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Logo of neuroncolAboutAuthor GuidelinesEditorial BoardNeuro-Oncology
Neuro-oncol. 2007 April; 9(2): 169–221.
PMCID: PMC1871663

Abstracts from the Twelfth International Symposium on Pediatric Neuro-Oncology

June 6–9, 2006, Nara, Japan


S.J. Laughton,1 T.E. Merchant,2 A. Broniscer,1 M. Fouladi,1 L.E. Kun,2 and A. Gajjar1; 1Division of Neuro-Oncology, Department of Hematology-Oncology, and 2Division of Radiation Oncology, Department of Radiological Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To estimate the frequency and severity of endocrine effects in a cohort of children with embryonal tumors treated with craniospinal and conformal primary site irradiation using clinical variables and hypothalamus–pituitary axis (HPA) dosimetry.

Methods: Clinical data were obtained from patient records and institutional databases for children treated at St. Jude Children’s Research Hospital on the SJMB96 protocol. Analysis was restricted to those 77 of 82 children with medulloblastoma, who survived at least two years from diagnosis. The craniospinal irradiation dose was 23.4 Gy for average-risk (AR) and 36.0–39.6 Gy for high-risk (HR) children. The posterior fossa compartment was boosted to 36 Gy in AR, and the primary site, for both risk categories, to 55.8–59.4 Gy.

Results: Radiation doses to the hypothalamus and pituitary were 38.7 Gy (range, 26.3–50.1) and 41.2 Gy (range, 28.8–54.8) in the 47 AR children, and 48.1 Gy (range, 39.3–56.2) and 50.1 Gy (range, 38.4–56.6) in the 30 HR children. Thyroxine (LT4) replacement therapy was commenced in 62 children at a median of 1.95 years (range, 0.90–4.62), hydrocortisone (HC) in 27 children at a median of 1.99 years (range, 0.86–5.65), and growth hormone (GH) in 44 children at a median of 2.23 years (range, 1.40–4.36) after irradiation. The mean hypothalamic radiation dose was higher in children who subsequently required LT4 replacement (42.6 Gy compared to 38.7 Gy, P = 0.04), as was the pituitary dose (45.6 Gy compared to 39.9 Gy, P = 0.003). No association between hypothalamic or pituitary radiation dose and HC or GH requirement was seen. Mean height Z scores fell from 0.21 at diagnosis to −0.47, −0.93, and −1.01 at one, two, and three years after radiation, respectively. Height Z scores at three years were lower in those who received a higher hypothalamic dose (−1.25 compared to −0.83, P = 0.052).

Summary: There was a statistically significant relationship between radiation dose to the HPA and the incidence of hypothyroidism requiring replacement therapy. Although other endocrine deficits are common after treatment, they appear to be multifactorial in their etiology. Minimizing dose to the HPA is an important treatment objective, and further investigation is warranted to determine the incidence, time course, and influence of clinical and dosimetric factors.


T. Tamura,1 I. Tsumanuma,2 K. Nishiyama,2 J. Yoshimura,2 and R. Tanaka2; 1Department of Neurosurgery, Niigata Prefectural Central Hospital, Joetsu, Japan, and 2Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan

There are some reports about growth retardation in patients after cranial irradiation, but little is known about childhood brain tumor survivors. We investigated 33 patients who received radiation therapy (RT) other than of the hypothalamopituitary region (HPR) before puberty. The height standard deviation score (SDS) after RT, time to menarche, results of endocrine tests, and results of GH treatment were assessed. In six patients in which HPR was not included among the radiation fields, mean height SDS suffered, with +0.64 during hospitalization, +0.48, +0.24, +0.26, −0.03, +0.39, −0.48, +0.75, and +0.15 after one, two, three, four, five, six, seven, and eight years, respectively. None of patients had stature short, and mean age at menarche was 12.5 years. In 27 patients whose treatment included HPR, mean height SDS suffered, with −0.17 during hospitalization, −0.63, −0.77, −1.10, −1.23, −1.71, −1.87, −1.49, and −2.11, respectively. Of these patients, 13 had short stature, and eight were treated with GH therapy. The mean last height of the short stature without GH therapy was −3.43 SDS (−2.60 to −4.77), whereas stature with GH was −2.45 SDS (−1.59 to −3.35). Mean age at menarche was 11.5 years. Endocrine tests were performed 22 times (from 1 year 6 months to 21 years 8 months) on 15 patients that had HPR included among the radiation fields. Six of 12 patients with short stature were completely GH deficient, eight were partially GH deficient, and none were normal. In those of normal stature, two of three were partially GH deficient. In conclusion, the incidence of short stature increases at a high rate when HPR is included among the radiation fields. GH treatment may be effective, but usually not effective enough.


D.J. Mabbott, M. Noseworthy, S. Laughlin, C. Rockel, and E. Bouffet; Toronto/Hamilton, Canada

Compromised white matter following cranial-spinal radiation (CSR) for pediatric brain tumors is associated with adverse intellectual outcome. Intelligence measures reflect a composite of multiple underlying cognitive processes, including processing speed, attention, and working memory: Delineating the impact of white matter injury on these core processes is necessary for understanding mechanisms of intellectual decline. We examined whether diffusion tensor MRI measures of white matter integrity accounted for differences in core cognitive processes for children treated with CSR for medulloblastoma (n = 8) relative to age-matched controls (n = 8). Data were acquired with a GE LX 1.5T MRI scanner using a single-shot spin echo diffusion tensor imaging sequence with echo planar imaging readout (25 directions, TE/TR = 100/6000 ms, 22 contiguous axial slices, 3 mm thick, 128 × 128 matrix, FOV = 24 cm, rbw = 125 kHz). ADC and FA were calculated for the genu of the corpus callosum, the anterior and posterior limbs of the internal capsule, inferior frontal white matter, high frontal white matter, and parietal white matter. Mean ADC and FA for all regions were used in analyses of covariance examining group differences in information-processing speed, sustained attention, and working memory. Working memory and attention were poorer for patients compared to controls, but these effects were not significant when controlling for overall mean FA or ADC (P > 0.10). Differences in processing speed between the groups remained, despite controlling for mean FA and ADC (P < 0.01). Poor intellectual outcome may be due to the impact of compromised white matter integrity on core neurocognitive functions.


D.C. Bowers,1 D.E. McNeil,2 Y. Liu,3 W. Leisenring,3 M. Stovall,4 J.G. Gurney,5 L.L. Robison,6,7 R.J. Packer,8 and K.C. Oeffinger9; 1University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA, 2Food and Drug Administration, Rockville, MD, USA, 3Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 4M.D. Anderson Cancer Center, Houston, TX, USA, 5University of Michigan, Ann Arbor, MI, USA, 6University of Minnesota, Minneapolis, MN, USA, 7St. Jude Children’s Research Hospital, Memphis TN, USA, 8Children’s National Medical Center, Washington, DC, USA, and 9Memorial Sloan-Kettering Cancer Center, New York, NY, USA, and the Childhood Cancer Survivor Study

Introduction: This project examines the incidence of and risk factors for stroke among patients who have survived childhood brain tumors for five years or longer.

Methods: The rate of late strokes was determined for childhood brain tumor survivors (n = 1871) and a random sample of cancer survivor siblings (n = 3846). Relative risks (RRs) and 95% confidence intervals (CIs) of stroke by treatment exposures were calculated by multivariate analysis.

Results: This study included 1229 patients with an astrocytoma/glioma, 147 patients with an ependymoma, 395 patients with a medulloblastoma/primitive neuroectodermal tumor, and 100 patients with an unspecified brain tumor. The mean age at tumor diagnosis was 7.7 years (SD = 5.2 years), the mean interval from diagnosis until time of study was 17.6 years (SD = 5.8 years), and the mean age at time of study participation was 25.8 years (SD = 7.9 years). At total of 63 childhood brain tumor survivors reported a late-occurring stroke at a mean of 9.4 years ( ± 7.9 years) after tumor diagnosis. The rate of stroke was 267.57 per 100,000 person-years (95% CI = 206.8–339.2); the RR of stroke compared with siblings was 28.9 (95% CI = 13.8–60.6; P < 0.0001). Among brain tumor survivors who suffered tumor progression, the rate of stroke was 707.3 per 100,000 person- years (95% CI = 428.8–1086.2); and the RR of stroke compared with siblings was 64.5 (95% CI = 27.3–152.7; P < 0.0001). The rate of stroke was higher among brain tumor survivors who were treated with cranial radiation therapy (P = 0.02). Doses of cranial radiation therapy of 30 Gy or more were associated with an increased risk of stroke.

Conclusions: Survivors of childhood brain tumors and particularly those treated with cranial radiation therapy are at an increased risk of stroke.


E.B. Morris, J. Okuma, D. Wallace, M. Fouladi, A. Broniscer, T. Merchant, L. Kun, A. Gajjar, and M. Hudson; St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: To describe the pattern of survival and late mortality among contemporary long-term survivors of pediatric CNS cancer.

Patients and methods: The study population comprised 645 pediatric patients with primary CNS cancer treated at St. Jude Children’s Research Hospital from 1985 to 2000 who survived five years or longer after diagnosis. Patients were classified according to original tumor type, location of tumor, and survival. Cause of death was obtained from the medical record and categorized as progression, malignant transformation, second malignancy, medical complication, or external cause.

Results: Overall survival estimates in CNS cancer patients surviving at least five years from diagnosis was 91.1% ± 2% and 85.5% ± 3% at 10 and 15 years, respectively. No difference in survival by tumor location or by age at diagnosis was evident. A significant difference in the survival rates according to original tumor type (P = 0.0002) was seen. Of 645 patients, 65 (10%) experienced late mortality. Of the patients, 33 (50.8%) died of progressive disease, whereas 14 (21.5%) died of second malignant tumor. Twelve patients (18%), predominantly with diencephalic tumor location, died of a specific medical condition: metabolic compromise, shunt malfunction, sepsis, cardiopulmonary failure, myocardial infarction, or cerebrovascular accident.

Conclusion: Late mortality occurs in a significant number of long-term survivors of pediatric CNS cancer. Progression of initial cancer remains the most common cause of death, followed by the development of secondary cancer. Recognition of survivors with at-risk medical conditions is important because of the potential for preventing death with appropriate educational and/or medical intervention.


K. Sugiyama, K. Arita, and K. Kurisu; Department of Neurosurgery, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan

Purpose: To assess quality of life (QOL) of long-term survivors with germinoma in 2005.

Patients and methods: A total of 52 patients with germinoma (median age, 14.2 years; 41 male and 11 female; 20 with germinoma in pineal, 15 in neurohypophyseal, 11 in both, and 6 in other regions) have visited our clinic regularly and received mainly irradiation (median doses, 48.2 Gy) following pathological or clinical diagnosis from 1968 to 1995. Clinical outcome and prognosis were evaluated from the medical records. Patients or their parents were asked directly about the patients’ academic and occupational career and marriage and social status.

Results: Median follow-up period was 226 months. Six patients had tumor recurrence. Five had treatment-related tumors (three gliomas, one meningioma, and one angioma). Causes of death included tumor progression in two cases, adrenal failure in three, treatment-related tumor in two, suicide in one, and others in three. Survival rate are 86.3% in 10 years, 70.7% in 20 years, and 44.4% in 30 years. Six patients had married, three had been divorced, and three male patients with solitary pineal tumor had a child. The academic career of 34 patients treated at the age of 15 years or younger was as follows: three graduated from junior high school, three from senior high school, eight from senior high school with special care, ten from community college, and ten from university or higher levels. Twenty-one had no occupation after graduation, and seven had left their jobs by age 30 or older. Two were no longer in contact with their family, and two suffered from schizophrenia.

Conclusion: Radiotherapy at 50 Gy provided patients with a satisfactory prognosis but an unsatisfactory, declining QOL. A long-term follow-up system targeting late sequelae should be established. We propose treatment for improving pituitary and psychological functions.


S. Sands, I. Dunkel, S. Gardner, J. Allen, A. Termuhlen, and J. Finlay; New York, NY, USA

Purpose: Follow-up on the quality of life (QoL) and social-emotional and behavioral (SEB) functioning of pediatric brain tumor survivors who were treated on the Head Start I study between 1991 and 1997.

Methods: Of 27 parents, 25 (93%) completed the Child Health Questionnaire and the Behavior Assessment System for Children about their children, who were on average 28.7 months of age at diagnosis (range, 2–63 months); 68.5 months (range, 13–96 months) had elapsed since diagnosis. Questionnaires were completed a second time by 16 (62%) of 26 of parents after an average follow-up of 131.1 months (range, 90–162 months).

Summary: Survivors were functioning within normal limits across all eight indices of physical and psychosocial QoL. Additionally, they were reported to be within the average range on all 18 indices of SEB functioning compared with healthy peers. This profile was stable over time, with the exceptions of a decline in general health (P = 0.000) and improvements in both physical limitations and emotional impact on parents (P = 0.037 and P = 0.021). Young age at diagnosis was correlated with lower adaptability (P = 0.023) and leadership skills (P = 0.008). Those further from diagnosis demonstrated a higher degree of hyperactivity (P = 0.009), attentional problems (P = 0.022), and behavior problems (P = 0.047) at time 1 only.

Conclusions: Long-term follow-up of pediatric brain tumor survivors treated with high dose chemotherapy and stem cell transplant that avoided cranial irradiation in two-thirds of survivors consistently reported QoL and SEB within normal limits. Age at diagnosis and months of follow-up represent significant variables for closer monitoring and proactive intervention.


S. Goldman, J.S. Lai, D. Cella, M. Newmark, M. Fouts, W. Stellpflug, and T. Tomita; Children’s Memorial Hospital, Northwestern University, Chicago, IL, USA

Though many children with pediatric CNS tumors are likely to live well through adulthood, the prevalence of the late effects is high. Monitoring their health-related quality of life (HRQL) throughout their lifetime becomes important. A valid and psychometrically sound instrument is needed to achieve this need. The Pediatric Functional Assessment of Cancer Therapy–Childhood Brain Tumor Survivor (pedsFACT-BrS) was developed to fill this need. The pedsFACT-BrS was developed in two phases. Phase I generated items via interviewing 20 survivors, 20 parents, and 12 clinicians/teachers. Items were rated by additional 20 clinicians for their prevalence and clinical relevance, and by 13 children for readability. Phase II tested the psychometric properties of the pedsFACT-BrS based on data collected from 46 survivors and their parents by using both classical test theory and Rasch analysis. The 37 items were generated from phase I were reduced to 31 items based on phase II analysis results. These 31 items covered domains of physical function, psychosocial function, and brain tumor specific concerns. They demonstrated acceptable internal consistency, and concurrent validity when compared to the Pediatric Quality of Life Inventory™. Rasch analysis supported the fit of items to the measurement model. In conclusion, the pedsFACT-BrS has well-documented face and content validity, and initial evidence of reliability (internal consistency) and concurrent validity. This instrument is ready to be validated to other subpopulations across the disease trajectory and life span and is soon to be used in clinical trials. Results of phase II of this analysis will be presented.


T. Chiang, Y.W. Chen, S.H. Yen, T.T. Wong, Y.F. Hsu, L.L. Liang, H.L. Lo, L.M. Chen, Y.L. Tsai, and T.H. Lin; Center for the Study of Leisure and Health Promotion, Department and Graduate Institute of Recreation and Sport Management, Taipei Physical Education College, Taipei, Taiwan, and Cancer Center, Division of Pediatric Neurosurgery, Occupational Therapy, Division of Neurosurgery, Neurological Institute, Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan

Purpose: To investigate the effects of using situationally modified social rank theory (SMSR) on decreasing learned helplessness (LH) in hospitalized children with brain tumors (HCBTs). Social rank theory stipulates that individuals in lower-rank positions tend to have de-escalating strategies, and it was also used to explain uncooperative and other negative behaviors in hospitalized patients. LH theory states that individuals learn to be helpless and tend to be sad and depressed after losing long-term self- controllability. HCBTs are likely to have negative behaviors with lower social ranks. It affects the quality of therapeutic process and their life quality. SMSR interventions have great potentials to decrease the level of LH and the negative behaviors.

Methods: Six HCBTs were intervened with an SMSR-based leisure education program provided by multidisciplinary collaboration between August 2005 and January 2006 at Taipei Veterans General Hospital. Quantitative and qualitative data were collected to triangulate the effects of interventions. SF-36 Health Survey and Learned Helplessness Scale were collected weekly, and in-depth interviews and observations were conducted with HCBTs and their caregivers. Descriptive statistics and nonparametric statistics were used to analyze quantitative data. Qualitative information was processed using constant comparison.

Results: Both qualitative and quantitative results demonstrated that the interventions enhanced the quality of life and decreased LH for HCBTs and their caregivers.

Conclusion: The results concluded that SMSR interventions are viable and valuable approaches for assisting in the therapeutic process and patient’s adaptation after discharge and for developing a holistic wellness medical service.


C. Moertel, T.J. Passe, S. Bobra, L. Hargens, T. Dahlheimer, and M. Finkelstein; Children’s Hospitals and Clinics of Minnesota and St. Paul Radiology, St. Paul, MN, USA

Posterior fossa syndrome (PFS) is often seen in children after posterior fossa surgery, which generally resolves within several weeks to months. Cerebellar atrophy is also common after treatment, specifically in children who receive radiation therapy, as are abnormal regions of T2/fluid attenuation inversion recovery (FLAIR) signal hyperintense changes in brain parenchyma. This study evaluated the association between PFS and parenchymal volume and T2/FLAIR signal changes preoperatively, postoperatively, and one year after surgery in children with posterior fossa tumors. A series chart review was completed for 35 children who were treated for posterior fossa medulloblastomas (12), astrocytomas (20), and ependymomas (3) over a seven-year period (October 1997 to October 2004). PFS was defined as having mutism and at least one of the following: irritability, quadriparesis, or ataxia. Severity was determined by length of time to recovery. Two neuroradiologists determined cerebellar atrophy by MRI analysis. Independent of diagnosis, 11 of 35 (31.4%) patients had PFS and higher incidence of cerebellar atrophy one year after diagnosis compared to children who did not have PFS (P < 0.05). Moderate or severe PFS in eight children was not associated significantly with greater atrophy or T2/FLAIR signal changes compared to mild or no PFS. Two children continue to exhibit severe deficits 20 and 76 months after diagnosis. The incidence of PFS in this population was higher than previously reported in the literature. PFS may be important in identifying patients at risk for cerebellar atrophy and long-term deficits. The presence of cerebellar atrophy at one year implicates cerebellar injury in the etiology of PFS.


D.S. Traynor; Pediatric Brain Tumor Foundation, Asheville, NC, USA

The disease of pediatric brain tumors is the number one cause of cancer deaths in children in the United States and second in incidence only to leukemia. The Central Brain Tumor Registry of the United States estimated there were 3410 new cases of childhood primary nonmalignant and malignant brain and CNS tumors expected to be diagnosed in the United States in 2005. Of these 3410 new cases, an estimated 2590 will be children less than 15 years of age. “Many children diagnosed today have the potential for fatal outcomes and nearly all experience side effects of therapy. All professionals involved in the treatment of children with brain tumors should be trained in the knowledge required to effectively provide care to patients experiencing the complex problems associated with the diagnosis of a brain tumor and throughout the disease continuum” (Lauria et al., Social Work in Oncology, 2001). Two key members of the multidisciplinary care team required for the treatment of children with brain tumors in the United States are the pediatric oncology nurse and the pediatric oncology social worker. These two medical and psychosocial professional subspecialties have accreditation programs in the United States that require specialized education and training in the treatment and care of children with cancer. The pediatric oncology nurse requires a cancer-specific knowledge base and demonstrated clinical expertise in cancer care beyond that acquired in a basic nursing program. Oncology nurses actively participate as a members of the multidisciplinary team, act as a direct caregivers, and have the ability to provide, guide, and evaluate nursing practice delivered to children diagnosed with cancer and their families. They may be trained in hematology/oncology, chemotherapy, biotherapy, radiation, surgical oncology, bone marrow transplant, symptom management, and palliative care. The pediatric oncology social worker in the United States is knowledgeable about oncology diseases and their treatments, psychological implications for individuals and families, appropriate interventions, and available community and governmental resources. Oncology social workers must have knowledge of the usual course of cancer and its treatments so that patients and families can be helped to anticipate and deal with changes in family life. Services to patients and families include “1. Completion of a psychosocial assessment of the patient and family responses to the cancer diagnosis. 2. Development of a case plan with patient and family based on mutually agreed upon goals to enhance, maintain, and promote optimal psychosocial functioning throughout cancer treatment and its outcome. 3. Utilization of a wide range of clinical interventions designed to address current and/or future problems as the patient’s medical and psychosocial needs evolve. 4. Utilization of high risk screening criteria for case finding and outreach activities. 5. Development of knowledge of cancer, its treatment, and current trends. 6. Maintenance of knowledge of community resources and governmental programs available from local and national health and welfare agencies including expertise in accessing these for patients and families. 7. Organization and facilitation of patient and family education. 8. Collaboration with other professional disciplines in the planning and provisions of services to cancer patients and their families, including advocacy for and protection of patients’ dignity, confidentiality, rights, and access to care; and development of research based knowledge that relates to clinical issues, interventions, and outcomes” (Standards of Practice, Standard II: Services to Patients, Association of Pediatric Oncology Social Workers). In addition to the inpatient/outpatient care for children and their families, charitable organizations exist to provide information prior to or after treatment received in the hospital setting. The Pediatric Brain Tumor Foundation (PBTF) is one such charitable organization in the United States that provides resources to assist patient families and their children with their emotional, educational, and resource needs. The PBTF has written, printed, and distributed educational books on the different types of childhood brain tumors; this material is designed to teach the basic information about a brain tumor to parents of children that are newly diagnosed. Additionally, there is a book provided to parents that contains questions they should ask of their medical care team about the treatment of their child’s brain tumor. The PBTF provides professional lectures to parents and survivors over the PBTF Web site through a program called the Informed Parent Internet Conference. These lectures are archived on the PBTF Web site ( and are available to parents worldwide to hear topics on medical issues related to pediatric brain tumors, treatment and late effects, issues related to the parents and healthy siblings of pediatric brain tumor patients, and issues on palliative care and on helping pediatric brain tumor survivors deal with issues they may face as survivors. Educational scholarships awarded by the PBTF for pediatric brain tumor survivors provide funding for college or vocational training. The PBTF has a social worker on staff to assist patient families in the United States and around the world through counseling and assistance in finding medical care for their child and financial resources provided by the government or other charitable organizations. This PBTF Family Support Program reaches out to the world via the Internet and e-mail to assist families.


H. Kondo, A. Katayama, M. Yokokawa, A. Suzuki, and A. Higuchi; Children’s Cancer Association of Japan, Tokyo, Japan

The Children’s Cancer Association of Japan (CCAJ) was founded in October 1968 by parents who lost their children to cancer for the purpose of supporting children with cancer and their families. The CCAJ has been and is the only nonprofit organization in Japan whose mission is to improve the quality of life of children and families by providing psychosocial support. Over the past 38 years, branches of the CCAJ have increased to 18, with over 3000 members working closely with the CCAJ. Our activities are as follows: (1) We fund medical research projects for doctors, nurses, and other staff members researching topics on the treatment or care for childhood cancer. (2) We provide information and counseling services by social workers for children and families, and fun events for children and families in the hospitals. Social workers also support the camps for children and siblings, educate and coordinate volunteers working in hospitals, and facilitate survivor groups and support groups for bereaved parents. (3) We provide financial assistance to families of those with childhood cancer and lodging assistance to children and families with chronic disease. (4) We publish brochures, pamphlets, and books for families to help them understand childhood cancer.


T. Sato; Division of Maternal and Child Health, Japanese Ministry of Health, Labor, and Welfare (MHLW), Japan

The Children’s Chronic Disease Support Program (CCDSP) is a national program that subsidizes out-of-pocket medical costs for patients who are younger than age 20. The program was launched in 1974 by the Ministry of Health, Labor, and Welfare (MHLW) and is implemented by local governments. The MHLW and local governments (47 prefectural governments, 15 special cities, and 36 core cities) contribute evenly to subsidize 23 billion yen ($200 million) annually, supporting 110,000 patients with chronic diseases. Altogether, 514 chronic diseases, such as pediatric cancer, asthma, and nephrosis, classified into 11 disease groups, are covered by this program. Based on the CCDSP annual reports from local governments, the research group of the National Registry of CCDSP Patients supported by the Research Grant for Maternal and Child Health of the MHLW annually records 20,000 cases of malignant neoplasm (roughly 20% of all CCDSP patients). The most common disease covered by the program is leukemia (6600 cases), followed by cranial tumor (3600), neuroblastoma (2800), and retinoblastoma (1000). Among cranial tumors (3600), the most common is craniopharyngioma (240), followed by medulloblastoma (190), glioma (170), and pituitary tumor (170). Longitudinal systematic follow-up studies on these diseases, as well as socioecological studies on registered patients, would be needed to improve this program further.


Y. Sasaki; Children’s Cancer Association of Japan, Tokyo, Japan

My daughter was diagnosed as having optic glioma and had an operation when she was 15 months old. She lost complete sight in her right eye and half the sight in her left, and the left side of her body was paralyzed. However, she hasn’t experienced much difficulty in daily life as yet because of her young age. She is 15 years old now. Those 15 years were filled with days of tests, treatments, and rehabilitation. As a mother, I have learned many things through my daughter’s illness. I’ve learned about the children suffering from the disease and disabilities and about the society surrounding them. There are many things I’ve found unreasonable. What makes me sad the most is that these children who have overcome painful treatments and loneliness are forced to face a harder situation when they return to the normal life. My daughter has a crossed eye due to the sight loss. Sometimes she is stared at, not only by children, but adults. If they knew of her 15 years of patience and effort, they would admire her instead of acting rude. When the children become of school age, many parents worry about the school’s inadequate preparation and negative attitude toward these children. Even after enrollment, children often suffer from the teasing by the classmates and teachers’ insufficient understanding of the children’s situation. Every time I hear those stories, I once again realize that it is very important for us to let society know how hard these children have fought against their illness, using all of their patience and effort. I want the children who have overcome or are still coping with illness to live proudly and strongly within our society.


T. Nakahachi; Children’s Cancer Association of Japan, Tokyo, Japan

Pilocytic astrocytoma developed in my cerebellum 27 years ago (when I was four years old). The cysts surrounding the tumor were resected in four operations. A ventricular-peritoneal shunt was constructed in two operations. I was irradiated twice with gamma knife radiosurgery. Since tumors still remain, I undergo an MRI every six months. The most trying experiences were the pain and fear of the treatments, and headache and nausea caused by hydrocephalus. In daily life, especially at school, I was distressed by other children insulting me about my poor motor coordination or scars from the operation. Anxiety also stemmed from expecting these reactions, and exhaustion from attempts to avoid them. Although I don’t know whether being depressed because of the cerebellar vermal lesion (cerebellar cognitive affective syndrome hypothesis by Schmahmann et al. 1998), the psychosocial negative experience in childhood, or an inborn personality trait have most influenced me, now I am very anxious and prudent about dealing with people. My struggle in studying for the future has contributed to my survival of cerebellar tumor, because, through the support provided by brain surgeons and parents, I strongly believe the medical dogma that defined the cerebellum as a structure controlling only motor function (Marie-Jean-Pierre Flourens, 1794–1867). Therefore, at age 11, I decided to live by study. I have a spirit of revenge against the world. Also, I have been supported by my warm, infant memories, by self-affirmation learned from people struggling through similar situations in adolescence, and by vague hopes and dreams for adulthood.


A. Higuchi, A. Katayama, M. Yokokawa, A. Suzuki, and H. Kondo; Children’s Cancer Association of Japan, Tokyo, Japan

The Children’s Cancer Association of Japan (CCAJ) was established in 1968 by parents who had lost their children to pediatric cancer. The CCAJ has provided unique social work services for pediatric cancer patients and their families in every aspect, from diagnosis to posttreatment follow-up or palliative and bereavement care. One of the services is a counseling service. In 2004, there were 11,401 counseling cases, including 876 cases for children with brain tumors and their families. Recently, counseling for survivors of brain tumors has increased because, even after their treatment for the tumors is finished, they need treatment and care for the side effects or late effects of the surgery, radiotherapy, and chemotherapy, and for their struggle with school life and social life. We supported one survivor who couldn’t go into society for more than eight years. This social work experience taught us that most important thing in supporting survivors of brain tumors is not just to offer them a place to work and the opportunity to learn social skills, but to foster sociability and improve their self-esteem; that is, to encourage survivors to regard themselves as valuable persons in the world. Through discussion of our social work experiences and analysis of trends with participants, we hope this presentation explores the benefits of social work for survivors of brain tumors.


H. Nagafuchi; Community Service Group Public Relations Department, AFLAC Japan

AFLAC Japan is a branch of AFLAC, a life insurance company with headquarters in Columbus, Georgia, USA. Since 1974, when we started selling cancer insurance in Japan, we have been pursuing our tenet to help people who are fighting against diseases such as cancer. We will maintain this goal for good and commit ourselves to support these patients, not only by selling insurance but by contributing to social welfare. As a symbol of this activity, we have established AFLAC Parents House, which is a general center for children and the families of children who suffer from serious diseases like cancer. AFLAC’s support for this center has two features. The first is that every AFLAC employee and agent (called associates) participate. Our support doesn’t take the form of a company donation as a way of returning part of the profits to society. The second feature is that Parents House is operated through the cooperation of three different organizations: the Children’s Cancer Association of Japan, the nonprofit organization Family House, and AFLAC, a private company. Each organization supports this activity, fulfilling their individual duties in the best way possible. This activity has taken root in the company as a way of realizing the strong desire of every AFLAC member to help persons in need, which is a desire felt by all members, from management and employees to associates, and fulfilled through our everyday work at AFLAC.


B. Dembowska-Bagińska, D. Perek, A. Brożyna, and J. Korzeniewska; Department of Oncology, Children’s Memorial Health Institute, Warsaw, Poland

Background: Childhood survivors of CNS tumors and the families of these survivors experience the negative impact of cancer and its treatment on their lives that cause a decline in their quality of life. The aim here is to assess psychosocial status of brain tumor survivors.

Materials and methods: A total of 74 patients (age, 8–22 years; median age, 14 years) with malignant CNS tumors, who had been off treatment for at least two years, and their parents were interviewed. The questionnaire for parents assessed their work and financial situation at diagnosis and presently, social service support, money spent on medical services, worries, and concerns. The questionnaire for survivors evaluated knowledge about their diagnosis, their treatment, schooling, cognition, social integration, self-esteem, body image, physical status, and future outlook.

Results: In 30% of families, one person had to quit work when their child fell ill, 47% suffered financial problems, 37% received financial help from social services, 48% judged social services as being fair/poor, 31% spent money on medical services, and 51% lived on a very low income. All worried about disease relapse and 80% worried about the child’s future education and work. Of 74 children, 12 (15.9%) have no idea of their diagnosis (parents’ refusal); 32% can name the disease properly, and 74% can name the treatment. During treatment, 89% of patients had teaching at home. At present, 21 are in elementary school, 36 are in gymnasium/high school (9 of them in special schools), 8 are university students, and 9 have finished their education but are unemployed. General problems include the following: 60% have poor concentration, 67% math problems, 64% poor memory, 51% deficits in auditory and visual memory, 46% poor performance under stress, and 89% poor grades (50% do not like school). Of school-age patients, 61% lost their friends at diagnosis, 74% at the time of treatment felt rejected, 22% presently have no friends, 48% feel different (94%, inferior, and 6%, superior), and 12% are dissatisfied with their own image. Despite different medical problems, 73% evaluate their health status as good, and 83% feel happy; however, 78% are pessimistic regarding their job future and plan on welfare.

Conclusions: Children with CNS tumors and their families face numerous difficulties. Our patients experienced some neglect from social services, and there was not enough attention and support from school. Long-term follow-up of patients and their families is essential to intervene in individual situations. Improvements in the care system of these patients is needed. This work was supported by grant C028/P05/2002.


A.D. Witol, B. Wagner, and M. Papsdorf; Stollery Children’s Hospital, University of Alberta, Edmonton, Canada, Children’s Health Care of Atlanta, Atlanta, GA, USA, Centre for Community Child Health Research, Maples Adolescent Treatment Centre, and Simon Fraser University, Vancouver, Canada

For children with brain tumors, very little is known about the relationship between quality of life (QOL), emotional support needs, differing community resources, and families’ travel demands. This study assessed these variables in 41 children with brain tumors receiving treatment in two major cities, one in Canada and one in the USA. All treatments followed standard Children’s Oncology Group protocols. We hypothesized that QOL and support needs would differ as a function of treatment intensity and the perceived difficulty of travel. Data from both sites were pooled because there was only one significant difference between the sites. Analysis of variance revealed that a more difficult commute was associated with families ranking respite, community, and professional support needs as more important, and a higher incidence of family and personal coping problems and social difficulties. There was also a significant interaction as children who were off treatment and who lived further away reported more school difficulties. Treatment type also appeared to have an impact as families of children who did not undergo radiation treatment ranked emotional support needs as less important and described fewer school difficulties than those whose children did undergo radiation treatment. These results indicate that QOL and family support needs for children with brain tumors are influenced by the child’s treatment phase and type, as well as families’ perceived difficulty in reaching the treatment center. Resource allocation and intervention should consider these issues as they impact the child’s functioning and quality of life.


A. Penn,1–3 S. Lowis,2 R. Shortman,1 R.J. McCarter,1 A.L. Curran,1 M. Stevens,2 and P.M. Sharples1,2; 1Frenchay Hospital, Bristol, and 2Bristol Royal Hospital for Children, UK, and 3University of the Witwatersrand, Johannesburg, South Africa

Aims: (1) To compare emotional health in mothers of children with brain tumors one month after diagnosis with that in control mothers. (2) To investigate the determinants of maternal and familial stress.

Methods: Longitudinal prospective study of brain tumor children and matched controls. Maternal emotional health was measured using Beck Depression and Anxiety Inventories (BDI-II and BAI), family stress by Impact on Family Scale (IFS), family functioning and support using Family Assessment Device (FAD) and Family Support Scale (FSS), and coping strategies using the Coping Health Inventory for Parents (CHIP). Cognitive outcome in the child was assessed by WISC III; emotional/behavioral status by Birleson Depression Scale (BDS), Impact of Events Scale (IES), Revised Children’s Manifest Anxiety Scale (RCMAS), and Child Behavior Checklist (CBCL); and quality of life by Health Utilities Index 3 (HUI-3).

Results: A total of 37 tumor patients and 37 controls were recruited (mean age, 8.2 years; and range, 0.4–16.6 years). Mothers of tumor patients had significantly higher BDI and BAI scores than did controls (both P < 0.01). Maternal depression/anxiety symptoms correlated with familial stress (IFS), family functioning (FAD general functioning, communication, problem solving, and roles), family support (FSS formal kinship), older age, and performance IQ (P < 0.05 for all). Family stress levels correlated with child’s physical dependency (HUI3 ambulation, vision, and dexterity), family functioning (FAD affective involvement), and familial coping (CHIP social) (P < 0.05 for all). There was no relationship between the child’s emotional/behavioral status and measures of maternal emotional health or familial stress.

Conclusion: Stress levels in mothers of children with brain tumors are increased compared to controls. Maternal and familial stress levels correlate with dependency and with family functioning and family support, but not with a child’s emotional/behavioral status.


D.M. Ashley, K.E. Enderby, A.C. Jackson, J. Miller, M. O’Toole, N. Tokatlian, M. Tsantefski, S.L. Khaw, and S.A. Thomas; Royal Children’s Hospital, Melbourne, Australia, University of Melbourne, Melbourne, Australia, and LaTrobe University, Melbourne, Australia

Much previous family-oriented research has started from a behavioral pathology or family dysfunction approach. However, there are contradictory findings on family impact of chronic illness. In addition, family impact studies rarely include families where there is a child with a brain tumor, because of variety in the condition and less certain illness trajectory compared with, for example, cystic fibrosis. This study explored the multidimensionality of adaptation and adjustment from a resiliency perspective, emphasizing hope, coping, stress, and support, and drew on the Resiliency Model of Family Adjustment and Adaptation. It sought to relate the patterns of adjustment to levels of wellness in the child and to the time frame over which the families are coping; to explore gender differences in coping style; and to translate the findings into guidelines for clinical intervention aimed at maximizing coping and minimizing burden. It is a multicenter, multimethod, international study spanning a three-year recruitment and observation period, which involved completion of a comprehensive questionnaire by both parents of child brain tumor patients. In addition, semistructured interviews producing qualitative data were administered to every fifth parent. This paper reports on a range of novel design elements and presents an overview of findings on coping and adaptation within these families.


M. Volz-Fleckenstein,1 R. Roberts,2 E. Blumenstock,1 and J.E. Wolff1,2; 1Pediatric Oncology, Regensburg, Germany, and 2University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Introduction: Palliative care for pediatric brain tumor patients is under-developed in Germany. This abstract describes the development of the palliative care program in 2001–2003 in the Pediatric Oncology Department in Regensburg, which serves a sparsely populated area, with 10 deaths from cancer per year previously occurring mostly in the inpatient unit.

Methods: The program included inpatient and home care, weekly rounds, standard operating procedures, and other elements. It was evaluated comparing the frequency of death at home and by parents of deceased children rating the care from 1 = very good to 6 = insufficient.

Results: The need for the palliative program was larger than expected: A total of 51 patients were treated in 2.5 years, only 56% from oncology. Cystic fibrosis was the most frequent nononcologic diagnosis. Of 65 questionnaires, 35 were answered. The proportion of patients dying in the hospital decreased significantly with the palliative care program (9/11 vs. 11/24, P = 0.049). Parents rated the quality of the palliative care as high, with 1.5 in average, independent of whether the care was done prior to (1.7) or with (1.25) the palliative care program. The percentage of parents separated increased from 8.6% to 17.1% during the cancer treatment of their child. There were tendencies for better ratings when patients died at home, and less favorable ratings from parents who had separated during the cancer treatment (not significant).

Conclusion: With the development of a palliative care program, choices of end of life environment changed more to home environment. This work was supported by VKKK Regensburg.


N.J. Ullrich, K. Marcus, C.D. Turner, M.A. Zimmerman, L.E. Lehmann, E. Gillan, M. Kieran, and S.N. Chi; Pediatric Brain Tumor Program, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Background and purpose: Traditional therapy for malignant brain tumors in children includes surgery, multiagent chemotherapy, and radiation. Given the poor prognosis with conventional therapy alone, newer treatment approaches have incorporated high-dose chemotherapy followed by autologous stem cell rescue (ASCR). The purpose of this study was to determine the neurologic sequelae of high-dose chemotherapy followed by ACSR for treatment of primitive neuroectodermal tumors (PNETs).

Methods: We retrospectively reviewed cases of children with PNET who underwent preinduction chemotherapy, followed by craniospinal irradiation, followed by high-dose chemotherapy and ACSR.

Results: In total, four patients with PNET have been treated at our institution with the exact same treatment and sequence of therapy at the same intervals, all of whom are survivors (range, 22–35 months after transplant). Two patients developed transverse myelitis, and the other two patients experienced esophageal strictures, but no neurologic sequelae. Six additional patients who received induction chemotherapy, radiation therapy, and high-dose chemotherapy followed by ASCR (the same consolidation regimen) with different time sequences have not experienced, as yet, these toxicities.

Conclusions: Treatment with chemotherapy and radiation is not without unanticipated and unwanted side effects. The frequency of radiation-induced damage to the CNS is thought to be acceptably low. Commonly accepted spinal cord radiation tolerances may be less applicable when followed by high-dose chemotherapy for transplant, and the timing of radiation with respect to chemotherapy may be of critical importance. Intravenous steroid therapy is helpful for stabilization of disease, though severe neurologic sequelae may remain.


M.A. Zimmerman, C. Turner, S. Chi, C. Chordas, R.M. Scott, L. Goumnerova, M. Proctor, K. Marcus, S. Pomeroy, N. Ullrich, and M.W. Kieran; Dana-Farber Cancer Institute, and Children’s Hospital Boston, Boston, MA, USA

Purpose: Carboplatin is an important component of a number of pediatric treatment regimens, especially in those with low-grade gliomas. We reviewed the serial serum creatinine levels, glomerular filtration rates (GFRs), and audiologic results (performed at baseline and then every three months) of all patients with low-grade gliomas treated with carboplatin over a six-year period.

Patients and methods: Between 1999 and 2005, a total of 45 patients were treated with vincristine and carboplatin for low-grade (WHO grade I/II) gliomas. Three patients demonstrated rapid disease progression requiring discontinuation of carboplatin before the end of induction, one transferred to another institution, and one did not undergo follow-up GFRs. A total of 40 patients are included in this review. Patients received carboplatin 175 mg/m2 weekly × 10 (induction) followed by four weekly doses repeated every 6–7 weeks for eight cycles (maintenance), with concomitant vincristine. The planned total duration of therapy was fifteen months.

Results: Of the 195 GFRs obtained, three were abnormal ( < 1 SD below the age-established norms) at baseline, and eight were abnormal during therapy (one of which also had an abnormal baseline value), for a total of 11 abnormal GFRs in 10 patients. Of these 10, all maintained creatinine values within their age-established norms, and nine maintained normal hearing. Two of the 10 patients required carboplatin dose reductions as a result of a decline in GFR; two additional patients required a dose reduction because of recurrent myelosuppression, both of whom had low GFRs, as well. The remaining patients did not undergo carboplatin dose reduction, and their subsequent GFRs normalized (four of six) or are pending their off-study evaluation.

Conclusions: GFR is a more sensitive measure of early kidney damage when compared to serum creatinine levels. Audiologic outcome was not correlated with kidney function.


P.I. Huang,1 Y.W. Chen,1 S.H. Yen,1 D.M. Ho,2 K.P. Chang,3 and T.T. Wong4; 1Division of Radiation Oncology, Cancer Cancer, 2Department of Pathology and Laboratory Medicine, 3Department of Pediatrics, and 4Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital and National Yang-Ming University, Taiwan

This study analyzed cases of radiation-induced secondary tumors following cranial irradiation in our institute. A total of 1269 pediatric patients with brain tumors treated at Taipei Veterans General Hospital from 1975 to 2005 were reviewed. Seven patients (six females and one male), 2.9–8.9 years old at the time of cranial irradiation, developed secondary tumors after radiotherapy for primary brain tumors. The median latency period was 16.1 years (range, 2.8–20.9 years). The primary tumors were medulloblastoma at the posterior fossa in four patients, craniopharyngioma at sellar region in one patient, germinoma at pineal region in one, and residue pilocytic astrocytoma at the temporal lobe in one. The secondary tumors were as follows: Multiple meningiomas developed 20.9 years after radiotherapy for medulloblastoma (craniospinal irradiation [CSI], 36 Gy; posterior fossa, 50 Gy) when the patient was 5.5 years of age. An anaplastic oligoastrocytoma was found 20.3 years after radiotherapy for medulloblastoma (CSI, 36 Gy; posterior fossa, 50 Gy) at 8.9 years of age. Atypical meningioma developed 13.1 years after radiotherapy with 54 Gy for residue pilocytic astrocytoma in a girl aged 3.4 years. An angiosarcoma over the occipital scalp occurred 2.9 years after irradiation for pineal germinoma (whole brain, 30 Gy; tumor, 50 Gy) when the patient was 5.5 years of age. A meningioma over the left frontal was found 19.6 years after the treatment for medulloblastoma (CSI, 27 Gy; posterior fossa, 54 Gy) in a girl aged 6.1 years. An atypical meningioma developed 16.1 years after radiotherapy for a medulloblastoma (CSI, 34 Gy; posterior fossa, 50 Gy) when the patient was 2.9 years of age. A glioblastoma multiforme at pons occurred eight years after radiotherapy with 54 Gy for craniopharyngioma when the patient was four years of age. Four patients are alive, but three patients (anaplastic oligoastrocytoma, angiosarcoma, and glioblastoma multiforme) died within one year of the diagnosis of secondary tumor despite salvage treatment. Patients receiving cranial irradiation should be carefully followed up for this late sequela.


A. Mahajan,1 E. Chang,1 J. Ater,2 M.H. Maor,1 and S.Y. Woo1; 1Department of Radiation Oncology and 2Division of Pediatric Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Purpose: To investigate the long-term growth sequelae of pediatric patients treated with craniospinal irradiation (CSI) using electron radiation for the spine.

Methods: After institutional review board approval, 37 patients treated from June 1983 to October 2000 with electron radiation to the spine were identified. Their medical records were reviewed, and their follow-up heights and weights were noted.

Results: In this group (20 males and 16 females), the primary histologies were 24 primitive neuroectodermal tumors, 5 ependymal tumors, 6 miscellaneous tumors, and 1 ALL with a median follow-up of 11.3 years (range, 0.2–21.9 years). CSI was delivered at a median age of 6.8 years (range, 2.6–10.6 years). The median dose to the spinal axis was 30 Gy (range, 13.5–45.0 Gy), and the median was 1.5 Gy/fraction (range, 1–2 Gy). One patient (treated at age 2.6 years) developed scoliosis requiring surgical intervention; no other patient had obvious scoliosis or lordosis. The median growth rate slowed in the third year in boys and in the second year for girls. The final height achieved was less than the third percentile in all but two male and three female patients. Four of these five patients received growth hormone (overall, four boys and two girls received growth hormone). No difference in any growth parameter was noted between children treated before or after the age of five.

Conclusions: Only one patient, who was treated at a very young age, developed scoliosis. Otherwise, no asymmetric growth was identified. No unexpected late effects were noted with long-term follow up of electron irradiation to the spine in young patients.


H.A. Spoudeas, A. D’Alessio, and A. Albanese; Departments of Paediatric Endocrinology, St. George’s Hospital and University College Hospitals, London, UK

Objectives: Optic pathway tumors, as well as antitumor therapy, may cause endocrinopathies which we evaluated according to tumor position, treatment, and time in survivors diagnosed prepubertally ( < 11 years).

Study design: Retrospective, descriptive case study analysis of endocrine data.

Patients: A total of 48 survivors (18 male) of optic nerve (n = 20), optic pathway (n = 24), or hypothalamic (n = 4) glioma diagnosed at 4.3 years (range, 0.2–11.0 years) and followed in two endocrine centers for 7.3 years (range, 1.0–19.4 years) after first-line chemotherapy or radiotherapy (5.0 [range, 1.0–12.6] vs. 9.5 [range, 5.7–19.4] follow-up years). Of the patients, 16 (33%) had surgical resection, 10 CSF shunting, 27 chemotherapy (13 as monotherapy), and 26 radiotherapy (13 with chemotherapy). Seven were simply observed.

Results: Most (n = 36 [75%]) had pituitary dysfunction. Except for five patients (three precocious puberty [PP], one growth hormone [GH] hypersecretion, and one postoperative diabetes insipidus), GH deficiency was always first and most prevalent (n = 30 [63%]). It occurred after cranial irradiation (23 [77%] of 30) (χ2, P < 0.01) with (n = 11 [55%]) or without (n = 12) chemotherapy, and depended on tumor (suprasellar) position (χ2, P < 0.02), but also after chemotherapy alone (n = 5 [16%]) and after simple observation (n = 2 [6%]). It was isolated (14 of 30) or combined with one (11 of 30), or two or more (5 of 30) pituitary deficits (seven hypothyroidism [14%] and five hypoadrenalism [10%]). In the youngest (n = 32, < 9 years), PP was frequent (n = 17 [53%]), but two later developed hypogonadism. Five (10%) had only PP. Time increased endocrine morbidity (r = 0.394, P < 0.006); cases without endocrinopathies were followed for only half the time.

Conclusions: Omitting radiation from the treatment protocol does not prevent endocrine morbidity. To avoid short stature and life-threatening anterior pituitary failure, all children with optic pathway tumors should be routinely referred for endocrine surveillance at diagnosis, regardless of therapeutic protocol.


W.E. Reddick,1 J.O. Glass,1 T.E. Merchant,1 X. Xiong,2 W. Zhao,2 and A. Gajjar3; Departments of 1Radiological Sciences, 2Biostatistics, and 3Hematology/Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: Longitudinal MR studies were performed in children with medulloblastoma to estimate the impact of radiation (RT) dosimetry on frontal lobe white matter (WM) volume development.

Methods: A total of 75 subjects (45 average risk and 30 high risk; 24 female and 51 male; age at RT 8.4 ± 3.9 years) were imaged before and after RT (N = 942) every three months for the first two years and every six months thereafter (median follow-up, 3.5 years). Therapy consisted of risk-adapted craniospinal irradiation (23.4 Gy, average risk; and 36–39.6 Gy, high risk): posterior fossa RT, 36 Gy (average risk); primary-site RT, 55.8–59.4 Gy (all patients); and adjuvant chemotherapy. An automated MRI segmentation technique was used to assess left and right frontal WM volumes across five oblique-axial sections covering most of the corpus callosum. Three-dimensional radiation dosimetry was registered with the initial MR examination. Longitudinal mixed-effects models were used to assess changes in volumes after RT and by region with age at RT and regional median dose as covariates.

Results: With follow-up extending to 7.3 years, older age at RT was associated with a larger initial WM volume. Radiation dose had a significant (P < 0.05) impact on longitudinal change in WM volume. Increasing dose was inversely related to rate of change in WM volume. The effect of radiation dose on WM volume change was illustrated for three intervals: WM volume increased for median dose levels of less than 40 Gy; no change was observed for median doses of 40 Gy; and median dose levels of greater than 40 Gy were associated with decreased WM volume over the time interval of the study.

Conclusions: Frontal WM volume development was substantially altered by radiation dosimetry, with the effect being largely observed for high-risk patients treated with doses in excess of 40 Gy.


W.E. Reddick,1 B.A. Taylor,1 J.O. Glass,1 X. Xiong,2 W. Zhao,2 and T.E. Merchant1; Departments of 1Radiological Sciences and 2Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: Longitudinal MRIs were quantified to test the hypothesis that supratentorial brain volume development in children with infratentorial ependymoma treated with conformal radiation therapy (CRT) using a 10-mm clinical target volume margin would follow typical maturation patterns.

Methods: A total of 59 subjects were imaged at least four times over the first two years after presentation (31 girls and 28 boys; age at CRT, 1.1–15.4 years; median, 2.61 years). Treatment and imaging protocols were approved by the hospital’s institutional review board, and written informed consent was obtained. An automated MRI segmentation technique was used to assess changes in white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) volumes across five oblique-axial sections covering most of the corpus callosum. Four regions were defined by the hemispherical midline and the anterior-posterior midpoint of the corpus callosum. Radiation dosimetry was fused with the initial MR examination. Longitudinal mixed-effects models were used to assess trends in volumes against time since CRT by region with age at CRT and CRT dose as covariates. The most recent examination from a subset of 13 patients was directly compared with 36 age-similar healthy controls.

Results: There was a measured increase of WM and GM volumes with a marked decrease in CSF volumes after CRT. Anterior WM development was greater than change in posterior regions consistent with differences in regional maturation rates. WM and GM volume increases exceeded the decrease in CSF volume over time with therapy or shunting. The magnitude and regional variation of WM and GM increase were most consistent with normal maturation. A comparison of the rate of change of WM and GM volume with age between patients and normal controls revealed no significant differences.

Conclusions: Quantitative MRI showed that CRT for infratentorial ependymoma does not substantially alter normal brain volume development.


D.J. Mabbott, L. Penkman, A. Witol, D. Strother, and E. Bouffet; Toronto/Calgary/Edmonton, Canada

Cranial-spinal radiation is associated with a decline in intelligence. Impairments in sustained attention, information-processing speed, and working memory have been documented in children with brain tumors who are treated with cranial radiation. This is the first study to examine concurrently the respective roles of these core neurocognitive processes in accounting for better or worse intellectual outcome in children with posterior fossa (PF) tumors. A total of 68 patients diagnosed with PF tumors participated in the study, including those treated with either (a) surgery and cranial- spinal radiation with a boost to the PF (n = 24), (b) surgery and radiotherapy to the PF only (n = 8), or (c) gross total resection without radiation (n = 36). Ten patients treated for non-CNS solid tumors were included for comparison. Patients were evaluated by using multiple measures of sustained attention, information-processing speed, and working memory. Based on causal modeling, we found that children treated with radiation (either PF only or cranial-spinal) had lower IQ scores than those treated without radiation (P < 0.01). Further, we found that slow information- processing speed accounted in part for the adverse impact of radiation on intelligence, both directly and indirectly through its impact on working memory (P < 0.01). Sustained attention and working memory were not sensitive to treatment differences (P > 0.10). When considering the role of multiple core cognitive processes within a single model, a novel finding was that only slow information-processing speed accounted for the adverse effect of cranial radiation on intellectual outcome.


R. Riccardi, L. Peruzzi, L. Iuvone, C. Colosimo, G. Tamburrini, L. Massimi, M. Caldarelli, I. Lazzareschi, V. Ridola, A. Di Giannatale, and C. Di Rocco; Division of Pediatric Oncology, Radiotherapy, and Pediatric Neurosurgery, Catholic University, Rome, Italy

Objectives: Children with cerebellar tumor (CT) are at risk for cognitive deficits (CDs) usually ascribed to surgery and radiotherapy. Few studies have analyzed the role of tumor in cognitive disfunction. Cognitive assessment before treatment is essential to evaluate the role of tumor on CDs. Moreover, baseline values will allow the assessment of the impact of different treatment modalities on CDs. Evaluating cognitive functions before treatment in children with CT is therefore the purpose of this study.

Methods: Children with CT were assessed at diagnosis for neurological state, IQ, and cognitive abilities, and with MRI.

Results: A total of 20 children were included (12 boys and 8 girls; median age, 7.6 years; age range, 1.5–14.8 years). Histology: pilocytic astrocytoma (9), medulloblastoma (9), ependymoma (1), and atypical teratoid rhabdoid tumor (1). Tumor location: cerebellar hemispheres (right, 4; left, 4) and vermis (12). Neurological deficits: major (4), mild (10), and absent (6). Hydrocephalus (10). Three patients had IQ values below the average, although mean IQ values were normal (mean, 99.6; range, 78–118). Sixteen patients had selective CDs mainly involving executive functions, attention, visual motor integration, and language. A correlation between tumor-specific sites in cerebellum and selective CDs was found. Language problems were associated mainly with right hemisphere and vermis locations (right-sided lesions, 2 of 4; vermis lesion, 4 of 12).

Conclusions: Our study demonstrates the presence of CDs at diagnosis in 80% of children with CT, mainly related to tumor location. Intelligence deficit was present in 15% of patients. These data will represent the baseline for further analysis on the impact of treatment on neuropsychological outcome. This work was supported by the FOP.


S.S. Khan,1 H.A. Spoudeas,2 N.A. Martin,1 R.J. Greenwood,3 and L. Cipolotti1; Departments of 1Neuropsychology, 2Paediatric Neuroendocrinology, and 3Neurology and Neurorehabilitation, Institutes of 2Child Health and 3Neurology, University College, London, UK

Purpose: To evaluate intellectual and functional outcomes in long-term ( > 8 years) cranially irradiated, adult survivors of childhood posterior fossa tumors (PFTs).

Methods: A total of 13 adult survivors of childhood PFT (eight male and five female; mean age ± SD, 22.6 ± 3.7 years; mean age at diagnosis ± SD, 5.5 ± 2.8 years) attending a late follow-up clinic were studied. All patients had received surgery and 30–35 Gy whole brain ± spinal irradiation and 20 Gy tumor boost as part of initial treatment. The Wechsler Adult Intelligence Scale-Revised (WAIS-R) was administered. Education years and occupational status were recorded.

Results: Patients had a mean WAIS-R FIQ of 80.6 ± 11.5 and 14.6 ± 2.1 years of education. Seven patients were in paid employment and only one was unemployed, four were academic students, and just one patient required support in the community. There was no significant correlation between the age at diagnosis and IQ.

Conclusion: PFTs in childhood hamper performance on tests of general intelligence, such as the WAIS-R, in adulthood without an obvious effect of age at diagnosis. Despite these relatively modest intellectual skills and the likely selection bias inherent in this cohort, all patients were able to accomplish a reasonable level of education, and the majority achieved gainful paid employment in adulthood.


J. Benjamin, H.E. Miller, S. Lowis, A.L. Curran, A. Penn, and P.M. Sharples; CLIC Childhood Brain Tumour Study, Frenchay Hospital, Bristol, and Bristol Royal for Children, UK

Aims: (1) To define neurological outcome in children with primary brain tumors presenting in the Southwest region. (2) To explore factors related to poor outcome.

Methods: Children aged 0–17 years presenting with a primary brain tumor over 1999–2002 were identified. Information concerning mode of presentation, investigation, management, outcome, and demographic details was obtained. Brain tumors were classified according to the WHO classification and outcome by the method of Seisha et al.

Results: A total of 125 children presented over the four years (mean, 31/year): 62 (50%) were boys. Mean age at presentation was 7.5 years (range, 0.01–17.0 years). Six (5%) had a genetic syndrome. Main presenting symptoms included headache and vomiting (38%), cranial nerve palsies (15%), seizures (13%), gait abnormality (10%), constitutional symptoms (8%), sensory symptoms (4%), mass lesion (3%), and hemiparesis (2%). Of the children, 93 (74%) had abnormal neurological signs at presentation, and 20 (16%) had endocrine problems. Tumor diagnostic categories were benign astrocytoma (44.4%), primitive neuroectodermal tumor (18.5%), malignant atrocytoma (14.5%), craniopharyngioma (5.6%), ependymoma (4.8%), germ cell tumor (1.6%), and others (10.5%). A total of 109 children (87%) underwent surgery, 59 (47%) radiotherapy, and 48 (38%) chemotherapy. Neurological outcome was good in 34 (27%); moderate in 74 (59%); and poor in 17(14%), of whom 11 (9%) died. Fifteen (12%) developed epilepsy. There was a significant negative correlation between poor outcome and radiotherapy (τ = −0.20; P = 0.027) and chemotherapy (τ = −0.26; P = 0.004). There was a significant negative correlation between year of diagnosis and neurological outcome, with outcome improving over time (P = 0.016).

Conclusion: Many children with primary brain tumors are now surviving. Neurological morbidity is significant, but appears to be improving.


T. Chiang, Y.W. Chen, S.H. Yen, T.T. Wong, Y.F. Hsu, and K.W. Lin; Center for the Study of Leisure and Health Promotion, Department and Graduate Institute of Recreation and Sport Management, Taipei Physical Education College, Tapei, Taiwan, and Cancer Center, Division of Pediatric Neurosurgery, and Occupational Therapy, Division of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

Purpose: To explore psychological experiences of using situationally modified social rank theory (SMSR)–based leisure education in a terminal oncological child with brain tumor and his or her primary caregivers. Social rank theory stipulates that individuals in lower-rank positions tend to have deescalating strategies, and it was also used to explain uncooperative and other negative behaviors of terminal oncological patients. Learned helplessness (LH) theory states that individuals learn to be helpless and tend to be sad and depressed after losing long-term self-controllability. Terminal oncological children are likely to have negative behaviors with lower social ranks, which affects the quality of the therapeutic process and their quality of life. SMSR interventions theoretically decrease the level of LH and the negative behaviors.

Methods: The 13-year-old terminal oncological child joined an SMSR-based leisure education program provided by multidisciplinary collaboration between September 2005 and January 2006 at the Taipei Veterans General Hospital. The child’s wish to see an elite professional basketball athlete was discovered and was achieved by the research team on September 25. Quantitative and qualitative data were collected to triangulate psychological experiences. Learned helplessness scale was determined and in-depth interviews and observations were conducted with the child and caregivers.

Results: Qualitative data showed that the child acquired LH during his condition, and quantitative results demonstrated that the intervention had a positive impact on the child and his caregivers.

Conclusion: The results concluded that SMSR-based leisure education has potential for terminal oncological children and their caregivers.


J. Grill, S. Escolano, V. Kieffer, G. Dellatolas, and C. Kalifa; Gustave Roussy Institute and INSERM U472, Villejuif, France

IQ measurement with the Wechsler scale is one of the cornerstones of neuropsychological evaluation in children with brain tumors. It has been shown to correlate with treatment-related variables and age at diagnosis. From a practical viewpoint, it would be desirable to reduce the length of the evaluation by limiting the number of subtests. We used as a learning set a group of 32 children receiving standard treatment for medulloblastoma to define three subtests highly correlated with full-scale IQ (FSIQ). A comparison with the three subtests selected by Palmer (J. Clin. Oncol., 2001) was also performed. The formulas used to estimate the IQ were tested on three different samples consisting of 25 children treated with hyperfractionated craniospinal irradiation for medulloblastoma (population 1), 31 children with malignant germ cell tumors treated mainly with focal irradiation (population 2), and 19 young children treated with high-dose chemotherapy and posterior fossa irradiation for recurrent medulloblastoma (population 3). The best selection of three subtests was able to predict close to 98% of the variation of the FSIQ in the learning set and 92%, 95%, and 94%, respectively, in the three test populations. The mean error with the estimated IQ was 3.8 points in the learning set and 7.5, 6.7, and 6.5, respectively, in the three test populations. Although estimated IQ could be a good surrogate for evaluating a large population of patients, it cannot describe the large variability in the samples of patients and cannot be used to perform a risk-factor analysis.


J. Korzeniewska, M. Drogosiewicz, B. Dembowska-Bagińska, M. Perek-Polnik, and D. Perek; Children’s Memorial Health Institute, Warsaw, Poland

Purpose: To assess psychological (intellectual and emotional) function status of patients with CNS germinoma after complex anticancer treatment.

Materials and methods: Between 1997 and 2004, 38 patients with CNS germinoma were treated with SIOP protocol (chemotherapy, neurosurgery, and local irradiation: 40 Gy). Up to now, 31 patients are alive with a follow-up of 10 months to 5 years 7 months (median, 1 year 9 months) after diagnosis. All of the patients are under periodic psychological observation and care. Age at psychological assessment ranged from 9 years 10 months to 20 years 10 months (median, 13 years 1 month). Patients with no pre-diagnosis history of neurological, developmental, or psychiatric disorder were examined using a battery of standardized psychological and neuropsychological methods.

Results: Intellectual outcome: FIQ (full-scale intelligence quotient) score ranged from 59 to 139 (median, 96). One patient is mildly mentally retarded, one is highly intelligent, and the others are of average intelligence. No other significant cognitive deficits were noticed. Emotional outcome: All patients haad emotional disturbances (of different grades), especially internalizing-type problems (immaturity, depression, anxiety, instability, slowness, inhibition, and negative attitude) or were considered to be at risk for psychological adjustment difficulties and a tendency to somatization. The analyzed group of patients also showed socially competent deficits. They may exhibit a deficit in age-appropriate social competence and peer relations. One child in our material displayed psychotic symptoms.

Conclusion: Emotional problems are more characteristic than intellectual ones in this group of patients. This seems to be specific for germinomas, compared with other childhood CNS tumors.


J.A. Takahashi, Y. Takahashi, Y. Kishi, M. Oda, K. Watanabe, S. Adachi, H. Nobuo, and A. Mochizuki; Departments of Neurosurgery and Pediatrics, Kyoto University Graduate School of Medicine and Graduate School of Science for Human Service, Ritsumeikan University, Kyoto, Japan

Background: As the incidence of children surviving brain tumors has improved, education of such patients has a social imperative to assure them a good quality of life as long-term survivors. However, childhood brain tumor survivors are often excluded in studies evaluating school performance of childhood cancer survivors, in part because of concerns about the impact of cognitive limitations on the validity of assessment or because of the concern that those with a history of a childhood brain tumor may not fairly represent the greater population of children with cancer.

Methods and results: Ten patients, 2–18 years of age at diagnosis, and their parents were interviewed with a structured list of their perceptions of their school experiences. Although two children with severe deficits (recent memory disturbance and severe hypothalamic dysfunction) performed well academically in community schools, four of eight children with lesser, milder, and intermediate deficits (hormonal replacement, one-eye blindness, mild cerebellar ataxia, and diplopia), none of which had cognitive dysfunction, had a history of truancy and performed poorly in community schools. Significant factors correlating with school attendance and school performance were the schoolteachers’ understanding about diseases and the children’s participation in school life.

Conclusions: Through the use of multidisciplinary teams, open communication between the school and the hospitals should be promoted.


J. Bernabeu, A. Canyete, C. Fournier, G. Almerich, and V. Castel; Pediatric Oncology Unit–Hospital Infantil La Fe, Research Methods and Diagnosis in Education, University of Valencia, Valencia, Spain, Psychology Unit, University Hospital Niño Jesus, Madrid, Spain

Purpose: To clarify treatment effects (cranial radiotherapy, methotrexate, etc.) on CNS cognitive and behavioral functioning, and to determine differences between children with CNS tumors and leukemia and healthy children in neuropsychological profiles.

Method: A total of 109 children were studied (boys, 63.3%; and girls, 36.7%): 25.7% with benign brain tumor, 28.6% with malign brain tumor, 31.4% with leukemia; and 14.3% were healthy controls. Assessment was performed with our neuropsychological protocol, about 5 h of testing per child. It includes 25 tests to measure 54 neuropsychological processes in nine cognitive areas (general cognitive abilities, motor function, visual perception, nonverbal abilities, language, memory, attention, executive functions, and academic abilities). Achenbach scales for parents and teachers and self-reports were used for psychopathological assessment. We also used Conners’ CPT-II to measured reaction times, vigilance, impulseness, and inattention. Statistical analyses (parametric, nonparametric, and analysis of variance) were carried out by using the SPSS 12.0 package.

Results: All clinical patients showed a deficit in neuropsychological assessment.

Significant results: (1) CNS treatment appears to be related to ADHD inattentive subtype; white matter damage is suggested. (2) Patients with malignant brain tumor haad the worst scores. (3) The longer from diagnosis, the worse were scores in cognitive general abilities, visual perception, memory, and attention areas. (4) Leukemia patients had mild deficits in all areas, excluding nonverbal abilities, motor function, and visual perception. Language processes are more affected (receptive vocabulary, denomination, semantic fluency, and VIQ).

Conclusions: Neuropsychological assessment offers information about cortical and subcortical cognitive and behavioral functioning. Knowing specific diagnosis-related neuropsychological late effects enables us to design target-oriented rehabilitation procedures (drugs, training, counseling, follow-up, etc.) to improve, compensate, and palliate those effects.


R. Shortman,1 R.J. McCarter,1 A. Penn,1–3 S. Lowis,2 M. Stevens,2 A.L. Curran,1 and P.M. Sharples1,2; 1Frenchay Hospital, Bristol, and 2Bristol Royal Hospital for Children, UK, and 3University of the Witwatersrand, Johannesburg, South Africa

Aims: To define cognitive function in children with brain tumors one month (t1) and six months (t6) after diagnosis and to investigate changes in cognitive outcome in brain tumor patients between t1 and t6.

Methods: A longitudinal prospective study of children with brain tumors compared with matched normal controls. Intellectual outcome was assessed by the Wechsler Intelligence Scale for Children (WISC III UK) and Wechsler Primary and Preschool Scale of Intelligence–Revised. Attention was assessed by the Test of Everyday Attention. Memory was assessed by the Children’s Memory Scales. Academic status was assessed using the Wechsler Quicktest.

Results: A total of 33 tumor patients and 33 controls at t1 and 25 patients and 25 controls at t6 have been studied. Mean age at diagnosis was 11.7 years (range, 5.97–16.6 years). At t1, there was a significant difference between patients and controls for verbal IQ (VIQ) (P = 0.006), performance IQ (PIQ) (P = 0.001), and processing speed (P < 0.0001), Using repeated measures analysis of variance, significant improvements were found between t1 and t6 for PIQ (P < 0.005), visual immediate memory (P = 0.007), verbal immediate memory (P = 0.05), visual delayed memory (P = 0.005), and selective attention (P = 0.011), but no significant improvement over time in VIQ (P = 0.408) or processing speed (P = 0.306). At t6, children with brain tumors showed significantly poorer results than did controls on measures of processing speed (P = 0.001), verbal delayed memory (P = 0.015), sustained attention (P = 0.05), mathematics (P = 0.018), and Wechsler Quicktest composite score (P = 0.019).

Conclusion: Children newly diagnosed with brain tumors have significant impairments in cognitive function that will negatively impact their performance in the school setting. There is some improvement over time, but significant deficits persist for at least six months.


V. Cutinho, J. Grill, G. Dellatolas, C. Patte, O. Hartmann, C. Kalifa, and V. Kieffer; Gustave Roussy Institute and INSERM U472, Villejuif, France

Purpose: Intracranial malignant germ cell tumors have a high cure rate with standard treatments, including chemotherapy and irradiation. Our aim was to evaluate the long-term cognitive sequelae and to establish the neuropsychological profile according to the localization of the tumor and the extent of irradiation.

Methods: Complete neuropsychological evaluation was performed at a median of three years after the end of irradiation for 31 children and adolescents with pineal (n = 20) or suprasellar (n = 11) malignant germ cell tumor treated between 1991 and 2004, at a median age of 13 years. All patients were treated with local radiotherapy, and five also had craniospinal irradiation.

Results: Intellectual efficiency was largely preserved with a mean full-scale IQ of 105 ± 22, a mean verbal IQ of 110 ± 22, and a mean performance IQ of 98 ± 21. A significant dissociation between the verbal and performance IQ (P < 0.001) was observed specifically in patients with pineal tumors. Children with pineal tumors had more specific impairment in memorization of visual material, visuoconstructive abilities, attention, and manual dexterity of the dominant hand. Children with suprasellar tumors had problems especially with long-term memory of verbal information. A slight decrease in full-scale IQ and in long-term memory abilities were observed on the longitudinal follow-up. Surgery had no effect on the cognitive abilities of patients.

Conclusion: Although children treated for an intracranial malignant germ cell tumor had intellectual efficiency preserved, specific neuropsychological deficits were observed depending on the tumor location.


N.J. Ullrich, C. Rey-Casserly, and L. Goumnerova; Department of Neurology, University Hospital, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA

Background and purpose: Endoscopic third ventriculostomy (ETV) is an effective technique for the treatment of obstructive hydrocephalus. The purpose of this study was to determine the neuropsychologic sequelae of ETV in children with primary brain tumors and aqueductal stenosis.

Methods: We retrospectively reviewed all cases of children who underwent ETV for hydrocephalus at our institution and who had undergone neuropsychologic testing.

Results: A total of 23 patients were evaluated. Neuropsychological outcomes varied widely in the group; overall IQ ranged from 62 to 129, with a mean of 94. Assessment of verbal learning was available for 17 of the patients, and scores were lower than average in the group. Significant verbal learning problems were seen in a substantial number of patients: 35% scored at or below 1.5 standard deviations in word-list learning, and 65% scored at or below 1.5 standard deviations on delayed recall of verbal information. Those patients who had received additional adjuvant therapy performed similarly to the patients who did not with respect to IQ, but memory scores were somewhat lower for patients receiving adjuvant therapy.

Conclusions: Postsurgical performance in our patient population ranged widely from significantly impaired to well above average. Verbal memory problems appear more prevalent in our patients overall, and there is evidence that patients without additional adjuvant therapy showed only milder deficits in verbal memory. These results suggest that ETV is relatively safe in terms of long-term cognitive sequelae, but that a subset of patients may be at more risk for unwanted neuropsychologic side effects.


A.D. Witol, D. Arndt, B. Wilson, and M. Whitehead; Stollery Children’s Hospital, University of Alberta, Edmonton, Canada

There is limited information regarding the quality of life (QOL) in children with brain tumors and less is known about their families’ needs. This study assessed QOL and its impact on families’ emotional support needs among children with brain tumors, using the PedsQL and Family Needs Questionnaire (FNQ). Subjects were children assessed in a neuro-oncology clinic over a one-year period (n = 63). Existing research often focused on children with suspected emotional/cognitive difficulties, which can be biased toward problem reporting. Thus, the current sample was chosen as a more inclusive method of studying this group. Quantitative analyses revealed that QOL varied by diagnosis and was related to family health information and emotional support needs. For example, parents described children with medulloblastomas as having significantly more concerns with their physical appearance, feeling embarrassed by their body, and described their children as more anxious. Two-thirds of the entire sample reported health information, respite, and emotional and community support needs as met. There was a positive correlation between the number of needs met and children’s mean physical, academic, emotional, and communication QOL scores. Although unmet health information and emotional support needs were not a significant issue for the majority of the families of this cohort of children, children’s QOL scores were influenced by the families’ perceptions of the degree to which these needs were met. Health care delivery may also influence parent’s perceptions of support needs. Screening of both QOL and family health and emotional support needs is strongly recommended in order to help identify those individuals in need of additional support.


A. Penn,1–3 S. Lowis,2 R. Shortman,1 R.J. McCarter,1 A.L. Curran,1 M. Stevens,2 L. Hunt,1 and P.M. Sharples1,2; 1Frenchay Hospital, Bristol, and 2Bristol Royal Hospital for Children, UK, and 3University of the Witwatersrand, Johannesburg, South Africa

Objectives: (1) To investigate HRQL in brain tumor patients one (t1) and six (t6) months after diagnosis. (2) To relate HRQL to child and family variables.

Methods: A longitudinal prospective study of children with brain tumors and normal matched controls. HRQL was measured using parental report Pediatric Quality of Life Inventory (PedsQL), cognition using WISC-III and WPPSI, and psychological outcome using Birleson Depression Scale (BDS), Revised Children’s Manifest Anxiety Scale (RCMAS), and Impact of Events Scale (IES). Primary carer’s emotional health was measured using Beck Depression and Anxiety Inventories (BDI-II, BAI); familial stress, family functioning, and family support using the Impact on Family Scale (IFS), Family Assessment Device (FAD), and Family Support Scale (FSS); and coping strategies using the Coping Health Inventory for Parents (CHIP).

Results: A total of 40 tumor patients and 38 matched controls completed t1 assessment, 34 patients and 27 controls t6. Patient scores were significantly reduced for PedsQL total score, psychosocial summary, and all four domains, compared to matched controls at t1 and t6 (all P < 0.001). Patient scores improved significantly from t1 to t6 (P < 0.05). PedsQL Total Score at t1 correlated with Performance IQ, RCMAS, BDS, CHIP Social, IFS, and FSS Social organizations. PedsQL Total Score at t6 correlated with BDS, IFS, FSS Social organizations, FSS Informal Kinship, FSS Total Level of Support, BDI, and BAI (P < 0.05 for all).

Conclusion: Brain tumor children have significantly reduced HRQL early after diagnosis. The relationship between HRQL and child and family variables is dynamic and changes over time. Determinants include cognitive and psychological status of the child, maternal mood, family support, and family stress levels.


A. Penn,1–3 S. Lowis,2 R. Shortman,1 R.J. McCarter,1 M. Stevens,2 L. Hunt,1 A.L. Curran,1 and P.M. Sharples1,2; 1Frenchay Hospital, Bristol, and 2Bristol Royal Hospital for Children, UK, and 3University of the Witwatersrand, Johannesburg, South Africa

Objectives: (1) To investigate changes in HRQL in brain tumor patients in the first year after diagnosis. (2) To relate HRQL at 12 months to tumor, child, and family variables.

Methods: A longitudinal prospective study. Semistructured interviews of patients and matched controls took place at one (t1), six (t6) and 12 (t12) months. HRQL was measured using parental report Pediatric Quality of Life Inventory (PedsQL) and Health Utilities Index Mark-3 (HUI-3). Tumor variables included site, malignancy, and presence of hydrocephalus. Child variables included age, gender, measures of cognition and behavior, and symptoms of depression/anxiety and event-related stress. Family variables included measures of family function, support, stress, and coping strategies; and symptoms of maternal depression/anxiety.

Results: A total of 26 patients and 20 controls have had t12 interviews. Patient scores were significantly reduced compared to controls for HUI-3 Multi Attribute Utility Function (MAUF) and PedsQL total scale score, and for psychosocial and physical summary scores, at all three time points (all P < 0.01). HRQL improved significantly with time, especially from t1 to 16. There was a significant correlation at t12 between PedsQL total scale score and tumor site, child behavior, family support, and family stress; and between HUI-3 MAUF and tumor site, child behavior, and family support (all P < 0.05). Behavior at t1 correlated with HRQL at t12 (P < 0.05). HRQL at t12 did not correlate with any other variables.

Conclusions: Brain tumor children have significantly reduced HRQL in the first year after diagnosis, which improves over time. Determinants of HRQL at one year include tumor site, the child’s behavior, family support, and family stress.


J.S. Lai, D. Cella, T. Tomita, M. Newmark, M. Fouts, and S. Goldman; Children’s Memorial Hospital and CORE, Northwestern University, Evanston, IL, USA, and Children’s Memorial Hospital Northwestern University, Chicago, IL, USA

Background: Fatigue is a major concern for cancer patients of all ages at any disease stage. A scale that demonstrates stable measurement properties across developmental stages is important because it can facilitate monitoring fatigue longitudinally in a psychometrically sound manner.

Purpose: To develop a pediatric Functional Assessment of Chronic Illness Therapy–Fatigue (pedsFACIT-F) scale, a component of the 51-item pediatric Fatigue Item-Bank (pedsFIB).

Methods and results: This was developed via literature review, patient/parent feedback, clinician evaluation, and a face-to-face consensus meeting. PedsFACT-F consists of 11 items (7 shared with the 13-item adult version of the FACIT-F) selected to maximize content validity and developmental issues. Psychometric properties of the pedsFACT-F were examined in 111 patients (ages 8–17; 57% boys, 46% with leukemia, and 21% with brain tumors). Treatment received: 95% had chemotherapy, 19% radiation, and 40% surgery; hemoglobin mean, 11.3 (range, 6.7–15.9). The pedsFACT-F demonstrated good internal consistency (alpha) for patients aged 8–12 (0.84) and 13–17 (0.90); acceptable Item-total correlations (range, 0.32–0.69 and 0.44–0.76); significantly correlated with hemoglobin (r = −0.37, P < 0.0001); and its concurrent validity was supported by comparing to pedsQL-fatigue (rho = 0.81, P < 0.0001).

Conclusion: The pedsFACT-F demonstrates acceptable psychometric properties using classical test theory criteria. Our next step is to test its measurement properties using Item Response Theory, which evaluates the stability of the item parameter across the life span, and scores between pedsFACT-F and adultFACT-F can then be equated and ultimately enable the better quality of long-term care.


J.E.A. Wolff,1 U. Hüttermann,2 and M. Askins1; 1Department of Pediatric Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; and 2Muenster, Germany

Background: As more patients survive childhood brain tumors, the emphasis in clinical research has begun to shift to long-term sequelae. Sequential improvements in treatment protocols will require tools capable of measuring health status in large patient populations. This abstract describes the validation of the FMH, a questionnaire rating independence in daily life as indicator of long-term survivors’ health status and quality of life in 56 yes/no items.

Procedure: We compared a newly developed and validated measure of health status (the FMH) with other frequently used instruments for feasibility of use in a pilot population of 21 medulloblastoma patients between 3 and 38 years of age. At the time of assessment, five patients were asymptomatic, six mildly handicapped, six significantly handicapped, and four severely handicapped.

Results: The number of patients (n) in whom the test could be administered, and the mean test result (m) and the range for the three methods, were IQ: n = 15, m = 92 (55–113); FMH, a simple health status questionnaire: n = 21, m = 56 (16–75); and Child Behavior Checklist (CBCL): n = 14, m = 73 (33–98). Of the three methods, the FMH showed the highest correlation with degree of handicap (P < 0.0005). This test took less than 10 min and was the only one feasible in all patients.

Conclusion: These results suggest that the FMH is useful as an objective, easily administered measure of health status in patients with medulloblastoma and other brain tumors.


A. Atherton, P. Swank, S. Noblin, H. Northrup, S. Peterson, J. Slopis, and B. Moore; University of Texas Health Science Center and University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder affecting approximately 1 in 3500 individuals. Its natural history has been well studied, but few studies have focused on the quality of life (QOL) in individuals with this condition. This study was undertaken to assess the overall QOL and the impact of disease severity in children and adolescents with NF1. A total of 64 children between the ages of 5 and 18 years from 53 families, and their respective parents, participated in this study. Each participant completed standardized questionnaires of QOL, and, in addition, medical chart review was done to establish disease severity. Children with NF1 and their parents reported a total QOL score that was significantly lower than the normative sample, with parents perceiving their child’s QOL much lower than the children themselves. Parents of children with NF1 reported significantly lower activities, fewer social interactions with peers, more problems in school, and more total behavioral problems in children with NF1 than expected from normative data. These findings indicate that children with NF1 have a lower overall QOL because of multiple contributing problems. However, when determining the effect of various predictor variables on overall QOL, disease severity and the number of friends were the only two predictors that were significantly associated with QOL. Counseling that focuses on those with increased disease severity and who report fewer friends may help to increase QOL and confidence, and decrease future psychological and psychosocial manifestations associated with NF1.


M. Pilz1 and J.E. Wolff1,2; Departments of Pediatric Oncology of 1Regensburg, Germany, and 2University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Introduction: Measuring quality of life (QoL) in pediatric neuro-oncology has proven to be a challenge. We tested two questionnaires hypothesizing that improved medical care would become measurable when comparing the QoL of patients diagnosed prior to or after 2002 in a pediatric oncology population.

Methods: Patients and parents filled in the FMH (Klin. Pädiatr., 208:294–298), asking about independence in daily life, and the Pedqol questionnaire, asking about well-being during the past week. This was compared to a global question (“How happy are you?”), school performance, and assessments by medical personnel.

Results: A total of 231 FMHs regarding 214 patients, and 125 Pedquols regarding 104 patients could be analyzed. This difference came from the broader age range of the FMH and some parents refusing the Pedquol because it is longer. The hypothesis could not be verified as assumed, because the patient group after 2002 included patients with large progressive brain tumors, whereas the earlier group only had long-term survivors, causing a bias contrary to the hypothesis. The school type correlated highly with other assessments. Comparing different diseases, brain tumor patients ranked lowest (average FMH = 43.33%), followed by patients with nephroblastoma and neuroblastoma (45.5%), whereas patients with lymphoma ranked highest (59.1%). The Pedquol data confirmed this ranking.

Conclusion: When QoL is used to measure quality of patient care, it should be done longitudinally, comparing averages obtained in different years. School type, a global question, and the FMH provide a broad, yet doable, repertoire.


S.L. Palmer,1 J. O’Grady,2 D. Wallace,1 A. Broniscer,1 M. Fouladi,1 M. Smeltzer,1 and A. Gajjar1; 1St. Jude Children’s Research Hospital, Memphis, TN, USA, and 2Central State Hospital, Petersburg, VA, USA

Due to the effects of developing disease, it is believed that scores of intellectual ability obtained from children following their diagnosis of medulloblastoma do not represent a true baseline measure. Therefore, this study was designed (1) to develop a demographic based model to predict premorbid intellectual quotient (IQ) and (2) to compare estimates of the decline in IQ over time from models with and without the premorbid estimate. Demographic data (including gender, race, age, parental education, and residence) from 2200 healthy children were used as potential covariates. A best subsets model-building strategy was used to select the most parsimonious model. A two-covariate model including race and level of parental education (r2 = 0.2745) resulted. For each race, as parental education increased, the estimate of IQ increased, as well. Those who were white had the highest IQ estimate, followed by those who were classified as other and black, respectively. A longitudinal model of IQ scores over time for 45 medulloblastoma patients was compared to a model of IQ scores including the premorbid estimate for the same population. Without premorbid estimates, the model demonstrated a nonsignificant loss of −1.55 IQ points per year. The model that included the premorbid estimate demonstrated a significant loss of −2.60 IQ points per year (P < 0.0001). Using only those scores obtained after diagnosis underestimates the adverse effects of medulloblastoma and its treatment on cognitive ability. Including premorbid estimates provides a benchmark against which current function can be compared, allowing the rate and degree of cognitive change to be accurately established.


A. Lindahl-Norberg and S. Steneby; Childhood Cancer Reseach Unit, Karolinska Institutet, Stockholm, Sweden

A number of studies have described the neuropsychological functioning of children after treatment for brain tumors. Impairment of motor function, verbal memory, and visuospatial organization is frequently reported. Common effects of this are attention and learning problems, and these children seem also to be at risk for difficulties with social relationships. The aim of this study was to present a broader picture of the posttreatment influence of childhood brain tumor and its treatment, as it is described by the parents. Any aspects of influence on the family’s everyday life were considered. To explore the suitability of this approach, we conducted a limited sample pilot study including parents from seven families. The selected cases represented various types of brain tumors, various treatment modes, and various degrees of remaining sequelae. The age of the former patients varied from 7 to 16 years, and cancer treatment was completed between 18 and 30 months prior to the investigation. We collected the data through open-ended individual interviews with parents, and used inductive thematic method for the analyses. The following areas of influence derived from the interviews are discussed in this presentation: Consequences for the child: academic performance, leisure time and activities, social interaction, and psychological and psychosocial influence. Consequences for the parent: supporting the child, parenting and the parent role, and worries about the future. These findings indicate that an exploration of the parents’ accounts can contribute valuable information for the planning of supportive interventions for these children and their families.


Y.W. Chen, I.T. Chiang, Y.C. Chu, L.L. Liang, S.L. Luo, L.M. Chen, Y.L. Tsai, T.H. Lin, S.H. Yen, and T.T. Wong; Cancer Center, Department of Anesthesiology, Department of Nursing, Division of Pediatric Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan, and Center for the Study of Leisure and Health Promotion, Department and Graduate Institute of Recreation and Sport Management, Taipei Physical Education College, Taipei, Taiwan

Objectives: General anesthesia (GA) or conscious sedation (CS) procedures were generally necessary for young children with malignant brain tumor undergoing radiotherapy. Young children, especially 3–6 years of age, find it hard to obey the instructions for radiation treatment because of fear or anxiety. Recent studies have called for better preparation to reduce the need of GA or CS in radiation therapy with the management of recreation therapy. Herein, we present our experience with using different methods of recreation therapy to help young pediatric brain tumor patients cooperate with the radiotherapy procedure smoothly without, or with reduced use of, GA or CS.

Methods: From July 2004 to January 2005, we recruited 10 young patients (age range, 3–6 years) who needed radiation treatment for brain lesions. We tried to reduce the necessity of GA/CS by using the theory of recreation therapy with a relaxed atmosphere (no white coat), video-cartoon watching, token rewards, game playing, skills learning (painting, clay playing, or paper folding), peer imitation, environment familiarity, verbal encouragement, and the like. We evaluated the behavior control with our pediatric psychotherapist by the objective scale of learned helplessness and psychological health survey. The necessity for GA/CS was also recorded during radiotherapy.

Results: Except for four children who still needed anesthesia/sedation during the entire radiation treatment or part of it, all patients completed the radiation treatment smoothly with good behavior control. No significant behavior disorder was found after treatment. Long-term effects are still being followed regarding both disease control and psychosocial behavior fitness.

Conclusion: Recreation therapy can reduce the need for GA or CS and is useful for young children with brain tumors undergoing radiotherapy. GA and CS can be reserved for those who really need it after a psychobehavioral evaluation. This patient-orientated strategy, we believe, can improve treatment quality both physically and psychologically.


S.E. Bates,1,3 D.S. Comeau,1–3 A. Golja,1,3 and R. Robertson1,3; 1Children’s Hospital Boston, Boston, MA, USA, 2Brigham and Women’s Hospital Boston, Boston, MA, USA, and 3Harvard Medical School, Boston, MA, USA

Purpose: To determine whether sedation status in children significantly affects the diagnostic quality of magnetic resonance imaging of the brain, scanning time, or need for repeat imaging.

Methods: This was a retrospective study of 125 children aged 4–7 years who underwent magnetic resonance imaging of the brain at Children’s Hospital Boston in 2004. All of these children were scheduled for sedation; however, upon further assessment of their behavior and temperament on the day of the examination, MRI was attempted in 70 by using alternative therapy techniques without sedation. A total of 67 children were imaged without sedation, and 65 were imaged with sedation. Population characteristics included age, gender, number of prior MRI scans, history of developmental delay, and history of malignancy. The images were then analyzed for quality by two blinded radiologists and one nonblinded radiologist for scan time and number of repeat sequences.

Summary: Sedated children were on average younger and had increased incidence of developmental delay. No significant difference was found in scan time; however, nonsedated children had more repeated sequences (43%) than did the sedated children (14%). Nonsedated children had significantly more examinations with motion artifacts (45% vs. 15%, P = 0.02). Examinations for both groups were determined by blinded and nonblinded readers to be adequate for diagnosis.

Conclusion: This study demonstrates that both nonsedated and sedated children who underwent brain MRI examinations received diagnostically adequate studies, even though the number of studies with motion artifact and the number of repeat studies were higher for the nonsedated group.


A. Johnson, C. Jordan, M. Drummond, and C. Mazewski; AFLAC Cancer Center and Blood Disorders Service, Children’s Healthcare of Atlanta, Atlanta, GA, USA

The purpose of this study is to determine the incidence, timing, and characteristics of headaches in a population of off-therapy pediatric brain tumor patients. Methodology involved a retrospective chart review of three subpopulations of pediatric brain tumor patients followed in a multidisciplinary clinic from January 1, 2003, through October 31, 2005. Seventy-two charts were reviewed: 28 medulloblastomas, 27 cerebellar juvenile pilocytic astrocytomas (JPAs), and 17 craniopharyngiomas. Patients with headaches at presentation were as follows: 20 of 28 (71%) medulloblastomas; 12 of 27 (44%) JPAs, and 9 of 17 (53%) craniopharyngiomas. Off-therapy headaches were noted in 6 (21%) of the medulloblastomas, 9 (33%) of the JPAs, and 9 (53%) of the craniopharyngiomas. Increased intracranial pressure was associated with headaches at diagnosis. Of 15 cerebellar patients with headaches off-treatment, 13 had hydrocephalus at diagnosis. Hydrocephalus did not correlate with headaches in the suprasellar group. Fewer than half of those patients with prediagnosis headaches had significant off-therapy headaches. Off therapy, the incidence of frequent headaches (more than once per week) and occasional headaches (one to two times per month) was greater in cerebellar JPAs (3 + 5)/9 and craniopharyngiomas (6 + 2)/9, compared with medulloblastomas (2 + 0)/6. Migrainous features were present in nearly half of the JPA (5 of 9) and craniopharyngioma (5 of 9) patients with off-treatment headaches, but in none of the six medulloblastoma patients off therapy. The higher frequency and associated migrainous features noted in cerebellar JPA compared with medulloblastoma warrants further study. A survey tool for better documentation and monitoring of off-therapy patients with headaches has been developed and will be presented.


J. Mühlisch,1 A. Schwering,1 G.H. Vince,2 N. Sörensen,2 T. Bajanowski,3 W. Paulus,4 H. Jürgens,1 and M.C. Frühwald1; 1Department of Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany, 2Department of Neurosurgery, University Hospitals of Wuerzburg, Germany, 3Institute of Legal Medicine, University of Münster, Münster, Germany, and 4Institute of Neuropathology, University Hospital, Münster, Germany

Introduction: Aberrant methylation contributes to the development of CNS tumors. We and others reported different frequencies for gene methylation in medulloblastomas, supratentorial primitive neuroectodermal tumors (sPNETs), and ependymomas. We thus analyzed the respective CpG islands by using a semiquantitative approach.

Methods: To quantify methylation demonstrated by methylation-specific PCR (MSP) experiments, we established calibration curves by mixing clones representing methylated and unmethylated DNA. Sequencing of bisulfite PCR fragments and calibrated Combined Bisuflite Restriction Analysis (COBRA) was used to asess the degree of methylation.

Results: Quantitative evaluation of MSP showed elevated methylation levels for CASP8 in sPNET, but also in normal appearing cerebrum. Bisulfite sequencing demonstrated varying methylation in the priming sites for MSP. Using clones with different methylation patterns as templates for MSP showed that 2/5 methylated CpGs in the priming site are sufficient for the appearence of strong methylation signals. In contrast, RASSF1A showed a homogeneous methylation pattern and a significantly higher degree of methylation in the tumors. Even though MSP of TIMP3, p16INK4A, p14ARF, and ECAD showed methylation signals in a number of samples, quantitative analysis demonstrated low-level methylation not differing statistically from that of controls. COBRA and sequencing confirmed the methylation at or below the detection limit of 1%–5%.

Conclusion: Only RASSF1A shows a degree and pattern of methylation in medulloblastoma, sPNET, and ependymoma expected to influence gene regulation. The significance of methylation of CASP8 and the low-level methylation of the other genes remains to be determined. These findings emphasize the need for more quantitative methylation assays. This work was sponsored by the Deutsche Krebshilfe.


A. Huang, M. Li, W. Lockwood, M. Zielenska, B. Behesti, A. Chan, M. Yoshimoto, P. Northcott, E. Bouffet, J. Rutka, H. Yan, M. Taylor, C. Eberhart, W. Lam, J.A. Squire, and C.E. Hawkins; Hospital for Sick Children, Toronto, Canada, British Columbia Cancer Agency, Vancouver, Canada, Ontario Cancer Institute, Toronto, Canada, Duke University Medical Center, Durham, NC, USA, and John Hopkins Medical School, Baltimore, MD, USA

Primitive neuroectodermal tumors (PNET), which include the cerebellar medulloblastoma (MB) and the supratentorial PNET (sPNET) comprise the largest group of pediatric malignant brain tumors and contributes substantially to childhood cancer related morbidity and mortality. The molecular pathogenesis of MB/sPNET remain poorly understood. In order to identify genetic loci important in the development of these tumors, we conducted high resolution array based comparative genomic hybridization analyses to map loci with copy number aberrations in MB/sPNET samples. In addition to previously reported alterations such as c-myc gene amplification, our studies identified multiple novel regions of gains and losses in MB/sPNET. These included copy number gains at the cyclin D1–D3 and cdk4 loci and high level gene amplification of the cdk6 locus. In silico analyses of SAGE libraries revealed cdk6 transcripts were highly represented in MB/PNET relative to normal brain tissue suggesting that CDK6 overexpression may have an etiologic role in MB/PNET development. To further evaluate the importance of CDK6 in MB/PNET pathogenesis, we have analyzed and correlated CDK6 expression in 81 MB/PNET with outcome parameters as well as other known markers implicated in MB/PNET biology. In addition, studies are underway to determine whether CDK6 knockdown or overexpression alters the growth phenotype and in vitro chemosensitivity of MB/PNET cell lines. As CDK6 expression is upregulated in a substantial number of MB/PNET tumors, these experiments will provide important clues as to the potential therapeutic role of CDK6 inhibitors in MB/PNET therapy.


D. Ellison, O. Onilude, J. Lindsey, M. Lusher, C. Weston, R. Taylor, A. Pearson, and S. Clifford; University of Newcastle, Newcastle-upon-Tyne, UK, CCSG, Leicester, UK, University of Swansea, Swansea, UK, and Institute for Cancer Research, London, UK

Nuclear accumulation of the b-catenin protein follows activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas (MBs). We tested the hypothesis that nuclear immunoreactivity for b-catenin is a prognostic marker in MB, and assessed the relationship between nuclear b-catenin immunoreactivity and mutations of CTNNB1 and APC. MBs from children entered onto the SIOP/UKCCSG PNET3 trial (n = 109) were examined for b-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathological variables, principally outcome. Children with MBs that showed a nucleopositive b-catenin immunophenotype (27/109; 25%) had significantly better overall survival (OS) and event-free survival (EFS) than children with tumors that showed either membranous/cytoplasmic b-catenin immunoreactivity or no immunoreactivity (P = 0.0015 and P = 0.0026, respectively). For b-catenin nucleopositive and nucleonegative MBs, five-year OS was 92.3% (95% CI, 82%–100%) versus 65.3% (95% CI, 54.8%–75.7%), and five-year EFS was 88.9% (95% CI, 77%–100%) versus 59.5% (95% CI, 48.8%–70.2%), respectively. Mutations in CTNNB1 were found exclusively among MBs that demonstrated nuclear b-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with b-catenin nucleopositive large cell/anaplastic MBs and b-catenin nucleopositive MBs presenting with meta-static disease are alive at least five years after diagnosis. Nuclear accumulation of b-catenin appears to be a marker of favorable outcome in MB, and should be investigated further in large groupwide trials.


A. Broniscer, S.J. Baker, A.N. West, M. M. Fraser, M. Kocak, G.P. Zambetti, A. Gajjar, R.J. Gilbertson, and C.E. Fuller; St. Jude Children’s Research Hospital, Memphis, TN, USA

We reviewed clinical, radiologic, and histologic characteristics of all affected patients younger than 22 years old treated at the St. Jude Children’s Research Hospital (SJCRH) from 1985 to 2004. Cumulative incidence estimates (CIEs) and risk factors were analyzed for subsets of patients. Molecular studies were performed in available samples. Of 15 patients identified (median age at diagnosis of low-grade glioma [LGG], 12.8 years), 8 had grade II astrocytoma. Treatment for LGG included irradiation (n = 6) and/or chemotherapy (n = 5). Median interval for malignant transformation (MT) was three years (range, 0.5–13.4 years). Most patients (60%) developed glioblastoma. The 15-year CIE of MT among 66 patients with grade II astrocytoma treated at SJCRH over 19 years was 8% ± 4%; none of the risk factors analyzed, including use of irradiation, were statistically associated with MT. Tissue was available for molecular analysis (FISH, immmunohistochemistry, and TP53 sequencing [exons 4–11]) in 14 patients (11 with paired samples). Molecular progression by these assays was observed in 9 of 11 patients at MT. TP53 mutations were found in 3 of 15 samples. P53 overexpression was more commonly seen at MT in paired samples (P = 0.08). Abnormalities of the retinoblastoma pathway were common (deletion of Rb1 and/or CDKN2A in 75% of LGGs and 92% of all tumors at MT). Four of 11 patients developed PTEN deletion at MT. Of five oncogenes (EGFR, ERBB2, PDGFRA and B, and CDK4) analyzed by FISH, only one amplification of PDGRFA was observed. In conclusion, previous treatment, in particular, use of irradiation, is not associated with the development of MT in children. Molecular abnormalities associated with primary and secondary adult glioblastoma were identified in our patients.


T. Kondo; Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Moreover, many tumors and cancer cell lines express stem cell markers, including CD133, CD44, and ATP-binding cassette transporters, by which the cells pump out a specific fluorescence dyes as well as anticancer drugs, suggesting that either cancer cells resemble stem cells or cancers contain stem cell–like cells. Using the flow-cytometry-based side population (SP) analysis that identifies a kind of stem cells, we have succeeded to identify stem cell–like cells (cancer stem cells) in rat C6 glioma and human MCF7 breast cancer cell lines. The purified C6 SP cells, but not the other cells, self-renew and form tumors when transplanted in vivo, suggesting that C6 SP cells are much more malignant than non-SP cells. Thus, the cancer stem cell might be a crucial target for the curable cancer therapy.


H. Saya, T. Ozawa, and N. Araki; Kumamoto University, Kumamoto, Japan

Neurofibromin is neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as GTPase-activating protein (GAP) and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the siRNA technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes such as excessive actin stress fiber formation with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, PI3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GAP–related domain (GRD) suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.


T. Miyashita; Department of Genetics, National Research Institute for Child Health and Development, Tokyo, Japan

Mutations in the human patched-1 gene are associated with autosomal dominant nevoid basal cell carcinoma syndrome (NBCCS; also called Gorlin syndrome) characterized by developmental abnormalities and tumorigenesis such as basal cell carcinoma (BCC) and medulloblastoma (MB). Sporadic BCCs and MBs often display loss of heterozygosity in this region, consistent with patched-1 being a tumor-suppressor gene. However, using PCR-SSCP analysis, mutations in patched-1 have been found in only a fraction (about one-third to one-half) of NBCCS patients. In this study, we designed new sets of primers and sequenced all of 23 coding exons. As a result, we identified mutations in 15 of 19 patients. Eleven of these mutations cause protein truncation due to the insertion or deletion of one to four nucleotides. Two of the mutations cause aberrant splicing by disrupting splice donor sites. The remaining two mutations were missense and nonsense mutations. During the mutation analysis, we discovered that the patched-1 gene undergoes complicated alternative splicing, and a number of mRNA isoforms are generated. Among them, we are interested in the isoform, patched12b, containing a novel exon 12b. This isoform is specifically expressed in the brain and in the heart. The biological significance of this isoform will also be discussed. In this disorder, clinical diagnosis during childhood is often difficult because several of the signs of the syndrome develop over time. Therefore, early genetic diagnosis is important for the prevention and early detection of cancers.


M. Mizuguchi; Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Tuberous sclerosis (TSC) is an autosomal dominant disorder in which various dysplastic and neoplastic lesions may develop in the brain, kidney, and various other organs. The TSC cerebral lesions include cortical tubers (dysplasia) and subependymal giant cell astrocytomas (neoplasm), the pathologic hallmark of which is giant cells showing abnormal size and differentiation. TSC is caused by a loss-of-function mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Their protein products, hamartin and tuberin, form a complex and negatively regulate the insulin signaling pathway. The TSC-associated neoplasms usually arise according to the Knudson’s two-hit theory, as evidenced by LOH shown in many of them. However, the incidence of LOH is very low in the tubers. To elucidate the role of hamartin and tuberin, we produced specific antibodies against them, and examined their expression by immunostaining and Western blotting. Both the proteins were abundant in control tissues, and colocalized with each other in many cells. TSC-associated hamartomas showed reduction in both of them. We also studied the neuropathology of the Eker rat, an animal model of TSC, and found two novel lesions: a cortical tuber and an anaplastic ganglioglioma. To determine the mechanism by which tubers arise, we collected cytomegalic neurons by microdissection, analyzed their Tsc2 gene by PCR, and demonstrated the absence of LOH, showing that the pathogenesis of cortical tubers is different from that of TSC-associated tumors.


R.M. Savill,1 Z.J. Yang,2 N. Somchand,3 P. Scotting,1 and B. Coyle1; 1Children’s Brain Tumour Research Centre, School of Human Development, University of Nottingham, Nottingham, UK, 2Department of Pharmacology and Cancer Biology, Duke University Medical Center, NC, USA, and 3Tokyo Cancer Center, Tokyo, Japan

Cancer cells are highly aberrant and depend on defective apoptotic signaling for survival. If however a functional apoptotic pathway can be identified in these highly stressed cells they would be more prone to undergo apoptosis than those in the surrounding normal tissue. Medulloblastomas arise from cerebellar granule cell progenitors. Mature granule neurons require Id2 to undergo low-potassium–induced apoptosis. We have investigated the functionality of this pathway in medulloblastoma. Id2-GFP or GFP control were overexpressed in D283 and DAOY human medulloblastoma cell lines and apoptosis detected by flow cytometric or caspase-3 immunohistochemistry and DAPI staining. Cell cycle analysis was performed using flow cytometry. Rat proliferating granule cell progenitors were transfected by whole cerebellum electroporation, dissociated postmitotic cells were transfected using the Amaxa system, apoptosis was detected by TUNEL. Id2 expression was detected by immunohistochemistry. A five- to sevenfold increase in apoptosis was observed in cell lines transfected with Id2-GFP relative to GFP controls after 24 and 48 h. A G2 cell cycle block was seen in Id2-GFP transfected DAOY cells. Whereas, the majority of Id2-GFP transfected proliferating granule cells died within 24 h, apoptosis of Id2-GFP transfected postmitotic cells did not occur until after three days in culture. A high level of Id2 expression (> 65%) was detected in 7/9 classic medulloblastomas and expression was found to correlate with exit from mitosis in rat cerebellar granule neurons both in vitro and in vivo. Thus, we have shown that although normally expressed at high levels, overexpression of Id2 is able to induce apoptosis in medulloblastoma and progenitor cells of the cerebellum. By further defining the apoptotic mechanism we hope to advance development of therapies for medulloblastoma treatment.


B.R. Rood, H. Zhang, T.J. MacDonald, and M. Santi; Children’s National Medical Center, Washington, DC, USA

The evolution of therapeutic strategies has dramatically improved the survival of children with medulloblastoma over the past two decades. However, survivors are affected by significant treatment sequelae including neurocognitive, endocrinologic, and hearing deficits. Current efforts are directed toward the development novel molecularly targeted agents to reducing these effects as well as to augment the treatment of high risk and relapsed disease. The identification of targets for these investigational agents is dependent upon an understanding of the molecular biology of these tumors. One of these potential targets is the platelet-derived growth factor receptor (PDGFR), activated forms of which have been found in medulloblastoma. Signaling through the PDGFR stimulates pathways involved in proliferation, antiapoptosis, angiogenesis, and cell migration. The ligand involved in PDGFR signaling has not been previously described as neither of the classical ligands, PDGF-A or PDGF-B, have been shown to be present in these tumors. Using qRT-PCR in 22 clinical medulloblastoma samples, we have found a high incidence of expression of the platelet-derived growth factor C (PDGF-C), encoding a novel ligand for the PDGFR. We have also found a significant correlation between the mRNA expressions of PDGF-C and PDGFRα. The source of PDGF-C has been confirmed to be the medulloblastoma cells by immunohistochemistry in a set of 20 tumors. Thus, PDGF-C is a biologically relevant molecule that is widely expressed in medulloblastoma and has the potential for autocrine activation of the PDGF receptor. Our findings further support the PDGF pathway as a potential therapeutic target in medulloblastoma.


S. Fattet,1 F. Doz,2 P. Legoix,3 I. Janoueix-Lerosey,1 A. Lellouch-Tubiana,4 S. Lair,5 D. Bours,6 M.A. Raquin,7 J. Grill,7 C. Sainte-Rose,8 and O. Delattre1; 1U509 INSERM, 2Pediatric Department, 3Transfer Department, 5Bioinformatics Department, 6Biostatistics Department, Curie Institute, Paris, France, 4Pathology Department, Necker Hospital, Paris, France, 7Pediatric Department, Gustave Roussy Institute, Villejuif, france, and 8Pediatric Neurosurgery Department, Necker Hospital, Paris, France

The WNT/Wingless signaling pathway is constitutively activated in approximately 15% of medulloblastoma (MB) supported by β-Catenin (CTNNB1), APC or AXIN1 mutations. Genomic profiles of 96 MB and 3 cell lines have been analyzed by comparative genomic hybridization on a 3.5 Kb BAC array. The exon 3 of the CTNNB1 gene was screened for mutations in the 99 samples. Moreover, histological subtype (OMS 2000 classification) and overall survival (OS) were known for the patients’ group. Six tumors present a missense mutation in exon 3 of CTNNB1. The mutations consist in S33F (n = 3), D32Y (n = 1), G34R (n = 1), and I35N or I35K (n = 1). The genomic profiles of the CTNNB1-mutated MB clearly differ from the nonmutated cases: in particular chromosome 7 and 17 are not altered but other specific chromosomal alterations are observed. All mutated tumors exhibit a classical histological subtype. Patients with a CTNNB1-mutated MB are older at diagnosis as compared to nonmutated MB patients. None of them had metastatic disease at presentation and the local tumors could be completely resected by initial surgery. After a standard-risk treatment, the 6 patients with CTNNB1 mutated tumors have a median OS of 100% at 50 months (range, 27–113) after diagnosis, higher than the OS of the nonmutated MB (60% at 50 months). In conclusion, we describe a strong correlation between particular genomic profiles and CTNNB1 mutations in MB. This subgroup exhibits specific clinical characteristics including a favorable prognosis. A therapeutic deescalate should seriously be considered in prospective studies for this subgroup of patients.


C. Haberler,2 I. Slavc,3 T. Czech,1 E. Gelpi,4 H. Heinzl,1 H. Budka,5 C. Urban,1 J. A. Hainfellner, and the Austrian Neuro-Oncology Network; 1Institute of Neurology, 2Department of Pediatrics, 3Department of Neurosurgery, 4Core Unit for Medical Statistics and Informatics, Medical University of Vienna, Vienna, Austria, and 5Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Graz Medical University Institute of Pathology, Graz Medical University, Graz, Austria

Medulloblastoma is the most common malignant primary brain tumor in children. Due to the high tendency to leptomeningeal dissemination, standard postoperative treatment consists of craniospinal irradiation and chemotherapy. Such treatment causes severe long-term sequelae including hormone disturbances, growth retardation, and neurocognitive impairment, which is particularly severe in young children. Currently, clinical factors are used for therapy stratification, but these do not identify a “good outcome” group that could be treated with a substantially less toxic treatment. To optimize treatment and patient outcome biological prognostic markers are needed. In previous studies different pathobiological parameters have been associated with patient outcome, but so far none of these parameters is used for therapy stratification. In the present study we tested the prognostic influence of five histopathological parameters considered in recent reports as prognostic factors in medulloblastoma. We analyzed a series of 82 medulloblastoma patients who were operated on between 1990 and 2004 in Austria and treated according to the consecutive HIT protocols for medulloblastoma conducted by the German Society of Pediatric Hematology and Oncology (GPOH). The histological subtype and immunohistochemical expression of p53, erbB-2, TRKC, and survivin were determined on paraffin embedded tumor tissue and correlated with patient outcome. Statistical analysis showed a significant correlation of high expression levels of survivin with decreased overall survival. None of the other investigated histopathological factors correlated significantly with patient outcome. Our data indicate that high survivin expression is related to unfavorable clinical outcome in medulloblastoma patients.


S. Ghatan,1 B. Hirsh,1 S. Gattis,1 P. Cannoll,2 and J.H. Garvin3; Departments of 1Neurological Surgery, 2Pathology, and 3Pediatrics, Columbia University and Morgan Stanley Children’s Hospital of New York Presbyterian, New York, NY, USA

Purpose: Advances in the understanding of medulloblastoma biology have come from the discovery of genes that control cell growth, differentiation, and death during development. A candidate gene receiving attention recently is the chemokine receptor CXCR4, which has an established role in granule cell development and migration, glioblastoma pathogenesis, and cancer metastasis. The purpose of this study was to evaluate the role of CXCR4 in the pathogenesis of medulloblastoma.

Methods: Flow cytometry and immunohistochemistry using a primary antibody against CXCR4 were used to determine levels in medulloblastoma and other intracranial neoplasms, in murine and human medulloblastoma cultures, and in murine cerebellar granule cell cultures. The chemoattractant properties of CXCR4 in tumor and granule cell cultures were tested using a transwell chemotaxis assay to CXCR4’s ligand, SDF-1.

Results: Elevated levels of CXCR4 immunofluorescence were detected in medulloblastoma, in comparison to other posterior fossa and supratentorial tumors. Medulloblastoma cell cultures derived from human brain tumors revealed up to a 10-fold increase in CXCR4 immunopositivity in comparison to murine granule cell culture levels. Medulloblastoma cells migrated up to five times faster in the transwell assay than normal cerebellar granule cells.

Conclusions: Medulloblastoma specimens and cell cultures contain elevated levels of CXCR4, which have stronger chemoattractant properties than CXCR4 found in normal granule cell precursors. Further studies are necessary to determine if CXCR4 promotes tumor development and progression, providing a potential target for therapy through small molecule inhibition.


S.C. Clifford,1 Y. Lu,1 D.K. Scott,1 H.K. Ng,2 and D.W. Ellison1; 1Northern Institute for Cancer Research, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK, and 2Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China

Defects of chromosome 8 have been widely reported in medulloblastoma (MB). To identify critical regions involved in MB development, we performed high-density mapping of genetic losses on chromosome 8 by loss of heterozygosity (LOH) analysis, alongside assessment of MYC amplification status using real-time PCR, in a panel of 39 primary MBs and 9 MB cell lines. Two independent common regions of genetic loss were identified. First, a 1.6 Mb common region of loss at 8p23.1 (affecting 23% of cases; 9 tumors, 2 cell lines) defined by polymorphic markers D8S520 and D8S1130. GATA4, a candidate tumor-suppressor gene in this region was assessed for evidence of genetic and epigenetic inactivation in MB. GATA4 transcriptional silencing associated with promoter hypermethylation was found in 22% (2/9) of MB cell lines. However, no consistent evidence of GATA4 hypermethylation or genetic mutation was found in primary MBs. Second, a 14 Mb minimal region of genetic loss was mapped to 8q23.1-q24.3 (affecting 13% of cases; 5 tumors, 1 cell line). Amplification of the MYC oncogene, which maps to 8q24.12, was detected in 10% of cases (5 cell lines), and occurred independently of genetic losses observed at 8q23.1-q24.3. These data indicate that defects of chromosome 8 play multiple and widespread roles in MB development, involving at least three independent loci (MYC, 8p23.1 and 8q23-q24). Although GATA4 is unlikely to play a major role, the loci identified at 8p23.1 and 8q23-q24 now warrant further investigation to identify the critical genes contained within and their clinicopathological roles.


M. Gruber-Olipitz, T. Strobel, M. Grotzer, F. Quehenberger, G. Lubec, and I. Slavc; Department of Pediatrics and Institute of Neurology, Medical University of Vienna, Vienna, Austria, University Children’s Hospital of Zurich, Zurich, Switzerland, and Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria

Medulloblastoma (MB) is the most common malignant childhood brain tumor. Due to its high risk of leptomeningeal dissemination intensive treatment is mandatory. However, massive therapy-induced long-term sequelae clearly demand a more sophisticated therapeutic approach. Recent reports identified high neurotrophin receptor TrkC mRNA expression as a powerful independent predictor of a favorable survival outcome in MB patients. However, the role of activated TrkC receptors in the development and biology of MB remains unclear. To determine downstream effector proteins of TrkC signaling, the medulloblastoma cell line DAOY was stably transfected with a vector containing the full-length TrkC cDNA sequence or an empty vector control. Accounting for the complexity of ligand-induced changes in cellular pathways and effector proteins, we investigated proteomic changes at multiple time points for up to 48 h following neurotrophin-3 induced TrkC receptor activation. We identified 18 proteins differentially expressed: Caldesmon; Cathepsin D; Metastasis inhibition factor nm23; Multidrug resistance-associated protein Mgr1-Ag; Vimentin; Vinculin; Superoxide dismutase (Mn); Glutathione S-transferase P; Stathmin, Lamin A/C, Valosin- containing protein, Annexin A1; ULIP protein; DJ-1 protein; Fascin; Mitofilin; Heterogeneous nuclear ribonucleoprotein H and K. The proteins affected play substantial roles in differentiation, migration, invasion, proliferation, apoptosis, and drug resistance. Almost all of the proteins have been described as being essential in the pathogenesis of different solid tumors, but have not been related to MB pathogenesis so far. We are currently evaluating their role in the pathogenesis of MB with respect to their potential as future therapeutic targets.


C.C. Lau, T. Chow, Y. Tsang, R. Nishikawa, M. Matsutani, H. Nakamura, H.K. Ng, K. Aldape, J. Su, A. Adesina, J. Allen, and K.K. Wong; Texas Children’s Cancer Center and Pathology Department, Baylor College of Medicine, Houston, TX, USA, Saitama Medical School, Kumamoto University, Kumamoto, Japan, Chinese University of Hong Kong, New York University, NY, USA, and University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Intracranial germ cell tumors (GCT) are relatively rare and heterogeneous brain tumors affecting primarily children and adolescents. Although pure germinomas in general have favorable prognosis, other malignant GCT such as embryonal carcinoma, yolk sac tumor, and choriocarcinoma have much poorer outcome. The goal of future developments in the management of intracranial GCT is to reduce treatment-related morbidity in germinoma patients and improve survival in those with nongerminomatous GCT. Such therapeutic advancements will depend on our improved understanding of the biology of these tumors. Since the phenotype and clinical behavior of every tumor is determined by the underlying genetic alterations, we hypothesize that the use of comprehensive genomic profiling to identify these genetic alterations is a systematic and unbiased approach to characterize these tumors. Using genomewide genotyping with 100K SNP array and microarray-based comparative genomic hybridization (CGH), we have analyzed 28 cases of intracranial GCT which consist of 19 cases of pure germinomas and 9 cases of nongerminomatous GCT (NGGCT). Overall, there were much more abnormalities found in NGGCT, and there were cases of pure germinomas that had no detectable genomic abnormalities. The most frequent recurrent abnormalities include gain of chromosomes 1q, 2p, 8q, 12p, 20, 21, and X as well as loss of 1p32.2-pter and 13q14-q21. In addition, a highly amplified region was noted in 12p12.1 and homozygous deletion was found in 19p13.12 where the mucinlike hormone receptor-like 3 gene is located. Functional studies of the candidate genes identified in these regions of recurrent abnormalities are in progress.


J.R. Crawford, M.R. Santi, and T.J. MacDonald; Children’s National Medical Center, Washington, DC, USA

Purpose: To determine whether human herpes virus 6 (HHV-6) is present in childhood CNS gliomas.

Background: HHV-6 is a common viral exanthematous disease of early childhood. HHV-6 has been detected in a variety of adult tumor types, however, a specific association with pediatric brain tumors has not been reported.

Materials and methods: Tissue microarrays (TMA) consisting of eighty-eight pediatric patients diagnosed with gliomas of varying grades (WHO I–IV) were probed with anti–HHV-6 gp116 antibody. Brain biopsy from a known HHV-6 temporal lobe epilepsy patient served as positive control. For confirmation, nested PCR using primers for HHV-6 major capsid protein (MCP) was performed on corresponding DNA samples extracted from paraffin embedded slides.

Results: Approximately 30% of the pediatric gliomas in the TMA were positive using anti–HHV-6 gp116 monoclonal antibody. While expressed in all grades of gliomas, there was an increased frequency of detection in the lower grade tumors. Signal intensity was approximately the same, however the signal distribution ranged from focal to diffuse. DNA extracted from a subset of positive and negative specimens was used to confirm the IHC findings using nested PCR with MCP primers.

Conclusion: HHV-6 is present in pediatric gliomas with an increased frequency in lower grade tumor type, especially juvenile pilocytic astrocytoma. Our results suggest that HHV-6 may play a role in transformation or tumor progression of childhood gliomas. Studies are underway to determine whether the HHV-6 is isoform specific and whether infectivity alters gene/protein expression of growth promoting signal transduction pathways.


C. Jones,1 S.E. Little,1 J.S. Reis-Filho,2 B. Costa,3 P. Wilkins,4 S. Al-Sarraj,5 A.J. Pearson,1 R.M. Reis,3 D.W. Ellison,6 and D.R. Hargrave1; 1Paediatric Oncology, Institute of Cancer Research/Royal Marsden Hospital, Sutton, UK, 2Breakthrough Breast Cancer, Institute of Cancer Research, London, UK, 3University of Minho, Braga, Portugal, 4St Georges Hospital, London, UK, 5Kings College Hospital, London, UK, and 6Newcastle General Hospital, Newcastle-upon-Tyne, UK

The epidermal growth factor receptor (EGFR) is a tyrosine kinase which is amplified, overexpressed, and/or mutated in a wide variety of human cancers. Adult glioblastoma multiforme (GBM) patients have a differential response to novel therapeutic strategies targeting EGFR inhibitors, with a variety of factors reported to be predictive for treatment efficacy. With corresponding data in the pediatric setting lacking, we have initiated a study to screen for the presence of such predictive factors in children with high-grade gliomas, treated by standard regimens. These include immunohistochemistry for wild-type receptor EGFR and the deletion variant EGFR-vIII, amplification by chromogenic in situ hybridisation (CISH), mutation screening of the tyrosine kinase domain, as well as immunohistochemistry of downstream effectors PTEN and phosphorylated Akt/PKB, and mutation screening of PTEN and PIK3CA. Initial data from a series of 22 grade IV glioblastomas demonstrated amplification in 18% (4/22) cases by CISH, with a corresponding overexpression of the wild-type receptor. These cases had a shorter median overall survival time (56.8 weeks) than those without amplification (82.6 weeks). A further 4/22 (18%) cases demonstrated a low-level gain. Cases with normal EGFR copy number predominantly had either low levels of receptor expression or were negative by immunohistochemistry. These data reveal a greater degree of EGFR amplification/copy number gain than has previously been reported, and demonstrate an association with receptor overexpression and poor outcome. Further screening of factors predictive of response to anti-EGFR therapies will assist in the assessment of the potential of these novel strategies in the treatment of pediatric high-grade gliomas.


D.M. Ashley, C.D. Riffkin, A.M. Muscat, and C. Hawkins; Childrens Cancer Centre Royal Children’s Hospital, Melbourne, Australia, and Murdoch Childrens Research Institute, Melbourne, Australia

Malignant glioma has a dismal prognosis, partly due to the inability of chemotherapy and radiotherapy to induce apoptosis in the tumor cells. Death ligands, including TRAIL/Apo2L, are attractive candidate therapeutic agents for unresponsive cancers like malignant glioma, as they induce apoptosis via a distinct pathway from that triggered by chemotherapy and irradiation. Caspase 8 is an apoptotic protease that plays a crucial role in apoptosis mediated by death ligands. Mutations or down regulation of caspase 8 have been reported in neuroblastoma and other tumor types, prompting its designation as a tumor suppressor gene. In this study, we analyzed the status of caspase 8, and other apoptosis pathway components, in ex vivo high grade glioma specimens. Caspase-8 protein expression, which mirrored mRNA levels, was frequently low or undetectable, while no tumors expressed significant levels of caspase 10, a closely related family member. Neither STAT-1 expression nor caspase-8 gene methylation correlated with caspase-8 abundance.

These data imply that many glioma patients would be unlikely to benfit from death ligand-based therapies, unless caspase-8 expression could somehow be elevated. Demethylating agents are unlikely to boost caspase-8 levels in glioma cells, but treatments that increase caspase-8 mRNA levels would be likely to up-regulate the expression of the protein.


A.M. Donson, S.O. Addo-Yobo, M.H. Handler, L. Gore, and N.K. Foreman; University of Colorado Health Sciences Center and Denver Children’s Hospital, Denver, CO, USA

Juvenile pilocytic astrocytoma (JPA) is the most common CNS tumor of childhood. The molecular mechanisms that are responsible for JPA growth are poorly understood. The ErbB tyrosine kinase receptors have been implicated in several CNS malignancies and thus we studied expression of ErbB1, ErbB2, ErbB3, and ErbB4 in JPA. Using microarray technology, we found ErbB3 mRNA to be uniquely overexpressed in JPAs (12.9-fold) versus a panel of other pediatric tumors (glioblastoma, choroid plexus papilloma, ependymoma, medulloblastoma, and atypical teratoid/rhabdoid tumor). Since Sox10 is known to promote the expression of ErbB3 during neural crest developmental, we investigated Sox10 expression. We found Sox10 to be uniquely overexpressed in JPA (10.6-fold) versus other tumors. We also found that Sox10 expression correlated with the expression of ErbB3 in our panel of pediatric brain tumors. Western blotting confirmed that ErbB3 and Sox10 proteins were overexpressed in JPA, and have a positively correlated protein expression pattern across our pediatric astrocytic tumors. This study finds that overexpression of ErbB3 mRNA and protein is unique to JPA versus other pediatric brain tumors. Our data also support what is known about the developmental biological relationship between ErbB3 and Sox10 expressions. In addition, this study suggests ErbB3 and Sox10 may be effective molecular targets for targeted therapies in treatment of JPA. The overexpression of Sox10 and ErbB3 in JPA suggests that aberrant developmental processes may be responsible for tumorigenesis in this tumor, although these molecules may merely be conserved from the normal nonmalignant precursors of JPA.


U. Tabori,1,3 E. Bouffet,1,3 U. Bartels,1,3 D. Malkin,1,3 and C. Hawkins2,3; 1Division of Hematology/Oncology, Department of Pediatrics, 2Department of Laboratory Medicine and Pathobiology, and 3Hospital for Sick Children and University of Toronto, Toronto, Canada

Background: Ependymoma is the third most common pediatric brain tumor with a highly unpredictable clinical and the biological behavior. As part of ongoing studies to identify potential biological and therapeutic markers for the disease, we analyzed the role of telomere maintenance, which is required for cancers to sustain growth and evade senescence.

Methods: We analyzed 111 primary and recurrent ependymomas that were resected at the Hospital for Sick Children in Toronto between 1986 and 2004. A tissue array was constructed. HTERT and gH2AX expression were evaluated. Thirty one frozen samples were additionally analyzed for telomere length (TRF) and telomerase activity (TRAP assay).

Results: Of the 111 samples, 40 tumors were hTERT(−) with progression- free survival (PFS) of 83% ± 15% and 71 were hTERT(+) with PFS of 21% ± 9% (P < 0.0001). Of the 65 patients with primary ependymomas, five-year overall survival (OS) was 84% ± 7% and 41% ± 7% for hTERT(−) and hTERT(+) tumors, respectively (P = 0.001). There was good correlation between telomerase activity and hTERT expression (κ = 0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathological, clinical, and treatment factors (HR 60.4 [CI, 6.4–561]). TRF measurement revealed lack of alternative lengthening of telomeres (ALT) and heterogenous telomere length in pediatric ependymomas. We observed a trend for better prognosis with telomere dysfunction manifested by shorter telomeres and positive gH2AX.

Conclusions: We suggest that telomere maintenance represents the first known biologic prognostic factor for intracranial ependymomas. Telomerase activity highlights the importance of senescence in carcinogenesis and a possible target for novel treatment approaches for the disease.


A.M. Donson, J. Straessle, M.H. Handler, L. Gore, and N.K. Foreman; University of Colorado Health Sciences Center and Denver Children’s Hospital, Denver, CO, USA

Ependymomas (EPN) account for 6%–12% of all intracranial tumors in children. Even after complete resection and radiation, almost half the patients are likely to relapse. Currently, there are no effective chemotherapies to treat EPN. In order to discover effective treatments for EPN we screened tumor specimens for novel targets of therapy using gene-expression microarray analysis. RNA was extracted from EPN specimens obtained at diagnostic surgery. Details of clinical outcomes were obtained from the neurooncology data base with IRB permission. Extracted RNA was applied to Affymetrix HG-U133 plus2 gene-expression microarray chips. To evaluate the results of microarray analysis, data mining programs GCOS and GeneSpring were utilized. Results gathered from data mining were validated by qRT-PCR and Western blot analysis. Microarray analysis showed a significant overexpression of IL-13RA2 mRNA in a number of EPN specimens. Using Western blot analysis we showed that IL13Ra2 protein expression in EPN was comparable to IL13Ra2 protein expression in adult glioblastoma (GBM), which is currently in a phase III clinical trial of IL13Ra2-targeted therapy. It transpired that the overexpression of IL13Ra2 correlated well with the risk of recurrence in EPN (P = 0.045). We were also able to show a correlation between protein levels of IL13RA2 and recurrence. The identification of IL-13RA2 expression in EPN, especially in those EPN most at the risk of recurrence, could represent a significant advancement in the treatment of EPN. IL-13RA2 is a target in EPN whose peotential value in targeted therapy is already being explored in GBM. IL13Ra2 has previously been shown to be absent in all normal human tissue apart from testis. Cytotoxic agents conjugated to IL-13 can thus be used to specifically target EPN.


J.H. Kreth,1 S. Schlosser,1 T. Lenschen,1 W. Paulus,2 D. Smiraglia,3 C. Plass,4 H. Jürgens,1 J. Mühlisch,1 and M. C. Frühwald1; 1Department of Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany, 2Institute of Neuropathology, Münster University Hospital, Münster, Germany, 3Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA, and 4Divison of Human Cancer Genetics, Ohio State University, Columbus, OH, USA

Introduction: Aberrant DNA methylation contributes to the development of malignancies including CNS tumors in children and adolescents.

Materials: We used the epigenome scanning properties of Restriction Landmark Genomic Scanning (RLGS) with AscI as landmark enzyme to evaluate methylation patterns in high risk brain tumors of childhood. We cloned candidate genes by a library based and a virtual genome based technique (VGS). The degree of methylation of associated CpG islands was quantified by calibrated Combined Bisulfite Restriction Analysis (COBRA). Methylation levels of the five most prevalent genes were quantified in eight normal cerebella, eight cell lines, 10 PBL preparations, 20 ependymomas (E), 11 sPNET and 24 medulloblastomas (MB).

Results: We demonstrate that the loci for ESTa5F32 (MB and E 57.0%, controls 2.1%), GPR92 (MB 75%, E 64.1%, controls 18.4%), HOXC4-6 (MB 21.1%, controls 3.8%), SFRP4 (MB 36.2%, controls 19.0%), and SLC16A8 (MB 45.2% , controls 21.2%) are methylated at a significantly higher level in CNS malignancies compared to control tissues. Epigenetic gene repression could be relieved by 5-Aza-2'-deoxycytidine and Trichostatin A in cell culture models.

Conclusion: We demonstrate that novel candidate genes identified by AscI-RLGS are differentially methylated in pediatric brain tumors and that this alteration and the resulting gene silencing can be reverted by pharmacological intervention. The role of these new genes in tumorigenesis of the examined entities is addressed in further studies. This work was supported by the Deutsche Krebshilfe and the Cora-Lobscheid Stiftung.


Y. Hirose, H. Sasaki, and T. Kawase; Department of Neurosurgery, Keio University, Tokyo, Japan

Recent progress in genetics for brain tumors revealed that genetic analysis provides information relevant to clinical course of glioma patients. However, knowledge in genetic aberrations in glioma has been obtained mainly from adult tumors, and little is known for pediatric tumors. To characterize pediatric nonependymal gliomas by their genetic features, we investigated DNA copy number aberrations (CNAs) in pediatric nonependymal gliomas using comparative genomic hybridization (CGH). To exclude intermixed normal brain tissue, especially in case of low-grade tumors, we microdissected the small pieces of paraffin-embedded tissue that were histologically confirmed as neoplastic region, and DNA extracted from those microdissected tissues were subjected to analysis. We found gain on chromosomal arm 1q and 7q frequently in our study cases. These CNAs were recognized in both supratentorial and infratentorial tumors. Especially, gain on 1q was frequent in tumors of histologically high grade irrespective to tumor location and tumor cell type, whereas gain on whole chromosome 7 and loss on 1p, the most frequent aberration in adult glioblastomas and oligodendrogliomas, respectively, were not recognized. Our analysis detected no CNAs in cerebellar pilocytic astrocytomas. Compared with CGH data which we have already obtained from more than 150 adult astrocytic and oligodendroglial tumors, pediatric nonependymal gliomas had CNAs distinct from adult cases. This difference of genetic features supports the idea that pediatric tumors develop via unique pathways. Further investigation is warranted to identify genetic markers which may help development of treatment strategy for pediatric gliomas.


C. Haberler,1 U. Laggner,1 Irene Slavc,2 Thomas Czech,3 Herbert Budka,1 and Johannes A. Hainfellner1; 1Institute of Neurology, 2Department of Pediatrics, and 3Department of Neurosurgery, Vienna Medical University, Vienna, Austria

Recently, immunohistochemical loss of nuclear INI1 protein expression has been described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs) and has been suggested as a useful marker to distinguish AT/RTs from other malignant pediatric CNS tumors. In this study we examined for the first time a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial PNETs, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Loss of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas nine embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but INI1 loss showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphological features of AT/RT. Furthermore a considerable number of embryonal tumors without rhabdoid features but loss of INI1 protein and aggressive biological behavior can be detected. We conclude that analysis of INI1 protein should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with loss of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.


M.C. Frühwald,1 H. Jürgens,1 R. Siebert,3 M. Hasselblatt,4 and R. Schneppenheim2; 1Department of Pediatric Hematology and Oncology, 4Institute of Neuropathology, University Children’s Hospital, Muenster, Germany, 2Department of Pediatric Hematology and Oncology, University Children’s Hospital, Hamburg, Germany, and 3Institute of Human Genetics, Schleswig Holstein University Hospital, Campus Kiel, Kiel, Germany

Introduction: Rhabdoid tumors represent an independent entity among embryonal neoplasms. They affect the kidney (RTK) and the CNS (AT/RT, atypical teratoid, rhabdoid tumor), but may also be found in soft tissues. Unifying features include characteristic immunohistochemistry and mutations of SMARCB1 (SNF5/INI1) in chromosome 22q. Familial cases have been summarized under the term rhabdoid tumor predisposition syndrome. In all published familial cases a mutation of SMARCB1 was detected in tumor tissues.

Results: We report on a family with three children, two of whom were affected by rhabdoid tumors, one a RTK, the other an AT/RT. While both children demonstrated the typical clinical features (age, imaging, rapid course, resistance to chemotherapy) and pathological findings, neither the RTK nor the AT/RT showed mutations of SMARCB1. Molecular studies including CGH, array-CGH, FISH, SSCP, and DNA-sequencing could not detect any molecular abnormality. Immunohistochemistry for SMARCB1 showed intact protein within tumor cells. As the parents’ constitutional DNA was not affected by mutations of SMARCB1, we demonstrated non-linkage with SMARCB1 by haplotype analysis.

Conclusion: Haplotype analysis including several SMARCB1 intragenic polymorphic markers revealed that both affected children had no haplotype in common, speaking against linkage of this locus with the disease in our patients. This finding indicates that other loci than 22q and the SMARCB1 may be involved in the origin of these tumors. Our data impact on the clinical counselling of affected families and warrant further studies into the molecular biology of these enigmatic tumors. This work was sponsored by Sonja Wasowicz, Karl-Bröcker Stiftung, and Fördergemeinschaft Kinder-krebszentrum Hamburg e.V.


A. Nakano,1 Y. Kanemura,2–4 K. Mori,1 E. Kodama,4 A. Yamamoto,2,4 H. Sakamoto,5 Y. Nakamura,6 H. Okano,7 M. Yamasaki,2,3 and N. Arita1; 1Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan, 2Insititute for Clinical Research and 3Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan, 4Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Hyogo, Japan, 5Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan, 6Department of Pathology, St. Mary’s Hospital, Kurume, Japan, and 7Department of Physiology, Keio University School of Medicine, Tokyo, Japan

Musashi1 (MSI1) is an evolutionarily conserved RNA-binding protein, selectively expressed in NSCs and considered a versatile marker for normal neural stem cells (NSCs) and tumor cell diagnosis. Medulloblastomas and ependymomas are representative primary brain tumors that occur in the cerebellum or paraventricular region of children and young adults. Recent molecular genetics studies suggest an association between the occurrence of medulloblastomas and disorder in the Sonic Hedgehog/patched signaling pathway, but the cellular origins of these tumors have remained unclear and controversial for a long time. Recent examinations have indicated an association of these tumors with NSCs. Here, we examined MSI1 expression in primary pediatric brain tumors, medulloblastomas, and ependymomas by double immunostaining with lineage phenotypic markers (Lin). Our present findings suggest these pediatric tumors are heterogeneous tumors consisting of both MSI1(+)/Lin(−) tumor cells in regions of high cellularity and proliferative activity and MSI1(+)/Lin(+) tumor cells in regions of relatively low cellularity. These findings suggest MSI1 may be a useful marker for characterizing tumor heterogeneity and for examining in situ the analogy between normal NSCs and MSI1-positive cells in pediatric brain tumors. This test could be easily applied to routine clinical diagnosis and it may also contribute to the design of future therapeutic strategies.


R. Riccardi, G. Cefalo, A. Ruggiero, M.E. Abate, M. Massimino, P. Zucchetti, M. Mascarin, M.L. Garré, S. Mastrangelo, A. Clerico, V. Ridola, G. Mazzarella, C. Di Rocco, A. Donfrancesco, and S. Sandri; Division of Pediatric Oncology, Institute of Neurosurgery, Division of Pediatric Neurosurgery, Catholic University, Rome, Italy, Pediatric Oncology, National Institute for Tumors, Milan, Italy, Institute of Pediatrics, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, Pediatric Oncology, Silvestrini Hospital, Perugia, Italy, Division of Radiotherapy, Aviano, Italy, Pediatric Oncology, Gaslini Hospital, Genoa, Italy, Institute of Pediatircs, La Sapienza University, Rome, Italy, Division of Pediatric Oncology, Bambino Gesù Hospital, Rome, Italy, and Division of Pediatric Oncology, Turin, Italy

Objectives: Temozolomide (TMZ) posses antitumor activity in adult high-grade glioma. TMZ has a limited myelotoxicity and shows good penetrance of blood brain barrier (BBB). We performed a phase II study in children and young adults with relapsed or refractory Medulloblastoma (MB)/PNET to evaluate TMZ activity in MB/PNET.

Methods: TMZ divided in three daily doses was administered for five days every 28 days to fasting patients (pts). Doses varied between 120 and 200 mg/mq/die for five days according to previous treatment and hematological values at treatment.

Results: A total of 34 pts with a mean age of 11 years (range, 2–28 years), histology of MB in 32 pts, and PNET in 2 pts. All 34 pts were M+. Pre-TMZ treatment: one regimen (4 pts), two regimens (30 pts), including high dose chemotherapy (CT), and hematological stem cells rescue in 14 pts. Cranio Spinal Irradiation (CSI) in 30 pts. Hematological toxicity: 196 cycles were evaluable for toxicity (2–36 per patients) grade III in 8.6%, and grade IV in 18%. Thrombocytopenia grade III–IV was 15%, neutropenia grade III–IV was 6%, and anemia grade III was in one patient. We observed six complete responses, seven partial responses, and three minor responses with antitumor activity of 47%. Progression-free survival at six months was 67%.

Conclusions: TMZ is very active in heavily pretreated children with MB. TMZ is safe and well tolerated, with limited hematological toxicity observed in a few pts. TMZ should be included in first line treatment of medulloblastoma/PNET.


K.J. Cohen,1 R. Heideman,2 T. Zhou,3 E. Holmes,3 P.C. Burger,1 D.J. Brat,4 M. Rosenblum,5 and I.F. Pollack6; 1Johns Hopkins University, Baltimore, MD, USA, 2University of New Mexico, Albuquerque, NM, USA, 3COG Operations Center, Arcadia, CA, USA, 4Emory University, Atlanta, GA, USA, 5Memorial Sloan Kettering Cancer Center, New York, NY, USA, and 6Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

Temozolomide (TMZ) has been widely adopted in the pediatric neurooncology community in both the setting of children with newly diagnosed high-grade gliomas (HGG) or at the time of recurrence/progression. Many practitioners point to the results reported by Stupp et al. (N. Engl. J. Med. 352 (10):987–996, 2005) in adults in which temozolomide in combination with radiation therapy followed by adjuvant temozolomide was demonstrated to be superior to radiation therapy alone in newly diagnosed adults with HGG. Pediatric practitioners cite ease of use, relatively modest toxicity for most patients, and anecdotal reports of efficacy. Data to support efficacy have been lacking with the exception of relatively small case series. To date, there has been no report of a larger multi-institutional trial that has shown compelling evidence of improved efficacy in the treatment of children with HGG. The Children’s Oncology Group ACNS0126 study is a single-arm phase 2 trial of chemoradiotherapy with TMZ (90 mg/m2/day × 42 days during XRT) followed by 10 cycles of adjuvant chemotherapy with TMZ (200 mg/m2/day × 5 days every 28 days). Historic control cohorts from CCG-945 served as the comparator group. Stratum 1 was restricted to patients with nonbrainstem glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or gliosarcoma (GS); 107 patients were accrued to this stratum (100 eligible). Seventy-one treatment failures have been reported (25 AA, 43 GBM, 3 GS), and 47 patients have died. The median follow up was 11 months. EFS may have been confounded in some cases by interpreting radiation-related injury in the setting of chemoradiotherapy as early disease progression. Extent of resection, a known predictor of outcome, is currently being analyzed in this cohort. Analysis of specimens for MGMT and MMR are ongoing to determine if individual patient specimens would have been predicted to be sensitive or resistant to TMZ administration.


R. Jakacki, A. Yates, T. Zhou, M. Krailo, A.M. Ingle, S.M. Blaney, P.C. Adamson, and I. Pollack; Children’s Oncology Group (COG), Arcadia, CA, USA

Background: Preclinical data show potential synergistic activity with the combination of temozolomide (TMZ) and nitrosoureas or TMZ and epidermal growth factor receptor (EGFR) inhibitors. We report the results of two Children’s Oncology Group (COG) phase 1 combination studies.

Methods: Study ADVL0011 evaluated TMZ with CCNU in newly diagnosed patients with unresectable high-grade gliomas. Two courses were given four weeks apart prior to radiation therapy; six courses were administered after radiation therapy. Study ADVL0214 evaluated the oral EGFR inhibitor erlotinib (ERL) alone for the first 28 days cycle and then in combination with TMZ 180 mg/m2/day × 5 days.

Results: In ADVL0011, 16 patients were treated at the maximum tolerated dose (MTD) (90 mg/m2 of CCNU on day 1 and 160 mg/m2/day of TMZ days 1–5). Diagnoses included glioblastoma (n = 8), anaplastic astrocytoma (n = 7) and anaplastic oligodendroglioma (n = 1). Three patients progressed and/or came off study after the first course. Of the 13 patients who received two courses, there was one complete response, two partial responses, two minor responses, and six with stable disease. Six patients remain alive. One-year and two-year overall survivals are 59% ± 13% and 25% ± 12%. In ADVL0214, the MTD of ERL was 85 mg/m2/day, with rash and diarrhea the most common toxicities. No pharmacokinetic interaction was observed between ERL and TMZ. Sixteen patients with recurrent CNS tumors were evaluable. Diagnoses included brainstem glioma (n = 5), ependymoma (n = 4), medulloblastoma/PNET (n = 5), and other (n = 2). One patient with a neurocytoma had a prolonged (15+ months) minor response, and one with a medulloblastoma had a PR to the combination.

Conclusions: TMZ combination pilot studies are encouraging and warrant further study.


I.F. Pollack, R.L. Hamilton, J. Burnham, R.W. Sobol, S.D. Finkelstein, A.J. Yates, E.J. Holmes, T. Zhou, and J.L. Finlay; Departments of Neurosurgery, Pathology, and Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, and the Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, Department of Pathology, Ohio State University, Columbus, OH, USA, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, USA, and Children’s Oncology Group, Arcadia, CA, USA

Background: Pediatric malignant gliomas are histologically similar to those from adults, although it is unclear if they are biologically distinct. Molecular studies involving adult malignant gliomas have noted that deletions of PTEN and amplification of EGFR are characteristic features, providing a rationale for several molecularly targeted therapies. However, the frequency of comparable abnormalities in childhood gliomas has been uncertain.

Methods: To address this issue, we have examined tumor samples from the CCG-945 study, a large randomized trial incorporating alkylatorbased therapy and irradiation for childhood malignant gliomas. Tumors were assessed for p53 overexpression/mutations, EGFR expression/amplification, PTEN deletions, 1p and 19q deletions, drug resistance markers, and other genomic alterations using a combination of immunohistochemistry, genotyping for loss of heterozygosity and mutations, and FISH.

Results: Amplification of EGFR and mutations of PTEN were rare in pediatric high-grade gliomas, detected in less than 5% of cases. In contrast, p53 mutations were frequent and constituted an adverse prognostic factor. Unlike the situation in adults, chromosome 1p and 19q deletion, although present in a subset of gliomas, was not associated with favorable prognosis. MGMT overexpression, which occurred in 10%–20% of tumors, was an extremely adverse feature, correlating with resistance to alkylator-based chemotherapy. This factor is now being assessed prospectively in ACNS0126 and 0423 studies involving temozolomide alone and with CCNU.

Conclusion: Childhood malignant gliomas share molecular similarities with secondary adult malignant gliomas, but differ from primary adult malignant gliomas. These observations have implications for translation of molecularly targeted therapies from the adult to pediatric contexts, and support efforts to identify molecular features that distinguish pediatric gliomas and to develop therapeutic studies directed toward childhood tumors.


M.C. Frühwald,1 S. Wagner,2 M. Hasselblatt,3 J. Mühlisch,1 J.E.A. Wolff,4 and H. Jürgens1; 1Department of Pediatric Hematology and Oncology, University Children’s Hospital, Muenster, Germany, 2Krankenhaus Barmherzige Brüder, University of Regensburg, Regensburg, Germany, 3Institute of Neuropathology, University Hospital, Muenster, Germany, and 4University of Texas M.D. Anderson Cancer Center, Section of Pediatric Neurooncology, Houston, TX, USA

Introduction: Aberrant methylation of the gene for the repair enzyme O6-MGMT is a common feature in adult patients with high-grade glioma (HGG), who show a response to temozolomide. It has been speculated that this marker may help stratifying patients.

Materials: Surgical specimens from HGGs of 26 children (25 glioblastomas, 1 anaplastic astrocytoma) aged 4–17 years were collected. All had received temozolomide for tumor relapse. Samples from normal brain tissue obtained at autopsy served as controls. Aberrant methylation of O6-MGMT was analyzed by methylation specific PCR (MSP) and quantitative COBRA (combined bisulfite restriction analysis). Protein expression of O6-MGMT was evaluated using immunohistochemistry. Methylation status and protein expression data were compared and the results of our experimental approach were correlated with clinical data.

Results: MSP showed aberrant methylation in 8 of 24 HGGs. As there was a positive signal for the PCR specific for the unmethylated sequence in all studied cases, we sought a more quantitative approach. COBRA essentially confirmed the findings of MSP with however low-level methylation. No correlation between methylation status and extent of protein expression could be delineated. Preliminary analysis of the survival data in 16 patients indicates a tendency toward a longer time to progression for patients with methylation.

Conclusion: O6-MGMT methylation might be a surrogate marker for therapeutic response to temozolomide in children with HGG. More quantitative measures such as COBRA are needed. A prospective study is in the planning stages. This work was supported by the Deutsche Krebshilfe.


A. Broniscer, S. Gururangan, S. Goldman, T. MacDonald, D. Wallace, C.F. Stewart, R. Jakacki, M.W. Kieran, M. Chintagumpala, A. Banerjee, J.R. Geyer, P. Phillips, H.S. Friedman, and A. Gajjar, on behalf of the Pediatric Brain Tumor Consortium; St. Jude Children’s Research Hospital, Memphis, TN, USA, Duke University Medical Center, Children’s Memorial Hospital, Children’s National Medical Center, Children’s Hospital of Pittsburgh, Dana-Farber Cancer Institute, Baylor College of Medicine, University of California, San Francisco, and Children’s Hospital and Regional Medical Center

Since the prognosis of children with recurrent brain tumors is poor, we conducted this study combining O6-BG (120 mg/m2 over 1 h followed by 30 mg/m2/day for 48 h) and escalonating doses of temozolomide (267, 355, 472, 628, and 835 mg/m2 administered at least 6 h after O6-BG bolus on day 1 only). Cycles were repeated after at least 4 weeks (maximum of 12 cycles). Eligibility criteria were standard for this type of study. There were 2 treatment strata: stratum 1 (str1) for patients who previously received no or focal irradiation, and stratum 2 (str2) for patients who received craniospinal irradiation or myeloablative chemotherapy. Forty-five eligible patients were enrolled on str1 and 26 on str2. Median ages at study entry were eight years (str1) and 11.3 years (str2). Predominant diagnoses consisted of high-grade glioma (52%) in str1 and medulloblastoma/PNET (61%) in str2. The maximum tolerated dose (MTD) of temozolomide was 472 mg/m2 in str1 and 355 mg/m2 in str2. Predominant dose-limiting toxicity (DLT) was grade 4 thrombocytopenia in str1 and grade 4 neutropenia in str2. Children younger than six years of age were more likely to develop DLT. Radiologic responses were seen in three patients (1 CR and 2PR) and disease stabilization in 25 (range, 1–11.8 months). Median (range) temozolomide clearance and area under concentration–time curve (AUC) at the MTD (str1) were 9.2 liters/h/m2 (5.1–15.9 liters/h/m2) and 51.8 μg/ml*h (29.6–91.6 μg/ml*h), respectively. The median (range) MTIC AUC at the MTD was 2.8 μg/ml*h (2.0–5.4 μg/ml*h), consistent with previously published pediatric data.


A.M. Donson, S.O. Addo-Yobo, M.H. Handler, L. Gore, and N.K. Foreman; University of Colorado Health Sciences Center and Denver Children’s Hospital, Denver, CO, USA

Methylation of the DNA-repair gene O6-methylguanine-DNA methyltransferase (MGMT) causes gene silencing. This epigenetic modification has been associated with a favorable prognosis in adult patients with glioblastoma (GBM) who receive temozolomide and other alkylating agents. We explored MGMT promoter methylation in pediatric GBM and its relationship to clinical data, in particular survival and temozolomide sensitivity. We performed a retrospective study of MGMT promoter methylation in ten pediatric GBM. The methylation status of the MGMT was determined using a two-stage methylation specific PCR analysis on DNA extracted from tumor specimens which had been snap frozen at surgery. The relationships between MGMT promoter methylation and patient outcome and response to temozolomide were evaluated. Four of our 10 pediatric patients with GBM were found to have methylation of the MGMT gene promoter. Methylation of the MGMT promoter was shown to correlate (P = 0.0005) with survival. The average survival time for patients with methyltated MGMT was 13.7 months as compared to 2.5 months for the six patients with unmethylated MGMT promoter. Of the seven patients that received temozolomide, those patients that had the methylated MGMT gene promoter responded better to treatment (P = 0.007). As in adults, pediatric GBM patients with methylated MGMT promoter benefited from temozolomide. However, a stronger correlation with overall survival, regardless of treatment, was observed in this group of patients. These data suggest that MGMT methylation may be a prognostic factor for survival in pediatric GBM, as well as a marker for temozolomide sensitivity.


M. Terasaki, K. Sakata, S. Fukushima, and M. Shigemori; Department of Neurosurgrey, Kurume University School of Medicine, Kurume, Japan

Background: Children and young adults with recurrent malignant gliomas have limited responses to temozolomide as a single agent. We postulated that a combination of these two drugs with oral VP-16 or CPT11 for patients with recurrent malignant gliomas might result in better and more prolonged responses.

Procedure: Three patients with recurrent malignant gliomas were treated with varying combinations of temozolomide (150–200 mg/m2/d for 5 days) with oral VP-16 (50 mg/m2/d for 12 days) or CPT11 (350 mg/m2/d for day 6). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record.

Results: The age of the three patients ranged from 14 to 17 years. Diagnoses included one recurrent glioblastoma, one malignant transformations of lower grade tumors, and one treatment-induced PNET. All three patients had received radiotherapy (including two who received concomitant radiation plus temozolomide), and tow had prior chemotherapy. Two patients were treated at first recurrence, one at second recurrence. One patient had a complete response, two had partial responses. The median progression-free survival was 8.7 months (range, 6–12+ months). There was one grade 4 neutropenia, but no other grade 3 or 4 toxicities.

Conclusions: These data suggest there is activity of temozolomide in combination with oral VP-16 or CPT11 for children and young adults with recurrent malignant gliomas.


R. Jalali,1 N. Rout,1 A. Jain,1 B. Arora,2 T. Gupta,3 and P. Kurkure2; 1Department of Radiation Oncology and 2Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, and 3Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Navi Mumbai, India

Purpose: To prospectively study the feasibility of concomitant and adjuvant temozolomide (TMZ) with radiotherapy (RT) in pediatric pontine gliomas.

Methods and materials: Eight children with intrinsic pontine gliomas treated with RT (54 Gy/30#/6 weeks) with concomitant TMZ at 75 mg/m2 have been accrued so far in this prospective study. One month after RT, patients were planned for adjuvant TMZ at 150–200 mg/m2 daily for five days, four weekly for nine cycles. Patients underwent MRI and FDG-PET before RT, four weeks after RT and at three monthly intervals or on clinical progression. Criteria for stopping TMZ included ANC < 0.5x109/L, platelets < 50x109/L, or CTC nonhematological toxicity grade 4.

Results: All eight patients (five boys and three girls; median age, nine years) completed RT plus concomitant TMZ without any delay. There have been no treatment related deaths. One patient had grade 3/4 vomiting and two had grade 3 cutaneous toxicity. All patients showed clinical improvement with KPS increasing from an initial median of 50 to 70. Improvement in motor power was seen with best response from 0/5 to 4/5 and least from 3/5 to 4/5. Cranial nerve involvement was also reversed in four patients. There was reduction in lesion size on the first follow-up MRI (minor response in four, stable in four). One patient developed grade IV thrombocytopenia 10 days after and another developed bacterial meningitis following drainage of a cyst 1 month after completing concomitant treatment. Six patients are currently on adjuvant TMZ. At a median follow up of 5.5 months (range, 2–9), one of two patients with disease progression (after two and three cycles of adjuvant TMZ) has died.

Conclusion: Concomitant temozolomide with radiotherapy is feasible in children with brainstem glioma.


A.M. Cappellano, J. Rogério, L.M.S. Pereira, C. Galvão, A.P. Pascoalichio, S. Cavalheiro, P.A. Dastoli, and N.S. Silva; São Paulo, Brazil

Background: The optimum management of unresectable low-grade gliomas (LGGs) remains controversial. Surgery and/or radiotherapy may result in significant neurological and cognitive sequelae. Within this context, temozolomide (TMZ) has been shown to be active in glioma. The goals of this study performed since March 2001, are to determine the efficacy, safety and tolerability of this agent.

Patients and methods: Seventeen patients with progressive LGGs were treated with TMZ 200mg/m²/day for five consecutive days every 28 days. Response criteria used a combination of MRI or computed tomography scan and physical examination.

Results: Median age: 8.9 years; 10 males and 7 females. Tumor sites: 11 diencephalic, 3 disseminated, 2 medullar, and 1 cerebelar. Histology: 13 astrocytoma grade I, 1 grade II, 1 ganglioglioma, and 2 oligodendroglioma. Fourteen patients were considered assessable to data. Two patients (14.3%) had partial response (PR), 2 (14.3%) minor response (MR), 9 (64.3%) stable disease (SD), and 1 (7.1%) progressive disease (PD) during the initial 12 cycles. A median of 15.7 cycles (1–32 cycles) were administered until January 2006. Seven patients are in SD (41.2%), 2 in treatment (gliomatosis), and 7 PD (4 alive in different protocols). Grade 3/4 hematological toxicity was the most frequent toxic event limited to five patients. The rate of progression-free survival was 85.7% at 12 months and 55.6% at 24 and 36 months.

Conclusion: TMZ is active in LGG with low toxicity and excellent quality of life. Further studies are indicated even with a promising long-term metronomic antiangiogenic treatment for a believable chronic disease.


D.M. Ashley and S.L. Khaw; Royal Children’s Hospital, Melbourne, Australia

We describe a series of patients with progressive low-grade glioma who received temozolomide as second-line therapy. Patients were retrospectively identified. Eligible patients had had a diagnosis of low-grade glioma with or without histological confirmation, and had received temozolomide as second-line chemotherapy for progressive disease. Temozolomide was administered at a dose of 200 mg/m2 daily for the first five days of every four-week cycle. Therapy was ceased on completion of the targeted 12 cycles or on evidence of tumor progression. Thirteen patients were identified, with a median age at diagnosis of 5.5 years (range, 2.6–15.0 years). Median age at commencement of temozolomide was 9.0 years (range, 3.8–15.2 years). There were eight male and five female patients. Nine patients had been diagnosed with pilocytic astrocytoma following biopsy. Twelve patients had received carboplatin prior to temozolomide, including three who received it in combination with vincristine. Six had completed planned treatment with carboplatin, while two commenced temozolomide because of progressive disease despite ongoing carboplatin. The remaining four patients switched from carboplatin to temozolamide because of difficulties with venous access (two patients), anaphylaxis after carboplatin (one patient), and status epilepticus after carboplatin (one patient). A total of 106 cycles of therapy have been administered. Median time to progression was 35 weeks (range, 6–179 weeks). Overall, 12 of 13 patients remain alive at the time of this report, 11 with stable disease. Temozolomide appears to be active in pediatric low-grade glioma, with the advantage of oral administration and excellent tolerability. Comparison with contemporary chemotherapy regimens in a randomized trial is indicated.


M.C. Frühwald,1 H. Jürgens,1 W. Paulus,2 and R. Sträter1; 1Department of Pediatric Hematology and Oncology, University Children’s Hospital, Muenster, Germany, and 2Institute of Neuropathology, University Hospital, Muenster, Germany

Introduction: Treatment results for high-risk MB/PNET are unsatisfactory due to the vulnerability of the developing brain at the predilection age and presence of metastases at diagnosis. We present a case series of children with high-risk MB/PNET, all of whom were deemed incurable at the time of initiation of therapy or relapse.

Cases: Patient 1 (13 years) was referred to us for palliative care due to disseminated MB, previously not treated. Radiotherapy plus concomitant and consolidation temozolomide produced a lasting response with minimal evidence of disease at 12 months. Patient 2 (two years) with leptomeningeal dissemination of an MB was referred to hospice care due to paraplegia and unstable clinical condition. Using temozolomide in the hospice setting neurologic symptoms improved enabling standard therapy. Due to a near complete response high-dose temozolomide followed by stem cell rescue and radiotherapy was initiated. The patient is 10 months after HDCT in CCR. Patients 3 and 4 are infants with disseminated MB/PNET. Standard therapy could not produce a CR. To prolong time to recurrence both receive monthly temozolomide. They have been in stable disease for 48 and 46 months. Patients 5 and 6 were young adults with multiple relapsed MB. Using temozolomide both remained stable for prolonged time (12 and 18 months), making regular school visits and work attendance possible. Both patients died of progressive disease.

Conclusion: Temozolomide may play an important role in disease stabilization of children with high-risk MB/PNET. It should be evaluated in future trials as a palliative and/or first-line chemotherapeutic agent.


A.J. Michalski; Great Ormond Street Hospital for Children NHS Trust, London, UK

Brain tumors in very young children represent a particularly difficult challenge. The spectrum of diseases is large and the numbers of children with each individual condition is too small for traditional randomized controlled trials to be performed by national groups. The tumors occur at a critical time in the child’s physical, neuropsychological, and endocrine development and quality of survival issues are as important as survival statistics. With particular reference to primitive neuroectodermal tumors, previous strategies and future directions will be reviewed.


S. Rutkowski,1 U. Bode,2 F. Deinlein,1 H. Ottensmeier,1 M. Warmuth-Metz,3 N. Soerensen,4 N. Graf,5 A. Emser,6 T. Pietsch,7 J.E.A. Wolff,8 P.G. Schlegel,1 R.D. Kortmann,9 and J. Kuehl1; 1University Children’s Hospital of Wuerzburg, Wuerzburg, Germany, 2University Children’s Hospital of Bonn, Bonn, Germany, 3Department of Neuroradiology and 4Department of Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany, 5University Children’s Hospital of Homburg/Saar, Homburg/Saar, Germany, 6Institute of Medical Statistics, University of Mainz, Mainz, Germany, 7Institute of Neuropathology, University of Bonn, Bonn, Germany, 8University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, and 9Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Background: Survival of young children with medulloblastoma is poor, and children are at high risk for cognitive deficits, especially after craniospinal radiotherapy. The HIT-SKK92 trial was designed to substitute radiotherapy by intensive postoperative chemotherapy alone.

Treatment: After surgery, 43 children received three cycles (six months) of i.v. chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide) and intraventricular methotrexate according to protocol. No radiotherapy was given if children reached complete remission.

Results: In children who had complete resection (n = 17), residual tumor (14), or macroscopic metastases (12), the five-year PFS and OS rates were 82% ± 9% and 93% ± 6%, 50% ± 13% and 56% ± 14%, and 33% ± 14% and 38% ± 15%, respectively. Desmoplastic histology (20 of 43 children) and metastatic disease were independent prognostic factors. In 19 of 23 children, clinically asymptomatic leukoencephalopathy was detected by MRI. No major unexpected toxicity was reported from systemic and intraventricular chemotherapy. A significant correlation was found between cumulative doses of intraventricular methotrexate and grade of leukencephalopathy (r = 0.53; P < 0.01). Full-scale IQ of nonirradiated children (n = 14) was significantly higher (P < 0.005, CPM 92 vs. 79, median 4.7 years after treatment) as compared to irradiated patients from the former trial HIT-SKK-87 (n = 14), who did not receive intraventricular MTX.

Conclusion: Desmoplastic histology may account for a significant portion of young children with medulloblastoma. HIT-SKK92 chemotherapy was highly effective, especially for children without metastases or postoperative residual tumor, and for children with desmoplastic histology. Omission of radiotherapy appears to contribute to a better quality of life in children cured from medulloblastoma. Further assessment of long-term neurocognitive outcome of surviving children is under investigation. This work was supported by German Children’s Cancer Foundation and by German Cancer Aid.


J.L. Finlay, S. Sands, S. Gardner, I.J. Dunkel, G. McGowage, S. Kellie, B. Diaz, M. Abromowitch, A. Termuhlen, R. Olshefsky, A. Cornelius, J. Garvin, J. Allen, D. Miller, M. Rosenblum, K. Haley, H. Grodman, M. Atlas, L. Ji, and R. Sposto; Los Angeles, CA, USA

Purpose: The Head Start I and II studies for children younger than three years of age with nondisseminated medulloblastoma (MB) aimed to improve cure with preserved intellectual functioning.

Methods: Between 1991 and 2002, a total of 21 eligible children were enrolled on the induction regimen (five cycles of vincristine, cisplatin, cyclophosphamide, etoposide at three- to four-week intervals) followed by consolidation with myeloablative chemotherapy (thiotepa, carboplatin and etoposide) and autologous hematopoietic cell rescue. No irradiation was used in complete responders.


R.J. Packer, A. Gajjar, G. Vezina, L. Rorke-Adams, P. Burger, P. Robertson, D. LaFond, L. Bayer, B. Donahue, M. Marymont, K. Muraszko, J. Langston, and R. Sposto; Children’s National Medical Center, Washington, DC, USA, and Children’s Oncology Group, Arcadia, CA, USA

A total of 421 children, between 3 and 21 years of age, with nondisseminated medulloblastoma, who had total or near total resections, were treated with 2340 cGy of craniospinal radiotherapy (CSRT) and concurrent vincristine. They were prospectively randomized to postradiotherapy treatment with eight cycles of CCNU, VCR and cis-platinum, or cyclophosphamide, VCR, and cis-platinum. All received 5580 cGy of local radiotherapy (RT). On central review, 42 patients were ineligible due to factors including excessive residual disease (15) or dissemination (15). Another 66 patients were considered eligible, but with “incompletely evaluable” neuroradiographic studies. Five-year event-free survival (EFS) and survival (S) was 81% ± 2.1% and 86% ± 9%, respectively, at a median follow up of over five years. There was no difference in EFS or S by chemotherapy regimen, gender, race, age, or brainstem involvement. Those with tumor anaplasia had a five-year EFS of 73% ± 6% compared to 83% ± 2% for those without. EFS was better for those with fully evaluable studies, and five-year EFS was 36% ± 15% in those with dissemination. Relapse was posterior fossa alone in 20, disseminated alone in 23, extraneural in 2, and mixed in 16. Seven patients developed secondary tumors, including malignant gliomas in three. Nearly 25% of patients had the posterior fossa mutism syndrome. The study discloses an encouraging survival rate after treatment with reduced-dose CSRT and chemotherapy during and after RT. Performance and interpretation of staging studies remains problematic and misinterpretation puts children at increased risk of relapse. Postoperative complications remain frequent. Reductions in dose of CSRT result in a similar rate and pattern of relapse in studies using higher-dose CSRT. The incidence of secondary tumor is worrisome. Further reduction of CSRT in nondisseminated patients with medulloblastoma may be possible.


S. Rutkowski,1 K. von Hoff,1 A. von Büren,2 T. Shalaby,2 W. Hartmann,3 F. Deinlein,1 M. Warmuth-Metz,4 N. Soerensen,5 A. Faldum,6 U. Bode,7 U. Mittler,8 C. Urban,9 M. Benesch,9 R.D. Kortmann,10 P.G. Schlegel,1 J. Kuehl,1 T. Pietsch,3 and M. Grotzer2; 1University Children’s Hospital of Wuerzburg, Wuerzburg, Germany, 2Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland, 3Department of Neuropathology, University of Bonn, Bonn, Germany, Departments of 4Neuroradiology and 5Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany, 6Institute for Medical Statistics, Epidemiology and Informatics (IMBEI), University of Mainz, Mainz, Germany, 7University Children’s Hospital of Bonn, Bonn, Germany, 8University Children’s Hospital of Magdeburg, Magdeburg, Germany, University Children’s Hospital of 9Graz, Graz, Austria, and 10Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Purpose: To assess the prognostic relevance of biological markers and clinical risk factors in homogeneously treated children with medulloblastoma.

Patients and methods: Paraffin-embedded samples of tumors from patients, treated within the prospective randomized multicenter trial HIT’91, were analyzed for DNA amplification of C-MYC and N-MYC (n = 133), and RNA expression of C-MYC and TrkC (n = 101) was assessed using quantitative PCR and RT-PCR. Results were related to clinical data and outcome.

Results: Very high TrkC mRNA expression (>9) was the strongest single biologic parameter, nine patients remained relapse-free regardless of metastatic disease (seven-year EFS, 100%; P = 0.022). Three risk groups were defined by clinical criteria and mRNA expression: All 12 patients (four metastatic) with very high TrkC levels or with high TrkC/low C-MYC levels remained relapse free (seven-year EFS, 100%; favorable risk). Ten of 15 patients with metastatic disease and high C-MYC/low TrkC levels relapsed (seven-year EFS, 33%; poor risk). The seven-year EFS of the remaining 74 patients was 63% (intermediate risk). Of 37 patients with high C-MYC/low TrkC expression (M2/3 stage: 7 patients), 19 relapsed (seven-year EFS, 48%). Among 47 M0-stage patients, all 10 patients with TrkC mRNA levels >1 remained relapse free, compared to 15 events in 37 patients with low TrkC levels (seven-year EFS, 100% vs. 62%, P = 0.055). TrkC and C-MYC mRNA expression were identified as independent prognostic factors.

Conclusion: Our results validate previous findings and demonstrate that routinely processed formalin-fixed, paraffin-embedded tissue samples can be used for the identification of a good-risk group of medulloblastoma patients. This will accelerate the improvement of stratification models for clinical use in multicenter trials. Supported by German Children’s Cancer Foundation, by German Cancer Aid, by the Swiss National Fonds and the Swiss Research Foundation Child and Cancer.


M. Fouladi, S.M. Blaney, T.Y. Poussaint, B.B. Freeman III, R. McLendon, C. Fuller, A.M. Adesina, M.L. Hancock, J.S. Remack, D. Hunt, M.K. Danks, P. Ivy, C. Stewart, L.E.Kun, and A. Gajjar; St. Jude Children’s Research Hospital, Memphis, TN, USA, Texas Children’s Cancer Center, Houston, TX, USA, Children’s Hospital Boston, Boston, MA, USA, Duke University, Durham, NC, USA, and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

Purpose: An open label, multi-instituitonal phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (sPNETs), and atypical teratoid rhabdoid tumors (ATRTs).

Patients and methods: Patients were stratified as follows: Stratum 1A: MB with measurable disease at first relapse; 1B: recurrent MB with only CSF positivity or linear leptomeningeal disease; 1C: MB at second or later relapse; stratum II: recurrent SPNET; and stratum III: recurrent ATRT. Patients received oxaliplatin at 130 mg/m2 i.v. over 2 h q 3 weeks. The primary end point was to estimate the sustained objective response rate in stratum 1A; a two-staged design was used. Serum pharmacokinetics and functional mismatch repair status in tumor and peripheral blood mononuclear cells were evaluated.

Results: A total of 43 patients (13 females [30.2%]), were enrolled with a median age of eight years (range, 0.2–18.9 years). Of the 15 evaluable for response in stratum 1A, two patients had PRs; only one with imaging documenting a sustained response. Thus, accrual was closed as designed. No responses were observed in the other strata. The most frequent grade 3 and 4 toxicities included thrombocytopenia (26.2%), neutropenia (16.7%), leukopenia (11.9%), vomiting (4.8%), hypersensitivity reaction (4.8%), and peripheral sensory neuropathy (4.8%). No grade 3 or 4 ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults with a median clearance of 12.2 liters/h (4.4–30 liters/h) and median AUC0–∞of 9.4 μg/ml-h (6.2–13.9 μg/ml-h). Six of 10 tumor samples demonstrated evidence of microsatellite instability.

Conclusion: Oxaliplatin was well tolerated in children and demonstrated similar pharmacokinetic parameters as for adults. For children with first recurrent MB, the observed response rate was 6.7%.


J. Fangusaro, S. Gardner, M. Abromowitch, J. Allen, M. Atlas, S. Asgharzadeh, S. Chi, M. Comito, A. Cornelius, B. Diez, R. Dubowy, J. Garvin, S. Halpern, B. Hom, J. Hukin, C. Hurwitz, S. Kellie, M. Saly, A. Termuhlen, S. Zacharoulis, and J. Finlay; Hospital Los Angeles and Participating Institutions in the United States, Argentina, Canada, and Australia

Purpose: The Head Start I and II studies for children less than 10 years old with supratentorial primitive neuroectodermal tumors (sPNETs) aimed to improve cure while preserving intellectual functioning.

Patients and methods: A total of 43 children less than 10 years old with newly diagnosed sPNET were treated on two serial studies: Head Start I and II. After maximal surgical resection, all sPNET patients on Head Start I and those patients without dissemination on Head Start II received five cycles of induction chemotherapy that included vincristine, cisplatin, cyclophosphamide, and etoposide. Following induction, eligible patients went on to receive a single cycle of high-dose chemotherapy with hematopoietic cell rescue. Patients enrolled on Head Start II (1997–2002) with metastatic disease at diagnosis (M1+) also received high-dose intravenous methotrexate with leucovorin rescue with each induction chemotherapy cycle.

Results: Among the 43 enrolled patients, the five-year event-free survival (EFS) and overall survival (OS) were 42% ± 8% and 49% ± 8%, respectively. Patients with nonpineal sPNETs faired significantly better than those patients with pineal sPNETs (pineoblastoma). Patients older than 36 months at diagnosis faired better than did those younger than 36 months of age. Metastatic stage and extent of surgical resection were not significant prognostic factors, and 65% of survivors are alive without any irradiation exposure. Toxic mortality rate was 4.7% (2 of 43).

Conclusion: The approach provides an improved EFS and OS for young patients who typically have a very poor prognosis, and the regimen has successfully reduced, and often eliminated, the exposure to radiation therapy in the majority of surviving patients.


A. Gajjar, M. Chintagumpala, D. Ashley, A. Broniscer, M. Fouladi, D. Wallace, T. Merchant, L. Kun, R. Gilbertson, and C. Fuller; St. Jude Children’s Research Hospital, Memphis, TN, USA, Texas Children’s Hospital, Houston, TX, USA, and Royal Children’s Hospital, Melbourne, Australia

Purpose: To determine the prognostic significance of tumor histology on the event-free survival (EFS) of MB.

Methods: A total of 134 patients with Medulloblastoma (MB) were enrolled on a prospective trial (SJMB 96) from October 1996 to July 2003. Patients were treated with risk adapted craniospinal irradiation (CSI) therapy (23.4 Gy for average-risk [AR] patients; and 36–39.6 Gy for high-risk [HR] patients) followed by four courses of chemotherapy that consisted of vincristine, cisplatin, and cyclophosphamide. Each course of chemotherapy was followed by stem cell rescue. Primary tumor material from 116 of the 134 patients was centrally reviewed by the study neuropathologist. Tumor samples were designated as classic, nodular desmoplastic, and large cell/anaplastic (LCA) according to WHO criteria. Prognostic significance of disease variables was estimated using the stratified Mantel-Haenszel test and the Cox Proportional Hazards Model.

Results: Of the 73 AR patients, 45 (62%), 16 (22%), and 12 (16%) had classic, nodular desmoplastic, and LCA histology. Tumor histologic types were similarly distributed among HR patients. Tumor histology was significantly related to EFS irrespective of clinical stage. The four-year EFS is as follows: classic 84% ± 5%; nodular demosplastic 85% ± 12% and LCA 54% ± 12%. Within the AR group, patients with LCA histology have a 3.7 (range, 1.2–11.5) times greater risk of failure compared with the classic and nodular desmoplastic groups combined. The four-year EFS for AR LCA histology is 56% ± 17% compared to 88% ± 6% and 85% ± 15% for AR classic and nodular desmoplastic histologies, respectively.

Conclusion: LCA histology negatively impacts the EFS for medulloblastoma patients.


K. von Hoff,1 T. Pietsch,2 F. Deinlein,1 M. Warmuth-Metz,3 U. Mittler,4 U. Bode,5 C. Urban,6 P.G. Schlegel,1 R.D. Kortmann,7 J. Kuehl,1 and S. Rutkowski1; 1Children’s University Hospital, University of Wuerzburg, Wuerzburg, Germany, 2Department of Neuropathology, University of Bonn, Bonn, Germany, 3Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany, 4Department of Pediatric Oncology, University Children’s Hospital of Magdeburg, Magdeburg, Germany, 5Department of Pediatric Oncology, 6Department of Pediatric Oncology, and 7Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Purpose: To analyze clinical factors and survival of children and adolescents with desmoplastic medulloblastoma (DMB), a medulloblastoma subtype characterized by nodular reticulin-free zones surrounded by densely packed proliferative cells producing a reticulin fiber network.

Patients and methods: We analyzed clinical data of 91 patients with DMB (age 0–21 years; confirmed by central neuropathological review, 85 patients) treated according to 3 different prospective multicenter trials (HIT-SKK92, 20 children less than three years of age, chemotherapy only; HIT91, 12 patients, neoadjuvant or postirradiation chemotherapy; HIT2000, 59 patients, different treatment regimen). Age at diagnosis was compared to 634 children with classic medulloblastoma (CMB) registered to the same trials.

Results: DMBs were most frequent in younger children (0–5 years, 42; 6–10 years, 25; 11–15 years, 14; and 16–21 years, 10). The relative frequency of DMB:CMB was 1:2 in children less than two years of age. 53 children with DMB had localized disease (M0), 23 children had macroscopic metastases (M2/3), and 8 children had M1 stage only (7 M0/1, no CSF analyses). Event-free survival (five-year EFS) of all DMB patients was 74%. EFS was not significantly different between children with M0 (77%) and M2/3 stage (71%), and not different between children younger (77%) and older (73%) than four years at diagnosis.

Conclusion: DMB may be as frequent as CMB in early childhood. A considerable portion of children with DMB has metastatic disease at diagnosis. In contrast to CMB, young age and metastatic disease may not be unfavorable prognostic factors in children with DMB. Supported by German Childhood Cancer Foundation and German Cancer Aid.


K. von Hoff,1 T. Pietsch,2 M. Grotzer,3 W. Hartmann,2 A. von Büren,3 F. Deinlein,1 U. Mittler,4 C. Urban,5 M. Benesch,5 M. Warmuth-Metz,6 N. Soerensen,7 R.D. Kortmann,8 J. Kuehl,1 and S. Rutkowski1; 1University Children’s Hospital of Wuerzburg, Wuerzburg, Germany, 2Department of Neuropathology, University of Bonn, Bonn, Germany, 3Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland, 4University Children’s Hospital of Magedburg, Magedburg, Germany, 5University Children’s Hospital of Graz, Graz, Austria, Departments of 6Neuroradiology and 7Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany, and 8Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Purpose: To analyze clinical data and outcome of patients with large-cell anaplastic medulloblastoma (LCA-MB), which has been associated in the literature with C-MYC amplification/overexpression and poor prognosis.

Methods: Data of 726 patients registered to the prospective multicenter trials HIT91, HIT-SKK92, and HIT2000 were screened for patients with LCA-MB. Clinical data and outcome were analyzed.

Results: Twenty-three patients, all with central histology review, were identified (age 1.6–16.2 years, median 5.2). Fifteen patients had localized medulloblastoma (65%, M0). Nine of 11 patients with M0 disease and younger than four years of age remain without relapse/progression 0.7–8.5 years after diagnosis (median, 2.7). One patient died after early tumor progression, and one patient remains alive six years after relapse. Two out of four M0 patients less than four years of age are alive without relapse/progression (2.9 and 1.7 years after diagnosis), and two children died after early tumor progression. Of eight patients with metastatic LCA-MB (five less than four years of age), seven had early progression or relapse (1 CR 2.6 years after diagnosis). In none of 5 tumors from M0 patients younger than four years of age available for biological studies was C-MYC DNA amplification detected; C-MYC mRNA expression was elevated in one patient (CR).

Conclusions: Our data confirm reports from the literature on a poor prognosis of LCA-MB only for children with metastatic medulloblastoma. LCA-MB may be more frequent in children with localized disease and may not be an unfavorable risk factor in these children (M0). Standardized histopathological criteria for LCA-MB and further studies on biology and outcome are needed. Supported by German Children’s Cancer Foundation and by German Cancer Aid.


K. von Hoff,1 B. Hinkes,1 F. Deinlein,1 U. Mittler,2 C. Urban,3 M. Benesch,3 M. Warmuth-Metz,4 N. Soerensen,5 A. Faldum,6 A. Emser,6 P.G. Schlegel,1 T. Pietsch,7 R.D. Kortmann,8 J. Kuehl,1 and S. Rutkowski1; 1University Children’s Hospital of Wuerzburg, Wuerzburg, Germany, 2University Children’s Hospital of Magdeburg, Magdeburg, Germany, 3University Children’s Hospital of Graz, Graz, Austria, Departments of 4Neuroradiology and 5Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany, 6Institute for Medical Statistics, Epidemiology and Informatics (IMBEI), University of Mainz, Mainz, Germany, 7Department of Neuropathology, University of Bonn, Bonn, Germany, and 8Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Purpose: To analyze the long-term outcome of patients treated according to the HIT91 trial.

Patients and methods: Between 1991 and 1997, 280 patients with medulloblastoma 3–18 years of age were included in the prospective randomized trial HIT91, comparing a postoperative “sandwich therapy” (multiagent neoadjuvant chemotherapy before radiotherapy) to a “maintenance therapy” (radiotherapy and maintenance chemotherapy). “As treated” analyses with and without patients with incomplete staging/histology review were performed.

Results: Tumors of 232 patients were centrally reviewed for histopathology, and 214 patients had complete staging. In all 280 patients, seven-year EFS and OS were 61% and 67%, respectively (median follow up, 7.6 years). EFS of 111 M0-stage patients with histopathological review was 88% (OS 91%) after maintenance therapy, and 59% after sandwich therapy (P = 0.002). EFS of 10 “maintenance” patients without histopathological review was 56% (P = 0.002). In 45 M2/3 patients, there was no significant survival difference between maintenance and sandwich treatment (EFS 28% and 48%, P = 0.86). In contrast, EFS of 40 M1-stage patients was significantly better after maintenance therapy (75% and 28%, P = 0.002). Eleven patients (10% of all relapse patients) relapsed more than five years after diagnosis (seven, sandwich), and five patients (2%) had second malignancies (four, sandwich).

Conclusions: Patients with localized medulloblastoma, complete staging, and histopathological review had an excellent long-term outcome after maintenance therapy. Our data suggest that the maintenance regimen might be more effective in patients with M1-stage medulloblastoma compared to the sandwich strategy. Late relapses were not rare. Patients need to be followed longer for second malignancies. Supported by German Children’s Cancer Foundation and by German Cancer Aid.


C. Dufour, J. Grill, D. Valteau-Couanet, C. Boccacio, D. Couanet, O. Hartmann, and C. Kalifa; Institut Gustave Roussy, Villejuif, France

Purpose: To evaluate feasibility and efficacy of an intensified chemotherapy regimen for children with high-risk medulloblastoma/PNET at diagnosis.

Patients and methods: Twenty-one patients with disseminated medulloblastoma (n = 18) or PNET (n = 3) aged 5–15 years were enrolled. They received as induction two cycles of etoposide (500 mg/m²)-carboplatine (800 mg/m²), followed by two myeloablative courses with autologous stem cell rescue: 12 patients received two cycles of Melphalan (100mg/m²) and 9 two cycles of Thiotepa (600mg/m²). Radiotherapy was planned around day 45 after second transplantation, that is, before day 120 after diagnosis; 55 Gy were given to the primary site and craniospinal irradiation (30 Gy to the brain and 36 Gy to the spinal cord) was only administered to children with medulloblastoma.

Results: At the end of chemotherapy, there were eight complete remission, nine partial response, two with stable disease, and two with progressive disease, for a CR + PR response rate 80%. At last update with a median follow-up of 3.25 years, 15 patients are alive: 12 in CR (7 after tandem thiotepa and 5 after tandem melphalan) and 3 with progressive disease. The three-year EFS was 52%, and the three-year OS was 70%. Toxicity was manageable.

Conclusions: This pilot study indicates that intensifying sandwich chemotherapy is feasible and may improve survival of high-risk medulloblastoma/PNET.


M. Nagane, T. Yoneyama, T. Mizutani, R. Yuyama, M. Ishii, H. Yoshino, F. Bessho, Y. Fujioka, and Y. Shiokawa; Departments of Neurosurgery, Pediatrics, and Pathology, Kyorin University School of Medicine, Tokyo, Japan, and Department of Neurosurgery, Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan

Ewing’s sarcoma (ES) predominantly affects bones and soft tissues in the extremities and body trunk of adolescents, and scarcely occurs intracranially. Here we present a 15-year-old girl having a large tumor in the middle cranial fossa which medially compressed left temporal lobe. The patient noticed multiple cervical subcutaneous masses at the age of 10, which regressed spontaneously. Four years later, she was suffered from left otitis media for two months and was referred to Fuchu Municipal Hospital when she underwent tympanostomy and had headache, fever, and vomiting. On admission, she was conscious without paresis, but presented anisocoria and left hearing disturbance. Neuroradiological images demonstrated a huge heterogeneously contrast-enhanced mass with calcification occupying almost the entire left-middle fossa with destruction of the temporal bone. She underwent craniotomy for subtotal removal of the tumor. Histopathologically, the tumor was mainly composed of small round cells, which were positive for vimentin, chromogranin A, S-100, and CD99/MIC2, but were negative for epithelial or lymphocytic markers. RT-PCR analysis of the resected tumor tissue demonstrated presence of transcripts of the EWS/FLI1 fusion gene, leading to diagnosis of Ewing’s sarcoma. Postoperatively, she was transferred to Kyorin University Hospital, where she received an intensive standard chemotherapy for ES consisting of three drugs of vincristine, doxorubicin, and cyclophosphamide, in alternation with courses of ifosfamide and etoposide, resulting in stable disease with no neurological deficits. Application of CD99 immunohistochemistry and specific detection of the EWS/FLLI1 gene should be considered against atypical intracranial tumor, which might lead to appropriate selection of therapeutic regimens.


I.J. Cohen, J. Stein, J. Kapelushnik, and I. Yaniv; BMT Unit, SCMCI, and Departments of Pediatric Hematology/Oncology, Schneider Children’s Medical Center of Israel and Saroka Medical Center, Beer Sheba, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Introduction: High-dose chemotherapy (HDC) followed by autologous peripheral stem cell rescue (APSCR) is an option for children with high-risk CNS tumors following chemotherapy.

Methods: Ten children (mean, 4.8 years) received a HDC regimen using two courses of thiotepa (T) and melphalan (M) a week apart followed by APSCR as per Hara et al. (BMT 22:7–12, 1998). Diagnoses included high-risk medulloblastoma, choroid plexus carcinoma, progressive PNET, disseminated ependymoma, and recurrent pineal germ cell tumor. Patients received APSCR (mean CD34+ cell dose, 10.25 × 106/kg; with supplemental bone marrow in 1 patient) on day 0. Granulocyte colony-stimulating factor was started on day +1. Initial doses of T + M were 900 and 280 mg/m2, respectively, on days −11, −10, then −4, and −3. Due to grade 4 gastrointestinal (GI) toxicity, the doses were reduced to T + M 800 and 200 mg/m2, but GI toxicity remains the main side effect.

Results: The median number of days <500 neutrophils was 12. Two patients succumbed to bacterial infections during the first three weeks after ASCR, one patient with progressive PNET relapsed after 11 months, and one infant with medulloblastoma that progressed four months after transplant is now in CR2 after radiation. Median follow up (of six continuous disease-free patients) is 37 months. The Lansky/Karnofsky scores are > 90 in all.

Conclusion: This double-conditioning regimen is feasible and may result in prolonged disease-free survival in childhood high-risk CNS tumors. Thiotepa and melphalan may have different pharmacodynamics in Japanese and Israeli children.


A. Kawamura,1 T. Nagashima,1 Y. Okamura,1 H. Akiyama,1 K. Kawasaki,2 D. Hasegawa,2 Y. Kosaka,2 E. Kohmura3; 1Department of Neurosurgery and 2Department of Hematology and Oncology, Hyogo Prefectural Kobe Children’s Hospital, Kobe Hyogo, Japan, and 3Department of Neurosurgery, Kobe University Postgraduate School of Medicine, Kobe Hyogo, Japan

The combination of surgery, radiotherapy, and chemotherapy in the treatment of brain tumors of childhood has resulted in improving survival rates over the past decade. Radiotherapy is a significant factor to improve survival rate and quality of life. But the survival rate of patients under three years old is still low and under one year old, much worse. It could be considered that the reasons of poor results were due to the apprehension of delayed complication induced by irradiation. In this study, our recent results of infantile malignant brain tumors treated by high-dose chemotherapy without radiotherapy are reported. We have experienced 36 cases of infantile brain tumors (male, 13 cases; and female, 23 cases). Among these cases, eight underwent surgery and chemotherapy without radiotherapy. Three of 8 cases were treated by high-dose chemotherapy; two were malignant ependymoma, and one was medulloblastoma. Two were totally and one was subtotally removed. After removal of tumors, high-dose chemotherapy was carried out using Thiotepa and Melphala. Peripheral blood stem cell transplantation (PBSCT) was done in all cases. Follow-up periods were 15–36 months and outcome were all CR (complete reaction) evaluated with MRI findings. No permanent complication was confirmed in these cases. The result of our series can bring the information that high-dose chemotherapy with PBSCT could give an infantile case of malignant brain tumor a useful life without radiotherapy.


S. Takano, T. Shimizu, T. Fukushima, A. Muroi, T. Yamamoto, K. Tsuboi, T. Tsurubuchi, E. Tamura, and A. Matsumura; Department of Neurosurgery and Department of Pediatrics, Institution of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan

Purpose: Treatment strategy for pediatric malignant brain tumors except for astrocytic tumors since 2002 in our institution is introduced especially focused on cooperation with pediatric oncology group.

Materials and methods: Seven malignant brain tumors (two atypical teratoid/rhabdoid tumors, two malignant germ cell tumors, two medulloblastomas, and one pineoblastoma) were managed in our institution between November 2002 and January 2006. Treatment strategy is first diagnosis by biopsy or tumor serum marker examination; second, induction chemotherapy (ifosfamide, cisplatin, and etoposide), and then radiation if the patient is older than three years. During these initial treatments, bone marrow stem cells (50 × 108) were harvested. If residual tumor is present, radical surgical removal intended, followed by high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR).

Results: A total of seven children with a median age of four years (range, 0.1–11.0 years) were treated according to this strategy. Two patients had disseminated disease followed by complete remission with ASCR. Six patients received radiotherapy at median doses of 30.6 Gy for whole brain and 19.8 Gy for local. Four patients received HDC followed by ASCR. Six patients are alive with no evidence of disease recurrence at a median of 22.5 months from diagnosis (range, 4 to 32 months). One patient has died of systemic infection after a second HDC at 10 months after diagnosis. Hospitalization was median 10 months supported by both parents and special nurses.

Conclusion: The use or preparation of HDC with ASCR in addition to radiotherapy seems to be effective treatment for malignant brain tumor patients with residual or disseminated disease after initial chemoradiation therapy. Cooperation with pediatric oncology group is highly important for the management of malignant brain tumor patients and their families.


T. Ichikawa,1 H. Kambara,1 K. Chayama,2 T. Miyamura,2 T. Tamiya,3 and I. Date1; 1Department of Neurological Surgery and 2Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, and 3Department of Neurological Surgery, Kagawa University School of Medicine, Kagawa, Japan

Purpose: This study was designed to determine the feasibility and safety of delivering postoperative sandwich chemotherapy and reduced-dose craniospinal radiotherapy to children with newly diagnosed medulloblastoma.

Materials and methods: Thirteen consecutive patients with medulloblastoma (seven with standard-risk disease and six with high-risk disease) treated between January 1997 and December 2005 were included. After surgical resection, standard-risk patients were treated with one cycle of ICE (IFOS, CBDCA, VP-16)/VCEC (VCR, CPA, VP-16, CDDP) followed by craniospinal irradiation and two cycles of ICE/VCEC. Treatment of high-risk patients consisted of two to three cycles of ICE/VCEC followed by craniospinal irradiation and two cycles of high dose ICE or TEC (Thio-TEPA, VP-16, CBDCA). Irradiation of the entire central nervous system (24 Gy for the whole brain and spine) was carried out, and a boost irradiation dose of 30 Gy was given to the extended local area to the patients older than three. Support with peripheral blood stem cells and granulocyte colony-stimulating factor was administered after each cycle of postradiation chemotherapy.

Results: With a median follow-up of 47 months (range, 9–110), 10 complete responses and one partial response were observed. No patient died of treatment-related toxicities. One patient with standard-risk disease developed dissemination after completing chemoradiotherapy and died 24 months after surgery. One patient with high-risk disease had early progression and died seven months after surgery. All of the survivors had no neurocognitive deficit.

Conclusion: We conclude that postoperative sandwich chemotherapy and reduced-dose craniospinal radiotherapy may improve survival rates and decrease the radiation-related late toxicity in pediatric patients with medulloblastoma.


M. Oda, J.A. Takahashi, Y. Kishi, T. Kodawara, D. Doi, H. Kataoka, K. Nozaki, and N. Hashimoto; Departments of Neurosurgery and Pharmaceutics, Kyoto University Graduate School of Medicine, Kyoto, Japan

A 16-year-old male suffered from headache and nausea since December 2001. The total removal of the tumor in the fourth ventricle was performed in April. The tumor was medulloblastoma. He received 53.9 Gy irradiation for the whole brain and whole spine and synchronized chemotherapy using vincristine. After radiation therapy, he received chemotherapy with ACNU, cisplatin, and vincristine eight times. There was no recurrence until August 2004, but there were a recurrence and dissemination to the spinal cord in December 2004. We planned high-dose chemotherapy with PBSCT and did chemotherapy for harvest in January 2005. The reaction to the tumor in the fourth ventricle was poor, but a spinal tumor disappeared. We did stereotactic radiosurgery for the tumor in the fourth ventricle in March and did total resection in July. There was no tumor found neuroradiologically at that time. He received high-dose chemotherapy with PBSCT twice, and he is now an outpatient without residual tumor. Usually, we use high-dose chemotherapy with PBSCT when the tumors disappear by high-dose chemotherapy for harvest. But we think that it is an effective method for a tumor in a recurrence to do high-dose chemotherapy for complete or partial remission tumors and direct surgery for stable tumors.


C.K. Tseng,1 N.M. Tsang,1 K.C. Wei,2 T.H. Jaing,3 and P.C. Pai1; 1Department of Radiation Oncology and 2Department of Surgery, Division of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taipei, Taiwan, and 3Department of Pediatric Hemo-Oncology, Chang Gung Children Hospital, Linkou Medical Center, Taipei, Taiwan

Objectives: To explore the outcome of medulloblastoma patients treated by postoperative adjuvant radiotherapy with or without chemotherapy.

Methods: Forty-four medulloblastoma patients received radiotherapy from 1990 to 2004. Of these, 27 are male and 17 female, aged 2.6 to 15.9 years old at diagnosis, with median age of 8.5. All patients except three received gross total removal of tumor, and the staging distributions are 13 of T2, 22 of T3a, 9 of T3b, 29 of M0, and 6 of M3. All patients received curative dose of radiotherapy, including CSA irradiation in 42 patients, median dose of 3240 cGy with range from 2340 to 4140 cGy, and posterior fossa boost to median at 5400 cGy (4860–5760). RT courses were finished in (median) 48 days (34–64). Chemotherapy (CT), mainly with cisplatin and VP-16, were used in 30 patients, 4 as induction, 22 as adjuvant after radiotherapy, and 4 as both. The median follow-up time is 87 months (8–184 months).

Results: Of the 44 patients, the overall survival rate is 75% at five years, with 80% at combined RT and CT patients, and 64% at RT only group (P = 0.22). Seventeen patients suffered from treatment failure. Four with disseminated CSF seeding, two spinal relapse, eight posterior fossa recurrence, and two had distant metastasis. Four were salvaged.

Conclusions: Even though the treatment results didn’t show statistically significant difference on overall survival, we preferred to have patients with medulloblastoma treated by surgery followed by combination of radiotherapy and chemotherapy.


J. Verlooy,1 E. Vandecruys,1 S. Bravo,4 T. Boterberg,2 E. Baert,3 and Y. Benoit1; Departments of 1Pediatric Hemato-Oncology, 2Radiotherapy, and 3Neurosurgery, Ghent University Hospital, Ghent, Belgium, and 4Department of Pediatric Hemato-Oncology, University Hospital, Free University, Brussels, Belgium

Children under three years of age with a highly malignant brain tumor, have a dismal prognosis because of the impossibility of craniospinal irradiation. Even with delayed craniospinal radiotherapy (after chemotherapy) at the age of three, they can suffer from severe neurocognitive and endocrinological dysfunctions. We report a series of patients with posterior fossa tumors treated with surgery, chemotherapy, and local irradiation at the age of two years. Between 1991 and 2003 nine patients (age: 12 to 24 months) were diagnosed with medulloblastoma (n = 7) and ependymoma (n = 2). Total resection was performed in eight patients, one underwent near-total resection. All patients received chemotherapy for at least four courses or until they reached the age of two years. Chemotherapy was based on a combination of vincristine/cyclophosphamide/carboplatin/etoposide (SIOP PNET3; n = 7) and methotrexate/cisplatin (UKCCSG-CNS9204; n = 1) or carboplatin/etoposide (n = 1). Patients were then locally irradiated on the fossa posterior (23.4–45.0 Gy) without/with a boost on the tumor bed (9–30 Gy). Two patients received additional chemotherapy (CCNU/vincristine). Seven of nine patients remain progression free: mean FU, 4.7 years (range, 3.3–13.1 years). Neurocognitive and endocrinological sequelae seem to be minimal: five patients showed laboratory findings of growth hormone deficiency but only one was in clinical need of substitution therapy. We observed no or limited neurocognitive dysfunction and no auditory problems. In young children, pre-radiotherapy chemotherapy may replace craniospinal irradiation as used in older children. Local posterior fossa irradiation at the age of two years seems to have minimal neurocognitive and neuroendocrine morbidity.


J. Yoshimura,1 K. Nishiyama,1 H. Mori,2 H. Takahashi,1 and R. Tanaka1; 1Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata City, Japan, and 2Division of Pediatric Neurosurgery, Jikei University Hospital, Jikei Women’s and Children’s Medical Center, Tokyo, Japan

Purpose: To analyze the effect of intrathecal (IT) chemotherapy in patients with disseminated medulloblastoma.

Methods: From 1979 to 2005, a total of 45 patients with medulloblastoma were treated with craniospinal irradiation and systemic chemotherapy following surgery. Twenty-one of these 45 patients received IT chemotherapy with systemic chemotherapy including nine patients for residual leptomeningeal lesions after initial therapy and 12 for leptomeningeal recurrence. In these 21 patients, 12 received lumbar and/or ventricular bolus injection, one received ventriculolumbar perfusion and eight received both perfusion and bolus injection. The chemotherapeutic agents were methotrexate (MTX) and nitrosoureas (ACNU, MCNU). The doses were 5–10 mg of both drugs and the cycles were 3–12 times for perfusion and 5–54 times for bolus injection. The effects were assessed by radiological and cytological examinations, and also clinical symptoms were assessed.

Results: Radiological and/or cytological responses were observed in 10 of 21 (47.6%) patients, including seven cases of complete remission. Seven of 18 patients underwent MRI showed improvement. These included four cases of complete response and three cases of partial response. Six of 11 cases evaluated by cerebrospinal fluid cytology attained clearance of malignant cells. Five patients received lumbar bolus injection of nitrosoureas more than seven times experienced paraplegia and double incontinence. A patient with 54 times of ventricular injection of nitrosoureas experienced truncal ataxia.

Conclusion: IT chemotherapy is effective in some cases with disseminated medulloblastoma and seems to be an appropriate treatment choice for leptomeningeal recurrence. However, many times bolus injection should be avoided to prevent side effects.


S.M. Blaney, S.L. Berg, M. Krailo, A.M. Ingle, F. Balis, R. Heideman, J.R. Geyer, M. Bernstein, and P.C. Adamson; Houston, TX, USA

Purpose: A phase II trial of intrathecal topotecan was performed in children with recurrent or refractory leptomeningeal medulloblastoma or other solid tumors with leptomeningeal metastases to determine therapeutic activity, defined as response rate and time to CNS progression.

Patients and methods: Twenty-five eligible patients with leptomeningeal dissemination of medulloblastoma (n = 14) or other solid tumors (n =11) received intrathecal topotecan (0.4 mg/dose for patients younger than three years of age) twice weekly (every three to four days) for six weeks during induction, weekly for four weeks during consolidation, and twice monthly for four months and then monthly thereafter during maintenance.

Results: Intrathecal topotecan was generally well tolerated. There were no objective responses (CR or PR). The median six-month progression-free survival for patients with leptomeningeal medulloblastoma was 19% ± 12%, and 13% ± 12% for patients with other solid tumors with leptomeningeal metastases.

Conclusion: Twice weekly administration of topotecan did not significantly prolong the event-free survival for children with leptomeningeal metastases from medulloblastoma or other solid tumors beyond six months. However, benefit in terms of disease stabilization greater than five months was observed in four children, two with supratentorial PNET, and one each with medulloblastoma and anaplastic glioma. A phase I study of IT topotecan using a daily × 5 schedule of administration has been initiated in an attempt to increase the antitumor activity of this agent based on preclinical data showing greater antitumor activity with protracted administration.


S. Moriuchi, M. Nonaka, T. Yamanaka, Y. Rinn, M. Ishihara, K. Yamanaka, S. Nakajima, and M. Yamasaki; Osaka National Hospital, Osaka, Japan

It is very difficult to treat refractory medulloblastoma patients against multimodality treatments, especially with cerebrospinal fluid (CSF) disseminations. We experienced a case of refractory pediatric medulloblastoma with a patient with CSF dissemination whose quality of life could be enhanced and survival prolonged after CSF disseminations by intrathecal administration of interferon-beta. A two-year-old boy with medulloblastoma accompanied by hydrocephalus had total resection of a primary medulloblastoma of 4 cm in diameter (T3M0 in Chang staging system). Postoperative chemotherapy (six courses of intravenous administration of CDDP, VP-16, VCR, CPA, and intrathecal administration of MTX) was performed with the use of PBSCT. Radiation was sustained for his young age. When he was four years old, he complained of severe back pain. CSF disseminations were detected in Pons, midbrain, and the spinal cord with MRI. Radiation therapy (WB 36Gy, local boost 14 Gy, spinal 32 Gy) was performed. Complete remission could not be obtained (partial response) and interferon-beta (3 million units) was administered intravenously once a week as an outpatient afterward. With administrations of intrathecal interferon-beta (3 million units), back pain was relieved and he could go to elementary school on foot every day for two years. Side effects, such as high fever, were easily controllable. He could have a useful life with going to elementary school by himself, until he died of CSF dissemination at seven years old. Intrathecal administration of interferon-beta was thought to be useful treatment for the refractory medulloblastoma patients with CSF dissemination to obtain enhanced quality of life.


I. Slavc, A. Peyrl, A. Gupper, A. Reinprecht, and C. Haberler; Departments of Pediatrics and Neurosurgery and Institute of Neurology, Medical University of Vienna, Vienna, Austria

Background: Neoplastic meningitis remains one of the greatest treatment challenges in cancer medicine. Because of the limited penetration of systemically administered anticancer drugs across the blood-brain/CSF barrier there is a compelling need for new drugs that can be administered intrathecally. Liposomal cytarabine (DepoCyt) is a novel slow-release formulation of cytarabine which is hoped to result in cell kill also in patients with leptomeningeal disease from solid tumors. The recommended dose for patients between 3 and 21 years is 35 mg versus 50 mg in adults. We report on the tolerability of intrathecal DepoCyt in 10 children who were either younger than three years or received higher doses.

Patients: From October 2004 to January 2006, 10 children aged 11 months to 15 years (median, 12 years) with various highly malignant solid tumors located in the CNS were treated with intrathecal DepotCyt. The dose was 25 mg in children 11 months to 3 years old, 35 mg in a five-year-old and 50 mg in older patients. DepotCyt was administered either intraventricularly (n = 27) or intralumbarly (n = 25) every two weeks with a median of 5.5 applications/patient and a maximal cumulative dose of 450 mg (median 225 mg). All patients received concomitant dexamethason.

Results: Except for grade 2 headache in two patients and a transiently decreased vision, unsteady gait, decrease in bladder control, and fatigue in one patient, no adverse effects were noted.

Conclusion: Repeated intrathecal DepoCyt therapy at a dose of 25–50 mg with concomitant oral dexamethason appears to be feasible and is well tolerated. Further research is warranted to determine the threshold dose required for solid tumors in children.


D. Walker,1 L. Howden,2 D. Giddings,2 A. Aroussi,2 H. Power,2 M. Garnett,3 and M. Vloeberghs1; 1School of Human Development, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK, 2School of Mechanical, Materials and Manufacturing Engineering, University of Nottingham, Nottingham, UK, and 3School of Pharmacy, University of Nottingham, Nottingham, UK

Introduction: Intrathecal drug delivery (ITRx) via the lumbar route is routinely used in the prophylactic treatment of leptomeningeal leukemias. The role of ITRx in leptomeningeal dissemination of CNS tumors is exploratory, recent preliminary results suggest intraventricular Methotrexate may benefit young children with medulloblastoma. The intraventricular route is thought to provide greater homogeneity of drug concentration throughout the spinal fluid spaces when compared to the lumbar route.

Hypothesis: Physical modeling of CSF fluid spaces and flows will permit refinement of drug delivery techniques and optimizing of intrathecal therapies for specific purposes

Methods: A 2:1 scale, plastic model of the human ventricular system has been constructed from a series of MRI scans of the brain. The MRI scans were transferred to the medical imaging package, MIMICS, which allowed construction of a mould of the ventricles. The plastic molded ventricular model was filled with water, and 5–7 ml (0.625–0.875 ml at 1:1 scale) of water-based dye was injected into the lateral ventricles using a 1.25mm diameter injection tube (approximately 20 gauge at 1:1 scale) and a 10ml volume syringe, at velocities of between 10cm/s and 40cm/s. The movement and concentration of the dye was examined over time. Two types of simulations were examined: low velocity (laminar injection) and high velocity (turbulent injection). The two injection types produced wildly different concentration and distribution results. The results suggest that each injection type can be utilized for different applications, with high velocity injections able to distribute a drug faster and further through the CSF than a slower injection, which seems to allow high concentration of drug over a longer period.

Conclusions: The findings suggest that injection velocity has a direct impact on the distribution and concentration of drugs injected into the ventricular CSF.


N.M. Ahmed, M.K. Ratnayake, B. Savoldo, L. Perlaky, G.P. Dotti, W. Wels, M.B. Bhattacharjee, H.D. Shine, C.M. Rooney, H.E. Heslop, and S. Gottschalk; Center for Cell and Gene Therapy, Texas Children’s Cancer Center, Houston, TX, USA, and Departments of Pediatrics, Immunology, Neurosurgery, Pathology, Medicine, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA

Background: The long-term objective of this project is to develop an innovative HER2-targeted immunotherapeutic approach for medulloblastoma. HER2 is expressed in 40% of medulloblastomas and at present less than one-third of patients with HER2-positive tumors are cured by conventional therapies. The aim of this study was to determine if T cells grafted with an artificial HER2-specific chimeric antigen receptor (CAR) recognize and kill HER2-positive medulloblastomas.

Methods: T cells from healthy donors and medulloblastoma patients were transduced with a retroviral vector encoding a HER2-specific CAR with a -signaling domain (HER2T cells). We analyzed the ability of HER2T cells to (1) proliferate, (2) produce immunostimulatory cytokines (IFN-γ and IL-2), and (3) kill HER2-positive targets in cytoxicity assays upon exposure to HER2-positive primary medulloblastoma cells and cell lines. The in vivo function was tested in an orthotopic murine xenograft model of human medulloblastoma by serial bioluminescence imaging.

Results: HER2T cells killed both HER2-positive primary medulloblastoma cells and cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. Stimulation of HER2T cells resulted in T-cell proliferation and secretion of IFN-γ and IL-2 in a HER2-dependent manner. In vivo, the adoptive transfer of HER2T cells resulted in sustained regression of established medulloblastomas and a survival advantage in treated animals. In contrast, delivery of nontransduced T cells did not alter tumor growth.

Conclusions: This study shows for the first time that HER2 is a target antigen for the immunotherapy of medulloblastoma. The adoptive transfer of HER2-redirected T cells may represent a promising immunotherapeutic approach for medulloblastoma.


H.L. Jung,1 J. Choi,2 D.H. Kim,2 Y.S. Yim,2 K.H. Yoo,1 K.W. Sung,1 and H.H. Koo1; 1Department of Pediatrics and 2Laboratory of Hematology and Oncology, Center of Clinical Research, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Survivin, a member of inhibitor of apoptosis gene (IAP) family, has been proposed as a promising target for new anticancer interventions. The aims of this study were to investigate whether overexpression of survivin could mediate resistance to etoposide treatment, and to determine the potentiality of combined treatment of survivin siRNA and etoposide in medulloblastoma. D283Med and Daoy cells were transfected with siRNA oligonucleotides of survivin for suppression, and pcDNA4/V5-His survivin vectors for overexpression of survivin. Survivin mRNA and protein levels were measured by real time RT-PCR (ABI systems) and Western blot (Bio-Rad) analysis after 48 h of transfection, and then were compared to those of nonsense siRNA treated cells (negative control). The transfected cells were treated with etoposide in various concentrations of 1.25 μM to 0.01 μM for 48 h, starting at 48 h after transfection. Cell viability was measured with WST8 reagent (CCK8-kit, Dojindo Laboratories, Japan). Survivin mRNA and protein expressions were reduced by siRNA of surviving, and increased by pcDNA vector of survivin after 48 h of transfection. In D283Med, combined treatment of survivin siRNA and 0.25 μM etoposide induced 40% reduction of cell viability, while combined treatment of pcDNA survivin and etoposide induced only 18.3% reduction. In Daoy, combined treatment of survivin siRNA and 0.625 μM etoposide induced 37.4% reduction of cell viability, while pcDNA vector of survivin and etoposide induced 22% reduction. Our results suggested that overexpression of survivin could mediate resistance to etoposide, and survivin siRNA could be used as a selective therapeutic tool to kill medulloblastoma cells.


S. Furchert,1 M. Jung,2 A. Loidl,3 H. Jürgens,1 and M.C. Frühwald1; 1Department of Pediatric Hematology and Oncology, University Children’s Hospital, Muenster, Germany, 2University of Freiburg, Institute of Pharmaceutical Sciences, Freiburg, Germany, and 3Innsbruck Medical University, Division of Molecular Biology, Biocenter, Innsbruck, Austria

Background: The epigenetic structure of DNA and its lesions play a role in the origin of medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RTs). Manipulation of the epigenetic backbone may thus offer opportunities for treatment.

Methods: We investigated the effects of histone deacetylase inhibitors (HDIs) on histone acetylation, cell proliferation, induction of apoptosis and gene expression in vitro. Thirteen cell lines (four MBs, five neuroblastomas, two AT/RTs, and two RTKs) were studied. MTT assays evaluated the toxicity of nine HDIs. Hyperacetylation was assessed by Western blot with an antibody to histone H4. Cell lines CH-LA 90, SHEP-FS, UW228-2, and D341 Med were analyzed by reexpression experiments employing M344, MS-275, trichostatin A (TSA), and valproic acid (VPA). Induction of apoptosis was investigated using annexin-V staining in UW228-2 and BT 12 cells treated with TSA and M344.

Results: All compounds inhibited cell growth. Highest concentrations were necessary for VPA (GI50 72 h 53.6 to 332.9 μM). TSA was most efficient (GI50 72 h, 0.01–8.8 μM). Western blot analysis revealed hyperacetylation of histone H4 after HDI treatment. Reexpression analysis by RT-PCR demonstrated reactivation of the proapoptotic CASP8 and other growth regulatory genes. Annexin-V staining demonstrated induction of apoptosis.

Conclusion: Our data indicate that HDIs inhibit the growth of medulloblastoma, neuroblastoma, and rhabdoid tumors in vitro. Treatment caused reactivation of growth regulatory genes and induced apoptosis. Our results warrant further studies and potentially clinical trials for the treatment of high-risk embryonal tumors of the nervous system. This work was sponsored by the Deutsche Krebshilfe.


D. Aguilera, H. Vasquez, C. Das, V. Gopalakrishnan, and J. Wolff; Children’s Cancer Hospital at University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Background: In medulloblastoma (MB), the promoter of the apoptosis genes such as casp-8 is frequently silenced by hypermethylation. This requires histone deacetylase (HDAC) activity. We hypothesized that cells will be more sensitive to HDAC inhibitors when preincubated with a demethylating agent.

Methods: MTT assays and flow cytometry were performed on DAOY cells exposed to various concentrations of the HDAC inhibition MS-275 and the demethylating agent 5-azacytidine (AZA), from for different exposure times and sequences.

Results: In single drug experiments, the cytotoxicity measured as IC50 (concentration resulting in 50% of cells) of MS275 was 3.75, 2, 1, 0.8, and 0.3 μM after 24, 48, 72, 96, and 144 h, respectively. For AZA, it was > 20, 10, 3.75, and 3.5 after 24, 48, 72, and 96 h, respectively. In combined drug treatments, the cytotoxicity depended on which drug was used first. AZA given first and MS275 second had less effect than each of the drugs alone. The opposite sequence resulted in synergistic cytotoxicity. Simultaneous treatment gave intermediate results. Flow cytometry indicated a G2 arrest after treatment with AZA, and G1 arrest after MS275 incubation, in a dose- and time-dependent fashion.

Interpretation: MS-275 and 5-azacytidine are cytotoxic to DAOY cells in vitro. Our hypothesis was falsified. The mechanism of the time-sequence potentiation might be because cells arrested in G1 are more sensitive to AZA, which needs to be incorporated into the DNA. Combinations of MS275 and AZA in the right time sequence might prove an effective treatment for medulloblastoma.


N. Baryawno, B. Sveinbjörnsson, S. Holm, A. Orrego, B. Gustavsson, J.I. Johnsen, and P. Kogner; Childhood Cancer Research Unit, Department of Woman and Child Health and Department of Oncology and Pathology, Karolinska Institutet, CancerCentrumKarolinska and Astrid Lindgren Children’s Hospital, Stockholm, Sweden

Background: Cyclooxygenases (COX-1 and COX-2) catalyze the rate-limiting step in the conversion of arachidonic acid to prostaglandins. COX-1 is constitutively expressed in normal tissues, whereas COX-2 expression is up-regulated in inflammation and several adult epithelial cancers. COX-2 expression is linked to cellular proliferation, resistance to apoptosis, meta-static invasion, increased angiogenesis, and decreased immunological surveillance.

Material: We analyzed primary clinical tumors from 41 patients of different ages and clinical subsets diagnosed with PNET/medulloblastoma (MB). We also investigated 11 different PNET/MB cell lines and established human xenografts in nude mice using D283 cells.

Results: Forty of 41 MB tumors showed specific cytoplasmic expression of COX-2 in the tumor cells. MB cell lines showed COX-2 mRNA using RT-PCR and protein expression using Western blot. MB cells irradiated in vitro showed increased COX-2 expression as analyzed with quantitative RT-PCR. Treatment of MB cells in vitro with the selective COX-2 inhibitor celecoxib, or the dual COX-1/COX-2 inhibitor diclofenac, resulted in dose-dependent growth inhibition as analyzed with MTT. In vitro IC50 ranged from 10 to 40 μM for celecoxib and from 10 to 125 μM for diclofenac. Clonogenic growth was completely inhibited with celecoxib. COX inhibitor-induced cell death was characterized by accumulation of cells in sub G1, altered mitochondrial transmembrane potential followed by a cleavage of caspase 3, caspase 9, and PARP and induction of apoptosis.

Conclusions: Medulloblastoma tumors and cell lines express high levels of COX-2. Experimental therapy indicates that COX inhibition may be a novel therapeutic option for children with PNET/medulloblastoma. The use of NSAIDs deserves further clinical evaluation in these patients.


T. Shalaby,1 A. von Büren,1 N. Meister,1 P. Rivera,1 C. Oehler,2 M. Pruschy,2 and M. A. Grotzer1; 1Neuro-Oncology Program, University Children’s Hospital of Zurich, Zurich, Switzerland, and 2Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland

Purpose: The molecular mechanisms for sensitivity and resistance of medulloblastoma (MB) toward chemotherapy and radiation are elusive. Loss of caspase-8 expression — which has been demonstrated in a subset of MB — might disable important apoptotic signaling pathways and therefore contribute to treatment resistance. To identify novel treatment approaches, we investigated the effects of interferon-γ (IFN-γ) mediated caspase-8 restoration on chemosensitivity and radiosensitivity of MB cells and evaluated IFN-γ receptors (IFN-γ R1 and R2) expression in primary MB.

Materials and methods: After pretreatment with IFN-γ in the presence or absence of the caspase-8 specific inhibitor z-IETD-fmk, MB cells were either exposed to radiation or incubated with cisplatin, doxorubicin or etoposide. Cell viability and cell death was determined by the MTS and apoptosis assay. IFN-γ receptors mRNA expression was determined using quantitative RT-PCR in 54 primary MB, and 13 normal brain samples.

Results: IFN-γ treatment resulted in sensitisation to radiation and chemosensitisation of MB cells to the drugs tested. These effects were more prominent in MB cells expressing low caspase 8 and were markedly reduced by the caspase-8 specific inhibitor z-IETD-fmk, indicating an important role of caspase 8 in IFN-γ mediated sensitization in MB cells. Compared to normal brain samples, IFN-γ R2 expression in primary MB was significantly lower (P = 0.005) indicating that defects in IFN-γ signaling contribute to MB biology.

Conclusions: Our results provide evidence that IFN-γ mediated up-regulation of caspase 8 in MB cells might restore apoptotic pathways relevant to the response to chemotherapy and radiotherapy.


A. von Büren,1 T. Shalaby,1 D. Stearns,2 C.G. Eberhart,2 L. Helson,3 and M.A. Grotzer1; 1Neuro-Oncology Program, University Children’s Hospital, Zürich, Switzerland, 2Department of Pathology, Johns Hopkins University, Baltimore, MD, USA, and 3Tapestry Pharmaceuticals, Boulder, CO, USA

Purpose: With current treatment strategies, nearly half of all medulloblastoma (MB) patients eventually die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, overexpression of c-MYC has been shown to correlate with anaplasia and unfavorable survival outcome. In neuroblastoma — an embryonal tumor with biological similarities to MB — the quassinoid NBT-272 has been demonstrated to down-regulate c-MYC protein expression and to inhibit cellular proliferation. To study NBT-272 mediated responses in MB cells, and to test whether these responses depend on the level of c-MYC expression, DAOY (wildtype, empty vector transfected, and c-MYC transfected), D341 (c-MYC amplification), and D425 (c-MYC amplification) human MB cells were treated with different concentrations of NBT-272.

Methods and results: Western blot and quantitative real-time PCR showed NBT-272 mediated c-MYC mRNA and up to 90% protein down-regulation. The percentage of down-regulation was independent from c-MYC expression. NBT-272 treatment resulted in dose-dependent inhibition of cellular proliferation (IC50 from 0.006 to 0.5 μg/ml), increased apoptosis, and S-phase arrest.

Conclusion: Independent from c-MYC expression level, treatment with NBT-272 results in down-regulation of c-MYC and inhibition of cellular proliferation in MB cells through different mechanisms, including induction of apoptosis and S-phase arrest. Targeting c-MYC — either by NBT-272 or by more specific antisense or siRNA approaches — might be a promising strategy to develop novel therapies for childhood MB.


A. Rosenfeld, D. Paul, M. Kletzel, Y. Tange, E. Bremer, T. Tomita, and S. Goldman; Department of Hematology/Oncology/Transplant, Children’s Memorial Hospital, Northwestern University, Chicago, IL, USA

Busulfex is known to cross the Blood Brain Barrier and has been used in a myeloablative setting at a dose of 40 mg/kg in mice. We obtained cell viability curves for three rat glioma cell lines (9L, RG2, and F98) and three human cell lines (U87, MO59K, and 13-06). Cells were grown in cell culture with cell specific supplemented DMEM media. After seven days cells were harvested and plated at concentrations of 2.5 × 103 cells/ml for the rat lines and 6.25 × 103 cells/ml for the human lines; these concentrations were chosen to avoid 100% confluency by the experiment’s end. After 24 h of reequilibration in a 96-well plate, cells were exposed to varying concentrations of Busulfex for approximately 2 h (1, 0.3, 0.1, 0.03, 0.01, and 0.003 mg/ml) after which the drug was replaced with fresh media. Following four days of cell growth, a photometric assay (Alamar blue) was performed. Cell viability curves were then constructed, with subsequent extrapolated LD50s. Results of these cell culture experiments thus reveal efficacious doses much less than the established myeloablative dose. Preliminary studies applying these doses to an animal model suggest a trend toward efficacy at much lower doses of Busulfex. Further studies are ongoing to find the optimal Busulfex dose — one which balances optimal efficacy without being myeloablative, making it an ideal up-front therapy candidate.


C.A. Kruchko,1 J.M. Propp,1,2 and B.J. McCarthy1,2; 1Central Brain Tumor Registry of the United States, Hinsdale, IL, USA, and 2University of Illinois at Chicago, Chicago, IL, USA

Large population-based data sources are necessary to describe primary brain tumors in the United States. This becomes crucial when describing brain tumors occurring in children, 0–19 years of age. Whereas childhood brain tumors are the most common solid tumor in children and the second cause of cancer death in children in the United States, their incidence is rare (4.3 per 100,000 person-years). In 1992, the Central Brain Tumor Registry of the United States (CBTRUS) was founded to collect accurate incidence data on all primary brain tumors, malignant and nonmalignant, from state cancer registries and to analyze these data in a clinically relevant way. It has also utilized data from other resources such as the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and the National Cancer Data Base of the American College of Surgeons. This presentation will examine the incidence, survival, and trends of common childhood brain tumors as well as to describe the datasets from which these statistics were derived. The challenges in analyzing brain tumor data in general, but especially data pertaining to children, will be presented. The descriptive epidemiology of childhood brain tumors as presented in the CBTRUS reports provides researchers with detailed reference data to support and to develop hypotheses concerning these devastating tumors. As more countries develop their own population-based central brain tumor registries, worldwide statistics on childhood brain tumors by histology will become readily available and will provoke more investigation into their etiology.


S. Shibui, Y. Narita, Y. Miyakita, and K. Nomura; Neurosurgery Divison, National Cancer Center Hospital, Tokyo, Japan

We present the statistical data of pediatric brain tumors in Japan. The Committee of the Brain Tumor Registry of Japan (BTRJ) was established in 1974 in order to investigate the frequency and survival of brain tumors in Japan. This presentation is based on the 11th edition of the BTRJ report which was issued as a supplement of Neurologia medico-chirurgica in Septemeber 2003. In this edition, 98,647 cases of brain tumors were registered. Four thousand and seventy children under 15 years of age with primary brain tumors were registered during 1984 and 1996; the most frequent tumor was astrocytoma, which accounted for 774 cases (19.0%), followed by medulloblastoma (484 cases, 11.9%), germinoma (387 cases, 9.5%), craniopharyngioma (364 cases, 8.9%), and anaplastic astrocytoma (230 cases, 5.7%). The frequency of medulloblastoma registered between 1969 and 1981 was as high as 17%, and that of germinoma was 7.5%. The frequency of astrocytoma and anaplasic astrocyoma was similar between these two periods. Five-year relative survival rates of patients with medulloblastoma and germinoma between 1979 and 1983 were only 31.2% and 82.1%, while those between 1991 and 1996 were 60.1% and 91.2%, respectively. Craniospinal radiotherapy and platinum-based chemotherapy were supposed to contribute to the improvement in survival of these malignant tumors. However, better survival of benign tumors, such as craniopharyngioma, noted in the recent report was considered to be derived from the improvement of microsurgical technique and postoperative management of the patients.


G.C.F. Chan,1 M.M.K. Shing,2 H.L. Yuen,3 A.C.W. Lee,4 C.W. Luk,3 S.Y. Ha,1 and C.K. Li2; 1Queen Mary Hospital, University of Hong Kong, 2Prince of Wales Hospital, Chinese University of Hong Kong, 3Queen Elizabeth Hospital, 4Tuen Mun Hospital, Hong Kong

Objective: Brain tumor is the second most common malignancy in childhood, and no population based study on its incidence in Chinese children existed. We review our patients’ data and aim to provide some insight in this aspect.

Materials and methods: Prospective collection of childhood pediatric brain tumor data from the five major public hospitals was performed since 1994. These five hospitals are the only institutes with pediatric oncology service in our locality. Standard data entry sheets were used, and the data collection and entry were performed by designated data managers. The data were further cross-checked with the Hong Kong Cancer Registry database, which collected all the pathology reports of cancer in the territory. Except for brainstem tumors, no brain tumors without histological or tumor markers (i.e., AFP in germ cell tumor) were not included in this analysis.

Results: From January 1994 to December 2004, a total of 276 cases of childhood ([less-than-or-eq, slant]18 years) brain tumors were diagnosed. Excluding 21 patients >15 years and 7 nonlocal or non-Chinese children, the incidence of brain tumor was 21/million [less-than-or-eq, slant]15 years children/year. There may be slight underestimation because low-grade brain tumors diagnosed by imaging alone without tissue diagnosis were not included in this analysis. Compared to the SEER data (1975–1995), we noted a lower frequency of astrocytoma (SEER vs. HK = 49.6% vs. 33.9%) and higher frequency of PNET (22.9% vs. 29.6%) in our cohort. The differences in other tumor subtypes differed even more strikingly. We have a lower frequency of other glioma (15.4% vs. 1.8%) and ependymoma (9.3% vs. 5.5%), but a much higher frequency of germ cell tumor (<2% vs. 18.6%). The high incidence of intracranial germ cell tumors have been noted in other Asian countries, such as Japan. In addition, even within each tumor type, the histological subtypes differed. Such as in medulloblastoma, only two of our patients belonged to desmoplastic type, and the rest were all classical medulloblastoma. The details of these differences in other tumor types will be presented.

Conclusion: We noted a different distribution pattern of brain tumor types in our southern Chinese patient cohort as compared to the SEER data. What accounts for such ethnic difference remains to be explored. The data managers were supported by the Children’s Cancer Foundation of Hong Kong.


P.G. Fisher, E.K. Curran, K.L. Cobb, G.M. Le, and J.M. Propp; Stanford University School of Medicine, Palo Alto, CA, USA, Northern California Cancer Center, Fremont, CA, USA, and Central Brain Tumor Registry of the United States, Chicago, IL, USA

Background: Past studies of medulloblastoma (MB) present conflicting claims about declines and rises in MB incidence, possibly due to misclassification. By using a strict classification of the disease and a rigorous analysis of a data registry, we aimed to determine the incidence trends of MB over the last three decades.

Methods: Four hundred and forty-one MB patients diagnosed between 1985 and 2002 were identified from the Central Brain Tumor Registry of the United States (CBTRUS), a data set representing approximately 5% of the American population (six registries). MB was strictly defined and non-cerebellar embryonal tumors (primitive neuroectodermal tumors [PNETs]) were excluded, using histology and site codes. Multiplicative Poisson regression and joinpoint regression were performed (Joinpoint Regression Program, version 3.0, Statistical Research and Applications Branch, National Cancer Institute) to determine the estimated average annual percentage change (EAPC) and sharp (i.e., acute) changes in incidence, respectively.

Results: A slight but nonsignificant (P = 0.18) increase in medulloblastoma was demonstrated (EAPC = 1.1), and no sharp changes in incidence were found (joinpoints = 0). The analysis was repeated with a less strict definition of MB (including noncerebellar PNETs), and 559 patients were identified. Using this broader classification scheme, there was a statistically significant increase in incidence (P = 0.02, EAPC = 1.6), but no sharp changes in incidence (joinpoints = 0).

Conclusion: MB incidence does not appear to have changed since the 1980s. Medulloblastoma incidence increased only when the diagnosis was not strictly defined and misclassified by including noncerebellar PNETs in the analysis. The observed increase in the combined MB/PNET classification may relate to the PNET hypothesis — a proposal that all brain tumors of apparently undifferentiated neuroepithelial cells be considered a unique diagnostic group — popularized in the 1980s and early 1990s.


P.G. Fisher, E.K. Curran, J.M. Propp, K.L. Cobb, and G.M. Le; Stanford University School of Medicine, Palo Alto, CA, USA, Central Brain Tumor Registry of the United States, Chicago, IL, USA, and Northern California Cancer Center, Fremont, CA, USA

Background: Males have a higher incidence of medulloblastoma (MB) than females, but studies examining whether gender affects survival are conflicting and limited. We aimed to determine the effect of gender on outcome in MB, via rigorous analysis of a large data set, comprised solely of MB patients.

Methods: A total of 1226 subjects (763 males and 463 females) were identified from 1973 to 2002, using the Surveillance Epidemiology End Results (SEER-9) registry. MB was strictly defined, using histology and site codes, to exclude noncerebellar embryonal tumors (primitive neuroectodermal tumors [PNETs]). Kaplan-Meier analysis and logrank tests were performed using SPSS 12.0. Because children less than three years of age are known to have worse survival, patients were stratified by age younger than three years at diagnosis (95 male and 82 female) and older than three years (668 male and 381 female).

Results: There was no significant difference in overall survival between males and females (logrank P = 0.22; median survival: males, 90 months and females, 152 months). Among subjects younger than three years of age, females had significantly greater survival than males (log-rank P = 0.02; median survival: males, 93 months and females, 211 months). In children younger than three years of age, there was a trend toward worse survival in females (median survival: males, 27 months and females, 13 months), although this was not significant (log-rank P = 0.24). Females younger than three years of age comprised a significantly greater proportion of patients with medulloblastoma, compared to individuals younger than three years of age (chi-squared test P = 0.01).

Conclusion: Females with MB have a survival advantage only in subjects younger than three years of age. Among children under three years of age, females no longer possess this survival advantage and possibly have a worse outcome. The effect of gender on survival and incidence in MB warrants additional biologic investigation, and may differ in very young children with MB.


P.G. Fisher, E.K. Curran, J.M. Propp, K.L. Cobb, and G.M. Le; Stanford University School of Medicine, Palo Alto, CA, USA, Central Brain Tumor Registry of the United States, Chicago, IL, USA, and Northern California Cancer Center, Fremont, CA, USA

Background: Adults have long been considered to experience diminished overall survival from medulloblastoma (MB) compared to children, although studies to support this are limited. We sought to determine whether adults and children with MB differ in survival, and to examine whether dissimilar use of chemotherapy might contribute to any difference.

Methods: A strictly defined MB cohort of 142 patients from the San Francisco–Oakland (SFO) Surveillance Epidemiology End Results (SEER) registry between 1988 and 2003 was assembled, using histology and site codes to exclude noncerebellar embryonal tumors (i.e., primitive neuroectodermal tumors [PNETs]). A second cohort of 1,226 MB subjects from 1973 to 2002 was identified through the national SEER-9 registry, although this sample lacked data on treatment. Because children under three years of age are known to have worse survival and often do not receive craniospinal irradiation (XRT), patients were stratified by age at diagnosis younger than three years (infants), 3–17 years (children), and older than 18 years (adults) at diagnosis. Kaplan-Meier analysis and logrank tests were performed using SPSS 12.0 for the SEER-9 cohort and SAS for the SFO cohort.

Results: There was no difference in overall survival between children and adults with MB in either the SFO (P = 0.89) or SEER-9 (P = 0.16) cohorts. Infants fared worse compared to children (P < 0.01) or adults (P < 0.01) in the SEER-9 cohort. Only when a less strict definition of “medulloblastoma” (including noncerebellar PNETs) was used in the SEER-9 cohort was there a significant survival difference (P = 0.0024) between adults and children. Among the 142 subjects in the SFO sample (88 males and 54 females; 17 infants, 73 children, and 52 adults), 49 children and 19 adults received chemotherapy plus XRT and did not differ in survival (P = 0.24); children treated with XRT alone showed increased survival (P = 0.04) compared to adults.

Conclusion: Children and adults with MB do not differ with respect to overall survival, yet infants fare significantly worse. Overall survival between adults and children appears to differ only when MB is misclassified by including noncerebellar PNETs, or treated with XRT alone. For children and adults with MB treated with both XRT and chemotherapy, we could not demonstrate a difference in survival. These similar outcomes between adult and childhood MB may justify the inclusion of adults in pediatric cooperative trials specifically for this tumor.


C. Kruchko,2 J.M. Propp,1,2 B.J. McCarthy,1,2 and F.G. Davis1; 1University of Illinois at Chicago School of Public Health and 2Central Brain Tumor Registry of the United States, Chicago, IL, USA

Customarily, overall survival estimates are used in standard cancer reports to provide a general description of disease outcome. However, these overall survival rates do not provide information on future survival for patients that have already survived for a specific period of time. Conditional survival rates by histology and age at diagnosis for children with malignant brain and CNS tumors were estimated using the SEER public-use data base. Between 1990 and 2002, 2,911 children (0–19 years) were diagnosed with malignant brain and CNS tumors (SEER, 9 regions). Conditional probabilities of surviving two years given survival to six months and 95% confidence intervals were calculated. Conditional survival for other time periods (1975–2002) and for other time intervals (n-year survival conditional on select lengths of time) were also estimated. Estimated six-month and two-year relative survival rates for children with malignant brain and other CNS tumors were 93.9% and 77.6%, respectively. However, the conditional probability of surviving to two years, given survival to six months, reached 82.6%. Conditional probabilities varied by histology and age at diagnosis. The conditional probability of surviving two years, given survival to six months, for children with gliomas, pilocytic astrocytoma, and medulloblastoma/embryonal/primitive tumors was 82.6%, 98.6%, and 78.3%, respectively. The conditional probability of surviving two years, given survival to six months, by age at diagnosis was 80.1% (0–4 years), 78.7% (5–9 years), 86.4% (10–14 years), and 87.7% (15–19 years). Conditional survival for other time periods and intervals will be presented. These data provide useful, encouraging information for brain tumor survivors.


S. Wilne,1 J. Collier,2 C. Kennedy,3 R. Grundy,1 and D. Walker1; 1Academic Division of Child Health, 2School of Nursing, University of Nottingham, Nottingham, UK, and 3Department of Child Health, Southampton General Hospital, Nottingham, UK

Background: CNS tumors in childhood may present diagnostic difficulties, resulting in a prolonged symptom interval. A meta-analysis of the presenting symptoms and signs of childhood CNS tumors was conducted as the first stage in the development of guidance to facilitate diagnosis of childhood CNS tumors.

Methods: All case series and cohort studies, published between 1990 and 2005, detailing the presenting symptoms and signs at diagnosis for a minimum of 10 children were identified and included in the analysis.

Results: Seventy-seven papers describing 4198 patients satisfied the inclusion criteria. Meta-analyses revealed that the most frequent presenting symptoms and signs were headache (33%), vomiting (32%), abnormalities of gait and coordination (27%), papilloedema (13%), seizures (13%), unspecified signs of raised intracranial pressure (10%), squint (7%), behavioral change or deterioration in school performance (7%), cranial nerve palsies (7%), macrocephaly (7%), lethargy (6%), abnormal eye movements (6%), and hemiplegia (6%). The most frequent presentation in young children (three years or younger) was with macrocephally (38%), vomiting (27%), irritability (23%), and lethargy (20%). Spinal cord tumors presented with pain (67%), abnormalities of gait and coordination (42%), spinal deformity (39%), focal weakness (21%), and sphincter disturbance (20%).

Conclusions: This analysis demonstrates the diverse presentation of childhood CNS tumors. Assessment of a potential tumor necessitates a thorough history (with specific enquiry about headaches, vomiting, gait and coordination abnormalities, changes in behavior and school performance, and visual disturbance) and examination including fundoscopy and assessment of vision, growth, and head circumference. The absence of focal neurological signs does not exclude a CNS lesion.


O. Peters,1 J. Marienhagen,2 P. Stadler,3 M. Friedrich,4 W. Ullrich,4 T. Pietsch,5 R.D. Kortmann,6 M. Warmuth-Metz,7 and J.E.A. Wolff8; 1Department of Pediatric Oncology, 2Center for Clinical Trials, 3Department of Radiotherapy, and 4Department of Neurosurgery, University of Regensburg, Regensburg, Germany, 5German Neuropatholgy Reference Center, University of Bonn, Bonn, Germany, 6German Radiotherapy Reference Center, University of Leipzig, Leipzig, Germany, 7German Radiology Reference Center, University of Würzburg, Würzburg, Germany, and 8University of Texas M.D. Anderson Cancer Center, Section of Neurooncology, Houston, TX, USA

Background: The atypical teratoid/rhabdoid tumor (ATRT) accounts for less than 1% of all CNS tumors. Usually newborns and infants are affected. The outcome is dismal (median overall survival, 6–11 months). Based on German pediatric survival data (51 children) from 1990 to 2004 and on a meta-analysis of international outcome data of treated children (205 case reports) from 1985 to 2004, we developed a novel anthracycline-based multimodality therapy.

Patients and methods: Children were enrolled in this study after the diagnosis of CNS ATRT was confirmed by the German Neuropathology Reference Center. After two induction chemotherapy cycles (each three weeks: doxorubicin, 25 mg/m2 12 h i.v., days 1–3; dactinomycin, 45 μg/kg i.v. push, day 1; cisplatin, 70 mg/m2 6 h i.v., day 4; VCR, 1.5 mg/m2 i.v. push, days 8 and 15; and MTX, 2.0 mg intraventricularly, days 1–4), conventional local 3D XRT (54 Gy) with simultaneous chemotherapy (carboplatin, 80 mg/m² 6 h i.v., days 1–4) was given. Thereafter, reinduction chemotherapy (same as first and seond cycles) was implemented, followed by consolidation chemotherapy (6 cycles/9 months: CCNU, 75 mg/m², day 1; cisplatin, 70 mg/m² 6 h i.v., day 1; VCR, 1.5 mg/m² i.v. push, days 1, 8, and 15; and MTX, 2.0 mg intraventricularly, days 1–4).

Preliminary results: All data were available in 15 of 16 children (13 boys and 3 girls; median age at diagnosis, 18.6 months). Tumor site: 11 hemispheric (2 bifocal), 3 cerebellum, and 2 pineal. In 20% of the patients, LMD was present. Primary surgery: one complete, three subtotal, eight partial resections, and three biopsy only. After induction chemotherapy, 14 of 15 children showed a response: 1 CCR, 1 CR 10 PR, and 2 SD (1 septic death before MRI could be done). Of 15 patients, 14 are alive (median observation time, 14 months). Five children completed the study and showed NED 14, 20, 22, 30, and 41 months after diagnosis. The two-year EFS (72%) and OS (94%) are significantly improved compared to the German pediatric survival data (P < 0.001). Toxicity (NCI): grade III–IV mucositis/infection in 48%/42% of the patients after the induction and reinduction chemotherapy, no grade III–IV toxicity after 52 cycles of the consolidation chemotherapy.

Conclusion: This anthracycline-based induction regimen appears effective, but has significant toxicity. The survival data are significantly improved.


T. Czech, C. Haberler, A. Peyrl, G. Widhalm, W. Dietrich, K. Dieckmann, and I. Slavc; Medical University of Vienna, Vienna, Austria

Background: Atypical teratoid/rhabdoid tumor (AT/RT) of the CNS is a rare and aggressive tumor of early childhood. Before immunohisto-chemistry with an antibody to INI1 was described as a specific means to distinguish AT/RT from other CNS tumors these tumors were often misdiagnosed as medulloblastoma or supratentorial PNETs because of the sometimes indeterminate histologic features. We report on the outcome of 12 consecutive patients with AT/RT of the CNS depending on initial diagnosis and treatment received.

Patients: A retrospective analysis applying the INI1 antibody to all highly malignant pediatric brain tumors treated at the University of Vienna between 1992 and 2005 disclosed 12 patients with AT/RT. Only the last five patients were originally diagnosed correctly. Diagnoses of the first seven patients included medulloblastoma, supratentorial PNETs, ependymoblastoma, and Ewing sarcoma. Metastatic disease was present at diagnosis in four, and not known in two.

Results: The five patients diagnosed initially as AT/RT were treated with an intensive, multiagent chemotherapy including cyclophosphamide, vincristine, cisplatin, ifosfamide, etoposide, methotrexate, and adriamycin followed by high-dose chemotherapy with autologous stem cell rescue (modified Finlay protocol) and local radiotherapy. Four of the patients are in CCR seven months and three, four, and eight years after diagnosis, respectively. The seven patients originally misdiagnosed were treated according to the HIT SKK 92 or HIT 91, and Ewing sarcoma protocols of the German Society of Pediatric Hematology and Oncology. Of this earlier cohort only one 11-year-old patient who was assumed to have a supratentorial PNET and had received an extendedchemotherapy including intraventricular therapy and a Gammaknife boost became a long-term survivor.

Conclusion: Because of the poor outcome and a median survival of 6–19 months with conventional infant brain tumor therapy proper diagnosis of AT/RT is essential.


R. Jakacki, T. Zhou, E. Holmes, R. Packer, J. Goldwein, M. Mehta, and I. Pollack; Children’s Oncology Group (COG), Arcadia, CA, USA

Purpose: To evaluate the outcome of children with pineal region primitive neuroectodermal tumors (PNET) treated prospectively on a cooperative group trial.

Experimental design: All patients underwent complete staging after the diagnosis of pineoblastoma was confirmed by biopsy or surgical resection. Radiotherapy (RT) consisted of 36 Gy to the craniospinal axis with boosts to the pineal region and sites of metastatic disease. During RT, patients received 15–30 doses of carboplatin (30–45 mg/m2/dose) given 1–4 h prior to each fraction, depending on the assigned dose and duration of carboplatin, as well as weekly VCR. All patients received adjuvant chemotherapy with six monthly courses of cyclophosphamide (CPM; 2 g/m2) and vincristine (VCR) weekly × 2.

Results: Twenty-two patients (median age 10.1 years, range 3.6–17.9 years, M/F ratio of 1.8:1) with an institutional diagnosis of pineal region PNET were enrolled between 1999 and 2003. Sixteen patients (73%) had localized tumors (M0) while six patients had metastatic disease. Overall survival and event-free survival at three years are 84% ± 11% and 73% ± 13%. Outcome is not significantly different between M0 and M+ patients. Of the M0 patients, none of the eight who underwent a gross total resection (GTR) recurred vs. four of eight who underwent less than GTR (Fisher’s exact test, P = 0.08).

Conclusions: The use of carboplatin as a radiosensitizer followed by six months of nonintensive non–cisplatin-containing adjuvant chemotherapy is a promising treatment strategy for patients with pineal region PNET.


B. Hinkes,1 K. von Hoff,1 F. Deinlein,1 M. Warmuth-Metz,2 N. Soerensen,3 U. Mittler,4 C. Urban,5 T. Pietsch,6 P.G. Schlegel,1 R.D. Kortmann,7 J. Kuehl,1 and S. Rutkowski1; 1Children’s University Hospital, 2Department of Neuroradiology and 3Department of Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany, 4Department of Pediatrics, University of Magdeburg, Magdeburg, Germany, 5Department of Pediatrics, University of Graz, Graz, Austria, 6Department of Neuropathology, University of Bonn, Bonn, Germany, and 7Department of Radiation Oncology, University of Leipzig, Leipzig, Germany

Background: We report on 12 children with pineoblastoma, a rare embryonal brain tumor, treated within the prospective multicenter trials SKK87, SKK92 and HIT91.

Treatment: Six children younger than three years of age received chemotherapy immediately after operation until eligible for radiotherapy (RT) (SKK87 and 92). Six children older than three years received either neoadjuvant chemotherapy before RT or maintenance chemotherapy after RT (HIT91).

Results: Five of the six older children remain in CCR with a median OS of 8.8 years and PFS of 7.4 years. The response rate to postoperative CTH was high (three CR and one SD). In this group only one girl died of acute bleeding into a relapse tumor. Compared to the older children, surgical reduction of tumor mass in the six young children was less complete and reponses to postoperative CTH were inferior (3 PD, 2 PR, 1 CR). All young children had either metastatic disease (M1) or postoperative residual tumor, and they all died of PD after a median OS of only 0.9 years (PFS 0.3 years). The only young child to reach CR with the SKK-92 protocol relapsed locally and systemically 15 months after completing the protocol. Only one of the younger children received radiotherapy after postoperative chemotherapy.

Conclusion: A combination of CTH and RT was feasible in the older age group, leading to prolonged remissions in five out of six children. Tumor biology appears to be more aggressive in younger children with pineoblastoma, where more intensified chemotherapeutic regimen, followed by radiotherapy, should be evaluated. Supported by German Children’s Cancer Foundation and by German Cancer Aid.


S.W. Gilheeney, C. Williams, U. DiGiorlani, S. Chi, C. Turner, N. Ullrich, L. Goumnerova, R.M. Scott, K. Marcus, L. Lehmann, and M. Kieran; Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, and Departments of Neuropathology, Neurology, Neurosurgery, and Radiation Oncology, Children’s Hospital of Boston, Boston, MA, USA

Background: Primitive neuroectodermal tumors (PNET) of the pineal region (a.k.a. pineoblastoma) represent a diagnostic subset of supratentorial PNET. While most studies report a poor outcome for this population, these studies have included children with high-risk medulloblastoma and other sPNETs. We now report our institution’s experience with treatment and outcome of pineoblastoma during a 20-year period.

Materials and methods: Between 1985 and 2005, 18 children with the diagnosis of pineoblastoma (as per WHO classification) were presented to our institution. The pathology was centrally reviewed in a blinded fashion by two neuropathologists (CW and UD). Records were reviewed for history of presentation, histology, treatment course, and outcome at last known follow-up.

Results: Of 18 children seen at our institution, 13 had complete medical records for review. The remaining five were patients seen in consultation only, and not treated at our institution. Six were male and seven were female. Median age at presentation was 8.5 years (range, 1–16 years). Four patients died of their disease. The remaining nine are currently alive and progression free at last follow-up a median of seven years from diagnosis (range, 5 months to 11 years). Of the patients who died of their disease, only one had metastatic disease at presentation. Surgical intervention, extent of resection, specific histological features, and treatment modalities (surgery, radiation, chemotherapy, high-dose chemotherapy with stem cell rescue) were evaluated in the population. Due to the surprisingly high percentage of survivors, none of the above factors was predictive of outcome.

Conclusions: We report a cohort of pineoblastoma patients with an overall survival of 70% a median seven years after treatment. This suggests a better overall survival rate than previously reported in spite of changing modes of treatment over time.


I.J. Dunkel,1 R. Jubran,2 S. Gururangan,3 H.S.L. Chan,4 S. Goldman,5 J.L. Finlay,2 C. Rodriguez-Galindo,6 Y. Khakoo,1 D. Lyden,1 and D.H. Abramson1; 1Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2Children’s Hospital of Los Angeles, Los Angeles, CA, USA, 3Duke University Medical Center, Durham, NC, USA, 4Hospital for Sick Children, Toronto, Canada, 5Children’s Memorial Hospital, Chicago, IL, USA, and 6St. Jude Children’s Research Hospital, Memphis, TN, USA

Purpose: Trilateral retinoblastoma (RB) has been lethal in virtually all cases reported. Here we describe a series of 10 North American patients treated with intensive chemotherapy, defined as the intention to include high-dose chemotherapy (HDC) with stem cell rescue.

Methods: Induction chemotherapy generally included vincristine, cis-platin or carboplatin, cyclophosphamide, and etoposide. Stem cells were generally harvested after the first or second cycle of induction, usually from peripheral blood. HDC regimens were thiotepa-based (n = 4), carboplatin, etoposide, and cyclophosphamide (n = 1), or melphalan and cyclophosphamide (n = 2).

Results: Trilateral sites were pineal (n = 8) and suprasellar (n = 2); five patients had M-0 disease, and five had leptomeningeal dissemination. Five patients had trilateral RB at original diagnosis of intraocular RB, and five had later onset (3–42 months). One patient died of toxicity (septicemia and multiorgan system failure) during induction, and two had disease progression prior to HDC. Seven patients received HDC at a median of five months (range, 4–9 months) after diagnosis of trilateral disease. Five patients survive event free at 17, 34, 39, 59, and 67 months, without radiation therapy. Four of five patients with M-0 disease are event free (one died of toxicity), while only one of five patients with M-1+ disease is event free (four had disease recurrence).

Conclusions: Intensive chemotherapy is effective for some patients with trilateral RB, especially those with M-0 disease. COG ARET 0321 will study this approach prospectively on a larger scale and would welcome international collaborators.


J. Grill, S. Puget, N. Boddaert, D. Viguier, G. Dellatolas, C. Sainte-Rose, C. Kalifa, and V. Kieffer; Gustave Roussy Institute and INSERM U472, Villejuif, France

Direct damage to the cerebellum caused by the tumor and/or the surgery has a strong impact on the impairement of cognitive functions (Grill, J. Neurosurg., 2004). Our aim was to define the correlations between the anatomical damages and the neurologic and neuropsychologic deficits in children with posterior fossa tumors. Sixty-one unselected children (mean age six years) treated mainly for medulloblastoma underwent a detailed neuropsychologic evaluation including a complete IQ score on average five years after the end of the treatment. Neurologic examination was performed at the time of the neuropsychologic evaluation. We scored the injury to the vermis, the dentate nuclei (DN), the cerebellar hemisphere, and the supratentorial brain on the MRI performed after a mean interval of 7 years after diagnosis. The severity of the damage to the DN was correlated with the severity of the cerebellar syndrome (P = 0.005). Fine motor dexterity was inversely correlated with the damage to the DN (P = 0.0002) and the vermis (P = 0.003). Full scale IQ scores were inversely correlated mainly with the severity of the damage to the DN (P = 0.009) and marginaly with the destruction of the inferior vermis (P = 0.02). This study established the impact of the damage to the cerebellar deep grey nuclei and to the inferior vermis on the neurologic and neuropsychologic outcome in children treated for posterior fossa tumors. While pursuing the goal of cure with minimal damage to the brain, the surgical risk should be clearly balanced with those related to the need of more agressive adjuvant therapies.


S. Sato, M. Saino, K. Sakurada, W. Mori, A. Sato, and T. Kayama; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan

Surgery around the fourth ventricle is still one of the challenging surgery to neurosurgeons, because severe deficits sometimes occur by injury to the delicate stuructures under the ventricle floor and in the cerebellum. For example, incision of the vermis may be implicated in the development of mutism, neurobehavioral symptoms, and oropharyngeal apraxia especially in children. As a conventional approach to the forth ventricle, an approach by splitting the vermis is widely used. However microsurgical tumor resection by transcerebellomedullary fissure approach was used for 15 patients (including five children) in our clinic in the last nine years. In this series, five children had various pathologies including medulloblastoma (n = 3), ependymoma (n = 1), and cavernous angioma (n = 1). Total removal was achieved in all patients without splitting the vermis. By a transcerebellomedullary fissure approach it is possible to provide sufficient operative space from aqueduct to obex, and it is easy to preserve the posterior inferior cerebellar artery and its branches. This approach is useful, but it needs meticulous dissection of the fissure. In this paper, we will present the surgical techniques and pertinent anatomy for this approach by video presentation.


J.U. Choi, D.S. Kim, and K.W. Shim; Department of Neurosurgery, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

Tumors that arise around the ventricular system of the brain represent a major neurosurgical challenge. These lesions located deep inside the brain must be approached from a considerable distance through normal brain tissue. Dissection and brain retraction should be minimized to avoid damage to important brain structures such as the thalamus, caudate nucleus, fornix, and others. In selected cases a neuroendoscopic approach to periventricular lesions might prove to be as effective as microsurgery and less invasive. We report our experience in 64 patients with intraventricular or periventricular tumors and associated hydrocephalus who underwent an endoscopic biopsy and other combined endoscopic procedures in a single sitting. Tumors were located on the pineal region in 24 patients, the hypothalamus in 16, the suprasellar region in 9, the lateral ventricle in 8, and the thalamus in 7. Histological diagnosis was successfully established in all patients, except two (they had the small pineal region tumor and were excluded in this series). All endoscopic procedures were successfully performed without complication in all patients; however, a ventriculoperitoneal shunt was eventually required in three pineal region tumors. We could obtain the histological diagnosis with very low risks because the origin of the blood supply and the amount of vasculature of the tumor capsule can be defined before obtaining a biopsy specimen of the tumor under the direct endoscopic vision. In the selected cases, we could totally remove the tumors. In addition to lesion removal it is often possible to restore obstructed CSF pathways via the same approach. This is accomplished by means of the third ventriculostomy and septostomy.


C. Di Rocco; Pediatric Neurosurgery, Catholic University Medical School, Rome, Italy

Craniopharingiomas are rare tumors accounting for 1%–2% to 4% in the various series. Their incidence is around 0.5–2.0 new cases/million/ year. The impact of such a low incidence is easily understood when evaluating the surgical results which demonstrate a strict relationships between the rate of successful outcomes and the surgeon’s experience with this kind of tumor. The same consideration applies to the postoperative management, which may be weighted by serious complications, the management of which should be limited to specialized centers. Craniopharyngiomas in the pediatric population exhibits particularly insidious characteristics, namely the frequent large size, the possible association with hydrocephalus, the prevalence of the adamantinomatous variant, marked by an intimate anatomical relationships with the hypothalamus, and a high recurrence rate. In spite of the difficulties offered by the surgical management of this tumor in children, most of the pediatric neurosurgeons claimed the total excision of the lesion to be the surgical goal and the most effective way to deal with it until recent times. Actually, owing to the progress recorded in surgical technique, perioperative anesthesiological management, and postoperative intensive care, near 60% of craniopharyngiomas may be totally excised nowadays. A further 10% of tumors may be subtotally resected. However, total tumor removal is associated to a higher rate of short-term and long-term complications, including panhypopituarism, defits of the visual function, severe obesity, and damage of the Willis circle. Furthermore, surgical deaths represent 4%–5% in series for the most credited neurosurgical centers. Even more important is the observation that radical tumor excision has been shown to not prevent tumor recurrence. Such an observation challenges the value of the aggressive surgical treatment and suggests the adoption of a more cautions surgical attitude. Actually, in the recent times, minimally invasive surgical management of craniopharyngiomas coupled with various types of adjuvant therapies appear to offer a valid surgical option in the management of this difficult tumor. On the grounds of a personal experience on 55 consecutive cases, all treated aggressively, the author emphasizes some criteria that could be of help in differentiating which tumors should be dealt with aggressively from those which can be more advantageously treated conservatively.


B.K. Cho, S.K. Kim, and K.C. Wang; Department of Neurosurgery(Pediatric), Seoul National University Children’s Hospital, Seoul, Republic of Korea

Objectives: To analyze the relationship between functional outcomes (visual, endocrine, learning, and social activities) and location/growth patterns of craniopharyngioma. Comparison of functional outcomes between attempted radical total resection and less radical resection with radiotherapy groups were also performed.

Method: Ninety-two craniopharyngioma patients were treated between December 1985 and March 2005 in the Seoul National University Children’s Hospital. Among them 68 patients were evaluable. Mean follow-up was 72 months (range 5–230 months). Retrospective analysis of charts, imaging studies, and telephone surveys were performed. Location, growth pattern, and the characteristics of the tumors, treatment modalities, recurrence, and functional outcomes were analyzed.

Results: In location, intrasellar, suprasellar prechiasmatic, suprasellar retrochiasmatic, and intraventricular were 10%, 21%, 63%, and 6% respectively. In the character of the mass, solid and cystic, mainly cystic, and mainly solid tumors were 65%, 23%, 12% respectively. Attempted radical total resections were accomplished in 93%, and less radical resections and radiotherapy were done in 7%. Comparisons between suprasellar prechiasmatic vs. retrochiasmatic groups revealed recurrence rate (0% vs. 23%) and academic achievement of attending colleges (40% vs. 7%) were better in the suprasellar prechiasmatic group than in the retrochiasmatic group, but there were no differences in visual, endocrine, and KPS among the groups. Comparisons between the treatment modalities, attempted radical total resection only vs. less radical resection and radiotherapy, revealed posttreatment improvement in vision (11% vs. 43%), recurrence rate (18% vs. 0%), and mortality rate (6% vs. 0%) were better in the less radical resection and radiotherapy group than in the attempted radical total resection only group; but endocrine outcome, academic achievement, and KPS score were similar between the groups. Overall outcomes showed mortality in 6%, visual improvementnin in 16% (aggravation in 36%), endocrine improvement in 4% (aggravation in 76%), and independent KPS in 84%.

Conclusion: To improve the functional outcomes in the treatment of childhood craniopharyngioma, location and growth patterns of the tumor, an individualized multimodal approach, and the role of radiotherapy should be considered as important factors.


S. Yano, H. Takeshima, K. Makino, H. Nakamura, and J Kuratsu; Department of Neurosurgery, Kumamoto University, Kumamoto, Japan

Purpose: Craniopharyngiomas often regrow and affect the patient’s ADL. Here we discuss the best treatment strategy for pediatric craniopharyngioma to maintain a good ADL by analyzing the degree of tumor removal and long-term follow-up results.

Patients and methods: Thirty craniopharyngioma patients who were under 15 years of age, operated on in Kumamoto University Hospital, and followed for more than five years were enrolled. Latest KPS, degree of visual deteriotration, and endocrinological functions were examined. Results were compared between the degree of tumor removal, such as total or subtotal removal, partial removal, or biopsy.

Results: Average follow-up period was 20.2 years. Twenty-four patients (80.0%) had better than 80 KPS, and 4 patients (13.3%) died. Visual deterioration during follow-up was observed in eight patients (26.6%), and hormonal replacement was received in 28 patients (93.3%). Postoperative irradiation was performed in three patients, and two had poor outcome. Although tumor recurrence was more in partial removal cases (9 of 10 patients) than total or subtotal removal cases (3 of 14 patients), good ADL was almost the same: 6 of 10 (60.0%) in partial removal and 8 of 14 (57.1%) in total or subtotal removal. Visual deterioration was observed only in the subtotal removal cases at the first or second operation.

Conclusion: To keep the good ADL for the long term, initial visual deterioration should be avoided. Tumor recurrence did not affect the long-term outcome as long as the operation was not aggressive, even in the repeated removal.


C.E.M. Gidding, K. Noordam, E. van Lindert, G. Janssens, and C. Erasmus; Departments of Pediatic Oncology, Endocrinology, Neurosurgery, Radiotherapy, and Neurology, Nijmegen University Medical Center, Nijmegen, The Netherlands

Presently standard treatment for craniopharyngioma is resection, followed by irradiation in case of unresectable regrowth. Although most patients can be cured with this treatment, a small percentage eventually die due to progressive disease. In 1998 Lippens et al. (Eur. J. Paediatr. Neurol.) reported the potential benefit of doxorubicin in combination with lomustine in four children with recurrent craniopharyngioma. An update is given here. Between 1985 and 1998 five children with recurrent craniopharyngioma were treated with doxorubicin and lomustine at the Department of Pediatric Oncology of the University Medical Center, Nijmegen, The Netherlands. All five patients had been treated with incomplete resection followed by irradiation at diagnosis. After several resections, and in one patient even after second irradiation had failed, chemotherapy was started. At least five cycles of doxorubicin (33 mg/m2/day, continuously for 3 days) and lomustine (80 mg/m2 at day 1) were given (6-week intervals). Three of five patients are alive without further relapses 7, 10, and 20 years after treatment with chemotherapy. Two patients died: one of progressive irradiation encephalopathy after 13 years; one of recurrent disease after one year. Although most patients received at least a cumulative doxorubicin dose of 500 mg/m2, in none of them cardiomyopathy was reported. In conclusion, we think that the combination of doxorubicin plus lomustine should be considered in patients with recurrent craniopharyngioma where other available treatment has failed. However, we recommend a maximum cumulative doxorubicin dose of 450 mg/m2 according to the present standard.


J.L. Finlay, A. Butturini, and S. Gardner; Children’s Hospital Los Angeles, Los Angeles, CA, and New York University Medical Center, New York, NY, USA

Conventional dose chemotherapy in addition to local field irradiation has had only a modest impact upon the outcome of children newly diagnosed with malignant gliomas, and then only in the subgroup who were able to undergo radical surgical resection of tumor. In the recurrent setting, conventional dose chemotherapy has been purely palliative at best. Several studies have attempted to improve outcome by using increasing drug doses, with or without AHPCR. Thiotepa (40–70 mg/m2) or cyclophosphamide (up to 7 g) alone were ineffective. Similarly, the use of HAHPCR to decrease hematopoietic toxicity after procarbazine, CCNU, and vincristine, to facilitate either decrease of intervals between cycles or administration of concurrent irradiation, had no favorable impact on outcome. Results of trials using myeloablative chemotherapy followed by AHSCR in recurrent or newly diagnosed malignant gliomas were poor in adults but somewhat more promising in children. Although neither myeloablative-dose BCNU (>800 mg/m2) or thiotepa (<600 mg/m2) alone appear effective, multidrug conditioning regimens have produced durable survival in a small proportion of patients, albeit in the face of significant morbidity and mortality of up to 20% in some earlier studies. The most important factor predictive of a favorable outcome following myeloablative chemotherapy is the extent of the initial surgical resection. The use of tandem myeloablative regimens and the addition of posttransplant biological agents (e.g., cis-retinoic acid, Avastin, Tarceva, metronomic dose temozolomide) merit investigation in order to increase the proportion of children with malignant gliomas who may benefit from such a treatment strategy.


A. Teplick, J. Aguayo, A. Butturini, A. Erdreich-Epstein, R. Jubran, J. Villablanca, D. Hyder, B. Britt, J. Derrickson, H. Kristall, and J. Finlay; Children’s Hospital Los Angeles, Los Angeles, CA, USA

Background: We reviewed our single institution experience to determine factors predictive of favorable outcome with high-dose chemotherapy/ autologous hematopoietic progenitor cell rescue (HDC/AuHPCR).

Methods: We retrospectively analyzed data on 53 patients undergoing HDC/AuHPCR for brain tumors at Children’s Hospital Los Angeles between 1992 and 2005. Ages were 4 months to 15.8 years at diagnosis and 9 months to 18.1 years at transplant. The conditioning regimens included thiotepa and/or etoposide and/or carboplatin. The variables considered were: age at diagnosis, histology, extent of disease, conditioning regimen, radiation therapy, stem cell type, and timing of transplant.

Results: Diagnoses included 33 medulloblastomas (MB) and other primitive neuroectodermal tumors (PNET), 8 high-grade gliomas, 5 epen-dymomas, 3 germinomas, 2 choroid plexus carcinomas, and 2 atypical teratoid/rhabdoid tumors. Event-free survival (EFS) at 36 months was 53% ± 9% for MB/PNET and 40% ± 15.5% for other histologies. Variables associated with improved EFS in MB/PNET were no prior progression (P = 0.00094) and age less than three years at diagnosis (P = 0.046). Patients with MB/PNET transplanted before progression had better EFS if they had localized disease at diagnosis (P = 0.00024). Patients with MB/PNET transplanted after progression had better EFS if there was no spread of disease into marrow (P = 0.00023), if they were male (P = 0.053), and if radiotherapy was given after transplant (P = 0.053). In patients with tumors of other histologies, the only variable associated with prolonged EFS was gross total resection (P = 0.026).

Conclusions: Children most likely to benefit from HDC/AuHPCR for brain tumors are those less than three years old who are newly diagnosed with MB/PNET that is locally confined, and those with a non-PNET diagnosis who have gross total resection of tumor.


S. Gururangan,1 J. Provenzale,2 and H.S. Friedman1; 1Preston Robert Tisch Brain Tumor Center at Duke and 2Department of Neuro-radiology, Duke University Medical Center, Durham, NC, USA

We performed a pilot phase II study of metronomic daily dosing of oral cyclophosphamide (CTX) and thalidomide (THAL) in children with recurrent, progressive, or refractory brain tumors. Eligible patients (pts) received oral CTX (60 mg/m2/day) and THAL (10–14 mg/kg/day) once daily without interruption unless there was unacceptable toxicity (grade IV myelosuppression, >grade II sedation or drug rash). Treatment was continued until progressive disease (PD) or a maximum of one year. Responses were assessed by MRI scan of brain and spine (baseline and then q 8 weeks) and functional imaging including MR perfusion/diffusion, MRS, and FDG-PET scans of brain (q 3rd cycle). Between April 2002 and February 2005, 21 patients (median age, 11 years; range, 5–18) were enrolled in this study (malignant glioma [MG], 11 pts; intrinsic brainstem glioma [BSG], 6; ependymoma, 3; and medulloblastoma, 1). Of 20 evaluable pts, one partial response (PR) was seen in a pt with BSG. Two pts (MG 1 and BSG 1) completed one year of treatment with stable disease (SD). Nineteen of 20 pts suffered PD at median of 1 month (range, 1–17) from enrollment on study. One pt with a recurrent BSG who had PR to treatment is currently alive with SD 42 months from enrollment. Serious toxicities included grade IV myelosuppression (2 pts) and grade II hematuria (1 pt) that required dose adjustment of CTX. Other side effects included < grade III myelosuppression, grade I–II neuropathy, and grade I somnolence. Metronomic daily dosing of CTX + THAL had only modest activity in this group of pts with manageable toxicity.


S. Wagner,1 C. Fels,1 P. Hau,2 G. Janssen,3 C.F. Classen,4 N. Jorch,5 O. Peters,1 U. Bogdahn,2 J.E.A. Wolff6; Departments of Pediatric Oncology of 1Regensburg, Germany, 3Düsseldorf, Germany, 4Duisburg Germany, 5Bielefeld, Germany, 6The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, and 2Department of Neuro-Oncology, Regensburg, Germany

Background: Combination of topotecan and doxorubicin was found to be synergistic in preclinical studies. Good results were obtained with pegylated liposomal doxorubicin (PEG-doxo) in a study of high-grade glioma in adults with a dose of 20 mg/m² every two weeks.

Patients and protocol: From May 2005 to June 2006 children with progressive malignant high-grade glioma (HGG) were registered. PEG-doxo was individually adapted starting with 10 mg/m² every two weeks over six weeks, increasing to 15 mg/m², if toxicity < °II (NCI-CTC), and to the maximum of 20 mg/m². Topotecan was given orally 0.3 mg/m² twice a day as a maintenance therapy.

Results: Six patients with anaplastic astrocytoma, one with glioblastoma, and three pontine gliomas were treated with a median maximal PEG-doxo dose of 15 mg/m² (10–20) every two weeks for a median time of six weeks (2–16) and a median topotecan dose of 0.3 mg/m² twice a day. The median total treatment time was eight weeks (2–22). Toxicity was tolerable: no toxic death, one °II cardiotoxicity, no °III/°IV dermatotoxicity, and 11% °III/°IV hematoxocitiy. Thirty percent developed gastrointestinal toxicity which could be stopped by changing topotecan administration. With a PEG-doxo dose of 15–20 mg/m², MR was found for 10 and 12 weeks, SD for > 24 weeks. PD was found after two (n = 2), three, four, five, and six (n = 2) weeks, without reaching the maximum dose.

Conclusion: Toxicity of PEG-doxo in children with a two-week schedule was tolerable. A dose of at least 15 mg/m² every two weeks is recommended for achieving clinical response. Supported by ESSEX Pharma.


S.W. Gilheeney, R.M. Scott, S. Chi, C. Turner, N. Ullrich, K. Marcus, E. Gillan, K. Dunsmore, and M.W. Kieran; Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Departments of Neurosurgery, Neurology, and Radiation Oncology, Children’s Hospital of Boston, Boston, MA, USA, Department of Oncology, Connecticut Children’s Medical Center, Hartford, CT, USA, and Department of Oncology, University of Virginia Children’s Medical Center, Charlottesville, VA, USA

Hemangioblastomas are vascular endothelial growth factor (VEGF)–dependent tumors, which can create severe and disabling location-related symptomatology if left untreated. Surgical excision is the current standard of care, but it is limited by location and risk of hemorrhage. We report our experience using anti-VEGF–directed therapy, specifically bevacizumab (Avastin). Patients with biopsy proven hemangioblastoma were treated with intravenous administration of bevacizumab 10 mg/kg every two weeks for three doses. Patients were followed for the development of therapy-related hypertension and by MRI scans after six weeks of therapy for evidence of bleed. To date, therapy has been well tolerated in the one patient that has completed treatment. This patient presented with four months of progressive swallowing difficulties and upper extremity weakness. MRI and biopsy at an outside institution was performed revealing a tumor in the area of the cervicomedullary junction consistent with hemangioblastoma. Ophthalmologic exam revealed retinal hemangioblastoma confirming the diagnosis of VHL. Attempted embolization and subtotal surgical resection was complicated by hemorrhage intraoperatively. Consideration of other treatment options including inhibitors of VEGF were explored for this and other patients with lesions at significant risk of hemorrhage during attempted resection. The use of anti-VEGF treatments in the adult VHL literature, mostly in the treatment of renal cell carcinoma, is well described. We review the current literature in VHL-associated hemangioblastoma and report our experience, suggesting a treatment alternative to surgery and/or stereotactic radiosurgery, especially in those with unresectable lesions or those at risk of hemorrhage.


T. Tomita; Division of Pediatric Neurosurgery, Falk Brain Tumor Center, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Objectives: Brainstem tumors remain a formidable challenge for pediatric neurosurgeons, as a majority is considered to be inoperable due to a high surgical morbidity rate. Malignant tumors which predominantly occur in the pons remain fatal in spite of aggressive multimodal therapies. Improved diagnostic and surgical techniques, however, have expanded the surgeon’s role in management of benign brainstem tumors. The author presents surgical indications and techniques for brainstem tumors in children based on his personal experience of more than 200 cases (Medulloblastoma and ependymoma are excluded).

Material and methods: There are 100 intrinsic pontine tumors, 30 dorsally exophytic (IV ventricular) astrocytomas, 16 cerebellar peduncle astrocytomas, 24 medulla oblongata astrocytomas, and 43 midbrain tumors. The location dictates histology; only 5% of pontine tumors are benign whereas 80% to 90% of the tumors in other locations are benign. Surgical indications are as follows: focal pontine tumor without rapid progression of symptoms; medulla oblongata or cervicomedullary junction astrocytomas; progressive, contrast enhancing tectal tumor; progressive cerebral peduncle tumor; and fourth ventricle and cerebellar peduncle tumors. Surgical approaches differ according to the location, and the direction of tumor extension.

Results: All patients with malignant tumor or diffuse pontine tumor died of tumor progression. However, only two patients with benign tumor died of disease.

Conclusion: Most benign brainstem tumors are amenable to surgical resection. Following incomplete resection, close observation or use of chemotherapy are acceptable for benign gliomas.


J. Ater, C. Mazewski, W. Roberts, R. Sposto, T. Zhou, D. Freyer, R. Jakacki, R. Kadota, K. Lazarus, R. Packer, J. Pearce, M. Prados, A. Ettinger, G. Vezina, J. Wisoff, A. Yates, and I. Pollack; Children’s Oncology Group (COG), Arcadia, CA, USA

Purpose: The primary aim of A9952 was to compare event-free survival as a result of treatment with either Regimen A consisting of carboplatin and vincristine (CV) or Regimen B consisting of a combination of thioguanine, procarbazine, CCNU, and vincristine (TPCV) in children with progressive or recurrent low-grade astrocytoma or other glioma with residual unresectable tumor. The majority of patients enrolled had hypothalamic-optic pathway or brainstem tumors.

Methods: Eligible patients were randomized at the time of study entry to one of two treatment regimens with stratification. Patients with neurofibromatosis type 1 (NF) were nonrandomly assigned to Regimen A, and must have radiographic progression.

Results: From April 1997 to January 2005, 422 eligible patients were registered, 150 on CV, 146 TPCV, and 126 NF patients nonrandomly assigned to CV. For non-NF patients, the five-year event-free survival (EFS) is 35% ± 4.3%, and overall survival (OS) is 87% ± 2.7%, with median time to progression of 46 months. Follow-up is currently not sufficiently mature to report or draw conclusions about the relative efficacy of the two chemotherapy regimens. For NF patients, the five-year EFS is 63% ± 6.5% and OS 97% ± 1.5%. The cumulative incidence of grade 3 or 4 toxicities differed in pattern for the two regimens (A vs. B): ANC: 93% vs. 78% (P < 0.001), thrombocytopenia: 18% vs. 46% (P < 0.001), hemoglobin: 24% vs. 40% (P = 0.003), SGPT: 3% vs. 11% (P = 0.007), and allergy 11% vs. 0% (P < 0.001).

Conclusions: At this point, there is no significant difference in efficacy between regimens, but further follow-up is needed.


E. Bouffet, U. Bartels, U. Tabori, V. Larouche, L. Lafay-Cousin, G. Nicolin, J. Rutka, and A. Huang; Division of Neurosurgery and Division of Pediatric Oncology/Haematology, Hospital for Sick Children, Toronto, Canada

Background: Young age (less than one year old) at the time of diagnosis has been reported to be associated with more aggressive behavior, poorer response to chemotherapy, and shorter progression-free survival in pediatric low-grade glioma.

Methods: Retrospective review (1990–2000) of children with low-grade glioma who were 1 year of age or younger at the time of diagnosis, with a focus on pattern of presentation, clinical course, and outcome.

Results: 13 patients were identified, all with chiasmatic/hypothalamic lesions. One had NF1. Ten presented with nystagmus, three with diencephalic syndrome. One patient had an acute onset of massive intracranial bleeding. Seven patients underwent a biopsy at the time of diagnosis. There were two JPA, four astrocytoma NOS, and one fibrillary astrocytoma. Two children underwent surgery at a later stage (one JPA, one pilomyxoid tumor). All patient received carboplatin-based chemotherapy at the time of diagnosis. Five experienced carboplatin allergy, and four continued on a different regimen. Ten children eventually progressed, two to 46 months after initiation of chemotherapy (median 18 months). Three children subsequently presented with evidence of tumor dissemination. Eight children received more than one line of chemotherapy, including three children who received six lines. Three children underwent repeated (two to four) debulking procedures. Only one child received radiation. At a median follow-up of 73 months, 11 children are alive. Six are still on treatment, three to 67 months after initial diagnosis. One child is blind.

Conclusions: This review confirms the aggressive behavior of low-grade glioma under the age of 12 months. However, tumor progression can be controlled without systematic use of radiation. In this context, the choice of chemotherapeutic agents in the management of these patients deserves careful consideration.


K. Makino, H. Nakamura, S. Yano, H. Takeshima, and J. Kuratsu; Department of Neurosurgery, Kumamoto University Graduate School, Kumamoto, Japan

Purpose: Astrocytoma is the most prevalent type of pediatric brain tumor. Here we evaluate the impact of the primary tumor site, age at the start of the treatments, extent of resection, and histology on overall survival in pediatric low-grade astrocytomas.

Patients and methods: Medical, pathological, and radio-imaging information were reviewed for 35 children (ages 8 months to 15 years) with low-grade astrocytoma treated between 1976 and 2005 at Kumamoto University Hospital. Surgery was followed by observation in 22 cases, radiation therapy in 8, chemotherapy in 2, and irradiation with chemotherapy in 3.

Results: There were 19 cases with cerebellar tumors, 7 with cerebral hemisphere, 5 with hypothalamus, and 4 with brainstem tumors. The 50% survival does not reach yet during this period. All of the 19 cases with cerebellar tumors survive until the most recent observation day. Additionally, all of the 17 cases with gross total resection also survive compared to partial resection (11 of 15 cases) and biopsy (two of three cases). Age at the start of the treatment was not related to overall survival. In histological examination, there were 23 cases of pilocytic astrocytoma. However, histology was not related to overall survival too.

Conclusions: The overall survival in this series of pediatric low-grade astrocytoma was good. The gross total resection and tumor location, but age at the start of the treatment and histology, may have a significant impact on overall survival.


M.J. Lee,1,6 Y.S. Ra,2 H.W. Goo,3 S.D. Ahn,4 S.K. Kang,5 J.S. Song,1 and T.T. Ghim1,7; Departments of 1Pediatrics, 2Neurosurgery, 3Radiology, 4Therapeutic Radiology, and 5Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 6Department of Pediatrics, Dankook University College of Medicine, Cheonan, Republic of Korea, and 7Department of Pediatrics, National Cancer Center, Ilsan, Republic of Korea

Background: Low-grade gliomas (LGGs), which account for about 30% of brain tumors in children, are usually treated with surgical excision and/or radiotherapy. For patients who have significant residual tumor after resection or relapse after radiation, the proper chemotherapy regimen has not yet been identified.

Methods: Fourteen children diagnosed with LGG outside the cerebellum between January 1998 and December 2004, all of whom had significant residual tumor after surgical resection, relapsed after radiation or showed visual deterioration, were treated for 18 months with a multidrug regimen of vincristine, etoposide, cyclophosphamide, and 5-fluorouracil.

Results: Of the seven patients who completed chemotherapy, one showed complete response (CR), five showed partial response (PR), and one had stable disease (SD). In six patients, chemotherapy was prematurely discontinued; five of these patients showed tumor progression; and one had SD. One patient is still undergoing treatment. The side effects of chemotherapy were manageable. The median time to tumor response was 29 months (range, 2 to 77 months).

Conclusions: Pediatric LGG patients with residual tumor after surgery or who undergo relapse(s) may be successfully treated using our combination chemotherapy regimen.


V. de Haas,1,2 V. Laithier,3 M.A. Raquin,1 D.C. Couanet,1 C. Kalifa,1 and J.Grill1; 1Department of Pediatric and Adolescent Medicine, Institut Gustave Roussy, Villejuif, France, 2Emma Children’s Hospital/AMC, Amsterdam, The Nertherlands, and 3Department of Pediatric Oncology-Hematology, University Hospital, Besançon, France

Background: Evaluation of radiological response of first-line treatment with chemotherapy (CT) of children with optic pathway tumors (OPT).

Patients and methods: Between 1990 and 2005, 115 patients were enrolled in a multicenter trial (J. Clin. Oncol. 2003; 24:4572–4578), since 2002 only patients treated in the IGR were included. Three-dimensional measurement of tumor volume during follow-up was performed by MRI, and all serial MRI files were retrospectively reviewed.

Results: Patients were divided in groups according to best response to BBSFOP. Best response observed any time was PR in 60 patients, SD in 30, and PD in 25. Median follow-up was 7.3 years. Compared to diagnosis, initial PD was present in 46 cases. Despite initial PD, 21 patients went on continuing BBSFOP chemotherapy. Among them, 13 patients had finally SD and 8 patients reached PR. Thirteen of 21 patients started to respond before the end of second cycle of CT (i.e., 6 months of treatment). Median size at the end of treatment with first-line CT was 7600 mm3, compared to 28160 mm3 at diagnosis. The relapse rate for the patients with a larger tumor size at the end of treatment was higher in comparison with the patients with a smaller size (70% vs. 42%; P = 0.01).

Conclusion: Response to chemotherapy should not be considered to early since the patients with initial PD finally ended up with SD or PR. The risk of relapse is higher when the tumor is large at the end of first-line CT.


H. Takei,1 S. Yogeswaren,2 K.K. Wong,2 C. Lau,2 M. Chintagumpala,2 R. Dauser,2 and A.M. Adesina1; 1Department of Pathology and 2Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

Purpose: Gene expression profiling recently demonstrated an inverse relationship between myelin basic protein (MBP) expression and progression-free survival (PFS) in pilocytic astrocytomas (PA). A recent report also showed a correlation between proliferation index (PI) and PFS in PA. We determined the pattern of expression of oligodendroglial differentiation markers (ODMs) in PA and correlated their expression with PI.

Methods: Sixty-nine patients with PA from TCH records (January 1995 to February 2005) were reviewed. Representative sections were selected for immunostaining for Ki-67 (PI) and ODMs, including MBP, platelet-derived growth factor receptor alpha, Olig-1, and Olig-2. Sections were graded semiquantitatively for intensity and extent of staining. PI was expresed as a percentage of positively stained cells out of 1000 tumor cells from the most mitotically active areas. Linear regression and Spearman rank-order correlation analysis were done. P values < .05 were considered statistically significant.

Results: The patients ranged in age from 8 months to 19 years (mean, 6.5 years). Cases were distributed as follows: 49 cerebellum, 7 brainstem/ spinal cord, 8 hypothalamus/chiasm, 4 cerebral hemisphere, and 1 pineal gland. PI ranged from 0% to 9.5% (mean 1.4%). No significant differences in gender or tumor locations were observed. There was a significant inverse correlation between MBP expression and PI (Spearman’s P = 0.0305, r2 = 0.696, P = 0.014, respectively). A positive correlation was observed between PI and PDGFRalpha (r2 = 0.727, P = 0.011).

Conclusion: An inverse relationship between MBP expression and PI is confirmed. We suggest that expression of ODMs and PI may identify clinical subsets of PA.


I.F. Pollack, R.I. Jakacki, S. Blaney, M.L. Hancock, M.W. Kieran, P. Phillips, L. Kun, H. Friedman, R. Packer, A. Banerjee, J.R. Geyer, S. Goldman, T.Y. Poussaint, M. Hayes, and J.M. Boyett; Children’s Hospital of Pittsburgh, Texas Children’s Hospital, Boston Children’s Hospital, Children’s Hospital of Philadelphia, Duke University Medical Center, Children’s National Medical Center, University of California, San Francisco, Children’s Hospital and Medical Center, Children’s Memorial Hospital, and the St. Jude Children’s Research Hospital, on behalf of the Pediatric Brain Tumor Consortium, Memphis, TN, USA

Purpose: The objectives of this study were to define the maximal tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsants (EIACDs).

Experimental design: In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage, was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage.

Results: Twenty-four evaluable patients received therapy before the amendment, and 3/6 with a brainstem tumor experienced dose-limiting toxicity (DLT), one asymptomatic intratumoral hemorrhage, one grade 4 neutropenia, and one renal insufficiency; 0/18 with recurrent glioma experienced DLT. After protocol amendment, 2/16 brainstem glioma patients and 2/11 recurrent glioma patients not receiving EIACDs experienced new hemorrhages, three symptomatic. In addition to the five hemorrhages during the DLT monitoring period, 14 patients experienced hemorrhages (eight symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m2. Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m2 but the MTD was not established with EIACDs, with no DLTs at 800 mg/m2.

Conclusion: Recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma not receiving EIACDs. Imatinib may increase the risk of ITH although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.


G. Fleischhack,1 S. Buchen,1 M. Warmuth-Metz,2 T. Pietsch,3 F. Bach,4 and U. Bode1; 1Department of Pediatric Hematology/Onocology, University of Bonn, Bonn, Germany, 2Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany, 3Institute of Neuropathology, University of Bonn, Bonn, Germany, and 4Oncoscience AG, Wedel, Germany

In children with refractory high-grade gliomas (HGGs) there are only a few therapeutic options and the expected life span is only several weeks. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserve a good quality of life. This phase II trial was designed to explore the feasibility and efficacy of nimotuzumab, a humanized h-R3 monoclonal anti-EGFR antibody, in advanced HGGs. Pediatric patients with glioblastoma multiforme, anaplastic astrocytoma, or intrinsic pontine glioma (PG) with radiologically proven progressive disease following primary or relapse treatment were eligible to the study. The treatment consisted of an induction therapy including a weekly infusion of 150 mg/m² nimotuzumab for six weeks, and in case of non-PD, a subsequent consolidation therapy of four infusions in a three-week interval. Between June 2004 and January 2006, 40 patients (median age, 11.4 years; range, 5.0 to 17.4 years) were enrolled. In the MRI of week 8, 12 of 37 evaluable patients showed response according to RECIST (PR, n = 1 and SD, n = 11) accompanied by clinical deterioration in four patients and markedly clinical improvement in three. Surprisingly, nine PR/SD were observed in 18 patients with PG. Eight patients continued with the consolidation therapy and showed three PR, one SD, and four PD in week 21. No severe side effects of the antibody were observed. Repeated application of nimotuzumab is well tolerated and safe. It has cytotoxic efficacy especially in intrinsic PG. A phase III study in patients with newly diagnosed PG is planned.


S.R. Burzynski, R.A. Weaver, T.J. Janicki, G.F. Jurida, B.G. Szymkowski, and E. Kubove; Burzynski Research Institute, Houston, TX, USA

The purpose of the studies is to evaluate the outcome of newly diagnosed diffuse, intrinsic brainstem glioma (NDBSG) in children treated with ANP in FDA-monitored phase II trials. Twenty assessable children were involved in the studies. Five patients had high-grade gliomas. Age ranged from three months to 20 years. ANP was administered intravenously daily through a subclavian venous catheter via a double-channel infusion pump. The median duration of the treatment was eight months and the average dosage of A10 was 10.0 g/kg/day and AS2-1 0.36 g/kg/day. NCI CTC were used for evaluation of toxicity and responses based on MRI and PET scans. Complete response (CR) was achieved in 30%, partial were response (PR) in 10%, stable disease in 20%, and progressive disease in 40% of patients. The overall survival (OS) at two years was 40% and five years 30%; median survival (MST) 16.4 months and the maximum survival is over 12 years. Serious toxicities included five cases of anemia and single cases of skin rash, hypokalemia, and elevation of transaminases. There were no chronic toxicities. The results compare favorably with the outcome of standard radiation therapy in combination with chemotherapy (RAT) which produced 2% CR, 31% PR, 7% two-year and 0% five-year OS, and MST 8.5 months (Mandell et al., 1999). In conclusion, ANP is well tolerated and provides encouraging results in the treatment of NDBSG. The results should be confirmed in randomized phase III trial comparing RAT and ANP scheduled to begin soon.


N. Larrier,1 S. Gururangan,2 and E. Halperin1; 1Department of Radiation-Oncology and 2Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

Purpose: To determine the feasibility and toxicity of concurrent twice-daily RT and CPT-11 followed by maintenance BCNU + CPT-11(MC) in patients (pts) with newly diagnosed brainstem glioma (BSG).

Methods: 3-D conformal radiotherapy (RT) was administered to 76 Gy (1.17 Gy b.i.d daily five days/week for six weeks). CPT-11 (20 mg/m2/day) was administered i.v. over 90 minutes within 2 h of the first dose of RT daily for two weeks and schedule repeated following a three-week break. Patients with stable or improved disease following RT received maintenance chemotherapy (MC) consisting of i.v. CPT-11 (125 mg/m2) weekly for four weeks and i.v. BCNU (100 mg/m2) delivered on day 1 just prior to the first dose of CPT-11. Each course was six weeks for a maximum of eight cycles. MRI scan of brain and FDG-PET scan of brain was obtained prior to each cycle.

Results: Nine pts were enrolled in the study. Eight of nine pts completed RT with concurrent CPT-11 as planned without toxicity. One pt developed progressive disease (PD) following RT and was taken off the study. Of seven pts who received MC, only two pts completed the planned eight cycles of treatment with stable disease. Four pts developed PD after a median of three cycles of MC (range, 3–5). One pt was lost to follow-up after one cycle of MC. Worst toxicities during MC included grade II–III myelosuppression (three pts) and grade II decrease in DLCO (two pts). Only one pt is currently alive with disease 38 months since enrollment.

Conclusion: CPT-11 can be safely administered with RT for children with BSG. The feasibility of maintenance chemotherapy is limited by PD.


T. Tsurubuchi, S. Takano, T. Yamamoto, K. Tsuboi, and A. Matsumura; Department of Neurosurgery, Institution of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan

Purpose: We evaluated the prognostic factors for 10 cases of pediatric pontine glioma who admitted in our hospital between October 1988 and November 2004 based on the clinical symptoms and MRI findings.

Materials and methods: There were three men and seven women, ranging from 4 to 15 years old (median 7.3 years). The patterns of tumors on MRI were seven diffuse types and three focal types. Biopsies were done for three cases, radiation therapy for all cases, and chemotherapy for four cases. Follow-up periods were 2 to 24 months (average 9.6 months). We evaluated whether or not clinical symptoms, MRI findings, and surgical procedures are prognostic factors. We also examined the differences of response rate after radiation therapy between pediatric (n = 5) and adult (n = 5) brainstem gliomas.

Results: Median survival time was 9.9 months. Dissemination on MRI was a significant prognostic factor (P = 0.0221). Other factors, such as clinical symptoms (cranial nerve sign, long-tract sign, ataxia, and time to diagnosis), MRI findings (diffuse or focal type and basilar invagination), chemotherapy, and surgical intervention (decompressive craniotomy, biopsy, and ventricular peritoneal shunt) were not significant. The response rate evaluated on T2 weighted MRI six months after radiation therapy was significantly lower in pediatric group compared to adult group (P = 0.0129).

Conclusion: The prognosis of pediatric pontine glioma was poor. Dissemination on MRI was a worse prognostic factor. Lower response rate with radiation therapy was one of the reasons for poor prognosis.


J. Fangusaro, R. Jubran, S. Gardner, I. Gonzalez, D. Miller, and J.L. Finlay; Children’s Hospital Los Angeles and participating institutions in the United States, Argentina, Canada, and Australia

Purpose: To evaluate the response rate and survival with an intensified induction chemotherapy regimen (Head Start Protocols) followed by myeloablative chemotherapy with autologous hematopoietic cell rescue in young children with newly diagnosed brainstem primitive neuroectodermal tumors (bsPNET).

Patients and methods: Six children with biopsy-proven bsPNET were treated with intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (HDCx + AuHCR). Five patients were enrolled on the Head Start I and Head Start II regimens, and one patient was treated as per Head Start II. After a maximal safe surgical resection of the tumor, patients on Head Start I (1991–1997) were treated with five cycles of induction chemotherapy that included vincristine, cisplatin, cyclophosphamide, and etoposide. Following induction, eligible patients went on to receive a single cycle of HDCx + AuHCR. Patients enrolled on Head Start II (1997–2002) with metastatic disease at diagnosis (M1+) also received high-dose IV methotrexate with leucovorin rescue as part of each induction chemotherapy cycle.

Results: Among the six patients treated, two patients survive at least 30 months, yielding an EFS and OS of 17 ± 15% and 33 ± 19%, respectfully. The four remaining patients died of progressive disease.

Conclusion: This approach provides a promising alternative for young patients with newly diagnosed bsPNET who in prior reports have had a uniformly fatal prognosis.


L. Gore,1 K.W. Maloney,2 A.A. Smith,3 and N.K. Foreman1; 1University of Colorado Health Sciences Center and Children’s Hospital, Denver, CO, USA, 2Medical College of Wisconsin, Milwaukee, WI, USA, and 3University of Florida, Shands Cancer Center, Gainesville, FL, USA

Purpose: To explore the use of oxaliplatin-based chemotherapy in pediatric patients with highly refractory malignancies involving the CNS.

Methods: Ten patients (median age, 11 years; range, 5–21) with recurrent or refractory malignancies involving the CNS were treated with oxaliplatin alone (n = 2) or in combination with 5-FU/leucovorin (n = 5) or thiotepa (n = 3). More than 34 cycles of therapy (median 4, range 1–8) have been delivered in the outpatient setting.

Results: Seven of 10 patients had clinically significant improvements in pain, narcotic use, neurologic exam, and prolonged stabilization of disease. For four patients, this was the first regimen (median prior regimens = 4; range 2–7) to offer any prolonged tumor control. Maximum toxicities over all courses included reversible grade 4 neutropenia, anemia, and thrombocytopenia; grade 2 laryngopharyngeal dysesthesia; and grade 2 diarrhea. Nine of 34+ cycles (26%) were delayed for up to two weeks due to delayed neutrophil recovery. Two patients electively discontinued therapy after six and eight courses. Two patients receiving single-agent oxaliplatin had progressive disease after two and four courses. Seven patients died due to progressive disease at a median of 10 months (range 1–11 months) following therapy. One patient with refractory glioblastoma multiforme had persistent myelosuppression for seven weeks before full hematologic recovery and remains disease free more than 21 months following treatment.

Conclusions: Combination oxaliplatin-based chemotherapy can be delivered safely to patients with refractory CNS malignancies in the out-patient setting and may provide significant disease stabilization.


A.M. Donson, S.O. Addo-Yobo, M.H. Handler, L. Gore, and N.K. Foreman; University of Colorado Health Sciences Center and Denver Children’s Hospital, Denver, CO, USA

Juvenile pilocytic astrocytomas (JPA) are the most common central nervous system tumors in children. If completely resected, JPAs are associated with an excellent outcome. However, there is need for additional therapeutic approaches for those JPAs which are incompletely resected and fail subsequent standard chemotherapy/radiation. To explore the possibility for a novel therapeutic approach, we measured the effect of the epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitor gefitinib on five JPA primary cell cultures. Due to a lack of established cell lines of JPA, very few in vitro drug sensitivity assays have been performed. In this study, we have succeeded in propagating short-term primary cell cultures established from surgical specimens. The effect of gefitinib on proliferation in JPA-derived primary cell cultures was measured by a standard tritiated thymidine incorporation assay. The level of expression of EGFR, the intended target of gefitinib, was measured by immunohistochemistry, flow cytometry, and RT-PCR. Gefitinib was shown to inhibit proliferation in all five JPA cell cultures tested, with IC-50s between 1.6 and 9.6 mM. However, EGFR protein and mRNA expression was undetectable. Further studies with cetuximab, an EGFR-specific inhibitory monoclonal antibody, showed no effect on proliferation in JPA. Based on these preclinical data, gefitinib may be a suitable salvage chemotherapy drug to explore further in those patients with JPA who have recurred after primary chemotherapy. Of interest, it appears that the antitumor effect of gefitinib in JPA cell cultures may be mediated through a pathway other than EGFR inhibition.


M. Terasaki, K. Sakata, S. Fukushima, and M. Shigemori; Department of Neurosurgrey, Kurume University School of Medicine, Kurume, Japan

Objective: Low-grade gliomas (LGGs) are the most common childhood brain tumors. Of childhood brain tumors, 36% are LGGs and over half of these occur in children less than 10 years of age. Surgical intervention has been the primary therapy for the vast majority of childhood LGGs. However, they are treated with individual protocol in each institution.

Materials and methods: This is a retrospective compilation of data collected on 36 children < 16 years of age diagnosed with brain tumor since 2000. Of 36 patients, 12 (33.3%) had suspected low-grade lesions.

Results: In supratentorial low-grade lesions, 67% had differentiated from astrocytoma: one is oligodendroglioma and another is DNT (no epileptic episodes). In infratentorial lesions, one suspected low-grade lesion was diagnosed as MELAS. Intrinsic brainstem glioma had poor prognosis, but some specific population with asymmetrical disease prolonged their survival.

Conclusions: Optimal timing of surgery should be considered depending on three points: (1) to verify that the lesion is in fact a tumor; (2) to allow early identification of an anaplastic tumor; and (3) to differentiate astrocytoma from other glial tumors, because these diagnoses carry different implications for management and outcome.


V. de Haas,1,2 J. Grill,1 M.A. Raquin,1 J.L. Habrand,1 C. Sainte-Rose,3 and C. Kalifa1; 1Department of Pediatric and Adolescent Medicine, Institut Gustave Roussy, Villejuif, France, 2Emma Children’s Hospital/ AMC, Amsterdam, The Netherlands, and 3Department of Pediatric Neurosurgery, Necker Hospital, Paris, France

Background: Conservative treatment of children with optic pathway tumor (OPT) consists of first-line chemotherapy. The most appropriate therapeutic strategy after first relapse has yet to be defined.

Patients and methods: Children with OPT treated with first-line BBS-FOP chemotherapy between 1990 and 2005 (J. Clin. Oncol., 2003, 24: 4572–4578). Single-center review of files of patients with relapse.

Results: Forty-four of 68 patients were diagnosed with one or several relapses. Median time of follow-up after first relapse was 4.2 years. Overall and progression-free survival rates after first relapse were 64% and 14%, respectively. Median time to first relapse was 1.8 years. Eleven patients died after progression of the disease. First relapse was treated with chemotherapy (CT), usually vincristine-carboplatine in 28/44 patients. Best response to second-line CT was PR in 10, SD in 15, and PD in three patients. Six patients underwent surgery and nine received radiotherapy (RT) at first relapse. Median TTP after first relapse was 1.7, 2.5, and 3.1 years after surgery, CT and RT respectively. Finally, 24 patients had RT at a median age of 6.7 years. By the age of ten, 23/24 patients had received RT. At the last follow-up visit, 19/30 patients had a visual acuity above 3/10; 84% of them did not receive RT.

Conclusion: Despite policy to avoid RT in treatment of OPT, radiotherapy was needed for 55% of patients, usually before the age of 10 years.


S. Yogeswaren, A. Adesina, S. Woo, A. Paulino, C. Lau, R. Dauser, S. Hilsenbeck, and M. Chintagumpala; Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

Management of patients with midline low-grade glioma is influenced by age, location, NF-1 status, and symptoms at diagnosis. We evaluated retrospectively the impact of initial therapy on the outcome of these patients. Thirty-one patients with midline low-grade glioma from 1983 to 2003 were identified. Pathology, radiology, and treatment records were reviewed and pathology was confirmed in 24 of 31. Twenty-five had chiasmatic/hypothalamic tumors, and 25 had juvenile pilocytic astrocytoma. Sixteen non–NF-1 patients received chemotherapy, and 15 received radiation therapy initially. The median age of patients receiving chemotherapy was 3.17 years (6 months to 10 years) and that of those receiving radiation therapy was 7.56 (range, 3–16 years). Fourteen of 16 patients (chemotherapy) received carboplatin-based therapy. Twelve of 15 (radiation) received conventional radiation, and 3 received intensity-modulated radiation therapy. The median dose was 5040 cGy. The median time to progression for patients who received chemotherapy as initial therapy was 1.83 years compared to 11.98 years for patients who received radiation therapy (P < 0.001 by log-rank test). Seven of 14 patients who progressed after initial chemotherapy were progression-free at the last follow-up following radiation therapy. Two of five who failed initial radiation therapy were progression free. The eight-year overall survival for both groups were 71% (chemotherapy) and 79% (radiotherapy). Toxicities associated with radiation therapy included vasculopathy and endocrine/growth hormone abnormalities. Outcome of patients with midline low-grade glioma is excellent. Although radiation therapy is more effective than chemotherapy, delaying radiation therapy in young children with midline low-grade glioma is not detrimental to long-term survival.


A. Peyrl, A. Azizi, T. Czech, C. Haberler, D. Prayer, and I. Slavc; Departments of Pediatrics, Neurosurgery, and Radiology, and Institute of Neurology, Medical University of Vienna, Vienna, Austria

Pilocytic astrocytomas of the hypothalamic-chiasmatic region account for up to 20% of tumors in patients below the age of two years. While most children respond to chemotherapy alternative treatment approaches are needed for those with refractory, progressive, and/or metastatic disease. Imatinib, a methylpiperazine derivat, inhibits the autophophorylation of essentially three kinases: BCR-ABL, c-KIT, and platelet-derived growth factor receptor (PDGFR). Imatinib is established as a safe and effective therapy in all stages of chronic myelogenous leukemia, but has also shown efficacy in numerous different cancers. We report on six patients who originally presented with an extensive pilocytic astrocytoma of the hypothalamus/visual pathway during infancy. None of the patients had neurofibromatosis. All six patients were treated with carboplatin/vincristine according to the European Low-Grade Glioma Protocol followed by additional surgeries and at least one or two additional chemotherapies including high-grade glioma regimens, vinblastine, and temozolomide. Because of further tumor progression, empiric therapy with imatinib at a daily dose of 215 mg/m2 was initiated. Therapy was well tolerated with only minor side effects (edema in one patient). One of the patients showed regression in tumor size, four remained stable during treatment, and one is too early to evaluate. We conclude that treatment with imatinib may warrant further study in children with refractory and progressive pilocytic astrocytoma.


I.J. Cohen,1 N. Cohen,2 L. Kornreich,3 S. Michovitch,4 R. Friling,2 A. Shufer,1 J. Atias,5 and I. Yaniv1; Departments of 1Pediatric Hematology-Oncology, 2Opthalmology, 3Imaging, and 4Neurosurgery, and 5Institute of Neurophysiology, Schneider Children’s Medical Center of Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Introduction: Visual recovery is not expected after blindness caused by direct tumor invasion. On two occasions this was achieved with a metronomic low-dose vincristine/carboplatin protocol.

Methods: Case 1. A recently blind 10.5-month-old girl without NF1 was found to have a chiasmatic optic tract glioma (biopsy showed pilocytic glioma). She was treated with weekly vincristine and carboplatin from November 1996 to April 2005 with a progressive decrease in size of the residual tumor. After 18 months she began to see in the nasal half of her left eye. She now studies in a normal class and is able to perform normal functions including reading, crossing roads, and shopping. Case2. A recently blind girl aged seven months without NF1 with a chiasmatic optic tract glioma was treated with vincristine and carboplatin from October 2003 until November 2004 then with weekly vincristine. A decrease in the size of her tumor has been seen without surgery. She recovered nasal vision with color vision in her left eye after four months of therapy.

Discussion: Recovery of nasal vision including color vision in one eye in each of these children is compatible with reversible damage of temporal fibers in one optic nerve. These fibers do not cross over in the chiasma and are thus under less pressure than other fibers.

Conclusion: Great care must be exercised in operating on such children to avoid irreversible anatomical damage that would prevent the possibility of recovery of vision. Therapy should be started as soon as possible.


J. Adachi,1 K. Mishima,1 R. Nishikawa,1 H. Nishimoto,3 T. Hirose,2 and M. Matsutani1; Departments of 1Neurosurgery and 2Pathology, Saitama Medical School, Irumagun, Saitama, Japan, and 3Department of Neurosurgery, Saitama Children’s Medical Center, Saitama, Japan

A 20-year-old woman presented to our hospital with the complaint of occasional headache. At the age of 4 and 14 years, she underwent resection of the mandible and ovarian fibroma, respectively. She did not have a history of cranial radiation therapy. Imaging studies revealed a large calvarium, extensive calcification of the falx and tentorium, and a calcified tumor between bilateral lateral ventricles. Gd-enhanced MRI showed heterogeneous enhancement of the tumor. We subtotally removed the tumor and a histological examination confirmed the diagnosis of a pilocytic astrocytoma. Clinical manifestations of this patient satisfied diagnostic criteria of Gorlin’s syndrome. Medulloblastoma, meningioma, and neurinoma associated with this syndrome have been described as involved with the central nervous system. To our knowledge, this is the first reported case of pilocytic astrocytoma in a patient with Gorlin’s syndrome. Neuro-oncologists should pay attention to the surveillance for not only medulloblastoma, but also low-grade glioma in affected patients.


D. George, T. Tomita, V. Rajaram, J. Monroe, K. Dulek, C. McCabe, and E. Bremer; Brain Tumor Research Program, Falk Brain Tumor Center, Children’s Memorial Hospital, Chicago, IL, USA

Juvenile pilocytic astrocytomas (JPAs) are the most common pediatric brain tumors, accounting for nearly 25% of all cases. Classified as a WHO grade I glioma, these tumors are classically thought to arise from astrocytes. Understanding the molecular changes in these tumors could lead to the identification of tumor markers and eventually to novel therapeutic targets. Using Affymetrix microarrays, expression profiles of JPAs were compared to malignant gliomas, ependymomas, and medulloblastomas to identify potential markers. We were able to identify two basic helix-loop-helix transcription factors, Olig1 and Olig2, which are highly expressed in the JPAs relative to the other tumor types. Confirmation by quantitative RT-PCR identified 4- to 200-fold higher expression levels of Olig1 and Olig2 in JPAs as compared to other tumor types. Immunohistochemically, JPAs exhibited either a strong scattered positive or strong diffuse positive staining pattern for Olig1, and a strong diffuse positive staining pattern for Olig2. Ependymomas showed a weak or negative staining pattern for Olig1 and Olig2. Oligodendrogliomas have a weaker positive staining pattern for Olig1 as compared to the JPAs, but have a similar Olig2 positive staining pattern as compared to JPAs. Other studies have shown Olig gene expression is a potential marker of oligodendroglial tumors. Olig1 and Olig2 also play an important role in fate of oligodendrocyte precursor cells. The expression of these two basic helix loop helix transcription factors may be important in understanding the biology and the linage of JPAs.


D.C. Bowers, L. Gargan, P. Kapur, B.E. Weprin, J. Rankin, and L.R. Margraff; University of Texas Southwestern Medical Center and Children’s Medical Center of Dallas, Dallas, TX, USA

Introduction: We have reported (J. Clin. Oncol. 2003; 21:2968) that an elevated MIB-1 Labeling Index (LI) correlates with an increased frequency of tumor progression among all children with pilocytic astrocytomas (PAs) but not the subset of incompletely resected PAs. This study includes an additional 24 consecutive children at our institution and further examines the MIB-1 LI among children with incompletely resected PAs.

Methods: Immunohistochemistry for MIB-1 was performed according to standard methods on 98 PAs from children who had an incomplete resection and were observed only (n = 61); treated with initial adjuvant carboplatin-based chemotherapy (n = 21); or treated with radiation therapy (RT) (n = 16). The MIB-1 LI was compared with tumor progression-free survival (PFS) and overall survival (OS) by log-rank analysis.

Results: The mean (± SD) MIB-1 LI of all tumors was 2.378% (± 2.94%) and the range was 0.08%–23.0%. The five-year PFS and OS among patients who were observed without adjuvant therapy were 45.0% and 97.3%, respectively. The five-year PFS and OS among patients treated with adjuvant chemotherapy were 24.4% and 90.0%, respectively. The five-year PFS and OS among patients treated with adjuvant RT were 56.3% and 93.3%, respectively. An MIB-1 LI of > 2.0 was associated with a shortened PFS among incompletely resected PAs who were observed without adjuvant therapy (P = 0.02). The MIB-1 LI as a continuous variable was also associated with PFS (P = 0.007). The MIB-1 LI was not associated with PFS among PAs treated with chemotherapy or RT.

Conclusions: An elevated MIB-1 LI is associated with a shortened PFS among children with incompletely resected PAs who were observed without adjuvant therapy. The lack of an association between MIB-1 LI and PFS among PAs treated with adjuvant therapy may be secondary to a lack of adequate statistical power. Prospective clinical trials of adjuvant therapy for PAs should include an evaluation of the MIB-1 LI.


S. Gururangan,1 R. Broaddus,2 M. McDonald,3 and J. Eastwood4; 1Preston Robert Tisch Brain Tumor Center at Duke and Departments of 3Genetics and 4Neuro-Radiology, Duke University Medical Center, Durham, NC, USA, and 2Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Herditary nonpolyposis colorectal cancer (HNPCC) can be associated with extracolonic tumors including malignant glioma and results from germline mutations in mismatch repair (MMR) genes, mainly MSH2, MLH1, or MSH6. We present the clinical, radiologic, pathologic, and molecular genetic analysis of a patient with HNPCC (based on Amsterdam criteria) and multifocal anaplastic oligoastrocytoma (AO) who also had other congenital anomalies previous unreported in association with HNPCC. The patient was one of twins born to consanguineous parents and presented at age three years with developmental delay and seizures. MRI scan of the brain revealed congenital cysts and absent corpus callosum. Both twins and an older male sibling were also diagnosed with Transcobalamin II deficiency and hypogammaglobulinemia as infants. The patient was successfully treated for a HPNCC at age 14 years. Five years later, he developed AO involving the left parietal and right temporal lobes and died of progressive disease despite multimodality therapy. Family history was positive for colorectal cancers in maternal grandmother and great grandmother and satisfied the Amsterdam criteria for HNPCC. The patient’s twin brother also died of AO at age 11. By immunohistochemistry, both the colon adenocarcinoma and the brain tumor retained positive nuclear expression for MLH1, MSH2, and MSH6 proteins. These immunohistochemical results correlated with the results of microsatellite instability (MSI) analysis for both tumors, which showed no allelic shift for all five microsatellites (BAT25, BAT26, D2S123, D5S346, and D173250) examined. Therefore, both the colon and brain tumors were considered micro-satellite stable. Ongoing work will demonstrate if other mutations were involved in the patient’s tumorigenesis.


B. Diez, G. Sevlever, H. Martinetto, and A. Taratuto; Institute for Neurological Research Dr. Raul Carrea (FLENI), Buenos Aires, Argentina

Pediatric oligodendrogliomas are infrequent. Literature examining treatment and outcome in this population is sparse. A retrospective analysis of children and adolescents treated between 1991 and 2005 was performed. Eleven had oligodendroglioma, 4 mixed oligodendroastrocytoma (M:F = 6:9; age range 1–19 years, median = 11). Presenting symptoms: 9 seizures with normal neurological examinations, 4 headache alone or with other symptoms, 3 weakness/paresis alone or with other symptoms, and 1 somnolence. Tumor locations: 12 cerebral hemisphere, 1 cerebellum/IV ventricle, 1 thalamus, and 1 pineal. All underwent craniotomy: 8 gross total resections, 3 subtotal, and 4 partial/biopsy. 1p32 and 19q13 deletions were detected in 3 of 7 samples studied. Two groups were identified; group 1: 10 children with normal neurological examination (epilepsy 9, cefalea 1). All were observed only after surgery. All are alive (NED 7, SD 3) after a median follow-up of 18.5 months (6–72). One had a local progression after 58 months, was operated on, and is alive with SD + 6 months post progression. Group 2: Five children with neurological symptoms. Two were observed and three received postoperative chemotherapy. Four progressed at a median time of 20 months, and two died +56 and +45 months. One is alive NED without relapse + 4 months, and two are alive post progression (one NED after PCV and radiotherapy +158 months, one with SD post two more surgeries +18 months). The present series shows a correlation between clinical presentation and survival in childhood cerebral oligoden-drogliomas.


J.E. Wolff,1,2 S.B. Berrak,3 M. Elope,1 and H. Hauch2; 1Department of Pediatric Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 2Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany, and 3Istanbul, Turkey

Introduction: Large phase III studies have been necessary to show survival benefits with chemotherapy in high-grade glioma. Numerous smaller trials had no control groups, possibly missing a positive effect. Expanding our former database (Anticancer Res., 25:3585), we analyzed the glioma literature from 1997 to 2005 in order to compare treatment results.

Methods: One database record represents a cohort of patients treated the same way. Cohort characteristics such as median age and outcome measures such as median overall survival (mOS) were documented. Factors influencing the outcome were analyzed, and a predicted outcome for each cohort was calculated. Survival gain was defined as the difference between predicted and observed outcome.

Results: 24,023 patients are reported in 503 cohorts in 362 publications. The male to female ratio was 1.55 to 1. The median age was 45 years; 9% of the studies included children only. The grade IV to grade III ratio was 3.3 to 1. Supratentorial to infratentorial: 7.1 to 1. Newly diagnosed to recurrent tumors: 1.9 to 1; mOS was 14.5 months. All major treatment modalities surgery, radiation, and chemotherapy had significant impact on survival. When ranking studies according to survival gain, the three highest ranking treatments were: BCNU + HFRT, MCNU + TNF-alpha, and PCV + DFMO. When grouping studies, nitrosurea ranked above temozolomide, which is still above other treatments.

Conclusion: This method is valid and will allow identifying promising treatments after more refinement, a part of which is ongoing implementing the Bayesian analysis model into the mathematic methods used.


N.K. Foreman, A. Alsultan, A. Donson, and M. Handler; Children’s Hospital, Denver, CO, USA

Secondary brain tumors are a rare but serious complication of therapy. Cranial radiation is the major risk factor for development of secondary brain tumors. In this study, we review our experience with glioblastoma multiforme (GBM) and look at the proportion of secondary GBMs. We biopsy all apparent recurrences to exclude secondary malignancies. Twenty-four patients between 6 months and 21 years with GBM (primary and secondary) diagnosed between 1997 and 2004 were eligible for this study. Patients under six months were excluded. For secondary GBM, details of primary tumors and time from radiation to GBM development were sought. Progression-free survival (PFS) and survival times were calculated. Sixteen patients had primary GBM (66.6%), and 8 patients had secondary GBM (33.3%). Children with secondary GBM had a variety of primaries; two with medulloblastoma, three with juvenile pilocytic astrocytoma, one with germinoma, and two with non-Hodgkin’s lymphoma. All received cranial radiation for their primary tumors. All children with secondary GBM were male, whereas children with primary GBMs were equally male and female. Overall, secondary GBM patients received less aggressive therapy as they were not reirrradiated. Median PFS for primary GBM was 6.5 months (range, 0–42 months) and 0 months (range, 0–5 months) for secondary GBM. Median survival time for primary GBM was 9.5 months (range, 1–70 months) and 4.5 months (range, 1–17 months) for secondary GBM. GBMs secondary to cranial radiation form a significant proportion of childhood GBMs. PFS and survival is very poor for children with secondary GBMs. Reirradiation should be considered.


A. Sato, S. Sato, M. Saino, K. Sakurada, W. Mori, and T. Kayama; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan

Introduction: Thalamic gliomas account for approximately 1% to 1.5% of all brain tumors, and are usually unilateral astrocytoma. We report a bilateral thalamic glioma treated with multiagent chemotherapy, including temozolomide (TMZ).

Case Report: A 16-year-old girl presented with a bilateral thalamic glioma manifesting as dysesthesia over the right side of the body and slight right motor weakness. T1-weighted magnetic resonance imaging revealed enlarged bilateral thalami with homogenous isointensity and no enhancement after gadolinium administration. Histological examination of a stereo-tactic biopsy specimen identified anaplastic astrocytoma. Radiotherapy and ACNU treatment failed to arrest tumor growth. The patient presented with consciousness disturbance by obstructive hydrocephalus. We performed direct surgery and the left thalamic tumor was removed partially. After surgery, she received TMZ (200 mg/m2/day × 5 per cycle of 28 days) treatment as outpatient of Saitama medical school. The residual tumor shrunk dramatically after TMZ administration (nearly CR). She showed a clinical improvement. But after eight cycles of TMZ treatment, her symptoms were aggravated again. MRI revealed local recurrence and multiple disseminated lesions. Thereafter she received chemotherapy with ifosfamide, cisplatin, and etoposide (ICE) and the tumor shrunk at present.

Conclusion: The diffuse and bilateral involvement of both thalami makes surgical therapy barely feasible, even at the present time. New agents and therapeutic strategies are needed to enhance the chance of cure of these diseases.


O. Cruz,1 J. Mora,1 R. Navarro,2 and A. Guillen2; Departments of 1Oncology and 2Neurosurgery, Sant Joan de Déu Hospital. Barcelona, Spain

Background: Spinal cord astrocytomas are rare diseases and their management controversial. High-grade astrocytomas require multidisciplinary intervention but for low grades, the role of chemotherapy is unclear. We report the successful experience of using irinotecan (I) and cisplatin (C) in progressing intramedullary astrocytomas (IAs).

Methods and results: A 16-month-old girl presented with a grade III lumbar IA that progressed after surgery and chemotherapy. Weekly C (30 mg/m2) plus I (50 mg/m2) was used to avoid radiotherapy (RT). Radiological complete remission was achieved 10 months after completion of therapy, and three years from diagnosis remains disease free. A 19-month-old boy with a C3-T4 grade II IA, who despite upfront vincristine (V) and carboplatin (CA) remained symptomatic; follow-up MRI showed progression was switched to I/C. After first cycle, clinical improvement occurred. MRI showed partial remission at the end of therapy, and one year after he remains symptom free. The third patient is a 10-month-old girl with a grade II C2-T3 IA. She presented with severe pain and paretic arms which worsened while on V/CA. When switched to I/C, it responded within days. MRI at the end of therapy showed significant reduction in tumor size and patient regained neurological deficits.

Conclusions: Treatment with I/C for IA provided clinicoradiological responses allowing avoidance of RT. The results suggest that I/C is an effective combination for childhood astrocytomas and deserves further evaluation.


T. Yanagisawa,1 M. Akiyama,1 Y. Terao,1 K. Fukuoka,1 K. Yokoi,1 K. Fujisawa,1 S. Ohi,2 and Y. Etoh1; Division of Pediatric Oncology, Departments of 1Pediatrics and 2Neurosurgery, Jikei University School of Medicine, Tokyo, Japan

Intramedullary spinal cord astrocytomas are uncommon tumors, accounting for less than 3% of central nervous system neoplasms. In view of the rarity of these lesions, few reports could incorporate sufficient number of patients enough to confirm the role of irradiation and/or chemotherapy in this location. It is still unclear whether children with low-grade astrocytomas of the cord also benefit from chemotherapy, as often seen in the chemotherapy with carboplatin and vincristine for the counterpart of the brain in children. Our experiences with three children with low-grade astrocytomas of the cord treated with chemotherapy are described. The first was a 10-month-old girl of low-grade astrocytoma of cervical cord that progressed after initial biopsy. The second was a 14-month-old girl of low-grade astrocytoma of thoracic cord that also progressed after initial biopsy, with the past treatment history of hydrocephalus. The third was a 10-year-old boy with a recurrent anaplastic astrocytoma of the thoracic cord. Chemotherapy with carboplatin and vincristine was administered in all, as an initial treatment for the first two patients. Clinical improvement was observed in all. Definite radiographic improvement was observed in the first two cases. In our patients, good outcome could be achieved by chemotherapy with carboplatin-vincristine alone, with very low morbidity. Our experiences, together with recently published reports on the benefit from chemotherapy, provided justification to proceed to a cooperative study of spinal cord astrocytomas to confirm the potential for chemotherapy in this rare disease.


M. Drogosiewicz,1 M. Perek-Polnik,1 I. Filipek,1 B. Dembowska-Bagiñska,1 E. Jurkiewicz,2 P. Daszkiewicz,3 and D. Perek1; Departments of 1Oncology, 2Radiology, and 3Neurosurgery, Children’s Memorial Health Institute, Warsaw, Poland

Introduction: Patients with brainstem tumors have poor prognosis. There are controversies concerning the role of chemotherapy in the treatment of these tumors. The aim of our study was to analyze treatment results of brainstem tumors treated with radiotherapy alone and with the addition of chemotherapy and to assess which chemotherapy is most efficient.

Material and methods: Between 1981–2004, a total of 126 patients were treated. Two groups were analyzed. The first group consisted of 49 patients treated with radiotherapy. In the second group 77 patients were irradiated and received chemotherapy. Overall survival (OS) at one and five years was analyzed in both groups. The efficacy of treatment in the second group was assessed by evaluating reaction to radiotherapy, to different chemotherapy protocols and duration of tumor response. OS was assessed separately for patients with low-grade gliomas treated in the second group.

Results: Seven out of 49 patients from the first group are alive, 8 years 9 months to 24 years (median, 6 years 7 months). In the second group 25 out of 77 patients are alive 7 months to 8 years 2 months (median, 1 year 7 months). OS at 1 and 5 years for radiotherapy alone is 48% and 14% and for those with additional chemotherapy 59% and 18% (P > 0.05). Best tumor response was achieved in 42% of patients with radiotherapy lasting in 75% of cases from 2 weeks to 1 year 3 months (median, 4 months). Addition of chemotherapy (cisplatinum and temozolamide) resulted in tumor regression in 27% of patients lasting from 4 weeks to 4 years 5 months (median, 4 months). OS for patients with LGG was 34.6% at 5 years.

Conclusions: Radiotherapy in brainstem tumors allows to achieve tumor regression but short duration of remission and poor final outcome forces to search for other treatment modalities. Chemotherapy consisting of temozolamide and cisplatinum might add to improvement of treatment results but further clinical studies are needed. Patients with LGG of the brainstem constitute a separate group with a better prognosis. Supported by grant C028/P05/2002.


B. Dembowska-Bagiñska,1 D. Perek,1 A. Broz yna,1 M. Drogosiewicz,1 E. Jurkiewicz,2 and M. Stypiñska1; Departments of 1Pediatric Oncology and 2Radiology, Children’s Memorial Health Institute, Warsaw, Poland

Background: Adolescents (15–19 years of age) are variably included in analyses of childhood cancer. Spectrum of cancers are distinctive and treatment results in this group of patients (pts) differ from those in younger children. Our aim was to describe distribution of CNS tumor types and treatment results in adolescents treated in Department of Pediatric Oncology.

Material and methods: Retrospective analysis of 68 pts with CNS tumors aged 15–19 years treated between 1998 and 2004 was performed. Gender, tumor type, outcome were analyzed and compared with the results in younger (aged 4–14) patients treated in our department.

Results: There were 31 girls and 37 boys (median age, 16 years 8 months). Among 68 pts, 21 (31%) were high-grade gliomas (HGGs) including 6 glioblastoma multiforme, 19 (28%) MB/PNET, 13 (19%) ependymoma including 10 anaplastic, 10 (15%) germinal tumors, 4 (6%) unverified brainstem tumors, and 1 (1%) chorioid plexus carcinoma (CPC); 39 pts (57%) are alive: 10/21 with HGG, 11/19 with MB/PNET, 10/13 with ependymoma, 6/10 with germinal tumors, 1/4 with brainstem tumor, and 1/1 with CPC with a follow-up from 1/12 to 7 9/12 (median, 2 8/12); 29 pts died (26 from disease and 3 (10%) from treatment-related complications). Comparison of treatment results at three years from diagnosis showed statistically better OS for children 4–14 years than for adolescents, 68% and 60%, respectively (P = 0.07). When children 0–3 years were included, the results are similar.

Conclusions: Among CNS tumors HGGs were the most common followed by MB/PNET, ependymoma, and germinal tumors. Outcome of treatment was inferior to that for younger pts aged 4–14 years. There was an excess of deaths 3 out of 29 (10%) from treatment-related complications. Supported by grant C028/P05/2002.


M. Matsutani for the Japanese Study Group for CNS Germ Cell Tumors; Department of Neurosurgery, Saitama Medical School, Saitama, Japan

Methods: After histological verification by surgery, two kinds of chemotherapy (three courses) were delivered prior to irradiation. A total of 256 patients were registered in this trial, and 228 of them were evaluated.

Results: (1) A total of 123 patients with germinoma were treated by CARE (carboplatin, 450 mg/m2 on day 1; and etoposide, 150 mg/m2 on days 1–3) followed by local irradiation (24 Gy). Whole brain irradiation was applied for widely disseminated tumor in the brain. Disease recurred in 16 patients, and two patients died. The five-year overall survival rate is 98%. The recurrent rate significantly differed among radiation volume: 0% by whole brain irradiation, 28% by limited local field irradiation with less than 2-cm margin, and 6% by extended local field irradiation. (2) A total of 38 patients with HCG-secreting germinomas were treated in the same strategy to the intermediate prognosis group because of their high recurrent rate. Despite five recurrences, the five-year OSR is 100%. (3) Nongerminomas were divided into two groups, the intermediate prognosis group (malignant teratoma and mixed tumors mainly composed of germinoma or teratoma) and the poor prognosis group (choriocarcinoma, yolk sac tumor, embryonal carcinoma, and mixed tumors). Patients in the intermediate prognosis group were treated by CARE followed by local irradiation (50 Gy). They received additional chemotherapy five times. Patients in the poor prognosis group were treated by ICE (IFOS, 900 mg/m2; cisplatin, 20 mg/m2; and etoposide, 60 mg/m2 on days 1–5) followed by whole neuroaxis irradiation. They received additional chemotherapy five times. The five-year overall survival rate in 40 patients in the intermediate prognosis group was 97%. The three-year overall survival rate for 27 patients in the poor prognosis group was 56%.


N.S. Silva, B. Diez, A.M. Cappellano, S. Cavalheiro, R. Brito, J. Wisoff, H. Weiner, S. Gardner, J. Dilday, and J. Finlay; São Paulo, Brazil, Buenos Aires, Argentina, New York, NY, USA, and Los Angeles, CA, USA

Between 2001 and January 2006 we treated patients with newly diagnosed primary intracranial germ cell tumors with one of two risk-tailored therapeutic regimens, administering two cycles of chemotherapy after complete radiographic resolution and tumor marker normalization, with avoidance of irradiation in such patients. Twenty-four patients aged four months to 24.5 years (median, 13.4 years) were stratified according to two regimens. Regimen A: one, three, and five cycles of carboplatinetoposide; and two, four, and six cycles of cyclophosphamide-etoposide for low-risk pure germinoma (G-LR) localized nonmetastatic, normal CSF, and serum tumor markers. Regimen B: 1–6 cycles of carboplatin-cyclophosphamide-etoposide for intermediate risk germinoma (G-IR), with either b-HCG syncytiotrophoblastic giant cell and/or CSF b-HCG < 50 mIU/ ml, and high-risk (NG-HR) biopsy-proven nongerminomatous germ cell or elevated serum/CSF alpha-fetoprotein and/or serum/CSF b-HCG > 50 mIU/ml (non-G) or disseminated disease as determined by MRI and/or CSF cytology (G-LR, 12.5%; G-IR, 37.5%; and HR, 50.0%). Of 24 patients, 17 achieved complete response (CR) after two courses (CR2 = 70.8%), and 18 achieved CR after four courses (CR4 = 75.0%). Cases were followed for 2.5–60.8 months (median, 37.4 months). Of 18 patients in CR, eight suffered a relapse, and two of them died of disease progression. Three patients received irradiation during the follow-up period. The two-year overall survival and event-free survival rates are 87.5% ± 7.0% and 66.0% ± 9.8%, respectively. The preliminary results obtained in this selected group of patients showed feasibility and effectiveness with this strategy. Longer follow-up is required to determine eventual durable survival.


T. Fujimaki,1 M. Matsutani,2 and the Japanese Pediatric Brain Tumor Study Group; 1Teikyo University School of Medicine, Teikyo, Japan, and 2Saitama Medical School, Saitama, Japan

Treatment strategy for intracranial germ cell tumors (GCT) differs according to histology. Thus preoperative presumption of histological diagnosis is important to make a proper surgical plan. Although tumor markers are important in preoperative diagnosis, neuroimages are also important. To identify the characteristic features of each histology, CT/MRI images of germ cell tumors were studied. Germinomas were slightly high density on plain CT scans. They were slightly low on MRI T1 and isointensity or hyper-intensity on T2. The border is often obscure on enhanced CT but clear on MRI. Cystic component might be accompanied and sometimes were large. Immature and mature teratomas showed heterogenous images. Presence of fat and big calcifications suggested the teratomatous components. Plain CT of yolk sac tumors showed isointensity to low density and irregular shapes which were different from germinomas. Majority of pineal and hypophyseal tumors (double location) were germinoma but sometimes more malignant forms were included. However, all cases of double location with dissemination were germinomas (with or without STGC). Although it is impossible to precisely predict histological diagnosis solely by neuroimages, their meticulous study helps preoperative presumption of histology of GCTs.


H. Katakami,1 S. Hashida,2 M. Matsutani,3 and the Japanese Pediatric Brain Tumor Study Group; 1Departments of Medicine, Miyazaki University College of Medicine, Miyazaki, Japan, 2Institue of Health Science, Tokushima Bunri University, Tokushima, Japan, and 3Department of Neurosurgery, Saitama Medical College, Saitama, Japan

Most CNS germinomas, including pure germinomas, produce and secrete minimum tumor markers. Conventional IRMAs or EIAs have so far failed to detect human chorionic gonadotropin (HCG) consistently in the peripheral blood (PB) or cerebrospinal fluid (CSF) of most germinomas. We developed a novel and ultrasensitive immune complex transfer–EIA (ICT-EIA) for HCG-beta (Hβ), which was 1000 times more sensitive (LDV, 0.03 pg/ml) than conventional IRMAs (LDV, 100.0 pg/ml) with high specificity (cross-reactivity with LH, <0.02%). In the present study, we examined gene expression (real-time PCR) and production of Hβ (ICT-EIA) in histologically verified CNS germ cell tumors. Plasma or CSF levels of Hβ from patients with germinomas as well as young healthy controls were far above LDV (2.0–30.0 pg/ml). High levels of Hβin the CSF of G with the increased CSF/PB ratio (>2.0) suggested possible production of Hβby tumors, which were immunohistologically negative for Hβ. Both gene expression and tissue content were high in germinomas as well as germinomas with STGC and normal placenta, whereas meningiomas and teratomas showed minimum Hβgene expression (real time PCR) and content. Hβlevels in both PB and CSF of patients with CNS degenerative diseases or non–germ cell tumors of young adults were 5–30 pg/ml with the CSF/PB ratio of less than 1.5, whereas active germinomas showed high levels of 47.5–1658.5 pg/ml with the CSF/PB ratio of 2.0–10.0. When patients were successfully treated, both the size of the tumor and Hβ levels in both CSF and PB became < 30 pg/ml with decreased CSF/PB ratios (around 1.0). These results suggest (1) that all germinomas produce and secrete Hβ, and (2) that Hβ in the CSF and PB as assessed by the ICT-EIA could be a useful tumor marker in all germinomas.


S. Tokimasa,1 Y. Kosaka,2 Y. Takeshima,2 T. Soejima,2 S. Suenobu,2 T. Nagashima,2 and J. Hara2; 1Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Osaka, Japan, and 2Japanese Pediatric Brain Tumor Consortium

Background: The optimal treatment for intracranial nongerminomatous germ cell tumors (NGGCT) remains unclear. The aim of this study was to evaluate the efficacy of multimodal therapy including high-dose chemotherapy (HDC) with autologous stem cell rescue for poor responders to induction chemotherapy.

Patients and methods: Patients diagnosed as NGGCT (by histopathology and/or tumor markers, serum/CSF AFP, and HCG levels) were enrolled. They received five courses of induction chemotherapy consisting of cisplatin, etoposide, cyclophosphamide, and vincristinel; 50 Gy of local irradiation was delivered to patients aged three years old and the older. Patients with disseminated disease received 18 Gy of craniospinal irradiation. Poor responders to induction chemotherapy underwent HDC consisting of thiotepa (800 mg/m2) and melphalan (280 mg/m2) substituted for the fifth course of chemotherapy.

Results: Sixteen patients were enrolled, aged 4 months to 16 years (median, 10 years). Histopathology at diagnosis was available in 11 patients; seven mixed germ cell and four others. One patient had disseminated disease. Two patients had gross total resection. Response rate of induction chemotherapy was 93% (4 CR and 9 PR) in 14 evaluable patients. Eight patients underwent HDC: CR, PR, and SD were obtained in three, one, and four patients, respectively. With a median follow-up of 37 months, 11 patients are alive without evidence of disease, three patients have stable disease, and two patients died of progressive disease. The four-year PFS and OS were 0.86 (95% CI, 0.68–1.00) and 0.93 (95% CI, 0.81–1.0), respectively.

Conclusion: This multimodal therapy was effective in patients with NGGCT.


K.H. Yoo,1 K.W. Sung,1 D.H. Lim,2 H.J. Shin,3 J.H. Kim,3 and H.H. Koo1; Departments of 1Pediatrics, 2Radiation Oncology, and 3Neurosugery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Sungkyunkwan, Republic of Korea

The purpose of this study was to evaluate the response and toxicity of risk-adapted chemotherapy in pediatric intracranial germ cell tumors (IC-GCTs). Among the 25 patients between 3 to 21 years of age who were diagnosed as having IC-GCTs between October 2002 and August 2005 in our institute, 24 received chemotherapy as an initial treatment modality. The low-risk (LR) group was defined as follows: (1) pure germinoma and normal AFP level, and (2) beta-hCG level of 50 mIU/ml or less. The others were regarded as high-risk (HR) group. Cisplatin-based regimen was applied for the initial 18 patients, and the other six patients received carboplatin-based regimen. We used a higher dose for HR patients. Median age at diagnosis was 13.8 years (range, 6.3–18.9 years), and 13 patients belonged to the HR group. Tumor markers were normalized after chemotherapy in all patients having elevated hormone levels at diagnosis. Eight LR patients (72.7%) and 10 HR patients (83.3%) showed complete response (CR) to chemotherapy before radiation therapy. All but one experienced infectious episodes that required hospitalizations. Four of the 13 HR patients (30.8%) complained tinnitus or hearing difficulty, and three of those developed sensorineural hearing loss. None of those receiving carboplatin-based regimen showed ototoxicity. All but one are surviving event-free with a median follow-up of 25 months (range, 5–39 months). Although high-dose cisplatin caused unexpectedly high incidence of ototoxicity, either cisplatin- or carbopla-tin-based regimen was very effective even in HR patients when adjusted according to the risk group.


D. Perek, M. Drogosiewicz, B. Dembowska-Bagiñska, and M. Perek-Polnik; Department of Oncology Children’s Memorial Health Institute, Warsaw, Poland

Aim: To assess treatment results of patients (pts) with pure germinomas (AFP, BHCG negative) treated according SIOP protocol and compare it with a historical group.

Materials and methods: Between 1988 and 2004 45 pts (28 boys and 17 girls, median age 12 years), were treated. Diagnosis was based on pathology in 42 patients. Tissue was obtained surgically by total and subtotal resections in 34 patients, partial in 5. Thirteen patients had biopsy and in 3 diagnosis was based on characteristic clinical symptoms and radiological imaging. Pts were divided into two groups according to treatment applied. Group I consisted of 21 pts treated (1988–1996) with surgery followed by craniospinal irradiation 24–35 Gy with a boost to tumor bed of 44–55 Gy. Group II consisted of 24 pts treated (1997–2004) with SIOP protocol. Focal irradiation was implemented and since 2000 ventricles were included in the field. Treatment results and failures in both groups were analyzed and compared.

Results: Group I: 17 out of 21 patients are alive, 2 with residual tumor less than 1 cm, 18 and 11 years from diagnosis. Three pts relapsed 6,11, and 19 months from diagnosis. All 3 pts had disseminated relapses: 1 spinal, 1 local + spinal, and 1 meningeal disease. Four patients died, 3 from disease and 1 from complications of disease. Group II: 19 out of 24 patients are alive, 3 with a residual tumor. Three patients relapsed 19, 31, and 76 months from diagnosis. All relapsed locally, 2 around the ventricle region. Five patients died, 3 from disease and 2 from difficult to control diabetes insipidus and severe fluid and electrolyte imbalance. Disease-free survival is 85% for group I and 78% for group II with no statistical differences between them; the overall survival is 80% and 75% respectively.

Conclusions: Treatment results are similar in both groups. Focal radio-tharapy including ventricular area combined with chemotherapy seems for now optimal treatment in this disease. Considering that more than half of the germinoma patients have diabetes insipidus we suggest that chemotherapy protocols should not include cytostatics requiring hydration. Supported by grant C028/P05/2002.


H. Nakamura, K. Makino, S. Yano, H. Takeshima, and J. Kratsu; Department of Neurosurgery, Kumamoto University Graduate School, Kuamomoto, Japan

Purpose: We have found that preoperative combined chemotherapy and radiotherapy (neoadjuvant therapy [NAT]), followed by complete excision of any residual tumor, improved the survival of patients with NGMGCT. In this study we examine the tumor recurrence, the survival, and the QOL in the patients with NGMGCT and indicate the future direction for the treatment of NGMGCT.

Patients and methods: Sixteen cases of NGMGT (five yolk sac tumors, two embryonal carcinomas, one choriocarcinoma, one immature teratomas, and six mixed germ cell tumors). Residual tumor was seen in 11 of 15 cases in NGMGT and all of them were removed (total removal in 11 cases and partial remval in one case). The tumor disappeared after chemotherapy and radiotherapy in 2 of 15 cases and in one case the removal was not able to be performed due to dissemination.

Results: One of 15 died because of the initial dissemination. In 3 of 15 cases the tumor recurrence was confirmed and the patient died. Tumor recurrence has not been found in other 11 cases, and the present QOL is 6 in PS 0, 3 in PS 1, and 2 in PS2. All removed tumors were pathologically examined, and there were viable tumor cells in four cases of NGMGT (three immature teratomas and one yolk sac tumor). The histologies of the other eight cases were three mature teratomas and five necrotic or mesenchymal tissues.

Conclusion: NAT may be effective treatment for prevention of tumor recurrence and dissemination because viable tumor cells were found in 4 of 11 cases in NGMGT.


S.I. Sugiyama, Y. Yamashita, M. Kanamori, R. Saito, T. Kumabe, and T. Tominaga; Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan

We analyzed the clinical characteristics of germ cell tumors (GCTs) originating in the basal ganglia (BG). Between 1985 and 2005, 14 patients with GCTs in the BG were treated in our institution. MRI (or CT) revealed that 11 patients had a solitary tumor and three had bilateral or multifocal ones. Pathologic verifications were obtained in 13 patients (germinomas, 9; embryonal carcinoma, 1; malignant teratoma, 1; mixed GCTs, 2). Irradiation was performed in twelve patients (whole brain irradiation, 1; local, 6; whole brain and local, 3; whole brain and spine, and local, 2). Additional chemotherapy was administered to six patients. Two patients received chemotherapy alone as initial treatment. Eleven patients had hemiparesis and four had precocious puberty at initial presentation. Mean interval between the onset and the initial treatment was 17.3 months (range 1–49). Twelve patients had typical neuroradiological findings for intracranial GCTs, while two had only slightly high intensity signals in the BG on MR T1-weighted images though they presented with clinical symptoms. Hemiparesis was not improved even after complete remission of the tumor in the 11 patients who had had hemiparesis before the treatments. The long interval between the disease onset and the initial treatment was one of the clinical characteristics of GCTs originating in the BG. To diagnose them in the earlier stage, they should be considered in the differential diagnosis of patients with hemiparesis or precocious puberty. Mild–high intensity signal in the BG on MR T1-weighted images is the clue to identify early GCTs.


Y. Sawamura and J. Ikeda; Department of Neurosurgery, Hokkaido University Hospital, Sapporo, Japan

Background: Survivors of childhood and adolescent brain tumors are at risk for long-term effects of treatment. This study investigates details on second neoplasms and cerebrovascular disease following CNS germ cell tumors.

Methods: The authors reviewed clinical data on 124 institutional patients who had a germ cell tumor and had survived for longer than five years. Median age at the initial therapy was 15 years and median follow-up period was 133 months (range, 60–384 months).

Results: Among the 124 patients, 25 patients (20%) suffered from secondary neoplasm and/or cerebrovascular disease. Median age of the 25 patients was 14 years at the time of initial treatment. The median interval from the initial treatment to the secondary events was 126 months (range, 24–276 months). The secondary events, therefore, mostly occurred at the third decade of age. The secondary neoplasms included seven cavernous hemangiomas, five glioblastomas, one meningioma, and one hemangiopericytoma. Four cavernomas caused an intracerebral hematoma. The cerebrovascular diseases included 14 cases with steno-occlusive disease of the circle of Willis, one aneurysm, and one dural arteriovenous fistula. All 25 patients had previously received radiotherapy, and six patients had received chemotherapy. The radiation field included the whole ventricle system or whole brain inevitably involving the basal cistern with a dose higher than 40 Gy; but only one patient received 24 Gy irradiation and cisplatin-based chemotherapy. Six of the 25 patients died, and 12 patients had additional sequelae due to these secondary events.

Conclusions: The risk of lethal malignant neoplasm and disabling cerebrovascular disease after CNS germ cell tumors is large. An extremely long-term observation by using MR angiography appears to be necessary to prevent a stroke.


J. Fangusaro, I. Gonzalez, R. Lavey, and J.L. Finlay; Children’s Hospital Los Angeles. Los Angeles, CA, USA

Purpose: To evaluate the responsiveness of recurrent progressive CNS germinoma to combination gemcitibine, oxaliplatin, and paclitaxel.

Patients and methods: A 14-year-old girl was diagnosed at age 10 with a suprasellar mass, pure germinoma on biopsy, with negative serum alpha-fetoprotein (AFP) and beta-hCG. Carboplatin and etoposide for two cycles followed by focal irradiation achieved a complete radiographic response. She relapsed in her ventricular system beyond the irradiation field within two years. High-dose cytoxan followed by myeloablative thiotepa, carboplatin, and temozolomide with autologous hematopoietic cell rescue again achieved complete radiographic response. One year after transplant her disease recurred in her ventricular system with biopsy-proven pure germinoma; both her serum and CSF beta-hCG were elevated. Treatments including systemic temozolomide, intra-Ommaya topotecan, and liposo-mal cytarabine proved ineffective, with nine months of unremitting tumor progression. She then received two cycles of combination paclitaxel (170 mg/m2), gemcitabine (800 mg/m2), and oxaliplatin (100 mg/m2).

Results: Both dramatic radiologic and tumor marker response to this regimen were achieved. Serum beta-hCG returned to a normal level from a high of 560 mIU/ml, and brain MRI revealed minimal residual disease. She died unexpectedly secondary to aspiration pneumonia after a hyponatremic seizure. Postmortem revealed minimal residual pure germinoma, and evidence of ARDS directly resulting in the patient’s death.

Conclusions: Paclitaxel, gemcitabine, and oxaliplatin may be a promising alternative regimen in multiply recurrent CNS germinoma. Also, beta-hCG can be significantly elevated in cases of pathologically proven pure germinoma. This underlines the need for alternative tumor marker criteria in defining CNS germinomas.


K. Taomoto,1 Hideyiki Ohnishi,1 Masamitsu Nishihara,2 and Hideki Sawa3; Departments of Neurosurgery, 1Ohnishi Neurological Center, 2Hyogo Medical Center for Adults, and 3Miki Municipal Hospital, Akashi, Hyogo, Japan

Purpose: We analyzed 21 patients with intracranial germ cell tumors which we have treated from1987 through 2005 focusing on long-term outcome and QOL of patients.

Materials and methods: Twenty-one patients of intracranial GCTs, including 15 germinomas, 3 germinomas with STGC, 2 choriocarcinomas, and 1 embryonal carcinoma were neurologically, neuropathologically, neuroradiologically, and endocrinologically analyzed. The tumor marker (HCG) and cognitive function with the MMS or HDS-R were also examined. Median follow-up for surviving patients was 10 years.

Results: There were 16 males and 5 females (median age: 9 years). The location of tumors were eight pineal, four suprasellar, five suprasellar and pineal, one basal ganglia, and one subarachnoid dissemination. Five cases had positive tumor makers. Surgery included 4 subtotal resections, 17 partial resections, and 5 biopsies. Histologically, there were 11 pure germinomas, 3 germinomas with STGC, 2 choriocarcinomas, and 1 embryocarcinoma. Radiation therapy was done in all cases. Seventeen cases received chemotherapy including ICE in five malignant germinomas, PE or PVB in other cases. Complete response was obtained in all cases, but three cases recurred. Diabetes insipidus has continued for a long time in three suprasellar germinomas and one dissemination. The exercise ability deteriorated in four out of nine schoolchildren.

Conclusion: Although memory disturbance and therapeutic results has improved as well as long-term survival some outstanding cases of memory disturbance and difficult cases of social adaptation were recognized. It seems to be necessary in the future that precise study on an irradiation field and doses for protecting cognitive disorders.


J.R. Crawford and R.J. Packer; Children’s National Medical Center, Washington, DC, USA

Central nervous system germ cell tumor (CNSGCT) is a potentially curable childhood malignancy and early diagnosis may affect treatment. Twenty-nine consecutive patients with CNSGCT (72% male; mean age, 11.1 years; range, 6–17 years) were evaluated at our institution between 1990 and 2006. Duration of symptoms prior to diagnosis ranged from five days to three years (mean, 7.6 months). Tumor location included pineal (14), suprasellar (7), pineal/suprasellar (3), pineal/thalamic (4), and basal ganglionic/thalamic (2). Four patients had disseminated disease at the time of diagnosis. Features including headache, nausea, vomiting, and visual changes led to earlier diagnosis. However, nonspecific symptoms including movement disorders, nocturnal enuresis, anorexia, and psychiatric complaints resulted in significantly delayed diagnosis in 8 of 29 patients; diagnosed seven months to three years (mean, 21 months) from symptom onset. In six of eight patients with delayed diagnosis, nocturnal enuresis was present. Sixteen of 29 patients had signs of endocrine dysfunction at presentation. Ophthalmologic complaints were present in 13 of 29 patients. There was no correlation between disseminated disease and length of symptoms or overall survival. Noncontrast imaging (CT and MRI) failed to detect tumor in two patients. In three patients with atypical basal ganglionic/ temporal lobe, thalamic, or pineal/suprasellar signal abnormalities on MRI, neuroradiographic diagnosis was delayed. We conclude that diagnosis of CNSGCT is often delayed; presentation may include movement disorders or mimic psychiatric disease; and occasionally MRI interpretation is difficult, requiring serum/CSF markers and biopsy for diagnosis.


D. Perek, M. Drogosiewicz, B. Dembowska-Bagiñska, and M. Perek-Polnik; Department of Oncology, Children’s Memorial Health Institute, Warsaw, Poland

Purpose: CNS nongerminomatous germ cell tumors (NGGCTs) are sensitive to chemotherapy and radiotherapy. Both of these methods are included in the strategy of treatment. Due to late effects of radiotherapy reduced irradiation field in combination with cisplatinum based chemotherapy have been introduced in SIOP protocol. Our aim was to compare results of SIOP protocol with historical group of patients (pts) with CNS NGGCT.

Materials and methods: Twenty-one pts (15 boys and 6 girls, aged 5 years 10 months to 19 years 8 months [median, 11 years]) were treated between 1988–1996. In 12 pts tumor was located at pineal region, 7 suprasellar, and 2 had bifocal disease. Two pts had spinal dissemination. All pts had secreting GCT. Pts were divided into 2 groups according to treatment applied. Group I consisted of 7 pts treated from 1988 to 1996. Treatment was based on surgery followed by 3 courses of PVB and craniospinal irradiation. Group II consisted of 14 pts treated from 1996 to 2004. Chemotherapy according to SIOP protocol was followed by surgery and/or irradiation (focal or craniospinal in case of dissemination).

Results: Group I: 5 of 7 pts are alive with no tumor residual. Two pts died from disease. One with spinal dissemination 1 year 2 months from diagnosis and the other who had a primary total resection from local relapse 1 year 4 months from diagnosis. Group II: 11 of 14 pts are alive, two with residual tumor (<1 cm). Three pts died, all from disease. One with spinal dissemination 10 months from diagnosis, 2 from leptomeningeal disease 12 months from diagnosis, 3 from local relapse, and leptomeningeal spread 6 years 11 m from diagnosis. EFS in group I and II is 75 vs. 70 and OS is 85 vs. 72, respectively (no statistical significance)

Conclusions: Treatment of CNS NGGCTs according to SIOP protocol is safe and allows to limit radiotherapy field without jeopardizing final results. Supported by grant C028/P05/2002.


H. Sakamoto,1 S. Kitano,1 S. Kawahara,1 K. Yamagata,2 K. Yamanaka,2 Y. Iwai,2 and Y. Osugi3; Departments of 1Pediatric Neurosurgery, 2Neurosurgery, and 3Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan

Purpose: We retrospectively analyzed clinical characteristics and neuro-radiological findings of intracranial germ cell tumors (GCTs) in nonpineal regions.

Materials and methods: From 1994 to 2005, there were seven neurophophyseal GCTs (six germninomas and one choriocarcinoma, four boys and three girls) and four basal ganglia GCTs (two germinomas and two mixed germ cell tumors, three boys and one girl). Ages ranged from 6 to 15 years. All GCTs except for one (choriocarcinoma) were histologically verified by tumor removal or biopsy.

Results: All neurohypophyseal GCTs initially manifested diabetes insipidus (DI), followed by progressive dysfunction of the anterior pituitary. Period from onset to diagnosis was from 4 months to 56 months with a mean of 20 months. Two basal ganglia germinoma cases initially manifested hemiparesis_and involuntary movement, followed by progressive mental deterioration within six to eight months after onset. MRI at the early stage after onset showed a small lesion at the pituitary stalk in the neurohypohyseal GCTs and an infiltrative lesion without mass effect in basal ganglia germinomas. Two mixed GCTs in the basal ganglia developed hemiparesis and disturbed consciousness and showed a large mass on MRI. Patients were treated mainly by chemotherapy and local radiation. Two with mixed GCT expired within one year after diagnosis. The remaining nine patients who survived tumor free made no improvement in hormone deficiency of the anterior pituitary or mental deterioration after treatment.

Conclusion: To improve the quality of life, tumor biopsy or high sensitive tumor marker studies could be considered for earlier diagnosis of germinoma while the symptoms remain DI or hemiparesis without manifesting neuroradiological findings typical for germinoma.


T. Koga, T. Ochi, K. Ohashi, and M. Usui; Departments of Neurosurgery and Pathology, Toranomon Hospital, Tokyo, Japan

Germinomas affecting bilateral frontal lobes are rare. We report a case of young male diagnosed as germinoma with STGC, in whom the lesion was observed in the suprasellar region and frontal lobe parenchyma around lateral ventricles in the both sides. In the presented case, the frontal lobe lesions seemed as hemorrhagic cysts. Review of literature found a case of germinoma appeared as a frontal lobe cyst in one side. No case of germinoma with bilateral frontal lobe cystic lesions has been reported previously. Chemotherapy and radiation therapy was applied, and complete remission has been achieved. A 32-year-old man presented psychosis of a few months’ duration was taken to our hospital by ambulance because of an epilepsy attack. CT scan of the head was performed immediately, and massive hemorrhage in bilateral frontal lobes was revealed. Though it seemed as if it were brain contusion, there was no history of trauma, and further investigation was carried out. MRI showed a suprasellar enhanced lesion and hemorrhagic cysts in bilateral frontal lobes. The cyst wall of those frontal lobe lesions showed contrast enhancement. Open biopsy was performed and resulted in the diagnosis of germinoma with STGC. Spinal dissemination was also revealed by MRI of the spine. Whole-brain and spinal radiation therapy with a dose of 30 Gy with a 30-Gy boost delivered to the generous local field and 2 cycles of ICE (ifosfamide, 900 mg/m2; cisplatin, 20 mg/m2; and etoposide, 60 mg/m2 on days 1 to 5) yielded complete remission. Germinoma with STGC showed a unique radiological appearance was reported.


H. Takahashi,1 J. Yoshimura,1 K. Nishiyama,1 R. Tanaka,1 K. Usuda,2 M. Matsunaga,2 C. Imai,3 T. Kitajima3; 1Brain Research Institute, 2Section of NICU, 3Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan

Objective: Treatment of congenital immature teratoma has been rarely reported due to the high frequency of fetal and postnatal death. We have experienced the successful surgical resection and following chemotherapy for the baby with immature teratoma.

Case report: At 34 weeks of gestation, an intracranial mass with hydrocephalus was detected by ultrasound in the mother. Mass lesion in the third ventricle and lateral ventricle was confirmed by fetal MRI. A male neonate was delivered with good Apgar score. He weighed 3500 g and head circumference measured 39 cm. Subsequent examinations revealed large head (head circumference, 45 cm) and bulging fontanels on postnatal day 40. With right frontal craniotomy, large tumor was encountered and subtotal removal of tumor was performed. Histological examination revealed the diagnosis of immature teratoma. The patient received adjuvant chemotherapy with ICE and MTX. Now the follow-up period was 10 months. The patient showed developmental delay about six months. Follow-up MRI revealed no regrowth and no dissemination.

Conclusion: However the massive extension of congenital teratoma has made neurosurgeons hesitant to perform surgical resection, aggressive treatment should be tried for the patient with congenital teratoma. Our successful treatment owed to the cooperation with NICU team, neuroanesthesiologist, and pediatric oncologist.


M. Saino, S. Sato, K. Sakurada, W. Mori, A. Sato, and T. Kayama; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan

By application of novel treatment protocol with irradiation and multi-drug combination chemotherapy adopted Ifosfamide, Cisplatin, and Etoposide (ICE) or Carboplatin and Etoposide (CARB-VP) in Japan, treatment results of patients with CNS germ cell tumors were improving. But some tumors resisted these treatments. In the past 10 years, 21 patients with CNS germ cell tumors were treated in our institute. Nineteen of 21 cases were treated with surgery and following irradiation/chemotherapy (nine germinoma, five germinoma with STGC, one yolk sac tumor, one choriocarcinoma, one embryonal carcinoma, and two teratoma). The most part of these patients acquired excellent outcome, but dissemination arose in four cases (one germinoma, three germinoma with STGC). These cases tended to show complete remission after initial treatment, but then dissemination occurred and was thereafter exacerbated. Considering these clinical courses, we speculate that tumor stem cell potential is concerned the biological behavior of CNS germ cell tumors. Nestin is an intermediate filament protein expressed in undifferentiated cells during CNS development and in CNS tumors, and used as a marker of stem cell. We investigated the expression of Nestin in CNS germ cell tumors by immunohistochemistry. We report the results of Nestin expression and discuss the role of tumor stem cell in CNS germ cell tumors.


M. Firdaus, H. Mahyuddin, and S. Ashari; Department of Neurosurgery, Faculty of Medicine University of Indonesia, Jakarta, Indonesia

Introduction: We present an interesting case of teratoma in child with unusual imaging appearance. Teratomas usually do not enhance after contrast administration. Most have hyperintense components on T1-weighted MRI due to the presence of fat, and they often appear very heterogeneous on T2-weighted images. Intracranial germ cell tumors are heterogenous group of tumors which include germinomas, teratomas, embryonal cell, endodermal sinus (yolk sac), choriocarcinomas, dermoid, and epidermoid tumors. Intracranial germ cell tumors occur most frequently between ages 10–12 years, with 70% occuring between 10–21 years and before age 33. Teratoma greatest number in children less than nine years. The heterogeneous composition of teratoma is reflected in their radiographic appearance. In MRI can be irregular, contrast enhancement, heterogenous, or ring enhancing.

Case report: This six-year-old boy with chief complain headache, blurred vision, and hemiparese sinistra. From another institution referred by hydrocephalus with tumors at third ventricle region. T2-weighted MRI scans showed a large, hyperintense cystic tumor.

Conclusion: A diagnosis of teratoma should be considered for a lesion that can be shown to contain intratumoral cysts admixed with calcified regions and foci having the low signal attenuation characteristic fat.


K. Kurisu, F. Yamasaki, A. Tominaga, R. Hanaya, Y. Kajiwara, T. Saito, M.A. Thohar, and K. Sugiyama; Department of Neurosurgery, Hiroshima University Hospital, Hiroshima, Japan

Purpose: To determine if apparent diffusion coefficient (ADC) can be used to differentiate brain tumors at MRI.

Materials and methods: MRIs were reviewed retrospectively in 275 patients with brain tumors: 147 males and 128 females 1–81 years old, treated between 1997 and 2003. ROIs were placed manually in tumor regions on MRI, and ADC was calculated with a five-point regression method at b values of 0, 250, 500, 750, and 1000 s/mm2. All brain tumor subgroups were analyzed. Logistic discriminant analysis was performed by using ADC, age, and patient sex as independent variables to discriminate among tumor groups.

Results: A significant negative correlation existed between ADC and astrocytic tumors of WHO grades 2–4 (grade 2 vs. grades 3 and 4, accuracy, 91.3% [P < 0.01]; grade 3 vs. 4, accuracy, 82.4% [P < 0.01]). ADC of DNTs was higher than that of astrocytic grade 2 tumors (accuracy, 100%) and other glioneuronal tumors. ADC of malignant lymphomas was lower than that of glioblastomas and metastatic tumors (83.6%; P < 0.01). ADC of PNETs was lower than that of ependymomas (100%). ADC of meningiomas was lower than that of schwannomas (92.4%; P < 0.01). ADC of craniopharyngiomas was higher than that of pituitary adenomas (85.2%; P < 0.05). ADC of epidermoid tumors was lower than that of chordomas (100%). In meningiomas, ADC was not indicative of malignancy grade or histologic subtype.

Conclusion: ADC is useful for differentiation of some human brain tumors, particularly DNT, malignant lymphomas versus glioblastomas and metastatic tumors, and ependymomas versus PNETs.


J. Garvin,1 R.J. Komotar,1 B.E. Zacharia,1 J. Mocco,1 B.S. Carson,2 J.N. Bruce,1 T. Tihan,2 P.C. Burger,2 A.G. Khandji,1 and R.C.E. Anderson1; 1Columbia University and 2Johns Hopkins University, New York, NY, USA

Objective: Pilomyxoid astrocytoma (PMA) is a recently identified pediatric low-grade neoplasm that was previously classified as pilocytic astrocytoma (PA), yet demonstrates unique histological features and more aggressive behavior. These tumors have been shown to have significantly shorter progression-free and overall survival than classical low-grade astrocytomas, as well as a high rate of cerebrospinal fluid (CSF) dissemination. This paper describes the radiographic features of PMA in an attempt to differentiate it from PA.

Methods: MRI was obtained for 10 PMAs. Radiographic characteristics of the tumor were recorded in each case. All tissue samples were independently reviewed for confirmation of pathological diagnosis.

Results: All tumors appeared well-circumscribed with no evidence of peritumoral edema or parenchymal infiltration on MRI. All tumors except one originated from the midline of the neuraxis. Specifically, five tumors (50%) were located in the hypothalamic region, two (20%) were located in the spine, two (20%) were located in the dorsal brainstem, and one was located in the right thalamus. Five tumors (50%) demonstrated solid composition, with the remaining five showing some cystic components. Mass effect, hydrocephalus, and central necrosis were observed in 62.5%, 50%, and 0% of cases, respectively. Eight tumors (80%) were hyperintense on T1-weighted MRI. Seven tumors (77.8%) were hyperintense on T2-weighted MRI. All tumors were hyperintense on fluid-attenuated inversion recovery (FLAIR) sequence and negative on diffusion-weighted imaging (DWI). Upon contrast administration, six tumors (60%) enhanced heterogeneously and four tumors (40%) enhanced homogenously. These PMAs were compared with a group of 10 age-matched patients with PA.

Conclusion: Pilomyxoid astrocytoma is a well-circumscribed pediatric neoplasm that commonly originates from the midline of the neuraxis and lacks peritumoral edema or central necrosis. The radiographic characteristics are not sufficiently distinctive from those of pilocytic astrocytoma to allow preoperative differentiation of PMA from PA using MRI.


Y. Shibata, W. Katayama, I. Anno, H. Kawamura, and A. Matsumura; Department of Neurosurgery and Radiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

Choroid plexus papilloma is a rare intraventricular tumor. There are few reports of proton magnetic resonance spectroscopy (H-MRS) and thallium 201 (Tl)–technetium 99m methoxyisobutylisonitrile (MIBI) single-photon emission computed tomography (SPECT) findings of choroid plexus papilloma. We report a patient with choroids plexus papilloma with these neuroradiological findings. A one-year-old girl with an intraventricular tumor found incidentally was admitted to our hospital. Neurological and developmental tests found no abnormality. CT and MRI showed a homogeneously enhanced tumor in the left trigone. Perifocal edema was not found. The ventricle size was slightly large as one year old. MIBI and Tl SPECT showed early hot uptake and moderate washout in delayed images. Quantitative single- voxel H-MRS demonstrated an increase of choline and myoinositol and a decrease of N-acethylaspartate and creatine compared with normal brain tissue. The intraventricular tumor was completely removed using microsurgery. Pathological diagnosis of choroids plexus papilloma was confirmed. No residual tumor was found and the patient was discharged without any symptoms. She has been followed in out-patient clinic and no recurrence has been observed so far. H-MRS, Tl, and MIBI SPECT are valuable to differentiate and diagnose intraventricular tumor. Increased myoinositol in H-MRS, and the accumulation of MIBI tracer in normal choroid plexus and tumor were diagnostic findings of choroid plexus papilloma.


J. Kalapurakal, S. Goldman, V. Sathiaseelan, J. Hernandez, M. Marymont, A. Reitman, and T. Tomita; Children’s Memorial Hospital, Northwestern University, Chicago, IL, USA

Purpose: This report describes the acute histopathologic (H/P) changes observed following intraoperative radiation (IORT) in normal adult rabbit brains. This study is correlative for our ongoing phase I recurrent CNS tumor trial.

Methods: The photon radiosurgery sytem (PRS) probe was inserted into the right cerebrum to a depth of 2 mm. Interstitial IORT doses studied ranged from 10–22 Gy prescribed to a depth of 2 mm. The probe was also inserted into the left cerebrum to induce a control lesion without RT. A total of 23 rabbits were studied. They were sacrificed 1.5–26.0 weeks later (median, 5.5 weeks). The brains were dissected, sectioned, and stained with hematoxylin-eosin for histopathologic (H/P) evaluation.

Results: The H/P lesions following IORT were seen only in the right cerebrum. Following IORT, two different categories of H/P brain damage were observed: only destructive lesions in rabbits sacrificed < 9 weeks, and proliferative and destructive lesions with longer survival. The destructive lesions included fibrinoid necrotizing angiitis (FNA), coagulative radiation necrosis (CRN), and secondary partial necrosis (SPN). The destructive lesions were well circumscribed, cylindrical shaped, and localized to the area of IORT. After 10 Gy of IORT in three rabbits, only one showed CRN. However, following higher doses all animals showed varying degrees of FNA and CRN.

Conclusions: This study shows that H/P changes like FNA and CRN that were classically described as late-radiation effects could develop within weeks following IORT with PRS. The higher RBE of low-energy x-rays and the dose-in homogeneity of interstitial IORT could be contributing factors. These results confirm the good tolerance of IORT to a dose of 10 Gy observed in our clinical protocol.


H. Fuji,1 Y. Ishida,2 A. Nemoto,2 S. Murayama,1 M. Omura,4 K. Sekido,5 and Y. Nakasu3; 1Proton Therapy Division, 2Division of Pediatrics and 3Division of Neurosurgery, Shizuoka Cancer Center, and 4Departments of Radiology and 5Neurosurgery, Kanagawa Children’s Medical Center, Nagaizumi, Japan

Proton beam has distinct physical properties on energy deposition known as the Bragg peak. The depth-dose curve of the proton represents a gradual increase of deposited dose by the peak and sudden dropping off after the peak. For this feature, proton beam from one direction delivers maximal dose to the tumor in the body, while other conformal radiation techniques intensify the dose to the target by using a multidirectional beam. Less proton beam irradiation can be beneficial for the treatment of children with skull base or brain tumor because critical and long-term side effects would follow even with a modest dose of irradiation to developing tissue. Since March 2004, seven children patients with tumors underwent proton beam therapy at our institute. A 10-year-old boy with a spindle cell sarcoma involving frontal skull base was referred to us in May 2003. Extreme numbers of feeding arteries precluded surgical removal or embolization of arteries. Proton beam therapy of 50GyE in 25 fractions was employed to reduce the dose to the organs at risk (OAR) near the tumor. Two years after the treatment, tumor has not recurred on CT, MRI, and PET image. No apparent toxicity of the organs around the tumor was observed. The unique dose deposition of proton beam can reduce the normal organ damages in the treatment of childhood skull base tumor.


C. Alapetite,1,3 J.L. Habrand,2,3 G. Noel,3 C. Sainte-Rose,4 S. Puget,4 L. Feuvret,3 M. Zerah,4 C. Nauraye,3 A. Beaudre,2 G. Gaboriaud,1 N. Boddaert,4 J. Grill,2 F. Doz,1 and P. Bey1,3; 1Institut Curie, Paris, France, 2Institut Gustave Roussy, Villejuif, France, 3Institut Curie-Centre de Protontherapie, Orsay (ICPO), France, and 4Hopital Necker-Enfants Malades, Paris, France

Craniopharyngioma is associated with severe morbidity related to hypothalamic extension and surgical procedure. After incomplete resection, radiotherapy (RT) substantially reduces recurrence rate although its place is debated especially for younger children. Improving dose gradient with critical structures (optic pathway) and reducing developing brain dose exposure, proton therapy optimizes the therapeutic ratio. We report the ICPO experience for children. Since 1995, eight children were irradiated at relapse (5–12 years), after 1–4 surgeries (median, 3). Prior to RT all children had anterior-pituitary dysfunction and diabetes insipidus, and six suffered from obesity, hyperphagia, and/or behavioral disorders. They received a combined photon-proton RT delivering 55 CGE conventionally fractionated (median proton dose, 27 CGE) without anesthesia. Supratentorial parenchyma exposure was substantially lower compared with 3D conformational photon only RT. At a median post-RT follow-up at 35 months (range, 3–114 months), no relapse, no RT-related optic neuropathy, and no hypothalamic morbidity was observed. Since 2004, given the significant preexisting morbidity of an approach reserving RT for relapse, patients with intermediate-severe hypothalamic involvement at diagnostic MRI have limited surgery followed by proton therapy. Six children (range, 6–14 years of age) with no significant hypothalamic symptoms have received this conservative approach and are prospectively monitored, including neuropsychological evaluation. Preliminary results show reduced post-therapeutic hypothalamic morbidity. In parallel, technical improvements were achieved including reduced planning-target-volume and exclusive proton therapy, that compares favorably to intensity-modulated XRT. To preserve hypothalamic function, limited surgery followed by RT is a promising approach. Proton therapy optimizes dosimetric distribution, potentially reducing risks of late sequelae and second malignancies. Multidisciplinary long-term follow-up and prospective monitoring are needed to improve children adaptation and assess risk and benefit for disease control, long-term morbidity, and quality of life with this combined-modality strategy.


B. Wrede,1 T. Kutluk,2 and J. Wolff1,3; 1Pediatric Oncology, University of Regensburg, Regensburg, Germany, 2Hematology/Oncology, Ankara, Turkey, and 3Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Background: Despite increasing research interest, choroid plexus carcinomas still have a dismal prognosis. The role of surgery is well established. In regards to the role of irradiation for older children, the known data are still controversial. As for the role of chemotherapy, any discussion lacks sufficient supporting data.

Methods: A database of all cases of choroid plexus tumors (CPT) reported in the literature up to 2004 was created to analyze prognostic factors and different therapeutic modalities. A preexisting database of cases until 1997 was used to validate the data entry.

Results: Of 857 published cases (median age at diagnosis: 3 years), 347 were choroid plexus carcinoma (CPC), 15 atypical choroid plexus papilloma (APP), and 495 choroid plexus papilloma (CPP). The 5-, 10- and 20-year overall survival rates of all patients were 64%, 58%, and 47% respectively. Histology was a significant prognostic factor (P < 0.0001; log rank). Within the subgroup of patients with CPC, both surgery and irradiation were linked to a better prognosis (P < 0.005). The 104 CPC patients who received chemotherapy had a statistically better survival rate than those without chemotherapy (log-rank test, P < 0.001; Cox multivariate regression, P = 0.0001). When subgroups were analyzed, chemotherapy remained beneficial in the subgroup of nonirradiated tumors (P = 0.0001) and in the subgroup of patients with less than completely resected CPC (two-year overall survival 55% vs. 24%, P < 0.001).

Interpretation: Patients with less than completely resected choroid plexus carcinoma should receive chemotherapy. International trials are necessary to find out which chemotherapy is best. There is currently one open for international accrual: gro.nosrednadm@fflowj. Supported by Kinderkrebs Stiftung.


J. Wolff,1,2 B. Wrede,2 T. Hassal,3 T. Kutluk,4 D. Ellison,5 R. Kortmann,5 and J. Finlay6; 1Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 2Pediatric Oncology, University of Regensburg, Regensburg, Germany, 3Pediatric Oncology, University of Brisbane, Brisbane, Australia, 4Pediatric Oncology, University of Ankara, Ankara, Turkey, 5Radiation Oncology, University of Leipzig, Leipzig, Germany, and 6Pediatric Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Introduction: Choroid plexus tumors (CPT) are extremely rare. In 2000, we started an international registry for all CPT, and a randomized trial for those treated. The treatment protocol contains surgery, postoperative chemotherapy for all patients, six weeks delayed irradiation for those who are older than three years, and further chemotherapy. A total of six blocks of chemotherapy with VP16, 100 mg/m2 × 5 days, and VCR, 1.5 mg/m2, and either carboplatinum, 350 mg/m2 × 2 days, or cyclophosphamide, 1 g/m2 × 2 days.

Results: Seventy-five patients were registered from 15 nations: age 0–45 years, median 2.1 years, 40 males, 30 choroid plexus carcinoma (CPC), 18 atypical choroid plexus papilloma (APP), and 26 choroid plexus papilloma (CPP). Histology was a significant prognostic factor with only one death among CPP. Within the group of CPC patients, irradiation was linked to better overall survival (P < 0.03) and EFS (two-year EFS 87.5% ± 11.6 SD vs. 29.3% ± 15.8 SD; P < 0.01). Twenty-seven patients were treated according to the protocol. In a preliminary blinded evaluation, there was an incorrect impression of a significant difference between the two arms (two-year EFS 90.0% ± 9.4 SD vs. 40.9% ± 17.5 SD, P = 0.01). However, the data monitoring committee found an unequal distribution of patients who had received radiotherapy between the two therapy groups.

Conclusion: Irradiation improved survival, the randomization for the chemotherapy question will continue, modified now by a stratification, which ensures equal distribution of irradiated patients. More patients are needed to answer the question; therefore, the study is open for international accrual: gro.nosrednadm@fflowj. Supported by Kinderkrebs Stiftung, Germany.


S. Ghatan,1 J.H. Garvin,2 R.G. Ellenbogen,3 N. Gupta,4 M. Souweidane,5 J.R. Geyer,6 and N.A. Feldstein1; Departments of 1Neurological Surgery and 2Pediatrics, Columbia University and Morgan Stanley Children’s Hospital of New York Presbyterian, New York, NY, USA, Departments of 3Neurological Surgery and 6Pediatric Oncology, Children’s Hospital/University of Washington, Seattle, WA, USA, 4Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, USA, and 5Department of Neurological Surgery, Cornell University and New York Presbyterian Hospital, New York, NY, USA

Purpose: Choroid plexus carcinoma (CPC) has been associated with a poor prognosis in children. The purpose of this study was to review the treatment and outcome of children less than five years of age with CPC.

Methods: The medical records of all children with choroid plexus neoplasms who presented to New York Presbyterian Hospital, Seattle Children’s Hospital, and UCSF between 1994 and 2005 were reviewed.

Results: Of these 32 patients, 17 had histologically proven CPC, and 10 of these cases were in children less than five years of age (range, 2 days to 48 months; mean, 22 months). All 10 underwent surgery, and 9 received adjuvant chemotherapy. Seven patients had gross total resection (GTR) of their tumors, while two had subtotal resection (STR) with cytoreductive chemotherapy and “second look” surgery achieving GTR. One patient with tumor infiltrating the brainstem had STR followed by myeloablative chemotherapy with stem cell support, and had regression of residual disease on subsequent imaging. Three patients (all with GTR) had tumor recurrence, and were managed with reoperation and tailored radiation therapy (XRT). One neonate presenting in extremis with tumor hemorrhage had GTR but expired shortly after the operation. Eight of ten patients are alive and well with mean follow-up of 60 months (range, 36–130 months).

Conclusion: Relative to data from recent meta-analyses, our results suggest that the prognosis of young children with CPC may be improving. Adjuvant chemotherapy, second look surgery, and delayed XRT in young children may be associated with better outcomes.


R. Grundy,1 D. Machin,1 C. Weston,1 K. Robinson,1 M.A. Raquin,2 S. Rutkowski,3 and J. Grill2; 1United Kingdom Children’s Cancer Study Group, UK, 2French Society of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France, and 3German Pediatric Oncology Group, University of Wurzburg, Wurzburg, Germany

Purpose: The role of chemotherapy in the management of ependymoma remains controversial, as does the scheduling and choice of chemotherapeutic agents. We therefore conducted a meta analysis of the outcomes of major European studies which set out to to evaluate the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in young children.

Method: Between 1990 and 2004, 212 children (91 in France, 88 in the UK, and 33 in Germany) registered in national trials running in the respective countries. All were treated according to national protocol. Median age was 23 months; 83% had infratentorial disease. Surgical resection was complete in 50% of cases. One hundred twenty-five tumors (59%) were grade III, but marked differences in histological grade were apparent by country; 83% of SFOP cases were grade III compared to 18% of UK cases, with a median follow up of 3.6 years (range: 0.1 to 13.9). Overall (OS) and event-free (EFS) survival varied by country; at 5 years the OS in the UK was 59% compared to 48% in the SFOP series and 42% in the German HIT series. The EFS in the UK was 37% compared to 23% SFOP and 25% HIT. Adverse prognostic factors include younger age, infratentorial site, WHO III, and extent of surgical resection. Median time to an event was 1.7 years and the median age at RT 3.5 years (range: 0.5 to 12).

Conclusion: The choice of chemotherapeutic agents and schedule affects both OS and EFS in infant ependymoma. Radiotherapy is effective salvage therapy and can be delayed without compromising outcome.


S.N. Chi, M. Snuderl, U. DeGirolami, L. Goumnerova, A. Gordon, A. Thomas, C.D. Turner, M. Zimmerman, C. Chordas, N. Ullrich, and M.W. Kieran; Dana-Farber Cancer Institute and Children’s Hospital Boston, Boston, MA, USA

Background: The impact of the histological grade of ependymomas on prognosis has previously been considered but remains controversial. We now evaluate retrospectively the histologic grade and other histopathologic measures to determine their clinical correlation in children with ependymomas.

Patients and methods: Histopathological and medical chart reviews were performed of patients diagnosed with intracranial ependymoma seen at the DFCI/CH between 1984 and 1998 for which clinical data were available. Patients with subependymomas and myxopapillary ependymomas were excluded. With three neuropathologists examining, final grade (grade II or III) was determined by consensus based on WHO criteria. Other histopathological parameters, p53, Bcl-2, topo-Iia, and Cyclin D1 were also performed and correlated with clinical outcome.

Results: Among 38 children (age range: 0.5–18.3 years; median age: 3.5 years), there were 26 patients with infratentorial tumors, 11 with supratentorial tumors, one in both compartments, and two with dissemination at diagnosis. Twenty-five patients (66%) had grade II tumors, 12 of whom had gross total resections (GTR, 48%). Overall, 14 of 25 patients died with a median survival of 14.4 years. There were 13 patients (34%) with grade III tumors, 9 of whom had GTR (69%). Seven patients died with a median survival of 3.8 years (two patients, lost to follow-up). Of the 21 patients who had GTR, 14 remain with no evidence of disease (NED), while only 1 of 17 patients who had subtotal resection remains alive. Correlations between grade and immunohistochemical staining will also be presented.

Conclusions: Based on these results, histologic grade, classic versus anaplastic, did not correlate with outcome for patients with ependymoma. However, median survival times between patients with grade II and III tumors were significantly different. Known prognostics factors such as age and degree of surgical resection confirm historical experience. Novel histopathologic evaluations that further subtype tumors may elucidate potential clinical associations not previously appreciated.


S. Zacharoulis,1 L. Ji,1,9 I.F. Pollack,2 P.K. Duffner,3 J.R. Geyer,4 J. Grill,5 S.E. Schild,6 T.H. Jaing,7 M. Massimino,8 J.L. Finlay,1 and R. Sposto1,9; 1Children’s Hospital Los Angeles, Department od Pediatric Hemtology/Onology, 2Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Brain Tumor Center, Pittsburgh, PA, USA, 3Department of Neurology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA, 4Pediatric Oncology, Children’s Hospital/University of Washington, Seattle, WA, USA, 5Department de Cancerologie de l’Enfant et de l’Adolescent, Institut Gustave Roussy, Villejuif, France, 6Mayo Clinic Arizona, Department of Radiation Oncology, Scottsdale, AZ, USA, 7Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan, 8Pediatric Neuro-Oncology, Instituto Nazionale Tumori, Milan, Italy, and 9Department of Biostatistics, Los Angeles CA, USA

Purpose: To identify prognostic factors in children with ependymoma metastatic at diagnosis.

Methods: We were able to collect information of diagnosis, treatment, and follow-up for 40 patients from eight of the identified studies.

Results: Seventeen (43%) patients were under 24 months of age at the time of diagnosis; 28% were females, and 90% of the patients had posterior fossa tumors. Gross total resection (GTR) of the primary tumor was achieved in 16 patients (40%). Adjuvant therapy was variable and included craniospinal irradiation (CSRT), chemotherapy alone, or chemotherapy with focal irradiation. The five-year event-free survival (EFS) and overall survival (OS) from the time of diagnosis were 29% (±7%) and 43% (±8%), respectively. Age at diagnosis was found to have prognostic significance with five-year EFS and OS of 6% and 26%, 66% and 73%, and 27% and 36% for patients < 24, 24–36, and > 36 months old, respectively (P < 0.001 for EFS, and P = 0.01 for OS). Patients with GTR achieved a five-year EFS of 35% and OS of 59%, compared to a five-year EFS of 25% and OS of 32% for patients who did not achieve GTR (P = 0.12 for EFS; P = 0.03 for OS). Receiving CSRT at diagnosis produced a better EFS (50% vs. 18%; P = 0.07), but not a better OS (P = 0.58).

Conclusions: GTR of the primary tumor should be attempted in patients with metastatic ependymoma. The use of CSRT as adjuvant therapy is not associated with benefit in OS. A subgroup of young patients between 24–36 months of age at diagnosis might have a more favorable biology and outcome.


A.M. Donson, K. Sowar, S.O. Addo-Yobo, M.H. Handler, L. Gore, and N.K. Foreman; University of Colorado Health Sciences Center and Denver Children’s Hospital, Denver, CO, USA

Ependymomas account for 6%–12% of all pediatric intracranial tumors. Despite complete resection and radiation, about 50% of patients relapse and have subsequent dismal prognoses. As no clinical findings reliably forecast tumor recurrence, we sought to determine if gene expression profiling could be used to distinguish patients at high risk for relapse at initial diagnosis, and thereby make them candidates for innovative treatments at an early stage. We extracted RNA from 13 ependymoma specimens: seven from patients who experienced tumor recurrence, and six from patients who have not recurred. RNA was applied to Affymetrix HG-U133 plus 2.0 microarray chips, and microarrays were analyzed with GeneSpring 7.0 and Prediction Analysis of Microarrays (PAM) software. The three-gene subset of PLEK (pleckstrin), NF-kB2 (nuclear factor kappa beta-2), and LOC374491 (TPTE and PTEN homologous inositol phosphatase pseudogene) was identified as the minimal subset capable of accurately distinguishing tumors according to recurrence. In summary, gene expression profiling may be valuable, perhaps in combination with clinical findings identified in some studies, for identifying children at high risk for ependymoma relapse.


M. Snuderl, S.N. Chi, J.A. Chan, M. Hladikova, M.A. Rubin, M.W. Kieran, and K.L. Ligon; Children’s Hospital Boston, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA

Background: Histopathologic prediction of clinical outcome for pediatric intracranial ependymomas is unreliable. Cell cycle marker expression has been extensively analyzed while developmental lineage specific markers have been less well studied. The oligodendroglial lineage marker OLIG2 has recently been shown to be expressed in subsets of ependymomas. We performed an immunohistochemical study of OLIG2 expression in clinically annotated tissue microarrays of 32 pediatric primary intracranial ependymomas.

Patients and methods: Pediatric ependymoma samples from the archives and clinical records of the Children’s Hospital Boston from 1972 to 2002 were analyzed. Tissue microarrays were constructed by the BWH/DFCI Tissue Microarray Core using 4 × 0.6-mm core samples from each block according to standard protocols.

Results: Most tumors exhibited little to no expression of OLIG2, 84% having < 5% of cells positive. Higher OLIG2 expression in grade 2 (mean score = 1) vs. grade 3 tumors (mean score = 0.44) was noted, but these differences did not reach statistical significance (P = 0.043). No correlation of OLIG2 expression to particular histologic subtypes of ependymoma was noted. Clear cell ependymomas, with numerous oligodendroglial areas, did not have noticeably higher OLIG2. Correlation of OLIG2 expression with the expression of Ki67, p53, cyclinD1, Bcl-2, and topoisomerase II alpha failed to detect any statistically significant associations. While the difference in mean progression-free survival (PFS) for the OLIG2– (113 months) and OLIG2+ (55 months) patients was not statistically significant (P = 0.15), there was a trend toward decreased PFS in OLIG2+ patients. No differences were noted in overall survival (OS) between the two groups (OLIG2–, 123 months; OLIG2+, 99 months; P = 0.74). A comparison of dead vs. surviving patients showed no correlation with OLIG2 expression.

Conclusions: OLIG2 is commonly expressed at low levels in pediatric ependymomas and is wide ranging in all grades of ependymoma. OLIG2 expression may be associated with decreased PFS but is not significantly correlated with OS.


D. Perek,1 B. Dembowska-Bagiñska,1 M. Perek-Polnik,1 I. Filipek,1 M. Drogosiewicz,1 E. Jurkiewicz,2 A. Koœciesza,2 S. Barszcz,3 and W. Grajkowska4; Departrments of 1Oncology, 2Radiology, 3Neurosurgery, and 4Pathology, Children’s Memorial Health Institute, Warsaw, Poland

Background: Effectiveness of chemotherapy in ependymoma remains controversial. Some authors question sensitivity to cytostatics in these tumors. The aim of our study was to evaluate the effect of chemotherapy in measurable and (in case of dissemination) visible disease.

Patients and methods: Twenty-three patients, aged 1 year 5 months to 17 years 7 months (median, 5 years 5 months) were evaluated. Fourteen patients had anaplastic, and 9 classic ependymoma. Ten patients had local relapses and 3 dissemination, 8 residual disease, 3 progression of residual disease, 1 residual tumor and dissemination, and 1 dissemination alone. Seven out of eight patients with residual disease were under three years of age and treated with chemotherapy alone. Protocols of chemotherapy applied will be presented. Response to chemotherapy was assessed using common response criteria and correlated with histological subtype. None of the children were irradiated during response assesssment.

Results: CR was achieved in two patients, PR and MR in 11. Tumor reduction ranged from 21% to 100%. Among 13 patients with CR, PR, and MR, 10 had anaplastic ependymoma. SD was observed in five patients: four anaplastic and one classic ependymoma. Five patients had PD. Duration of remissions for CR was six years and eight months and two years and six months and for PR and MR from 3 to 35 months. Stabilization lasted from 2 to 18 months. Out of 23 patients, 6 are alive, and two are disease free, 2 years 10 months and 7 years 8 months from diagnosis. Four patients are alive with disease 15 months to 4 years 5 months from diagnosis. Most responses (42.8%) were obtained using chemotherapy containing Ifosfamide.

Conclusions: Best responses were observed in anaplastic ependymoma but were also seen in the classic type. This indicates that chemotherapy should be incorporated in the treatment in this disease. This work was supported by grant C028/P05/2002.


M. Hishii,1 M. Miyajima,2 H. Ishii,2 H. Nakanishi,2 and H. Arai2; 1Department of Neurosurgery, Juntendo University Nerima Hospital, Tokyo, Japan, and 2Department of Neurosurgery, Juntendo University Hospital, Tokyo, Japan

Childhood ependymomas remain a highly problematic group of tumors to treat. The most consistent prognostic factor for cure has been the extent of surgical resection. Radiotherapy is considered the standard adjuvant treatment, although the exact role of radiotherapy is poorly defined. We report the case of a 10-year-old boy with disseminated intracranial ependymoma who received radiotherapy. This boy presented with nausea, headache, and double vision at the age of eight years. MR imaging demonstrated a heterogeneous tumor in the fourth ventricle. Subtotal removal of the tumor was performed. Minimal residue was left attached to the medulla oblongata. The histological diagnosis was ependymoma. The post operative course was uneventful, and no adjuvant therapy was administered. One year later, brain MRI showed local recurrence and intracranial dissemination. In the follow-up, he had two partial reexcisions due to clinical deterioration and progression of the lesion on MRIs. He received radiotherapy following the third surgery. Delivered dose was 46 Gy to the whole brain and 60 Gy to the enhanced lesion in the posterior fossa and the third ventricle. His cerebellar ataxia improved during radiotherapy. MR imaging obtained after radiotherapy demonstrated that the disseminated tumor had almost disappeared. This case showed effectiveness of the radiotherapy for disseminated ependymoma. In this report, we discuss the role of radiotherapy for ependymomas.


A. Fernández-Teijeiro and A. Navajas, on behalf of CNS Tumors Committee of Sociedad Española de Oncología Pediátrica (SEOP); Pediatric Oncolgy Unit, Hospital de Cruces-Bilbao, Spain

Background: To avoid morbidity derived from radiation therapy (RT) in children under three years of age with brain tumors, from June 1992 to February 2001 SEOP developed a protocol consisting on six courses of chemotherapy (CT), including four pairs of drugs administered consecutively every three weeks. RT was retained for those patients with stable disease (SD) during or after CT but older than age three, or for those with progressive disease (PD) or relapse. Our objective was to analyze long-term survival and sequelae five years after study close.

Methods: Data collection of patients from collaborating hospitals and follow-up sheets for sequelae. Statistical analysis and Kaplan-Meier survival test.

Results: A total of 53 patients were registered: 30 boys and 23 girls (median age, 19.6 months [range, 2–34 months]); 15 patients were less than one year old. There were 42 evaluable patients (11 patients less than one year old), with 11 patients out of protocol. Tumor locations: 25 (60%) infratentorial and 17 (40%) supratentorial. Disseminated disease was present in 12 of 42 (29%) patients. Total resection was achieved in 12 (29%). Main histologic diagnoses were medulloblastoma (13), ependymoma (9), PNET (6), high-grade glioma (5), and glioblastoma (4). RT was administered in 13 patients: two at three years of age, six after relapse, four because of PD, and one over tumor rest after CT completion. With a mean follow-up of 64 months, overall survival (OS) and event-free survival (EFS) are 50% and 38%, respectively, at five years. OS is lower for patients under one year of age and for those with medulloblastoma. Reported sequelae are endocrine and neuropsycological impairment mainly in children who received RT.

Comments: OS in our series is 50% with a low EFS under 40%. Prolonged CT strategy avoids or delays RT in younger children. Relevant sequelae are mainly observed in those survivors who received RT. International strategies would be desirable in order to improve survival with minimal sequelae, especially in babies and in patients with medulloblastoma.


M. Nonaka, S. Moriuchi, Y. Kanemura, T. Yamanaka, J. Yamada, N. Kagawa, and M. Yamasaki; Department of Neurosurgery, Osaka National Hospital National Hospital Organization, Osaka, Japan

Objectives: Brain tumors during the first year of life are extremely rare, affecting 1.1 in every 100,000 live or stillborn infant, and referred to as infantile brain tumors. We summarize our experience with 11 patients with infantile brain tumors and discuss their clinical features.

Materials and methods: From 1988 to 2005, we encountered 11 patients with infantile brain tumors. The initial diagnosis was made in utero in three patients, two months postnatal in two, four months in four, eight months in one, and 11 months in one. The seven patients were comatose at the time of diagnosis. All had increased intracranial pressure and revealed marked ventricular dilatation. Location of the tumors was supratentorial intraventricle in five, supratentorial cortex in one, pineal regions in two, and posterior fossa in three cases. Emergency decompression, including ventricular drainage and tumor removal, was required in seven cases.

Results: Histological diagnosis of the patients included three teratomas, two choroid plexus papillomas, two pineoblastomas, one ependymoma, one primitive neuroectodermal tumor, one desmoplastic infantile astrocytoma, and one cavernous angioma. Six patients are dead, and others are alive with severe developmental delay in one, mild developmental delay in three, and completely normal in one case.

Conclusion: Although prognosis of most infantile brain tumors appears to be poor, there are some cases that recover to normal after treatment. Immediate diagnosis and appropriate treatment strategies may improve the prognosis of infantile brain tumor.


K. Niizuma, T. Kumabe, R. Saito, M. Kanamori, R. Shirane, and T. Tomonaga; Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan

Purpose: For very young children, there is particular concern regarding heightened somatic and nervous system toxicities, including neurocognitive deficits associated with craniospinal irradiation. We evaluated the feasibility of giving preradiation chemotherapy to children younger than three years of age with malignant brain tumor.

Materials and methods: Between October 1996 and July 2005, 10 consecutive patients (age range, 1–29 months) with malignant brain tumors were enrolled. Mean follow-up is 62.1 months, with a range of 3–111 months. Four tumors were diagnosed as medulloblastoma, two as anaplastic ependymoma, one as anaplastic pilocytic astrocytoma, one as primitive neuroectdermal tumor, one as anaplastic astrocytoma, and one as immature teratoma. After surgical resection, patients received three courses of intensive chemotherapy using ifosfamide, cisplatin, and etoposide (ICE) or cisplatin and etoposide (PE), followed by maintenance chemotherapy using ICE or PE every three months until the patients reached three years of age. After the patients were three years old, 24 Gy of craniospinal irradiation and 24–30 Gy of local brain irradiation were administered. Additional salvage surgery was performed on two patients.

Results: The estimated 48 months of progression-free and overall survival rates among the 10 children were 46% and 90%, respectively. Nine patients remain alive and independent in activities of daily living. Three patients belong to special classes because of neurocognitive deficits. One patient died during initial chemotherapy because of complications with severe myelosuppression.

Conclusions: Preradiation chemotherapy could delay the start of craniospinal irradiation in children younger than three years of age with malignant brain tumor and avoid decisive damage.


D. Perek,1 B. Dembowska-Bagiñska,1 A. Broz yna,1 M. Perek-Polnik,1 and E. Jurkiewicz2; Departrments of 1Oncology and 2Radiology, Children’s Memorial Health Institute, Warsaw, Poland

Background: Malignant brain tumors in newborns are a rare entity. Our aim was to present our experience with congenital malignant brain tumors treated in our department.

Materials and methods: Retrospective analysis was performed on seven patients (three girls and four boys; age range, one day to three months; median, six weeks) treated between 1999 and 2005 in our department. Assessment concerned first symptoms, tumor types, their localization, treatment outcome, and tolerance of chemotherapy.

Results: Tumors in two patients were diagnosed prenataly. Seven patients had a hydrocephalus; two vomiting, two nystagmus, one squint, and one hemiparesis. Two patients had malignant teratomas, one desmoplastic infantile astrocytoma, one medulloblastoma, one PNET, one oligodendroglioma, and one glioblastoma multiforme. Three tumors were located in the brain lobes, one in the brain lobe and midline, two in the third ventricle, and one in posterior fossa with involvement of midline. Surgery (three total, one subtotal resections) was performed in four patients: one glioblastoma, one desmoplastic infantile astrocytoma, one malignant teratoma, and one oligodendroglioma. Three patients had biopsy only. Six out of seven patients received chemotherapy according to protocol for children under three years of age. Four out of seven patients are alive and three disease-free at nine months, one year and six months, and six years and five months from diagnosis; one with disease one year and one month from diagnosis. Three patients died of disease (malignant teratoma, PNET, oligodendroglioma) two months, three months, and one year and four months from diagnosis. Tolerance of chemotherapy was acceptable. There were no deaths related to treatment.

Conclusions: Congenital brain tumors represent a wide spectrum. Despite young age and immaturity of organs chemotherapy in such young babies can be administered. Supported by grant C028/P05/2002.


K. Yoshida, K. Sato, T. Kubota, R. Kitai, and T. Nakajima; Department of Neurosurgery, Faculty of Medicine, Fukui University, Fukui, Japan

Choroid plexus tumors are relatively uncommon intraventricular neoplasms of neuroectodermal origin, accounting for less than 1% of all intracranial tumors. Most cases occur in children under two years of age. Choroid plexus carcinoma (CPC) is even rarer, representing no more than 25% of all plexus tumors. In spite of temporary improvement brought about by surgery, chemotherapy and even radiotherapy, CPC generally has a grave prognosis. Some choroid plexus tumors are rarely associated with adrenal tumors. We report on a case of CPC in a 20-month-old girl who presented with vomiting and hemiparesis, and who four months later underwent premature puberty caused by adrenocortical adenoma. Although CPC of large size in the lateral ventricle was totally removed, leptomeningeal metastases occurred five months later. The intracranial lesion regressed with radiation therapy and chemotherapy. The adrenal tumor was entirely resected, resulting in resolution of the symptoms. Molecular examinations of tissues from the brain tumor, adrenal tumor, and her blood WBC were performed for known p53 gene mutations. Using PCR-direct sequencing, no mutation was detected in any of the DNA samples (exons 4–9) extracted from the specimens, but the infant with no known family history of cancers may have genetic predispositions toward malignancy.


M. Nagane, T. Yoneyama, T. Mizutani, R. Yuyama, M. Ishii, H. Yoshino, F. Bessho, Y. Fujioka, and Y. Shiokawa; Departments of Neurosurgery, Pediatrics, and Pathology, Kyorin University School of Medicine, Tokyo, Japan, and Department of Neurosurgery, Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan

Ewing’s sarcoma (ES) predominantly affects bones and soft tissues in the extremities and body trunk of adolescents, and scarcely occurs intracranially. Here we present a 15-year-old girl having a large tumor in the middle cranial fossa which medially compressed the left temporal lobe. The patient noticed multiple cervical subcutaneous masses at the age of 10, which regressed spontaneously. Four years later, she suffered from left otitis media for two months and referred to Fuchu Municipal Hospital, when she underwent tympanostomy and had headache, fever, and vomiting. On admission, she was conscious without paresis, but presented anisocoria and left with hearing disturbance. Neuroradiological images demonstrated a huge heterogeneously contrast-enhanced mass with calcification occupying almost the entire left middle fossa with destruction of the temporal bone. She underwent craniotomy for subtotal removal of the tumor. Histopathologically, the tumor was mainly composed of small round cells, which were positive for vimentin, chromogranin A, S-100, and CD99/MIC2, but were negative for epithelial or lymphocytic markers. RT-PCR analysis of the resected tumor tissue demonstrated presence of transcripts of the EWS/FLI1 fusion gene, leading to a diagnosis of Ewing’s sarcoma. Postoperatively, she was transferred to Kyorin University Hospital, where she received an intensive standard chemotherapy for ES consisting of three drugs of vincristine, doxorubicin, and cyclophosphamide in alternation with courses of ifosfamide and etoposide, resulting in stable disease with no neurological deficits. Application of CD99 immunohistochemistry and specific detection of the EWS/FLLI1 gene should be considered against atypical intracranial tumor, which might lead to appropriate selection of therapeutic regimens.


A. Fernández-Teijeiro, J. Prats, J. Aurrecoechea, B. Mateos, I. Astigarraga, and A. Navajas; Pediatric Oncology Unit, Pediatric Neurology Unit, Neurosurgery Department, Neuroradiology Unit, Hospital de Cruces-Bilbao, Spain

Dysembryoplastic neuroepithelial tumors (DNET) are benign cortical lesions mainly located in the supratentorial cortex, usually presenting with intractable seizures. The presence of partial seizures with a normal neurological exam and typical features on MRI allow to establish the diagnosis. In most cases, total or partial resection achieves seizure control while avoiding long-term complications. However, when the tumor is located in an eloquent area, a conservative approach is appropriate. A five-year-old girl was admitted with mild headache and recurrent motor seizures on the right limbs. She developed dizziness and unstable gait over the prior month. Neurological examination, including funduscupy, was normal. Contrast-enhanced CT showed a low-density, nonenhancing left supratentorial lesion with slight medium-line shift, without perilesional oedema. MRI revealed a left frontoparietal infiltrative lesion, highly suggestive of DNET. EEG showed intense left hemysphere activity, mainly in the temporal lobe area. Complete seizure control was achieved with carbamazepine. A conservative approach was decided considering the difficulty of a complete resection together with the absence of neurological impairment and complete seizure control. Biopsy was ruled out, since it can be misleading due to the histological heterogeneity of these tumors. MRI at three months showed no changes from previous MRI. She remains asymptomatic, after three years of follow-up, on anticonvulsant therapy. Although early resection would be the treatment of choice when DNET is suspected on MRI, those cases with high risk of severe sequelae can benefit from a conservative approach, keeping surgery for those with refractory epilepsy or when significant mass growth is observed.


C. Tanaka,1 K. Okada,1 Y.D. Park,1 Y. Osugi,1 S. Kitano,2 H. Sakamoto,2 and J. Hara1; 1Department of Pediatric Hematology and Oncology and 2Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan

Introduction: In children, central neurocytoma is an extremely rare disease. Most cases were reported to be histologically and clinically benign. Recently, several cases with recurrence and therapy resistance have been described. We experienced two cases of central neurocytoma with therapy resistance. We describe the progress and the efficiency of each therapy.

Cases: The first case is a seven-year-old girl with a tumor near the right ventral horn and meningial dissemination. The second case is a 12-year-old girl with a tumor near the right thalamus. In these cases, tumor subtotal resection was performed, and the tumor was diagnosed as central neurocytoma. In case 1, 18 Gy of irradiation was delivered to the whole brain and spinal axis. In case 2, 50 Gy of local irradiation was delivered. Chemotherapy (cisplatin, VP-16, cyclophosphamide, and carboplatin) was administered in both cases, and additional high-dose chemotherapy (thio-tepa and melphalan) was administered in case 1. In case 1, once the tumor was reduced, regrowth occurred and she finally died. In case 2, the treatments were not effective at all, but nimustine hydrochloride stabilized her tumor.

Discussion: In case 1, chemotherapy was only temporarily effective. In case 2, chemotherapy was not effective, but nimustine hydrochloride was effective. Radiation was not effective in either case. Optimal treatment should be developed.


K. Sakurada, S. Sato, M. Akasaka, M. Saino, W. Mori, A. Sato, and T. Kayama; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan

Objective: Pituitary adenomas are rare in the adolescence population, and account for approximately 2.7% of all supratentprial tumors in childhood and 3.5%–6.0% of all surgically treated pituitary adenomas at all ages. We investigated the endocrinological profile, radiological findings and clinical presentation of pituitary adenoma in adolescence in our clinic cases.

Patients: In the past 10 years, we treated 10 cases of pituitary adenomas in adolescences, whose ages at the time of onset were under 18 years old. All cases was operated and diagnosed histologically.

Results: Five cases (50%) were nonfunctioning adenoma, two cases (20%) were prolactin (PRL)-secreting adenoma, two cases (20%) were adenocorticotropic hormone (ACTH)–secreting adenoma, and one case (10%) was growth hormone (GH)–secreting adenoma. Radiological findings suggested that the suprasella extension was conspicuous in nonfunctioning adenoma and the shape of the sella turcica was not changed. Intratumoral bleeding was observed in nine cases (90%).

Conclusion: Pituitary adenomas in adolescense has clinical characteristic figures, whitch shows the higher incidence of nonfunctioning adenoma and intratumoral bleeding, and lower incidence of enlargement of Sella Turucica than previous caucasian reports.


M. Perek-Polnik,1 I. Filipek,1 B. Dembowska-Bagiñska,1 M. Drogosiewicz,1 E. Jurkiewicz,2 and D. Perek1; Departments of 1Oncology and 2Radiology, Children’s Memorial Health Institute, Warsaw, Poland

Aim: To analyze types of disorders in pediatric population of NF1 patients treated in the Children’s Memorial Health Institute and to present schedule of care adopted in our institution.

Materials and methods: Medical records of 130 children, (70 girls, 60 boys) were analyzed. Type of mutation (familial or sporadic), age at diagnosis, and type and frequency of disorders in the whole group of patients and in the familial and sporadic types were assessed.

Results: The familial type of NF 1 was found in 58 patients, sporadic in 40, and in 32 the type of mutation is unknown. The age at diagnosis ranged from 3 months to 17 years (median, 6 years). The most frequent disorders were: T2-weighted hyperintensities of the white matter in 59%, schooling problems in 46%, and skeletal deformations in 37%. There was a correlation between white matter hyperintensities and the optic nerve gliomas (71%), schooling problems (58%), hyperactivity (77%) and dysartria (85%). In 53% optic nerve gliomas were found, 45 patients required treatment. Plexiforme neurofibroma requiring treatment was found in 19%. Malignant tumors were found in 7 patients (5%). Skeletal disorders occurred more frequently in sporadic type (P = 0.05). A schedule of care at the time of diagnosis includes examination by oncologist, neurologist, ophthalmologist, geneticist, and additional studies: abdominal ultrasound, chest x-rays, MR of the brain; disorders found indicate further consultations and studies. The checkup should be repeated annually and include all previous studies that revealed any abnormalities.

Conclusions: Diagnosis of NF 1 is delayed until complications of the disease occur. In the studied group skeletal disorders were more frequent in the sporadic type. The pediatric population with NF1 varies from the adult patients in type of disorders and diagnostic and treatment requirements. Therefore there is a need for different care standards. Supported by grant C028/P05/2002.


D.A.Walker; Children’s Brain Tumour Research Centre, School of Human Development, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK

Clinical trial organizations have identified CNS tumor groups/committees and formed consortia which has resulted in measurable improvements in survival for children with CNS tumors over the past decade, internationally. The oncologists with their organizational infrastructure promoted trials, while clinicians with neuroscience expertise have brought the added value of neurology, neuroimaging, neuropathology, and neurosurgery, thereby interpreting the facts of tumor behavior for the neural environment in which the tumors grow, leading initially to diagnosis and then to specific approaches to treatment and clinical evaluation. There are a number of new clinical and scientific developments that will shape priorities for designing clinical trials in the next five years. They will be driven by enhanced scientific understanding of mediators of surgical and radiotherapy brain injury and their inhibition, prophylactic and specific treatment of leptomeningeal tumor dissemination with less toxic therapy, overcoming primary drug resistance in ependymal and glial tumors, studying patients within trials designed to measure reductions in brain injury as their primary purpose, and translation of the emerging and remarkable success story of clinical pediatric neuro-oncology into adolescent and young adult practice. To achieve these goals pediatric neuro-oncologists will have to enhance collaboration with neuroscientists, rethink their practices in CSF drug delivery, focus on the new biologic information emerging from gene screening of resistant tumors, consider QoL outcomes as primary measures of treatment success, and forge working relationships with adult neuro-oncology specialists to ensure that the current generation of neural tumor survivors are carefully considered, as new problems emerge in their adult lives. These factors will change clinical and trials’ practice in neuro-oncology, leading us further into the applied fields of clinical and scientific neuroscience.


E. Bouffet, A.S. Carret, B. Crooks, J. Hukin, D. Eisenstat, B. Wilson, I. Odame, S. Zelcer, D. Johnston, M. Silva, C. Mpofu, Y. Samson, J. Brossart, A. Moghrabi, and D. Strother, on behalf of the CPBTC

Background: Cooperation requires communication between institutions, which is limited by financial resources (to travel) and availability (time to travel). Teleconferencing can overcome these limitations.

Methods: The CPBTC is a group of 17 tertiary care Canadian centers involved in the development and conduct of studies related to pediatric brain tumors. Members of this group instituted in 2002 a bimonthly brain tumor round using teleconferencing, in order to facilitate cooperative development.

Results: Between December 2002 and June 2005, 27 conferences took place. Conferences were held bimonthly initially and then monthly since 2004. Each conference last 1 h and is held at 2:00 PM Eastern time in order to accommodate the time difference between institutions in Canada (4:30 time difference coast to coast). five institutions joined the initial conferences. The number of participating institutions increased steadily during the first year and ranged between 11 and 15 in 2004–2005. Ten institutions attended ≥ 75% of the conferences in 2004–2005, and 21 different proposals were discussed during this period, including 12 retrospective studies, 4 prospective studies, and 6 clinical trials. In addition specific organizational issues were discussed (such as cost of clinical trials across institutions, differences in REB approval) in order to facilitate participation in cooperative studies. The PBTC successfully completed six studies, which were presented at national/international meetings, had two peer-review publications in 2005 and three manuscripts submitted.

Conclusions: Teleconferencing is a new tool, which can facilitate communication and cooperation between institutions. This experience demonstrates the feasibility of national studies using these services.


I. Qaddoumi,1 A. Mansour,2 A. Musharbash,3 J. Drake,4 M. Sweedan,5 D. Odeh,6 M. Qudamat,7 and E. Bouffet8; 1–3, 5–7Departments of Pediatrics, Radiology, Surgery, and Nursing, KHCC, Amman, Jordan, and 4,8Division of Neurosurgery and Division of Pediatric Oncology/Haematology, HSC, Toronto, Canada

Background: Twinning between a well-established individual institution and a pediatric cancer unit in a developing country (DC) has essentially been described in the context of childhood leukemia. These programs have demonstrated significant impact on survival and have led to improvement in access to treatment. Pediatric neurooncology is barely recognized in the majority of DC, despite the presence of oncology, radiation oncology and neurosurgery services in most DC. Herein we share our experience in videoconference as one aspect of the twinning and telemedicine initiative in pediatric neurooncology.

Methods: A laptop, an EMLO visual presenter HV-7600SX document camera, and a TANDBERG 6000 model videoconference unit where used to present data. For connectivity we used a six-channel ISDN telephone line. Each channel is 64 mega bit per second. Conferences were held at 3:00 PM in Amman, in order to accommodate the time difference between institutions (7 h).

Results: From December 2004 till December 2005, 15 one-hour videoconferences were held to discuss 46 cases of 43 patients (3 patients were discussed twice). Ten patients were non-Jordanians. Diagnoses were 13 low-grade glioma, 8 high-grade glioma, 5 medulloblastoma, 3 sPNET, 3 ependymoma, 2 germ cell tumors, 2 brainstem tumors, and 7 various diagnoses. In 14 patients (32%) major changes from original plans were recommended on different aspects of patients care. In 11 patients (78%) those recommendations were followed, with significant positive impact on patients’ care.

Conclusions: Clinical telemedicine in pediatric neurooncology is technically achievable at an affordable cost. Such initiative proves to have a major positive impact on patients care and on families. It also provides a model of promotion of pediatric neurooncology in DC.

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press