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Neuro-Oncology � JANUARY 2003 23

Tenth International Symposium on Pediatric Neuro-Oncology

June 9–12, 2002

London, England

Neuro-Oncology

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1. HIGH RESPONSIVENESS TO CHEMOTHERAPY OF ABRAIN STEM GLIOMA: A CASE REPORTAbate ME,1 Garrè ML,2 Perilongo G,3 Scarzello G,4 Paolucci P1;1Department of Pediatrics, Casa Sollievo della Sofferenza Hospital, SanGiovanni Rotondo, Italy; 2Pediatric Neurosurgery, Istituto G. Gaslini,Genova, Italy; 3Pediatric Hematology-Oncology, University of Padua,Italy; 4Institute of Radiotherapy, University of Padua, Italy

A brain stem glioma represents a therapeutic challenge. Treatment plansusually incorporate radiation therapy +/– chemotherapy, but the results arestill dismal. We present the case of a ten-year-old boy who was admitted toour care with unsteady gait, weakness of the left arm and leg, VI and VII cra-nial nerves dysfunction, and abnormal level of consciousness. The MRIdemonstrated a 3x3x3 cm lesion of the pons extending to the right portionof the midbrain, hyperintense on T2-weighted sequences and hypointense onprecontrast T1-weighted sequences with heterogeneous enhancement aftergadolinium. The spinal MRI was negative for metastatic disease. Hydro-cephalus was present and a shunt was implanted, but a surgical approach tothe lesion was not indicated because of the anatomic localization of thetumour. On the basis of the clinico-radiological findings, we suspected a low-grade glioma and started a 1-year chemotherapy with Vincristine (1,5 mg/m2)and Carboplatin (550 mg/m2) according to the Low-grade Glioma SIOP Pro-tocol, with careful clinical and radiological monitoring. The tumour responseto chemotherapy at 12, 24, 35, and 47 weeks demonstrated a gradualdecrease of the greatest dimensional diameters and of the contrast enhance-ment of the tumour, while the patient showed a concomitant improvementof the neurological findings. At week 54 the patient was on clinical com-plete remission, and the MRI demonstrated a reduced hypo-isointense brainstem lesion without contrast enhancement on T1-weighted sequences. Thus,he was referred to the radiotherapist to start fractionated stereotactic radio-therapy of the residual lesion. The patient is alive with clinical completeremission at 20 months from diagnosis. In this case a careful clinical and radi-ological evaluation of the brain stem tumour, even without the histologicaldiagnosis, permitted us to obtain an extremely good response with a chemo-therapy protocol for low-grade glioma.

2. PATTERNS OF RELAPSE FOLLOWING CARBOPLATIN-BASED CHEMOTHERAPY AND FOCAL IRRADIATION OFINTRACRANIAL GERMINOMA: THE SFOP EXPERIENCEAlapetite C, Carrie C, Brisse H, Thiesse P, Habrand J-L, Gaboriaud G,Frappaz D, Cuilliere J-C, Moncho V, Baranzelli M-C, Patte C, on behalfof the SFOP (Société Française d’Oncologie Pédiatrique); RadiationOncology Department, Institut Curie, 26 rue d’Ulm, 75005 Paris, France

Craniospinal irradiation (CSI) is considered to be the standard treatmentin patients with localised intracranial germinomas (ICG). In order to reducethe potential toxicity associated with this treatment, the SFOP attempted inthe TGM-TC90 to replace CSI by chemotherapy (alternating courses ofetoposide-carboplatin and etoposide-ifosfamide for a total of 4 courses) fol-lowed by focal irradiation limited to the initial tumour volume plus 2 cm mar-gins (40 Gy). We report the pattern of relapse for this combined approach.Between 1990 and 1999, 79 patients were registered, 66 patients withlocalised and 13 patients with metastatic disease (median age 13 yrs, range5–24). Median follow-up was 62 months. Overall survival and EFS were97% and 82%, respectively. In patients with initially localised ICG, OS andEFS were 98% and 84%. Among those patients, 62/66 were treated accord-ing to the protocol and 9 relapsed (14%). Median time to relapse was 36months (10–57). All MRI/CT scans at diagnosis, at relapse, and at radiationtreatment related parameters were reviewed. Seven relapses occurred as mul-tiple subependymal dissemination in the supratentorial ventricular system(combined with tumour bed in 2, positive CSF in 1, subarachnoidal posteriorfossa in 1). All ventricular relapses were partly or exclusively outside the radi-ation field. In 2 patients, distant leptomeningeal relapses outside the fieldsoccurred (bulbo-medullary junction and medullary axis). No relapse out-side the CNS was observed. Treatment of relapse included second-line chemo-therapy in all patients followed by re-irradiation in 2, high-dose chemo-therapy (HDC) and re-irradiation in 2, and HDC only in 5 patients. Insummary, of patients with localised ICG, 84% benefited from this combinedapproach with focal irradiation and 14% relapsed. The predominant patternof relapse was ventricular, observed in 7/9 patients. In comparison to the pat-tern of relapse reported after CSI, this suggests that chemotherapy alone may

not be sufficient to control subclinical ventricular disease and supports con-sidering a combined approach with an extended radiation treatment vol-ume that encompasses the entire ventricular system at prophylactic doses,particularly in older children.

3. LONG-TERM RESULTS IN CHILDREN WITHMEDULLOBLASTOMA: THE EXPERIENCE OF INSTITUT CURIE Alapetite C, Larrouy A, Gaboriaud G, Bours D, Mosseri V, Brisse H,Pontvert D, Zucker JM, Doz F; Institut Curie, Paris, France

We report the 20-year experience in children with medulloblastomatreated in Institut Curie from 1980 to 2000. Seventy-two patients (pts) wereincluded successively in unicentric, multicentric, and national (SFOP) proto-cols. Pts characteristics and treatment results were analysed with specialemphasis on the 2 consecutive approaches for definition of the radiation vol-ume of the posterior fossa (PF) boost: inclusion of the tumor bed with a mar-gin before 1992 and irradiation of the whole PF when registered in the SFOPstudy. Whenever possible, the conventional PF limits tend to be reduced inorder to lower the risk of adverse late effects. Median age of the 72 pts was8.5 yrs. There were 45 males and 27 females. Complete or subtotal resec-tion was performed in 60 pts (83%). Forty-two (58%) were standard-risk(SR), and 30 (42%) were high-risk (HR) pts (postoperative residue in 9,including positive CSF in 2, isolated positive CSF in 2, and M2-M3 in 19).Radiotherapy was delivered to all patients. Mean doses were 26 Gy to thecraniospinal axis (CSI) and 54 Gy to the PF for SR pts, and 32 Gy CSI and54 Gy PF for HR pts. Sixty-nine children received chemotherapy with vari-ous schedules. Median follow-up is 10 yrs. Progression-free survival rate at5 and 10 yrs was 69%. All PF relapses were within the radiation field. Theonly significant prognosis factor was the staging: 5-year OS was 82% forSR pts, 64% for HR pts (57% for M2-M3). Interestingly, modalities of irra-diation for the PF boost did not significantly influence the outcome. Thirty-eight percent of the surviving patients required adapted schooling. This ret-rospective unicentric study shows good long-term survival even in metastaticpatients. Reduced radiation volume for the PF boost did not alter the patients’outcome.

4. MOLECULAR ANALYSIS OF TRANSCRIPTION FACTORSIN MEDULLOBLASTOMASAppleby V, Lee C, Orme A, Punt J, Walker D, Scotting P; NottinghamChildren’s Brain Tumour Research Centre, Institute of Genetics, Universityof Nottingham, QMC, Nottingham, UK

Medulloblastomas, the most common paediatric brain neoplasms, areembryonal tumours of the cerebellum which vary widely in their malignancyand aggression. Clinically, however, these variants are indistinct due to lackof reliable prognostic markers, and consequently a similar intensity of treat-ment is used for each patient, with associated side effects. In order to improvethe prognosis for these patients, a greater understanding of the biology of thetumours is required. Neoplastic cells within these tumours are thought to par-tially recapitulate stages in the maturation of normal human neuroblasts;therefore embryological studies of the earliest events in the development ofthe cerebellum may provide vital information about the molecular behaviourof the tumour and hence about its likely clinical outcome. The dissection ofpaediatric brain tumours at a molecular level, by analysis of the expressionof several families of transcription factors, should provide insight into thebiological behaviour of these primitive lesions. Members of the bHLH andzinc-finger families of transcription factors are known to regulate key stepsin neuronal maturation, and hence expression of these factors in tumour sam-ples may reflect the maturational state of individual tumours. RU49 and theGLI transcription factors are members of the zinc finger family of proteinsand provide additional information regarding the lineage of tumour cells(RU49) and their capacity to proliferate (RU49/ GLIs). The expression of thegenes encoding these factors has been analysed in a cohort of tumour sam-ples using in situ hybridisation, and preliminary results showing variableexpression of all transcription factors suggest that the tumours are very com-plex heterogeneous lesions. Functional studies of RU49 and GLI, includingtransfection of expression constructs into primary granule cell culture and

Neuro-Oncology

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Neuro-Oncology � JANUARY 200326

consequent analysis of the transfected cells by immunohistochemistry for avariety of markers, are currently in progress. FAC sorting of these transfectedprimary cultures has also allowed us to perform RT-PCR with bHLH geneprimers. These functional studies should allow us to further assess the roleof these factors in tumorigenesis and their potential to affect tumour behav-iour in such a way that they might act as potent prognostic markers.

5. PHASE 2 PILOT STUDY OF CONCURRENT CARBOGEN AND RADIATION THERAPY IN CHILDRENWITH HIGH-GRADE DIFFUSE BRAIN STEM TUMORSAquino-Parsons C,1 Hukin J,2 Green A,1 Poskitt K; 1Department ofRadiation Oncology, Vancouver Cancer Center, BC Cancer Agency;2Department of Pediatrics, Division of Oncology and Neurology, BCWomen’s and Children’s Hospital, Vancouver, British Columbia, Canada

Background: Children with diffuse brain stem tumors have a dismalprognosis. As there is data demonstrating the existence of hypoxia in braintumors, this resistance to therapy may be due to intra-tumoral hypoxia. Lab-oratory data demonstrate that hypoxic tumors are rendered more sensitiveto radiation damage with carbogen (95% oxygen and 5% carbon dioxide)inhalation given during radiation treatment. Aim: To assess the feasibilityand outcome of the addition of 5% carbogen inhalation to standard dailyfractionated external beam radiation therapy in paediatric patients with high-grade diffuse brain stem gliomas. Method: Patients referred to the PaediatricOncology group with a clinical and/or pathologically confirmed high-gradediffuse brain stem glioma were assessed for suitability for entry into an ongo-ing clinical trial of the addition of 5% carbogen inhalation for 4 minutesprior to and during standard once-daily radiation therapy. Eligibility crite-ria: age <18 years; a high-grade primary brain stem glioma or unbiopsied dif-fuse brain stem tumour to be treated with partial brain external beam radi-ation; duration of symptoms less than 3 months at time of diagnosis; thepresence of at least two of the following in unbiopsied cases: pyramidal tractinvolvement, cerebellar signs and symptoms, cranial nerve deficits; in unbiop-sied cases, diffuse involvement of the brain stem on MRI. Ineligibility crite-ria: inability to tolerate the carbogen breathing apparatus, inability toundergo radiation therapy without sedation, and neurofibromatosis type 1.Results: Between July 1998 and July 2001, only 3 patients were eligible forentry into this trial. The median age of the patients was 11 years. All threewere boys; all were able to inhale carbogen for greater than 95% of the radi-ation treatments. While all three have progressed and subsequently died,the median overall survival was 1.7 years (0.5–2.6). Conclusion: It is feasi-ble to offer this therapy to this select group of patients. While all patients dideventually succumb to their disease, the overall survival of these patientscompared favourably to our historical controls, where the median survivalis 0.5 years. Exploration of novel therapies is required if significant advancesin this devastating disease are to be made.

6. PRIMARY INTRACRANIAL GERM CELL TUMOURS: 12-YEAR EXPERIENCE FROM UNIVERSITY OF MALAYAMEDICAL CENTRE , MALAYSIAAriffin H, Lin HP, Shekhar K, Chong LA, Chan LL, Ariffin WA;Department of Paediatrics, University of Malaya Medical Centre, 50603Kuala Lumpur, Malaysia

Objectives: To study the clinical features, treatment, and outcome of chil-dren with primary intracranial germ cell tumours (IGCT) managed in ourunit. Methods: Case records of patients admitted with IGCT between 1 Jan1990 and 31 Dec 2001 were reviewed. Results: During the study period, atotal of eight patients with IGCT were treated and followed up. During thistime, 64 primary intracranial malignant tumours were diagnosed and man-aged in our institution. There were 5 boys and 3 girls, with a mean age of 9years (range 3.5 to 16 years). The presenting symptoms were precociouspuberty (n = 3), raised intracranial pressure and focal neurological deficits (n= 4), diabetes insipidus (n = 3), and visual disturbances (n = 3). Commonestlocations of the tumours were the pineal region (n = 4) and suprasellar area(n = 3). One patient had synchronous tumours in both the suprasellar andpineal regions. Histology was available in 6 patients; these were germinomas(n = 3), mixed germ cell tumour (n = 2), and immature teratoma (n = 1). Allpatients were treated with platinum-based chemotherapy and radiotherapy,while three patients had surgical resection in addition to the two treatmentmodalities. Seven out of 8 patients are still alive, with the longest follow-upbeing 10 years. Conclusions: Germ cell tumours accounted for 12.5% ofprimary intracranial tumours in our unit. Our experience demonstrated thatplatinum-based chemotherapy and irradiation, with or without surgical exci-sion, is an effective treatment strategy for these tumours.

7. CHARACTERISATION OF APOPTOTIC PATHWAYS ANDRESISTANCE MECHANISMS IN GLIOMAAshley D, Knight M, Riffkin C, Muscat A, Hawkins C; Department ofHaematology and Oncology, Royal Children’s Hospital, and MurdochChildren’s Research Institute, Victoria, Australia

High-grade gliomas in childhood are refractory to conventional anti-cancer treatments in part because the glioma cells are resistant to the apop-totic death induced by those treatments that act via a mitochondrial depen-dent pathway. The possibility of using ligands such as TRAIL, which in othercell types have been shown to induce cell death using divergent pathways, isunder exploration. We have therefore investigated the sensitivity of gliomacells to TRAIL, and the pathways and mechanisms of resistance used by these cells. Glioma cell lines were heterogeneous with respect to sensitiv-ity to TRAIL-induced apoptosis. In some sensitive glioma lines, mitochon-drial amplification was required. In other glioma cells a direct receptor-adapter-caspase pathway was used, obviating the necessity for mitochondr-ial involvement. Important factors that influenced both whether glioma cellswere sensitive to TRAIL-induced death and, for the sensitive cells, whethermitochondrial amplification was required for apoptosis include the expres-sion levels of Caspase-8 and Bcl-2 family members. These studies providevaluable information regarding the likely utility of newly developed candi-date therapies (such as TRAIL, cytotoxic cytokines, or vaccines) to treatglioma.

8. A RISK-ADAPTED TREATMENT PROTOCOL FORCHILDHOOD MEDULLOBLASTOMASAyan I, Yaman Agaoglu F, Kebudi R, Dizdar Y, Gorgun O, Darendeliler E;Istanbul University Institute of Oncology, Istanbul, Turkey

From January 1994 onward we conducted a study of risk-adapted treat-ment for children with newly diagnosed medulloblastoma. Risk groups I–IIIincluded patients (pts) ≥ 3 yrs of age and are defined as follows: group I,totally resected tumors of any size (Chang T1-4) but Mo disease; group II,subtotally resected tumors of any T but Mo disease; group III, totally orsubtotally resected tumors of any T and M 1-3 disease; group IV, any patients<3 yrs of age or with metastases outside CNS. Treatment plan consisted ofconventional cranio-spinal radiotherapy (RT) [54/36/36 Gy] for risk groupI pts; concomitant cisplatinum (Ccis) [40 mg/m2/wk] and cranio-spinal RTfor risk group II; Ccis and cranio-spinal RT followed by 8 courses of adju-vant chemotherapy (ChT) [Ctx, Vcr, CCNU, Proc] for risk group III. Patientswho were <3 yrs of age received ChT only until disease progression or 3rdbirthday. Patients with metastatic disease outside CNS had ChT 2 coursesbefore and 8 courses after Ccis and cranio-spinal RT. A total of 30 pts(17M/13F) with a median age of 6 yrs (6 mos–14 yrs) are included in thisstudy. There were 4 pts in risk group I, 4 pts in risk group II, 17 pts in riskgroup III, and 5 pts (<3 yrs old) in risk group IV. The following table demon-strates the disease extent of pts.

Sub-total

Risk Total resec- Rel./Group T1 T2 T3 T4 Mo M1 M2 M3 LLMI* resec. tion PD**

I(n=4) – 2 2 – 4 – – – – 4 – 1 II(n=4) – – 4 – 4 – – – – – 4 1 III

(n=17) – 1 12 4 – 5 2 6 5 11 6 8 IV(n=5) – – 4 1 – 1 1 1 1 2 3 4 Total – 3 22 5 8 6 3 7 6 17 13 14

* Local lepto-meningeal invasion**Relapse or progression

Thirteen pts had progression or relapse within a median of 11 mos (4–21 mos), 11 of whom died. The median follow-up time was 40 months(4–6 mos). The 5-year overall survival rate was 51.76% for the whole series,and progression-free survival rate was 46.72%. Patients with LLMI negative(p = 0.01, 5-year survival rate 73.8% vs 39.6%), and Mo (p = 0.02, 5-yearsurvival rate 66.6% vs 15.7%), and >3 years of age (p = 0.05, 5-year survivalrate 54.3% vs 40%) had significantly better outcome.

9. PROGNOSTIC VALUE OF CLINICAL AND BIOLOGICALPARAMETERS IN MEDULLOBLASTOMABadal D, Hernández M,* Alvarez JA,** Roldan S, Pastor J, Cañete A,***Castel V,*** Petschen I; Departments of Radiation Oncology, *Pathology,**Neurosurgery, ***Pediatric Oncology, La Fe Hospital, Valencia, Spain

Introduction: The role of different clinical and biological parameters inmedulloblastoma is still controversial. We have analysed our experience overthe last decades. Materials and Methods: Patients referred to our Departmentof Radiation Oncology between 1970 and 1999 were retrospectivelyreviewed. We analysed the following parameters: age, sex, tumor location,symptom duration, stage (Chang), hemoglobin levels (g/dl), LDH, perfor-

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mance scales (Lansky, Karnofsky), shunt, surgical resection and complica-tions, radiotherapy technique and delay, chemotherapy, p53, Ki-67, GFAP,NP differentiation, DNA index, and pathological variety. Statistical Analy-sis: Kaplan-Meier for survival and progression-free survival (PFS), univariate(Mantel-Cox, Tarone-Ware, Peto-Prentice), and multivariate analysis (Coxmodel). Results: Ninety-three patients were analysed: 80 children, 13 adults.There were 46 radical resections, 22 with minimal rest, 23 subtotal, 2 biop-sies. Radiotherapy was delivered to 87 patients (34.5 Gy neuraxis, 55 Gy pos-terior fossa); it was suboptimal in 13/93 cases. Seventy-one patients receivedchemotherapy (SIOP studies). Seventy-eight patients achieved completeresponse; 43/93 relapsed (42% in posterior fossa). Five- and ten-year survivalrates are 48 and 37%, respectively; PFS is 43 and 37%. Survival was betterfor patients treated in the 1980–1990 decade (55–39%) compared to the1970–1980 decade (27–19%). The low-risk group (complete resection, nometastasis) had a 5–10 year survival of 74–67% and PFS of 70–60%, respec-tively. Patients with the poorest survival in the univariate analysis were stageT3b-T4, tetraploid DNA, subtotal surgery, shunt, and surgical complications,low radiotherapy doses (<30 Gy CNS, <50Gy posterior fossa), radiotherapydelay >40 days, technique employed, and general status<80. In the PFS stage,DNA index, surgery extension, shunt, and radiotherapy delay kept statisti-cal power. The most important prognostic independent factors were stage,surgical complications, and DNA index for survival and stage for PFS (Coxregression). Conclusions: (1) Improvements in surgery, radiotherapy tech-nique, and chemotherapy lead to a better survival in medulloblastoma. (2) Inour experience, stage and DNA index are the only independent prognosticfactors in multivariate analysis. Collaborative studies of molecular andgenetic factors will allow us to classify and treat patients according to riskfactors, as in other diseases.

10. MEDULLOBLASTOMA WITH FATAL REACTION TO RADIATION THERAPY IN NIJMEGEN BREAKAGESYNDROMEBakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, Bhambhani K; Division of Pediatric Hematology Oncology,Department of Pediatrics, Children’s Hospital of Michigan, Wayne StateUniversity School of Medicine, Detroit, MI, USA

PR was a small-for-gestational-age child with microcephaly, facial dys-morphism (receding forehead, left-sided ptosis, upward slanting eyes, andanteverted nares), and clinodactyly. At 3 years of age, he was still failing tothrive with developmental delay. He was diagnosed with localized medul-loblastoma that was resected. Craniospinal radiation of 23.4 Gy and poste-rior fossa boost of 32.4 Gy over a 7-week period resulted in severe radiation-induced dermatitis along with gastro-esophagitis unresponsive to medicaltherapy. He had multiple infections during his 3-months’ hospital stay, withinterstitial pneumonitis at the time of his death. The terminal event was bleed-ing from an aortic-esophageal fistula. Patient was lymphopenic with normalimmunoglobulins, but on retrospective evaluation there was no prior historyof recurrent infections. Colony survival assay on patient’s EBV-transformedlymphocytes revealed a high degree of radiosensitivity ex vivo. Presence ofradiation sensitivity, both clinically and ex vivo, in association with micro-cephaly and growth retardation, prompted the diagnostic workup forNijmegen breakage syndrome (NBS). No detectable NBS protein, nibrin, wasfound by Western blot analysis of the protein lysates. Mutational analysis ofpatient’s DNA by single strand conformational polymorphism showed vari-ants in exon 6 and exon 10 of the NBS1 gene; sequencing revealed the com-mon founder mutation of NBS 675del5 in exon 6, and 1142delC in exon 10.Wild type alleles were also present for both exons, indicating that the patientwas a compound heterozygote for these mutations. Since radiation is animportant component of therapy for brain tumors, caution needs to be exer-cised in all cancer patients with associated microcephaly and growth retar-dation, as they may prove to be NBS.

11. DISCONTINUATION OF ANTICONVULSANT THERAPYIN CHILDREN WITH BRAIN TUMORSBaleeiro JAK, Hamre MR, Smietana S, Sharadashree DR, Bhambhani K;Division of Pediatric Hematology/Oncology, Children’s Hospital ofMichigan, Detroit, MI, USA

Objective: To determine whether anti-epileptic drug therapy (AET) canbe safely discontinued in children with brain tumors. Background: Childrenwith brain tumors frequently develop seizures. Improved treatment for braintumors has led to increased survival. However, the timing for discontinuationof AET has not been adequately addressed. Since AET can result in adverseeffects, it is important to determine when it can be discontinued withoutseizure recurrence. Materials/Methods: We studied all patients admitted toChildren’s Hospital of Michigan with the diagnosis of a brain tumor from1983 to 2000. Records of children with brain tumors who developed seizureswere reviewed. All patients were started on AET. Characteristics for children

on AET were compared with those in whom AET was discontinued. Results:Forty-eight children with brain tumors experiencing seizures were identi-fied. Descriptive characteristics of the 19 patients for whom AET was with-drawn follow.

Seizure Type: 52% Complex-partial, VP shunt insertion: 42% 31% Tonic-clonic

Age: Median: 7.3 years, Chemotherapy: 47% ReceivedRange .3 –15.8 years

Race: 58% Caucasian, Radiation therapy: 78% Received 42% African-American

Sex: 42% Male, 58% Female Neurologic deficits: 52% Diagnoses: 68% Gliomas Tumor Recurrence: 31% Site: 90% Supratentorial Endocrine deficits: 36% Initial Surgery 42% Gross Total Resection, EEG: No epilepti- 68%

47% Partial form activity

There were no statistically significant differences in the demographics ofpatients weaned off AET versus patients still taking AET. Median intervalfrom time of last clinical seizure until weaning off AET was 3.3 years (range9 months to 8 years). Median interval for follow-up of patients off AETwas 2.2 years (range 0 to 10 years). No seizure recurrence was observed inany of the patients following discontinuation of AET. None of the patientswho continued to demonstrate epileptiform activity on EEG (6/19 = 31%)had seizure recurrences. Conclusions: Using criteria similar to discontinua-tion of AET in patients with seizures unrelated to brain tumors, our findingssuggest that AET may be safely discontinued in children with primary braintumors receiving multi-modality therapy. Furthermore, continued epilepti-form activity on EEG in these children is not an accurate predictor for whenAET can be discontinued.

12. PHASE I STUDY OF ORAL CONTINUOUSADMINISTRATION OF LOW-DOSE TEMOZOLOMIDE IN PEDIATRIC BRAIN TUMORSBaruchel S,1 Hargrave D,1 Stempak D,1 Coppes M,2 Moghrabi A,3

Gammon J,1 Klein J,1 Bouffet E,1 Koren G,1 Leclerc JM4; 1Hospital ForSick Children, Toronto, Canada; 2Alberta Children’s Hospital, Calgary,Canada; 3Ste Justine Hospital, Montreal, Canada; 4Schering PloughCanada

Temozolomide is an imidazotetrazine; in vivo it is spontaneously cleavedto MTIC. It is licensed in adults (PO qd x 5 days, every 4 weeks) for the treat-ment of anaplastic astrocytoma. This 5-day regimen has been unsuccessful inpediatric CNS tumors. Extended dosing (75 mg/m2/day PO qd for 6 weeks)has been studied in adults. Objectives: To determine the pediatric maximumtolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics(PK) of temozolomide administered continuously as a 42-day cycle in chil-dren with recurrent CNS tumors. Design: Patients were stratified into heav-ily pretreated or less heavily pretreated groups, and the starting doses forthese groups were 50 mg/m2 and 75 mg/m2 daily x 42 days. Between cyclesthere was a 3-week rest. Results: 22 patients entered, 16 were evaluable (6failed to complete cycle 1). Median age, 11.3 (range 3–18) years; 10 males,12 females; total number of cycles received, 48 (range 1–9). Diagnosis: 4brain stem glioma; 3 ependymoma; 4 PNET/medulloblastoma; 7 high-gradeglioma; 3 low-grade glioma, and 1 meningioma. Responses were documentedin 6 patients: 1 CR (recurrent medulloblastoma post ABMT) and 5 PRs(gliomatosis cerebri, gliosarcoma, medulloblastoma, and 2x low-gradeglioma). Stable disease was seen in 1 ependymoma, 1 meningioma, and 1high-grade glioma. Patient accrual is ongoing with additional patients receiv-ing 85 mg/m2 to confirm the MTD in the heavily pretreated group. PK datawill be discussed and are comparable to adult PK data with a similar proto-col. Conclusion: Continuous low doses of temozolomide are well toleratedand associated with a significant response rate (27%) in this phase I study.The DLT is thrombocytopenia at 100 mg/m2, and the recommended dose forphase II is 75 mg/m2. The response rate is extremely encouraging and war-rants the development of this schedule into phase II.

13. SURGICAL MANAGEMENT OF RECURRENTEPENDYMOMA IN CHILDRENBaumgartner J, Ater J; The University of Texas MD Anderson CancerCenter, Houston, Texas, USA

We reviewed the outcome of children treated surgically for recurrentependymoma at the MD Anderson Cancer Center using the charts of chil-dren treated for ependymoma at MD Anderson since 1980. Fifteen childrenwith surgically treated recurrent ependymoma were identified (7 female, 8male). Initial resections were gross total in 10 patients and subtotal in 5.Initial pathology was ependymoma in 4 cases, anaplastic ependymoma in 8cases, and mixed ependymoma in 3 cases. Patients under 5 years of age weretreated with a variety of chemotherapeutic regimens after their initial surgery,while those older than 5 years received conventional radiation therapy. Time

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to tumor recurrence (or progression) ranged from 3 months to 7 years andwas shorter in subtotally resected patients. Twelve patients had local recur-rence: 2 had cranial recurrence with spinal disease, and 2 developed lep-tomeningeal disease. While 4 patients (with brain stem invasion) succumbedto complications following reoperation, the remaining patients survived from2 to 17 years after their second surgery. Patients whose tumors were totallyresected at their second surgery had the best survival. One patient survived3 reoperations for locally recurrent disease over 5 years. One patient, treatedas an infant with chemotherapy, developed leukemia. A patient treated withradiation therapy developed a chondrosarcoma of the skull. Locally recur-rent ependymoma can be successfully treated with reoperation. Ependymo-mas are less likely to recur than anaplastic ependymomas. Secondary tumorssometimes develop with prolonged survival. Excellent long-term survival canbe achieved in some patients.

14. THE USE OF RECOMBINANT FACTOR VIIA (RFVIIA) TO CONTROL INTRAOPERATIVE BLEEDING IN PEDIATRICBRAIN TUMOR PATIENTSBendel A, Mahmoud N, Madsen L, Alshiekh M, Heisel M; Children’sHospitals and Clinics, Minneapolis, MN, USA

Brain tumors are the most common solid tumors of childhood. Tumorresection may be complicated by significant blood loss due to anatomic loca-tion or increased vascularity of the tumor. Advances in neurosurgery, neuro-anesthesia, and hemostatic techniques have improved survival, but blood losscontinues to be an issue for some patients. This abstract describes the use ofrFVIIa (NovoSeven®, Novo Nordisk, Denmark) to control intraoperativebleeding in five pediatric patients undergoing neurosurgical resection of braintumors. The use of rFVIIa was first considered when Patient 1 (see table)developed life-threatening blood loss unresponsive to neurosurgical tech-niques and blood product replacement. Within 30 minutes of rFVIIa (118mcg/kg) administration, all bleeding ceased and the tumor was successfullyresected. rFVIIa was subsequently administered to 4 pediatric patients under-going surgical resection of brain tumors (2 of whom had multiple proce-dures). Overall, rFVIIa provided excellent hemostatic control, was well tol-erated, and resulted in no obvious adverse events.

Blood rFVIIaPatient Age; Loss Administered Hemo-# Months Diagnosis (cc/kg) (mcg/kg) statis?

1 24 Choroid plexus 509.80 118 (to control Yes carcinoma bleeding)

2 204 High-grade glioma 5.01 275 (to control Yes bleeding)

3 (a) 3 Meningeal sarcoma 139.30 98: 2 doses No (to control bleeding)

3 (b) 3.5 32.20 98 (prophylaxis) Yes 3 (c) 5 29.11 93 (prophylaxis) Yes 4 (a) 2 Choroid plexus carcinoma 18.90 97 (prophylaxis) Yes 3 (b) 5 13.70 74 (prophylaxis) Yes 5 156 Anaplastic oligodendro- 25.70 102 (to control Yes

glioma bleeding)

At our institution we currently recommend that rFVIIa be considered for pediatric brain tumor patients undergoing surgical resection if life-threatening bleeding occurs, unresponsive to conventional interventions.Unreconstituted rFVIIa should be available in the operating room for suchsituations. If the child is <15 kg and has evidence of a highly vascular tumoror has previously experienced massive blood loss, a prophylactic dose of90mcg/kg rFVIIa may be administered at the time of tumor excision. Recentstudies have shown successful use of 30mcg/kg rFVIIa for hemostasis in pedi-atric patients with coagulopathic disorders. Clearly, additional studies arewarranted to assess dosing strategy.

15. SLEEP DISTURBANCES IN CHILDREN WITH BRAINTUMORSBendel A, Hargens L, Moertel C, Rosen G; Children’s Hospitals andClinics-Minneapolis/St. Paul, MN, USA

Sleep is a complex neurological process that is controlled by and benefitsthe brain. Sleep can be disturbed by a number of CNS insults. Children withbrain tumors may develop difficulties with some aspect of sleep due to irre-versible brain injury from the tumor and treatment. Comprehensive sleepstudies on brain tumor patients may define a specific sleep abnormality forwhich treatment could be directed. A retrospective chart review was per-formed on all brain tumor patients tested for sleep disturbances by our insti-tution’s sleep clinic. Between 1994 and 2001, 10 patients with brain tumorswere evaluated by polysomnogram (PSG). In addition, a multiple sleeplatency test (MSLT) was performed on 8 patients and actigraphy on 2patients. Tumor types included 3 medulloblastomas, 3 brain stem tumors, 1optic chiasm glioma, 1 craniopharyngioma, 1 pineoblastoma, and 1 hypo-

thalamic glioma. The referrals were made for daytime sleepiness (9/10), sleepapnea (3/10), continuous movement during sleep (1/10), and snoring (2/10).All of the children demonstrated a clinically significant problem based on theresults of the PSG, MSLT, and actigraphy: 6/10 excessive daytime sleepiness(1 optic chiasm glioma, 1 brain stem tumor, 1 pineoblastoma, 1 cranio-pharyngioma, 1 hypothalamic glioma, 1 medulloblastoma) with 3 of the 6meeting the criteria for symptomatic narcolepsy; 3/10 moderate to severe cen-tral apnea (1 brain stem tumor, 1 medulloblastoma, 1 craniopharyngioma);1/10 nocturnal seizures (optic chiasm glioma); and 1/10 continuous move-ment during sleep (medulloblastoma). Following the sleep study, 2 centralapnea patients started nocturnal positive pressure ventilation, and 1 begannocturnal oxygen with clinical improvement in sleep. Four of 6 patients withexcessive daytime sleepiness were prescribed a stimulant, and all showed clin-ical improvement. Pediatric brain tumor patients with daytime sleepinessoften have definable sleep abnormalities. The most common sleep disordersdiagnosed in this series were excessive daytime sleepiness and central apnea.All 6 patients with excessive daytime sleepiness had evidence of hypothalamic/pituitary injury, and 2 of the 3 patients with central apnea had tumors local-ized to the posterior fossa. Further sleep studies in brain tumor patients mayelucidate mechanisms by which the brain affects sleep and assist in the devel-opment of new interventions.

16. ANALYSIS OF NEUROCOGNITIVE SEQUELAE IN BRAINTUMOR SURVIVORS.Bernabeu J, Cañete A, Barahona A, Badal MD,* Castel V; PediatricOncology Unit, *Radiation Oncology, La Fe Hospital, Valencia, Spain.Financed by EVES (Escuela Valenciana de Estudios para la Salud)049/2001

Introduction: Neurocognitive sequelae due to brain tumors and theirtreatment have been known in the last decades, when survival after these dis-eases improved. Rehabilitation of these sequelae in the pediatric populationis feasible; however, in order to begin a rehabilitation program, we need toknow the patient status after treatment. Measures of that are not well estab-lished in the pediatric populaton. Materials and Methods: Patients with anytype of brain tumor diagnosed and treated in our institution in the last 10years were prospectively studied. A complete neurological examination wasperformed, followed by two types of tests: the Streng Difficulties Question-naire (SDQ) and Wechsler scales. The SDQ was answered by parents (n = 10)or by patients (n = 12). The following Wechsler scales were used: WIPSI from4 to 6 years, WISC-R from 5 to 15 years, and WAIS over 16 years. Results:From December 2001 up to February 2002, 27 patients have been completelystudied. Fourteen patients were male and 13 female, median age at the studyof 11 years (range: 6–19 years) and pathological diagnosis of 14 PNET and8 low-grade gliomas and 5 more rare brain tumors. Thirteen were locatedin the cerebellum. Ten patients were treated according to SIOP-PNETIII and5 according to SIOP-LGG. Eleven patients had both radio and chemotherapy,7 had only radiotherapy, and 3 only chemotherapy. Verbal IQ: 4 high, 13average, 4 low. Manipulative IQ: 2 high, 14 average, 5 low. Total IQ: 3 high,14 average, 4 low. We found meaningful differences between verbal andmanipulative IQ in 14/21 patients (67%). SDQ was answered in 22 cases.Most of the patients considered themselves or were considered by their par-ent normal in the following items: emotional and behaviour (15/22, respec-tively), hyperactivity (14/22), peer relations (15/22), and prosocial behaviour(21/22). Conclusions: Although the sample is small and the study is ongoing,preliminary analysis shows that Wechsler scales and SDQ offer general infor-mation about the neurocognitive status of our patients. In order to developa neurocognitive rehabilitation program, more refined measures and sequen-tial studies are needed.

17. SIMULTANEOUS OCCURRENCE OF PRIMARYGLIOSARCOMA AND PRIMARY MALIGNANT MENINGIOMAIN THE SAME PATIENTBerrak S,* Dagçınar A,** Türkkan E,* Sav A,** Canpolat C,* ÖzekM**; *Department of Pediatric Hematology-Oncology, **Department ofPediatric Neurosurgery, Marmara University Medical Center, Istanbul,Turkey

Gliosarcoma and pediatric meningiomas are rare malignancies of the central nervous system. These malignancies are usually seen after radiationtherapy or in association with neurofibromatosis (NF). Simultaneous devel-opment of histologically different primary brain tumors aside from phako-matosis or previous irradiation is rare. We report a patient who had gliosar-coma and malignant meningioma, with no history of either irradiation orphakomatosis. A 2-year-old female child presented with right-sided motorweakness. Neurological examination on admission revealed right hemipare-sis. She had no stigmata or family history of NF or other phakomatosis. MRIdemonstrated two distinct tumors. The first was localized to the left frontallobe and measured 43x43 mm. The other one was found to be originating

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from the tentorium, attached to parenchyma of the left temporooccipital lobe.It was 36 x25 mm in size. Both tumors had marked contrast enhancement,cystic component, and peritumoral edema. Histopathologic examination ofthe frontal lobe tumor revealed gliosarcoma, while the temporo-occipitaltumor was found to be malignant meningioma. The patient received chemo-therapy consisting of vincristine, VP-16, carboplatin, ifosfamide cyclophos-phamide, and mesna. A tumor recurrence was detected during chemotherapy,for which a second surgery was performed. Histopathologic examination wasagain compatible with gliosarcoma, and this time the patient was treated withpaclitaxel. Another tumor recurrence was noted after 4 courses of chemo-therapy, and the patient died of tumor progression 18 months after admis-sion. Extensive review of the literature revealed occasional reports that men-tion the presence of meningioma in association with glioblastoma,oligodendroglioma, glioma, ependymoma, and adenoma, but not withgliosarcoma. Neither NF, irradiation, nor any other etiologic factors sup-posedly associated with multiple primary brain tumors was present in ourcase. Although the presence of a genetic dysregulation leading to the devel-opment of these tumors can be speculated, there is no specific cytogeneticabnormality reported that is common to both gliosarcoma and malignantmeningioma. Although this may be a case of coincidental occurrence of twoseparate neoplasms, further investigations for aberrations of the tumor sup-pressor genes should be performed.

18. CNS TUMOR EPIDEMIOLOGY AND OUTCOME IN THE YOUNG, 2000–2009: TEN PREDICTIONS FOR/FROMTHE UNITED STATESBleyer A, Montello M, Budd T, Ries L; University of Texas MD AndersonCancer Center, Houston, TX, USA; Children’s Oncology Group, Arcadia,CA, USA; Cancer Therapy Evaluation Program and Cancer StatisticsBranch, National Cancer Institute, Bethesda, MD, USA

Purpose: We examined the latest national NCI Surveillance, Epidemiol-ogy, and End-Results (SEER) data to determine the incidence and outcomeof brain tumors in patients 0–44 years old in the United States in order to dis-cern trends in brain tumor epidemiology and outcome. Methods: The annualrates in SEER incidence, U.S. mortality, and SEER 5-year survival for eachquintile from 0 to 39 years of age were analyzed for each year from 1975 to1998. Average annual percent changes were derived from linear regressionsof each of the reported annual rates. Children are defined as age <15 years,older adolescents and young adults (AYAs) as age 15–29, and 30–44 as adults(As). Predictions: (1) Children will continue to have a higher proportion ofbrain tumors relative to all cancer than AYAs or As. In contrast, AYAs willcontinue to have the lowest incidence of brain tumors. (2) Regardless ofage, males will continue to have a higher incidence of brain tumors thanfemales and astrocytomas and other gliomas will continue to predominate.(3) The increasing incidence of brain tumors will cease except in <5 year-olds;ependymomas will continue to increase, at least in boys. (4) Despite the abate-ment in increasing incidence, more children with brain tumors will still needto be treated. (5) The dependence of the type of brain tumor as a functionof age will change; the pattern of the past will no longer apply. (6) Survivalduration after brain tumor diagnosis will accelerate in children relative toAYAs and As, but a plateau on the survival curve will not be achieved. Chil-dren <5 years of age and children with ependymoma will continue to lagbehind. (7) In children and AYAs, cancer will continue to be the #1 diseasekiller and brain tumors the second most common cause of cancer mortality.(8) Progress will depend directly and on the number and proportion ofpatients entered into rigorous clinical trials. AYAs with brain tumors have thelowest participation rate and will have the least improvement in outcome. (9)AYAs and As with ependymomas and oligodendrogliomas will be mostaffected by lack of clinical trial participation, and the outcome in AYAs withastrocytomas will fall behind. (10) Rigorous clinical trials, and especiallythose with translational research, will determine progress more than anyother factor. Conclusion: If the predicted outcome is to be exceeded, partic-ipation in robust clinical trials will have to be augmented, particularly in<5-year-olds and in AYAs. Addressing the survival deficit will require broadsupport to increase clinical trial participation. Awareness, education, and col-laboration are paramount.

19. CLINICAL TRIALS FOR BRAIN STEM GLIOMA (BSG)PATIENTS: CRITICAL REVIEW OF STATISTICAL ENDPOINTSAND RESULTSBouffet E, Hargrave D, Baruchel S; The Hospital for Sick Children,Toronto, Canada

Aims: To critically review statistical design and results in clinical trials forchildren with BSGs. Method: Review of published prospective studies forBSG patients. Data collected: Type of trial (single-arm, randomised), eligi-bility criteria, statistical methodology used (historical comparison, sequen-tial analysis, etc.), statistical endpoint, stopping rules, response rate (RR),

median progression-free survival (MPFS), median overall survival (MOS), 1-and 2-year survival rate. Results: Seventeen clinical trials including 703patients between 1987 and 2001 were reviewed. There were 15 single-armstudies and 2 randomised trials. The median number of patients per studywas 34 (9–130). The median duration of a study was 2.5 years (1–4 years).In 14 trials inclusion was limited to patients with diffuse intrinsic pontineglioma, and in 3 to BSG patients (with a clinical history < 3months in 2).Twelve of 17 aimed at determining the toxicity and efficacy of hyperfrac-tionation. Statistical methodology was the following: randomisation (2), his-torical control (1), sequential analysis (1), not specified (11). Three single-arm studies used a phase I methodology. Only one single-arm study hadstopping rules. Postradiation RR was reported in 14 studies (436 patients),with an overall RR of 40.4% (CR: 2.1%, PR: 26.3%, MR: 12%) and a pro-gression rate of 16.9%. MOS is available in 16 studies (10 months, range8–12). MPFS is reported in 14 studies, but definition of time to progressionis specified in 3 reports only (2 clinical, 1 MRI). Sixteen studies provide sur-vival curves, 16 1-year survival data (median 38.5% (25–48%)), and 12 2-year survival data (median 12% (6.3–23%)). Only one study correlatesresponse data to survival data. Two of 3 phase I studies were terminated fortoxicity reasons. Two studies (1 randomised, 1 single-arm) were terminatedon statistical rational (no survival benefit). Conclusion: The statisticalmethodology used in clinical trials for children with BSG remains to be deter-mined. There is no evidence that response to RT correlates with survival, andstatistical design should be based on overall survival. Based on the currentknowledge of BSG in children, the number of patients included in single-armstudies should not be fewer than 20 (unless there is dramatic survivalimprovement) and should not exceed 40.

20. PROGNOSTIC FACTORS IN CHILDREN ANDADOLESCENTS WITH PILOCYTIC ASTROCYTOMASBowers DC, Shapiro KN, Mulne AF, Reisch JS, Gargan L; The Neuro-Oncology Program, Children’s Medical Center of Dallas and UT Southwestern Medical School, Dallas, TX, USA

The Pilocytic Astrocytoma (PA) is a distinct subtype of low-grade gliomaand the most frequently occurring childhood brain tumor. Few reports exam-ine risk factors for event-free survival (EFS) among cohorts restricted to PAs.We performed a retrospective, single-institution review of children with adiagnosis of PA from 1985 to 2000. Risk factors examined for subsequenttumor progression included sex, age at diagnosis, tumor location, neuro-fibromatosis, treatment, and degree of surgical resection. Log-rank and step-wise logistic regression analyses were utilized to identify significant risk fac-tors for subsequent tumor progression. One hundred forty-one children witha PA were identified [mean age: 7.51 years, range: 0.43–18.56 years; 79(54.9%) males]. After a mean follow-up period of 4.45 years, the EFS andoverall survival (OS) were 62% and 94%, respectively. Not surprisingly, theability to obtain a complete resection was highly dependent upon the tumor’slocation, especially for tumors located in the cerebellum, optic pathways, andbrain stem. By log-rank analysis, tumors located in the cerebellum, treatedwith surgery only, which had a complete resection were less likely to progress(all p values = 0.001). Children with coexisting neurofibromatosis (p = 0.021)and tumors located within the optic pathways (p = 0.001) were more likelyto progress. The patient’s sex, age at diagnosis, and tumors that were locatedin other locations were not significantly associated with subsequent pro-gression. By logistic regression analysis, significant predictors for EFS weretumors located in the cerebellum (Odds Ratio (OR): 0.15, 95% ConfidenceIntervals (CI): 0.05–0.40), brain stem (OR: 0.23, 95% CI: 0.08–0.70) andthat were completely resected (OR: 0.07, 95% CI: 0.023–0.23) (Hosmer-Lemeshow Goodness of Fit: 0.74; p = 0.86). Although PA is labeled a“benign” tumor, over one-third of children with PA suffer tumor progression.When possible, complete surgical resection remains the ideal and sufficienttreatment. PAs that occur in locations that are difficult to completely resect,such as the brain stem, remain a problem. Much work remains to betterunderstand the influence of tumor biology of PAs upon subsequent progres-sion.

21. GLIOMATOSIS CEREBRI, INITIALLY A DIFFICULTDIAGNOSIS: PRESENTATION OF THREE CHILDRENBroere D, Schouten–van Meeteren N, Smit L, Barkhof F, Knaap vd M;Department of Child Neuro-Oncology, Free University Medical Centre, De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands

Gliomatosis cerebri (GC) is the unifying term applied to diffuse glial infil-tration extending into the cerebral hemispheres and spinal cord. Diagnosisduring life is difficult because of conflicting pathological and/or radiologicalfindings in combination with emergence of severe neurological symptoms dueto diffuse invasion. There are few pediatric cases reported. The presentingsymptoms are intractable epilepsy, corticospinal tract signs, headaches,lethargy, and developmental delay. Signs of acute encephalomyelitis or symp-

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toms of intracranial hypertension with papilledema have also been reported.The diagnosis is considered based on MRI and showing poorly circumscribedT2-weighted lesions with swelling of involved areas without contrastenhancement and involving multiple brain areas. With CT/MRI-guidedstereotactic biopsy the diagnosis can be confirmed neuropathologically (astro-cytoma grade I–IV). The prognosis of GC is generally poor, with a mediansurvival time of approximately 12 months. Focal irradiation can temporar-ily stabilize neurologic function. We report on 3 children with different man-ifestations of GC. A 5-year-old girl presented with intractable epilepsy. MRIshowed a diffuse lesion and swelling in the left insula region concerning thecortex and adjacent white matter. A mitochondriopathy was excluded. Biopsyshowed astrocytoma grade III. She was treated with brain irradiation 5400cGy. At neurological progression after 1 year temozolomide was started andinterrupted after 1 course because of severe thrombopenia. The secondpatient was a 13-year-old boy with developmental disorder and a hemipare-sis. Partial resection showed grade II astrocytoma followed by focal radio-therapy. After 8 months and clinical progression, he was treated with pred-nisone, vincristine, and CCNU, but despite this treatment he died 5 monthslater. The third patient was an 8-year-old boy presenting with rapidly pro-gressive fatal neurological deterioration and papilledema. The first MRIshowed marked involvement of the frontal white matter and cortex, withsome extensions parietal and involvement of the corpus callosum. The abnor-mal white matter has a swollen appearance without contrast enhancement.The differential diagnostic considerations were a mitochondriopathy, PML,or gliomatosis cerebri. Neuropathology showed astrocytoma grade II–III. Thedifficulties in the differential diagnosis of GC, advances in neuroimaging andneuropathology, and the pros and cons of therapeutic options are discussed.

22. OVEREXPRESSION OF THE ERBB2 RECEPTORINCREASES THE SENSITIVITY OF MEDULLOBLASTOMACELLS TO THE ANSAMYCIN 17AAG VIA AN AKT-DEPENDENT MECHANISMCalabrese C, Maclean K, Hernan R, Frank A, Gilbertson R; Departmentof Developmental Neurobiology, St. Jude Children’s Research Hospital.Memphis, TN, USA

Overexpression of ERBB2 is associated with aggressive disease behaviorin medulloblastoma. Recently, overexpression of this receptor was reportedto increase the sensitivity of human tumor cells to the geldanamycin deriva-tive 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507).Therefore 17AAG is a potentially attractive novel therapeutic agent forpatients with ERBB2 expressing medulloblastoma. 17AAG inhibits themolecular chaperone HSP90 and its homologue GRP94. HSP90 and GRP94are involved in the correct folding and function of a number of proteins thatinclude ERBB2, mutant TP53, RAF-1, and AKT-1. However, the mecha-nism by which ERBB2 overexpression increases sensitivity to this compoundis not known. Therefore we have used ERBB2 transfected derivatives of thelow ERBB2 expressing Daoy and MHH-MED-8A medulloblastoma cell linesto investigate the impact of ERBB2 expression on the sensitivity of medul-loblastoma cells to 17AAG. 17AAG significantly inhibited the growth in cul-ture of Daoy and MHH-MED-8A cells. In 96-hour continuous exposureexperiments, ERBB2-overexpressing DAOY cells (two clones Daoy.2H andDaoy.2G) were 60% more sensitive to 17AAG (in terms of IC50) comparedwith empty vector controls (Daoy.v). This increased sensitivity was alsoobserved in shorter exposure time-course studies (16, 24, 48h). Western blot-ting analysis demonstrated characteristic depletion of HSP90 client moleculesand induction of HSP90 and HSP70 in a 17AAG concentration-dependentmanner in both ERBB2-overexpressing and control Daoy cells. However,comparison of basal AKT-1 levels showed significantly lower (>30%(p<0.05)) expression of this HSP90 client in ERBB2-overexpressing clonescompared with controls. Furthermore, transient transfection of Daoy.2G and2H cells with wild type (wt)AKT-1 restored basal expression level of AKT-1and reduced the sensitivity of these cells to 17AAG, returning their IC50 valueto that of empty vector control cells. In contrast, wtAKT-1 had no impacton the sensitivity of Daoy.v cells to 17AAG. Our data demonstrate thatERBB2 overexpression increases the sensitivity of medulloblastoma to17AAG. This is determined in part by the expression level of AKT-1, whichitself is dictated by the expression level of ERBB2. 17AAG warrants furtherstudy in clinical trials in children with medulloblastoma.

23. MALIGNANT CNS GERM CELL TUMORS (CNS GCTS): A REVIEW OF THE STATE OF THE ARTCalaminus G; University Children’s Hospital, Düsseldorf, Germany

Objectives: Primary CNS GCT account for about 2% of all intracranialneoplasms before 20 years of age. Histologically, CNS GCT are analogous toextracranial GCT. They can be divided into germinoma and nongermino-matous GCT (NGGCT). NGGCT include teratoma, embryonal carcinoma,yolk sac tumors, and choriocarcinoma, occurring as mixed tumors in about

30%. In case of expression of tumour markers (AFP-representing yolk sacelements, ß-HCG-representing choriocarcinoma) in serum/CSF, they arecalled “secreting.” Markers can be used for clinically guided diagnosis andtreatment response. Germinoma are exquisitely radiosensitive and chemosen-sitive; NGGCTs are less sensitive to RT. In the past 10 years increased clini-cal research reflected in institutional/multicenter trials in Europe, the UnitedStates, and Japan has been initiated. Research targets: In germinoma theattempt is to decrease late effects of extensive radiotherapy and in malig-nant NGGCTs to define risk-adapted treatment and increase survival rates.In key publications of the last 5 years, 3 main issues are targeted. Germinoma:Is chemo + RT equal to craniospinal RT (Alapetite MPO, Abstr., 2001,Fouladi Child’s Nerv. Syst, 1998)? Is chemo equal to RT at all (BalmacedaJCO, 1999)? In the case of RT alone, what are the lowest dosages necessaryfor disease control (Shibamoto Radiology, 2001; Bamberg JCO, 1999; Hard-enbergh Int. J. Rad. Oncol. Biol. Phys., 1997)? Malignant NGGCT: What arethe most effective drug regimens (Buckner JCO, 1999, Itoyama Neurosur-gery, 1995; Calaminus Neuropediatrics, 1994)? What is the necessary dosageand extent of RT (Aoyama JCO, 2002)? Are they curable by chemo alone(Balmaceda JCO, 1999; Baranzelli J Neurooncol, 1998)? Results and Con-clusion: For germinoma, data of the French SFOP protocol and the ongoingSIOP, CNS GCT 96 reveal that focal RT with chemotherapy is not able tocontrol subclinical paraventricular disease. In malignant NGGCTs, accord-ing to the SIOP data, the extent of AFP elevation and residual disease afterRT seem to be of prognostic value. Prognosis of malignant CNS GCTs hasbeen improved. The majority of patients are cured by combined treatmentwith lowered RT dosages. Treatment planning has to take into considerationextent of disease, markers, histology, and response to treatment.

24. DISABILITIES, PSYCHOSOCIAL REINTEGRATION, ANDQUALITY OF LIFE (QOL) IN SURVIVORS OF CNS GERMCELL TUMORS (GCTS)Calaminus G, Neubauer M, Bamberg M, Berthold F, Havers W, Janka-Schaub G, Kühl J, Göbel U; University Children’s Hospital,Düsseldorf, Germany

Objectives: CNS GCTs mainly appear in the adolescent age group.Patients of this age specifically acquire self-determination. The experienceof disease and treatment together with periods of hospitalisation/side effectsof therapy are often associated with physical, mental, and psychosocial prob-lems. Therefore this evaluation intends to highlight the rehabilitation of thepatients (pts) as well as their QoL. Patients and Methods: 155 protocol ptswith CNS GCTs are registered as survivors in 1.CCR in the German MAKEIdatabase. One hundred eleven had a follow-up of at least one year after treat-ment, of whom 92 patients were evaluable. Forty-eight were <16 years (yrs),17 were between 16 and 21 yrs, 27 were >21 yrs. A questionnaire concern-ing education, hobbies, family, friends, support needs, and possible disabili-ties together with 3 age-specific self-rating instruments (PEDQOL 8–16 yrs,J3 16–21 years, EORTC QLQ-30 >21 yrs) were sent to the hospitals incharge of the patients. Results: 70/92 patients have supplied relevant dataabout psychosocial status, disabilities, and support needs. Twenty-one reportvisual disturbances, 3 are deaf, 12 have walking disabilities, 3 need a wheel-chair, and 2 need an additional walking aid. Thirty-six of 70 patients requirepermanent hormone substitution. Forty-one of 70 patients have already fin-ished their school careers (30 secondary schools and 11 grammar schools),and 14/70 have completed professional training. Nearly all patients reporthaving hobbies and close friends. Thirty of 70 participants have partners.Overall QoL of all patients is predominantly positive. QoL in patients <16yrs reflects higher negative ratings for physical functioning, body image, rela-tion to peers, and cognition. Additionally, patients >16 yrs express negativeQoL with respect to self-determination. Conclusion: Survivors of CNS GCTsshow impairment in physical abilities but are well reintegrated in educationaland social processes. This is also reflected in a predominantly positive QoL,although more detailed evaluation reveals problematic areas of QoL whichneed further attention.

25. INTRAMEDULLARY LOW-GRADE GLIOMAS (LGG) IN CHILDREN: STAGING, FOLLOW-UP, AND PATTERN OF RESPONSE TO CHEMOTHERAPY (CT)Cama A,* Piatelli GL,* Ravegnani M,* Fondelli P,° Milanaccio C,^ BarraS,# Garrè ML^; *Neurosurgery Department, °Neuro-radiologyDepartment, ^Neuro-Oncology Department, Giannina Gaslini Children’sHospital, #Department of Radiotherapy IST, Genoa, Italy

CT has only recently entered the therapeutic armamentarium for intra-medullary LGG. Criteria to define extension of resection are not standard-ised due to the peculiar pattern of tumour growth inside the spinal cord anddifficulties in distinguishing postoperative changes from residual tumours. Inthe period 1995–2001 there were 12 cases: 7 Pilocytic Astrocytoma (PA), 1Oligodendroglioma (O), 2 Gangliogliomas (GG), 1 Fibrillary Astrocytoma

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(FA), 1 Astrocytoma NOS (AN) were recruited; 10 M, 2 F; sites were: 2bulbo-medullary; 1 cervical; 5 dorsal; 3 dorso-lumbar; 1 holocord. Age atdiagnosis (dx) ranged from 10 mos to 11yrs (median 26 mos); 11 cases wereoperated at dx; in 5/11 tumour resection required 2 operations. For a patientwith a lepto-meningeal dissemination associated to a C1-C6 lesion showingMRI features of PA, a clinico-radiological dx was considered sufficient to startCT. Staging included preoperative and postoperative CNS MRI and evalua-tion of surgical reports. A cleavage plan between tumour and normal tissueand absence of signs of residual tumour at postoperative MRI were criteriato define complete resection. Chemotherapy (VCR/CARBO) was proposedonly if there was a residual or regrowing tumour. MRIs were performed at3 and 6 mos from operation, then every 6 months for 2 years, and yearly sub-sequently. In 5 cases (41%; 1 PA, 1 AN, 1 FA, 2 GG), no tumour regrowthwas observed at 30–54 mos from dx. One patient (disseminated, clinico-radiological dx) underwent CT soon at dx. Six patients (5 PA, 1 O) under-went CT after 11–16 mos. All cases improved during CT; 3 are still on CT;3 ended it, and 2/3 of them are at 36 and 60 months, respectively, free oftumour progression; 1 patient had a regrowth of residual tumour at 3 mosafter stopping therapy; and a further treatment with Vinblastine was adopted.In cases treated with CT, MRI showed a pattern of tumour regression (cys-tic involution), sometimes difficult to interpret. Conclusions: More than 60%of cases of intramedullary LGG in our series needed further treatment afterinadequate surgery or because of disseminated disease; CT was demonstratedto be an efficient modality allowing prolonged remissions without jeopar-dizing quality of life.

26. USER-FRIENDLY METHOD FOR EXPLAINING ANATOMYOF BRAIN INJURY TO CHILDREN AND THEIR FAMILIES(AND EVEN THEIR DOCTORS!)Caney A, Caney J, Punt J, Parker T, Forman K, Hewitt M, Walker D;Children’s Brain Tumour Research Centre, Academic Division ChildHealth, University of Nottingham, UK

Explaining patterns of neuro disability with respect to neuroanatomy ofbrain injury to injured children and their families is a difficult task. Conse-quently, many children and their families do not fully comprehend the natureof their neurological disability. In response to this, in our neuro-oncologypractice we have made two educational systems for explaining regional func-tional neuroanatomy to children, their families, and professionals. A 3-Dmodel was created, with removable function labels, for training and testingpurposes. A brain anatomy cap was also developed, with brain surfacegraphic and removable function labels. Preliminary assessment found the sys-tems to to and be acceptable to professionals and usable in the clinic settingwith children and their families. The systems were presented to Paediatriciansand GPs at a RCPCH medical education training day. The participantsworked in groups, to attach function labels to pre-fixed anatomical land-marks. Feedback was obtained through a structured and free-text question-naire. Using both systems, we were able to score participants’ knowledge ofregional functional neuroanatomy. Feedback established that both systemswere easy to understand, simple to use, appropriately pitched for families,and better than other methods the participants had used previously. Free-textstatements revealed that the anatomy cap was considered fun, appealing tochildren, interactive, and easily related to child’s own surface anatomy. The3-D model was practical, allowed identification of midline structures, andreflected standard anatomical models used in undergraduate training. Weconclude that the cap will be a useful aid for explanation of brain anatomyand function to children and their families, and the model will be more use-ful in training of professionals. Together, they create a useful and much-needed system for explanation of regional functional neuroanatomy.

27. REPEATED HIGH-DOSE CARBOPLATIN WITH STEMCELL REINFUSION IN HIGH-RISK MEDULLOBLASTOMA(MB) PEDIATRIC PATIENTSCappelli C, Libera F, De Pasquale MD, Amoroso L, Di Salvo S, Russo D,Clerico A; Pediatric Oncology Unit, University of Rome “La Sapienza,”Italy

Background: High-risk and relapsed MB are actually of major concern,although every approach and overall survival for these patients (pts) remainspoor. Good results have been obtained increasing the chemotherapy dose.Considering that, since 1997 in our unit we have been using a protocol thatincludes a high dose of carboplatin and stem cell support. Materials andMethods: From November 1997 to November 2001, 9 patients wereincluded; 4 were at onset and 5 at relapse. The administrated therapy, for ptsat onset, included neurosurgery, 2 chemotherapy courses (carboplatin 1000mg/mq + etoposide 300 mg/mq) before radiotherapy (RT), a standard doseRT (35 Gy on SNC +20 Gy on posterior fossa), and 4 courses after RT, eachone followed by stem cell reinfusion (CD34+). For pts at relapse, therapyincluded a second surgical look or a stereotactic RT and repeated high-dose

chemotherapy associated with CD 34+ reinfusion. The treatment-related tox-icity was evaluated considering period of ANC < 500/mm3 and number ofplatelet and blood red cell (BRC) transfusions. Results: Three pts out offour treated at onset have an EFS of 32, 36, and 20 months, respectively. Thefourth pt had a partial response followed by a progressive disease and died2 years after diagnosis. All patients with relapsed MB died of disease, evenif they achieved a long-lasting partial remission. Pts treated at onset had amedian number of 2 days for ANC < 500/ mm3 (range 0–12) and a mediannumber of platelet (PLT) and BRC transfusions of 0 (range 0–5; 0–2, respec-tively). For every CD 34+ reinfusion the median number was 2 x106/kg(range:0.86–3). In relapsed pts group, median time of ANC < 500/mm3 was6 days (range 0–11). The median number of PLT transfusions was 2 (range0–9), while for BRC it was 0 (range 0–2 ). The median number of CD 34+

infused was 2.4 x 106/kg (range: 1.13–19.42). No toxic effects were observedin either group. Conclusions: High-dose chemotherapy with carboplatin, fol-lowed by stem cell reinfusion, appears to well tolerated and useful for pts atonset. For pts at relapse, we obtained only a disease control.

28. SIGNIFICATIVE CORRESPONDENCE BETWEEN MRI ANDOCTREOTIDE SCINTIGRAPHY (SRS) IMAGES ON CENTRALNERVOUS SYSTEM TUMORSCappelli C, Schiavetti A, Russo D, Libera F, Massa R, Amoroso L, ClericoA; Pediatric Oncology Unit, University of Rome “La Sapienza,” Italy

Aim: Central Nervous System tumors (CNS) represent 20% of pediatrictumors, the largest group of solid tumors in infancy. In recent years theresponse rate increased up to 70%. At present we are looking for ameliorat-ing techniques to verify complete resection and relapse. Recently it wasdemonstrated that a large variety of tumoral and normal tissues expresssomatostatin receptors. The aim of our study was to evaluate sensibility andspecificity of octreotide scintigraphy for CNS tumors. Materials and Meth-ods: We evaluated 21 patients affected by CNS tumors. We performed an SRSand a brain MRI to study concordance or discordance between these twomethods. Results: The 21 evaluated patients had a median age at diagnosisof 10 y (range 3–24) and were affected by Medulloblastoma (MBL) in 15;Astrocytoma in 3; Germinoma, Ependymoma (E), and PNET in 1 case each.Analyzing the radiologic examinations, we found in 2 cases (1E, 1 pilocyticastrocytoma) a discordance between MRI and SRS, with evidence of diseasein the first not found in the second; in 13 patients (2 high-grade astrocytoma,10 MBL, 1 PNET ) both exams were concordant for presence of disease. Inthe last 6 patients (5 MBL, 1 germinoma) both exams showed absence of dis-ease in all evaluations after surgery. In 1 out of 10 patients with MBL, aftersurgery, the SRS demonstrated in all images the presence of an area of patho-logic tissue, while the MRI, because of the stability of the lesion for a longtime (1 year and 3 months), was considered positive for a possible scar. Afterthis period the lesion grew and a new frontal lesion appeared; from thismoment the patient had a progressive disease. Conclusions: The SRS seemsto have a significance for the evaluation at onset and during follow-up ofpatients with CNS tumors; in fact, we observed a discordance between MRIand SRS in only 2 cases with a mature histology. On the basis of these resultswe intend to perform a study including in vitro evaluation of the somatostatinreceptors presence in the patient’s tumor tissue.

29. NEUROPSYCHOLOGICAL FUNCTIONING AFTERSURGERY AND PRIOR TO STEREOTACTIC RADIOTHERAPYIN CHILDREN WITH BRAIN TUMOR Carpentieri S, Waber D, Scott M, Goumnerova L, Pomeroy S, Kieran M,Tarbell N; Department of Pediatric Oncology, Dana-Farber CancerInstitute, Boston, MA, USA

Pediatric brain tumors are associated with mild to severe cognitive mor-bidity, potentially related to effects of the tumor itself as well as to therapiesincluding surgery, radiotherapy, and chemotherapy. Dana-Farber CancerInstitute (DFCI) Protocol 92-077 evaluated efficacy and late effects associ-ated with stereotactic radiotherapy (SRT) in children with localized lesionswhose postoperative tumor mass size was 5 cm or less. After surgery, chil-dren were assigned to SRT or surgery-only based on eligibility criteria. Neu-ropsychological testing was performed at baseline (after tumor diagnosis andresection and within 3 months after surgery). Follow-up was carried out upto 6 years thereafter, with patients serving as their own controls. One hun-dred and six patients (60 male, 46 female; mean age = 9.6 years, range = 4to 20 years) were evaluated at baseline. We report on the 77 children whowere of school age (6 to 16 years). They constituted the majority of the sam-ple (73%) and could be tested on the same measures. Six functional domains(cognitive, language, visuo-spatial, motor, executive control, and achieve-ment) were assessed. Descriptive statistics were generated; binomial distri-bution analyses were carried out to assess whether the proportion of indi-viduals with impaired performance on each measure exceeded normativeexpectations. An impairment index assessed whether poor performance was

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due to a few children or reflected the performance of the cohort as a whole.Although full scale IQ was within normative expectations (median = 103),verbal IQ (median = 106) was higher than performance IQ (median = 95);45% of individuals showed a significant discrepancy (p<.01) between thesescales. There was an increased prevalence of poor performance for meas-ures of motor output, verbal memory, and visuospatial organization. The dis-tribution of the impairment index indicated moderate impairment acrossthe cohort rather than severe impairment in a few patients. The results doc-ument a moderate level of cognitive morbidity among children with braintumors prior to SRT, presumably referable to the tumor itself and the surgery.The extent to which SRT may increase this burden will be assessed by eval-uating the longitudinal data.

30. EFFECT OF TOPIRAMATE ON BODY MASS INDEX ANDHYPERPHAGIC BEHAVIOUR OF MORBIDLY OBESECHILDREN, AFTER CRANIOPHARYNGIOMA TREATMENTCatsman-Berrevoets CE,1 Van den Akker ELT,2 Aarsen FK,1 Drop SLS2;Departments of 1Child Neurology and 2Child Endocrinology, UniversityHospital Rotterdam/Sophia Children’s Hospital, Rotterdam, TheNetherlands

Reduced appetite and weight loss were found in clinical trials of topira-mate for epilepsy. In children treated for craniopharyngioma, hyperphagiaand therapy-resistant morbid obesity frequently occur. In a pilot study weexplored the effectiveness and the tolerability of topiramate in children withobesity after craniopharyngioma treatment. We evaluated the response of 5children after 3 and 6 months of treatment with topiramate. Response ofhyperphagia, weight, effect on hypothalamic-dependent hormones, and neu-ropsychological side effects were evaluated. One male and four females (aged8.7–17.2 years) with a body mass index (BMI) 2.75–4.4 sd above the age-related were included. After participants began topiramate treatment at dosesranging from 2.7–3.5 mg/kg/day, parents of all five children reported amarked reduction of the obsessive hyperphagia. On the child behaviouralchecklist they all scored higher on items of self-esteem. BMI at 3 monthsranged from +0.15 to –3.78 (mean –1.51) in comparison to BMI at the startof the study. After 6 months, BMI differed + 1.44 to –4.47 (mean–0.66) withBMI at the start of the study. No important changes in blood parameters weredetected. Neuropsychological evaluation in comparison to that at the start ofthe study mainly showed a decreased performance on tests of attention andconcentration, verbal short-term memory, verbal sequential memory, and areduced verbal fluency. These problems started to occur with a dosage exceed-ing 4 mg/kg/day and were reversible. Results of this small pilot study sug-gest that topiramate stabilizes weight in children who have been treated fora craniopharyngioma but does not lead to important weight loss. Doses oftopiramate exceeding 4 mg/kg/day mainly have adverse but reversible effectson performance and on attention, concentration, verbal memory, and ver-bal fluency tasks. Topiramate seems to have a positive effect on the obsessive,“craving” behaviour of the child with respect to food.

31. HIGH RESPONSE RATE TO TEMOZOLOMIDE INHEAVILY PRETREATED CHILDREN AND YOUNG ADULTSWITH MEDULLOBLASTOMACefalo G,* Ruggiero A,# Abate ME,° Massimino M,* Zucchetti P,†

Mascarin M,§ Garrè ML,^ Spreafico F,* Mastrangelo S,# Clerico A,*Ridola V,# Mazzarella G,# Di Rocco C,# Donfrancesco A,∆ Perilongo G,*Lazzareschi I,# Sandri S,” Riccardi R#; *Istituto Nazionale Tumori, Milan,Italy; #Catholic University, Rome, Italy; °Casa Sollievo della Sofferenza, S. Giovanni Rotondo, (FG) Italy; +Hospital Silvestrini, S. Andrea delleFratte (PG), Italy; §Centro Di Riferimento Oncologico, Aviano, Italy;^Insitut G. Gaslini, Genova, Italy; *University La Sapienza, Roma, Italy;∆Hospital Bambin Gesù, Roma, Italy; *University of Padua, Padua, Italy;“Hospital Regina Margherita, Turin, Italy

Temozolomide (Temo) is a new oral alkylating agent that has demon-strated clinical antitumor activity in phase 1–2 trials in patients with malig-nant glioma. Temo is rapidly and completely absorbed by the oral route andreaches adequate brain concentration with approximately 35% of the circu-lating compound crossing the blood-brain barrier. We conducted a multi-centric phase 2 trial in 24 children and young adults (males 17, females 7)with recurrent or progressive medulloblastoma refractory to standard treat-ment. Temo was administered orally for five days in 3 daily doses varyingfrom 120 to 200 mg/m2 according to previous treatment and hematologicalvalues. Median age was 10 years, range (3–27). All patients had measurablelesions. All patients had received standard chemotherapy protocol with cran-iospinal irradiation and a second- or third-line treatment including high-dosechemotherapy with PBSC reinfusion. A mean of 4.4 cycles were administered(range 2–17). Response was assessed in all 24 patients. We observed 4 CR,4 PR, 3 MR, 5 SD, and 8 PD. Among responders, PFS at 6 months was 83%.Grade III–IV WHO thrombocytopenia was registered in 8 out of 106 cycles.

With dose reduction, thrombocytopenia was a rare event, although objectiveresponses were observed even when doses were reduced up to 40% of the rec-ommended dose for phase 2 studies in high-grade glioma. In conclusion, atthe doses utilized Temo is very active in heavily pretreated children withmedulloblastoma and is well tolerated, with negligible haematological toxi-city. If our data are confirmed in a larger group of patients, Temo may beincluded in future first-line treatment for medulloblastoma. Supported byFOP and AIRC.

32. HEALTH STATUS (HS) EVALUATION OF A COHORT OF CHILDREN OFF THERAPY FOR A MALIGNANT DISEASE(MD), INCLUDING PRIMARY CENTRAL NERVOUS SYSTEM(CNS) TUMORS, AS MEASURED BY THE HEALTH UTILITYINDEX (HUI): PRELIMINARY DATACereda C, Varotto S, Masiero L, Scarzello G, Rigobello L, Drigo P,Battistella PA, Picker A, Faggin R, Perilongo G; Pediatric Neuro-oncologyProgram of the Department of Pediatrics, Padua, Italy

For many children bearing a MD, the survival rates are not the only validendpoints for measuring treatment effect; data on late effects potentially influ-encing the HS and in general the quality of life (QoL) must be considered toevaluate the real treatment “efficacy.” Preliminary data of the HS of a cohortof children off-therapy for a MD, including primary CNS tumors, tested bythe HUI questionnaire are reported. Affected children (“self-evaluation”) andtheir parents (“proxy-evaluation”) were asked to complete the HUI (recruit-ment time 6/2000–5/2001). HUI, by DH Feeny et al, is a comprehensive butcompact method to measure HS and calculate Health Related QoL. Sixty-four children with acute leukemia/lymphoma, 52 with solid tumors, and 16with CNS neoplasm and off-therapy from 6 months to 9 years were investi-gated. In the abstract, data derived from BT patients will be compared tothe ones derived from all the others (reading score: 0.00 = death; 1.00 thebest HS).

F/M Age at interview (M) Self HUI score Proxy HUI scoreAll Pts. 44/57 14.2 (8–31) YRS 0.93 (0.25–1.00) 0.97 (0.37–1.00)BT Pts. 4/12 12.8 (8–28) YRS 0.87 (0.36–1.00) 0.96 (0.35–1.00)

Conclusions: Children with CNS neoplasm had a lower mean “self” and“proxy” HUI score than the other children; parents tended to estimate theirchildren’s HS better than the children themselves. Due to the unexpected highvalue of the HUI mean score, it seems that the sensitivity and specificity ofthe HUI on the HS of long-term survivors of childhood cancer deserve con-firmation. Quality of life data and psycho-cognitive data are necessary for amore comprehensive evaluation of the well being of these children.

33. TREATMENT OF CHILDHOOD MEDULLOBLASTOMAWITH COMBINED CHEMOTHERAPY AND CRANIOSPINALIRRADIATION: THE HONG KONG EXPERIENCEChan GCF, Li CK, Luk CW, Lee ACW, Ling SC; Hong Kong PaediatricHaematology/Oncology Study Group (HKPHOSG), Department ofPaediatrics, Queen Mary Hospital, The University of Hong Kong, HongKong SAR, China

Objectives: We review the local incidence and treatment outcome of Chi-nese children with medulloblastoma based on our registry data from Jan 1994to Dec 2001. Methods and Results: There were 44 children diagnosed withmedulloblastoma within this 8-yr period. The median age was 5.8 yrs (range0.2 to 17 yrs); M:F = 24:20. The estimated annual incidence was 3.7/millionChinese children ≤15 yrs/year (excluding non-Chinese [n = 1], >15 yrs [n =2]). More than 60% of them had Chang’s staging T3 disease, and 7 had overtleptomeningeal involvement (M3) at diagnosis. For treatment modality,chemotherapy based on baby-POG (alternate cycles of vincristine +cyclophosphamide [cycle A] with VP16 + cisplatinum [cycle B]) protocol wasused for children ≤3 yrs and also for older patients prior to 1999. Cran-iospinal RT was postponed for children ≤3 yrs. After 1999, Packer’s proto-col (8 cycles of cisplatinum + vincristine + CCNU) was adopted for children>3yrs. In some patients with leptomeningeal involvement or relapse, autolo-gous peripheral blood stem cell transplantation was used for consolidation.The 4-year overall survival (OS) for all patients was 79%, and event-free sur-vival (EFS) was 66%. The OS and EFS at 4 years for the baby-POG proto-col (n = 23) were 82% and 65%, respectively. Whereas for the CCV proto-col (n = 13), the 18-month OS and EFS were 100% and 83%, respectively.Due to the short follow-up, the comparison between the 2 protocols is notmeaningful at the moment. Two patients received chemotherapy (AAB) with-out RT, and they both survived at 2 and 4 years after the diagnosis. Eightpatients had surgery and RT alone; 3 of them died of disease progression orrelapse, and another 2 patients were lost in follow-up. The 4-yr EFS ofpatients below 3 years of age had a relatively inferior outcome of 4-yr EFS of65% as compared to the 82% of the older age group. Two of the 7 patientswith gross leptomeningeal involvement at diagnosis died of disease progres-

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sion or relapse after current combination therapy. Conclusion: Medulloblas-toma might have a slightly higher incidence in Chinese children and has afavourable outcome with current multimodality treatment approach.

34. PATTERNS OF RELAPSE OF CNS GERM CELL TUMORSChu RL, Hamre M, Fontanesi J, Bhambhani K; Departments of Pediatricsand Radiation Oncology, Wayne State University School of Medicine,Detroit, MI, USA

Object: To determine the pattern of relapse of central nervous system(CNS) germ cell tumors (GCT) in children. Background: CNS GCTs areknown to be radiosensitive tumors. Recent studies have also shown that CNSGCTs are sensitive to platinum-based chemotherapy. However, the role ofradiation (dose and volume) and of chemotherapy in the management ofGCTs remains controversial. We performed an institutional review to deter-mine the pattern of relapse of CNS GCTs relative to the volume and dose ofradiation therapy (RT). Methods: A total of 15 cases were identified withCNS GCTs diagnosed from 1993 to 2001 at Children’s Hospital of Michi-gan. Two patients with metastatic disease at diagnosis and one patient witha mature teratoma were excluded from further consideration. Demographic,disease, treatment, and follow-up information were obtained from chartreview. Results: Of the 12 cases evaluated, pathological diagnoses were ger-minoma (8), mixed germ cell tumor (2), and immature teratoma (2). Theanatomic sites were as follows: pineal (9), suprasellar (2), and bifocal (1).Four patients had a gross total resection, 3 had partial resection, and 5 hadonly tumor tissue biopsies. Six patients received whole brain RT (2/6 alsoreceived spinal), and 6 received limited field RT. Ten received both chemo-therapy and RT. Three cases had recurrence of disease 0.5, 1.1, and 1.8 yearsafter diagnosis. Two of these patients diagnosed with germinoma receivedchemotherapy with reduced dose (30.6 Gy) involved-field RT. The third diag-nosed with immature teratoma was treated with chemotherapy withinvolved-field standard dose (50 Gy) RT. All three patients had recurrencesoutside the field of radiation. None underwent a gross total resection. Theevent-free 5-year survival was 72% (se = 13%). Univariate analyses revealedthat field of radiation (involved field vs. whole brain) was associated withrecurrence (p = 0.02). Less than gross total resection did not achieve statisti-cal significance (p = 0.09) in this small study. Conclusion: Our observationssuggest that only involved-field RT may not be adequate treatment for malig-nant GCTs. The efficacy of reduced dose radiation of the whole brain needsfurther investigation.

35. THE CLINICAL IMPACT OF ACCURATE DIAGNOSIS OF NF1Cohen IJ,1 Luria D,2 Weitz R,3 Shuper A,1 Michowitz S,4 Yaniv I,1 ZaizovR,2 Avigad S2; Departments of 1Pediatric Hematology Oncology,3Neurology, and 4Neurosurgery, Schneider Children’s Medical Center ofIsrael; 2Molecular Oncology, Felsenstein Medical Research Center, PetahTikva, and Sackler School of Medicine, Tel Aviv University, Israel

Neurofibromatosis type 1 is the most common autosomal dominantlyinherited cancer predisposition disorder. Nearly half of the patients are spo-radic, representing new mutations. Patients with NF1 exhibit a markeddegree of variability in clinical expression even in members of the same fam-ily. The clinical diagnosis is inexact and may change with time. One of themain risks of NF1 is the development of malignancy. The gene responsiblefor NF1 is located on chromosome 17q11.2, and the protein encoded byNF1, Neurofibrin, contains a domain homologous to the GTPase activatingprotein (GAP) family and down-regulates ras oncogene activity. Germlinemutations were examined in the blood of 36 children with NF1. Mutationswere identified in 91% of the patients. Eighty-one percent were frame shiftand 16% were missense mutations evenly distributed over the whole gene.Half of the mutations identified were novel. Although in 9 children with opticgliomas without NF1 no germline mutations were found, all 9 children withNF1 who had developed optic tract gliomas were found to harbor mutationsin the 5’ end of the gene (exons 10a–28). In 6 of 7 NF1 children who devel-oped other malignancies, the mutation was in the 3’ end of the gene (exons31–42). In 1 patient with optic tract glioma and malignant nerve sheathtumor, the whole gene was deleted. In addition, 16 brain tumors were avail-able for examination in children without signs of NF1. Nine MalignantGliomas, 5 Ependymomas, 1 Choroid Plexus Carcinoma and 1 PrimitiveNeuroectodermal Tumor. Somatic mutations were found in 2, a high-gradeGlioma and PNET. The PNET patient was alive, and her blood showed agermline mutation. She has no clinical evidence of NF1 at the age of 12 years,11 years after tumor diagnosis. Menarche at 9 years of age. Conclusions:(1) Following validation with larger numbers, prediction of an associationbetween type of tumor and site of NF1 germline mutations may be possible.(2) Patients who show no clinical evidence of NF1 may have the associatedcancer predisposition, and tumors may develop before clinical diagnosis canbe made.

36. FINAL OUTCOME OF A PHASE I TRIAL OF LOW-DOSETEMOZOLOMIDE GIVEN CONCURRENTLY WITHRADIATION THERAPY IN CHILDREN AND ADOLESCENTSWITH BRAIN TUMORSCohen K, Aronson L, Siffert, J, Fisher P, Goldman S, Jakacki R, Allen J;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,Baltimore, MD, USA

Temozolomide has been administered in a variety of schedules includinga high-dose 5-day schedule (200 mg/m2/day) given every 3–4 weeks and alow-dose schedule with temozolomide given on a daily basis over 6 to 7weeks. The low-dose schedule has been given during radiation therapy, andin adults a maximally tolerated dose (MTD) of 85 mg/m2/day was deter-mined but has been routinely administered in most adult trials at a dose of75 mg/m2/day. To determine the MTD of this schedule in children receivingconcomitant focal radiation therapy, a phase I multi-institutional trial wascommenced. Eligibility criteria included the following: patients being < 21years of age at study entry, a brain tumor being treated with focal radiationtherapy only, and adequate organ function and performance status. Spinalcord primaries were not eligible. Twenty patients were enrolled on the study.Diagnoses included brain stem glioma (8), anaplastic astrocytoma (6),glioblastoma multiforme (3), gliosarcoma (1), pilomyxoid astrocytoma (1),well-differentiated astrocytoma (1). Six children were enrolled at Dose Level1 (75 mg/m2/day x 42 days). Eight children were enrolled at Dose Level 2 (90mg/m2/day x 42 days). Six children were enrolled at Dose Level 3 (105mg/m2/day x 42 days). Three of 20 patients were inevaluable, one due to pro-gressive disease during treatment and two due to failure to obtain requiredlaboratory studies. There were two dose-limiting toxicities (DLT) of Grade3/4 thrombocytopenia in two patients at Dose Level 3. Among all patients,an additional 12 toxicities were reported, none of which were considered doselimiting. Grade 3 or 4 non-DLTs included lymphopenia (4), hepatic (1), infec-tion (1), neuro-motor (1). The therapy was well tolerated and easily admin-istered, including in young children, where a regimen was designed for safeadministration of opened capsules. The MTD of temozolomide given over asix week period in children receiving focal radiation therapy is 90 mg/m2/dayx 42 days.

37. THE IMPACT OF TREATMENT ON VISUAL FUNCTIONIN CHILDHOOD LOW-GRADE GLIOMAS OF THE ANTERIORVISUAL PATHWAY: A COMPARISON OF PATIENTS WITHAND WITHOUT NEUROFIBROMATOSIS TYPE 1Cohen V, Newbury L, Nicholson J, Williams D, Moore A; Department ofOphthalmology, Addenbrookes Hospital, Cambridge, UK

A single-centre, retrospective analysis was performed on a cohort of chil-dren with anterior visual pathway, low-grade gliomas diagnosed between1981 and 2001. Age, sex, NF1 status, treatment, and visual outcomes wererecorded. Thirty-one patients were identified. Forty-five percent had NF1,and 61% were female. The median age at presentation was 4.3 years in theNF1 negative group and 3.2 years in the NF1 positive group, with no signi-ficant difference between the two groups p = 0.6 (Mann-Whitney U). Of thepatients with NF1, 66% had tumor confined to the optic nerve and 34% hadchiasmal involvement. One hundred percent of cases without NF1 had chi-asmal involvement at presentation. Visual symptoms including squint, poorvision, and proptosis were seen in all optic nerve gliomas. Visual symptomswere seen in 68% of cases with chiasmal tumors, 16%% of which had nys-tagmus. Only one patient was detected at screening. Sixteen out of 31 patientswere treated. Thirty-one percent (5 out of 16) were treated for progressivevisual deterioration with radiotherapy or chemotherapy, but treatment wassuccessful in preserving vision in only one patient who had chemotherapy.Visual acuity improved in 4 patients, 3 were NF1 negative. In the first case,vision improved 95 months after chemotherapy, in the second (NF1 positive)73 months after chemotherapy. In the third case, vision improved 8 monthsafter surgical resection; in the fourth, vision spontaneously improved from6/36 to 6/18 after 112 months of follow-up. Spontaneous tumour regres-sion occurred in 4 patients (2 had NF1); 3 of the 4 tumours involved thechiasm and hypothalamus. Visual acuity deteriorated in 6 patients after treat-ment; 4 were NF1 negative. Vision deteriorated in 2 patients following thecomplications of radiotherapy and in 1 immediately after surgery. Thirty-fivepercent (6 out of 17) of patients in the NF1 negative group and 21% (3 outof 14) patients with NF1 were registered blind. In summary, all NF1 nega-tive patients presented with chiasmal involvement. They did not present anylater than NF1 positive patients. Treatment had little influence on visual acu-ity in either group. Spontaneous tumour regression may result in visualimprovement regardless of NF1 status.

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38. DEFECTS IN VISUAL SHORT-TERM MEMORY INSURVIVORS OF PEDIATRIC BRAIN TUMORS: PREDICTIVEFACTORSCornelius A, Snyder K, Axtell R, Pastyrnak S; Department of PediatricHematology/Oncology, DeVos Children’s Hospital, Grand Rapids, MI,USA

Children with brain tumors are known to be at risk for neurocognitiveproblems including disturbances of visual-motor function, memory, balance,coordination, and speech. During the past 12 years we have treated 157 chil-dren with brain tumors. Because of concerns regarding school performance,31 of these patients have undergone detailed neuro-psychological testing,including 19 patients with VMI and WISC-III. Nine of these 19 patients hadevidence of severe impairments of visual short-term memory as evidencedby a score of <5 on the coding subset of the WISC. Patients with posteriorfossa PNET (medulloblastoma) were more likely to have severe problems ofvisual short-term memory, with lower performance IQ and VMI scores. Thatis, performance on the coding subtest was disproportionately low as com-pared to the full-scale IQ and VMI scores. Surprisingly, age at diagnosis, ahistory of visual symptoms, tumor location, physical findings of nystagmus,and the use of radiation or chemotherapy were not consistently associatedwith visual short-term memory deficits.

Mean Mean Coding Age Posterior Full Mean

# of score at Cranial fossa Scale IQ VMIPts (range) diagnosis XRT tumor (range) (range)

Poor Visual Short-term 9 2.8 (1–5) 6.5 years 8/9 8/9 75.8 74 Memory (53–105) (64–85)

Better Visual Short-term 10 9.4 (6–13) 5.6 years 7/10 7/10 107 98.3 Memory (90–119) (86–119)

Visual short-term memory loss is frequently seen in children survivingbrain tumors and is likely to be an important contributing factor in theirschool performance because of the visual presentation of most new infor-mation used in classrooms. We strongly suggest that neuropsychological test-ing, including specific age-appropriate subtests, be performed on children sur-viving brain tumors to determine if visual short-term memory is affected.Multisensory presentation of new material could then be targeted to the neu-ropsychological pathways that remain intact to improve the retention of newinformation.

39. RADIATION DOSE REDUCTION TO THE OPTICPATHWAY IN A PEDIATRIC PATIENT WITH GLIOSARCOMA:A COMPARISON OF 3-D CONFORMAL RADIATIONTHERAPY TO INTENSITY MODULATED RADIATIONTHERAPYCulp L, Bayouth J, Colman M, Pena J, Hatch S; Department of RadiationOncology, The University of Texas Medical Branch, Galveston, TX, USA

Objective: Radiation therapy is an essential component of the treatmentof CNS gliosarcoma tumors in the pediatric population. However, treat-ment raises the concern of late radiation-related toxicities to the normalsurrounding structures such as the optic pathway. In this paper, we comparethe use of forward planning 3-D conformal radiation therapy (3DCRT) toinverse planning Intensity Modulated Radiation Therapy (IMRT) to reducethe dose delivered to critical elements of the optic pathway. Methods AndMaterials: A twelve-year-old child with compromised vision of the right eyefrom neurofibromatosis type I (NF1) presented with gliosarcoma involvingthe anterior inferior left temporal lobe. Two different plans were compared,one using 3DCRT and the other using IMRT. Endpoints used to compare thetwo treatments were the median and maximum doses delivered to the eyes,optic nerves, optic chiasm, and the planning target volume. Results: Whencomparing IMRT and 3DCRT plans with an equivalent median dose deliv-ered to the target volume as a function of the prescribed dose of 6120 cGy,the approach using IMRT proved superior to that of 3DCRT. IMRT resultedin a 40% reduction in the median dose delivered to the right optic nerveand the optic chiasm and a 35% median dose reduction to the left optic nerve.In addition, the IMRT plan provided maximum doses to these critical struc-tures below the threshold for probable complications, whereas the 3DCRTdid not. Conclusions: IMRT planning technique can reduce the dose to sur-rounding critical structures of the optic pathway when treating intra-cranialCNS neoplasms to prevent future vision loss. This treatment approach is dosi-metrically superior when the goal of visual preservation is otherwise difficultto accomplish.

40. TECHNICAL ASPECTS AND FEASIBILITY OF PERIPHERALBLOOD PROGENITOR CELL (PBPC) COLLECTION IN 20CASES OF INFANTS WITH CENTRAL NERVOUS SYSTEM(CNS) TUMOURS TREATED WITH MYELOABLATIVETHERAPYDallorso S,* Rivabella L,° Cefalo G,^ Milanaccio C,* Scarso L,° MorrealeG,* Garrè ML*; *Paediatric Haematology-Oncology Department and°Blood Service, G. Gaslini Children’s Hospital, Genova; ^PaediatricOncology, National Institute of Cancer, Milan, Italy

High-dose therapy with stem cell rescue is now part of up-front treatmentstrategy for high-risk infants’ malignant brain tumours (poor histology,incomplete resection, metastasis, or recurrent disease). PBPC collection insmall children is, however, sometimes difficult to perform outside specialisedcentres. In 1997 we started a 2-phase chemotherapy protocol on behalf ofthe Italian Association of Paediatric Haematology Oncology Infants Study(Phase A = induction, B = double PBPC transplantation), including the use ofhigh-dose chemotherapy and PBPC rescue. We report technical data regard-ing our experience in 20 children younger than 5 years and weighing < 20 kg(median 13, range 9–19). Diagnoses were the following: Medulloblastoma(10), PNETs (5), miscellaneous (5). PBPC collection was performed duringPhase A, under rHu-G-CSF 10 γ/kg/day stimulus, started in the recoveryperiod after high-dose Etoposide and/or Cyclophosphamide. The goal ofPBPC apheresis was to harvest a number of CD34+ cells allowing two rescueprocedures. Collection was carried out when the value of circulating CD34+cells was higher than 40/µL (median 187, range 53–484), irrespective ofplatelet count, using a monolumen central catheter and a temporary periph-eral venous access. Children were not sedated during the procedure. A continuous-flow cell separator with small-volume collection chamber + small-volume separation chamber holder was used. Nine patients underwent 1 col-lection, 8 pts 2 collections, 2 pts 3 collections, and only 1 child needed a totalof 5 apheresis. In the case of single collection, the cells were frozen in twoor more bags. The median number per patient of collected CD34+/kg x 106

was 16.5 (4.8–117). The blood volume processed was 2445 ml (2000–3243);the blood withdrawal per apheresis was 22 ml/min (16–27) and was com-parable with that reported by other teams using a double lumen or an arte-rial catheter. No clinical signs of citrate toxicity were observed. Our experi-ence shows that collection of PBPC has a high rate of efficacy and that it issafe and feasible even in children of low weight. Potential problems due tovenous access and extracorporeal shift of blood volume are manageable bya multidisciplinary team.

41. CAN PROTON MAGNETIC RESONANCE SPECTROSCOPYBE OF ANY VALUE AS A PROGNOSTIC FACTOR INMEDULLOBLASTOMA?Dembowska-Baginska B, Perek-Polnik M, Drogosiewicz M, Jurkiewicz E,*Kosciesza I,* Perek D; Department of Oncology, Children’s MemorialHealth Institute, Warsaw, Poland; *Department of Radiology, Children’sMemorial Health Institute, Warsaw, Poland

HMRS is a noninvasive chemical analysis of metabolites in brain tissue.Metabolite ratios are useful because age-dependent normal values are knownand differ significantly from the values obtained in various diseases of braintissues. Aim: The aim of our study was to evaluate whether MRS correlateswith MRI and course of disease and can be of prognostic value in patientswith advanced, primarily unresected medulloblastoma (MB). Materials andmethods: Eight patients with histologically proven MB were studied. Allpatients underwent MRS and MRI at diagnosis and after neoadjuvant chemo-therapy consisting of VCR, VP, CTX, CBCA. Preoperative chemotherapy wasfollowed by surgery, radiotherapy, and maintenance chemotherapy. Assess-ment whether MRI correlates with MRS after preoperative chemotherapywas performed. Additionally, MRS was correlated with the course of disease.Results: Out of 8 patients, 5 had partial remission of their tumors on MRI.Two of them had favorable reaction on MRS defined as elevation of NAAand Cr decrease in Cho, Lac/Lip. Both are alive and disease-free 24 and 27ms from diagnosis. In 2 patients no changes, comparing with MRS at diag-nosis, were found. Both died of disease. One had an indistinct positive changeand died. Stabilization on MRI was observed in 1 pt, who also had a goodreaction on MRS. He is alive and disease-free 21 months from diagnosis. Twopatients had disease progression on MRI. Both had poor reaction on MRS:1 died, 1 is alive with disease. The small number of patients does not allowus to draw conclusions, but our results signal that HMRS might be of prog-nostic value in brain tumors.

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42. EXPRESSION OF NEUROTROPHINS AND THEIRRECEPTORS IN 80 CHILDHOOD BRAIN TUMORS ATDIAGNOSIS: A REPORT FROM THE ITALIAN ASSOCIATIONOF PEDIATRIC HEMATOLOGY-ONCOLOGY (AIEOP)Dominici C, Castello MA, Cordero di Montezemolo L, Di Rocco C,Fidani P, Forni M, Genitori L, Giangaspero F, Morra I, Natali PG, NicotraMR, Riccardi R, Madon E; La Sapienza University and CatholicUniversity; Bambino Gesù Children’s Hospital; Regina Elena CancerInstitute, Rome, Italy; Regina Margherita Children’s Hospital, Turin, Italy

In the developing CNS, neurotrophins (NTs) and their TRK and p75NTR

receptors regulate proliferation, differentiation, survival, and programmedcell death of both neuronal and glial cells. Recent evidence suggests that NTsmay also affect medulloblastoma behavior in vivo. We assessed the mRNAand protein expression for NTs and their receptors in a large series of child-hood brain tumors collected in an ongoing multicenter Italian study. Eightycases were evaluated at diagnosis, including 18 medulloblastomas (MBs), 5supratentorial PNETs, 32 pilocytic astrocytomas (PAs), 1 desmoplastic astro-cytoma (DA), 2 pleomorphic xanthoastrocytomas (PXs), 9 glioblastomas(GBs), 10 ependymomas (EPs), 2 anaplastic ependymomas (APs), and 1 rhab-doid tumor (RT). Expression of mRNA was determined by Northern blotand by expression of protein by immunoperoxidase (Vectastain, Vector Lab-oratories, Burlingame, CA) using mAbs against TrkA (H10), TrkB, and TrkC(kindly provided by D.R. Kaplan, Montreal Neurologic Institute, Montreal),and p75NTR (20.4) as well as commercially available pAbs against NGF,BDNF, and NT3 (Santa Cruz Biotechnology, Santa Cruz, CA). MB expressedNGF in 15/18 cases, TrkA in 0/18, BDNF in 14/18, TrkB in 14/18, NT3 in15/18, TrkC in 13/18, and p75NTRin 5/18. PA expressed NGF in 26/32 cases,TrkA in 0/32, BDNF in 30/32, TrkB in 19/32, NT3 in 21/32, TrkC in 11/32,and p75NTR in 10/32. EP was positive in all 10 cases for NGF, BDNF, andNT3, 7/10 for TrkB, 2/10 for p75NTR, but in no case for TrkA and TrkC.Expression was also detected in PNETs, DA, PXs, GBs, Aps, and RT. Regard-ing prognosis, a better outcome was demonstrated in MB for the 12 pts withNT3/TrkC+ve tumors (p<0.03) after a median follow-up of 36 mos (range,10–56); a similar trend was shown in EP for the 7 pts with TrkB+ve tumors(p = 0.08) after a median follow-up of 32 mos (range, 7–51). These findingssupport the role of NTs and their receptors in influencing tumor behavior andclinical outcome in different brain tumor histotypes.

43. ABROGATION OF IMMUNOSUPPRESSIVE GANGLIOSIDESIN GLIOBLASTOMA Donson A, Fleitz J, Handler M, Foreman N; University of ColoradoHealth Sciences Center, 4200 E 9th Avenue, Denver, CO, USA

Tumor vaccines for glioblastoma are being explored as an alternative tothe dismal prognosis offered by surgery, radiotherapy and chemotherapy. Onemodel of this involves the inoculation of the tumor, genetically modified toexpress IL-2, in order to elicit an anti-tumor immune response. The efficacyof this model has been hampered by tumor-derived immunosuppressive fac-tors, such as TGF-beta, which have been targeted in an attempt to improvethis vaccine model. We have demonstrated the presence of potently immuno-suppressive gangliosides in glioblastoma. Gangliosides are a family of gly-colipids that differ in their oligosaccharide head groups. The gangliosidespecies GM2 and GM3 are reported to be particularly immunosuppressive.Using high-performance thin-layer chromatography, we demonstrated theseto be among the major species of ganglioside expressed on our glioblastomacell lines. We hypothesized that by inhibiting ganglioside expression we wouldincrease the immunogenicity of glioblastoma tumor vaccine. By treatingglioblastoma cell lines with (1) ganglioside synthesis inhibitor 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP) and (2) transfection ofGD3 synthase gene (a key enzyme in the ganglioside biosynthetic pathway),we were able to significantly reduce ganglioside expression. Allogenic lym-phocytes exposed to immunosuppressive ganglioside-depleted glioblastomacell lines were subsequently shown to have increased antitumor lymphocyteactivity, as measured by IFN-gamma release and cytotoxicity assays, whencompared to lymphocytes exposed to ganglioside-expressing control tumor.These results suggest that the efficacy of a glioblastoma tumor vaccine couldbe significantly improved by abrogation of ganglioside expression.

44. CNS GERM CELL TUMORS (GCT): TREATMENTRESULTS FROM ONE INSTITUTIONDrogosiewicz M, Perek-Polnik M, Dembowska-Baginska B, RoszkowskiM,* Perek D; Department of Oncology, Children’s Memorial HealthInstitute, Warsaw, Poland; *Department of Neurosurgery, Children’sMemorial Health Institute, Warsaw, Poland

Aim: To assess treatment results of patients with GCT treated accordingto SIOP protocol and compare them with a historical group. Materials andMethods: Fifty-five pts were treated. The historical group consisted of 29 pts

treated between 1987 and 1996. Diagnosis was based on pathology ofresected tumors. Germinoma was diagnosed in 22 pts and secreting germ celltumor (SGCT) in 7. All were irradiated to the craniospinal axis. Patients withSGCT received adjuvant chemotherapy (3 x PVB). Since 08.96 SIOP proto-col was implemented, 26 pts have been treated—11 pts with SGCT and 15with germinomas. In the SGCT group, 5 pts underwent delayed surgery,and 6 pts had CR after chemotherapy. In the nonsecreting group, 2 pts under-went primary tumor resection and 13 pts had biopsy; in all, CR was observedafter chemotherapy. In case of relapse second-line chemotherapy was imple-mented. Results: In the historical group 23 out of 29 pts are alive, medianfollow-up 6 years 3 months. Six patients died (2 pts SGCT, 4 pts germino-mas) from disease recurrence. In the second group, 24 out of 26 pts are alive.In the SGCT, 10 out of 11 pts are alive, 9 in first CR from 11 months to 5years 4 months, 1 in second CR 1 year from relapse. One patient died ofrelapse 1 month from completing radiotherapy. Of the germinomas 13 ptsare alive in first CR 4 months to 5 years 5 months, 1 pt in second CR 2 years6 months from relapse. One patient died of reasons not related to disease.Five-year EFS for the historical group is 79%, and it is 66% for the currentgroup; OS is 79% and 89%, respectively. Conclusions: No statistically signi-ficant differences were found in the results of treatment in both groups. Omit-ting craniospinal radiotherapy did not jeopardize outcome. Second-linechemotherapy is effective in obtaining remissions in relapsed patients.

45. PAPILLARY ENDOTHELIAL HYPERPLASIA ASSOCIATEDWITH CORTICAL DYSPLASIADu Plessis DG, Balsmurali, Javadpour M, Smith ET, Broome JC, Pizer B,Mallucci CL; Department of Neuropathology, Walton Centre forNeurology and Neurosurgery, Liverpool, UK

Objectives: We report a unique case of papillary endothelial hyperplasia(PEH) presenting as a subcortical mass lesion intimately associated with focalcortical dysplasia (CD) and consider a possible causal relationship. Casereport: A 6-year-old girl presented with a 10-month history of a painless,frontoparietal skull “bump” associated with slowly progressive localisedbossing and a 4-month history of absence attacks. MRI revealed an adja-cent parietal enhancing mass lesion beneath dysplastic appearing cortex. Ahaemorrhagic vascular lesion with histological features consistent with thoseof papillary endothelial hyperplasia was completely resected. Biopsies of theadjacent cortex showed cortical dysplasia. The patient has been symptom freefor 12 months with no MRI evidence of recurrence. Discussion: Although nota neoplastic lesion, PEH falls within the spectrum of intracranial mass lesionspresenting to paediatric neuro-oncologists and neurosurgeons dealing withchildren’s brain tumours. Intracranial PEH is very rare, and half of reportedcases lack a demonstrable vascular origin. CD may be associated with intrin-sic capillary hypervascularity, vascular malformations, and tumours (eg,DNT) of a potential hypervascular of haemorrhagic nature. An associationbetween PEH and CD may not be incidental given the not-infrequent butunderemphasised presence of abnormal vasculature found in or adjacent tothe latter. These could predispose to haemorrhage and/thrombosis, the organ-isation of which may rarely be complicated by PEH.

46. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOUR: A REVIEW OF 18 RESECTED CASES OF SPECIFIC TYPE WITHPAEDIATRIC ONSET EPILEPSYDuPlessis DG, Broome JC, Javadpour M, Mallucci CL, May P, McDowellH, Pizer B; Department of Neurosurgery, Walton Centre for Neurologyand Neurosurgery, Liverpool, UK

Objectives: An investigation of the clinicopathological profile of dysem-bryoplastic neuroepithelial tumours (DNT) resected for intractable epilepsyof paediatric onset. Methods: During a retrospective study of epilepsy-relatedsurgical specimens, all cases of DNT with paediatric onset of seizures, spe-cific histology (simple or complex types containing glioneuronal elements),and supportive clinical and radiological features were selected for review.Results: Eighteen suitable cases were identified, 9 male and 9 female. Theaverage age at presentation was 9 years (range 7 months to 17 years), and theaverage age at surgery 20 years (4 to 38 years). The mean duration of seizuresprior to surgery was 10.5 years (1 to 22 years). A significant improvementin seizure control was obtained in 11 patients, whereas poor outcome in theremaining 7 patients was almost invariably associated with incomplete exci-sion. Significant control was later obtained in 3 of 4 of the latter patients rere-sected. In one of these cases resection was performed following slow regrowthover 2 years of an otherwise classical complex-type DNT. One additionalreresected case with typical histology on both occasions (7-year interval) wasunusually associated with limited mass effect, but did not show evidence ofconvincing regrowth. One case with complex histology was associated witha gangliogliomatous component with a strikingly dysplastic cortex. Conclu-sions: Most of the current series’ cases conformed fully to the accepted clin-icopathological profile of DNT and affirm its indolent nature. The presence

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of regrowth and mass effect, respectively, in 2 otherwise typical cases of DNTwith specific histology, however, challenges the validity of these as absoluteexclusion criteria. The rigid application of clinical and imaging criteria ismandatory for a confidant diagnosis of nonspecific forms of DNT, but mayartificially restrict the biological spectrum of cases with specific histology.

47. A PILOT TRIAL OF REDUCED VOLUME BOOST VIAINTENSITY-MODULATED RADIATION THERAPY (IMRT)WITH CRANIOSPINAL RADIATION THERAPY (RT) ANDCHEMOTHERAPY FOR PATIENTS WITH NEWLYDIAGNOSED MEDULLOBLASTOMADunkel I, Souweidane M, Lyden D, Khakoo Y, Antunes N, Lis E, WoldenS; Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Purpose: Newly diagnosed medulloblastomas are curable with conven-tional therapy (craniospinal RT, posterior fossa boost, +/– chemotherapy),but long-term morbidities (neuropsychological, neuroendocrine, audiomet-ric) are often significant problems for the survivors. We have treated a pilotseries of patients with a reduced volume boost via IMRT to attempt to min-imize long-term effects. Methods: Patients with newly diagnosed medul-loblastoma were treated with surgery, craniospinal RT, boost to the tumorvolume + 2 cm margin via IMRT, weekly vincristine during RT, and vin-cristine, lomustine, and cisplatin chemotherapy. Patients received craniospinaldoses of 2340 cGy (standard-risk disease, n = 8) or 3600 cGy (high-risk dis-ease, n = 2). The boost brought the total tumor volume dose to 5580 cGy.Results: Ten patients have been treated since July 1999. Ages ranged from 4to 22 years (median 8.5 years) at initiation of RT. The high-risk cases weredue to M-2 disease (n = 1) and > 1.5 cm2 postoperative residual tumor (n =1). In all cases, the dose conformality to the tumor target volume wasimproved while doses to the inner ears and other critical tissues were mini-mized. Follow-up has ranged from <1 to 30 months (median 16 months).Event-free survival is 100%. Conclusions: These preliminary results suggestthat diminishing the boost volume via IMRT may be safe for patients withnewly diagnosed medulloblastoma, but longer follow-up and additionalpatients are necessary to confirm that excessive failures are not occurring.Formal neuropsychological, neuroendocrine, and audiometric evaluationswill be done to determine whether the expected clinical benefits will ensue.

48. LANGERHANS CELL HISTIOCYTOSIS OF THE CNS: A UNIQUE CASE PRESENTATIONDvir R, Tabori U, Ben-Sira L, Burstein Y; Tel-Aviv Sourasky MedicalCenter, Pediatric Hemato-Oncology Unit and Pediatric Radiology Unit,Tel-Aviv, Israel

Langerhans Cell Histiocytosis (LCH) of the central nervous system ismost commonly manifested by involvement of the hypothalamic pituitaryregion with diabetes insipidus as its cardinal manifestation. However, LCHcan evoke different types of CNS disease beginning from asymptomaticlesions of the pineal gland, through extraparenchymal lesions in the meningesor choroid plexus, or in other sites. A rare neurodegenerative syndrome withcerebellar or pontine signal alterations has been described in a small num-ber of patients. Its clinical manifestations vary and may include behavioraland intellectual impairment and in many cases ataxia, dysarthria with pro-gressive neurological deterioration leading to severe disability and even death.We describe the case of a six-year-old girl whose disease started at the age of1 year with skeletal involvement of multiple sites. She was treated by variouschemotherapeutic regimens with partial remissions and a chronic relapsingcourse of disease restricted to the bones. She later developed diabetesinsipidus. Her MRI revealed a typical LCH lesion of the pituitary stalk, anddiffuse cerebellar signal abnormalities. The child remained asymptomatic fora short while and then developed progressive ataxia and dysarthria. The childresponded clinically to treatment with dexamethasone with only minor radi-ological response. This case is unique in three aspects: the appearance of MRIfindings appeared before clinical symptoms, the young age at the appearanceof neurodegenerative disease concomitant with active disease in the stalk, andthe response to steroids. In our presentation we shall discuss the clinicalcourse and the various therapeutic options of LCH-CNS neurodegenerativesyndrome, and present the unusual MRI findings of this disease.

49. GENOMIC IMBALANCES PREDICT OUTCOME INPAEDIATRIC EPENDYMOMASDyer S, Prebble E, Davison E, Ramani P, Ellison D, Grundy R; RegionalGenetics Laboratory, Birmingham Women’s Hospital, Edgbaston,Birmingham, UK

The clinical behaviour of paediatric ependymomas is difficult to predictbased on clinical and histological parameters. Our hypothesis was thattumour-specific genetic changes would more accurately predict patient out-come. Using a validated technique, we performed a CGH screen of 58archived (46 primary and 12 recurrent) paediatric ependymomas and corre-lated the genetic findings with patient outcome. Sixty-one percent of tumourswere unbalanced (mean no imbalances/tumour = 3.4, range = 0–25), andthe most common imbalances were gains of chromosomes 1q, 7, 9, and 18and losses of 3, 6, and 15. Unbalanced tumours revealed one of two distinctgenetic profiles. Group 1 tumours (n = 19) were characterised by few, mainlystructural, imbalances. Group 2 tumours (n = 9) had four or more apparentlynonrandom whole chromosome imbalances—eight out of nine of thesetumours had gain of whole chromosome 7, which was significantly associ-ated with gains of chromosomes 8 (p = 0.044), 9 (p = 0.004), and 18 (p =0.009) and losses of 3 (p = 0.0001) and 6 (p = 0.044). Kaplan-Meyer survivalanalysis revealed that Group 1 tumours had a worse outcome when com-pared with Group 2 tumours (p = 0.027). Indeed, 13 out of 19 patients witha Group 1 tumour profile died compared with only 1 out of 9 having a Group2 profile. In addition, a Group 1 profile was significantly associated withtumour recurrence (p = 0.05). Gain of 1q was significantly associated with aGroup 1 profile (p = 0.0039) and with tumour recurrence (p = 0.0039), rais-ing the possibility that it plays an important role in the progression of pae-diatric ependymomas. Thirty-nine percent of tumours had a balanced CGHprofile, which in turn was significantly associated with a young age at diag-nosis (p<0.0001), suggesting that ependymomas arising in infants are bio-logically distinct. A young age at diagnosis traditionally confers a poor prog-nosis in ependymoma, and our data suggest this may in part be explainedby the distinct biology of the infant tumours. We have assembled CGH datafrom the largest set of paediatric ependymomas to date and report the firstwhole genome, prognostic study of paediatric ependymoma. We concludethat the tumour-specific CGH profile can divide ependymomas into biologi-cally favourable and unfavourable disease.

50. METHYLATION OF CASPASE-8, P16, MGMT, TIMP-3,AND E-CADHERIN IN MEDULLOBLASTOMAEbinger M, Senf L, Scheurlen W; Children’s Hospital, 68135 Mannheim,Germany

Objective: Silencing of tumor suppressor genes is a well-known mecha-nism in tumorigenesis. Gene silencing is often achieved by methylation of thepromotor region of a gene. In a total of 37 medulloblastoma specimens, weexamined the methylation pattern of caspase-8, part of Fas-induced apopto-sis cascade, of p16, the inhibitor of CDK4 and CDK5, of MGMT, a DNA-repair protein, of TIMP-3, an inhibitor of the proteolytic activity of matrixmetalloproteinases, and of E-cadherin, a growth inhibitor via cell-cell adhe-sion. Methods: Methylation-specific PCR according to Herman et al. (1996)was performed with specific primers for unmethylated and methylatedsequences of CpG islands in the promotor region. Results: Caspase-8: pro-motor regions of 30/37 specimens and 3/4 cell lines were found to be methy-lated. P16: 1/35 specimens and 2/4 cell lines were hypermethylated. MGMT:0/31 specimens methylated. TIMP-3: 0/20 specimens and 1/2 cell lines methy-lated. E-cadherin: 2/35 specimens and 1/4 cell lines methylated. Conclusion:Methylation does not seem to be a general phenomenon of tumor suppres-sor gene silencing in medulloblastoma, but a specific alteration restricted tosingle genes. Silencing of Caspase 8 methylation of the promotor may lead tosuppression of death receptor induced apoptosis providing a selective advan-tage. The other genes examined did not show significant methylation rates,suggesting that they do not play a crucial role in the pathogenesis of medul-loblastoma.

51. NEUROLOGIC EFFECTS OF CHEMOTHERAPY ONCHILDREN WITH CANCERErgurhan Ilhan I, Berberoglu S, Deda G, Cila A, Duzgun E; Department ofPaediatric Oncology, SD University 34.cadde Ankara, Turkey

Many types of cancer in childhood are curable, but the life-saving treat-ments may produce lasting damage to the developing central nervous sys-tem (CNS). Complications related to high-dose methotrexate treatment maybe seen as transient acute cerebral dysfunction or as a delayed process. In thisstudy clinical neurotoxicity and neuropsychologic functioning in childrenwith osteosarcoma receiving HDMTX have been studied prospectively. Thestudy group consisted of 18 osteosarcoma patients with an age range of 7 to18 years. None of these patients had laboratory evidence of CNS involvement

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at the time of diagnosis. No brain irradiation or intrathecal MTX was given.All patients received six course of HDMTX (12 gr/m2 total) with CFR, cis-platinum, and doxorubicin, except three. Intelligence quotient (IQ) wasassessed by the Wechsler Intelligence Scale for Children (WISC). In addi-tion, clinical neurologic examination and cranial magnetic resonance imag-ing (MRI) were performed to assess the neurologic status. Cerebrospinal fluid(CSF) was obtained from patients to check for the presence of myelin basicprotein (MBP), a specific component of the myelin sheath and an indicatorof demyelination. MRI showed mild or diffuse hyperintense white matterlesions in parieto-occipital lobes after the third and the ninth months of theinitial treatment in 5 patients. One of them developed mild cerebral and cere-bellar atrophy with no changes in white matter. There was an increase in MBPconcentration in CSF in 3 patients who had abnormal MRI scanning. WISCwas found normal in all patients except one who developed epileptic seizuresand personality changes during the treatment. This study supports HDMTXas one cause of subclinical or clinical demyelination and suggests that MBPcan be detected early enough in the preclinical stages of this disorder to be ofvalue in identifying patients at risk for this syndrome. Whether these abnor-malities contribute to the late cognitive deficits requires further investiga-tion in long-time.

52. NEWLY DIAGNOSED MEDULLOBLASTOMA WITHLEPTOMENINGEAL DISSEMINATION IN YOUNG CHILDREN:RESPONSE TO “HEAD START” INDUCTIONCHEMOTHERAPY INTENSIFIED WITH HIGH-DOSEMETHOTREXATEFinlay J, Chi S, Gardner S, Brualdi L, Levy A, Knopp E, Miller D, WisoffJ, Weiner H, Cervone K, Satterman D, Abramowitch M, Allen J, ComitoM, Diez B, Halpern S, Hurwitz C, Janss A, Parker R, Kellie S; Divisions ofPediatric Oncology, Neuroradiology, Neuropathology, and PediatricNeurosurgery, New York University Medical Center, New York, NY, USA;and participating institutions in the USA, Argentina, and Australia

The prognosis remains poor for young children with medulloblastomawho present with leptomeningeal dissemination. The “Head Start II” chemo-therapy regimen commenced in 1997 in an attempt to improve upon theresponse rate of the induction regimen for patients with leptomeningeal dis-semination. As in the predecessor “Head Start I” regimen, following diag-nosis and clinical staging, children receive induction chemotherapy consist-ing of 5 cycles of vincristine, cisplatinum, high-dose cyclophosphamide, andetoposide (each cycle administered over 3 days every 28 days). In addition,induction is intensified with high-dose methotrexate (12 gm/m2 infused over4 hours on day 4 of each cycle). Children without disease progression bythe completion of induction chemotherapy are offered consolidation withmyeloablative chemotherapy (thiotepa, etoposide, and carboplatin) followedby autologous hemopoietic stem cell rescue. We now present our initialcohort of patients and their responses to the intensified induction chemother-apeutic regimen. To date, 18 patients with medulloblastoma and lep-tomeningeal spread have been enrolled (14 boys and 4 girls, aged 0.7 to 8.86years). At diagnosis, 4 presented with M1 disease, 1 with M2 disease, and 13with M3 disease. Eleven patients underwent gross total resection, 4 near total/subtotal resection, and 3 partial resection. Magnetic resonance imaging stud-ies of the brain and spine, in addition to cerebrospinal fluid (CSF) cytologyevaluation, were performed after cycles 2 and 5. Radiographic and CSF cyto-logic responses are as follows: 13 complete responses, 1 partial response, 1stable disease, and 3 too early to evaluate. There have been no toxic deathsin this cohort. Other toxicities of this intensified regimen will be presented.This complete response rate is the highest yet reported with chemotherapyregimens in young children with medulloblastoma and leptomeningeal spreadat diagnosis. However, longer follow-up will be required to determine if thisresponse rate translates into improved survival following myeloablativechemotherapy and stem cell rescue.

53. TEMOZOLOMIDE FOR LOW-GRADE GLIAL TUMORS OF CHILDHOODFinlay J, Kuo D, Russo D, Brualdi L, Wisoff J, Weiner H, Miller D,Knopp E; Departments of Pediatrics, Neurosurgery, Pathology, andRadiology, New York University School of Medicine, New York, NY, USA

The optimal treatment for unresectable or recurrent childhood low-gradegliomas (LGGs) is unknown. Temozolomide (TM), which has shown efficacyin high-grade gliomas, may have utility against LGGs. This pilot studyassesses the efficacy and tolerability of TM in children with unresectablerecurrent or progressive LGGs. Since 1999, 12 children from 6 months to 19years old with LGGs and MRI evidence of unresectable tumors were treatedwith oral TM. Four unbiopsied patients received TM at tumor progression(one received prior chemotherapy). Five patients had prior tumor resectionbut no other treatment. Three patients had received radiotherapy and/orchemotherapy in addition to surgery. Pathological examination showed juve-

nile pilocytic astrocytoma in 6 patients and fibrillary astrocytoma in two.Three patients received a 5-day regimen (TM 150–200mg/m2/day x 5 daysevery 28 days), and 9 patients received a 42-day regimen (TM 75mg/m2/dayx 42 days every 56 days). Nine patients on the 42-day regimen received amedian of 6 cycles (range: 1 to 10 cycles), and 3 patients on the 5-day regi-men received a median of 15 cycles (range: 4 to 19 cycles). Nausea, emesis,fatigue, and thrombocytopenia were the most common toxicities. Twopatients discontinued therapy due to malaise, nausea, and/or emesis (one oneach regimen). Platelet transfusions were required in 3 patients (two on the5-day regimen), one discontinuing TM thereafter. Four patients demonstrateddurable objective MRI responses to TM, three on the 42-day regimen. Twoof these 4 discontinuing TM remain stable to date. The median time to max-imal MRI response was 4.5 months (range: 1.5 to 10 months). Four patientsdemonstrated tumor progression while on TM (three on the 42-day regimen).Three patients had stable disease at discontinuation of TM. One other patientremains with stable disease on MRI scans 6 months into treatment. Temo-zolomide is active in childhood LGGs. The 42-day regimen appears less toxicand more effective than the 5-day regimen. Any impact upon long-term sur-vival for these patients remains to be demonstrated.

54. MARROW ABLATIVE CHEMOTHERAPEUTICSTRATEGIES IN THE TREATMENT OF HIGH-RISK BRAINTUMORS OF EARLY CHILDHOODFinlay J, Stephen D; Hassenfeld Children’s Cancer Center, New YorkUniversity School of Medicine, New York, NY, USA

Since the mid-1980s, studies in children with recurrent malignant braintumors have documented efficacy of marrow ablative regimens employingthiotepa/etoposide+/= carboplatin, thiotepa/busulfan, and cyclophosphamide/melphalan, followed by autologous haemopoietic stem cell rescue (ASCR)in medulloblastoma, other cerebral PNET, malignant gliomas, and CNS germcell tumors. Conversely, several studies have failed to demonstrate any ben-efit from such strategies in children with recurrent ependymoma or brain stemtumors. All studies demonstrated benefit only for children treated in a stateof minimal residual tumor burden—although the exact definition of “mini-mal tumor burden” has varied. Furthermore, studies indicated that thosepatients with localized rather than disseminated tumor have fared best withthese strategies. Two studies on children less than three years of age withmalignant brain tumors recurrent after initial “baby” chemotherapy proto-cols have demonstrated the efficacy of marrow ablative chemotherapy withautologous stem cell rescue, with about 50% of patients so treated provingdurable disease-free survivors. The “Head Start” series of protocols, initiatedin the early 1990s, have attempted to improve the cure rate for young chil-dren with newly diagnosed malignant brain tumors while minimizing thesequelae of treatment through avoidance or at least minimization of irradia-tion. These protocols utilize an intensive but conventional dose “induction”chemotherapy regimen (vincristine, cisplatin, cyclophosphamide, and etopo-side) administered over three days, repeated every three weeks for a total of5 courses. Patients responding to this treatment then undergo “consolida-tion” with marrow ablative chemotherapy and ASCR. Irradiation is avoidedin children with no evidence of residual tumor burden following the “induc-tion” chemotherapy. In 1997, a second protocol intensified the “induction”regimen for children with disseminated disease with incorporation of high-dose intravenous methotrexate (12Gm/M2) with each cycle. All children lessthan 3 years old at diagnosis are eligible, while children with high-risk tumorsare eligible up to 9 years old. Five-year event-free and overall survival data,as well as quality of survival data, will be presented which justify the incor-poration of these strategies into the management of young children newlydiagnosed with medulloblastoma and other PNET, both with localized andwith disseminated disease.

55. DIENCEPHALIC SYNDROME: CLINICAL FINDINGS IN ACASE SERIES OF 10 CHILDRENFleischman A, Brue B, Young-Poussaint T, Kieran M, Cohen L; Children’sHospital and Dana-Farber Cancer Institute, Boston, MA, USA

In 1951, Russell described the diencephalic syndrome as profound ema-ciation in infancy with absence of subcutaneous adipose tissue in spite of nor-mal or slightly diminished caloric intake in association with a neoplasm ofthe anterior hypothalamus. Other features included locomotor overactivity,hyperalertness and hyperkinesis, and euphoria. Evaluation has shownincreased levels of growth hormone, frequently paradoxical responses tohyperglycemia and hypoglycemia, and normal or suppressed IGF-1 levels. Todescribe the clinical characteristics in children presenting with diencephalicsyndrome in a single institution, a retrospective review of the clinical recordsof all patients with diencephalic syndrome at Children’s Hospital Boston/Dana-Farber Cancer Institute over the last 32 years. Ten children (4 female,6 male) who presented with failure to thrive from 1970–present were foundto have central nervous system neoplasms. Median age at diagnosis was 18

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months (range 4–57). Hyperkinesis was reported in only 2/10 (20%) ofpatients. Vomiting was present in only 4/10 (40%). Hydrocephalus orenlarged ventricular size was present in 5/10 (50%), similar to publishedreports of 33–58%. Optic atrophy was not reported in any patient, althoughnystagmus was present in one. Basal growth hormone levels were elevated in5 patients (range 12.7–35.5 ng/mL), while IGF-1 concentrations were foundwithin (n = 2) or below (n = 2) the normal range for age. Median tumor sizewas 12 cm2 (range 1.3–17.6). Pathologic diagnosis was low-grade hypothal-amic glioma in all cases, but 2/10 (20%) patients had spinal seeding at thetime of presentation. Based on this single institutional experience, (1) classicsymptoms of hyperkinesis, hyperemesis, and nystagmus were less commonin this series of diencephalic syndrome than in other reports; (2) althoughvisual impairment often represents the first manifestation of hypothalamicgliomas, it was not observed in this population in association with dien-cephalic syndrome; (3) the tumors are large at presentation and are morelikely to be metastatic than in nondiencephalic syndrome patients; (4) testingis consistent with growth hormone resistance, but the patients had weightloss without a fall-off in linear growth, the opposite of what would beexpected. Further evaluation is needed to determine the etiology of the fail-ure to thrive.

56. ACCUMULATION OF CERAMIDE RESULTS IN APOPTOSISIN GLIOBLASTOMA TREATED WITH TAMOXIFENFleitz J, Donson A, Handler M, Foreman N; University of ColoradoHealth Sciences Center, Denver, CO, USA

Tamoxifen has been shown to have an antitumor effect in glioblastoma.Clinical trials have ensued but with disappointing results. Tamoxifen isbelieved to effect glioblastoma by inhibition of protein kinase C, althoughthis mechanism is not well understood. It has recently been demonstrated inother tumors that tamoxifen can cause accumulation of intracellularceramide, which in turn triggers apoptosis. In this study we sought to inves-tigate whether tamoxifen caused accumulation of ceramide in glioblastomaand whether this led to apoptosis. Our results were that in 3 out of 4 humanglioblastoma cell lines studied ceramide accumulation occurred and this ledto apoptosis. In the cell line in which ceramide accumulation did not occur,apoptosis was not seen. All 4 glioblastoma cell lines showed increased apo-ptosis in response to endogenously added C2-ceramide. Together, these datasuggest that tamoxifen can induce apoptosis in glioblastoma and that thismechanism is mediated by ceramide accumulation. We investigated the mech-anism of ceramide mediated apoptosis be using by Boc-D-fmk, a pan-caspaseinhibitor. We showed that in 1 of the 4 cell lines ceramide-induced apopto-sis occurred via the caspase-signaling pathway. This research provides insightinto the mechanism of the tamoxifen antitumor effect. This in turn may helpus improve the efficacy of tamoxifen chemotherapy in glioblastoma.

57. POSTRADIATION CEREBROVASCULAR INCIDENTS IN 5 ADOLESCENTS, SURVIVORS OF CHILDHOOD CENTRALNERVOUS SYSTEM TUMOURSFock JM,1 Begeer JH,1 Hoving EW,2 Leeuw JA,3 Dolsma WV4;Departments of 1Child Neurology, 2Neurosurgery, 3Pediatric Oncology,and 4Radiation Oncology, University Hospital, Groningen, TheNetherlands

Five male adolescents presented with cerebrovascular accidents duringthe period December 1998–January 2002. All of them were treated with radi-ation therapy in childhood because of tumours of the central nervous system.Four underwent craniospinal axis irradiation with an additional boost on theposterior fossa, and one underwent local radiotherapy only. Four of them suf-fered from ischaemic incidents, and one patient had a hemorrhage in the brainstem without radiation necrosis. The interval between radiation therapyand these cerebrovascular accidents varied from 6 and a half years to 15years. The last patient is considered a special case because he had irradia-tion twice for recurrent acute lymphatic leukemia at the age of 4 and a sec-ondary glioblastoma at the age of 15. Vasculopathy as a side effect of radia-tion therapy is mentioned in the literature only in adults and in some casereports in children until now. Radiation induces endothelial changes in thecerebral vessels. As a cause of the haemorrhage, a rupture of a thin-wallednew blood vessel, proliferated in the radiated tissue, can be mentioned. Theischemic incidents are probably caused by capillary occlusion or due to steno-sis in the damaged blood vessels. We expect to be confronted more often withadolescent survivors of childhood CNS tumours with postradiation cere-brovascular incidents in the future.

58. NEURORADIOLOGIC FEATURES OF OPTIC PATHWAYSGLIOMAS (OPG) IN NF1Fondelli M, Garrè M,* Bonioli E,** Cama A***; Neuroradiology,*Oncology, **Pediatric, ***Neurosurgery Departments, The GianninaGaslini Children’s Hospital, Genoa, Italy

To focus on the importance of magnetic resonance imaging (MRI) in eval-uating behaviour of OPG in patients with NF1, with the aim of allowing apolicy of clinical surveillance instead of chemo-radiotherapy, a series of 15consecutive OPG in NF1 observed at G. Gaslini Children’s Hospital from1993 to 2000 and evaluated by modern MRI protocols has been retrospec-tively reviewed. This series has been included in a large cooperative EuropeanSIOP (Societé International d’Oncologie Pediatrique) study (LGG93),enrolling 407 low-grade gliomas (78 in NF1), in order to investigate thenatural history of the disease and to clarify the role of chemotherapy in thosecases showing clinical and radiological tumor progression. Brain MRIs wereanalyzed focusing on the modifications of tumour size, structure, signal,and contrast enhancement in time. Isolated orbital glioma was present in 1case, while anterior OPG and anterior + posterior OPG were present in 11and 3 cases, respectively. Involvement of hypothalamus was documented in3 cases. In 1 case radiological features of both NF1 and Tuberous Sclerosiswere seen. A procedure of surveillance has been adopted: 6 patients showedclinical worsening and various MRI signs of tumor progression, and they hadbeen subsequently treated with chemotherapy; in 7 cases the clinical and radi-ological data remained unvaried. In 1 patient who showed a progressiveimprovement of visual function, a spontaneous involution of OPG has beenobserved. Out of the 6 cases treated, 3 regressed with a radiologic patternquite similar to the case of spontaneous regression and 3 remainedunchanged. Spontaneous regression or indolence of OPG is frequentlyobserved on MRI in NF1, allowing a policy of surveillance instead of appli-cation of radiotherapy or chemotherapy. A careful analysis of MRI changes,besides the evaluation of visual function, is imperative in defining tumor pro-gression. A MRI follow-up is crucial, especially in younger children, in whomthe evaluation of visual acuity is often difficult to obtain. The MRI datamay contribute to the establishment of more precise guidelines in evaluationand treatment of children with NF1.

59. ERBB2 OVEREXPRESSION ALTERS THE CELL CYCLE,APOPTOSIS AND GENE EXPRESSION PROFILES OFMEDULLOBLASTOMA CELLSFrank A, Hernan R, Calabrese C, Gilbertson RJ; Department ofDevelopmental Neurobiology, St. Jude Children’s Research Hospital,Memphis, TN, USA

Overexpression of the ERBB2 receptor has been implicated in the patho-genesis of pediatric medulloblastoma. The aim of this study was to charac-terize the impact of ERBB2 overexpression on cell cycle, apoptosis, and genetranscription control in cultured medulloblastoma cells. To do this, we trans-fected Daoy (de novo low ERBB1 and ERBB2 expressing) and MHH-MED-8A (de novo low ERBB2 expressing) human medulloblastoma cellswith wild type human ERBB2. First, by covalently cross-linking cell surfaceproteins, we demonstrate that ERBB2 overexpression results in constitutivereceptor homodimerization and activation, and in increased ligand bindingaffinity (assessed by binding of [I125]-EGF to DAOY cells) in medulloblas-toma cells. Using Western and flow cytometric analysis of Daoy ERBB2 trans-fected (Daoy.2H) versus vector-only control cells (Daoy.v), we also show thatERBB2 overexpression promotes hyperphosphorylation of Rb, increasedexpression of cyclins D and E, and cell cycle progression. Parallel annexin Vstaining of these cells also revealed significant up-regulation of apoptosis inthe presence of overexpressed ERBB2. To investigate the impact of ERBB2on gene expression profiles, we conducted Affymetrix microarray analysis ofDaoy.2H and Daoy.v cells. We used the extensive 12,000 Human GeneU95av2 chip. Cells were treated for 45 min, 8 hours, and 24 hours with 10%serum or 50ng/ml EGF. Remarkably similar gene expression profiles wereobserved between ERBB2 overexpressing and control cells up to 8 hoursfollowing stimulation. However, by 24 hours, significant differences in geneexpression profiles were observed. At this time, Daoy.2H cells demonstrated5–10 fold increased expression of genes within the angiogenesis (eg, VEGFand VCAM-1) and metastatic (eg, uPA and uPA receptor) cascades. Our dataindicate that ERBB2 overexpression by medulloblastoma may promoteaggressive disease behavior through the deregulation of cell cycle control andby the generation of a pro-invasive gene expression profile.

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60. HIGH-GRADE GLIOMAS (HGG) IN CHILDREN: ONGOING DEBATESFrappaz D; Department of Pediatrics, Centre Léon Berard, Lyon, France

Supratentorial HGGs is an orphan disease since it constitutes only 10%of brain tumors reported to registries. Moreover, when expert neuropathol-ogists review the studies, they agree on a specific diagnosis in only 25% ofcases (discrepancies between glial versus nonglial tumors, glioblastomasversus anaplastic astrocytomas, and gliomas versus oligodendrogliomas). Thedemonstration in adults that 1 p 19 q deletion is specific and may partici-pate in chemosensitivity of oligodendrogliomas will further complicate inter-pretation of clinical trials. Thus in the future, central review and molecularbiology will become mandatory. Evidenced-based medicine for the treatmentof pediatric HGG is scarce. Expert consensus suggests that debulking surgerymay lead to improved quality of life and increased survival. Randomised evi-dence that a 60 Gy focal radiotherapy increases survival is largely demon-strated in adult series only. It may, however, be extended to pediatric popu-lation, though specific sequelae must be considered. Hyperfractionationshowed no benefit, at least in brain stem gliomas. The CCG 943 study sug-gests that chemotherapy (vincristine, CCNU, PDN) delivered post radio-therapy significantly increases 5-year EFS and OS. Despite several method-ological problems, this randomised study served as the basis of furtherrandomised and/or frontline chemotherapy studies using nitrosoureas. Nonehas, for the time being, demonstrated major advances either at standard orat high dose, confirming 2 meta-analyses of adult series that suggest the minorrole of current chemotherapy strategies. Whether new drugs (such as temo-zolomide) will result in a major breakthrough is still matter of debate. Thecurrent role of biological modifiers, antigrowth factors, anti-angiogenesis, orgene therapy is currently explored by several teams, and their association withchemotherapy will probably be a major challenge in the future. This will obvi-ously require identification of specific cellular targets and innovative ways ofassessing the response. Finally, follow-up of these patients will require stan-dardisation to allow meaningful comparisons with retrospective data whileminimizing economical costs. High-grade gliomas still represent a major chal-lenge for the pediatric neuro-oncology community, both in term of qualityand quantity of life. Only large cooperative efforts may lead to major break-throughs.

61. INTRACRANIAL EPENDYMOMAS: THE SFOPEXPERIENCE WITH HYPERFRACTIONNATEDPOSTOPERATIVE FOCAL RADIOTHERAPY (BIDRT)Frappaz D,* Bernier V, Geoffray A, Plantaz D, Gentet JC, Gomez F,*Flandin I,* Carrie C*; Centre L Bérard, Lyon, France for the SFOP

Rationale: To prospectively investigate the role of BifRT in the optimaltreatment of intracranial ependymoma. Materials and Methods: Postopera-tive focal BidRT was proposed to every child (more than 5 years at diagno-sis) with localised intracranial ependymoma. According to postoperativecranio-spinal MRI, in the case of complete removal (CompRem) 60 Gy, andin the case of less than complete removal (IncompRem) 66 Gy, were deliv-ered in two daily fractions of 1 Gy. Results: From 11/1996 to 12/2001, 19children with infratentorial (16) or supratentorial (3) ependymomas wereincluded. Median age was 9 years (5–17). CompRem was reported by localphysicians in 10 (2 doubtful at review) and IncompRem in 9 (1 CompRemat review). WHO grade was II in 8 and III in 9 (nonassessable in 2). Dose tolocal tumor was 54 Gy (1 IncompRem), 60 Gy (10 CompRem and 2 Incom-pRem), and 66 Gy (6 IncompRem). The 3-year overall survival is 58% andEFS 46%. Five patients had a relapse; all were local (4/16 infratentorial and1/3 supratentorial). Two of 8 grade II, 2 of 9 grade III, and 1 of 2 grade notassessed relapsed. According to assessment by local physicians, 2/10 Com-pRem and 3/9 IncompRem relapsed. Conclusion: BidRT is a safe procedureafter optimal removal of intracranial ependymoma. Further follow-up is war-ranted to show that the rate of sequelae is diminished by this procedure.Grants from Comité du Rhone Ligue Nationale Contre le Cancer and Asso-ciation Sébastien à Boston.

62. MAY PRERADIATION CHEMOTHERAPY IMPROVESURVIVAL RATE OF BRAIN STEM GLIOMAS?Frappaz D,* Marec Berard P,* Schell M,* Thierry P,* Alain Vighetto A,**Bergeron C,* Mottolese C,** Buclon M,* Carrie C*; *Centre Léon Bérardand **Hôpital Neurologique, Lyon, France

Rationale: Despite numerous attempts (standard RT, hyperfractionatedRT, standard or high-dose chemotherapy), the usual median survival ofpatients with diffuse brain stem tumors does not exceed 9 months. Weprospectively proposed to delay radiotherapy as long as no progression wasobserved under multidrug chemotherapy. Methods and Patients: As soon asMRI showed a diffuse BSG, cycles of chemotherapy were initiated. Each cycleincluded 3 monthly courses alternating � (Tamoxifen + BCNU and CDDP

40 mg/m2/d x 4 days in continuous infusion), course � and � (High-doseMTX: 12 g/m2). Cycles were delivered until progression, or to a maximumof 4 (1 year of treatment). Standard radiation therapy was then delivered tothe tumor with maintenance hydroxyurea. Results: Sixteen patients wereprospectively included. They were compared with a historical control groupof 8 patients treated in the same institution, by frontline radiotherapy onlyand/or Procarbazine. The median number of courses was 9 (1 to 12). Only3 patients died before 9 months: two of tumor progression (for one patient,parents refused radiation therapy at time of progression after chemo) and oneof septicemia while on maintenance hydroxyurea. The median survival is 17months. This is significantly better than the historical group (median survival:10 months; p = 0,0005). Moreover, the survival calculated from time of radi-ation therapy to death (12 patients) was 7 months and did not significantlydiffer from the historical group receiving frontline radiation therapy (p =0.07). Conclusion: Multidrug chemotherapy delivered until progression mayprolong the median survival rate. This suggests that no cross resistancebetween chemotherapy and radiotherapy may be detected in this schedule.

63. EXPRESSION OF ERBB2 PREDICTS OUTCOME INAVERAGE-RISK MEDULLOBLASTOMAGajjar A, Wallace D, Kun LE, Boyett J, Gilbertson R; Brain TumorProgram, St Jude Children’s Research Hospital, Memphis TN, USA

Aim: ERBB2 expression has previously been demonstrated to negativelyinfluence event-free survival in medulloblastoma patients. We sought to val-idate this finding in a contemporarily staged group of medulloblastomapatients treated at our institution. Methods: Snap-frozen tumor specimensfrom 40 medulloblastoma patients (>3 yrs of age) treated between 1985 and2001 were evaluated for ERBB2 expression using Western blot analysis.The patients were staged using the Chang staging system. All patients weretreated with craniospinal radiation therapy. Thirty-one patients also receivedchemotherapy. Overall survival and progression-free survival were calculatedfrom the date of diagnosis using Kaplan-Meier methods. Exact log-rank testwas used to compare the distributions of progression-free survival. Results:The median age of the patients was 7.3 yrs (range 3.2–19.0). The cohort con-sisted of 26 males and 14 females. The median follow-up for the cohort was4.4 yrs (range 0.7–15 yrs). Twenty-two patients were staged as average-risk(AR), and 18 patients were staged as high-risk (HR). ERBB2 expression wasreadily detectable by Western blotting in patient samples. This expressionincluded both a full-length (185 kDa) and a truncated (~90kDa) variant ofthe ERBB2 protein. Both species were confirmed to derive from the c-termi-nal region of active ERBB2 by repeat Western analysis using a phospho-specific ERBB2 antibody. Of the 22 AR patients, 13 pts (59%) demonstratedERBB2 (full and truncated) detectable levels; similarly, 11 of the 18 HR pts(61%) expressed ERBB2. The 5 yr PFS for the entire cohort is 69 ±10%; the5-yr PFS for the HR patients is 65 ±15% and for the AR patients 73±12%(p = 0.15). Expression of ERBB2 protein identified a cohort of patients withinthe AR group with significantly worse clinical outcomes. Importantly, 5-yrPFS of AR/ERBB2 negative patients is 100% compared to 55 +16% forERBB2 positive AR patients (p = 0.034). Conclusions: ERBB2 expressionincludes full-length and truncated forms in medulloblastoma. Expressionselects a group of AR patients that are at greater risk of relapse and may war-rant additional therapy. Further characterization of the truncated ERBB2form and the value of ERBB2 Western analysis for risk stratification areunderway.

64. HYPERFRACTIONATED ACCELERATED RADIOTHERAPY(HART) FOR METASTATIC MEDULLOBLASTOMAGandola L, Cefalo G, Massimino M, Navarria P, Spreafico F, Pignoli E,Luksch R, Giombini S, Castelli E, Ferrari A, Casanova M, Polastri D,Terenziani M, Fossati Bellani F; Radiotherapy and Pediatric Oncology,Istituto Nazionale Tumori, Istituto Neurologico Besta, Milan, Italy; IRCCSEugenio Medea, Bosisio Parini, Italy

To improve prognosis of patients with metastatic medulloblastoma, weelected to test the efficacy and toxicity of a hyperfractionated acceleratedradiotherapy regimen delivered after intensive postoperative sequentialchemotherapy. Radiobiological rationale for HART selection was reductionof overall treatment time (acceleration) to lessen the effect of cancer cellproliferation during radiotherapy, thus ameliorating the probability of tumorcontrol without increasing severity of radiation sequelae (hyperfractionation).Between January 1997 and August 2001, 24 consecutive patients (medianage 10 years) received postoperative sequential high-dose MTX (8g/sqm),VP16 (2.4g/sqm), CTX (4g/sqm), and CBDCA (0.8g/sqm) given as soon aspossible after recovery from hematological toxicity of previous cycle. Accord-ing to the Chang staging system of metastatic spread, patients were classifiedas follows: M1 = 9 patients (5 with postsurgical residual disease in posteriorfossa), M2 = 3 patients, M3 = 11 patients, and M4 = 1 patient. HART wasdelivered 3 weeks after the end of chemotherapy at a total dose of 39 Gy to

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the neuraxis (1.3 Gy/fraction, 2 fractions per day) with a boost to the poste-rior fossa up to 60 Gy (1.5 Gy/fraction, 2 fractions per day). Nine childrenyounger than 10 years and in CR after chemotherapy received a reduced doseto the neuraxis of 31.2 Gy. In case of persistent disseminated disease beforeHART, patients were consolidated with 2 courses of myeloablative chemo-therapy and PBSC rescue. Twenty-three of 24 patients responded to postop-erative chemotherapy; one showed disease progression. Eighty percent of thepatients required transfusional support during chemotherapy, and 3 devel-oped a bacterial sepsis. HART was completed as scheduled in all cases. Fourpatients relapsed at a median time of 11 months (3 of them were staged asM1). After a median follow-up of 32 months, actuarial 3-year DFS and OSare 78% and 86%, respectively. No severe clinical complications of HARTwere detected so far. However, neurocognitive and growth development aswell as endocrinological status of the present series are objects of prospectiveevaluation. Hyperfractionated accelerated radiotherapy combined with inten-sive postoperative chemotherapy proved to be feasible without major toxic-ity in children with metastatic medulloblastoma, and therapeutic results com-pare favorably with our and other series treated with conventional therapies.

65. IMPACT OF RADIOTHERAPY VOLUME EXTENT IN COMBINED TREATMENT OF NONMETASTATICINTRACRANIAL GERMINOMAGandola L, Cefalo G, Massimino M, Navarria P, Spreafico F, Pignoli E,Luksch R, Ferrari A, Casanova M, Polastri D, Terenziani M, FossatiBellani F; Radiotherapy and Pediatric Oncology, Istituto NazionaleTumori, Milan, Italy

Intracranial germinoma is the most radiosensitive and chemosensitiveCNS primary tumor. Combined modality treatment of germinoma is beinginvestigated worldwide, mainly in the attempt to avoid craniospinal irradia-tion and therefore to reduce radiation sequelae in children. Optimal radio-therapy treatment volume and total dose, in association with chemotherapy,are still controversial and the object of clinical investigations. From 1990 to2001, 19 consecutive patients (15 male, 4 female; median age 15 years, range7–37 years) with histological (16 patients) or clinical (3 patients) diagnosisof intracranial germinoma were treated with 2 cycles of PEB regimen (cis-platinum, etoposide, and bleomycin, monthly) followed by radiotherapy and2–4 additional PEB courses. In none was CNS dissemination documented.Initial surgery was gross total resection in 6 patients and subtotal in 10.Two PEB courses induced a complete remission in 8 out of 13 patients withmeasurable disease. Between 1990 and 1994, 6 patients received irradiationonly to a “focal” volume including the initial tumor extent plus 2 cm mar-gins (median total dose 45 Gy). Four of 6 patients relapsed outside radia-tion fields but within brain ventricles at a median time of 24 months. Twoof 4 relapsers are alive in second CR at 85 and 98 months after salvage treat-ment. Two died after 16 and 18 months from progression. From 1995,because of the observed excess of treatment failures, radiotherapy wasextended to the whole ventricular system (total dose 45 Gy). All 13 patientsirradiated so far to the brain ventricles are alive in CCR at a median time of29 months. Our results confirm the chemosensitivity of intracranial germi-noma and strongly suggest that CNS irradiation can be safely avoided. In ourexperience, both initial tumor extent and the whole ventricular system shouldbe included in the irradiated volume to minimize the risk of relapse. Mod-ern conformal 3-D radiation techniques allow an excellent coverage of thetarget volume, including the brain ventricles, with a substantial sparing ofsurrounding normal tissues. In combined modality treatments, the minimumradiation dose required to control intracranial germinoma still needs to bedefined.

66. HIGH-RISK MALIGNANT CNS TUMOURS IN INFANTS:STANDARD VS MIELOABLATIVE CHEMOTHERAPY: THEEXPERIENCE OF THE ITALIAN COOPERATIVE STUDY FORCHILDREN <3 YEARS OF AGEGarrè ML,* Massimino M,° Cefalo G,° Perilongo G,^ Abate M,# SandriA,§ Franzone P,@ Burnelli R,** Dallorso S,* Milanaccio C,* Gandola L,°°Madon E§; *Ped. Hemato-Oncology Giannina Gaslini Hospital, Genoa;°Ped. Oncology and °°RT Dept INT, Milan; ^Ped. Hemato-OncologyUniversity, Padua; #Casa Sollievo Sofferenza S.G. Rotondo; §Hemato-Oncology Regina Margherita Hospital, Turin; @Radiotherapy Dept IST,Genoa; **Ped. Hemato-Oncology Sant’Orsola Hospital, Bologna, Italy

The Italian cooperative study (opened in 1995) for infants affected bymalignant CNS tumours evaluated the efficacy of a CT protocol obtainedby the intensification (HDMTX) of the “Baby POG” CT (N Engl J M 1993).A preliminary analysis (39 cases) identified characteristics of pts having earlyrelapse/progression: medulloblastoma with metastasis (M+) or residualtumour (T+) (EFS = 0, OS at 5 yrs 22%) and histologies (AT/RT, PNETs, Ch.Plexus Ca, Ependymoblastoma, M. Gliomas) that did badly irrespective ofstaging. In 1997, pts with these high-risk features or relapsed after SNC 9501

were enrolled in a 3-phase protocol: Phase A, induction and PBPC collec-tion ( VCR/HDMTX; HDVP16; VCR/HDCTX; VCR/CARBO); Phase B,double PBPC transplantation (CARBO/VP16; THIOTEPA/MEPHALAN);Phase C, irradiation if T+ after CT or M+ at dx. Forty cases have beenrecruited, 22 M, 18 F. Follow-up ranges from 3 to 50 mos (median 20). Mainfeatures of pts and responses to CT are in the following table.

N° of ResponseTumour Type cases Staging (phase A –B) Outcome

Medulloblastoma 17* 11 M+/T+/-6 T+/M- CR 9 PR 6 PD2 10 ANED 1AWD 4 DOD 2 NV

PNETs 9 5 T+/M-4 T-/M- CR 5 PR 4 8 A NED 1 DOCU†

AT/RT 5 5 T+/M-1 T-/M+ 1 CR 2PR 2PD 2 ANED 2 DOD 1 NV

M. Gliomas 4 3 T+/M- 1 T+/M+ 2PR 1CR 1SD 3* ANED 1 DOCU†

Ependymobl. 2 1 T+/M- 1 1PD 2 DOD T-/M- 1PR

Others 3 (2 M. 2 T-/M-1 T+/M+ 1CR 1PR 1PD 1 ANED 1DOD NOS T. 1 NV 1CH.Pl Ca)

*5 at PD after SNC9501 †Death from complications unrelated to Tx

Thirteen cases (32%) at the end of CT did not receive RT; 16 (40%)underwent RT(CSI 20–24Gy, boost 45–50Gy). Acute toxicity was manage-able, and no toxic deaths occurred.

Conclusions: The best results were in high-risk medulloblastomas (88%CR+PR, 58% OFF-therapy, NED; 50% of them without RT) and PNETs andin malignant gliomas. In other rare malignant tumours peculiar to infants, alonger follow-up and an increased number of cases are needed in order todefine the real benefit of this strategy.

67. OPTIC PATHWAY GLIOMAS (OPG) IN CHILDREN WITHNEUROFIBROMATOSIS TYPE 1 (NF1): NATURAL HISTORYAND RESULTS OF TREATMENT (TX): THE EXPERIENCE OFSIOP LOW-GRADE GLIOMA STUDYGarrè ML,* Perilongo G,° Zanetti I,° Walker D,^ Scarzello G,** GnekowA,# on behalf of the SIOP Low-grade Glioma Study; *Neuro-OncologyDepartment, Giannina Gaslini Children’s Hospital, Genoa, Italy; °Ped.Oncology and **Radiotherapy Department, University of Padua, Italy;^Ped. Oncology Department, Queen’s Medical Center, Nottingham, UK;#Ped. Oncology Department, Ausburg, Germany

Gliomas in NF1 are mainly pilocytic astrocytoma involving optic path-ways; 3 possible behaviours are reported: spontaneous regression (SR), sta-bility (SD), and rapid growth (PD). Vision impairment may pose limitationsto the approach of “wait and see.” On the other hand, there is reluctance inproposing RT or aggressive CT for a genetic disease predisposing to cancer.Chemotherapy became a useful instrument in OPG Tx especially for youngerchildren. We report on 82 (50 F, 32 M) cases enrolled in the SIOP Low-gradeGlioma Study in the period 1993–2000 in Germany and Italy, where the studyopened first. Diagnosis (dx) was clinico-radiological in 83% of cases. The“wait and see” approach was adopted before Tx unless the child was clearlysymptomatic or with evident advanced disease. Follow-up ranged from 24 to108 mos (median 84). Main features of cases and Tx results are reported inthe following table.

Observation Only Chemotherapy Radiotherapy

N° of cases 31 39 12 Age range (median) 1.5–15 (6) 1–12 (3.5) 4–11.7 (9) Site-Optic Nerve(s) 11 7 --Chiasma/Chias+ X 14 28 6-Hypoth./Chiasma 7 4 6Interval dx and tx(median) - 0 – 84 (6) 0.8 – 88.5 (32.5) Response-CR - 1 --PR/OR* - 22 4-SD - 12 7-PD - 4 1*objective response PD after CT or RT - 8 3 Status-SR 2 - --CR 1 2 --SD 28 33 10-PD - 3 1-DOD - 1 1

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Conclusions: Spontaneous regression or stability in NF1 OPG only“observed” is the most frequent behaviour justifying a policy of surveillancebased on strict and objective criteria before CT or RT is started. However,CT demonstrated efficacy in controlling disease (PR/OR = 58.9%).

68. THE COMPARATIVE RESULTS OF SURGERY, COMBINED,AND COMPLEX THERAPY OF NEWLY DIAGNOSEDMEDULLOBLASTOMA IN CHILDRENGeludkova O, Livshits M, Popov V, Gorbatykh S, Poloushkina O,Kholodov B, Tarassova I; Research Institute for Pediatric HematologyRussian Federation, Morozovskaya Children’s Clinical Hospital, RussianChildren’s Clinical Hospital, Research Practical Center, Russia

Medulloblastoma (MB) is the most common brain tumor in children.There are some significant results in the treatment of MB as the result of com-plex therapy that includes surgery, radiation therapy (RT), and poly-chemotherapy (PCT). Retrospective study of 107 patients with MB treatedwith surgery alone (22 patients), surgery plus RT (25 patients), surgery plusPCT (12 patients), PCT alone (3 patients), and complex therapy includingsurgery, RT, and PCT (45 patients) was performed. The mean age was 7.4years. Patients received PCT after surgery and RT (11 patients) and aftersurgery (34 patients). Tumor staging (35 patients) was M0 (16), M1 (13), M2(5), M3 (1); 62.6% of the patients had tumor stage T3b. Tumor removal:total–57.5% of patients, subtotal–33%, partial–8.5%, biopsy–0.9%. RTwith 30–35Gy to the craniospinal axis plus 50–55Gy to the posterior fossa(PF) was performed in 19 patients, only PF in 2 patients, and to the wholebrain plus PF in 5 patients. PCT included two 28-day alternative cycles (VCR1.5 mg/m2–day 1, CPM 600 mg/m2–days 1,2 and CDDP 40 mg/m2–days1,2,3, VP-16 150 mg/m2–days 1,2). Two-year PFS was 0% in patients treatedwith surgery only, 20% with surgery plus RT, and 42% with complex ther-apy. Five-year OS was 35% in patients treated with surgery plus RT, and 80%with complex therapy (p = 0,016). Patients with total removal of the tumorhad a 5-year PFS rate of 55%, as compared to 27% with residual tumor (p= 0,008). Patients with stage T2 and T3b had better 5-year PFS rate of 80%in contrast to 37% with stage T3b and T4 (p = 0.014). Five-year PFS was75% in children with stage M0 versus 25% with stage M1 (p = 0.003).Shunted patients had inferior 5-year PFS as compared with nonshuntedpatients (25% versus 57% (p = 0.025)). In summary, the survival of chil-dren with MB was significantly better when PCT was used as a part of com-plex therapy. The main factors influencing survival of patients with MB werethe presence of residual tumor and shunt, the Chang T/M stage, and the addi-tion of RT and chemotherapy to the treatment of certain subsets of patients.

69. INTRINSIC FOCAL TUMOURS OF THE MEDULLAOBLONGATA IN CHILDREN: A SERIES OF 14 CASESGenitori L,* Giordano F,* Peretta P,* Mussa F,* Ricardi U^; *Division ofNeurosurgery, ^Division of Radiotherapy, Regina Margherita Children’sHospital, Turin, Italy

From 1994 to 2001, 14 patients were admitted to the Division of Neuro-surgery of Regina Margherita Children’s Hospital of Turin for focal tumoursof the medulla oblongata (FTM): 8 males and 6 females, mean age 6.1 years.First symptoms were torticollis (3), motor deficits (2), 7th cranial nerve (1)and lower ccnn disturbances (2), diplopia and strabismus (2), ataxia (1),raised ICP (1), respiratory complaints (1), and seizures (1). Average timebefore diagnosis was 6.5 months. Neurological examination showed lowerccnn deficits (13), cerebellar syndrome (4), hemiparesis (4), and 6th (4) and7th (4) cn impairment. All patients had MRI. Twelve tumours were solid, 2cystic-solid. Tumoral growth was exophytic (5) and purely intrinsic (9).Extension was posterior (11), right (1), and left (1); other extensions in 7cases were middle (3), inferior cerebellar peduncle (1), and upper cervical cord(3). All patients underwent median suboccipital craniotomy. Purely intrinsicFTMs were approached by splitting the posterior median sulcus in 4 cases;in 5 cases the route was planned beside the oliva (4) and under the facialcolliculus (1). Exophytic FTMs were removed through the cerebellar pedun-cle (4) and the tumoral cyst (1). Extent of resection was total (6), subtotal (5),and partial (3). Histology showed 13 low-grade tumours (8 WHO grade Iastrocytomas, 3 grade I–II astrocytomas, 2 gangliogliomas) and 1 vasculartumour. No mortality was observed. Postoperative morbidity was centralpontine myelinolysis (1) and 4th cn deficit (1) with good outcome. Twopatients developed hydrocephalus treated with CSF shunt (1) and endoscopic-third-ventriculostomy (1). Early outcomes were improvement in 9 childrenand worsening in 2 children, respectively; 3 cases were unchanged. Mean follow-up was 31.5 months. Three patients underwent 3D-conformal radio-therapy (54 Gy/30 fractions) at 6, 8, and 9 months because of tumour pro-gression after partial resection. Eleven patients required neither radiotherapynor chemotherapy during the entire follow-up (38.2 months). All patients arealive without tumour progression and Glasgow Outcome Scale 5 (9 patients),4 (3), and 2 (1). Our experience confirms the role of aggressive surgery in

childhood FTMs in terms of good clinical outcome and tumour control with-out immediate adjuvant treatment, as observed in 11/14 cases.

70. LOW-GRADE GLIOMAS (LGG) WITH EXTENSIVELEPTOMENINGEAL DISSEMINATION (LMD) IN CHILDRENWITH UNUSUAL HISTOLOGICAL APPEARANCE: A CRITICALREAPPRAISALGiangaspero F, Gardiman M, Canesso A, Rigobello L, Carollo CA,Battistella PA, Laverda AM, Candusso M, Sperli D, Burnelli R, Garrè ML,Perilongo G; Neuro-oncology Program, Department of Paediatrics, Padua,Italy

A critical reappraisal of LGGs with extensive LMD, 3 with a spinal lesionand 2 without a primary, occurring in 3 boys and 2 girls, aged 18, 40, 84,120, and 144 months (m), respectively, is proposed based on the hypothesisthat they may represent a distinctive clinico-pathological entity. Despite sometreatment, 2 patients died of disease at 9 m and 9 years, 3 are alive with sta-ble disease at 2, 6, and 33 m. The LMD took the MRI form of a diffusemicrocystic meningo-encephalopathy in 1 (extensive presence along the brainand spine surface of multiple small cysts) and of areas of diffuse sub-arachnoidal enhancement in the others. Histological findings were as follows:Spinal LGG Case #1: Low-grade lesion composed of relatively monomor-phous cells with round/oval nuclei, some of which with scanty fibrillary cyto-plasm; few multinucleated cells; no mitoses and Rosenthal fibres; scatteredGFAP positivity; Ki67/Mib1 Li <1%; no p53 expression. Case #2: Tumourcomposed of monomorphous, small cells with round/oval nuclei and finelydispersed chromatin; no Rosenthal fibers, granular bodies, mitoses, vascularproliferation and necrosis; negative P53, GFAP and neurofilaments immunos-taining; focal positivity for synaptophysin (SYN); Ki-67/Mib1 LI < 2%. Case#3: Lesions composed of “rosette” neuropil islands made of SYN positivecells, scanty cytoplasm, and loose sheets of GFAP cells with mild fibrillarybackground in the intervening areas. Rare neuronal like cells. LGG withoutPrimary Case #1: Neoplasm composed of relatively monomorphousround/oval cells without features suggestive of pilocytic tumor with few mult-inucleated cells; presence of fragments of thickened, infiltrated leptomeninges;no mitoses; scattered GFAP and SYN positivity occasionally expressed in cellaggregates. KI67/Mib1 LI <1%; no p53 expression. Case #2: Lesions madeup of SYN and MAP2 positive small cells with clear cytoplasm with no p53expression; no mitosis and necrosis; Ki67/Mib1 Li <1%. The cases describedand the similar ones found in the literature share histological, clinical, andneuroradiological findings that cannot be comfortably put in the presentWHO classification for brain tumors.

71. DISSEMINATED OR MULTIFOCAL LOW-GRADE GLIOMA(DLGG): THE ROLE OF VINCRISTINE (VCR)/CARBOPLATIN(CBDCA): DATA FROM THE SIOP/GPOH LOW-GRADEGLIOMA STUDYGnekow AK,1 Walker DA,2 Zanetti I,3 Soellner S,1 Perilongo G,3 on behalfof the International Research Consortium on Low-grade Glioma (ICLGG);Augsburg, Germany

Introduction: DLGG is a rare and poorly understood clinical phenome-non. The lack of large numbers of patients has hampered progress. We reportthis subgroup of patients recruited since 1992 within the first ICLGG study.Patients: 41 children with DLGG were registered (12 female, 29 male, medianage 4.0 (0.2–13.8) years, 13/41 below 1 year of age); none had neurofibro-matosis. Location of primaries: 24 supratentorial midline, 10 posterior fossa,5 cerebral hemispheres, 1 spinal canal (1 not known). Local pathologic diag-nosis: 30 pilocytic astrocytoma I°, 1 astrocytoma II°, 3 astrocytoma nos, 1ganglioglioma, 1 pleomorphic astrocytoma II°, 1 giant cell astrocytoma I°.Four children were diagnosed without biopsy. Primary surgical management:3 complete resection, 8 subtotal, 10 partial, 16 biopsy. [1] Six children wereobserved at progression: 1 died, 3 continue to progress, 2 stabilized. [2] Ini-tial radiotherapy was given to 5 children median age 1.8 (0.8–24.0) monthsfollowing diagnosis: 2 responded, 2 continued to progress, 1 not known. Cur-rently 4 children show stable disease, 1 child died. [3] CT recommendedwas VCR 1.5 mg/m2 wkly, CBDCA 550 mg/m2 3 wkly for 10 weeks, thenVCR/CBDCA 4 wkly until week 53. Thirty children were treated at a medianof 1.5 months (0.2–67.5) following diagnosis; responses were 9 OR, 14 SD,6 PD, 1 inevaluable. Of the 18 who progressed, 2 underwent a second resec-tion, 3 received a second CT, 7 went on to radiotherapy (1 died). Six childrenhad no further therapy (4 died). Following an observation period of 8.0 to98.2 months, 24/30 children are alive: 3 with responding, 18 with stable, and3 with progressing disease. Outcome: The 3-year OS is 79%, the 3-year PFSis 37% following CT and 20% following RT. Conclusion: A multimodal ther-apeutic approach for this subgroup of patients will be presented. The earlyOS is not dissimilar to nonmetastatic LGG, although the PFS is worse. Moreprolonged follow-up is required for this group. It would be helpful if clini-cal or biological factors indicative of tumour behaviour could be determined.

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72. THALIDOMIDE AND CARBOPLATIN IN THETREATMENT OF BRAIN STEM GLIOMAGoldman S, Tomita T, Marymont M, Kalapurakal J, Carlson A, Bendel A,Hyder D, Etzel M, Cohen K; Division of Oncology, Children’s MemorialHospital, Chicago, IL, USA

Brain stem gliomas account for approximately 10% of pediatric CNStumors. Multiple clinical trials of radiation with standard cytotoxic regimenshave failed to increase survival. This protocol incorporates an antiangiogenicagent (thalidomide) with carboplatin and radiation therapy to increase PFS.Materials and Methods: Fourteen patients with pontine gliomas age 4.2 to19.8 years (mean 7.6 yrs) were treated on a protocol that included Carbo-platin and thalidomide. Ten patients were treated at diagnosis; 4 were treatedafter progression. The newly diagnosed patients received 54–60 Gy irradia-tion concurrent with this regimen. Nine females and 5 males (9 Caucasian,4 Hispanic, and 1 Native American) were enrolled. The lesions were intrin-sic in 13, with 1 patient having a partially extrinsic tumor. Carboplatin wasadministered at a dose of 560mg/m2; thalidomide is dosed at 300 mg/m2 esca-lating to 700mg/m2 daily. Results: Best response data for 12 evaluable pts:5PR, 4SD, 3PD; 2 patients with SD had neurologic deterioration with stableMRI but were coded as PD due to clinical deterioration. Mean time to pro-gression was 194 days (range 22–537 days); 3 pts remain PFS at 100+, 288+,358+ days. Mean TTP for 8 evaluable pts treated at diagnosis was 288 days(3 pts remain PFS); the mean TTP for the 4 pts treated following progres-sion was 48 days. Two patients progressed with disseminated disease, with-out evidence of increase in tumor in the pons. Toxicities include gram nega-tive bacteremia (1), rash (3), Stevens-Johnson syndrome leading towithdrawal from study (1), pulmonary emboli (1). Constipation was seen inmost patients but well controlled with prophylactic regimens. Somnolencewas easily controlled with titration of dosing. Conclusion: This regimen isfeasible and well tolerated. This protocol in the treatment of newly diagnosedpediatric brain stem gliomas, appears promising. This study continues toaccrue patients and further follow-up is warranted.

73. THE IMPACT OF REPEATED OVERNIGHT HOSPITALADMISSIONS ON BEHAVIOUR OUTCOMES IN PAEDIATRICBRAIN TUMOUR PATIENTSGrapsas N, Howe V, Rowe P, Stargatt R, Ashley D; Department ofClinical Haematology and Oncology, Royal Children’s Hospital, Victoria,Australia

Behavioural problems are a common concern for parents of a child witha brain tumour. In this study, the parents of 28 children successfully treatedfor a brain tumour completed a short assessment evaluating their child’sbehaviour at the time of diagnosis and 12 months following the completionof treatment. The tools used included the following: the Child BehaviourChecklist (CBCL), a widely used and well-standardised measure to assessinternalising and externalising behaviours and social competency; theVineland Adaptive Behaviour Scale, a semistructured interview conductedwith the parents in a standardised fashion by trained personnel; the Neuro-logical Severity Score rating system. Our study reviewed a total of 28 patients.Histological grades of tumours included Medulloblastoma (11), Ependy-moma (7), low-grade glioma (Pilocytic Astrocytoma) (5), high-grade glioma(Glioblastoma Multiforme) (1), Immature Teratoma (2), and Germinoma (2).Tumour locations included cerebellum (16), cerebral hemispheres (5), mid-line supratentorial tumours (7). The results indicated multiple areas of signi-ficant deterioration on the behavioural measures. In particular, the external-ising t-score [p = 0.001] and adaptive behaviour measures, particularlycommunication [p = 0.014]. Further analysis indicated that a strong rela-tionship was evident between the number of overnight hospital admissionsand negative behavioural outcome rated on the CBCL externalising meas-ure [p = 0.024]. Surprisingly, this relationship was independent of the neu-rological severity score. These preliminary investigations suggest that repeatedovernight hospital admissions may cause significant psychological distress,evident in externalising behavioural patterns 12 months following treatment.Further studies are required to determine what appropriate interventionsare to be taken.

74. A NEW KIND OF RADIOCHEMOTHERAPEUTICINTERACTION AFTER HIGH-DOSE CHEMOTHERAPYREGIMEN CONTAINING BUSULFAN IN CHILDREN WITHBRAIN TUMORSGrill J, El Khoury M, Kieffer-Renaux V, Valteau-Couanet D, Couanet D,Hartmann O, Kalifa C; Department of Pediatric Oncology, GustaveRoussy Institute, Villejuif, France.

To avoid radiation damage in the developing brains of young children,chemotherapy is increasingly used to delay or limit the use of irradiation. Wehave shown that a combinationa of high-dose chemotherapy and local irra-

diation is a valuable alternative to craniospinal irradiation for a local relapseof a medulloblastoma in young children (Dupuis-Girod et al., J Neuro-oncol. 1996;27:87–98). However, the combination of irradiation and certainchemotherapy can cause deleterious effects on the central nervous system(Kieffer-Renaux et al., J Child Neurol. 2001;16:698–704). We undertook asystematic review of all young children (<5y) treated with high-dose busulfan-thiotepa followed by local irradiation at 55 Gy for a recurrent medulloblas-toma in our department since 1989. Sixty-five children with at least 1 yearfollow-up were evaluated. Clinical files, radiographic films, and irradiationdosimetry were compared to the neuropsychological outcome. The MRI offifteen children (23%) showed contrast enhancing lesions in the radiationfields occurring during the first two years after treatment. Eight were symp-tomatic at the onset of the disease with worsening of the cerebellar syndromeand signs of increased intracranial pressure. The lesions were located mainlyin the white matter and in the periventricular regions of the irradiation field.Evolution was variable: complete regression in 7, persistence in 5, and calci-fication and atrophy in two. The neurological symptoms regressed slowly,sometimes under corticosteroids, in most of the patients. Four of them hada subsequent relapse outside the fields involved with the initial neurotoxic-ity. Mean full-scale IQ of these 14 children was 72.5 (40–110) with a medianfollow-up of 4 years. Neither busulfan alone nor posterior fossa irradiationalone has been complicated with such side effects, and the topography ofthe lesions delineates clearly the irradiation field in most cases. We thusbelieve this syndrome to be due to the radiosensitizing effect of busulfan, espe-cially on the vasculature. Consequently, despite its striking efficacy, alterna-tives to this regimen have to be explored and radiation fields or doses shouldbe reduced in case of busulfan-containing regimens.

75. LOSS OF CASPASE-8 MRNA EXPRESSION IS COMMON IN CHILDHOOD PRIMITIVE NEUROECTODERMAL BRAINTUMORS/MEDULLOBLASTOMAGrotzer MA, Zuzak T, Phillips PC, Eggert A; Division of Oncology,University Children’s Hospital of Zurich, Switzerland

Upon binding of TNF-related apoptosis inducing ligand (TRAIL), theagonistic TRAIL receptors DR4 and DR5 activate caspase-8 leading to apo-ptosis. In primitive neuroectodermal brain tumor (PNET) cell lines, TRAIL-induced apoptosis was recently shown to correlate with caspase-8 mRNAexpression (Grotzer MA et al. Oncogene 2000;19:4604–4610). In this study,we analyzed the expression of the TRAIL death pathway in 27 primaryPNET/medulloblastoma (PNET/MB). As shown by semiquantitative RT-PCR, all PNET/MB evaluated expressed DR5, the adapter protein FADD,and caspase-3, but only 48% caspase-8. The mRNA expression of caspase-8was significantly lower in primary PNET/MB compared to normal brain sam-ples. PCR revealed >75% methylation of the caspase-8 promoter region in3 of 7 PNET cell lines and in 55% of the primary PNET/MB evaluated. InPNET cell lines, the methylation status correlated with the caspase-8 mRNAexpression. We conclude that loss of caspase-8 gene expression is common inPNET/MB, suggesting that suppression of death receptor induced apoptosismay play an important role in the pathogenesis of this common childhoodbrain tumor.

76. QUANTIFICATION OF MYC AND TRKC GENEEXPRESSION IN CNS PRIMITIVE NEUROECTODERMALBRAIN TUMORS (PNET) WITH A REAL-TIME REVERSETRANSCRIPTION PCR ASSAY Grotzer MA, Lang D, Peyerl A, Janss A, Patti R, Phillips PC, Slavc I,Shalaby T; Division of Oncology, University Children’s Hospital of Zurich,Switzerland

Central nervous system PNET, including medulloblastoma, are the mostcommon malignant brain tumors in childhood. High neurotrophin receptorTrkC mRNA expression and low oncogene MYC mRNA expression haverecently been shown to be powerful independent predictors of favorable clin-ical outcomes in PNET. To optimize quantification of MYC and TrkC mRNAexpression, we developed a real-time quantitative RT-PCR assay based onTaqMan fluorescence methodology using 40 primary tumor and 7 normalbrain samples. We validated the method on a series of PNET cell lines withknown TrkC and MYC mRNA expression (Northern blotting results). The18S rRNA housekeeping gene showed an optimal performance as an endoge-nous control. In addition, a commercially available reference RNA was usedto establish future interinstitutional reproducibility. TrkC and MYC mRNAexpression levels in primary PNET showed a wide range with >1000-fold(TrkC) and >100-fold (MYC) differences between the highest and lowest val-ues. This is much higher than previously measured with less quantitativemethods. When compared to normal cerebellum, MYC was overexpressedin 60% and TrkC in 25% of the evaluated PNET samples. Our simple, rapid,and reproducible assay method is suitable for routine quantification of TrkCand MYC mRNA expression in PNET and will be a powerful tool in large

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prospective cooperative group trials. The goal of these important biologicalstudies will be to evaluate whether TrkC and MYC mRNA expression canbe incorporated in future risk classification systems for clinical use.

77. INFANT EPENDYMOMA: THE UKCCSG EXPERIENCEGrundy, RG, for The UKCCSG Brain tumour committee; University ofLeicester, Hearts of Oak House, Leicester, UK

The unacceptable late effects of radiotherapy led to the adoption ofchemotherapy-based strategies designed to avoid/delay irradiation. TheUKCCSG “baby brain” protocol started in 1992 and was open to all histo-logical types of brain tumour occurring in children under 3 years at diagno-sis. We report on the outcome of infants with ependymoma treated on thisprotocol. The chemotherapy strategy involved alternating blocks of myelo-suppressive and nonmyelosuppressive chemotherapy given every 14 days.Radiotherapy was delivered only if there was evidence of progressive disease.Forty-seven children with a histological diagnosis of ependymoma weretreated. Median age at diagnosis was 1.75 years (range: 0.4–3.2). Fortytumours were infratentorial. Twenty-seven patients had residual diseasebefore starting chemotherapy, of whom 3 had metastatic disease. Seventy-two percent of children completed 1 year of chemotherapy. Only 7 progressedon therapy, of whom 4 underwent biopsy/minimal resection. Fifty percenthad imageable residual disease at completion of therapy; none were electivelyirradiated. With a median follow-up of 51 months (range: 3–87), OS at 5years was 54.6% (95% CI: 38.1–71.2) and 5-year EFS was 33.8%(20.0–48.2). Relapse resulted from failure of local control in 86% of patients.Complete resection conferred a survival advantage for both OS (p = 0.006)and EFS (p = 0.019) with 5-year OS of 73.9% (95% CI: 51.3– 96.4) and 5-year EFS of 54.2% (95% CI: 33.1–75.3) compared to OS of 38.1% (95%CI: 16.6–59.5) and EFS of 15.2% (0.0–30.8) for incomplete resection. The5-year radiotherapy-free survival was 43.4% (95% CI: 27.6–59.3). Medianage at irradiation was 3.5 years (range: 2.2–5.0). We were able to avoid radio-therapy in 51% of our cohort. Furthermore, the relatively low rate (15%)of progression on chemotherapy and a high overall EFS of 65% at 2 yearssuggest this protocol has particular merit for ependymoma. This may relateto the dose intensity of platinum agents and/or the use of high-dosemethotrexate. However, children with postsurgical residual disease fare badly,forming a high-risk group for which new strategies based on internationalcollaboration are now required.

78. THALIDOMIDE AND TEMOZOLOMIDE IN CHILDRENWITH PROGRESSIVE LOW-GRADE GLIOMAGustafson K, Bendel A, Bostrom B, Christiansen S, Drehner D, Nelson S;Children’s Hospitals and Clinics–Minneapolis, University of Minnesota,Minneapolis, MN, USA

Approximately 35% to 65% of pediatric brain tumors are low-gradegliomas. Conventional therapy for low-grade glioma may include surgery,radiation, and/or chemotherapy. Although complete surgical resection is thepreferred treatment, the anatomic location of the tumor often makes thisimpossible. The risk of profound late effects of radiation in the very youngchild can limit its usefulness. Due to these factors, several chemotherapeuticagents have been investigated in low-grade gliomas and have shown activ-ity. The use of thalidomide and temozolomide has been reported in severalmalignancies, including high-grade glioma. In this study, we report the use ofthalidomide and temozolomide in 3 pediatric patients with progressive low-grade glioma after treatment with standard chemotherapy regimens. We pre-sent 2 boys and 1 girl with a mean age of 7.6 years (range 3–12 years). Lengthof therapy ranged from 3 to 14 months (mean 7.5 months). Patient #1 witha brain stem glioma showed radiographic improvement but developed pro-gression after 6 months of treatment. Patient #2 with neurofibromatosis I andan optic glioma had significant improvement in visual fields and remains ontherapy now, 14 months into treatment. Thalidomide and temozolomide werewell tolerated except for headaches in one patient and expected somnolencein all three. Patient #3 also had improvements in visual fields. However, after3 months of therapy, Patient #3 developed optic neuritis in his unaffected lefteye that resolved after therapy was stopped. Optic neuritis has not been pre-viously reported with these agents used alone. Thalidomide and temozolo-mide warrant further evaluation in pediatric patients with progressive low-grade glioma.

79. CYTOGENETICS IN RECURRENT EPENDYMOMAHandler M, Ashmead-Wyatt J, Fleitz J, Foreman N; Departments ofNeurosurgery and Pediatrics, University of Colorado Health SciencesCenter, Denver, CO, USA

Ependymomas are best treated by initial complete surgical resection, yetnevertheless may recur. Recurrent tumors are much more resistant to treat-ment and are associated with a worse prognosis. Cytogenetic studies havebeen useful in assessing prognosis in some tumors and may be useful in assess-ing ependymomas. Eighteen patients were treated at the Children’s Hospital,Denver, Colorado, with recurrent ependymoma. Of the 18, 10 had a secondrecurrence, 4 a third recurrence, 3 a fourth recurrence, and 1 a fifth recur-rence. The age at original tumor resection ranged from 1.7 years to 14 years(average 5.7 years, with 73% less than 5 years of age). The male:female ratiowas 5:4. Cytogenetic studies were available in 13 of 18. There were com-plex cytogenetic abnormalities most often involving chromosomes 1, 6, 7,and 22 (including monosomy 22). In 5 of 13, cytogenetic studies were avail-able in the original tumors as well as in their recurrences. Karyotypes showedincreasingly complex and unstable cytogenetic abnormalities accompanyingtumor progression. Cytogenetic abnormalities did not correlate well withtumor histology. Cytogenetic abnormalities in ependymomas may indicatethe potential for recurrence and may be useful in assessing prognosis in thesetumors. Complex karyotypic progression at the time of recurrence may cor-relate with short subsequent survival.

80. DURAL BASED TUMORS IN CHILDRENHandler M, Sarin H; Department of Neurosurgery, University of ColoradoHealth Sciences Center, Denver, CO, USA

It is unusual for children to develop tumors involving the dura, which inadults are most typically meningiomas. While these can occur in children, wehave seen a wide variety of other tumors that share some of their MagneticResonance Imaging (MRI) features. The pathology and MRI findings of 14patients with dural-based tumors are reviewed. Three patients hadhistopathology consistent with meningioma, 1 with atypical features. Therewere 3 juvenile pilocytic astrocytomas (JPAs), 1 atypical. Two had neuro-blastomas, and other patients had an unusual primitive neuroectodermaltumor (PNET), a capillary hemangioma, a clear cell ependymoma, a desmo-plastic infantile ganglioglioma, a low-grade sarcoma, and an unusual inflam-matory process. All but one manifested the classic “dural tail,” most oftenseen with meningiomas. The broader spectrum of dural-based tumor pathol-ogy in children must be recognized for optimal surgical management of thesetumors.

81. SMALL PITUITARY STALK LESIONS WITH DIABETESINSIPIDUSHandler M, Beauchamp K, Foreman N; Departments of Neurosurgery andPediatrics, University of Colorado Health Sciences Center, Denver, CO,USA

Small lesions of the inferior hypothalamus and pituitary stalk may pre-sent with diabetes insipidus, with or without other endocrinopathy. Oftenthey are felt to represent histiocytosis X, but other pathologic entities thatrequire different forms of therapy are sometimes seen. Four patients withsmall pituitary stalk lesions and diabetes insipidus underwent open cran-iotomy for biopsy without attempt at total resection, for pathologic diagno-sis to guide subsequent treatment. Another patient refused such a diagnosticprocedure when an outside institution made a clinical diagnosis of hypophysi-tis based on imaging studies. Three of the patients proved to have Langer-hans cell histiocytosis. They responded well to treatment and radiographi-cally regressed. The endocrinopathies persisted. One patient had benignhypophysitis, with no further clinical progression of disease, and with reso-lution of abnormalities on MRI. The last, carrying a clinical diagnosis ofhypophysitis, had explosive growth of a nongerminomatous germ cell tumorwhich was life-threatening at the time of her operation four weeks after pre-sentation. Small pituitary stalk or inferior hypothalamic lesions require tis-sue biopsy for correct diagnosis and treatment.

82. CAN RADIOLOGICAL CHARACTERISTICS PREDICTLENGTH OF SURVIVAL IN PONTINE GLIOMA?Hargrave DR, Chaung N, Tariq N, Bouffet E; Paediatric Brain TumourProgram, Hospital for Sick Children, Toronto, Canada

Diffuse intrinsic pontine glioma has a dismal prognosis with little/noprogress in improving the length of survival of these unfortunate children;the standard therapy offered is radiotherapy. Objectives: To assess the radi-

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ological characteristics of children with pontine glioma in diagnostic and posttreatment MRI and to seek correlations with length of survival. Methods: Allcases listed as brain stem glioma were reviewed, both clinical records andavailable radiology (separately/blinded, by the authors). Only cases withavailable MRIs and a tumour centred on and involving >50% of the ponsvolume were included. Demographics, treatment details, and the followingradiological characteristics were studied: % of pons, tumour-border, tumour-extension, exophytic, heterogeneity, T1-signal intensity, cysts/necrosis,tumour-dimensions, gadolinium-enhancement, encasement of basilar, plusoverall survival. Results: 82 cases of brain stem glioma identified at HSC(1985–2001), of which 30 met the inclusion criteria. Median age was 6.8(range 0.2–14.6) years and M:F ratio (13:17). Treatment consisted of radio-therapy in 29 (plus chemotherapy in 12), and one infant received chemo-therapy only. Median survival was 7.2 (1.7–151) months. There were 2 long-term survivors; these will be discussed. Diagnostic radiological characteristicsincluded: all tumours centred on pons (median = 95%/volume); commonesttumour-extension was medulla; 22 had an exophytic component (thisincluded any degree); 13 were tumour-border defined; 9 were heteroge-nous; 11 had cystic/necrotic changes, 16 had hydrocephalus, gadolinium-enhancement 50%; basilar-encasement was seen in 93%. Posttreatment MRIwas available in 15/30 cases and showed increased cystic/necrotic change in20%, change in enhancement pattern in 80%, and a decrease in tumour-dimensions in 52%, but this was not statistically significant. Analysis of 16radiological characteristics in both diagnostic and post treatment scansrevealed no statistically significant correlation with survival (analysiswith/without the two long-term survivors, = no difference seen) and no evi-dence of a relationship between treatment response and overall survival. Con-clusions: Intrinsic diffuse pontine glioma is a major challenge for paediatricneuro-oncology, and the lack of predictive power of available radiology isdisappointing.

83. QUALITY OF HEALTH INFORMATION ON THEINTERNET IN PAEDIATRIC NEURO-ONCOLOGY:MEDULLOBLASTOMA AND EPENDYMOMA WEB SITESHargrave DR, Bouffet E; Paediatric Brain Tumour Program, Hospital forSick Children, Toronto, Canada

Objectives: To review the information available on the internet by rat-ing the content of websites in the context of childhood ependymoma andmedulloblastoma. Methods: The search terms “ependymoma” and “medul-loblastoma” were separately entered into the top 6 US search engines. Thefirst 30 results from each search engine were visited and assessed for theirgeneral information content, and all evaluable sites were fully rated, inde-pendently, by the two authors using the validated DISCERN instrument (forrating consumer health information) and by assessing the presence/absenceand accuracy of 13 core elements (CE) in the management of these braintumours. Results: There was a median of 5875 (MB) and 4007 (EP) results/search engine, and 172 EP/167 MB sites were visited. Surprisingly few web-sites failed (3%), but there was a large degree of duplication of sites (62%).The type of websites were: academic (53%), charity (13%), hospital (12%),commercial (7%), personal (6%), support groups (6%), and government(3%). Most websites did not contain general information on EP/MB and wereexcluded, leaving 36 (EP 19, MB 17) evaluable sites to be fully rated. Agree-ment between the two authors in both the DISCERN instrument and theCE ratings was very good, with kappa scores of 0.82 and 0.93, respectively.The median DISCERN score was 70 (range 30–103) for EP and 67 (43–102)for MB out of a maximum of 150. There was a median of 7 (1–11) correctand 1 (0–3) inaccurate statements/website as judged against the 13 core ele-ments of EP/MB management. There was a highly significant correlation (p= 0.0003) between the two ratings tools, and these effectively allowed thewebsites to be ranked for quality of consumer health information. Conclu-sion: Websites providing information on paediatric brain tumours are lack-ing in number, factual content, and clarity. Those that rate well in contentstill suffer from unimaginative design, and there are no quality websites forthe children themselves.

84. EVALUATION OF DIETETIC INTERVENTION IN CHILDREN WITH MEDULLOBLASTOMA ANDSUPRATENTORIAL PNETHargrave DR, Bakish J, Tariq N, Bouffet E; Paediatric Brain TumourProgram, Hospital for Sick Children, Toronto, Canada

Aims: To evaluate the effect of dietetic intervention in a cohort of chil-dren treated for medulloblastoma and supratentorial PNET over a 10-yearperiod. Patients and Methods: Retrospective chart review of medulloblastoma/supratentorial PNET cases (1992 to 2002); hospital records reviewed for dataincluding demographics, tumour site, treatment modality, dietetic interven-tion, and heights/weights. Percentage change in body weight was calculatedat time points associated with stages in treatment and dietetic intervention.

Results: 103/112 cases were evaluable (M:F, 64:39); 10 had a supratentorialPNET and 93 medulloblastoma; the median age was 6.1 (range 0.1 to 15.4)years. Treatment: palliative surgery (7.8%); surgery/radiotherapy (16.5%);surgery/chemotherapy (14.5%); and surgery/radiotherapy/chemotherapy(61.2%). There was no significant change in children’s weight as a result ofsurgery (median change body weight (MCBW), –0.35%) or radiotherapy(MCBW, –0.78%). However, children had a significant weight loss (MCBW,–4.35%, p<0.0001) 3 months after commencing chemotherapy; this did nottranslate into a significant weight loss over the whole treatment period. Ageat diagnosis was not a factor in predicting weight loss. A dietician saw 53/103children, and dietetic input was significantly (p<0.0001) more likely if thechild received chemotherapy (67%) compared to those who did not (4%).There were 84 dietetic interventions in 53 patients (high energy diet 36%,gastrostomy 31%, TPN 27%, NG feeds 6%). Enteral feeds (gastrostomy orNG) resulted in a significant weight gain at 1 month (MCBW +4.8%, p =0.006) and 3 months (MCBW +11.8%, p<0.0001), but TPN was associatedwith significant weight gain only at 1 month (MCBW +2.7%, p = 0.03),and a high-energy diet did not lead to weight gain. Conclusion: Current mul-timodality therapy of intracranial PNET results in significant nutritional mor-bidity, mainly as a result of intensive chemotherapy regimens. Dietetic inputin paediatric neuro-oncology teams is essential, and implementation of enteralfeeding in these children can help to reverse their nutritional decline.

85. SHORT-COURSE CHEMOTHERAPY IN LOW-GRADEGLIOMAHarigopal S, May P,* Abernathy L,* McDowell H; Department ofOncology, *Department of Surgery, *Department of Radiology, Alder HeyChildren’s Hospital, Liverpool, UK

The role of chemotherapy in the treatment of low-grade gliomas (LGG)continues to be explored. We report 8 patients with histology-proven LGGtreated with short-course chemotherapy at one institution from August 1993to June 1996. Eight patients diagnosed as LGG with clinical or radiologicalprogression of disease were treated on a 9-week course of chemotherapy con-sisting of weekly Vincristine 1.5 mg/m2 and 3 weekly Carboplatin 600mg/m2.Follow-up after treatment consisted of three monthly MRI scans for twoyears and six monthly scans for the third year. Median age at diagnosis was5.6 years (IQR: 4.2–7.1 years). Median follow-up time was 6.2 years (IQR:5.9–6.7 years). Prior to chemotherapy, 4 had biopsies, of whom 2 receivedradiotherapy, and 4 underwent surgery. Following chemotherapy, 1 patientunderwent surgery and then radiotherapy. Three received radiotherapy only,and 4 did not require any further treatment. Overall, 2 out the 8 patientsdid not receive radiotherapy for disease progression. One patient had a timedelay for radiotherapy of 5 years post chemotherapy. The chemotherapy usedwas of short duration and limited toxicity. Two patients avoided radiother-apy altogether, and 4 had no further relapse after chemotherapy. The ques-tion of duration and intensity of chemotherapy for LGG needs further explo-ration.

86. ANZCCSG BABY B99: SYSTEMIC CHEMOTHERAPY,SECOND-LOOK SURGERY, AND INVOLVED-FIELDRADIATION FOR CHILDREN LESS THAN FOUR YEARS OF AGE WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMOURSHassall T,1 Sexton M,2 Houlihan J,3 Grapsas N,3 Chow L,3 and Ashley D3;Departments of Haematology and Oncology, 1Royal Children’s HospitalBrisbane, 3Royal Children’s Hospital Melbourne; 2Peter MacCallumCancer Institute, Melbourne, Australia

Postoperative patients less than 4 years of age with a newly diagnosedmalignant CNS tumour were eligible to be enrolled in this pilot study. Courses1 and 2 consisted of Etoposide Phosphate 2mg/kg/day nasogastric for 21 daysand cisplatin 4mg/kg intravenously (IV). Course 3 consisted of cyclophos-phamide 40mg/kg IV daily D1-3, Etoposide phosphate 7.5mg/kg IV, and vin-cristine 0.05mg/kg IV. Course 4 had cyclophosphamide increased to 70mg/kgIV daily D1-3, followed by stem cell rescue. Second-look surgery was thenconsidered. Course 5 consisted of carboplatin AUC 12 mg/ml.min and Mel-phalan 4.6mg/kg followed by stem cell rescue. Treatment was completed withinvolved-field radiation to 54Gy. Between January 1998 and July 1999, 11patients (average age 16.9 months, 6 males and 5 females) with ependymoma(4), medulloblastoma (2), glioblastoma multiforme (2), others (3) weretreated on study. Five patients had disseminated neuraxis disease at presen-tation. Postoperative MRI confirmed 3 total resections only. The 8 patientswith residual disease were evaluated after Course 2: 3 partial responses, 3stable disease, and 2 progressions. One patient has maintained a partialresponse 46 months after diagnosis. One patient has stable disease 40 monthspost diagnosis. Nine patients have progressed—5 during treatment and 4 fol-lowing treatment. Seven patients have died (median time to death 11.4months) with 4 current survivors (median 37.7 months from diagnosis).

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The courses and the associated toxicities were as follows: Courses 1 and 2(22): Anaemia grade 3 (2), Thrombocytopenia grades 3 (2) and 4 (1), Neu-tropenia grades 3 (5) and 4 (4), Infection grade 3 (5), Biochemical grade 4(1); Course 3 (9): Anaemia grades 3 (3) and 4(1), Thrombocytopenia grades3 (6) and 4 (1), Neutropenia grade 4 (8), Febrile neutropenia grade 3 (5);Course 4 (8): Anaemia grade 3 (3), Thrombocytopenia grades 3 (2) and 4 (3),Neutropenia grade 4 (7), Febrile neutropenia grade 3 (5); Course 5(7):Anaemia grade 3 (5), Thrombocytopenia grades 3 (4) and 4 (2), Neutrope-nia grade 4 (5), Febrile neutropenia grade 3 (2). Involved-field radiation(50.4–60Gy) was completed in 4 patients with no significant toxicity noted.In summary, the treatment was well tolerated. Despite the evidence of goodearly response, there was no overall improvement in the poor early progres-sion-free survival rates seen in similar studies. Novel approaches must there-fore be investigated in these patients.

87. NITROSOUREA IMPROVE THE OUTCOME OF PATIENTS WITH HIGH-GRADE GLIOMA: RESULTS OF A META-ANALAYSISHauch H,1 Sajedi M,2 Peters O, 1 Wolff JEA1; 1Department of PediatricOncology of St. Hedwig Hospital, Regensburg, Germany; 2OncologyProgram, Alberta Children’s Hospital, Calgary, AB, Canada

Background: Nitrosourea such as CCNU and BCNU have been used fre-quently in malignant glioma treatment. However, the success of chemo-therapy remains limited. We conducted a meta-analysis to address the ques-tion whether nitrosourea are beneficial in high-grade glioma (HGM).Method: We searched for clinical trials published between 1979 and 2000.Keywords were astrocytoma, phase I to III study, anaplastic astrocytoma(AA), glioblastoma multiforme (GBM), and brain stem glioma (BSG) in allpossible combinations. Information extracted from the papers was enteredinto a data base using one record for each patient group. The 1-year overallsurvival rate was the most frequently reported endpoint, but even this wasnot documented in all publications. Therefore we created a variable “calcu-lated 1-year survival rate“ (1YCAL) based on a regression analysis for otherreported endpoints, such as median survival. Correlation test, U-test, scatterplot, and linear regression analysis were used to evaluate the relationshipbetween different eligibility criteria or modalities of treatment. With thisanalysis we computed an expected 1-year overall survival rate (1YEXP) ofthe study population. After that we calculated the differences between 1YEXP and 1YCAL and determined influences of treatment. Results: 238different groups with a total number of 10908 patients were entered into ourdatabase. Mean age: 41 ± 17 years, males and females: 1.53:1; the more AAregistered in a study, the higher was 1YCAL (1YCAL = AA [%] * 0.189 +43.27). Studies with adult patients had a significantly lower 1YCAL (1YCAL= age [mean] * (-0.261) + 57.67). Furthermore, the higher the proportion ofgross total resection (GTR), the higher was 1YCAL (1YCAL = GTR [%] *0.194 + 46.88) . If multiagent chemotherapy was used, 1 YCAL was signifi-cantly better (p<0,01). If nitrosoureas were used, the 1YEXP was shorter thanthe observed, indicating better survival rates for treatment protocols, whichincluded nitrosourea (p<0.05). Conclusion: This meta-analysis supports theuse of nitrosourea as an element of multiagent treatment for high-gradeglioma.

88. CHEMOTHERAPY FOR PROGRESSIVE LOW-GRADEGLIOMAS IN CHILDREN OLDER THAN 10 YEARSHeath JA, Scott RM, Goumnerova G, Proctor M, Kieran MW;Departments of Pediatric Oncology and Pediatric Neurosurgery, Dana-Farber Cancer Institute and Children’s Hospital, Boston, MA, USA

Low-grade gliomas are the most common brain tumor of childhood, andalmost half of these occur in children older than 10 years. The purpose of thisretrospective study was to examine the clinical and radiological response oflow-grade gliomas to chemotherapy in children older than 10 years. BetweenJune 1999 and January 2001, 7 consecutive children between the ages of 10and 15 years were treated with chemotherapy. Pathologic diagnoses were 4pilocytic astrocytomas and 1 ganglioglioma. In addition, 2 children with NF1had a radiographic diagnosis of optic glioma. Six children commenced treat-ment following progression (median time 4 years, 10 months), and 1 patientwas treated immediately following diagnosis. Patients were treated withvincristine and carboplatin according to the protocol of Packer et al. Anypatient who experienced a significant allergic reaction to carboplatin wasswitched to TPCV according to the UCSF regimen. All 7 children (5 boys, 2girls) completed induction vincristine/carboplatin. Four children experiencedgrade III/IV haematopoietic toxicity on this therapy, requiring a dose reduc-tion. Three children had an allergic reaction to carboplatin necessitating aswitch to TPCV chemotherapy. Two of these 3 children suffered Grade III/IVhaematopoietic toxicity. No patient with an optic tract tumor showed a dete-rioration on visual field testing, and no child showed clinical neurologic dete-rioration while on chemotherapy. No patient experienced significant hearing

loss or any impairment of renal function. Overall, 2 patients had a minorradiographic response to treatment with chemotherapy (objective responserate 29%), 4 showed stable disease, and 1 patient was switched to radiationtherapy following radiologic progression on treatment. Five of 6 children witheither an objective response to treatment or stable disease remained stable orimproved with a median follow-up of 24 months (range 15 to 31 months).One patient developed asymptomatic radiographic progression after 29months. The results suggest that the response rates in children older than 10years of age may not be significantly different from those observed in youngerchildren. These data suggest that a prospective clinical trial of chemotherapyfor progressive low-grade gliomas in children older than 10 years is war-ranted.

89. THE S100A4 METASTASIS-INDUCING GENE IS UP-REGULATED BY ERBB2 IN MEDULLOBLASTOMAHernan R, Fasheh R, Calabrese C, Frank A, Maclean K, Allard D,Barraclough R, Gilbertson R; Department of DevelopmentalNeurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Overexpression of the ERBB2 (also known as HER-2/neu) oncogene isassociated with metastasis in a number of human cancers, including medul-loblastoma. Therefore, we attempted to identify target genes of ERBB2 sig-naling that may be instrumental in mediating tumor invasion. To accomplishthis, we used Affymetrix microarray (HG-95Av2 12,000 gene chip) analysisto expression-profile cultured Daoy medulloblastoma cells transfected withthe complete ERBB2 cDNA (Daoy.2H) or vector only (Daoy.v). This analy-sis demonstrated the metastasis-inducing gene S100A4 to be up-regulated ~5fold in Daoy.2H compared to Daoy.v cells. We confirmed the relationshipbetween ERBB2 and S100A4 expression levels in medulloblastoma usingWestern and Northern analysis of four separate ERBB2 transfected Daoyderived clones and 53 samples of primary childhood medulloblastoma. Todetermine whether ERBB2 directly affects S100A4 transcription control, welinked sequences from the promoter region of S100A4 to the pGL luciferasereporter and assessed their activity in luciferase assays of Daoy.2H andDaoy.v cells. These analyses identified an ERBB2 response element betweenbase pairs –1487 and –1011 of the S100A4 transcriptional start. Using phar-macological and genetic inhibitors of ERBB2 and second messenger path-ways, we next demonstrated that ERBB2 signaling via PI3K and ERK con-verges on the S100A4 promoter to enhance expression. We also showedthat AKT1, which functions downstream of ERBB2, can negatively regulatethis signal by inhibiting ERK pathway activation and thereby S100A4 expres-sion. Finally, using a xenograft model of ERBB2 overexpressing medul-loblastoma, we demonstrated the ability of an oral inhibitor of ERBB2 tyro-sine kinase activity to inhibit ERBB2 receptor signaling and S100A4expression in vivo. Our study has identified a new ERBB2/PI3K-dependentpro-metastatic pathway. In addition, it highlights a novel potential mecha-nism by which ERBB2 targeted therapies may inhibit tumorigenesis.

90. INCIDENCE OF CENTRAL NERVOUS SYSTEM TUMORS(CNST) IN MALAGAHerrero Hernández A, Ortega Acosta MJ, Acha García T, Martínez LeónM, Martínez Arán T, Rojas Gracia ME; Department of PediatricOncology, Hospital Carlos-Haya, Málaga, Spain;

Introduction: Public and scientific concern about the rising incidence ofmalignant brain tumours has been heightened in recent years. Data fromthe United States, Europe, and Australia have shown that brain cancer inci-dence has increased substantially in children over the past two to threedecades. Materials and Methods: Data from the Department of PediatricOncology of Malaga’s Hospital were used to calculate incidence and inci-dence rate among children younger than 14 years of age at diagnosis. Ouranalysis was restricted to the 1981–2001 time period. We included all malig-nant and nonmalignant neoplasms, intracranial and medullar tumours. Weused a linear model. Results: Correlation was detected between incidence andyear in the 1981–1993 time period (Spearman’s constant: 0.58, p = 0.048, R2

= 0.46), and CNST incidence increased (incidence = –1.501´32 + 0.759 xyear; p = 0.015). The incidence rate increased substantially over 1981–1993,and the estimated average percentage change did also. Correlation was notdetected in 1993–2001 time period (Spearman’s constant: 0.40, p = 0.28);incidence remained essentially stable (mean: 9.4 +/– 2.92), and the incidencerate was stable too. Discussion: (1) We found (using a linear model) a sharpincrease in incidence rate of CNST from 1981 to 1993 and a stable incidencerate from 1994 to 2001; (2) MRI-detection effect in the mid-1980s accountedfor the increased incidence from 1981 to 1993.

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91. BRAIN METASTASES AND CLEAR CELL SARCOMA OFTHE KIDNEYHerrero Hernández A, Ortega Acosta MJ, Acha García T, Martínez RubioA, Sastre Urguellés A, García Miguel P; Department of PediatricOncology, Hospital Carlos-Haya, Málaga, Spain; Department of PediatricHematology-Oncology, Hospital La Paz, Madrid, Spain

Introduction: Clear cell sarcoma of the kidney (CCSK) is a rare malig-nant tumor, most common in children between 6 months and 3 years of age.Although clinically similar to Wilms´ tumor, this tumor has distinctive his-tologic features and a more aggressive clinical behavior with a tendency tometastasize to bone, lung, and rarely to brain. Case 1: A female infant 4months old developed a left abdominal mass in 1997. Abdominal CT andechography: renal tumour with central necrosis, 9 x 7 x 6 cm. She underwentcomplete surgical resection, and the histologic examination showed a CCSK.She received chemotherapy with etoposide, carboplatin, ifosfamide, andepirubicin (SIOP/93-01; high-risk, stage I), with complete remission (CR).Four months later she developed vomiting and lethargy. CT scan had 14nodular foci of enhancements. She was then treated with 4 courses of etopo-side and carboplatin (SIOP-phase II study) with a very good partial response.After high-dose melphalan, etoposide, and carboplatin (MEC, SFOP) fol-lowed by Autologous Stem-cell rescue, she was in second complete remission.Five months later, she showed recurrent brain metastases. Palliative irradia-tion was administered and she died 3 months later. Grade III renal toxicityand grade IV mucositis were related to the chemotherapy. Case 2: A 4-year-old girl had a right abdominal mass in 1997. Abdominal CT andechography showed a renal tumour, 12 x 10 x 8 cm. She underwent surgicalresection, and in the histologic analysis presented a CCSK, stage II. She wastreated with local radiation, etoposide, carboplatin, ifosfamide, and epiru-bicin (SIOP/93-01; high-risk), with CR. Fifteen months later she developedhemiparesis and seizures. MRI detected two supratentorial metastases. Aftercomplete surgical resection she received a high dose of MEC followed byAutologous Stem-cell rescue. She was in second complete remission as of Jan-uary 2002. Discussion: (1) CCSK is exceptional in children less than 6 monthsold (case 1). Brain metastases are rare in CCSK. (2) The brain metastasesshowed good response to chemotherapy, surgery, and radiotherapy. (3) TheMEC followed by Autologous Stem-cell rescue is an effective regimen inCCSK´s brain metastases. The related toxicity is high.

92. THE MANAGEMENT OF OPTIC PATHWAY GLIOMAWITH MALIGNANT COMPONENTInagaki T, Yoshimuwa K, Yamahara T, Kasai H, Yamanouchi Y, NakanoT,* Kawasaki H*; Departments of Neurosurgery and *Pediatrics, KansaiMedical University, Moriguchi, Osaka, Japan

Astrocytomas arising within the optic pathway represent a distinct clin-icopathologic entity among pediatric brain tumors. Their incidence rangesfrom 3% to 6% of tumors in the pediatric age group. Pathologically, thesetumors are considered pilocytic astrocytoma, which may be indistinguishablefrom similar tumors occurring in the cerebellum. On the other hand, tumorsof the optic chiasm and hypothalamus may be extremely aggressive with poorprognosis. We are currently managing a patient with optic pathway astrocy-toma, which have malignant component. The patient is 3-month-old girl withdiencephalic syndrome of Russell and macrocephaly. She was born at 40weeks of gestation. Her body weight was 2980g and circumference of thehead was 33.5cm at birth. Her body weight and head size were 3826g and42 cm at admission. The level of growth hormone was 30.1ng/ml. CT andMRI revealed a huge mass with homogeneous enhancement by contrastmedium at chiasmatic and hypothalamic region. The other contrast-enhancedspots were observed in posterior fossa on initial MRI. Neurologically hori-zontal nystagmus was noticed. Surgery was undertaken and pathologicaldiagnosis was astrocytoma with malignancy. After partial removal of thetumor, she is under treatment with chemotherapy with Etoposide, CDDP,CPM. The MRI immediately after surgery also revealed metastatic lesionsin spinal CSF space. The treatment of such lesions is still controversial. Wediscuss the management of optic pathway glioma with malignant component.

93. CHILDHOOD MENINGIOMA: A SINGLE-CENTERFOLLOW-UP STUDYIttner K,1 Kordes U,1 Hagel C,2 Kammler G,3 Bentele KHP1; 1Departmentof Paediatrics, University Hospital Eppendorf, Hamburg, Germany;2Department of Neuropathology, University Hospital Eppendorf,Hamburg, Germany; 3Department of Neurosurgery, University HospitalEppendorf, Hamburg, Germany

We evaluated the clinical data and reassessed the histopathology of 8patients with meningioma and 1 with meningiosarcoma who were treatedin our institution between 1982 and 2001. The age at diagnosis rangedbetween 4 and 16 years. Of the 8 meningioma patients, 3 were associated

with NF-2. One patient was diagnosed with a linear naevus sebaceus syn-drome (LNSS), a phacomatosis so far not described in association withmeningioma. This patient and 2 of the 3 NF-2 patients relapsed 1, 3, and 4years after complete resection at first diagnosis and had or developed multi-ple disease. They died 2 (LNSS), 9, and 8 years (NF-2) after diagnosis. Thehistopathological subtype was atypical meningioma WHO grade II in bothrelapsed NF-2 patients and in the LNSS patient. The 4 patients with sporadicmeningioma all had a meningotheliomatous subtype. One presented withan extracerebral encapsulated mass eroding the temporal bone. Three had aventricular, retrobulbar or suprasellar meningioma. Relapse occurred in 1patient 4 years after subtotal resection and in 1 patient 7 years after completeresection; the latter case was associated with histopathological progress to anatypical WHO grade II tumor. This patient was effectively treated by reop-eration, the former with surgery and radiotherapy. Both are alive and with-out signs of progression 19 and 12 years after first diagnosis. Our data con-cur with the observation that paediatric meningioma associated with anunderlying syndrome such as NF-2 may have a poor prognosis. The clinicalphaenotype of LNSS may include multiple intracerebral meningioma. Inpatients with sporadic disease, relapse was seen after partial and also aftercomplete surgical removal of the tumor several years after first diagnosis, butthese recurrences could be well controlled and there were no deaths in thisgroup.

94. MENINGEAL MELANOCYTOMA OF THECEREBELLOPONTINE (CP) ANGLE IN A CHILDJavadpour M, Mallucci C, DuPlessis D, Pizer B, Broome J, Foy P;Department of Neurosurgery, Walton Centre for Neurology andNeurosurgery, Liverpool, UK

Objectives: To report a case of CP angle meningeal melanocytoma, a rarebenign tumour derived from leptomeningeal melanocytes. Case Report: A 10-year-old girl presented with headache, vomiting, and diplopia. On exam-ination, she had papilledema and partial left V, VI, and VII cranial nervepalsies. MR scan showed a large mass in the left CP angle causing severe brainstem compression and hydrocephalus. Endoscopic third ventriculostomy wasperformed to relieve the hydrocephalus. One week later she underwent acombined transpetrous, supratentorial, and infratentorial exploration of thetumour. At surgery a black, highly vascular, encapsulated tumour was foundin the CP angle, anterior to the brain stem and the cranial nerves. Even minormanipulation of the tumour resulted in severe haemorrhage, and the proce-dure was therefore limited to biopsy of the tumour. Eight hours after surgerythe patient’s condition deteriorated, and CT scan revealed haemorrhage intothe tumour. Despite re-exploration and evacuation of the haematoma, thepatient died 3 days later. Histological and electron microscopy appearanceswere consistent with the diagnosis of meningeal melanocytoma. Conclu-sion: Meningeal melanocytoma is particularly rare in children. The diagno-sis should be kept in mind in cases of atypical CP angle tumours in children,and potential difficulties in resection of these tumours need to be considered.

95. CEREBELLAR DAMAGE AND INTELLECTUAL OUTCOMEOF CHILDREN TREATED FOR A POSTERIOR FOSSA TUMORKalifa C, Grill J, Kieffer-Renaux V, Viguier D, Hartmann O, Dellatolas G;Department of Pediatric Oncology, Gustave Roussy Institute, Villejuif,France

The main risk factors for intellectual impairment after treatment of a pos-terior fossa are age at diagnosis, radiation therapy, and surgical complica-tions. In order to decrease the neuropsychological sequelae associated withradiotherapy of the CNS, especially in young children, we have designedalternative therapeutic approaches including reduced field or doses of irra-diation and high-dose chemotherapy adapted to the age of the patient andthe risk factors of the tumor. We designed a cross-sectional study to explorethe neuropsychological outcome of 90 long-term survivors of a posteriorfossa treated at the Gustave Roussy Institute. We used Wechsler Scales com-pleted with specific tests to explore laterality, memory, language, reading, andfine motor skills. The association of IQ scores with the following factors wasstudied: age, socio-economical status, presentation, surgical complication,histology, residuum/metastasis, treatment protocol, and neurological deficits.Mean age at diagnosis was 5.7 +/– 4.1 y, and median interval between radio-therapy and evaluation was 2 y (1–11). Intellectual outcome was significantlyimproved with the protocols that did not use irradiation (BBSFOP) or usedreduced doses or volume of irradiation. The presence of a persisting clinicalcerebellar syndrome was strongly correlated with the intellectual impairment,both on the nonverbal and verbal skills (mean full-scale IQ = 72 vs 87, p =0.003). Moreover, the scores of the Purdue-Pegboard test, designed to explorefine motor skills, were strongly correlated with most of the tests performedto explore both verbal and nonverbal skills (eg, correlation with full-scale IQ,p = 0.0001). Irrespective of the therapeutic protocol, cerebellar damage seemsto play an important role in the neuropsychological outcome in these chil-

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dren. New therapeutic strategies should try to protect the cerebellum fromthe cumulative toxicities of multimodal therapies. This study further empha-sizes the role played by the cerebellum in the cognitive development of youngchildren.

96. BRAIN METASTASIS IN EXTRACRANIAL PEDIATRICSOLID TUMORSKebudi R,1 Görgün Ö,1 Ayan

.I,1 Yaman Agaoglu F,2 Vural S,1 Darendeliler

E2; Istanbul University, Oncology Institute, 1Division of PediatricOncology, 2Division of Radiation Oncology, Istanbul, Turkey

Objectives: The brain is a rare site of metastasis in most extracranial solidtumors. The aim of this study is to investigate the incidence, treatment, andprognosis of brain metastasis in extracranial pediatric solid tumors in a sin-gle institution. Methods: From September 1989 to December 2001, 1050pediatric extracranial solid tumors including lymphomas were diagnosed andtreated in the Division of Pediatric Oncology, Oncology Institute, IstanbulUniversity. Patients with parenchymal metastases in the brain were assessed.Results: 13 of 1050 patients (12%) with extracranial solid tumors developedbrain metastases. The median age of the patients was 10 (1–16) years. Fourwere male and 9 female. The diagnosis was osteosarcoma in 4, Ewing’s sar-coma in 3, Wilms’ tumor in 2, germ cell tumor in 2, rhabdomyosarcoma in1, and clear cell sarcoma of the soft tissue in 1. Three patients (2%) had brainmetastasis at diagnosis, 10 developed brain metastases during therapy orrelapse at a median duration of 16 months (3–36 mo.) from diagnosis. Ten(77%) of the 13 patients had metastasis to various sites other than brain, pri-marily lung at diagnosis. All patients had metastasis to various sites (lung,bone, bone marrow) at the time the brain metastases were detected. Fivepatients complained of headaches, 4 had convulsions, 3 nausea and vomit-ing, 3 hemiparesia/hemiplegia, 1 nistagmus, 1 pitosis, 1 head tilt before diag-nosis of brain metastasis; 2 were unconscious when admitted. All patientswere given dexamethasone ± anticonvulsives. Two underwent surgery: onedied postoperatively, one received adjuvant radiotherapy and chemotherapybut developed new brain lesions three months later and died with widespreaddisease. Five received palliative radiotherapy, three followed by chemo-therapy. Four refused all treatment. Two were admitted to the intensive careunit and died without being able to get further therapy. All patients died ata median time of 1 month (2 days–6 months) from the time of diagnosis ofbrain metastasis with widespread progressive disease. Conclusions: Brainmetastases were detected in 12% of children with extracranial solid tumors.Metastatic patients who develop headaches or any other neurologic symp-tom should be investigated for possible brain metastasis. The outcome forthese patients is dismal.

97. RESULTS OF THE SECOND INTERNATIONAL CNS GERMCELL TUMOR (GCT) STUDY GROUP PROTOCOLKellie S, Boyce H, Lichtenbaum R, Dunkel I, Diez B, Balmaceda C,Rosenblum M, Finlay J, for the Second International CNS Germ CellTumor Study Group; New York, NY, USA

Introduction: The prognosis for patients with malignant GCT arising out-side the CNS has been dramatically improved by the addition of cisplatin intobrief but intensive protocols. The primary objective of this study was to deter-mine whether intensive cisplatin-based chemotherapy without irradiation waseffective in patients with CNS GCT. Patients: 39 patients with previouslyuntreated CNS GCT, including 15 with diabetes insipidus (DI). Sex: M, 30;F, 9. Age: range 1–41 years; median 13 years. Diagnoses: Germinoma 20patients, NGGCT or mixed tumors 19 patients. Treatment: Regimen A: (Cis-platin 105mg/m2 day 1, Etoposide 150mg/m2 days 1, 2 and 3, Cyclophos-phamide 2Gm/m2 days 1, 2, and 3, and Bleomycin 15mg/m2 day 3). RegimenB: (Carboplatin [AUC 7mg/ml*min] days 1 and 2, Etoposide 150mg/m2 days1, 2, and 3, and Bleomycin15mg/m2 day 3). Treatment comprised A→A→B→Bfor patients achieving CR after the first 2 courses, and A→A→B→B→A→Bfor patients achieving CR after the first 4 courses. Patients not in CR after 4courses underwent “second” surgery if feasible +/– irradiation. Results: Out-come data at a median follow-up of 6.3 years: Germinoma: CR1 9 patients(45%), CR2/alive with disease 4 patients, died of disease (DOD) 4 patients,died of toxicity (DOT) 3 patients. Thirteen of 20 patients remain in completeremission (65%). Of these, 10 have not received irradiation. NGGCT: CR18 patients (42%), CR2+ 6 patients, DOD 4 patients, DOT 1 patient. Four-teen of 19 patients (74%) with NGGCT remain in stable CR. Only 1 of 9patients in CR1 received irradiation. Four patients died from treatment-related causes. Severe myelosuppression was common. Renal, audiologic, andmild pulmonary function abnormalities were common. Conclusion: Resultsof therapy in patients with NGGCT are encouraging; however, this protocolwas associated with unacceptable treatment-related morbidity and mortality,particularly among patients with DI.

98. TUMOR MARKERS IN THE CSF OF INFANTS: WHAT ISTHE NORMAL RANGE OF AFP AND B-HCG IN CSF?Kellie S, Nath C, Cooke-Yarborough C, Coakley J; Department ofOncology, The Children’s Hospital at Westmead, Sydney, NSW, Australia

Introduction and Objectives: Approximately 6% of germ cell tumors(GCT) arise within the CNS. These tumors encompass a wide histologic spec-trum, making biopsy desirable; however, open or stereotactic biopsy may beassociated with unacceptable risk because many tumors are located in deep-seated midline regions and may be highly vascular. In these patients the meas-urement of AFP and B-HCG in serum and CSF may identify the presence ofimmature germ cell elements. To date, there are no published reference inter-vals for AFP or B-HCG in the CSF of infants. We therefore measured AFPand B-HCG in the CSF of infants aged <4 months who did not have malig-nancy to determine these reference intervals. Methods: AFP (n = 84 infants)and B-HCG (n = 10 infants) in CSF were measured by a microparticle enzymeimmunoassay on an Axsym analyser. Samples with >5000 rbc’s/ml wereexcluded. Paired plasma samples were obtained from some patients. Results:B-HCG was present in low concentrations in normal CSF. The limited datashowed no variation in concentration with age. Using corrected ages, AFPmeasurements (IU/ml) showed the following.

Age No. Mean CSF AFP No. Mean Plasma AFP 0–15 days 20 167 (2 – 362) 14 5640 (137 – 135070) 16–30 days 13 37 (4 – 81) 11 1683 (357 – 6450) 31–60 days 27 3 (1 – 13) 13 273 (67 – 1308) 61–110 days 26 1 (1 – 4) 16 55 (2 – 447)

Conclusion: CSF AFP levels are much lower than those found in plasma,and by age 6 weeks in most infants, the levels are close to those found inadults. It is necessary to correct the age of the subject for prematurity becausewhen this is done all values obtained over 2 months of age were <5 IU/ml.These results have implications for the identification of CNS tumors, partic-ularly congenital CNS tumors in infants, containing immature germ cell ele-ments.

99. NEURO-ENDOCRINE AND NEUROPSYCHOLOGICALEFFECTSKennedy C; Southampton General Hospital and University ofSouthampton, UK

The function of many children treated for brain tumours is severelyimpaired. Many factors determine these impairments and the extent to whichthey prevent the child (and later adult) from achieving full social integration.These factors include the premorbid state of the child and family, the impair-ments caused by the tumour at presentation, the biology of the tumour, andthe effects of treatments. The relative merits of the antitumour effects of alter-native treatments are, in many cases, assessed in small numbers of cases atsingle institutions or in multicentre clinical trials. Attempts to measure theireffects on the developing brain, however, have had limited success. Treat-ments can be compared only if, in addition to survival rates, health status andhealth related quality of life are assessed. Obstacles to this include the diffi-culty of obtaining psychometric information across multiple centres and thelack of a framework in which to place psychometric and other equally impor-tant information (see below). Experience with other forms of neuro-disablingconditions (eg, posthaemorrhagic hydrocephalus, extremely low birth weight)suggests that reliable, useful data can be collected on large numbers ofaffected children using brief questionnaires completed by parents, nurses, andteachers. Simplistic and misleading explanations for poor neurological andendocrine outcomes, such as the attribution all problems to radiotherapy, per-sist. The antidote for this is systematic collection of data on sufficient num-bers of patients to inform our understanding of the multiple factors con-tributing to outcome. The difficulties encountered and some evidence forthe need for more sophisticated models of causation will be illustrated by ref-erence to studies on primitive neuroectodermal tumours, optic glioma, ger-minoma, and craniopharyngioma. An approach will be suggested for futurecollection of data on health status, behaviour, emotion, growth and endocrinefunction, use of medication and paramedical therapies, educational provisionand achievement, social integration and the subjective experience of the childand family. The most reliable information will be “longitudinal” coming fromrepeated measurement on individual patients over time. This will help toestablish the extent to which problems are temporary, continuing, or onlybecome apparent after an interval.

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100. NEUROLOGICAL COMPLICATIONS IN CHILDHOODLEUKEMIA AND LYMPHOMA: EXPERIENCE OF KKNGHKhattab T, Felimban S, Fryer C, Abbas A, Yousef A, Hussein A; KingKhalid National Guard Hospital (KKNGH), Jeddah, Saudi Arabia

Although the central nervous system (CNS) is the most common site ofextramedullary leukemia, fewer than 10% of children with acute lym-phoblastic leukemia (ALL) have CNS involvement at the time of diagnosis.Usually, CNS disease is asymptomatic. To identify neurological complicationsassociated with childhood leukemia and non-Hodgkin lymphoma (NHL) andoutcome, all patients with leukemia and NHL diagnosed from January 1986until January 2002 were reviewed. We divided the neurological problems intodisease related, either at diagnosis or at relapse, or treatment related. Therewere 58/392 (15%) patients with acute leukemia and NHL identified as hav-ing neurological problems. There were 3 groups: Group I (27 pts) had CNSdisease at diagnosis (ALL 22 pts, NHL 3, AML 2); 17/27 pts had asympto-matic CNS disease (+ve CSF); 10/27 pts were symptomatic, 6/10 (+ve CSF)including (2 facial palsy, 1 proptosis, 1 paraplegia, 2 hemiparesis) and 4/10(-ve CSF) (2 paraplegia, one of them paravertebral NHL on C.T. abd. scan,other epidural hematoma, 1 ophthalmoplegia, 1 compressed vertebral frac-ture). Group II (27 pts) developed CNS relapse (ALL 25, NHL 2), 15 isolatedCNS relapse, 11 CNS & BM relapse, and 1 vertebral spine involvement. Sev-enteen pts were still on therapy at the relapse; these pts were nearly asymp-tomatic at the time of CNS relapse: 7 were off therapy, 3/7 had headache, 3/7had lower backache, and 1/7 had seizure with local brain mass and –ve CSF.Three cases were diagnosed on completion of therapy. There were 4 pts inGroup III; all were ALL, treatment-related neurological problems; one hada stroke secondary to L-Asparginase, one steroid myopathy, one TB of spine,one epidural hematoma post intrathecal therapy. In summary, neurologicalproblems associated with ALL and NHL may be secondary to the disease orto complications. Signs and symptoms may be similar. Accurate diagnosis andevaluation are essential for proper management.

101. INTELLECTUAL DETERIORATION AFTER TREATMENTOF A POSTERIOR FOSSA TUMOR: A LONGITUDINAL STUDYOF 41 PATIENTSKieffer-Renaux V, Viguier D, Leroy-Malherbe V, Dellatolas G, Oberlin O,Kalifa C, Grill J; Département d’Oncologie Pédiatrique, Institut GustaveRoussy, Villejuif, France; Centre Ressources, Hôpital National de Saint-Maurice, France; Inserm U472, Epidémiologie et Biostatistique, Villejuif,France

After standard treatment of a medulloblastoma including craniospinalirradiation (CSI), intellectual capacities are known to decline with time sincediagnosis. We undertook this study to confirm this yearly decline, even afterextended follow-up, and to test whether different treatment strategies wouldhave a different impact on the cognitive outcome of children with a posteriorfossa tumor. Forty children were evaluated at least 2 times more than 1 year(y) after the end of their treatment. Mean interval between the two evalua-tions was 2.6 y (1 y to 4.3 y). Four groups of patients were made accordingto the treatment schedule: Group 1 = 12 children treated with reduced CSI at25 Gy; Group 2 = 10 children treated with standard CSI at 35 Gy; Group 3= 7 children receiving posterior fossa irradiation only; Group 4 = 11 childrentreated with high-dose chemotherapy and posterior fossa irradiation. At firstevaluation (mean interval since diagnosis 3.7 y), mean IQ score was 80(42–115) and was significantly different among the 4 groups. Only patientsin group 3 have a mean IQ score of 92 in the normal range. Mean IQ scoresof the children in groups 1, 2, and 4 are 85, 70, and 74, respectively. At sec-ond evaluation, mean IQ scores are significantly lower, with a mean differ-ence of 2.4 points and a yearly decline of 1 point. The magnitude of thedecline is positively correlated with the first IQ score and inversely correlatedwith age at diagnosis (p = 0.02). IQ score decline is observed in all the ther-apeutic groups except group 3. The differences in IQ scores observed betweenthe 4 therapeutic groups are conserved. This study shows that IQ scores con-tinue to decline more than 4 years after diagnosis except in children treatedwith reduced field irradiation only. Long-term follow-up until adulthood isnecessary to adapt the rehabilitation of these patients.

102. EXPRESSION OF ERBB-2 (HER-2) AND ERBB-4 INPATIENTS WITH MEDULLOBLASTOMAKieran M, Louis DN; Department of Pediatric Oncology, Dana-FarberCancer Institute and Children’s Hospital, and Department of Pathology,Massachusetts General Hospital, Boston, MA, USA

Human epidermal growth factor receptor 2 (ErbB-2, HER-2, neu) is a receptor tyrosine kinase located on the cell surface of many normal tis-sues. It has been found to be overexpressed on the surface of many tumors,most notably epithelial tumors, including breast cancer. Overexpression ofErbB-2/HER-2 has been correlated with poor clinical outcome in patients

with breast cancer and osteosarcoma. Expression of ErbB-2/HER-2 in breastcancer led investigators to look for overexpression in other tumors. Medul-loblastoma has been found to be positive for ErbB-2 in up to 87% of sam-ples; normal cerebellum has no expression of HER-2. The mechanism for theaberrant expression of ErbB-2 in these tumors is unknown, although geneamplification has not been found. ErbB-2 expression in medulloblastomaappears to correlate with outcome: 25-year survival was 46 percent if <50%of the tumor cells were positive versus 17% if >50% were positive for HER-2. Preliminary Result: Using paraffin sections from patients with a con-firmed diagnosis of medulloblastoma, ErbB-2 and ErbB-4 staining were per-formed. The staining of normal cerebellum for ErbB-2 was negative, consis-tent with the absence of this receptor within the normal cerebellum. Incontrast, there was a low but steady background staining of ErbB-4 withinthe cerebellum, as previously reported (data not shown). Tumor samples werescored for the percentage of ErbB-2 positive cells, and for the percentage ofcells that were ErbB-4 positive above background. Four major patterns wereobserved: (1) ErbB-2/4 –/–; (2) ErbB-2 +/ErbB-4 –; (3) ErbB-2 –/ErbB-4 +; and(4) ErbB-2/4 +/+. To date, samples from 10 different patients have been ana-lyzed. Twenty percent demonstrated focal areas of >50% positivity for ErbB-2, 70% demonstrated staining in 10–20% of the tumor cells, and 10% werenegative in this analysis for ErbB-2 staining. Background levels of ErbB-4were present in all samples. These results are similar to those published bythe European group and confirm their results. Approximately 30 othermedulloblastomas are being analyzed for expression of ErbB-2 and ErbB-4,and these results will be correlated with patient outcome.

103. NEOADJUVANT CHEMOTHERAPY AND CRANIAL ORINVOLVED-FIELD RADIOTHERAPY IN BIOPSY-CONFIRMEDINTRACRANIAL GERMINOMAKim IH,*# Shin HY,† Huh DS†; *Departments of Therapeutic Radiology,†‡Pediatrics, †Internal Medicine, #Cancer Research Institute, SeoulNational University College of Medicine, Korea

Intracranial germinoma is a highly radiosensitive or chemosensitivetumor with successful survival rate. To keep the good survival and reduce thelate neurologic sequelae from wide-field radical radiotherapy alone, we com-bined neoadjuvant chemotherapy and cranial or involved-field radiother-apy. We here analyze its efficacy in terms of acute toxicity and short-termrelapse patterns. Between 1995 and 2000, 14 patients were treated with com-bined neoadjuvant chemotherapy and radiotherapy. Male to female ratio was12:2, and median age was 14 years. Tumors were located in the pineal glandin 7 patients, in the sellar/suprasellar region in 3, in both the pineal and sel-lar/suprasellar in 1, and in other supratentorial regions in 3. Chemotherapyregimen was cisplatin, cyclophosphamide, VP-16, vincristine for 5 patientsyounger than 16 years; BEP (Bleomycin, VP-16, cisplatin) for 8 patients; andEP (VP-16, cisplatin) for 1 adolescent. The extent of radiotherapy was thewhole craniospinal axis for 6 patients, the whole and partial brain for 1, andthe partial brain (involved field) for 7. Response to neoadjuvant chemo-therapy was complete remission in 4 patients, partial remission in 9, and noresponse in 1. But after radiotherapy all except one experienced completeremission. Toxicity during or after chemotherapy equal to or more than gradeIII was remarkable; hematologic toxicity in 10 patients, liver toxicity in none,kidney toxicity in none, gastrointestinal toxicity in 1. Reduction of chemo-therapy intensity was necessary in 9 patients. One patient cannot continuechemotherapy because of septic shock. One patient suffered from bleomycin-induced pneumonitis, causing radiotherapy to be withheld, and eventuallydied of respiratory failure. The other 13 were alive without evidence of dis-ease or relapse for 3 to 53 months. We cannot conclude at the present timethat neoadjuvant chemotherapy and cranial or involved-field radiotherapy isequal to or superior to wide-field radical radiotherapy in overall therapeuticgain. The pattern or rate of late toxicity with longer follow-up is required forthe comparison.

104. POSTERIOR FOSSA BOOST BY INTENSITY-MODULATED RADIATION THERAPY (IMRT) VS LATERALBEAMS (LB): IMPACT ON CISPLATIN DOSING ANDOTOTOXICITY Kim S, Olch A, Villablanca J, Leonard E, Hyder D, Lavey R; Children’sCenter for Cancer and Blood Diseases, The Children’s Hospital, LosAngeles, CA, USA

Introduction: Pediatric medulloblastoma is commonly treated with radi-ation therapy covering the craniospinal axis with a boost to the entire pos-terior fossa, followed by 8 cycles of cisplatin-containing chemotherapy. Irra-diation of the cochlea limits the cisplatin dose by enhancing ototoxicity. Thisstudy examined whether boosting the posterior fossa using IMRT results inless hearing loss and cisplatin dose-reduction than boosting with opposed lat-eral beams. Methods: Twenty-one pediatric patients with medulloblastomawere treated at our institution between 1994 and 2001 with craniospinal irra-

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diation followed by a boost giving a cumulative dose of 5400–5580 cGy tothe entire posterior fossa in daily fractions of 180 cGy with concurrent vin-cristine, followed by up to 8 cycles of cisplatin, vincristine, and either CCNUor cyclophosphamide given at 6-week intervals. The posterior fossa boostwas delivered using opposed LB in the 17 patients irradiated in 1994–2000and using 5 noncoplanar IMRT beams in the 4 patients irradiated in 2001.Bilateral audiometric evaluations were performed prior to each chemotherapycycle and periodically after completion of therapy. Cisplatin was dose-reducedfor COG Grade 3 ototoxicity and held for Grade 4 ototoxicity. Patient med-ical records were reviewed to obtain radiotherapy, chemotherapy, andaudiometry information. Results: The IMRT and LB groups did not differsignificantly in gender or age distribution. Mean cochlear dose was 5527+85cGy in the LB group vs. 3464+88 cGy in the IMRT group (p<0.001). After4 cycles of chemotherapy, mean threshold hearing level in the 0.25–12 kHzrange was 37.6+3.2 dB in the LB group vs. 23.1+6.3 dB in the IMRT group(p = 0.05). Grade 2–4 ototoxicity was present in 14/17 (82%) LB vs. 1/4(25%) IMRT patients (p = 0.05). Cisplatin was stopped prior to cycle 8 dueto hearing loss in 2/17 (12%) LB vs. 0/4 IMRT patients. Sixty-seven percentof LB patients followed post-chemotherapy had Grade 3–4 ototoxicity, and53% required hearing aids. Conclusion: Ototoxicity is a serious problemfor medulloblastoma patients receiving lateral beam irradiation followed bycisplatin-containing chemotherapy. Using IMRT for the posterior fossa boostpermits higher maintenance cisplatin dosing with less ototoxicity.

105. RADIOTHERAPY RESULTS OF CHILDHOOD BRAINSTEM GLIOMAS IN A SINGLE INSTITUTE Kim IH,†‡ Hong S*; *Department of Therapeutic Radiology, †Institute ofRadiation Medicine, Medical Research Center, ‡Cancer Research Institute,Seoul National University College of Medicine, Korea

The dismal prognosis of the brain stem gliomas has not changed much,although various regimes of radiotherapy, chemotherapy, or both have beentried. We evaluated outcome and prognostic factors in brain stem gliomastreated by radiotherapy methods. Between 1983 and 1998, we treated 46childhood patients with brain stem glioma. There were 27 boys and 19 girls,and median age was 7 years (range 3–18 years). Histopathologic diagnosiswas confirmed in 16 patients. Histology revealed low-grade glioma in 6patients and high-grade glioma in 10 patients. Treatment consisted of radio-therapy delivered to local fields. Before 1993, radiation therapy using an 18to 2.0 Gy qd regime was employed in 19 cases; thereafter a 1.1 Gy bid regimewas used in 18 cases, and a 1.5 Gy bid regime was used in 9 cases. Medianbiologically effective dose was 89.2 Gy. Nine patients were treated withadjunctive chemotherapy. Response was evaluated at 4 weeks after radio-therapy by MRI findings. After radiotherapy, neurologic deficit improved in43 of 46 patients (93%). MRI responses were as follows: partial remission19/40 (47.5%), minimal to no remission 19/40 (47.5%), and tumor pro-gression 2/40 (5%). The median time to disease progression was 7 months,and the median time to death 12 months; overall survival rate at 1 year was50%. The survival after radiotherapy was significantly associated with tumorlocation (pons vs nonpontine) and preradiotherapy performance status. Progression-free survival was influenced by tumor location (pons vs. non-pontine), biologically effective dose (< 90 Gy3 vs. >90 Gy3), and postradio-therapy performance status. Ototoxicity occurred in four patients and steroiddependency in 12 patients. From these data, the survival of the patient witha brain stem glioma depended upon the total radiation dose among manyradiotherapy-related parameters. Although dose fractionation methodsseemed less likely to be influential, we think we need more cases to get a finalconclusion, especially on the efficacy of the accelerated radiotherapy regime.

106. QUALITY OF LIFE FOR CHILDREN TREATED FORBRAIN TUMORS, DETERMINED BY MENTAL ANDNEUROLOGICAL DISORDERS: A PROSPECTIVE-LONGITUDINAL STUDYKingma A, Fock J, Begeer J, Aarnoudse C, Leeuw J; PediatricOncology Center and Pediatric Neuro-Oncology Working Group,University Hospital of Groningen, Groningen, The Netherlands

Objectives: (1) to study long-term neuropsychologic function and qual-ity of life as determined by mental and neurological handicaps in a prospec-tive design; (2) to identify risk factors for impairment; (3) to identify pts whoneed intensive school support. Methods: 62 (93% of 108 eligible pts, 38 died)consecutive newly diagnosed brain tumor pts aged 1–16 yrs. (median 9 yrs.)entered this single-institution study between 1981 and 1996 and were annu-ally evaluated with an extensive test battery until ≥ 5 years after surgery. Pre-operative neuropsychologic evaluation was feasible in 70%; the others hada first assessment within 4 weeks after surgery before further treatment. Stan-dard neurological examinations were done preoperative and repeated every3 to 6 months. Main diagnoses included 28 astrocytoma and 12 medul-loblastoma. Primary tumor site was 27 infratentorial and 35 supratentorial

(14 hemisphere) tumors; 28 pts needed shunting for increased intracranialpressure. Irradiation was given to 33 pts, and 9 pts received adjuvant chemo-therapy. Test scores were analyzed for the effects of age, supratentorial tumorsite, and irradiation and were compared between pts and the normative mean.At the endpoint evaluation, quality of life was determined by presence andseverity of permanent cognitive, neurologic, and neuro-behavioral handicaps.Results: Compared to the normative means, pts showed significant cogni-tive deficit(s) on at least 1 measure of intelligence, memory, attention, speed,or visual-motor skills, resulting in special educational placement in 40%.Cognitive deficits were primarily related to tumor in 11%, to surgery in 16%,and to whole-brain irradiation in 32%, with young age as an additional riskfactor. Forty-one percent had mental handicaps of mixed etiology. At the endpoint evaluation, mild to moderate neurological handicaps were still present in 55%, epilepsy in 19%, and visual disorders in 13%. Neurologicoutcome could be determined long before neuropsychologic outcome. Seri-ous neurobehavioral disorders were mostly related to a midline tumor-localization. Conclusions: (1) Permanent cognitive impairment can beexpected in a majority of children treated for brain tumors; (2) Seriousimpairment of quality of life, including severe mental and neurologic handi-caps, was seen in 25%; these pts cannot live an independent life and need ourmultidisciplinary, intensive, lifelong support.

107. TEMOZOLOMIDE IN PAEDIATRIC BRAIN TUMORS:RESULTS OF A SURVEYKordes U,1 Sträter R, Wolff J; 1Department of Paediatric Oncology andHaematology, University of Hamburg, Germany

Objective: The role of Temozolomide (TMZ) in paediatric neurooncol-ogy is being addressed by several studies. TMZ has also been used by physi-cians on an individual basis in difficult-to-treat paediatric brain tumours. Wepresent data on these patients collected by a recent survey done for the Ger-man Paediatric Oncology Group. Methods: Fourteen institutions respondedto a questionnaire; a total of 33 patients were treated, aged 4–9 years (mean12 years). One to sixteen cycles of TMZ were given at 150–200 mg/sqm/d x5 d q 28 d (mean 5 cycles); 1 patient was treated with continuous low-doseTMZ. Nine patients received concurrent Thalidomide; 1 received concomi-tant radiation. Twelve patients had received other salvage chemotherapy priorto TMZ. Toxicity: Only mild gastrointestinal and myelotoxicity was noted.Results are as follows:

(secondary) glioblastoma multiforma, n = 2: 2 PR(recurrent) glioblastoma multiforma, n = 7: 2 SD, 5 PD(new) diffuse pons glioma, n = 5: 3 SD, 2 PD(recurrent) anaplastic astrocytoma, n = 4: 3 SD, 1 PD(recurrent) medulloblastoma, n = 6: 1 CR, 1 PR, 2 SD, 2 PD(recurrent) PNET, n = 2: 1 CR, 1 CCR(recurrent) anaplastic ependymoma, n = 4: 1 SD, 3 PD(recurrent) low-grade glioma, n = 2: 2 PD(recurrent) plexus carcinoma, n = 1: 1 PDClinical details of responders: Two patients with a secondary GBM fol-

lowing radiochemotherapy for medulloblastoma had a PR to TMZ lasting 6,respectively, 4, months. Neither of them received repeat radiation; one wasgiven concurrent Thalidomide. Both patients with a PNET had aggressiveprior therapy for multiple relapses. One was kept in CCR for 13 months withTMZ; the other had a PR at 6 months and went into a short CR at 12months. Two patients with second relapse of a medulloblastoma (one afterHDCT) were treated with TMZ monotherapy; one had a CR at 6 months;the other had a PR to TMZ lasting 12 months. Conclusion: TMZ shows effi-cacy in some paediatric high-risk brain tumours, especially medulloblastomaand PNET. Further study of combination or neoadjuvant treatment is war-ranted.

108. COMPARISON OF IQ IN PATIENTS TREATED FORMALIGNANT TUMORS OF POSTERIOR FOSSA ANDSUPRATENTORIAL REGIONKorzeniewska J,* Perek-Polnik M, Dembowska-Baginska B, DrogosiewiczM, Perek D; *Department of Psychology, Children’s Memorial HealthInstitute, Warsaw, Poland; Department of Oncology, Children’s MemorialHealth Institute, Warsaw, Poland

The aim of our analysis was to compare IQ scores of patients who com-pleted treatment of malignant tumors localized in the posterior fossa andsupratentorial region. Materials and Methods: Twenty-six patients (17 withposterior fossa and 9 with supratentorial tumors) were studied. All patientsunderwent surgery, received chemotherapy, and were irradiated. Patients withposterior fossa malignancies received craniospinal irradiation of 35 Gy to thebrain and spine and additionally 20 Gy to posterior fossa. Patients with hemi-sphere tumors were irradiated to tumor’s bed only with a dose of 55 Gy.Wechsler and neuropsychological panel of tests were given. Comparison ofthe IQ scores in the two groups was done. Gender, age at the time of irradi-

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ation, and time from completing treatment were analyzed. Results: In thegroup with posterior fossa tumors there were 9 boys and 8 girls with ages atstarting irradiation ranging from 5 3/12 to 15 1/12 years (median 9 3/12);time from completing treatment ranged from 3/12 to 8 7/12 years (median2 5/12). Among the patients with hemisphere tumors there were 6 boys and3 girls with ages at starting irradiation between 7 5/12 and 14 11/12 years(median 14 6/12); time from completing treatment ranged from 2 2/12 to 311/12 years (median 1) The IQ scores in patients irradiated to CNS axisranged from 40 to 97 (mediana 79). Patients with low IQ scores haddecreased motor skills. In the other group, IQ scores ranged from 42 to 110(median 94). Patients with low IQ scores in this group had a history ofepilepsy. Comments: In our group of patients, tumor localization and irradi-ation field might have had the most powerful influence on IQ scores.

109. PRERADIATION (PRE-RT-C) VERSUS POSTRADIATION(POST-RT-C) CHEMOTHERAPY IN STANDARD-RISKMEDULLOBLASTOMA (SR-MB): FINAL RESULTS OF THEHIT’91TRIALKühl J, Kortmann RD, Mittler U, Urban Ch, Deinlein F, Becker J,Berthold F, Flentje M, Graf N, Kaatsch P, Pietsch T, Rating D, Schulte FJ,Slavc I, Sörensen N, Warmuth-Metz M, Wiestler OD, Willich N, WolffJEA, Bamberg M, for the German Paediatric Brain Tumour Study Group;Universitäts–Kinderklinik, Würzburg, Germany

The optimal timing of chemotherapy, before or after radiotherapy, is afocus of contemporary clinical research in paediatric neuro-oncology. TheHIT’91 trial was designed to compare a PRE-RT-C arm (Kühl J et al. Am JPediatr Hematol Oncol 1993) with a POST-RT-C arm (Packer RJ et al. J Neu-rosurg 1991). From 73 institutions in Germany, Austria, and Switzerland,280 eligible patients between 3 and 18 years of age with medulloblastomawere analysed in February 2002. Forty-six patients had initial stage M2/3.Of 234 SR-MB, 69 had a residual tumour on early postoperative MRI, and49 stage M1. Patients were randomised to PRE’RT-C consisting of 8 coursesof DDP, CCNU, and VCR, or POST-RT-C consisting of PROC followed by2 cycles of IFO/VP16, hd MTX, and DDP/ARAC. All patients received radio-therapy to the neuroaxis (35.2 Gy) followed by a boost (20 Gy) to the pos-terior fossa. Poor responders to PRE-RT-C received 8 cycles of CARBO,CCNU, and VCR after RT. Including all 280 patients, the 5-year PFS was70% (SE 4%) in SR-MB without and 68% (SE 6%) in SR-MB with a resid-ual tumour versus 41% (SE 7%) in children with M2/3 stage. SR-MB patientswith M1 stage had an inferior PFS (p = 0.08) and EFS (p = 0.03). The 5-yearPFS of SR-MB was 79% (SE 5%) in children randomised to POST-RT-C ver-sus 60% (SE 5%) randomised to PRE-RT-C (p = 0.007). The correspondingEFS was 78% versus 57% (p = 0.004). Two second malignancies and 1 fatalsepsis were related to the PRE’RT-C arm, and 1 death (LEP) was related tothe POST-RT-C arm. In SR-MB randomised to POST-RT-C the 5-year PFSwas 80% (5%) in children without and 76% (7%) in children with a resid-ual tumour (n.s.). HIT’91 demonstrated a striking superiority of POST-RT-Cover PRE’RT-C in children with SR-MB. A residual tumour had no impacton outcome. There was a remarkable tendency of an inferior PFS/EFS of stageM1. The excellent results in SR-MB/M0 achieved with POST-RT-C probablyallow a dose reduction of CSI. HIT 2000 and SIOP-PNET-4 were constructedto investigate the utility of CSI using 23.4 Gy (conventional) versus 36 Gy(hyperfractionated). Supported by the German Cancer Aid and the GermanChildhood Cancer Foundation

110. MEDULLOBLASTOMA: 5-YEAR TREATMENT RESULTSIN A SCANDINAVIAN MULTICENTRE STUDY Lannering B, Strömberg B, for the Swedish and Wesenberg F for theNorwegian Pediatric Brain Tumor Group; Department of Oncology, The Queen Silivas Children’s Hospital, Göteborg, Sweden

A treatment study of Medulloblastoma (Mb) in the posterior fossa inchildren >3y was initiated in 1995 in Sweden and later in Norway. Ten cen-tres participated. The purposes were to (a) standardise treatment, (b) improveor maintain current 5-year treatment results for standard-risk (SR) ~60% andhigh-risk (HR) ~ 40%, (c) improve quality of staging and radiotherapy (RT),and (d) reduce long-term morbidity. Protocol: surgery, postoperative MR forlocal staging within 3 days, spinal MRT. From 2–10 weeks a short intensivepre-RT chemotherapy. SR patients received RT 30/55 Gy, treatment com-pleted. HR patients received 35/55 Gy + Vincristine weekly followed by alter-nating high-dose Cyclophosphamide +Vcr and CCNU+Vcr. RT. Quality con-trol in the SR group: Staging: SR; tumor residual ≤ 1.5cm2, no metastasis;CSF cytology not routine HR; residual tumor > 1.5 cm2 and/or metastatic dis-ease. Results: Over 90% of children with Mb, in all 45 patients, wereincluded. SR 7-year pEFS (n = 20 ) 0.57, median follow-up time 4 years;HR 7-year pEFS (n = 25) 0.52, median follow-up time 5 years, of whichM2+M3 pts (n = 18) 0.51, median follow-up time 5 years. Conclusions:These are mature data with no patients lost to follow-up. Seven-year pEFS in

the HR arm 0.52 was considered good for this severely affected group, mostlyincluding children with metastatic disease, M1-M2. No relapses after 2.5years. Renal and audiological toxicity was mild compared to cisplatinum-containing regimens. Seven-year pEFS in the SR arm 0.57 was considered sub-optimal. Therefore this arm closed in 2000. One late relapse (outside tumorboost) occurred at 5 years. Staging procedures were not optimal since CSFcytology was not routine and some M1 pts may have been included. Thequality of RT delivered was good in all cases. Pre-RT chemotherapy is notof benefit for SR patients. SR patients need adjuvant chemotherapy when thecraniospinal dose is reduced.

111. SUSTAINED REMISSION AFTER RECURRENT CENTRALNERVOUS SYSTEM ATYPICAL TERATOID/RHABDOIDTUMOR: A REPORT OF TWO CASESLefrancois M-A, Scott M, Goumnerova L, Proctor M, Marcus K, PomeroyS, Chordas C, Turner C, Kieran M; Pediatric Neuro-Oncology andDepartments of Neurosurgery, Radiation Oncology, and Neurology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, MA, USA

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous sys-tem is a highly malignant neoplasm primarily affecting children less than 5years of age. First described in 1985, there are estimated to be only 188 casesdescribed to date. Despite aggressive up-front multimodality therapy includ-ing surgical resection, chemotherapy, and irradiation, prognosis is dismal withonly a few reported cases of extended survival. There have been no reportsof survival or even long-term remission in children whose disease hasrecurred. Despite additional therapy, patients rapidly succumb to their dis-ease within weeks to a few months after recurrence. We report 2 consecu-tive cases of young children with recurrent AT/RT. Following initial ther-apy, both children experienced rapid local recurrence of disease. Treatmentat the time of recurrence consisted of surgical resection, limited field irradi-ation, and intensive chemotherapy based on a previously published rhab-domyosarcoma-based protocol (IRS-III). Continued sustained remission(10–20 months) has been achieved in both cases. The patients were 2 females,both 14 months of age at presentation. Tumor location was supratentorialwithout radiographic or cytospin evidence of metastatic disease. Initial ther-apy consisted of gross total surgical resection followed by aggressive chemo-therapy (vincristine/cisplatin/cyclophosphamide/etoposide and intrathecalmafosfamide). Relapse occurred locally within 12 weeks of initial presenta-tion. Postrecurrence treatment consisted of surgical resection, 3-D conformalirradiation to a dose of 5400 cGy to the tumor bed, and concurrent chemo-therapy (doxorubicin/etoposide/temozolomide/dactinomycin and intrathecalmethotrexate/cytarabine hydrocortisone). Both patients are alive and wellwithout evidence of disease with a median of 16 months from time of recur-rence. Both patients received only local radiation treatment and avoided cran-iospinal radiation fields. In summary, sustained remission after recurrentAT/RT can be achieved through the use of multimodality therapy to includemaximum surgical resection, limited field irradiation, and chemotherapy.

112. IMPAIRMENTS, DISABILITY, AND HANDICAP INCHILDREN TREATED FOR BRAIN TUMORSMacedoni-Luksic M,1 Zadravec-Zaletel L,2 Zupancic N,1 Korenjak R,3

Stirn-Kranjc B,4 Todorovski L,5 Jereb B2; 1Department of Child Neurology,2Institute of Oncology, 3Railway Health Centre, 4Department ofOphthalmology, 5Institute Jozef Stefan, Ljubljana, Slovenia

In long-term survivors after treatment of brain tumor in childhood, latesequelae have become a major concern. We evaluated a group of long-termsurvivors to determine neurological impairments, disability, and handicapafter treatment. The group comprised 61 patients (pts), 20 females and 41males, who were at least 15 years old with a follow-up of at least 3 years.Nine pts had only surgery, 3 had only radiotherapy (RT), 4 RT and chemo-therapy (CHT), 15 surgery, RT, and CHT, and 30 had surgery with RT. All61 pts were interviewed regarding their social life, schooling, and employ-ment for evaluation of their handicap. All had neurological examination, CT,or MRI of the brain; 47 also had ophthalmological examination. Psycho-logical evaluation (54 pts) included Wechsler Bellevue Intelligence test. Dis-ability was classified into 4 categories (none–severe) regarding pts ability forself care. The data were analysed using a decision-trees method. Thirty-eightpts (70%) had at least one impairment. Visual impairment was detected in14 pts (24%), associated with recurrence (p = 0.012). Thirty-four pts (56%)had motor impairment; in the group of the irradiated pts, sex (female) wasthe most important risk factor. Thirteen pts (21%) had epilepsy, associatedwith supratentorial location of tumor (p = 0.001). CT scan showed gener-alised brain atrophy in 13 pts (21%); risk factors were hydrocephalus at diag-nosis and perioperative complications. We found subnormal IQ (<80) in 16pts (30%). Associated with subnormal IQ were young age at first treatment(p = 0.006) and recurrence (p = 0.043). Twenty-seven pts (44%) were dis-abled—12 mild, 14 moderate, and 1 severely. Epilepsy was the most signifi-

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cant risk factor for disability. Cognitive impairment was associated with edu-cation (p = 0.000), whereas cognitive (p = 0.005), motor impairment (p =0.024), and epilepsy (p = 0.029) with employment (43%). None of the eval-uated impairments influenced the ability for partnership. We found at leastone neurological impairment in 70% of the patients, but moderate or severedisability was found only in a small proportion of them (25%). However,handicap still remains a prominent social problem.

113. GLUTATHIONE S-TRANSFERASE P1 EXPRESSION INMEDULLOBLASTOMAMadden R, Kuttesch J, Pleasants-Stephenson L, Foreman N, Ater J,Bruner J, Ali-Osman F; Division of Pediatrics and The Brain TumorProgram, The University of Texas MD Anderson Cancer Center, Houston,TX, USA

Glutathione S-transferase P1 (GSTP1) belongs to a multigene family ofproteins involved in phase II metabolism and cell signaling in response toredox perturbations, stress, and growth factors. We previously reported anassociation between increased GSTP1 expression and its nuclear localizationwith increased histologic grade and poor patient survival in adult gliomas(Clin Cancer Res 3:2252, 1997). Our laboratory also reported, for the firsttime, that the GSTP1 gene locus is polymorphic, with the cloning of cDNAsof three GSTP1 alleles, GSTP1*A, GSTP1*B, and GSTP1*C, and showedthat the genes encode functionally different GSTP1 proteins (J Biol Chem272:10004, 1997). In this present study, we hypothesize that the level oftumor GSTP1 expression and polymorphism of the GSTP1 gene are majordeterminants of risk in patients with medulloblastoma. Formalin-fixed, paraf-fin-embedded tissue from 47 cases was evaluated for GSTP1 protein expres-sion by immunohistochemical analysis and GSTP1 polymorphisms. GSTP1expression was graded, based on intensity and extent of tumor staining, from0 to +4 and grouped into low (< +2) and high (> +3) expression. Cytoplas-mic and nuclear distribution of GSTP1 was determined. GSTP1 allelotypingwas performed by TaqMan-PCR discrimination analysis of GSTP1 exons 5and 6. Among 43 cases obtained at diagnosis, 18 cases had high GSTP1expression and 25 cases low GSTP1 expression. Of 34 cases with clinical riskassessed, 19 were high-risk and 15 were average-risk. Among the average-risk cases we were unable to define a relationship between GSTP1 expressionand survival. Among the high-risk group, high GSTP1 expression (n = 8) wasassociated with early treatment failure, with deaths occurring at 11, 13, 14,and 32 months, in comparison to cases with low GSTP1 expression (n = 11)with death occurring at later intervals, 18, 22, 32, and 34 months. These pre-liminary results suggest that early failure in these high-risk medulloblas-toma patients may be due to GSTP1-associated chemoresistance. Data, cur-rently being obtained, on the GSTP1 allelotyping may clarify the role ofGSTPI polymorphisms in therapeutic outcome in medulloblastoma. (Sup-ported by the UTMDACC Children’s Art Project; RO1 CA79644, 5-P30CA16672-27; T32/NCI/NIH)

114. INTRACRANIAL CHILDHOOD EPENDYMOMA: FINALRESULTS OF THE FIRST AIEOP (ASSOCIAZIONE ITALINA DIEMATOLOGIA-ONCOLOGIA PEDIATRICA) STUDYMassimino M, Gandola L, Giangaspero F, Sandri A, Ricardi U, Garrè ML,Perilongo G, Spreafico F, Forni M, Genitori L, Scarzello G, Barra S, CefaloG, Mascarin M, Pollo B, Gardiman M, Andreussi L, Navarria P, FranzoneP, Brisigotti M, Balter R, Fidani P, Stefanelli M, Sotti G, Madon E, for theItalian Pediatric Neuro-oncology Group of AIEOP; Istituto NazionaleTumori, Milan, Italy

Ependymoma (EPD) often recurs even if completely excised. In 1994 a“stage-based” protocol for intracranial EPD was designed. All children weregiven (1) focal hyperfractionated-radiotherapy (HFRT) in case of absence ofdisease (NED) or (2) 4 monthly courses with VCR/VP16/CTX(VEC) followedby HFRT in case of residual disease (ED). Total HFRT dose delivered was70.4 Gy (1.1 Gy/fraction bi-daily) to tumor volume plus a 2 cm-margin; VECconsisted of VCR 1.5 mg/sqm d-1/w, courses one and three, VP16 100mg/sqm/d x 3 d,CTX 3 g/sqm d 1. In any treatment phase a second-looksurgery was recommended. Sixty-three consecutive children were enrolled:46 NED and 17 ED; 39 M, 24 F, median age 6 years; in 47 children tumororigin was posterior fossa and in 16 supratentorial areas; one child presentedwith a spinal metastasis. In the NED group, 31/47 have been treated withHFRT; 4 had VEC before RT, 8 RT with 1 fraction/d, and 3 no treatment, 2because of supratentorial benign EPD (local physician decision), 1 becausetoo compromised for treatment.Twelve of 46 pts have relapsed: 5 locally and7 outside RT fields; 5 died. At a median follow-up of 5 yrs, OS and PFS are81.5% and 65%, respectively. Of the 17 ED pts, 9 received VEC+HF-RTaccording to protocol; violations (because of postsurgical impairment orextensive disease) were: HF-RT(2), conventional RT(3) + VEC(2), no ther-apy(1). Objective responses (OR) to VEC were seen in 54%, PD in 1 case;OR to RT in 75%, PD in 1 pt. Eleven of 17 relapsed, 10 locally, 1 at cauda;

8 died. OS and PFS for ED group were 61% and 35%, respectively. OS andPFS for all 63 children are 75% and 55%, respectively. At univariate analy-sis residual disease, grading, age ≤ 6 yrs, infratentorial origin, and ventricu-lar shunt represent prognostic factors; at multivariate analysis residual dis-ease, grading, and age maintain significance. Nineteen of 63 pts did notreceive the scheduled treatment, the majority being too compromised bysurgery; multiple surgical acts (8) appeared less dangerous than too “heroic”d’emblée excisions impairing successive therapeutic options. Future EPDstrategies should consider also grading when stratifying treatment indications.

115. INTRINSIC BRAIN STEM TUMOR: CHANGINGSTRATEGIES, CHANGING RESULTS? Massimino M, Gandola L, Spreafico F, Navarria P, Cefalo G, Mazza E,Pignoli E, Casanova M, Ferrari A, Luksch R, Feroli P, Polastri D,Terenziani M, Fossati-Bellani F; Istituto Nazionale Tumori, Milan, IstitutoNeurologico C. Besta, Milan, Italy

Due to the known dismal prognosis of intrinsic brain stem glioma (IBSG),we adopted 3 consecutive different pilot protocols from 1987 onwards totreat 50 children. Study 1: 1987–1996, 23 patients enrolled; the schedule wasthe same used for all malignant glioma, utilizing a concomitant chemo-radio-therapy (CT-RT) program with VP16, ARA-C, IFO, CDDP, DACT (Med PedOncol, 2000, 34:147–150) + focal RT. One out of the 23 pts is alive CCR at7 yrs; median survival was 13 mos and median PFS was 7 mos, with onedeath for toxicity. Study 2: 1996–2000; 10 consecutive children were treatedwith a pre-RT sequential HD-CT, comprehending CDDP+VP16, CTX+MTX+VCR, HD-Tiothepa followed by focal RT. Nine pts died of disease andone of pneumonia at 22 mos, with 11 mos and 9 mos the median OS andPFS, respectively. This program, whose intensity was not paid back by bet-ter results, was therefore closed. Study 3: From 2000 onwards we haveadopted a combined program with CDDP (30 mg/m2) + VP16 (150 mg/m2)days 1–3 for 10 monthly courses, together with focal RT, planned after thesecond course in case of neurological stability; after each CT courseisotretinoine 50 mg/m2 bid per os on days 10–25. A total of 17 pts (8M, 9F;median age 7 yrs; median follow-up 8 mos) have been accrued so far. Twohad a biopsy-proved pilocytic astro., 6 anaplastic glioma, while in 9 the diag-nosis was made on radiological grounds. All children presented with cranialnerve palsies, accompanied by pyramidal signs in 16. Fourteen pts are evalu-able for results: 6 obtained an MRI volumetric response after RT, 5/11 couldbe completely waned from steroids, and 7/14 had symptomatic improvement.Eight have died of disease progression. OS and PFS at 1 yr are 49% and 48%,respectively. Radiologic response represented a prognostic factor both for PFS(86% vs 0%, p .0002) and for OS (86% vs 21%, p .04) at 1 yr. Radiother-apy remains the main tool in controlling symptoms and in prolonging sur-vival: current strategies should pursue the improvement of its activity.

116. INTERVERTEBRAL DISCITIS CAUSED BYPSEUDOMONAS AERUGINOSA MIMICKINGMEDULLOBLASTOMA SPINAL RECURRENCE IN A YOUNG BOYMazza E, Massimino M, Spreafico F, Gandola L, Cefalo G, Navarria P,Casanova M, Ferrari A, Luksch R, Polastri D, Terenziani M, FossatiBellani F; Pediatric and Radiotherapy Department, Istituto NazionaleTumori, Milan, Italy

We report the case of a 15-year-old boy suffering from fourth ventricledesmoplastic medulloblastoma with leptomeningeal and nodular spread toposterior fossa, cervical, and thoracic tracts of the spine (Chang classificationT3M3). Treatment consisted of subtotal resection of the primary tumor, adju-vant sequential high-dose chemotherapy, and delayed hyperfractionatedcranio-spinal radiotherapy. Two months after the end of radiotherapy, whileon maintenance vincristine/lomustine based chemotherapy, the boy developeda septic status related to Pseudomonas Aeruginosa (cultured in blood andurine samples; no abnormal findings at lumbar puncture), clinically respon-sive to netilmicin and levofloxacin. Other symptoms/signs were low backpain, 45° Lasègue, hyposthenia, and hypotropism at the four limbs. MRIshowed abnormal signal enhancement in the fourth ventricle and in thedorso-lumbar spinal tract. These pathological findings suggested medul-loblastoma recurrence, so the patient started a second-line chemotherapy reg-imen. One month later, due to a worsening of back pain, a second spine MRIwas performed that showed a spondylodiscitis of T11-T12 and L1-L2 discs.A fine-needle-aspiration biopsy at L1-L2 disc revealed the presence ofPseudomonas A. but no malignant cells. Chemotherapy was interrupted, andan intensive antibiotic therapy (ceftazidime, amikacin, and meropenem) deter-mined the resolution of the infection. Spondylodiscitis is a rare complica-tion in cancer patients, perhaps related to immunodeficient status or invasiveprocedures such as lumbar puncture. This case demonstrates that, eventhough spinal MRI can be considered a useful method in differentiatingbetween spondylodiscitis and malignancy, radiological findings may be mis-leading. In selected cases the histologic assessment is mandatory.

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117. TUMOR BIOLOGY OF PNETMacDonald, T; Department of Hematology/Oncology, Children’s NationalMedical Center, Washington, DC, USA

Primitive neuroectodermal tumors (PNET) are the most common malig-nant central nervous system neoplasm in children. Medulloblastoma, supra-tentorial PNET, and ependymoblastoma constitute this group of embryonaltumors. All share the background of an undifferentiated round-cell tumor butshow divergent patterns of differentiation. In medulloblastoma, loss of 17pdistal to TP53 and isochromosome 17q are the most common cytogeneticabnormalities. Medulloblastoma is associated with the nevoid basal cell car-cinoma syndrome, caused by a germline mutation of the Shh receptor PTCH,and Turcot syndrome, which results from mutations of APC or DNA mis-match repair genes. The desmoplastic variant of medulloblastoma accountsfor 10–20% of sporadic cases and is characterized by mutations in the PTCHpathway. Histologic features of PNET tumors do not reliably predict behav-ior; however, increased expression of the neurotrophin-3 receptor, TrkC, pos-itively correlates with survival, while increased expression of the proto-oncogene, c-myc, and the neuregulin receptors, ErbB2 and ErbB4, is associ-ated with less favorable outcome. Recently oligonucleotide microarray geneexpression studies showed that medulloblastoma is molecularly distinct fromsupratentorial PNET. Furthermore, outcome of patients with medulloblas-toma was better predicted by gene expression analysis than by clinical param-eters currently used to stratify risk. This method has also been used to iden-tify genes associated with metastasis. These studies, as well as the potentialrole of genomics and proteomics to help further define classification, prog-nosis, biology, and therapeutic targets of these tumors, will be presented indetail.

118. DIFFERENTIAL OVEREXPRESSION OF INSULIN-LIKEBINDING PROTEIN-2 IN PEDIATRIC HIGH-GRADE GLIOMASIDENTIFIED BY MICROARRAY GENE EXPRESSIONPROFILINGMacDonald T, Becher O, Khatua S, Peterson K, Lawlor C; Department ofHematology/Oncology, Children’s National Medical Center, Washington,DC, USA

Gliomas are the most common neoplasm of the central nervous systemduring childhood. Approximately 30% of these tumors are high grade, whichhave a poor prognosis. Adult glioma studies show that malignant glial trans-formation results from overexpression of growth factor receptor-mediatedpathways. Therapeutic agents that inhibit these pathways may be clinicallyuseful; yet little is known regarding the expression of these pathways in pedi-atric gliomas. We expression profiled 40 frozen pediatric gliomas (20 LGGand 20 HGG) using the Affymetrix Gene Chip U95A (12,000 gene tran-scripts). Differential expression of key genes was confirmed by immunohis-tochemistry using an independent set of 40 paraffin-embedded pediatricgliomas (20 LGG and 20 HGG). The functional role of key genes was meas-ured using bioassays of proliferation, migration, and invasion in the presenceof function-blocking antibodies to the selected gene target. Microarray analy-sis revealed that the insulin-like growth factor binding protein-2 (IGFBP2)was highly significantly overexpressed by 8.3-fold in HGG compared to LGG(p = 0.0004). Down-regulated genes included the insulin-like growth factorreceptor 1 (IGFR1) (2.5-fold, p = 0.03), insulin-like growth factor 1 (IGF-1)(4.0-fold, p = 0.006), and bFGF (1.7-fold, p = 0.02) in HGG. Interestingly,unlike adult gliomas, no significant differences in expression were observedfor EGFR, FGFR, PDGF-A, PDGFR alpha, VEGF, and VEGFR. Immuno-histochemistry correlated with array analysis. Functional bioassays showedthat IGFBP2 contributes to the invasive nature of pediatric HGG, and thatIGFBP2 exerts its function independent of the insulin-like growth factorreceptor signaling pathway. In summary, this is the first study to performglobal gene expression analysis of pediatric gliomas exclusively. IGFBP2 issignificantly overexpressed in pediatric HGG and regulates the invasivity ofHGG cells independent of IGFR. This is the first study to uncover the poten-tial role of IGFBP2 in pediatric HGG. Complete gene expression analysisfor HGG vs. LGG will be presented in detail.

119. SURVEILLANCE SCANNING FOR MEDULLOBLASTOMA:IS IT WORTH IT? A TEN-YEAR EXPERIENCE AT ALDER HEYMcDowell H, Skiming J, Pizer B, Mallucci C, Abernethy L; OncologyUnit, RLC NHS Trust, Alder Hey, Liverpool, UK

Debate surrounds the value of surveillance scanning in the follow-up ofchildren treated for medulloblastoma (MB). Current practice at Alder Heyinvolves surveillance scanning over a 36-month period after completing treat-ment. Initially, children are scanned at 3 monthly intervals during the first 24months of follow-up and then at 4–6 monthly intervals over the third year.Case notes and scan reports of all those diagnosed with MB between 1991and 2001 were reviewed. This involved 28 patients and a total of 152 sur-

veillance scans (133 MRI and 19 CT). The mean age at diagnosis was 62months, and 12 out of 28 patients are disease free at 60 months (43%). Witha median follow-up period of 27 months, 10 patients experienced recurrence,5 during treatment and 5 during the surveillance scanning period. The meantime to relapse from diagnosis was 19 months in the surveillance group.Asymptomatic relapse occurred in 3 patients and was detected on routinescanning. The other 2 relapses had clinical symptoms of vomiting and ataxia,with relapse confirmed on emergency scanning. As of January 2002, 2 ofthe 3 asymptomatic recurrences are still alive 66 months and 72 months postrelapse, respectively. Neither of those with symptomatic recurrences survived(p = 0.6). Despite the small numbers involved, our experience lends supportfor the view that earlier detection of asymptomatic recurrences carries a bet-ter prognosis compared to those that are identified as a result of new clini-cal symptoms. However, the cost-benefit issues surrounding scanning remain.At present we continue to employ surveillance scanning, together with regu-lar clinical examination in the follow-up of these patients.

120. FEASIBILITY AND UTILITY OF THE BEHAVIORALASSESSMENT SYSTEM FOR CHILDREN (BASC) AS APSYCHOSOCIAL SCREENING TOOL WITH ADOLESCENTSURVIVORS OF A CHILDHOOD BRAIN TUMORMeyer T, Carpentieri S, Delaney B, Victoria M-L, Gannon B, Doyle J,Kieran M; Department of Pediatric Oncology, Dana-Farber CancerInstitute, Boston, MA, USA

Survivors of childhood brain tumors are at risk for experiencing numer-ous adjustment difficulties. There is currently no widely accepted screeningmeasure of adjustment for these patients. Such a screening measure is essen-tial in order to proactively identify survivors who are experiencing or are atrisk for experiencing such difficulties. The investigators examined the feasi-bility and utility of using the Behavioral Assessment System for Children(BASC) as an adjustment screening measure in a large pediatric long-term fol-low-up clinic. The feasibility issues included: (a) questionnaire acceptabilityto patients, parents, and teachers; (b) time burden; and (c) patient’s ability tocomplete the measure independently. The utility issues included the BASC’sability to identify those survivors who are experiencing behavioral and/orpsychosocial difficulties. The BASC provides multiple respondent informa-tion regarding a child’s psychological adjustment: self-report, parent report,and teacher report. Each questionnaire is made up of multidimensional scalesthat measure aspects of child behavior and personality, including adaptiveand clinical dimensions in the home, school, and community settings. Thirty-two (18 male, 14 female) pediatric brain tumor survivors completed theself-report version of the BASC. Median age at assessment was 14y 3mo(range 12yr–18yr). Median time off treatment was 3 years (range 1.5 to 12years). Parent and teacher BASC questionnaires were also collected. In termsof feasibility, a clear majority of this sample of families and teachers foundcompleting the BASC to be an acceptable task, and both participation andcompletion rates were high. Seventy-eight percent of the patients in this studycompleted the BASC within 30 minutes. In terms of utility, responses wereanalyzed to assess whether the proportion of survivors receiving scores in theclinical range for each scale was significantly higher than for the normativepopulation. There were no significant elevations on any of the scales of theSelf-Report. However, on the Parent-Report, there were significant elevationson the Somatization, Attention Problems, and Leadership scales. On theTeacher-Report, there were significant elevations on the Somatization andLearning Problems scales. This pattern of significant elevations will be dis-cussed in terms of specific relevance to the pediatric brain tumor popula-tion.

121. SPINAL GROWTH AFTER WHOLE CENTRAL NERVOUSSYSTEM RADIOTHERAPYModgil R, Sugden E; Department of Radiotherapy, Churchill Hospital,Old Road, Headington, Oxford, UK

Approximately a quarter of all brain tumours in childhood are treatedwith whole central nervous system (CNS) radiotherapy. One of the major sideeffects of this treatment is a reduction in final height. Spinal growth aftercraniospinal irradiation in childhood has been poorly researched, and beforetreatment it is difficult to provide an assessment of the expected reductionin final height. The spinal growth of 13 children treated with whole CNSradiotherapy with or without adjuvant chemotherapy was analysed retro-spectively using recorded measurements of sitting height (SH) and subis-chial leg length (SLL). Using growth charts these heights were transformedinto standard deviation scores (SDS) and analysed over time post treatment.The degree of disproportion between SH and SLL was calculated by (SLL-SH) SDS. The final height was compared with expected final height cal-culated from parental height values. Complete MRI studies in 3 childrenallowed more detailed measurement of total spinal height (SPH) and seg-mental spinal height (SSPH). After treatment, SH did not increase over time

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even with the addition of growth hormone, whilst SLL did increase with time,causing disproportionate growth. The use of growth hormone (to improvefinal height) increased disproportion. The influence of age at treatment, nutri-tion, mobility, and chemotherapy were also considered, as was the psycho-logical implications of a short stature. Only 5 of the 13 children had com-pleted puberty and hence final height by the time of the study; 2 had reachedthe predicted range for final height. This work is an attempt to quantify whathas been clearly observed in the clinic setting. Craniospinal irradiation affectsspinal growth. The extra height that can be achieved with growth hormoneis at the expense of increasing disproportion.

122. ANTERIOR VISUAL PATHWAY GLIOMAS: A COMPARISON OF NONVISUAL OUTCOMES IN CHILDREN WITH AND WITHOUT NEUROFIBROMATOSISTYPE 1Newbury L, Cohen V, Morley Jacob C, Hartley L, Moore A, NicholsonJC, Williams DM; Department of Paediatric Oncology, AddenbrookesHospital, Cambridge, UK

A single-centre retrospective analysis was performed on a cohort ofpatients with anterior visual pathway, low-grade gliomas diagnosed between1981 and 2001. The tumour locations, treatment undertaken, and the sub-sequent growth, endocrine status, intellectual outcome, and mobility of thepatient were all recorded. The NF1 status of the patient was also recorded.A total of 31 patients with anterior visual pathway gliomas were studied, ofwhom 14 had systemic features of NF1. Seventeen patients were NF1 nega-tive, and 16 (94%) of these had gliomas extending outside the optic tract atpresentation. In contrast, patients with NF1 had tumour confined to the opticnerve in 7 (50%), tumour involving the chiasm 4 (29%), and extension out-side the optic tract in 3 (21%.). Sixteen out of 31 patients were treated. Fiftypercent (8 of 16) were treated for hydrocephalus with a shunt and /or surgi-cal debulking. Surgical resection was more frequently undertaken in the NF1negative patients (6 out of 7 cases). Thirty-one percent (5 out of 16) weretreated for reduced vision with radiotherapy or chemotherapy. Nineteen per-cent (3 out of 16) were treated for tumour growth with surgery or chemo-therapy. The median follow-up was 4 years and 5 months (range 3months–16 years). Only one patient died. Forty-two percent of patients (13out of 31) had impaired growth, and 10 of these required endocrine replace-ment. Only 6 had received radiotherapy. Growth was impaired in 9 out of 17patients (53%) without NF1 and in 4 out of 14 patients (28%) with NF1.Mobility was impaired in 4 out of 17 without NF1 and 2 out of 14 with NF1.Six patients had developmental delay, of whom half had NF1. In summary,patients without neurofibromatosis type 1 present with extensive chiasmalgliomas are more likely to require treatment and have a worse physical out-come. However, there was no difference between the two groups in the inci-dence of developmental delay.

123. INCIDENCE OF CHILDHOOD CNS MALIGNANTTUMORS IN THE LUBLIN REGION OF POLANDNurzynska-Flak J, Wisniewska-Slusarz H, Drabko K, Dudkiewicz E,Kowalczyk JR; Department of Hematology and Oncology, Children’sUniversity Hospital Lublin, Chodzki Street, Poland

Introduction: Tumors of the central nervous system (CNS) represent thesecond largest disease group among childhood neoplasms, accounting foraround 20% of cases in many regions of the world, especially in the devel-oped countries. These tumors appear with annual incidence of 20–30 per 1mln and are more frequent in boys, especially those under 10 years of age.The Lublin region is the southeastern part of Poland. Six percent of the wholePolish population (2.3 mln) live there. The aim of the analysis was to evalu-ate incidence of childhood CNS malignant tumors in the Lublin region.Results: During the years 1988–2000, in this area 184 cases of CNS tumorsin children 0–17 years old were reported (48.9% of them boys). These con-stituted 19.5% of all the neoplastic diseases in children of this region. Themajority of the patients lived in town areas (54.3%). The incidence of thesereported tumors was 22.5 per 1 mln. The incidence in boys was stable, whilein girls it varied significantly during the years of observation. Additionally,the incidence was stable and higher in town patients than in village ones (25.7vs. 19.7 per 1mln). After the year 1997, the incidence decreased. The meanmorbidity rate, changing in different years, ranged from 4.8 to 35.4 per 1mln. The highest morbidity was noted in the year 1992. The mean morbid-ity was lower in male than in female children (21.5 vs. 23.6 per 1 mln). Thehighest morbidity was noted in children aged 5–9 (28.1 per 1 mln) and also10–14 (26.4 per 1 mln). Conclusions: The incidence of malignant CNStumors in children in southeastern Poland is similar to the average reportedin developed countries. The higher incidence of CNS malignant tumors inpatients living in urban regions is probably caused by the concentration ofthe pollution in the environment.

124. SAFETY AND FEASIBILITY OF ACTIVEIMMUNOTHERAPY IN 6 CHILDREN WITH RECURRENTBRAIN TUMOURS USING AUTOLOGOUS DENDRITIC CELLSPULSED WITH TUMOUR-DERIVED RNA (DCRNA)Orme L, Caruso D, Gardiner A, Grapsas N, Ashley D; Department ofClinical Haematology and Oncology, Royal Children’s Hospital, Victoria,Australia

Despite combined multimodality therapy, a significant proportion of chil-dren with brain tumours succumb to their disease, and outcomes for recur-rent disease are dismal. Novel therapeutic approaches are required. The den-dritic cell (DC) network plays a quintessential role in the induction ofhumoral and cellular immunity in vivo. Active immunization using DCsprimed with tumour antigens may provide a powerful method of inducing aclinically effective, cell-mediated, antitumour immune response. This studyaims to test the safety and feasibility of active immunotherapy using autolo-gous DCs pulsed with tumour-derived RNA in patients with recurrent braintumours. Eligible patients are <25 years with recurrent brain tumours forwhich there is no effective therapy. Tumour biopsy is mandatory (minimum1g) for histology and RNA extraction. DCs are prepared by culturing leukapheresis-derived peripheral blood monocytes with GM-CSF and inter-leukin 4. Phenotype is confirmed by FACS analysis (>50% HLA-DR+ and<15% CD14+). DCs are pulsed with RNA and cryopreserved. ThawedDCRNA is administered to each patient both intradermally (ID) and intra-venously (IV) on weeks 0, 2, and 4 (dose 0.5x107 cells/m2). Three subsequentvaccination days are scheduled if treatments are well tolerated and quantityof vaccine allows. Two IV dose escalations are planned. Toxicity is monitoredaccording to the NCI Common Toxicity Criteria. The proportion of patientsfor whom adequate DCRNA (3.0x107 cells/m2) is generated from one leuka-pheresis sample determines feasibility. We present preliminary results of 6patients entered so far. Patients included 5 females and 1 male, age range 9–22years, with high-grade astrocytoma (n = 3), low-grade astrocytoma (n = 1),ependymoma (n = 1), and medulloblastoma (n = 1). Biopsy material gener-ated adequate RNA in 5 of 6 patients. All 5 patients undergoing leukapheresisgenerated sufficient DCs for vaccine preparation but not enough for doseescalation. One patient was not treated due to tumour progression. The 4remaining patients received a total of 22 vaccines (11 ID and 11 IV). Noadverse events have occurred. This study has excellent feasibility and safetyto date. Immune response data and clinical correlations are in progress.

125. WUERZBURG PSYCHOLOGICAL CONCISEDIAGNOSTICS (WUEPCD) OF MENTAL ANDSENSOMOTORIC FUNCTIONS IN CHILDREN WITH BRAIN TUMORSOttensmeier H, Kühl J; Department of Pediatrics, University ofWuerzburg, Germany

Neuropsychological investigations of children after the treatment of braintumors are necessary to evaluate the neurocognitive sequelae and to estimatethe quality of life. The results can be used for the development of risk-adaptedtherapy, in particular for young children, because of the influence of radia-tion therapy (RT) or chemotherapy (CH). Is there a chance of replacing anIQ-test-battery administration like the K-ABC, which takes more than 1 hour,by some short tests (WUEPKD) which additionally test sensory-motoric, reac-tive, and attentional functions in 45 minutes? The WUEPCD consists of theRaven’s “Coloured Progressive Matrices” (CPM-k) adaption for the meas-urement of the g-factor, a form-copying test “Developmental Test of Visual-Motor Integration” (VMI), and a sequential auditive memory task “numberrecall” (NR). Additional computerised tests are used for fine-motoric veloc-ity: rapid-tapping (RT), simple visual and auditive reaction times (Reac T vis;Reac T aud), and a multiple-choice reaction task to discriminate reaction fail-ures, Continuous Performance Test (short form) (CPT-sf). In a study theresults of a comparison of K-ABC and WUEPCD with 23 children less than3 years of age who show a medulloblastoma (MB) were analysed. A regres-sion analysis points out that nearly 74% of the full IQ of the K-ABC is pre-dicted by tests of the WUEPCD: RT, CPM-k, VMI, and Reac T (R = .859; R2

= .738). With RT, CPM-k, VMI, and Reac T vis, 80% of the skala “simulta-neous processing” of the K-ABC (R = .889; R2 = .791) is estimated in a sim-ilar way. The second major scale of the K-ABC, “sequential processing” (R=.501; R2 = .251) does not adjust like K-ABC-GD. Consequently, we added ashort test, “number recall” (NR), to get a better prediction. In summary, ina pilot study the WUEPCD can sufficiently estimate essential scales of theK-ABC in a group of children with MB. The WUEPCD allows additionalanalysis such as form reproduction, fine-motoric velocity, reactivity, andattention. The WUEPCD can be performed faster, requires no psychologistfor administration, and is useful in smaller medical centres. It is also a low-cost product. If there are impairments in the WUEPCD, a wider neuropsy-chological assessment may take place.

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126. RADICAL RESECTION OF EXOPHYTIC CHIASMIATIC-HYPOTHALAMIC GLIOMASOzek MM, Dagcinar A, Baykan N, Kurtkaya O, Pamir MN; MarmaraUniversity Medical Center, Division of Pediatric Neurosurgery,

.Istanbul,

Turkey

Optic chiasmatic-hypothalamic gliomas constitute an important subsetof optic pathway gliomas. Between the years 1994 and 2000, 32 childrenwith exophytic chiasmatic-hypothalamic gliomas underwent resection of theirtumors. Patients were evaluated in 3 groups based on age at the diagnosis: 8infants were < 1 year old, 8 children were between 1 and 5 years old, and16 were older than 5 years. There were 28 pilocytic astrocytomas and 4 low-grade astrocytomas. Six patients had neurofibromatosis. Eighteen childrenhad a pterional craniotomy. In 14 cases with a tumor predominantly in theIII.ventricle, a transcallosal approach was used. Both progression-free sur-vival and functional outcome were related to the age at the time of the diag-nosis. Four of the 5 deaths occurred in children diagnosed during infancy.In 88% of the children >5 years, a permanent remission with a mean fol-low-up of 48 months was achieved. Overall, 75% of these children have arelatively independent life with Karnofsky/Play Performance Scores of80–100. Functionally disabling visual deficits, developmental delays, or intel-lectual impairment were more common in young children. The authors con-clude that exophytic chiasmatic-hypothalamic gliomas are amenable to rad-ical resection with acceptable morbidity. Surgery may suffice as the soleprimary treatment for older children. Infants have biologically aggressivetumors in spite of benign histology and require multimodality treatment.

127. MAGNETIC RESONANCE SPECTROSCOPIC ANALYSISOF PEDIATRIC TECTAL TUMORS: INSIGHT INTOPATHOLOGY AND BEHAVIORPalasis S, Jones R, Mazewski C, Hudgins RJ, Grattan-Smith JD;Departments of Radiology, Hematology-Oncology, and Neurosurgery,Children’s Healthcare of Atlanta, Atlanta, GA, USA

Tectal tumors in children constitute a subcategory of brain stem tumorswith unique clinical, imaging, and spectroscopic features. The majority ofthese tumors are pathologically benign and show no or minimal growth. Theyare often incidentally diagnosed in the imaging workup of children withhydrocephalus. Not all tectal plate tumors, however, have this typicallybenign course. Some can manifest a more aggressive behavior. We are pre-senting 14 cases of pediatric tectal tumors, which is the largest series that hasbeen reported in the literature to date. Our population was composed of 7females and 7 males with a median age of 10 years. All cases were evaluatedwith MRI and single voxel proton MRS using both short and long TEsequences. At our institution, we have determined a metabolite pattern thatsuggests tumor grade with high accuracy. A unique spectroscopic appearancewas observed in the typical benign tectal plate glioma. The metabolite pat-tern had a typical low-grade appearance with a high choline peak, low NAApeak, normal creatine peak, no significant lactate peak, and very elevatedmyoinositol peak. The tumors with this metabolite profile remained stableon follow-up MRI and MRS studies. Two of the tumors had a differentmetabolite pattern, and these demonstrated interval growth. Our study showsthat MRS can be a useful tool in distinguishing between tectal tumors thathave the potential to act more aggressively and those that have the typicalbenign course. This new information can help guide the management andtreatment of these tumors.

128. MANAGEMENT STRATEGIES FORMEDULLOBLASTOMA/PNETPacker RJ; Children’s National Medical Center and The GeorgeWashington University, Washington, DC, USA

Treatment approaches have rapidly evolved for medulloblastoma, themost common form of childhood malignant brain tumor. Over the past twodecades, chemotherapy has been accepted as an important component ofmanagement for children with medulloblastoma, and studies have demon-strated that adjuvant therapy with drugs such as vincristine, cisplatinum, andCCNU improves survival. Despite multiple studies utilizing chemotherapybefore radiotherapy, there is no evidence that such sequencing of treatmentimproves survival and no data to show that delaying radiation therapy maybe detrimental, especially in those children with average-risk disease. In addi-tion, for those children with localized disease at the time of diagnosis, thereis suggestive evidence that the dose of craniospinal radiation therapy can bereduced from 3600 cGy to 2400 cGy, as long as adjuvant chemotherapy isgiven. Despite these improvements and refinements in treatment, many chal-lenges remain. Children, with average-risk medulloblastoma, older than 3years of age at the time of diagnosis may have an 80% or higher likelihoodof 5-year, progression-free survival; but even with reduced doses of radio-therapy, many, especially those less than 7 years of age at the time of diag-

nosis, will have significant intellectual sequelae. The potential additive effectsof chemotherapy in the causation of these sequelae has also not been fullyelucidated. For those children with disseminated disease at the time of diag-nosis or those with histologically similar tumors arising outside the posteriorfossa, conventional treatment offers possibly a 50–65% likelihood of 5-year, progression-free survival, and attempts, to date, to improve this survivalrate by the use of preradiation chemotherapy or different fractionations ofradiotherapy have failed. Studies are underway attempting to use chemo-therapy during radiation therapy or chemotherapy at high dose, with periph-eral stem cell rescue, to improve survival. The treatment of infants and veryyoung children demonstrated significant strides over this time period, andalthough a subset of patients (possibly up to 30%) can be cured with chemo-therapy alone, the majority of patients will develop progressive disease. Theuse of more aggressive chemotherapeutic regimens and earlier introductionof focused radiotherapy is being explored. Probably of more importance thanthe therapeutic alterations being made are the greater understanding of theneurobiology of medulloblastomas and other primitive neuroectodermaltumors, the separation of such tumors from other tumor types such as atyp-ical teratoid tumors, and the utilization of this information in developing newstrategies. Patient stratification remains based on clinical parameters suchas age at diagnosis, tumor extent at the time of diagnosis, and degree of resec-tion, but it will probably soon incorporate or be replaced by moleculargenetic classifications. In addition, these molecular genetic findings haveopened the possibility of new approaches for medulloblastoma, including thepotential utilization of maturation agents and drugs targeted at disruptingsignal transduction.

129. EVALUATION OF TERMINAL CARE PROTOCOL FORCHILDREN WITH BRAIN TUMORSPearson J, Nelson G, Schissel D, Foreman N, Handler M; Department ofNeuro-Oncology, The Children’s Hospital, Denver, CO, USA

Background/Problem Statement: In 1996, a Terminal Care Protocol wasimplemented to guide the staff in the education and preparation of the fam-ily caring for their child during terminal care and the dying process. The pro-tocol guided the discussion with 25 families of children who died. Purpose:The tool organizes staff to deliver terminal care preparation. It is importantto elicit feedback from parents about the effectiveness of their preparationand the impact on their child’s care in order to improve the quality of carefor future children and families. Method: A program evaluation was con-ducted using focus groups to gather feedback about care delivery. Four focusgroups were conducted between 2000 and 2002, with a total of 10 parentsparticipating. Each focus group was asked the same series of 6 questions byan experienced facilitator with bereavement skills. An assistant took notes.The facilitator and assistant were nondirect care providers. Outcome: Thefocus groups were successful in obtaining constructive feedback. Familieswere appreciative of the terminal care preparation they received. Physician“bluntness” and “honesty” made them deal with what was happening totheir child. The relationship with staff from the beginning influenced howfamilies received the terminal care information. Families liked the phonefollow-up, availability of staff pagers, home visits by staff, especially thephysician, and the Christmas cards sent annually. Initially some familiesreported being unclear which was the terminal care discussion since theyalways received “bad news.” Families needed education about adjusting dosesof morphine and midazolam via pumps to have more control of their child’spain management. Families needed more education about the dying processand coma. Home/Hospice staff needed more education about the care ofthe child dying from a brain tumor. Families expressed the loss of the rela-tionship with staff along with their child. Conclusion: The focus groupsenabled us to evaluate the effectiveness of our terminal care preparationand make changes to benefit children and families. Future directions includeincorporating the focus group into our program, assisting families with thechange in staff relationship, and developing tools for pain assessment and thedying process.

130. NEOADJUVANT CHEMOTHERAPY INMEDULLOBLASTOMAPerek D, Drogosiewicz M, Perek-Polnik M, Dembowska-Baginska B,Roszkowski M*; Department of Oncology, Children’s Memorial HealthInstitute, Warsaw, Poland; *Department of Neurosurgery, Children’sMemorial Health Institute, Warsaw, Poland

Aim: To evaluate the benefits of neoadjuvant chemotherapy in terms ofdisease control and feasibility of neurosurgical procedures in patients withlocally advanced or disseminated medulloblastoma. Materials and Methods:The study included 11 pts with posterior fossa tumor. Nine patients were T3;3 pts had M3 stage of disease at diagnosis. In case of mild ventricular dilata-tion, stereotactic biopsy was performed (3 pts). Patients with huge ventricu-lar system and tumor invading lower part of aqueduct underwent endoscopic

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biopsy (8 pts). Due to hydrocephalus, endoscopic ventriculostomy was per-formed in 4 pts. All 11 pts were diagnosed with medulloblastoma frombiopsy specimen. Chemotherapy (VCR, VP-16, CTX, CBDCA) was imple-mented. After 3 courses, surgery was performed; 1 more course of chemo-therapy was given and craniospinal irradiation implemented, followed by 8cycles of VCR, CCNU, CDDP. Results: MRI performed after preoperativechemotherapy showed PR in 7 pts, stabilization in 1, and progression in 3.Ten patients underwent surgery. Partial tumor regression did not facilitateresections. Tumor’s interface and normal brain tissue could not be clearly seenbecause it is in primarily operated tumors. One patient who did not undergosurgery due to dissemination during chemotherapy was T1 M0 at diagnosisand had endoscopic biopsy. Pathology of resected tumors did not confirmmedulloblastoma in 1 pt; ependymoma was diagnosed. No tumor cells, justnecrotic tissues were found in 1 patient. Five out of 10 patients are alive, 4in first CR and 1 with disease, follow-up 21/12–27/12. Five patients died,all from disease. Conclusions: Neoadjuvant chemotherapy, despite causingtumor shrinkage, did not facilitate resections. A transventricular endoscopicapproach can result in tumor dissemination. Small tumor tissue obtainedfrom biopsy can cause pathological misdiagnosis. Although a small groupof patients was presented, due to the issues mentioned above we would bevery cautious in recommending this method of treatment.

131. THE TREATMENT RESULTS OFMEDULLOBLASTOMA/PNET PATIENTS TREATEDACCORDING TO OUR OWN PROTOCOLPerek D, Perek-Polnik M, Drogosiewicz M, Dembowska-Baginska B,Barszcz S*; Department of Oncology, Children’s Memorial HealthInstitute, Warsaw, Poland; *Department of Neurosurgery, Children’sMemorial Health Institute, Warsaw, Poland

Aim: The aim of the study was to assess the survival of patients withmedulloblastoma (MB)/PNET treated according to our own protocol andto compare it with the historical group. Materials and Methods: Analysis of85 patients was undertaken. For the purpose of this study we divided ourpatients into 2 groups. The first group consisted of 42 pts (25 HR, 11 SR, 6unknown) treated with surgery and radiotherapy and surgery followed bychemo and radiotherapy. The second group included 43 pts (25 HRMB, 6SRMB, 11 supratentorial PNETs, 1 unknown) treated according our ownprotocol since 1997. Surgery was performed in all patients. Four courses ofchemotherapy were administered (VCR, VP, CBDCA, CTX, IF, CDDP) andcraniospinal irradiation implemented. Maintenance chemotherapy consistingof 8 courses of VCR, CDDP, CCNU was given. EFS in the two groups and inHR patients of both groups were compared. Results: In the historical group,3-yr EFS was 44% versus 77% in recently treated patients. In HR patients,3-yr EFS was 42% (with no plateau on the curve) in the historical groupand 71% in those currently treated. Conclusions: Introduction of our pro-tocol resulted in marked improvement in treatment results, especially con-sidering that most of our patients were HR.

132. TREATMENT RESULTS OF MB/PNET IN CHILDRENUNDER 3 YEARS OF AGE, TREATED ACCORDING TO OUROWN PROTOCOL IN CHILDREN’S MEMORIAL HEALTHINSTITUTEPerek-Polnik M, Drogosiewicz M, Dembowska-Baginska B, Barszcz S,*Perek D; Department of Oncology, Children’s Memorial Health Institute,Warsaw, Poland; *Department of Neurosurgery, Children’s MemorialHealth Institute, Warsaw, Poland

Aim: We assessed the results of treatment of MB/PNET in children under3 years of age treated according to own protocol consisting of surgical treat-ment and 18 months of chemotherapy with VCR, VP-16, CTX, CDDP,excluding radiotherapy in LR pts and delaying it in the HR group. In relapsecases second-line chemotherapy and radiotherapy were implemented. Sideeffects of treatment were also analyzed. Materials and Methods: Between08.96 and 08.01 we treated 21 pts, 13 boys and 9 girls, aged from 2/12 to 29/12 (median 1 10/12) with MB in 12 and supratentorial PNET in 9 cases.We divided our patients in two groups. One included 10 patients (MB-6,PNET-4) with removed tumor, no metastases; the other included 11 patients(MB-6, PNET-5) with active disease. We compared the results of treatmentof our patients with those of the historical group, treated with craniospinalirradiation in spite of young age. Results: In the whole group, 3-year EFS is50%, 5-year EFS 39%. In group I, 7 out of 10 pts are alive DF, with 3-yearEFS 71% (4/12–43/12, median 20/12), and 1 is in second CR. OS for thisgroup is 6/12–63/12. In the second group, 4 out of 11 patients are alive DF,with 3-year EFS = 20% (2/12–55/12, median 15/12), and 1 patient is in sec-ond CR. OS for this group is from 2/12–55/12. One patient with CR died oftreatment complications. In the historical group 3-year EFS = 42%. The only2 who benefited from second-line treatment were MB patients. Patients whocompleted treatment have normal psychomotor development, mild hearing

loss, and mild if any nephropathy. Those who were irradiated present withdelayed development and marked hearing impairment. Conclusions: Our pro-tocol seems to be effective, and the results of treatment are promising. Weobtained results comparable to the historical group, and we did not irradiateour patients.

133. GLIOBLASTOMA MULTIFORME IN TWO SIBLINGS: A FAMILY HISTORY OF MALIGNANCIESPerek-Polnik M, Drogosiewicz M, Dembowska-Baginska B, KurzawskiG,* Jakubowska A,* Lubinski J,* Perek D; Department of Oncology,Children’s Memorial Health Institute, Warsaw, Poland; *Department ofGenetics, Pomeranian Academy of Medicine, Szczecin, Poland

Two siblings with glioblastoma multiforme were treated in our Institu-tion. A 7-year-old girl was diagnosed with a large tumor located in the rightcerebral hemisphere. Subtotal resection of the tumor was performed, andpathology revealed glioblastoma multiforme. She received chemotherapy andradiotherapy, relapsed, and died of disease 9 mos from diagnosis of the pri-mary tumor. A year later her 8-year-old brother was diagnosed with glioblas-toma multiforme of the left cerebral hemisphere. After total tumor resectionhe received chemo and radiotherapy followed by maintenance radiotherapyand is disease free 2 years from diagnosis. Family history of cancer wasreviewed, revealing cancer in mother’s family. The mother of our pts and all(two) of her siblings died of cancer at a young age. Both of her parents alsodied of cancer. Cancers in the patients’ grandfather’s brothers from themother’s side and their children could also be established. Pathology speci-mens were retrieved from 8 deceased family members. Genetic studies as linkage analyses and sequencing of p53 gene were performed and will be presented.

134. TREATMENT RESULTS OF HIGH-GRADE GLIOMAS(HGG)Perek-Polnik M, Drogosiewicz M, Dembowska-Baginska B, DaszkiewiczP,* Perek D; Department of Oncology, Children’s Memorial HealthInstitute, Warsaw, Poland; *Department of Neurosurgery, Children’sMemorial Health Institute, Warsaw, Poland

Aim: We assessed the survival of children with HGG (AIII and GM)treated in our institution according to our own protocol and compared it withthe historical group. Materials and Methods: Between 1982 and 2001, 103pts were treated. We divided the cohort into two groups. The historical groupconsisted of 64 pts (35 A III and 29 GM). Surgery was the primary treatment.In the A III group, total or subtotal removal was performed in 24 pts, par-tial or biopsy in 11 pts. Out of 29 GM pts, 18 had total or subtotal and 11partial resections or biopsy. All patients were irradiated; no chemotherapywas given. The second group consisted of 39 pts (22 with A III and 17 withGM). All pts were treated according to our own protocol starting withsurgery. In the A III group, 11 pts had subtotal or total resections and 11 ptshad partial or biopsy. In the GM group, 9 pts underwent subtotal or totalresections, in 8 partial or biopsy. Surgery was followed by 4 courses ofchemotherapy with VCR, VP-16, CTX, CBDCA until December 1997 andthen changed to VP-16, ADM, IF. All patients had irradiation to the tumorbed and 8 courses of chemotherapy (VCR, CCNU, CDDP). Results: In thehistorical group 5-yr EFS is 28% compared to 32% in current with OS of29% and 49%, respectively. According to histology subtypes, 5-yr EFS for AIII patients is 34% for the historical group and 36% for the current group,and for GM 18% and 32%, respectively (p< 0.05). Conclusions: Treatmentresults in HGG remain unsatisfactory. Treatment results of AIII are compa-rable in both groups, but there were more patients with radical resections inthe historical groups. Introduction of chemotherapy in our protocol improvedEFS in patients with GM.

135. LOW-GRADE ASTROCYTOMA (LGA) OF THE OPTICCHIASM AND HYPOTHALAMUS (OCH): WHAT DOESCHEMOTHERAPY (CT) ACHIEVE?Perilongo G; Division of Hematology-Oncology, Neuro-oncologyProgram, Department of Pediatrics, University Hospital of Padua, Padua,Italy

The first report on the use of CT for childhood OCH LGA, describing along-lasting stable disease (SD) to vincristine (VCR) alone on a radioresistanttumor, dates from 1976 (Rosenstock C). A critical reappraisal of the experi-ence accumulated in the 26 years since is proposed. Therapy refinements inLGA did not progress through classical phase II/III studies. Comparisonsbetween old and recent studies are difficult. However, lessons have beenlearned, old problems better defined, new ones identified. We have learned

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that LGA are chemo-treatable/sensible neoplasms, regardless of the primarytumor site. CT allows temporary disease stabilization, reducing in some casesthe actual tumor volume, relieving symptoms/signs (eg, diencephalic syn-drome), and deferring the use of radiotherapy in a developing brain. VCR,carboplatin (CARBO), etoposide (VP16), cyclophosphamide, and morerecently temozolomide are the drugs tested alone in rather small phase II studies. VCR/Actinomycin-D, VCR/CARBO, CARBO/VP16, VP16/VCR, cisplatin/VP16, cisplatin/VCR, Tamoxifen/CARBO, and nitrosourea-basedmultiagent CT are the drug cocktails proven effective. Objective tumor vol-ume reduction rates vary from 33% to 42% and from 70% to 100% if SDsare also included. The 3-year progression-free survival (PFS) ranged from30% to 70%. Considering that no convincing plateau is seen in any of thecurves, the long-term PFS of the CT-treated population needs to be deter-mined. The better-defined problems can be summarized as follow. First, chil-dren bearing OCH LGA represent a heterogeneous group of patients by (i)clinical characteristics (age, NF-status); (ii) macroscopic/neuroradiologicappearance (dimension, structures involved/resectability, exophytic/cysticcomponent, distant spread, possibly MRS characteristics); and (iii) micro-scopic and biologic tumor profile (eg, monomorphous pilomyxoid LGA;Ki67-LI). Thus, the issue of assigning children to different risk groups andconsequently of treatment stratification has emerged. Second, comprehensiveways of evaluating the effects of treatment for these children, most of whomare expected to be long-term survivors, are needed. Health status (HS includ-ing visual, endocrinologic, neuro-cognitive/psychological function as well assystemic late effects of CT) and HS-related quality of life are end points thathave only recently been investigated. Third, most of these children deservecomprehensive, long-lasting treatment delivered by expert, multidiscipli-nary teams. The emerging problems relate to the need for (i) further refiningthe “old” CT in term of indications (older children also?), drug combinations,scheduling, and treatment duration, (ii) looking for novel agents, and (iii)strengthening international cooperation.

136. LOW-GRADE OLIGODENDROGLIOMA IN CHILDHOODPeters O,1 Gnekow AK,2 Rating D,3 Hauch H,1 Kühl J,4 Wolff JEA1;Departments of Paediatric Oncology and Haematology, 1Regensburg,2Augsburg, 3Heidelberg, and 4Würzburg; St. Hedwig Hospital,Steinmetzstrasse 1-3, 93049 Regensburg, Germany

Background: Pure oligodendrogliomas represent only 0.7–1.1% of allintracranial neoplasms in childhood. Most of them are of low-grade histol-ogy (92%) and supratentorial location (90%). Treatment recommendationsfollow guidelines of childhood low-grade astrocytomas or adult oligoden-drogliomas: Complete tumour resection is felt to provide the best opportu-nity for long-term survival, while irradiation and chemotherapy are still con-sidered controversial in children. Methods: In order to evaluate the relevanceof complete resection in paediatric oligodendrogliomas, we pooled data fromtwo prospective multicentre studies (HIT-DOC and HIT-LGG) performedin the German-speaking group (GPOH). Eligibility criteria were (1) primarymalignant disease, (2) pure oligodendroglioma (excluding mixed oligoastro-cytoma), (3) WHO grade II, (4) intracranial location (excluding spinaltumours), (5) age: < 18 years, and (6) date of diagnosis 1990 to 2000. Results:Data from 31 patients were found (12 female, age at diagnosis 0.6 to 16.4years, median 10.8 years). Tumour locations included 25 cerebral cortex/cerebellum (22 cerebral hemispheres, 3 cerebellum) and 6 brain stem/basalganglia (5 diencephalon, 1 mesencephalon). Surgery was classified as com-plete resection in 19, and less than complete in 12 patients (subtotal resec-tion: 3, partial resection: 6, and biopsy: 3). The 5-year event-free survival(EFS) of all patients was 81%; the 5-year overall survival was 87%. All ofthe 25 children with tumours of the cerebral hemisphere/cerebellum werealive and progression-free. All children with brain stem/basal ganglia tumoursexperienced progressive disease (1 to 3 times) regardless of whether adjuvanttreatment was applied. Four of 6 patients of this group died of disease witha median time to death of 3.58 years (range 0.92 to 3.67). The survival dif-ference between those two groups of tumour locations was statistically signi-ficant (p<0.05 log-rank test) regardless of whether EFS or OS was used foranalysis. There was no significant survival difference between complete resec-tion versus incomplete resection. Conclusion: We conclude that the outcomeof children with low-grade oligodendrogliomas of the basal ganglia/brainstem is particularly poor, independent of the result of tumour resection, whiletumours of the cerebral hemisphere/cerebellum offer an excellent prognosis,even with incomplete tumour resection.

137. EPENDYMOMA IN CHILDHOODPierre-Kahn A, van Veelen M-L, Sainte Rose C, Zerah M; Department ofPediatric Neurosurgery, Hôpital Necker Enfants Malades, Paris, France

To determine prognostic factors in intracranial ependymomas, wereviewed the charts of the 83 children treated in our Institute from 1980 to1998 for such a tumor (38 females, 45 males; median age 4 years, 53% less

than 3 years). Histological diagnoses were reviewed according to WHO clas-sification, and ependymoblastomas were excluded. Malignant tumors werepredominant (76%). Sixty-five tumors were infratentorial (78%) and 18supratentorial (22%). The tumor resection was “gross total” in 60 cases(73%), incomplete in 21 (25%), and limited to a biopsy in 2. The peri-oper-ative mortality was 7.2% for the whole series, but limited to 1 (2.5%) after1990. Air embolism, tumor bleeding, and cardiovascular instability wereresponsible for 4 peri-operative deaths and 7 incomplete removals. Two otherpatients died of medical complications within the first postoperative month.Fifteen patients suffer from permanent neurological deficits, mainly cranialnerve palsies, but only 1 remains severely disabled. Two patients died within6 months of surgery. Complications, more frequent after gross total (43%)than after incomplete resections (25%), were noted in 30% of the childrenwith a normal academic level, 60% of those with a delayed school perfor-mance, and 75% of the institutionalized children. Before 1990, 67% of thechildren were irradiated postoperatively, and 22% were given chemotherapyalone. After 1990, these figures were, respectively, 38% and 51%. Chemo-therapy was mostly BBSFOP (89%). Before 1990, 19 patients had a cranio-spinal irradiation. After 1990, irradiation was directed only to the tumor bed.The mean and median follow-up were, respectively, 70 and 59 months.Recurrence or metastasis developed in 40 patients (52%) with a median delayof 27 months (1 to 211 months). Twenty-eight patients were reoperated onfor local recurrence, 12 more than once. The median survival time was 145months for the whole group, and 50 months after recurrence or metastasis.Multivariate analysis identified “total” removal and radiotherapy as positiveprognostic factors. The 5-year event-free survival rate was 53% after “total”removal and 33% after incomplete resection. It was >60% after radiother-apy, compared to 33% in the chemotherapy group.

138. RENAL FAILURE AND HYPERTENSION ARE MAINLYASSOCIATED WITH CISPLATIN TREATMENT IN BRAINTUMOR PATIENTS DIAGNOSED IN CHILDHOODPietilä S, Ala-Houhala M, Lenko HL, Harmoinen A, Turjanmaa V,Haapasalo H, Mäkipernaa A; Department of Paediatrics, TampereUniversity Hospital, Tampere, Finland

Objectives. To evaluate the renal consequences of the treatment of braintumor patients diagnosed in childhood and especially those treated with cis-platin. Patients: One hundred four primary brain tumor patients diagnosedbefore 17 years of age from 1983 to 1997 have been treated at Tampere Uni-versity Hospital, Finland. Of the 80 survivors, 52 participated in the study atthe median age of 14.4 years (range 3.8–28.7) and median 6.0 years (range1.2–14.8) after last treatment. Seventeen of the participants were treated withchemotherapy; 14 of them received a regimen including cisplatin. In 7 of 20irradiated subjects, radiotherapy reached renal level. Methods were the meas-urement of blood pressure by an oscillometric method and evaluation ofglomerular and tubular function by measuring the blood levels of, eg, crea-tinine, cystatin C, uric acid, magnesium, and phosphate, and urine levels of,eg, alpha-1-microglobulin. Glomerular filtration rate (GFR) was determinedby plasma clearance of Cr-EDTA. Results: Eight patients (15.4%) had hyper-tensive blood pressure, and antihypertensive medication was later started tothree patients. Radiotherapy, cisplatin treatment, and renal failure increasedthe risk of hypertension. Spinal radiation did not increase the risk of hyper-tension. Four of the 14 patients in the cisplatin group had renal failure (GFR<87 ml/min/1.73 m2). The cumulative dose of cisplatin (mg/m2) seemed tocorrelate with the renal effects, but a great deal of individual variation inthe cisplatin nephrotoxicity was seen. GFR did not decrease in most of thepatients during the years following therapy. Ten of 14 subjects had hypo-magnesemia (p<0.001), indicating tubular dysfunction. One patient hadsevere symptomatic hypomagnesemia. Other signs of tubular dysfunction(low plasma phosphate (p = 0.016) and potassium (p = 0.026), hyperuricemia(p = 0.114), metabolic alkalosis (p = 0.071), and tubular proteinuria (p =0.055) were also more common in the cisplatin group. Spinal radiation didnot increase the risk of abnormal renal function tests. Conclusions: A ten-dency toward hypertension and renal failure, as well as the signs of tubulardysfunction in brain tumor patients diagnosed in childhood, are mainly asso-ciated with cisplatin treatment. Special follow-up for these patients is needed.

139. INTEREST OF COMBINING POSITRON EMISSIONTOMOGRAPHY AND MAGNETIC RESONANCE IMAGING IN THE PLANNING OF STEREOTACTIC BRAIN BIOPSIES IN CHILDRENPirotte B, Goldman S, Van Bogaert P, Levivier M, Salzberg S, Brotchi J;Department of Neurosurgery, Erasme Hospital, Free University ofBrussels, Brussels, Belgium

Because brain tumors are histologically heterogeneous, stereotactic brainbiopsies (SBB) may lead to inaccurate diagnosis/grading. We developed a tech-nique allowing routine integration of positron emission tomography (PET)

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data into the planning of SBB (Neurosurgery 31:792–797, 1992). The com-bination of PET and magnetic resonance (MR) in the planning of SBBincreased the technique’s diagnostic yield in adults (J Neurosurg 82:445–452,1995). We report our preliminary experience applied to children. Since 1996,212 newly diagnosed pediatric brain tumors were treated in our department.Thirty-two were surgically unresectable and required a stereotactic brainbiopsy for histological confirmation of the diagnosis. In 20 of them, a targetwas easily defined on MR images, and 2 serial trajectories were performedwhenever possible. The other 12 children (7M/5F, aged 2–14y) had infiltra-tive, ill-defined brain lesions located in highly functional areas (4 brain stem,5 supratentorial-hemispheric, 2 pineal, 1 suprachiasmatic) where MR imagesalone could not easily define representative multiple targets for biopsy. Theywere biopsied using a combination of stereotactic PET (Fluorodeoxyglucosein 4; Fluorodeoxyglucose and Methionine in 6; Methionine in 2) and MR.This technique was analysed in view of routine prospective application. Thistechnique allowed us to (1) obtain histological diagnosis in all patients; (2)reduce the number of trajectories in highly functional brain areas (4 brainstem and 2 pineal tumors); (3) select targets in hypermetabolic tumoral areas(5 supratentorial-hemispheric tumors); (4) allow 4 PET-guided resections afterthe biopsy procedure; and (5) exclude malignancy by guiding biopsy to anhypermetabolic area in a suprachiasmatic lesion. This preliminary seriesshows that this technique (1) is applicable to children; (2) renders a high diag-nostic yield in infiltrative, ill-defined tumours; and (3) allows us to reduce thenumber of trajectories in highly functional brain areas.

140. PSEUDO-TUMOR CEREBRI DUE TO A CAPILLARYHEMANGIOMA OF THE SUPERIOR SAGITTAL SINUS IN A CHILD: CASE REPORTPirotte B, Salmon I, Balériaux D, Rodesch G, Brotchi J; Department ofNeurosurgery, Hôpital Erasme, Free University of Brussels, Brussels,Belgium

The so-called Pseudo-Tumor Cerebri (PTC) syndrome may have variouscauses not easy to identify. We present a case due to a compression of thesuperior sagittal sinus (SSS) by an intracranial capillary hemangioma (CH).This 10-year-old girl suffered from slowly progressive headaches. Fundoscopyrevealed bilateral papilledema. First brain magnetic resonance (MR) imagingincluding gadolinium injections revealed neither intracranial lesion nor hydro-cephalus. Cellularity and proteins in the cerebro-spinal fluid (CSF) were nor-mal. Lumbar intrathecal pressure recorded in lying position rose to 50 cm.Based on the diagnosis of idiopathic PTC, the patient was treated for 12months with oral Acetazolamide° (250mg/day) and weekly LP that tran-siently reduced symptoms. In our department, examination of MR imagesindividualized abnormal narrowing of the SSS in its parieto-occipital portion.Multiplanar MR/angio-MR imaging and selective angiography showed a contrast-enhanced extradural 3cm lesion reducing the SSS lumen. A secondlesion was suspected near the straight sinus. Physical examination was nor-mal. Differential diagnosis included SSS thrombosis, giant arachnoid granu-lations, meningiomas, metastases, and vascular tumors. Diagnosis of PTCdue to venous impairment was raised. A soft tumor compressing/infiltratingthe right wall of the SSS was subtotally removed. The SSS lumen wasreopened. Symptoms and fundoscopic signs disappeared. Histopathologyrevealed a benign CH. MR imaging showed a stable (1-year follow-up) rem-nant in the patent SSS; the straight sinus went back to normal shape. CHare commonly found on mucosae and skin, rarely in the retina. Spinalintradural extramedullary CH are reported. Contrast-enhancing intracranialmeningeal-based masses can be found with extracranial CH. As mostextracranial CH regress spontaneously, a conservative approach is recom-mended for presumed intracranial CH. Surgery should be avoided unlesstumor growth is demonstrated. Here, no extracranial CH was found, and thesuspected second lesion appeared to be a straight sinus loop probably dueto raised venous pressure. The clinical improvement demonstrated a rela-tionship between intracranial hypertension and SSS compression. Tumoralobstacle to the venous circulation should be included in the differential diag-nosis of the so-called PTC syndrome. A direct surgical approach may nor-malize the venous circulation and avoid permanent CSF shunting.

141. INTRACRANIAL EPENDYMOMAS IN CHILDHOOD: A COMBINED SERIESPirotte B,1 Van Calenbergh F,2 Brotchi J,1 Plets Ch2; Departments ofNeurosurgery, 1Hôpital Erasme, Free University of Brussels, Brussels, and2U.Z. Gasthuisberg, Catholic University of Leuven, Leuven, Belgium

Intracranial ependymomas are relatively rare tumors in childhood, con-stituting somewhat less than 5% of intracranial tumors. Because of this lowincidence, we decided to analyse the series from our two centers together. Inthe literature, some prognostic factors have been described, but there is noconsensus about management, especially concerning the need for adjuvanttherapy following complete resection, and also about management in case of

tumor recurrence. We identified 38 children (26 infratentorial, 12 supraten-torial) in the period from 1982 to 1999. The files were retrospectively stud-ied after we had reached a consensus about terminology, criteria, prognosticfactors, and outcome parameters. A complete resection was possible in 28tumors: 17/26 infratentorial, 11/12 supratentorial. There was no surgicalmortality, and the morbidity was as described in other series (1 case ofmutism, 1 hemiparesis, 1 cranial nerve deficit). Incomplete resection was usu-ally the result of brain stem invasion. Adjuvant treatment varied, dependingon age, local policy in the two centers over this 18-year period, and chemo-therapy study protocols. After an average follow-up of 5 years, the outcomewas: good in 22, moderate disability in 5, dead in 11 (all because of the dis-ease). Of the living patients, 23 were in complete remission, 3 in stable dis-ease, 1 in progressive disease. In 19 patients, tumor relapse occurred. In 6/7supratentorial cases, a second surgery was performed, with good results in 5.In the 12 infratentorial cases, surgery was possible only in 5: in the others thedisease had spread diffusely (cisterns, spinal cord, even supratentorial). Theprognostic value of cerebro-spinal fluid analysis, spinal magnetic resonanceimaging at diagnosis, completeness of resection, and adjuvant treatmentwill be presented. For rare tumors, like ependymomas, evidence-based guide-lines will not easily be made, since these require very large international mul-ticenter trials. Information exceeding that of a single-center experience canbe obtained from the combined analysis of the data from different hospi-tals.

142. PROGNOSTIC HETEROGENEITY OF INTRACRANIALJUVENILE PILOCYTIC ASTROCYTOMASPirotte B, Lubansu A, David Ph, Van Bogaert P, Dain E, Lipszyk M,Brotchi J; Department of Neurosurgery, ERASME Hospital, FreeUniversity of Brussels, Brussels, Belgium

Pilocytic astrocytomas (PAs) are defined as grade 1 tumors and presentas indolent or slowly growing neoplasms. Secondary malignancy or seedingis rarely reported, mainly in adults. We observed that a significant propor-tion of juvenile intracranial PAs presented with aggressive evolution. Since1990, we operated on 32 children (14 girls/18 boys, mean age 7.7 years) withintracranial PA: 16 infratentorial (9 cerebellar, 7 brain stem), 16 supratento-rial (7optochiasmatic, 9 thalamic/hemispheric). Treatment combined surgery(total removal (TR) 13, partial (PR) 11, biopsy 8) with chemotherapy, radio-therapy, or radiosurgery. We retrospectively analysed clinical symptoms, diag-nostic presentation on magnetic resonance imaging (MRI), and postopera-tive outcome (follow-up/survival (months), tumour progression (TP),secondary lesion/malignancy). All PAs appeared as well-delineated lesions onMRI (gadolinium-enhancement in 29). Postoperative outcome was excel-lent (6–120 months) in 21 children (11 without recurrence after TR, 10 with-out TP after PR/biopsy). Ten children had unexpected presentation/evolution(8 supratentorial, 2 infratentorial): (a) Seven children showed significant TP(MR follow-up: 12–37 months) after PR/biopsy (n = 5) or progressing recur-rence after TR (n = 2). In this group, 4 children developed a secondaryintracranial lesion respectively 12, 24, 24, and 36 months after initial treat-ment. Three of them were operated on: 2 remained histologically benign(grade 1), 1 had become anaplastic (grade 3) and died 3 months later. (b)Three children presented an aggressive TP: 1 of them presented with intracra-nial multiple lesions at diagnosis and showed an early rapid TP after surgery;1 child developed multiple intracranial metastases associated with a rapid TP8 months after initial surgery; another died 6 months after initial treatmentfrom rapid TP after PR. Two reoperations confirmed the remaining grade 1histology. In these last 2 children, rapid TP presented on MRI as a multicys-tic focus in the center of the initial lesion. At reoperation, both lesions (ini-tial lesion and newly formed focus) remained histologically grade 1. No cor-relation was found between histology, radiological presentation/therapyapplied, and outcome. Aggressive evolution of PAs could be more frequentthan reported. Moreover, prognostic parameters should be found to differ-entiate subtypes of PAs and adapt the therapeutic guidelines.

143. ANALYSIS OF PATIENTS WITH SUPRATENTORIAL PNET(STPNET) ENTERED INTO THE SIOP PNET III TRIALPizer B, Taylor R, Weston C, Robinson K, Ellison D, Saran F, Ironside J,Lashford L, Bailey C; Department of Paediatric Oncology, Alder HeyHospital, Liverpool, UK, on behalf of the UKCCSG Brain Tumour Group

Introduction: The PNET III trial (1991 to 2000) examined the benefit ofpre-irradiation chemotherapy (CT) with carboplatin, cyclophosphamide,etoposide, and vincristine in children with PNETs aged at least 3 years.Patients were randomised to receive “sandwich” chemotherapy prior toradiotherapy (RT) or RT alone. RT consisted of a 35 Gy craniospinal com-ponent with a tumour boost of 20 Gy. Patients and Methods: There were atotal of 65 patients with an institutional diagnosis of StPNET (37 males and28 females). Median age at diagnosis was 6.6 years (range = 3.0–16.6 years).Only 12 children were randomised, and for this analysis randomised and non-

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randomised patients were considered together. Results: Median follow-up is4.7 years (range 0.2–8.7 years). Forty-one patients received sandwich CT, and24 received RT alone. Fourteen patients had M0 disease and 38 patientsM0/1 disease (CSF not analysed, spinal MRI negative). Ten patients haddefinite evidence of metastatic disease. For all patients, overall survival (OS)is 53.9% at 3 years and 51.9% at 5 years. Event-free survival (EFS) is 49.8%at 3 years and 45.7% at 5 years. Of 32 relapses, most occurred locally (localalone = 23, local + metastatic = 2, metastatic alone = 7). There was no signi-ficant difference in either OS or EFS whether or not the patients received pre-irradiation CT. Likewise there was no difference in OS or EFS according togender, age, extent of tumour resection, M-status, residual tumour postsurgery, time to RT, or duration of RT. The only significant prognostic vari-able was tumour site. The 14 patients with pineal tumours had a better OS(p = 0.054) and EFS (p = 0.016) than 51 patients with nonpineal sites (pineal5-year OS and EFS = 75.7%; nonpineal OS 45.1%, EFS 37.2%). Conclusion:This is the largest cohort of children with StPNETs yet reported. As opposedto medulloblastoma patients in this trial, there was no improved EFS forpatients receiving sandwich chemotherapy. This study confirms the improvedsurvival of pineal tumours as opposed to nonpineal tumours. The prognosisfor nonpineal StPNETs remains poor. Further ways of increasing survival,particularly by improved local control, may include the use of altered radio-therapy schedules and high-dose CT.

144. MOLECULAR AND BIOLOGICAL MARKERS OFPROGNOSIS IN CHILDHOOD MALIGNANT GLIOMASPollack I; Children’s Hospital of Pittsburgh, PA, USA

Background: The prognosis of children with high-grade gliomas is onlypartially accounted for by known clinical and histologic factors. In previousstudies of an institutional cohort, we found a strong association betweenprognosis and both p53 alterations and proliferation indices. These obser-vations formed the basis for the current study, which examined the prog-nostic relevance of these and other factors in the multi-institutional cohort ofChildren’s Cancer Group study CCG-945, the largest group of children withhigh-grade gliomas analyzed to date. Methods: One hundred thirty-threetumors had sufficient tissue for proliferation index assessment, microdissec-tion-based TP53 genotyping analysis was feasible in 121, and p53 immuno-histochemical analysis was accomplished in 115. For TP53 genotyping stud-ies, topographic targets that contained malignant glioma were isolated bymicrodissection and subjected to polymerase chain reaction (PCR)-basedamplification and sequencing of TP53 exons 5 to 8. Immunohistochemicalanalysis for p53 expression incorporated a microwave antigen enhancementtechnique with an antibody that recognized wild-type and mutant p53. MIB-1 labeling was performed in a similar fashion, and indices were calcu-lated by percent labeling in approximately 2000 cells. Results: A significantassociation was apparent between p53 overexpression and outcome. Five-year progression-free survival was 44 + 6 percent in 74 tumors with lowlevels of p53 expression versus 17 + 6 percent in 41 tumors with p53 over-expression (p<0.001). A weaker association was observed between TP53mutations and outcome, although a strong interaction between age and fre-quency of p53 mutations was noted. The association between p53 overex-pression and adverse outcome was apparent even after stratifying for histo-logic subgrouping (eg, anaplastic astrocytoma or glioblastoma multiforme, p= 0.005), as well as age, extent of resection, and tumor location (p<0.001).A similarly strong association was observed between MIB-1 labeling and out-come. Five-year event-free survival was 44% + 6% among 71 tumors withMIB-1 indices < 18%, 30% + 8% in 33 tumors with indices between 18and 36%, and 10% + 6% in 29 with indices > 36% (P<0.0001). Prognosticvalue transcended histologic subgroups (P<0.0001) and was apparent intumors classified as anaplastic astrocytoma (AA) (p = 0.002) and glioblas-toma multiforme (GBM) (p = 0.002), notwithstanding the independent asso-ciation between MIB-1 labeling index and histologic diagnosis (18.2 + 2.36for AA versus 29.2 + 2.82 for GBM, p = 0.004). Conclusions: P53 alterationsare common in childhood malignant gliomas and are strongly associated withan adverse outcome, independent of other previously reported clinical prog-nostic factors. Elevated MIB-1 labeling is also strongly associated with anadverse prognosis. These results indicate that molecular and biological mark-ers may supplement routine histological evaluation as a way to refine prog-nostic stratification for children with malignant gliomas. Analysis of the prog-nostic utility of an extended panel of genotypic and biological targets is inprogress.

145. SYNCHRONOUS POSTERIOR FOSSAMEDULLOBLASTOMA AND INTRADURAL TERATOMA IN A 5-YEAR-OLD FEMALEPuccetti D, Osenga K, Schloegel D; Department of Pediatric Oncology,University of Wisconsin Children’s Hospital, Highland Avenue, Madison,WI, USA

Spinal cord teratomas are rare tumors of questionable pathogenesis,while medulloblastomas are the most frequent high-grade brain tumor in thepediatric population. The case of a young female with synchronous medul-loblastoma and intradural spinal teratoma is presented. No such cases havebeen reported in the literature to our knowledge. This child presented witha one-month history of headaches. Brain MRI at that time demonstrated aposterior fossa mass that proved to be medulloblastoma following gross totalresection. CSF cytology performed 10 days postoperatively was negative. Afollow-up craniospinal MR scan with contrast was performed 13 days post-operatively and revealed nonspecific enhancement in the operative field and no evidence of cervical, thoracic, or lumbar spread. A mass with cysticand solid components was also noted in the spinal canal at the level of S1 andextended superiorly to the tip of the spinal canal. A sacral laminectomy wasperformed, and the mass was subtotally resected with sacrifice of the S3 nerverootlet. Pathology of this lesion revealed a teratoma. The patient was placedon the CCG 9961 protocol and received chemotherapy and craniospinal irra-diation. While medulloblastomas are the most common high-grade braintumor in children, spinal cord teratomas, which are often benign, are rareand of uncertain pathogenesis. Medulloblastoma has been described inpatients with other primary malignancies, such as osteosarcoma and imma-ture teratoma of the ovary, especially with the increasing long-term survivalin pediatric cancer patients. However, these tumors are often metachronousand not synchronous in time. To our knowledge, this is the first report ofmedulloblastoma synchronous with an intradural spinal teratoma.

146. FALSE-POSITIVE SURVEILLANCE MR IMAGES IN A YOUNG MALE WITH MEDULLOBLASTOMAPuccetti D, Iskandar B, Osenga K, Schloegel D; Department of PediatricOncology, University of Wisconsin Children’s Hospital, Highland Avenue,Madison, WI, USA

Surveillance scanning for pediatric patients with central nervous systemtumors with gadolinium enhanced MR images has become the standard oftreatment. However, as the sensitivity of imaging procedures has increased,the possibility of false-positive images of presumed recurrence has alsoincreased. The literature is replete with the well-known difficulties in distin-guishing residual/recurrent tumor from postoperative enhancement. Nor-mally, postoperative MRI findings due to inflammatory changes can beexpected to be stable or improve over the course of several months. New orincreased enhancement occurring on surveillance scanning is often thoughtto be disease progression, but may in fact represent a nonneoplastic process.A 3-year-old male presented with a 2-week history of headache and laterdeveloped nausea and vomiting unrelated to meals. He subsequently under-went a near total gross resection of a posterior fossa medulloblastoma fol-lowed by craniospinal irradiation with a posterior fossa boost. He was alsotreated for extensive craniospinal disease with etoposide, vincristine, cis-platinum, and cyclophosphamide. The patient did well, with no radiographicevidence of recurrence on follow-up craniospinal MRI scanning at recom-mended intervals until 39 months post diagnosis, when increased pial anddural enhancement developed in the region of the conus. Along with the newradiographic findings were the development of bilateral clonus and briskerdeep tendon reflexes. CSF at that time was negative for malignant cells. AnL1 laminectomy with conus biopsy was performed to reveal fibrosis and norecurrent tumor. It is known that recurrence enhances, but also that cran-iospinal tissue and leptomeninges may also enhance due to previous irradia-tion, gliosis, irritation from subarachnoid blood, or prior craniospinalsurgery. In this case surgical intervention and definitive histology avertedthe initiation of new, unwarranted therapies. This report accentuates the needfor an attempt at histologic proof of recurrence prior to instituting new,potentially toxic salvage therapies.

147. RAPIDLY GROWING EMBRYONAL CARCINOMAARISING IN THE MESENCEPHALON OF A YOUNG CHILD: A CASE REPORTPuccetti D, Nguyen PH, Salamet S, Iskandar B, Norton L; Departments of Pediatric Hematology/Oncology, Pediatric Neurological Surgery, andNeuropathology, University of Wisconsin Children’s Hospital, HighlandAvenue, Madison, WI, USA

Intracranial germ cell tumors are rare. Review of the literature revealsthat these tumors have a high predilection for children and young adults, andthe majority of these tumors tend to occur in the supratentorial compartment

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and infrequently in the infratentorial compartment. We report a rare occur-rence of an embryonal carcinoma arising in the mesencephalon, causing con-stitutional signs and symptoms with lower cranial nerve dysfunctions. A 12-month-old infant presented with a droopy right eyelid of 1-week dura-tion. Prior to this, the patient was reported to be a healthy child with normaldevelopmental milestones and neurological function. Detailed cranial nerveexamination was positive for a right third cranial nerve palsy. The rest ofthe neurological evaluation was normal. A brain MRI demonstrated the pres-ence of an expansile mass involving and occupying the right side of the mid-brain. The initial differential diagnosis included a low-grade glioma, or lesslikely a PNET. Because of the critical location of the mass, we did not rec-ommend any immediate surgical intervention. The patient was being moni-tored clinically, and serial MRIs of the head had been scheduled to followtumor growth. Two months after the diagnosis, the patient’s neurological sta-tus was found to be rapidly deteriorating. Repeat MRI of the head showeda drastic increase in the lesion size. The patient subsequently underwent asubtemporal craniotomy for confirmatory tumor biopsy. Histologically, thetissue had occasional epithelial cells that stained immunohistochemically pos-itive for cytokeratin. The final diagnosis was consistent with an embryonalcarcinoma. The tumor grew rapidly, eventually leading to the patient’s deathdespite optimal therapy. Intracranial germ cell tumors are rare, and theembryonal carcinoma subtype makes up less than 5% of all germ cell tumors.Frequently, neoplastic lesions involving the brain stem are grouped or labeledas low-grade gliomas without positive histological confirmation. This caseconstitutes an occurrence of a rare embryonal carcinoma involving the brainstem. Because the prognosis and therapeutic interventions can vary greatlywith different tumor pathology, it is important that germ cell tumor be con-sidered as part of the differential diagnosis of mass lesions involving the brainstem in children and young adults.

148. CAN WE IMPROVE THE COLLECTION OF BRAINTUMOUR TISSUE FOR BIOLOGICAL STUDIES? A UKCHILDREN’S CANCER STUDY GROUP (UKCCSG) SURVEYPunt J, Grundy R, Walker D, on behalf of the UKCCSG Brain TumourBiological Studies Committee; Children’s Brain Tumour Research Centre,Academic Department of Child Health, School of Human Development,University of Nottingham, Nottingham, UK

This study reports the findings of a postal survey of UK neurosurgeonswith a declared interest in children’s neurosurgery. Thirty-eight consultantneurosurgeons working in 22 neurosurgical units in all 4 countries of the UKwere sent closed question questionnaires; 27 neurosurgeons at 17 unitsresponded. Five surgeons had exclusively paediatric practices. All 27 surgeonsentered children into national or international clinical trials of brain tumourtherapy. Only 11 surgeons entered adults into trials. Twenty-one surgeonswere aware of the existence of the biological studies group of the UK Chil-dren’s Cancer Study Group (UKCCSG). Although 19 surgeons stated a spe-cial research interest in neuro-oncology, only 6 were personally involved inbiological studies; only 1 of these concerned UKCCSG. Twenty-three sur-geons always discussed elective tumour cases with a paediatric oncologist pre-operatively; 16 had a paediatric oncologist on site. Twenty-six surgeonsemployed intra-operative histology; 24 gave the histopathologist advancewarning and had histopathology on the same site. Twenty-six surgeons sentthe maximum feasible volume of excised tumour tissue to the histopathologylaboratory as fresh unfixed tissue. Nineteen surgeons thought that informedconsent was required to retain tissue for research; 17 thought it should beobtained preoperatively. Of 21 surgeons not engaged in biological studies,the measures that would make them prepared to collect tissue included con-sent obtained by a paediatric oncologist; routine prompting by a paediatriconcologist or a neuropathologist; and being kept informed of specific stud-ies. Collection of tissue from the operating room by a member of the researchteam was regarded as only slightly more helpful than routine banking. Recog-nition of institution in publications was more important than personalacknowledgment or financial contribution to research funds. Conclusion: Inthe absence of greater personal involvement of neurosurgeons in basic neuro-oncology research, the step most likely to result in more successful accrual ofchildren’s brain tumour tissue for research purposes in the UK would be theestablishment of standard procedures for obtaining consent by a paediatriconcologist linked with a system for prompting the surgeon, and routine bank-ing by a neuropathologist in conjunction with the research laboratory.

149. NEUROPSYCHOLOGICAL OUTCOMES IN CHILDREN FOLLOWING POSTERIOR FOSSA SYNDROME: A REPORT OF 4 CASES Rey-Casserly C, Scott RM, Goumnerova L, Proctor M, Marcus K,Pomeroy S, Kieran M; Children’s Hospital, Boston; Dana-Farber CancerInstitute, Boston, MA, USA

Posterior fossa syndrome (“cerebellar mutism”) has been described as aninfrequent complication of posterior fossa surgery; it is more common fol-lowing surgery for medulloblastoma than for other tumor types. A retro-spective study from our center reported on 8 patients with this syndromediagnosed between 1986 and 1992. These patients developed decreasedspeech, comprehension deficits, apathy/lack of initiative, and global cerebel-lar dysfunction. The speech and communication problems resolved over aperiod of 4 weeks, but these children required extensive rehabilitation ofadaptive and motor functions. Other series of patients have demonstratedpersistent associated neurological complications or residual neuropsycho-logical deficits involving higher-order language and cognitive skills after pos-terior fossa syndrome. Given that longitudinal studies of children with medul-loblastoma demonstrate increasing neurocognitive morbidity in yearsfollowing treatment, the additional impact of posterior fossa syndrome needsto be evaluated. We present the neuropsychological outcomes of 4 childrentreated with surgery, radiation (craniospinal), and chemotherapy (11 months)on DFCI 97-019 (POG-A9961) for medulloblastoma who developed poste-rior fossa syndrome post surgery. These children were diagnosed from 1998to 2000 (1 male, 3 females; mean age at evaluation 10.25, range 6 to14years). Neuropsychological evaluations were completed at a mean of 14months post craniospinal radiation. The full scale IQ’s ranged from 73 to 89;all showed slow motor output, speed of processing deficits, working memoryproblems, and internalizing psychological symptoms (anxiety, depression,withdrawal, somatization). In our cohort, significant medical complicationsand symptoms that persisted beyond the treatment phase (fatigue, weight loss,motor deficits) and neuropsychological deficits have compromised academicand adaptive outcomes and have significant implications for both psycho-logical and medical management. Based on our experience with medul-loblastoma, these patients present with more difficulties than expected. Therelative impact of posterior fossa syndrome on the neurocognitive outcomesin this population will be discussed. Findings will be better interpreted inthe context of an appropriate comparison group. In summary, although acutesymptoms of posterior fossa syndrome resolve, our findings indicate that chil-dren with posterior fossa syndrome may be at increased risk for neuropsy-chological sequelae and should be followed carefully.

150. THE ROLE OF THE PAEDIATRIC NEURO-ONCOLOGYCLINICAL NURSE SPECIALISTReynolds M, Ward B; Paediatric Neuro-oncology Clinical NurseSpecialists; Great Ormond Street Hospital for Children NHS Trust, GreatOrmond Street, London, UK

Primary central nervous system tumours are the most common type ofsolid tumour in children, accounting for 20–25% of all childhood malig-nancies. Great Ormond Street Hospital is the largest neuro-oncology centrein the UK, and we see approximately 80–95 newly diagnosed children peryear. In addition to this, another 40–50 children present with disease pro-gression or recurrence. Our team consists of 2 neuro-oncology clinical nursespecialists, who cover a 50-mile radius around London and provide a 24-houron-call telephone advice service. We work closely with a large multidiscipli-nary team and aim to support children and their families from diagnosis tocure and long-term follow-up, or to palliative care. Treatment can includesurgery, chemotherapy and radiotherapy, or symptom control. We link closelywith paediatric community nurses, schools, and GPs to provide a seamlessservice. Teaching and student supervision is key to educating others aboutour role. The post is both challenging and rewarding and enables holistic careto be given from hospital to home.

151. TEMOZOLOMIDE PHARMACOKINETICS IN CHILDRENAND IN ADULTS WITH BRAIN TUMORSRiccardi A, Mazzarella G, Barone C, Cefalo G,° Garrè ML,+ MassiminoM,° Sandri A,^ Ridola V, Ruggiero A, Mastrangelo S, Lazzareschi I,Madon E,^ Riccardi R; Catholic University of Rome, °Istituto dei Tumori,Milan, +Istituto G.Gaslini, Genoa, ^University of Turin, Italy

Temozolomide (TMZ) is a DNA-methylating agent that appears activein high-grade glioma and, in our experience, also in relapsed or refractorymedulloblastoma. The pharmacokinetics of TMZ has been investigated in arelatively small number of patients in phase I studies conducted on paediatricand adult patients. These reports suggest that systemic exposure (AUC) is upto 40% higher in children as compared to adults (Estlin, 1998) and that inadults higher AUC correlates with haematological toxicity (Hammond,

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1999). To evaluate these aspects in a larger group of patients, we conducteda pharmacokinetic study in children and adults treated with TMZ 180–200mg/m2/day for 5 consecutive days administered every 8 hours. Forty courseswere studied in 22 children (mean age 11 y, range 3–16) and in 8 adults (meanage 30 y, range 19–54). Blood samples were collected at 0-0, 5-1-1, 5-2-3-4-6,and 8 h. Samples were centralized from five participating institutions forTMZ assay and pharmacokinetic analyses. Results: peak plasma concentra-tion: 4.2 µg/ml (children), 3.8 µg/ml (adults); AUC: 12.2 µg.h/ml (children),10.9 µg.h/ml (adults); elimination half-life: 1.7h (children), 1.7h (adults);total body clearance: 99 ml/min/m2 (children), 105 ml/min/m2 (adults). Nostatistically significant difference was observed. Similarly, no significant dif-ference was observed in time to peak concentration, peak plasma concen-tration, and volume of distribution. Our results demonstrated a completeoverlaying between paediatric and adult pharmacokinetics. A linear rela-tionship was found for both peak plasma concentrations and AUC withincreasing doses of TMZ. Intrapatient and interpatient variability of systemicexposure was limited (respectively, 13% and 20%). Analyses of AUC corre-lation with hematological toxicity was performed only in children since inadults only 1 toxic course was reported. No statistically significant differencewas found between TMZ AUC in children who experienced grade IV throm-bocytopenia (n = 6) and children without haematological toxicity (n = 22).In conclusion, our data indicate that (1) there is no difference between adultsand children in pharmacokinetic parameters and that (2) no correlation wasfound between haematological toxicity and AUC. Supported by Fondazioneper l’Oncologia Pediatrica and A.I.R.C.

152. CHROMOSOMAL IMBALANCES IN CHOROID PLEXUSTUMOURSRickert CH, Wiestler OD, Paulus W; Institute of Neuropathology,University Hospital, Münster Germany

We studied 49 choroid plexus tumours by comparative genomichybridization. Chromosomal imbalances were found in 32/34 choroid plexuspapillomas and 15/15 choroid plexus carcinomas. Choroid plexus papillo-mas frequently showed +7q (65%), +5q (62%), +7p (59%), +5p (56%),+9p (50%), +9q (41%), +12p, +12q (38%), and +8q (35%), as well as –10q(56%), –10p, and –22q (47%); choroid plexus carcinomas mainly showed+12p, +12q, +20p (60%), +1, +4q, +20q (53%), +4p (47%), +8q, +14q(40%), +7q, +9p, +21 (33%), as well as –22q (73%), –5q (40%), –5p and–18q (33%). Several chromosomal imbalance differences could be foundwhich were characteristic for a tumour entity or age group. In choroid plexuspapillomas +5q, +6q, +7q, +9q, +15q, +18q, and –21q were significantlymore common, while choroid plexus carcinomas were characterised by +1,+4q, +10, +14q, +20q, +21q, –5q, –9p, –11, –15q, and –18q. Among choroidplexus papillomas, children more often showed +8q, +14q, +12, and +20q;adults mainly presented with +5q, +6q, +15q, +18q, and –22q. While thenumber of aberrations overall, as well as of gains and losses on their own,bore no significance for survival among choroid plexus tumours, a signifi-cantly longer survival among patients with choroid plexus carcinomas wasassociated with either +9p or –10q. Our results show that aberrations differbetween choroid plexus papillomas and choroid plexus carcinomas, as wellas between paediatric and adult choroid plexus papillomas, supporting thenotion of different genetic pathways. Furthermore, gain of 9p and loss of 10qappear to be correlated with a more favourable prognosis in choroid plexuscarcinomas.

153. CEREBELLAR MUTISM SYNDROME (CMS) AFTERPOSTERIOR FOSSA SURGERY: A PROSPECTIVE STUDY OFTWO LARGE COHORTS OF MEDULLOBLASTOMARobertson P, Muraszko K, Gajjar A, Packer R, Allen J; The University ofMichigan Medical Center, Ann Arbor, MI, USA

The CMS (also called posterior fossa syndrome) has been retrospectivelyreported in 8–25% of patients following resection of midline cerebellartumors, most often medulloblastomas. It is a partially reversible syndromeconsisting of decreased speech production, ataxia, hypotonia, and labile emo-tional status, often with onset delayed 1–2 days after the posterior fossasurgery. The improved survival recently shown to result from aggressive resec-tion of medulloblastoma makes the potential for such increased postopera-tive neurological morbidity an important consideration in these patients. Theincidence and risk factors for development of the CMS are poorly under-stood. As part of two cooperative group clinical trials for both high-risk(CCG 9931) and standard-risk (CCG/POG 9961) medulloblastoma, weincluded a questionnaire to survey for symptoms of the CMS to prospectivelyascertain its incidence in newly diagnosed patients immediately followingsurgery. Data was submitted on 460/510 patients for a compliance rate of90% (87/90 from CCG 9931 and 373/420 from CCG/POG 9961). The CMSwas definitely present in 24% and suspicious in 2% of high-risk patients, anddefinitely present in 23% and suspicious in 1% of standard-risk patients.

There was no correlation of the CMS with tumor size, primary tumor loca-tion, degree of resection, M-Stage, or occurrence of CSF leak in either group.There was a trend toward an association with postoperative meningitis andintracranial hematoma in the high-risk patients. Overall, the duration of theCMS was >4 weeks in 50%, 1–4 weeks in 40%, and <1 week in 10% of thepatients. Mutism and ataxia were the features of the syndrome most fre-quently present at the highest degree of severity. In summary, nearly 1 in 4patients who underwent attempted aggressive resection of a medulloblastomadeveloped the CMS, of which >80% were moderate or severe in intensity. Nospecific risk factors were associated with its occurrence. These prospectivestudies indicate that CMS is an important and generally underdiagnosed com-plication of surgical resection of posterior fossa tumors. The ultimate degreeand temporal profile of recovery and the impact the CMS on quality of liferemain to be determined.

154. METHYLATION OF THE O6-METHYLGUANINEMETHYLTRANSFERASE DNA REPAIR GENE IN CHILDHOODMEDULLOBLASTOMARood B, Zhang H, Cogen P; Children’s Research Institute, Children’sNational Medical Center, Washington, DC, USA

Medulloblastoma is the most common malignant brain tumor of child-hood. The cornerstone of treatment for medulloblastoma is radiotherapy.Adjuvant chemotherapeutic regimens including alkylating agents have beenemployed as a means to delay and/or reduce radiotherapy in an attempt tominimize the neuro-cognitive sequelae suffered by the irradiated developingbrain. The ability to distinguish the tumors for which such a strategy is likelyto be effective would allow its pursuit with less risk of tumor relapse anddeath. Chemotherapeutic agents known as alkylators adduct alkyl groupsto the O6 position of guanine residues of DNA, resulting in mutation andcytotoxicity. The DNA repair protein O6-Methylguanine Methyltransferase(MGMT) removes alkyl groups adducted to DNA, ameliorating the cytotoxiceffects of alkylating agents and reducing their effectiveness. DNA methyla-tion of gene regulatory elements results in suppression of their transcrip-tion. The expression of the MGMT gene has been identified as being sup-pressed by methylation in a wide range of tumors, including adult braintumors. A significant correlation between MGMT methylation and favorableoutcomes with alkylator chemotherapy in adult high-grade glioma patientshas been demonstrated. We investigated the incidence of MGMT promotermethylation in the most common malignant brain tumor of childhood,medulloblastoma. Using methylation-sensitive PCR, we have found that 19of 30 (63%) medulloblastoma specimens exhibit methylation of the MGMTgene in a region that has been found to confer transcriptional silence. Thisfinding may have significance for the prospective stratification of treatmentgroups as well as the identification of a subgroup of patients who would ben-efit from treatment with the MGMT inhibitor O6-Benzylguanine. Furtherstudies will seek a correlation between outcomes from alkylator-based chemo-therapy and MGMT methylation status in medulloblastoma.

155. HYPOPHOSPHATEMIA (HYPO) IN CHILDRENUNDEROING PERIPHERAL BLOOD STEM CELLS (PBSC)TRANSPLANTATIONRusso D, Cappelli C, Libera F, Properzi E, Gonfiantini M, De PasqualeMD, Amoroso L, Ragni G, Clerico A; Pediatric Department–University ofRome, Italy

Background: Severe Hypo can cause several complications, includingmyopathy, cardiomyopathy, paraesthesia, seizures, thrombocytopenia, andosteomalacia. Some studies about bone-marrow transplantation (BMT) inadults showed a severe Hypo during peri-BMT period in a high percentageof patients. Our study aims to evaluate the degree of Hypo in pediatricpatients affected by solid tumors undergoing PBSC transplantation. Patientsand Methods: From October 1997 to October 2001, 51 patients underwenthigh-dose chemotherapy (HD-CT) supported by PBSC transplantation. Therewere 35 males and 16 females, and the median age was 9 years (range 1–18).HD-CT regimens included Thiotepa, Melphalan, Carboplatin, Etoposide, andBusulfan in different associations. Phosphatemia was evaluated from the dayof transplantation to time of hematological recovery (ANC >500/ml; Hb >9g/dl; Plts >50.000/ml). Intravenous phosphate substitution was given whennecessary. Results: For their transplantation our patients received a mediannumber of 2x106 CD 34+ cells (range 1.2–4.5). Forty-nine out of 51 patients(92%) presented severe Hypo during peri-BMT period. Hypo nadir medianvalue was 1.6 mg/dl (range 1.0-1.8), and median day of Hypo nadir was 8days post-BMT (range 6–9). Median time of ANC <500/ml was 6 days (range3–12), median first and last day of ANC <500/ml were +4 (range 2–5) and+10 (range 9–13). In all 49 patients Hypo was noted from 24 hours beforethe first day of ANC <500/ml up to 48 hours after the first day of ANC>500/ml. Intravenous phosphate substitution was necessary in every case ofHypo and was administered every 24 hours. We didn’t observe any side

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effects of Hypo. Conclusions: Almost all our patients (92%) experiencedsevere Hypo, without relevant side effects, during peri-PBSC transplanta-tion period. Hypo, though severe, was manageable with intravenous phos-phate substitution. It was greatly correlated to neutrophil proliferationprocess and time of recovery. Hypo, in fact, lasted a little more than ANC <500/ml and covered the same period. Thus, we concluded that a prophylac-tic intravenous phosphate substitution has to be taken into account duringPBSC transplantation in children.

156. DENDRITIC CELL-BASED IMMUNOTHERAPY INPATIENTS WITH MALIGNANT GLIOMA: RESULTS OF APILOT STUDYRutkowski S,1 De Vleeschouwer S,5 Kaempgen E,2 Keikavoussi P,2 OttoK,2 Opitz A,3 Wolff JE,4 Kuehl J,1 Van Gool SW5; Departments of1Pediatrics, 2Dermatology, 3Transfusion Medicine, University ofWuerzburg, Germany; 4Pediatric Oncology, St. Hedwig, Regensburg,Germany; 5Department of Pediatric Oncology, Laboratory of ExperimentalImmunology, University of Leuven, Belgium

Objectives: Prognosis of patients with malignant glioma remains poor,although multimodal treatment including surgery, radiotherapy, and chemo-therapy has been improved. Animal models and human trials have shownthat dendritic cell-based immunotherapy can elicit antitumoral immuneresponses. In this pilot study, toxicity and the in vivo generated immuneresponse of dendritic cell-mediated immunotherapy has been investigated in5 patients with relapsed malignant glioma. Methods: In 3 children and 2adults with relapsed malignant glioma (3 glioblastoma, 1 anaplastic astro-cytoma, 1 rapidly recurring pleomorphic xanthoastrocytoma), tumors wereat least subtotally resected except in 1 patient with partial resection. Den-dritic cells were generated from PBMC of patients and loaded with inacti-vated autologous tumor-homogenate ex vivo. Vaccinations were administeredintradermally at weeks 1, 3, 7, 11 and continued every 4 weeks, if applica-ble. Tumor size was assessed by MRI-scan before each vaccination. T cell acti-vation was analyzed in serial PBMC-samples of 2 patients. Results: Vacci-nations were well tolerated except in 1 patient with partial resection, whosuffered intermittently an increased peritumoral edema after vaccinations2–5. Three patients remain in remission 9, 6, and 3 months after surgery. Thepatient with partial resection had stable disease for 2 months before pro-gression. In 1 patient tumor relapse was observed after 3 months. Analysisof T cell activation and cytotoxicity against glioma cell-lines is under way.Conclusion: This pilot study indicates the feasibility and safety of dendriticcell-mediated immunotherapy in patients with malignant glioma and repre-sents a potential immunotherapeutic approach. Further recruitment ofpatients is ongoing.

157. REVIEW OF CURRENT PRACTICE IN DIAGNOSTICPROCEDURES OF MIDLINE CNS GCT’S: EXPERIENCE OFTHE P-SIOP AND SIOP CNS GCT 96 TRIALSaran F, Alapetite C, Frappaz D, Garrè ML, Koch S, Kortmann RD,Nicholson J, Ricardi U, Calaminus G; Department of Radiotherapy, RoyalMarsden Hospital, Sutton, Surrey, UK, for the SIOP CNS GCT Group

Purpose: Intracranial germ cell tumours are rare but represent the mostcommon diagnosis in teenage patients presenting with a localised or bifocalmidline mass lesion in the suprasellar and/or pineal region often accompa-nied by endocrine dysfunction. We compared the diagnostic pathway ofpatients entered in the pilot study (P-SIOP) and SIOP CNS GCT 96 studywith protocol recommendations. Materials and Methods: All case reportforms (CRFs) of patients entered into study were reviewed. Of 280 patientsregistered up to 31.12.00, 237 patients (85%) presented with a solitary mid-line lesion and 43 with a bifocal lesion (15%). Median age at diagnosis was13 years (range: 1–28 years), and 81% of cases were aged over 10 years. Onehundred six of 126 patients with suprasellar lesions (84%) had diabetesinsipidus as a presenting symptom. In the absence of obstructive hydro-cephalus serum and CSF tumour markers (αFP + ßHCG), CSF-cytology andMRI imaging of brain and spine prior to surgery were requested. Otherwisestaging procedures were completed intra-operatively by obtaining CSF cytol-ogy and CSF tumour markers. Results: 247/280 patients (88%) had completeradiological imaging. CSF cytology was performed in 206/280 patients(74%). In 132/280 patients (47%) tumour markers (serum and/or CSF) wereobtained prior to surgery. In 34/105 patients (32%) with secreting germ celltumours (sGCTs) the diagnosis was based solely on tumour markers. Fifty-seven of 105 patients (54%) with secreting germ cell tumours underwent up-front biopsy or excision with 12/57 patients (21%) suffering from serioussurgical toxicity, including 3 fatalities. Incomplete staging procedures havebeen recorded for 54/175 patients with germinoma (31%) and 33/105patients (31%) with sGCTs. Conclusion: Clinical symptoms, radiologicalappearance, and age in patients with solitary midline suprasellar and/or pinealmass lesions should alert clinicians to consider the diagnosis of a CNS GCT.Despite clear protocol recommendations, a significant number of deviationsin staging procedures were reported in patients enrolled in the study. Appro-

priate multidisciplinary management from the onset is necessary to improveoutcome and reduce treatment-related morbidity in the future.

158. HIF-1 DECOY INHIBITS A HYPOXIA-INDUCED UP-REGULATION OF VEGF IN GLIOMACELLSSasaki M, Tamaki N, Kohmura E; Department of Neurosurgery, KobeUniversity Graduate School of Medicine, Kobe, Japan

Background: Up-regulation of VEGF induced by hypoxia plays a piv-otal role in tumor angiogenesis. Hypoxia-inducible factor-1 (HIF-1) is thebest-characterized regulator of the VEGF gene transcription. In its activeform, it is a dimer composed of two distinct subunits, both of which belongto the basic helix-loop-helix-per-arnt-sim (bHLH-PAS) protein family: HIF-1alpha and HIF-1beta, the aryl hydrocarbon receptor nuclear translo-cator (ARNT). Under hypoxic conditions, active HIF-1 complexes accumu-late in the cell nucleus. They bind to the target DNA sequence (HIF-1 bind-ing site) within the hypoxia-response element (HRE) and enhance thehypoxia-inducible gene transcription rate. Objectives: To control the hypoxia-induced up-regulation of VEGF on the transcriptional level, we used a decoyDNA corresponding to HIF-1alpha binding site and investigated the feasi-bility of HIF-1 decoy for the inhibition of tumor angiogenesis. Methods:20-mer double strand DNAs including HRE of HIF-1alpha (TACGTGGG)were synthesized, along with scramble and mismatch sequences as a con-trol. Lipofection was used for transduction of these constructs in vitro and invivo. Results: In vitro experiments, transduction of HIF-1 decoy showed asignificant reduction of message and protein level of VEGF on 9L cells underhypoxic condition. In vivo experiments, local injection of liposomes con-taining HIF-1 decoy into 9L subcutaneous tumors resulted in a significantdown-regulation of VEGF, followed by an inhibition of angiogenesis on a peri-necrotic areas and antitumor effect. No significant side effects were noticedon animals. Conclusions: HIF-1 decoy corresponding to HRE inhibited thehypoxia-induced up-regulation of VEGF in vitro and in vivo. This led to anti-angiogenic effect and antitumor effect on tumor-bearing animal model with-out any significant adverse effects. These results suggest the feasibility of thesedecoys in the treatment of angiogenesis-dependent tumors, such as malignantgliomas.

159. STEREOTACTIC FRACTIONATED RADIATIONTHERAPY (SFRT) IN CHILDHOOD HIPOTALAMIC-CHIASMATIC LOW-GRADE GLIOMAS (HC-LGG):EXPERIENCE OF A SINGLE INSTITUTIONScarzello G, Buzzaccarini MS, Perilongo G, Faggin R, Calderone M,Viscardi E, Pinello L, Rigobello L, Battistella A, Sotti G, for the PaediatricNeuro-oncology Group of the Paediatric Department of Padua; RadiationTherapy Department of the Azienda Ospedaliera of Padua, Italy

From October 1997 to December 2001, 21 selected children (median age:7 years; range: 3–21) affected by an HC-LGG underwent SFRT using anadapted 6 MV Siemens MX2 Linear Accelerator equipped with the X KnifeStereotactic Radiotherapy System, Radionics Inc., according to the indica-tions of the SIOP LGG protocol. Treatments were given daily by 3 to 7 arcs,median 4, up to a total dose of 54 Gy, in 27 fractions of 2 Gy each. The col-limators size ranged from 25 to 50 mm, median 40, to encompass the MRIT2-weighted tumour volume with 3–5 mm margins. The Gill-Thomas-Cosman, the Boston Children’s Hospital, or the Tarbell-Loeffler relocatableframes were used for treatment planning and delivery; 4 babies were irradi-ated under anaesthesia; the compliance of collaborative children to all thethree instruments was good. At a median follow-up of 31 months, all chil-dren are alive with a nonprogressive disease. All had at least 1 follow-upMRI: 2 achieved complete remission, 9 had some tumour volume reductionand/or decreased contrast enhancement, and 10 had stable disease; no oneprogressed under treatment. All children had visual function (VF) assessmentincluding visual acuity, visual field measurements, and evoked visual poten-tials; VF improved in 7, remained stable in 14, deteriorated in no one. Chil-dren also had endocrinologic follow-up assessment; at diagnosis 6 had a somepituitary dysfunction; after treatment no one had significant improvement,20 remained stable, and 1 had some deterioration. Presently 4 are in hormonereplacement therapy. SFRT seems to be well tolerated and effective for smallwell-circumscribed HC-LGG. More patients and longer follow-up are neededto determine whether this regimen improves tumour control without increas-ing the complication rate, capitalising the physical advantages of the stereo-tactic technique and the biological benefits of a fractionated regimen.

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160. MEDULLOBLASTOMA AS A SECONDARY MALIGNANCYAFTER RADIOTHERAPY-FREE TREATMENT FOR ACUTELIMPHOBLASTIC LEUKEMIASchiavetti A, Moleti ML,* De Pasquale MD, Di Salvo S, Cappelli C,Bernardini L**; Division of Paediatrics, *Haematology, University ofRome “La Sapienza,” Italy; **Institute for Medical Genetics C.S.S.Mendel, Rome, Italy

Introduction: Malignant brain tumours have been reported to occur insurvivors of childhood acute lymphoblastic leukemia (ALL) more frequentlythan in a noncancer control population. The strongest risk factor seems to becranial radiotherapy (RT), employed as central nervous system (CNS) pro-phylaxis. Medulloblastoma (MB) as a secondary malignancy after radio-therapy-free treatment for ALL has not been reported as so far. Case Report:A 9-year-old patient was admitted with headache and vomiting. A cerebel-lum mass and spinal cord metastasis were detected by craniospinal MRI. MBwas diagnosed at histological examination, after partial resection. Six yearsbefore the patient had received chemotherapy for ALL according to AIEOP9102. CNS prophylaxis consisted of intrathecal Methotrexate plus Cytara-bine (20 administrations) and high-dose Methotrexate for four courses; noprophylactic cranial RT was administered. The child, in first complete remis-sion, was well until the occurrence of a second tumour. The patient was alsotreated for MB: pre-RT chemotherapy with Carboplatin (CBDCA) 800mg/m2 and Etoposide (VP16) 200 mg/m2 for 2 courses; craniospinal RT (35Gy craniospinal with a boost of 20 Gy on the posterior fossa); post-RTchemotherapy with CBDCA 500 mg/m2 and VP16 200 mg/m2 for 4 courses.At present she is alive without disease. Because of the unusual association ofthese two malignancies in this patient, the p53 status was investigated usingFISH analysis by specific DNA-probe; the p53 mutation was not detected.Conclusion: This is the first observation of MB after ALL when craniospinalRT is not previously administered. A genetic predisposition or a possibleoncogenic role of the intrathecal or antimetabolite CHT should be consid-ered.

161. IN VITRO DRUG RESISTANCE AND DIFFERENTIATIONAND PROLIFERATION IN CHILDHOOD EPENDYMOMASchouten-van Meeteren AYN, Van der Valk P, Hollebrandse E,Broekhuizen AJF, Huismans DR, Veerman AJP; VU University MedicalCenter, Department of Pediatrics, Subdivision Hemato-oncology,Amsterdam, The Netherlands

Introduction: The effectiveness of cytostatic drugs in childhood ependy-moma seems to be limited. Consequently, children with relapsing or dissem-inated ependymoma have a poor prognosis. The determination of cell bio-logical features that are related to drug resistance of ependymoma could bevaluable in the development of future chemotherapy protocols. Materials andMethods: From 13 fresh surgical specimens of primary ependymoma, the pro-liferation was estimated with immunohistochemistry for Ki67 and PCNA aswell as with S-phase analysis by FACS. The glial and neuronal differentiationwas determined by immunohistochemistry for GFAP and NSE. The LC50 val-ues of the tumor cell suspensions for 10 cytostatic drugs were determinedwith the adapted automated MTT assay. Results: Drug resistance levels wereobtained in 77% of the samples. In 4 tumors immunomagnetic beads wereapplied to remove contaminating leucocytes and endothelial cells from thetumor cell suspension. The immunohistochemical positivity varied for Ki67from 10–30% (median 20), for PCNA from 25–100% (median 80), forGFAP from 0–80% (median 50), and for NSE from 0–70% (median 10). Thenumber of cells in S-phase ranged between 1.3–17.5% (median 10.2). Thetumor cells showed cross resistance for both platinum compounds and bothanthracyclins applied in the MTT assay. A higher percentage of PCNA pos-itivity was related to increased carboplatin sensitivity (p 0.029). A higher levelof Ki67 was related to increasing sensitivity for actinomycin D and ifosfamide(p 0.011). In an earlier study we also observed this phenomenon for actino-mycin D in the drug resistance profiles of central PNET. In conclusion:Ependymoma shows large differences in the degree of proliferation and dif-ferentiation. Tumors with increased expression of proliferation markers aremore sensitive to actinomycin D, ifosfamide, and carboplatin.

162. MEDULLOBLASTOMA RELAPSE PRESENTING WITHSUDDEN DEAFNESSSchouten-van Meeteren AYN, van Ouwerkerk WJR, Goverts ST, VerbekeJITM; VU University Medical Center, Department of Pediatrics,Subdivision Hemato-oncology, Amsterdam, The Netherlands

We present the case report of a 2-year-old boy who was treated formedulloblastoma (stage M0) with total neurosurgical resection. Subsequentlyhe received a chemotherapy regimen with alternating courses consisting ofcisplatin, carboplatin, vincristine, methotrexate, and cyclophosphamideaccording to the Baby Brain protocol of the UKCCSG and SIOP. The chemo-

therapy was continued for a year without severe complications. No signs ofnephrotoxicity or ototoxicity were present. Five months after the end ofchemotherapy, the boy presented with complete sudden bilateral deafness.The MRI evaluation revealed contrast enhancement and thickening of bothacoustic nerves and spinal drop metastasis. A potential curative treatmentincluding craniospinal radiotherapy and stem cell transplant at the age of 3.5years would most probably induce severe neurocognitive and endocrinesequelae together with the most probable persistence of the deafness. Thistype of treatment still would include a dismal prognosis and was not agreedto by the parents. Thus palliative treatment consisting of a course of oraletoposide was started, together with the supply of a hearing aid. However,fast recovery of hearing was perceived, and a subsequent MRI revealedimpressive regression of the lesions. Despite this improvement, the boy died6 months later. Conclusion: Sudden deafness after medulloblastoma treat-ment could be a sign of relapse. Palliative treatment with oral etoposide couldinduce (temporary) restoration of hearing.

163. IMMUNITY AGAINST VACCINE-PREVENTABLENEUROTROPIC DISEASES AFTER HIT-91 THERAPYSchuller E, Cokoja L, Slavc I, Maurer W; Vienna University Children’sHospital, Währinger Gürtel 18-20, 1090 Vienna, Austria

Protective immunity against endemic neurotropic infectious diseases is ofspecial importance in patients with brain tumors. We assessed measles,mumps, rubella, varicella zoster (VCV), and tick-borne encephalitis (TBE)serum antibodies as surrogates of protection (Plotkin) in 28 patients aged4–22 years (mean 12.4) in complete remission after HIT-91 chemotherapyand radiotherapy. Seroprofiles were compared to those of 57 patients aged1.5–24 (mean 11.5) with benign brain tumors and 35 healthy controls regard-ing neoplasm and immune function aged 2–22 years (mean 9.3). No signifi-cant effect of age or gender was found using unilateral Pearson Chi-Squaretests. Measles IgG was not protective in 20 of 27 patients after HIT-91, in 26of 57 patients with benign brain tumors, and in 11 of 32 controls (p =0.0035). This lack was observed although 15 of 20 patients were vaccinatedprior to and 7 of 20 after HIT-91. Mumps IgG was not detected in 14 of 26patients after HIT-91, in 29 of 57 patients with benign brain tumors, and in10 of 32 controls (p = 0.68). Rubella IgG was not detected in 10 of 27patients after HIT-91, in 9 of 57 patients with benign brain tumors, and in 7of 34 controls (p = 0.035). A significant rubella seronegativity in the HIT-91treated group compared to the other groups was observed. VCV IgG was notprotective in 7 of 24 patients after HIT-91, in 10 of 57 patients with benignbrain tumors, and in 7 of 32 controls (p = 0.25). TBE antibodies were notprotective (<120 VU/ml) in 6 of 27 patients after HIT-91, in 5 of 50 patientswith benign brain tumors, and in 3 of 29 controls (p = 0.15). In 16patients vaccination history was evaluated 24–108 months after HIT-9: 2patients were not vaccinated at all, 6 patients received MMR, 7 diphtheria-tetanus, 10 TBE, 1 influenza vaccination. Natural rubella immunity wasunexpectedly low in the HIT-91 group, as was vaccine-induced measlesimmunity. We propose assessment of seroprofiles and tailored vaccinationschemes after treatment of malignant brain tumors. Plotkin SA. Immunologiccorrelates of protection induced by vaccination. Ped Inf Dis 20: 63-75, 2001.

164. A PHASE II STUDY OF THIOTEPA,CYCLOPHOSPHAMIDE, AND CARBOPLATIN (TCC) WITHAUTOLOGOUS STEM CELL RESCUE IN CHILDREN WITH HIGH-RISK BRAIN TUMOR AND NEUROBLASTOMA (CHOC 95-036)Shen V, Eckroth E, Evans J; Children’s Hospital of Orange County,Orange, CA, USA

From July 1995 to November 2001, 15 children, aged 19 months to 11years (median 6 years) with malignant brain tumor or neuroblastomareceived a high-dose TCC regimen (CHOC 95-036) as a consolidation ther-apy. The TCC regimen consists of thiotepa 125 mg/m2/day and cyclophos-phamide 1500 mg/m2/day given from day –7 to –4, carboplatin 500mg/m2/day (or use AUC 7 for CCr<100) on day –3 and –2 followed by autol-ogous peripheral blood stem cell transplant on day 0. Diagnostic categoryincluded recurrent medulloblastoma (5), infants with PNET (5), glioblastomamultiforme (1), germinoma, second relapse (1), and stage 4 neuroblastoma(3). Minimal residual disease status was required before starting high-dosetherapy. All patients developed severe mucositis requiring TPN support. Bac-terial sepsis occurred in 3 patients, and 2 patients experienced transientchange of mental status. No patient died from a transplant-related com-plication. The average length of hospital stay following stem cell transplantwas 23 days. The median time to ANC recovery of >0.5x103/mm3 and>1.0x103/mm3 was 11 and 12 days, respectively. The platelet recovery greaterthan 50,000/mm3 and 100,000/mm3 was achieved at median of 35 and 45days, respectively. Eight patients received additional chemo and/or XRT, 3patients with neuroblastoma received 13-cis-retinoic acid, and 6 patients

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received no further therapy following stem cell transplant. Ten patientsremained free of progressive or recurrent disease at the median follow-up of48 months (range: 1 to 75 mos). The Kaplan-Meier estimate of survival is82% and 68% at 1.2 and 3 years, respectively. Conclusion: The TCC regi-men is well tolerated, and prompt hematopoietic recovery following stem cellrescue allows posttransplant delivery of additional chemotherapy or radia-tion therapy.

165. SIGNIFICANCE OF EPILEPSY IN THE MANAGEMENT OF PEDIATRIC BRAIN TUMORSShuper A,* Cohen IJ, Michowitz S, Kornreich L, Schwartz M, Yaniv I;Departments of Oncology, Neurosurgery, and Radiology, SchneiderChildren’s Medical Center of Israel, Petah Tikva, Sackler School ofMedicine, Tel Aviv University, Israel

Objectives of the Study: Brain tumors are considered a significant causeof epilepsy. The aim of the study was to evaluate its clinical significance in acohort of children with brain tumors. Methods: The charts of 251 childrenfollowed at our neuro-oncology service since January 1991 were reviewed.Results: Twenty-four children (9.6%) had epilepsy. Their clinical character-istics are summarized in the table. Most of the affected patients had corticalglial tumor, PNET, and medulloblastoma.

No Cases with epilepsy

of CNS Tumor TumorDiagnosis Pts damage presence progression Unrelated

Glial 139 3 2 5 4 PNET and medullo 75 4 3 Brain lymphoma 1 1Meningioma 5 1 Hamartoma 1 1 Other 30 Total 251 8 4 8 4

In 3 patients increase in seizure frequency was the first sign of eithertumor progression (2) or mass lesion due to radiation necrosis (1). In 4 otherpatients CNS irradiation was the most likely cause of epilepsy. Conclusion:In children with brain tumors, the incidence of epilepsy may be as high as10%. Clinically, epilepsy may serve as a sensitive marker of tumor progres-sion or radiation injury. Thus, epilepsy surveillance should be an integral partof the follow-up and management of this patient population.

166. CLINICAL EXPERIENCE OF COMBINED CRANIOSPINALRADIOTHERAPY AND PACKER CHEMOTHERAPY FOR PNET Sims E, Phipps K, Hayward R, Michalski A, Gaze M; Department ofOncology, The Hospital for Sick Children, London, UK

Approximately 60% of children with PNET are cured by surgery andradiotherapy alone. The addition of adjuvant CCNU, vincristine, and cis-platin was described by Packer et al. From 1995, we treated patients withmetastatic medulloblastoma ineligible for PNET III with this regime. Fol-lowing the closure of PNET III, which confirmed the benefit of chemotherapy,and encouraged by the results of Packer chemotherapy from the US, theUKCCSG adopted this regimen as standard therapy until PNET IV (whichwill also use Packer chemotherapy) opens. We report our experience of thepotential morbidity of this schedule. From 1995–2002, 27 patients (medianage 7 years) referred to Great Ormond Street Hospital with localized (70%)or metastatic (30%) PNET have received craniospinal radiation with Packerchemotherapy. These children have been closely monitored with clinicalexamination, audiometry, and GFR assessment both during treatment andfollow-up. Patient outcome has been audited, and evidence of significant audi-ological, renal, haematological, neurological, and cognitive sequelae has accu-mulated. Dose modification has been necessary in nearly all patients (78%),chiefly as a result of hearing loss, renal impairment, or severe peripheral neu-ropathy. In-patient treatment for severe toxicity has again been required inthe majority of patients (56%). Anorexia and weight loss requiring supple-mentary enteral feeding during treatment has been a previously unforeseentoxicity. We have developed new guidelines so that toxicity can be anticipated,monitored, and prevented.

167. TOLERABILITY OF LONG-TERM INTRAVENTRICULARETOPOSIDE THERAPY WITH HIGH CUMULATIVE DOSES INPEDIATRIC BRAIN TUMOR PATIENTS Slavc I, Schuller E, Falger J, Günes M, Czech T, Dieckmann K, Prayer D,Hainfellner J; Department of Pediatrics, University of Vienna, Wien,Austria

Treatment options for leptomeningeal disseminated brain tumors are lim-ited by the lack of effective drugs for intrathecal therapy of nonhematologicmalignancies. Recently, the feasibility of intraventricular etoposide at a doseof 0.5 mg daily for 5 consecutive days was demonstrated in 16 patients,including 10 children with brain tumors, and showed that CSF peak levelsexceeded more than 100-fold those achieved with intravenous infusion. Themaximum cumulative dose reported in this series was 30 mg in an adultpatient with median doses of 8.5 mg in children. We report on the tolerabil-ity of long-term intraventricular etoposide therapy using much higher cumu-lative doses in 10 pediatric patients with heavily pretreated brain tumors.Between March 1998 and November 2001, 10 patients 2 to 15 years old withvarious disseminated brain tumors were treated with intraventricular etopo-side at a dose of 0.5 mg daily for 5 consecutive days. The courses wererepeated every 3 to 6 weeks. Etoposide was administered over a period of 1to 31 (median 8.5) months with a total of 114 5-day cycles in 10 patients(range 1 to 29 cycles). The maximum cumulative dose was 71.5 mg with amedian of 27 mg. Etoposide did not cause any discomfort during or afterintraventricular administration. No immediate toxicities such as infectiouscomplications, pleocytosis, or aseptic meningitis occurred, and none of thepatients had a seizure or transient coma. No long-term toxicities as evidencedby MRI or neurologic evaluation occurred. Our results demonstrate thatintraventricularly administered etoposide at a dose of 0.5 mg x 5 d forpatients over 2 years is feasible and safe and may be a valuable addition tothe limited number of drugs that can be administered by this route.

168. STEREOTACTIC INTENSITY-MODULATEDRADIOTHERAPY (IMRT): ITS ROLE IN PAEDIATRICINTRACRANIAL TUMOURSSmee R, Schneider M, Hoban P; Department of Radiation Oncology,Prince of Wales Hospital, Randwick, Australia

Aim: IMRT has been shown in many adult tumours to provide improvednormal tissue sparing whilst delivering high doses to the tumour. A single-centre experience with intracranial tumours using the same approach is pre-sented. Materials and Methods: IMRT provides the means of varying theintensity of the radiation dose across a directed beam by dividing it into mul-tiple beamlets. Ten children have been treated so far, with posterior fossaependymomas and brain stem gliomas the dominant conditions treated. Theplanning for this involves fusing MR images onto a stereotactic CT scan.All computer planning is via a dedicated inverse planning system with thetypical planning times of 30–60 minutes. All patients are treated stereotacti-cally with 4mm leaf width Mini Multileaf Collimator for beam shaping. Forchildren aged less than 4 years all treatments are given under general anaes-thesia. Results: Five to 7 fixed fields are chosen with 50–70 segments in total,in a “step and shoot” fashion, with coplaner or noncoplaner fields useddependent upon best dose distribution. This is now standard treatment forall 4th ventricular ependymomas, the target being the ventricle providingtumour dose to posterior brain stem, but less than 10% of dose on anteriorbrain stem. Acutely this treatment is tolerated very well with treatment timesof 15–20 minutes depending upon the number of segments used. Only 1ependymoma patient has failed, the treatment being to a large multiply recur-rent tumour. Conclusion: IMRT provides an ideal opportunity to give highlyconformal radiotherapy to paediatric patients. Time will tell whether thisapproach being so conformal increases the risk of geographic misses.

169. INTRACRANIAL GERM CELL TUMORS: A SINGLE INSTITUTION EXPERIENCE AND A REVIEW OF THE LITERATURESmith A, Weng E, Handler M, Foreman N; Department of Oncology, The Children’s Hospital, Denver, CO, USA

There is little literature to guide therapy in children and young adults withintracranial germ cell tumors. We present an experience with 17 consecutivelydiagnosed intracranial germ cell tumors at the Children’s Hospital, Denver,from 1995–2001. The age range of the patients was 2 to 25 years with amedian of 12 years. Of the 17 patients, 2 children had considerable delaysin diagnosis of their suprasellar tumors and presented with dementia, blind-ness, and pan-hypopituitarism. Seven had germinoma, 3 of whom hadmetastatic disease at diagnosis. Ten had nongerminomatous germ cell tumors(NGGCT), 5/10 were AFP positive only, one was βHCG positive only, 3 werepositive for AFP and βHCG, 1 had a malignant teratoma. Therapy for the 3disseminated germinomas consisted of chemotherapy followed by cran-

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iospinal radiation. Therapy for the 12 patients with localized disease waschemotherapy followed by local radiation. Two patients received chemo-therapy only, 1 child died of sepsis while receiving chemotherapy and 1because he suffered such significant neurologic injury postoperatively that hisparents elected no radiation. Three patients have died, 1 of tumor recurrence,1 from a remote complication of surgery, and 1 of sepsis. Twelve patients arealive and without evidence of tumor at a range of 3–68 months (median 26months). One patient, metastatic at diagnosis, is in second relapse after high-dose chemotherapy and is now receiving IV Cytoxan. The child who didnot receive radiation due to injury is without radiographic evidence of dis-ease, but has persistently positive and rising CSF βHCG. All 5 children withonly AFP positivity, treated with Bleomycin, Etoposide, and Carboplatin fol-lowed by local XRT are alive without evidence of tumor at 7, 8, 16, 37, and40 months. In this patient cohort, there is little evidence that craniospinalradiation is necessary in germinomas and nongerminomatous germ celltumors when combined chemotherapy and radiation is used. However, com-plications of surgery and chemotherapy are an important cause of mortality,with only 1 patient dying of tumor.

170. FIBRINOLYSIS IN PEDIATRIC BRAIN TUMORSSmith A, Jacobson L, Foreman N, Handler M, Manco-Johnson M;Department of Hematology/Oncology, The Children’s Hospital, Denver,CO, USA

Background: Intracranial hemorrhage is recognized as a complicationof some brain tumor types. The incidence has decreased as neurosurgical tech-niques have improved. However, there remains a subset of patients that pre-sent with intracranial hemorrhage or bleed excessively at the time of surgerywho have normal screening laboratory tests. Abnormal fibrinolysis has beenimplicated in many of these cases, but its role is not well defined. Methods:We prospectively collected 10 pediatric brain tumor patients. Blood wasdrawn before initial surgery and intraoperatively. Screening labs included PT,PTT, fibrinogen, fibrin split products, and platelet count. Euglobulin clot lysistimes were done in our lab by a new automated spectrophotometric kineticassay in 96 well microtiter plates measuring absorbance at 405nm every 2minutes for 360 minutes, adapted from the standard manual method. Results:PT’s ranged from 10. 4 to 15.1 seconds, normal (10.9–13.7). Mild prolon-gation by 1 to 2 seconds occurred intraoperatively. PTTs were 19.2–42.5 sec-onds; only one patient demonstrated a prolongation during surgery from 28.4to 42.5 seconds, without clinical hemorrhage. Platelet counts were normalwithout any transfusions. Fibrinogens were 109–283mg/dL (normal 200–420mg/dL). ELTs were 51.6 to >360 minutes, median 260 minutes. The lysistimes were not abnormal, but the maximal optical density, which correlateswith peak clot formation, was significantly lower than the standards andappeared to decrease during surgery consistently. Maximum OD ranges from(0.36–1.35), median 0.5 for preoperative samples and (0.2–0.98), median0.37 for intraoperative samples with standards at 1.0–1.6. This suggested thatour patients all had abnormal clot formation without evidence of DIC.Crossed immunoelectrophoresis for fibrinogen did not reveal dysfibrinogen-emia. Dilutional studies revealed that fibrinogen positively correlates withmaximum OD; however, this does not account for the intraoperative changes.Conclusions: It appears that even patients who do not experience intracra-nial hemorrhage have low to low normal fibrinogen which is not wellexplained and may be due to utilization for new tumor blood vessels or ispotentially being down-regulated. The fibrinogen is also dysfunctional by notforming a strong clot, even accounting for the level of fibrinogen.

171. STEREOTACTIC CONFORMAL RADIOTHERAPY INPATIENTS WITH CRANIOPHARYNGIOMASoomal R, Saran F, Traish D, Hines F, Sardell S, Guerrero D, Ashley S,Brada M; Neuro-oncology Unit, The Institute of Cancer Research and TheRoyal Marsden Hospital, Sutton, UK

Purpose: Stereotactic conformal radiotherapy (SCRT) uses improvedimmobilisation, target localisation, and treatment delivery allowing accurateand highly conformal irradiation of localised brain tumours to reduce irra-diation of normal brain. We report early experience of SCRT in 33 patientswith craniopharyngioma. Methods: 3 patients were treated between 1994and 1996 during the development of SCRT, and since 1997, 30 consecutivepatients referred for radiotherapy were treated with SCRT as standard ther-apy. Median age at diagnosis was 16 years (range 3–54). Twenty patientswere aged < 21 years. All had at least one conservative surgical procedure(biopsy, cyst aspiration, and/or partial excision) before radiotherapy. Threepatients had acute haemorrhage following surgery, and 1 severe hypothala-mic damage following attempted radical excision. All patients were CTplanned with MRI fusion and received SCRT with 3–6 field technique usingcustomised conformal blocks to a dose of 50Gy in 30–33 fractions over 6–6.5weeks. Results: 2-year progression-free survival (PFS) is 96% and overall sur-vival 100% at a median follow-up of 14 months (range 2–78 months). One

patient had multiple cyst aspirations and required further debulking surgery7 months after radiotherapy, and this is classified as disease progression. Thiscompares with our previously reported historical series of conventional radio-therapy with a 97% 2-year PFS and 96% survival. Four patients had acuteclinical deterioration during radiotherapy due to cystic degeneration andrequired a 2–3 week cessation of treatment for cyst aspiration. Cystic degen-eration occurred in a further 5 patients within 8 months of completion of SCRT. Acute radiotherapy side effects on scalp skin and hair were ofRTOG grade 1–2 with no grade 3–4 toxicities. Two patients experiencedsomnolence for 3 weeks immediately after completing radiotherapy. Onepatient with impaired but residual vision experienced visual deterioration 6months after radiotherapy. Conclusion: SCRT is a feasible and well-toleratedhigh-precision technique of localized irradiation with minimal acute toxicity.With limited follow-up, PFS and survival are excellent, currently within theconfidence intervals of historical series treated with conventional radiother-apy. Longer follow-up is required to confirm the effectiveness and potentiallow morbidity of this technique.

172. CONVECTION-ENHANCED DELIVERY INTO THE RATBRAIN STEM: A POTENTIAL DELIVERY MECHANISM FORTHE TREATMENT OF DIFFUSE PONTINE GLIOMASSouweidane M, Occhiogrosso G, Sandberg D, Edgar M; Department ofNeurological Surgery, The Weill Medical College of Cornell University andMemorial Sloan-Kettering Cancer Center, New York, NY, USA

Purpose: Convection-enhanced delivery (CED) has been shown to safelydeliver large volumes of distribution in the cerebral hemispheres in animalmodels. We tested the feasibility of using CED in the rat brain stem as apotential novel delivery mechanism for the treatment of diffuse pontinegliomas. Methods: Cannula insertion, small-volume infusions (total volumeof infusion [Vi] = 0.5,1.0, 2.0,4.0 microliters), and large-volume infusions(total Vi = 200 microliters and 2 ml) were tested in the rat brain stem.Sprague-Dawley rats were anesthetized and underwent stereotactic cannulaplacement into the pontine nucleus oralis (PnO). The initial 18 animals under-went cannula insertion without infusion in order to test the safety of target-ing. CED using fluorescein isothiocyanate (FITC)-dextran at a constant rate(0.1 microliters/min) was infused on a short-term schedule (5–40 minutes)and on a chronic schedule (24 hours-7days). Following infusions, the ratswere assessed for neurologic deficits. The animals were then sacrificed at var-ious times following infusion (immediate, 48 hours, 14 days, and 4 weeks).Coronal brain stem sections (20 microns) were analyzed for histologicchanges and volume of distribution (Vd). Results: No animal demonstratedneurological deficit or significant histologic injury. For the animals undergo-ing small-volume infusions, Vd increased linearly (range 15.4 to 55.8 mm3)with Vi (p = 0.022). Vd/Vi ratio ranged from 14.0 to 30.9. Maximal cross-sectional area of fluorescence (range 9.8 to 20.9 mm2) and cranio-caudalextent of fluorescence (range 2.8 to 5.0 mm) increased with increasing Vi.Chronic infusions resulted in a variable Vd, but in all cases fluorescence wasdetected throughout the entire pontine segment of the brain stem. This wide-spread distribution differs from the small-volume studies in that the infusateis additionally concentrated in the perivascular and subarachnoid spaces dis-tant from the infusion site. Conclusions: CED can be safely applied in the ratbrain stem. Distribution volumes are predictable and linearly related to infu-sion volumes. Chronic perfusion appears to have no anatomical limitationsof distribution within the brain stem. These findings support the novelapproach of using CED as a potential delivery mechanism for the treatmentof diffuse pontine gliomas.

173. SURVIVAL RESULTS IN ADULTS TREATED FORMEDULLOBLASTOMASpreafico F, Mazza E, Massimino M, Gandola L, Cefalo G, Siena S,Versari P, Casanova M, Ferrari A, Luksch R, Polastri D, Terenziani M,Navarria P, Fossati-Bellani F; Pediatric and Radiotherapy, IstitutoNazionale Tumori, Milan, Italy; Neurosurgery, IRCCS San Raffaele,Milan, Italy; Oncology, Ospedale Ca’ Granda Niguarda, Milan, Italy

Medulloblastoma is one of the most common primary brain tumors inchildren (peak age 5 yrs). The low incidence in adults results in a lack of dataconcerning the optimal treatment: maximally surgically feasible resection,craniospinal irradiation (CSRT), and a “Packer-like” maintenance are con-sidered the gold standard. Our aim was to better evaluate the benefit of adju-vant chemotherapy (CT). A retrospective record review of 21 adult ptsaffected by medulloblastoma treated between 1987 and 2001 was performed.Pts characteristics are: median age 24 yrs (range 18.4–41.1); 10 female, 11male. Seventeen pts had gross total resection, 4 had subtotal resection. Fourpts had positive spinal MRI, and 1 positive spinal fluid cytology. Treatmentconsisted of surgery, CSRT + local boost, and 1 of 2 adjuvant CT regimens:(1) VCR concomitant to RT, intrathecal MTX, and 12-mos VCR/CCNU (12pts, 1987–97) or (2) pre-hyperfractionated-accelerated-radiotherapy (HART)

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sequential high-dose CT (HDMTX, HDVP16, HDCTX, HDCBDCA, VCR)and 6-mos VCR/CCNU (7 pts, 1997–2001). Two pts had only craniospinalHART and VCR/CCNU due to medical decision. Eight of 21 pts relapsed(7/12 treated according to the “standard-dose” CT, 1/7 treated according tothe HDCT). Six of 7 pts in the “HDCT group” are alive relapse-free, and theonly one experiencing an event is alive after gross total reresection. Two ofthe 4 pts with postsurgical residual disease died of relapse (all in the “stan-dard dose” regimen). Median time to relapse is 36 mos. None of the 4 “high-risk” pts with spinal dissemination, all enrolled into the HDCT study, haverelapsed at 11 mos median follow-up (7–49 mos). One of these high-risk ptshas been intensified with HD thiotepa and autologous PBMC rescue. Toxic-ity, mainly myelosuppression, was moderate and never life-threatening. Forthe whole series the 5-yr actuarial EFS and OS by Kaplan-Meier method are52% and 64%, respectively. Even considering the small sample size, the mainlimit in analyzing medulloblastoma in adults, we consider “sandwich”sequential HDCT (before HART) the best treatment option, and thisapproach seems to overcome previously recognised risk factors. A longer follow-up will confirm our results.

174. EXPRESSION PROFILING IN EPENDYMOMA REVEALSDIFFERENCES BETWEEN BENIGN AND ANAPLASTICSAMPLESSuárez-Merino B, Hubank M, Hayward R, Harkness W, Thompson D,Phipps K, Revesz T, Darling J, Thomas D, and Warr T; Neuro-OncologyGroup, Department of Molecular Pathogenesis, Institute of Neurology,Queen Square, London. UK

Ependymomas arise from the ependymal cells lining the ventricular sys-tem of the CNS and account for approximately 10% of paediatric braintumours. Approximately 70% of ependymomas are histologically benign andcorrespond to WHO grade II, whilst the remainder are anaplastic (WHOgrade III). The 5-year survival rates in children are 34–45%, with local recur-rence being the major source of therapeutic failure. Anaplasia does not appearto be associated with worse prognosis, and at present there are no molecu-lar or genetic markers which can be used as predictors of outcome. Indeed,the genetic events that contribute to the pathogenesis of ependymoma areessentially unknown. We have used human oligonucleotide arrays to gener-ate gene expression profiles in 10 ependymoma samples from patients withdifferent histopathological/clinical parameters in order to identify new prog-nostic markers. Our sample group is composed of 7 ependymoma (WHOgrade II) and 3 anaplastic ependymoma (WHO grade III). Three patients were<3 years of age at first presentation. Five tumours have chromosomal aber-rations identified by comparative genomic hybridisation (CGH). Our pre-liminary data show that overexpression of specific functional categories ofgenes is dependant on histology when compared to normal controls. Cellcycle and adhesion related genes, oncogenes, and genes involved in apopto-sis were mainly overexpressed in anaplastic tumours. Benign tumours, how-ever, overexpressed mainly growth factor related genes. Some common can-didates emerged for all tumours; Wee1+, a cell cycle related gene thatregulates entry into mitosis, was up to six fold overexpressed in tumours. Theoncogene c-myc, which maps to an amplicon at 8q24 detected by CGH in asubset of ependymomas, was also overexpressed in some tumours and maybe an interesting candidate in their development. To our knowledge, noneof these genes have been associated previously with this class of braintumours. Further analysis of differential gene expression profiles using largeseries of tumours will help in the identification of molecular markers. Thisinformation, when linked to clinical and pathology data, could also help inthe classification of these tumours and the choice of therapy.

175. ASSESSMENT OF ANTI-ANGIOGENESIS TREATMENTUSING PERFUSION MRI IN A GBM INTRACRANIAL MURINEMODELSun Y,1 Mulkern RV,2 Albert MS,2 Burstein D,3 Carroll,4 Kieran MW5;1Department of Radiology, 4Department of Neurosurgery, Brigham andWomen’s Hospital, Boston, MA, USA; 2Department of Radiology,Children’s Hospital, Boston, MA, USA; 3Department of Radiology, BethIsrael Deaconess Medical Center, Boston, MA, USA; 5Department ofPediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Despite surgical and traditional adjuvant therapies such as radiotherapyand chemotherapy, malignant gliomas still have a poor prognosis and highrecurrence rate. The inhibition of angiogenesis is an important mechanismfor controlling the growth of glioblastomas. Assessing the potential of can-cer agents and drug delivery systems can be greatly facilitated by combiningMRI methods with animal models. The possibility of quantified perfusionimaging with MRI offers valuable information in the evaluation of new ther-apeutic approaches. Our first goal was to initiate perfusion imaging studiesto assess the perfusion of an U87 mouse brain tumor model. One of the prob-lems in applying the MRI techniques to mouse tumors during growth is that

the tumors are difficult to differentiate from normal brain during the earlyphases of growth. Preferential enhancement of the tumor with an MR con-trast agent is used to delineate the tumors at this stage. However, the contrastagent may interfere with perfusion imaging if the concentration of contrastagent varies over the time course of the experiment. Therefore, our secondgoal was to determine the time course of contrast agent in the tumor. In 2mice at 24 days of growth, the images showed that tumor perfusion wasdistinguishable from that of normal brain tissue and from surrounding mus-cle. The average tumor perfusion was 51 ml/100 g/min, and that of normalbrain tissue was 130 ml/100 g/min. These values are consistent with previousliterature on gliomas. Secondly, in 4 mice we determined that the MRI con-trast agent was at a stable concentration in the tumors for a time period of15 to 90 minutes post injection. Therefore, the perfusion imaging protocolscan be combined with contrast enhanced MRI to obtain perfusion images atmuch earlier time points in the tumor growth and can be monitored duringgrowth. Although performed clinically, perfusion MRI has, hitherto, been dif-ficult to implement in a mouse model. The results shown here demonstratethe ability to perform quantitative perfusion MRI in a mouse model using ahuman U87 tumor. Future studies will evaluate the response of novel anti-angiogenic treatments.

176. CORRELATION BETWEEN IMMEDIATE OR LONG-TERM SEQUELLAE AND MRI FINDINGS IN PATIENTS WITH MEDULLOBLASTOMASSzathmari A,1 Thiesse P,2 Galand-desmé S,1 Mottolese C,1 Bret P,1 SindouM,1 Deruty R,1 J Guyotat,1 Lion-François L,3 Frappaz D2; 1NeurosurgicalDepartment, Hôpital Wertheimer, Lyon, France; 2Centre Léon-Bérard,Lyon, France; 3Centre Hospitalier Lyon Sud, France

Introduction: After removal of a medulloblastoma, immediate postop-erative neurological complications will usually correlate to long-term cere-bellar sequelae. To help neurosurgeons, we investigated whether preopera-tive and long-term MRI-follow-up may predict such sequelae.

Materials and Methods: We retrospectively reviewed 31 cases of patientsoperated on for medulloblastoma (median: 8 years, range 1 to 39) who wereuniformly treated by irradiation (all had received 54 Gy on PF) +/– chemo-therapy and had at least one year follow-up without tumor relapse. Wereviewed preoperative (ventricular dilatation, ratio of the surface of thetumor/posterior fossa) and postoperative MRI (amount of cerebellarparenchyma removed, degree of cerebellar atrophia, and ischemic regions).We correlated (Fischer Exact test) these data with immediate (major cere-bellar syndromes, motor deficits, cerebellar mutism) and long-term (speechdisorders, global adaptation to daily tasks) outcome. Results: There was astatistically significant difference between the immediate postoperative neu-rological complications and follow-up MRI: postoperative cerebellar syn-drome vs. ischemic territory in cerebellar parenchyma on MRI (p = 0.01),postoperative motor deficit vs cerebellar atrophia on MRI (p = 0.069), cere-bellar mutism vs amount of cerebellar territory removed or ischemic on MRI(p = 0.087). There was a statistically significant difference between long-termsequelae on speech and ratio of preoperative MRI surface ratio (p = 0.0027),or presence of tonsillar hernia (p = 0.05). The amount of global sequelae wasrelated to presence of initial supratentorial ventricular dilatation (p = 0.002)and presence of cerebellar atrophia (p = 0.002). Due to small numbers, nomultivariate analysis was possible to exclude an effect of age at diagnosis.Conclusion: Cerebellar atrophia detected by long-term MRI follow-up cor-related with immediate and long-term cerebellar sequelae. Whether this is dueto vascular or parenchymal damage is speculative. Further investigationsare warranted to document the mechanism.

177. THE ROLE OF COMPARATIVE GENOMICHYBRIDIZATION IN THE DIAGNOSIS AND MANAGEMENTOF PEDIATRIC BRAIN TUMORSTabori U,1,2 Dvir R,2 Rienstein S,3 Aviram A,3 Rozner E,4 Amariglio N,4

Golan H,1 Izraeli S,1 Rechavi G,1 Constantini S,5 Toren A1; 1PediatricHemato-Oncology Department, Sheba Medical Center, Tel-Hashomer,Israel; 2Pediatric Hemato-Oncology Department, Dana Children’sHospital, Tel-Aviv, Israel; 3Institute of Human-Genetics, Sheba MedicalCenter, Tel-Hashomer, Israel; 4Institute of Hematology, Sheba MedicalCenter, Tel-Hashomer, Israel; 5Pediatric Neurosurgery Department, DanaChildren’s Hospital, Tel-Aviv, Israel

Brain tumors constitute the second largest group of tumors among pedi-atric patients and the most common solid tumor in this population. Althoughmany systems for the classification of this heterogeneous group of tumorshave been developed, great variability exists between experts regarding spe-cific diagnoses. Even with the same histopathological entities, the biologicbehavior is extremely variable, ranging from rapid progression to prolongedsurvival. Precise diagnosis is important since there is an emerging associationbetween certain types of brain tumors and response to therapy. Unlike

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leukemias and other pediatric solid tumors, molecular techniques are rarelyused in diagnostic evaluation of brain tumors. We have applied comparativegenomic hybridization (CGH) as a part of diagnostic workup of pediatricbrain tumors. So far, 42 patients have been analyzed. DNA copy numberchanges were observed in 35 cases (83%). The high-grade tumors had signi-ficantly more DNA changes than low-grade tumors. In 4 patients CGHrevealed specific chromosomal abnormalities that led to reclassification of thehistopathological diagnosis. CGH was further used for prognostic purposesin patients with oligodendrogliomas and to diagnose malignant cells in theCSF by combining CGH and FISH. Molecular diagnostic techniques, such asCGH, may add to classification, prognosis, and detection of minimal dis-ease in pediatric brain tumors and thus play an important role in evaluationand management of these tumors.

178. SPECTRAL KARYOTYPING AND COMPARATIVEGENOMIC HYBRIDIZATION FOR THE DETECTION OFCLONAL EVOLUTION IN PEDIATRIC NEURONAL TUMORS Tabori U,1 Rienstein S,2 Aviram A,2 Trakhtenbrot L,3 Cohen N,3 AmariglioN,3 Niggli F,4 Betts D,4 Golan H,1 Constantini S,5 Toren A,1 Rechavi G1;1Pediatric Hemato-Oncology Department, Sheba Medical Center, Tel-Hashomer, Israel; 2Institute of Human-Genetics, Sheba Medical Center,Tel-Hashomer, Israel; 3Institute of Hematology, Sheba Medical Center, Tel-Hashomer, Israel; 4Department of Oncology, University Children’sHospital, Zurich, Switzerland; 5Pediatric Neurosurgery Department, DanaChildren’s Hospital, Tel-Aviv, Israel

Clonal evolution is an important part of tumor genesis and spread. Therole of this phenomenon has been especially important in adult gliomagene-sis where low-grade tumors transform into high-grade tumors after a longlatency. The genetic pathways that govern this transformation are not known.Furthermore, clonal evolution has not been shown in pediatric neuronaltumors, and its significance is unknown. Spectral karyotyping (SKY) is anovel cytogenetic technique based on simultaneous hybridization of 24 fluo-rescently labeled chromosome painted probes. Comparative genomichybridization (CGH) compares painted probes from the tumor to normalchromosomes and detects quantitative abnormalities of genetic material.We applied SKY and CGH to pediatric neuronal tumors. Fifty-five cases werestudied by these methods, including 10 serial biopsies from recurrent pedi-atric brain tumors. Multiple clones were detected in 11 of the 15 cases stud-ied by SKY. Most of these changes could not be detected by classic cytoge-netics due to poor morphology and polyploid mitoses. Clonal evolutionmanifested by duplication of abnormal chromosomes and additionalrearrangements of already translocated chromosomes became apparent evenat the same tumor sample. CGH was applied to 40 cases in which correla-tion between tumor aggressiveness and number of chromosomal abnormal-ities was noted. Of the 10 serial biopsies from recurrent tumors that werestudied, all cases had additional chromosomal abnormalities in the secondand third biopsies which correlated well with disease progression. We con-clude that different clones can evolve in the same tumor concomitantly, andadditional chromosomal abnormalities over time may be an important partof the pathogenesis and disease progression. Advanced cytogenetic techniquessuch as CGH and SKY are powerful tools that enable us to characterise thegenetic heterogenicity of childhood neuronal tumors and can contribute tobetter understanding of the chromosomal abnormalities associated withclonal evolution.

179. HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUSSTEM CELL RESCUE FOR PATIENTS WITH RECURRENTGERMINOMA AND NONGERMINOMATOUS GERM CELLTUMORSTada T,1 Tanaka Y,1 Hongo K,1 Kobayashi S,1 Shigeta H,2 Ishii E3;1Department of Neurosurgery, Shinshu University School of Medicine,Japan; 2Department of Neurosurgery, 3Department of Oncology, NaganoChildren’s Hospital, Japan

Since 1991, 11 patients with recurrent germinoma and nongerminoma-tous germ cell tumors (NGGCT) were treated with high-dose chemotherapy(HDC) followed by autologous stem cell rescue (ASCR). The follow-up dataof these patients are reported here. Patients and Methods: Patient age was 4years to 20 years (median 14 years). The diagnoses included germinoma (3),choriocarcinoma (4), yolk sac carcinoma (1), embryonal carcinoma (1), andimmature teratoma (1). The complete remission was induced by using surgi-cal removal, irradiation, and from 4 to 7 courses of induction chemotherapy.The patient was administrated cisplatin 40 mg/m2 x 5 days (day –7, –6, –5,–4, and –3), etoposide 250 mg/m2 x 5 days (days –7, –6, –5, –4, and –3), andACNU, 150 mg/m2 x 1 day (day –7). A patient received carboplatin 160mg/m2 x 5 days instead of cisplatin to prevent renal dysfunction. The storedstem cells were infused intravenously on Day 0. All patients received radia-tion therapy. The tumor was basically irradiated with 50 Gy, and the sur-

rounding area was irradiated with 30 Gy with conventional fractionation (2Gy/day, 10 Gy/week). Results: Ten patients remain alive and are progression-free. Duration of follow-up after HDC is 11 years to 2 years (median 6.5years). Toxicity included hearing loss (3), avascular necrosis of femoral head(1), renal failure (1). A boy who suffered the second relapse of germinomadied of sudden renal failure and blood loss during the second HDC. A boyhaving visual disturbance caused by the suprasellar mass further worsenedhis quality of life with the hearing disturbance. Conclusions: This HDC fol-lowed by ASCR may provide long-term survival for most patients with recur-rent germinoma and NGGCT.

180. POSITRON EMISSION TOMOGRAPHY IN THECLINICAL MANAGEMENT OF PEDIATRIC BRAIN TUMORSTamir S, Pirotte B, Goldman S, Van Bogaert P, Dain E, David Ph, BrotchiJ; Department of Neurosurgery, ERASME Hospital, Free University ofBrussels, Brussels, Belgium

Some similar pediatric brain tumors (PBT) may show variable growthpotential and response to therapy. Positron emission tomography (PET) pro-vides independent and complementary information on activity/distributionof tumor metabolism. We present our preliminary experience of clinical appli-cation of PET in PBT. Since 1991, 160 PET studies were performed in 74selected children with PBT (28F/46M). The tracer 18F-fluoro-deoxy-glucose was used for 32 PET studies (FDG-PET), 11C-methionin for 51(MET-PET), and both tracers for 38. PET was performed as a diagnosticapproach (n = 72), integrated in the planning of stereotactic image-guidedbrain biopsies/resections (n = 19), or for oncological follow-up (n = 71). In160 PET studies, we retrospectively analyzed the information provided byPET according to the type of tracer, the tumor type/grading, and clinicalexpectations. The choice of tracer evolved over time, but indications remainedselected by the questions raised in the therapeutic management. DiagnosticPET was performed to determine precisely the tumoral nature of a brainlesion found on imaging with no/few symptoms (n = 41) or to complete pre-operative workup in chronic epileptic children with images suspecting tumor(n = 31). In the oncological follow-up, PET was performed immediately aftersupposed gross total resection (PET confirmed tumor residue (to reoperate)in 6 cases, verified absence of tumor residue in 5) or in the long-term fol-low-up to detect/confirm recurrence on suspicious images (n = 6); to studytumor growth under conservative option (n = 15); and to assess tumorresponse to radio/chemotherapy (n = 39). MET-PET appeared specific todetect and delineate tumoral tissue at the diagnostic or follow-up stage. Com-bined FDG-PET/MET-PET helped in the early detection of aggressive pro-gression. The specificity of FDG-PET in representing anaplastic tissue in PBTremains under evaluation. Integrating stereotactic PET in the planning ofimage-guided biopsies/resections rendered a high diagnostic yield in infiltra-tive, ill-defined tumors and allowed reduction of the number of biopsy tra-jectories in high-risk regions. PET data increased the accuracy of the thera-peutic decision, choice, or targeting. Further studies are required to establishguidelines for clinical indications of PET application in PBT. PET will help tobetter understand and assess prognosis in PBT.

181. INTRACRANIAL GERM CELL TUMOUR: EXPERIENCE OF A MULTIRACIAL ASIAN POPULATIONOVER AN 11-YEAR PERIODTan AM, Wong LC, Yang TL, Gao F, Lou J, Sethi VK; PaediatricHaematology/Oncology Service, KKH; Department of TherapeuticRadiology, National Cancer Centre, Singapore

Primary intracranial germ cell tumours (IGCT) are uncommon. Theyaccount for less than 2% of all intracranial malignancies before the age of 20in the West but contribute 7.5% of all brain tumours in children in EastAsia and 11.8% of all brain tumours in children in Singapore. We describeby retrospective study 25 patients with IGCT who received treatmentbetween January 1988 and January 1999 in the Department of TherapeuticRadiology, National Cancer Centre and Paediatric Haematology/OncologyService, KK Women’s and Children’s Hospital. The median age at diagnosiswas 13 years (range 6–22). The majority of patients, 22 (88%), were Chineseby race. The tumours were mainly pineal germinoma (72%). All patients hadhistological diagnosis by either biopsy or resection (gross or partial) prior tochemotherapy or radiotherapy. Spinal disease was assessed by MRI of spineor CSF cytology. It was positive in 1 patient. Serum markers were measuredin 84% of the patients, but only half of these had CSF markers measured.Median follow-up for living patients was 2.57 years (range 0.12–10.8).Median radiotherapy (RT) dose to the whole brain, primary site, and spinewas 35.3, 54, and 30 Gys, respectively. Four to 6 cycles of BEP or JEB chemo-therapy (CM) were given to 10 patients. Of these 10 patients only one hadchemotherapy alone. The remainin 9 patients had combined chemo-radio-therapy treatment. Kaplan-Meier methods were used to calculate O.S. (over-all survival) and RFS (recurrence-free survival) rates. The 10-year OS and

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RFS were 75% and 86%, respectively, for the germinoma group. The mixedgerminoma and nongerminoma germ cell tumours (NGGCT) group had a50% 1-year RFS and a 44% 2-year OS. Acute side effects of radiotherapyand chemotherapy were minimal. Intellectual dysfunction was significantlyassociated with posttreatment neurological or ambulatory side effects (p =0.009). Conclusion: Combined chemo-radiotherapy is recommended toimprove the survival rate of mixed germinoma and NGGCT. We hope touse combined modality of chemo-radiotherapy to decrease the long-term neu-rological sequelae from radiotherapy in young children with intracranial ger-minoma germ cell tumours.

182. RESULTS OF A RANDOMISED STUDY OF PRE-RADIOTHERAPY CHEMOTHERAPY (CARBOPLATIN,VINCRISTINE, CYCLOPHOSPHAMIDE, ETOPOSIDE) WITHRADIOTHERAPY ALONE IN M0/M1 MEDULLOBLASTOMA:THE SIOP/UKCCSG PNET-3 STUDYTaylor R, Bailey C, Robinson K, Weston C, Lucraft H, Gilbertson R,Lashford L; United Kingdom Children’s Cancer Study Group (UKCCSG),University of Leicester, Leicester, UK

The objective was to determine whether 4 cycles of chemotherapy withvincristine 1.5 mg/m2 weekly for 3 weeks, etoposide 100mg/m2 daily for 3days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophos-phamide 1.5 g/m2 given after surgery and before radiotherapy (RT) wouldimprove the outcome for patients with nonmetastatic (M0-1) medulloblas-toma compared with RT alone. Patients aged 3–16 inclusive were randomisedto either chemotherapy followed by craniospinal RT 35 Gy in 21 fractionswith a boost of 20 Gy in 12 fractions to the posterior fossa, or RT alone. Twohundred seventeen patients were randomised, and 179 were eligible for analy-sis (chemotherapy + RT: 90, RT alone: 89). Median age was 7.67 years.Median follow-up was 4.71 years. For all eligible patients, overall survival(OS) was 78.9% at 3 years and 71.4% at 5 years. Event-free survival (EFS)was 71.5% at 3 years and 66.7% at 5 years. A significant difference in EFSwas demonstrated for chemotherapy + RT compared with RT alone. Forchemotherapy + RT, EFS was 78.7% at 3 years and 73.4% at 5 years com-pared with 64.2% at 3 years and 60.0% at 5 years for RT alone (p = 0.0419).There was no statistically significant difference in 3-year and 5-year OSbetween the two arms (82.1% and 76.1% for chemotherapy + RT comparedwith 75.8% and 66.5% for RT alone, p = 0.1662). For patients who hadundergone a total resection, EFS was significantly better with chemotherapy+ RT than with RT alone (p = 0.0346), but this was not the case for patientswho had undergone a less than total resection (p = 0.4835). There was a signi-ficantly better EFS (p = 0.0184) for patients completing RT within 50 dayscompared with those taking more than 50 days to complete. Multivariateanalysis identified extent of surgical resection (p = 0.0398), use of chemo-therapy (p = 0.0228), and time to complete RT (0.0056) as having a signifi-cant impact on EFS. This is the first multicentre, randomised study to demon-strate an improved EFS for medulloblastoma patients treated with pre-RTchemotherapy compared with RT alone. The importance of avoiding gaps inRT schedules has been confirmed.

183. PSYCHOSOCIAL SURVIVORSHIP ISSUES: PARENTS’ PERSPECTIVETilley, K, Foreman, N, Handler, M; Department of Neuro-Oncology, TheChildren’s Hospital, Denver, CO, USA

As more and more children survive childhood cancer and reach adult-hood, survivorship issues grow. Many of these children, especially those whohave had brain tumors, have life-long disabilities that impact their ability toreturn to premorbid levels of functioning and/or to achieve independence asadults. Social workers in the Long-term Survivor Clinic at The Children’sHospital in Denver, Colorado, have gathered data on the long-term impactof illness on families of children with cancer. This has been done through aFamily Stress Inventory Survey given to families at the time of their atten-dance at this Clinic. Preliminary results of this data show that many of theseparents suffer from unresolved anxiety and depression related to their child’sdiagnosis. This presentation will discuss, from the parents’ perspective, thechallenges unique to this population throughout the treatment process andgaps in services for long-term survivorship. The importance of psychosocialintervention with parents at specific points along the continuum of care willbe addressed. The goal of these interventions is to help parents regain a senseof control over their lives and to empower them to deal with the demandsand challenges of their child’s needs. With more clearly identified long-termissues, needs can be addressed earlier and more specifically. Education andguidance can lead to identification of resources and/or gaps in services, whichmay be proactively sought out by parents. Advocacy for programs and ser-vices to fill the gaps must come both from the parents and the healthcareteam.

184. THALAMIC/MIDBRAIN TUMORS IN CHILDREN:SURGICAL EXPERIENCETomita T, Goldman S, Marymont M; Divisions of Pediatric Neurosurgery,Neuro-Oncology, and Radiation Oncology, Children’s Memorial Hospital,Northwestern University Medical School, Chicago, IL, USA

Objectives: To identify ideal therapy for thalamic and midbrain tumors,a personal series of 50 patients operated on from 1988 to 2000 are reviewed.Surgical approaches, extent of tumor resection, type of adjuvant therapies(radiation therapy and/or chemotherapy) and their results are correlated.Materials and Methods: There were 40 thalamic tumors and 10 midbraintumors. Tectal plate tumors were not included. Due to anatomical proxim-ity, tumors had a tendency to invade both structures or beyond these bound-aries. All patients had surgical biopsy, and histology was proven in all cases.Thirteen thalamic tumors and 2 midbrain tumors were biopsied by stereo-taxic method, but all others were directly removed through craniotomy.Surgical approaches were either anterior/posterior interhemispheric (tran-scallosal) approach or temporal trans-ventricular approach for thalamictumors. Subtemporal transtentorial approach was used in cases of midbraintumors. Results: Twenty-three of 40 thalamic tumors and all 10 midbraintumors were benign astrocytoma. Total or near total resection was possiblein 20, and subtotal resection in 14. Surgical morbidity was minimum despiteradical tumor resection. All patients with malignant thalamic tumor died, fre-quently within 12 months, despite radical tumor resection and adjuvant ther-apy. Patients with benign astrocytoma had prolonged remission without adju-vant therapy following radical or sometimes partial tumor resections.Conclusion: Benign tumors are more prevalent in the midbrain location thanthe thalamus. Thalamic/midbrain tumors can be radically removed if appro-priate approach is used. If the tumor is successfully removed, patient withbenign astrocytoma could be observed without adjuvant therapy. Patientswith malignant tumor have very poor prognosis despite aggressive surgicaland adjuvant therapies.

185. PHASE II TRIAL OF THALIDOMIDE WITH RADIATIONIN CHILDREN WITH BRAIN STEM GLIOMASTurner C,1 Marcus K,1 Dutton S,1 MacDonald T,2 Packer R,2 Baez K,1

Lefrancois M,1 Xu L,1 Kieran M1; 1Dana-Farber Cancer Institute, Boston,MA, USA; 2Children’s National Medical Center, Washington, DC, USA

A phase II feasibility study combining radiation therapy with the admin-istration of thalidomide in children with brain stem gliomas (BSG) was con-ducted at Dana-Farber Cancer Institute in Boston, MA, and Children’sNational Medical Center in Washington, DC. The primary objective of thisstudy was to assess the feasibility of administering 1 year of thalidomide. Sec-ondary objectives were to obtain preliminary evidence of biologic activity ofthalidomide in conjunction with radiation therapy and to evaluate toxicitiesfrom chronic administration of thalidomide in this patient population. Four-teen patients (2 to 17 years old) with newly diagnosed BSG were enrolledbetween July 1999 and June 2000. All patients received a standard 6-weekcourse of focal radiotherapy to a total dose of 5580 cGy. Oral thalidomidewas administered once daily beginning on the first day of radiation therapyand continued for 12 months or until the patient came off study. The start-ing dose was 12 mg/kg (rounded down to the lowest 50 mg) and wasincreased by approximately 20% weekly, if tolerated, to 24 mg/kg. Contrast-enhanced MRI with perfusion/diffusion and PET scans were performed inmost patients every 8 weeks. Thalidomide was suspended for grade 2 periph-eral neuropathy, any grade 3 or 4 nonhematologic toxicity, or grade 4 hema-tologic toxicity. If a given toxicity resolved to a grade 1 or lower level within3 weeks, then thalidomide was resumed at 50% of the last dose. Otherwise,the patient was removed from the study. The 14 patients received a medianof 5 months (range 1 to 12 months) of thalidomide before coming off study.One patient completed 12 months of thalidomide but had progressive disease(PD) at the time of off therapy evaluation. Six patients were taken off studyfor PD. Three patients came off study due to toxicity. Four patients wereremoved from study due to withdrawal of consent. There was one grade 4toxicity (a deep venous thrombosis), and there were 8 grade 3 nonhemato-logic toxicities that included constipation, hypersensitivity, weakness, infec-tion, hydrocephalus, and elevated LDH. Five patients had grade 3 hemato-logic toxicity. Data on feasibility, response, and biologic correlates will bepresented.

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186. A NEW APPROACH TO SUBCLASSIFYMEDULLOBLASTOMASUrberuaga A,*1 Navajas A,*1 Burgos J,**1 Mercapide J,**1 Saez deCastresana J,**1 Pijoán JI,***1 Pardo N,*2 Matias-Guiu X,**2 Melo M,*3

Rey i Ruhí M,**3 Calvo C,*4 Alfaro J,**4 Couselo JM,*5 Lòpez JC,**5

Antuña MJ,*6 Ablanedo P**6; *Pediatric Oncology Unit, **PathologyDepartment, and ***Clinical Epidemiology, 1Hospital de Cruces-Baracaldo,Vizacay; 2Hospital Sant Pau, Barcelona; 3Hospital de Sabadell,Barcelona; 4Hospital Miguel Servet, Zaragoza; 5Hospital General deSantiago, La Coruña; 6Hospital Central De Asturias, Asturias, Spain

Medulloblastoma is the most common malignant brain tumor in child-hood, accounting for 20% of all childhood primary central nervous systemneoplasms. Due to the different survival of the affected children, it is under-stood that there must be a feature related to the biology of these tumorsthat directs them into a more aggressive behavior. The purpose of this studywas to find any feature of prognostic significance among the characteristicsevaluated at diagnosis which could be useful to plan the initial treatment.According to this, those children with any feature related to bad prognosiswould receive more intense chemotherapy and radiotherapy regimens. Wereviewed retrospectively the clinical charts and paraffin blocks of 50 childrendiagnosed as medulloblastoma between 1980 and 2001. Six different hospi-tals from the north of Spain collaborated in this study. Clinical and diagnos-tic features included were age, sex, Chang classification, surgical resection,and adjuvant treatment. Tissue markers studied were: MIB-1 (Ki-67), retic-ulin, synaptophysin, GFPA, CD-31, and p53. Overall and event-free survivalwere analyzed in relation to the obtained results. Fifty patients (p) wereincluded. Mean age at diagnosis was 8 years and 2 months. There were 29males and 21 females. Chang classification was as follows: T2-7 p, T3a-29 p,T3b-12 p, T4-2 p; M0-30 p, M1-2 p, M3-5 p (M stage could not be deter-mined in 13 p). Surgical resection was total in 33 p and subtotal in 17 p.Treatment received according to current protocols was: SIOP I-5 p, SIOP II-13 p, SIOP III-19 p, others 12 p; 1 p did not receive any treatment. Witha mean follow-up of 117 months (range 18–313 months) 23 p are alive with-out evidence of disease, 3 p are alive with disease, and 24 p are dead. Dur-ing the last decades, different approaches in the treatment of medulloblas-toma have been elucidated based on age, Chang classification, and surgicalapproach. We will describe here the importance of some tissue markers whenthe diagnosis of medulloblastoma is established in order to subclassify thesetumors to different risk groups.

187. PATTERNS OF PROGRESSION IN SUPRATENTORIALPAEDIATRIC HIGH-GRADE GLIOMAS (HGGS)Vaidya S, Soomal R, Saran F, Pinkerton R, Britton J, Marsh H, ChandlerC, Stapleton S, Bouffet E; The Royal Marsden NHS Trust, Sutton, UK

Background: Few studies have systematically assessed the pattern ofrelapse and incidence of seeding in paediatric HGGs. Pattern of failure isreported to be either recurrence within, or continuous extension beyond theprimary site. Materials and Methods: Eighteen children with supratentorialHGGs were referred to RMH at diagnosis from 7/97 to 6/01. Only one childhad macroscopic complete excision. Nine children were treated with RT, 7with RT followed by chemotherapy. One infant received chemotherapy only.One died shortly after surgery due to progressive disease. We examined allMRI scans at recurrence/progressive disease and compared the site of recur-rence to the planning radiotherapy (RT) fields. Relapse was defined as localif it occurred within the high-dose volume of RT. Median age was 11 years(range: 6 months to 17 years). Histopathology was reported as glioblas-toma (n = 12), anaplastic astrocytoma (n = 5), and bi-thalamic astrocytomagrade II (n = 1). Results: Eight of 9 patients who received RT alone relapsed,5 locally, 2 with only distant seeding (1 spine, 1 multiple sites), and 1 local+cerebellum. Six of 7 children with adjuvant chemotherapy relapsed, 3locally, 2 with local and distant, and 1 with distant (spinal) progression only.Time to relapse from diagnosis ranged from 4 months to 19 months (median9 months). Survival from progression was 1 day to 9 months (median 3months). Three patients are alive disease free (at 32, 32, 54 months). One isalive with disease. Overall, 6 out of 14 relapsed children (42%) metastasised,of whom 4 had thalamic primaries. Conclusion: In our experience, the inci-dence of relapse outside the high-dose irradiation volume seems to be higherthan previously reported. Better understanding of the risk of seeding mayhave implications in the management of paediatric HGG, particularly withregard to the role of chemotherapy and radiological imaging.

188. LOCAL POSTERIOR FOSSA IRRADIATION AT THE AGEOF 2 YEARS IN 4 CHILDREN WITH EPENDYMOMA ORMEDULLOBLASTOMAVandecruys E,1 Verlooy J,1 Laureys G,1 Caemaert J,2 De Neve W,3 BenoitY1; Departments of 1Pediatric Hemato-Oncology, 2Neurosurgery, and3Radiotherapy, Ghent University Hospital, Belgium

The prognosis of children younger than 3 years of age with a malignantbrain tumour who receive no irradiation or in whom chemotherapy is usedto delay irradiation is often worse than in older children. Even after treat-ment with delayed craniospinal irradiation at 3 years of age, many childrenhave significant neurocognitive and endocrinologic dysfunction. We reportour experience of treating very young children with nondisseminated ependy-moma or medulloblastoma of the posterior fossa with surgery, chemotherapy,and local irradiation at the age of 2 years. Between February 1991 and Feb-ruary 2000, 4 children between 17 and 23 months of age (mean age 20months) were diagnosed with ependymoma or medulloblastoma of the pos-terior fossa (ependymoma grade II in 1, anaplastic ependymoma in 1, andmedulloblastoma in 2) without disseminated disease. Three out of 4 childrenreceived a gross total resection, and 1 child with medulloblastoma a near-total resection. All children were treated with chemotherapy based on vin-cristine, cyclophosphamide, carboplatin, and etoposide for a minimum of 4courses or until the age of 2 years. Then local irradiation to the posterior fossawas given in a total dose of 40 to 45 Gray. The child with a near-total resec-tion received post irradiation additional chemotherapy based on lomustineand vincristine for 6 courses. With a mean duration of follow-up of 5 years5 months (from 2 to 11 years), all children remain progression free with min-imal sequelae, ie, limited or no neurocognitive dysfunction, normal growth(3 out of 4 partial growth hormone deficiency on stimulation test but grow-ing normally), and no auditory problems. Conclusion: As in older childrenin whom irradiation is the most effective additional treatment for localtumour control, this could be also true in very young children with nondis-seminated ependymoma or medulloblastoma of the posterior fossa. Replace-ment of craniospinal irradiation by chemotherapy seems possible. Local pos-terior fossa irradiation given as early as 2 years of age seems to have minimalneurocognitive and neuroendocrine morbidity.

189. BRAIN TUMORS IN CHILDREN LESS THAN 5 YEARSOLD AT DIAGNOSIS (1968–1999)Velensek Prestor V,1 Dolnicar Benedik M,1 Jereb B,2 Kopac S,1 ZupancicN1; University Medical Centre, 1Department of Paediatrics, 2Institute ofOncology, Ljubljana, Slovenia

The risk of severe late sequelae in children with brain tumours less than5 years old at diagnosis is high; the treatment is therefore difficult and theprognosis poor. Between 1968 and 1999, 120 children less than 5 years oldwith brain tumors were registered at the Cancer registry of Slovenia; 36 arealive after at least 4 years. The histology was glioma in 59 (17 high-grade,none alive; 22 low-grade, 18 alive; 20 not defined, 1 alive), 22 medulloblas-tomas (6 alive), 22 ependymomas (6 anaplastic, 2 alive; 4 benign, 4 alive;12 not classified, none alive), 7 choroid plexus tumours (3 alive), 3 malignantmeningiomas (2 dead), 2 pineoblastomas (dead), 1 schwannoma (dead), 1PNET (dead), one gangliocytoma (alive), 1 craniopharyngioma (alive).Ninety-three children had surgery; 50 of them received postoperative radio-therapy, and 13 also chemotherapy. Four children had only radiotherapy, and2 had radiotherapy and chemotherapy. Twelve children who had no treat-ment died on admission; for 9 data are missing except that they died withinmonths. Chemotherapy for brain tumors was introduced in 1980. Of the 58children with brain tumors registered before 1979, 10 (17%) are alive. Ofthe 62 registered between 1980 to 1999, 26 (42%) are alive. None of the 17children with high-grade gliomas survived, regardless of method of treatment.Since 1980 the survival of children with brain tumors (except high-gradegliomas) has improved due to better surgery and radiotherapy, and proba-bly also because of additional chemotherapy. Besides neurological andendocrine disturbances, the majority of the survivors have psychosocial prob-lems (education, employment, social relations).

190. IN VITRO INVASION OF LOW-GRADE ASTROCYTOMASCORRELATES WITH CLINICAL OUTCOMEVerlooy J, Langenbick F, Van de Velde S, Vandecruys E, Dhooge C,Caemaert J, Benoit Y, de Ridder L; Department of Pediatric Hemato-Oncology, Ghent University Hospital, Ghent, Belgium

Objective: Comparison between in vitro and in vivo behaviour of paedi-atric low-grade astrocytomas. Methods: Tumour fragments from low-gradeastrocytoma (LGA) patients were collected during surgery or biopsy. Aftermonolayer cell culture, tumour cells were confronted with embryonic chickenheart fragments in vitro for 1, 2, 4, and 7 days. The histological confronta-tion-growth patterns were evaluated microscopically and were classified as

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I: regression of tumour; II: non-invasion; or III: invasion of chicken hearttissue by tumour cells. Clinical evaluation included histopathological diag-nosis, the extent of surgical intervention, and follow-up. Results: Histopatho-logical diagnosis was confirmed for all tumours by immunochemistry. Cellculture and confrontation succeeded for tumour fragments of 10 LGApatients who underwent biopsy (n = 1), partial resection (n = 5), or total resec-tion (n = 4). Of these 10 tumours, 7 showed noninvasion (confrontation typeII). Clinically, none of the 7 patients showed recurrence. Four of them under-went surgery (1 biopsy, 1 partial, and 2 total resection) with no other treat-ment. Only 3 patients received adjuvant therapy (2 chemotherapy, 1 radio-therapy). Three confrontation cultures resulted in a type III growth pattern.Two of these patients showed a recurrence. Patient 1 was treated with irra-diation after total resection but relapsed after 2 years. Patient 2 had an ini-tial partial resection but showed recurrence (after 1 year) while still receivingchemotherapy. The third patient underwent a total resection and received noadjuvant therapy. This patient remained disease free with a follow-up of 7years. Conclusion: Our results show a good correlation for low-grade astro-cytomas (9 out of 10 cases) between the in vitro behaviour of the tumour cellsand the clinical course of the patients.

191. ROLE OF IMAGING IN TUMORS OF THE BRAIN STEMAND SPINAL CORDVezina G; Children’s National Medical Center, Washington, DC, USA

Developments in imaging technology have redefined the roles and chal-lenges of imaging of pediatric patients with tumors of the brain and spinalcord. While the primary role of imaging remains the identification of a brainstem or spinal cord lesion, new techniques allow for a variety of functionsto help the clinician in management of the patient: characterization of thetumor, including spatial localization, definition of extent, and to more lim-ited extent classification (histological); staging of the tumor, including esti-mation of tumor burden; assessment of response to therapy, using anatomi-cal and biochemical markers; treatment planning, with use of imaging datato perform intraoperative navigation and to plan radiation treatment; role ofsurveillance scanning in early detection of tumor recurrence. Lesions withinthe posterior fossa and the spinal canal have historically been difficult to eval-uate with computed tomography given the proximity of dense bony struc-tures. Anatomically, magnetic resonance imaging (MRI) is without parallelin evaluation of these locations. Tissue biochemistry can be investigated withspectroscopy and perfusion imaging. The latter are currently utilized in thebrain stem; in the spine, the presence of susceptibility artifacts from the adja-cent bony structures, physiologic motion, and the small size of the target vol-ume limit the applications of MR spectroscopy and MR perfusion. Theseissues, and the typical presentation of the major tumor types affecting thespinal cord and the brain stem (benign tectal lesions, focal brain stem masses,infiltrated brain stem tumors, cervico-medullary tumors), will be reviewedduring this presentation.

192. VISUAL FUNCTION OUTCOMES OF CHILDREN WITHHYPOTHALAMIC/OPTIC CHIASM GLIOMAS (H/OPG): A 5-YEAR FOLLOW-UP STUDYViscardi E, Pinello P, Albiero E, Zannin ME, Cermáková I, Menegotti A,Laverda AM, Scarzello G, Sotti G, Rigobello L, Faggin R, Perilongo G;Paediatric Neuro-oncology Program of the Department of Paediatrics ofPadua, Italy

This study aims to investigate the visual function outcomes of a cohortof 25 children (12 males and 13 females) affected by an H/OPG followed bythe Paediatric Neuro-oncology Program of the Paediatric Department of theUniversity Hospital of Padua, Italy, according to homogenous treatmentguidelines in the modern MRI era between 6/1993 and 12/2000. The medianage at diagnosis was 4 years (range 3 months to 14 years); 7 had neurofi-bromatosis type 1 (NF1). Due to the young age of many of these children, anaccurate ophthalmological examination was not always possible. It consistedof a preferential looking test technique, LH chart, contrast sensitivity test,colour vision test, visual field, orthoptic and ophthalmoscopic examinations.Results: Initial therapy was surgical resection in 3 patients, radiation in 13(52%), chemotherapy in 5 (20%), and no treatment (“wait and see”) in 5(33%). The median follow-up was 54 months. At the end of the study period,one patient died of tumour progression, while the others are all alive withstable disease. Of 25 children, 11 maintained good vision (V.A. 8/10–10/10),only 1 child became legally blind (V.A. 1/20), and 3 children had low vision(V.A. 4/10 or less). Nine experienced improvement in acuity, 12 remained sta-ble, and 5 experienced vision deterioration. Of 7 children with visual fieldfollow-up, 7 improved, 8 remained stable, and only 3 had some increase inthe visual field defects. Conclusions: The study confirmed the good progno-sis of these children and thus the importance of a “treatment approach” aim-ing to guarantee the quality of life as much as reasonably possible, which inthis context means a good visual function. The authors underline the impor-

tance of serial neuro-ophthalmic examinations together with MRI in the man-agement of H/OPG in infancy and childhood.

193. TOXICITY OF ORAL TOPOTECAN IN CHILDREN WITH RECURRENT HIGH-GRADE GLIOMAS Wagner S,1 Längler A,2 Gnekow A,3 Kühl J,4 Janssen G,5 Peters O,1

Johannes Wolff, 1 on behalf of the brain tumor group of GPOH; PediatricOncology Departments of 1Regensburg, 2Herdecke, 3Augsburg,4Wuerzburg, 5Düsseldorf, Germany; St. Hedwig Hospital, Regensburg,Germany

Objective: To evaluate the maximal tolerated dose and the toxicity pro-file of oral topotecan in pediatric patients with recurrent high-grade gliomas.Protocol: Pediatric patients (0–18 years) with histologically proven recurrenthigh-grade glioma were eligible. Injectable formulation of topotecan wasgiven orally in individually increasing doses (steps of 0.2 mg/m2/d per week)starting with 0.4 mg/m2/d up to a maximal dose of 2.0 mg/m2/d. Treatmentwas discontinued in case of tumor progression or after 1 year. Results: 27heavily pretreated (combined radiochemotherapy) patients were enrolled (agerange 3.3–18.6 years, median 10.15 years; 12 males). Tumor progressionoccurred in 11 patients before relevant toxicity occurred. Additionally miss-ing data left data of 14 patients available for this toxicity analysis. The tox-icity profile (NCI-CTC) of these patients was anemia: III° 29%, IV° 7%;leukopenia: III° 36%, IV° 7%; thrombopenia: III° 43%, IV° 0%; infectionIII° 14%; IV° 0%, nausea and vomiting III° 8%; diarrhea I° 27%; fever I°21%; stomatitis I° 7%, II° 7%. There was no toxic death. The median max-imal tolerated dose was 0.97 mg/m2/day (range: 0.5–2). Conclusion: Whenused in this patient population, oral topotecan should be started at a doseof 1mg/m2/day. The dose should be modified using hematotoxicity as guid-ing parameter.

194. CORRELATION OF COPY NUMBER ABERRATIONSWITH CLINICOPATHOLOGICAL CRITERIA IN PAEDIATRICGLIAL TUMOURSWard S, Hayward R, Harkness W, Phipps K, Thompson D, Harding B,Wilkins P, Darling J, Thomas D, Warr T; Neuro-Oncology Group,Department of Molecular Pathogenesis, Institute of Neurology, QueenSquare, London, UK

Glial cell tumours represent the largest group of brain tumours in child-hood and include astrocytoma (WHO grades I-IV) and ependymoma (WHOgrade II-III). However, little is known about the pathogenesis of thesetumours. We have used comparative genomic hybridisation (CGH) to inves-tigate the genetic alterations in 128 tumours from children and young adults(< 30 years of age) comprising 52 ependymoma, including 40 samples thathave previously been reported (44 grade II and 8 grade III) and 76 astrocy-toma (consisting of 34 grade I, 17 grade II, 7 grade III, and 18 grade IV).Genetic alterations were compared to clinicopathological data such as his-tology, tumour recurrence, and survival in order to identify potential prog-nostic markers. In ependymoma, 39% of the tumours had no detectable copynumber aberrations (CNAs). In the remaining tumours, the most commonregions of gain were 4q (29%), 6q (21%), 1q (17%), and 2q (15%). Themost common regions of loss were 22 (29%), 16p (17%), 17p (13%), and20q (13%). Three regions of high copy number amplification were observedin 3 tumours at 1q24-31 (3 cases), 8q21-23 (3 cases), and 9p (1 case). Therewas no association between any CNA and histology, tumour recurrence, orlength of survival. In contrast, in the astrocytoma group there was a clearassociation between histology and the presence of CNAs. The pattern ofgenetic alterations became increasingly complex with tumour grade, andgrade IV tumours were more likely to have CNAs than lower grade tumours(p = 0.0502). Overall, the most frequent alterations observed in astrocytomawere gain of 4q (11%), loss 16p (10.5%), and loss 17p (10.5%). However,several CNAs were seen predominantly in grade IV tumours (gain 1q, 2q, 4q,and 5q). Fourteen amplicons were observed in 8 tumours of all grades, ofwhich the most common were localised to 7q31 (4 cases), 8q21-22 (3 cases),19p (2 cases), 2q (2 cases), and 12q15-21 (2 cases). From this study, it appearsthat paediatric glial tumours are much more genetically heterogeneous thantheir adult counterparts, and further molecular investigations are needed todefine clinically useful subgroups.

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195. TP53 MUTATION IS INFREQUENT IN ANEUPLOIDCHOROID PLEXUS TUMOURSWarr T, Idowu M, Suarez-Merino B, Ward S, Harkness W, Hayward R,Thompson D, Darling J, Thomas D; Neuro-Oncology Group, Departmentof Molecular Pathogenesis, Institute of Neurology, Queen Square, London,UK

Choroid plexus tumours are uncommon primary brain tumours that arisepredominantly in the paediatric population. Although cytogenetic studies arelimited, it appears that in both benign choroid plexus papilloma (WHO gradeI) and histologically malignant choroid plexus carcinoma (WHO grade III),there is a prevalence of numerical rather than structural chromosomal aber-rations. In particular, additional copies of chromosomes 7, 8, 12, 15, 18, and20 have been reported in several tumours. In the present study, we analysed10 choroid plexus tumours comprising 9 papillomas and 1 carcinoma forgenomic loss or gain using comparative genomic hybridisation. Four caseshad no detectable regions of imbalance. The remaining tumours had multi-ple copy number aberrations (CNAs) ranging from 2 to 22 (mean 8.2), andall of the autosomes were involved at least once. The most common changeswere gains of 7, 9p, and 20, and losses of 3p and 10q, which were each seenin 3 cases. In contrast to previous reports, chromosome loss was as frequentas gain. Additionally, imbalance of single chromosome arms was observed in3 tumours, which may be indicative of structural abnormalities. In manyother tumour types, aneuploidy is often associated with loss of functionalp53. To investigate the role of TP53 in the development of choroid plexustumours, we screened all 10 cases for mutations by direct sequencing of exons4–8 and their corresponding splice junctions. In 1 papilloma, a missensemutation was detected at codon 273 in which a G to A transition results inthe replacement of an arginine residue by a histidine residue. Codon 273 isa hotspot for mutation in many types of tumour, including astrocytoma.Interestingly, this tumour was aneuploid for every autosome. There were nomutations present in the remaining 9 cases, and it is unlikely that TP53 inac-tivation is critical to the pathogenesis of choroid plexus tumours. Furtherinvestigations are necessary to elucidate the genetic pathways involved intumourigenesis.

196. CONFORMAL RADIOTHERAPY FOR THE POSTERIORFOSSA IN MEDULLOBLASTOMA: STUDY INVOLVING 15 CLINICIANSWilliams M, Coles C, Twyman N, Hoole A, Taylor R, Kortmann R;Oncology Centre, Cambridge, UK

In order to facilitate the introduction of a new treatment protocol formedulloblastoma, a planning exercise was undertaken. Fifteen ConsultantPaediatric Radiotherapists participated. All were sent electronic files con-taining a patient history and results of investigations. In addition, electronicimages of CT and MRI scans and a planning CT file were attached, togetherwith a draft PNET-IV protocol specifying target volumes for the posteriorfossa and the tumour bed boost. At a subsequent meeting, participantsreceived 3 lectures covering the treatment of posterior fossa tumours, a reviewof medulloblastoma trials, and a tutorial on planning posterior fossa volumesin the treatment of medulloblastoma. Planning computers were made avail-able, and the participants drew volumes to outline the posterior fossa andtumour bed. For the posterior fossa there was close agreement in the regionof the clivus and cervical vertebrae, but the posterior meningocele wasincluded fully by only 9/15. The protocol was therefore modified to stateclearly that the meningocele should be included. There was also considerablevariation in defining the tentorium cerebellae, and clearer guidance is requiredin this respect also. Lateral images should be reviewed in conjunction withMRI scans to ensure adequate coverage, and fusion techniques could alsobe helpful. The protocol indicated that in planning the tumour bed all tissuesthat had been in contact with the tumour should be irradiated with a 5 mmmargin. In the event, the surgical defect was irradiated partially because noneof the clinicians took adequate account of the preoperative tumour extentaround the brain stem and particularly towards the left internal auditory mea-tus. This was clearly visible on the preoperative MRI scan. This study illus-trates the importance of defining as precisely as possible surgical and radio-logical parameters that should be taken into account when defining theclinical target volume. It also demonstrated the difficulty of a planning exer-cise in which radiological information was presented in an unfamiliar andinconvenient format. In conducting planning studies it is important to repli-cate normal clinical working conditions as closely as possible if volumesdrawn are to reflect clinical practice.

197. A METHOD FOR ASSESSING AND LIMITING OVARIANDOSES IN WHOLE NEUROAXIS IRRADIATION FORMEDULLOBLASTOMAWilliams M, Twyman N, Burnet N, Harden S, Tabor S; Oncology Centre,Cambridge, UK

Medulloblastoma can be cured in approximately 70% of cases overall.Late effects are therefore a very important consideration in the managementof this disease, and many parents are concerned about future fertility for theirchildren. In males the testicles are usually well clear of the inferior border ofthe spinal field and the dose can be checked directly by applying lithium fluo-ride dosimeters. In girls it is difficult to estimate the position of the ovariesand phantom measurements are therefore of limited assistance because thiscritical piece of information is missing. We have studied 6 female patientsaged 4 to 11. MRI scans were undertaken prone in the treatment positionto identify the position of their ovaries prior to whole neuro-axis radiother-apy. The position of the ovaries was transferred to the radiotherapy planningsystem, and plans were generated using conventional symmetrical spinal fieldsand then using two fields incorporating either a half beam blocking techniqueat the inferior border or substituting the lower photon field with electrons.Primary and scatter dose to the ovaries were then calculated for all threeplans. The identification of the position of the ovaries enabled their dose tobe estimated. A modified technique using asymmetry of the inferior borderof the spinal field was most satisfactory in reducing the dose. In two cases,an 80% dose reduction was achieved. In one case only an 18% dose reduc-tion was achieved because the ovary lay on the border of the field. Resultsfrom further cases will be presented. Determining ovarian position using MRIscanning enables the dose to the ovaries to be estimated and minimised.This is important in counselling patients and their parents about future fer-tility and gonadal function. For optimal radiotherapy planning, the inferiorborder of the field is determined using spinal MRI to define the lower limitof the thecal sac. The use of asymmetry at this inferior border can reducethe dose to the ovaries. Thus the combination of locating the ovaries withMRI and subsequently minimising their dose should improve long-termgonadal function for female survivors of this childhood tumour.

198. MEGACHEMOTHERAPY IN HIGH-RISK BRAINTUMORS: A SINGLE CENTER EXPIERIENCEWisniewska-Slusarz H, Drabko K, Nurzynska-Flak J, Wojcik B,Kowalczyk JR; Department of Hematology and Oncology, Children’sUniversity Hospital, Chodzki Street, Lublin, Poland

Background: The outcome of children with high-risk (HR) brain tumor(especially with cerebral fluid involvement) is poor. Megachemotherapy isproposed to be one of the ways to improve results of treatment in this groupof children. The aim of the analysis is estimation of the outcome for chil-dren with HR brain tumor treated with megachemotherapy. Materials andMethods: In our newly developed pediatric BMT unit in Lublin, since June2000 4 children with HR brain tumors have been transplanted (3 boys and1 girl; median age 9.5). Three patients were diagnosed with medulloblastomaand 1 with ependymoma anaplasticum. Indications for megachemotherapywere HR group and cerebral fluid involvement at the time of diagnosis. PriorBMT treatment of tumor consisted of surgery, chemotherapy, and radio-therapy. PBSCT was performed in 3 children and PBSCT+BMT in 1 child.High-dose chemotherapy consisted of carboplatin 300mg/m2, etoposid200mg/m2, and melfalan 50 mg/m2. Average CD 34 cell dose transfused was3.8 x 106. The retrospective control group was 5 children (3 boys and 2 girls;median age 11). Three patients were diagnosed with medulloblastoma and2 with ependymoma anaplasticum. They had the same treatment as the studygroup except megachemotherapy. Results: There were no serious clinicalcomplications during transplantation, and hematological recovery was nor-mal. Three children are alive and well after megachemotherapy, median fol-low-up time from diagnosis 19.5 months and from transplantation 11.5months. One child died due to progression of disease (ependymoma, trans-planted in partial remission). In the control group 2 patients are alive and inI CR, median follow-up time 38 months. Three children died due to pro-gression of disease. Conclusion: Megachemotherapy in children with HRbrain tumor with cerebral fluid involvement in I CR appears to be a safe pro-cedure and may improve results of treatment. Although the group was smalland follow-up short, observation needs to be continued.

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199. IMPACT OF SURGICAL RESECTION ON LOW-GRADEGLIOMAS OF CHILDHOOD: A REPORT FROM THECCG9891/POG 9130 LOW-GRADE ASTROCYTOMA STUDYWisoff JH, Sanford R, Holmes E, Sposto R, Kun L, Heier L, for theChildrens Oncology Group, Arcadia, CA, USA

Surgical intervention has been the primary therapy for the vast majorityof low-grade gliomas of childhood. Most pediatric neurosurgeons believe thatgross total excision of low-grade tumors offers the potential for long-termevent-free survival or possible cure; however, the heterogeneity in location,treatment regimens, and neurodiagnostic evaluation, and the unclear naturalhistory have resulted in extensive controversy and debate in the literature with10-year survivals ranging from 10–94%. The CCG 9891/POG 9130 proto-col prospectively evaluated the impact of surgical resection of low-gradegliomas of childhood. Between October 1991 and August 1996, 726 childrenwith low-grade gliomas were entered into a natural history study: centralreview of resection, residual disease, and pathology was confirmed in 559patients who received only surgical resection and supportive care. Tumorlocation was cerebellar hemisphere, cerebellar vermis, cerebral hemisphere,midline tumors, and chiasmatic-hypothalamic. Of the children in the study,76.4% had juvenile pilocytic astrocytomas, 6.4% low-grade astrocytomas,7.5% gangliogliomas, and 9.7% other low-grade gliomas. Extent of resec-tion was gross total resection 65.1%, near total resection 17.0%, subtotalresection12.4%, partial resection 3.4%, and biopsy 2.1%. Overall survivalfor the entire group at 5 years was 96+8%. Extent of resection, residual dis-ease, location, and pathology were significant factors for progression-free sur-vival (PFS). Five-year PFS was 92+1% with gross total resection vs. 53+5%with near total resection and 60+5% with < subtotal resection (p<0.0001).By location, 5-year PFS was significantly worse in midline tumors (59+6%)and chiasmatic-hypothalamic tumors (50+10%) compared to cerebellarhemisphere (89+2%), cerebellar vermis (84+3%), and cerebral hemisphere(80+3%) tumors (p<0.0001). Pathology was not a significant variable for<near total resection; however, following gross total resection, 5-year PFS wasbetter for gangliogliomas (100%) and juvenile pilocytic astrocytomas(95+1%) than for low-grade astrocytomas (80+13%, p = 0.0094). Age byhemidecade was not significant. Gross total resection provides durable long-term event-free survival and possible cure in childhood low-grade gliomas.In the presence of residual disease, pathology does not impact PFS. Less thantotal resection will result in disease control at 5 years in 50%–60% ofpatients. Implementation of stereotactic guided resection may improve extentof resection and PFS, particularly in deep, midline tumors.

200. CHILDHOOD EMBRYONAL MALIGNANT BRAINTUMORSYaman Agaoglu F, Ayan I, Kebudi R, Gorgun O, Dizdar Y, Darendeliler E;Istanbul University Institute of Oncology, Istanbul, Turkey

Purpose: To present the clinicopathologic features, prognostic factors,and outcomes of children with embryonal malignant brain tumors. Patientsand Methods: From September 1989 to December 2001, sixty-nine children(45 M, 24 F), 4 months–14 years years of age, were treated in a single insti-tute with the diagnosis of embryonal brain tumors. Thirteen (18%) patients(pts) were <3 yrs of age. There were 54 medulloblastoma (MB), 5 ependy-moblastoma (EB), 4 pineoblastoma (PB), 3 PNET, 2 atypical teratoid/rhabdoid tumors, and 1 astroblastoma. Location was in posterior fossa in 57pts, supratentorium in 6, pineal in 4, brain stem in 1, and supra-infra tento-rium in 1. Surgery was total in 38, subtotal in 28, and biopsy only in 3.Twenty-seven pts (39%) had neuroaxial dissemination at presentation. Post-operative treatment consisted of craniospinal radiotherapy (RT) for standard-risk MB pts; RT+ chemotherapy (ChT) for high-risk MB pts and all otherembryonal brain tumor pts; and ChT only for all pts <3 yrs of age. Results:Thirty-eight pts had disease recurrence, some of whom included primary site.The 5-year overall survival rate was 42.9% for the whole series, and themedian survival was 36 months. Patients with MB (5-year survival rate50.3% vs. 14.1% p = 0.01), and >3 yrs of age (5-year survival rate 47.7%vs. 18.7% p = 0.02), and totally resected pts (5-year survival rate 52% vs.33% p = 0.05) had significantly better outcomes. Conclusion: The outcomeis dismal in childhood embryonal brain tumors. Both local and neuroaxiscontrol have to be improved in all ages and histologic subtypes, especially ininfants and pts with less common embryonal subtypes.

201. EPENDYMAL TUMORS IN CHILDHOODYaman Agaoglu F, Ayan I, Gorgun O, Kebudi R, Akinci F, Darendeliler E;Istanbul University Institute of Oncology, Istanbul, Turkey

Between 1989 and 2000, 39 (23M/6F) previously untreated patients (pts)with a median age of 6 yrs (3 mos–15 yrs) with histologically proven ependy-mal tumors (except for ependymoblastomas) were referred to the Universityof Istanbul Institute of Oncology. The localization was supratentorial in 17,infratentorial in 20, both supra and infratentorial in 2. Histologic subgroupswere 17 ependymomas (43.6%) and 22 anaplastic ependymomas (56.4%).Total tumor resection was performed in 17 pts (43.6%), subtotal in 20 pts(51.3%), and biopsy only in 2 (5.1%) pts. Postoperative treatment consistedof regional (8 pts) or craniospinal (6 pts) radiotherapy in patients withependymoma; regional (7) or craniospinal radiotherapy (11) and chemo-therapy in patients with anaplastic ependymoma; chemotherapy only in ptsless than 3 yrs of age (2 pts). Six patients had no adjuvant therapy. A totalof 39 pts were included in the outcome and survival data. The 5-year over-all survival rate was 61.5%, and the 5-year progression-free survival rate was48.7% for the whole series. Median time for progression or relapse was 24.3mos, and there were 17 pts (43.6%) with relapse or progression. Totallyresected pts (p = 0.01, 5-year survival rate was 86% vs. 35%), and pts >3 yrsof age (p = 0.05, 5-year survival rate was 69% vs. 28%) had significantly bet-ter outcomes. In conclusion, the results of this series are comparable with theliterature.

202. GENE EXPRESSION CHANGES IN DIFFERENTIATINGCEREBELLAR GRANULE NEURONSYang Z, Appleby V, Chan W, Tahmaseb M, Orme A, Scotting P; Instituteof Genetics, University of Nottingham, QMC, Nottingham, UK

Medulloblastomas are primitive neuroectodermal tumours of the cere-bellum that occur predominantly in children. Although most are believed toderive from disrupted differentiation of granule neurons, their origins andmolecular pathology remain to be definitively determined. We aim to eluci-date changes in gene expression during the differentiation of normal gran-ule neurons, so that we can better understand the changes these cells undergoduring tumorigenesis to form medulloblastomas. We are also analysing theeffects of genes known to play a role in medulloblastoma aetiology. In orderto gain clear data on the expression profile in granule cells, we are develop-ing highly pure granule cell cultures from cerebellum. Using immunostaining,in-vivo electroporation, and FACS we are able to separate proliferating cellsfrom differentiating cells. Using cultures derived from only the most imma-ture granule cell precursors, we will use microarrays to determine theirexpression profile. We can thus determine gene expression changes as thesecells differentiate. We are analysing the response of the cell to altering thefunction of those genes implicated in medulloblastoma development. Our pre-liminary results demonstrate that this system can be used to show how spe-cific genes encoding transcription factors (Hes-1, RU49, Gli1) affect prolif-eration and differentiation. The next step is to try to complete the links in thechain between these transcription factors and downstream events in terms oftarget genes activated or repressed.

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