohort of pHGG collated by the UK CCLG (n ¼ 150). Mitotic P-HGG.01. ASSOCIATION OF IMMUNE FACTORS WITH index was assessed with a Ki67 (MiB1) antibody. Microvessel density was LONG-TERM SURVIVAL IN GLIOBLASTOMA assessed with staining for endothelial wall marker CD31 (PECAM) and A. M. Donson, D. K. Birks, V. N. Barton, B. K. Kleinschmidt-DeMasters, CD105 (endoglin), a glycoprotein associated with angiogenic blood vessels; A. E. Waziri, M. Wang, M. H. Handler, and N. K. Foreman; University of which is suggested to be a more accurate marker of new vessel formation Colorado Denver, Aurora, CO, United States within tumours. Using these measurements, we have supervised analysis of the copy number and gene expression array data previously published by our Glioblastoma (GBM), the most common primary brain tumor, is currently group on the same cohort of samples. RESULTS: The mitotic index was calcu- best treated by surgical removal, chemo- and radiation therapy. lated for 128 samples, giving a range of 0% to 29.3%. Microvessel density was Unfortunately, mortality from GBM represents the most significant also calculated, and comparisons drawn between CD31 and CD105 based problem in neuro-oncology with a median survival of only 14.6 months. methods. Immunohistochemical markers were in turn correlated with clinical Despite the severity of this disease, little progress has been made in identify- factors such as age and survival. Correlations have also been drawn between ing the factors that contribute to survival in patients with GBM. To identify these factors and the SNP / gene expression array data. CONCLUSIONS: ii70 NEURO-ONCOLOGY † JUNE 2010 Abstracts

Mitotic index, as assessed by Ki67 immunohistochemistry, and microvessel Moreover, recent studies have associated glioma stem cells with impeccable density (as measured by CD31 or CD105 immunostaining) correlate with chemo-resistance mechanisms, leading to an overall poor survival and failure genetic and clinical factors in paediatric high grade glioma. among patients treated by conventional adjuvant chemotherapy. Since a wide range of steroid receptors are expressed in gliomas, our objective was to investigate whether novel classes of steroid inhibitor drugs can be used efficiently to inhibit glioma growth. To achieve this, we studied the effect of these drugs on the growth of glioma stem cells. METHODS AND P-HGG.04. HOMOZYGOUS DELETION OF ADAM3A IN RESULTS: We screened using a candidate chemical structure approach, a PAEDIATRIC HIGH GRADE GLIOMA AND BRAINSTEM library of 400 steroid inhibitor drugs on 5 human glioma stem cells estab- GLIOMA lished from surgeries (n ¼ 2) and cell lines (n ¼ 3), and a normal human neu- J. H. Barrow1, M. Adamowicz-Brice1, J. Lowe2, K. Robson2, B. Coyle1, and roprogenitor cell line. We discovered 5 potent new steroid inhibitor drugs R. Grundy1; 1Children’s Brain Tumour Research Centre, University of belonging to the methyl-piperazine family that can induce significant death Nottingham, Nottingham, United Kingdom; 2Neuropathology, University of of glioma stem cells (n ¼ 5/5) within a 24 hour period, and with some Nottingham, Nottingham, United Kingdom death of normal human neuro-progenitor cells. These drugs induced significant apoptosis resulting in an overall decreased viability and proliferation of The prognosis for high grade glioma in childhood is extremely poor in part the cells in a dose dependent manner (5 mM and 10 mM). Furthermore, sig- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 due to our lack of understanding of the underlying biology. DNA was isolated nificant inhibition of transformation was noted. CONCLUSIONS: We have from 38 formalin-fixed paraffin embedded paediatric high grade glioma discovered a novel chemically distinct class of drugs that can significantly samples, including 13 brainstem gliomas, and hybridised to 244k oligo com- inhibit the growth of glioma stem cells. Current efforts are undertaken to parative genomic hybridisation arrays (Agilent Technologies). Homozygous study more of the mechanistic function of these drugs. loss at 8p12 was seen in 6/38 (15%) of high grade gliomas. This deletion has not been previously reported in adult or paediatric high grade gliomas. The minimal deleted region is of the gene ADAM3A. Homozygous deletion of ADAM3A was confirmed by quantitative real time PCR (qPCR). Little is known about ADAM3A, but several other members of the ADAM gene P-HGG.07. A CHEMICAL GENETICS SCREEN IDENTIFIES family have been implicated in cancer. This novel homozygous deletion of NOVEL STEROID INHIBITOR DRUGS THAT INHIBIT THE ADAM3A merits further study. MYCN amplification was seen in 2/38 GROWTH OF GLIOMA CELL LINES samples (5%) by oligo aCGH; one brainstem glioma and one anaplastic astro- N. Ajewung1, M. Rana1, D. Poirier2, and D. Kamnasaran1; 1Department of cytoma. MYCN fluorescent in situ hybridisation (FISH) was performed on a Pediatrics, Centre de Recherche du CHUL & Laval University, Quebec, QC, series of high grade glioma tissue microarrays (TMAs). Two addition ampli- Canada; 2Laboratory of Medicinal Chemistry, Oncology and Molecular fications of MYCN were seen by FISH, which were both in anaplastic astrocy- Endocrinology, Centre de Recherche du CHUL & Laval University, Quebec, tomas. MYCN amplification was shown to be significantly associated with QC, Canada anaplastic astrocytomas (p ¼ 0.03). Loss of CDKN2A/B was seen in 4/38 (10%) samples by oligo aCGH and 13% samples by FISH on TMAs. BACKGROUND: Giomas are among the top 5 causes of cancer related Interestingly none of the brainstem gliomas or infratentorial tumours deaths, representing about 60% of the cases in adults and 30% in chil- showed deletion of CDKN2A/B by aCGH or by FISH, and all deletions dren. Despite current treatments (surgery, radiation, and chemotherapy), were seen in supratentorial glioblastoma multiforme. the overall survival is still poor. Current promises exist with patients treated with adjuvant temozolomide, however only 10-15% typically have a positive response with combined surgery and radiation therapies leading to prolonged survival of up to 2 years. Since a wide range of steroid receptors P-HGG.05. A NOVEL METHOD TO ENRICH FOR GLIOMA STEM are expressed in gliomas, our objective was to investigate whether novel CELLS FROM GLIOMA CELL LINES classes of steroid inhibitor drugs can be used efficiently to inhibit glioma N. Ajewung, M. Rana, and D. Kamnasaran; Department of Pediatrics, growth. To achieve this, we studied the effect of these drugs on the growth Centre de Recherche du CHUL & Laval University, Quebec, QC, Canada of glioma cell lines. METHODS AND RESULTS: We screened using a candidate chemical structure approach, a library of 400 steroid inhibitor drugs BACKGROUND: Glioma stem cells (GSC) are inherently similar to stem on 5 human glioma cell lines, and a normal human astrocyte cell line. We cells except they can transform into tumors reminiscent of the pathological discovered 4 potent new drugs of the androsterone family that can induce sig- ¼ features of the originated tumor mass. GSCs serve as an excellent pre-clinical nificant death of glioma cell lines (n 5/5) within a 24 hour period in con- model to comprehend tumor re-growth and treatment resistance. Several trary to normal human astrocytes. These drugs induced significant apoptosis approaches were previously described to purify GSCs, but seemingly resulting in an overall decreased viability and proliferation of the cells in a appeared to be laborious, costly and sometimes with poor yield. Our objec- dose dependent manner (5 mM and 10 mM). Furthermore, significant inhi- tive was to investigate alternative strategies to cost-effectively and efficiently bition of transformation was noted. CONCLUSIONS: We have discovered enrich for GSCs. METHODS AND RESULTS: We grew 3 glioma cell lines in a novel chemically distinct class of drugs that can significantly inhibit the a modified serum free media that promotes the growth of stem cells over a 10 growth of glioma cell lines. Current efforts are undertaken to study more day period and with ease of harvesting from the supernatant. The tumor- of the mechanistic function of these drugs. spheres had cell line specific morphologies. For instance, those from U87 and DB54MG were significantly larger with tightly associated spheres, in comparison to those from U251. The tumorspheres expressed stem cell markers and in fact were 80-96% rich in CD133 + ve cells. Upon growth in DMEM/10% FCS tumorsphere diffentiation occurred. In addition, the P-HGG.08. ANALYSIS OF MICRO-RNA (MIR) EXPRESSION PROFILE IN PEDIATRIC GLIOBLASTOMA tumorspheres can transform in in-vitro and with the ability to grow into 1 1,2 3 4 4 tumors having similar pathological hallmarks but faster growth in compari- I. Sardi , L. Giunti , A. M. Buccoliero , F. Giordano , F. Mussa , B. Spacca4, M. Genuardi2, M. Massimino5, L. Genitori4, and M. Arico` 1; son to xenograft tumors derived from the growth of glioma cell lines. These 1 findings were overall similar with passages 1, 10 and 30 GSCs examined. Department of Pediatric Hematology Oncology, Anna Meyer Children’s Hospital, Florence, Italy; 2Department of Genetics, Anna Meyer Children’s CONCLUSIONS: We have discovered an alternative strategy to enrich for 3 glioma stem cells from glioma cell lines in a cost-effective, easy and efficient Hospital, Florence, Italy; Department of Human Pathology and Oncology, University of Florence, Florence, Italy; 4Department of Neurosciences, Anna manner. Current efforts are undertaken to utilize our protocol to enrich for 5 glioma stem cells from surgical tissues. Meyer Children’s Hospital, Florence, Italy; Department of of Pediatrics, IRCCS Foundation, National Cancer Institute, Milan, Italy

MicroRNAs are single-stranded RNA molecules of 19-24 nucleotides in length that do not encode proteins and regulate post-transcriptional ′ P-HGG.06. A CHEMICAL GENETICS SCREEN IDENTIFIES genetic expression through imperfectly pairing with sites in the 3 -UTR of NOVEL STEROID INHIBITOR DRUGS THAT INHIBIT THE their target mRNAs leading to cleavage of mRNAs or directly to inhibition GROWTH OF GLIOMA STEM CELLS of translation processes. Several data indicate that microRNAs are key regu- M. Rana1, N. Ajewung1, D. Poirier2, and D. Kamnasaran1; 1Department of latory molecules of biological mechanism like cellular differentiation, cellu- Pediatrics, Centre de Recherche du CHUL and Laval University, Quebec, lar proliferation, apoptosis, development, anti-viral defense and QC, Canada; 2Laboratory of Medicinal Chemistry, Oncology and Molecular tumorigenesis. Recently studies have shown distinct patterns of microRNA Endocrinology, Centre de Recherche du CHUL & Laval University, Quebec, expression in adult glioblastoma (GBM) and have indicated that QC, Canada microRNAs play a role in genesis of glioma including cell proliferation, invasion, glioma stem cell behavior, and angiogenesis. We have studied a set of BACKGROUND: Glioma stem cells represent a fraction of cells within a ﬁve microRNA (miR-21, miR-7, miR-124, miR-137 and miR-128) by tumor mass which are postulated to be responsible for tumor re-growth. using quantitative RT-PCR in parafﬁn-embedded tissue of ten pediatric

NEURO-ONCOLOGY † JUNE 2010 ii71 Abstracts

GBM. Over-expression of miR-21 was shown in all samples while expression P-HGG.11. ROLE OF MRK KINASE IN RADIATION-INDUCED levels of other microRNAs (miR-7, miR-124, miR-137 and miR-128) were INVASION IN HIGH-GRADE GLIOMAS low compared to our control (brain biopsy of pediatric patient who under- I. Vanan1,2, Z. Dong2, M. Symons2, and M. Ruggieri2; 1Schneider Children’s went brain surgery for any reason other than the presence of tumor). Our Hospital, New Hyde Park, NY, United States; 2Feinstein Institute for data suggest that up-regulation of miR-21 and down-regulation of other Medical Research, Manhasset, NY, United States miRs investigated may contribute to GBM development. These preliminary data seem similar to those reported in the literature concerning case BACKGROUND: High-grade glioma is one of the most aggressive studies of adult GBM. In the future we want to extend the series of pediatric human cancers, is highly resistant to radiation and chemotherapy and GBM to validate the accuracy of our data and we would like to quantitatively invariably tends to recur after treatment. MRK, a stress-regulated MAP compare the differences in the expression profile of a set of five microRNAs kinase kinase kinase (MAPKKK) is activated by ionizing radiation (IR) in pediatric GBM against those of adulthood. and is required for invasion stimulated by growth factors in different types of tumors. Previous studies have shown that IR induces glioblastoma cell invasion in vitro and upon IR treatment, MRK activates the p38g MAP kinase and contributes to Chk2 activation. Because MRK is acti- P-HGG.09. NPAS3 IS A NOVEL LATE-STAGE ACTING vated by IR and is important for invasion, we examined the role of MRK in IR-induced glioblastoma cell invasion. METHODS: We used PROGRESSION FACTOR IN GLIOMAS WITH TUMOR Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 SUPPRESSIVE FUNCTIONS SNB19, T98G and U87 glioblastoma cell lines in our experiments. To N. Ajewung1, M. Rana1, P. Gould2, and D. Kamnasaran1; 1Department of study in vitro invasion and migration, we used transwell chambers with Pediatrics, Centre de Recherche du CHUL & Laval University, Quebec, QC, or without extracellular matrix (Matrigel). RNA interference was per- Canada; 2Department of Pathology, Laval University, Quebec, QC, Canada formed using transient transfection of at least two different siRNA oligo- nucleotides, to control for off-target effects. RESULTS: We found that BACKGROUND: In our effort to better comprehend the genetics of gliomas, siRNA-mediated MRK depletion in glioblastoma cells inhibits we explored new therapeutic targets. We previously cloned NPAS3, a transcrip- IR-induced invasion and migration. We also found that depletion of tion factor which maps to human chromosome 14. Our principal aim is to com- either p38g or Chk2 inhibits IR-induced invasion and migration. prehend the disease associations of NPAS3, since we recently identified Moreover, the inhibitory effect of Chk2 or MRK depletion on cell expression in human astrocytes. We investigated NPAS3 as a candidate for migration was reversed by blocking cell cycle progression. astrocytomas based on findings archived from the Cancer Genome Project CONCLUSIONS: Our observations establish a critical role for MRK in demonstrating a loss of NPAS3 expression and with loss-of-function deletions IR-induced glioblastoma invasion and validate MRK and of human chromosome 14 with NPAS3 in 30-50% of astrocytomas. MRK-controlled signaling elements as novel therapeutic targets in the METHODS AND RESULTS: After undertaking extensive functional analyses, treatment of high-grade gliomas. Our data also indicate that MRK and we now have novel evidence supporting NPAS3 as an astrocytoma tumor sup- Chk2 contribute to IR-induced invasion via control of the cell cycle. pressor involved in late-stage tumor progression, based on: 1) Absent NPAS3 expression is predominant in high grade astrocytomas (79-83%), in comparison to low grade astrocytomas (29-35%). 2) Loss of function mutations of NPAS3, which are associated with a loss of heterozygosity of the NPAS3 locus are identified in GBMs. 3) Absent NPAS3 expression is predominant in P-HGG.12. THE ROLE OF THE COFILIN ACTIVITY CYCLE IN .60% of malignant human glioma cell lines. 4) An over-expressed NPAS3 in GLIOMA MIGRATION AND INVASION malignant glioma cell lines suppresses the transformation potential, while the C. Smith, S. Nagai, O. Moreno, and J. Rutka; Hospital for Sick Children, converse reduced expression promotes an increase in transformation potential. Toronto, ON, Canada 5) A reduced NPAS3 expression (efficiency .90%) in concert with other gliomagenesis genes can transform a well characterized TERT immortalized human The most common brain tumour arising in the central nervous system (CNS) astrocyte cell line and promote the growth of anaplastic astrocytomas. is the astrocytoma which accounts for 65% of all primary brain tumours.The CONCLUSIONS: Our data provide compelling findings of NPAS3 as a novel majority of astrocytomas are histologically malignant neoplasms. The malig- gene involved in the cause of astrocytomas, with tumor suppressive and late- nant astrocytoma is a highly proliferative and invasive neoplasm that infiltrates stage acting progression factor roles. diffusely into regions of normal brain rendering total surgical extirpation impossible and effective local radiation therapy difficult. The cofilin pathway plays a central role in the regulation of actin polymerization and the formation of protrusions that are essential for cell migration. Phosphorylation of cofilin at Ser3 is a key regulatory mechanism modulat- P-HGG.10. SUB-CELLULAR LOCALIZATION OF Y-BOX ing cofilin activity. Cofilin expression is altered in a variety of cancers PROTEIN 1 REGULATES PROLIFERATION, INVASION, AND including ovarian, renal cell, and oral-squamous carcinomas. Expression INCREASED MESENCHYMAL PHENOTYPE IN of cofilin and other proteins in the cofilin pathway such as Rac and ASTROCYTOMAS LIMK are upregulated in invasive tumor cells, and that the activation X. Liu1,2, D. Faury1, C. Sollier1, N. Gerges1, J. Rak1,2, and N. Jabado1,2; status of cofilin may be directly linked to tumor invasion. In this study, 1Montreal Children’s Hospital - Research Institute, Montreal, QC, Canada; cofilin expression was increased and correlated with increasing grade malig- 2McGill University, Montreal, QC, Canada nant astrocytoma. In addition both cofilin and LIMK had elevated expression in glioma cell lines. Knockdown of cofilin altered glioma cell Y-Box-Protein-1 (YB1) is a DNA/RNA-binding protein implicated in morphology and inhibited glioma migration and invasion. Conversely, over- cancer progression. YB1 is mandated for embryonic development and acts expression of a cofilin phosphorylation mutant in an in vivo xenograft a transcriptional/translational regulator. Akt-dependent phosphorylation model of brain tumours, resulted in exacerbation of the invasive phenotype of S102YB1 induces nuclear translocation and potentially oncogenicity. in 100% of animals characterized by invasion into the contralateraly cer- We previously established elevated YB1 levels in Pediatric Glioblastoma ebral hemisphere or corpus callosum. Taken together these data indicate (GBM), an aggressive high-grade brain tumor, possibly driving oncogenesis that the cofilin pathway may represent a novel therapeutic target to in this cancer. We investigated herein the effects of stable knock-down or ablate invasion in these highly malignant tumours. ectopic expression of YB1/mutant S102AYB1 in 4 GBM cell lines and HTert-immortalized astrocytes. Complete stable silencing of YB1 was never achieved, indicative of the role of this protein in cell survival. In all shYB1-stable clones, residual YB1 was nuclear, and cells showed increased proliferation (monolayer/soft-agar), increased EGFR levels and sustained P-HGG.13. ANTITUMOR IMPLICATIONS OF PLATINUM activation of Ras compared to empty-vector transfectant-cells. Ectopic COMPOUNDS USING CONVECTION-ENHANCED DELIVERY HA-tagged-YB1 was predominantly cytoplasmic in 3 GBM cell-lines, INARODENTGLIOMAMODEL similar to endogenous YB1, and moderately increased cell proliferation in Y. Tange1, K. Shimoji1, T. Shimizu1, M. Hishii1, A. Kondo2, and K. Mori3; only one GBM cell line. Both wild-type- and S102A-YB1 increased cell 1Juntendo University, Nerima Hospital, Tokyo, Japan; 2Juntendo University migration in all cell lines. In HTert-immortalized astrocytes, silencing YB1 Hospital, Tokyo, Japan; 3Juntendo University, Shizuoka Hospital, Shizuoka, increased proliferation and decreased cell migration while ectopic expression Japan induced the reverse, in addition to the induction of marked mesenchymal features in these cells. In one GBM cell-line, overexpressed HA-tagged-YB1 was Direct intracerebral drug infusion using convection-enhanced delivery predominantly nuclear, similar to endogenous YB1. This led to increased cell method has been utilized in both basic research fields and clinical trials. proliferation and EGFR levels and no alteration in cell migration. Our results The advantages of this technique have been well-documented but few suggest that YB1 modulates cellular proliferation and mesenchymal proper- studies have focused how a cytotoxic agent affects on the particular site ties, including migration, based on its sub-cellular localization. While ascer- after infusion. In our current experiments, carboplatin or oxaliplatin taining the role of nuclear YB1 in driving cell growth, our data argue for loaded osmotic mini-pumps were implanted in malignant glioma-bearing caution in targeting YB1 for therapeutic intervention. rats to evaluate the implications of intracerebral direct infusion in a tumor- ii72 NEURO-ONCOLOGY † JUNE 2010 Abstracts

harboring brain. First, to evaluate the distribution of agents in the rat brain, improve the therapeutic index with temozolomide in children with HGG. 0.5% Evans Blue or FITC-dextran was infused using an osmotic mini-pump. This study confirms that treatment decisions based on the molecular charac- The rat brains were infused at the rate of 1 ml/h up to 1 week with platinum teristics of the tumor are feasible, providing opportunities to develop more compounds in the toxicity or efficacy study. The tumor volume was serially molecularly-based tumor stratification or selection. Analysis in a larger measured by magnetic resonance imaging in the efficacy study, and the sur- population is required and will be performed as more patients are included. vival period of the rats and the histological specimens of the brains were assessed. Last, the tumor-bearing brains infused with drugs were examined after intravenous injection of 2% Evans Blue to elucidate the topical influence of intracerebral direct infusion. The use of an osmotic-mini pump for intracerebral direct infusion of fluid attained the adequate coverage of the P-HGG.16. TEMOZOLAMIDE OVER DOSING OR OPTIMAL whole tumor mass in our rat model. Among rats in the efficacy study, DOSING? A CASE REPORT treated animals with high dose carboplatin showed decreased tumor size Z. J. Wang1, J. Poulik1, D. Altinok1, A. Konski2, W. Kupski2, resulting in longer survival period than the animals in the control group. K. Bhambhani1, and S. Sood1; 1Children’s Hospital of Michigan, Detroit, The high dose administration of chemotherapeutic agents, however, MI, United States; 2Karmanos Cancer Institute, Detroit, MI, United States caused extensive topical edema, supplementary therapies might be required for clinical application. Temozolamide is one of the milestones in the treatment of malignant glioma Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 and is the first drug which has improved the survival of glioblastoma multiforme (GBM) in adults since the mid-1970s. However, the results of pediatric studies have not shown similar improvements. The reason for this difference in response is largely unknown. We report a case of temozolamide overdose P-HGG.14. HSP90 INHIBITORS SENSITIZE HUMAN U87MG which may shed light on the inferior response in pediatric population. The GLIOBLASTOMA XENOGRAFTS TO TEMOZOLOMIDE patient was a 7-year-old Caucasian male who presented with left facial N. Gaspar1,2,S.Y.Sharp2, S. A. Eccles2, S. Popov2, C. Jones2, A. Pearson2, palsy, double vision, headache and unsteady gait. MRI revealed a pons-based G. Vassal2, and P. Workman2; 1Institut de cance´roligie Gustave Roussy, brainstem tumor extending to the midbrain and left cerebellar peduncle with Villejuif Cedex, France; 2Institute of Cancer Research, Sutton, United compression of the fourth ventricle and significant ventriculomegaly. He Kingdom underwent biopsy and VP-shunt placement, and the pathology was consistent with mixed anaplastic glioma. Tumor cells expressed MGMT but no deletion PURPOSE: The primary brain tumour glioblastomas (GB) are resistant to of 1p/19q was detected. His symptoms were resolved following completion of current treatments with surgery, radiotherapy and temozolomide (TMZ). conformal radiation (56 Gy). Three months later, he developed left facial palsy Molecular chaperone HSP90 inhibitors are therapeutic agents which block again with radiological evidence of tumor progression. He was then started on the activation of multiple oncogenic client proteins and induce their temozolamide (160 mg/m2) and CCNU (90 mg/m2). Due to a pharmacy proteasome-mediated degradation. They sensitize several tumor types to error, he continued to receive temozolamide 5 days a week for 3 consecutive radiotherapy and different chemotherapeutic agents. We explored the weeks instead of prescribed 5 days every 4 weeks, but tolerated well except for therapeutic efficacy of two HSP90 inhibitors from different chemical a mild thrombocytopenia. His left facial palsy significantly improved over the classes (the geldanamycin analog 17-AAG and the resorcinylic isoxazole 3 weeks following the starting of temozolamide and subsequently resolved. amide NVP-AUY922) combined with TMZ in both adult and pediatric We speculate that higher dose of temozolamide in pediatric patients may be GB models. Experimental design: We evaluated antiproliferative, necessary and tolerable due to the well recognized difference in drug metab- pro-apoptotic, antiangiogenic and biomarkers modulation induced by olism of this population. single agents and TMZ/HSP90 inhibitor combinations, in vitro and in vivo, in GB models. RESULTS: In vitro, cytostatic concentrations of HSP90 inhibitors were mostly antagonistic with TMZ and associated with inhibition of TMZ-induced G2/M arrest and caspase 3-dependent apoptosis. This antagonism was sustained by GB intrinsic MGMT status and P-HGG.17. IRINOTECAN (CPT11) AND TEMOZOLOMIDE other factors implicated in TMZ resistance (e.g. induction of ER stress (TMZ) AS ADJUVANT TREATMENT OF NEWLY DIAGNOSED response) that we showed were modulated by effective HSP90 blockade. In GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY contrast, non-growth inhibitory concentrations of HSP90 inhibitors were REPORT additive/synergistic. In subcutaneous U87MG GB xenografts, the antitu- E. Gorender, P. L. J. Meirelles, and S. Epelman; Santa Marcelina Hospital, mor effect of TMZ/HSP90 inhibitor combinations was greater than Sao Paulo, Brazil with either agent alone. In vivo responses were associated with AKT, HIF1a and MET depletion and inhibition of TMZ-induced GRP78 upre- OBJECTIVES: Prognosis of GBM is very poor. Median survival is 14.3 gulation. The antitumor activity was sustained by antiproliferative, months with fractionated radiotherapy (RT) and daily oral TMZ. This pro- pro-apoptotic and antiangiogenic effects, and was maximal during the tocol aims to improve the survival of newly diagnosed GBM patients by treatment period with no observed disease progression in the combination adding a topoisomerase I inhibitor with TMZ after chemotherapy and RT. treated groups. CONCLUSION: TMZ/HSP90 inhibitor combinations may METHODS: Four male patients (PT), median age 15 years (range, 10-22 have promising potential for anti-GB therapy. years) were treated after surgery with 5 cycles of carboplatin, vincristine and TMZ, administered every 28 days. One PT had total resection surgery and 3 had partial resection. The protocol is standard local RT 60 Gy in 30 fractions with daily concurrent TMZ (75 mg/m2), followed by adjuvant courses with CPT11 (20 mg/m daily x 10 days) and TMZ (200 mg/m2/ P-HGG.15. METHYLATION STATUS OF METHYLGUANINE daily x 5 days) for 5 cycles. RESULTS: Three PT completed 5 courses of METHYLTRANSFERASE (MGMT) AS A POTENTIAL MARKER TMZ and CPT11 and 1 PT received 14 courses due to progressive disease IN HIGH-GRADE GLIOMAS IN CHILDREN: PRELIMINARY after RT and presented stable disease. All PT developed diarrhea grade (G) REPORT 3, vomiting G 2 and thrombocytopenia G 4. The three PT with partial resec- S. Epelman1, P. L. B. J. Meirelles1, M. Gouveia E2, and I. R. Zalcberg2; tion showed a partial response. All PT are alive with no evidence of progress- 1Santa Marcelina Hospital, Sao Paulo, Brazil; 2Laborato´ rio Progenetica ive disease with a median time of follow up of 23 months. CONCLUSIONS: Diagno´ stico Molecular, Rio de Janeiro, Brazil The addition of adjuvant chemotherapy with CPT11 and TMZ is feasible and well tolerated. This schedule improved overall survival for these high BACKGROUND: The prognosis of patients with high-grade glioma risk patients. More patients are warranted. (HGG) is poor. MGMT is a DNA repair protein that may influence the efficacy of chemotherapy in HGG. MGMT promoter methylation is associated with survival benefit and sensitivity to temozolomide, but its relationship to MGMT protein is unclear. This study examined MGMT methylation status in children with HGG. We explored MGMT promoter methylation in pedi- P-HGG.18. VINCRISTINE IN HIGH GRADE GLIOMA atric HGG and its relationship to survival. METHODS: It was analyzed ret- B. Aydin1,2, M. Patil3, and N. Bekele4; 1Department of Pediatric Oncology, rospectively MGMT promoter methylation in 12 newly diagnosed pediatric Ankara Oncology Hospital, Ankara, Turkey; 2Department of Pediatrics, HGG. The methylation status of the MGMT promoter was determined by Unit 87, The University of Texas M. D. Anderson Cancer Center, Houston, methylation-specific PCR after sodium bisulphite treatment. All patients TX, United States; 3The University of Texas School of Public Health, received temozolomide, carboplatin, vincristine, irinotecan and local radio- Houston, TX, United States; 4Department of Biostatistics, Unit 1411, The therapy. RESULTS: 8 (66%) of 12 patients with HGG were found to have University of Texas M. D. Anderson Cancer Center, Houston, TX, United methylation and 5 are alive with median time of follow up of 24 months. States Two died of progressive disease and 1 of toxicity. Four (34%) had no methylation and only 1 is alive with no evidence of disease after 21 months. PURPOSE: Numerous chemotherapeutics have been used in the treatment CONCLUSIONS: This preliminary data provides the background to of high grade glioma (HGG). However, the efficacy of the drugs is difficult to

NEURO-ONCOLOGY † JUNE 2010 ii73 Abstracts

assess in most patient cohorts because the studies were done without control treatment. Patient was treated with radiation and bevacizumab for four groups. The purpose of our study was to evaluate the therapeutic value of months, with mild radiographic progression noted. Both patients tolerated vincristine (VCR) in the treatment of HGGs. METHODS: We performed a the regimen well with no significant side effects. DISCUSSION: The combi- meta-analysis of HGG studies to evaluate the benefits of chemotherapy nation of bevacizumab and hypofractionated radiation therapy is well tolerated drugs on survival gain, which was calculated for each published patient andmay represent a viabletherapy for recurrent pediatric high gradegliomas. A cohort as the difference between observed and predicted median overall sur- phase II pediatric protocol is currently under development at our institution. vival as previously described. The means of survival gains from various studies were used to compare chemotherapy drugs. RESULTS: We found that patient cohorts treated with VCR-containing regimens had a significant survival gain advantage over cohorts treated with other chemotherapy drugs (p , 0.0001). In subgroup analyses, VCR was most effective in treating P-HGG.21. RESULTS OF TREATMENT OF ANAPLASTIC newly diagnosed adult (p , 0.0001) and elderly patients (p ¼ 0.0001). We ASTROCYTOMA IN CHILDREN also compared drug combinations. The effect was antagonistic when VCR O. G. Geludkova1, M. V. Mushinskaya1,2, O. I. Scherbenko3, was combined with nimustine, carmustine, cytarabine, or etoposide. Effect I. D. Borodina1, A. G. Rumyantsev1, A. G. Melikyan4, and U. V. Kushel4; was synergistic when VCR was combined with lomustine, procarbazine, cyclo- 1Federal Research Clinical Center of Pediatric Hematology, Oncology and phosphamide, dacarbazine, hydroxyurea, or cisplatin. CONCLUSION: We Immunology, Moscow, Russian Federation; 2Children’s Clinical Hospital, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 recommend that VCR be included in chemotherapy regimens for patients Perm, Russian Federation; 3Russian Research Centre of Radiology, Moscow, being treated for newly diagnosed or recurrent HGG. Our meta-analysis of pub- Russian Federation; 4Research Institute of Neuroseurgery N.N.Burdenko, lished datafound that VCRis effective in the treatment of HGG when combined Moscow, Russian Federation with lomustine, procarbazine, cytarabine, or etoposide. INTRODUCTION: Anaplastic astrocytoma (AA) is a rare tumor of the CNS in children, which differs the adverse forecast after realization only surgical treatment. MATERIALS AND METHODS: We observed 37 patients at the age from 5 months till 16 years (median, 8 years) with verified AA. 4 P-HGG.19. OUTCOME OF CHILDREN WITH NEWLY OR patients received only surgery, 8 surgery and radiotherapy (RT) and 25 RECURRENT DIAGNOSED HIGH GRADE CENTRAL NERVOUS complex treatment (surgery, RT and chemotherapy (CHT)). Total removal SYSTEM GLIOMAS TREATED WITH CARBOPLATIN AND of a tumor was performed in 15 patients, subtotal in 7, partial in 12, and IRINOTECAN biopsy in 3 patients. 33 patients received RT at a dose of 50-60 Gy N. Sirachainan, S. Pakakasama, U. Anurathapan, A. Visudhibhan, (median, 55 Gy). The patients ,3 years (n ¼ 6) received CHT according A. Boongird, M. Dhanachai, N. Larbcharoensub, and S. Hongeng; Faculty of to the protocol «Baby» POG, patients .3 years - temozolomide 200 mg/ Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand m2 (n ¼ 11), protocol HIT-91 (n ¼ 5) or PCV (n ¼ 3). RESULTS: The median observation time was 46 months (7-150 months). 5-year PFS and INTRODUCTION: High grade gliomas (HGGs) account for 8-12% of all OS was 40% and 50% respectively. The median PFS and OS were 24 and pediatric central nervous system tumors. Surgery and focal radiation are the 60 months, respectively. PFS in patients after total removal was 69 %, mainstay of treatment. Although treatment with adjuvant chemotherapy after subtotal and partial removal 42% and 10 %, and after biopsy 0 % post surgery and radiation showed a better survival compared to no treat- (p ¼ 0,01). PFS was higher after complex treatment than after surgery + ment, the various chemotherapy regimens demonstrated a 5-year progression RT or surgery only (56% vs. 10%, p ¼ 0,02), and higher in patients under free survival (PFS) of only 16-33%. This study aims to determine the 3 years compared to patients older than 3 years (80% vs. 24%, p ¼ outcome of adjuvant carboplatin and irinotecan after local treatment in chil- 0,002). There were no significant differences of PFS in patients older 3 dren with new or recurrent HGGs. MATERIALS AND METHODS: Patients years receiving different schemes of CHT. CONCLUSIONS: These results with newly diagnosed or recurrent HGGs were enrolled. Two weeks after permit to consider CHT as an effective and obligatory element of complex surgery, all patients received focal radiation for 6 weeks with 54-56 Gy treatment of AA. and followed by 4-week cycle of carboplatin 560 mg/m2 and irinotecan 125 mg/m2 on day 1 until tumor progression or 1-2 years. RESULTS: Eleven patients (5 females, 6 males), aged 9.9 + 3.1 years (mean + SD) were involved in the study. The diagnosis included 5 glioblastoma multiforme, 3 anaplastic astrocytoma, 2 anaplastic oligodendroglioma and 1 ana- P-HGG.22. SECONDARY DISSEMINATION (SD) IN DIFFUSE plastic ependymoma, including 2 diagnosed recurrent cases. The 5-year PFS INTRINSIC PONTINE GLIOMA (DIPG) IS CORRELATED TO and OS were 45.5 + 0.2% (95% CI 33.7-89.5) and 70.7 + 14.3% (95%CI PATIENTS AGE 16.7-70.7), respectively. The toxicities were grade 3-4 anemia in 6 patients P. Potepan1, V. Biassoni1, L. Gandola1, I. Bongarzone1, F. Spreafico1, (54.5%), grade 3-4 leucopenia in 8 patients (72.7%), grade 3-4 neutropenia E. Pecori1, P. Modena2, F. Bach3, and M. Massimino1; 1Fond. IRCCS Istituto in 10 (91%) and grade 3-4 thrombocytopenia in 8 patients (72.7%). No Nazionale Tumori, Milano, Italy; 2Centro di Riferimento Oncologico, treatment related death was found. CONCLUSION: This adjuvant Aviano, Italy; 3Oncoscience AG, D-22880 Wedel, Germany regimen with carboplatin and irinotecan yielded a substantial efficacy and could be another option for the treatment of pediatric HGGs. BACKGROUND: DIPG patients present with a short clinical history characterized by cranial nerve, pyramidal, cerebellar deficits. MRI findings are diagnostic, precluding the need for histologic confirmation. Median PFS/OS are 6/9 months, respectively, in the majority of reported series. The negative outcome is generally due to local progression. Rarely DIPG P-HGG.20. HYPOFRACTIONATED EXTERNAL BEAM have SD (13% in German series); literature reports are scarce. MATERIAL RADIATION WITH BEVACIZUMAB FOR THE TREATMENT OF AND METHODS: From January 2006 to March 2009 we treated 36 con- RECURRENT HIGH GRADE GLIOMA - REPORT OF TWO CASES secutive children with DIPG. The treatment - continuation of a phase 3 mul- S. W. Gilheeney, S. Wolden, I. J. Dunkel, and Y. Khakoo; Memorial ticentric trial - consisted of an induction therapy with weekly infusions of Sloan-Kettering Cancer Center, New York, NY, United States 150 mg/m2 nimotuzumab (anti-EGFR monoclonal antibody) for twelve weeks, concomitantly with standard radiotherapy (54 Gy) at weeks 3 to 8; BACKGROUND: High grade gliomas carry a poor prognosis at initial pres- nimotuzumab biweekly followed until disease progression. Results. entation and recurrence. An institutional trial in the adult population suggested Median age at diagnosis was 7.5 years (3.1-17.3), M/F was 0.8. Ten had promising survival data with the combination of hypofractionated external been biopsied and 14 had needed a ventricular shunt at some point of beam radiation and bevacizumab for recurrent high grade gliomas. We their history. Median PFS was 7 months, median OS 10 months thus a present the case reports of two pediatric patients treated on this regimen. little better than literature reports and without any side effects correlated METHODS: Patients were treated with hypofractionated RT (3000 cGy to nimotuzumab. Of the 35 relapsing patients, 8 had SD (23%) diagnosed total dose in 5 fractions administered every other day) and bevacizumab with MRI. Neither surgery nor shunt correlated with SD; PFS/OS were (10 mg/kg IV every two weeks). RESULTS: Patient 1 was diagnosed at age not significantly different in this population. The only significantly correlated 10 years with anaplastic astrocytoma. Initial treatment consisted of standard variable with SD was age, being 7/8 children with SD ≥ 7.5 years (chisquare radiation and temozolomide as per COG ACNS0126. Recurrence was con- 0.029). CONCLUSIONS: Risk of DIPG dissemination is not correlated to firmed 24 months post treatment. Treatment with temozolomide was surgical acts but to age, thus hinting biological differences among age reinstated, but the patient progressed after 2 cycles. Treatment with radiation groups in this ominous and poorly study disease. and bevacizumab was initiated, and the patient is a progression free survivor at 22 months. Patient 2 was diagnosed at age 5 years with glioblastoma multiforme. She underwent gross total resection and was treated with standard radiation, temozolomide and lomustine as per COG ACNS0423. Lomustine was discontinued after one cycle due to prolonged thrombocytopenia and development of subdural hematoma. Recurrence was diagnosed 9 months post ii74 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-HGG.23. THE INFLUENCE OF PATIENT AGE ON DRUG (WHO). Most of the published cases describe a diffuse process involving EFFICACY IN HIGH GRADE GLIOMA: A META-ANALYSIS FOR white matter with few data on grey matter extension. The goal of our RANKING DRUGS IN CHILDREN AND ADULTS study was to describe more accurately the grey matter involvement. M. Patil1 and B. Aydin2,3; 1The University of Texas School of Public Health, METHODS: We conducted a multicentric observational study from 1990 Houston, TX, United States; 2Department of Pediatric Oncology, Ankara to 2007 to collect the clinical, neuroradiological, pathological, and Oncology Hospital, Ankara, Turkey; 3Department of Pediatrics, Unit 87, outcome data of cases of GC involving grey matter of at least two lobes The University of Texas M. D. Anderson Cancer Center, Houston, TX, and concomitant impairment of thalami. RESULTS: 14 children aged 3 to United States; 4Department of Biostatistics, Unit 1411, The University of 14 fulfilled those criteria. First symptoms were seizures (50%), ending in Texas M. D. Anderson Cancer Center, Houston, TX, United States refractory epilepsy (64%), intra-cranial hypertension (86%), and motor deficit (64%). Brain MRI, especially FLAIR sequences, showed an infiltrative PURPOSE: High grade gliomas (HGG) have been treated by numerous process involving temporal (100%) and insular cortex (86%) both with chemotherapeutic agents in both, the adult and pediatric age group. thalami (100%) and basal ganglia (79%). Raised myo-inositol and choline Despite a large amount of published data, age guided drug choices remain levels on MR spectroscopy suggested respectively the glial origin and the with very little evidence. The purpose of the study was to identify which aggressive nature of the tumor, that were confirmed on biopsy specimen. drugs have the highest efficacy in treating adult and pediatric age groups in FISH analysis was performed in 4 patients using probes spanning the 1p36 published studies. METHODS: Building on a literature database of 581 and 19q13 regions but without discriminating results. Despite chemotherapy Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 patient cohorts and a total of 26429 patients, we performed a meta-analysis alone or combined with radiotherapy or partial surgery, the mean OS was 11 of HGG studies to evaluate the benefits of chemotherapeutic drugs. Median months. CONCLUSION: We define an homogenous entity of infantile survival gain was chosen as endpoint, as defined previously. This measure primitive GC with grey matter involvement. In such cases, it seems reason- reflects the difference of the observed median survival in a published able to perform tumoral biopsies, in order to undertake molecular studies patient group to the average outcome adopted for risk factors. It was calcu- and identify a biological profile that could lead to a better understanding lated separately for every published cohort. The means of the median survi- and better treatment. val gain from various studies were used to compare chemotherapy drugs. RESULTS: In adults we found that cohorts treated with regimes containing drugs Vincristine, Lomustine, ACNU, Procarbazine, and Cytarabine had a significant advantage with survival gains of 12.6, 11.2, 10.2, 9.7, and 8.5 months respectively (p ,0.001). On the contrary, in children, drugs ranks P-HGG.26. GIANT CELL GLIOBASTOMA OF CHILDHOOD very differently with Ifosfamide, Etoposide and Cisplatinum leading the L. G. Darrigo, Jr, M. Brassesco, E. T. Valera, M. Volpon, V. S. Silveira, list with survival gains of 17.3, 6.9, and 4.8 months respectively ( p , H. R. Machado, R. S. Oliveira, C. A. Scrideli, and L. G. Tone; School of 0.001). CONCLUSION: The efficacy of chemotherapeutic drugs differs Medicine of Ribeirao Preto. University of Sao Paulo, Ribeirao Preto, Brazil between adults and children. INTRODUCTION: Giant cell glioblastoma (GCG) is a rare and peculiar variant of glioblastoma multiforme (GBM). Clinically, despite the poor prognosis for GCG in most reports, this variant is associated with a longer survival compared with GBM. Little is known in regard to cytogenetic aber- P-HGG.24. GLIOBLASTOMA IN CHILDREN: A SINGLE rations in GCG. CASE 1: A 16-year-old female, presented with facial hypal- INSTITUTION EXPERIENCE gesia followed by tonic-clonic seizure. Magnetic resonance imaging (MRI) S. Perkins1, J. B. Rubin2, J. R. Leonard3, M. D. Smyth3, I. El Naqa1, disclosed multiple heterogeneous tumors in the frontal lobes. Biopsy was J. M. Michalski1, J. R. Simpson1, T. S. Park3, and D. B. Mansur1; undertaken and the diagnosis of GCG was established. The child received 1Department of Radiation Oncology, Washington University School of local radiotherapy. CASE 2: A 7-year-old female presented with weakness, Medicine, St Louis, MO, United States; 2Division of Pediatric Hematology headaches, vomiting and somnolence. MRI disclosed a large mass within and Oncology, Washington University School of Medicine, St Louis, MO, the left temporal lobe. Partial surgical resection was performed and the diag- United States; 3Department of Neurological Surgery, Washington University nosis of GCG was obtained. Following surgery, the child received Temodarw School of Medicine, St Louis, MO, United States plus local radiation. Cytogenetic analysis of tumor cultured cells by GTG-banding from case 1 showed a normal karyotype (46,XX). PURPOSE: Glioblastoma is a rare diagnosis in children. Current treatment Conversely, the analysis of chromosome metaphase spreads from case 2 recommendations include surgery, chemotherapy and radiation therapy. showed cytogenetic heterogeneity, with structural and numerical aberra- However, even with this multi-specialty approach, overall survival remains tions. No normal cells were found. The composite karyotype was denoted poor. To assess outcome and evaluate treatment related prognostic factors, as 45-48, X, -X [3], -6[3], -10[3], -13[3], -15[3], -22[3], +mar [9], [cp20]. we retrospectively reviewed the experience of our institution. METHODS DISCUSSION: Cytogenetic information on GCG is limited and controver- AND MATERIALS: Twenty-four glioblastoma patients under the age of 21 sial. While some groups have reported gains of chromosome material, were treated with radiation therapy with curative intent at Washington others have shown loss of several chromosomes, from which loss of chromo- University in Saint Louis since 1970. Patients underwent either gross total some 13 is the most recurrent. Our observations showed different cytoge- resection (GTR), sub-total resection (STR) or biopsy alone. Fourteen (58%) netic patterns for both patients which is in agreement with previous of patients received chemotherapy. All patients received radiation therapy. reports, where chromosome imbalances and aneuploidy were remarkable, Radiation consisted of whole brain radiation therapy (WBRT) in 7 patients particularly for chromosome 13. with a median dose of 5040 cGy. Seventeen patients received 3D-confor- mation radiation therapy with a median dose of 5400 cGy. RESULTS: Median follow-up was 12.5 months from diagnosis. One and 2-year overall survival were 57% and 32%, respectively. Median overall survival was 13.5 months. There was no difference in overall survival based on patients’ age, P-HGG.27. ANTIEPILEPTIC DRUGS (AEDS) INTERACTION race, gender, tumor location, radiation volume, radiation dose or the use of WITH AUTOLOGOUS PERIPHERAL CD341 BLOOD STEM chemotherapy. There was a significant improvement in overall survival for CELLS (PBSC) MOBILISATION IN A PEDIATRIC POPULATION patients in which a GTR was achieved (p ¼ 0.023). There were three patients WITH HIGH GRADE GLIOMA alive five years after GTR with two patients alive 10 and 24 years after diag- E. Schiavello1, V. Biassoni1, P. Coluccia2, S. Catania1, E. Barzano` 1, nosis. CONCLUSIONS: Survival for children with glioblastoma remains R. Luksch1, F. Spreafico1, F. Ravagnani2, and M. Massimino1; 1Fondazione poor. Data from this study and others demonstrate the importance of achiev- IRCCS Istituto Nazionale Tumori, Pediatric Oncology Unit, Milano, Italy; ing a GTR when possible. Continued investigation into new treatment options 2Fondazione IRCCS Istituto Nazionale Tumori, Immunohematology and is needed in an attempt to improve outcome for these patients. Transfusion Medicine Service, Milano, Italy

INTRODUCTION: According to our institutional protocol, patients ≤18 years old affected by high-grade glioma need PBSC harvesting after standard chemotherapy to be re-infused after high dose chemotherapy. Thereafter P-HGG.25. INFANTILE PRIMITIVE GLIOMATOSIS CEREBRI radiotherapy and maintenance phase are given. AEDs are widely used in INVOLVING GREY MATTER: A NEW ENTITY? RESULTS OF A patients with central nervous system malignancies being their toxicity on MULTICENTRIC STUDY OF 14 CASES haematopoiesis well known. The aim of this study was to evaluate the influ- C. Chappe´1, L. Riffaud1,C.Tre´guier1, B. Carsin-Nicol1, K. Chouklati1, ence of AEDs on autologous CD34+ mobilisation and harvest in pediatric S. Saikali1, J. Grill2, D. Frappaz3, N. Andre´4, F. Millot5, M. Vinchon6, and patients. MATERIALS AND METHODS: In 60 high grade glioma patients, C. Edan1; 1CHU Rennes, France; 2IGR, Paris, France; 3CLB, Lyon, France; CD34+ PBSC monitoring and harvest were conducted after the first cycle of 4CHU Marseille, France; 5CHU Poitiers, France; 6CHU Lille, France chemotherapy (cisplatin 40 mg/m2/d and etoposide 150 mg/m2/d x 3 days). Mobilisation with G-CSF (10 g/kg/d) started on day +7 from chemotherapy BACKGROUND: Gliomatosis cerebri (GC) is a rare neoplasia consisting beginning. 24/60 patients (40%) were taking AEDs during CD34+ moni- in a diffuse glial cell infiltration involving more than two cerebral lobes toring and harvesting, while the other 36 (60%) didn’t assume any AEDs,

NEURO-ONCOLOGY † JUNE 2010 ii75 Abstracts

being our control group. CD34 + /ml peak value, days from chemotherapy differentiates CNST survivors from controls. However, disability varies to apheresis and total CD34 + /kg harvested have been evaluated. significantly by domain of functioning, a finding that points out directions RESULTS: Patients taking AEDs had a significant lower harvest compared for an individualised surveillance that effectively addresses the needs of to the control group (9.3 x 106 vs. 13 x 106 CD34 + /kg; p ¼ 0.0238) and patients at increased risk for persistent late effects. a significant delay in stem cell harvesting (day 11.4 vs. 10.6; p ¼ 0,008). No difference was observed in median CD34 + /ml peak value between the two groups (112 vs. 134; p ¼ 0,43). CONCLUSIONS: For the first time we demonstrate AEDs delaying mobilisation and reducing number of CD34 + /kg harvest, thus suggesting a damage on haematopoietic stem P-PSY.03. HIT-SKK2000: BEHAVIORAL AND FUNCTIONAL cells. Autologous hematopoietic stem cell rescue was anyway feasible with PROBLEMS OF YOUNG CHILDREN WITH an adequate PBSC amount in all patients. MEDULLOBLASTOMA AND EPENDYMOMA 5 YEARS AFTER DIAGNOSIS S. Frahsek1, S. Rutkowski2, A. Faldum3, and H. Ottensmeier1; 1University Children’s Hospital, Wu¨ rzburg, Germany; 2Department of Pediatric P06 NEUROPSYCHOLOGY Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Germany; 3Institute of Medical Biostatistics, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Epidemiology and Informatics, University Medical Center of Mainz, P-PSY.01. NEUROCOGNITIVE CONSEQUENCES OF Germany TREATMENT FOR PEDIATRIC BRAIN TUMORS; A META-ANALYSIS BACKGROUND: Behavioral problems and deficits of health status includ- M. A. de Ruiter1, J. Oosterlaan2, A. Y. N. Schouten - van Meeteren1, ing everyday skills are reported in survivors of medulloblastoma and ependy- M. A. Grootenhuis1, and R. van Mourik2; 1Emma Children’s Hospital moma. We present the results of 55 children diagnosed between January AMC, Amsterdam, Netherlands; 2VU University, Amsterdam, Netherlands 2001 and March 2005 less than 4 years of age, treated according to the HIT 2000 protocol. At the time of assessment, median age of all children OBJECTIVE: Many studies report poor neurocognitive functioning in was 7.6 years (5.4-9.7). Forty four children without relapse (3 children pediatric brain tumor survivors (PBS) resulting from neurotoxicity, particu- with HDCT) were assessed at a median of 4.8 (4.2-6.7) years after larly in terms of intelligence and attention. Goal of this meta-analysis is to surgery, and 11 children with one relapse after 5.2 years (4.4-6.2). estimate the magnitude of deficits in intelligence and attention after treat- METHODS: Parents completed questionnaires of behavioral functioning ment. METHODS: This meta-analysis includes studies reporting on PBS in (CBCL), health status (Fertigkeitenskala Muenster-Heidelberg, FMH), and the age range 6 to 16 years, assessed with the Wechsler Intelligence Scale a semi-structured interview on behavioral and physical deficits of the for Children-III (WISC-III), or the Conner’s Continuous Performance Test patients. RESULTS: In the group of patients without relapse, severe behav- (CPT). From the databases PubMed, Web of Science and Embase, 27 ioral psychosocial difficulties were reported in 24% of the children. studies were retrieved. A total of 623 children were included for the Children with medulloblastoma were more affected (35%) than children WISC-III and 372 children for the CPT. Meta-analytic effect sizes were cal- with ependymoma (14%). In the relapse-group, the rate of behavioral and culated separately for full scale IQ (FSIQ), verbal IQ (VIQ), performance IQ psychosocial deficits was 20%. Health status was below average in 16 % (PIQ), errors of omission (inattentiveness), errors of commission (impulsiv- of the children without relapse. Again more patients with medulloblastoma ity), and hit reaction time (processing speed). RESULTS: PBS performed showed these deficits (29%) compared to patients with ependymoma (6%). below average on all 3 scales of the WISC-III: effect sizes for both FSIQ In the group of patients with relapse the rate was 30%. In semi-structured and PIQ are large (d ¼ -1.1), and for VIQ medium (d ¼ -0.7). On the CPT interviews, most parents and children of all groups named specific physical PBS showed slower processing speed; (d ¼ -0.7) and poorer attentiveness and social deficits. CONCLUSION: Higher rates of behavioral problems (d ¼ -1.0) than average, while scores on impulsivity are within the average and diminished health status were reported in survivors of medulloblastoma range. CONCLUSIONS: This meta-analysis highlights the negative neuro- than in survivors of ependymoma. Additional monitoring of these children cognitive effects of treatment for pediatric brain tumors. Inhibition seems may provide more information of deficient everyday life skills. unaffected; however, treatment has a major effect on intellectual functioning, attention and processing speed. Since these deficits are a risk factor for poor academic achievement and quality of life, it is of utmost importance to develop and evaluate interventions to improve neurocognitive functioning P-PSY.04. NEUROPSYCHOLOGICAL PROFILES IN PEDIATRIC ONCOLOGY PATIENTS: AN APPROXIMATION TO COMPLEX INFLUENCE OF PERSONAL AND CLINICAL VARIABLES J. Bernabeu1,2,3, A. Can˜ ete1, J. Suarez2, G. Almerich2, C. Fournier4, and 1 1 P-PSY.02. POPULATION-BASED FUNCTIONAL OUTCOMES V. Castel ; Pediatric Oncology Unit, University Hospital La Fe, Valencia, 2 AND DOMAINS OF DISABILITY IN ADULT SURVIVORS OF Spain; Research Methods and Diagnosis in Education, University of 3 CHILDHOOD AND ADOLESCENT CENTRAL NERVOUS Valencia, Valencia, Spain; Brain Injury Unit, El Carmen-Red Menni, 4 SYSTEM CANCER Valencia, Spain; Psychiatry and Psychology Unit, University Hospital Ninõ K. K. Boman1, E. I. Hoveń1, M. Anclair1, B. Lannering2, and G. Gustafsson1; Jesus, Madrid, Spain 1Karolinska Institutet, Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Stockholm, Sweden; 2University of INTRODUCTION: The increasing survival rate of pediatric oncology Gothenburg, Department of Pediatrics, Pediatric Oncology, Gothenburg, patients introduced the study of neurocognitive sequelae through neuropsy- Sweden chological examinations and imaging (focal damage in both white and grey matter, related to brain maturation stages). METHOD: One hundred and PURPOSE: To study and present long-term functional outcomes and eighteen children were assessed: 65% CNS tumor, 35% leukemia. 44% domains of disability in adult survivors of childhood central nervous treated with RT (11% leukemia, 33% CNS tumor). The mean age was 7 system tumours (CNST). METHODS: The study cohort nationally covered years (range 0-19). Clinical variables were pathology, RT, age at diagnosis, 710 patients at least 18 years old, for whom 5 years or more had passed time since diagnosis, and sex. A comprehensive neuropsychological protocol since diagnosis. Nation-wide data collection targeted 708 CNST survivors, was performed, including 54 cognitive measures, psychopathology 708 parent proxies, and 2500 general population controls. Functional dis- (Achenbach), executive functions (BRIEF), and attention (Conners CPT-II). ability, sensory and cognitive impairment, emotional status, and pain was Statistical analyses (univariate, discriminant analysis, Logistic regression assessed using the Health Utilities Index Mark 2/3. In main analyses and Categorical Principal Components Analysis) were carried out by using patient and control outcomes were contrasted, and within patient group ana- SPSS 17.0 package. RESULTS: 1. CNS tumor: generalized deficit related to lyses diagnostic subgroups were contrasted to identify the relative risk for more time elapsed and early age at diagnosis. Patients with RT are more late-effects by sub-diagnosis. RESULTS: Compared to controls, CNST survi- affected. Less psychopathology from less awareness of deficit. 2. LLA: vors had persistent disability in the domains of sensation, mobility, self-care, focal deficit in VIQ, receptive language, working memory and attention and cognition, while emotional and pain outcomes were similar. Patients related to: early age at diagnosis, more time elapsed and female. 3. LLA treated for medulloblastoma, germ cell CNS-tumour, and other glioma RT: the same deficit areas as LLA with worse scores. Leukemia patients (including oligodendroglioma and other unspecified, excluding astrocytoma) show mild difficulties in receptive language, working memory and attention most frequently suffered from late-effects. Lowest disability was found for that can determine academic, social and work functioning. Older age at diag- the other specified/unspecified CNST (incl. nerve sheath tumours), and nosis is a good protection against neurocognitive deficit in CNS pathologies, astrocytoma (mostly low-grade) groups. CONCLUSIONS: The group-level not in leukemia patients. CONCLUSIONS: These learning difficulties are persistent disability in adult CNST survivors significantly exceeds that of often attributed to parental overprotection or absenteeism due to illness. non-clinical comparisons of the community. Late-effects involve multiple Imaging and neuropsychological studies reveal the complex origin of these domains including sensory and motor functioning, cognition, and deficits (brain maturation, age, chemo), allowing us to dismiss false speech. The portion presenting with severe disability particularly attributions. ii76 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-PSY.05. DEVELOPMENT AND PSYCHOMETRIC PROPERTIES P-PSY.07. COGNITIVE LATE COMPLICATIONS AFTER OF THE PARENT-REPORTED PEDIATRIC PERCEIVED PEDIATRIC BRAIN TUMOR IN A CLINICAL SAMPLE RELATED COGNITIVE FUNCTION ITEM BANK TO PREDICTING FACTORS J. Lai1, Z. Butt1, F. Zelko2, D. Cella1, and S. Goldman2; 1Northwestern I. Tonning Olsson and J. Lundgren; Department of Paediatrics, Lund University, Chicago, IL, United States; 2Children’s Memorial Hospital, University, Lund, Sweden Chicago, Chicago, IL, United States Cognitive late complications (CLC) are common among children treated OBJECTIVE: This paper reports the development and psychometric prop- for brain tumors, especially difficulties with attention, tempo, executive erties of a parent-reported pediatric perceived cognitive function item bank functions, and memory. CLCs are multidetermined, depending on the (pedsPCF-IB). METHODS AND RESULTS: PedsPCF items (n ¼ 45) were child’s age at diagnosis, type of treatment given, localisation of the field-tested with 1,409 parents (60% mothers, average age ¼ 40) of children tumor, neurological complications, and presence of a syndrome. Low age aged 7-17 (57% male, average age ¼ 12.8y, 29.3% with neurological diag- at diagnosis and cranial radiation therapy (CRT) are the factors most con- nosis). Items were developed via literature review and interviews with chil- sistently shown to have a negative impact on cognition. In this study clinical dren, parents, clinicians, and teachers. The final pedsPCF item bank neuropsychological data collected during the years 1995-2006 (n ¼ 70) consisted of 43 unidimensional items and did not demonstrate item bias were reviewed and compared with the data of the whole population; all (i.e., no differential item functioning). The information function of the children living in the south of Sweden diagnosed 1993-2004, surviving Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 pedsPCF-IB was estimated using item response theory and converted into more than one year (n ¼ 136, including the 70 examined patients). The reliability functions. Results showed PCF scores to be reliably measured examined group of patients was considered representative, but included with 92% at r . 0.90. Receiver operating characteristic curves were used more girls, more malignant tumors, more intensive treatment, more recur- to evaluate how well the pedsPCF-IB predicted diagnosis of attention rences and a higher frequency of high intracranial pressure at diagnosis deficit disorder (ADD) and clinical range of parent-report Child Behavior compared to the whole population. Of the whole population, a quarter Checklist (CBCL) problems scores. Acceptable accuracy was supported, had mental retardation or was borderline to it. Predicting factors for cogni- area under curve ¼ 0.83, 0.92, 0.86 and 0.77 for ADD, attention problems, tive late complications (CLC) were age, size of tumor at diagnosis, and social problems and thought problems, respectively. Accordingly, cut-off growth hormone replacement therapy (GHRT). Treatment with CRT was scores (in T-score unit: M ¼ 50 and SD ¼ 10) were estimated using discrimi- not a predicting factor. The examined children had generally suppressed nant function analysis, which were 59.9, 59.4, 58.0 and 60.8; specificity at IQ and difficulties with cognitive processing speed, executive functions, the corresponding cut-off scores was .0.9 while sensitivity ranged from and memory and were sensitive to cognitive overload. Boys had more diffi- 0.40-0.68. CONCLUSIONS: The pedsPCF-IB posses sound psychometric culties than girls. This study questions the main detrimental role of CRT, properties, with good reliability and acceptable prediction accuracy for clini- since CRT was not a predicting factor of unfavorable cognitive outcome. cal problems areas. US general population based norms are available. Future The need for GHRT was a more accurate prognostic factor for CLC applications include a PedsPCF computerized adaptive testing platform, to than CRT. allow brief-yet-precise measurements that would be practical in a clinic setting.

P-PSY.08. IMPACT OF CEREBELLAR TUMOUR INJURY SUSTAINED IN EARLY CHILDHOOD ON MOTOR AND P-PSY.06. PRETREATMENT NEUROPSYCHOLOGICAL COGNITIVE DEVELOPMENT: A LONGITUDINAL STUDY DEFICITS IN CHILDREN WITH BRAIN TUMORS E. E. Davis1, N. J. Pitchford1, T. Jaspan2, and D. Macarthur3; 1University of L. Iuvone1, L. Peruzzi2, C. Colosimo3, A. Ruggiero2, G. Tamburrini4, Nottingham, Nottingham, United Kingdom; 2University of Nottingham M. Caldarelli4, C. Di Rocco4, A. Di Giannatale2, D. Battaglia5, F. Guzzetta5, Hospital, Nottingham, United Kingdom; 3University of Nottingham S. Misciagna6, and R. Riccardi2; 1Unit of Child Neuropsychiatry, Hosptial, Nottingham, United Kingdom Fondazione Don Gnocchi, Centro Santa Maria della Pace, Rome, Italy; 2Division of Pediatric Oncology, Catholic University - A. Gemelli Hospital, BACKGROUND: Motor and cognitive impairment is common following Rome, Italy; 3Institute of Radiology, Catholic University - A. Gemelli cerebellar tumor injury in early childhood but the extent to which recovery of Hospital, Rome, Italy; 4Unit of Pediatric Neurosurgery, Catholic University - function can occur is unclear due to a paucity of longitudinal investigations. A. Gemelli Hospital, Rome, Italy; 5Division of Child Neuropsychiatry, AIMS: To determine the longitudinal impact of early cerebellar tumor injury Catholic University - A. Gemelli Hospital, Rome, Italy; 6Unit of on motor and cognitive development. METHODS: Twelve patients (4-14 Neurological Rehabilitation, Fondazione Don Gnocchi, Centro Santa Maria years) with cerebellar tumor injury sustained before 5-years-of-age were each della Pace, Rome, Italy given a comprehensive standardised test of motor and cognitive skill. Tests were re-administered on two further occasions, separated by six months. To BACKGROUND: Treatment of childhood brain tumor (BT) has often measure the effect of practice on these tests, patient performance was compared been associated with long-term cognitive morbidity in children. Cognitive tothatof 41 typically-developing children who were given these teststwice, over sequelae may differ as a function of surgery, radiotherapy, chemotherapy, a minimal interval of 10 months. RESULTS: Significant impairment to either tumor, and tumor-related factors (T-FR). OBJECTIVES: We investigated motor (5/12) and/or cognitive (4/12) skill was found although not all patients the cognitive status of children with primary BT before any treatment in were impaired. This illustrates that cerebellar injury can have differential effects order to evaluate the role of the tumor and the T-RF (tumor site, on motor and cognitive development within and across individuals. Reliable volume, edema, brain herniation, hydrocephalus, intracranial hypertension) predictors of outcome were age at diagnosis and tumour type/treatment. in determining neuropsychological deficits (ND). METHODS: Patients with Over time, significantly more patients demonstrated improvement in cognitive previous developmental difficulties and multiple tumor sites were excluded. (10/12) than motor (4/12) skill. Furthermore, a greater extent of improvement Intelligence and sectorial cognitive abilities were evaluated. Cognitive was found for cognitive (mean gain ¼ .5 SD) than motor (mean gain ¼ .25 SD) results were compared with clinical characteristics related to patient (symp- ability. As this difference was not observed in typically-developing children it toms duration, neurological status, epilepsy) and T-FR obtained by mag- cannot be attributed to practice effects. CONCLUSIONS: Rehabilitation netic resonance imaging. RESULTS: Eighty three patients (53 males, 30 should be targeted at both domains. Greater improvement in cognitive func- females) with newly diagnosed BT completed tests before any treatment. tioning is likely to occur, however rehabilitation for motor skills may be particu- The mean age at diagnosis was 103 months (range 7-200 months). The larly necessary given the lack of improvement over time. tumor location was supratentorial hemispheric in 45.8%), supratentorial midline in 25.3%, and posterior cranial fossa in 28.9%. Cognitive difficulties were detected at diagnosis in a percentage of children that attains to 50% in some cognitive domain; 6% of patients presented mental retardation. Tumor location was the principal determinant of ND. Symptoms P-PSY.09. INTERRELATION OF COGNITIVE AND MOTOR duration and epilepsy were significantly associated with ND. FUNCTIONING FOLLOWING CEREBELLAR TUMOUR INJURY Neuroradiological T-RF were not clearly correlated with cognitive data. SUSTAINED IN EARLY CHILDHOOD CONCLUSIONS: ND are present at diagnosis in a considerable number E. E. Davis1, N. J. Pitchford1, T. Jaspan2, D. MacArthur2, and D. Walker1,3; of children. Knowledge of the pre-existing ND is critical to evaluate the 1University of Nottingham, Nottingham, United Kingdom; 2University of results of treatment, providing a baseline to assess the impact of therapy Nottingham Hospital, Nottingham, United Kingdom; 3Universtiy of in determining cognitive decline. Supported by Association Ali di Scorta, Nottingham Hospital, Nottingham, United Kingdom Fondazione Oncologia Pediatrica BACKGROUND: The cerebellum is increasingly recognised as participating in both motor and cognitive functioning. Whilst development of these domains has traditionally been studied independently, emerging evidence from both atypically- and typically-developing children suggests these domains are associated across childhood. AIM: To determine the extent of

NEURO-ONCOLOGY † JUNE 2010 ii77 Abstracts

interrelation across motor and cognitive development and the role of the cer- neuropsychological methods, e.g. Wechsler Intelligence Scale, Benton ebellum in this relationship by investigating the nature of association follow- Visual Retention Test, L. Bender, E. Koppitz Visual Motor Test, analysis ing early cerebellar tumour injury compared to that of typically-developing of previous educational career and medical history. RESULTS: In our children. METHODS: Fifteen patients (4-11 years) with cerebellar tumor series we observed specific cognitive development, as well learning disability. injury sustained before 5-years-of-age and 248 typically-developing children Some of these symptoms are similar to developmental or acquired dyslexia, were recruited. Each completed a standardised battery of motor and cogni- but also have differential features. Scheme of specific neuropsychological tive tests. These yielded an overall cognitive and motor ability index and diagnostic procedures including differential and comorbid symptoms of cog- scores on broad ability levels within each domain. RESULTS: A high nitive deficits and dyslexia, as well recommendation for psychological reha- degree of association was found across domains, and the interrelation bilitation for childhood brain tumor survivors will be presented and between motor and cognitive development was comparable across the discussed. patient (r ¼ .597, p ¼ .017) and control (r ¼ .508, p ¼ .001) groups. In addition significant, positive correlations were found between many of the broad ability areas, and the pattern of association was similar for both groups. Finally, a principal component analysis suggested that visual processing and fine manual skills largely mediate the interrelation between motor P-PSY.12. MIND-READING AND RELATIONAL COMPETENCE and cognitive development. CONCLUSION: Seemingly, motor and cogni- IN CHILDHOOD BRAIN TUMOR SURVIVORS Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 tive skills are tightly bound across childhood. Early insult to the cerebellum A. Adduci1, E. Sironi1, M. Zettin2, G. Geminiani2, S. Strazzer1, C. Clerici3, can lead to these skills being compromised resulting in delayed development. M. Massimino3, and G. Poggi1; 1IRCCS E. Medea, Bosisio Parini (Lecco), However, the nature of association between motor and cognitive develop- Italy; 2Universita` degli Studi di Torino, Turin, Italy; 3National Tumor ment is unaffected by early cerebellar injury, resulting in a qualitatively Institute, Milan, Italy typical developmental pathway. INTRODUCTION: It is assumed that mind-reading ability in brain tumor survivors can be compromised and that these difficulties could contribute to the onset of relational problems, together with mood disorders and personal autonomy problems. The relational competence and mind-reading abilities P-PSY.10. ACADEMIC ATTAINMENT IN RELATION TO IQ of a group of childhood brain tumor survivors were explored and compared FOLLOWING INJURY FROM CEREBELLAR TUMOUR with those of a group of post-traumatic children. METHODS: All the SUSTAINED IN EARLY CHILDHOOD patients (42 brain tumor survivors, 16 post-traumatic patients), age 4-14 E. E. Davis1, N. J. Pitchford1, and D. Walker2; 1University of Nottingham, years (time from brain lesion: 12-24 months, IQ ¼ .75) received a protocol Nottingham, United Kingdom; 2University of Nottingham Hospital, including the WISC-R, the Child Behavior Checklist as well as emotional and Nottingham, United Kingdom cognitive role-taking tests. The relationship between the testing results and the clinical and demographic data was analyzed. RESULTS: Besides the cog- BACKGROUND: Poor scholastic attainment is common following cer- nitive impairment and relational difficulties, brain tumor survivors did not ebellar tumor in childhood. However, it is not clear if impairments in specific perform well on cognitive-emotional role-taking tests, even though the per- academic skills, such as literacy and mathematics, are underpinned by more formance of post-traumatic children was poorer. These difficulties are signifi- general cognitive difficulties, thus making it difficult to know where to target cantly more marked in children with supratentorial tumor, causing an rehabilitation. AIMS: To establish the extent of academic impairment, above impairment of relational and socialization skills, as in post-traumatic and beyond general cognitive processing, following cerebellar tumor injury patients. CONCLUSIONS: The results of this study suggest that a tailored during the preschool years. METHOD: Eleven children (aged 5-15 years) intervention geared to improving the cognitive-emotional role-taking skills were each given a comprehensive standardised academic achievement test along with a more traditional psychological support intervention can (Wechsler Individual Achievement Test - 2nd UK Edition; WIAT-II) together improve relational abilities and re-entry into community of children surviv- with a general measure of cognitive functioning (Wechsler Intelligence Scale ing a brain tumor. for Children - 4th Edition; WISC-IV). These measures enable individual performance on subtests of the WIAT-II to be predicted from IQ scores on the WISC-IV. RESULTS: Significant impairment in Reading, Mathematics and Written Language were found in 6/11 patients and Oral Language was affected in 4/11 children. IQ was significantly compromised for 7/11 P-PSY.13. FEASIBILITY OF NEUROFEEDBACK FOR REDUCING patients, being less than 2 SD from the test norm. IQ-achievement test discre- NEUROCOGNITIVE DEFICITS AFTER A CHILDHOOD BRAIN pancy analyses revealed significantly poorer performance than expected on TUMOR the basis of IQ in 6/11 children for Reading and Mathematics, 7/11 children E. Aukema1, M. de Ruiter1, B. Last1, N. Schouten2, R. Breteler3, for Written Language, and 3/11 children for Oral Language. Conversely, J. Hogeweg4, and M. Grootenhuis1; 1Psychosocial Department, Emma significantly better attainment than predicted on the basis of IQ was found Children’s Hospital, Academic Medical Center, Amsterdam, Netherlands; for 2/11 children in Reading, 0/11 children for Mathematics, and 1/11 chil- 2Department of Pediatric Oncology, Emma Children’s Hospital, Academic dren for Written Language and Oral language skills. CONCLUSION: Medical Center, Amsterdam, Netherlands; 3EEG resource Institute, Academic attainment can dissociate from IQ in this population so rehabilita- Nijmegen, Netherlands; 4Pels Institute, Amsterdam, Netherlands tion needs to be targeted to specific individual needs. BACKGROUND: Survivors of a childhood brain tumor experience neurocognitive deficits, including decreased processing speed, attention and memory, resulting in problems with learning and social functioning. Therefore, the need for effective cognitive rehabilitation possibilities in this P-PSY.11. COGNITIVE PROBLEMS OR DYSLEXIA IN PATIENTS group of survivors is high. There is growing evidence that neurofeedback, WITH CHILDHOOD BRAIN TUMORS - DIFFERENTIAL a ‘brain wave’ feedback training in which the brain activity is regulated, is DIAGNOSES OR COMORBID DISORDERS? a valuable treatment for children with brain disorders (e.g. ADHD, epilepsy, J. Korzeniewska, B. Dembowska-Bagin´ ska, M. Perek-Polnik, TBI) and could be helpful for pediatric brain tumor survivors. In this pilot M. Drogosiewicz, and D. Perek; Pediatric Oncology Department, The study we explored the feasibility and neurocognitive impact of neurofeed- Children´ s Memorial Health Institute, Warsaw, Poland back. PROCEDURE: Seventeen survivors with cognitive problems were invited to join this pilot-study. Before starting the training a quantitative elec- SUBJECT: Neurological and cognitive problems are frequent late effect troencephalogram (QEEG) was made and a neurocognitive assessment was associated with childhood brain tumors. Low IQ, eye-motor coordination performed. The QEEG and assessment were repeated after 30 training ses- and lateralization disturbances, grapho-motor development delay, speech, sions. RESULTS: Neurofeedback treatment plans were generated based on memory and attention disabilities are most commonly registered. Most of each participant’s QEEG profile. Nine survivors (mean age 16.96 years, 4 them are also specific symptoms of developmental or acquired dyslexia. female/5 male) completed the 30 training sessions. No side-effects of the train- For that reason, in many patients dyslexia is over diagnosed. It is more coming were reported, although the sessions were perceived as tiring and time- plicated, because dyslexia is thought to be the result of a specific neurological consuming. Most parents and survivors were positive towards the intervention. defect, not an intellectual disability. PURPOSE: The aim of the study was to Comparison of the neurocognitive assessment pre- and post Neurofeedback assess neuropsychological status of survivors of childhood brain tumors and seems to indicate improved speed of processing. Attention scores seem to to identify coexisting and differential symptoms of cognitive consequences of remain unaffected. CONCLUSIONS: The pilot study indicates that neurofeed- brain tumors and developmental or acquired dyslexia. PATIENTS: back is a feasible intervention for childhood brain tumor survivors, although Psychological testing was performed in 350 childhood brain tumor survivors the impact of the intervention is not clear yet. The effectiveness of neurofeed- (various type and localization of tumor). Age at psychological diagnosis: back is currently under investigation in a double blinded randomized controlled 6-26 years. METHODS: In each case intellectual and educational abilities trial called the PRISMA study. in each case were evaluated several times (usually yearly). The patients were examined using a battery of standardized psychological and ii78 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-PSY.14. CLINICAL APPLICATION OF THE ICF-BASED 651 high risk diagnosis pediatric brain tumors presented to our center, SCHOOL PARTICIPATION SCALES (SPS) IN CHILDREN WITH eight of whom had abruptly collapsed. They had profound neurologic BRAIN TUMORS deterioration requiring ventilatory and cardiovascular support. 5 of the 8 T. Pletschko1, S. D. Khoss2, S. Gmoser2, L. Leeb2, I. Slavc1, and U. Leiss1; children died from neurologic devastation within a matter of days. 7 of the 1Medical University of Vienna, Vienna, Austria; 2University of Vienna, 8 children had a posterior fossa mass and hydrocephalus. Of the 3 who sur- Vienna, Austria vived, two had long term morbidity following the event. In review of these children’s records, a concerning management pattern emerged. Most had PURPOSE: As survival rates of pediatric CNS-tumors rise due to better treat- had symptoms lasting at least one month and as long as 2 years. All had ment options, research on late effects becomes an important issue. Long-term an acute escalation of symptoms just days prior to the final presentation. sequelae affect many areas of the child’s life, especially school reintegration All but 2 of the 8 were given large volumes of IV fluids shortly before their after treatment. Consequentially, it seems essential to develop instruments rapid decline. Of the two who did not receive IV fluids, one, being trans- that are able to describe how these children can participate in everyday life. ported by private vehicle, herniated en route to our center and the other suf- Therefore, the purpose of this study is to investigate functions that are needed fered an acute hemorrhage into the tumor. It is important to recognize that in order to fully manage school after treatment for a neurooncological pediatric brain tumors can present with a rapid neurologic deterioration that disease. METHODS: To investigate the resources and deficits in school life, a can, at times, be worsened by medical interventions. Symptoms of headache, questionnaire based on the International Classification of Functioning, vomiting, and neurologic signs warrant imaging of the brain prior to initiat- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Disability and Health (ICF) was developed. The School Participation Scales ing any management therapy, and IV fluids must be used judiciously. (SPS) include versions for pupils, parents and teachers, providing a comprehensive view. The single items meet different (neuropsychological) functions as listed in the ICF (e.g. dividing attention, working memory) and describe them using everyday language. Additionally, data from the neuropsychological assessments of the patients were recorded. RESULTS: The sample consists of P-MULTI.03. PSYCHOSOCIAL ASPECTS OF TWO CHILDREN 45 school-aged children (patients during neurooncological aftercare), 49 WITH DIFFUSE BRAINSTEM GLIOMA: A DELAYED DIAGNOSIS, parents and 39 teachers. Testtheoretical analyses show high quality of all ver- AND REWARDING PALLIATION WITH RADIOTHERAPY sions regarding reliability/validity scores. Clinical application shows that L. Schindler, S. Edelman, Z. Zochovoy, I. Zetzerov, E. Mandel, R. Elhasid, parents, teachers and pupils rate functions like dividing attention, handling and R. Dvir; Tel-Aviv Sourasky Medical Center, Tel_aviv, Israel stress, psychomotor control etc. to be the most severe problems in school integration. DISCUSSION: According to testtheoretical data and clinical appli- AIM: To describe psychosocial aspects of the presentation of two children cation, the SPS are a reliable, valid and useful tool for investigating problems with Diffuse Brainstem Glioma (BSG), and the importance of radiotherapy that can occur during school integration. The SPS integrate different perspec- to the families. CASE 1: A 4-year old girl complained a year before diagnosis tives and can therefore result in immediate (neuropsychological) interventions. of nonspecific signs: frequent urination, behavioral changes, sadness, and sleep disturbances. The mother, a nurse, felt intuitively that there was a problem and began consulting numerous doctors from many disciplines without reaching a diagnosis. The mother was very active in pursuing P07 MULTIDISCIPLINARY APPROACH TO THE every clue to a disease, and was not properly guided by a primary physician. PATIENT AND FAMILY Each doctor felt as a consultant and was not aware of the whole clinical setup, and did not follow up the case. Eventually the complaints worsened, and a pediatric neurologist found somnolence, long tract signs, and a diagnosis of BSG was established. Upon diagnosis the girl looked drowsy and P-MULTI.01. CLINICAL GUIDELINES FOR THE AVOIDANCE OF depressed, but did not complain of headaches or vomiting. Radiotherapy INFECTIOUS COMPLICATIONS OF OMMAYA RESERVOIRS to the tumor had a dramatic effect on her well being and most of her com- DURING LONG TERM USE EXPERIENCE WITH 3570 DRUG plaints resolved. CASE 2: An 8-year old boy whose complaints started APPLICATIONS IN 74 CONSECUTIVE PATIENTS about a year prior to diagnosis. He had abdominal pain and vomiting R. Weinhapl, S. Huber, A. Peyrl, and I. Slavc; Medical University of Vienna, without headaches. Helicobacter pylori was found and approriate treatment Department of Pediatrics, Vienna, Austria given. Eventually he developed depression and apathy and imaging revealed BSG. CONCLUSIONS: Both cases had prolonged misleading clinical symp- BACKGROUND: The Ommaya reservoir is a pharmacologically rational toms and delayed diagnosis. Behavioral changes and nonspecific complaints system for administering intrathecal chemotherapy and facilitates repetitive should arouse suspicion of a brain tumor. Families can enjoy a "honey- delivery of drugs into the CSF. However, previous studies have found a moon" after radiotherapy despite the dismal prognosis of BSG. rate of infection ranging from 4.8 to 19%. METHODS: Between 1992 and 2009, 74 patients aged 4 months to 18 years with various poor prognosis brain tumors received 3570 administrations of intrathecal chemotherapy via an Ommaya reservoir. All patients received perioperative antibiotics. Only personnel undergoing a special training are allowed to administer the P-MULTI.04. NEUROPSYCHOLOGICAL AND QUALITY OF LIFE intrathecal therapy. During the procedure nobody is allowed to enter or OUTCOMES OF PATIENTS WITH NEUROFIBROMATOSIS AND leave the treatment room. The procedure is performed under aseptic tech- OPTIC PATHWAY GLIOMAS WHO WERE TREATED WITH AND nique, including hand disinfection, mask, and sterile gloves. If necessary, WITHOUT RADIATION THERAPY - NURSING the puncture site is shaved immediately before usage. After appropriate CONSIDERATIONS sterile preparation of the reservoir site, all necessary equipment is prepared T. Dahlheimer1 and A. Kunin-Batson2; 1University of Minnesota, under aseptic conditions on a sterile drape (butterfly scalp vein set, syringes, Department of Pediatrics, Division of Hematology, Oncology, Blood and intraventricular drug, artificial CSF). The reservoir is punctured with a but- Marrow Transplantation, Minneapolis, MN, United States; 2University of terfly scalp vein set, and a minimal volume of 5 mL CSF is removed and used Minnesota, Department of Pediatrics, Division of Pediatric Clinical for routine examination. The diluted drug is injected and the reservoir is Neuroscience, Minneapolis, MN, United States flushed with 5 ml of artificial CSF. RESULTS: Only one infection of the Ommaya reservoir with Staphylococcus epidermidis occurred in a 7-year BACKGROUND: This retrospective study examined neuropsychological old girl. The infection resolved with intensive intravenous and intrathecal data from patients with neurofibromatosis and optic pathway glioma who vancomycin therapy. CONCLUSION: Use of Ommaya reservoirs is safe in were treated with and without radiation. METHODS: A retrospective immunocompromised children with brain tumors if physicians and nurses medical record review of 70 patients seen at the University of Minnesota administering the drug undergo special training, strictly adhere to antiseptic from 1982 to 2009. RESULTS: The cohort included a convenience sample guidelines, and systemic antibiotics are used perioperatively. of patients that was elucidated from the comprehensive medical record review noted above and were included if they had a diagnosis of Optic glioma, Neurofibromatosis type 1 and completed neuropsychological testing as part of their standard of care. The radiation sample included 8 P-MULTI.02. CATASTROPHIC PRESENTATIONS IN PEDIATRIC patients who received radiation therapy as part of their treatment for their BRAIN TUMORS Optic gliomas. The average radiation dose was 5096 cGy (ranging from P. L. Batchelder, N. K. Foreman, J. Madden, C. Wilkinson, and M. Handler; 5040 cGy to 5400 cGy). The average age at treatment was 10.8 years The Childrens Hospital and the University of Colorado, Aurora, CO, United (ranging from age 4 to age 23). Half of the subjects had neuropsychological States testing prior to their radiation treatment. There were 22 patients in the non- irradiated sample who had documented neuropsychological testing. The Children with brain tumors are notoriously difficult to recognize among Verbal IQ, Performance IQ, Full scale IQ, Working Memory Index, the four the myriad of others with similar symptoms. Furthermore, some may indexes of the TOVA and fine motor speed bilaterally as well as other areas deteriorate quickly and catastrophically. We retrospectively reviewed our were examined in these two groups. CONCLUSION: Two case studies of chil- records between 1997 and 2010 for such events. During this time period, dren with Neurofibromatosis and Optic glioma who received radiation and

NEURO-ONCOLOGY † JUNE 2010 ii79 Abstracts

were longitudinally tested are presented. The similarities and differences of the poor prognosis. Communication about prognosis and advanced care plan- patient cohorts who received radiation and those who did not are reviewed ning is critical to empowering parents to make decisions about PC/EOL and recommendations are made for comprehensive care for these patients. for their children. A single-group study to refine and pilot test a PC/EOL Quality of Life findings and nursing implications are discussed. communication intervention is entitled, Communication Plan: Early through End of Life (COMPLETE). COMPLETE is designed to be delivered during parent meetings and features: (a) a physician-nurse (MD/RN) team approach to PC/EOL communication; (b) printed visual aids and parent P-MULTI.05. PARTICIPATION OF CHILDREN IN RESEARCH resource forms; and (c) hope and non-abandonment messages tailored by a WITH MAGNETIC RESONANCE IMAGING MD/RN team to their communication style and parental preferences for A. Y. N. Schouten - van Meeteren, E. A. Aukema, and M. A. Grootenhuis; information. During Phase I, an interdisciplinary approach involving Emma Children’s Hospital AMC, Amsterdam, Netherlands nurses, physicians, PC/EOL expert consultants, and bereaved-parent consultants met to develop a standardized protocol and training procedures. BACKGROUND: MRI is increasingly used to study children with a brain During Phase II, this protocol will be evaluated with 24 parents and MD/ tumor and late effects and voluntary age-related controls are necessary to RN teams. We will evaluate parental outcomes regarding the cooperate. Aim of study: To investigate if children are able to decide about par- COMPLETE’s influence on: (a) information needs, emotional needs/ resources, appraisal of MD/RN information and of symptom management; ticipation as a volunteer in medical research with MRI with age-specific coach- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 ing and how they judge the burden of participation. PATIENTS AND and (b) parental distress, uncertainty, decision regret, hope, satisfaction with METHODS: Children participating in medical research with MRI scan of 20 MD/RN communication, and advance care planning over time. Findings minutes were coached by a play-therapist and according to the guideline of from this study address NIH priorities related to: 1) an underserved popu- the Dutch Association of Pediatrics. A structured questionnaire before and lation (i.e., parents of children with brain tumors); 2) an under-examined after MRI was administered about their experience in the MRI and partici- ethical concern about early integration of PC/EOL communication for pation in research. RESULTS: Thirty children 8,8-17 years (mean 13,5) partici- parents of children with poor prognosis; 3) improved communication pated in the study after giving informed consent. For 23 children this was their about PC/EOL among physicians, nurses, and parents; and 4) the potential first experience with MRI. The illustrated information leaflet was read by 27 for changing health care practice. out of 30 children. All children judged themselves capable of the decision to have a MRI-scan. They described the experience on 5-points scales with mean scores for interesting 4,2; exciting 4,0 and scary 2,0. Three children would not repeat a MRI (two due to noise and one was too frightened). Twenty-nine children stated that MRI participation in medical research P-MULTI.08. END OF LIFE FOR PEDIATRIC BRAIN TUMOR could be asked from any child. Most children had altruistic reasons to partici- PATIENTS: STANDARDIZING COMMUNICATION ACROSS pate, arguing that their effort might benefit others (mean score 4,6). DISCIPLINES TO PROVIDE PROPER CARE CONCLUSION: Children above 8 years of age consider themselves capable H. N. Bess, M. T. Richey, E. O. Pickle, and A. A. Smith; University of to decide about voluntary participation in medical research with MRI and gen- Florida, Gainesville, FL, United States erally describe this as a positive experience. BACKGROUND: The World Health Organization defines palliative care as “an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impec- P-MULTI.06. ‘EVENINGS WITH NEURO-ONCOLOGY’: A cable assessment and treatment of pain and other problems, physical, MULTIDISCIPLINARY EDUCATIONAL/SUPPORT PROGRAM psychosocial and spiritual.” By definition, palliative care requires a multi- FOR PEDIATRIC BRAIN TUMOR PATIENTS AND THEIR disciplinary and comprehensive approach based upon input of multiple dis- FAMILIES ciplines. Previous research has shown ineffective communication as a barrier E. Z. Braly, A. E. Haggard, C. Williamson, K. Campbell, and J. C. Murray; which limits consistent and appropriate care. PURPOSE: Identify an effective Cook Children’s Medical Center, Fort Worth, TX, United States method to ensure optimal communication between multiple disciplines, ancillary services, and the family when a pediatric brain tumor patient The diagnosis of a pediatric brain tumor can have a profound effect on the reaches EOL. METHODS: We are conducting a retrospective chart review patient and their family. With great diversity in the types of tumors and their of approximately 50 now deceased patients who were followed by our treatment, parents often feel isolated and have little opportunity to network program from 2003 to 2009. Using this information we will identify with other families facing the same diagnosis. A review of the literature revealed system breakdowns and needs among terminal BT patients and create a stan- that little is known about the educational and support needs of this population. dardized EOL checklist and plan that: 1-is accessible by all staff involved, A multidisciplinary team collaborated to develop a support program for brain 2-clear and appropriate to each patient and his/her disease 3-is discussed tumor patients and their families. The program, “Evenings with between patient family and provider using two-way communication, and 4- Neuro-Oncology”, is held quarterly and includes a casual dinner, educational provides contact person within the neuro-oncology team for questions and and discussion sessions for parents and separate fun activities for patients and follow-up. RESULTS: Ensure that the implementation of appropriate and their siblings. Baseline and post-session evaluation surveys were completed by consistent EOL care specific to the pediatric BT patient has been communi- the families at each session. Forty evaluations were received from 3 sessions, cated to all staff in a multi-disciplinary environment thereby increasing staff representing 25 different families who attended at least one session. One comfort level and consistency in caring for these patients and minimizing hundred percent of parents who completed the evaluations believed it was emotional and physical suffering for patient and family at EOL. important for themselves and their children to have the opportunity to interact with other families. Their overall satisfaction with interaction opportunities rose from 5.9 to 8.7 (1-10 scale). Parent knowledge scores increased from 5.18 to 7.64 for the general education session on pediatric brain tumors and 6.2 to 7.3 for the self care information session. Qualitative data indicated P-MULTI.09. SERIAL CASTING IN PATIENTS WITH CENTRAL that parents were very satisfied with the program. “Evenings with NERVOUS SYSTEM (CNS) TUMORS FOR THE TREATMENT OF Neuro-Oncology” provides a model of a successful program that can be used SEVERE ANKLE CONTRACTURES SECONDARY TO by multidisciplinary teams to improve family support for patients and families VINCRISTINE AND PLATIN INDUCED NEUROPATHY impacted by pediatric brain tumors. L. R. Tanner, C. Hansen, L. B. Madsen, M. B. Hansen, S. J. Giesar, and A. E. Bendel; Children’s Hospitals and Clincs of Minnesota, Mpls, MN, United States

Vincristine and platin agents are commonly used to treat CNS tumors, but P-MULTI.07. INTERDISCIPLINARY DEVELOPMENT OF A neuropathy is a common side-effect, resulting in ankle contractures in severe COMMUNICATION INTERVENTION FOR PARENTS OF cases. Patients with CNS tumors might be more susceptible to vincristine/ CHILDREN WITH BRAIN TUMORS platin induced ankle contractures due to underlying hemiparesis. There are V. L. Ferguson1, J. E. Haase2, K. R. Pradhan3, J. R. Kane4, and P. S. Hinds5; no published reports regarding the management of vincristine/platin 1Barnes Jewish College, St Louis, MO, United States; 2Indiana University induced ankle contractures in patients with CNS tumors. METHODS: School of Nursing, Indianapolis, IN, United States; 3Indiana University, Physical therapy (PT) records of CNS tumor patients treated with serial Indianapolis, IN, United States; 4St. Jude Children’s Research Hospital, casting at Children’s Hospitals and Clinics of Minnesota, Minneapolis Memphis, TN, United States; 5Childen’s National Medical Center, (2005-2010) were reviewed. Only patients with previous vincristine or Washington DC, WA, United States platin exposure were included. Passive range of motion (PROM) of the ankle measured before and after serial casting was assessed to measure A national priority for health care providers is to initiate early communi- success of casting. RESULTS: 6 patients were identiﬁed (2 medulloblastoma, cation about palliative and end-of-life care (PC/EOL) for children with a 2 pineoblastoma, 1 low-grade glioma, 1 germ cell tumor). Three had ii80 NEURO-ONCOLOGY † JUNE 2010 Abstracts

underlying hemiparesis as an added risk factor. 4 patients required bilateral 13Saskatoon Cancer Centre, Saskatoon, SK, Canada; 14Alberta Children’s casting and 2 underwent unilateral casting (both had underlying hemipar- Hospital, Calgary, AB, Canada esis). All patients recovered optimal passive ankle dorsiflexion at completion of serial casting. Unfortunately, long term maintenance of PROM wasn’t For most pediatric malignancies, treatments are protocol based and many well documented. CONCLUSION: Serial casting is a successful intervention centers are part of cooperative groups like the Children’s Oncology Group for ankle contractures from vincristine/platin in patients with CNS tumors, (COG) or SIOP (Societe International d’Oncologie Pediatrique). The however long-term outcomes are not known. It is prudent to address restric- purpose of protocols is to optimize treatment strategies and outcome. The tion in range of motion before structural breakdown occurs, which will per- aim of this survey was to analyze the current practice within the 16 academic manently impair ankle function. A prospective study is underway at our centers in Canada treating children with CNS tumors. An online based institution to better study the long-term functional benefit of PT, survey was sent out to all academic centers in Canada collecting information Ankle-foot orthoses and serial casting in vincristine/platin induced ankle about the currently used treatment protocols, annual number of newly diag- contractures seen in patients with CNS tumors. nosed and relapsed patients and the number of patients who were registered in institutional/national/international approved protocols. So far responses from 10 centers are available representing the largest centers in the country. In 2009, 315 children were treated in these centers, only 17% of them were enrolled in an open protocol (range 0 -15 patients per participating centers). Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 P-MULTI.10. NUTRITIONAL IMPAIRMENT OF CHILDREN Analyzing specifically the registration pattern, participation was limited to WITH PEDIATRIC BRAIN TUMORS low grade glioma and medulloblastoma protocols, which are used in all T. Fujimaki1,2, T. Yanagisawa2, T. Suzuki2, K. Fukuoka2, K. Mishima2, centers. In all other CNS malignancies a variety of protocols are used mainly M. Matsutani2, W. Fujimaki3, and R. Nishikawa2; 1Saitama Medical recruited from closed COG trials (range 2 to 5 protocols). Our survey shows University Hospital, Moroyama, Japan; 2Saitama Medical University, that participation in clinical research is closely related to available studies, International Medical Center, Hidaka, Japan; 3Kagawa Nutritional and low patients accrual essentially reflect the lack of open studies for the University, Sakado, Japan most common diagnoses. In the absence of open studies, monthly teleconfer- ence meetings within the Canadian Brain Tumor Consortium function as the Children with pediatric brain tumors (PBT) have nutritional problems. Most appropriate platform for setting a standard of care. of the patients suffer from emaciation, partly because of side effects from chemotherapy or radiotherapy, whereas some have a tendency to obesity. Our preliminary survey of children with PBTshows that body weight of more than 80% of the patientsfalls within 10 percentile whereas their average heightmatches the P-MULTI.13. A MULTIDISCIPLINARY NEUROONCOLOGY normal range. To investigate the nutritional status of these children, the follow- CLINIC; AN EFFECTIVE WAY TO MEET THE COMPLEX NEEDS ing study is planned. METHOD: Children with PBT are surveyed for diet intake OF PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS and food preference on a daily basis together with nutritionists. Food intake is M. B. Hansen; Children’s Hospitals and Clinics of Minnesota, St Paul, MN, surveyed by direct interviewing and/or questionnaire. The relation of food United States intake to in-house served food or to each treatment timing is examined. Hematological data such as albumin, cholesterol, RTP, and triglycerides are Patients with central nervous system tumors often require a collaborative measured. Body parameters including body weight and body height are approach to most effectively treat, establish assessment needs, and improve measured weekly. The gain of body weight and height are plotted as growth quality of life. (1) At Children’s Hospitals and Clinics of Minnesota we curves and will be statistically analyzed. As a control the national survey avail- follow patients through a multidisciplinary Neurooncology Clinic in addition able from the ministry is used. All of these surveys are supported by multidisci- to regular appointments for follow up and chemotherapy. Our goal is to plinary PBT conference team composed ofmedical doctors, nurses, improve communication between staff and families, and improve patient out- nutritionists, social workers, and other healthcare related workers. The proto- comes and quality of life. The clinic is coordinated by the Neurooncology col is under review of the institutional review board. CNP and involves multiple pediatric disciplines. Prior to the clinic a confirmation letter and questionnaire is sent to the patient/family. Most patients will have an MRI scan within one day of the appointment. Before the clinic, patient clinic visit summaries are created or their previous visit summary is P-MULTI.11. DYSPHAGIA REHABILITATION OF PEDIATRIC updated. Completed summaries are sent by email to neurooncology staff for PATIENTS WITH BRAIN TUMORS review. On the day of clinic, the interdisciplinary staff meet to review the M. I. R. Gonçalves1, B. M. Chiari2, N. S. Silva1, A. Cappellano1, present scan, review returned patient questionnaires, decide appropriate staff S. Cavalheiro1, F. T. Menezes1, N. Bortolatto1, P. Dastoli1, D. F. Curcio1, to assess the patient, and determine future appointments. As patients arrive and T. Radzinsky1; 1Pediatric Oncology Institute Federal University of Saõ they are roomed and seen by staff in a sequential manner. Patient satisfaction Paulo, Saõ Paulo, Brazil; 2Speech Pathology Department Federal University surveys are periodically sent. Forms used include patient scheduling, confir- of Saõ Paulo, Saõ Paulo, Brazil mation letter for appointment andscan, preclinic questionnaire, neurooncology clinic visit summary, and patient satisfaction form. Based on patient and family PURPOSE: To verify the efficacy of swallowing rehabilitation of pediatric surveys all respondents felt the patient’s needs were best met in a multidisciplin- patients with brain tumors. METHOD: We retrospectively studied the files ary clinic, nearly all felt they see the necessary staff, and most felt that the length of 31 patients with brain tumor and diagnosis of swallowing difficulties (dys- of time spent in the Neurooncology Clinic was at least satisfactory. phagia) from September 2003 to July 2009. Rehabilitation was performed bedside during hospital stay. Twenty three patients were males and 8 females; age ranged from 11 months to 22 years. Rehabilitation duration depended on the difficulties, evolution and patient’s clinical conditions. The functional oral intake scale (FOIS) it was used to classify each patient P-MULTI.14. REGIONAL COORDINATION OF PEDIATRIC regarding the feeding way (oral or tube feeding). A swallowing severity ONCOLOGICAL CARE IN NORTH WESTERN LOWER SAXONY, sacle was used to classify the dysphagia degree. Both scales were performed GERMANY - NETWORK FUNDED BY HEALTH INSURANCE before and after rehabilitation. The results were submitted to statistical COMPANIES analysis. CONCLUSIONS: it was observed significant statistical difference K. Otten, B. Bonse, S. Dittjen, S. Nu¨ hsmann, N. Haferkamp, M. Reuhs, in the FOIS scale before and after swallowing rehabilitation, and most S. Reslo, A. Abken, V. Wessel, R. Kolb, L. Lo¨ ning, and H. L. Mu¨ ller; patients presented reduction in the swallowing severity scale. Department of Pediatrics and Pediatric Hematology / Oncology, Klinikum Oldenburg gGmbH, Oldenburg, Germany

Due to low population density in north western Lower Saxony (Weser-Ems), Germany, pediatric oncological treatment in specialized P-MULTI.12. PEDIATRIC NEUROONCOLOGY IN CANADA - DO centers results in frequent and time consuming transports for the patients WE HAVE A STANDARD OF CARE? and their families and leads to relevant risks for patients. Accordingly, in K. Scheinemann1, E. Bouffet2, A. Carret3, B. Crooks4, J. Hukin5, 2001 11 departments of pediatrics in the Weser-Ems region, local support D. Eisenstat6, B. Wilson7, S. Zelcer8, D. Johnston9, V. Larouche10, groups, and an outdoor pediatric patient care service founded a regional M. Silva11, N. Jabado12, M. Christopher13, and L. Lafay-Cousin14; association (Verbund Pa¨dOnko Weser-Ems) in order to reduce the burden 1McMaster Children’s Hospital, Hamilton, ON, Canada; 2The Hospital for and the costs of transport and to assure high standards in quality of regional Sick Children, Toronto, ON, Canada; 3Hopital Sainte Justine, Montreal, treatment. Since October 2005, a medical doctor, two pediatric nurses and a QC, Canada; 4IWK, Halifax, NB, Canada; 5BC Children’s Hospital, medical documentalist have provided care at patients´ home and coordinated Vancouver, BC, Canada; 6Cancer Care Manitoba, Winnipeg, MB, Canada; the cooperation within the network between local hospitals in the 7Stollery Children’s Hospital, Edmonton, AB, Canada; 8CHWO, London, Weser-Ems region. The project was ﬁnanced as a prototype model by a ON, Canada; 9CHEO, Ottawa, ON, Canada; 10Centre Hospitalier Laval, grant of Deutsche-Jose´-Carreras-Leuka¨mie-Stiftung e.V. from October Quebec City, QC, Canada; 11Kingston General Hospital, Kingston, ON, 2005 to September 2007. From 2005 to 2009 (559 visiting days), the Canada; 12Montreal Children’s Hospital, Montreal, QC, Canada; mobile oncological team provided 1379 visits for 133 patients at home.

NEURO-ONCOLOGY † JUNE 2010 ii81 Abstracts

The mobile team traveled overall 111.645 km, which otherwise would have created physical therapy role, the Rehabilitation Oncology Clinical been traveled by the patients and their families. The project was very well Specialist (ROCS), provides rapid access to services by high priority patients accepted by the patients and their families. Short-term indoor treatments as well as continuity and oversight of the rehabilitation plan, and increased (,48 hours) could be reduced due to sufficient regional infrastructure of interdisciplinary collaboration. The ROCS utilizes an evidenced based prac- outdoor patient services. Due to high quality standards infectious and tice model to perform detailed neuromuscular assessments and collaborates other complications of pediatric oncological therapy could be reduced. with the family to create a developmentally tailored intervention plan. Based on these successful achievements the network “Verbund Pa¨dOnko Physical therapy evaluations are used by oncology providers to guide toxicity Weser-Ems” is currently financed by German health insurance companies modifications and by local physical therapists to assist with intervention in a on a long-term basis (Integrierte Versorgung). likely unfamiliar field. Families benefit from the accessibility of the specialist to assess and make recommendations during their oncology clinic visit without the complexity of scheduling additional appointments. When planning for the role implementation, the financing and scheduling of the role P-MULTI.15. NURSING CARE OF THE CHILD AFTER was negotiated between the rehabilitation and oncology departments. The CRANIOTOMY FOR BRAIN TUMOR RESECTION IN A STEP-UP ROCS has been successful in integrating and communicating current UNIT SETTING research findings to both the family and clinical team. New assessment and 1,2 1,2 1,2 1 clinical intervention pathways are being developed through this role utilizing D. Shiers , K. Sheehan , and M. Gregory ; Children’s Hospital Boston, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Boston, MA, United States; 2Dana Farber Cancer Institute, Boston, MA, an evidence-based and multidisciplinary approach. The specialist partici- United States pates in ongoing research studies evaluating peripheral neuropathy and physical performance in children with cancer, integrates these findings into It is common practice to monitor children who have undergone craniotomies current practice, and disseminates knowledge to medical professionals for brain tumor resection in an ICU for 24 hours post-operatively before trans- locally and nationally. This role has been instrumental in identifying chil- ferring to an inpatient unit. The recent creation of a Neuroscience Step Up Unit dren’s needs and improving the rehabilitation care in the Children’s system. (SUU) at our organization allows us to provide intermediate care to patients with Neurological, Neurosurgical and Neuro-Oncologic disorders. With the opening of this unit, the question: “What is the required nursing care of a child following resection of an intracranial tumor in the first twenty-four P08 EPIDEMIOLOGY hours?” was raised. Review of the literature identifies several benefits to monitoring children recovering from craniotomies in a SUU rather than in an ICU setting. Admitting patients to the SUU postoperatively will increase ICU bed P-EPI.01. CENTRAL NERVOUS SYSTEM (CNS) TUMOUR availability, provide for 24/7 neurological expertise, consistency in care TRENDS IN CHILDREN IN A WESTERN CANADIAN PROVINCE: amongst the nursing/physician team, earlier implementation of discharge A POPULATION-BASED 22 YEAR RETROSPECTIVE STUDY planning, education and ultimately improved patient outcomes. Based on the R. J. Rosychuk, A. Witol, and K. Stobart; University of Alberta, Edmonton, results of our literature review, we determined that it may be possible to care AB, Canada for these patients in our SUU. A retrospective chart review of craniotomies performed for brain tumor resection, over a one year period during 2007 and 2008 BACKGROUND: In Canada, CNS and miscellaneous intracranial and revealed similar findings as demonstrated through the literature. To conclude, intraspinal neoplasms (hereafter CNS tumours) accounted for nearly 22% through the utilization of inclusion and exclusion criteria, children may be of the new childhood cancer diagnoses during 1995 to 2000 in the under safely cared for in a Neuroscience Step Up Unit. This change in practice will 15 year age group. The objective of this study was to describe children and likely improve patient outcomes, shorten length of stay and ensure appropriate youth (age , 20 years) diagnosed with CNS tumours in Alberta, Canada utilization of resources. Our next steps will be collaboration with the appropri- over 22 years. METHODS: The Alberta Cancer registry was used to ate departments to initiate this significant change in practice. extract information on all CNS (ICCC-3 III) tumour diagnoses during April 1, 1982, and March 31, 2004. Data extracted included sex, age, and diagnosis. Population data were also obtained. Analyses included summaries and rates. RESULTS: During 22 fiscal years, 568 Alberta children were diag- P-MULTI.16. NURSE CONSULTANT FOR CHILDREN WITH nosed with CNS tumours and nearly 82% of the cases were malignant (461). BRAIN TUMOURS Of the malignant cases, the majority were male (58%) and the median age at A. Sjolund1, C. Castor2, L. Paulsson O¨ dmark3, A. Bjo¨ rklund4, and A. Ho¨ o¨ k5; diagnosis was 7 years. The crude rate per 100,000 children increased over the 1Queen Silvias Childrens Hospital, Gothenburg, Sweden; 2The Children´ s study period from 1.98 in 1982/1983 to 3.23 in 2003/2004. Astrocytoma Hospital, Lund, Sweden; 3University Hospital, Umea˚, Sweden; 4University was the most common diagnosis (251, 54%), followed by medulloblastoma Childrens Hospital, Uppsala, Sweden; 5University Hospital, Linko¨ ping, (15%), mixed and unspecified glioma (11%), and ependymoma (9%). There Sweden were 86 diagnoses of malignant juvenile pilocytic astrocytoma (55% male) and the crude rates per 100,000 increased during the study (,0.5 in the In Sweden there are around 80 children (0-18 years) with newly diagnosed early years to 1.15 in 2003/2004). CONCLUSIONS: Although a relatively brain tumors every year. The diagnosis and treatment is directed from one of rare number of children and youth in Alberta were diagnosed with CNS six childhood cancer centres. The treatment is given by several different care- tumours, there were suggestions that an increase occurred over the study givers such as neurosurgery, radiotherapy, endocrine unit, the local hospital, years. Further investigations may be warranted to help explain these trends. the outpatient clinic and the rehabilitation unit. In order to improve coordination and quality of care for children with brain tumours and to support the families a special category of nurses assigned for children with brain tumours started to work in 2005. These nurses are employed at each of the six centres and are financed by the Childhood Cancer Foundation. The nurse consultant P-EPI.02. POPULATION-BASED EPIDEMIOLOGICAL STUDY OF gives information and educates the child and the family all along the course PRIMARY INTRACRANIAL TUMORS IN CHILDHOOD IN of the disease. One of the roles is to coordinate the multidisciplinary team. JAPAN The nurse consultant also visits schools to inform the classmates and the tea- J. Kuratsu, K. Makino, and H. Nakamura; Department of Neurosurgery, chers about diagnose and treatment. Information to the school about late Kumamoto University, Kumamoto, Japan complication and learning difficulties is also provided together with members of the multidisciplinary team. If cure is not possible the nurse con- OBJECT: The aim of this study was to determine the epidemiology of sultant also plays a major role to help the family through this period. The childhood primary intracranial tumors in Kumamoto prefecture, Japan. care is focused on the possibility to let the child die at home. METHODS: We surveyed 210 patients younger than 15 years who were CONCLUSION: Nurse consultants play a major role in caring for children diagnosed with primary intracranial tumors between 1989 and 2008; 159 with brain tumours and their families. The national network guarantees (75.7%) of the tumors were confirmed microscopically. RESULTS: The that the support to patients and families is equalised in the country. age-adjusted annual incidence rate was 36.1 cases per million children. The boys/girls ratio was 1.31. The age-specific annual incidence rate was 28.5, 40.9, and 38.4 cases per million for the 0-4, 5-9, and 10-14 year age group, respectively. The most common tumor was astrocytoma (35.7%) with an annual incidence rate of 13.2 per million, followed by germ cell P-MULTI.17. REHABILITATION CLINICAL SPECIALIST ROLE tumor (14.3%, 5.0 per million), craniopharyngioma (10.5%, 3.8 per DEVELOPMENT million), medulloblastoma (10.0%, 3.7 per million), and ependymoma L. B. Madsen, S. J. Giesar, L. R. Tanner, and M. C. Hooke; Childrens (4.8%, 1.5 per million). The distribution of the tumor type varied with the Hospital of Minnesota, Minneapolis, MN, United States patient age and gender. Although there were no germ cell tumors in 0-4-year-old boys, they were the second most common tumor in Recent research publications and clinical observations demonstrate that 10-14-year-old boys. Conversely, while there were no medulloblastomas in children with brain tumors have complex rehabilitation needs. A newly 10-14-year-old girls, their incidence was high in 0-4-year-old girls. ii82 NEURO-ONCOLOGY † JUNE 2010 Abstracts

CONCLUSIONS: In this Kumamoto survey, the incidence rate of primary intracranial tumors in children was similar to that in Western countries. The high-grade gliomas (HGGs) cause significant morbidity and mortality However, the incidence and relative frequency of particular histological in the pediatric population. A multimodal treatment approach is needed to types of childhood brain tumors such as germ cell tumors and craniopharyn- control these tumors. The aim of this study was to analyze all cases of chil- giomas was different between Japan and Western countries. dren with histologically confirmed HGGs operated on for the first time at our clinic during the period 2006-2008. The study includes 55 consecutive cases of children (0-18 years of age) with different types of gliomas. In 14 (25.4%) of them the histology revealed a HGG. The group consisted of 9 female and 5 P-EPI.03. CHILDHOOD BRAIN TUMORS INCIDENCE IN THE male patients with a median age of 12 years. The localization of the tumor OSH RURAL REGION IN KYRGYZSTAN was as follows: brain stem (n ¼ 7), supratentorial (n ¼ 4), infratentorial E. Makimbetov; Kyrgyz-Russian Slavic University, Bishkek, Kyrgyzstan (n ¼ 2), spinal cord (n ¼ 1). Histology revealed glioblastoma in 7 patients, anaplastic ependymoma in 3, and anaplastic astrocytoma in 2 patients, ana- BACKGROUND: To study the brain tumor incidence, sex, and ethnic plastic oligoastrocytoma and anaplastic ganglioglioma in 1 patient each. The differences. METHODS: There were 408 children registered with a new onset was seizures in 4 patients, headache (n ¼ 3), hemiparesis (n ¼ 3), visual diagnosis of cancer between 1988 and 2005, including 18 (4.4%) with disturbances (n ¼ 2), progressive head enlargement (n ¼ 1), back pain (n ¼ 1). The median time between the onset and admission was 2 months. brain tumors. We counted crude, age-standardized rates (ASR) per 1 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 million and the estimated relative risk for the population in urban and Gross total tumor excision was achieved in 3 patients, subtotal in 3, rural areas. RESULTS: The total age-standardized annual childhood partial in 1, and biopsy in 7 patients. No surgical complications occurred. cancer incidence in Kyrgyzstan was 74.8, and 50.1 in the rural Osh region. Five patients improved after the intervention, in 7 the condition remained The most frequent diagnostic groups were leukaemias (23.6), lymphomas the same, 2 patients deteriorated. Until January 31, 2010 ten of the patients (7.1), retinoblastomas (3.9), Wilms tumors (4.2). Brain tumors were on the (71.4%) have died. The histological type and grade of the tumor, as well as 7th place with an ASR 2.4. Histological verification in brain tumors was its localization are the most important prognostic factors for survival. done in 82%. Boys (ASR 4.5) were affected 1.8 times more often than girls (2.5). Analyses of geographical variations showed the highest incidence in the Osh city (3.8), which was statistically significantly higher (RR-4.2, 95% CI: 3.4-8.1) compared with rural (Kara-Kuldga, Alai, Naukat) regions (0.9). Incidence rate in brain tumors was significantly higher in P-EPI.06. LOW-GRADE GLIOMAS IN CHILDREN - A CLINICAL Uzbeks (2.5), Russians (3.2) compared with 1.8 in Kyrgyzs. There were STUDYOF41CONSECUTIVECASES 1 1 1 1 1 some important obstacles regarding pediatric brain tumors registrations E. Naydenov , C. Tzekov , K. Minkin , V. Bussarsky , K. Romansky , 1 1 1 2 1 and cares in the Kyrgyz republic. Only one pediatric oncology department A. Bussarsky , K. Georgiev , R. Tanova , and S. Nachev ; Department of 2 (30 hospital beds) exists in Bishkek (capital) for the whole republic. Neurosurgery, Sofia, Bulgaria; Laboratory of Neuropathology, Sofia, Surgical treatment is performed at the National (adult) hospital, but Bulgaria without radiation or chemotherapy facillities. About 60% of childhood populations (south part) do not have the possibility to receive any treatment, Pediatric low-grade gliomas (LGGs) are a heterogeneous group of tumors not even chemotherapy or adequate initial brain surgery. CONCLUSIONS: characterized by different clinical course and biological behavior. The aim of Childhood brain cancer incidence in the Osh region of Kyrgyzstan was very this study was to analyze all cases of children with histologically confirmed low, especially in the native ethnic groups. We need a larger descriptive epi- LGGs operated on for the first time at our clinic during the period 2006- demiologic study including other Central Asia republics. 2008. The study included 55 consecutive cases of children (0-18 years of age) with different types of gliomas. In 41 (74.5%) of them the histology revealed a LGG. The group consisted of 25 female and 16 male patients with a median age of 9 years 5 months. The localization of the tumor was as follows: vermis and/or cerebellar hemispheres (n ¼ 12), brain stem (n ¼ P-EPI.04. PINEAL MASSES IN CHILDREN: A RETROSPECTIVE 12), cerebral hemispheres (n ¼ 8), optic nerves and/or diencephalon (n ¼ VIEW FROM A SINGLE CENTER 8), and spinal cord (n ¼ 2). Histology revealed pilocytic astrocytoma in 29 A. Urberuaga1, A. Miguelez1, M. Martinez2, I. Astigarraga1, A. Echebarria1, patients, fibrillary astrocytoma in 4, ganglioglioma in 4, and ependymoma R. Adan1, and A. Navajas1; 1Hospital de Cruces, Pediatric Hematology/ in 2 patients, pilomyxoid astrocytoma in 1 and oligodendroglioma in 1 Oncology, Bilbao, Spain; 2Hospital de Cruces, Pediatric Neurology, Bilbao, patient. The onset was headache in 15 patients, visual disturbances (n ¼ Spain 10), seizures (n ¼ 6), gait instability (n ¼ 4), hemiparesis (n ¼ 1), vomiting (n ¼ 1), dysphonia (n ¼ 1), puberty praecox (n ¼ 1), back pain (n ¼ 1), INTRODUCTION: Pineal masses constitute 2% of the central nervous and scoliosis (n ¼ 1). Gross total tumor excision was achieved in 15 patients, system tumors in children being a challenging diagnosis. subtotal in 3, partial in 6, and biopsy in 17 patients. In 20 patients the con- METHODOLOGY: We reviewed retrospectively patients up to 18 years dition remained the same after the intervention, 18 patients improved, 3 diagnosed of a pineal mass. Studied variables included: age, symptoms at patients deteriorated. Until January 31, 2010 thirteen of the patients presentation, diagnostic work-up (imaging, germinal markers, CSF cytology, (31.7%) have died. The extent of surgical excision is the most important surgery), treatment and outcome. RESULTS: Between March 1975 and May prognostic factor for survival of children with LGG. 2006, 26 patients were diagnosed as follows: 4 pinealoblastomas, 3 germ cell tumors, 6 pineal masses supposedly malignant with subsequent treatment, and 13 pineal cysts. In the first group, 2 patients were diagnosed with CSF cytology and 2 patients had subtotal surgery. All received chemotherapy P09 INFANTILE TUMORS plus radiotherapy (RT). Two patients are alive. The 3 germ cell tumors were a germinoma, a germinoma with mature teratoma, and a b-HCG secreting tumor, diagnosed by imaging plus CSF markers, surgery, and CSF markers, respectively. They received treatment according to SIOP proto- P-INF.01. CHARACTERISTICS OF FETAL BRAIN TUMORS WITH cols and are free of disease. All the 6 malignant pineal masses without his- GENETIC ANALYSIS 1 1 2 1 1 1 tology received local RT but 1 also had craniospinal RT. Three patients T. Miwa ,S.Oi , H. Sasaki , Y. Nonaka , and R. Tamogami ; Division of relapsed and died. Pineal cysts were divided in typical cysts, 9 cases, and aty- Pediatric Neurosurgery, Jikei University School of Medicine, Women’s and 2 pical cysts, 4 cases. Only atypical cysts had an extended work-up. Children’s Medical Center, Tokyo, Japan; Department of Neurosurgery, SUMMARY: Although this is a heterogeneous sample, we would like to Keio University School of Medicine, Tokyo, Japan make two considerations. Regarding those malignant pineal masses without histology, although surgery is a challenging decision it should be It is extremely rare that brain tumors are discovered at a fetal stage. Their considered to offer the right treatment. In our opinion, those patients with pathological diagnosis is various and the treatment is not yet established. As atypical cysts should be followed closely and diagnostic tissue should be for the malignant tumors, they show rapid progress and the prognosis is very taken when imaging shows changes. bad. We experienced six cases of brain tumors that were discovered by ultra- sonic echo or MRI during 30-35 weeks at a fetal stage and we also used MRI for following them. Operation (biopsy: 3 cases, resection: 0 case) or autopsy was performed after birth and their pathological diagnoses were 2 cases of immature teratoma, and one case of each primitive neuroectodermal P-EPI.05. HIGH-GRADE GLIOMAS IN CHILDREN - A CLINICAL tumor (PNET), congenital neuroectodermal tumor, desmoplastic infantile STUDY OF 14 CONSECUTIVE CASES astrocytoma, and hamartoma. All cases except hamartoma showed rapid E. Naydenov1, C. Tzekov1, K. Minkin1, V. Bussarsky1, K. Romansky1, growing and died within several weeks or months after birth. Because of A. Bussarsky1, K. Georgiev1, R. Tanova1, and S. Nachev2; 1Department of their high intracranial pressure, 2 cases were forced to drain cerebrospinal Neurosurgery, Sofia, Bulgaria; 2Laboratory of Neuropathology, Sofia, fluid in emergency just after birth. Chemotherapy was done for 2 cases but Bulgaria the tumors showed chemoresistance. We also analyzed genetic aberrations of these tumors by comparative genomic hybridization (CGH).

NEURO-ONCOLOGY † JUNE 2010 ii83 Abstracts

Interestingly, they present none or little number of chromosomal aberrations limited, but prognosis seems to be better (1). We here describe additional within few weeks after birth, regardless of their malignancy. This result patients younger than 3. METHODS: We retrospectively studied all children might suggest a difference between children and fetus about tumorigenic under the age of 3 with pontine glioma admitted to our hospital between 1990 pathway with genetics. Fetal malignant brain tumors showed rapid and 2010. All patients were diagnosed on clinical grounds plus MRI. growing and aggressiveness just after birth irrespective of pathological diag- RESULTS: Three patients under the age of 3 were admitted to our hospital nosis. It seemed that there are some growing factors clinically and genetically between 1990 and 2010 with PG. All presented with typical neurological at perinatal stage compared with general pediatric brain tumors, and their triad and MRI compatible with diffuse intrinsic pontine glioma (DIPG). treatment and management are still difﬁcult. The duration of symptoms however was longer than in typical DIPG: .6 months. None of them had NF-1. None was treated at diagnosis. All are alive, two of them long term: one .6 years, without treatment, and one .5 years with recent radiation therapy; the third has only just been diagnosed but seems to have stable symptoms for over 6 months. CONCLUSIONS: P-INF.02. CHARACTERIZATION OF INTRACRANIAL Also in our series the prognosis of children under the age of 3 with PG is NEOPLASMS IN THE FIRST 120 DAYS OF LIFE better than in older children. However, in our series this might correlate I. Qaddoumi1, S. Carey1,2, H. Conklin1, D. Ellison1, N. Sabin1, F. Boop1, more with duration of symptoms than with age. More data are needed. (1) A. Pai-Panadiker1, B. Morris1, J. Baker1, A. Broniscer1, and A. Gajjar1; Broniscer, et al. Young age may predict a better outcome for children with Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 1St. Jude Children’s Research Hospital, Memphis, TN, United States; diffuse pontine glioma. Cancer 2008, 113 (3) 566-572 2University of Arizona College of Medicine, Austria

BACKGROUND: Little is known about brain tumors in the early infancy period. It is imperative to document clinical characteristics, survival and late effects that strongly influence treatment selection. METHODS: We reviewed P-INF.05. A ROLE FOR ADJUVANT CHEMOTHERAPY IN 27 patients referred to our institution between 1985 and 2008 that were CONGENITAL INTRACRANIAL HAEMANGIOPERICYTOMA diagnosed with brain tumors within 120 days of life. This included clinical K. Kerl1, R. Stra¨ter1, M. Hasselblatt2, A. Brentrup3, and M. C. Fru¨ hwald1; presentation, treatment modality, survival data and late effects. RESULTS: 1University Children’s Hospital Mu¨ nster, Mu¨ nster, Germany; 22Institute of The study included 12 males and 15 females with a median age of 66 days Neuropathology, University Hospital Mu¨ nster, Mu¨ nster, Germany; (range, 0-110 days) at diagnosis. The patients most frequently presented 3Department of Neurosurgery, University Hospital Mu¨ nster, Mu¨ nster, with increased head circumference (n ¼ 14), emesis (n ¼ 10), seizure activity Germany (n ¼ 8), and oculovisual symptoms (n ¼ 7). The most common histopathology was astrocytoma (n ¼ 9) and tumor location was equally distributed Malignant infantile haemangiopericytoma of the CNS is a rare entity in between the infratentorial and supratentorial hemispheres. 14 patients children. Only seven cases have been reported in the current literature. received adjuvant chemotherapy and 6 patients received adjuvant che- Herein we report on the first case of a 5-day old girl with this diagnosis success- motherapy and radiotherapy. The median age at the initiation of radiother- fully treated by preoperative adjuvant chemotherapy. CASE REPORT: The apy was 1.8 years old (range, 1.0-5.4 years). The median follow-up was 2.1 female patient presented shortly after birth on routine ultrasound examin- years (range, 0.2-21.6 years). At last encounter, 15 patients were alive; 11 ation with a 4x3x4cm mass in the left occipital lobe. Following biopsy histo- with no evidence of disease. Twelve patients died; 10 from progressive pathology yielded the diagnosis of a haemangiopericytoma. As neurosurgery disease and 2 from treatment-related sequelae. All patients suffered some was deemed too risky due to size, location and age of the patient an anthracy- form of late effects with endocrine, neurologic and cognitive most prevalent. cline based chemotherapeutic regimen was applied. The regimen combining CONCLUSION: It is feasible to achieve cure in brain tumors in early infancy vincristine, actinomycin-D, cyclophosphamide, and doxorubicin resulted in with aggressive therapy but with a price on quality of life. Further studies are a significant decrease in tumor size, making a post-chemotherapy complete needed to maximize survival with least late effects. surgical resection possible. The postoperative course was unremarkable, especially no sign of haemorrhage was noted. Side effects of chemotherapy were negligible as age adjusted (per kg) dosing was employed. During the three years of follow-up the patient continues to develop according to age P-INF.03. EMBRYONAL CNS TUMORS IN CHILDREN LESS and a shows normal neurologic function. No sign of relapse has been noted. THAN 4 YEARS OF AGE: AN EQUALLY POOR OUTCOME WITH CONCLUSION: Chemotherapy may be of significant benefit in patients OR WITHOUT RADIATION THERAPY (RT) with congenital haemangiopericytoma especially if the tumor can initially M. Yankelevich, Z. J. Wang, S. Sood, A. A. Konski, J. M. Poulik, not be treated by a complete neurosurgical resection. W. J. Kupsky, D. Altinok, and K. Bhambhani; Children’s Hospital of Michigan/ Wayne State University, Detroit, MI, United States

Historically, patients with medulloblastoma (MB) and PNET younger P10 CANCER PREDISPOSITION SYNDROMES than 3 years of age are considered to have worst outcome, partially due to limited options for RT. We conducted a retrospective review of our patients ,48 months of age with intent to compare results in children less than 36 months mostly treated without RT and older than 36 months who are P-CPS.01. CEREBELLAR HEMANGIOBLASTOMA ASSOCIATED expected to receive RT. A retrospective review of patients diagnosed in WITH VISCERAL AND CUTANEOUS HEMANGIOMATOSIS IN 1999-2009 was done. Statistics for demographics, treatment modalities, AN INFANT T. Patiroglu1, D. Coban2, E. Unal1, A. Yikilmaz3, B. Tucer4, M. Karakukcu1, and survival were obtained. There were 17 cases. Seven (41%) of the patients 1 5 2 1 had leptomeningeal dissemination. GTR was obtained in 6 (35%). The “ , M. A. Ozdemir , O. Canoz , and M. Akcakus ; Erciyes University, Faculty 36 months” group comprised of 10 patients (MB 4, desmoplastic MB (DMB) of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Kayseri, Turkey; 2Erciyes University, Faculty of Medicine, 2, PNET 3, and ATRT 1). Only 2/10 patients in this group received RT. The 3 “36-48 months” group comprised of 7 patients (MB 3, DMB 1, and PNET Department of Neonatology, Kayseri, Turkey; Erciyes University, Faculty of 3). All patients in this group received RT (6-CSI, 1-focal). Distribution of Medicine, Department of Radiology, Division of Pediatric Radiology, Kayseri, Turkey; 4Erciyes University, Faculty of Medicine, Department of metastases and residual tumors was equal in both groups. EFS rate for the 5 whole group was 6.6% after 22 months. EFS after 14 months and median Neourosurgery, Kayseri, Turkey; Erciyes University, Faculty of Medicine, EFS time were 13.3%/5 + SE1.2 months and 28.5%/12 + SE3.9 months Department of Pathology, Kayseri, Turkey in younger and older groups respectively (p ¼ 0.56). The only 2 children who survived without progression (8 and 72 months) had DMB and were INTRODUCTION: Hemangioblastoma is the most frequent vascular under 36 months. Another patient with DMB and Neimejen syndrome tumor of the central nervous system, and can be associated with von died from RT-induced corrosive esophagitis. RT prolonged EFS in our Hippel-Lindau disease. Although histologically benign, its development is cohort of young patients, however without statistical signiﬁcance. The pres- often unfavorable due to high risk of recurrence and multimodality. We ence of desmoplastic histology was the strongest predictor of EFS. present a case of a cerebellar hemangioblastoma associated with multiple visceral and cutaneous hemangiomas in an infant. CASE REPORT: A 5-day-old male baby was referred with complaints of multiple cutanous lesions. From his medical history, it was learnt that he was born with a weight of 3350 g, at 38 weeks of gestation via uncomplicated spontaneous vaginal delivery P-INF.04. CHILDREN WITH PONTINE GLIOMA UNDER THE from a 21-year-old gravida 2 para 2 mother. Apgar scores were 8 and 9 at 1 AGE OF THREE YEARS and 5 minutes, respectively. At the initial physical examination, signiﬁcant C. E. Gidding, B. Goraj, J. Schieving, E. van Lindert, and G. Janssens; small purple papules were noted on the trunk and extremities and the head. Radboud University Medical Centre, Nijmegen, Netherlands Thoracal MR imaging demonstrated multiple hyperintense lesion on the chest-wall and apex of the right lung consistent with hemangiomas. The BACKGROUND: Prognosis of Pontine Glioma (PG) is very poor despite biopsy from the skin revealed hemangioma. Cranial ultrasonography treatment. Under the age of 3, pontine glioma is rare and our knowledge is showed mild dilatation of lateral and the third ventricles and a hyperechogenic ii84 NEURO-ONCOLOGY † JUNE 2010 Abstracts

mass was detected. Cranial MR imaging showed 3x2 cm mass lesion with pro- the effect of imatinib mesylate in the treatment of neurofibromas. minent enhancement in the left cerebellar hemisphere. Total resection of the PATIENT: A 4-year-old boy with diagnosis of NF 1 was admitted in mass and a ventriculoperiteonal shunting was performed. Histopathological November 2007 with multiple cutaneous neurofibromas, cafe´ au lait examination confirmed the diagnosis of hemangioblastoma. Steroid treat- macules and chest deformity. Computed tomography confirmed large thor- ment was administered for disseminated hemangiomatosis and the lesions acic mass and magnetic resonance imaging of the brain showed a tumor showed regression. CONCLUSION: According to our knowledge this the involving the thalamus diagnosed as hamartoma. He received chemotherapy second case of cerebellar hemangioblastoma associated with diffuse skin with cyclophosphamide, vincristine and carboplatin and had stable disease and visceral hemangiomas in the English medical literature. in the brain. He had progressive disease of thoracic tumour and after one year of diagnosis a biopsy was performed showing neurofibroma with mixoid areas. Positron emission tomography scan (PET scan) presented with high metabolic activity at posterior mediastinal mass involving thoracic P-CPS.02. PRELIMINARY EXPERIENCE WITH SIROLIMUS FOR vertebral bones and adenoids with extension to the oropharynx and to cervi- DYSPLASTIC CEREBELLAR GANGLIOCYTOMA cal lymph nodes. A compassionate use protocol was initiated with imatinib J. H. Garvin, P. L. Faust, E. M. Stark, R. C. E. Anderson, and N. A. Feldstein; mesylate 200 mg/m2/day. RESULTS: After 6 month of treatment, PET scan Columbia University Medical Center, New York, NY, United States showed no metabolic activity. No side effects were observed. The patient is still on treatment to complete 1 year. CONCLUSIONS: Imatinib mesylate Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD) exhibited efficacy against neurofibroma in this patient, reducing the uptake causes progressive mass effects in the posterior fossa, and may be associated at PET scan but with no reduction in tumor size. Additional investigation with cerebellar dysfunction. Surgical resection is limited by blending of is required to demonstrate the role of tyrosine kinase inhibitor in patients lesions into normal cerebellar parenchyma. LDD is associated with with neurofibromatosis type 1. Cowden disease and PTEN mutations; further analysis has revealed activation of PTEN/AKT/mTOR pathway, suggesting potential therapeutic benefit of mTOR inhibition. We treated two children (age 18 months and 22 months) with symptomatic biopsy proven dysplastic cerebellar gangliocytoma with sirolimus 0.083 mg/kg/day, adjusted to maintain trough levels P-CPS.05. RAPID PROGRESSION OF between 3 and 12 ng/ml. Both patients have stable disease response at + + NEUROFIBROMATOSIS-ASSOCIATED MOYAMOYA AFTER 34 and 7 months, with improvement in symptoms of head tilt and gait BEVACIZUMAB FOR GLIOBLASTOMA ataxia. Both patients experienced transient rash, and one had mild influenza N. J. Ullrich1,2, M. Zimmerman2, E. Smith3, M. B. Irons4, K. J. Marcus5,2, B and herpetic stomatitis. Sirolimus merits further investigation in LDD to and M. W. Kieran6,2; 1Department of Neurology, Children’s Hospital determine optimal dose and efficacy and safety of long term administration. Boston, Boston, MA, United States; 2Pediatric NeuroOncology, Dana-Farber Cancer Institute, Boston, MA, United States; 3Department of Neurosurgery, Children’s Hospital Boston, Boston, MA, United States; 4Department of Genetics, Children’s Hospital Boston, Boston, MA, United States; 5Department of Radiation Oncology, Children’s Hospital Boston, Boston, P-CPS.03. TOLERABILITY OF THE MTOR INHIBITOR MA, United States; 6Department of Hematology/Oncology Children’s SIROLIMUS IN A PHASE II STUDY FOR NEUROFIBROMATOSIS Hospital Boston, Boston, MA, United States TYPE 1 (NF1)-ASSOCIATED PLEXIFORM NEUROFIBROMAS: A NEUROFIBROMATOSIS CONSORTIUM STUDY 1 2 3 1 1 PURPOSE: Moyamoya-type vasculopathy is observed in children with B. Weiss , B. C. Widemann , A. Cantor , J. Perentesis , A. Vinks , Neurofibromatosis type 1 (NF1). We report a case of rapidly progressive N. Ullrich4, D. Gutmann5, B. Korf3, R. Packer6, and M. J. Fisher7; 1 NF1-associated moyamoya in a child treated with bevacizumab for glioblas- Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United toma. CASE: A 9 year old boy with NF1 presented with headache, vomiting States; 2National Institutes of Health, Bethesda, MD, United States; 3 and lethargy and was found to have a right frontal tumor with contrast University of Alabama at Birmingham School of Medicine, Birmingham, enhancement, mass effect and midline shift. Neuroimaging at 5 years and AL, United States; 4Children’s Hospital Boston, Boston, MA, United States; 5 repeated at 7 years for developmental delay demonstrated no intracranial Washington University School of Medicine, St Louis, MO, United States; lesions or focal areas of vascular stenosis. Pathology demonstrated glioblas- 6Children’s National Medical Center, Washington, DC, United States; 7 toma, with necrosis and vascular proliferation. He was treated with lomus- Children’s Hospital of Philadelphia, Philadelphia, PA, United States tine, temozolomide and confocal radiation therapy. After resection of recurrent disease at 9 months, he began treatment with bevacizumab/irino- Plexiform neurofibromas (PN) cause potentially debilitating complications tecan. After three cycles, he experienced recurrent transient ischemic attacks in NF1. The NF1 tumor suppressor regulates mTOR pathway activation. of escalating frequency. MRA demonstrated progressive signal dropout and Administration of sirolimus in cyclosporine-based regimens for kidney allo- ≥ multifocal areas of restricted diffusion despite antiplatelet treatment. He suc- graft rejection results in the following toxicities ( 20%): cytopenias, hyper- cumbed to progressive strokes and disease 30 months after initial presen- lipidemia, hypertension, headache, tremors, and gastrointestinal toxicity. tation. CONCLUSIONS: NF1-associated glioblastoma in children has been We are performing a multi-center Department of Defense-funded phase 2 reported and may have a more favorable prognosis compared to non-NF1 study of sirolimus for progressive (stratum 1) and radiographically stable / ≥ patients. Up to 2 3 of patients with moyamoya experience symptomatic pro- (stratum 2) PN. Subjects with NF1 and 1 inoperable PN are eligible. gression over a 5-year period. Inhibition of VEGF and its receptors is a promis- 2 ¼ Sirolimus (0.8 mg/m /dose po q12 h continuous dosing, 1 course 28 ing therapeutic strategy for glioblastoma and resulted in a progression-free days) trough levels are maintained between 10-15 ng/ml. Therapy continues interval of .16 months in our patient; however, it is possible that bevacizumab until progression or unacceptable toxicity, or for a maximum of 6 courses in may have contributed to the rapid progression of stenoocclusive disease and absence of radiographic response (stratum 2 only). Moderate toxicities underlying ischemia by inhibiting collateral formation. The use of VEGF inhibi- require dose interruption and/or target level reduction; severe toxicities tors in children with NF1 and risk of moyamoya should be carefully considered. require sirolimus discontinuation. Fourty-five patients (22f, 23m), median age 8 years (range, 3 - 45 yrs) have enrolled as of December 2009. Median treatment duration with sirolimus is 6 months (range, 1-21 mo). Sirolimus has been well tolerated. Only 5 sirolimus toxicities required target reductions ¼ in 4 subjects (11%): mild hyperlipidemia (n 2), mucositis causing signifi- P-CPS.06. GLIOMATOSIS CEREBELLI IN ¼ ¼ cant discomfort (n 2), and grade 3 neutropenia (n 1). Sirolimus was per- NEUROFIBROMATOSIS TYPE-1, A CASE REPORT ¼ 1 2 3 4 5 manently discontinued for reversible grade 2 pneumonitis (n 1), and for S. Nunes , S. Vinhais , J. Migueńs , J. Pimentel , P. Oliveira , and acute respiratory distress syndrome after respiratory syncytial virus bronch- D. Salgado1; 1Pediatric Neuro-Oncology Unit, Instituto Portugueˆsde ¼ 2 iolitis (n 1). Sirolimus toxicities in subjects with NF1 PN have been less Oncologia de Lisboa, Lisboa, Portugal; Radiology Department, Instituto severe and less frequent compared to kidney allograft recipients. Portugueˆs de Oncologia de Lisboa, Lisboa, Portugal; 3Neurosurgery Evaluation of whether sirolimus can prolong the time to progression of pro- Department, Hospital de Santa Maria, Lisboa, Portugal; 4Neuropathology gressive PN (primary study aim) is ongoing. Laboratory, Hospital de Santa Maria, Lisboa, Portugal; 5Pathological Anatomy Department, Instituto Portugueˆs de Oncologia de Lisboa, Lisboa, Portugal

We report a case of a boy with Neurofibromatosis type-1 and a diffuse cer- P-CPS.04. IS IMATINIB MESYLATE USEFUL TO PATIENTS WITH ebellar lesion, suggestive of Gliomatosis Cerebelli. The child was born in NEUROFIBROMATOSIS TYPE 1? Cape Vert and Neurofibromatosis was diagnosed at 11 month- old. At five E. Gorender and S. Epelman; Santa Marcelina Hospital, Sao Paulo, Brazil years of age, he developed walking difficulties and paroxistic events resembling epileptic seizures, which improved under carbamazepine. Five BACKGROUND: Neurofibromatosis type one (NF1) is the most common months later, axial tonus and speech deteriorated, and head CT was per- genetic disease in human that results in a predisposition to cancer.These formed, revealing tetraventricular hydrocephalus and a diffuse cerebellar tumors usually do not respond to chemotherapy. This case report presents

NEURO-ONCOLOGY † JUNE 2010 ii85 Abstracts

hypodense lesion. Evacuated to Portugal, he underwent ventricular shunt P-CPS.09. REGRESSION OF SUBEPENDYMAL GIANT CELL placement. Cranial MRI showed diffuse abnormalities in both cerebellar ASTROCYTOMAS WITH RAD001 (EVEROLIMUS) IN hemispheres involving the white matter, with low signal on T1-weighted TUBEROUS SCLEROSIS COMPLEX images (WI) and hyperintensities on T2-WI, also extending to the cerebellar M. Yalon1, L. Ben-Sira2, S. Constantini2, and A. Toren1; 1Sheba medical peduncles and pon with few local enhancement foci. Biopsy suggested center, Tel-Hashomer, Israel; 2Dana children’s hospital, Tel-Aviv, Israel Gliomatosis Cerebelli versus Fibrillary Astrocytoma and carboplatin plus vincristine protocol for low grade gliomas was started. Next MRI examin- BACKGROUND: TSC is a genetic disorder caused by inactivating ations documented variations of the lesion´ s appearance, subtle in size, mutations in the TSC1 or TSC2 genes, and characterized by slow growing some signal changes on T1-WI, more brightness on T2-WI, evolution of tumors in multiple organs. 10% of affected individuals display subependy- the enhancement pattern to a cerebellar hemisphere nodule, and afterwards mal giant cell astrocytomas (GCA), which can lead to substantial neurologi- some reverse trend to normalization. MR-spectroscopy was compatible with cal morbidity. The TSC1/TSC2 protein complex is a negative regulator of tumour lesion. Now with 10 years old, he has improved from the cerebellar the mTOR pathway. Hence, mutations of these gene products in preclinical syndrome. Gliomatosis cerebri is a rare neoplasm, particularly at paediatric models are associated with increased mTOR pathway activation and heigh- age. Primary lesion usually arises from the cerebrum and progresses to cer- tened sensitivity to mTOR inhibitors. Indeed, treatment with the mTOR ebellum, brainstem and spinal cord, the prognosis being usually grim. To inhibitor sirolimus (rapamycin), displayed regression of astrocytomas in our knowledge, only one case of this entity arising from the cerebellum several patients with TSC. We hereby report our experience with RAD001 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 has been reported, like ours in a young child with a favourable outcome. (Everolimus) therapy, a novel mTOR inhibitor, in inducing regression in a patient with TSC-associated GCA. METHODS: a 28 years old man with clinically definite TSC and several GCAs, s/p multiple surgeries for those lesions, was treated with 10 mg/day oral RAD001 for 10 months. Magnetic resonance imaging scans and neuro-ophtalmological exams were P-CPS.07. THE ROLE OF NEUROIMAGING IN YOUNG performed before and at regular intervals following initiation of therapy. CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 RESULTS: The lesions exhibited significant regression in several lesions L. J. Klesse, L. Gargan, R. Elterman, and D. C. Bowers; UT Southwestern and stabilization in others, accompanied with some improvement of his Medical Center, Dallas, TX, United States visual function. Treatment was well tolerated, but was discontinued due to hypertension and elevated CPK, without evidence for rhabdomyolysis. INTRODUCTION: Low-grade gliomas of the optic pathway affect a sub- Since relation to therapy could not conclusively rule out, therapy was stantial number of children with Neurofibromatosis type 1 (NF1), a genetic stopped. Yet, during 6 months following interruption of therapy, GCA ’s cancer predisposition syndrome. Optic pathway gliomas (OPGs), especially remained unchanged. CONCLUSIONS: Oral RAD001 demonstrated pre- in children with NF1, demonstrate unpredictable growth. Screening and liminary encouraging results as treatment of astrocytomas associated with management for OPGs continues to be controversial, especially in very TSC. It may therefore be an alternative to surgery in these lesions. young children. METHODS: We conducted a single-institution, retrospective review of young children with NF1 who underwent screening neuroimaging. RESULTS: Seventy two patients with NF1 underwent screening magnetic resonance imaging (MRI) examinations prior to the age of 3 years. Ten of seventy two (14%) patients had an initial MRI scan positive P-CPS.10. CASE REPORT: BECKWITH-WIEDEMANN for an OPG. No patient younger than 18 months (1.5 years) was found to SYNDROME AND EPENDYMOMA have an OPG on their initial MRI. The average age at initial positive MRI A. A. Smith, A. Miloff, H. N. Bess, and D. W. Pincus; University of Florida, scan was 1.88 +/- 0.31 years. On follow-up MRI, 45/62 patients (73%) Gainesville, FL, United States continued to have no OPGs while 17 patients (27%) subsequently developed an OPG. The average age for development of an OPG was 2.46 +/- 1.08 We present a patient with Beckwith-Wiedemann Syndrome (BWS) who years. Of the 27 patients with OPGs identified by screening MRI, 7 patients developed a posterior fossa (PF) ependymoma. This is the only case of epen- (26%) required therapy. The average age at treatment was 2.76 +/- 0.9 dymoma with BWS patient that we have found. The genetics of BWS are years. CONCLUSIONS: Our analysis demonstrates that screening MRI strongly associated with the 11p15 chromosome and the growth regulatory did not identify clinically significant OPGs in young children, especially genes located within this region. The genetics of ependymomas are highly those younger than eighteen months of age. variable, and potentially could parallel BWS tumorgenesis mechanisms. For example, pediatric cases of PF ependymomas often show loss of chromosomes 22, 6 and 17. There are data to suggest that loss of imprinting in some genes may play a role in the development of ependymoma. CASE: The child was diagnosed with BWS as a newborn. Diagnosis of PF ependymoma was P-CPS.08. BRAIN TUMOUR AS PRESENTING SYMPTOM IN 2 done at age 2 years. He had 3 recurrences within 5 years before dying of CHILDREN WITH AN NF-1 LIKE PHENOTYPE IN his disease. DISCUSSION: Ependymomas have been associated with chro- CONSTITUTIONAL MMR-DEFICIENCY SYNDROME DUE TO mosomal anomalies, however many chromosomes have been implicated. BI-ALLELIC PMS-2 MUTATIONS Loss of imprinting has also been found to play a role in ependymoma, and J. Fock, R. Lunsing, M. Olderode-Berends, J. Herkert, E. Hoving, other gliomas as well. The gene PEG3 (paternally expressed gene 3) is impli- R. Scheenstra, and R. Tamminga; University Medical Center Groningen, cated in the development of these cancers, and thought to play an important Groningen, Netherlands role as a tumor suppressor, as well as in cell proliferation and apoptosis, although the exact mechanisms are not understood. Imprinting dysfunction Constitutional MMR-deficiency Syndrome (CMMR-D) is a hereditary has been linked to various other types of cancers in addition to those linked childhood cancer syndrome with high risk to develop brain tumours at with BWS, and may provide insight into tumor development once it has been median age 2-35 years. 25 % of the diagnosis is made before the age of 25 studied in more depth. years. We describe two children with rare brain tumours and clinical diagnosis of Neurofibromatosis-I, turning out to have CMMR-D. A 2-year old boy presented with a positive p53, high Ki-67 angiosarcoma in the left frontal lobe. At examination he showed more than 6 Cafe´ Au Lait Maculae (CALM), axillary freckling and attention deficit and hyperactivity disorder. P-CPS.11. GERMLINE TP53 MUTATION PRESENTING WITH NF-I mutation analysis was negative. Two years later second resection, METACHRONOUS MALIGNANCIES INCLUDING because of relapse was needed. No adjuvant therapy was given. At age 6 MEDULLOBLASTOMA rectal blood loss was reported and 2 rectal adenoma were resected. D. Sumerauer1, S. Cyprova1, M. Kyncl2, V. Krutilkova3, R. Kodet4, Revieuw of the angiosarcoma showed microsatellite instability (MSI). Loss E. Kabickova1, and Z. Sedlacek5; 1Department of Pediatric Hematology and of PMS-2 expression was observed. Two pathogenic germline PMS-2 Oncology, Prague, Czech Republic; 2Department of Radiological mutations were found. A 9-year old girl presented with haemorrhage in a Techniques, Prague, Czech Republic; 3Gennet, s.r.o., Prague, Czech tumour in the ventricle. Resection and, because of residual tumour, Republic; 4Department of Patology and Molecular Medicine, Prague, Czech re-exploration were done. Histology showed a highly mitotic, diffuse p53, Republic; 5Department of Biology and Medical Genetics, Prague, Czech high Ki-67 ganglioglioma, WHO grade 3. Because of .6 CALM, axillary Republic freckling, no NF-1 or SPRED1 mutation found, suspicion of CMMR-D was raised. The tumour showed MSI and loss of PMS-2 expression; mutation Li-Fraumeni syndrome is a rare autosomal dominant disease, which pre- analysis is pending. A rectal adenoma was resected recently. disposes individuals to a wide range of cancer including brain tumors. We CONCLUSION: In children with a NF-I like phenotype and a brain describe a case of a 10-year-old male with germ line TP53 mutation, who tumour CMMR-D Syndrome should be considered developed 3 consecutive malignancies. He presented in year 2000 at the age of 18 months with adrenal cortical carcinoma which was completely resected. Due to the positive family history of cancer genetic counselling was recommended and granted in 2003. Genomic DNA sequencing ii86 NEURO-ONCOLOGY † JUNE 2010 Abstracts

identified heterozygous C . T mutation in codon 342 in exon 10 resulting in dramatically impairs proliferation and induces apoptosis, via a process a shift from arginine to a premature stop codon. The boy was regularly fol- associated with telomerase inhibition. The proposed mechanism of lowed up including the MRI of the brain. Despite this he presented in July TSA-mediated effects will be discussed, with respect to epigenetic regu- 2004 with large cerebellar medulloblastoma. The medulloblastoma was lation of telomerase. HDACi effects on childhood brain tumour stem/pro- completely resected, the child underwent craniospinal radiation with boost genitor cells, likely to be critical for tumour initiation and propagation, are to the posterior fossa. Following radiotherapy, the patient completed eight being investigated. series of chemotherapy using cisplatin, vincristine, and lomustine and was without any complaints until 12/2007 when he presented with recurrent infections and pancytopenia. The diagnosis of MDS-RAEB was established and the patient underwent succesfful allogeneic bone marrow transplant from MUD. Unfortunately two months after BMT he succumbed to P-DRUG.02. ANTINEOPLASTONS INITIATE CASPASE massive cerebral hemorrhage. The case demonstrates the difficulties of man- INDUCED APOPTOSIS BY SUPPRESSING SURVIVIN agement of individuals with Li-Fraumeni syndrome. The treatment of famil- EXPRESSION IN U87 GLIOBLASTOMA CELLS ial brain tumor is identical to their sporadic counterparts. Screening brain S. Patil, S. R. Burzynski, E. Mrowczynski, and K. Grela; Burzynski Research MRI is usually not helpful given the rapid development of brain tumors as Institute, Houston, TX, United States in our case. Methods and frequency of follow-up are still debated. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Supported by IGA NS/9997-4 and MZOFNM2005 Antineoplastons have been used with success in FDA supervised Phase II clinical trials for several different types of brain tumors and have now been approved for Phase III trials. Our research is based on studies with Phenylacetylglutaminate (PG) and Phenylacetate (PN), which are ingredients of antineoplaston AS2-1. We have recently, gained insight into the possible P-CPS.12. RADIATION THERAPY AND ADJUVANT mechanisms by which antineoplastons exert their inhibitory effect on CHEMOTHERAPY IN A PATIENT WITH A HIGH GRADE growth of cancer cells. Using the U87 glioblastoma cell line we have GLIOMA AND UNDERLYING ATAXIA TELANGIECTASIA shown previously that upon treatment with a combination of PG and PN, M. D. DeWire, A. S. Pai Panandiker, D. E. Ellison, P. J. McKinnon, the G2/M checkpoint kinase, Chk1 is suppressed, causing inability to M. B. Kastan, and A. Gajjar; St. Jude Children’s Research Hospital, repair damaged DNA leading to apoptosis. We show in this presentation Memphis, TN, United States that this apoptosis is due to activation of the caspase pathway and suppression of survivin expression. Survivin is a member of the inhibitor of apoptosis We describe a case of a 12 year old female with ataxia telangiectasia (A-T) (IAP) gene family. The expression of survivin is widely deregulated in cancer diagnosed with a malignant glioneuronal tumor of the right parietal lobe. and is upregulated in most phases of the cell cycle, more so in the G2/M This tumor was considered a high grade glioma for therapeutic purposes. phase. Survivin has also been identified as a target of wild type p53. The standard therapy for high grade glioma includes surgical resection and Additionally the expression of survivin in patients has been correlated to radiation therapy; yet, clinical data is limited regarding how a patient with decreased survival, increased recurrences and resistance to therapy. Along A-T will respond to cranial radiotherapy. Two subtotal resections were per- with survivin, the expression of Aurora B kinase, a potential binding formed; however, the tumor continued to reveal progression on diagnositic factor, is also suppressed in response to antineoplastons in U87 cells. imaging. Based on documented scientific data, a therapeutic plan was Targeting the survivin pathway by antineoplastons sheds new light on the implemented to include radiotherapy modified with daily fractionation and mechanism of action of these compounds in treating this highly malignant molecular targeted therapy including Bevacizumab and Everolimus. brain tumor. Radiation therapy was divided into two phases. The first phase totaled 600 cGy with 50 cGy fractions. Due to the lack of toxicity with this dose of irradiation, the second phase included 75 cGy fractions with a cumulative total dose of 2100 cGy. This is the first reported case in the A-T literature receiving this treatment regimen with minimal toxicities. The patient had P-DRUG.03. PEROXISOME PROLIFERATOR-ACTIVATED grade 3 skin toxicities at the radiation site 1 week post completion of radi- RECEPTOR g AGONIST, CIGLITAZONE, IN HUMAN ation therapy which resolved over the next 2 weeks. Additionally, she devel- GLIOBLASTOMA CELLS oped grade 2 mucocitis which resolved upon holding everolimus for 2 weeks. H. Jung, Y. Noh, M. Lee, D. Kim, H. Kim, H. Kim, H. Cheuh, S. Lee, At 6 month follow up visit, the patient had progressive disease on imaging K. Yoo, K. Sung, and H. Koo; Sungkyunkwan University School of and was enrolled on a Phase I therapy protocol. Medicine, Seoul, Republic of Korea

Activation of peroxisome proliferator-activated receptor g (PPARg) leads to inhibition of cell proliferation and/or induction of apoptosis or terminal P11 CLINICAL TRIALS AND DRUG differentiation. In this study, we examined in vitro cytotoxicity and apoptotic DEVELOPMENT response of Ciglitazone (CGZ), a PPARg agonist, against the human glioblastoma cells T98G. CGZ over 30 mM, but not below 30 mM, induced sig- niﬁcant cytotoxicity and cell-cycle arrest in T98G cells. Although individual treatment with 20 mM CGZ or 30 mM GW9662, an antagonist of PPARg, P-DRUG.01. HISTONE DEACETYLASE INHIBITION could not provoke cell death, co-treatment with 20 mM CGZ and 30 mM ATTENUATES CELLULAR GROWTH IN HIGH GRADE GW9662 synergistically induced apoptosis and cell cycle arrest in T98G PAEDIATRIC BRAIN TUMOURS WITH ASSOCIATED cells. Treatment with CGZ after down-regulating PPARg by siRNA also TELOMERASE INHIBITION AND APOPTOTIC INDUCTION. 1 1 2 1 2 induced cell death. Our results showed that CGZ can induce cell death inde- R. Rahman , T. Osteso-Ibanez , R. Hirst , J. Levesely , C. O’Callaghan , pendent of PPARg in T98G cells. We observed Bid, a proapoptotic Bcl-2 B. Coyle1, and R. Grundy1; 1University of Nottingham, UK, Nottingham, 2 member, cleavage and then triggering Bax, indicating that mitochondrial United Kingdom; University of Leicester, UK, Leicester, United Kingdom proteins are critical initiating events. In addition, treatment with 20 mM CGZ alone or 20 mM CGZ after 30 mM GW9662 induced activation of Inhibition of histone deacetylases (HDACs) increases acetylation of Akt, but co-treatment with 20 mM CGZ and 30 mM GW9662 decreased histone and non-histone proteins, leading to an increase in transcriptionally activation of Akt in T98G cells. These data support that CGZ treated active chromatin. We have observed anti-proliferative and pro-apoptotic below 30 mM could enhance antiapoptotic effects by binding to PPARg, effects of malignant childhood brain tumour cells following treatment with but free CGZ activate PPARg-independent cell death via Akt inactivation the HDAC inhibitor (HDACi) Trichostatin A (TSA). Cessation of prolifer- because GW9662 could prevent interaction between CGZ and PPARg by ation upon 48h TSA treatment (0.5-3.0 mM) was observed in the majority binding to PPARg. Therefore, we suggest the combination of CGZ and of PFSK-1 (CNS PNET), DAOY (medulloblastoma), EPN-2 (ependymoma; GW9662 could be used as a novel therapeutic approach for treatment of derived in-house) and BT-4 (glioblastoma multiforme; derived in-house) glioblastoma. cells. EPN-2, BT-4 and DAOY show a distinct reduction in S-phase cells with a concurrent increase in G2/M-phase cells. Prolonged TSA exposure results in signiﬁcantly high levels (30-80%) of apoptosis indicated by the proportion of sub G0/1 cells. All lines show activation of the pro-apoptotic factor, caspase-3. Apoptosis appears p53/p21-independent in PFSK-1, P-DRUG.04. AURORA KINASE A AS A RATIONAL TARGET FOR EPN-2 and BT-4 cells; in contrast DAOY cells show upregulation of p21. THERAPY IN GLIOBLASTOMA There is marked inhibition of telomerase activity in the PFSK-1, DAOY V. N. Barton, N. K. Foreman, A. M. Donson, D. K. Birks, and R. Vibhakar; and EPN-2 lines. As etoposide-treated cells reveal apoptotic induction University of Colorado Denver, Aurora, CO, United States without concomitant telomerase inhibition, the observed effects are due to TSA function and not simply a consequence of apoptotic cells. No cel- BACKGROUND: Despite better understanding of glioblastoma multiforme lular toxicity was observed in a rat ependymal ex vivo model exposed to (GBM) tumor biology, the clinical outcome of GBM tumors remains poor. The TSA. In summary, childhood brain tumour cells treated with TSA

NEURO-ONCOLOGY † JUNE 2010 ii87 Abstracts

design of many molecularly targeted therapies in GBM has focused on inhibit- resulted in an at least additive anti-clonogenic effect in combination with ing molecular abnormalities present in tumor cells compared to normal tissue clinically relevant doses of IR (2 or 5 Gy). Patupilone induced pronounced rather than patient outcome associated factors. We hypothesized that inhi- apoptosis in D425 and DAOY cell lines and autophagy in D341 cell line. bition of a molecular target associated with poor outcome would impact Cell cycle analysis revealed a sequential G2/M-arrest and sub-G1 accumu- GBM cell proliferation. METHODS: The present study correlated pediatric lation in a dose and treatment-dependent manner after exposure to patupi- and adult patient survival data with tumor gene expression profiling and lone. CONCLUSION: Patupilone demonstrates potent efficacy against gene ontology analysis. Genes associated with shorter survival were identified medulloblastoma cell lines and represents a promising candidate to replace and one of these was selected for therapeutic targeting in an in vitro system. vincristine as part of a combined treatment strategy with ionizing radiation. GBM cell growth suppression was measured by H3-thymidine uptake, colony formation, and flow cytometry. RESULTS: The gene expression microarray and ontology analysis revealed that genes involved in mitotic processes, including Aurora Kinase A (AURKA), were associated with poor prognosis in both pediatric and adult GBM. Inhibition of AURKA suppressed GBM cell P-DRUG.07. A SMALL MOLECULE IAP INHIBITOR SENSITISES growth. Moreover, inhibition of AURKA was synergistic with radiation in MEDULLOBLASTOMA CELLS TO RADIATION THERAPY AND GBM cells at high radiation doses. CONCLUSIONS: Relative expression of CYTOTOXIC CHEMOTHERAPY IN VITRO AND IN VIVO AURKA may be of prognostic value and warrants further investigation with D. S. Ziegler1,2, J. Keating2, L. Zawel3, and M. Haber2; 1Sydney Children’s Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 larger, prospective studies. Pharmacological inhibition of AURKA is a poten- Hospital, Randwick, Australia; 2Children’s Cancer Institute, Australia for tially promising therapy for GBM. Medical Research, Randwick, Australia; 3Novartis Institute for Biomedical Research, Cambridge, MA, United States

Novel strategies for treating medulloblastoma are urgently needed. Strategies to sensitise medulloblastoma cells to the effects of radiation P-DRUG.05. DASATINIB ACTIVITY ON GLIOBLASTOMA CELLS therapy have been proposed as a mechanism to both decrease toxicity and IS DUE TO ANOIKIS enhance efficacy. The Inhibitor of Apoptosis Proteins (IAPs) represent the M. Gruber-Olipitz1,2, S. K. Dabral1,2, K. L. Ligon3,4, and R. A. Segal1,2; last molecular barrier to programmed cell death, are over-expressed in 1Pediatric Oncology and Cancer Biology, Dana-Farber Cancer Institute, medulloblastoma and correlate with poor patient outcomes. We hypoth- Boston, MA, United States; 2Department of Neurobiology, Harvard Medical esized that targeting the IAPs in conjunction with conventional cytotoxic School, Boston, MA, United States; 3Department of Medical Oncology and therapies would significantly enhance their anti-tumor activity. We have pre- Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, viously shown that the small molecule IAP inhibitor LBW242 penetrates the Boston, MA, United States; 4Department of Pathology, Children’s Hospital blood brain barrier and accumulates in intracerebral tumours. We therefore Boston, Boston, MA, United States tested LBW242 in medulloblastoma in combination with the standard-of-care therapies of irradiation and cytotoxic chemotherapy. In PURPOSE: Recent studies identified SRC as a new potential target in glio- vitro experiments demonstrated that administration of LBW242 in combi- blastoma (GBM) therapy. In addition, the SRC inhibitor dasatinib demon- nation with radiotherapy and chemotherapy led to both caspase 8 and 9 acti- strated anti-proliferative activity on GBM cell lines. Since modern vation resulting in direct activation of both the intrinsic and extrinsic treatment efforts include targeting cancer stem cells to achieve better apoptotic pathways. Annexin staining showed that this ultimately led to control of tumor recurrences, we asked whether dasatinib is also effective medulloblastoma cell death and clonogenic assays showed that the combi- at targeting GBM cancer stem cells. METHODS: Cancer stem cells were iso- nation therapy led to a synergistic anti-medulloblastoma effect in multiple lated from primary GBM patient samples and grown as neurospheres under cell lines. Athymic mice bearing established human medulloblastoma stem cell conditions or as monolayer attached to laminin. In parallel, the tumor xenografts treated with LBW242 plus cisplatinum demonstrated a GBM cell line LN428 was also grown either as monolayer or as neuro- profound suppression of tumor growth in the in vivo setting. Taken together spheres. After treating all different conditions with increasing dasatinib con- these experiments show that the pro-apoptotic and anti-tumour effects of centrations for 7d, viability as well as neurosphere size was measured as radiotherapy and chemotherapy can be enhanced by the addition of a appropriate. RESULTS: We did not observe any anti-proliferative effect of small molecule, orally bioavailable IAP inhibitor. These results are readily dasatinib on GBM cancer stem cells or cell lines grown as neurospheres. translatable to clinical trial, and offer the potential for improved treatment However, when we cultured the same cells under adherent conditions, a sig- outcomes for medulloblastoma patients. nificant, dose-dependent decrease in viability was observed (50% in cancer stem cells, 60% in LN428), potentially due to loss of attachment (anoikis). CONCLUSION: The SRC-inhibitor dasatinib demonstrated a significant effect on GBM cancer stem cells and cell line viability only when cells P-DRUG.08. SIMULTANEOUS BLOCKADE OF HER1/2AND were grown on an adhesive substrate, not when grown as neurospheres. VEGFR1/2PATHWAYSBYAEE788RESULTSINGREATER These studies indicate that 1) the effectiveness of Src inhibitors reflects an GROWTH INHIBITION OF HER2-OVEREXPRESSING ability to induce anoikis in GBM cells, 2) Src inhibitors are effective in MEDULLOBLASTOMA (MB) XENOGRAFTS: POTENTIAL GBM cancer stem cells as well as cell lines, and 3) differences in drug efficacy THERAPEUTIC IMPLICATIONS? depend on the particular growth conditions used. T. Servidei, D. Meco, G. F. Zannoni, M. G. Prisco, E. Martinelli, V. Ridola, C. de Waure, C. Di Rocco, and R. Riccardi; Catholic University of Rome, Rome, Italy

OBJECTIVE: HER1/2 pathway and VEGFR-dependent angiogenesis P-DRUG.06. THE MICROTUBULE STABILIZER PATUPILONE have a crucial role in tumorigenesis. We investigated the effects of simul- (EPOTHILONE B) IS A POTENT RADIOSENSITIZER IN taneous blockade of HER and VEGFR signaling by the multitargeted MEDULLOBLASTOMA CELLS kinase inhibitor AEE788 in MB models, including established lines (Daoy C. Oehler1, A. O. von Bueren2,3, P. Furmanova1, S. Rutkowski2, K. Frei4, and D283), ectopically HER2-overexpressing (DaoyHER2) and cisplatinum- M. A. Grotzer3, and M. Pruschy1; 1Department of Radiation Oncology, resistant (DaoyPt) cells. RESULTS: Lines expressed diverse levels of total and University Hospital, Zurich, Switzerland; 2Department of Pediatric activated AEE788 target receptors. In vitro, AEE788 inhibited proliferation Hematology and Oncology, University Medical Center of lines to a similar extent and prevented ligand-induced HER1, HER2 and Hamburg-Eppendorf, Hamburg, Germany; 3Department of Pediatric HER3 activation, being scarcely effective on constitutively active HER2. Inhibition of Akt paralleled that of receptors. In vivo, AEE788 inhibited Oncology, University Children’s Hospital, Zurich, Switzerland; 4Department of Neurosurgery, University Hospital, Zurich, Switzerland Daoy and DaoyPt xenografts by 50%, and DaoyHER2 xenografts by 70%. Treatment lowered activated HER1. In DaoyHER2 xenografts, PURPOSE: We investigated the antiproliferative effect of patupilone along with high HER2 expression, high VEGFR2 staining in tumor and (EPO906, epothilone B), a novel non-taxane-related and non-neurotoxic endothelial cells and increased CD31 expression were observed. AEE788 microtubule-stabilizing natural compound, and its cytotoxic and radiosensi- reduced HER2 and VEGFR2 activation. In cell-based assays, VEGF and tizing potential in human medulloblastoma (MB) cell lines. MATERIAL VEGFR2 expression was upregulated by ligands or hypoxia to a greater AND METHODS: The anti-proliferative and cytotoxic effects of patupilone extent in HER2-overexpressing cells. In 21 MB samples HER2 expression ¼ alone and in combination with ionizing radiation (IR) was determined in correlated (p , 0.01) with the angiogenesis-related genes VEGFR2 (r ¼ ¼ DAOY, D341, and D425 MB cell lines using the MTS proliferation, the 0.56), VEGF (r 0.61) and bFGF (r 0.60). CONCLUSIONS: AEE788 Trypan blue viability, and the clonogenic survival assay, respectively. A shows similar growth-suppressive activities in chemosensitive and chemore- patupilone-mediated effect on cell cycle distribution was assessed by sistant MB cells in vitro and in vivo. Ectopic HER2 overexpression sensitizes ﬂuorescence-activated cell sorter (FACS). Mode of cell death was determined cells to AEE788 in vivo, probably because AEE788 inhibits both using a caspase-3 activity assay, and by FACS (acridine orange). RESULTS: HER2-induced angiogenesis and an autocrine signaling mediated by de Patupilone alone effectively reduced proliferative activity and clonogenicity novo expression of VEGFR2 in tumor cells. In human MB HER2 correlates of all MB cell lines tested at picomolar concentrations (50 - 200 pM) and with VEGF, VEGFR2 and bFGF. MB, most likely HER2-overexpressing MB, might beneﬁt from AEE788 treatment. ii88 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-DRUG.09. FROM MT3 MODULATION TO HDACI Here we report a preliminary retrospective chart review of patients treated this TREATMENT IN BRAIN TUMORS way. In seven patients our charts contained outcome information. The histologi- C. Dantas-Barbosa1, G. Bergthold1, G. Dieffenbach1, H. Blockus1, S. Puget2, cal diagnoses included: PNET (3), GBM (2), ATRT (1), and choroid plexus car- C. Sainte-Rose2, B. Geoerger1, G. Vassal1, and J. Grill1; 1Institut Gustave cinoma (1). The markers resulting in the final treatment decision included Roussy, Villejuif, France; 2Hoˆ pital Necker Enfants Malades, Paris, France ERK-P, Topo IIa, BCL2, VEGFa, p-STAT 3, ER, mTORC1, and p-NF-kappaB. The drugs chosen included sorafenib, bevacizumab, fluvestrant, Microarray analysis in 27 relapses of ependymomas revealed down regu- rapamycine, bortezomib, and curcumin. The early response was 0/2/2/1/and lation of metallothionein 3 (MT3) in 87% of relapses. MT3 is mostly 1 classified as CR/PR/CCR/SD/PD/ and undetermined, respectively. By expressed in the brain and exhibits growth inhibitory activity in a variety January 2010 three patients lived in remission, one with tumor, one had of cell types, a characteristic not shared by other members of the MT passed away from tumor progression, and one had passed away by unknown family. We postulated that MT3 downregulation confers an advantage to reasons. When comparing response and EFS of these treatment attempts to tumor growth. Besides in ependymomas, MT3 downregulation was detected the previous ones in the same patients, the response appeared superior, but by q-PCR in malignant gliomas and medulloblastomas. The HDAC inhibi- data were insufficient to show a benefit for EFS. Both, the algorithm and the tors TSA and vorinostat (SAHA) induced MT3 expression by 10-100 fold, analysis methods need to become more concrete as the treatment approach and reduced cell viability of DAOY medulloblastoma, SF188 pediatric develops further, before this can be turned into a formalized study protocol. glioma, Res196, Res253 and Res254 ependymoma cell lines and NEM78 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 and NEM94 primary ependymoma cultures with IC50 doses of 1.5 to 3.0 mM at 72 hours of treatment, without inducing apoptosis. In contrast, the ependymoma NEM65 seemed resistant (80% viability at 72 hours), along with low induction of MT3 expression. FACS analysis showed G2/ P-DRUG.12. HIT-HGG-CILMETRO - A PHASE II STUDY USING M arrest in the sensitive NEM78 cells and approximately 10% increase in CILENGITIDE AND METRONOMIC TEMOZOLOMIDE FOR sub-G1 population in the Res196, 253 and 254 cells, after 48h of SAHA RELAPSED OR REFRACTORY HIGH GRADE GLIOMAS OR treatment. Transfection of SF188 and NEM78 with the plasmid pMT3 DIFFUSE INTRINSIC PONTINE GLIOMAS IN CHILDREN AND resulted in 80% cell growth reduction compared to plasmid control. MT3 ADOLESCENTS downregulation appears to be an important phenomenon in brain tumors C. Classen1, J. Steighardt2, A. Wienke3, U. Rausche4, and C. Kramm4; progression and its upregulation is associated with reduced cell proliferation. 1University Childrens Hospital, Rostock, Germany; Sensitivity to SAHA was associated with MT3 expression levels in tumor 2Koordinierungszentrum fu¨ r Klinische Studien, Halle, Germany; 3Institut fu¨ r cells. This class of drugs may represent a potential new treatment for epen- Medizinische Epidemiologie, Biometrie und Informatik, Halle, Germany; dymoma, glioma and medulloblastoma. 4University Childrens Hospital, Halle, Germany

Relapsed or refractory high-grade gliomas (HGG) or diffuse intrinsic pontine gliomas (DIPG) in children and adolescents have a dismal prognosis, with no current standard therapy. None of numerous new substances, as single agents, P-DRUG.10. CURING BRAIN TUMORS IN DOGS AND represented a therapeutic breakthrough. In our opinion, a relapse treatment CHILDREN: THE TEXAS COMPARATIVE NEURO-ONCOLOGY regimen for pediatric HGG and DIPG should include one of the promising sub- PROGRAM stances, use a combined treatment strategy, and display limited overall toxicity. S. A. Fletcher1, J. Wolff2, J. Levine3, P. Gildenberg1, L. Cooper2, and The combination of the integrin inhibitor cilengitide and metronomic temozo- J. Slopis2; 1University of Texas Medical School at Houston, Houston, TX, lomide may fulfill these criteria and will be investigated in the multi-center United States; 2University of Texas M.D. Anderson Cancer Center, Houston, single arm phase II clinical trial HIT-HGG-CilMetro for relapsed pediatric 3 TX, United States; College of Veterinary Medicine, Texas A&M University, HGG and DIPG patients. Cilengitide selectively inhibits integrins aVb3 and College Station, TX, United States aVb5 expressed on tumor cells during growth and invasion and on activated endothelialcells.Metronomic temozolomideacts byanti-angiogenesisand cyto- Successful therapy for brain tumors is associated with high cost, frustration, toxicity and is still effective after conventional temozolomide first-line treat- failures and triumphs, and is compounded by the limitations of time and ment, partly due to O6-methylguanine-DNA methyltransferase depletion. For volume of patients studied. Spontaneous brain tumors in canines have been both, safe pediatric doses are defined, thus, patients will receive intravenous estimated to be as high as 20 per 100,000, almost 5 times the rate in cilengitide (1800 mg/m2) twice weekly, and oral temozolomide (75 mg/m2/ humans. Similar histological typing and neuro-imaging provide tremendous d) for 6 weeks, followed by one week rest (with a mandatory platelet dependent potential for comparative studies in humans. This source of spontaneous dose adaptation rule). Study treatment is scheduled for 1 year unless tumor pro- tumors provides a rich environment for clinical comparative studies in vir- gression or unacceptable toxicity. Primary study end point is 6 month overall tually all fields of neuroscience and provides a framework to establish standar- survival after relapse diagnosis. Secondary endpoints include safety, toxicity, dized canine human research models, the intent of which is to cure these response rates, and pharmacokinetics. The study is conducted by the tumors in both dogs and man. We have established a cooperative program GPOH-HIT-HGG Study Group and supported by Merck KGaA, Darmstadt, among investigators at a cancer center, a veterinary medical center and a chil- Germany, with Cilengitide, a grant and with the editorial works. It will be dren’s hospital that will enter companion dogs into a diagnostic and thera- initiated in late 2010. peutic protocol designed to cure the dog. All dogs undergo either image guided biopsy or resection of their tumor. Basic science studies including tumor biology, genetics, molecular biology, immunology, and imaging characteristics will compliment a detailed analysis of clinical response to stan- P-DRUG.13. A PHASE II PILOT STUDY OF THALIDOMIDE AND dardized therapies or targeted therapies. At death all dogs will undergo TEMOZOLOMIDE IN PATIENTS WITH RELAPSED OR PROGRESSIVE BRAIN TUMORS autopsy. We present the rationale for developing an evidence based 1,2 1 1,2 1,2 1,2 program using companion canines with spontaneously occurring brain P. E. Manley , J. Pietrantonio , S. N. Chi , M. Lee , N. Robison , N. J. Ullrich1,3, M. Zimmerman1, C. Chordas1, L. Goumnerova1,4, and tumors to circumvent the problems of low volume and time so crucial in estab- 1,2 1 lishing treatment protocols for children. We advocate the development of like M. W. Kieran ; Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; 2Hematology/Oncology, Children’s Hospital cooperative programs around the world where resources permit and present 3 the basic organizational and technical aspects of our program. Boston, Boston, MA, United States; Neurology, Children’s Hospital Boston, Boston, MA, United States; 4Neurosurgery, Children’s Hospital Boston, Boston, MA, United States

PURPOSE: Recurrent and progressive brain tumors have a poor prognosis in P-DRUG.11. TARGETED PERSONALIZED THERAPY FOR children. Patients have exhausted most standard chemotherapies. A feasibility PEDIATRIC PATIENTS WITH REFRACTORY BRAIN TUMORS trial using a combination of an antiangiogenic agent plus chemotherapy was J. E. Wolff1, R. Brown2, M. Rytting1,T.Vats1, R. Bingham1, R. Epps1, conducted in pediatric patients with relapsed or progressive brain tumors and S. Fletcher2, S. Pfister3, L. Ketonen1, J. Slopis1, M. Nagel1, and P. Thall1; neuroblastoma to evaluate the radiographic response and the overall survival 1MDAnderson Cancer Center, Houston, TX, United States; 2U of Texas in patients. PATIENTS AND METHODS: After IRB approval, all patients Medical School, Houston, TX, United States; 3DKFZ, Heidelberg, Germany received thalidomide and temozolomide. Thalidomide was given initially daily at 3mg/kg and increased to a maximum dose of 24 mg/kg or 1000 mg Classical histological diagnoses are increasingly enriched with molecular as tolerated. Temozolomide was administered once a day for the first 5 days information resulting in smaller patient groups. Many novel agents will never of each 28-day cycle. Treatment continued for 6 months and could be extended be studied for pediatric malignancies with traditional methods. We have recently if disease progression had not occurred. RESULTS: Between 2002 and 2007, 15 ¼ ¼ personalized the treatment byadding agents based on tumor markers. The algor- subjects were enrolled, female (n 9), brain tumor (n 8). All patients ithm starts with the treatment history and evidence based drug rankings, and received thalidomide and temozolomide. Six patients completed treatment (3 creating a first personalized treatment cycle. In addition, each tumor is analyzed patients with brain tumor, 3 with neuroblastoma), 6 patients had progressive for a panel of markers resulting in novel drugs to be added to the second cycle. disease, 2 patients stopped due to toxicity (suicidal ideation and allergic symptoms), one patient responded but then underwent stem cell transplant. Overall

NEURO-ONCOLOGY † JUNE 2010 ii89 Abstracts

best response was 1 PR, 9 SD, 5 PD. Median overall survival time is 12.8 months tumors. For children with high-grade or recurrent brain tumors, new drugs (95% CI [6.7, 41.2]. Overall survival at one and two years is 60% + 13% and and new combinations of drugs are needed. METHODS: Patients were 33% + 12%, respectively. CONCLUSION: Temozolomide and thalidomide selected for this therapy based on relapsed or progressive disease with no was well tolerated and led to disease stabilization in the majority of patients other standard therapy available. Treatment cycles were 28 days and the with relapsed brain tumors and neuroblastoma. Further study is warranted drugs were dosed as follows: bevazicumab 10 mg/kg day 1 and 15, irinote- using this oral treatment regimen, which permits outpatient treatment in this can 125 mg/m2 day 1 and 15, and temozolomide 125 mg/m2 days 1-5 for heavily pretreated patient population. cycle 1, then escalated to 150 mg/m2 for subsequent cycles if , grade 2 toxicities. Toxicities were collected and graded prospectively. RESULTS: Four patients with relapsed/progressive disease after standard therapy have been treated with this regimen. Diagnoses include choroid plexus carcinoma (n ¼ 1), low-grade glioma (n ¼ 2), and anaplastic astrocytoma (n ¼ 1). The P-DRUG.14. TOXICITY PROFILE OF BEVACIZUMAB BASED median age was 14.5 years (range, 4-18 years). The patients have received REGIMENS IN THE TREATMENT OF PEDIATRIC MALIGNANT 2-10 cycles. There was only one grade 4 toxicity (neutropenia, n ¼ 1) and BRAIN TUMORS - A SINGLE INSTITUTION’S EXPERIENCE no grade 3 toxicities. Grade 2 toxicities were neutropenia, vomiting, and V. T. Huynh, T. Templeman, and V. Shen; CHOC Children’s Hospital of infection with normal ANC. One patient had a partial response (low-grade Orange County, Orange, CA, United States glioma) and the remainders have stable disease. All patients continue on Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 therapy. CONCLUSION: The combination of bevacizumab, irinotecan, OBJECTIVE: To assess the toxicity of bevacizumab (BV) in the treatment of and temozolomide has been tolerable at these doses. A phase I study is in pro- pediatric brain tumors. METHODS: A retrospective, single institution review gress to escalate the temozolomide. of patients with malignant brain tumors treated with BV based regimens was conducted. There were 16 patients (7 high grade gliomas, 4 metastatic medulloblastomas, 5 brain stem gliomas) with median age 8.5 years. Eight patients received BV, irinotecan (IRN) and temozolomide (TMZ). Seven patients received BV and IRN and one received BV alone. BV was administered P-DRUG.17. TREATMENT OF PEDIATRIC GLIOMAS WITH every two weeks at 10 mg/kg and TMZ at 150 mg/m2 orally on days 1-5 IRINOTECAN AND CISPLATIN and repeated every 28 days. The IRN dose depended on the patient’s tolerance O. Cruz1, M. Sunõl1, C. de Torres1, J. Muxart1, C. Fons1, E. Rodriguez1, (25-125 mg/m2 IV every two weeks). The median treatment duration was 8 C. Jou1, H. Salvador1, A. Parareda1, E. Lopez1, A. Guillen1, months (2-25 months). RESULTS: The common toxicities include thrombo- G. Garcia-Fructuoso1, C. Trampal2, T. Cardesa1, J. Vinent1, J. Costa1, cytopenia (8 patients; 1 grade 4), anemia (4 patients; 3 grade 2), neutropenia L. Riaza1, J. Blanch1, M. Martin1, M. Roig1, and J. Mora1; 1Hospital St Joan (4 patients; 2 grade 3), nausea and vomiting (7 patients; 4 grade 2), diarrhea (5 de Deu /University of Barcelona, Esplugues de Llobregat, Barcelona, Spain; patients; 1 grade 3), constipation (6 patients; all grade 1), hypertension (7 2PET Unit-CRCCORP, Barcelona, Spain patients; 4 grade 2), proteinuria (5 patients; 1 grade 2), elevation of ALT (8 patients; 3 grade 3), and poor wound healing (2 grade 3). Grade 1 bleeding BACKGROUND AND OBJECTIVES: After a pilot study suggesting that occurred in 6 patients. Six episodes of grade 3 infections were reported. irinotecan/cisplatin (I/C) may be effective for pediatric spinal cord astrocy- One patient developed seizures on treatment. Eleven patients had stable tomas (Mora et al, Neuro-Oncol, 2007), we initiated a phase II trial for pedi- disease lasting two to 25 months and three patients had radiographic improve- atric high-risk gliomas with the aim to assess I/C safety and efficacy. ment. Kaplan-Meir survival analysis showed an overall survival of 83% at one METHODS: Pediatric patients without prior I/C and high-risk (HR) year and 73% at two years. CONCLUSION: BV based regimens have accep- gliomas (cohort 1 ¼ HGG, cohort 2 ¼ DIPG, cohort 3 ¼ HR low-grade table toxicity in the treatment of malignant pediatric brain tumors. glioma) were eligible for this phase II trial. Therapy consisted of 8 weekly iv cycles of C (30 mg/m2) and I (50 mg/m2). If evaluation of response showed complete remission (CR), partial remission (PR) or stable disease (SD) 8 more cycles of C (30 mg/m2) and I (65 mg/m2) were given. RESULTS: Since 2003, 55 patients aged 3 months-16 years (median, 6.9 P-DRUG.15. STRIAE AND WOUND DEVELOPMENT WITH years) received this outpatient-based regimen. In 18 patients (8 DIPG, 10 BEVACIZUMAB OPG, 1 spinal NF1) no biopsy was performed. The distribution among treat- M. E. Rytting, R. Bingham, J. Wolff, and T. Vats; M.D. Anderson Cancer ment cohorts was: 16 HGG, 31 HR-LGG (10 without biopsy) and 8 DIPG Center, Houston, TX, United States patients. At this time, 12 patients have died of disease (10 HGG or DIPG). Objective response using conventional radiological/ophthalmological Bevacizumab, an antibody to vascular endothelial growth factor (VEGF), is measurements were found in 8 patients (1 HGG, 7 LGG), SD in 29, progress- used in adult patients with solid tumors. Trials with bevacizumab are now being ive disease in 12, 5 non-evaluable, one still on treatment. Overall survival conducted and reported in various pediatric tumors, including brain tumors. (OS)/progression-free survival (PFS) for each cohort group is: HGG ¼ We report on an unusual side-effect that may be attributed to bevacizumab 60%/70%, DIPG-OS ¼ 12,5%, HR-LGG ¼94%/90%, median follow-up use in brain tumor patients. A sixteen year-old female patient with a progressive is 116 months (3-93 months). No grade 3-4 toxicities were observed, vomit- glioblastoma multiforme of the right temporal lobe was entered on a clinical ing was the most common side effect, but was easily controlled. All but DIPG trial of bevacizumab and temsirolimus. The patient tolerated the initial cycle or relapsed HGG patients completed the protocol, with no documented oto- of treatment well, and repeat MRI scanning showed a marked decrease in con- toxic, renal, or GI side effects on follow-up. Radiation was avoided in all trast enhancement in the tumor. The patient also physically improved. As the HR-LGG patients. CONCLUSION: The I/C regimen is well tolerated and number of cycles increased, the patient developed progressive and debilitating allows outpatient treatment of HR-gliomas. Objective radiological/clinical skin ulcerations at the sites of abdominal striae; the striae were secondary to responses show clinical benefit in 78% of cases. Further studies are moderate obesity as well as significant corticosteroid use. The patient did not ongoing using MRI-volumetric/DTI-analysis, metabolic changes in tumors take corticosteroids during treatment with bevacizumab and temsirolimus. (methionine-PET), and biological profile (MGMT-promoter-methylation/ Attempts to improve wound healing were ineffective, and the investigational MSI/IDI1) to better define I/C response. combination therapy was discontinued. Given the known side-effect of impaired wound healing with bevacizumab, the severe skin breakdown at sites of striae was attributed to the bevacizumab. Impaired wound healing or skin breakdown is not a reported side-effect of temsirolimus. Skin breakdown and wound development at sites of striae has not been reported in published P-DRUG.18. EFFICACY OF TOPOTECAN, IFOSFAMIDE, AND Medline trials of bevacizumab. Physicians should be aware of this potential CARBOPLATIN (TIC) IN CHILDREN AND ADOLESCENTS WITH side-effect of VEGF antibody therapy, and skin dehiscence should be reported RECURRENT CNS EMBRYONAL AND GERM CELL TUMORS in patients taking bevacizumab with or without mTOR inhibitors. A. E. Fernbach1, A. Lee1, J. S. Menell2, C. Fanelli1, L. A. Harrison1, M. S. Cairo1, and J. H. Garvin1; 1Columbia University Medical Center, New York, NY, United States; 2Saint Joseph’s Children’s Hospital, Paterson, NJ, United States

P-DRUG.16. FEASIBILITY OF COMBINATION THERAPY WITH For children and adolescents with recurrent CNS embryonal or germ cell BEVACIZUMAB, IRINOTECAN, AND TEMOZOLOMIDE IN tumors, effective re-induction regimens are required in order to achieve a CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS state of minimal residual disease and facilitate collection of peripheral S. Stapleton1, F. Hamblin1, S. Steinbrueck1, S. Bradﬁeld2, G. Tuite1, blood stem cells (PBSC) for possible intensive consolidation with autolo- C. Carey1, and B. Storrs1; 1All Children’s Hospital, St Petersburg, FL, United gous stem cell rescue. We treated 5 patients (ages 2-19 years) with ﬁrst States; 2Nemours Children’s Clinic, Jacksonville, FL, United States recurrence of medulloblastoma (MB) (1), supratentorial PNET (1), pineal germinoma (1), extra-neural progression of medulloblastoma (1), INTRODUCTION: Bevacizumab, irinotecan, and temozolomide have or brain metastasis of mediastinal endodermal sinus tumor (EST) (1) each shown promising activity in a variety of central nervous system with a novel regimen of topotecan 0.5-0.75 mg/m2/day x 3 days, ii90 NEURO-ONCOLOGY † JUNE 2010 Abstracts

ifosfamide 1800 mg/m2/day x 5 days, and carboplatin 250 mg/m2/day morphine. Lipid peroxidation was not statistically different among (or dosed by Calvert formula or modified pediatric Calvert formula with treated and control groups. This result will be able us to generate new che- AUC ¼ 3mg/ml/min, if less) x 3 days (TIC). Responses assessed by motherapy approaches for treatment of brain tumors or other neurological MRI were 3 CR (MB, sPNET, germinoma), 1 continuing CR (EST), and malignancies by administration of agents that usually do not cross the 1 inevaluable because of clinical deterioration during the first cycle (extra- blood brain barrier. neural MB). PBSC were collected successfully in 2/3 patients attempted; 1 patient had PBSC collected prior to TIC, and one family refused PBSC collection. Consolidation therapies in 3/4 responders included autologous transplant (1), surgical resection of necrotic tissue (1), or radiation therapy (1); 1 family refused further therapy. All 4 responders are surviv- P-DRUG.21. LIPOSOMAL CYTARABINE - RARE ing 7 + ,18+ ,36+ , and 36+ months from relapse. Toxicity of TIC COMPLICATION OF THE TREATMENT included pancytopenia, renal insufficiency, bacteremia, fungemia, and K. Husakova and Z. Subova; Clinic of Pediatric Hematology and Oncology, transient encephalopathy. We conclude that TIC is an active regimen in Children’s Faculty Hospital, Bratislava, Slovakia recurrent CNS embryonal and germ cell tumors, with manageable toxicity, and merits further study. INTRODUCTION: Liposomal cytarabine (DepoCytew) is used in children with leptomeningeal disease but recently also as a first line therapy of Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 high risk CNS tumors and as CNS prophylaxis in ALL or AML. The most frequent side effects are headache, nausea and vomiting, arachnoiditis, pyrexia, back pain, convulsions. Other adverse events are rare. CASE P-DRUG.19. SUCCESSFUL PALLIATION OF METASTATIC PRESENTATION: A 7-year-old girl presented with back pain and bilateral MEDULLOBLASTOMA WITH ORAL ETOPOSIDE AND papilledema. MRI showed a tumor in the temporo-parietal region with infil- RISENDRONATE tration of the spinal canal. She underwent complete resection of the tumor, a S. Wilne1, L. MacPherson1, M. Brundler1, D. Ford2, and A. Peet1; histologically proven atypical choroid plexus papilloma. Treatment accord- 1Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, ing to the protocol CPT-SIOP-2000 (carboplatin, etoposide, vincristine United Kingdom; 2University Hospitals Birmingham NHS Foundation Trust, [CarbEV]), and radiotherapy was applied. More than 3 years after com- Birmingham, United Kingdom pletion of therapy, only stable low vision and atrophy of the papillae nervi optici were observed. Routine MRI control confirmed relapse of the BACKGROUND: Development of extra-neural metastases in medullo- tumor. After second complete resection (histology: choroid plexus carci- blastoma is usually associated with rapid disease progression. We report noma) 2 cycles of second line chemotherapy (doxorubicin, actinomycin D, the prolonged palliation of medulloblastoma metastatic to bone with oral vincristine, cisplatinum) and concomitant intrathecal liposomal cytarabine etoposide and risendronate. CASE: The patient was diagnosed in October with systemic dexamethasone for 5 days were administered. The fifth dose 2004, age eight, with metastatic (M2) medulloblastoma and treated with of DepoCytew was followed by local radiotherapy. 27 days later, after the chemotherapy and radiotherapy based upon POG 9031 (November 2004 fourth fraction, the patient suddenly developed weakness, dizziness, to August 2005). In May 2008 the patient developed severe (unable to reduced level of consciousness, and loss of vision. Systemic dexamethasone weight bare) right hip pain. Imaging was suggestive of metastatic disease therapy led to a rapid improvement. Radiotherapy was continued and com- in the femoral metaphysis and this was confirmed on biopsy. Imaging in pleted, followed by temozolomide therapy afterwards. CONCLUSION: August 2008 showed progressive disease with extensive abnormalities in Visual loss or blindness were only rarely observed and appeared up to 14 the pelvis and both femora. Palliative chemotherapy, oral etoposide days after intrathecal administration of DepoCytew, including papilloedema. (50 mg/m2 21 out of 28 days), was started in September 2008. Oral risen- This complication in our patient could have an association with local radio- dronate 35 mg weekly was started in November 2008. Pain resolved therapy. Persistence of low vision is a consequence of initial papilledema and rapidly and function returned to normal. Imaging in October 2009 showed long lasting atrophy of the papillae nervi optici. marked improvement in all bony lesions. Etoposide was stopped after 12 courses. At last review (January 2010) the patient remained asymptomatic on risendronate monotherapy. CONCLUSION: As the efficacy of CNS directed treatment for paediatric malignant brain tumours improves the frequency of late, systemic metastases may increase. Bisphophonates are stan- P-DRUG.22. MULTIPLE CYCLES OF HIGH DOSE dard care for the management of metastatic bone disease in adults, CHEMOTHERAPY IN CHILDREN WITH RECURRENT OR improving quality of life and reducing skeletal events, however there is REFRACTORY BRAIN TUMORS little published information about their use in children. The efficacy of oral A. Marachelian, A. M. Butturini, G. Dhall, A. Gurunathan, R. Tang, and etoposide and risendronate in our patient suggests that this regime merits J. L. Finlay; Childrens Hospital Los Angeles, Los Angeles, CA, United States use in other children developing bony metastatic disease. BACKGROUND: Children with brain tumors have poor survival following relapse or suboptimal treatment response. METHODS: A retrospective review was conducted to review toxicity and outcomes of children with relapsed or persistent brain tumors treated at CHLA with multiple cycles P-DRUG.20. MORPHINE FACILITATES BLOOD BRAIN BARRIER of thiotepa-based myeloablative chemotherapy and autologous hematopoie- PENETRATION OF DOXORUBICIN IN RAT MODEL tic cell rescue (tandem transplant). RESULTS: 17 patients underwent tandem I. Sardi1, G. la Marca2,3, M. G. Giovannini3, E. Sieni1, S. Malvagia2, transplants, 14 relapsed, 3 refractory. Diagnoses included malignant gliomas R. Guerrini2, L. Genitori2, M. Massimino4, and M. Arico` 1; 1Department of (5), malignant embryonal tumors (7) and germ cell tumors (5). Nine patients Pediatric Hematology Oncology, Anna Meyer Children’s Hospital, Florence, had minimal residual disease and 8 had large measurable tumors, 14 had Italy; 2Department of Neurosciences, Anna Meyer Children’s Hospital, prior radiatiotherapy. Patients had a median of 2.5 prior regimens (range, Florence, Italy; 3Department of Pharmacology, University of Florence, 1-5). Therapy consisted of thiotepa with either carboplatin or etoposide + Florence, Italy; 4Department of Pediatrics, IRCCS Foundation, National temozolomide. Forty tandem transplant cycles were completed. Median Cancer Institute, Milan, Italy time to engraftment of neutrophils was 10 (range, 8-31) and platelets was 11 (range, 6-32) days. Eight patients received all 3 tandem transplants, the The blood brain barrier closely monitors the crossing of several molecules remaining had only 2 (8 patients) and 1 (1 patient) cycles due to insufficient into the brain. This hinders the passage of some fundamental chemical stem cells (2), progressive disease (3) or toxicity (4; intracranial hemorrhage agents, as doxorubicin, for treatment of brain tumors and others nervous 2, renal dysfunction 1, death 1). Twenty-eight of 40 cycles resulted in hospi- malignancies. On the basis of previous results that demonstrated the talization with a median of 7.5 days per cycle (range, 3-29 days). Four ability of morphine to generate severe, yet fully reversible disruption of patients were admitted to the intensive care unit for hypotension with resol- barrier, we attempted of analyzing the crossing of doxorubicin into the ution, one for pulmonary infection and died. The 1-year post-transplant brain in a rat model. We carried out a quantitative analysis of doxorubicin event-free survival was 33% + 13% with a 1-year post-transplant overall (12 mg/kg, i.p.) by mass spectrometry in rats after co-administration with survival of 56% + 13%. CONCLUSIONS: Tandem transplant therapy is morphine (10 mg/kg, i.p.). All animal manipulations were carried out feasible, toxicities are tolerable and may be a promising regimen for this according to the European Community guidelines for animal care (DL patient population. 116/92, application of the European Communities Council Directive 86/ 609/EEC). We analyzed the safety of this combination by detecting doxorubicin levels in heart and kidney, the plasma LDH activity and tissue lipid peroxidation. The level of doxorubicin was significant higher in all brain areas from rats treated with morphine than in controls. We found significant statistically differences of doxorubicin levels for treated rats compare to control groups (P , 0.001). No difference in LDH activity was found between rats treated with doxorubicin alone and rats also treated with

NEURO-ONCOLOGY † JUNE 2010 ii91 Abstracts

P12 LOW GRADE GLIOMA profiles which will serve as a basis for future examination of drivers of growth in these enigmatic tumors. DISCUSSION: Gangliogliomas have the highest prevalence of V600E mutations of all subtypes of pediatric low-grade gliomas analyzed, an important finding with BRAF specific inhibitors already in clinical trials. Molecular signatures of non-V600E expressing tumors are being evalu- P-LGG.01. GENE PROFILING IN PEDIATRIC TEMPORAL LOBE ated for other pathways dysregulated in these tumors. EPILEPSY TISSUE RELATED TO DIFFUSE CORTICAL DYSPLASIAS AND DYSEMBRIOPLASTIC NEUROEPITHELIAL TUMORS V. S. Silveira1, E. T. Valera2, P. P. Junior3, B. Paixao4, L. C. Pires5, P-LGG.03. BRAF MUTATION AND PAEDIATRIC V. C. Terra4, L. Neder6, and H. R. Machado7; 1Department of Genetics, ASTROCYTOMA University of Sao Paulo, Ribeirao Preto, Brazil; 2Pediatric Oncology, J. Liu, L. Meen, B. Coyle, R. Grundy, J. Lowe, and D. A. Walker; University University of Sao Paulo, Ribeirao Preto, Brazil; 3Department of Genetics, Sao of Nottingham, Nottingham, United Kingdom Paulo State University, Sao Jose Rio Preto, Brazil; 4Department of Neuroscience and Behavioral Science, University of Sao Paulo, Ribeirao INTRODUCTION: Childhood low grade glioma (LGG) includes pilocytic Preto, Brazil; 5Department of Genetics, Sao Paulo State University, Sao Jose grade 1 and diffuse grade 2 astrocytoma. They can occur throughout the brain do Rio Preto, Brazil; 6Department of Pathology, University of Sao Paulo, and spinal cord, presenting at different ages. Recent reports suggest that Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Ribeirao Preto, Brazil; 7Department of Neurological Surgery, University of mutations in the MAPK pathway, specifically 7q34 duplication, KIAA 1549 Saõ Paulo, Ribeirao Preto, Brazil and BRAF fusions, and V600E point mutation occur at relatively high frequency. OBJECTIVES: To conduct a meta-analysis of published reports of BACKGROUND: Epilepsy is the most prevalent CNS disease. In children LGG genetic studies. To look for associations to known patient variables its frequently associated with brain lesions, both of neoplastic and non- and tumour factors currently known to influence tumour behaviour and neoplastic etiology, such as disembrioplastic neuroepithelial tumors hence assist with planning further sample collection for genome surveillance (DNET) and cortical developmental malformation (CDM) respectively. studies. METHODS: Four papers with sample size ranges from 28 to 90 The multifactorial pathogenesis of the epilepsies includes complex molecular were included in this preliminary meta-analysis. Descriptive analysis was mechanisms which still need to be clarified. OBJECTIVES: to evaluate the used to compare age, pathology and tumour site distribution between differences in the expression profile between pediatric DNET and CDM cohorts. RESULTS: There was no association between age and 7q34 dupli- tissues associated to pharmacoresistant temporal lobe epilepsy. cation, BRAF fusion or V600E point mutation. WHO grade 1 tumours METHODS: Rapid Subtraction Hybridization (RaSH) and in silico Serial showed a strong correlation with 7q34 duplication (pooled OR 21.61). Analysis of Gene Expression (SAGE) between dysplastic lesions and Tumours outside the hindbrain were less likely to have 7q34 duplication or normal control samples was developed to identify genes of potential rel- BRAF fusion (KIAA 1549) (pooled OR 0.08-0.14). Forebrain tumours were evance. The selected genes were then validated by quantitative PCR in pedi- associated with V600E mutation (pooled OR 17.44). Genetic sample set com- atric samples of DNET (n ¼ 5) and CDM (n ¼ 15) microdissected tissues parison to a national population cohort (SIOP-LGG1) revealed a higher pro- and CNS controls. Association among the variables analyzed and gene portion of diffuse astrocytoma (20.8% versus 5.9%) yet a lower proportion of expression levels were evaluated by Mann-Whitney test and correlations mid brain tumours (5.2% versus 24.6%). CONCLUSION: To further inves- by Spearman’s test. RESULTS: Statistical correlation was observed among tigate these genetic mutations, larger sample sets with comparative pro- the genes HADHA, INPP5F, CALM1 and CCT6B (p , 0.03) and among portions to population cohorts would reduce selection bias. In particular, STMN2, GOT1, AMPH, HINT1, CALM1 and MAP2 (p , 0.01). There special efforts to obtain specimens of midbrain and spinal tumours are needed. is an overexpression rate of the genes HADHA, APOE and CST3 among the DNETs compared to the controls (p , 0.03). The CST3 gene was also upregulated among the CDM patients (p ¼ 0.04). No significant differences P-LGG.04. MAP KINASE PATHWAY ACTIVATION IN JUVENILE were observed among the other genes analyzed and the clinical features. PILOCYTIC ASTROCYTOMAS DISCUSSION: The present data suggest that the expression of some of the T. Nicolaides, S. Hariono, S. Archambeault, S. Mueller, J. Phillips, analyzed genes, specially CST3, may influence the etiology of the pharma- C. Cowdrey, M. Berger, A. Banerjee, N. Gupta, D. Haas-Kogan, D. James, coresistance epilepsy, thus suggesting that they might be interresting and W. Weiss; University of California San Francisco, San Francisco, CA, therapy targets. Financial Support: FAPESP - grant 2007/04538-4. United States

INTRODUCTION: Juvenile Pilocytic Astrocytomas (JPAs) are common pediatric brain tumors, occur throughout the central nervous system, and have a wide range of clinical outcomes. Recurrent or unresectable disease is P-LGG.02. GANGLIOGLIOMAS AND V600E STATUS associated with poorer prognosis. Recently, gain-of-function alterations in IDENTIFIED BY EXTENDED MUTATIONAL ANALYSIS BRAF and other members of the MAP kinase pathway have been described. M. W. Kieran1,2, B. E. Rich3, S. Santagata4,5, J. A. Chan6,5, In this report, we describe the spectrum of alterations including activation L. MacConaill7,4, D. Goff3, C. Stiles3, L. Garraway8,4, T. Golub1, of the MAP kinase pathway in 15 JPAs from our institution. METHODS: T. Golub1,4, and K. L. Ligon3,5; 1Pediatric Neuro-Oncology, Dana-Farber We identified 15 JPA’s with both paraffin-embedded and fresh frozen tissue. Cancer Institute, Boston, MA, United States; 2Pediatric Hematology/ We analyzed these for the presence of BRAF V600E by sequencing, Oncology, Children’s Hospital Boston, Boston, MA, United States; 3Cancer KIAA1549:BRAF fusion products by RT-PCR, and PTPN11 activating Biology, Dana-Farber Cancer Institute, Boston, MA, United States; 4The mutations by sequencing. MAPK pathway activation (P-ERK) was assessed Broad Institute of MIT and Harvard, Cambridge, MA, United States; both by Western blot (WB) and by immunohistochemistry (IHC). 5Department of Pathology, Brigham and Women’s Hospital, Boston, MA, RESULTS: 9/15 tumors had KIAA1549:BRAF fusion products. 1/15 United States; 6The Broad Institute of MIT and Harvard, Boston, MA, tumors had a PTPN11 mutation. No tumors carried the BRAF V600E United States; 7Medical Oncology, Dana-Farber Cancer Institute, Boston, mutation. 8/14 tumors had high p-Erk levels by WB, and 9/15 tumors had MA, United States; 8Adult Oncology, Dana-Farber Cancer Institute, Boston, high levels of p-Erk by IHC. CONCLUSIONS: The MAPK pathway is fre- MA, United States quently altered genetically in JPAs, with 10/15 tumors harboring alterations in BRAF or PTPN11. Levels of P-Erk did not correlate with genetic alterations BACKGROUND: Gangliogliomas are rare pediatric gliomas consisting of an of the pathway and the amount of Erk activation was not consistent when astrocytic and ganglion cell neuron component. While generally considered measured by either WB or IHC. With the majority of tumors showing WHO grade 1, patient outcome is variable. We performed gene expression pro- increased levels of P-Erk, targeting the MAPK pathway, either at the level of filing of samples with complete clinical information. METHODS: A total of 16 BRAF or MEK, may improve outcomes in patients with unresectable disease. pediatric gangliogliomas were evaluated with gene array and mutational analysis using fresh frozen paraffin embedded (FFPE) tissue after IRB approval was obtained. Gene array analysis was performed on the Illumina DASL platform while mutational status of over 400 mutations in 20 genes was performed P-LGG.05. ACTIVATION OF PI3K/MTOR PATHWAY IN with OncoMap Sequenom based somatic mutation genotyping platform. PEDIATRIC LOW-GRADE GLIOMAS AND INFLUENCE ON Samples were also assayed for BRAF-KIAA duplication using FFPE based CLINICAL OUTCOME FISH assay. RESULTS: OncoMap analysis revealed that BRAF V600E S. Mueller1, E. Romero1, A. Onar2, T. Sottero1, T. Nicolaides1, J. Phillips1, mutations are the most common alteration in gangliogliomas and were ident- S. Zheng1, J. K. Wiencke1, S. M. McBride1, C. Cowdrey1, M. D. Prados1, ified in 9/16 (56%) of samples. One sample had BRAF duplication in combi- M. S. Berger1, A. Banerjee1, N. Gupta1, and D. A. Haas-Kogan1; 1University nation with BRAF V600E mutation. Therefore BRAF duplication was not a of San Francisco, California, San Francisco, CA, United States; 2St. Jude common feature in ganglioglioma andserved to aid in diagnosticdiscrimination Children’s Research Hospital, Memphis, TN, United States of these two tumor types. Other than V600E, mutations were rarely identified in ganglioglioma samples. Gene expression profiling signatures of V600E mutated PURPOSE: Activation of the PI3K-mTOR pathway correlates with versus non-mutated gangliogliomas showed significant differences in gene array outcome in adult low-grade gliomas (LGG). We sought to evaluate this ii92 NEURO-ONCOLOGY † JUNE 2010 Abstracts

signaling cascade in pediatric LGGs. PATIENTS AND METHODS: presence of phosphorylated VEGFR2, and suggested that VEGFR2 activity Thirty-two pediatric newly diagnosed LGG specimens were analyzed for is primarily localized on endothelial cells. With laser microdissection we sep- phosphorylation of S6 and PRAS40 and expression of PTEN using immuno- arated the endothelium from the remaining tumor tissue. qPCR analysis of histochemistry. Methylation of the putative 5′-promoter region of PTEN endothelial markers and VEGF receptors showed a 10 to 30-fold enrichment using methylation-specific PCR was investigated in 22 samples. of VEGFR2 expression in the dissected endothelium compared to whole Relationships between molecular markers and progressions were evaluated tumor. Also the expression of VEGFR1 and -3 was highly enriched in the by Fisher’s exact test; associations between molecular markers and pro- endothelium fraction with a median 15.3-fold and 56.0-fold enrichment, gression free survival (PFS) were assessed using Kaplan-Meier methods and respectively. In conclusion, pVEGFR2 could be detected in pediatric pilocy- log-rank tests. RESULTS: The cohort included 13 girls and 19 boys tic astrocytoma. Furthermore, endothelial cells are the main source of (median age 5 years). Seven of 25 Grade I tumors and three of seven pVEGFR2 in pilocytic astrocytoma. This suggests a crucial role for VEGF/ Grade II tumors recurred. Nine of 12 patients with subtotal resection VEGFR-induced angiogenesis in the progression and maintenance of these (STR) recurred whereas only one patient of 20 with gross total resection tumors. Thus, counteracting the VEGFR angiogenic signaling likely has (GTR) recurred (P , 0.001). Extent of resection correlated with PFS (P , potential as a therapeutic strategy in the treatment of pediatric pilocytic 0.001). Of the 32 tumors, 14 demonstrated positive staining for astrocytoma. phospho-S6. Of 14 phospho-S6 positive tumors, six recurred whereas only four of 18 phospho-S6 negative tumors recurred (P¼ 0.2665). No statisti- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 cally significant difference was observed in PFS distributions of patients who were phospho-S6 positive versus those who were phospho-S6 negative (P ¼ 0.249). Eleven out of 22 tumors demonstrated PTEN promoter methyl- P-LGG.08. PREDICTIVE FACTORS FOR EARLY SYMPTOMATIC ation. Of these, two recurred and of 11 unmethylated tumors four recurred RECURRENCE IN PILOCYTIC ASTROCYTOMAS: DOES (P¼ 0.635). CONCLUSIONS: Almost half of pediatric LGGs show acti- ANGIOGENESIS HAS ANY ROLE TO PLAY? vation of the PI3K-mTOR pathway, as reflected in expression of N. S. Kurwale, A. Suri, V. Suri, D. K. Gupta, C. Sarkar, B. S. Sharma, and phospho-S6. Inhibition of this survival pathway may prove efficacious in A. K. Mahapatra; All India Institute of Medical Sciences, New Delhi, India treatment of LGGs. OBJECTIVE: To study predictive factors for early symptomatic recurrences in pilocytic astrocytomas with regards to angiogenesis and proliferative indices. MATERIAL AND METHODS: Patients operated for pilocytic astrocytoma were divided in nonrecurrent and early symptomatic recurrence P-LGG.06. IMP3 (IGF2BP3) IS A DIAGNOSTIC MARKER OF groups and studied for clinico-radiological and immuno-histopathological PILOMYXOID ASTROCYTOMA (n ¼ 26) parameters. OBSERVATIONS: Eighty seven patients operated for V. N. Barton, A. M. Donson, B. K. Kleinschmidt-DeMasters, A. L. Faliano, pilocytic astrocytoma (M:F-59:28) with mean age of 10.3 + 4.8 years D. K. Birks, and N. K. Foreman; University of Colorado Denver, Aurora, (range 1-18 years). Thirteen patients were operated for early symptomatic CO, United States recurrence (,4 years). Mean follow up was 48.5 + 18.5 months (range 16-78 months). Nonrecurrent tumors presented with mean duration of Recently identified as a variant of pilocytic astrocytoma (PA, WHO grade 9.7 + 8.6 months while recurrent tumors presented slightly early 6.0 + 3.0 I), pilomyxoid astrocytoma (PMA, WHO grade II) displays a more aggres- months. Infra-tentorial (cerebellum and brainstem) tumors were present in sive phenotype and often necessitates additional therapy. To date, no charac- 46 (52.9%) patients followed by opticho-chiasmatic in 25 (28.7%). teristic immunohistochemical (IHC) marker exists to distinguish PMA from Recurrent tumors were mostly observed in infra-tentorial location (69%). PA, which often exhibits overlapping histological features. To characterize Imaging and contrast enhancement pattern were similar. Cellularity and ple- the biology of PMA, the gene expression profiles of PMA and pediatric PA morphism expression were similar in two groups. Extensive endothelial pro- were compared using Affymetrix U133plus2 microarray chips. Insulin-like liferation was observed in 15.4 % while rest cases showed focal pattern. growth factor-II mRNA-binding protein 3 (IMP3), which plays a key role Diffuse VEGF expression was observed in 38.5 % cases while 61.5% in both CNS development and carcinogenesis, was significantly up-regulated showed mild to moderate focal expression. Surprisingly endothelial prolifer- in PMA compared to pediatric PA. IMP3 was further examined by IHC in a ation and VEGF expression were more conspicuous in non recurrent cases, larger cohort of pediatric PA, PMA, and in specimens in which the tumor had but statistical significance could not be established. MIB labeling indices evolved from a pure PMA phenotype to a PA phenotype by histological cri- were similar (1-4%) in both the groups. CONCLUSION: Symtomatic recur- teria. IMP3 protein was strongly expressed in all PMA samples tested and rences were common in infratentorial pilocytic astrocytomas. Radiology, his- absent in the majority of pediatric PA. Expression decreased over time in topathology and proliferative indices did not offer any prognostic those PMA that evolved to PA as documented on successive surgeries. information. Angiogenesis markers like endothelial proliferation and Independent of histology, positive IMP3 staining was significantly associated VEFG expression did not predict early symptomatic recurrence. Diffuse with tumor recurrence. IMP3 may play an important role in the aggressive VEGF expression and endothelial proliferation were observed in tumors phenotype of pediatric low grade astrocytomas. Positive IMP3 staining that show strong contrast enhancement. may represent a prognostic biomarker to identify tumors with pilomyxoid features and a propensity for early recurrence.

P-LGG.09. LEPTOMENINGEAL DISSEMINATION (LMS) OF PILOCYTIC ASTROCYTOMA (PA) AT DIAGNOSIS P-LGG.07. VASCULAR EXPRESSION OF PVEGFR2 IN PEDIATRIC B. Diez, A. Muggeri, N. Arakaki, and F. Meli; Institute for Neurological PILOCYTIC ASTROCYTOMA SUGGESTS THERAPEUTIC Research (FLENI), Buenos Aires, Argentina POTENTIAL AS A TARGET FOR ANTI-ANGIOGENIC TREATMENT STRATEGIES LMS of PA can occur at or shortly after diagnosis or as long as 10 years A. H. Sikkema1, E. S. J. M. de Bont1, G. Molema2, A. Dimberg3, after. The incidence of neuroaxis dissemination at the time of diagnosis P. J. Zwiers2, S. H. Diks1, E. W. Hoving4, W. A. Kamps1, was found in 3.7 to 5.3 %. We report 5 patients with disseminated PA at M. P. Peppelenbosch5, and W. F. A. den Dunnen2; 1Beatrix Children’s diagnosis.Three were males with a median age 13 years (9 -24). The Hospital, University Medical Center Groningen, Groningen, Netherlands; primary tumor sites were III ventricle hypothalamic-optic chiasm (3), brain- 2Department of Pathology and Medical Biology, Medical Biology section, stem (1), and cerebellum (1). Two had extensive subarachnoid metastatic University Medical Center Groningen, Groningen, Netherlands; disease to the spine and three only cauda equine/conus medullaris metasta- 3Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala sis. Initial management included resection/ biopsy of the primary in 4, resec- University, Uppsala, Sweden; 4Department of Neurosurgery, University tion of metastasis in 2. One was only observed for 16 months (m), had a Medical Center Groningen, Groningen, Netherlands; 5Department of biopsy of metastatic site + chemotherapy at progression and is alive with Gastroenterology and Hepatology, Erasmus MC, Rotterdam, Netherlands stable disease for +18 m. Post surgery treatment of the other 4 was chemotherapy (2), craneospinal irradiation (1) and observation (1). One is For enhanced tumor cell survival and progression tumors depend on alive with stable disease at + 85 m. Three progressed at 3 m, 9 m and angiogenesis. Vascular endothelial growth factor receptor (VEGFR) signal- 32 m and had further treatment. One received chemotherapy (2 lines) and ing plays a major part in this process. In our previous study we evaluated died of progressive disease at 15 m. Two had craneospinal irradiation + ven- tyrosine kinase activity in pediatric brain tumor tissue lysates using a triculoperitoneal shunting, decompressive laminectomy with spinal tumor peptide microarray containing 144 different tyrosine kinase peptide sub- debulking, and chemotherapy (4 lines).One died of progressive disease at strates (Sikkema et al, Cancer Res 2009). When applied to pediatric pilocytic 71 m, one is alive with stable disease at 74 months. MRI survey of the neur- astrocytoma tissue, this analysis revealed extensive phosphorylation of axis in children with PA may improve the early detection of distant spreads VEGF receptor-derived peptides. The aim of the current study was to vali- and change treatment. We review the literature and discuss treatment strat- date this result and localize VEGFR2 activity in pediatric pilocytic astrocy- egies for this challenging disease. toma. Proximity ligation assays (PLA) on tumor cryosections showed the

NEURO-ONCOLOGY † JUNE 2010 ii93 Abstracts

P-LGG.10. MR PERFUSION AND SPECTROSCOPY TO STUDY NF1-patients. In NF1 we frequently found additional tumours in other BIOLOGICAL HETEROGENEITY IN PILOCYTIC parts of the brain and diffuse tumours resembling gliomatosis cerebri, ASTROCYTOMA IN CHILDREN while non-NF1 patients were affected by a meningeal dissemination quite M. Manita1, A. Napolitano1, T. Jaspan2, R. Grundy1, and D. Auer1; frequently (8%). The age of the disseminated children (mean age: 1.8 y) 1University of Nottingham, Nottingham, United Kingdom; 2Nottingham was considerably below that of the whole non NF1-group (mean age: 4.13 University Hospital, Nottingham, United Kingdom y). CONCLUSION: Our goup of 143 children with optic pathway tumours is the largest worldwide with a detailed description of Pilocytic astrocytomas (PA) are the most common childhood brain MR-morphology. Detailed description of the tumor extension in LGG of tumours classed as WHO grade I. While survival rate is excellent after com- the optic pathways allows the identification of children with and without plete macroscopic resection, the course may be more aggressive with early NF1. If these morphologic differences are related to differences in the clinical recurrence and dissemination. Prediction of unfavourable outcome is not course has to be evaluated in the future. possible on clinical or histological grounds alone and hypermetabolic features identified on PET were recently found to predict progression-free survival. MR perfusion (MRP) studies allow accurate grading of adult gliomas, so we hypothesise that MRP detects important biological features in paediatric P-LGG.13. PLEOMORPHIC XANTHOASTROCYTOMA IN PA. 14 patients with histologically proven PA (age range 4-16 years) under- CHILDHOOD 1,2 3 3 1,2 3,4 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 went a standardised clinical image acquisition protocol at 3T (Philips P. Bandopadhayay ,X.Wu ,J.Ng , D. M. Ashley , and C. W. Chow ; 1Children’s Cancer Centre, Royal Children’s Hospital, Melbourne, Achieva) with dynamic susceptibility weighted 3D MRP (PERF-PRESTO; 2 TR: 16 ms/ TE: 24 ms/ FA: 78) and single voxel MRS (PRESS, TR: Australia; Murdoch Children’s Research Institute, Melbourne, Australia; 3Department of Anatomical Pathology, Royal Children’s Hospital, 2000 ms/ TE: 35 ms). Maximum CBV in 10 enhancing lesions (7 infra-, 3 4 supra-tentorial) relative to white matter were on average 5.8 + 2.0. Most Melbourne, Australia; Departments of Paediatrics and Pathology, tumours fell into the range of (3.0-6.6) of low grade gliomas in adults with University of Melbourne, Melbourne, Australia the exception of one with rCBV of 10.5. In 3 tumours, we found a prominent leakage pattern with early enhancement that was most pronounced in the Pleomorphic xanthoastrocytoma (PXA), is a rare astrocytic tumour. We youngest patient. Correlation analysis with MRS suggested a positive corre- retrospectively reviewed 15 children diagnosed at our institute between lation with glutamine (r ¼ 0.741, P , 0.05) and negative with guanidine 1979 and 2009. Median age at diagnosis was 7 years (1.4 to 15 years) and ¼ , 12 children (80%) had supratentorial tumours. Median event free survival acetate (r -0.743, P 0.05). These preliminary data support the hypothesis + that MRP depicts heterogeneity in vascularisation in PA which seems to (EFS) was 60 months, with a EFS at 5 years of 46% ( /-13.8%) and median overall survival (OS) of 157 months with OS at 5 years of 64% translate in altered metabolic profiles. Further studies are warranted to + assess the clinical relevance of these biological imaging markers. ( /-14%). Initial treatment in all cases was surgical, and a complete resection was achieved in 5 (33%) patients. 5 children (33%) had adjuvant therapy (2 radiation, 2 chemo-radiation, 1 chemotherapy). On progression or recurrence, most children underwent further surgery. Those that had a P-LGG.11. CONTRAST BEHAVIOUR OF LOW GRADE GLIOMAS complete resection had no further therapy, whilst the other children had DURING FOLLOW-UP adjuvant therapy with radiation and/or chemotherapy. 3 (20%) tumours M. Warmuth-Metz1, B. Bison1, M. Schneckenburger1, C. Mirow2,and underwent malignant transformation to high grade tumours. Of these, 1 A. K. Gnekow2; 1Dept. Neuroradiology University of Wu¨ rzburg Reference child developed leptomeningeal and pulmonary metastasis. Histologically Center for Neuroradiology, Wu¨ rzburg, Germany; 2Kinderklinik Klinikum 3 distinct patterns were identified: 1, Typical PXA 2, Pretypical PXA SIOP LGG Study Center, Augsburg, Germany -superficial tumours composed of compact bundles of spindle astrocytes without wild pleomorphism, xanthoma cells or eosinophilic granular INTRODUCTION: Contrary to high grade gliomas contrast behaviour bodies, which develop typical features on recurrence and 3, transformation does not have a prognostic value in LGGs. Little is known about the spon- to high grade malignancy. In summary, PXA is rare. Surgery was the main- taneous course of enhancement of LGGs. Frequently progression is suspected stay of treatment, with adjuvant therapy used mostly at progression. Whilst if the contrast enhancement increases. PATIENTS AND METHODS: We the overall prognosis is good, there is a potential for malignant transform- evaluated 382 MR examinations of 79 LGGs in 74 patients registered to ation, with an incidence in our series of 20%. the SIOP-LGG-study concerning the amount of contrast enhancement and a change of contrast behaviour over time. Treatment was not considered. Tumorsize was measured simultaneously and we compared the relative changes in tumorsize with a change of enhancement. RESULTS: 234 P-LGG.15. PROGNOSTIC, RADIOGRAPHIC AND BIOLOGICAL samples showed no change in contrast behaviour, 34 showed a decrease, CHARACTERISTICS OF BRAINSTEM GANGLIOGLIOMAS and 35 an increase of enhancement. As well size decrease and increase S. Z. Rush, L. Z. Fenton, A. M. Donson, D. K. Birks, B. K. Demasters, were found disproportionately frequent in the respective groups. However, M. H. Handler, and N. K. Foreman; University of Colorado, Aurora, CO, in each group also a discrepant behaviour could be seen. In patients with a United States new enhancing lesion (n ¼ 14) we also evaluated if the patients progressed in the future and found that a considerable number of new enhancement Gangliogliomas are an uncommon low grade tumor of ganglion cells. They was seen in tumors (57%) without a significant change in tumor volume are most often supratentorially located however there are rare occurrences of (+/-25%) and even in decreasing tumors. CONCLUSION: Even if the these tumors in the brainstem. The radiologic features of these uncommon majority of LGGs with an increase or decrease of contrast enhancement tumors of the brainstem are not well described and there is little information shows a relative increase or decrease in tumor size discrepant behaviour is about their molecular biology. Prognosis for children with brainstem ganglio- found in a considerable number of tumors and therefore a change in contrast gliomas is often poor and current radiation and chemotherapy regimens are behaviour must not be taken for a regression or progression if tumor size ineffectual in the treatment of these tumors. Six children with brainstem gang- remains stable. New enhancing lesion did not mean progression in more liogliomas presented to the institution between 2000 and 2009. Four children than half of the cases. progressed with a median time to progression of 16 months. Radiologic features of each tumor were evaluated by a single radiologist. Molecular features of the tumors were evaluated using gene expression microarray technology. Gene expression of three pediatric brainstem gangliogliomas was compared with P-LGG.12. MRI OF OPTIC PATHWAY GLIOMAS IN CHILDREN the gene expression of brainstem pilocytic astrocytomas and also supratentorial WITH AND WITHOUT NF1 gangliogliomas. Radiologically these tumors appeared as expansile, infiltrative M. Warmuth-Metz1, S. Leykamm1, B. Bison1, B. Thieme2, C. Mirow2, and masses that demonstrated patchy enhancement with gadolinium. Five of 6 A. K. Gnekow2; 1Dept. Neuroradiology University of Wu¨ rzburg, Wu¨ rzburg, demonstrated a predilection for enhancement along the dorsal surface of the Germany; 2SIOP/LGG-study center, Augsburg, Germany brainstem. The brainstem gangliogliomas reveal an up-regulation in homeobox A5 (HOXA5) of 180-fold compared with supratentorial gangliogliomas and INTRODUCTION: Optic pathway gliomas are often related to a 54-fold compared with brainstem pilocytic astrocytomas. HOXA5 Neurofibromatosis type 1 (NF 1). Are there morphological differences on up-regulation has been implicated in tumorigenesis as well as aberrant neuronal cranial MRI between patients with and without NF1? PATIENTS AND migration and apoptosis. There is also up-regulation of genes associated with METHODS: We reviewed retrospectively cranial MR-examination of 143 neuronal differentiation, especially prepronociceptin (PNOC). These findings patients registered to the European Low-Grade-Glioma-(LGG)-study for suggest that brainstem gangliogliomas have unique radiologic features and differences in MR-morphology like extension of the tumour, enhancement, have a distinctive patternof gene expression thatdifferentiates them from supra- meningeal dissemination and additional cerebral tumours. RESULTS: 44 tentorial gangliogliomas and brainstem pilocytic astrocytomas. children suffered from NF1 and 99 did not. The NF1-patients were all over 1 year of age while patients without NF1 were younger than 1 year in 16 cases. The glioma frequently involved the chiasm in both groups, but while in non NF1-patients this was often the only localisation, a wide spread extension along the visual pathway was frequently found in ii94 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-LGG.16. A CHILD WITH DISSEMINATED PRIMARY SPINAL pilomyxoid variants need not be considered, since the platinum-based che- CORD OLIGODENDROGLIOMA motherapeutic strategies applied to both types of tumors are identical and sur- D. M. Pucccetti1, N. Patel1, B. Iskandar1, M. Ward1, K. Casey2, and gical morbidity should also be considered. In contrast, bulk-reduction surgery S. Salamat1; 1University of Wisconsin, Madison, WI, United States; might be needed to treat obstructive hydrocephalus. CONCLUSION: Surgical 2American Family Children’s Hospital, Madison, WI, United States biopsy appears to be dispensable for clinically or radiologically typical OPHA.

Oligodendroglioma is an uncommon spinal cord tumor in childhood. Oligodendrogliomas have a tendency for neuroaxis dissemination along the subarachnoid space but dissemination is rarely reported in children. We present a case of a 9 year-old boy who was diagnosed with cervicothor- P-LGG.19. OPTICOHYPOTHALAMIC GLIOMAS IN CHIDREN: acic intramedullary low grade oligodendroglioma at 30 months of age. The RESULTS OF SURGICAL TREATMENT tumor did not have loss of 1p or 19q. He underwent two surgical resections L. G. Valentini1, P. Bianca1, M. Maura2, V. Sergio1, C. Cecilia1, C. Luisa1, followed by involved field radiotherapy. At the time he presented to our insti- L. Federico1, and S. Carlo1; 1Fodazione Istituto Neurologico Carlo Besta, tution at four years of age, he had widely disseminated disease involving the Milano, Italy; 2Istituto Nazionale Tumori, Milano, Italy brain and spine. After 4 cycles of procarbazine, lomustine and vincristine he had radiographic evidence of progression. Treatment with temozolomide Opticohypothalamic gliomas are rare CNS tumors in children (4-6%), Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 given 5 days out of every 28 days was begun and he remained on this being more frequent in NF1. Even more rarely they need surgical treatment. regimen for 24 months with clinical improvement and without evidence of Since 1990 30 children (age ¼, 16 anni) have been operated on for an progressive disease. Fifteen months after completing his chemotherapy he Opticohypothalamic glioma at Fondazione Istituto Neurologico “Carlo developed progressive disease and temozolomide was reinstituted. He con- Besta” (FINNB) of Milan, Italy; mean age at first surgery was 6 years and 6 tinues to have stable disease and no toxicity now nearly one year into were infants; only 4 of them were affected by NF1. All the operated cases pre- therapy. Here, we will review the literature on childhood spinal oligodendro- sented a symptomatic, bulky (diameter ¼. 3cm) lesion with a mass effect, glioma, emphasizing the value of imaging the brain and total spine and its contrast enhancement and evolution at subsequent neuroimaging. A craniot- responsiveness to temozolomide. omy was performed with the aim to reduce significantly tumor mass, but not to obtain its complete removal; chemotherapy for low grade gliomas have been administered both preoperatively in some cases, that after surgery to treat further evolutions. Pylocitic Glioma was documented in almost all the cases, except one astro blastoma and one gangliocitoma; two lesions had a P-LGG.17. A PHASE II STUDY OF ANTINEOPLASTON A10 AND malignant pattern in some areas; two small babies ha a “failure to thrive” syn- AS2-1 INJECTIONS IN CHILDREN WITH LOW-GRADE drome and disseminated disease at diagnosis, despite the low grade patten of ASTROCYTOMAS the specimen. 20 children are evaluable at a mean follow-up of 7 years and the S. R. Burzynski, R. A. Weaver, T. Janicki, B. Szymkowski, S. S. Acelar, and long term results of surgery will be discussed in details. In fact, the aim of the G. S. Burzynski; Burzynski Clinic, Houston, TX, United States study is to evaluate the results of surgery associated with chemotherapy on visual, hormonal and superior functions and the efficacy on disease control. This report summarizes the efficacy and toxicity of a single-arm Phase II study of antineoplaston A10 (Atengenal) and antineoplaston AS2-1 (Astugenal) [ANP] in children with recurrent and/or progressive low-grade astrocytomas (LGA). Patients received escalating doses of intravenous A10 and AS2-1 six times daily. Response to ANP was monitored by MRIs of the P-LGG.20. ANGIOCENTRIC GLIOMA IN AN ELOQUENT AREA: brain every eight weeks. Patients evaluable for efficacy received 12 or more SURGERY OR CONSERVATIVE ATTITUDE? weeks of ANP or at least 4 weeks of ANP but developed progressive disease A. Fernandes, J. Pereira, L. Castro, S. Nunes, M. do Bom Sucesso, and M. Gil (PD). All patients were evaluable for safety. Seventeen patients with a da Costa; Hospital de Saõ Joaõ, Porto, Portugal median age of 129 months (range, 20-210 months) were accrued. Three patients (18%) presented with untreated aggressive tumors. Five patients INTRODUCTION: Angiocentric glioma, codified as a new brain tumour (29%) presented with recurrent and/or persistent tumors after surgery. type in the 2007 WHO Classification of Tumours of the Central Nervous Nine patients (53%) presented with recurrent and/or persistent tumors System, was first identified in 2005. It has been described as a novel after chemotherapy. Eight of these nine patients had surgery prior to che- epilepsy-associated tumour with distinct clinico-pathologic features. motherapy, while two patients had radiation after chemotherapy. Of the 17 CLINICAL REPORT: The authors report the youngest paediatric patient patients, nine had multicentric disease (53%). Fifteen evaluable study patients diagnosed to date with angiocentric glioma. She is a girl of 22 months received a median of 83 weeks of ANP. Seven evaluable patients had an objec- with uneventful past history who presented at the emergency room with tive response (47%): six had a complete response (40%) and one had a partial left hemibody tonico-clonic seizures that recurred in 24 hours. EEG docu- response (7%). Stable disease was documented in five patients (33%) and PD mented right frontal paroxystic activity. The MRI image revealed a huge was seen in three patients (20%) after a median of 60 days (range 47 to 85 T2-hyperintense lesion of the right temporal lobe. Under treatment with val- days) of ANP. In our small study of children with recurrent and/or progressive proic acid, seizures did not recur. Biopsy revealed a paucicellular glial tumor LGA, ANP appears to be very effective in resolving or stabilizing disease in whose cells were arranged predominantly around vessels. They stained posi- 80% of treated patients, with minimal toxicity. tively for glial fibrillary acidic protein, vimentin, protein S100 and epithelial membrane antigen. During 3 months follow-up the patient has been seizure- free with a normal development. An expectant attitude was chosen, since the lesion involved an eloquent area, and global resection would probably be deleterious for the child. CONCLUSIONS: The authors report the youngest P-LGG.18. ROLE OF SURGERY FOR OPTIC PATHWAY/ case in the literature of this novel entity and highlight the option of a close HYPOTHALAMIC ASTROCYTOMA IN CHILDREN follow-up without surgical resection because of the benign biological behav- A. Gomi, H. Oguma, T. Annou, S. Miyata, and E. Watanabe; Jichi Medical iour which has been described in this tumour, in view of the good clinical and University, Tochigi, Japan neurological condition of the child with no seizure recurrence.

INTRODUCTION: Optic pathway/hypothalamic astrocytomas (OPHA) in children are usually pathologically diagnosed from surgical biopsies and treated by chemotherapy. A recent report suggests a restricted role of surgery for OPHA considering the associated risk and chemotherapeutic P-LGG.21. THE COMPLEXITY OF MANAGING effectiveness. Here, we evaluate the role of surgery for OPHA based on our INTRA-TUMORAL CYSTS ASSOCIATED WITH recent experience. METHODS: We analyzed the clinical features of suprasel- HYPOTHALAMIC ASTROCYTOMAS R. E. Mixer1 and S. P. Lowis2; 1Bristol Royal Hospital for Sick Children, lar/chiasmatic tumors in four children who have been treated at our institute 2 from January 2008. RESULTS: Bilateral optic nerve tumors in a 2-year-old Bristol, United Kingdom; Bristol Royal Hospital for Children, Bristol, boy with neurofibromatosis-1 (NF-1) spontaneously regressed. Of two radi- United Kingdom ologically apparent OPHA treated by chemotherapy without surgical biopsy, one was reduced by carboplatin and vincristine over a period of 10 Hypothalamic astrocytomas present particular management difficulties. months, and disease stabilized within 6 months in the other. In a Most are low grade with high survival rates. Treatment goals are to reduce 10-year-old girl with a chiasmatic tumor MRI also identified an enlarged morbidity without compromising survival. We report two children present- pineal body. Pathological diagnosis of a surgical biopsy confirmed germi- ing with diencephalic syndrome, hydrocephalus and signs of raised intracra- noma, so this patient underwent chemotherapy and radiotherapy. nial pressure aged 4 and 8 months of age. Both developed large cystic DISCUSSION: Although initial surgical resection aims to confirm a diagnosis collections adjacent to the tumour bed. The patients underwent debulking of OPHA, this type of tumor can be correctly diagnosed from clinical and of their tumours, were treated with chemotherapy according to current radiographic features. Pathological diagnosis, pilocytic astrocytomas or SIOP LGG protocol but then switched to UKCCSG Baby Protocol after poor response. Patient 1 re-presented with visual loss related to tumour

NEURO-ONCOLOGY † JUNE 2010 ii95 Abstracts

progression. A large cyst was discovered and she underwent placement of an P-LGG.24. DIAGNOSIS AND TREATMENT OF CEREBELLAR intracystic catheter. She had two further courses of chemotherapy and ulti- ASTROCYTOMAS IN CHILDREN (REPORT OF 58 CASES) mately, radiotherapy. Attempting to reduce the frequency of cyst drainage, G. Jia; Beijing Tiantan Hospital, Beijing, China intra-cystic phosphor colloid was administered. She currently attends school, visiting her General Practitioner twice weekly for cyst drainage. OBJECTIVE: Retrospective study on cerebellar astrocytoma in children Patient 2 developed progression, and underwent further debulking and vinblas- according to clinical features, therapeutic strategy and prognosis. tine chemotherapy following disease relapse. A VP shunt failed repeatedly METHODS: This is an analysis of 66 cases of cerebellar astrocytoma includ- because of proteinaceous CSF, and eventually had to be externalised. ing 33 male and 33 female patients. The age ranged from 2 to 16 years Temozolomide and intraventricular methotrexate and later, radiotherapy (mean:8.2 yrs), and the diameter ranged from 3 to 5.5cm (mean: 4.5cm). were used, attempting to reduce the CSF protein content. These failed, but she There were 33 solid tumors including partial cystic lesions and 33 cystic managed to attend school with external ventricular drainage for over one tumors with tumor nodus. Tumors were located in the hemisphere in 35 year. Management of large intra-tumoralcystsin low grade tumours may bepro- cases and the vermis in 31 cases. RESULTS: 46 patients had total and 20 sub- blematic and does not necessarily relate to tumour growth. Novel approaches total resection. As for histopathology, there were 8 oligodendrocytomas, 57 including intracystic chemotherapy, custom-made shunts and novel drugs astrocytomas including 48 pilocytic astrocytomas, and one case of astrocy- such as anti-angiogenic agents all have a role to play in management. toma with active growth. Follow up of 58 cases ranged from 2 years to 4 years and ten months (mean: 36 months). 18 patients received radiotheraphy Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 and none chemotheraphy. No patient deceased. DISCUSSION: Cerebellar astrocytomas were located in the cerebellar hemispheres or the vermis with special radiological features and in most of cases were pilocytic astrocytoma P-LGG.22. MORTALITY IN PEDIATRIC LOW GRADE GLIOMA - or grade II astrocytoma. Radical resection in microsurgery is a critical treat- A 25 YEARS POPULATION BASED STUDY ment and subtotal resection should be adjunctive with radiotherapy. The I. Fried, U. Tabori, K. Scheinemann, U. Bartels, A. Huang, A. Kulkarni, general prognosis is satisfying. C. Hawkins, and E. Bouffet; Hospital for Sick Children, Toronto, ON, Canada

Low grade gliomas (LGG) are the most common brain tumors in children. Mortality rate varies between studies and information on specific death P-LGG.25. PRELIMINARY RESULTS OF MULTIDRUG causes is limited. OBJECTIVES: to retrospectively study prevalence and CHEMOTHERAPY REGIMEN FOR LOW-GRADE GLIOMA IN disease characteristics of mortality cases in a large population based KOREAN CHILDREN cohort. RESULTS: Seven hundred and thirty patients with LGG (56% males, M. Lee1, T. Ghim2, H. Park2,Y.Ra3, H. Lim4, H. Kim5, S. Park6, S. Won7, median age -6.8 years) were diagnosed in our center between 1985 to 2009. D. Kim7, J. Kim8, S. Kim9, K. Park10, H. Jung11, B. Cho10, J. Park12, and Thirty two patients died during that time (59% males, median age-4.5 years). T. Jung13; 1Dankook University Hospital, Cheonan, Republic of Korea; Death causes were progression (17), malignant transformation (5), second 2National Cancer Center, Ilsan, Republic of Korea; 3Department of brain tumor (4), infection (3), unknown (2) and other disease (1). None of Neurosurgery Asan Medical Center, Seoul, Republic of Korea; 4Asan the 225 patients with non disseminated tumors of the cerebellum or spinal Medical Center, Seoul, Republic of Korea; 5Kyemyung University Dongsan cord died of their disease. We subgrouped the patients according to time to Medical Center, Daegu, Republic of Korea; 6Ulsan University Hospital, death: Eighteen patients died within 3 years from diagnosis (0.22-2.78 years), Ulsan, Republic of Korea; 7Yonsei University Severance Hospital, Seoul, and fourteen died after more than 3 years (3.58-10.7 years). Tumor progression Republic of Korea; 8Chungbuk University College of Medicine, Cheongju, was the cause of death in13/18 (72%) patients with early death vs. 4/14 (28%) Republic of Korea; 9Chungnam University Hospital, Daejun, Republic of with late death .Early death due to progression was seen almost invariably in Korea; 10Seoul National University Hospital, Seoul, Republic of Korea; cases with highly worrisome characteristics on diagnosis including dissemina- 11Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; tion (2), atypical pathology (8) or pontine /thalamic disease (7 and 3 respect- 12Department of Neurosurgery Ulsan University Hospital, Ulsan, Republic ively). Death due to tumor transformation occurred within 4 years. All of Korea; 13Chonnam University Hospital, Hwasoon, Republic of Korea patients had highly concerning areas in primary pathological specimens. CONCLUSION: Mortality due to tumor progression or transformation is Complete surgical resection is the treatment of choice for low-grade extremely low in LGG patients surviving more than 4 years. Early death second- glioma (LGG). The progressive/symptomatic residual LGGs are usually ary to tumor progression or transformation is suggestive of higher grade of the treated with chemotherapy and/or radiotherapy. However, in young chil- original tumor. dren, late adverse effects of radiotherapy are problematic. The Korean Society for Pediatric Neuro-Oncology (KSPNO) developed chemotherapy for progressive/symptomatic LGG to be administered after operation. This prospective nationwide study was designed in order to avoid or defer radiotherapy in those patients. The regimen was composed of vinblastine/vincris- P-LGG.23. PILOMYXOID ASTROCYTOMA: ARE MORE tine, etoposide, 5-fluorouracil and cyclophosphamide every 3 weeks for 18 AGGRESSIVE THERAPIES WARRANTED? months. The patient diagnosed as LGG between July 2005 and December S. Stapleton1, S. Steinbrueck1, E. Salman2, and I. Gonzalez-Gomez1; 1All 2009 was eligible for this protocol. Nineteen patients (8 boys, 11 girls) were Children’s Hospital, St Petersburg, FL, United States; 2Children’s Hospital of registered from 7 hospitals. The median age of diagnosis andstart of chemother- Southwest Florida, Fort Myers, FL, United States apy were 85 months (mo) (range, 7 - 241) and 90 mo (range, 8-245), respectively. Of the 8 patients who completed chemotherapy, one showed complete INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a relatively new response, 2 partial responses and 3 stable diseases while 2 had relapse. In the entity described in the past 10 years. It is related to the pilocytic astrocytoma remaining 11, 4 had premature discontinuation of chemotherapy, 3 progressive (PA), although it is WHO grade II. PMA typically occurs in young children, diseases and 1 lost to follow-up. Seven patients are still undergoing treatment. but older children and adults can also be affected. The exact incidence is not Immediate side effects of chemotherapy were manageable. The median follow known. Compared to PA, PMA has increased rates of recurrence and cerebrosp- up duration was 19 mo (range, 2-54). The overall and progression-free survival inal fluid dissemination, and shorter progression free and overall survivals. rates were 90.9 + 8.7 % and 41.0 + 21.1 %, respectively. The result of this METHODS: Patients were selected from a database and records reviewed to regimen is effective for children with progressive/symptomatic LGG and is collect clinical information. Tissue was available on 4 of 5 patients for second comparable to other chemotherapy regimens for LGG. This multidrug che- neuropathology review to confirm PMA. Follow up data was available on all motherapeutic study is currently being continued further to verify the effective- 5 patients. RESULTS: Between 2001 and 2009, 5 patients (2 male, 3 female) ness of the strategy of delaying/eliminating the radiotherapy. with PMA were seen at our institution. The median age at diagnosis was 1.5 years (range 0.5-12 years). Four patients had primary hypothalamic tumors and one was cervical spine. One had metastasis at diagnosis. Three patients had a biopsy only, and 2 had subtotal resections. All patients were treated with carboplatin and vincristine (3 with additional temozolomide) as initial P-LGG.26. VINCRISTINE AND CARBOPLATIN therapy. Two patients progressed on therapy and died at 7 and 11 CHEMOTHERAPY FOR UNRESECTABLE AND/OR months post diagnosis. Two relapsed quickly after completing therapy at 5 RECURRENT LOW GRADE ASTROCYTOMA OF THE and 11 months post therapy and one died. One patient continues on primary BRAINSTEM therapy without relapse at 1 year post diagnosis. CONCLUSION: Optimal M. D. Ronghe1, D. Hargrave2, U. Bartels3, U. Tabori3, S. Vaidya2, treatment has not been established for PMA. More aggressive therapies may C. Chandler2, A. Kulkarni3, and E. Bouffet3; 1Royal Hospital for Sick be indicated. Children, GLASGOW, United Kingdom; 2Royal Marsden Hospital, Sutton, United Kingdom; 3The Hospital for Sick Children, Toronto, ON, Canada

BACKGROUND: Radiotherapy remains a widely accepted postoperative treatment modality for unresectable or recurrent Low Grade Glioma (LGG). ii96 NEURO-ONCOLOGY † JUNE 2010 Abstracts

However, there is increasing evidence to suggest that chemotherapy can 1 mg over 1 minute; 15 minute break; carboplatin 10 mg over 10 delay and may obviate the need for radiotherapy in progressive/recurrent minutes; 15 minute break; remaining carboplatin (total carboplatin LGG. The majority of the published experience is in children with hypothala- dose 175 mg/m2) over 2 hours. One patient also received cyclophospha- mic/optic chiasmatic lesions and little information is available regarding its mide 500 mg/m2 at week 4 of each cycle. All patients were successfully use in LGG of the brainstem. PROCEDURE: We describe clinical character- desensitized in an outpatient setting. CONCLUSIONS: Pediatric patients istics and course of children with LGG of the brainstem who received carbo- receiving weekly carboplatin and vincristine have a high incidence of platin based chemotherapy in two institutions over 10 years (1996 to 2006). hypersensitivity to carboplatin. Desensitization is safe and allows for con- This was a retrospective review of consecutively treated children with LGG tinued use of this drug regimen. of the brainstem (midbrain, pons, medulla and upper cervical cord). Vincristine and carboplatin was ﬁrst line chemotherapy regimen used in all patients. RESULTS: In this series, there were 16 children (9 males) with median age at diagnosis of 4.2 years (range- 0.5 - 8). Eight children were treated at diagnosis while the remaining 8 received chemotherapy after P-LGG.29. CHILDREN <1YEARDONOTBENEFITFROM either radiological progression or clinical deterioration. After a median CONVENTIONAL LGG TREATMENT STRATEGY- REPORT follow up of 57 months (range-20 to 136) from initiation of chemotherapy FROM THE GERMAN MULTICENTER TRIAL HIT-LGG 1996 all children are alive and 11 remain progression free (1 complete response, FOR CHILDREN AND ADOLESCENTS WITH LOW GRADE Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 8 with partial response + minor response and 2 stable diseases). GLIOMA (LGG) CONCLUSIONS: The efﬁcacy of this chemotherapy regimen in this series C. Mirow1, T. Pietsch2, S. Berkefeld3, B. Thieme1, S. von Hornstein1, and supports its role in children with progressive unresectable LGG of brainstem. A. K. Gnekow1; 1Children´ s Hospital, Augsburg, Germany; 2Department of Neuropathology, University of Bonn, Germany; 3IMBEI, University of Mainz, Germany

Children diagnosed with LGG at an age ,1 year are reported to have an P-LGG.27. INCIDENCE OF CARBOPLATIN HYPERSENSITIVITY impaired prognosis in comparison to older patients. Analysis of this sub- REACTIONS IN LOW GRADE GLIOMA PEDIATRIC PATIENTS & group could reveal the necessity to develop separate treatment approaches. IMPACT ON CONTINUATION OF THERAPY 68 Children ,1 year at diagnosis within the HIT-LGG 1996 cohort were S. Mohamed and S. Hisham; Children Cancer Hospital Egypt, Cairo, Egypt analysed with respect to risk factors for EFS, PFS and OS. Median age was 7.3 months, 35 female, no NF1, 39 visual impairment, 22 diencephalic PURPOSE: To determine the incidence of carboplatin hypersensitivity reac- syndrome (DS), 50/68 with supratentorial midline (SML) location, 9 tion (CHSR) in Low Grade Glioma (LGG) pediatric patients receiving weekly primary dissemination (DLGG). Extent of resection (55 patients): com- Carboplatin, and analyzing the characteristics, predictive factors, manage- plete/subtotal 13, partial 15, biopsy only 27. Histology (primary central ment and impact on therapy continuation. METHODS: Medical records of pathology review in 32/55): 38 pilocytic astrocytoma 8I (2 pilomyxoid), all LGG patients treated per CCHE LGG protocol were retrospectively 9 other WHO I8 and 8 WHO II8 tumours. Re-review in 2009 discovered reviewed for data on age, tumor type, total number of doses, cumulative 1 additional pilomyxoid astrocytoma. 1-Year-EFS was 0.35. dosage, Neurofibromatosis type 1 and allergic reaction. RESULTS: Out of SML-localisation, minor extent of surgery, pilocytic astrocytoma, DLGG the 24 patients currently under treatment per CCHE LGG protocol (Weekly and DS were unfavourable predictive factors. 26 received no additional doses of 175 mg/m2 Carboplatin), 8 patients (5 Females, 3 Males) developed non-surgical therapy, 36 VCR/Carboplatin-chemotherapy, 6 radiotherapy Carboplatin allergy (33%). Patients age ranged between 1.3 months & 13 yrs, (5 brachytherapy, 1 external beam radiotherapy 8 years after diagnosis). out of the 8, 4 patients had pilocytic astrocytoma, 2 had fibrillary astrocy- 5-year-PFS following non-surgical therapy was 0.29, DS and DLGG were toma, 1 ganglioglioma & 1 with radiographically-defined bilateral optic unfavourable factors. 5-year-OS was 0.80, lower for children ,6 months nerve glioma. None of the patients received prior chemotherapy. All eight at diagnosis, with DS, or with DLGG. After median follow up of 7.4 patients developed Grade 1 or Grade 2 hypersensitivity reactions recorded years, vision in 31 living children was impaired or severely impaired in as urticaria, facial erythema, and facial swelling after 6-16 carboplatin infu- 26. Children ,1 year at diagnosis have a conspicuously impaired survival sions (Cumulative dose/m2 ranged between 1050mg-2800mg) except for and appear not to benefit sufficiently from current treatment approaches. one infant (dose of 5.83 mg/kg) developed allergy after only 3 infusions. Future studies have to investigate into treatment adaptations (intensifica- For all 8 patients, symptoms resolved after immediate discontinuation of tion, prolongation) to improve outcome and molecular genetics to reveal the infusion and treatment with H1 antihistamines/corticosteroids. mechanisms of tumour aggressiveness. CONCLUSION:Incidence of carboplatin allergy in our hospital (33%) is relatively higher than that previously reported (7-32%). None of the patients with CHSR required discontinuation of carboplatin therapy. Higher percentage of allergy was reported in females (62.5%). No other risk factor showed direct correlation with allergy development. P-LGG.30. THE EFFICACY OF RADIATION THERAPY FOR PEDIATRIC PILOCYTIC ASTROCYTOMAS D. B. Mansur, J. B. Rubin, E. A. Kidd, A. A. King, A. S. Hollander, M. D. Smyth, D. D. Limbrick, T. S. Park, and J. R. Leonard; Washington University School of Medicine, Saint Louis, MO, United States P-LGG.28. CARBOPLATIN HYPERSENSITIVITY IN CHILDREN WITH LOW GRADE GLIOMA - SUCCESSFUL OUTPATIENT PURPOSE: Radiation therapy is generally considered the most effective DESENSITIZATION 1 2 2 2 2 treatment for unresectable pilocytic astrocytomas in children, however R. Magid , B. C. Bostrom , L. B. Madsen , S. J. Giesar , M. B. Hansen , there are few data to support this claim. To examine the efficacy of radiation K. Slagerman2, and A. E. Bendel2; 1University of Minnesota Medical School, 2 therapy for pediatric pilocytic astrocytomas, we retrospectively reviewed the Mpls, MN, United States; Children’s Hospitals and Clincs of Minnesota, experience at our institution. METHODS AND MATERIALS: Thirty-five Mpls, MN, United States patients 18 years old or younger with unresectable tumors and without evidence of neurofibromatosis have been treated since 1982. Patients BACKGROUND: Weekly carboplatin and vincristine is a standard treat- were treated with local radiation fields to a median dose of 54 Gy. Six ment for low-grade glioma. Unfortunately, this regimen causes frequent patients were treated with radiosurgery to a median dose of 15.5 Gy. hypersensitivity reactions to carboplatin. The literature reports only 12 Five patients were treated with initial chemotherapy and irradiated fol- cases of successful carboplatin desensitization in children. OBJECTIVE: To lowing progression. RESULTS: After a median follow up of 5.4 years, determine the incidence of hypersensitivity to carboplatin in children with one patient has died resulting in an overall survival of 97%. The low-grade glioma and success of desensitization. METHODS: Medical progression-free survival, however, was only 70.0%. None of 11 infraten- records of children with low-grade glioma treated with weekly carboplatin torial tumors progressed compared to 6 of 20 supratentorial tumors. A and vincristine between January 1997 and January of 2010 at Children’s trend towards improved progression-free survival was seen with radiosur- Hospitals and Clinics of Minnesota, Minneapolis were reviewed to deter- gery (80%) compared to external beam alone (66%), but this difference mine the incidence and timing of hypersensitivity to carboplatin and did not reach statistical significance. Eight of the 9 patients progressing success of desensitization. RESULTS: Twenty patients were identified after therapy did so within the irradiated volume. One patient progressed who completed a full course of this treatment. Thirteen patients (65%) with leptomeningeal dissemination. CONCLUSIONS: While the survival experienced hypersensitivity reactions. The hypersensitivity reaction of these children is excellent, thirty percent of patients have progressive occurred at re-initiation of carboplatin after a 2-week break in 11/13 disease following radiation therapy. Improvements in outcome are patients (85%). 6/13 patients (46%) tolerated reintroduction and con- needed in this patient population, and the optimal therapy has not tinuation of carboplatin with pre-medication alone. 7/13 patients been defined. Prospective trials comparing initial chemotherapy to radi- (54%) continued to experience hypersensitivity reactions despite pre- ation therapy are warranted. The pattern of failure observed supports medication and required desensitization. The desensitization protocol the continued use of local radiation therapy fields. consisted of: pre-medication (diphenhydramine, methylprednisilone, rani- tidine); carboplatin 0.1 mg over 1 minute; 15 minute break; carboplatin

NEURO-ONCOLOGY † JUNE 2010 ii97 Abstracts

P-LGG.31. TREATMENT RESULTS OF CHILDHOOD PILOCYTIC involvement were more affected than with tumors in other locations is due ASTROCYTOMA IN KUMAMOTO, JAPAN to a greater dissociation of VIQ and PIQ. In summary, this study confirms K. Makino, H. Nakamura, and J. Kuratsu; Department of Neurosurgery, the importance of multidisciplinary treatment for neuropsychological func- Kumamoto University Graduate School, Kumamoto, Japan tions and points to the necessity of careful follow-up for these children to provide them with the necessary help to achieve full integration into pro- PURPOSE: Pilocytic astrocytoma is the most popular glial tumor among the fessional life. pediatric brain tumors and characterized by a good prognosis. Here, we evaluated the impact of primary tumor site and extent of resection on the outcome of these patients. PATIENTS AND METHODS: Medical and radio-imaging information of 29 (16 boys, 13 girls) patients under 15 years with pilocytic astrocytoma were reviewed from 1976 to 2007. RESULTS: The median age P-LGG.34. DIENCEPHALIC LOW-GRADE GLIOMAS IN at the start of treatments was 8 (2 to 15) years and the median follow-up CHILDREN: LONG-TERM RESULTS OF MULTIMODAL was 101.3 (1.6 to 356.3) months. The most common site of tumor was the cer- MANAGEMENT ebellum (15 cases), followed by hypothalamus (5), cerebral hemisphere (4), M. Vinchon1, P. Leblond2, I. Delestret1, and J. Sankaredja1; 1Lille university brainstem (3), and optic nerve and tracts (2). Both overall survival and hospital, Lille, France; 2Centre Oscar Lambret, Lille, France progression-free survival didn’t reach median time yet. 5-years survival rate Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 was 96.3%. Thirteen cases, including 12 cases in the cerebellum, were BACKGROUND: Low-grade gliomas (LGG) of the diencephalic region treated with total resection. Disease has not recurred, and adjuvant therapy (LGGDR) represent a large group of tumors in children, which are difficult wasn’t performed. However, 4 of 5 patients with hypothalamic tumors or impossible to remove, have a good overall outcome but high morbidity. showed disease progression; 2 of these patients died of subarachnoid dissemi- Several treatment modalities have been developed, with the aim of control- nation. CONCLUSIONS: The overall survival and progression-free survival ling the tumor while preserving function. PURPOSE: In order to define the in this series were good. The patients with cerebellar tumors had a good clini- present role of surgery and other treatment modalities in the management cal outcome. Furthermore, the gross total resection of tumors had a significant of LGGDR, and evaluate the result of this multimodality treatment on onco- impact on the outcome of these patients. However, progressive disease was logical and functional outcome we reviewed cases of LGGDR from our data- common among patients with hypothalamic tumors. base. MATERIAL AND METHODS: We studied retrospectively cases of LGG involving the optic chiasm, hypothalamus, third ventricle, basal ganglia, and thalamus, in children treated since 1979. Surgery aimed at performing tumor resection whenever feasible, obtaining tumor material for P-LGG.32. LONG-TERM FOLLOW-UP OF CHILDREN TREATED diagnosis, and relieving intracranial hypertension and hydrocephalus. FOR LOW GRADE GLIOMA RESULTS: We treated 94 patients with a mean follow-up of 100.5 J. L. Ater, A. Xu, S. C. Cruz, A. Mahajan, and J. S. Weinberg; UT MD months. 64 patients underwent at least one surgical resection (0 to 5), the Anderson Cancer Center, Houston, TX, United States mean number of surgeries per patient, including stereotactic procedures and shunts, was 2.8 (0 to 10); the mean number of oncological treatments PURPOSE: The purpose of this study was to determine the long-term was 1.1 (0 to 6). Fourteen patients (15%) died of tumor progression; the survival, rate and types of secondary tumors, and medical outcomes of 10-year and 20-year overall survival rates were 78.5% and 68.2% respect- children diagnosed with low grade glioma. METHODS: A retrospective ively. Among survivors, 36% are tumor-free, 57% have stable disease; chart review was performed identifying subjects from our Children’s 57% live a normal life, 29% require minor help, and 14% are dependant. Cancer Hospital database diagnosed with low grade glioma (LGG) CONCLUSION: The management of LGGDR is a life-long, multidisciplin- between 1970 and 2006, at age less than 18 years, and having follow-up ary challenge. The aim should be good functional outcome with stable information available. RESULTS: There were 199 subjects identified, 55% disease rather than cure at any cost. boys, ranging in age from 1 month to 18 yrs. (median 5 yrs.) at diagnosis and 30.7 % had neurofibromatosis type 1 (NF1). Period of follow-up ranged from 0.6 to 39 years with age at last follow-up 4 to 54 years. Tumors were located in cerebellum: 30 (15.2%); hypothalamic/optic P-LGG.35. MORBIDITY IN LONG TERM SURVIVORS (> 10 pathway 111 (56.1%); brainstem 25 (12.6%); and cerebral hemisphere/ YEARS) OF PEDIATRIC LOW GRADE GLIOMA thalamus 28 (14.1%). Tumor types were 52% pilocytic astrocytoma, S. Mathur, H. Samater, J. Duckworth, N. Barr, and K. Scheinemann; 27% optic pathway without biopsy, and 21% other LGG. Treatments McMaster Children’s Hospital, Hamilton, ON, Canada included various combinations of surgery, chemotherapy, and radiation. Many had multiple treatments. The survival rates at 5, 10, and 15 years Low grade glioma (LGG) is the most common brain tumor in children. As were: 93%, 81%, and 74% respectively. Two patients had malignant long term survival is excellent long term morbidity needs to be addressed. transformation and 5 had malignant tumor at another area of the brain The purpose of this study was to assess the morbidity and its risk factors from the original. Details of second malignancies will be presented. Late in long term survivors (. 10 years) of pediatric LGG. We constructed a occurring morbidity included overweight/ obesity 58%, visual deficits LGG database at the McMaster Children’s Hospital in Hamilton (catchment 17%, need for hormonal replacement 28%. CONCLUSIONS: Long-term area of 2.5 million people). Data collection included treatment toxicity, survival into adulthood is possible for children with low grade glioma, follow up and long term morbidities. Complete data were available in 41 even after recurrence. However, morbidity and risk of recurrence continues patients who are all alive. Mean age at diagnosis was 6.5 years (range 1.2 throughout life. Occurrence of malignant transformation or second malig- to 14.83 years). Most common tumor location was cerebellum in 20 patients, nancy is low. followed by hemispheric and tectal with 5 patients each. Patients with tectal location underwent VP-shunting/third ventriculostomy only. Twenty-two patients were treated with surgery only, 12 underwent radiation therapy, 2 patients received chemotherapy and 2 patients a combined approach. P-LGG.33. LONG-TERM SEQUELAE AFTER Within the surgical group 12 patients suffer from long term neurological def- MULTIDISCIPLINARY TREATMENT OF PILOCYTIC icits and 9 patients from visual problems. Long term morbidities post radi- ASTROCYTOMA ation included neurological deficits in 9 patients, endocrinopathies in 5 M. Terasaki, H. Inada, S. Nakashima, M. Maeda, Y. Sugita, and patients and visual problems in 4 patients. Progression of disease was M. Shigemori; Kurume Univeristy, Kurume, Japan observed in 4 patients, one with a malignant transformation to an anaplastic astrocytoma. All were salvaged with repeated surgery or chemotherapy. BACKGROUND: The importance of neuropsychological functions after Long term morbidity is common in survivors of pediatric LGG. Risk multidisciplinary treatment is becoming more evident for long survivors of factors include location, surgical approach and the chosen adjuvant treat- pediatric brain tumors. The influence on long-term sequelae from multidisci- ment. Further and larger multicenter studies including assessing biological plinary treatment in children with pilocytic astrocytoma (PA), however, is factors are needed to enhance risk adapted treatment. not well known. PROCEDURE: We present follow-up data from 10 patients, who received multidisciplinary treatment upon during childhood for PA. Data on clinical course and intelligence quotient (IQ) were retrospectively obtained from the medical record or received by telephone. RESULTS: The mean age of the 10 patients at onset was 8 years (range 0-18 years). P-LGG.36. VISUAL OUTCOME OF CHILDREN WITH OPTIC Tumor location included cerebellum (1), optic / hypothalamic (5), pineal PATHWAY GLIOMA (OPG) WITHOUT NEUROFIBROMATOSIS (1) and fornix (1). All had surgery (in total 20 operations). Five of six pro- TYPE 1 (NF-1) gressive cases required chemotherapy. Four required radiotherapy during E. Opocher1, M. Campagna1, E. Viscardi1, M. Calderone2, M. S. Severino2, treatment (3 with local, 1 with CSI) for tumor control. With a median I. Cermackova1, and G. Perilongo1; 1Department of pediatrics, University follow-up period of 9 years, six go to school (2 in a special-education class- Hospital, Padua, Italy; 2Department of Neuroradiology, Padua, Italy room) or have a part-time job. These children had a mean IQ of 76, performance IQ of 82 and verbal IQ of 62. Three required hormonal replacement. AIM: To evaluate visual outcome in children (aged ,18 years) with OPG CONCLUSIONS: The observation that patients with optic / hypothalamic without NF-1 managed by a paediatric neuro-oncology team according to ii98 NEURO-ONCOLOGY † JUNE 2010 Abstracts

standardized strategies. PATIENTS AND METHODS: 32 consecutive chil- were associated with an increased risk of patient death. CONCLUSIONS: dren meeting the eligible criteria, referred to the paediatric department of Death is an uncommon for children with pilocytic astrocytomas. Certain Padua, between 1989 and 2008, represent the study population. variables, including tumor location in hypothalamus/optic pathways, RESULTS: At presentation visual acuity (VA) was normal in both or in the extent of surgical resection, co-existing neurofibromatosis and sex were best eyes in 9 and 13 children respectively while it was reduced in 11. associated with an increased risk of death and should be considered in Eight children were treated with chemotherapy only, 10 with radiotherapy, making patient treatment decisions. 7 with combined treatment, while 7 were observed. After a median follow-up of 6 years, 26 patients are alive with stable disease. The VA improved in 6 patients, it was stable in 8 and worsened in 18. The visual field (VF), assessed at follow-up in 29 children was normal in 9 and reduced in 20. The number of children into the WHO “visual impairment” categories raised from 7 to P-LGG.39. VASCULOPATHY IN CHILDREN TREATED FOR 10. Among the 17 children with a reduction in tumour size the VA improved HYPOTHALAMIC AND CHIASMATIC GLIOMAS: CLINICAL only in 6, was stable in 3, worsened in 8. Six children had VA improvement OBSERVATIONS AND POTENTIAL RISK FACTORS and were older than 8 years, received only radiotherapy treatment and had a U. Tacke1, D. Karger1, J. Spreer2, A. Berlis2, G. Nikkhah3, and normal or mildly pale papilla at the funduscopic examination. R. Korinthenberg1; 1Division of Neuropediatrics and Muscular Disorders, CONCLUSIONS: Visual improvement was documented in few children University Hospital, Freiburg, Germany; 2Department of Neuroradiology, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 with OPG, more often in older patients who received radiotherapy. University Hospital, Freiburg, Germany; 3Department of Stereotactic and Tumour volume shrinking is not always a synonymous of visual improve- Functional Neurosurgery, University Hospital, Freiburg, Germany ment. Funduscopic examination should be considered for visual prognosis assessment. OBJECTIVE: Interstitial radiosurgery is a well tolerated treatment approach for low grade glioma in childhood. Compared to external brain irradiation it offers an equivalent tumour control with less side effects. Vascular alterations after external radiotherapy have been reported in adults, no data exist so far on these sequelae in children after interstitial P-LGG.37. VISUAL OUTCOME FOLLOWING CHEMOTHERAPY radiosurgery for low grade glioma. PATIENTS AND METHODS: We FOR PROGRESSIVE OPTIC PATHWAY GLIOMAS report on thirteen children with low grade glioma (WHO I-II), which had B. Shofty1,2, L. Ben-Sira3, S. Freedman1, M. Yalon4, R. Dvir1, been diagnosed in 1988-1999. Median age at diagnosis was 54 months M. Weintraub5, H. Toledano1, A. Kesler3, and S. Constantini1; 1DANA (range 11-119m). All had interstitial radiosurgery with Iodine 125 seed Children’s Hospital, Tel Aviv Medical Center, Tel Aviv, Israel; 2Sackler implantations as first line treatment or adjuvant following surgery (9 vs. 4 faculty of medicine Tel-Aviv university, Israel; 3Tel Aviv Medical Center, Tel patients). All those patients scheduled for their regular follow up in 2001 Aviv, Israel; 4Sheba Medical Center, Tel-Hashomer, Israel; 5Hadassah after neurological examination underwent MRI plus MR-angiography. Hebrew University Medical Center, Jerusalem, Israel RESULTS: Six out of 13 revealed cerebral vasculopathies like stenosis and / or aneurysms at the Circle of Willis. Only one of them had symptoms of Optic pathway gliomas (OPG) are relatively indolent tumors. Treatment intermittent cerebral ischemia. Neurofibromatosis type 1 was not present is generally initiated only when a clear clinical or radiological deterio- in any affected patients. DISCUSSION: The etiology of the cerebrovascular ration is documented. Chemotherapy is the standard first line of treatment. pathologies observed in the present cases is not fully understood. MRA In this study, we looked at the detailed visual outcome in patients with maybe a helpful tool to estimate vascular changes due to tumour encasement progressive OPGs who received chemotherapy, and correlated it with and / or a stenosis caused by interstitial radiosurgery. To understand this imaging findings. We retrospectively reviewed 24 children with OPG complex pathophysiology further a careful and prospective evaluation of that were treated with chemotherapy. Included were only patients that vasculopathies in these patients is highly recommended. had a complete data-set of reliable pre-, and post-intervention information on imaging, visual status, and treatment. Nineteen patients met our criteria. Eleven (57%) had neurofibromatosis I. Indications for treatment were radiological tumor progression (6 patients), visual decline (6 patients) or both (7 patients). Fourteen patients (73%) had to change to a second P-LGG.40. CHEMOTHERAPY WITH BBSFOP REGIMEN FOR line of chemotherapy. Over the chemotherapy treatment period, 11 CHILDREN WITH HYPOTHALAMIC OPTIC PATHWAY GLIOMA (57.8%) patients had radiological progression of tumor, 4 (21.5%) (HOPG) AND DIENCEPHALIC CACHEXIA (DC): A SFCE stable tumor, 4 (21.5%) regression. During the treatment period 14 (SOCIE´ TE´ FRANÇ AISE DES CANCERS DE L’ENFANT) (73.6%) had visual deterioration, 4 (21%) were with stable vision, 1 RETROSPECTIVE STUDY patient (5.2%) improved. The visual acuity of 38 eyes was examined; S. Bobillier-Chaumont1, V. Laithier2, M. Raquin3, L. Jochault4, two were excluded for being completely blind. 17 (47.2%) eyes deterio- X. Rialland5, E. Sariban6, F. Fanny7, A. Bertozzi8,F.Doz9, D. Frappaz1, and rated, 14 (38.8%) were stable, and 5 (13.8%) improved. Ten (27.7%) J. Grill3; 1IHOP, LYON, France; 2HOP, Besançon, France; 3IGR oncologie eyes deteriorated to legal blindness. There was no correlation between pediatrique, Villejuif, France; 4CHU, Besançon, France; 5CHU, Anger, the radiological tumor behavior and visual changes during the treatment France; 6Hopital des enfants de la reine Fabiola, Bruxelle, Belgium; period. In our study, the majority of patients who received chemotherapy 7Hemato-oncologie pediatrique, Hopital d’enfants, Nancy, France; 8Hopital for progressive OPGs experienced a marked decline in visual function over des enfants, He´mato-oncologie, Toulouse, France; 9institut Curie-pediatrie the treatment period! Our current strategy should be re-evaluated. oncologie, Paris, France

OBJECTIVE: To evaluate the role of chemotherapy, in patients with HOPG and DC, on improving weight, causing tumor shrinkage, and delaying radiotherapy. Methods : 35 children (median age: 10 month) received the BBSFOP P-LGG.38. RISK FACTORS FOR DEATH AMONG CHILDREN regimen consisting in 7 cycles (alternating carboplatin / procarbazine, etopo- WITH PILOCYTIC ASTROCYTOMAS side / cisplatinum and cyclophosphamide / vincristine) during sixteen D. C. Bowers1, L. J. Klesse1, L. Gargan2, R. D. Elterman2, and B. E. Weprin2; months. RESULTS: Four had a NF1. Histological diagnosis was pilocytic astro- 1UT Southwestern Medical Center at Dallas, Dallas, TX, United States; cytoma in 19, low grade astrocytoma NOS in 4. Nine had leptomeningeal dis- 2Children’s Medical Center, Dallas, TX, United States semination. Only 18/35 pts completed the BBSFOP regimen. The MRI best response was: GPR (2), PR (5), OR (5), SD (14) and PD (9). 13/35 had INTRODUCTION: Little is known about risk factors for death among weight gain during treatment, without correlation to response to treatment. children with pilocytic astrocytomas. METHODS: A single-institution Disease progression occurred in 34/35 patients (median time was 22.5 chart review of children with pilocytic astrocytomas. Variables, including months [2-137]). 17 pts were irradiated (median interval from diagnosis was demographic, tumor and treatment factors, were examined for an associ- 54 months [21-114]). 5-year OS is 83% [67-92] and PFS is 8.6% [3-22] with ation with subsequent patient death. RESULTS: 264 children (134 females, a median follow-up of 89 months. 11 pts died (progressive disease: 7, toxicity 48.5%) with pilocytic astrocytomas were identified. The mean age at diagno- during further lines: 4). PFS is lower than for HOPG patients without DC sis was 7.96 + 4.98 years (range ¼ 0.41 - 18.71 years) and mean duration of (34%). PFS is especially low for children younger than 6 months (p ¼ 0.01), follow-up was 6.20 + 4.55 years (range ¼ 0.06 - 23.45 years). The 5 and 10 but their OS remains favourable (87.5%). At the end of follow-up 10 had year PFS were 61.7% and 54.0%, respectively. The 5 and 10 year OS were obesity, 8 had GH deficiency, and 19 had abnormal puberty. 94.9% and 92.4%, respectively. 15 children died at a mean of 10.77 + CONCLUSIONS: The goal of this strategy, which was to delay or obviate the 6.93 years (1.61 - 21.12 years) of age and 4.76 + 4.51 years (0.2 - 16.96 need of radiotherapy, was reached for these very young patients. years) after diagnosis. The cause of death was tumor progression (n ¼ 9), Chemotherapy may achieve transient tumour control in children with HOPG other (n ¼ 5), and unknown (n ¼ 1). Tumor location in hypothalamus/ and DC, but long term result remains disappointing. optic pathways vs. other locations (p , 0.001), complete surgical resection vs. less than complete surgical resection (p ¼ 0.005), presence of co-existing neurofibromatosis vs. none (p ¼ 0.017) and male vs. female sex (p ¼ 0.048)

NEURO-ONCOLOGY † JUNE 2010 ii99 Abstracts

P13 EPENDYMOMA P-EPEN.03. IDENTIFICATION OF FREQUENTLY ALTERED GENE NETWORKS IN INTRACRANIAL EPENDYMOMAS J. M. Bischof1,2, K. Arndt1, D. Wang1,3, and M. B. Soares1,3; 1Children’s Memorial Research Center, Chicago, IL, United States; 2Northwestern University, Evanston, IL, United States; 3Northwestern University’s Feinberg P-EPEN.01. A NOVEL EPENDYMOMA CELL LINE WITH STEM School of Medicine, Chicago, IL, United States CELL-LIKE PROPERTIES 1 2 3,4 5,6 7 8 T. Milde , S. Kleber , A. Korshunov , H. Witt , H. Kopp , M. Jugold , Studies of chromosomal aberrations in ependymomas have shown that 1,6 1 1,6 3,4 5,6 H. E. Deubzer , I. Oehme , M. Lodrini , A. von Deimling , S. Pfister , regions that exhibit copy number alterations, i.e. loss or gain, seldom recur 2 1,6 1 A. Martin-Villalba , and O. Witt ; CCU Pediatric Oncology (G340), in these tumors. We hypothesize that this phenomenon is due to the complex- German Cancer Research Center (DKFZ), Heidelberg, Germany; ity of ependymoma tumorigenesis and that instead of the same gene being 2 Department of Molecular Neurobiology (G381), German Cancer Research recurrently disrupted, an underlying gene interaction network exists that is 3 Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, recurrently perturbed in one of more ways by the various genomic aberra- 4 University Hospital Heidelberg, Germany; CCU Neuropathology (G380), tions that have been found to occur in pediatric ependymomas. In this 5 German Cancer Research Center (DKFZ), Heidelberg, Germany; Division study, arrayCGH datasets from published literature were obtained and ana- Molecular Genetics (B060), German Cancer Research Center (DKFZ), lyzed in an attempt to identify these commonly affected gene networks. The 6 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Heidelberg, Germany; Department of Pediatric Oncology, Hematology and genes found within regions of loss and gain were then used to perform 7 Immunology, University Hospital Heidelberg, Germany; Department of network analysis with MetacoreTM’s GeneGo in an attempt to identify 8 Hematology/Oncology, University Hospital Tu¨ bingen, Germany; Project gene networks that are altered in a statistically significant number of Group Small Animal Imaging, Division of Medical Physics in Radiology tumors. We performed 10,000 simulations to randomly select regions of (E020), German Cancer Research Center (DKFZ), Heidelberg, Germany loss and gain, equal in gene number to the actual data, to use as controls for comparison. Several networks and processes were found to be altered Despite intensive radio- and chemotherapy, nonresectable ependymomas at a greater level in the regions of loss and gain when compared to the simu- are associated with poor prognosis, and novel treatments are difficult to lated data (p , 0.05). We further investigated these networks in an effort to develop due to the lack of appropriate pre-clinical models. We here report discern which genes and subnetworks are relevant to the development and on the generation of a first ependymoma cell line (termed DKFZ-EP1NS) progression of ependymomas. This study was supported by The Everett/ with long term self-renewal capacity. We were able to isolate ependymoma O’Connor Charitable Trust; Dr. Ralph & Marian C. Falk Medical cells growing in spheres using serum-free neurosphere media conditions, Research Trust; Gus Foundation; and the Medical Research Institute Council which were then characterized for genetic aberrations, marker expression and tumorigeneity in an orthotopic xenotransplant model. The DKFZ-EP1NS cells were kept under neurosphere culture conditions for up to 9 months, displaying long term self-renewal. Freezing for storage and thawing was routinely possible. Genetic aberrations (loss at 1p36, chromo- P-EPEN.04. CHARACTERISING GENOMIC IMBALANCES IN some 9 and 14q) found in the DKFZ-EP1NS corresponded to the aberrations PAEDIATRIC EPENDYMOMA; THE IMPORTANCE OF discovered in the primary ependymoma and subsequent recurrent tumors of CHROMOSOME 1Q GAIN the patient. DKFZ-EP1NS cells display several markers associated with J. Kilday1, K. Wright2, S. Leavy2, J. Lowe3, E. C. Schwalbe4, S. C. Clifford4, normal stem cells as well as cancer stem cells. Orthotopically transplanted R. G. Gilbertson2, B. Coyle1, and R. G. Grundy1; 1Children’s Brain Tumour mice displayed first tumors after 9 months in the striatum of the brain, and Research Centre, School of Clinical Sciences, University of Nottingham, tumors phenotypically recapitulated the original tumor. Serial transplan- Nottingham, United Kingdom; 2Department of Developmental tation yielded secondary tumors in half the time. Since subcutaneous or Neurobiology, St. Jude’s Children’s Research Hospital, Memphis, TN, intraperitoneal transplantation did not recapitulate the original intracranial United States; 3Children’s Brain Tumour Research Centre, School of phenotype, the orthotopic niche seems to be required for the induction of the Molecular Medical Sciences, University of Nottingham, Nottingham, United typical tumor histology. In conclusion, we were able to establish a first epen- Kingdom; 4Northern Institute for Cancer Research, University of Newcastle, dymoma cell line with stem cell-like properties recapitulating human disease Newcastle, United Kingdom in an orthotopic xenograft model, allowing for pre-clinical evaluation of drugs targeting the cancer stem cell compartment in ependymoma. Despite advances in neurosurgery, imaging and adjuvant therapies, paediatric ependymomas are central nervous system (CNS) tumours that remain a clinical challenge with a relatively poor patient prognosis. An improved understanding of ependymoma biology may identify new correlates of disease outcome and novel therapeutic agents. Affymetrix 500K P-EPEN.02. EPIGENOMIC AND TRANSCRIPTOMIC SNP arrays were used to identify genomic imbalances in 42 primary and ALTERATIONS IN PEDIATRIC EPENDYMOMAS 21 recurrent paediatric ependymomas. 53 (84.1%) of the tumours were ana- 1 1 1 2 1 M. Wang , H. Xie , M. d. F. Bonaldo , V. Rajaram , A. D. Andrade , lysed against patient-matched constitutional DNA. Gene copy number 2 2 2 2 1 W. Stellpflug , S. Goldman , T. Tomita , and M. B. Soares ; Children’s alterations were validated by quantitative real-time polymerase chain reac- 2 Memorial Research Center, Chicago, IL, United States; Children’s tion (qPCR). Gain of chromosome 1q was the most frequent anomaly in Memorial Hospital, Chicago, IL, United States primary and recurrent intracranial tumours (19.4% and 30% respectively), while ependymomas from different CNS locations harboured characteristic Ependymomas are the third most prevalent childhood brain tumors aberrations. Certain gene anomalies were associated with clinical subgroups, accounting for approximately 10% of neuroepithelial tumors, and among such as CHI3L1 gain (1q32.1) in posterior fossa tumours (p ¼ 0.014). the most common tumors in the posterior fossa region. The genetic and epi- Unsupervised hierarchical clustering of cytoband abnormalities identified a genetic aberrations underlying development and progression of ependymo- group of samples characterised by 1q21.2 gain with a worse 5 year event mas have not been fully understood. In this study, we performed an free survival (0% vs. 56.1%; univariate analysis p ¼ 0.003, multivariate integrative analysis of whole genome DNA methylation and gene expression analysis p ¼ 0.02). Within 1q21.2, gain of PRUNE and BNIPL were associ- in pediatric ependymomas using Illumina HumanMethylation27 and ated with a reduced 5 year overall survival for the entire cohort (65.6% vs. HumanRef-12 BeadChip respectively. A series of 36 pediatric ependymoma 88.1%; univariate analysis p ¼ 0.025). Identification of aberrations in this samples from 30 patients were included in this study. In addition, 6 micro- high resolution, genome-wide study has uncovered potential prognostic cor- dissected tissue samples from the ventricle linings were included as normal relates. Indeed, protein expression of PRUNE, BNIPL and NAV1 (1q32.1), controls. The results showed that hypermethylated CpG sites were significantly the most frequently gained gene in the recurrent cohort, are now being ana- enriched in CpG islands, while the hypomethylated sites frequently localized lysed on a panel of ependymomas from children treated within the confines outside the CpG islands. From the analysis of both methylation and expression of two clinical trials (CCLG CNS 92 04 and SIOP CNS 99 04). data sets, we found that genes implicated in blood vessel morphogenesis, Sonic Hedgehog andNotch signaling pathways, cell cycle regulation,andECM remodeling were altered in ependymomas compared to normal controls. In addition, ependymomas derived from supratentorial and infratentorial regions demonstrated methylation and expression differences in the pathways of neurogenesis including axonal guidance and synaptogenesis. By combining epigenomic and transcriptomic profiles from this collection of ependymoma tumor samples, we identified potential genes and pathways that are involved in the initiation and development of ependymomas, which may lead to possible molecular targets for therapeutic interventions.

ii100 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-EPEN.05. IDENTIFICATION OF DIFFERENTIALLY P-EPEN.07. EXPRESSION OF A DRUG RESISTANT STEM CELL EXPRESSED MICRORNAS IN EPENDYMOMAS PHENOTYPE PREDICTS POORER OVERALL SURVIVAL IN F. F. Costa1, J. M. Bischof1, E. F. Vanin1, M. Wang1, S. T. Sredni1, PAEDIATRIC EPENDYMOMAS V. Rajaram2, J. Eusebio2, H. Xie1, M. Bonaldo1, S. Goldman3, T. Tomita4, L. C. D. Storer, M. Kessler, J. Kilday, R. Armstrong, J. Lowe, I. D. Kerr, and M. B. Soares1; 1Cancer Biology and Epigenomics Program, Children’s R. G. Grundy, and B. Coyle; University of Nottingham, Nottingham, United Memorial Research Center, Chicago, IL, United States; 2Department of Kingdom Pathology and Laboratory of Medicine, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL, United States; 3Pediatric Neuro-oncology, Limited chemoresponsiveness and the very poor prognosis of ependymo- Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL, United mas are consistent with a drug resistant phenotype. ABC B1 and ABC G2 States; 4Pediatric Neurosurgery, Children’s Memorial Hospital, 2300 are ATP-binding cassette (ABC) multidrug transporters, which can efflux Children’s Plaza, Chicago, IL, United States chemotherapeutic substances. We therefore examined the relationship + between CD133 ‘Cancer Stem Cells’ (CSCs) co-expressing ABC B1 or Ependymomas are tumors that present great challenges in treatment ABC G2 and survival in paediatric ependymoma. Patient samples were despite the advances in neurosurgical techniques and adjuvant therapy. In from the CNS 9204 (,3 years of age) and CNS 9904 (.3 years of age) clini- order to identify possible molecular markers that could improve clinical cal trials. Double immunofluorescence was performed on tissue microarrays management we have profiled ependymomas for the expression of from 46 primary and 12 recurrent paediatric ependymomas. ABC G2 Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 microRNAs (miRNAs). miRNAs are ncRNAs that can block mRNA trans- expression was significantly higher in anaplastic ependymoma compared lation and affect mRNA stability. Several lines of evidence have recently to ependymoma (0.94% compared to 0.62%, p ¼ 0.043). Patients from shown that up- or down-regulation of miRNAs correlate with many CNS 9204, but not from CNS 9904, who expressed ABC B1 or co-localised human cancers. In this study, we have evaluated with the use of TaqMan CD133/ABC B1 had a significantly worse overall survival than those who Low Density Arrays (TLDAs) expression profiles of 365 miRNAs in ependy- did not (54.9 vs. 109.2 months, p ¼ 0.006 and 45.9 vs. 111.2 months, moma samples and normal brain tissue. We first compared the correlation of p , 0.0005 respectively). These findings held true on multivariate analysis expression profiles using paired frozen tissue (FT) and paraffin (formalin- (p ¼ 0.013 and p ¼ 0.004 respectively). Higher ABC G2 expression in ana- fixed paraffin-embedded, FFPE). Then, we analyzed the miRNA expression plastic ependymomas may be due to a role in promoting cell-division in this profile of 34 ependymoma samples using FFPE tissue compared to 8 more proliferative ependymoma subtype. CNS 9204 was a primary normal brain control samples enriched for ependymal cells. miRNA chemotherapy-based regime; hence the presence of highly tumourigenic che- expression profiles was correlated with clinico-pathological parameters, moresistant cells may have resulted in the relatively poorer survival. CNS morphological features and the location of the tumor in the brain. Using 9904 patients received chemotherapy and radiotherapy, consequently the this strategy, we were able to identify miRNAs that were up- and down- presence of such cells is likely to have a lesser impact. Thus, the presence regulated in ependymomas. We have also identified and are currently con- of CSCs expressing ABC B1 predicts a poorer overall survival in ependy- firming some of the targets for these miRNAs in ependymoma samples moma patients less than 3 years of age on a chemotherapy dependent treat- and in normal controls by different methods. In conclusion, FFPE can be uti- ment regime. lized for miRNA studies as an invaluable source when FT is not available. Moreover, using different strategies, we have been able to identify ncRNAs that are differentially expressed in ependymomas compared to normal ependymal tissue. SUPPORT: CMRC, Falk Brain Tumor Foundation and Maeve McNicholas Memorial Foundation. P-EPEN.08. ECOTROPIC VIRAL INTEGRATION SITE 1 (EVI-1) IS OVER-EXPRESSED IN TUMOR CELLS LASER-MICRODISSECTED FROM INTRACRANIAL EPENDYMOMAS B. Koos1, A. Koblitz1, S. Mertsch1, J. Felsberg2, R. Beschorner3, W. Paulus1, P-EPEN.06. EPENDYMOMA-SPECIFIC EXPRESSION and M. Hasselblatt1; 1Institute of Neuropathology, University Hospital SIGNATURES IDENTIFY PROMISING PROGNOSTIC AND Mu¨ nster, Germany, Muenster, Germany; 2Department of Neuropathology, THERAPEUTIC MARKERS Heinrich-Heine University, Du¨ sseldorf, Germany., Duesseldorf, Germany; P. Modena1, M. Boeri2, E. Lorenzetto1, F. Facchinetti2, C. Verri2, 3Institute of Brain Research, Eberhard-Karls University, Tu¨ bingen, A. Giuliano1, P. Collini2, G. Finocchiaro2, F. Giangaspero3,4, I. Sardi5, Germany, Tuebingen, Germany L. Genitori5, R. Maestro1, G. Sozzi2, and M. Massimino2; 1CRO National Cancer Institute, Aviano, Italy; 2Fondazione IRCCS Istituto Nazionale BACKGROUND: The pathogenesis of intracranial ependymomas, glial Tumori, Milano, Italy; 3Universita’ La Sapienza, Roma, Italy; 4IRCCS tumors of presumably ependymal origin, remains poorly understood. We Neuromed, Pozzilli, Italy; 5Ospedale Pediatrico Meyer, Firenze, Italy thus aimed to identify pathways operative in the development of these frequently recurring neoplasms. METHODS: Gene expression profiles obtained BACKGROUND: Improvements in the diagnosis and therapy of ependy- from tumor cells laser-microdissected from 17 intracranial ependymomas moma still requires a major thrust to better define the biological features [seven ependymomas (WHO grade II) and 10 anaplastic ependymomas of this tumor entity. METHODS: Fresh tumor material was collected from (WHO grade III)] were compared to that of ependymal cells laser- primary and recurrent ependymomas (n¼ 59), low-grade gliomas (n¼ 30) microdissected from autopsy tissue (n ¼ 7). RESULTS: On DNA microarray and embrional tumors (n¼ 12). Real-time-PCR, western blotting, microar- analysis, 30 probe sets were found to be significantly over-expressed (.5-fold) ray analysis, including microRNA and methylation profiling, were used to while 98 genes were significantly under-expressed (,0.2-fold). In addition to identify discriminating signatures and to monitor transcript and protein genes known to be involved in the biology of ependymomas, EVI1 (ecotropic expression. Ependymoma short-term cell cultures were used for pharmaco- viral integration site 1), known to promote proliferation but not yet described logic studies. RESULTS: Unsupervised hierarchical clustering of gene in brain tumors, was highly over-expressed in ependymal tumor cells expression data robustly distinguishes the different tumor types and class com- (,24.4-fold; -3.95 vs. 0.65, p , 0.001). Over-expression of EVI1 was con- parison analyses define ependymoma-specific genes signatures (p , 0.001). A firmed by quantitative reverse transcription-PCR and also on protein level miRNA signature of 10 genes suggestively discriminates primary versus relap- using immunohistochemistry. The functional role of EVI1 as well as other dif- sing ependymoma (p ¼ 0.07 for global test accounting for multiple testing), ferentially expressed genes is being investigated using an RNAi approach in mir-10a and 10b are frequently de-methylated and mir-10a is highly expressed primary ependymoma cultures. CONCLUSION: Using gene expression profil- at relapse. No significant associations with overall survival were identified. ing, several genes differentially expressed in tumor cells of intracranial ependy- Methylation profiling identified RASSF1A epigenetic inactivation in infraten- momas could be identified. Among those, EVI1 is highly expressed and might torial tumors, further supporting the observation that NF2, YAP1 and play a role in the biology of ependymomas. Supported by DFG (HA 3060/3-1). RASSF1A components of the Salvador-Warts-Hyppo pathway are differentially altered in all ependymoma subsets. We also identified IGF2 loss-of-imprinting and concurrent high expression of IGF1R, suggesting the existence of an aberrant autocrine/paracrine insulin signalling. Finally, despite elevated expression of multiple receptor tyrosine kinases, constitutive P-EPEN.09. EPENDYMOMA IN INFANT - CASE REPORT AKT activation and cytotoxic response to AKT inhibitor in ependymoma T. Syriopoulou, D. I. Konstantelos, A. Koulouri, and N. Karli; General cells, the antiproliferative effect of several RTK inhibitors individually evalu- Hospital of Kalamata, Pediatric department, Kalamata, Greece atedwas limited. CONCLUSION:Weestablished robust ependymoma-specific signatures that further elucidate the biology of this tumor entity and highlight BACKGROUND: Ependymoma is responsible for 10% of all pediatric candidate prognostic and therapeutic markers. brain tumors. Its signs and symptoms depend on the site and size of the tumor and the patient’s age. AIM: We present the case of a female infant with intracranial ependymoma. PATIENTS AND METHODS: A 7-month-old female infant presented with vomiting, irritatability alternating with somnolence, and loss of head control for the last 3 days. The fully termed infant was born to phenotypically healthy parents by cesarean

NEURO-ONCOLOGY † JUNE 2010 ii101 Abstracts

section due to obstructed labor, had a normal perinatal period and showed international findings; however, our treatment schedule has proved to be sporadic vomiting, intermittent loss of head control for 2 months. On phys- well tolerated without any significant side effect. ical examination the infant was sleepy with an open anterior fontanel, normally hydrated and developed seizures (eye deviation, tonic posture of arms and legs, facial grimasing, sialorrhea). Light reaction of pupils was normal and tendinous reflexes symmetrical. The episode was brief and was termi- P-EPEN.12. SECOND-LOOK SURGERY (SLS) FOR EPENDYMOMA: THE ITALIAN EXPERIENCE nated after rectal administration of diazepam. Hematological and biochemi- 1 2 2 3 4 4 cal analyses and cultures from blood and urine were normal as was analysis M. Massimino , M. L. Garre´ , A. Cama , C. Solero , L. Genitori , I. Sardi , C. Di Rocco5, E. Viscardi6, P. Modena7, S. Barra8, G. Scarzello9, of aminoacids in serum and urine. Cytological examination of cerebrospinal 10 11,12 13 1 fluid (CSF) showed few monocytes, lymphocytes and ependymal cells. E. Galassi , F. Giangaspero , and L. Gandola ; Pediatrics Unit Fond. IRCCS Istituto Nazionale Tumori, Milano, Italy; 2Neurosurgery Unit, Findings of brain magnetic resonance spectroscopy were compatible with 3 ependymoma of increased cellularity. RESULTS: The tumor was removed. IRCCS Giannina Gaslini, Genova, Italy; Neurosurgery Unit, Fond.IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; 4Neurosurgery Unit, Histological examination revealed supratentorial primitive neuroectodermal 5 tumor of the CNS grade IV. Chemotherapy and antiepileptic treatment was Ospedale Pediatrico Meyer, Firenze, Italy; Neurosurgery Unit, Ospedale A. Gemelli, Roma, Italy; 6Pediatrics Unit Universita`, Padova, Italy; 7Unit of administered. 13 months later the patient showed eye deviation to the right, 8 horizontal nystagmus and no eye contact. Increased muscle tone of the extre- Experimental Oncology 1, Cancer Center, Aviano, Italy; Radiotherapy Unit, Istituto per la Ricerca sul Cancro, Genova, Italy; 9Radiotherapy Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 mities and opisthotonus were also observed. CONCLUSIONS: 1) Effective 10 treatment of intracranial ependymoma remains a challenge in pediatric Department, University, Padova, Italy; Neurosurgery Unit, Ospedale Bellaria, Bologna, Italy; 11Neuropathology Unit, Universita` La Sapienza, oncology. 2) Despite the rarity of the disease, ependymoma should be 12 13 included in the differential diagnosis in infants with nausea, vomiting, sleepi- Roma, Italy; Neuromed, Pozzilli, Italy; Radiotherapy Unit Fond. IRCCS ness, seizures or behavioral disorders. Istituto Nazionale Tumori, Milano, Italy INTRODUCTION: Complete resection carries better ependymoma PFS/ OS; smaller residues carry better prognosis than “bulky” residues. SLS on P-EPEN.10. LONG-TERM SURVIVAL OF PARTIALLY RESECTED smaller tumors can be associated with less anesthesiologic complications INFRATENTORIAL EPENDYMOMA IN A CHILD and reach complete removal. There is an uncertain role for neo-adjuvant che- S. Song, S. Kim, and J. Seong; Chungnam National University Hospital, motherapy in favouring further surgeries. METHODS: From 1994 we Daejeon, Republic of Korea adopted two subsequent protocols for intracranial ependymomas: in both a phase of adjuvant chemotherapy was prescribed for surgical residues, in Ependymomas are rare neoplasms of the central nervous system that have view of possible SLS before radiotherapy. In the first, accruing 63 children, been associated with a poor outcome. According to the literature, the 9 were submitted to more than one surgical act: 4 after the 1st excision majority of clinical reports emphasize the role of the gross total resection and 5 after surgery and chemotherapy: 3/4 plus 3/5 were rendered CR when such a procedure is safe and feasible to get a best clinical outcome. without additional sequelae, and their prognosis both for PFS and for However, total removal remains a challenge even for the most skillful sur- freedom from local relapse was comparable to that of children operated geons because of the vicinity of important brainstem and cranial nerve struc- once. In the subsequent protocol the efforts toward complete resection tures involved and is particularly difficult in lateral extensions and the value were improved. RESULTS: Of 95 patients accrued from 2001, 29 had resi- of the total removal is still controversial. We are going to present a case dues after 1st surgery and/or adjuvant chemotherapy. Twenty-two were report of a 6-year-old female with partially removed huge sized infratentorial re-operated: 5 after 1st surgery, 15 after chemotherapy and 2 soon after ependymoma that lay dormant for 10 years without changes in size of radiotherapy; 2 children had 3 and 1 had 4 excisions. Eleven of 22 patients residual mass on follow-up MRI. Pathological examination revealed histo- obtained CR: one had neurologic worsening. We compared the outcome of logical features consistent with a low grade ependymoma. We performed the 58 patients in CR after one surgical act with those 11 in CR after more local field radiation therapy. Currently, at 10 years follow-up, the patient acts: both groups had 3/5 year PFS of 66% and 3year freedom from local remained neurologically intact and attended school without symptoms. relapse was 82/87%, respectively. DISCUSSION: SLS has been demon- The clinical features, radiologic images, pathology and surgical management strated to be feasible without morbidity; results improved during time. of ependymoma are discussed and briefly reviewed on the relevant literature. Local tumor control with SLS was comparable in patients with one and multiple resections.

P-EPEN.11. PROGRESSION FREE SURVIVAL WITH THE HUNGARIAN EPENDYMOMA PROTOCOL IN PATIENTS WITH ANAPLASTIC EPENDYMOMA 1 1 1 2 3 4 P-EPEN.13. ROLE OF ADJUVANT RADIOTHERAPY (RT) IN P. Hauser , Z. Jakab , D. Schuler , B. Markia , K. Bartyik , I. Szegedi , PEDIATRIC SUPRATENTORIAL EPENDYMOMAS: A J. Cservena´k5, K. Nagy6, B. Kocsis7, J. Vı´zkeleti7,C.Kiss4, L. Bogna´r8, and 1 1 RETROSPECTIVE REVIEW WITH LONG-TERM FOLLOW-UP M. Garami ; Semmelweis University, 2nd Dept of Pediatrics, Budapest, FROM THE MAYO CLINIC Hungary; 2National Institute of Neurosurgery, Budapest, Hungary; 3University 4 N. N. I. Laack, J. W. Rooney, G. F. Keating, and N. M. Wetjen; Mayo Clinic, of Szeged, Department of Pediatrics, Szeged, Hungary; University of Debrecen Rochester, MN, United States Medical Center, Department of Pediatric Oncology, Debrecen, Hungary; 5 Child Welfare Center, Borsod County Teaching Hospital,Department of PURPOSE: Management of pediatric supratentorial ependymoma after Hematology, Miskolc, Hungary; 6Department of Hematology, Child Welfare 7 complete resection is controversial. METHODS: Retrospective review of Center, Borsod County Teaching Hospital, Miskolc, Hungary; National ≤ 8 patients 18 years of age with primary supratentorial ependymoma diag- Institute of Oncology, Radiotherapy Unit, Budapest, Hungary; University of nosed at the Mayo Clinic between 1969 and 2008. The extent of surgical Debrecen, Department of Neurosurgery, Debrecen, Hungary resection was determined by intraoperative impression and post-operative imaging. RT dose ranged from 40-60 Gy at 1.49-2 Gy per fraction. BACKGROUND: There is no widely used highly effective treatment in RESULTS: Of the 20 patients in our series, 13 were alive. Median follow-up patients with anaplastic ependymoma. In 2002 a new treatment schedule, for surviving patients was 8.3 years. Overall survival (OS) at 5 and 10 years called Hungarian Ependymoma Protocol was introduced for patients with was 73% and 58%. Eleven have recurred (55%) at a median of 2.8 years anaplastic ependymoma in Hungary. PATIENTS AND METHOD: Between (range 3.2 months to 4 years). Five-year recurrence free survival (RFS) was 2002 and 2008, there were 29 patients diagnosed with anaplastic ependy- 38%. Factors associated with recurrence are headache at presentation (p ¼ moma in Hungary. 1 patient rejected chemotherapy, 4 patients were treated 0.031), hemispheric location (p ¼ 0.025), and extent of resection (p ¼ with another schedule. 24 patients has been treated according to our treatment 0.048). RFS after gross total resection (GTR) was significantly improved by schedule, Hungarian Ependymoma Protocol containing 3 cycles of VCDDPE adjuvant RT (p ¼ 0.0038); 4 of 6 patients who did not receive RT after GTR (vincristine1.5 mg/m2, cisplatin 3 x 30 mg/m2, etoposide 4 x 100 mg/m2) and + and 2 of 8 who received RT after GTR have recurred. Median RFS after irradiation (36 Gy CSI 20 Gy boost) in those patients older than 3 years. In GTR without RT was 2.8 years; median RFS for patients who received both patients with subtotal resection after 3 cycles without progression by MRI, 3 GTR and RT was not reached. Neither extent of surgery nor use of RT was additional cycles were given. Progression free survival was analyzed by associated with overall survival. However, use of RT was significantly associ- Kaplan-Meier and log rank methods as function of tumor localization, ated with improvement in OS (p ¼ 0.004) when adjusted for extent of resec- extent of resection, radiotherapy and age of patients. RESULTS: Median pro- tion. CONCLUSION: Adjuvant RT reduces the risk of recurrence in patients gression free survival was 1.63 years, and 5-year progression free survival was who have undergone a GTR (67% to 25%). Adjuvant RT may improve survival 27%. There was no tumor recurrence after 2.6 years. Survival of patient seems when patients with similar extent of resection are compared. to improve after complete resection, irradiation and in supratentorial localization, but the differences were not statistically significant. The treatment schedule was well tolerated with minor hematological side effects. CONCLUSION: Hungarian Ependymoma Protocol achieved similar progression free survival of patients with anaplastic ependymoma compared to ii102 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-EPEN.14. EPENDYMOMAS IN CHILDREN OVER THE LAST 15 YEARS: A RETROSPECTIVE STUDY FROM CHU Children with recurrent ependymoma need intensive chemotherapy to SAINTE-JUSTINE prolong progression-free survival (PFS). Two children with recurrent epen- M. Marzouki1, L. Crevier1, C. Mercier1, Y. Robitaille1, P. Rousseau2, dymoma illustrate the need for chemotherapy, and the concept of metro- J. C. Dećarie1, L. Hershon1, G. H. Zhang1, and A. S. Carret1; 1CHU nomic therapy as maintenance. AK, a 3-year-old female child first Sainte-Justine/Universite´ de Montreál, Montreál, QC, Canada; 2CHUM/ presented with headache and vomiting in May 2006. Papilledema and Universite´ de Montreál, Montreál, QC, Canada torpor were detected. Brain MRI showed an enhancing cerebellar lesion. She underwent occipital craniotomy with near total excision of an ependy- BACKGROUND: Ependymoma is the third most common paediatric brain moma. Deferred radiation (54.0 Gy) was given for recurrence in May tumour. The extent of surgical resection remains the principal risk factor. 2007. Then six chemotherapy cycles including ifosfamide, carboplatin, eto- Despite a multimodal treatment, survival rates are disappointing with a very poside (ICE) with amifostine support were given by October 2007. The child poor prognosis in case of relapse. METHODS: A retrospective study was had grade IV febrile neutropenia following three cycles, but no thrombocy- done on all children , 18 years with histologically diagnosed ependymoma topenia. Since then she has received oral cyclophosphamide, oral etoposide between 1992 and 2007. Information included demographics, location of and tamoxifen for 18 months. She remains well with no neurological tumour, stage, degree of resection, grade, treatment modalities and outcome. deficit, and with good scholastic performance for 46 months since craniot- RESULTS: Among 33 cases, five were myxopapillary type and analyzed separ- omy. AV, a 9-year-old male patient underwent occipital carniotomy in Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 ately.Twentyeightpatients presented withcommon type, at a median ageof 3.6 October 2007 for a cerebellar ependymoma, followed by 3 dimensional con- years (3 months-16 years). There was a male predominance (sex ratio:1/3.6). formal radiation with a PFS of 20 months. In May 2009 he was noticed to 68% hadinfratentorial tumours, 32% were supratentorial and11% were meta- have weakness of the left lower limb. MRI showed an enhancing lesion at static. Surgical resection was complete in 74%. 6/28 patients hadan incomplete LV1-LV5. Decompression and gross total excision of the spinal lesion was resection with fatal outcome in all cases. Pathology consisted of 20 grade II and done. Histopathological examination disclosed myxopapillary ependymoma 7 grade III (5/7 died) tumours. Two patients with focal anaplasia died despite which was locally irradiated with 45 Gy. He received 3 cycles of adjuvant complete resection for one of them. Initially, 9/28 had surgery only, 12 radio- ICE chemotherapy followed by metronomic therapy with oral cyclophopha- therapy (10/12 were . 3 years), 6 chemotherapy (5/6 were ≤ 3 years) and 1 mide, oral etoposide and tamoxifen. He had uncontrolled anger and poor self multimodal therapy. The median follow-up was 44 months (range, 0-180). control which improved on counseling. Disease-free survival is now 7 PFS was 46% at 5 years and OS was 52% at 5 years. CONCLUSION: Our months post laminectomy. The two patients illustrate the need for salvage series reflects the current data on paediatric ependymoma where surgical resec- treatment of recurrent ependymoma with oral metronomic therapy as tion is the most important modality. In order to improve the outcome new mod- "maintenance" for recurrent ependymoma. alities should be explored and be part of multi-institutional clinical trials, especially in case of relapse.

P-EPEN.17. CURRENT MANAGEMENT OF PAEDIATRIC EPENDYMOMAS: REPORT OF AN INTERNATIONAL SURVEY P-EPEN.15. LATE EPENDYMOMA RELAPSES: A CANADIAN G. A. Solanki1,2 and N. Ganesalingam3; 1Birmingham Children’s Hospital, PEDIATRIC MULTICENTRE STUDY Birmingham, United Kingdom; 2University Hospitals Birmingham, J. Hukin1, U. Tabori2, T. Ailon3, D. Mcneely4, A. S. Carret5, D. Eisenstat6, Birmingham, United Kingdom; 3Southampton University Hospitals NHS L. Lafay-Cousin7, D. Johnston8, B. Wilson9, N. Jabado10, S. Zelcer11, Trust, Southampton, United Kingdom M. Silva12, R. Barr13, R. A. Milner14, M. Bucevska1, and C. Fryer1; 1BC Children’s hospital, Vancouver, BC, Canada; 2Hospital for Sick Children, In ependymomas, the surgical strategy and the ideal adjuvant therapy Toronto, ON, Canada; 3Vancouver General Hospital, Vancouver, BC, combination are changing and need to be clarified. Recent reports suggest Canada; 4IWK HEalth Centre, Halifax, NS, Canada; 5Montreal University, improved outcomes with a more radical resection strategy and that radio- Montreal, QC, Canada; 6Manitoba cancer centre, Winnipeg, MB, Canada; therapy is given in children under 18 months aiming at improving survival 7Alberta Children’s hospital, Calgary, AB, Canada; 8Children’s hospital of and cure. In the UK over 50% of the paediatric ependymomas are below 5 Eastern Ontario, Ottawa, ON, Canada; 9Stollery Children’s hospital, years of age. For those under 3 years of age, irrespective of the extent of sur- Edmonton, AB, Canada; 10University of Mcgill, Montreal, QC, Canada; gical resection, radiotherapy is not currently used as first line adjuvant 11University Hospital of Western Ontario, London, ON, Canada; therapy. In order to understand current practice, we performed a short 12Kingston General hospital, Kingston, ON, Canada; 13McMaster survey. Members and attendees of a recently held international online neuro- University Health Sciences Center, Hamilton, ON, Canada; 14University of surgery conference were surveyed. Further surveys were forwarded to paedia- British Columbia, Vancouver, BC, Canada tric neurosurgery units around the world. In England, ependymomas account for 30-35 cases/year. Incidence in most units is between 1-5 new cases per INTRODUCTION: Occasional case reports of late relapses in childhood year. Few centres do have .10 new cases/year. A surgical strategy of cura- ependymoma have been reported. The prognosis is unclear. We hypothesized tive resection attempting to preserve function is preferred though more units that patients who have a late relapse may have an indolent course at relapse, perform radical resection now than in the past. Most units report gross total and that the incidence is low. METHODS: We performed a retrospective resection (GTR) in 60-95% of cases but some units have GTR in .95%. review of children diagnosed with ependymoma in Canada from Radiotherapy is generally accepted as adjuvant therapy for children above 1986-2006. All Canadian pediatric centres were invited to participate. We 3 years. An increasing number of units use chemotherapy prior to second identified all patients who had a relapse from the date of diagnosis, early look surgery following recurrence or surgery for residual disease. Surgical relapse was defined as,/ ¼ 5 years and late relapses . 5 years. RESULTS: strategy and adjuvant therapy vary between units. This variation is greater 12/16 centers participated in this multicentre study. 7/257 had a late geographically. The evidence for these management choices is discussed in relapse (median age, 7 year; range, 2.2-12): 3 WHO grade 1, 3 grade 2, 1 light of the survey findings. grade 3, 4 spinal tumors (SP), 2 supratentorial tumors (ST), and 1 posterior fossa (PF), none were disseminated at diagnosis. 3 had gross total resection (GTR) alone, 2 GTR plus radiotherapy, 2 subtotal resection (STR) plus radiotherapy. 4 had local relapses and 3 disseminated, 4/7 are alive at a median follow-up since relapse of 4.2 years (range, 1-10.5), 3 SP (1 dissemi- P-EPEN.18. SPINAL RECURRENCE OF EPENDYMOMA OF nated) and 1 ST. At relapse three of the survivors received radiation plus MYXOID HISTOLOGY: A CASE REPORT resection, 1 radiation alone. 45/125 early relapses are still alive (median P. G. Chitalkar and A. Verma; Batra Hospital & Medical Research Centre, follow-up, 1.6 years; range, 0.0-18.1). The incidence of late relapse in New Delhi, India relapse free survivors at 5 years from diagnosis is 6%. CONCLUSIONS: The risk of late relapses in childhood ependymoma long-term survivors is Recurrent ependymoma needs intensive chemotherapy to prolong 6%; in contrast, the incidence of relapse in the first five years is 49%. progression-free survival. Novel approaches like metronomic chemotherapy Durable survival is possible in childhood relapsed ependymoma. may improve the outcome. Two children with recurrent ependymoma illustrate the intensive chemotherapy and the supportive care necessary to achieve disease control and the use of metronomic chemotherapy as maintenance. PATIENT A: AK, a 3-year-old girl first presented in May 2006 with headache and vomiting. Papilledema and torpor were noted and the MRI P-EPEN.16. RECURRENT EPENDYMOMA: THE INDIAN brain showed an enhancing cerebellar lesion. Occipital craniotomy and EXPERIENCE WITH CHEMORADIOTHERAPY AND near total excision of the cerebellar ependymoma was performed. Deferred METRONOMIC THERAPY cranio-spinal radiation (36 Gy, with 14 Gy boost to the posterior fossa) P. G. Chitalkar1, A. Verma1, S. Nangia1, B. Arora2, and R. Jalali3; 1Batra was given between May and July 2007, for a brain stem recurrence, which Hospital & Medical Research Centre, New Delhi, India; 2Tata Memorial was not biopsied. She suffered Steven Johnson syndrome with “target skin Centre, Mumbai, India; 3Tata Memorial Centre, Mumbai, India lesions” all over the body during the radiation with resultant delay of

NEURO-ONCOLOGY † JUNE 2010 ii103 Abstracts

three weeks. Adjuvant ifosfamide, carboplatin, etoposide (ICE) chemother- motor symptoms in 31 patients (89%) among 35 whose initial manifestation apy in 6 cycles with amifostine support were completed in March 2008. was described. Interval between onset and diagnosis ranged from 1 to 36 Grade III neutropenia was noted in three cycles. No thrombocytopenia months (mean 14.6, median 12). Serum or cerebrospinal fluid beta-human was encountered. Since then she has received oral metronomic chemotherapy chorionic gonadotropin level was elevated in 8 (33%) among 24 patients with tamoxifen, etoposide and cyclophosphamide over 12 months. She who were evaluated. Forty-four patients (96%) underwent radiation remains well, with no neurological deficit and good scholastic performance, therapy (RT). Fifteen patients (33%) were treated by chemoradiotherapy 46 months since surgery. PATIENT B: AV, a 7-year-old boy, diagnosed and 2 (4%) received chemotherapy only. Modality of RT was described with cerebellar ependymoma in October 2007, underwent gross total for 33 patients and treatment for 26 patients (79%) included whole brain resection with adjuvant 3D conformal radiation. He was well for 20 RT (WBRT). Five-year overall survival rate was 82%. CONCLUSIONS: months thereafter when he developed weakness in the left lower limb in Germinomas of the BG predominantly affected male in first and second May 2009. MRI showed an enhancing lesion in the cauda equina. decades of life. Although presenting symptoms were specific, period Decompression and gross total excision was done showing a myxopapil- between first onset and diagnosis was relatively long. Majority of the patients lary recurrence of ependymoma. He received spinal radiation (45 Gy) received WBRT and short-term outcomes were acceptable. Longer follow-up with adjuvant ICE chemotherapy followed by metronomic chemotherapy and multi-institutional study is necessary to evaluate the best treatment of with oral cyclophosphamide, etoposide and tamoxifen. Uncontrolled choice for BG germinomas. anger, poor self-control and attention-seeking behavior improved with Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 counseling. The child is well, with a disease free interval of 7 months now.The two cases illustrate the efficacy of amifostine as a myeloprotec- tive agent, sparing the need for platelet support after intensive chemotherapy. Metronomic chemotherapy is worthy of investigation as a modality P-GCT.03. ANALYSIS OF DIAGNOSTIC SURGICAL STRATEGIES for long-term disease control in recurrent ependymoma. FOR INTRACRANIAL GERMINOMAS N. Kagawa1, N. Hashimoto1, Y. Chiba1, M. Kinoshita1, Y. Okita1, F. Yamamoto1, N. Kijima1, M. Maruno2, and T. Yoshimine1; 1Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, P14 GERM CELL TUMOR Japan; 2Department of Neurosurgery, Osaka medical center for cancer and cardiovascular diseases, Osaka, Japan, Osaka, Japan

P-GCT.01. GENOMIC PROFILING OF INTRACRANIAL GERM PURPOSE: To choose the best strategies for intracranial germ cell tumors CELL TUMORS (GCTs), we analyzed results of surgical procedures and diagnostic methods K. Terashima1,2, J. Hsu1,2, T. W. Chow1,2,A.Yu1,2, R. Nishikawa3, for germinomas and the relationship between tumor recurrence and them. M. Matsutani3, H. Nakamura4,H.K.Ng5, J. Allen6,J.Su1, MATERIALS AND METHODS: Thirty two patients (24 males, 8 females, M. B. Bhattacharjee2, A. Adekunle2, K. K. Wong7, H. E. Leung1,2, T. Man1,2, age 8-35: median 12 years) with GCTs treated from onset in our institution and C. C. Lau1,2; 1Texas Children’s Cancer Center, Houston, TX, United were enrolled from 1994 to 2009. Tumor markers (HCG, HCG-beta, AFP) States; 2Baylor College of Medicine, Houston, TX, United States; 3Saitama in serum or cererebrospinal fluid (CSF) were measured in all cases. Ten GCTs Medical University, Hidaka, Japan; 4Kumamoto University, Kumamoto, were classified as poor prognosis. Twenty two cases were expected as pure Japan; 5Chinese University of Hong Kong, Hong Kong; 6New York germinoma or HCG-producing germinoma, located in 8 pineal, 3 neurohy- University, New York, NY, United States; 7M. D. Anderson Cancer Center, pophyseal, 2 bifocal and 10 basal ganglia lesions. Operations were per- Houston, TX, United States formed in 16, including 6 removals or open biopsies (OB group), 6 endoscopic tumor biopsies (ETB group) and CSF samplings for intraventri- PURPOSES AND METHODS: Our current knowledge and understand- cular lesions, 4 stereotactic biopies (SB group) for basal ganglia lesions. ing of the biology of intracranial germ cell tumors (GCTs) is extremely Chemotherapies without histological evidence were done in 6 (NOP limited due to the scarcity of tissues available for research. To comprehen- group). RESULTS: They were classfied as 7 pure germinomas and 15 sively analyze the DNA copy number aberrations (CNAs) of intracranial HCG-positive germinomas. Histopathological diagnosis was made expect GCTs, we have studied a series of 29 iGCTs by single nucleotide poly- one case shrinking spontaneously. In small specimens from ETBs, immuno- morphism (SNP) microarray, Affymetrix GeneChipw Human Mapping histochemistry of c-kit was postive in all, although placental alkaline phos- 100K Arrays. The result was validated by qPCR methods and gene phatase staining was positve in two of six. Three recurrent cases were expression profiling. RESULTS: CNAs were detected in virtually all intra- observed in OB group, though no recurrence was seen in ETB, SB and cranial GCTs and most tumors have multiple CNAs with various sizes. We NOP groups. There was no relationship between recurrence and age, used the Genomic Identification of Significant Targets in Cancer (GISTIC) tumor location and HCG value. CONCLUSION: We conclude the combi- tool to identify the most significant regions of CNAs. GISTIC identified nation of endoscopic or stereotactic biopsies and CSF sampling with c-kit distinct focal peak regions within previously described broad regions of immunostaining can be effective to decrease risk of recurrence. CNAs such as gains at chromosomes 1q, 7, 8, 12p, 21 and X, and losses at 1p, 11q, 13q and 18q. In addition to multiple oncogenes and tumor suppressor genes such as CCDN2, TP53 and RUNX3, many stem cell genes such as NANOG, NR5A2, SOX17 and DPPA3 are located in those peak regions. Multiple candidate genes such as CCDN2 showed P-GCT.05. INTRACRANIAL NON-GERMINOMATOUS GERM good correlation between copy number and corresponding expression. CELL TUMORS: SECRETION OF AFP AND bHCG AND Overall, there was good concordance in the copy number calls between IMPLICATION FOR RADIATION TREATMENT VOLUMES 1 1 2 1 the SNP array and qPCR. The concordance rates at chromosomes 12p, M. S. Hemenway , J. R. Madden , L. E. Gaspar , M. H. Handler , 1 1 1 13q and X are 77%, 62% and 68%, respectively. CONCLUSIONS: We N. Foreman , and A. Liu ; The Children’s Hospital, University of Colorado 2 reported the first whole-genome copy number analysis of intracranial Denver, Aurora, CO, United States; University of Colorado Denver, School GCTs by SNP microarray. International multicenter collaboration resulted of Medicine, Aurora, CO, United States in the largest genomic profiling series of these rare tumors. BACKGROUND: Intracranial non-germinomatous germ cell tumors (NGGCT) are treated with a combination of chemotherapy and radiation therapy with overall survival in the range of 60%. The radiation treatment volume is controversial. PROCEDURE: We reviewed our experience of chil- P-GCT.02. CHARACTERISTICS OF CENTRAL NERVOUS dren with intracranial NGGCT treated at The Children’s Hospital and SYSTEM GERMINOMAS INVOLVING THE BASAL GANGLIA: A Department of Radiation Oncology at University of Colorado Denver from LITERATURE REVIEW 1995 to 2008. RESULTS: Eighteen children with NGGCT were treated T. Koga1 and M. Matsutani2; 1Department of Neurosurgery, the University from 1995 to 2008. Seven had elevated AFP alone (range: 12-2310 ng/mL of Tokyo Hospital, Tokyo, Japan; 2Department of Neuro-Oncology, in serum) and the remaining eleven had elevated bHCG (range: 9-574 IU/L Saitama Medical University International Medical Center, Saitama, Japan in serum) with or without elevations in AFP (range: 12-136 ng/mL in serum). One child died after one cycle of chemotherapy due to sepsis. PURPOSE: Because of the rarity of germinomas involving the basal Children with elevated AFP alone received local radiation. Four of the remain- ganglia (BG), clinical characteristics and outcome of this disease are not ing 10 children received local radiation therapy and six received craniospinal well studied. The purpose of this study was to review the characteristics of radiation with a local boost. All seven with elevated AFP alone are alive with BG germinomas and to discuss treatment considerations. METHOD: A no evidence of disease at a median follow up of 76 months. In the children review of English literature that describes characteristics or clinical course with elevated bHCG with or without elevated AFP, all four children who of individual cases was performed. RESULTS: Individual data was available received limited field radiation relapsed (at 8, 16, 20, and 43 months following for 46 patients with BG germinomas. Age at onset ranged from 7 to 41 years diagnosis). Two of the four relapsed patients have died. CONCLUSIONS: (mean 12.6, median 11.5) and 43 patients (93%) were younger than 20 years Intracranial NGGCT are a heterogeneous group, with prognosis dependent of age. Thirty-eight (83%) were male. Presenting symptoms were lateralized on the biochemical characteristics of the tumor. Children with elevated AFP ii104 NEURO-ONCOLOGY † JUNE 2010 Abstracts

alone do well with chemotherapy and limited field radiation. In contrast, chil- teratomas, 6 mixed germ cell tumors) were enrolled in this study. Residual dren with elevated bHCG, are at increased risk of relapse when excluding the tumor was seen in 11 of 15 cases in NGMGT and all of them were craniospinal axis from radiation treatment. removed (total removal in 11 cases and partial removal in 1 case). The tumor disappeared after chemo- and radiotherapy in 2 of 15 cases and in one case the removal was not able to be performed due to dissemination. RESULTS: In 3 of 15 the tumor recurrence was confirmed and they died. One of 15 died because of the initial dissemination and 1 of 15 P-GCT.06. INTRACRANIAL GERM CELL TUMORS: died due to second intracranial tumor (glioblastoma) induced by radiother- TREATMENT AND SURVIVAL apy. Tumor recurrence has not been found in other 11 cases and the D. R. Cernea, S. Neamtu, E. Mihut, and R. Cosnarovici; Oncology Institute present QoL is that 6 in PS 0, 3 in PS 1, and 2 in PS2. All removed Cluj-Napoca, Cluj-Napoca, Romania tumors were pathologically examined and there were viable tumor cells in 4 cases of NGMGT (3 immature teratomas and 1 yolk sac tumor). BACKGROUND: Intracranial germ cell tumors are rare tumors which The histologies of other 7 cases were 3 mature teratomas and 4 necrotic occur in the pineal region, the anterior third ventricular region or in the or mesenchymal tissues. CONCLUSION: NAT may be effective treatment suprasellar region. We present our experience in treatment of such tumors. for prevention of tumor recurrence and dissemination because of the MATERIAL AND METHODS: Between 2000 and 2009 we treated 6 chil- viable tumor cell were found in 4 of 11 cases in NGMGT. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 dren (age between 6 and 17 years) with intracranial germ cell tumors: 2 suprasellar tumors, 3 pineal tumors and one suprasellar and pineal tumor. Symptoms before diagnosis were signs of increased intracranial pressure, ocular signs, diabetes insipidus, and obesity. Diagnosis was confirmed by MRI and limited resection in 5 patients: 2 germinomas and 3 mixed P-GCT.09. CAN CYTOREDUCTIVE THERAPY PRIOR TO RT tumors (immature teratoma with embryonal carcinoma, seminoma or germi- IMPROVE OUTCOME IN CNS NON-GERMINOMA GERM CELL noma). High values of total HCG in serum (389,7 mIU/ ml) and bHCG in TUMORS (NGGCT)? CSF (1790 mUI/ ml) confirmed the diagnosis for one patient. P. L. Robertson1, R. Jakacki2, J. Hukin3, J. Siffert4, and J. C. Allen5; TREATMENT: Four patients were treated with craniospinal irradiation 1University of Michigan, Ann Arbor, MI, United States; 2Children’s Hospital and chemotherapy: cranial irradiation, TD ¼28 Gy- 30,6 Gy, with boost of Pittsburgh, Pittsburgh, PA, United States; 3Children’s & Women’s on tumor bed to 45 Gy; total dose for the spinal volume was 28,8 Gy- Hospital, Vancouver, BC, Canada; 4Ceregene, San Diego, CA, United States; 30,6 Gy. Irradiation of the primary tumor (TD¼ 45 Gy) was performed in 5NYU Medical Center, New York, NY, United States 2 patients. Five patients received chemotherapy (PEI and BEP protocols). One patient refused chemotherapy treatment. RESULTS: Five patients are INTRODUCTION: The prognosis of intracranial NGGCT has become alive with no evidence of disease, survival between 6 and 31 months from more favorable with the use of multi-modality therapy, i.e., radical diagnosis. CONCLUSIONS: Intracranial germ cell tumors are radiosurgery, chemotherapy (CHT) and radiotherapy (RT). We hypothesized chemosensitive. The use of combined chemotherapy and limited-volume or that elimination of all measurable disease prior to RT would improve limited-dose irradiation have also been reported and could be a better treat- outcome. To accomplish this goal, our pilot protocol utilized pre-RT inten- ment option to avoid the late effects of radiation therapy. sification of chemotherapy and 2nd look surgery to render patients free of measurable disease. METHODS: NGGCT diagnosis was established in 26 pts by biopsy (n ¼ 20) or elevated serum &/or lumbar CSF markers (n ¼ 6). Primary tumor sites: pineal (n ¼ 12), suprasellar (n ¼ 10) bifocal (n ¼ 3) and posterior fossa (n ¼ 1). Tumor staging assessment revealed: M0/ P-GCT.07. THE ROLE OF CHEMOTHERAPY IN MULTIMODAL M+ -19/7. Initial CHT1 consisted of 4 monthly cycles of cisplatin, etopo- TREATMENT OF INTRACRANIAL GERM CELL TUMORS side & ifosfamide. For pts with residual disease, 2nd-look surgery was M. A. Dragomir, E. Gruber, R. Milcu, C. Comsa, R. Anghel, M. Savu, and encouraged, followed by 2 courses of dose-intensive, stem-cell supported I. Ionescu; Institute of Oncology, Bucharest, Romania CHT2 (carboplatin & cyclophosphamide) All pts received RT: whole ventricular (WV) RT plus boost for localized disease and craniospinal (CS) RT plus The treatment of intracranial germ cell tumors (GCT) in children and young boost for disseminated disease. RESULTS: Tumor response after CHT1 in 22 adults is still a vexed question. Many studies suggested that total dose and irra- pts with evaluable disease: CR (12); PR (10). Eight additional patients were diated volume necessary to achieve tumor control could be decreased using rendered CR with additional CHT2 (3) & surgery (5). Of the 7 pts who multi-drug chemotherapy before radiotherapy (RT). Several studies demon- relapsed after RT, 6 M0/CR pts received WVRT, of whom 4 recurred strated complete remission after chemotherapy (CT), but this doesn’t with spinal disease outside the RT field, without local recurrence. There exclude radiotherapy as part of multimodal treatment. The aim of study is was a trend toward improved outcome among the cohort of pts in CR to assess the efficiency of the neoadjuvant policitostatic chemotherapy in intra- prior to RT. CONCLUSIONS: This protocol permitted 20/26 pts (77%) cranial germ cell tumors. Between 2004 and 2009 15 children and adolescents to become free of measurable disease prior to RT. Eliminating CSRT may with intracranial GCT were treated and followed-up in the Institute of adversely affect outcome in M0 pts. Oncology Bucharest - Oncopediatric Department. Multimodal treatment consisted in limited surgery (only for diagnosis), chemotherapy (2 x CarboPEI, 2-4 x CisPEI) and RT (40 Gy focal irradiation for germinomas, 30 Gy cranial + 24 Gy tumor secreting tumors) +/- spinal irradiation (CSF + ). Clinical, biological and imaging assessment was performed after first and second cycles P-GCT.10. RETROSPECTIVE REWIEW OF TREATMENT OF CarboPEI and after RT. We recorded complete remission (CR) in 7/15 INTRACRANIAL GERM CELL TUMORS IN CHILDREN cases after first cycle of chemotherapy and in 12/15 cases after the second ACCORDING TO SIOP CNS GCT 96 PRITOCOL. SINGLE cycle; partial remission (PR) was registered in 8/15 cases after the first INSTITUTION EXPERIENCE cycle-CT and in 3/15 cases after the second cycle-CT. Postradiotherapy assess- M. Belogurova1,2, G. Radulesku1,2, T. Victorovich1,2, E. Chavpezova2, ment showed 12/15 CR and residual tumor in 3 patients. Recurrence with lep- L. Shatz1,2, J. Dinikina1, and A. Haritonova1; 1St Petersburg State Pediatric tomeningeal metastasis was recorded in 2 cases (stabile disease with CT for 3-4 Medical Academy, St Petersburg, Russian Federation; 2City Hospital 31, years). Overall survival was 90% at 1 year and 60% at 5 years, with a median St Petersburg, Russian Federation survival of 66.8 months. Tumor remission after chemotherapy allows tumor control using lower doses radiotherapy and smaller irradiating fields with We describe 12 cases of GCT in children treated in 1998 -2009 years less later side effects. (11male, 1 female; mean age 10.9 y) with radiochemotherapy according to the SIOP CNS GCT 96 protocol. Tumor localization in 3 patients was pineal, in 9 suprasellar areas; 3 patients had spinal metastases. Seven patients (58.3%) had secreting GCT, in 5 patients(41.7%) histology confirmed pure germinoma. Normalization of tumor markers of secreting GCT was achieved P-GCT.08. EVALUATION OF THE TREATMENT OF after 2 courses of chemotherapy in 85.7% of patients and after 3 courses in INTRACRANIAL NON-GEMINOMATOUS MALIGNANT GERM 14.3%. The follow up period ranged from 2 to 141 months, (median: 53 CELL TUMORS BY NEOADJUVANT THERAPY month); OS was 100%, EFS 100%. After completion of therapy 2 patients H. Nakamura; Dept.of Neurosurgery, Kumamoto University Medical had no residual tumor (1 after total surgical removal); in 10 patients School, Kumamoto, Japan (83.3%) remained a residual tumor. According dynamic MRI data 2 of them had no local contrast enhancement, 4 had moderate and 4 had PURPOSE: We have found that preoperative combined chemo-and radio- intense enhancement. In 3 patients with intensive enhancement PET was therapy [NAT (neo-adjuvant therapy)], followed by complete excision of any carried out: 2 of them had an ametabolic lesion, in 1 case the AI was 1.4. residual tumor, improved the survival of patients with NGMGCT. Initially, 25% of patients had endocrine disorders, dynamic follow up PATIENTS AND METHODS: Fifteen cases of NGMGT (5 yolk sac revealed endocrine disorders in 83.3% (diabetes insipidus in 50%, secondary tumors, 2 embryonal carcinomas, 1 choriocarcinoma, 1 immature hypothyreosis in 30%, secondary adrenal insufficiency in 40%,

NEURO-ONCOLOGY † JUNE 2010 ii105 Abstracts

neurosensory hard of hearing in 30%). The SIOP CNS GCT 96 protocol in This treatment regime was well-tolerated and improved long term survival our department conﬁrmed its high effectiveness. Existence of residual tumor for patients with secreting GCT. after therapy has no inﬂuence on survival and does not require additional therapy; the role of PET needs additional investigations. Such patients have a high percentage of endocrine complications and require careful follow up and endocrinological corrections. P-GCT.14. A MULTI-CENTRE CLINICAL TRIAL OF CNS GERM CELL TUMOURS IN HONG KONG M. M. K. Shing1, G. C. F. Chan2, H. L. Yuen3,R.Li4, and S. C. Ling5; 1Lady Pao Children’s Cancer Centre, Prince of Wales Hospital, The Chinese P-GCT.11. MULTIMODALITY TREATMENT ON LONG TERM University of Hong Kong, Hong Kong, Hong Kong; 2Dept. of Paediatrics, OUTCOME OF INTRACRANIAL GERM CELL TUMORS IN Queen Mary Hospital, Univeristy of Hong Kong, Hong Kong, Hong Kong; CHILDREN: A SINGLE INSTITUTION STUDY 3Dept. of Paediatrics, Queen Elizabeth Hospital, Hong Kong, Hong Kong; R. Kebudi1,2, E. Darendeliler3, I. Ayan1, O. Gorgun1, F. Y. Agaoglu4, 4Dept. of Paediatrics, Tuen Mun Hospital, Hong Kong, Hong Kong; 5Dept. H. Emiroglu1, Y. Dizdar3, and F. Darendeliler5; 1Istanbul University, of Paediatrics, Princess Margaret Hospital, Hong Kong, Hong Kong Oncology Institute, Division of Pediatric Hematology-Oncology, Istanbul, 2

Turkey; Cerrahpas¸a Medical Faculty, Division of Pediatric BACKGROUND: Hong Kong Paediatric Haematology and Oncology Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Hematology-Oncology, Istanbul, Turkey; 3Istanbul University, Oncology Study Group started this clinical trial involving 5 regional public hospitals Institute, Division of Radiation Oncology, Istanbul, Turkey; 4Istanbul since January 2008. METHODS: Patients who were suspected to have germi- University, Oncology Institute, Division of Radiation Oncology, Istanbul, noma received a biopsy, followed by chemotherapy with carboplatin (600 mg/ Turkey; 5Istanbul Medical Faculty, Dept. of Pediatric Endocrinology, m2 on day 1) and etoposide (150 mg/m2/d, day 1 to 3), alternating with ifos- Istanbul, Turkey famide (1.8 mg/m2/d and etoposide 150 mg/m2/d, day 1 to 5). A total of 4 cycles of chemotherapy were given, followed by radiotherapy. The dose and Intracranial germ cell tumors (iGCT) constitute 1% of all malignant neo- volume of radiotherapy depend on the response and site of involvement. plasms in children. In this study, 15 children (8 female, 7 male) with a Patients with non-germinomatous germ cell tumors received operation to median age of 11 years (10 months to 18 yrs), treated according to our insti- remove the tumor (if possible), chemotherapy as above for 6 cycles and cra- tutional protocol between 1990-2007 were retrospectively evaluated. Patients niospinal radiotherapy. The patients may need a second look operation if with germinomas .13 yrs old recieved radiotherapy (2520 cGy craniospinal/ necessary. RESULTS: There were 19 patients until January 2010. The male 1980 cGy local boost), patients ,13 yrs received 2 courses of etoposide and to female ratio was 5.3:1. The median age was 10.8 years (0.4 to 17.1). The cisplatine followed by cranial radiotherapy. Nongerminoma patients received pathology was germinoma (n ¼ 11) and no-germinomatous germ cell 3 courses of bleomycine, etoposide, and cisplatine followed by 3600 cGy cra- tumours (n ¼ 8). The locations of the tumors were suprasellar (n ¼ 2), pineal niospinal/1980 cGy local boost RT. Presenting clinical features were diabetes gland (n ¼ 9), suprasellar & pineal gland (n ¼ 3) and basal ganglia (n ¼ 3), insipidus (n ¼ 7), raised intracranial pressure (n ¼ 12), visual and others (n ¼ 1). Three patients had metastatic disease at presentation. changes-oculomotor palsies (n ¼ 6), hypopituitarism (n ¼ 4). Seven had ger- After treatment, 18 patients achieved complete remission, one patient had minomas and 8 nongeminomatous GCT. Nine were suprasellar and 6 pineal. partial response. No patient had relapse and all of them were alive. The AFP and BHCG were evaluated both in serum and CSF. Three had seeding in median follow up time was 16 months (3.8 to 24.3). CONCLUSION: A the spinal axis in MRI. One had widespread systemic metastasis. Two had a good outcome is achieved though the follow up period is short. total resection, 12 had a biopsy, one was clinically/radiologically diagnosed, 5 had a shunt. Two nongerminamatous iGCT patients died. 13 patients are alive at a median follow-up of 12 years (2-17 years) from diagnosis. One with motor and mental retardation needs special care. Others have a moder- P-GCT.15. PATTERN OF DEFICITS IN CHILDREN WITH ate/good quality of life. One is married and has a child. Four are at school. Five INTRACRANIAL GERM CELL TUMOR ACCORDING TO are employed. One has received growth hormone. Cisplatine based che- TUMOR LOCATION motherapy and radiotherapy is successful and well tolerated in children C. Dufour1, V. Coutinho1, C. Lalande1, V. Kieffer1, C. Patte1, J. Habrand1, with iGCT. To reduce the risk of late side effects, attempts to further decrease L. Negretti1, G. Dellatolas2, and J. Grill1; 1Institut Gustave Roussy, Villejuif, total doses of radiotherapy are suggested. France; 2CNRS UMR 8189, Boulogne-Billancourt, France

PURPOSE: To describe the neuropsychological profile of patients with intracranial germ cell tumors treated at Institute Gustave Roussy between P-GCT.13. SECRETING GERM-CELL TUMOURS (GCT) OF THE 1991 and 2004. PATIENTS AND METHODS: Neuropsychological evalu- CENTRAL NERVOUS SYSTEM (CNS): A ations including measures of verbal and nonverbal intellectual functioning, MONOINSTITUTIONAL EXPERIENCE WITH A LONG working memory, processing speed, verbal and nonverbal memory and execu- FOLLOW-UP tive functioning were analyzed for 31 patients with intracranial pure germino- V. Biassoni1, L. Gandola2, F. Spreafico1, E. Pecori2, E. Seregni3, mas (GCT; n ¼ 22) and secreting tumors (sGCT; n ¼ 9) at a median time of M. Terenziani1, R. Luksch1, F. Pallotti3, E. Schiavello1, M. Casanova1, 3.4 years (range: 2 months to 12.2 years) after the end of radiation therapy. C. Meazza1, G. Cefalo1, A. Ferrari1, D. Polastri1, M. Podda1, and The patients were divided into 2 groups according to the tumor location M. Massimino1; 1IRCCS Foundation, National Cancer Institute, (pineal, n¼ 20; suprasellar, n ¼ 11). RESULTS: Mean last full scale IQ in Department of Pediatrics, Milan, Italy; 2IRCCS Foundation, National patients with pineal tumor and suprasellar were 102.88 (Standard deviation Cancer Institute, Department of Radiotherapy, Milan, Italy; 3IRCCS (SD): 16.6) and 108.27 (SD: 29.53), respectively. PIQ was below VIQ in the Foundation, National Cancer Institute, Department of Nuclear Medicine, 2 groups, but with a significant difference only in patients with pineal tumor Milan, Italy (p ¼ 0.01). Mean processing speed was lower in pineal tumors than in suprasellar ones. Short-term memory was within the normal range in the 2 groups. INTRODUCTION: Intracranial GCT account for less than 5% of CNS Deficit of working memory was observed whatever the tumor location. pediatric tumors, with a peak during adolescence. Among these, secreting Patients with pineal tumor presented significant deficit of visual memory GCT represent 1% with a less encouraging prognosis than germinoma. and visuospatial skills (p ¼ 0.05) and patients with suprasellar tumor had They are characterized by aFP/bHCG secretion in cerebrospinal fluid long-term omission of the verbal information. Longitudinal follow-up (CSF) and/or serum. MATERIAL AND METHODS: From June 1988 to showed decreased overall IQ within the normal range. CONCLUSION: The July 2008, 22 patients (20 males, 2 females, median age 14 years) affected mean IQ for the whole cohort reached values almost comparable to the by secreting CNS-GCT were accrued at our institution. aFP and bHCG normal population. There was a trend toward lower performance in some subt- were considered pathologic when above 25 IU/ml and 50 mIU/ml, respect- ests that were different according to the tumor location. ively, in serum and/or CSF. Patients received 6 cycles of chemotherapy (4 before and 2 after radiotherapy) with cisplatin, etoposide and bleomycin and radiotherapy (craniospinal irradiation 24/30 Gy plus a boost to the tumour site until 1994 and to the whole ventricular system from then on, P-GCT.16. COGNITVE OUCTOME FOLLOWING TREATMENT up to a total dose of 45 Gy). RESULTS: Twenty one/22 patients had PR/ FOR GERMINOMA CR after chemotherapy. Four/22 died for progression/relapse, 1/22 died E. Monslaves1, N. Andrews1, E. Bouffet1, B. Spiegler1, U. Bartels1, of pneumonia, 17/22 are alive. Three/4 pts with progression/relapsing L. Janzen1, S. Guger1, N. Laperriere2, J. Rutka1, and D. Mabbott1; 1Hospital disease had markers above 1000 in serum and/or CSF at diagnosis so a for Sick Children, Toronto, ON, Canada; 2Princess Margaret Hospital, further patient with aFP . 1000 received high-dose chemotherapy and 2 Toronto, ON, Canada myeloablative courses obtaining a CCR. At a median follow-up of 75 months 5 years EFS, PFS and OS are 77%, 81%, and 81 %, respectively. CNS germ cell tumors tend to occur in the central regions of the brain, CONCLUSIONS: Secreting CNS-GCT require a combined chemo-radio- typically either the pineal or suprasellar/pituitary regions. Treatment therapic approach. Treatment intensification is mandatory for patients involves focal radiation with or without chemotherapy and if the tumour with “high risk disease” according to markers levels rather than to stage. ii106 NEURO-ONCOLOGY † JUNE 2010 Abstracts

has metastasized, cranial-spinal radiation is used. Cognitive outcome in oral celecoxib 100mg, daily oral fenofibrate 70mg/m2, twice daily oral ima- patients with germ cell tumors has received relatively minimal attention tinib 270 mg/m2 augmented with biweekly intravenous bevacizumab 10mg/ (but see Sands et al., 2001; Lafay-Cousin et al., 2006). We explore neurocog- kg and alternating 21-day cycles of daily oral etoposide 50mg/m2 and cyclo- nitive outcome in germ cell patients seen for neuropsychological evaluation phosphamide 2mg/kg in patient 1 and etoposide 20mg/m2 for a total of 31 at a single institution. Thirty-five children (21 males) were seen for neuro- days only in patient 2. RESULTS: Both patients showed an impressive response cognitive evaluation following diagnosis and treatment for a germ cell to therapy. In patient 1, AFP in serum returned to normal values within six weeks tumor. Mean age at diagnosis was 11.65 years. Tumor location was and in patient 2, AFP in serum decreased from 6516 kU/lto535kU/l within 60 anterior/suprasellar in 11 patients, and posterior/pineal in 24 patients. days, and MRI showed marked regression of his extensive meningeal disease. Patients were treated with either focal radiation (mean ¼ 4505 cGy) or Patient 1 died 33 months after first initiation of antiangiogenic therapy due to cranial-spinal radiation (mean ¼ 2967 cGy). Standardized cognitive tests tumor progression, patient 2 experienced sudden death of pneumonia after six of intelligence, receptive language, visual motor function, and memory months. CONCLUSION: Antiangiogenic therapy may present a promising were administered (mean time from diagnosis to assessment ¼ 3 years). approach in recurrent secreting NGGCTs and further studies are warranted. Mean full scale IQ (SS ¼ 95) and receptive language (SS ¼ 98) scores were within the average range. However mean visual-motor (SS ¼ 80) and global memory (SS ¼ 85) scores were significantly lower falling a standard P-GCT.19. METRONOMIC CHEMOTHERAPY WITH DAILY deviation below normative means. Patients with posterior/pineal tumors ORAL ETOPOSIDE FOR RECURRENT REFRACTORY GERM Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 showed poorer memory than those with anterior tumor location (SS ¼ 81 CELL TUMOURS versus SS ¼ 94). Although intellectual and language function is relatively T. Yanagisawa1, T. Suzuki1, K. Fukuoka1, K. Wakiya2, J. Adachi2, preserved in patients with germ cell tumors, they display problems in K. Mishima2, M. Matsutani2, T. Joki3, T. Fujimaki2, and R. Nishikawa2; 1Div visual motor and memory function. Tumor location appears important as of Paediatric Neuro-Oncology, Dep of Neuro-Oncology, International patients with posterior/pineal tumors presented with memory impairments. Medical Center, Saitama Medical University, Hidaka, Japan; 2Dep of Neuro-Oncology, International Medical Center, Saitama Medical University, Hidaka, Japan; 3Dep of Neurosurgery, Jikie University, Tokyo, Japan P-GCT.17. FEASIBILITY PILOT OF DASATINIB IN CHILDREN AND ADOLESCENTS WITH CENTRAL NERVOUS SYSTEM BACKGROUND: Previous studies have demonstrated tumor responses (CNS) GERM CELL TUMORS (GCT) after oral administration of low-dose etoposide in various recurrent refrac- R. J. Brown1, G. Dhall1, S. Goldman2, D. D. Eisenstat3, F. Gilles1, A. Evans1, tory malignancies in children including brain tumors. There are few papers and J. L. Finlay1; 1Childrens Hospital Los Angeles, Los Angeles, CA, United showing the effectiveness in CNS germ cell tumors. MATERIALS AND 2 METHODS: Three cases with recurrent CNS germ cell tumors are presented States; Children’s Memorial Hospital, Northwestern University, Chicago, 2 IL, United States; 3CancerCare Manitoba, Winnipeg, MB, Canada here. Patients were treated with oral etoposide (50mg/m /day given daily for 21 consecutive days every 4 to 5 weeks) after the failure(s) in chemotherapy INTRODUCTION: Irradiation-avoiding strategies for CNS GCTs are and/or radiotherapy for their recurrent tumors. PATIENT 1: 13-year-old boy desirable for low-income areas of the world and for patients presenting with mixed germ cell tumor diagnosed 5 years ago. After failing in ICE and BEP with neurocognitive deficits. METHODS: Since 2008, 6 patients with newly- regimen chemotherapies and gamma-knife treatment for recurrent tumor, oral diagnosed (n ¼ 3) or recurrent (n ¼ 3) CNS GCTs (germinoma ¼ 5; etoposide was begun. Until progression, he was fine with little tumor response. NGGCTs ¼ 1) received oral twice-daily single agent dasatinib. Tumors were Progression freesurvival(PFS) was27 months.PATIENT 2:10-yearoldgirlwith all c-kit (CD117 + ) positive. Three patients were treated in complete response immature teratoma diagnosed 3 years ago. After failing in high-dose chemother- (CR1) following initial chemotherapy; one was in CR2 following focal apy with thiotepa and etoposide for her reuccrent tumor, oral etoposide was irradiation and chemotherapy; one was in CR3 after chemotherapy and cra- begun. PFS was 12 months. PATIENT 3: 31-year-old man with germ cell niospinal irradiation; and one had overt radiographic disease following mul- tumor diagnosed 4 yearsago. After failing in cranio-spinalradiotherapyand che- tiple recurrences. For patients in CR1, dasatinib was initiated for young age motherapy for recurrent disseminated tumors, with oral etoposide, he has been in 1 and for cognitive deficits in 2. Three patients started dasatinib six weeks clinically stable with minor tumor responses for 25 months. CONCLUSION: after myeloablative chemotherapy with autologous hematopoietic cell rescue Metronomic chemotherapy with oral etoposide has apparent tumor control (AHCR). Starting doses of 20-80 mg/m2/dose twice daily were escalated to activity in the patients with refractory, recurrent CNS germ cell tumors. It is 85 mg/m2/dose as tolerated. RESULTS: Maximum dose achieved was worth while trying to find the new role of oral etoposide in the earlier treatment 50-85 mg/m2/dose. Dasatinib was well-tolerated without grade III or greater for refractory tumors in clinical trials. toxicities. The single patient with evaluable disease experienced a radiographic CR followed by progressive disease. Of 5 patients treated in CR, two patients developed recurrent subependymal disease after 10 and 12 months, respectively. The three patients with prior AHCR continue in remission. P-GCT.20. PRIMARY AND SECONDARY BRAIN METASTASES SUMMARY: Dasatinib appears to be a well-tolerated oral agent for mainten- IN CHILDREN AND ADOLESCENTS WITH EXTRACRANIAL ance therapy in newly diagnosed and heavily pretreated recurrent patients GERM CELL TUMORS - RISK PROFILES AND OUTCOME with CNS GCTs. Our limited experience in sustaining complete remission fol- G. Calaminus1, S. Scho¨ nberger2, C. Teske1, and D. T. Schneider3; lowing standard-dose chemotherapy alone for newly diagnosed patients is not 1University Hospital Mu¨ nster, Dep.of Pediatric Hematology and Oncology, encouraging; however, there may be a role for dasatinib either as maintenance Mu¨ nster, Germany; 2University Hospital Du¨ sseldorf, Dep.of Pediatric therapy following myeloablative chemotherapy/AHCR or in combination Hematology, Oncology and Clinical Immunology, Du¨ sseldorf, Germany; therapy. 3Childrens Hospital Dortmund, Dortmund, Germany

BACKGROUND: Brain metastases are a serious and rare event in children. We analyzed 15 children and adolescents with extracranial GCT and P-GCT.18. OBJECTIVE RESPONSE TO ANTIANGIOGENIC brain metastases reported to the MAHO/MAKEI registry. PATIENTS METRONOMIC THERAPY INCLUDING BEVACIZUMAB AND AND METHODS: Between 1982 and 2009, 2193 patients were prospec- IMATINIB IN TWO PATIENTS WITH MULTIPLY RECURRENT tively enrolled. The sex ratio was 1:2.8, median age was 7.5 years. All SECRETING INTRACRANIAL NONGERMINOMATOUS GERM patients with advanced malignant GCTs received cisplatin-based chemother- CELL TUMORS 1 1 1 1 2 apy (overall survival: 0.80 + 0.04, median survival: 62 months). RESULTS: A. Peyrl , M. Heinrich , A. A. Azizi , B. Reismueller , M. W. Kieran , Fifteen patients with brain metastases were reported. In 9 patients, the brain A. Woehrer3, D. Prayer4, and I. Slavc1; 1Medical University of Vienna, 2 metastases were diagnosed during follow-up (6 weeks-28 months after end of Department of Pediatrics, Vienna, Austria; Department of Pediatric therapy). Most patients were male (13/15) and adolescent (10/15). Eight Oncology, Dana-Farber Cancer Institute and Childrens Hospital Boston, patients suffered from mediastinal GCTs. Pure Choriocarcinoma (CC) or Boston, MA, United States; 3Medical University of Vienna, Institute of 4 CC in combination with other histologies was diagnosed in twelve patients. Neurology, Vienna, Austria; Medical University of Vienna, Department of Clinical symptoms were reported in most patients. In all patients with sec- Radiology, Vienna, Austria ondary brain metastases the previously normalized tumor markers AFP and/ or HCG increased again prior to the onset of neurological symptoms. BACKGROUND: Treatment strategies for multiply recurrent intracranial One out of six with primary metastases survived, four of nine with secondary non-germinomatous germ cell tumors (NGGCTs) are limited. We report on metastases are in remission after additional treatment including operation, prolonged objective responses to antiangiogenic metronomic therapy includ- chemotherapy and in some cases irradiation. CONCLUSION: The risk for ing bevacizumab and imatinib in two patients with secreting mixed NGGCTs. extra- and intracranial metastases increases with age, male gender and med- PATIENTS: Two 13-year-old male patients with pineal NGGCTs suffered iastinal respectively testicular primary site and CC histology. Development multiple recurrences despite intensive chemo-radiotherapy (SIOP CNS of neurological symptoms at initial diagnosis or during follow-up should GCT-96 protocol) followed by double high-dose chemotherapy (patient 1), lead to rapid clinical reevaluation. Treatment of brain metastases includes repeated irradiation, intrathecal therapy (patient 1) and intensive systemic intensiﬁed chemotherapy, surgical resection and irradiation in special clinical chemotherapy for two consecutive recurrences. At their third recurrence situations like resistance to chemotherapy or residual non-resectable brain both patients were treated with daily oral thalidomide 3mg/kg, twice daily metastases. Supported by the Barbara and Hubertus Trettner foundation

NEURO-ONCOLOGY † JUNE 2010 ii107 Abstracts

P-GCT.21. A HUGE INTRACRANIAL CHORIOCARCINOMA IN A P-QOL.03. PREVALENCE OF AND FACTORS ASSOCIATED 10-YEAR-OLD BOY SUCCESSFULLY TREATED WITH WITH POST-CANCER PAIN IN A COHORT OF CHILDHOOD MULTIDISCIPLINARY THERAPY INCLUDING BRAIN TUMOR SURVIVORS ENDOVASCULAR EMBOLIZATION C. Chordas1, P. Manley1,2, C. Medeiros-Nancarrow1, A. Merport1, E. Unal1, M. A. Ozdemir1, O. Kontas2, H. Donmez3, T. Patiroglu1, E. Zwemer1,2, C. Liptak1,2, and C. Recklitis1,2; 1Dana-Farber Cancer M. Karakukcu1, A. Yikilmaz4, and A. Selcuklu5; 1Erciyes University, Faculty Institute, Boston, MA, United States; 2Harvard Medical School, Boston, of Medicine, Department of Pediatrics, Division of Pediatric Hematology MA, United States and Oncology, Kayseri, Turkey; 2Erciyes University, Faculty of Medicine, Department of Pathology, Kayseri, Turkey; 3Erciyes University, Faculty of BACKGROUND: Clinical experience and literature suggests that survivors of Medicine, Department of Radiology, Kayseri, Turkey; 4Erciyes University, childhood brain tumors experience pain as long-term effects of treatment. We Faculty of Medicine, Department of Radiology, Division of Pediatric assessed the prevalence of pain in survivors of childhood brain tumors and the Radiology, Kayseri, Turkey; 5Erciyes University, Faculty of Medicine, influence of medical and treatment factors on pain. METHODS: Participants Department of Neourosurgery, Kayseri, Turkey were 48 childhood brain tumor survivors (62.5% male; Mean age ¼ 20) followed in neuro-oncology outcomes clinic who participated in Project INTRODUCTION: Intracranial choriocarcinoma (ICC) is an infrequent REACH, a local longitudinal survivor cohort study. Participants were over 1 tumor of children and young adults, prone to locate at pineal and suprasellar year from treatment completion. Pain measurements included a pain ther- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 regions. We present a huge ICC successfully treated multidisciplinary mometer, the PEDSQL brain tumor pain module, and a 15-item adapted therapy including endovascular embolization. CASE REPORT: A 10-year- version of the Brief Pain Inventory (BPI). Participants reporting any severe old boy presented with headache of one month’s duration associated with pain, or moderate pain for ≥2days in the past week on the BPI were considered nausea, vomiting and weakness in the lower limbs when walking. On admis- to have significant pain. RESULTS: Seventeen participants (37.8%) reported sig- sion he was drowsy, irritable, dysarthric, and atactic; bilateral papilledema, nificant pain on the BPI. 47.8% of survivors with LGG reported significant pain poorly reacting pupils and symptoms of puberty precocious were also noted. compared with only 21.4% of those with embryonal tumors. Comparing the Cranial MR showed huge suprapineal hypervasculer mass. The patient was pain thermometer and the PEDSQL to the BPI, there was a discrepancy identify- found to be unsuitable for surgery, so endovascular tumor embolization and ing significant pain. Of patients reporting significant pain on the BPI, the pain then subtotal resection were performed. Histopathological examination con- thermometer and the PEDSQL did not identify (43%) and (35%) of these firmed the diagnosis of ICC, the serum level of beta human chorionic gon- patients, respectively. CONCLUSIONS: Improved symptom assessment may adotrophin (bHCG) was 81.216 mIU/ml. The patient underwent a optimize detection of survivors most at risk for post-treatment pain. However systemic chemotherapy including cisplatin, etoposide and ifosfamide current screening measures may not be ideal for identifying pain in brain (according to the SIOP CNS GCT II protocol) and cranial radiation with a tumor survivors. Further investigation, including examination of the relation- good clinical recovery and normal HCG levels without any evidence of ship to quality-of-life with an expanded cohort of 100 survivors is underway. residue or recurrence at 6-month follow-up. CONCLUSION: We conclude that endovascular treatment can provide an opportunity of respectability. And intensive chemotherapy, radiation, and tumor resection, if feasible, offer the best chance of curing this otherwise fatal disease. P-QOL.04. SLEEP COMPLAINTS IN PEDIATRIC BRAIN TUMOR PATIENTS C. Jordan1, A. Johnson2, C. Mazewski3, P. McElfresh1, and R. Shabo2; 1Children’s Healthcare of Atlanta, Atlanta, GA, United States; 2Kennesaw P15 QUALITY OF LIFE State University, Atlanta, GA, United States; 3Emory University, Atlanta, GA, United States

P-QOL.01. A DETAILED PROSPECTIVE LONGITUDINAL PURPOSE: To determine the incidence, frequency, and character of sleep dis- ASSESSMENT OF HEALTH STATUS IN CHILDREN WITH BRAIN orders incurred by a population of off-therapy pediatric brain tumor patients. TUMOURS IN THE FIRST YEAR AFTER DIAGNOSIS METHODOLOGY: Retrospective chart review was conducted on three sub- A. Penn1,2, S. P. Lowis3, M. C. G. Stevens4,5, L. P. Hunt5, R. I. Shortman6, populations of brain tumor patients followed in a pediatric multidisciplinary R. J. McCarter7, A. L. Curran1, and P. M. Sharples1; 1Department of clinic in the Southeastern USA from January 1, 2003 through August 1, Paediatric Neurology, Frenchay Hospital, Bristol, United Kingdom; 2008. All patients were at least one year off therapy and without evidence of 2University of the Witwatersrand, Johannesburg, South Africa; 3Department shunt malfunction, uncontrolled endocrinopathy, or evidence of recurrence. of Paediatric Oncology, Bristol Royal Hospital for Children, Bristol, United RESULTS: Of 116 charts reviewed from patients with three distinct subtypes Kingdom; 4Bristol Royal Hospital for Children, Bristol, United Kingdom; of tumors, fifty were identified as having off-therapy sleep disorders: 17/26 5Department of Clinical Sciences at South Bristol, University of Bristol, (65%) craniopharyngiomas (C), 19/42 (45%) medulloblastomas (M), and United Kingdom; 6Department of Neuropsychology, Frenchay Hospital, 14/48 (29%) cerebellar juvenile pilocytic astrocytomas (JPA). Sleep problems Bristol, United Kingdom; 7Department of Neuropsychology, Frenchay were noted as sleep latency (SL), sleep maintenance (SM), or daytime sleepi- Hospital, Bristol, United Kingdom ness/fatigue (DS/F). Eighty-two percent of those with sleep problems and 35 % of the total 116 charts reviewed showed DS/F. Median ages in years for AIMS: To compare health status (HS) in children with brain tumours one patients with sleep problems were 15 (M), 11 (C), and 10.5 (JPA). Posterior (t1), six (t6) and twelve (t12) months after diagnosis with matched ‘normal’ fossa mutism was noted in 5/19 M (26%) and 1/14 JPA (7%) with sleep dys- controls. To assess the relationship between parent- and self-report HS for function and 3/23M (13%) and 5/34 JPA (15%) without sleep problems. patients at t12. METHODS: HS was assessed using the Health Utilities Hydrocephalus incidence was similar for M and JPA patients with or without Index Mark III parent-report at all time points and self-report at t12. 29 sleep dysfunction. Fifty percent of patients with sleep problems also had head- patients and 32 controls were included in analysis of parent-report, and 21 aches.CONCLUSION: Sleep complaints are common among survivorsof pedi- patients and 22 controls in self-report HS at t12. Non-parametric analyses atric C, M, and JPA and warrant further analysis were used. RESULTS: Patients scored significantly lower than controls for global overall HS (HUI3 MAUF) for all comparisons (p max 0.009). Twenty-one (81%), 16 (62%) and 18 (62%) of patients had parent-report HUI3 MAUF scores in the moderate/severe range at t1, t6 and t12 respect- P-QOL.05. ART THERAPY: HOW DO I SEE MY ILLNESS? ively, compared with 6 (21%), 1 (4%) and 4 (13%) for controls. For M. Benko; Oncology and Hematology Department, Referral Center of the Self-report at t12, 10 (48%) of patients rated their overall HS as moder- Ministry of Health and Social Welfare for Children’s Solid Tumors, ate/severe, compared with 3 (14%) for controls. For parent-report, patients Rehabilitation Center for Cancer Kids and Their Families, Children’s scored significantly lower than controls in the attributes of emotion, cogni- Hospital Zagreb, Zagreb, Croatia tion and pain at t1 and t6, ambulation at t1, dexterity at t6. At t12, the difference was significant for parent-report cognition only (all p,0.01). No Art therapy is an important part of the supportive care for cancer kids on attributes reached significance for self-report at t12. Correlations between Oncology and Hematology Department of Children’s Hospital Zagreb. parent and self-report HS were good (rs.0.73) for all HUI3 scores with Among other, art therapy is used to facilitate and to improve the adjustment the exception of emotion and pain. INTERPRETATION: HS is measurable, of newly diagnosed children. It is conducted during the first or second che- and significantly compromised in children with brain tumors over the first motherapy with hospitalized children. The trained psychologist explains the year after diagnosis, but improves with time. Parent- and self-report differ, assignment to a child and provides him/her with a drawing kit (pencils, and both should be considered in assessing outcomes or defining colored pencils, felt pens, wax crayons, water crayons, and collage paper) interventions. and leaves. After the short period of time, the psychologist returns to the child and checks if the child has some clue of what he/she wants to draw. If he/she does, the psychologist provides him/her with the poster and the child draws his/her vision of the illness. The participants are newly diagnosed cancer kids, aged 10-17. The poster reveals that children see their cancer as an intruder, a man in black, a devil, a combat, or some other abstract drawing. ii108 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-QOL.06. ASSESSMENT OF PSYCHOLOGICAL DISTRESS IN for central nervous system tumors were compared with individuals who ADOLESCENT AND YOUNG ADULT BRAIN TUMOR were treated for other types of cancer. METHODS: Surveys and consent SURVIVORS: THE VALUE OF PARENT AND SURVIVOR forms were sent to 468 parents of patients age 6 to 17 years or to patients age SELF-REPORT 18 and over who had been treated for cancer for at least six months at our C. Liptak1,2, E. Zwemer1,2, A. Merport1, P. Manley1,2, and C. J. Recklitis1,2; center. Medical records were reviewed to determine type of cancer and treat- 1Dana-Farber Cancer Institute, Boston, MA, United States; 2Harvard ments received. A factor analysis of the learning difficulties scale revealed 6 sub- Medical School, Boston, MA, United States scales on which the subjects with central nervous system tumors and those with other types of cancer were compared. RESULTS AND CONCLUSIONS: One PURPOSE: This study examined utility of self-report psychological screen- hundred fifty six surveys were returned, 28 from patients who had been treated ing in survivors of pediatric brain tumors, a population not well studied in for a central nervous system tumor (primarily astrocytoma, and medulloblas- previous psychological screening research. METHODS: Participants were toma). The 128 patients in the comparison group were primarily treated for drawn from a neuro-oncology outcomes clinic. 44 adolescents (age 12-18) ALL, AML, Wilms, and Hodgkins Lymphoma. The group with central completed the Beck Youth Inventory (BYI) and 52 young adults (age nervous systemtumors cancershadsignificantly higher scores than the compari- 19-30) completed the Brief Symptom Inventory-18 (BSI-18). Parents com- son group on the overall scale and five of the six subscales: activity, learning pleted either the Child or Adult Behavior Checklist (CBCL/ABCL) depend- skills, verbal skills, attention, and school/solving. Information regarding ing on survivor age. Previously established cut-off scores were used to specific tumors will be described. Implications for clinical screening and Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 identify cases of significant distress. RESULTS: Eighty-four percent of partici- support of patients with central nervous system tumors will be discussed. pants completed measures in ,30 minutes, and 90% reported no distress associated with participation. In the young adults, 8.5% reported clinically significant distress and 34% reported moderate distress. Adolescent survivor and parent ratings had significant correlations ranging from .41-.44 (p , .01). Among adolescents, 38% reported clinically significant distress. Association P-QOL.09. PSYCHOLOGICAL INTERVENTIONS AT THE of adolescent ratings of depression with parent ratings were strong (.51, p , SCHOOL INTERFACE IMPROVE THE HEALTH-RELATED .01), but adolescent report of anxiety was not associated with any parent QUALITY OF LIFE FOR CHILDREN WITH CENTRAL NERVOUS ratings. Overall case agreement between survivor and parent ratings was only SYSTEM TUMOURS moderate, and cases identified as distressed by one reporter were not consist- L. Talbot1, J. Williams1, E. Howie1, C. Verduyn1, I. Kamaly-Asl1, ently captured by the other. CONCLUSIONS: Many pediatric brain tumor sur- R. Gattamaneni2, and E. Estlin1; 1Royal Manchester Childrens Hospital, vivors are capable of completing self-report psychological measures in a clinical Manchester, United Kingdom; 2Christie Hospital, Manchester, United setting without associated distress or burden. While survivors and parents Kingdom demonstrate general agreement in ratings, each group provides unique information not available from the other. Accessing adolescent self-report may be The neuropsychological sequelae that are described for children with of particular importance given that parent report does not provide a cohesive tumours of the central nervous system (CNS), can lead to poorer educational picture of important issue such as anxiety. attainment, prospects for employment and significantly impact on health-related quality of life (HRQL). In particular, the interface of children with CNS tumours and school is important, but there have been very few studies of systematic psychological interventions for this population in this setting. Twenty-four children with CNS tumours, treated at the Royal P-QOL.07. LONG-TERM TREATMENT OF BRAIN TUMORS: Manchester Children’s & Christie Hospitals in Manchester, and diagnosed SUFFERING EXPERIENCED BY PATIENTS AND THEIR between 1 and 4 years previously were supported in relation to their school FAMILIES issues, cognitive abilities, emotional issues, behavioural issues and social con- C. L. Epelman, S. Epelman, P. L. B. J. Meirelles, and A. R. Andrijauskas; cerns as required. Measures of psychological functioning and HRQL were Santa Marcelina Hospital, Sao Paulo, Brazil made at the beginning and end of a year of this support. The impact of this on HRQL differed depending upon whether this was parent or child reported. BACKGROUND: The experience of having cancer always presents a tre- From the perspective of parents, a minimally important difference (MID) in mendous challenge to children and their families in many respects. Facing HRQL score was found for 13/24 patients; with females benefiting more fre- malignant brain tumors, patients pose unique problems. They are confronted quently than males (p ¼ 0.025). MID score improvements were identified for with more severe disease and side effects and poor prognosis. Today, with the emotional domain (relating to age . 10 years at diagnosis; p ¼ 0.034) and advances of pediatric neuro-oncology, many patients have been treated for also the social domain where females were felt to derive benefit more fre- a longer period of time. This research was developed to explore the experi- quently than boys (p ¼ 0.048). However, the child reports indicated only ence of long-term treatment of brain tumors and to describe the unique chal- time since diagnosis (over two years) as being a statistically significant (p , lenges these patients and families faced. METHODS: This study was 0.05) towards a MID improvement in their overall HRQL scores, and also conducted using qualitative methods. Parents of children with brain those for the physical, emotional and psychosocial domains as determined tumors treated for at least 3 years were eligible to participate in a semi- by the PedsQLTM generic scales. structured interview which was taped. Grounded theory was used to classify data into emerging themes. RESULTS: Twenty parents participated (12 whose children were alive and 8 were dead). Median time of treatment was 5 years. Parents provided important insights about challenges experi- P-QOL.10. EDUCATIONAL AND PROFESSIONAL CAREERS enced by patients and families. Emerging themes included: anxiety related AMONG SURVIVORS OF MALIGNANT BRAIN TUMORS to surgery, feeling of loneliness and “standing by”, and fear of death. TREATED DURING THE LAST 15 YEARS - AN OBSERVATIONAL SINGLE CENTER REPORT Parents reported siblings’ severe problems. Difficulties of coping most 1,2 3 3 1 4 often described were defering familial, professional, social, and educational A. Gupper , P. Cartier , H. Schweinfurth , K. Wenninger , U. Tacke , and J. Roessler1; 1Division of Pediatric Hematology and Oncology, University projects. Endless waiting for “an answer” and fear of a new relapse were par- 2 ticularly distressing. Most parents persevered their search for cure despite the Hospital Freiburg, Freiburg im Breisgau, Germany; Katharinenhoehe, overwhelming experience and expressed their desire to undergo everything Pediatric Oncology Rehabilitation, Schoenwald im Schwarzwald, Germany; 3Children’s Hospital School, University Hospital Freiburg, Freiburg im again. CONCLUSIONS: Suffering and challenges experienced by these 4 patients are unique and intense. Optimal supportive care may improve Breisgau, Germany; Division of Pediatric Neurology, University Hospital quality of life and definition of preventive interventions for this population. Freiburg, Freiburg im Breisgau, Germany INTRODUCTION: Better outcome of malignant brain tumor patients has resulted in a growing population of survivors within the education system. PATIENTS AND METHODS: We followed the educational and professional P-QOL.08. LEARNING DIFFICULTIES OF CHILDREN AND careers of 12 patients after malignant brain tumors (9 medulloblastoma, 1 ger- YOUNG ADULTS FOLLOWING TREATMENT FOR CENTRAL minoma, 1 malignant astrocytoma and 1 PNET) diagnosed since 1994. NERVOUS SYSTEM TUMORS Treatment consisted of surgery, chemotherapy (HIT 91, HIT 2000 and D. M. Pucccetti1, J. Eichoff2, S. Farrell3, K. Millin1, T. Pellino1, A. Plumb1, MAKEI protocols), and radiation of the CNS with cumulative doses of greater P. Possin3, G. Williams1, and J. Wish4; 1University of Wisconsin, Madison, than 50 Gy. Educational status at diagnosis, subjective educational prospects, WI, United States; 2Colorado State University, Fort Collins, CO, United subsequent educational/professional career, grade repetition, and special 3 States; American Family Children’s Hospital, Madison, WI, United States; needs education services were recorded. RESULTS: Two patients completed 4 University of Wisconsin Hospital and Clinics, Madison, WI, United States final secondary education, 1 finished professional school, 4 patients completed compulsory secondary education - 1 changed afterwards to grammar school, 3 PURPOSE: The overall purpose of the study was to examine the preva- are doing now an apprenticeship as are 2 patients who dropped out of school. lence of learning difficulties reported by parents of children/young adults Two patients are still attending secondary school, 1 is attending special needs who were treated at our cancer center for childhood cancer. As a sub- school. Eight patients reported lack of concentration and slow learning curve, analysis, reported here, learning difficulties in individuals who were treated 7 problems with memorizing. Two patients who reached highest educational

NEURO-ONCOLOGY † JUNE 2010 ii109 Abstracts

outcome were .13 years of age at diagnosis, 5 patients who in their educational P-QOL.13. QUALITY OF LIFE AND BEHAVIORAL FOLLOW-UP career had the lowest outcome and needed special educational services were , 6 STUDY OF HEAD START I IN PEDIATRIC BRAIN TUMOR years at diagnosis. CONCLUSION: The data of 12 survivors of malignant brain SURVIVORS tumors do not allow a distinct conclusion with respect to a correlation between S. A. Sands1, K. P. Pasichow2, R. A. Weiss3, J. Garvin1, and J. L. Finlay4; therapy of the affected individual and the educational outcome. However, the 1Columbia University College of Physicians and Surgeons, New York, NY, results imply that after brain tumor therapy the level of pedagogic and psycho- United States; 2Mount Sinai School of Medicine, New York, NY, United social support needed varies greatly among patients. States; 3Fordham University, New York, NY, United States; 4Children’s Hospital of Los Angeles, Los Angeles, CA, United States

PURPOSE: To evaluate the Quality of Life (QoL) and Social-Emotional/ P-QOL.11. PSYCHOSOCIAL WELL BEING IN PEDIATRIC BRAIN Behavioral functioning of survivors treated on the “Head Start I” protocol at TUMOR SURVIVORS participating medical centers across the United States between1991 and Z. E. Dreyer, J. Yan, M. Carroll, J. Griggsby, R. Bryant, H. Suzawa, 1997. PATIENTS AND METHODS: Parents of 25 of 27 (92.5%) patients M. Okcu, E. Fruge, G. Hamor, and M. Chintagumpala; Baylor College of completed the Child Health Questionnaire PF-50 (CHQ), to assess their Medicine, Houston, TX, United States child’s QoL, along with the Behavior Assessment System for Children (BASC), to assess their social-emotional/behavioral functioning, after a Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 OBJECTIVES: Fifty four pediatric brain tumor survivors (PBTS) were mean follow-up of 5.7 years (range 13-96 months). Eighteen (72%) of the evaluated for educational achievement, employment status and psychosocial ≥ 25 parents subsequently completed the same instruments after a mean of well being. PATIENT POPULATION: 54 PBTS 18 years of age were eval- 11.58 years (range 90 -181 months), three (12%) patients passed away ¼ uated between 2005-2009. Diagnoses were medulloblastoma (n 20), and four (16%) were lost to follow-up. RESULTS: Both mean Physical ¼ ¼ ¼ astrocytoma (n 15), ependymoma (n 4), glioma (n 3), germ cell and Psychosocial QoL Summary Scores on the CHQ at Time 1 (T1) and ¼ ¼ ¼ tumor (n 5), germinoma (n 2), and miscellaneous rare tumors (n 5). Time 2 (T2) were within the normal range. Of the ten individual means The median age at diagnosis was 8.1 years, at completion of treatment 8.5 for the CHQ subscales, nine were within normal limits with the exception years, and at evaluation time in survivor clinic 24.2 years. Prior treatment of Parental Emotional Impact at T1 and General Health at T2. ¼ was chemotherapy (CTX), surgery and radiotherapy (XRT) (n 39), Additionally, mean scores on the BASC at T1 and T2 were within normal ¼ ¼ ¼ surgery and XRT (n 9), surgery and CTX (n 2), and surgery only (n limits for Externalizing and Internalizing Behaviors as well as Adaptive ≤ ¼ ≤ th ¼ 4). RESULTS: Highest grade level completed: 8th (n 2), 11 (n 8), Skills. Serial analyses between T1 and T2 revealed non-significant changes th ¼ th ¼ th ¼ 12 (n 19), 14 /associate degree (n 5), 16 /college degree (n 5), over time with the exception of decreased General Health on the CHQ. ¼ ¼ post graduate degree (n 1). Currently in: high school (n 1), college CONCLUSION: The lack of QoL and Social-Emotional/Behavioral deficits ¼ ¼ ¼ (n 8), vocational education (n 4), and life skills (n 1). suggests that the “Head Start I” protocol, involving intensive induction fol- ¼ ¼ ¼ EMPLOYMENT: employed (n 7), student (n 9), unemployed (n lowed by myeloablative chemotherapy and autologous stem cell transplant ¼ ¼ ¼ 38). Survivor lives with: parent (n 40), alone (n 6), at college (n 5), in order to avoid or delay cranial irradiation, provides encouraging pilot ¼ ¼ spouse/significant other (n 3). Marital status: single (n 51), married data warranting continued monitoring. (n ¼ 3). Mental health: stable/ happy (n ¼ 27), depressed (n ¼ 12), anxious (n ¼ 3), issues with anger management (n ¼ 5), substance abuse (n ¼ 3), body image (n ¼ 3), mental retardation (n ¼ 1). Six PBTS did not receive XRT: 4 attend/graduated from college, 2 employed, 2 married. P-QOL.14. QUALITATIVE ASSESSMENT OF A SOCIAL CONCLUSIONS: PBTS are challenged academically and socially. They are PROGRAM FOR ADOLESCENT AND YOUNG ADULT BRAIN unlikely to live independently, be married, employed or attain educational TUMOR SURVIVORS levels higher than 12th grade. Despite this, half of PBTS reported their C. Liptak1,2, T. Brinkman1,2, J. Ing2, C. Chordas1, B. Delaney1,2, and mental health to be stable/happy. To improve lifestyle long-term in PBTS, P. E. Manley1,3; 1Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, continued research efforts must focus on reducing the overall impact of Boston, MA, United States; 2Pediatric Psycho-Oncology, Dana-Farber therapy, particularly XRT, on the developing brain. Cancer Institute, Boston, MA, United States; 3Hematology/Oncology, Children’s Hospital Boston, Boston, MA, United States

PURPOSE: Given the increasing data on social functioning difficulties experienced by survivors of pediatric brain tumors, the Success through Education, P-QOL.12. RESOURCE AND INFORMATION NEEDS OF BRAIN Psychosocial Support, and Socialization (STEPS) Program was developed in TUMOR SURVIVORS 2007. The goal of STEPS is to provide social contact, psychosocial support, C. Chordas1, C. Liptak1,2, B. Delaney1,2, J. Barnes3, J. Chabot3, and psychoeducation for adolescent and young adult survivors of pediatric L. Northman2, M. Morris2, R. Gambhir2, C. Rey-Casserly1,4, T. Diver4, and brain tumors and their caregivers. PATIENTS AND METHODS: The STEPS P. E. Manley1,5; 1Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Program offers monthly dinners for survivors and their caregivers that include Boston, MA, United States; 2Pediatric Psycho-Oncology, Dana-Farber social activities for patients and education for parents. This structure allows 3 Cancer Institute, Boston, MA, United States; Pediatric Oncology, for consistent and frequent contact amongst participants, which differs from 4 Dana-Farber Cancer Institute, Boston, MA, United States; Psychiatry, the traditional support group format. Additionally, recreational activities are 5 Children’s Hosptial Boston, Boston, MA, United States; Hematology/ offered which focus on team building, self-esteem, and communication. Oncology, Children’s Hospital Boston, Boston, MA, United States RESULTS: In the first year, the average number of attendees was 27 and in its second year, attendance increased 35%. Based on an informal quality improve- PURPOSE: Advancements in brain tumor research and treatment has ment survey, patients and parents noted that participants benefitted from resulted in an increase in survivors. The long term effects of brain meeting others who have similar medical experiences. Clinical observation tumors and its treatment can be complex and place a significant strain demonstrated improvement in patient self-esteem, increased interest in social on the patient and their family. As a result survivors and caregivers involvement outside of the group, and improvement in interpersonal skills. often need access to current and relevant information, resources and Parents reported that the group provides a safe opportunity for socialization support. The Neuro-Oncology Outcomes Program at Dana-Farber and they look forward to the events to see their child socialize successfully. Cancer Institute helps identify individual needs and is often able to CONCLUSION: Given the success of the program, the need to understand the provide appropriate guidance and support. We identified the resource perceived impact of STEPS attendance through qualitative investigation and and information needs requested by brain tumor survivors seen in the provide baseline data to develop a quantitative study is warranted Neuro-Oncology Outcomes Program at Dana-Farber Cancer Institute. andunderway.Thiswillprovideaprospectiveapproachinstudyingpsychosocial PATIENTS AND METHODS: After IRB approval, we reviewed a data- interventions that target the social challenges experienced by this population. base of all resource and information requests of patients and families seen in the Neuro-Oncology Outcomes Program from July 2008 thru July 2009. Requests were then categorized and frequency statistics obtained. RESULTS: Over 12 months, 300 brain tumor survivors were approached at a routine clinic visit and 134 (45%) requested resources P-QOL.15. BRAIN TUMOR IN CHILDHOOD AND and information. Requests included social opportunities (n ¼ 41), financial ADOLESCENCE: REHABILITATION NEEDS AND assistance (n ¼ 35), scholarship prospects (n ¼ 34), disability services (n ¼ INTERVENTIONS 1 2 3 3 3 4 24). CONCLUSIONS: Survivors of brain tumors have a wide variety of G. Poggi , M. Massimino , F. Giordano , I. Sardi , L. Genitori , M. Garre` , 2 1 1 1 1 resource and information needs. Recognizing these needs is integral to a L. Gandola , S. Strazzer , A. Degrate , E. Beretta , and A. Adduci ; 1 2 comprehensive outcomes program. Providing access to resources and infor- Scientific Institute E. Medea, Bosisio Parini-Lecco, Italy; National Cancer 3 4 mation can improve the quality of survivorship and empower survivors in Institute, Milano, Italy; Meyer Children’s Hospital, Florence, Italy; Gaslini self-advocacy. Future aims include introducing a resource specialist to all Children’s Hospital, Genoa, Italy brain tumor survivors. PURPOSE: To describe the rehabilitation needs of children treated for brain tumors, examine the relationship between demographic and clinical variables ii110 NEURO-ONCOLOGY † JUNE 2010 Abstracts

and the outcome, and the changes occurred in the last decade. METHODS cancer kids and their families, centers shall additionally work with the survi- AND MATERIALS: The data collected about patients with brain tumors vors, medical staff and grieving families. It is our intention to organize for assessed between 1993-2009 (first admission: 250 patients; 12- and summer camps for the survivors, to publish brochures and educational 60-month follow-ups: 72 patients and 23 patients, respectively) were exam- books, to develop a website for cancer kids, to improve the pediatric palliative ined. RESULTS: Speech therapy, physical therapy and neuropsychological care, to increase the general public awareness of the problems that cancer kids remediation were reported more frequently (45.6%, 14% and 6% of patients, face, and to spark sufficient interest among professionals with various back- respectively). Speech therapy, physical therapy and neuropsychological reme- grounds for the pediatric psychooncology and palliative care. Project of diation were more frequently reported for patients with neurosurgical lesions national strategy for developing rehabilitation centers will greatly improve and radiotherapy-related damage. Psychomotor treatment was more fre- supportive therapy for cancer kids and their families during chemotherapy quently administered to younger children. A brainstem tumor is associated and radiotherapy, for survivors, for dying children and for grieving families with a greater need for speech therapy, while psychological support is not in Croatia. This is the first project in Croatia that includes neuropsychological associated with any of the clinical variables under study. Patients diagnosed (psycho-)therapy, which is in focus of this paper. with a brain tumor after 2000 present with a better cognitive outcome and a greater number of indications for rehabilitation interventions, in particular neuropsychological treatment. CONCLUSIONS: The longer survival and the improved global outcome are not associated with a reduced need for reha- P-QOL.18. OUTPATIENT CISPLATIN FOR AVERAGE RISK Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 bilitation. In contrast, there is an increase in rehabilitation requests which can MEDULLOBLASTOMA; 15 YEAR EXPERIENCE be due to a greater focusing on the patients’ outcomes and their quality of life, J. R. Madden, M. Hemenway, L. Dorneman, R. Strecker, and N. Foreman; resulting in a greater accessibility to rehabilitation services. The Children’s Hospital, University of Colorado, Aurora, CO, United States Standard of care for average risk medulloblastoma consists of craniospinal radiation and a posterior fossa boost, followed by adjuvant maintenance chemotherapy. The current standard maintenance chemotherapy (CCG study P-QOL.16. POSSIBILITIES OF PSYCHOSOCIAL SUPPORT AND ACNS 0331) consists of cycles of cisplatin, lomustine, vincristine alternating REHABILITATION FOR CHILDREN WITH BRAIN TUMORS with cyclophosphamide, vincristine. The cisplatin and cyclophosphamide K. Tothova and I. Vlckova; University Hospital Brno, Clinic of Pediatric traditionally require extensive overnight post-hydration. We pioneered Oncology, Brno, Czech Republic home care intravenous fluid (IVF) post-hydration for all chemotherapy cycles. Between 1994 and 2009, we have treated 49 average risk medullo- Our proposal focuses on possibilities of neurocognitive rehabilitation of blastoma patients, with 47 of them receiving home care IVF. Specialized sequelae as an improvement of the quality of life in pediatric cancer patients home care orders were created for the delivery of home care IVF and the treated at the Clinic of Pediatric Oncology in Brno. We intend to present hour 6 intravenous mesna bolus. Home care coordination for registered practical approaches to rehabilitation by the form of case studies. In nurse (RN) teaching included: IVF bag change, mesna administration, flush- quality of life research, results show cancer patients surviving brain tumor ing, de-accessing the port. Patients who lived more than one hour away were diagnoses as the group at high risk. Reduced quality of life has been identified asked to stay locally. Two patients received therapy in a distant state by a in many domains: educational problems, attention deficits, and reduced local physician after diagnosis at our center. Complications included social competence. Further severe effects include lesions of neurocognitive battery failure, disconnection of tubing, and filter disconnection from the functions, which are the basis for recognition and orientation in the world, tubing. Complications were easily resolved at the emergency department learning abilities, remembering, and integration of obtained information. with RN trouble-shooting at the discretion of the on-call MD. Forty-four Children with these types of cognitive sequelae report handicaps in their of 47 of these children are alive and well (1 patient died of radiation social reintegration, especially into the educational system. As such, selection changes and 2 patients died of radiation-induced gliomas), suggesting that of appropriate prevention, diagnostics, and rehabilitation is essential. Our outpatient post-hydration was no hindrance to long-term survival. We had approach to neurocognitive rehabilitation includes completion of a practical no hemorrhagic cystitis or long-term renal insufficiency. Patients and rehabilitation plan and education of the patient’s closest social surroundings. parents routinely express increased satisfaction with the reduced amount A plan of psychological and pedagogical care should be developed during of hospital days. Home care post-hydration in our experience is safe, effi- treatment, and consecutive care should be ensured in schools and specialized cient, and improves patient satisfaction. pedagogical centers. The goal is to improve the quality of life in pediatric cancer survivors, facilitate re-involvement into the educational process and social rehabilitation. The possibility to actively compensate sequelae of pedi- P-QOL.19. HEALTH-RELATED QUALITY OF LIFE OF atric cancer has a positive effect on patients and parents in order to prevent PEDIATRIC BRAIN TUMOR PATIENTS ON PROTON feelings of helplessness and failure. The ability to keep on participating in the TREATMENT educational process and social surroundings positively influences the child’s K. A. Kuhlthau, M. Pulsifer, J. Delahaye, S. M. MacDonald, N. J. Tarbell, self-esteem and further development of personality. and T. I. Yock; Massachusetts General Hospital, Boston, MA, United States

PURPOSE: This study prospectively examines the quality of life of children P-QOL.17. NATIONAL STRATEGY FOR DEVELOPING with brain tumors treated with proton radiation. Radiotherapy has been pre- REHABILITATION CENTERS FOR CANCER KIDS IN CROATIA viously associated with decreased QoL. Proton radiotherapy treats less M. Benko; Oncology and Hematology Department, Referral Center of the normal brain causing fewer late effects and thus potentially improves Ministry of Health and Social Welfare for Children’s Solid Tumors, HRQoL. METHODS: All study participants are pediatric brain tumor Rehabilitation Center for Cancer Kids and Their Families, Children’s patients (ages 2-18) treated with proton therapy. We assessed child self Hospital Zagreb, Zagreb, Croatia and parent proxy reported HRQoL using the PedsQL during treatment and annually thereafter. RESULTS: Among the 122 patients assessed, There are four regional Rehabilitation Centers for Cancer Kids in Croatia - mean HRQoL was 66.7 for the generic core module based on parent Zagreb, Rijeka, Split and Osijek. All were formally founded by a report and 71.8 for the brain tumor module. Child self-report figures are Government’s decision in 2007, while only Zagreb and Split centers are cur- 74.3 and 75.7 respectively. Parent and child reports are generally highly cor- rently operational. Each of them employs a psychologist, an occupational related except for several of the sub-domains of the tumor module. therapist and a nurse. However, there is a lack of coordination and mutual Children’s HRQoL seems worse for school, treatment anxiety, procedural programs among the centers, and the staff education needs to be brought to anxiety, and emotional well-being relative to other domains. Reports of a more adequate level. The Rehabilitation Center for Cancer Kids from the HRQoL are fairly stable over. Overall HRQoL is significantly associated Children’s Hospital Zagreb proposed to the Ministry of Health and Social with IQ, behavioral problems, independent behavior, and diagnosis Welfare and the Ministry of Family, Veteran’s Affairs and Intergenerational (p-values range from ,.0001-.008). CONCLUSIONS: This is a first Solidarity to initiate a project for further development and better coordination HRQoL study in a large cohort of children with brain tumors treated with of the four Rehabilitation Centers. It is envisaged that each of the protons. Correlations of parent and child reports of HRQoL are strong, Rehabilitation Center’s consists of two organizational units. First is the but indicate that children have a more optimistic view of their own quality Support, Counseling and Psychotherapy Unit, employing a psychologist and of life. We will present our proton data in the context of previously published an occupational therapist, while the second is the Neuropsychological HRQoL data in photon treated brain tumor patients. Diagnostics and Therapy Unit, employing a psychologist, a rehabilitation therapist, a speech therapist, a physiotherapist and a nurse. The staff in the Support, Counseling and Psychotherapy Unit should work with the hospitalized children on the Oncology and Hematology Department, the Oncology and Hematology Outpatient Clinic (daily treatment) and in the Sterile Unit for Transplantation of Stem Cells. The staff in the Neuropsychological Diagnostics and Therapy Unit, on the other hand, should primarily work with the outpatients, but also with the hospitalized children. In addition to

NEURO-ONCOLOGY † JUNE 2010 ii111 Abstracts

P16 OUTCOME STUDIES intracranial radiation, but it is unknown whether those patients who complain of severe headaches are at increased risk for neurovascular complications. METHODS: The database of children with brain tumors at a large tertiary care center was searched for patients who received intracranial radiation, aged 0-21 years at diagnosis, with initial treatment between 1/1/93-12/31/ P-OUT.01. SECONDARY MALIGNANT NEOPLASMS 02 and .2 follow-up visits with neuro-oncology. The institutional stroke reg- FOLLOWING THE TREATMENT OF PRIMARY BRAIN TUMORS istry database was queried for events of stroke or transient ischemic attack IN CHILDREN (TIA). Patients were considered to have severe recurrent headache or migraine C. Wang, K. Chang, T. Wong, T. Hsu, T. Yang, F. Chang, D. Ho, and S. Yen; if these appeared as a chief complaint on .2 visits. Headaches attributed to Taipei Veterans General Hospital, Taipei, Taiwan disease progression, shunt malfunction, infection, or appearing at the end of life were excluded. RESULTS: Of 242 subjects, stroke or TIA occurred in 7/ OBJECTIVE: This study analyzed the secondary malignant neoplasms that 38 (18.4%) with severe headaches or migraine compared to 6/204 (2.9%) have developed as a result of the treatment of primary brain tumors in chil- without these symptoms (hazard ratio 4.5, 95%CI: 1.4-14.5, p ¼ 0.013). dren. METHODS: We retrospectively analyzed 615 pediatric patients with Adjusting for field of radiation did not attenuate this risk. Median follow-up primary central nervous system tumors. The primary treatment strategy was was 6.7years (interquartile range, 2.2-9.5 years), while median time to first neu- gross total removal by surgery whenever possible. There were 378 patients rovascular event was 4.9 years (interquartile range, 1.7-5.5 years). Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 who received adjuvant radiotherapy with or without chemotherapy or che- CONCLUSIONS: Severe recurrent headache or migraine appears to be a risk motherapy alone. Any newly developed neoplasm that was distinct from the factor for cerebral ischemia in pediatric brain tumor survivors treated with radi- initial tumor by histopathology was considered to be a secondary neoplasm. ation, which could have significant implications for closer monitoring and iden- MAIN RESULTS: There were six patients who developed secondary malig- tifying a population in which to target primary stroke prevention. nant neoplasms after treatment of primary brain tumors with surgery, radiotherapy, with or without conventional chemotherapy. The histopathologic diagnosis of primary brain tumors were atypical teratoid/rhabdoid tumor (n ¼ 2), germ cell tumor (n ¼ 2), ependymoma (n ¼ 1), and medulloblastoma (n ¼ 1). The histopathologic diagnosis of secondary malignant neoplasms P-OUT.04. MOYAMOYA SYNDROME AND BRAIN TUMORS IN were malignant spindle cell tumor (n ¼ 1), osteosarcoma (n ¼ 1), rhabdo- CHILDREN myosarcoma (n ¼ 2), atypical teratoid/rhabdoid tumor (n ¼ 1), and acute T. Hsu, K. Chang, T. Wong, C. Wang, T. Yang, F. Chang, D. Ho, and S. Yen; lymphoid leukemia (n ¼ 1). The median latency time to the development of Taipei Veterans General Hospital, Taipei, Taiwan the secondary malignant neoplasms was 3.4 years (range, 1.8-6.5 years). Four patients died with a mean survival period of 1.4 years (range, 0.8-2.5 OBJECTIVE: Moyamoya syndrome is a basilar stenotic and occlusive years) after diagnosis of secondary malignant neoplasm. Two patients still disease occurring in the large arteries of the circle of Willis with identifiable survive now with a mean follow-up period of 1.3 years after diagnosis of sec- etiology such as radiation vasculopathy. The aim of the study was to review ondary malignant neoplasm. CONCLUSION: A wide spectrum of secondary the relationship between moyamoya syndrome and pediatric brain tumors. malignant neoplasms was found. Most commonly secondary malignant neo- METHODS: Pediatric moyamoya vasculopathy was reviewed at Taipei plasms occurred in the central nervous system, followed by hematological Veteran General Hospital retrospectively since January 1990 till December malignancy. The prognosis of the secondary malignant neoplasms was poor. 2009. In addition to clinical manifestations, moyamoya vasculopathy was documented by either brain MRA and/or carotid angiography. MAIN RESULTS: There are total 75 patients with moyamoya vasculopathy in the study period and nine of them, 5 boys and 4 girls, had moyamoya vasculopathy and brain tumors, including 4 cases with craniopharyngiomas, 4 P-OUT.02. SECOND NEOPLASM AND CEREBROVASCULAR with optic pathway tumors and 1 with dysembryoplastic neuroepithelial DISEASE IN SURVIVORS WITH GERM CELL TUMOR - tumor. The median age at tumor diagnosis is 5 years and 8 months old HOKKAIDO AND HIROSHIMA EXPERIENCE (range from 7 months to 10 years). The median period for moyamoya syn- 1 2 1 1 K. Sugiyama , Y. Sawamura , and K. Kurisu ; Hiroshima University drome to develop after tumors diagnosis was 42 months (range from 0 to 2 Hospital, Hiroshima, Japan; Hokkaido University Hospital, Sapporo, Japan 10 years and 10 months). For the 9 patients, 5 patients had moyamoya syndrome without radiation exposure, including 3 neurofibromatosis type 1 BACKGROUND: Survivors of childhood and adolescent brain tumors are at patients with optic pathway tumors. For the other 4 patients who had radi- risk for long-term effects of treatment (Tx). This study investigates details on ation exposure, the median period for moyamoya syndrome to develop was 7 second neoplasm and cerebrovascular disease of long-term survivors with years (range from 7 months to 10 years and 7 months). CONCLUSION: For CNS germ cell tumors (C_GCTs). METHODS: The authors reviewed clinical pediatric patients with brain tumors, moyamoya syndrome is prone to data on 203 institutional patients (pts) who had a C_GCT and survived more develop no matter radiotherapy has been given to the patient or not. than 5 years. Median age of initial Tx was 15.0 years and median follow-up period was 168 months (60-448 months). RESULTS: Among these pts, 32 pts (15.4%) suffered from second neoplasm and/or cerebrovascular disease. Median age of 32 pts was 14.6 years at the initial Tx. Median interval to event was 151 months (24-456 months). The secondary events, therefore, P-OUT.05. MORPHOMETRY OF TUMOUR AND occurred at the third decade of age. The second neoplasm included 8 cavernous INTRATUMOUR HAEMORRHAGE VOLUMES AT angiomas, 7 GBMs, 3 meningiomas, 2 G-III glioma, 1 hemangiopericytoma, PRESENTATION: DOES IT MATTER WHICH METHOD IS USED? and 1 leukemia. Four cavernous angiomas caused a hematoma. The cerebrovas- D. Roy, B. Pettorini, M. K. Hossain-Ibrahim, Y. Sun, M. English, A. Peet, cular disease included 14 steno-occlusive diseases of circle of Willis, 1 aneur- and G. A. Solanki; Birmingham Children’s Hospital, Birmingham, United ysm, and 1 dural AVF. Four pts sufferred from both neoplasm and Kingdom cerebrovascular disease. All 32 pts had previously received radiotherapy and 6 pts had undergone chemotherapy. Radiation field included whole ventricle OBJECTIVE: Intracerebral haemorrhage (ICH) occurring in paediatric brain system or whole brain involving basal cistern with the dose of more than 40 tumours is rare and accounts for just fewer than 10% of de novo cases. The aim Gy, except for one patient who received 24 Gy followed by P-E chemotherapy. of this study was to evaluate tumour and ICH volumes to survival using differ- Eight of 32 pts died and 14 pts had additional sequelae due to these secondary ent techniques (Ellipsoidshape calculation andSegmentation). Report on how a events. CONCLUSIONS: The risk of lethal malignant neoplasm and disabling simple and easy volumetric determination technique compares with a complex cerebarovascular disease after Tx for C_GCTs is extremely large. and time-consuming method in terms of ease of use and accuracy. PATIENTS & METHODS: Between 2001-2008, 212(77 boys/135 girls) children were identified from the prospective Regional Tumour Registry database. 20 children presented with ICH (within the tumour) at diagnosis. All children underwent a preoperative MRI and neurological assessment. We also reviewed histological P-OUT.03. HEADACHE AS A RISK FACTOR FOR diagnosis, symptomatology and outcome. Volumes were calculated on contrast NEUROVASCULAR EVENTS IN PEDIATRIC BRAIN TUMOR T1-weighted sequences using the modified ellipsoid method for clot volumes. PATIENTS We correlated these results with those of the segmentation method and with 1 2 1 2 2 S. M. Kranick , C. J. Campen , S. E. Kasner , S. Kessler , R. Ichord , survival. RESULTS: The incidence of intra-tumoural haemorrhage was 9.4% 2 2 2 2 1 D. J. Licht , S. E. Smith , L. A. Beslow , and M. J. Fisher ; Hospital of the (20/212). Using the modified ellipsoid method, average volume was 2 University of Pennsylvania, Philadelphia, PA, United States; Children’s 46.6 mm3 and with no evidence of bleeding was 24.5 mm3.Therewasnosig- Hospital of Philadelphia, Philadelphia, PA, United States nificant difference between boys and girls (39.4mm3 vs 28.82mm2, p ¼ NS). In alive children tumour volume was 28.5 mm3 while it was 60.7 mm3 for non- OBJECTIVE: To determine if severe recurrent headache or migraine is a risk survivors. Non-survivors presenting with haemorrhage had a mean volume of factor for neurovascular events in children who received radiation for brain 84.1 mm3 but only 37 mm3 without haemorrhage (p¼ 0.0157). tumors. BACKGROUND: Vasculopathy is known to be a late effect of CONCLUSION: Using a simplified technique of measurement, overall ii112 NEURO-ONCOLOGY † JUNE 2010 Abstracts

mortality appears related to tumour volume. The difference is more significant development. A small proportion of children diagnosed and treated for a in the presence of haemorrhage. The correlation between the two techniques is brain tumour are later found to have social interaction and communication discussed. problems with their peers. OBJECTIVE: To determine the predictors of social communication difficulties for children with a diagnosis of a brain tumour. METHODS: Parents of 50 children (mean age, 8 years 9 months) referred for neuropsychological assessment as part of treatment protocol following diagnosis, completed questionnaires on emotional, behavioural and P-OUT.06. SPINAL CORD COMPRESSION: ONCOLOGIC social development (SDQ) and communication skills (Social EMERGENCY IN CHILDREN’S SPINAL TUMORS Communication Questionnaire - SCQ). The results were analysed by cogni- M. A. Dragomir, E. Gruber, R. Milcu, C. Comsa, R. Anghel, and M. Savu; tive profile, age at diagnosis, tumour and treatment factors. RESULTS: Institute of Oncology, Bucharest, Romania Children diagnosed under the age of four years were more likely to present with higher scores of difficulty with social communication and peer relation- Spinal cord compression (SCC) occurs in 3-5% of children with solid ships than those diagnosed after four years of age. There was no significant malignant tumors. Favorable response to treatment directly correlates with effect of tumour type or treatment modality on the scores. There was a weak early recognition of the symptoms of SCC syndrome. SCC constitutes a effect of tumour location on the scores. CONCLUSION: The diagnosis and true emergency because the initial injury will lead to permanent loss of treatment of a brain tumour is associated with difficulties with social com- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 neurologic function if the pressure of the tumor on the cord is not relieved munication and peer relationships, especially for children diagnosed under quickly. AIM: to evaluate the epidemiology, symptoms, and outcome of the age of 4 years. The reasons include vulnerability of the developing spinal tumors in children and adolescents. PATIENTS AND METHODS: brain in infancy and earlier childhood, and disruptive effects of the tumour A retrospective review on 28 patients treated between 1999 and 2008 in and treatment on critical stages in acquisition of social communication the Institute of Oncology, Bucharest. RESULTS: Location of the tumor: cer- skills. It is important to prepare effective social skills interventions for chil- vical area (14%), thoracic area (43%), lumbar area (32%), sacral area dren at risk. (11%). Extradural tumors (bones and paravertebral soft tissues) represent 57% of cases, intradural-extramedullary tumors 32%, and intramedullary tumors 36%. The histopatological types of tumors were soft tissue sarcoma (46.5%), bone tumors (18%), ependymoma (18%), and some rare tumors for this location ( NHL, germ cell tumor). SCC syndrome was P-OUT.09. CHARACTERS AND OVERALL OUTCOME OF BRAIN present in 92% of thoracic and lumbosacral tumors and in 50% of the cer- TUMORS IN CHILDREN UNDER 3 YEARS OF AGE - AN vical tumors. Overall survival was 80% at 1 year and 41.1% at 5 years with a EXPERIENCE OF A SINGLE INSTITUTE median survival of 66.14 months. Neurological recovery was CR in 38% and T. Yang1, T. Hsu1, C. Wang1, K. Chang1, and T. Wong2; 1Department of PR in 22%. No remission was achieved in 50%. CONCLUSIONS: 1. SCC is Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of an oncologic emergency that needs to be identified, evaluated, and treated China, Taipei, Taiwan; 2Department of Neurosurgery, Neurological promptly for favorable patient outcomes. 2. Irreversible, permanent loss of Institute, Taipei Veterans General Hospital, Taipei, Taiwan neurologic function occurs if this condition is not treated promptly. 3. Multidisciplinary diagnosis and treatment are mandatory for BACKGROUND: Brain tumors are the second most common neoplasm in a favorable outcome of these cases. children. The survival rate in children is approximately 60%, however, it varies with the type of the tumor and the age of onset. In this article, we had focused on the clinical characteristics of brain tumors in children below the age of 3 years. METHODS: We retrospectively reviewed the children who were diagnosed of brain tumor below the age of 3 years at Taipei P-OUT.07. DURATION OF IN-PATIENT Veteran General Hospital since January 1990 to December 2009. The NEUROREHABILITATION COURSE AND IMPROVEMENT IN characteristics of these children were represented including: the diagnostic NEUROLOGIC FUNCTION FOR POSTERIOR FOSSA timing, pathology of tumor, treatment and prognosis. RESULTS: Fifty-six SYNDROME: DIFFERENCES BETWEEN BENIGN AND children (27 boys and 29 girls) under 3 years of age were diagnosed of MALIGNANT TUMORS brain tumor. The average age at diagnosis was 17 months (range, 5 days-3 L. M. Harrell, W. A. Marks, J. C. Murray, B. Colaluca, and E. Z. Braly; years). 67 % of tumors were astrocytoma, ependymoma and medulloblas- Cook Children’s Medical Center, Fort Worth, TX, United States toma. The less common tumors included primitive neuroectodermal tumors (PNET), atypical teratoid rhabdoid tumors, dysembryoplastic neu- OBJECTIVE: Posterior fossa syndrome (PFS) is a condition characterized roepithelial tumor, neuroblastoma, pineoblastomas, immature teratoma, by loss of speech, dysphagia and emotional lability, and can occur in 20-30% melanocytic nevus, and pontine glioma. Most of the children received of children following posterior fossa tumor resection. We investigated the partial resection of the tumor and underwent conventional chemotherapy relationship between tumor type, length of hospitalization and time to recov- or temozolamide. The overall mortality rate was 25% and the medium ery for children experiencing PFS. METHODS: Thirteen in-patient neuror- time from diagnosis to death was 12 months. Children with low grade astro- ehabilitation patients over a 4 year period were studied. Malignant tumors cytoma had 100% survival rate while PNET had 100% mortality rate. included 6 patients with medulloblastoma and 2 with ependymoma (all CONCLUSION: Although most of the brain tumors in children under the received craniospinal radiation for 6 weeks and most received concurrent age of 3 years belong to low grade astrocytoma which is associated with a chemotherapy). The comparison group included 5 patients with benign pretty good prognosis, the overall mortality is still high in these children. astrocytomas. RESULTS: Malignant tumor patients had a mean hospitalization duration of 84 days and average time to vocalization and verbalization of 11 and 34 days, respectively. Mean time to recover ability to swallow was 87 days. Average length of stay, time to vocalization, time to verbalization and time to swallow were 49, 0.6, 7 and 2 days, respectively for the P-OUT.10. GANGLIOGLIOMA AND DYSEMBRYOPLASTIC benign group. In an independent-samples t-test, length of stay (t ¼ 2.208, NEUROEPITHELIAL TUMOUR (DNET) IN CHILDREN IN A p ¼ 0.049), time to vocalization (t ¼ 3.583, p ¼ 0.009), and time to verbali- SWEDISH SINGLE CENTRE DURING 1990-2008. A zation (t ¼ 2.655, p ¼ 0.022) for malignant tumors were significantly longer RETROSPECTIVE STUDY OF LONG TERM FOLLOW-UP AFTER than for benign tumors. Also, a positive correlation was found between SURGERY length of stay and duration of symptoms. CONCLUSION: Length of hospi- C. Ehrstedt1, E. Laurencikas2, G. Ahlsten1, and B. Stro¨ mberg1; 1Department tal stay and time to functional recovery of swallowing and language for of Women´ s and Children´ s Health, Uppsala University Hospital, Uppsala, patients with PFS is longer for patients with malignant tumors. A relation- Sweden; 2Department of Radiology, Uppsala University Hospital, Uppsala, ship may exist between the severity of PFS and the extent of surgery required Sweden to achieve gross total excision. More study is needed. OBJECTIVE: Lesionectomy is a well-established neurosurgical procedure for treating tumour-related childhood temporal lobe epilepsy. In some of these cases histopathology reveals glioneural tumours such as ganglioglioma and DNET. We made a retrospective study of children with these tumour P-OUT.08. THE RELATIONSHIP BETWEEN SOCIAL diagnosis in Uppsala during 1990-2008, in order to evaluate preoperative COMMUNICATION DISORDERS AND AGE AT DIAGNOSIS FOR neuroradiological findings and outcome after surgery. METHODS: CHILDREN WITH BRAIN TUMOURS Medical records and neuroradiological examinations were reviewed for all D. Gumley, P. Lurie, K. Phipps, and C. de Sousa; Great Ormond Street children with ganglioglioma or DNET operated in Uppsala. RESULTS: 27 Hospital for Children NHS Trust, London, United Kingdom patients with a histopathological diagnosis was found, 20 gangliogliomas, 3 infantile desmoplastic gangliogliomas and 4 DNETs. Male/female ratio BACKGROUND: As more children survive into adult life, the focus is on was 1.1:1. All patients had neuroimaging performed, preoperatively with measuring outcomes in terms of cognitive profiles and social and emotional CT/MR or both and postoperatively with MR in order to evaluate radicality.

NEURO-ONCOLOGY † JUNE 2010 ii113 Abstracts

Mean age at surgery was 11:1 years. 70% of the tumours were temporal, P-OUT.13. GONADAL TOXICITIES IN EMBRYONAL BRAIN 30% extratemporal. 24 children had complex partial seizures with or TUMOR SURVIVORS TREATED ON THE SJMB96 TRIAL without secondary generalisation. 13 children had medically intractable sei- INCLUDING RISK ADAPTED CRANIOSPINAL AND zures. Gross total resection (GTR) was achieved in 18/27, subtotal resection CONFORMAL PRIMARY-SITE IRRADIATION AND HIGH DOSE (STR) in 7/27 and 2 children were just biopsied. Tumour recurrence with CHEMOTHERAPY WITH STEM CELL RESCUE malignant progression occurred in 1 patient, who developed a glioblastoma M. D. DeWire1, T. E. Merchant1, C. A. Sklar2, G. T. Armstrong1, multiforme and died. At follow-up after . 5 years in most cases, 15/18 chil- A. Broniscer1, E. B. Morris1, I. Qaddoumi1, J. Shelso1, S. Lesh1, D. Wallace1, dren with GTR were seizure free, compared to 3/7 with STR. Post-operative and A. Gajjar1; 1St. Jude Children’s Research Hospital, Memphis, TN, complications were seen in 3. CONCLUSION: Gangliogliomas and DNETs United States; 2Memorial Sloan-Kettering Cancer Center, New York, NY, are low-grade tumours that seldom undergo malignant progression in chil- United States dren. In most cases these tumours give rise to seizure disorders, which in many cases are medically intractable. Outcome for these children is related PURPOSE: To estimate the overall incidence of precocious puberty and to seizure control, which is achieved by GTR if possible. gonadal failure in a cohort of children with embryonal brain tumors treated identically with a risk- adapted craniospinal irradiation (CSI), conformal primary site irradiation, followed by high dose chemotherapy. PATIENTS AND METHODS: Clinical data and hypothalamic-pituitary Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 axis radiation dosimetry were obtained from 71 eligible children (27 P-OUT.11. OUTCOME OF AND PREDICTORS OF SEIZURES IN females and 44 males). Precocious puberty was evaluated in patients diag- LONG-TERM SURVIVORS OF PEDIATRIC BRAIN TUMORS nosed with CNS tumors prior to age 8 years in females and age 9 years in N. J. Ullrich1,2, S. L. Pomeroy1,2, P. Manley3,2, C. Chordas2, and males. Of the 27 females, 13 patients were eligible for assessment of preco- T. Loddenkemper1; 1Department of Neurology, Children’s Hospital Boston, cious puberty. Fourteen of the 44 males were eligible for evaluation. Delayed Boston, MA, United States; 2Pediatric NeuroOncology, Dana-Farber Cancer puberty was evaluated in patients diagnosed with CNS tumors prior to age Institute, Boston, MA, United States; 3Department of Hematology/ 13 years in females and 14 years in males. Eighteen females and 26 males Oncology, Children’s Hospital Boston, Boston, MA, United States were evaluated for delayed puberty. All eligible patients received endocrine follow up upon the completion of high dose chemotherapy and were evalu- PURPOSE: Seizures are common during and after treatment for a primary ated by laboratory gonadal hormonal data in addition to clinical obser- brain tumor. The goal of this study is to estimate the incidence of seizures in vation. RESULTS: The overall incidence of precious puberty in females survivors of pediatric brain tumors and to determine risk factors for poor and males at an average of 4 years from diagnosis was 7.7% and 14.3%, seizure control. PATIENTS AND METHODS: In a retrospective, cross- respectively. Delayed puberty occurred in 16.7% of females and 7.7% of sectional study, we reviewed all patients evaluated during a 12-month males. Primary ovarian failure, confirmed by elevated FSH and LH for period who were at least two years after completion of treatment for a age, was 48% in 27 eligible female patients. CONCLUSION: Children CNS tumor. Clinical data, length of follow up, imaging studies, treatment with embryonal CNS tumors have a significant risk for treatment-related modalities were collected. For patients with seizures, we noted frequency, hormone deficiencies, including gonadal deficiency. This is the largest anticonvulsant use and seizure outcome. RESULTS: Patient cohort included uniform treated cohort evaluating the impact of therapy on gonadal func- 298 patients. Average age at tumor diagnosis was 7.6 years and mean follow tion. up 7.6 years. Initial surgical resection was gross-total in 110 patients, and subtotal for 143. Tumor localization included posterior fossa (35%), midline (33%), cortical (28%) and other (4%). Most frequent pathologies P-OUT.14. ECHOCARDIOGRAPHIC FINDINGS FOLLOWING included low grade glioma, medulloblastoma and ependymoma. Recurrent TREATMENT FOR CHILDHOOD MEDULLOBLASTOMA: A tumors occurred in 91 patients. 71 patients experienced seizures; 36/71 SINGLE CENTER’S EXPERIENCE were medically refractory, with failure of two anticonvulsants and failure C. Chordas1, M. Zimmerman1, M. W. Kieran1,2, S. N. Chi1,2, M. Lee1,2, to be . 6 months seizure free two years after seizure diagnosis. Risk N. Robison1,2, N. Stratton1, L. Goumnerova1,3, N. J. Ullrich1,4, factors for seizures included tumor location (cortical), tumor histology K. J. Marcus5,6, and P. E. Manley1,2; 1Pediatric Neuro-Oncology, (glial/glial-neuronal), tumor recurrence and incomplete initial resection. Dana-Farber Cancer Institute, Boston, MA, United States; 2Hematology/ Cortical location, recurrence of tumor and pathology were all risk factors Oncology, Children’s Hospital Boston, Boston, MA, United States; for refractory seizures. Age at diagnosis and treatment regimen did not 3Neurosurgery, Children’s Hospital Boston, Boston, MA, United States; predict seizures at any time. CONCLUSIONS: Seizures are a frequent 4Neurology, Children’s Hospital Boston, Boston, MA, United States; comorbidity in pediatric brain tumor survivors. Factors most predictive of 5Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, United poor seizure control included tumor location and presence of residual tumor. States; 6Radiation Oncology, Children’s Hospital Boston, Boston, MA, United States

PURPOSE: Photon spinal radiation used in the treatment of medulloblastoma in children includes a portion of the heart in the treatment field. P-OUT.12. A TERTIARY CARE HOSPITAL’S Potential late effects may include left ventricular scarring and dysfunction, NEURO-ONCOLOGY PROGRAM EXPERIENCE WITH HIGH valvular damage, and atherosclerosis. PATIENTS AND METHODS: DOSE CHEMOTHERAPY FOR CNS TUMORS Between 1982 and December 2008, 133 patients were evaluated or treated M. S. Hemenway, N. K. Foreman, and J. R. Madden; The Children’s for medulloblastoma at DFCI/CHB. A retrospective chart review was con- Hospital, University of Colorado Denver, Aurora, CO, United States ducted on living patients who received photon craniospinal irradiation and had an evaluable echocardiogram (n ¼ 38). Data was extracted after High dose chemotherapy regimens followed by autologous stem cell rescue approval from the IRB. The photon dose to the spine was greater than are a frequently utilized method of treatment for patients under three years 30Gy in 34% (n ¼ 13). Echocardiograms were done in 68% of survivors old, those with high grade tumors, and for relapsed tumors. The between 5 and 15 years (n ¼ 26) off therapy. RESULTS: All patients had neuro-oncology program at a tertiary care hospital has performed autolo- normal findings on examination. Echo reports showed that the shortening gous bone marrow transplants (BMT) for 68 patients between September fractioning was greater than 28% in 95% (35/36). Of patients who had 1995 and May 2009. The patients’ age at time of first BMT was 3.9 years left ventricular ejection fraction evaluated 96% had a value greater than old (range from 0.4 to 28.3 years old). The diagnoses included medulloblas- 55% (23/24). Asymptomatic decline in left ventricular function was toma, primitive neuroectodermal tumor, germinoma, non-germinomatous reported in four patients who received greater than 30 Gy described as bor- germ cell tumor, high grade tumor NOS, atypical teratoid rhabdoid derline contractility and function (n ¼ 1), mild reduction in thickness (n ¼ tumor, choroid plexus carcinoma, glioblastoma multiforme, anaplastic 1), and moderate reduction in cavity size (n ¼ 2). CONCLUSIONS: While astrocytoma grade III, peripheral nerve sheath tumor, and desmoplastic clinically evident heart disease is rare in this cohort, subclinical findings infantile ganglioglioma. At follow-up in January 2010, 23 of the 68 trans- may indicate additional cardiac assessment in a subset of patients. Other car- planted patients were alive. In patients less than 3 years old at the time of diovascular risk factors need to be considered such as family history, dyslipi- transplant, 13 of 28 (46%) were alive. In patients greater than or equal to demia, hypertension, smoking, obesity, growth hormone deficiency and 3 years old, 10 of 40 (25%) were alive. Of those patients who were other endocrinopathies. Education and counseling should be provided tar- treated at diagnosis as their initial therapy, 16 of 44 (36%) were alive. geting these areas. Further evaluation of cardiac function and risk factors Seven of 24 (29%) patients treated at relapse were alive. The outcomes for in this cohort is warranted. the under 3 year olds were encouraging. The outcomes for children over the age of 3 were less satisfactory. We are exploring factors relating to outcomes in the over 3 year olds to potentially change eligibility criteria for bone marrow transplant.

ii114 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P17 NEUROIMAGING treatment-related morbidity. Microhemorrhage (MCH) is commonly observed on follow-up MRI, but the incidence is not well known. We studied the effect of patient age and RT dosage on the rate of MCH. METHODS: A retrospective cohort study of 89 patients undergoing serial surveillance MRI for treated MB since 1998 was performed. Of those, 47 (ages 1-21 years; median 7.4 P-IMAG.01. INTRA-OPERATIVE MRI FOR PAEDIATRIC BRAIN years) had 486 exams (median follow-up 4 years) with at least two T2* post- TUMOURS - INITIAL EXPERIENCE WITH A DEDICATED treatment sequences. Patients were classified into (a) early age at RT (1 to 6 HIGH-FIELD (3T) SYSTEM years, n ¼ 20) vs. late age at RT (7 to 21 years, n ¼ 27) groups, and (b) 1 1 1 1 2 C. Mallucci , S. Avula , L. Abernethy , R. Al-Mahfoudh , M. Jenkinson , low-dose RT (1800-2340 cGy, n ¼ 22) vs. high-dose RT (2920-3960 cGy, 1 1 1 J. Gooden , and B. L. Pizer ; Alder Hey Children’s Hospital, Liverpool, n ¼ 25) groups. T2*-detectable MCH was tallied by a pediatric neuroradiolo- 2 United Kingdom; Walton Centre for Neurology and Neurosurgery, gist. Incidence rate ratios (IRR) were calculated for age at RT and RT dosage by Liverpool, United Kingdom negative binomial regression. RESULTS: The annual rate of MCH occurrence was higher for the late age at RT group (3.18 vs. 0.82, IRR ¼ 3.76, 95% CI: INTRODUCTION: The degree of tumour excision has been shown to be a 1.96-7.24, p , 0.0001). Higher RT dosage alone was not significantly associ- major prognostic factor in the majority of paediatric CNS tumours. The use ated with higher MCH rate (2.08 vs. 2.29, IRR ¼ 0.94, 95% CI: 0.50-1.76, of Intra-operative MRI (IoMR) and advanced neuroimaging has, however, p ¼ 0.841). There was significant overdispersion (alpha ¼ 1.02, 95% CI: Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 only been well documented in adult neuro-oncology with little evidence for 0.64-1.62, p , 0.0001), indicating that MCH rates varied for reasons in their use in children. We describe our initial experience with intra-operative addition to age at RT. CONCLUSION: Children treated for MB at older ages 3T MRI to aid neurosurgery for paediatric brain tumours. METHODS: Since had a significantly higher risk of MCH. Radiation dose and younger age did September 2009, a Philips Achieva 3T XL MRI scanner has been used for not contribute to MCH rate. intra-operative scanning at Alder Hey Children’s Hospital. The scanner is co-located with the neurosurgical operating suite, which is equipped with a BrainLAB image-guided navigation system. RESULTS: We are currently under- taking1-2 tumourexcisions each week using IoMR. Data is presented regarding the indications for use of IoMR as well as outcomes, paying particular attention P-IMAG.04. NEUROMETABOLIC LONG-TERM ALTERATIONS to the effects on surgical planning and the intraoperative identification of OF SUPRATENTORIAL NORMAL-APPEARING CEREBRAL tumour. The technical considerations are also reported, together with the PARENCHYMA IN CHILDREN AFTER TREATMENT FOR MRI sequences used. Of the first 14 operations, 2 cases had confirmed unex- POSTERIOR FOSSA TUMORS AS DETECTED BY MR PROTON pected residual disease leading to further resection and avoiding subsequent SPECTROSCOPY second look surgery. All patients had diagnostic quality scans at the end of S. M. Rueckriegel1,2, P. Hernaíz Driever1, and H. Bruhn1; surgery confirming the final surgical result. CONCLUSIONS: In addition to 1Charite-Universita¨tsmedizin Berlin, 13353 Berlin, Germany; the avoidance of potentially harmful but necessary second look surgery, the 2Universita¨tsklinikum Wu¨ rzburg, Wu¨ rzburg, Germany ability to acquire intra-operative (pre-closure) high resolution scans also avoids the need for delayed post-operative imaging to assess extent of resection Pediatric posterior fossa tumor survivors suffer from significant motor and and offers the chance for immediate reassurance of patients and parents that the cognitive sequelae. Different therapy-associated and tumor-related effects lesion has been excised. like hypoperfusion, internal hydrocephalus, chemotherapy, and irradiation add together to a high neurotoxic impact on these patients. Proton MR spectroscopy (MRS) is a noninvasive tool to assess pertinent neurometabolic alterations by measuring several parenchymal metabolites of white matter (WM) and grey matter (GM) in vivo. In this study 15 patients with pilocytic P-IMAG.02. HIGH-DOSE BUSULFAN-THIOTEPA WITH astrocytoma (PA, WHO I) who were treated by resection only, 24 patients AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) AND with medulloblastoma (MB, WHO IV) who received chemotherapy and cra- RADIATION THERAPY: GUILTY BY ASSOCIATION? niospinal irradiation in addition, and 34 control subjects were included for L. Negretti, E. Benhamou, J. Habrand, F. Dhermain, D. Valteau-Couanet, MRS of parietal normal-appearing WM and GM. Concentrations of J. Grill, and C. Dufour; Institut Gustave Roussy, Villejuif, France N-acetyl aspartate (NAA) were significantly decreased in WM (p , 0.0009) and GM (p , 0.0009) of patients followed up after medulloblas- PURPOSE: To evaluate radiological lesions occurring in children with brain toma and in GM (p , 0.0009) only of those after pilocytic astrocytoma tumors treated with high-dose busulfan-thiotepa, ASCT and radiotherapy when compared to the control subjects. Young age at diagnosis significantly (RT). PATIENTS AND METHODS: Charts of 111 children (81 medulloblas- correlated with age-corrected levels of GM creatines in both MB patients tomas / PNET, 14 ependymomas and 16 high-grade gliomas) were reviewed. (Pearson’s correlation, two-tailed, p ¼ 0.009, r ¼ 0.52) and PA patients Treatment consisted of surgery and chemotherapy, followed by one cycle of (p ¼ 0.006, r ¼ 0.7). A long time since diagnosis was significantly correlated 2 2 high-dose busulfan (480 or 600 mg/m ) and thiotepa (720 or 900 mg/m ) with low age-corrected NAA levels in WM of PA patients (p ¼ 0.008, r ¼ with ASCT, preceded or followed by focal RT (50.4-55 Gy) or craniospinal 0.66). Since NAA is involved in myelination and myelin lipid turnover and RT (25-35Gy) with a tumor bed boost (20-30 Gy). 30/111 patients were represents an important marker for neuronal viability and number. The treated at diagnosis (13 medulloblastomas/PNET, 1 ependymoma and 16 high- observation of constantly decreased levels of neuroaxonal NAA in the grade gliomas) and 81/111 at relapse (68 medulloblastomas / PNET, 13 epen- follow-up of these patients implies a permanent loss of neuroaxonal tissue. dymomas). RESULTS: 23 patients (19 medulloblastomas, 1 PNET, 3 ependymomas) developed radiological lesions with a median delay of 6 months (range 1-109 months) after radiotherapy. Brain lesions were characterized by abnormal contrast enhancement with a punctiform or giriform aspect without mass effect. The lesions were limited to the irradiation field. 11/23 P-IMAG.05. MAGNETIC RESONANCE SPECTROSCOPY patients were symptomatic. These lesions resolved, spontaneously or after cor- BIOMARKERS PREDICT OUTCOME IN PAEDIATRIC BRAIN ticosteroids in 9 patients with a median time of 10 months (range 2-17 months) TUMOUR PATIENTS after onset. 6/23 patients experienced local or metastatic recurrence 8 months M. Wilson1,2, C. L. Cummins2, L. MacPherson2, Y. Sun1,2, K. Natarajan1,3, to 7.7 years after diagnosis. At last update 41/111 children were alive in com- T. N. Arvanitis2,4, R. A. Kauppinen5, and A. C. Peet1,2; 1Cancer Sciences, plete remission, 17 of whom presented with radiological lesions. University of Birmingham, Birmingham, United Kingdom; 2Birmingham CONCLUSIONS: The lesions described are due to the combined therapy, as Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom; they are not seen with either busulfan-thiotepa or radiotherapy alone. In light 3Imaging & Medical Physics, University Hospital Birmingham NHS of these results, refinement of the dose and volume of RT is discussed. Foundation Trust, Birmingham, United Kingdom; 4School of Electronic, Electrical & Computer Engineering, University of Birmingham, Birmingham, United Kingdom; 5Department of Radiology, Dartmouth College, Hanover, NH, United States P-IMAG.03. EFFECT OF PATIENT AGE AND RADIOTHERAPY DOSAGE ON THE INCIDENCE OF MAGNETIC RESONANCE Brain tumours cause the highest mortality rate of all childhood tumours IMAGING (MRI) DETECTED MICROHEMORRHAGE and new predictive biomarkers of tumour outcome would aid clinical man- FOLLOWING TREATMENT FOR PEDIATRIC agement. 1H magnetic resonance spectroscopy (MRS), allows the non- MEDULLOBLASTOMA invasive measurement of lipid and metabolite quantities offering the poten- S. Partap, J. K. Rosenburg, N. Telischak, Y. Minn, P. G. Fisher, tial to provide novel molecular biomarkers of prognosis. The aim of this M. S. B. Edwards, P. D. Barnes, and K. Yeom; Stanford University, Stanford, study was to investigate whether MRS biomarkers measured at diagnosis CA, United States can predict the outcome of paediatric brain tumour patients. Short echo time (30ms) single voxel spectroscopy was performed on 155 patients with a PURPOSE: Medulloblastoma (MB) is a malignant pediatric brain tumor suspected brain tumour prior to treatment and LCModelTM wasusedtoesti- requiring radiation therapy (RT) for cure. Survival is associated with significant mate metabolite and lipid quantities. All tumours in the cohort were included

NEURO-ONCOLOGY † JUNE 2010 ii115 Abstracts

in the study. 41 patients were excluded from the analysis for poor data qualityor low grade and 44 high grade cases remained. Glycine concentrations were non-involved brain within the voxel. Patients were followed-up for a mean significantly higher in high grade vs low grade tumours (P , 0.0001, period of 40 months and Cox-Regression was used to build a model of survival mean + standard error was 3.0 + 0.4 and 0.7 + 0.2 respectively). The area for MRS detectable molecules. High tumour lipids and scyllo-inositol and low under the ROC curve was 0.79 with an optimised cut-off giving a sensitivity glutamine were found to be biomarkers of poor prognosis. The combination of of 82% and specificity of 71%. Most of the low grade tumours with high glutamine, scyllo-inositol and lipids was optimal for predicting overall survival estimated glycine concentration were WHO grade II and behaved aggres- (p ¼ 0.0197). Lipids alone were also predictive of overall survival (p ¼ 0.049) sively. CONCLUSIONS: Glycine is a biomarker of malignancy in childhood and Kaplan-Meier plots revealed their concentration had an inverse relation to brain tumours that can be measured non-invasively using MRS and should survival. Glutamine alone was found to be a significant predictor of be evaluated as a prognostic indicator. progression-free survival (p ¼ 0.011). MRS detectable lipids and metabolites can predict outcome in paediatric brain tumour patients. These biomarkers offer additional information that could be used to guide clinical management and improve molecular understanding of these diseases. P-IMAG.08. ALTERATION OF P53, BCL-2, CASPASE-3, O6-METHLYGUANINE-DNA METHYLTRANSFERASE AFTER TREATMENT AND CORRELATION WITH PERFUSION MRI IN Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 HUMAN GLIOBLASTOMA P-IMAG.06. NON-INVASIVE DIAGNOSIS OF RELAPSE IN K. Shim; Yonsei university, Seoul, Republic of Korea CHILDHOOD BRAIN TUMOURS USING THE INVARIANCE OF METABOLITE PROFILES AT PRESENTATION AND RELAPSE Glioblastoma is the most common and dismal malignant brain tumor. H. Crosby1,2, N. P. Davies1,3,Y.Sun1,2, L. MacPherson4, M. English4, Treatment protocols have been improved with introduction of temozolomide K. Natarajan1,3, T. N. Arvanitis1,2, R. G. Grundy5, and A. C. Peet1,4; and new irradiation techniques. Temozolomide is under influence of methyl- 1University of Birmingham, Birmingham, United Kingdom; 2Birmingham guanine methyl-transferase (MGMT). The methylation of the CpG island of Children’s Hospital, United Kingdom; 3University Hospital Birmingham, MGMT gene promoter will guarantee the good response of glioblastoma to United Kingdom; 4Birmingham Children’s Hospital, Birmingham, United temozolomide. Because the most popular protocol begins with concomitant Kingdom; 5University of Nottingham, Nottingham, United Kingdom radiation and temozolomide the incidence of early radiation necrosis and pseudoprogression, is increasing. We misinterprate the meaning of tumor BACKGROUND: 1H Magnetic Resonance Spectroscopy (MRS) is a non- cell within the specimen from necrotic tumor which is considered as pseudo- invasive method determining tissue metabolite profiles and a powerful diag- grogression. Will the tumor cell disappear as time goes by? So the real charac- nostic aid. Whilst surgery often provides a tissue diagnosis at presentation, a teristics of the tumor cell within the necrotic tumor will be helpful to non-invasive diagnosis can be preferable at relapse. We compare MRS pro- determine whether or not to continue treatment. This will also be helpful files at diagnosis and relapse to determine whether diagnostic MRS can be when correlating the imaging with these characteristics. In this study we ana- used to aid the diagnosis of relapse. METHODS AND PATIENTS: Single lyzed the most common factors involved in cell cycle or apoptosis p53, Bcl-2, voxel MRS (TE 30ms, TR 1500ms) was performed at diagnosis and relapse caspase-3. MGMT expression will be added to this test as the marker for on 15 children with 8 local and 8 distant relapses. Histology showed: 3 response to temozolomide. Balance between these factors and CBV in per- medulloblastomas, 3 ependymomas, 2 diffuse astrocytomas, 3 glioblastoma fusion MRI will influence the progression of residual tumor and patient sur- multiforme, 2 pineoblastomas and 2 ATRTs. All patients received che- vival. Especially, MGMT was correlated with treatment response and Bcl-2 motherapy and/or radiotherapy. One ependymoma had 4 relapses. MRS influenced the tumor progression. P53 influenced the change of CBV in per- was processed using LCModelTM to yield 15 metabolite and 5 lipid values. fusion MRI. However interrelationship of these factors should be considered An MRS comparator cohort had more than 100 children with non-tumour to influence progression of tumor or survival of patients. conditions. RESULTS: No significant difference existed between diagnostic and relapse MRS in any metabolite or lipid levels (paired T-test, P . 0.05). This held for: all cases; 8 local relapses and 8 distant relapses. All MRS were markedly different from non-tumour controls. With multiple relapses, there were progressive differences in MRS (increasing lipid and P-IMAG.09. APPARENT DIFFUSION COEFFICIENT AND choline/creatine). For 3 patients, the MRI scans were reported as likely PERFUSION MR IMAGING IN THE DIFFERENTATION OF radiotherapy changes or peri-tumoural oedema when MRS was indicative BRAIN NEOPLASTIC AND NON-NEOPLASTIC LESIONS - AN of the presence of active tumour and the subsequent course showed INSTITUTIONAL PRELIMINARY EXPERIENCE tumour progression. CONCLUSION: Tumour metabolite profiles are E. Jurkiewicz, B. Dembowska-Baginska, I. Pakula-Kosciesza, K. Nowak, similar at first relapse to diagnosis aiding interpretation of MRI scans after S. Chelstowska, K. Malczyk, M. Roszkowski, M. Perek-Polnik, treatment. Subsequent relapses can be associated with a more aggressive M. Drogosiewicz, W. Grajkowska, and D. Perek; The Children’s Memorial metabolic phenotype. Health Institute, Warsaw, Poland

BACKGROUND: Diffusion and perfusion weighted imaging are used to evaluate different brain diseases and can be of value in diagnosing patients with brain tumors. The aim of our study was to assess whether introducing P-IMAG.07. GLYCINE AS A POTENTIAL NON-INVASIVE these techniques will add new information to conventional MRI in the diag- PROGNOSTIC BIOMARKER IN CHILDHOOD BRAIN TUMOURS nosis of children with brain tumors. MATERIAL AND METHODS: N. P. Davies1,2, M. Wilson1,3, K. Natarajan2,3, E. Orphanidou-Vlachou1,3, Thirty-six children with brain lesions were studied. In addition to standard Y. Sun1,3, L. MacPherson3, M. A. Brundler3, T. N. Arvanitis4,3, MR imaging diffusion-weighted MRI with apparent diffusion coefficient R. Grundy5,6, and A. C. Peet1,3; 1Cancer Sciences, University of Birmingham, (ADC) maps and perfusion-weighted MRI by using a first-pass gadopente- Birmingham, United Kingdom; 2Medical Physics, UHB NHS Foundation tate dimeglumine T2-weighted gradient echo single-shot echo-planar Trust, Birmingham, United Kingdom; 3Birmingham Children’s Hospital sequence were performed. ADC values and relative cerebral blood volume NHS Foundation Trust, Birmingham, United Kingdom; 4Department of (rCBV) ratios were calculated on the solid portion of the tumor, on peritu- Electrical, Electronic and Computer Engineering, University of Birmingham, moral area, and on the contralateral normal white matter. Results were cor- Birmingham, United Kingdom; 5University of Nottingham, Nottingham, related with pathologic diagnosis. RESULTS: Among the studied patients United Kingdom; 6University Hospital Nottingham, Nottingham, United there were 17 with malignant diseases (7 high grade gliomas, 6 embryonal Kingdom tumors - Medulloblastoma/PNET, 1 CPC, 1 meningeal sarcoma, 1 metastatic neuroblastoma,1 lymphoid granulomatosis), 13 patients with low BACKGROUND: Glycine has been shown in in-vitro studies to be elev- grade tumors (8 low grade gliomas, 5 ependymomas), 3 brain abscesses ated in high-grade adult and paediatric brain tumours and can be measured and 3 focal cortical dysplasias. ADC 1.75 was characteristic for malignant non-invasively using Magnetic Resonance Spectroscopy (MRS). The aim of tumors whereas ADC . 1.1x10-3mm2/s and rCBV ,1.75 were more this study was to measure glycine in paediatric brain tumours using MRS typical for benign lesions. In 24 cases these techniques were more accurate and correlate with grade and clinical behaviour. METHODS: Single-voxel than conventional MRI and were helpful in distinguishing and differentiating MRS (TR/TE 1500/30 ms) was acquired on a clinical 1.5 T MR scanner. between low and high grade tumors. CONCLUSION: Perfusion and diffu- Cubic voxels of side 15 mm (256 averages) or 20 mm (128 averages) were sion weighted MR imaging provide information on brain lesions mor- placed within the solid/enhancing part of the tumour as delineated by phology that are not available with conventional MR imaging. Study MRI. PATIENTS: 123 children (M/F80/43, mean/SD 7.6/4.7 yrs) with a supported by grant R130011 06/2009; Ministry of Science, Poland brain tumour confirmed and graded by histopathology were scanned before treatment (WHO grade I/II, N ¼ 75, WHO grade III/IV, N ¼ 48). MRS was analysed by LCModelTM using a simulated basis set containing 17 metabolites (including glycine) and 9 macromolecular/lipid components. RESULTS: After quality control (SNR . 5, water linewidth , 10 Hz), 48 ii116 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-IMAG.10. METHYL-[11C]-L-METHIONINE (MET) POSITRON Intensifying both chemotherapy and radiation programs has been attempted EMISSION TOMOGRAPHY (PET) FOR THE EVALUATION OF without success. Further characterization of these tumors is needed to PEDIATRIC BRAIN TUMORS-ETHIONINE (MET) POSITRON develop more effective therapies. Positron Emission Tomography (PET) EMISSION TOMOGRAPHY (PET) FOR THE EVALUATION OF with both 18[F] fluorodeoxyglucose (FDG) and 11[C] methionine (CMET) PEDIATRIC BRAIN TUMORS",4] has been used for tumor profiling, detecting residual or recurrent tumors, L. I. Shats1,2, T. D. Victorovich1,2, E. D. Chavpetsova1, G. G. Radulesku1,2, and guiding sterotactic biopsy. OBJECTIVES: To determine if PET can G. V. Kondratiev2, J. A. Konusova2, and M. B. Belogurova1,2; 1City Hospital characterize a specific metabolic pattern of DIPGs and correlate this with 31, St Petersburg, Russian Federation; 2St Petersburg State Pediatric Medical patient survival. METHODS: We performed a retrospective review of Academy, St Petersburg, Russian Federation patients with DIPGs and PET scans performed at diagnosis. Data for FDG and CMET PET scans were collected. Treatment and survival were also METHOD: retrospective review of data in patients with brain tumors reviewed. RESULTS: We identified 30 patients with DIPGs, 25 of whom treated in our institution between 2000 and 2009. RESULTS: Sixty three had FDG and/or CMET PET scans. Scans showed both focal and general- MET-PET scans from 25 patients 2 - 21 years (median of age 7 years) ized metabolic activity. No correlation with survival was noted. The were analyzed. Metabolic characteristics assessed with MET standardized average length of survival from diagnosis for all 30 patients was 358 days. uptake values (SUV). One patient with medulloblastoma died from the Patients with both FDG and CMET positive scans had a mean survival of disease recurrence 6 months after negative PET (at the end of the treatment). 380 days, whereas those negative for both isotopes had a mean survival of Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 In other patient with medulloblastoma SUV was 1,1-1,4 in the time of recur- 446 days. CONCLUSION: No specific pattern was identified in patients rence. In one patient with germ cell tumor SUV was 1,05 at the end of the with metabolically active tumors. This may be due to the lack of power of treatment, later SUV became normal; the residual tumor is visualized by the study. The metabolically active areas may suggest potential sites for MRI during 24 months but without signs of progression. In one patient biopsy. We believe that biopsy is essential for conducting molecular, with glioblastoma after radio/chemotherapy MET-PET was used success- genetic, and biologic studies in hopes of improving therapy for this patient fully to differentiate radionecrosis from the tumor recurrence. All children population. (4 patients) with HGG without MET uptake at the end of the treatment are in remission (follow up 36-40 months). CONCLUSION: Differentiation between malignant lesions and low grade tumors is not always possible. MET- PET is a tool in the detection of tumor recurrence, malignant degeneration and radiation reaction. Negative PET is a significant P-IMAG.13. THERE IS NO ADDITIONAL ROLE FOR FLT-PET/ good prognostic factor during and at the end of a treatment in patients with CT SCAN IN PEDIATRIC BRAINSTEM TUMORS HGG. G. O. R. J. Janssens, C. E. M. Gidding, E. J. van Lindert, J. Schieving, and W. J. Oyen; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

RATIONALE: The combination of short symptom duration, neurological P-IMAG.11. AMINO ACID PET TRACERS IN PAEDIATRIC features and MR-imaging is unable to select the small group of patients with NEURO-ONCOLOGY - PROMISING SINGLE CENTER a potential more indolent tumor arising in the pons. Although recent publi- EXPERIENCE cations suggest limited morbidity and mortality after brainstem biopsy, these C. Rottenburger1, P. T. Meyer1, A. Gupper2, U. Tacke3, K. Storm3,V.van invasive procedures are still reserved to dedicated centers. We tried to Velthoven-Wurster4, T. Reithmeier5, C. Hader6, R. Korinthenberg3, develop a non-invasive method, based on the PET proliferation tracer fluor- W. A. Weber1, and J. Ro¨ ssler2; 1Clinic for Nuclear Medicine, University othymidine ((18)F-FLT PET), to obtain additional information on tumor be- Hospital Freiburg i.Br., Freiburg, Germany; 2Clinic for Paediatric Oncology, havior at diagnosis. MATERIAL AND METHODS: Between October 2006 University Hospital Freiburg i.Br., Freiburg, Germany; 3Clinic for Paediatric and March 2009, five patients (age 3.5-14.0) presenting with a primary Neurology, University Hospital Freiburg i.Br., Freiburg, Germany; 4Clinic pontine lesion, underwent MR-imaging and additional (18)F-FLT PET/ for Neurosurgery, University Hospital Freiburg i.Br., Freiburg, Germany; CT-scan. Three patients with all characteristics of a DIPG, one patient 5Departement of Stereotactic Neurosurgery, University Hospital Freiburg with a diffuse brainstem lesion and symptoms lasting .12 months before i.Br., Freiburg, Germany; 6Neuroradiology, University Hospital Freiburg diagnosis and one patient with a pathology proven pilocytic astrocytoma i.Br., Freiburg, Germany participated in this pilot study. RESULTS: No proliferation activity on (18)F-FLT PET/CT scan was observed in 3 patients without contrast INTRODUCTION: Amino acid (AA) radiotracers for positron emission enhancement on MR-imaging; 2 of them died within 12 months after diag- tomography (PET) are widely used for management of adult brain tumors. nosis. In one patient with DIPG, proliferation activity matched perfectly to However, the use of AA tracers in children and young adults with brain neo- the focus of contrast enhancement on MR-imaging. High uptake on plasms is still uncommon. We report on our experience with AA-PET in pae- (18)F-FLT PET/CT was seen in one patient with a pathology proven pilocy- diatric neurooncology. PATIENTS AND METHODS: Since 2008, 7 tic astrocytoma. CONCLUSION: In our analysis, proliferation activity on AA-PET were performed in 6 patients at the age of 6.6- 15.8 years with (18)F-FLT PET/CT imaging was limited to the focus of blood-brain brain tumors of different histology: 3 low-grade astrocytomas, 1 high-grade barrier disruption on MR-imaging and was unable to differentiate a pathol- glioma, 1 ependymoma, 1 medulloblastoma. Indications were differentiation ogy proven low-grade from high-grade brainstem tumor. Because additional between residual or recurrent tumor and postherapeutic changes, determi- information on tumor behavior at diagnosis by (18)F-FLT PET/CT-scan was nation of tumor activity, distinction between tumor and benign lesion and lacking, this pilot study ended early. extension of residual tumor after surgery. PET scans were performed after injection of 11C-methionine (n ¼ 1) or 18F-fluoroethylthyrosine (n ¼ 6) (measured attenuation correction, 3D mode). Contrast enhanced MRI has been performed in all patients in parallel. RESULTS: AA-PET was helpful for further clinical management in all patients: 3 exams with negative P-IMAG.14. RADIONUCLIDE CSF FLOW STUDIES PRIOR results confirmed the absence of vital tumor tissue after therapy in 3 patients INTRATHECAL CHEMOTHERAPY IN CHILDREN WITH (2 with pronounced radiation induced changes in MRI). 4 exams with posi- RELAPSED OR REFRACTORY BRAIN TUMOURS tive results helped to initiate tumor therapy in 3 patients and close follow-up G. Fleischhack1, S. Reichling1, C. Weber1, M. Zimmermann1, of an active residual tumor in 1 patient. CONCLUSION: AA-PET seems to M. Warmuth-Metz2, S. Ezziddin3, and U. Bode1; 1Dept. of Pediatric be a useful new method in pediatric neuro-oncology that can help to clarify Hematology/Oncology, Medical Center, University of Bonn, Bonn, uncertain situations in brain tumors of different histology. It should be used Germany; 2Dept. of Neuroradiology, University of Wuerzburg, Wuerzburg, in the context of clinical evaluation, MRI exams and an interdisciplinary Germany; 3Dept. of Nuclear Medicine, University of Bonn, Bonn, Germany therapy boards. Leptomeningeal metastases are common in pediatric patients suffering from relapsed or refractory brain tumours. Therefore radionuclide CSF flow studies were recommended prior to intrathecal chemotherapy in patients treated in the HIT-REZ-97 or HIT-REZ-2005 studies. P-IMAG.12. THE USE OF POSITRON EMISSION TOMOGRAPHY Radioisotope CSF flow studies were performed by injecting (PET) IN THE EVALUATION OF DIFFUSE INTRINSIC PONTINE (111)-Indium-DTPA into either the ventricular or lumbar CSF compartment. GLIOMAS IN CHILDREN According to the physiological times to appearance of (111)Indium-DTPA A. Rosenfeld1, M. Etzl1, A. Gieseking1, D. Carpenteri1, D. Bandy2, and the images were obtained every 5 minutes for 60-90 minutes and delayed A. Kaplan1; 1Phoenix Children’s Hospital, Phoenix, AZ, United States; after 24 hours. In the HIT-REZ-97 seven out of 15 patients (47%) with a 2Banner Good Samaritan Hospital, Phoenix, AZ, United States CSF flow study had a documented compartmentalization. Two patients showed an incomplete or complete spinal subarachnoid space block, four BACKGROUND: Diffuse intrinsic pontine gliomas(DIPGs) in children patients had an incomplete distribution in the cerebral subarachnoid space, remain the most difficult tumors to treat and have a very poor prognosis. and enrichment without obstruction was detected in a spinal

NEURO-ONCOLOGY † JUNE 2010 ii117 Abstracts

pseudomyelomeningocele in one patient. In the HIT-REZ-2005 protocol the complications, systemic complications, and overall morbidity and mortality. CSF flow studies were strongly recommended for all patients who enrolled a Various risk factors assessed included clinico-epidemiological, tumor- phase II study for intraventricular therapy with etoposide. In this study the related, and surgery-related factors. RESULTS: There were 44 (68%) supra- CSF flow study was performed in 25 out of 32 eligible patients and revealed tentorial and 21 (32%) infratentorial tumors. Fifty-nine underwent resec- a disturbed distribution in the cerebral subarachnoid space only in one tions (38 supratentorial craniotomies and 21 posterior-fossa approaches). patient. In 3 of 7 patients (43%) without CSF flow study and in 6 out of Fourty-five percent had had prior treatment. Fourteen presented with 25 patients (24%) with CSF flow study the intraventricular therapy has to altered sensorium necessitating emergency surgery. A large proportion be stopped early for toxicity reason or rapid progressive disease. (54%) had a poor KPS (,70). The majority (73%) had large tumors Radioisotope CSF flow studies in patients with leptomeningeal metastasis (.4cm). Significant neurological morbidity, regional, and systemic compli- seem to have practical benefits: the prediction for homogeneous distribution cations occurred in 14%, 20% and 18%, respectively. Overall major mor- of intrathecal chemotherapy and the prediction of rapid leptomeningeal bidity occurred in 24% and the perioperative mortality rate was 10%. disease progression. Children had a higher morbidity than adults undergoing brain tumor surgery. CONCLUSIONS: Our paediatric patients had larger tumors and were more likely to present in poor performance status, often after prior treatment. Despite the unavailability of advanced intraoperative aids we could achieve acceptable levels of morbidity and mortality. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 P-IMAG.15. THE CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) FUNCTIONAL IMAGING E-REPOSITORY FOR CLINICAL TRIALS OF CHILDHOOD BRAIN TUMOURS T. N. Arvanitis1,2, K. Natarajan3, J. Rossiter1, J. I. H. Ting1,4,Y.Sun1,2, M. Wilson1,2, N. P. Davies1,2, E. Orphanidou-Vlachou1,2, R. Grazier2, P-NSX.02. EFFICACY AND RISK OF BRAIN BIOPSIES IN J. Crouch1,2, D. P. Auer5,6, C. A. Clark7, R. Grundy5,6, D. Hargrave8, CHILDREN F. Howe9, T. Jaspan6, M. O. Leach8,10, L. MacPherson2, G. S. Payne8,10, M. von Lehe1, M. Degenhardt1, R. Sassen2, and H. Clusmann1; D. E. Saunders11, and A. C. Peet1,2; 1University of Birmingham, Birmingham, 1Neurosurgery, University Bonn, Bonn, Germany; 2Epileptology, University United Kingdom; 2Birmingham Children’s Hospital NHS Foundation Trust, Bonn, Bonn, Germany Birmingham, United Kingdom; 3University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; 4University of OBJECTIVE: Brain biopsy in children is rarely necessary and little is Wolverhampton, Wolverhampton, United Kingdom; 5University of known about its efficacy and risk. Nevertheless, this invasive diagnostic Nottingham, Nottingham, United Kingdom; 6University Hospital tool is essential for treatment planning in some conditions. METHODS: Nottingham, Nottingham, United Kingdom; 7University College London, Seventy-four brain biopsies were performed in 71 children and adolescents London, United Kingdom; 8Royal Marsden Hospital, London, United (mean 7.9 years, range 4 months to 17 years) between 1990 and 2009: Kingdom; 9St George’s Hospital Medical School, London, United Kingdom; Thirty-four children (47%) had tumors in eloquent areas or multilocular 10The Institute of Cancer Research, London, United Kingdom; 11Great tumors; 33 (46%) had suspicion of encephalitis; 4 (6%) patients had disse- Ormond Street Hospital, London, United Kingdom minated lesions in the MRI and epileptic seizures; one patient suffered from status epilepticus with normal MRI. RESULTS: 90% of all biopsies Novel imaging techniques, used to support the clinical understanding of were for supratentorial lesions and 43% were stereotactically guided (18% tumour properties, are playing an increasing role in tumour characterisation frameless/open, 25% frame-based needle biopsy). Post-operatively, 6% and assessment. However, incorporating functional imaging into clinical had local complications (e.g. liquor fistula); 4% had transient and 3% had trials presents particular challenges due to the lack of standardisation in permanent new neurological deficits. One patient died from tumor bleeding data collection, quality control and analysis. Furthermore, there is an ever- two days after stereotactic biopsy of a large glioblastoma in the basal ganglia. increasing need for expert analysis of novel imaging data, which may only Two patients had immediate re-biopsy because of inconclusive histopathologi- be available at a remote location. The establishment of secure, cal results; one patient had a re-biopsy after 27 months for a recurrent tumor. internet-accessible research data repositories can provide a solution to this Overall, 75% of all biopsies provided a definite diagnosis. In 30 of 34 patients problem. We have developed an e-Repository, made of a remote data entry the suspected tumor was confirmed or specified (88%), whereas suspected system and an associated database, for functional imaging data used in clini- encephalitis was proven in 22 of 33 patients (67%, p , 0.01). cal trials for children with brain tumours. The database is accessible through CONCLUSION: In selected pediatric patients brain biopsies can be performed a secure shell connection on a web browser, allowing role based access acceptably safe. Open procedures seem to be without a significant higher risk control for the addition, editing and reviewing of data by principal investi- than frame-based guided needle biopsies. In case of suspected tumor the diag- gators, study coordinators, data managers, and researchers through remote nostic yield is higher than in patients with suspected encephalitis. access. Clinical and laboratory data as well as conventional and functional imaging data (DICOM images and raw MRS data), are contained within the database. Currently there exist 232 cases in the repository. Furthermore, all data are made available for both central and remote processing, through the use of integrated automated data processing software. P-NSX.03. TRANSVENTRICULAR BIOPSY OF BRAIN TUMOR Extra functionality has been built to allow uploading research image sets WITHOUT HYDROCEPHALUS USING NEUROENDOSCOPY onto Picture Archiving and Communications Systems (PACS), allowing WITH NAVIGATION their use for the purposes of central radiological review. The overall design H. Shin, D. Kong, J. Kim, and M. Jeon; Department of Neurosurgery, of the e-Repository has been made to be modular and expandable to accom- Sungkyunkwan University School of Medicine, Samsung Medical Center, modate future plans for data growth. Seoul, Republic of Korea

PURPOSE: It is usually difficult to perform the neuroendoscopic procedure in patients without hydrocephalus because of presumed difficulties with ven- P18 NEUROSURGERY tricular cannulation. The purpose of this study was to describe the value of navigation guided neuroendoscopic biopsy in patients with peri- or intraventricular tumors without hydrocephalus. METHODS: During the last 2 years, 6 patients with brain tumors without hydrocephalus underwent P-NSX.01. PERIOPERATIVE OUTCOMES FOLLOWING navigation-guided neuroendoscopic biopsy. The procedure was indicated SURGERY FOR PEDIATRIC BRAIN TUMORS - OBJECTIVE for verification of the histological diagnosis of the neoplasm, which was ASSESSMENT AND RISK FACTOR PREDICTION planned to be treated by chemotherapy and/or radiotherapy as first line treat- A. Moiyadi and P. Shetty; Neurosurgical services, Department of Surgical ment, or establishment of the pathological diagnosis for further choice of the Oncology, Tata Memorial Centre, Mumbai, India most appropriate treatment strategy. RESULTS: Under the guidance of navigation, targeted lesion was successfully approached in all patients and the BACKGROUND: Perioperative outcomes following surgery for brain intended goal was accomplished. Navigational tracking was helpful in enter- tumors are an important endpoint to be considered in any study assessing ing small ventricles and in approaching the third ventricle when the foramen of efficacy of surgical intervention providing a feedback for care provided, Monroi was narrow. The histopathologic diagnosis was established in all of and objective documentation for comparision in various trials. We document the 6 patients: 3 germinomas, 2 astrocytomas, 1 dysembryoplastic neuroe- ¼ our experience at a tertiary care referral, dedicated neuro-oncology centre in pithelial tumor. The tumor biopsy sites were ventriclular wall (n 3), surpra- ¼ ¼ India. MATERIALS AND METHODS: Sixty-five children (of 276 patients) sellar area (n 2), and subcallosal area (n 1). There were no operative undergoing various surgeries for brain tumors were analyzed over a period of complications related to the endoscopic procedure. CONCLUSION: 3 years from a prospectively maintained database which exhaustively docu- Endoscopic biopsy or resection of peri- or intra-ventricular tumors in patients mented the epidemiological, clinical, radiological, operative and periopera- without hydrocephalus is feasible. Image-guided neuroendoscopic procedure tive events. Endpoints assessed included immediate postoperative improved the accuracy of the endoscopic approach and minimized brain neurological status, neurological outcome at discharge, regional ii118 NEURO-ONCOLOGY † JUNE 2010 Abstracts

trauma. The absence of ventriculomegaly in patients with a brain tumor signiﬁcant morbidity related to surgery. One patient required reoperation should not be served as a contraindication to endoscopic tumor biopsy. for symptomatic residual tumor. The average follow-up period was 6.3 years. All patients are leading active and independent lives. Radical surgery for pineal region epidermoid tumors is rewarding and long term outcome is usually excellent.

P-NSX.04. ENDOSCOPIC BRAIN SURGERY A. Musharbash; Jordan University & King Hussein Cancer center, Amman, Jordan P-NSX.07. SURGICAL PATHWAY AND MANAGEMENT OF AIM: To present our experience in brain endoscopy in 46 patients with a PINEAL REGION TUMOURS IN CHILDREN total of 49 procedures in a variety of pediatric brain pathologies over a period R. Al-Mahfoudh1, T. Kenney2, J. Goodden1, M. Lee3, M. Jenkinson3, of 5 years. PATIENTS: Mean age was 6.1 years, hydrocephalus was present B. Pizer1, and C. Mallucci1; 1Alder Hey Hospital, Liverpool, United in 23 patients, intracranial cyst in 11 patients, tumors in 10 patients, and Kingdom; 2Liverpool University, Liverpool, United Kingdom; 3The Walton slipped shunts in 2 patients. RESULTS: We will present the pathological var- centre for Neurology and Neurosurgery, Liverpool, United Kingdom ieties and the complications reaching up to 30% The most common compli- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 cations were failure of fenestration and infection 8%, followed by CSF leak BACKGROUND: Pineal region tumours are rare, accounting for around 5 in 4%, subdural hygroma in 4%, subdural hematoma in 2%, intraoperative % of childhood brain tumours. Surgery has traditionally been associated bleeding in 2%, and seizures in 2%, with no mortality. CONCLUSIONS: with high morbidity and mortality, and historically there has been some With the availability of better endoscopes, improved lighting and increased reluctance to undertake resection of tumours in this area. METHODS & instrumentation, brain endoscopy is now safer and more frequently used PATIENTS: Patients with pineal, tectal plate, midbrain, and posterior for a variety of brain pathologies in experienced hands. third ventricular tumours were identified from the neuro-oncology database, casenotes retrieved and retrospectively reviewed. Data collected included presentation, germ cell markers, tumour size and location, imaging, histology, treatment, and control/relapse rates. RESULTS: Thirty patients were treated at Alder Hey Children’s Hospital between 1998 and 2010. P-NSX.05. TRANSCALLOSAL INTERFORNICEAL APPROACH Median age at diagnosis was 12y 7m (range 3y 6m to 17y). Twenty-one TO A TUMOR IN THE THIRD VENTRICLE: A CASE REPORT patients (70%) presented with hydrocephalus. Eighteen were successfully M. Tsujimoto1,2, N. Morota1, N. Araki1, and S. Ihara3; 1Department of treated with endoscopic third ventriculostomy, with the remainder requiring Neurosurgery, National Children’s Medical Center, Tokyo, Japan; shunt insertion. Seventeen patients (57%) had endoscopic biopsies, 14 of 2Department of Neurosurgery, National Toyohashi Medical Center, Aichi, which were at the same time as third ventriculostomy (71% diagnostic). Japan; 3Department of Neurosurgery, Tsukuba University, Ibaraki, Japan Eight (27%) had stereotactic biopsies (100% diagnostic). No morbidity or mortality was associated with endoscopic or stereotactic procedures. OBJECTIVE: Surgical resection of a tumor in the third ventricle remains a Thirteen tumours underwent resective surgery via an appropriate midline challenge for neurosurgeons. We report on the usefulness of a transcallosal approach, taking into account the morphology and anatomy of each interforniceal approach applied for a child who had a cavum septi pellucidi, tumour. Significant tumour debulking was achieved in all patients, with a septum pellucidum that has a separation between its two leaflets containing gross total resection in 70%. There was one intraventricular haemorrhage cerebrospinal fluid. CASE: A 6-year-old boy presented with headache, vomit- (full recovery) and one mild hemiparesis. There was no surgical mortality. ing, and seizures and was transferred to a local hospital where a CT scan CONCLUSIONS: A multi-disciplinary approach is required for this hetero- revealed a huge third ventricular tumor with hydrocephalus. The tumor genous group of paediatric tumours. The mainstay of hydrocephalus man- was 40x35mm in size on an axial MRI view occupying the third ventricle. agement is endoscopic third ventriculostomy. In our experience, There was CSF space between the tumor and the optic chiasm. A transcallo- craniotomy and tumour resection is effective and safe. sal interforniceal approach was the choice of surgical approach because of the presence of a cavum septi pellucidi. The corpus callosum was opened, and wide exposure of the dorsal aspect of the tumor enabled a gross total resection of the tumor. The histology of the tumor was diffuse astrocytoma grade 2. No adjuvant therapy was indicated and the boy remained tumor free P-NSX.08. OUTCOME FOLLOWING SKULL BASE SURGERY IN for 1 year after surgery. CONCLUSION: Surgical indication of transcallosal CHILDREN: A 10 YEAR REVIEW interforniceal approach seems to be quite limited in order to avoid damage to C. Hayhurst, D. Williams, D. Richardson, P. May, B. Pizer, and the bilateral fornix. Presence of a cavum septi pellucidi opens the way to C. L. Mallucci; Alder Hey Children’s NHS Foundation Trust, Liverpool, direct approach to the third ventricle with minimum risk for damaging the United Kingdom fornix. Since the cavum septi pellucidum often remains in childhood, the approach could be applied more frequently for pediatric patients with BACKGROUND: Skull base tumors in children are rare but require third ventricular lesions. complex approaches with potential morbidity to the developing craniofacial skeleton in addition to tumour related morbidity. Reports of long term outcome and functional outcome following skull base approaches in children are scarce. We report long-term outcome in children with tumours undergoing multidisciplinary skull base surgery. METHODS: A retrospective P-NSX.06. EPIDERMOID CYST OF THE PINEAL REGION. analysis of children undergoing surgery in a single institution between SURGICAL EXPERIENCE IN 14 CASES 1998 and 2008, for benign and malignant lesions of the anterior, middle D. Muzumdar and A. Goel; Seth Gordhandas Sunderdas Medical College or posterior cranial base was undertaken. Craniopharyngioma, pituitary and King Edward VII Memorial Hospital, Mumbai, India, MUMBAI, India tumors and optic glioma were excluded. Histology, surgical morbidity, length of hospital stay, progression free survival and adjuvant therapy Pineal region epidermoid tumors are rare. They have a propensity to were recorded. Functional and cognitive outcome was assessed prospec- invade into crevices and spread in the subarachnoid spaces. Consequently, tively. RESULTS: 24 children, aged 13 months to 15 years, underwent they tend to be large in size at diagnosis and have subtle symptomatology. skull base approaches for resection of tumours during the study period. The surgical approach includes infratentorial-supracerebellar and the pos- Median follow up is 42 months. Tumour types include meningioma, schwan- terior parietooccipital interhemispheric route. Radical excision of the noma, rhabdomyosarcoma, neuroblastoma, angiofibroma and chordoma. pineal region epidermoid tumors is advocated and is possible. The long Complete resection was achieved in 15 (62.5%) patients. 14 (58.3%) had term outcome of radically resected tumors is excellent. Fourteen six cases benign histology. Median hospital stay was 8 days. There were 2 deaths, 1 of pineal region epidermoid cysts were surgically treated over the past 16 peri-operative. 2 patients had CSF leak (8%) and 2 developed meningitis years (1992-2008). A retrospective analysis is presented. The average age (8%). 3 patients (12.5%) have residual neurological deficit at last follow of presentation was 12 years and duration of complaints was 9 months. up. 13 children went on to adjuvant therapy (54%). The majority remains Headaches and ataxia were commonest complaints. The infratentorial in mainstream education, one patient has memory loss and hypopituitarism. supracerebellar route was used predominantly in 12 patients. Total excision CONCLUSIONS: Children tolerate complex skull base procedures well, of tumor was carried out in 12 patients while near total excision was per- with minimal surgical related morbidity and good long term functional out- formed in 2 cases. Dissection around vital neurovascular structures in the comes. Tumour histology is the main determinant of outcome. vicinity precluded radical excision in the remainder cases. Transient Parinaud’s syndrome was seen in three patients but resolved completely at followup. One patient who had mild residue developed postoperative meningitis, hydrocephalus, tonsillar herniation and cervicodorsal syringomyelia in the immediate postoperative period. Ventriculoperitoneal shunt was required in one patient postoperatively. There was no mortality nor any

NEURO-ONCOLOGY † JUNE 2010 ii119 Abstracts

P-NSX.09. JUVENILE XANTHOGRANOLUMA OF THE SKULL P-NSX.12. SURGICAL SIMULATION OF PEDIATRIC BRAIN BASE IN AN INFANT TUMORS USING VOLUME RENDERED 3D RECONSTRUCTION S. Candela1, M. Alamar1, G. Garcia-Fructuoso1, I. Catala2, C. Rovira3, WITH FUSION IMAGES OF MULTIPLE HIGH-RESOLUTION 3D J. Muchart4, E. Lopez5, O. Cruz5, A. Guillen1, and J. Costa1; 1Neurosurgery, MR IMAGING TECHNIQUES Hospital Sant Joan De Deú, Barcelona, Spain; 2Neurosurgery, Hospital Sant A. Gomi, H. Oguma, T. Annou, Y. Kawamura, S. Miyata, H. Fujii, A. Fujita, Pau, Barcelona, Spain; 3Pathology, Hospital Sant Joan De Deú, Barcelona, and T. Aihara; Jichi Medical University, Tochigi, Japan Spain; 4Radiology, Hospital Sant Joan De Deú, Barcelona, Spain; 5Pediatric Oncology, Hospital Sant Joan De Deú, Barcelona, Spain OBJECTIVES: To determine the value of surgical simulation of pediatric brain tumors using volume rendered 3D reconstruction with fusion images INTRODUCTION: Juvenile Xanthogranuloma (JXG) is a acquired from multiple high-resolution 3D magnetic resonance (MR) non-Langerhans histiocytosis. Extracutaneous manifestations and solitary imaging modalities. METHODS: Surgical simulation with volume rendered bone lesions are very rare. We report the case of an infant with a solitary 3D reconstruction has been applied at our institution since November 2007 JXG of the skull base. CASE REPORT: A 3-months-old child presented to 11 pediatric patients (age range, 1-13 years; mean, 7 years) with brain with a rapid growing mass in the retromastoid area. CT and MRI showed tumors (4 germ cell tumors, 1 ependymoma, 4 medulloblastomas, 1 atypical an intracranial retromastoid lytic lesion with destruction of petrous bone teratoid rhabdoid tumor and 1 dysembryoplastic neuroepithelial tumor). All and occipital condyle and hydrocephalus secondary to a mass-effect over MR images of the patients were acquired using a 1.5-T scanner. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 the IV ventricle. A confirmative biopsy was taken followed by a radical High-resolution anatomical 3D MR images, MR angiographic and macroscopic resection of the mass, completely extradural. There were no contrast-enhanced MR venographic images were simultaneously acquired. postoperative complications and hydrocephalus resolved during the next All 3D sequences were constructed by submillimeter isovoxel acquisition. days. After a one year follow-up, the baby is asymptomatic and disease-free. Specific image datasets of the patients were co-registered and fused by the CONCLUSION: After a revision of the literature, we think it is important to workstation. Volume rendered 3D reconstruction of the fusion images was per- include JXG in the differential diagnosis of intracranial lytic lesions in chil- formed using a different workstation to maximize the visualization of tumors dren, since surgical treatment may be curative. and important surgical landmarks such as arteries, veins and ventricles. RESULTS: High-resolution 3D images reconstructed using datasets acquired from multiple imaging modalities clarified relationships between tumors and surgical landmarks such as surrounding arteries and veins, ventricles and cisterns. The use of other sequences, such as fluid-attenuated inversion recovery, P-NSX.10. MAY NEUROENDOSCOPY HAVE A ROLE ON as additional input provided clearer images of less enhanced tumors. All surgi- POSTERIOR FOSSA MEDULLOBLASTOMA STADIATION IN cal procedures were safely completed with minimal complications. CHILDREN? CONCLUSION: We recommend surgical simulation with 3D MRI volume B. Spacca1, F. Giordano1, I. Sardi2, L. Sardo1, M. Scagnet1, R. Mura1, rendered fusion images to achieve good outcomes for pediatric patients. F. Mussa1, and L. Genitori1; 1Department of Paediatric Neurosurgery, “Anna Meyer” Children’s Hospital, Florence, Italy; 2Department of Paediatric Oncology, “Anna Meyer” Children’s Hospital, Florence, Italy

Prognosis of posterior fossa medulloblastoma strongly improved over P-NSX.13. SAFETY AND COMPLICATION RATE ASSOCIATED the past decades in term of survival, although there is still a high cost in WITH OMMAYA RESERVOIRS IN PATIENTS RECEIVING term of quality of life. This happened thanks to a better understanding RADIOIMMUNOTHERAPY (RIT) FOR CENTRAL NERVOUS of the biology of the tumor and administration of chemotherapy with or SYSTEM (CNS) MALIGNANCIES without radiotherapy tailored according to the disease status. The role M. Smith, K. Kramer, and M. M. Souweidane; Memorial Sloan-Kettering of surgery in newly diagnosed medulloblastomas is both to deal with Cancer Center, New York, NY, United States the tumor, with the aim of a gross total resection, and the associated complications. A common presentation is triventricular hydrocephalus. In our BACKGROUND: We reviewed the safety and complication rate associ- institution of Pediatric Neurosurgery at the “Anna Meyer” Children’s ated with ventricular access devices in patients receiving RIT for CNS Hospital in Florence, Italy, endoscopic third ventriculostomy (ETV) is tumors. PATIENTS AND METHODS: 100 patients with recurrent always the first choice of treatment in these cases. Out of ninety-four primary or metastatic CNS tumors (60 males, 1-63 years) had a ventricular patients admitted between 1995 and 2009 for medulloblastomas, twenty- access device (92 Ommaya reservoirs, 8 VP shunts with programmable six (27.6%) presented with hydrocephalus treated with ETV. In eight of valves) placed for RIT drug administration and cerebrospinal fluid (CSF) them (30.7%) during the endoscopic procedure the walls of the lateral acquisition. Patients received 2-5 serial injections 124I- or 131I- labeled ventricles and/or of the third ventricle appeared covered by multiple monoclonal antibody 3F8 or 8H9. For each injection, catheters remained small whitish dots suggestive of metastatic disease. After major surgery accessed for pharmacokinetic studies up to 48 hours or were individually one was staged as M0 and started on standard risk treatment, three as accessed 3-6x/injection. Thereafter catheters were accessed for periodic M1 and four as M3 and started on high risk treatment. At last follow routine cytology. RESULTS: Six patients (6%) had complications including up (mean, 22.7 months) two had died of disease, two were alive with 3 with catheter migration in the newly- placed setting requiring surgical revi- disease progression and four had no evidence of disease. Even if this is a sion. Three patients had pericatheter cyst formation (with cyst formation small group it appears that there is a strong correlation between the find- before RIT administered in 1 patient) resulting in elective removal and endo- ings observed at endoscopy and the disease status. scopic cystoventriculostomy in 2 patients. There were no catheter-related infections, hemorrhages, seizures, focal deficits, or valve malfunctioning. Four patients later required Ommaya conversion to VP shunts because of hydrocephalus secondary to p disease progression. CONCLUSION: This is the largest series reporting the safety of ventricular access devices in patients P-NSX.11. THE TREATMENT ON HYPOTHALAMIC receiving RIT. Minimal acute complications are observed despite the fre- ASTROCYTOMA OF CHILDREN IN MICROSURGERY BY quency of CSF acquisition; long term complications are rare. TRANSCALLOSAL-INTERFORNICEAL APPROACH Programmable VP shunts are a safe and effective alternative to Ommaya Z. Ma; Beijing Tiantan Hospital, Beijing, China catheters.

OBJECTIVE: To explore the clinical features,diagnosis and efﬁciency of microsurgical treatment on hypothalamic astrocytoma in children by transcallosal interforniceal approach. METHODS: A total of 42 pediatric cases P19 CRANIOPHARYNGIOMA of hypothalamic astrocytoma were operated by transcallosal-interfomiceal approach.All eases received post-operative radiotherapy and follow up visits.The clinical and imaging data were analyzed retrospectively. P-CRANIO.01. RANDOMIZED MULTICENTER TRIAL ON RESULTS: High ICP and hypothalamic lesions were the main clinical PATIENTS WITH CHILDHOOD CRANIOPHARYNGIOMA manifestations.All patients suffering from hydrocephalus were operated by (KRANIOPHARYNGEOM 2007) - UPDATE AFTER 27 MONTHS transcallosal interfomiceal approach.17 cases received subtotal resection OF RECRUITMENT and 25 in partial resection. None was deceased. All cases received post- U. Gebhardt1, S. Schro¨ der1, F. Pohl2, R. Kortmann3, I. Zwiener4, operative radiotherapy.29 cases were followed up from 1 to 7 years (Mean A. Faldum4, M. Warmuth-Metz5, T. Pietsch6, G. Calaminus7, R. Kolb1, 50 months).Of all the cases,25 recovered to a normal life and 4 could take C. Wiegand8,N.So¨ rensen8, and H. L. Mu¨ ller1; 1Department of Pediatrics care of themselves. CONCLUSIONS: Hypothalamic astrocytom in children and Pediatric Hematology / Oncology, Klinikum Oldenburg gGmbH, have some features in clinical manifestations and radiology.Microsurgery by Oldenburg, Germany; 2Department of Radiotherapy, University Hospital, transcallosal interfomiceal approach is an effective method on treating hypo- Regensburg, Germany; 3Department of Radiotherapy and Radiooncology, thalamic astrocytoma in children.Radical resection is not imperative and the University Leipzig, Leipzig, Germany; 4Institute for Medical Biometrics, radiotherapy should be strongly recommended. Epidemiology and Informatics, University of Mainz, Mainz, Germany; ii120 NEURO-ONCOLOGY † JUNE 2010 Abstracts

5Department of Neuroradiology, University Wu¨ rzburg, Wu¨ rzburg, P-CRANIO.03. ENDOSCOPIC CYST FENESTRATION Germany; 6Department of Neuropathology University of Bonn, Bonn, FOLLOWED BY GAMMA KNIFE RADIOSURGERY AS A Germany; 7Department of Pediatric Hematology and Oncology, University RADICAL TREATMENT OF CYSTIC CRANIOPHARYNGIOMA of Mu¨ nster, Mu¨ nster, Germany; 8Department of Neurosurgery, B. I. G. Gustavsson1 and E. Ulfarsson2; 1Dept of Neurosurgery; Karolinska Evangelisches Krankenhaus, Oldenburg, Germany University Hospital, Stockholm, Sweden; 2Dept of Neurosurgery, Landspitali, Reykjavik, Iceland Despite high survival rates (92%) in patients with childhood craniopharyngioma (CP), quality of life (QoL) is frequently impaired due to sequelae To diminish the risk of long time adverse effects after the treatment of cra- such as severe obesity resulting from hypothalamic involvement of CP. niopharyngioma, we initiated a treatment plan for patients presenting with Based on the results of the multicenter prospective study raised ICP due to mainly cystic craniopharyngioma. The cysts was fene- KRANIOPHARYNGEOM 2000 radical surgery is no appropriate treatment strated endoscopically, up front, to relieve the mass effect, get a histological strategy in patients with hypothalamic involvement. Furthermore, tumour diagnosis and to resituate the CSF-circulation. An MRI was done 4-6 months progression/relapses are frequent early events in CP patients. The analysis following the cyst fenestration to control the residual solid part of the tumour of event-free survival-rates (EFS) in 117 prospectively evaluated patients and the remnants of the cyst walls. At this time a GKRS was scheduled to give with CP showed a high rate of early events in terms of tumour progression a high enough dose to treat the tumour radical. The first patient was treated after incomplete resection (EFS:0.31 + 0.07) and relapses after complete for the cyst 2003 followed by a gamma knife treatment six months later. At Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 resection (EFS:0.63 + 0.09) during the first three years of follow-up. that time it was possible to cover the residual solid part of the tumour, Accordingly, in KRANIOPHARYNGEOM 2007 QoL, and survival rates including the cyst walls, with a low dose 8 Gy to the tumour border. The in CP pts (.5yrs at diagnosis) are analyzed after randomization of the volume treated was small and the risk for radiation necrosis minimal and time point of irradiation (XRT) after incomplete resection (immediate with such a low dose the risk for the optic apparatus was acceptable. The XRT versus XRT at progression of residual tumour). Up to now (12/09) patient has now been followed for six years without recurrence. At latest 52 pts with CP were recruited (28 pts in the randomization arm; 19 pts in follow up there was no significant visual defect and just growth hormone the surveillance arm; 5 pts in the process of review of imaging). 10 of 28 substitution. The two following patients are treated during the last year pts were randomized. 7 pts could not be randomized due to parental and again show that the cyst walls fell down to the lower part of the third decision, late schedule (7 pts) and due to decision of the physician (4 pts). ventricle and made it possible to give GKRS with low risk of sequele from In conclusion, KRANIOPHARYNGEOM 2007 represents the first random- the vital surrounding brain structures. ized trial in CP and the first study in pediatric neurooncology analyzing QoL as an endpoint. Aim of the study is to analyze the appropriate time point of XRT in order to improve QoL in patients with hypothalamic involvement.

P-CRANIO.04. OUTCOMES OF PEDIATRIC CRANIOPHARYNGIOMA TREATED WITH PROTON RADIATION THERAPY P-CRANIO.02. NEUROSURGICAL HYPOTHALAMIC LESIONS A. L. Chang, J. Bratton, M. Fitzek, and A. Thornton; Midwest Proton AND POSTOPERATIVE OUTCOME IN CHILDHOOD Radiotherapy Institute, Bloomington, IN, United States CRANIOPHARYNGIOMA - RESULTS OF THE MULTINATIONAL PROSPECTIVE TRIAL PURPOSE/OBJECTIVE(S): Craniopharyngiomas constitute approximately KRANIOPHARYNGEOM 2000 8% of childhood brain tumors. Although they are benign without potential for U. Gebhardt1, S. Schro¨ der1, F. Pohl2, R. Kortmann3, I. Zwiener4, spread, they can lead to significant morbidity from mass effect. Gross total A. Faldum4, M. Warmuth-Metz5, T. Pietsch6, G. Calaminus7,N.So¨ rensen8, resection of craniopharyngiomas is curative, however, this is not often poss- C. Wiegand8,R.Kolb1, and H. L. Mu¨ ller1; 1Department of Pediatrics and ible due to the proximity of critical structures. Conventional external beam Pediatric Hematology / Oncology, Klinikum Oldenburg gGmbH, radiation therapy improves the chances of local control. This is an update of Oldenburg, Germany; 2Department of Radiotherapy, University Hospital, outcomes of patients with craniopharyngioma treated at the Midwest Proton Regensburg, Germany; 3Department of Radiotherapy and Radiooncology, Radiotherapy Institute (MPRI) with proton radiation therapy (PRT). University Leipzig, Leipzig, Germany; 4Institute for Medical Biometrics, MATERIALS/METHODS: From 2004 through 2008, 14 patients with cra- Epidemiology and Informatics, University of Mainz, Mainz, Germany; niopharyngioma have been treated at MPRI. They ranged in age from 5 to 19 5Department of Neuroradiology, University Wu¨ rzburg, Wu¨ rzburg, years of age (median 13.5 years) at time of treatment. Each patient had path- Germany; 6Department of Neuropathology University of Bonn, Bonn, ology proven craniopharyngioma after biopsy or surgical resection. Germany; 7Department of Pediatric Hematology and Oncology, University Radiation was delivered in a daily fractionated rate of 1.8 Cobalt Gray of Mu¨ nster, Mu¨ nster, Germany; 8Department of Neurosurgery, Equivalent (CGE) per fraction, 5 fractions per week to a total of median Evangelisches Krankenhaus, Oldenburg, Germany 54.0 CGE (range 50.4 - 57.6 CGE). Post-radiation therapy imaging and records were reviewed for outcome. RESULTS: At a mean followup of 25 Multivariable analyses of risk factors and descriptive analyses of overall months (range 13 - 48 months), local control is 100%. There have been no (OS) and event-free-survival (EFS) rates were performed in 117 patients deaths. There was no difference in outcomes regardless of extent of from Germany, Austria and Switzerland, recruited prospectively surgery nor number of surgical resection. Vision has stabilized or improved (2001-2006) and evaluated after 3 yrs of follow-up in all patients. None had further decline of visual symptoms after radiation (KRANIOPAHRYNGEOM 2000). Body-mass-index (BMI) and QoS therapy. CONCLUSIONS: Proton radiotherapy after minimal surgical resec- (PEDQOL) at diagnosis, 12 and 36 mo after diagnosis were analyzed in tion results in excellent control of craniopharyngioma. The treatment is well relation to neuroradiological reference assessment of tumour localization tolerated with minimal complications. Further follow-up is needed to deter- and a score of post-surgical hypothalamic damage (anterior, posterior or mine neuro-cognitive outcomes. no hypothalmic lesions). We observed a 3-yrs-OS of 0.97 + 0.016 and a 3-yrs-EFS of 0.50 + 0.05, indicating high recurrence rates after complete resection (CR) (n ¼ 47;3yrs-EFS:0.63 + 0.09), and high progression rates after incomplete resection (IR) (n ¼ 66;3-yrs-EFS:0.31 + 0.07). The risk of an event decreased by 80% after CR compared to IR (HR ¼ 0.20;p , P-CRANIO.05. ASSESSMENT OF QUALITY OF LIFE AND 0.001). Irradiation (XRT) had protective effects von EFS. XRT-patients EXECUTIVE FUNCTIONS IN CHILDREN TREATED BY had an 88% lower risk of progression compared to patients without/ PROTON BEAM THERAPY FOR CRANIOPHARYNGIOMA before XRT (HR ¼ 0.12;p , 0.001). Growth hormone therapy had no BETWEEN 1995 AND 2007 impact on 3-yrs-EFS. BMISDS at diagnosis was similar in patients without C. Laffond1, G. Dellatolas2, S. Puget3, C. Alapetite4,5, J. Grill6, J. Habrand5, and with hypothalamic involvement of anterior/posterior hypothalamic F. Doz7, and M. Chevignard1,8; 1Rehabilitation department for children with areas. Surgical lesions of posterior hypothalamic areas were associated acquired brain injuries; Hoˆ pital National de Saint Maurice, Saint Maurice, with increases in BMI-SDS during the first 12 mo (+2.2BMISDS;p , 0.01) France; 2Rene´ Descartes University; FRE 3292-CNRS, Boulogne Billancourt, and 36 mo (+3.2BMISDS;p , 0.01). Postsurgical QoS deteriorated in France; 3Pediatric neurosurgery department, Hoˆ pital Necker Enfants patients with posterior hypothalamic lesions. Postoperative increases of Malades, Paris, France; 4Radiation oncology department, Institut Curie, BMI (.2SD) were associated with lowest QoS. We conclude that tumour Paris, France; 5Medical division, proton beam therapy center of Institut recurrences/progressions occur early after initial treatment of craniopharyn- Curie, Orsay, France; 6Pediatric oncology department, Institut Gustave gioma. Growth hormone therapy had no impact on high recurrence/pro- Roussy, Villejuif, France; 7Pediatric oncology department, Institut Curie, gression rates observed during short-term follow-up. A radical surgical Paris, France; 8ER-6, Pierre et Marie Curie university, Paris, France strategy leading to damage of posterior hypothalamic areas is not recommended. XRT was efficient in preventing recurrences/progressions. PURPOSE: Although childhood craniopharyngioma is a benign tumour with a good survival rate, neurocognitive and psychological morbidity is important and reduces quality of life (QOL). The aim of this retrospective study was to analyse QOL, mood disorders, everyday executive functioning

NEURO-ONCOLOGY † JUNE 2010 ii121 Abstracts

(EF) and disease’s impact on family life in 29 patients consecutively treated BMI was 52.1 leading to severe orthopedic problems and considerable mobi- for childhood craniopharyngioma by surgery combined with proton beam lity restrictions. The girl ﬁnally started stealing sweets to manage excessive therapy between 1995 and 2007. METHODS: Assessment included a semi- food cravings and developed a reactive depression. At this time a ﬁrst structured interview and standardised scales evaluating self-report of QOL attempt of bariatric surgery was made, but the gastric band had to be (Kidscreen 52) and depression (MDI-C), and proxy reports of QOL removed due to hemorrhagic gastritis. At the age of 16 years the patient (Kidscreen 52), EF (BRIEF) and disease’s impact. Univariate analyses were underwent laparoscopic gastric bypass surgery including truncal anterior performed. RESULTS: Mean age at diagnosis was 7.8 + 4.1 years; mean vagotomy. BMI prior to surgery was 61.8. Over the following six months follow-up period was 6.2 + 4.5 years since diagnosis and 4.1 + 2.9 years she achieved an impressive loss of BW (BMI at last follow-up: 46.7) resulting since the end of the proton beam therapy. Twenty-three answers were in improved physical mobility and quality of life. The patient is still managed obtained (80%). Overall QOL self report was within the average range, by a multidisciplinary team aiming at further reducing her BW. Bariatric but 50% of the patients judged “social support and peers” dimension surgery has to be considered in children with brain tumors and extreme affected. QOL proxy report was lower than self report. Half of the patients hypothalamic obesity (BMI .35), when conventional interventions are not reported depression. A third of the patients had possible cognitive dysfunc- successful. tions according to the BRIEF scale. 56% of the families felt “very concerned” by the disease. Depression, low parental educational level and child school grade were associated with lower QOL and/or executive dysfunctions. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 DISCUSSION: Morbidity associated with childhood craniopharyngioma is high, regardless of the treatment. Screening for psychosocial outcome, cogni- P-CRANIO.08. APPETITE REGULATING HORMONE CHANGES tive functioning (especially EF) and QOL should be systematic and include IN PATIENTS WITH CRANIOPHARYNGIOMA ecological measures, in order to develop focused interventions. K. Otten1, U. Gebhardt1, S. Schro¨ der1, C. L. Roth2, and H. L. Mu¨ ller1; 1Department of Pediatrics and Pediatric Hematology / Oncology, Klinikum Oldenburg gGmbH, Oldenburg, Germany; 2University of Washington, Seattle Children’s Hospital Research Insitute, Seattle, WA, United States

P-CRANIO.06. VISUAL OUTCOMES IN PEDIATRIC Patients with craniopharyngioma (CP), an embryological tumor located in CRANIOPHARYGIOMAS: OUR EXPERIENCE the hypothalamic and/or pituitary region, often suffer from uncontrolled D. Gogi, O. Nelson, S. Bansal, J. Norris, R. Pilling, S. Picton, and eating and severe obesity. We aimed to compare peripherally secreted hor- I. Simmons; St. James’s University Hospital, Leeds, United Kingdom mones involved in controlling food intake in lean and obese children and adolescents with CP versus controls. Plasma insulin, glucose, total ghrelin and PURPOSE: Craniopharyngioma is the most common non-glial brain peptide-YY (PYY) levels were assessed under fasting conditions as well as tumour in children. 70% of patients have visual disturbance or visual field 60 minutes after liquid mixed meal in four groups: Lean (n ¼ 12) and obese loss at presentation. We present our experience of monitoring visual function (n ¼ 15) CP patients, and 12 lean and 15 obese otherwise healthy BMI-, in children with craniopharyngioma over a five year period. SETTING: A ter- gender- and age-matched controls. Homeostasis assessment of insulin resist- tiary referral teaching hospital in UK. METHODS: Cases were identified ance (HOMA-IR), as well as quantitative insulin sensitivity check index through the pediatric oncology database as patients attending the joint pedi- (QUICKI) were calculated. Obese CP subjects had significantly higher atric ophthalmology-neurooncology clinic. RESULTS: Ten patients were HOMA-IR, higher baseline and post-meal insulin but lower ghrelin levels, identified. The mean follow up was 70 months (range 12-132). Two were weaker post-meal changes for PYY, and lower QUICKI compared to obese registered blind, five had moderate visual acuity and/or field loss and three controls. QUICKI data from all CP patients correlated positively with had normal vision and field at most recent assessment. Five had hypothala- ghrelin and PYY % post-meal changes (ghrelin: r ¼ 0.38, p ¼ 0.023; PYY mic involvement which conferred no worse visual prognosis. Those present- r ¼ 0.40, p ¼ 0.017) and negatively with standard deviation score BMI ing with poor vision or visual field loss were unlikely to recover. Those with (SDS-BMI: r ¼ -0.49, p ¼ 0.002). Tumor growth of 87% obese and 58% of good vision at presentation had this preserved. Two children with recurrent lean CP patients affected the hypothalamic area which was associated with cysts underwent progression loss of vision or field. Only one child had serial higher SDS-BMI and weaker % post-meal ghrelin changes (p ¼ 0.014) com- colour vision and contrast sensitivity measurements. These showed slow pared to CP patients without hypothalamic tumor involvement. Blunted post- improvement after radiotherapy. CONCLUSIONS: This is the first report meal ghrelin and PYY responses in obese CP subjects are likely due to their of visual outcomes in craniopharyngioma in the United Kingdom. There higher degree of insulin resistance and lower insulin sensitivity compared to are limitations in assessing visual acuity and fields particularly in young chil- matched obese controls. Thus, insulin resistance in CP patients seems to dren and those having recently undergone surgery. Our small cohort of affect eating behavior by affecting meal responses of gut peptides. patients has shown that children under the age of 6 years have poorer visual outcome. Serial visual acuity & visual field assessment is a good tool to identify recurrence of tumour post surgery. Serial colour vision & contrast sensitivity measurements show a trend towards slow improvement post treatment P-CRANIO.09. PERIPHERAL ALPHA-MELANOCYTE STIMULATING HORMONE (a-MSH) IN CHILDHOOD OBESITY AND CRANIOPHARYNGIOMA K. Otten1, U. Gebhardt1, T. Reinehr2, P. J. Enriori3, M. A. Cowley3, C. L. Roth4, and H. L. Mu¨ ller1; 1Department of Pediatrics and Pediatric P-CRANIO.07. IMPRESSIVE WEIGHT REDUCTION Hematology / Oncology, Klinikum Oldenburg gGmbH, Oldenburg, FOLLOWING LAPAROSCOPIC GASTRIC BYPASS SURGERY IN A Germany; 2University of Witten/Herdecke, Vestische Children Hospital 16-YEAR-OLD GIRL WITH SUPRASELLAR Datteln, Witten/Herdecke, Germany; 3Oregon Health and Science CRANIOPHARYNGIOMA AND EXTREME HYPOTHALAMIC University, Division of Neuroscience, National Primate Research Center, OBESITY Beaverton, OR, United States; 4University of Washington, Seattle Children´ s K. Wiegele1, G. Prager2, M. Benesch1, A. Nebl1, H. Lackner1, M. Mokry3, Hospital Research Institute, Seattle, WA, United States E. Suppan4, and C. Urban1; 1Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Alpha-melanocyte stimulating hormone (a-MSH), posttranslational University of Graz, Graz, Austria; 2Division of General Surgery, Department product of the POMC prohormone and the pituitary melanotrophs, is con- of Surgery, Medical University of Vienna, Vienna, Austria; 3Department of sidered to be the major source of circulating a-MSH. Recent evidence Neurosurgery, Medical University of Graz, Graz, Austria; 4Division of shows that a-MSH plays a role in thermal regulation by increasing free General Pediatrics, Department of Pediatrics and Adolescent Medicine, fatty acid oxidation (FAO) and glucose uptake in skeletal muscle via acti- Medical University of Graz, Graz, Austria vation of MC5R through the PKA-AMPK pathway. In this study, we aimed to investigate peripheral a-MSH levels in 1) obese children 2) lean Craniopharyngioma is a benign intracranial tumor involving the sellar or children, 3) children with hypopituitarism, 4) patients with craniopharyn- less commonly the supra- or infrasellar region. Hypothalamic obesity is a gioma (CP) to study the role of peripheral a-MSH in obesity and CP. CP major therapeutic challenge in patients with craniopharyngioma. A patients were recruited in HIT-Endo, KRANIOPHARYNGEOM 2000/ 10-year-old girl (BMI: 15.9 [25th percentile]) presented with recurrent head- 2007. We measured fasting a-MSH, leptin, insulin and glucose. aches and vomiting. Neuroimaging revealed a predominantly suprasellar cra- Interestingly, in patients with hypopituitarism or CP very low a-MSH niopharyngioma. After subtotal resection the patient underwent levels were measured (healthy:26.6fmol/ml vs hypopituitarism:8.4fmol/ml conventionally fractionated local radiotherapy. Postoperatively a combined vs craniopharyngioma:7.7 fmol/ml). Compared to patients with simple stimulation test revealed complete anterior pituitary insufficiency. Despite obesity, patients with CP presented with lower (p , 0.001) fasting serum appropriate hormone replacement BMI dramatically increased over a a-MSH levels, but there were no differences in terms of a-MSH levels period of five years (BMI 24 months after the end of radiotherapy: 45.1). between obese and lean children. Low a-MSH levels in CP did not increase Sibutramine, dietary interventions and intensive psychological therapy one hour after a 500kcal mixed-liquid meal. CP patients had higher fasting could not stop further gain of body weight (BW). At the age of 15 years insulin, insulin resistance index HOMA and leptin levels compared to ii122 NEURO-ONCOLOGY † JUNE 2010 Abstracts

patients with simple obesity and similar BMI-SDS. The low serum a-MSH P-RTX.03. EARLY POST-CRANIAL IRRADIATION CEREBRAL levels in patient groups, which have low- or non-functioning pituitaries, VASCULOPATHY, HOW SOON DO WE NEED TO WORRY? verify that the pituitary is the critical source for circulating a-MSH. The C. A. Sabapathy, C. Freeman, C. Saint-Martin, J. Atkinson, and N. Jabado; very low a-MSH levels in CP can be explained by their pituitary or hypo- McGill University Hospital Centre, Montreal, QC, Canada thalamic damage and might contribute to severe obesity associated with low thermogenesis. CASE: CNS vascular events are known complications of cranial irradiation. We describe herein a CNS vascular event occurring within 1-year post-cranial irradiation in a child treated for ependymoma. A 3 year-old female with left insular WHO grade III anaplastic ependymoma, P20 RADIOTHERAPY was treated with radiotherapy and surgery. Tumour was intimately associated with the middle cerebral artery (MCA) and despite two resections, macroscopic disease was found at the MCA bifurcation. She subsequently P-RTX.01. PEDIATRIC CRANIOSPINAL AXIS IRRADIATION underwent 59.4Gy tomotherapy. She presented one year post-therapy with WITH HELICAL TOMOTHERAPY: PRELIMINARY RESULTS sudden onset of recurrent transient right hemiparesis. Neurological symp- A. Pica1, M. Beck-Popovic2, N. Von der Weid2, A. Sajadi3, and B. Rilliet3; toms were due to transient ischemic attacks. Angiography confirmed stenosis 1 2 of branch M1 of left MCA with extensive revascularization. Initiation of Radiation Oncology, Lausanne, Switzerland; Pediatric Oncology, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 Lausanne, Switzerland; 3Neurosurgery, Lausanne, Switzerland anti-platelet aggregant therapy (ASA/clopidrogel) led to a decrease in the number of events. DISCUSSION: Strokes are rare events in children and OBJECTIVE: To present the preliminary experience in 6 paediatric studies often show delay in their diagnosis. Although prior studies patients treated with helical tomotherapy for the craniospinal irradiation mostly indicate that cerebral vascular events are late findings post- (CSI) for a variety of neoplasms. MATERIALS AND METHODS: A total radiation therapy, this case indicates that it may occur earlier in the evol- of 6 patients received craniospinal axis with helical tomotherapy between ution of a patient. Therefore, in children with brain tumours who receive October 2007 and August 2009 (3 medulloblastomas, 2 atypical teratoid high-dose of cranial radiation-therapy, and potentially more so in those rhabdoid tumors (ATRT), 1 chordoid rhabdoid meningioma). Five patients where the vasculature was unavoidably close or within the radiation underwent surgical removal of the gross primary tumor achieving a complete field, the index of suspicion for vascular events should be high. In these removal in 3, a partial in 2. One patient underwent biopsy only. Five out 6 cases, especially if the artery was manipulated during surgical resection, patients received chemotherapy according to the histologic diagnosis. A anti-platelet aggregant prophylaxis should be discussed or at least a high CSI dose of 36 Gy was prescribed to the planning target volume (PTV) in index of suspicion for vascular events be present to avoid a delay in diag- 3 patients (high risk medulloblastoma and chordoid meningioma) and nosis that may lead to permanent loss of function. 23.4 Gy in 3 patients (ATRT and low risk medulloblastoma). Patients received a radiation boost to the posterior fossa (55.8 Gy) or tumor bed (59.4 Gy), according to the diagnosis. RESULTS: At the last follow-up, 4 patients are alive without disease and 2 patients are alive with disease. No grade 4 or 5 toxicities were observed. Tomotherapy provided safe dose- P-RTX.04. FAVORABLE OUTCOMES OF PEDIATRIC PATIENTS volume histograms to all organs at risks (OARs), in particular for cochlear TREATED WITH RADIOTHERAPY TO THE CENTRAL doses in patients planned to receive 55.8 Gy in the posterior fossa (Dmean NERVOUS SYSTEM WHO DEVELOP RADIATION-INDUCED 41 Gy), for heart doses (Dmean 8.7 Gy). CONCLUSION: Craniospinal MENINGIOMAS 1 2 1 1 1 axis irradiation using helical tomotherapy is favourable in terms of target T. Galloway , D. Indelicato , R. Amdur , E. Swanson , C. Morris , and 2 1 volume coverage, OARs sparing and image guidance for precise dose R. Marcus ; Department of Radiation Oncology at the University of 2 delivery. Florida, Gainesville, FL, United States; University of Florida Proton Therapy Institute, Jacksonville, FL, United States

PURPOSE: Meningiomas are the most common radiation-induced second tumor of the central nervous system (CNS). This study reports the outcome P-RTX.02. ENDOCRINOLOGIC ASSESSMENT IN PATIENTS of patients treated at the University of Florida who developed meningiomas WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) after radiation to the CNS for childhood cancer. METHODS AND 1 2,3 4 1 1,5 ≤ M. Zimmerman , K. J. Marcus , L. E. Cohen , C. Chordas , S. N. Chi , MATERIALS: We retrospectively identified 10 patients 19 years old who M. Lee1,5, P. E. Manley1,5, N. Robison1,5, N. J. Ullrich1,6, L. Goumnerova1,7, received radiation therapy to sites in the craniospinal axis and subsequently and M. W. Kieran1,5; 1Pediatric Neuro-Oncology, Dana-Farber Cancer developed a meningioma. We report the histology of the radiation-induced Institute, Boston, MA, United States; 2Radiation Oncology, Dana-Farber meningioma, treatment received, and ultimate outcome among this cohort Cancer Institute, Boston, MA, United States; 3Radiation Oncology, Children’s of patients. RESULTS: Meningioma was diagnosed at a median of 23.5 Hospital Boston, Boston, MD, United States; 4Endocrinology, Children’s years after completing the primary radiation. Fifty percent of second menin- Hospital Boston, Boston, MA, United States; 5Hematology/Oncology, giomas were World Health Organization (WHO) grade II (atypical) or Children’s Hospital Boston, Boston, MA, United States; 6Neurology, higher. All cases were managed with a single modality: resection alone, 7; frac- Children’s Hospital Boston, Boston, MA, United States; 7Neurosurgery, tionated radiation therapy, 2; and stereotactic radiosurgery, 1. The actuarial Children’s Hospital Boston, Boston, MA, United States event-free survival and overall survival at 5 years after treatment for a radiation-induced meningioma was 89%. Three patients who underwent PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive resection for retreatment experienced a grade 3 toxicity. CONCLUSIONS: pediatric malignancy that cannot be cured with currently available therapy. Radiation-induced meningiomas following treatment of pediatric CNS Though radiation therapy frequently results in disease stabilization, the tumors are effectively managed with single-modality therapy. Such late-effect majority of patients experience progression and rapidly succumb to data informs the overall therapeutic ratio and supports the continued role of disease. Since dose to the hypothalamus and pituitary regions can be con- selective irradiation in managing pediatric CNS malignancies. siderable, we performed a retrospective chart review of patients seen at the DFCI/CHB for DIPG to assess the dose of radiation to the hypothalamus and pituitary and frequency of endocrinological evaluation. PATIENTS AND METHODS: Between 1994 and 2009, 108 patients were evaluated for the diagnosis of DIPG. Patients receiving focal radiotherapy whose radi- P-RTX.05. THE USE OF GAMMA-KNIFE SURGERY IN ation summaries were available and who had clinical follow-up at DFCI/ PALLIATIVE CARE OF RELAPSING EPENDYMOMAS WITH CHB were included for review. Data was extracted after approval from the DURABLE QUALITY OF LIFE 1 2 3 4 3 1 IRB. RESULTS: A review of the radiation fields demonstrated that over G. Giraud , S. Holm , B. Gustavsson , J. Lundgren , and E. Dodoo ; Dept. 2 90% of patients received a minimum dose of 3000 cGy of radiation to the of Oncology-Pathology, Karolisnka Institutet, Stockolm, Sweden; Dept. of 3 hypothalamus and pituitary. Many patients reported symptoms such as Women and Child Health, Karolinska institutet, Stockolm, Sweden; Dept. 4 fatigue and constipation towards the end of life. The minority of patients, of Neurosciences, Karolinska Institutet, Stockolm, Sweden; Dept. of however, underwent endocrinologic evaluation, despite a median time to Paediatric Neurology, Lund University hospital, Lund, Sweden death of 15 months (range 3-59 months) CONCLUSIONS: Screening for endocrine function is done infrequently despite the significant dose of radi- Ependymomas are the third most common type of CNS paediatric ation delivered to the hypothalamus / pituitary in patients with DIPG. tumours, and are especially prominent in young children , 5 years. Greater attention to endocrine status, despite the terminal nature of this Gamma-knife-based stereotactic radiosurgery (GKNS) could be an alterna- disease, might enhance symptom management towards the end of life and tive to conventional radiotherapy and to second-look surgery in case of improve quality of life for these patients. residual tumour. Less controversial is the use of GKNS in the treatment of relapses, which appears to be a feasible and safe treatment modality. The final aim is to be curative but more realistic is the optimization of the quality of life and palliative care of the patients. We present two cases

NEURO-ONCOLOGY † JUNE 2010 ii123 Abstracts

from the Karolinska University Hospital with the use of GKNS in comp- system (CNS) complications including DI and neurodegeneration should lement of optimal surgery in multi-relapsing tumours. The first case was be monitored. Further studies are required to clarify the role of chemother- operated first in 1994 at the age of five, for a posterior fossa ependymoma apy in prevention of CNS complications. grade II and received conventional fractionated radiotherapy. After the first local relapse in 1999 and during the following 11 years, he underwent totally twelve operations and nine GKNS, in addition with medical treatments, because of local and metastatic relapses. The other patient was first P-RARE.03. HYPOTHALAMIC-PITUITARY TUMORS IN operated in 2002 at the age of 19 months, for a posterior fossa ependymoma LANGERHANS CELL HISTIOCYTOSIS grade II. Originally he underwent a partial resection complemented by che- B. Fahrner1, H. Prosch2, M. Minkov1, M. Wnorowski1, H. Gadner1, motherapy. After the first local relapse in 2004 and during the following 6 D. Prayer3, and N. Grois1; 1St. Anna Children’s Cancer Research Institute, years, he underwent totally four operations and six GKNS, because of Vienna, Austria; 2Sozialmedizinisches Zentrum Baumgartner Ho¨ he, Vienna, local and metastatic relapses. In these two cases presented, the quality of Austria; 3University Clinic of Neuroradiology, Vienna, Austria life was maintained for several years despite relapses and metastases. Langerhans Cell Histiocytosis (LCH) is a rare disease of the dentritic cell system affecting multiple organs. Hypothalamic-pituitary (HP) disease, the

most common CNS manifestation, frequently leads to diabetes insipidus (DI) Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 P21 RARE TUMORS and/or anterior pituitary hormone deficiencies (APD). Furthermore signal changes on magnetic resonance imaging (MRI) in the cerebellum, basal ganglia or pons are found in a number of patients. Some patients also show neu- P-RARE.01. CREATIVE BIOSTATISTICS FOR RARE DISEASES: A ropsychological disabilities. The frequency and the course of HP tumors and NEW BAYESIAN TECHNOLOGY TO MERGE DATASETS neurodegeneration (ND) are not well-understood. In this retrospective survey Y. Yuan1, P. Thall1, S. Berrak2, B. Wrede3, and J. E. Wolff4; 1MDAnderson we focused on patients with clinical and MRI data available at diagnosis of Cancer Center, Biostatistics, Houston, TX, United States; 2Pediatric HP disease and at least 3 follow up investigations. We retrieved clinical and Oncology, Istanbul, Turkey; 3Pediatric Oncology, Regensburg, Germany; MRI follow-up information on 22 LCH patients with HP disease for central 4MDAnderson Cancer Center, Houston, TX, United States review. They had median 6 MRI studies done over a period of median 6 years. At diagnosis the median size of the tumor was 11.5 millimeter. Many Rare tumors cannot be studied using classical phase III designs. Finding a different chemotherapy regimens were applied for variable periods. cure or at least an evidence-based standard of care requires innovative Regression of the tumor was seen in the majority, but all patients had APD or methods based on more sources of information. Here we present a method ND on MRI at last follow up. In none of the patients APD and ND regressed for combining literature based meta-analysis data on 674 patients (J or resolved. A deterioration of the ND imaging findings was noted in 17 Neurooncol 85:345-51) with prospectively collected registry data on 106 patients, leading to overt clinical neuropsychological impairment in five of patients (J Neurooncol 95:383-92) for choroid plexus tumors. Aside from them (30 %). LCH patients with HP tumors appear to be at high risk to administrative censoring, the literature data had overall survival times but develop permanent and severe neuroendocrine consequences. Co-ordinated no disease progression times, hence no event free survival (EFS) times, therapeutic studies for LCH patients with HP disease including thorough while the registry data had both. Because EFS times were needed to design MRI monitoring and neuropsychological tests are needed. the future international protocol CPT-SIOP-2009, the challenge was to combine the information available in both data sets to estimate EFS. For data having these missingship structures, we formulated a family of Bayesian parametric models and derived a statistical method for estimating P-RARE.04. A CASE REPORT OF A PRIMARY BURKITT LIKE the EFS time distribution. The underlying idea is that estimating the associ- LYMPHOMA OF CNS (PCNSLS) IN A 9-YEAR-OLD PATIENT ation between time to progression and subsequent survival time from sub- A. Tragiannidis, Z. D. Pana, V. Tsotoulidou, T. Papageorgiou, and jects having complete data provides a basis for utilizing covariates and F. Athanassiadou-Piperopoulou; AHEPA Hospital, Thessaloniki, Greece partial event time data of other subjects to infer their missing progression times. In the resulting fitted model, the highest hazards were found for BACKGROUND: Burkitt lymphomas constitute tumors that commonly patients with histology ¼ grade III and metastases (beta ¼ 2.25 + 0.87, affect abdominal organs. Few cases of immunocompetent pediatric patients and 1.49 + 1.02, respectively). The relevance of metastatic disease was not with the primary Burkitt type lymphomas of the CNS (PCNSLs) are reported significant in the prospective data only, and only became apparent after in the literature. CASE REPORT: A 9- year- old boy, complaining of frontal merging these two data sets. This confirms that the clinical relevance of headache and vomiting in the last ten days, was admitted to our hospital. this statistical methology. Because of a recent history of sinusitis, the symptoms were attributed to a paranasal infection and the patient received antibiotic therapy. As the symptoms worsened, a funduscopy was conducted, showing bilateral papilledema. Brain imaging detected a mass of the left frontal lobe. A surgical resection was performed and the histological examination revealed P-RARE.02. EXCELLENT LOCAL RESPONSE TO primary Burkitt type lymphoma with expression of Bcl-2. The imaging CHEMOTHERAPY IN PATIENTS WITH INTRACRANIAL control after surgery, showed almost total resection. Postoperatively, his EXTENSION OF CRANIOFACIAL LANGERHANS CELL physical examination revealed right hemiparesis, and speech disorders. The HISTIOCYTOSIS CT scan of chest and abdomen, the ultrasound of abdomen, testicles and 1 1 1 1 2 1 R. Dvir , D. Levin , D. Sayar , Y. Burstein , M. Weintraub , L. Ben-Sirah , bone scan were normal. The CSF and the bone marrow infiltration were 1 1 1 S. Constantini , and R. Elhasid ; Tel-Aviv Sourasky Medical Center, also normal. The patient underwent chemotherapy with BFM-NHL protocol 2 Tel-Aviv, Israel; Hadassah Medical Center, Jerusalem, Israel for pediatric Burkitt’s lymphoma including short courses with VCR, Dexamethasone, MTX, ARA-C, VM16, Ifosfamide and Doxorubicin AIM: A Retrospective review of the role of chemotherapy in children with repeated with an interval of at least 15 days for 4-5 months with concurrent intracranial extension of craniofacial Langerhans Cell Histiocytosis (LCH) radiation (total dose of CNS 3.480cGy). After treatment, MRI revealed no treated in Tel-Aviv Medical Center. PATIENTS: Eleven children with cranio- residual or recurrent lesion. Our patient, one year after the treatment, is facial LCH presented between 1997- 2009. Nine patients had direct intracra- free of disease. CONCLUSION: Primary Burkitt lymphoma of the brain in nial extension. Craniofacial lesions included pre-auricular lesions in 2 children is a rare entity. Total resection, chemotherapy, and radiotherapy patients, orbital lesions in 3 patients, auditory in 2 patients, and multiple were used in the management of this patient’s disease. facial bones in 2 patients. Four of the patients had additional disease sites. The median age at diagnosis was 1.75 years, and the median follow up time was 4 years. TREATMENT: All patients received Vinblastine and Steroids according to LCH 2 and LCH3 protocols. 8/9 children underwent P-RARE.05. UNUSUAL CASE OF ALK-1 POSITIVE PRIMARY biopsy only and were then referred for chemotherapy. All children had excel- CENTRAL NERVOUS SYSTEM ANAPLASTIC LARGE CELL lent local response to systemic treatment. None required surgical interven- LYMPHOMA (PCNSL) IN AN IMMUNOCOMPETENT HIV tion. One child underwent local drainage due to suspected orbital abscess, NEGATIVE CHILD: CASE REPORT AND REVIEW OF but the lesion recurred within two weeks and responded well to chemother- LITERATURE apy. CLINICAL COURSE AND COMPLICATIONS: Three children who S. U. Bochare, V. Subbiah, N. Fitzgerald, G. Fuller, J. Manning, J. Wolff, were diagnosed before the age of 18 months developed diabetes insipidus L. Ketonen, T. Vats, A. Kumar, R. Wells, and M. Rytting; M. D Anderson (DI) 1,2 and 5 years after diagnosis, two of whom developed radiological Cancer Center, Houston, TX, United States neurodegenerative disease. One child developed secondary hemophagocytic syndrome three months after diagnosis and was successfully transplanted BACKGROUND: Primary central nervous system lymphoma (PCNSL) is using an unrelated donor. All but one patient are currently in remission. a very rare brain tumor in children. Because of it rarity, the optimal manage- CONCLUSIONS: Craniofacial LCH can be treated successfully with che- ment and prognosis of pediatric patients are based on a few case reports and motherapy, without a need for surgical intervention. Central nervous ii124 NEURO-ONCOLOGY † JUNE 2010 Abstracts

have yet to be defined. METHODS: We present the clinical, radiological, P-RARE.09. XANTHOGRANULOMA OF THE SELLAR REGION - pathological, immunohistochemical analysis of a case of ALK-1 positive RESULTS OF A MULTICENTER PROSPECTIVE STUDY ON primary central nervous system lymphoma. RESULTS: A 6 year old Arabic DIAGNOSTICS, THERAPY AND PROGNOSIS IN CHILDREN male presented with a 1 week history of headache, high grade fever, new AND ADOLESCENTS onset seizure and right hemiparesis. MRI showed lesion in the brain invol- U. Gebhardt1, S. Schro¨ der1, F. Pohl2, R. Kortmann3, I. Zwiener4, ving the corpus callosum and medial aspect of the frontal lobes. Labs A. Faldum4, M. Warmuth-Metz5, T. Pietsch6,R.Kolb1, G. Calaminus7, showed elevated ESR (30) and LDH (931). A complete infectious disease N. So¨ rensen8, C. Wiegand8, and H. L. Mu¨ ller1; 1Department of Pediatrics panel including HIV, CMV, HHV6, CMV, Brucella, tuberculosis, and Pediatric Hematology / Oncology, Klinikum Oldenburg gGmbH, EBV-PCR, toxoplasma, malaria and fungal cultures were all negative. CT Oldenburg, Germany; 2Department of Radiotherapy, University Hospital, guided stereotactic biopsy showed a malignant neoplasm infiltrating brain Regensburg, Germany; 3Department of Radiooncology, University Leipzig, parenchyma. Immunophenotyping revealed strong tumor cell positivity for Leipzig, Germany; 4Institute for Medical Biometrics, Epidemiology and LCA, CD30 and ALK-1 and reactivity for CD2 and CD3, EMA and Informatics, University of Mainz, Mainz, Germany; 5Department of MIC-2 consistent with ALK-positive anaplastic large cell lymphoma of Neuroradiology, University Wu¨ rzburg, Wu¨ rzburg, Germany; 6Department T-cell origin. Patient was treated based on protocol CCG- 5961 which of Neuropathology University of Bonn, Bonn, Germany; 7Department of includes high-dose-Methotrexate and cytarabine with intrathecal che- Pediatric Oncology, University of Mu¨ nster, Mu¨ nster, Germany; motherapy. DISCUSSION: Other than HIV positive PCNSL, the prognosis 8Department of Neurosurgery, Evangelisches Krankenhaus, Oldenburg, Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 for pediatric patients with this tumor type is significantly better than Germany adults. Most children with PCNSL can achieve long-term remissions with chemotherapy alone without undergoing radiation. Multi-center prospective In KRANIOPHARYNGEOM 2000 117 patients with childhood cranio- studies are warranted to validate these results in a larger number of patients. pharyngioma (CRA) from Germany, Austria and Switzerland were recruited A follow up of the patient will be presented. (2001-2007). Additionally, 14 patients with xanthogranuloma (XTO) were included in our observational study. All patients were prospectively analyzed for clinical manifestations, treatment and prognosis. Histological diagnoses were assessed by a reference panel in all cases. Differences between XTO/ CRA patients were not detectable for gender, age at diagnosis, endocrine P-RARE.06. ATYPICAL LYMPHOPLASMACYTE-RICH deficits, functional capacity at last evaluation and height-SDS and MENINGIOMA IN A CHILD - CASE REPORT body-mass-index-SDS at the time of diagnosis and at last evaluation. H. Chen1, N. Travers2, C. Sainte-Rose3,4, M. Bourgeois3,4, M. Zerah3,4, We observed a 3-year-OS and 3-year-EFS of 1.00 in patents with XTO T. Roujeau3,4, and S. Puget3,4; 1Taipei Veterans General Hospital, Taipei, in comparison with CRA (3-yrs-EFS: 0.63 + 0.09 after complete resection Taiwan; 2Hopital Clocheville, Tours, France; 3Hopital Necker-Enfants and 0.31 + 0.07 after incomplete resection). The localization was intra- Malades, Paris, France; 4Universite Paris-Descartes, Paris, France sellar in 8%/3%, extrasellar in 0%/23% and intra- + extrasellar in 92%/76% and hypothalamic involvement 46%/68% for patients with A rare case of atypical lymphoplasmacyte-rich meningioma (LRM) XTO and CRA, respectively. The median duration of history was observed in a 15 year old girl is reported. The first clinical manifestations 18mo (1-96) in XTO and 5mo (0.3-84) in CRA. A complete resection of the disease were seizures. Neuroradiological images favored the existence was achieved in 100% of XTO and 41% of CRA. Irradiation was per- of a parasagittal meningioma over right posterior frontal region. Gross total formed in 27% of CRA and in none of XTO patients. Median tumour resection was achieved. The tumor was histologically confirmed as atypical volume: 2.8 cm3 (0.3-9.2) in XTO and 13.5 cm3 (0.9-2.4) in CRA. meningioma with massive infiltrates of type T lymphocytes and angiomatous Visual disturbances were less frequent observed in XTO (18%) when change. No abnormalities in the patient’s blood chemistry were associated compared with CRA (60%). Hydrocephalus was not observed in XTO with the disease. Fourteen cases of LRM have been reported to date including (35% CRA). We conclude that the prognosis in terms of EFS, visual dis- 3 pediatric patients after first publication in the 2nd edition of World Health turbances and hydrocephalus was better in XTO in comparison with Organization classification in 1993. Literature is reviewed. CRA. XTO patients presented with smaller tumors and longer history. Surgical resection seems to be the treatment of choice in XTO.

P-RARE.08. AGGRESSIVE INTRACRANIAL EPITHELOID HEMANGIOENDOTHELIOMA RESPONSIVE TO THE MTOR INHIBITOR SIROLIMUS P-RARE.11. MULTI-MODALITY MANAGEMENT OF CLIVAL S. Stapleton1, K. Potthast1, S. Steinbrueck1, H. Monforte1, E. Harris1, and CHORDOMAS - EXPERIENCE FROM A TERTIARY CARE D. Adams2; 1All Children’s Hospital, St Petersburg, FL, United States; CENTER 1 1 1 1 1 2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United I. Vanan , A. S. Redner , A. Quinlan , M. Mittler , S. Schneider , 2 1 1 States N. J. Leibsch , and M. P. Atlas ; Schneider Children’s Hospital, New Hyde Park, NY, United States; 2Francis H Burr Proton Therapy center, Epithelioid hemangioendothelioma (EHE) is a rare malignancy with vari- Massachusetts General Hospital, Massachusetts, MA, United States able biologic behavior. It can occur in any organ and is uncommon in the central nervous system. We report an aggressive multifocal tumor occurring BACKGROUND: Chordomas are rare, slow growing, locally aggressive in a 16-year-old female. The patient presented with a soft tissue mass in her neoplasms of the primitive notochord remnants and account for 5-15% arm, and then developed hemoptysis and aphasia. A chest CT showed mul- of all intracranial tumors in children. These arise more commonly in tiple pulmonary nodules, and a brain MRI showed four lesions, the largest a the skull base and behave more aggressively than those in adults. We hemorrhagic 4.5 x 3 cm lesion in the left temporal/occipital region. A lung analyzed the treatment and outcome of children with Clival biopsy confirmed the diagnosis of EHE. Primary treatment was Chordomas treated with the same adjuvant chemotherapeutic regimen alpha-interferon for 10 months. The initial brain and pulmonary lesions (Vcr/Dox/CPM/ifos/VP-16) prior to radiotherapy at Schneider improved, but she developed additional new brain lesions plus seizures. Children’s hospital from 2005-2009. METHODS: The medical records Treatment was changed to sunitinib with paclitaxel, but she had continued of three patients diagnosed with Clival Chordomas were reviewed for radiographic progression plus new left sided weakness; therefore, treatment history, treatment and outcome. RESULTS: Patient #1 had Chondroid was stopped after 2 months. At the peak of her disease, 14 months after diag- chordoma and STR (sub total resection) surgery at diagnosis after nosis, she had 15 brain lesions ranging from punctuate to 5.2 cm in diameter, which he received 2 cycles of chemotherapy with significant toxicity. many hemorrhagic. She then started single-agent therapy with the mTOR Patient #2 had a GTR (gross total resection) of his Chondroid chon- inhibitor sirolimus, maintaining target levels of 10-15 ng/ml. After 12 droma at diagnosis and proton beam therapy. He received 4 cycles of months of treatment with sirolimus, there has been an excellent response pre-radiation chemotherapy at first relapse (approximately 1 year from with reduced number and size of lesions (8 lesions, maximum diameter diagnosis) and now has stable disease. Patient#3 had de-differentiated 2 cm), no new lesions or hemorrhage, intact normal neurologic exam, and Chordoma and was started on chemotherapy after debulking surgery no breakthrough seizures on one antiepileptic. Therapy with an mTOR due to metastatic disease at presentation (cervical lymph nodes) with dra- inhibitor may be a good option for patients with EHE in which there is no matic improvement. All three patients received proton beam therapy standard of care. Further clinical and laboratory research are needed. (TD ¼ 75.6 to 77.4 CGE (1.8CGE/fraction, 42 to 43Fxs) and are alive and doing well. CONCLUSIONS: Chemotherapy may play a role in the management of young patients with disseminated /unresectable disease or patients with tumor recurrence. This chemotherapeutic regimen induced very good partial remission in one patient with bulky, unresectable disease and stable disease in the other 2 patients. Further study of this regimen is warranted in patients with unresectable disease.

NEURO-ONCOLOGY † JUNE 2010 ii125 Abstracts

P-RARE.12. BIOLOGICALLY DIRECTED THERAPY FOR received cranial radiation (54 Gy). MRI obtained a week after RT com- METASTATIC CHORDOMA, CASE REPORT pletion demonstrated disease progression. Dexamethasone was weaned M. M. Etzl and A. Rosenfeld; Phoenix Children’s Hospital, Phoenix, AZ, and he received a total of 6 biweekly intradermal vaccinations of autolo- United States gous dendritic cell vaccine loaded with a mixture of allogeneic melanoma tumor lysates. After 3rd vaccination DTH skin reaction was noted at the INTRODUCTION: Chordoma is a rare tumor in children and adoles- vaccination sites. The patient’s skin nevi visibly became paler. We cents. Response to treatment, especially with metastatic disease, is generally observed clinical improvement and stable MRI over 1.5 month period. poor. Case Report: We report on the clinical course of an adolescent female The patient died of progressive tumor 4 months after first vaccination. with a chordoma of the thoracic spine who recurred in her lungs and chest New treatment approaches should be sought for this rare and uniformly wall approximately 7 months following a gross total resection of her fatal disease. spinal tumor. Because of the lack of effective therapeutic options, molecular profiling was performed on her original tumor, and treatment with bortezomib was started based on up regulation of the NFKB2 gene. Following 2 cycles of therapy there was a marked decrease in the size of most of the metastatic lesions, however following 6 cycles, CT scans revealed progressive P-RARE.15. SKULL BASED MELANOTIC NEUROECTODERMAL disease. Based on SPARC up regulation, her treatment was changed to 28 TUMOR OF INFANCY WITH EXTENSIVE NEUROGLIAL Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 day cycles of Paclitaxel, Vinblastine, and Cyclophosphamide, but unfortu- DIFFERENTIATION AND FOCAL OSTEOID PRODUCTION nately, after 2 cycles there was radiographic evidence for tumor progression. S. Garg1, J. Poulik1, W. Kupsky2, and S. Sood1; 1childrens’ hospital of Her genomic data was again reviewed. PTGS2, SSTR1, SSTR3, and SSTR1 Michigan, Detroit, MI, United States; 2Harper University hospital, Detroit, were all up regulated. Treatment was changed to daily celecoxib and MI, United States monthly IM Octreotide. Following 5 cycles there was a decrease in the size of most of the lesions, and following 13 cycles there were no new lesions. BACKGROUND: Melanotic Neuroectodermal Tumor of Infancy (MNTI) However, some of the pulmonary lesions were smaller while others were is a rare and mostly benign neoplasm, diagnosed in early infancy.The main slightly larger. CONCLUSION: Tumor genomic profiling was a benefit to site of development is the maxilla (68-80%), followed by skull (11%), mand- our patient, and can help direct therapy in patients with rare tumors for ible (6%) and the brain (4%). DESIGN: We report a case of MNTI in a 5 which there is no effective treatment. Genomic profiling together with pro- year old male. RESULTS: A 5 year old Caucasian male presented incidentally teomics will increase our understanding of rare tumors. after a fall. CT-scan and MRI revealed a large skull based tumor involving the temporoparietal and occipital bones with dural and parenchymal extension.The tumor was excised in multiple stages due to the large size. Microscopically the tumor was composed of clusters of heavily pigmented cells focally surrounding neuroglial elements. The tumor invaded bone, P-RARE.13. MELANOMA MALIGNUM OF THE BRAIN. CASE dura and focally the brain parenchyma. Focal bone formation and small REPORT islands of osteoid were seen in the cellular fibrous component. The pigmen- H. Wisniewska-Slusarz1, J. Zawitkowska1, M. Mitura-Lesiuk1, ted cells showed NSE, S-100 and HMB 45 immunoreactivity. Neuroglial J. Kowalczyk1, A. Podkowinski2, B. Jarosz2, and K. Paprota3; 1Children’s cells showed synaptophysin immunoreactivity in cells with neuronal differ- University Hospital, Dept of Hematology and Oncology, Lublin, Poland; entiation and GFAP immunoreactivity in cells with glial differentiation. 2University Hospital, Dept of Neurosurgery, Lublin, Poland; 3University Ki-67 labeling was high in the cellular stroma. No chromosomal abnormality Hospital, Dept of Radiotherapy, Lublin, Poland was found. Despite extensive resection the entire tumor could not be excised and chemotherapy and radiation therapy were given. No recurrence to this Malignant melanoma (MM) is one of the most malignant cancer. The date has been detected (3 years). CONCLUSION: MNTI of the cranial prognosis is poor due to early matastases and resistance to therapy. The vault are tumors that show local invasion. These tumors generally have a most common localisations are skin, mucosa, retina, and the central biphasic phenotype with neuroblastic and pigmented components and nervous system (CNS).This tumor occurs very rarely in children, but the have been described to have neuroglial differentiation. No osteoblastic peak incidance is observed in teenagers. CASE REPORT: A 9-years old differentiation has been described to our knowledge. girl (A.B.) was admitted to the ward following car accident. Computed tomography of the CNS was performed and multifocal lesions in the brain were diagnosed. Subtotal surgery was performed and histopathological examination revealed MM. As a first line chemotherapy, a protocol with temozolomide and cisplatin was given. Unfortunately, progression of the disease was P-RARE.16. PERIPHERAL PRIMITIVE NEUROECTODERMAL observed and the therapy was changed to second line consisting of adriamy- TUMOUR (PPNET) OF DURA / INTRACRANIAL EWINGS cin and dacarbazine, and radiotherapy of cns was performed. However, no SARCOMA (ES) effect of therapy was observed and the patient died 12 months later. U. P. Uparkar, W. Nicholls, and T. Hassall; Royal Children’s Hospital, Brisbane, Australia

Ewings sarcoma of skull vault constitutes less than 1% of all bone tumours. There are only 17 cases of intracranial ES reported in literature. P-RARE.14. PRIMARY LEPTOMENINGEAL MELANOMA IN We describe two cases of CNS presentation of pPNET-ES. It is important CHILDREN: AN ATTEMPT OF IMMUNOTHERAPY to distinguish this entity from the more common cPNET (central primitive M. Yankelevich1,2, G. Chkadua2, J. R. Taub1, M. Budarin2, J. M. Poulik1, neuroectodermal tumor) of brain, as management of latter is different G. Mentkevich2, and K. Bhambhani1; 1Children’s Hospital of Michigan/ from pPNET. CASE 1: 4 year boy presented with headache, vomiting mild Wayne State University, Detroit, MI, United States; 2N.N.Blokhin Russian ataxic gait and nystagmus. MRI showed extra-axial mass in posterior Cancer Center, Moscow, Russian Federation fossa. He had complete resection followed by 4 cycles of chemotherapy (VCR,Cyclo, Ifos and Vp16) Child tolerated his chemotreatment well and 1 Primary leptomeningeal melanoma (PLM) is rare and fatal disease of the 7 years post diagnosis, still is in remission. CASE 2: 4 2 year boy presented CNS of childhood. Most of the reported cases are resistant to chemora- with vomiting and weight loss and recent onset head tilt. Examination diotherapy. Here we report 2 cases of PLM in which we attempted immu- revealed bilateral papilledema and trochlear nerve palsy. MRI showed extra- notherapy. Histological diagnosis of melanoma was conﬁrmed after biopsy dural lesion with osteopenia of underlying bone. He underwent subtotal of the meninges and CSF cytology in both patients. A 21-month-old boy resection followed by chemotherapy. Two years post-diagnosis he relapsed presented with unsteady gate. MRI demonstrated diffuse leptomeningeal and was started on more intense chemotherapy but unfortunately succumbed process with severe compression of the brain stem. He probably had to progressive disease 6 months after relapse. In both cases diagnosis was had the lesions for at least several months since 3 months earlier he conﬁrmed by demonstration of t(11,22) (q24: q12) and CD 99+ immunohis- was found to have hydrocephalus and the VP shunt was placed. The tochemically while histologically there was presence of intracellular glyco- patient’s condition was getting worse progressively and rapidly. gen. While prognosis for patients with CNS pPNET is not clearly known, Immunotherapy was attempted and he received one intrathecal injection there is some suggestion that these patients have more favorable outcome. of interleukin-2. He died 48 hours after the injection from his disease. Our cases conform to the limited literature to date suggesting primary intra- A 12-year-old previously healthy boy developed severe headaches and cranial ES/pPNET may present as space occupying lesions with its attendant vomiting, and soon became comatose. MRI demonstrated diffuse signs and symptoms. Dural invasion was rarely noted. cranial leptomeningeal involvement. He improved on steroids and

ii126 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-RARE.17. EMBRYONAL TUMOR WITH ABUNDANT developed GBM in the left frontal lobe at 8 years old. He had a gross total NEUROPIL AND TRUE ROSETTES: REPORT OF CLINICAL, resection of the mass followed by chemotherapy with oral etoposide and MORPHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF IFN-gamma. A local relapse was recognized on the image 5 months later. ACASE Administration of ACNU showed significant effect, but it was transient A. Woehrer1, A. Peyrl2, B. Streubel3, D. Prayer4, T. Czech5, I. Slavc2, and and the tumor grew 5 months later. 34.2 Gy of irradiation was delivered C. Haberler1; 1Institute of Neurology, Medical University of Vienna, Vienna, to the tumor lesion concomitant with administration of 75 mg/m2 of temo- Austria; 2Department of Pediatrics, Medical University of Vienna, Vienna, zolomide. The tumor completely disappeared on the image. Three months Austria; 3Department of Pathology, Medical University of Vienna, Vienna, later, enhanced lesions developed in both lateral ventricles outside the first Austria; 4Department of Radiology, Medical University of Vienna, Vienna, radiation field under the administration of temozolomide. After the second Austria; 5Department of Neurosurgery, Medical University of Vienna, combined therapy with 34 Gy of local radiotherapy and temozolomide Vienna, Austria administration, the tumors completely disappeared. Finally, he developed new tumor lesions out of the previously irradiated field, one month later. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is Tumors were found in the lateral horn of the left ventricle and disseminated a rare, recently recognized variant of CNS PNET. So far, 33 cases have been to the lumbar spine. He died 18 months after the diagnosis. As previously reported in the literature. All tumors occurred in children aged less than five reported in the adults, we observed synergism between radiotherapy and years. Molecular genetic data are only available in 7/33 tumors. The most temozolomide. GBM cells infiltrate all over the CNS system and the fre- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 common genetic alteration constitutes extra copies of chromosome 2 in 5/ quency of distant metastasis and/or recurrence will increase in the temozo- 7 tumors. We report an ETANTR in a 33-month-old female patient. She pre- lomide era. Prophylactic radiotherapy to the whole brain may be necessary sented with increased head circumference (above 97th percentile). with concomitant administration of temozolomide for treatment of GBM. Neuroimaging revealed a 9.6 x 8.6 x 11.7 cm left parieto-occipital inhom- ogenous, partly cystic, partly solid lesion. Near total neurosurgical resection was performed. Histopathology revealed a primitive neuroectodermal tumor with highly cellular areas composed of undifferentiated hyperchromatic P22 CHOROID PLEXUS TUMOR cells. In addition, hypocellular areas rich in neuropil (neuropil-islands) and multilayered ependymoblastoma-like rosettes were present. Immunohistochemistry demonstrated widespread expression of neuronal P-CPT.01. CHOROID PLEXUS TUMORS markers including synaptophysin and neurofilament. Epithelial membrane R. Kebudi1, C. Canpolat2, T. Celkan1, G. N. Ozdemir1, S. Berrak2, antigen was detected within rosettes in a dot-like and luminal surface A. Kafadar3, and M. Ozek4; 1Istanbul University, Cerrahpas¸a Medical pattern. SMARCB1 (INI1) protein expression was retained. Array CGH dis- Faculty & Oncology Institute, Division of Pediatric Hematology-Oncology, played trisomy of chromosomes 2, 14, 17, 19, and 20. No small regions of Istanbul, Turkey; 2Marmara University Medical School, Division of gains, losses, or amplifications were detectable. Currently, four months post- Pediatric Hematology-Oncology, Istanbul, Turkey; 3Istanbul University, operation, the patient is treated with intensive conventional and intrathecal Cerrahpas¸a Medical Faculty, Dept. of Neurosurgery, Istanbul, Turkey; chemotherapy (cyclophosphamide, vincristine, methothrexate, etoposide, 4Marmara University Medical School, Department of Neurosurgery, carboplatin), and shows stable disease. This case extends the series of so Istanbul, Turkey far described ETANTRs. In line with previous reports the tumor occurred in a young patient and displays trisomy of chromosome 2. Choroid plexus tumors (CPT) are rare brain tumors ranging from papillomas (CPP), atypical CPP (ACPP) to carcinomas (CPC). We present 4 children with CPTs. CASES: (1) A 13 year-old girl, admitted with headache, vomiting P-RARE.18. EVOLUTION OF LOW GRADE GANGLIOGLIOMA had a mass in the left ventricle. She underwent a total resection. The diagnosis was ACPP. After 6 weeks she had a local relapse. She was reoperated. INTO GLIOBLASTOMA AND BACK + C. E. Gidding, J. Jeuken, B. Goraj, E. van Lindert, G. Janssens, J. Schieving, Pathology was CPC. She recieved chemotherapy radiotherapy. She is in and P. Wesseling; Radboud University Nijmegen Medical Centre, Nijmegen, remission. (2) A 9 months-old boy had a convulsion and had a mass in the Netherlands right lateral ventricule. The tumor was totally resected. Pathology was CPC. He recieved chemotherapy and intrathecal methotrexate. After 2 INTRODUCTION: While progression of childhood low grade ganglio- years the patient was in remission. (3) A 5 months old boy had a convulsion glioma into glioblastoma has been rarely described, histologically proven “ret- and a mass in the right lateral ventricule. The tumor was totally resected. The rogression” back to ganglioglioma is extremely rare. Here we report such a case diagnosis was CPP. A month later an abdominal mass was detected. with some molecular findings. CASE REPORT: A 3 year old girl presented with Pathology revealed alveolar rhabdomyosarcoma. The grandmother had died of breast cancer, the uncle of bone cancer, the father of rectum strange sensations in her mouth. She was treated succesfully with carbamaze- + pine. At the age of 14 symptoms relapsed and she developed signs of increased cancer. p-53 was in tumor cells. (4) A 2 year old girl had a convulsion, left hemiparesis. There was a mass on the right lateral ventricle. The ICP. MRI showed a large temporoparietal mass. Debulking was performed. + Histopathology showed low grade ganglioglioma. One month later she had tumor was totally resected. Pathology was CPC. p-53 was in the tumor already tumor progression. After second debulking histopathology now cells. In conclusion, total resection is important, the addition of chemother- showed glioblastoma. She was treated with radiation therapy plus concomit- apy and radiotherapy seems to improve prognosis. CPT necessitate an experi- tant and maintenance temozolomide. The residual tumor decreased. After enced pathology review. An association with Li-Fraumeni syndrome and 10 months a third debulking was performed. Pathology now showed low CPT has been suggested. grade ganglioglioma again. Now 15 months later she is alive with stable disease. Molecular analysis (MLPA) of both the original low grade ganglioglioma and the GBM showed partial loss of chromosome 1p and a complete loss of chromosome 19, which is indicative of high-grade malignancy in diffuse gliomas in adults. Furthermore, other molecular aberrations character- P-CPT.02. EPIDEMIOLOGY & TREATMENT OUTCOME OF istic for (adult) GBMs like EGFR gain or CDKN2A and PTEN loss were not CHILDHOOD CHOROID PLEXUS TUMORS: REPORT FROM detected. Interestingly a loss of TP53 was only identified in the GBM biopsy. THE HONG KONG PEDIATRIC HEMATOLOGY ONCOLOGY CONCLUSION: Evolution of low grade ganglioglioma into glioblastoma STUDY GROUP G. Chan1, M. Shing2, H. Yuen3,R.Li4, A. Ling5,S.Ha1, and C. Li2; 1The and back is extremely rare. Clinical course supported this. Histological “retro- 2 gression” may be explained by therapy. University of Hong Kong, Hong Kong, China; The Chinese University of Hong Kong, Hong Kong, China; 3Queen Elizabeth Hospital, Hong Kong, China; 4Tuen Mun Hospital, Hong Kong, China; 5Princess Margaret Hospital, Hong Kong, China P-RARE.19. DISTANT RECURRENCE OF GLIOBLASTOMA MULTIFORME AFTER COMBINED THERAPY WITH LOCAL OBJECTIVE: Choroid plexus tumors (CPT) are rare and are mostly found RADIOTHERAPY AND TEMOZOLOMIDE; IS WHOLE BRAIN in infancy period. Its epidemiology & outcome in Chinese children remains RADIOTHERAPY REQUIRED IN THE COMBINED THERAPY unknown. MATERIALS AND METHODS: Prospective collected childhood WITH TEMOZOLOMIDE? cancer data was retrieved and reviewed. The data was derived from 5 hospi- C. Tanaka1, K. Okada1, Y. Park1, Y. Osugi1, Y. Matsusaka2, H. Sakamoto2, tals which captured almost all children with cancers locally. Data accrual and J. Hara1; 1Department of Pediatric Hematology and Oncology, was performed by designated data managers and was further crosschecked Children’s Medical Center, Osaka City General Hospital, Osaka, Japan; with the Hong Kong Cancer Registry which collected all the local pathology 2Department of Pediatric Neurosurgery, Children’s Medical Center, Osaka reports for cancers. RESULTS: From January 1999 to December 2008, only City General Hospital, Osaka, Japan 6 cases of CPT (carcinoma n ¼ 2, papilloma with atypia n ¼ 1, papilloma n ¼ 3) were diagnosed. Their median age was 1.4yrs (range 0.4-3.13y rs) We report a patient who developed secondary glioblastoma multiforme and M:F ratio was 4:2. Children with carcinoma and atypia were older at (GBM). He suffered from acute lymphoblastic leukemia when he was one diagnosis (1.5, 1.9 & 3.1yrs vs. 0.3, 0.4 & 1.2 yrs of papilloma). The inci- year old. 15Gy of radiotherapy was delivered to the whole brain. He dence was 0.55/million ≤ 15yrs/year. The distribution were even at the

NEURO-ONCOLOGY † JUNE 2010 ii127 Abstracts

cerebral (n ¼ 3) and posterior fossa (n ¼ 3). Chemotherapy P-CPT.05. IS THERE A ROLE FOR MYELOABLATIVE (CPT-SIOP-2000) was given to 3 children with carcinoma or relapsing papil- CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC loma with atypia. Cranial RT was given to one with multiple relapses (n ¼ 4) CELL RESCUE IN THE MANAGEMENT OF over a span of 6.4yrs and he had papilloma with atypia at diagnosis. All NEWLY-DIAGNOSED CHOROID PLEXUS CARCINOMA (CPC)? patients with carcinoma or atypia died (duration 0.8, 4.4 & 6.4yrs). All A PRELIMINARY ANALYSIS patients with papilloma survived with surgery alone (follow-up 5.1, 2.5 & R. J. Brown1, G. Dhall1, A. Marachelian1, A. Gozali1, A. Butturini1, 1.4yrs respectively). CONCLUSION: Chinese CPT was also found in F. Gilles1, S. J. Thompson2, S. Gardner3, and J. L. Finlay1; 1Childrens infant and young children. Surgery alone achieved good long term Hospital Los Angeles, Los Angeles, CA, United States; 2Joseph Sanzari outcome for papilloma. For those with carcinoma or atypia, more innovative Childrens Hospital, Hackensack University Medical Center, Hackensack, therapeutic approach is needed to achieve better outcome. NJ, NJ, United States; 3New York University Medical Center, New York, NY, United States

INTRODUCTION: CPCs in young children have a poorer prognosis and often require irradiation for treatment with long-term sequelae. METHODS: P-CPT.03. CPT-SIOP-2009: GEOMETRIC SELECT-AND-TEST We evaluated our multi-center experience (2002-2009) with newly- DESIGN BASED ON TREATMENT FAILURE TIME AND diagnosed children with CPC treated with high-dose chemotherapy intend- Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 TOXICITY: SCREENING CHEMOTHERAPIES FOR CHOROID ing to avoid irradiation. RESULTS: Eight patients included 5 boys (mean PLEXUS TUMORS age, 18 months; range, 2-54 months; two with p53 mutations). Five pre- P. Thall1, L. Wooten1, H. Nguyen1, X. Wang1, P. Nagel2, and J. E. Wolff2; sented supratentorially, and 3 had leptomeningeal dissemination. Four 1MDAnderson Cancer Center Biostatistics, Houston, TX, United States; underwent gross total resection. Six patients received 5 cycles of vincristine, 2MDAnderson Cancer Center, Houston, TX, United States cisplatin, cyclophosphamide, etoposide, and high-dose methotrexate followed by 1 cycle of myeloablative chemotherapy (thiotepa/carboplatin/eto- Rare tumors can not be studies with traditional phase III studies. For poside) with autologous hematopoietic cell rescue (AHCR); 2 patients choroid plexus tumors, not even phase II studies were available to suggest received 3 cycles of vincristine, cisplatin, cyclophosphamide, and etoposide promising treatments. Therefore, in the CPT-SIOP-2009 study, we have followed by 3 cycles of thiotepa/carboplatin, each followed by AHCR. combined the necessary phase II elements with the phase III question if the One received irradiation following a single transplant aborted for toxicity. most promising protocol is superior to standard. The data generated in the Two received irradiation at progression. Five received no further treatment first part will be included in the final analysis. Also, a new study endpoint following AHCR; one with p53 and a simultaneously diagnosed low-grade was defined combining toxicity and two year event free survival in a two- glioma received 12 months of temozolomide and celecoxib. Five achieved dimensional treatment effect parameter. Bayesian regression models for complete remission (CR) before transplant, one being M3. Five remain in failure time and the probability of toxicity that account for prognostic cov- CR without irradiation at a mean of 35 months (range, 9-72 months), includ- ariates were used to define two-dimensional covariate-adjusted treatment ing one relapse. Three patients relapsed at a mean of 22 months (range, effect parameter sets. Traditional formulae to calculate patient numbers 12-42 months); one in the spine after 42 months; two within the primary did not apply to that study design, and the challenge was to find a way to site at 12 and 13 months, respectively. CONCLUSIONS: Findings suggest determine how many patients will be necessary. Using the historical data intensive induction chemotherapy followed by myeloablative chemotherapy of the CPT-SIOP-2000 study and the literature based meta-analysis database and AHCR as initial strategy may permit long-term progression-free survival we simulated various possible scenarios for patient populations and study without irradiation in children with CPC. A larger international results. The frequency of positive study results in these scenarios was used meta-analysis is currently underway. to optimize parameters minimizing the expected sample size. Assuming the least favorable configuration, an alpha ¼ 0.05, and generalized power 80%, the necessary patient number to come to an answer calculated this way was 171 patients in 5.4 years. This was less than half of the patient P-CPT.06. SURGERY AND CHEMOTHERAPY IN CHOROID number necessary for an equivalent traditional design. After a final vote in PLEXUS TUMORS. A SET OF POSSIBLE COMBINATIONS FOR the international choroid plexus tumor group, the protocol was started. TREATMENT M. Tufano1, A. Verrico1, V. Vitale1, L. Quaglietta1, A. Passariello1, M. Capasso1, G. Zanotta1, R. Migliorati1, and G. Cinalli2; 1Department of Pediatric Oncology, AORN Santobono Pausilipon, Naples, Naples, Italy; 2Department of Neurosurgery, Santobono-Pausilipon Hospital, Naples, Italy P-CPT.04. CHOROID PLEXUS PAPILLOMA OF THE FOURTH VENTRICLE WITH FORAMEN EXTENSION AND BACKGROUND: Choroid plexus tumors (CPT) are neuroectodermal neo- COMPRESSION OF THE CERVICAL SPINAL CORD: PITFALLS IN plasms that include choroid plexus carcinoma (CPC), choroid plexus papilloma PREOPERATIVE DIAGNOSIS OF AN UNCOMMON POSTERIOR and atypical plexus papilloma (APP). The aim of the study is to describe a series FOSSA TUMOR of 5 children presenting with CPT. METHODS: Data on clinical assessment, J. C. Murray, R. A. Roberts, C. A. Galliani, E. Z. Braly, and D. G. Oshman; tumor location, radiological imaging, histological characteristics and thera- Cook Children’s Medical Center, Fort Worth, TX, United States peutic management of 5 children affected by CPT were compiled by reviewing retrospectively patients records. Chemotherapy included: carboplatin 200 mg/ INTRODUCTION: Choroid plexus tumors are uncommon, accounting m2 an day 1 and 2, cyclophosphamide 1.800 mg/m2 plus etoposide 80 mg/m2 for only 1-3% of pediatric central nervous system neoplasms. They typically on 1 day, doxorubicin 20 mg/m2 as a continuous infusion on day 1 and 2 and occur in the first decade of life, are most commonly histologically benign methotrexate 700 mg/m2 as a 6-hour infusion, on 1 day RESULTS: In 3 choroid plexus papillomas (CPP) and surgical resection is usually curative. patients affected by APP a complete surgical resection was achieved while 1 The most common location of CPP is the lateral ventricles, with only a min- patient with CPC needed a second-look surgery. Both children with CPC and ority of cases occurring in the third or fourth ventricle. Extension of a fourth 2 patients with relapsed APP underwent adjuvant chemotherapy. The overall ventricle CPP through the foramen of Luschka has only been reported rarely, survival (OS) and the event-free survival (EFS) for children with APP were with extension into the cervical spine being extremely unusual. REPORT: A 100% after a median period of 33 months (range: 30-68) from remission. healthy 4 year-old girl presented with progressive headaches and ataxia. The OS and EFS for children with CPC were 100% after a period of 22 and Magnetic resonance imaging revealed a 4x4x5cm,heterogeneously enhan- 109 months from remission. CONCLUSION: The clinical results achieved in cing mass in the fourth ventricle with extension through the foramen of our series confirm this therapeutic regimen as a possible adjuvant treatment Luschka and into the cervical spinal canal, with cord compression to the for both CPC and APP. level of C2-C3. There was also brainstem compression and obstructive hydrocephalus. Computed tomography revealed tumor calcification. Ependymoma was considered the most likely diagnosis. At craniotomy, the tumor extended into the cerebellopontine angle, was adherent to the lepto- P23 CASE REPORTS meninges of the brainstem, but was nonadherent to the cervicomedullary region. Visualization of the lower cranial nerves was possible. Gross total P-CASE.01. ISOCHROMOSOME 17Q, MYC AMPLIFICATION resection was accomplished. Histopathologic examination revealed a well- AND LARGE CELL PHENOTYPE IN A CASE OF differentiated CPP. CONCLUSION: Choroid plexus papilloma of the MEDULLOMYOBLASTOMA WITH EXTRACRANIAL fourth ventricle is rare and can mimic ependymoma on neuroimaging. Our METASTASES case demonstrates that CPP must always be considered in the differential K. D. Wright, J. Coleman, Z. Patay, T. Merchant, D. Ellison, and A. Gajjar; diagnosis of posterior fossa tumors and CPP can be extensive, with St. Jude Children’s Research Hospital, Memphis, TN, United States foramen of Luschka extension and cervical spinal canal involvement. Medullomyoblastoma remains a rare variant of medulloblastoma comprised of both neuroectodermal and myoblastic features. Gain of the myc gene on 8q and sequences on 17q have been implicated in the pathogenesis ii128 NEURO-ONCOLOGY † JUNE 2010 Abstracts

of medullomyoblastoma; however, little information exists in regard to clini- followed for one year with a suspected diagnosis of acute disseminated ence- cal characteristics, tumor behavior and prognosis. We present a case of phalomyelitis. Symptoms included chronic fatigue, imbalance and tripping. medullomyoblastoma (T3b M3) with large cell phenotype in a 4 year old Evaluations for multiple sclerosis were negative and empiric intravenous female who developed extensive extracranial metastatic disease following immune globulin immunotherapy was ineffective. Three contrast-enhanced her initial 6 weeks of irradiation and prior to the start of high dose che- MRI scans were performed over the one year period, revealing non-enhancing, motherapy in the absence of a ventricular peritoneal shunt. In particular, non-progressive, circum-4th ventricular signal change, without evidence of a the patient presented with significant hepatomegaly 4 weeks after completion tumor. The patient eventually developed acute headaches and worsened of 39.6 Gy craniospinal radiation, followed by 55.8 Gy boost to the primary imbalance. MRI revealed a 4.5x3.8x3.5 cm midline/vermian mass. site. Follow-up radiologic studies were notable for innumerable masses Resection revealed classic medulloblastoma. CONCLUSION: A chronic within the liver. PET scan showed additional soft tissue abnormalities in symptom prodrome preceding the diagnosis of medulloblastoma is unusual. the neck, chest and abdomen, consistent with nodal involvement, and wide- The significance of circumventricular MRI signal change preceding medullo- spread osseous lesions throughout the axial and appendicular skeleton, blastoma in our case is unclear, but demonstrates a rare natural imaging including multiple vertebral bodies, the sternum, both humeri, the right history suggesting that this imaging finding may be a harbinger of ultimate scapula, the pelvis, lower sacrum and both proximal femurs. Core needle medulloblastoma. Similar scenarios should be reported and clinical vigilance biopsy of the liver revealed small round blue cell tumor, cytologically iden- should be maintained and repeat MRI scanning pursued for children with per- tical to her primary brain tumor, which was notable for isochromosome sistent or unexplained cerebellar dysfunction. Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 17q formation. FISH analysis of her brain tumor also revealed double minutes of c-myc amplification on 8q. This case reveals 3 markers of poor prognosis, reflected by the presence of large cell phenotype, isochromosome 17q and c-myc amplification, supporting the notion that medullomyoblas- P-CASE.04. MR SPECTROSCOPIC FINDINGS IN BI-THALAMIC toma may follow an aggressive course. ASTROCYTOMA: CASE REPORT AND REVIEW OF LITERATURE C. Dhamne, V. Subbiah, T. Vats, L. Ketonen, A. Mahajan, J. Wolff, and M. Rytting; MD Anderson Cancer Center, Houston, TX, United States

P-CASE.02. UNUSUAL MORPHOLOGY OF EMBRYONAL BACKGROUND: Thalamic tumors are a very rare entity in pediatric brain TUMORS WITH ABUNDANT NEUROPIL AND TRUE ROSETTES tumors. Moreover the incidence of pediatric tumors of both thalami is even (ETANTR) less clear. Treatment, prognosis and outcomes are based on experience of M. P. Gardiman1, E. Orvieto1, D. Danieli2, E. G. S. D’Amore2, E. Opocher3, case reports. When biopsy becomes challenging novel imaging techniques R. Faggin4, D. D’Avella4, E. Viscardi5, and G. Perilongo5; 1Department of are needed. METHODS: We report a rare case of a pediatric primary bilat- Oncological and Surgical Sciences, Division of Pathology University eral thalamic tumor (PBTTs) with MR spectroscopic (MRS) findings in a Hospital of Padua, Padova, Italy; 2Pathology Unit S.Bortolo Hospital child who presented at the children’s cancer hospital at MD Anderson Vicenza, Vicenza, Italy; 3Pediatric Department University Hospital of Padua, Cancer Center and reviewed available literature. CASE REPORT: A Padova, Italy; 4Department of Neurosurgery University Hospital of Padua, 5-year-old hispanic male presented with right hand tremors. CT scan Padova, Italy; 5Pediatric Department Division of Haematology-Oncology showed a lesion in bilateral thalami. Biopsy showed a low grade pilocytic University Hospital of Padua, Padova, Italy astrocytoma. On MR Spectroscopy choline:creatine ratio suggested low grade nature of tumor. Several unusual peaks were present between the cre- Embryonal Tumor with Abundant Neuropil and True Rosettes atine and N-acetyl aspartate peaks. The patient received proton radiation (ETANTR) constitute a distinctive entity inside the group of Central with resolution of presenting symptoms. He presented with seizures 6 Nervous System (CNS) Primitive Neuro-ectodermal Tumors (PNET). Most months after the radiation. MRI revealed decrease in tumor with an area of ETANTR occur in children younger than 3 years of age, arising in the pos- of contrast enhancement. MR spectroscopy showed choline:creatine terior fossa region or in the frontal lobes. Prognosis of ETANTR is very poor ratio . 2 suggesting tumor progression and patient clinically progressing. with an overall survival of less than 2 years. We present 4 cases of ETANTR, CONCLUSIONS: The description of MRS assumes significane in this 2 of them with unusual histologic characteristics. Usually these neoplasms tumor in unusual location with variable clinical course. Usually PBTTs are are characterized by the presence of undifferentiated neuro-epithelial cells low-grade astrocytomas (grade II WHO classification), but some anaplastic with broad zones of well-differentiated neuropil and ependymoblastic areas may be found in some patients, so that grade III and IV astrocytomas rosettes arising abruptly from paucicellular regions of neoplastic neuropil. may be expected. MR Spectroscopy may help in grading and following chal- Immunohistochemical reactions show a negative stain for GFAP, neurofila- lenging cases. Further large case studies are warranted. ment and synaptophysin in the undifferentiated blue cells while the neuropil is positive for synaptophysin. In one of our cases, a sarcomatous, reticulin- rich component of elongated spindle cells showing diffuse immunoreactivity P-CASE.05. A REPORT OF FOUR NEWBORNS WITH for smooth muscle actin and focal desmin staining was present, a combi- CONGENITAL BRAIN TUMOURS nation of large “anaplastic” elements with round to oval highly pleomorphic M. P. Gardiman1, M. Fassan1, D. Salmaso2, D. D’Avella3, L. Denaro3, nuclei, as it is seen in anaplastic medulloblastoma, and pseudo-stratified M. Calderoni4, E. Viscardi5, and G. Perilongo5; 1Department of Oncological glandular-like and epythelial-like cells aggregate in cord or tubular strucu- and Surgical Sciences, Division of Pathology University Hospital of Padua, tures, reminding a medulloepythelioma, was found in another case. An abun- Padova, Italy; 2Department of Gynecological Science and Human dant neuropil background with true ependymoblastic rosettes confirmed the Reproduction University Hospital of Padua, Padova, Italy; 3Department of ETANTR diagnosis among both of these two unusual cases. These peculiar Neurosurgery University Hospital of Padua, Padova, Italy; 4Pediatric hystological features of ETANTR suggest these neoplasms are undifferen- Department Division of Haematology-Oncology University Hospital of tiated neuroepithelial tumours which may display divergent differentiation Padua, Padova, Italy; 5Neuroradiological Service University Hospital of towards other type of embryonal tumours or mesenchimal component Padua, Padova, Italy with acquisition of sarcomatous phenotype. Congenital Central Nervous System Tumors (SNC) (i.e. tumours relate to diagnosis during the fetal life or in the first 28 days of life) are now more often diagnosed through the more widespread and accessible neuroimaging. Malignant histology is common with persistently poor outcomes despite evol- P-CASE.03. CHRONIC CIRCUM-4TH VENTRICULAR MRI ving adjuvant therapy. A retrospective review was performed of paediatrics SIGNAL ABNORMALITY PRECEDING THE DIAGNOSIS OF tumours surgically treated at Paediatric Oncology Department of the MIDLINE/VERMIAN MEDULLOBLASTOMA University Hospital of Padua over a 10-year period (1999-2009). Four cases J. C. Murray, W. A. Marks, J. H. Honeycutt, R. J. Gerstle, E. Z. Braly, and of congenital SNC tumors were identified; all of them were supratentorial. A. M. Gomez; Cook Children’s Medical Center, Fort Worth, TX, United There was hydrocephalus in 2 cases and all cases presented with an increasing States head circumference. Histology revealed one case of ETANTR (Embrional Tumor with Abundant Neuropil and True Rosettes), two cases of glioblastoma INTRODUCTION: Medulloblastoma is the most common malignant multiforme (GBM), and one case of teratoma. After the birth, the patient with brain tumor of childhood. The typical midline cerebellar vermian epicenter ETANTR and the two with GBM underwent surgical resection. The infant characteristically causes symptoms to occur over a short 1-2 month period. with ETANTR and one of those with GBM died within few days after the diag- Relatively rapidly progressive headaches, nausea, vomiting and cranial neuro- nosis. The other patient with GBM received chemotherapy and he is tumor free pathies result from obstructive hydrocephalus and brainstem compression. A 30 months after the end of therapy with good outcome. The child with tera- chronic prodrome lasting more than a few months is atypical. The evolution of toma died within the first post-natal week and an autopsy was performed MRI changes that might occur before actual tumor development is unknown. after death. Histological examination revealed a huge teratoma of the suprasel- We present a unique case of an adolescent with chronic cerebellar signs and lar region with mature and immature component. Central Nervous System circum-4th ventricular MRI signal changes (no tumor) who eventually devel- tumors in infants are suggestive of some oncogenic prenatal factors. Scant oped medulloblastoma. REPORT: A previously healthy 14 year-old girl was

NEURO-ONCOLOGY † JUNE 2010 ii129 Abstracts

literature remains about management and ethics of the treatment of babies diagnosed at this very fragile stage of development. Dropped head syndrome (DHS) is a rare condition, secondary to neck extensor weakness, resulting in abnormal persistent flexion of the neck, although correctable by passive extension. Several neurological conditions can present with DHS, namely neuromuscular and neurodegenerative dis- P-CASE.06. OUTCOME OF PATIENTS WITH INCIDENTALLY eases. It also has been described as a delayed complication in patients sub- DISCOVERED ASYMPTOMATIC POSTERIOR FOSSA (PF) mitted to radiotherapy and chemotherapy. We report a case of a MASSES 14-year-old girl with medulloblastoma and late onset DHS. K. C. De Braganca1, I. J. Dunkel1, M. M. Souweidane1,2, J. P. Greenfield1,2, Medulloblastoma was diagnosed at 7 years of age. She underwent surgery, and Y. Khakoo1; 1Memorial Sloan-Kettering Cancer Center (MSKCC), with total resection, followed by radiotherapy (36 Gy to the craniospinal New York, NY, United States; 2Weill Cornell Medical College, New York, axis and 56 Gy boost radiation to the posterior fossa) and chemotherapy NY, United States (weekly vincristine during radiotherapy and eight 6-week cycles of CCNU, cisplatin and vincristine). Although in remission, the patient developed INTRODUCTION: Increasing use of brain MRIs has led to more inciden- severe visual impairment with optic nerve atrophy, severe bilateral deafness tal findings, the appropriate management of which is uncertain. A lesion dis- related to radiogenic mastoiditis and seizures. Four years after treatment, difficulty in sustaining an erect posture of the neck and chin lifting was noted. covered in the PF is of particular concern, as most pediatric brain tumors Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 originate from here. METHODS: We retrospectively reviewed the records MRI revealed abnormal cervical kyphosis, in association with paravertebral of all patients seen by the pediatric neuro-oncology team at MSKCC with muscles atrophy and local discrete hyperintensities on T2-weighted images, PF masses from July 1, 1993 to January 22, 2010. RESULTS: A total of suggestive of an inflammatory process. Diagnostic work-up also included 393 patients were identified. 81 patients were excluded from analysis due electrophysiological study, which showed signs of C7, C8 and T1 roots to incomplete records. Of the remaining 312 patients, 7 patients were chronic denervation. Both baseball cap orthosis and cervical collar were found to have asymptomatic, incidental PF lesions. Indications for imaging tried but, at 12 months of follow-up, there is no improvement in muscle were unique: head trauma, traumatic hearing loss, headaches, NF-1 surveil- strength. To our knowledge this is the first reported case of DHS in the lance and endocrinologic evaluation, with the exception of 2 patients pre- setting of pediatric brain tumour and craniospinal irradiation. senting with seizures. 5 patients underwent surgery for removal, 2 of whom had asymptomatic tumor progression. The median time between initial scan and surgery was 9 months. All pathology was low grade: 3 juvenile pilocytic astrocytomas; 1 low grade neuroepithelial neoplasm (patient with NF-1); and 1 choroid plexus papilloma. A patient with seizures and P-CASE.09. UNUSUAL PRESENTATION OF TWO CASES OF another with hearing loss did not undergo surgery. All patients are doing DIFFUSE INTRINSIC PONTINE GLIOMA well to date with a median follow-up of 17 months since initial scan. R. J. Patterson, L. B. Madsen, S. J. Giesar, M. B. Hansen, and A. E. Bendel; CONCLUSION: No patient who underwent surgery had high grade Children’s Hospitals and Clincs of Minnesota, Mpls, MN, United States disease and none required adjuvant therapy post-operatively. This small series suggests asymptomatic PF lesions can be followed clinically and radio- Diffuse Intrinsic Pontine Glioma (DIPG) typically presents with acute onset graphically. Therefore, it may be reasonable to monitor these lesions with of symptoms along with MRI evidence of T2/FLAIR signal abnormality and clinical exam and surveillance MRIs instead of neurosurgical intervention. expansion involving the majority of the pons. Two year survival is ,10%. Presented are two cases of DIPG with unusually long presentations, but typical clinical courses once the MRI findings met the criteria for a DIPG. CASE ONE: A 6-year-old boy presented with intermittent dizziness and a P-CASE.07. A 10 YEAR-OLD BOY WITH AN INCIDENTALOMA normal neurological exam. MRI showed an ill-defined area of T2/FLAIR 1 signal abnormality within the central and right pons measuring 1.5cm x DIAGNOSED AS A MEDULLOBLASTOMA 22 YEARS LATER U. B. Zeilhofer1, N. U. Gerber1, I. Scheer1, M. Warmuth-Metz2, B. Bison2, 1cm x 1.5cm. He was lost to follow-up. Four years later he presented with H. Bertalanffy3, E. Boltshauser1, and M. A. Grotzer1; 1University Children’s headache and a normal neurological exam. MRI was diagnostic of a DIPG. Hospital, Zurich, Switzerland; 2Department of Neuroradiology, University He received local radiation, but died from the DIPG 6 years from initial pres- of Wu¨ rzburg, Wu¨ rzburg, Germany; 3Department of Neurosurgery, entation and 18 months following MRI confirmed diagnosis of DIPG. CASE University Hospital Zurich, Zurich, Switzerland TWO: A 3-year old boy presented with acute onset right 5th cranial nerve dysfunction and an otherwise normal neurological exam. MRI showed an area of INTRODUCTION: Medulloblastoma usually presents with symptoms of increased T2/FLAIR signal in the left pons measuring 1 cm x 7 mm x 6 mm. cerebellar dysfunction and/or hydrocephalus. Corresponding to its highly Serial MRIs showed stable size of this lesion. Three and a half years later he malignant behavior, the prediagnostic symptomatic interval is in the range developed left 6th cranial nerve paresis. MRI was diagnostic of DIPG. He of several days to weeks. As surgery is usually performed directly upon detec- received local radiation, but died from the DIPG 5 years from initial presen- tion, little is known about its natural growth behavior prior to therapy. tation and 15 months following MRI confirmed diagnosis of DIPG. These CASE REPORT: We present a 10 year-old boy, who was incidentally diag- two cases suggest that ill-defined pontine lesions, even with minimal symp- nosed with a cerebellar vermian mass of 2 cm in diameter on a CT scan toms, might represent early DIPG and warrant continued follow-up. after a concussion in April 2006. No further diagnostic measures were taken. A CT scan performed 14 months later after another head trauma revealed an identical lesion, which on MRI appeared not clearly demarcated P-CASE.10. NATURAL BEHAVIOUR OF CEREBELLAR and inhomogeneous. No abnormal neurological findings were detected. In PILOCYTIC ASTROCYTOMA view of the clinical course, a low-grade glioma was suspected. A control A. Y. N. Schouten - van Meeteren1 and R. W. Koot2; 1Emma Children’s MRI 6 months later showed only slightly progressive disease. In April Hospital AMC, Amsterdam, Netherlands; 2Leiden University Medical 2008 the boy developed mild balance and coordination disturbance, Centre, Leiden, Netherlands however, tumor size was stable. In December 2008 the tumor showed clear local progression without evidence for metastases. Subtotal resection Pilocytic astrocytoma is considered to be a slowly growing WHO grade I was performed, leading to the diagnosis of a classical medulloblastoma, glioma mostly presenting in childhood. This indolent behaviour is especially which was confirmed by two reference pathologists. Therapy according to known in post-surgical residues which can remain stable for years. A case of the HIT 2000 protocol was started consisting of craniospinal radiotherapy an 8-year old girl is presented with vomiting and headache during the year followed by maintenance chemotherapy, under which the patient currently before. Additionally she developed strabismus and was presented in the hos- shows stable disease. CONCLUSION: To our knowledge, such a slow pital. No additional neurological abnormalities were found at physical exam- tumor growth over a period of more than two years has not been reported ination The MRI scan showed a large cystic cerebellar tumor. A pilocytic before for medulloblastoma. The well-documented natural history suggests astrocytoma was considered most likely, fitting with the prolonged history in this particular medulloblastoma a relatively slow multi-step pathogenesis. of vomiting and the radiologic features of the tumor. The proposed neurosurgical resection was refused by the father and the girl was lost to follow up. Two years later she visited the clinic with persisting signs of increased intracranial pressure, increasing loss of balance and weight loss. Meanwhile she was P-CASE.08. DROPPED HEAD SYNDROME AS A LATE POST treated with oleander extract as alternative treatment, considered by the TREATMENT COMPLICATION OF CEREBELLAR father to have anti-cancer properties. At this second admittance the repeated MEDULLOBLASTOMA IN A CHILD MRI showed a stable tumor volume. After final parental agreement a subtotal 1 2 3 4 1 1 S. Nunes , S. Vinhais , J. Nunes , M. Olias , and D. Salgado ; Pediatric neurosurgical resection was performed and histology showed a pilocytic Neuro-Oncology Unit, Instituto Portugueˆs de Oncologia de Lisboa, Lisboa, astrocytoma. Three years after tumor resection the girl is in excellent health, 2 Portugal; Department of Radiology, Instituto Portugueˆs de Oncologia de besides slight balance disturbance, and will graduate to high school. This 3 Lisboa, Lisboa, Portugal; Department of Neurology, Instituto Portugueˆsde case underlines the indolent natural behaviour of pilocytic astrocytoma. Oncologia de Lisboa, Lisboa, Portugal; 4Department of Rehabilitation, Instituto Portugueˆs de Oncologia de Lisboa, Lisboa, Portugal ii130 NEURO-ONCOLOGY † JUNE 2010 Abstracts

P-CASE.11. MULTICENTRIC PLEOMORPHIC incomplete because of the infiltrative behaviour of the lesion; still after a XANTHOASTROCYTOMA WITH SUBDURAL second resection, there was microscopical and radiological residual tumour. DISSEMINATION: A CASE REPORT Histology revealed a chordoid meningioma (OMS grade II) with a compart- M. P. Gardiman1, L. Iaria1, M. Calderoni2, R. Faggin2, D. D’Avella2, ment of rhabdoid cells. Immunohistochemistry revealed the nuclear INI-1 E. Viscardi3, and G. Perilongo3; 1Department of Oncological and Surgical protein in all tumour cells, except in those of rhabdoid morphology, where it Sciences, Division of Pathology University Hospital of Padua, Padova, Italy; was absent in the nucleus but surprisingly present in the cytoplasm. Complete 2Department of Neurosurgery University Hospital of Padua, Padova, Italy; work-up showed CSF dissemination without metastases outside the CNS. 3Pediatric Department Division of Haematology-Oncology University The patient underwent craniospinal radiotherapy (36 Gy) with a local boost Hospital of Padua, Padova, Italy up to 59.4 Gy. Adjuvant chemotherapy according to the DFCI/ATRT protocol (Zimmerman et al., J Neuro Oncol 2005; 72:77-84) was started because of the Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor that persistence of local active residue on the MRI and tumour cells in the CSF. After usually occurs in the superficial cerebral hemispheres of children and 4 courses of this intensive treatment and by the patient poorly tolerated therapy young adults and has usually a favorable prognosis. We report on an combining systemic and triple intrathecal drugs, the disease was considered unusual case of multicentric PXA with subdural dissemination. A stable locally but tumour cells could not be fully eradicated in the CSF, so 14-year-old girl was admitted to Paediatric Neurosurgery Department of that an alternative treatment is currently discussed. Meningiomas in children the Hospital University of Padua with a recent history of sciatic pain syn- are rare, usually low grade, and have a good overall prognosis after complete Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 drome and atactic gait. MRI revealed multiple lesions: two large cystic excision. This case illustrates a previously undescribed histological subtype of lesions in the cerebellar vermis and in the left cerebellar hemisphere, a pediatric meningioma which seems to be extremely resistant to conventional solid intramedullary enhancing nodule at the dorsal level with diffuse enlar- therapies. gement of the spinal cord with extensive edema and multiple sub-meningeal nodules in both acoustic inner meati and in the sellar region. There was also a diffuse enhancement along the cerebellar and brainstem surface. After surgery, histological examination showed spindle cells intermingled with pleomorphic mono- or multinucleated giant cells. We observed abundant P-CASE.14. A CASE OF MALIGNANT RHABDOID TUMOR IN eosinophilic granular bodies, Rosenthal fibers and perivascular lymphoid THEEPIDURALSPACEOFTHESPINE infiltration, and absence of necrosis. The tumor cells were surrounded by N. J. Patel, C. A. Diamond, M. S. Salamat, K. Bradley, V. Gondi, basement membranes that stained positively for reticulin. Glial fibrillary T. A. Kennedy, L. Keller, B. Iskandar, and D. Puccetti; University of acid protein (GFAP) confirmed the astrocytic origin, whereas synaptophysin Wisconsin, Madison, WI, United States and neurofilament stains were negative. MIB1 showed a very low proliferation index (,3%). The pathologic diagnosis was multicentric pleomorphic Malignant rhabdoid tumors are highly aggressive neoplasm of childhood xanthoastrocytoma with subdural dissemination. To our knowledge, this is and carry a poor prognosis. When they involve the spinal cord, they are fre- the third case of multicentric PXA with disseminated disease reported in quently located intradurally, and/or intramedullary. Extradural location is the literature. Hence, it was considered important to describe this case in rare, and our case is only the second such case reported. We report the order to add further information regarding the spectrum of the presenting case of a 13 year old boy who presented with several months’ history of pro- clinical features of this rare neoplasm. gressively worsening neck pain. MRI scan of the spine revealed a homoge- neously enhancing epidural mass at the C2-C4 levels, with extension through the left C2-C3 neural foramen, erosion of the C3 vertebral body and displacement of the spinal cord. Given its close proximity to the left vertebral artery, a partial debulking was achieved. Histologically, the tumor P-CASE.12. LATE ONSET EPILEPSY WITH ATONIC SEIZURES IN revealed solid sheets of epithelioid cells with eccentric nuclei, and eosinophi- MEDULLOBLASTOMA LONG-TERM SURVIVORS lic cytoplasm. Immunohistochemistry was positive for vimentin and cytoker- J. Marques1, S. Nunes2, J. P. Foreid3, and D. Salgado2; 1Neurology atin and negative for hSNF5/ INI1, consistent with the diagnosis of Department, Instituto Portugueˆs de Oncologia de Lisboa, Lisboa, Portugal; malignant rhabdoid tumor. Metastatic work-up revealed no disease else- 2Pediatric Neuro-Oncology Unit, Instituto Portugueˆs de Oncologia de where in the rest of the spinal cord, brain, chest, abdomen, pelvis, bone Lisboa, Lisboa, Portugal; 3Neurophysiology Department, Instituto and bone marrow. Postoperatively, the patient received an alkylator-based Portugueˆs de Oncologia de Lisboa, Lisboa, Portugal intense multi-agent chemotherapy regimen and localized radiotherapy to a total dose of 50 Gy to the gross disease. He is currently receiving on-going Epilepsy is one of the most frequent sequelae in children treated for chemotherapy, and remains free of disease progression, now 8 months tumors, especially leukaemia or central nervous system (CNS) tumors. In from his initial diagnosis. Through this case report the authors would like the largest published series regarding neurological disability in adults to call attention to this aggressive neoplasm in the differential diagnosis of treated for CNS tumors in their childhood, 25% of the patients reported sei- an epidural spinal mass. zures, which in 6.5% started 5 or more years after the oncological treatment. Epileptic syndromes are not well characterized and it is assumed that they are related to the toxic effects of treatment, radiation and chemotherapy. In this regard, there are only few reported cases of epilepsy with atonic seizures, frequently associated with leukoencephalopathy and cognitive decline, and P-CASE.15. PRIMITIVE NEUROECTODERMAL TUMOR OF THE refractory to treatment. We report two patients with medulloblastoma and SPINE IN A PATIENT WITH A LONG LASTING HISTORY OF late onset epilepsy with atonic seizures. The first is an 11-year-old boy, diag- HYDROCEPHALUS. nosed with medulloblastoma at age 5, and the second a 20-year-old female N. J. Patel, M. S. Salamat, D. A. Puccetti, V. Gondi, K. Bradley, L. Keller, patient, diagnosed at age 7. Both patients are in complete remission since K. Casey, T. A. Kennedy, and B. Iskandar; University of Wisconsin, the end of the treatment (which included surgical removal, radiotherapy Madison, WI, United States and chemotherapy), and in both there is a history of atonic seizures (starting 5 and 12 years post-treatment). EEG of both patients reveals multifocal par- Primitive neuroectodermal tumor (PNET) of the spine is a rare entity in oxystic activity (and in the first case, also generalized paroxysms). The first children. No standard of treatment exists, and the prognosis is poor. We patient is being treated with sodium valproate, zonizamide, topiramate report a case of a boy who had a long standing history of hydrocephalus and vigabatrin and remains without seizures for ten months. The female since birth and then at 9 years of age developed back pain with difficulty patient has still a poor seizure control despite the association of several anti- straightening his back. Imaging revealed an extensive intradural, extrame- epileptic drugs. dullary and nodular mass involving the entire spinal cord and a 12mm gadolinium enhancing area in the cerebellar vermis. Histologically, the biopsy specimen showed a densely cellular neoplasm with hyperchromatic nuclei and scant cytoplasm. Immunohistochemistry was positive for vimentin, NSE and GFAP and negative for CD99 and synaptophysin, diagnostic of P-CASE.13. MIXED CHORDOID AND RHABDOID central PNET. He was treated with craniospinal irradiation plus boost to MENINGIOMA: AN INTRIGUING AND UNDESCRIBED the posterior fossa, and to bulky disease at T11-T12 levels, with concurrent HISTOLOGICAL SUBTYPE IN CHILDHOOD daily carboplatin and weekly vincristine. Following the completion of che- S. Pernet Fattet1, M. Beck Popovic1, M. Osterheld1, D. Paccaud2, B. Rilliet1, moradiotherapy, imaging revealed complete resolution of his tumor and cer- and N. Von der Weid1; 1University Hospital CHUV, Lausanne, Switzerland; ebrospinal fluid was negative for malignant cells. He then received four 2Regional Hospital Chablais, Monthey, Switzerland courses of dose-intensive adjuvant chemotherapy consisting of high-dose cyclophosphamide, vincristine, cisplatin and autologous stem cell rescue. A 12-year-old boy presented with acute frontal headaches, myoclonias of the He is now alive and well, eleven months from the time of diagnosis. Here, tongue and bilateral papillary oedema. On MRI a heterogeneous tumour initi- we highlight the development of spinal PNET after a 9 year history of hydro- ating from the dura mater and infiltrating the right frontal cortex, extending cephalus and its dramatic response to chemoradiotherapy despite the exten- posteriorly close to the motor cortex was found. Initial surgical resection was sive disease. This report, discusses the clinical course of this case,

NEURO-ONCOLOGY † JUNE 2010 ii131 Abstracts

emphasizing the importance of differentiating the central PNET from periph- Overall incidence of secondary malignant tumors in children varies between eral PNET, and review the literature on central spinal PNET. 8 - 12% after 20 years from diagnosis of the primary malignant process. The incidence of RIG is growing up due to more intensive oncology care and increasing number of surviving patients. The paper presents a patient who underwent subtotal resection of cerebellar medulloblastoma at the age of 10 (in the year 2000), followed by radiotherapy (SJMB 96 protocol, up to P-CASE.16. BREATH-HOLDING SPELL AS UNUSUAL 54 Gy) and chemotherapy (VCR, CDDP, CYC). Complete remission was PRESENTING PICTURE OF A CERVICOMEDULLARY GLIOMA: described in 2001. Routine follow up MRI examinantion revealed a cerebel- ACASEREPORT. lar tumor in 2006, classified as glioblastoma multiforme after radical neuro- P. Fidani, F. del Bufalo, M. A. De Ioris, M. D. De Pasquale, F. Demelas, surgery. The patient subsequently received treatment with temozolomide I. Ilari, A. Serra, A. Jenkner, L. De Sio, R. Cutrera, S. Bottero, G. Fariello, and VP-16. MRI remission was described after 4 months, but the patient and E. Procaccini; Ospedale Pediatrico Bambino Gesu` IRCCS, Rome, Italy died due to extensive tumor progression with brainstem infiltration after 7 months. This course illustrates the generally poor prognosis of RIG. Cervicomedullary gliomas are a distinct subset of brainstem tumors, Standard chemotherapy is not sufficiently effective, also high dose che- usually characterized by a long history of localizing symptoms. We present motherapy and stereotactic radiotherapy have not yielded convincing the rare case of a 28-month-old boy with a 2-year history of breath-holding results and these patients are candidates for experimantal therapy. Despite Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 spells and sleep apnea that presented to our hospital for respiratory insuffi- the known causal relationship between radiotherapy exposition and second- ciency secondary to breath-holding. An MRI revealed a large cervicomedul- ary malignant tumors, the individual risk for a particular patient or possible lary mass that was considered by the neurosurgeon not amenable to prophylactic measures are not known. Therefore, all patients with a history resection. The child underwent surgical decompression and biopsy disclosed of radiotherapy in childhood should be followed up for a long time due to the a pylocitic astrocytoma. MRI performed 1 month after surgery showed an high risk for secondary malignant tumors. increase in size of the lesion. Given the very young age of the patient, radiotherapy was omitted and chemotherapy with vincristine-carboplatin was started, according to SIOP-LGG 2004 protocol. Three months after diagnosis a severe apnea episode occurred and the patient developed cardiorespira- tory arrest requiring resuscitation. The severity of central and mixed apneas P-CASE.19. CHEMOTHERAPY INDUCED SECONDARY and the very poor compliance of the child to Non-Invasive-Ventilation (NIV) INTRACRANIAL MALIGNANCIES eventually led to tracheostomy. This procedure allowed a more appropriate D. Kim; Department of Neurosurgery, Yonsei University College of management of the apnea episodes and an effective nocturnal ventilation, Medicine, Seoul, Republic of Korea improving the median oxygen saturation. The MRI performed at the end of the induction phase showed a reduction in size and in contrast enhance- With increased survival of pediatric tumor patients with multimodality ment of the lesion. Even if cyanotic breath-holding spell is a benign clinical treatments including chemotherapy and radiation therapy, incidence of sec- condition, usually occurring in otherwise healthy infants and young children, ondary malignancy rate is increased as well. Secondary malignancies in the we suggest that an early onset, especially when associated with other relevant central nervous system (CNS) due to chemotherapy alone are uncommon. symptoms, could be related to an underlying organic disorder and should be Most of the chemotherapy-induced secondary malignancies are hematopoie- given due consideration. tic in origin and CNS malignancies are rare especially with chemotherapy alone. We will present two cases of chemotherapy-induced secondary CNS malignancies. The first one is a 5-year-old boy with cerebellar medulloblastoma mixed with pilocytic astrocytoma. He had a history of left nephrect- omy and chemotherapy for clear cell sarcoma at one year old. The other P-CASE.17. HIGH GRADE GLIOMA IN 2 PATIENTS WITH one is a 8-year-old boy who presented with headache and vomitting. He CYSTIC FIBROSIS TREATED WITH RADIATION AND underwent chemotherapy after resection of multiple malignant fibrous his- CHEMOTHERAPY WITHOUT COMPLICATION tiocytomas of the skull. Imaging study revealed a left frontotemporal mass V. S. Kanwar1 and A. Broniscer2; 1Albany Medical Center, Albany, NY, and resection was done. Glioblastoma multiforme (GM) was diagnosed United States; 2St Jude Children’s Research Hospital, Memphis, TN, United and concurrent chemo/radiation therapy with temozolomide was done. States After the 1st maintenance cycle of temozolomide, he was admitted to hospital for pelvic pain and general weakness with fever. Image work up revealed a BACKGROUND: Cystic fibrosis has been associated with pancreatic and right pelvic lesion and bone marrow biopsy confirmed acute lymphocytic leu- gastrointestinal cancers, but is rarely associated with high grade glioma. The kemia (ALL). He underwent ALL induction and consolidation chemother- treatment of high grade glioma in patients with cystic fibrosis is therefore apy for 6 months. Brain MR revealed recurrence of GM. Secondary CNS poorly documented, and there are no data as to whether these patients toler- malignancies are rare after chemotherapy alone. Unveiling genetic alterations ate chemotherapy without significant morbidity. PATIENTS AND in these cases may lead to pathways to understand tumorogenesis. METHODS: We describe 2 pediatric patients with cystic fibrosis who were treated for high grade glioma with no excessive therapy-related complications. PATIENT 1: A 17-year-old female with a butterfly glioma (glioblastoma multiforme) was treated with radiation and temozolomide, and continued on monthly cycles of temozolomide (Stupp regimen) until P-CASE.20. POST-SURGICAL HYPERTROPHIC OLIVARY disease progression 8 months from diagnosis. Until progression she had DEGENERATION (HOD): EXPERIENCE IN A PAEDIATRIC only one hospital admission for a seizure, and no infectious episodes. POPULATION PATIENT 2: A 12-year-old female with gliomatosis cerebri (anaplastic astro- M. P. Gardiman1, M. Calderone2, R. Mardari2, C. Carollo2, R. Faggin3, cytoma) was treated with radiation and erlotinib, and continued on daily D. D’Avella3, E. Viscardi4, and G. Perilongo4; 1Department of Oncological oral erlotinib until disease progression 4 months from diagnosis. She suffered and Surgical Sciences, Division of Pathology University Hospital of Padua, no infectious episodes. CONCLUSION: Pediatric patients with cystic fibrosis Padova, Italy; 2Neuroradiology Unit, University Hospital of Padua, Padova, and high grade glioma may tolerate a standard chemotherapy regimen Italy; 3Pediatric Neurosurgery, Pediatric University Hospital of Padua, without significant morbidity, and it is reasonable to offer them this option. Padova, Italy; 4Oncology University Hospital of Padua, Padova, Italy

Hypertrophic olivary degeneration (HOD) is a rare complication of an injury to the dentato-olivary pathway. HOD hallmarks include at magnetic resonance imaging increased T2 signal of the olive with or without hypertro- P-CASE.18. RADIOTHERAPY INDUCED GLIOBLASTOMA phy. The aim of our study was to evaluate the incidence of HOD after surgical MULTIFORME IN THE CHILD TREATED FOR CEREBELLAR treatment of cerebellar neoplasms in a paediatric population. We retrospec- MEDULLOBLASTOMA tively analyzed 125 pre- and post-operative brain MRIs of 50 paediatric E. Brichtova1, Z. Pavelka2, L. Kren3, J. Skotakova4, A. Oltova4, and patients (26 males, mean age 8.5 years, age range 9 months to 16.9 years) P. Slampa5; 1Neurosurgery Dpt., Clinic of Pediatric surgery, orthopaedics followed-up in our centre from 1992 to 2009 with histopathologically con- and traumatology, Brno Faculty Hospital, Brno, Czech Republic; 2Clinic of ﬁrmed posterior fossa tumors (90% medulloblastomas and pylocytic astrocy- Pediatric Oncology, Brno Faculty Hospital, Brno, Czech Republic; 3Dpt. of tomas) undergoing cerebellar surgery. Six cases (12%) of HOD were found. Pathology and Anatomy, Brno Faculty Hospital, Brno, Czech Republic; All six patients developed HOD postoperatively, between 4 and 15 months 4Clinic of Pediatric Radiology, Brno Faculty Hospital, Brno, Czech Republic; after surgery. In all cases the HOD was attributed to resection of the contro- 5Clinic of Radiation Oncology, Masaryk Oncology Center, Brno, Brno, lateral dentate nucleus. Four patients had unilateral HOD, whereas 2 pre- Czech Republic sented bilateral HOD. Only in one patient HOD showed T2 olivary hyperintensity without hypertrophy. None of the patients had contrast Radiotherapy induced malignant gliomas (RIG) are the most common enhancement on T1 weighted images. It is important to consider HOD as a central nervous system malignant tumors observed after radiation treatment. potential complication in patients undergoing cerebellar surgery. Care ii132 NEURO-ONCOLOGY † JUNE 2010 Abstracts

should be taken not to mistake at magnetic resonance imaging HOD for for 4 weeks. The symtoms of neck pain and stiffness dramatically decreased malignancy relapse or post-operative vasculopathy. High signal intensity con- after 3 days of treatment and mostly subsided in one week. The follow-up fined to the area of the inferior olivary nucleus, accompanied by a remote images after 3 months showed complete resolution of inflammation lesion, suggests HOD even if clinical manifestations are absent. without recurrence. Clival osteomyelitis could present clival syndrome and mimic central skull base neoplasm. This problem mainly happens in old age and immuno-compromised patients, or results from spread of infection through otitis media, sphenoid sinusitis, or fossa navicularis magna. The possible cause of clival osteomyelitis in this healthy 7-year-old boy might P-CASE.21. MANAGEMENT OF AN INTRACRANIAL MATURE attribute to innate fossa navicularis magna with lymphoid tissue residing. TERATOMA RECURRING AS A GERMINOMA S. Kay, S. Singh, J. Provias, M. A. Alyman, and K. Scheinemann; McMaster Children’s Hospital, Hamilton, ON, Canada P24 EMERGING PROGRAMS IN DEVELOPING Germ cell tumors (GCTs) of the central nervous system in pediatric COUNTRIES patients are rare. Tumor markers, specifically AFP and b-hCG, and histology are pertinent to classification and management of GCTs. In this report, we Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 present a nine year old who had an intracranial mature teratoma recur as a germinoma. Few cases exist with this pattern of recurrence. Here we focus P-EMERG.01. RISK ASSIGNATION IN MEDULLOBLASTOMA: on the importance of pathology and adequate tissue sampling in guiding WHAT HAVE WE LEARNED IN PANAMA appropriate management, as tumor marker levels alone may not reflect a M. S. Ah Chu; Panama Children’s Hospital, Panama´, Panama comprehensive diagnosis. Our patient presented with recurrent severe headaches for four days. MRI demonstrated a pineal lesion extending into the BACKGROUND: The treatment of children with medulloblastoma rep- suprasellar cistern. He underwent a biopsy suggesting mature teratoma; resents a challenge in any possible scenario. When we address topics however, pathology following surgical gross-total resection indicated areas related to technical resources, the difficulties could be even more accentuated suspicious for germinoma. The resected areas, serum, and cerebrospinal in low-middle income countries. METHOD: This is a retrospective review of fluid (CSF) levels were tumor marker negative, so no further therapy was 22 cases of medulloblastoma, diagnosed and treated in Panama Children’s administrated. Subsequent MRI scans were negative for recurrence. Three Hospital from January 1998 to December 2009. Medical records and diag- years post-resection, he presented with marked neurological deterioration, nostic images (CT scan, brain MRI and spine MRI in those cases who had it) including an internally abducted left arm with posterior deviation. MRI were reviewed. Clinical characteristics are presented, as well as a comparison showed extensive subependymal lesions, which biopsy confirmed as germi- of outcomes of truly high risk (HR) medulloblastoma and those without noma. Tumor markers were immunonegative in the resected tissue and enough evidence of spinal compromise, and the standard risk (SR) patients. serum, but CSF w b-hCG as positive. He was treated with three cycles of car- RESULTS: We decided to treat all, but three cases as HR medulloblastoma, boplatin/ etoposide followed by craniospinal radiation. Post-treatment MRI because we lack the evidence to rule out spinal compromise.19 patients were revealed complete resolution of the tumor, and CSF b-hCG normalized. originally assignated HR. Of these, 5 patients were actually SR according to Clinically, he returned to pre-relapse levels of functioning. Chang classification, but instead, they were treated as HR. The five patients Histopathological confirmation cannot be underestimated in achieving the are alive and in remission. The mortality rate among those patients that were most accurate GCT subtype to ensure effective treatment, estimate progno- truly HR is 85.7%. The survival among those treated as HR is 36.8%. The sis, and reduce recurrence risk. OS was 43% at five years. Myelosupression, infection, and long-term neurological sequelae were the main secondary effects. The median time for recurrence is 9 months. CONCLUSION: We emphasize the importance of learning from the past to better shape the future, to be consistent with treatment protocols, and not to spare efforts in diagnostic accuracy, particularly P-CASE.22. CONGENITAL HEMANGIOPERICYTOMA OF THE when our actions may provide a chance for survival. SCALP: A CASE REPORT T. Inagaki, Y. Yamanouchi, and K. Kawamoto; Department of Neurosurgery, Kansai Medical University, Moriguchi, Osaka, Japan

INTRODUCTION: Malignant soft tissue tumors of the scalp are relatively P-EMERG.02. EPIDEMIOLOGY AND SURVIVAL OF rare. We surgically treated a soft tissue tumor of the scalp and followed for 5 CHILDHOOD PRIMARY CENTRAL NERVOUS SYSTEM years without recurrence. CASE REPORT: A girl was referred to our institute MALIGNANCIES IN IRAN: RESULTS FROM A SINGLE a couple of days after birth because of the mass at the top of head which was INSTITUTE thought to be a encephalocele by local gynecologist. The physical examin- K. Arjmandi Rafsanjani, G. Bahoush, and P. Vossough; IUMS, Tehran, Iran ation revealed a soft mass which is movable from the skull. CT also revealed no skull defect beneath the soft mass. The laboratory data showed no BACKGROUND: Childhood primary CNS malignancies are one of the abnormality. We surgically removed the tumor with 0.5 cm safe margin. most important concerns in pediatric oncology. Therefore, epidemiologic The histology was hemangiopericytoma of the scalp. Because of the possible and survival data are very helpful for future planning. METHOD AND malignant in nature, we followed her carefully after surgery without che- MATERIAL: In the retrospective cross-sectional analytic study 82 patients motherapy or irradiation. The patient remains so far asymptomatic. treated in Ali-Asghar Children’s Hospital between 1985 and 1995 were eval- CONCLUSION: We reported on an extremely rare congenital hemanigoper- uated for age, gender, type of treatment, tumor pathology and survival. icytoma of the scalp which was successfully removed without recurrence. RESULTS: The records of 38 female (46.3%) and 44 male (53.7%) patients were included. The mean age was 6.8 + 3.3 years (6 months-14 years), 45 (58.6%) patients had medulloblastoma, 18 (22%) astrocytoma, 13 (15.9%), ependymoma, and 3 (3.7%) glioma. Total resection, radiotherapy and chemotherapy were done in 42.7%, 82.5% and 87.2% of patients, P-CASE.23. CLIVAL OSTEOMYELITIS MIMICS CENTRAL SKULL respectively. Mean follow-up time was 51.3 months (1-106 months). The BASE NEOPLASM IN A HEALTHY 7-YEAR-OLD BOY 5-year cumulative survival probability was near 42%. CONCLUSION: M. Liang, F. Chang, and T. Wong; Taipei Veterans General Hospital, Taipei, Inferior survival rate in comparison with developed countries may be associ- Taiwan ated with delay in diagnosis and refers to oncologist and a more progressive tumor at diagnosis. A 7-year-old boy presented with severe painful torticollis, headache and neck stiffness for 20 days. Progressive neck pain with fever happened 2 days before admission. Elevated white blood cell and inflammatory reactive protein were also noted. CT scan of brain and cervical spine revealed an osteolytic lesion with soft tissue mass over clivus, suspected to be leukemia, P-EMERG. 02A. PATTERN OF BRAIN TUMORS AMONG eosinophilic granuloma, Ewing sarcoma or chordoma. MRI of brain dis- CHILDREN IN CENTRAL SUDAN closed an enhancing margin lesion over clivus with a few fluid accumulations A. Elha, N. Osman, A. A. Elobied, A. Abdallah, and D. Abuidris; National over retropharyneal space. Initially, central skull base neoplasm with related Cancer Institute, University of Gezira, Gezira, Sudan meningitits was impressed; however, the diagnosis changed to clival osteomyelitis after fine needle CT-guided biopsy through pterygo-mandibular BACKGROUND: The incidence of childhood cancer varies greatly fossa. The pathology of the specimens showed lymphoid cells and histiocytes throughout the world depending on its type. Though lower compared with including CD20(+) B-lymphoid cell, CD3(+) T-lymphoid cells, CD138(+) the incidence of some adult cancers, cancer comes next to accidents as the plasma cells, neurtrophils and eosinophils, and negative for malignant cells. leading cause of death among children in the developed world (1). The Antibiotic treatment using clindamycin and claforan started and continued pattern of childhood cancer in America and Europe is almost the same with leukemia and central nervous system tumors account for over one-

NEURO-ONCOLOGY † JUNE 2010 ii133 Abstracts

half of the new cases. Data on childhood cancer incidence and patterns in pediatric-cancer-sufferers were noted and priorized. RESULTS: Since 2006 Africa are sparse. Although there are many papers published reporting inci- 347 new pediatric cancer cases were diagnosed in rural/tribal india. Only dence and patterns in some African countries. (1, 2, 3, 4, 5, 6, 7, 8). seven specialized cancer care centers are available. There is no follow-up OBJECTIVE: To determine the patterns of childhood brain tumors in center for palliative care and counseling. 160 specialist palliative care beds Gezira State, central Sudan during a period of 10 years. Patients and are required with 15 palliative oncologists for these services. Currently we methods : The study was a retrospective analytical study included all patients have strength of 11. CONCLUSIONS: Palliative care is neglected in develop- who were 15 years or younger at the time of first presentation to NCI and ing nations. Our NGO project data is forwarded to other NGO’s and govt who were diagnosed with primary brain tumors. The study covered a hospitals for palliative care advocacy in this vulnerable pediatric age period of 10 years from 1999 to 2008. The study looked at many variables group. But we need a strong-platform like the ISPNO concerning the patients and their tumors. These variables included age, 2010-Vienna-conference to show our findings to researchers/activists from sex, residence, duration of symptoms prior to presentation, type of tumors, the developed world and get guidance on this difficult issue of mode of diagnosis and presenting symptoms. These variables were then ana- pediatric-oncology. LESSONS LEARNED: Our Indian-cancer-NGO taken lyzed and discussed. RESULTS: During the study period there were 5296 initiative by training in pediatric palliative care. But such initiatives need patients attended the NCI for management.464 (8.7 %) of them were chil- support for implementation in poor rural/tribal pediatric neuro-cancer dren. 17 (3.7 %) patients of these children presented with one of the brain patients. tumors. Male: female ratio was approximately 0.9:1, the majority of them Downloaded from https://academic.oup.com/neuro-oncology/article/12/6/ii1/1000776 by guest on 30 September 2021 were between 5 and 10 years of age (47 %) and most of them came from rural origins (59 %). Glioma was the predominant diagnosis. Astrocytoma was either pilocytic astrocytoma grade 1 (3 patients) or diffuse fibrillary Astrocytoma grade 2 (one patient). Gliomas were seen more frequently in P-EMERG.04. HOW TO APPROACH PATIENTS IN PEDIATRIC the brainstem (4 patients out of 6). Ependymoma grade 2 and DNET NEURO-ONCOLOGY: EXPERIENCES OF INDIAN CANCER grade 1 were diagnosed in only one patient for each condition. The most NGOS common presenting symptoms among the study group were headache D. Pramod; Health alert Organization of India [NGO], Dhule, India (53 %), defective vision/squint (35.3 %), and ataxia (29.4). Most of these patients presented within 3 months after developing symptoms (59 %). BACKGROUND: Pediatric neuro-oncology is challenging in The disease was confirmed by histopathology examination and scans in 7 resource-poor-nations. We undertook a 1 year project in rural/tribal patients (41 %) and by scans only in 10 patients (59 %). Unfortunately 7 India to address this burning issue and to improve rural health set-up. patients (41 %) died during this period, 8 (47.1 %) alive, and 2 (11.8%) METHODS: Eleven tertiary-care-hospitals and 2 NGOs were included in escaped from the hospital. A surgical attempt for excision was only per- study. A questionnaire on the needs of pediatric patients was given to formed in 5 patients (29 %). CONCLUSION: The study reflects the 132 healthcare providers. Thirty four terminally ill children with a life overall poor referral rate of childhood brain tumors and the inadequate sur- expectancy of 2 years were interviewed / evaluated. Standardized evalu- gical management which led to high mortality rate reported. The study also ation was essential for multidisciplinary discussion. It is important to showed that, Gezira region pattern is similar to other African region where improve QoL. Due to the enormity of the project we took frailty / brain tumors do not predominate. depression as primary parameter. Responses of cancer-service providers were rated against suggestions by parents. RESULTS: GIT solicited 34 patients over a 2-year period. The mean age was 6 + 42.1 years, 59% were male, 41% female. 45% of the subjects showed symptoms of cognitive disorder. Mini-GDS were used to detect depression, and were positive in P-EMERG.03. PALLIATIVE CARE FOR PEDIATRIC NEURO 74%. We identified disabled patients who did not receive counseling / psy- CANCER PATIENTS: NEED BASED ANALYSIS BY INDIAN chotherapy. 89% pointed out to lack of psycho-social care, currently there CANCER NGO is a lack of adequate counseling. Inadequate patient education on nutrition, D. Pramod; Health alert Organization of India [NGO], Dhule, India social support and absence of trained-psychologist were mentioned as a dominant factor by 64 healthcare providers. CONCLUSIONS: Our OBJECTIVE: Past studies indicate a very high incidence of pediatric 3-year on-hand experience clearly shows the need for and the benefit of psy- neuro-cancers in Asian population. Approximately 117 children die per chosocial support for pediatric neuro-oncology. Sadly, counseling care is year in rural India. Most of the diagnosed children have fatigue (.72%), non existent. As indicated by 82% of the patients improvement is war- pain (.81%), depression (.92%), and/or lethargy (.84%). Individual ranted. We need a strong platform like ISPNO-2010 to show our findings variation, ethnic, economical, educational & racial factors decides the type to researchers / activists from developed world and get their guidance on of palliative care every patients needs. There is no scientific study done in this difficult issue. The government must carry out supportive-care- India on this issue. Hence, our 10 year-old-cancer NGO decided to programs with NGOs to bring down incidence of frailty / depression. explore this issue. METHODS: Regional cancer registry data and statistics LESSONS LEARNED: Our Indian-cancer-NGO took the initiative on from local charitable clinics from 2006 to September 2009 were analyzed. this difficult issue. Our project is awaiting further guidance / funding Children were divided on basis of economic/educational parameters. The from government agencies for implementation to serve poor rural / tribal opinion of 21 cancer caregivers about palliative care was evaluated. pediatric populations. Twelve weeks follow-up. Issues of concern to families of

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