Roujeau T, Di Rocco F, Dufour C, et al.
Shall we treat hydrocephalus associated to brain stem glioma in children?
Childs Nerv Syst. 2011; 27(10):1735-9 [PubMed]

PURPOSE/METHOD: Brain stem glioma accounts for 6-9% of brain tumors in children. Tumor progression may lead to CSF pathway obstruction and development of hydrocephalus. We retrospectively reviewed charts of patients consecutively treated in our institution with diffuse intrinsic pontine glioma in order to assess incidence of hydrocephalus, its management, and its impact on overall survival. All patients had brain stem glioma not amenable to surgery. Cases with exophytic brain stem glioma were excluded.
RESULTS: Fifty-one children were treated from January 2005 to December 2010 for brain stem glioma in the Pediatric Neurosurgery Department of Necker Enfants Malades, Paris, France. Hydrocephalus occurred in 11 of them (22%). They were six boys and five girls; the average and median time from tumor diagnosis to onset of hydrocephalus were 5.3 and 3.2 months, respectively, while average and median time from onset of hydrocephalus to death were 5.3 and 2.8 months, respectively. Hydrocephalus was treated in nine patients by a ventriculoperitoneal (VP) shunt and in two patients by an endoscopic third ventriculostomy. Because of early failure, a VP shunt was implanted in one child.
CONCLUSION: The overall 1-year survival rate was 33%. Survival rate of patients with such obstructive hydrocephalus was not significantly different from patients harboring brain stem glioma who did not develop hydrocephalus. Furthermore, hydrocephalus was not related to terminal tumor progression. Considering both risks and benefit of treatment, VP shunt could be proposed, on the base of our experience, as the first option in spite of the apparently obstructive nature of the hydrocephalus associated to a brain stem tumor.

Zukotynski KA, Fahey FH, Kocak M, et al.
Evaluation of 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: a report from the Pediatric Brain Tumor Consortium.
J Nucl Med. 2011; 52(2):188-95 [PubMed] Free Access to Full Article

UNLABELLED: The purpose of this study was to assess (18)F-FDG uptake in children with a newly diagnosed diffuse intrinsic brain stem glioma (BSG) and to investigate associations with progression-free survival (PFS), overall survival (OS), and MRI indices.
METHODS: Two Pediatric Brain Tumor Consortium (PBTC) therapeutic trials in children with newly diagnosed BSG were designed to test radiation therapy combined with molecularly targeted agents (PBTC-007: phase I/II study of gefitinib; PBTC-014: phase I/II study of tipifarnib). Baseline brain (18)F-FDG PET scans were obtained in 40 children in these trials. Images were evaluated by consensus between 2 PET experts for intensity and uniformity of tracer uptake. Associations of (18)F-FDG uptake intensity and uniformity with both PFS and OS, as well as associations with tumor MRI indices at baseline (tumor volume on fluid-attenuated inversion recovery, baseline intratumoral enhancement, diffusion and perfusion values), were evaluated.
RESULTS: In most of the children, BSG (18)F-FDG uptake was less than gray-matter uptake. Survival was poor, irrespective of intensity of (18)F-FDG uptake, with no association between intensity of (18)F-FDG uptake and PFS or OS. However, hyperintense (18)F-FDG uptake in the tumor, compared with gray matter, suggested poorer survival rates. Patients with (18)F-FDG uptake in 50% or more of the tumor had shorter PFS and OS than did patients with (18)F-FDG uptake in less than 50% of the tumor. There was some evidence that tumors with higher (18)F-FDG uptake were more likely to show enhancement, and when the diffusion ratio was lower, the uniformity of (18)F-FDG uptake appeared higher.
CONCLUSION: Children with BSG for which (18)F-FDG uptake involves at least half the tumor appear to have poorer survival than children with uptake in less than 50% of the tumor. A larger independent study is needed to verify this hypothesis. Intense tracer uptake in the tumors, compared with gray matter, suggests decreased survival. Higher (18)F-FDG uptake within the tumor was associated with enhancement on MR images. Increased tumor cellularity as reflected by restricted MRI diffusion may be associated with increased (18)F-FDG uniformity throughout the tumor.

Beaty O, Berg S, Blaney S, et al.
A phase II trial and pharmacokinetic study of oxaliplatin in children with refractory solid tumors: a Children's Oncology Group study.
Pediatr Blood Cancer. 2010; 55(3):440-5 [PubMed]

BACKGROUND: Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population.
PATIENTS AND METHODS: Subjects, < or =21 years of age at original diagnosis, received oxaliplatin (130 mg/m(2)) intravenously every 21 days. Prior platinum exposure was acceptable. Histologies included: Ewing sarcoma/peripheral PNET, osteosarcoma, rhabdomyosarcoma, neuroblastoma, high and low grade astrocytoma, brain stem glioma, ependymoma, hepatoblastoma and selected rare tumors. A two-stage design, enrolling 10 + 10 subjects, was used for each disease stratum. Limited sampling pharmacokinetic studies were performed.
RESULTS: Of 124 eligible subjects (75 males), 113 were evaluable for response and 69 (62%) had received platinum previously. Only one objective response was observed, a partial response in a 6-year-old child with ependymoma. An additional 13 subjects with various other solid tumors had stable disease, receiving a median (range) of 13.5 (2-17) cycles. Five subjects completed 17 treatment cycles. Thrombocytopenia was the most common toxicity observed. The median (range) terminal half-life and clearance for ultrafiltrable platinum were 293 (187-662 hr) and 14.0 (1.9-24.9 L/hr/m(2)), respectively (n = 49).
CONCLUSIONS: Although reasonably well tolerated, oxaliplatin administered as a single agent has limited activity in pediatric patients with relapsed or refractory solid tumors.

Okada H, Low KL, Kohanbash G, et al.
Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas.
J Neurooncol. 2008; 88(3):245-50 [PubMed] Free Access to Full Article

We investigated the protein expression of three glioma-associated antigens (GAAs) in pediatric brain stem glioma (BSG) and non-brain stem glioma (NBSG) cases with a view to their possible use in immunotherapy. Expression of EphA2, IL-13Ralpha2 and Survivin were studied by immunohistochemistry on paraffin-embedded tissues using a series of 15 BSG cases and 12 NBSG cases. Thirteen of 15 BSGs and all 12 NBSGs expressed at least one of GAAs; and 7 BSGs and 9 NBSGs expressed at least two of these GAAs at higher levels than non-neoplastic brain. There was no association between the tumor grade and levels of GAA expression. Although many cases demonstrated diffuse expression of GAAs throughout specimens, partial or patchy expression was noted in a small number of cases, suggesting a need for targeting multiple GAAs in immunotherapy. These results suggest that EphA2, IL-13Ralpha2 and Survivin are suitable targets for developing vaccine strategies for pediatric glioma.

Seymour ZA, Panigrahy A, Finlay JL, et al.
Citrate in pediatric CNS tumors?
AJNR Am J Neuroradiol. 2008; 29(5):1006-11 [PubMed]

BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors.
MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute "apparent" concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined.
RESULTS: "Apparent" citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 +/- 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. "Apparent" citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 +/- 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 +/- 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 +/- 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 +/- 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,.
CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.

Nicholson HS, Kretschmar CS, Krailo M, et al.
Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group.
Cancer. 2007; 110(7):1542-50 [PubMed]

BACKGROUND: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors.
METHODS: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles.
RESULTS: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent.
CONCLUSIONS: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy.

Spacca B, Mallucci C, Riordan A, et al.
HSV encephalitis in a child with brain stem glioma: a rare complication of therapy. Case report and review of the neurosurgical literature.
Childs Nerv Syst. 2007; 23(11):1347-50 [PubMed]

BACKGROUND: Herpes simplex virus (HSV) encephalitis is a rare association with pediatric neurosurgical pathologies.
CASE REPORT: A 13-year-old boy was diagnosed with an inoperable, biopsy-proven pontine grade II astrocytoma. During radiotherapy, he developed status epilepticus controlled by thiopentone with intubation and ventilation. Empiric cefotaxime and aciclovir were given. Lumbar cerebrospinal fluid (CSF) showed a normal white cell count, normal glucose, and a slightly elevated protein level. However, the CSF showed a positive polymerase chain reaction (PCR) for HSV type 1 DNA. Intravenous aciclovir was given for 21 days and foscarnet for 7 days. He was extubated after 4 weeks at which time he was aphasic with spastic diplegia. After 8 weeks, MRI brain scan showed the typical bitemporal pattern of HSV encephalitis. He made slow improvement but died 8 months after diagnosis from tumor progression.
CONCLUSION: HSV encephalitis is a rare but life threatening complication in neurosurgical patients. A low threshold for both investigation with CSF PCR and empirical treatment with intravenous aciclovir is warranted. As in this case, initial microscopic examination of the CSF may be normal. The literature on HSV encephalitis in neurosurgical patients is discussed.

Korones DN
Treatment of newly diagnosed diffuse brain stem gliomas in children: in search of the holy grail.
Expert Rev Anticancer Ther. 2007; 7(5):663-74 [PubMed]

Diffuse brain stem glioma is the most devastating of pediatric malignancies. Virtually all children with this disease die within 1-2 years of diagnosis. After three decades of exhaustive research, the key to controlling this malignancy still eludes us. Attempts to improve survival using radiation, chemotherapy and biologic agents have yet to culminate in meaningful advances. Recent advances in molecular biology have led to the development of more targeted therapies, which are now being introduced in clinical trials for children with brain stem glioma. As our understanding of the biology of this disease improves, so too will our ability to target it more effectively. Real strides in improving the lives of children with brain stem glioma may finally be within our grasp.

Korones DN, Fisher PG, Kretschmar C, et al.
Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children's Oncology Group phase II study.
Pediatr Blood Cancer. 2008; 50(2):227-30 [PubMed]

BACKGROUND: The prognosis for children with brain stem glioma remains grim. Based on studies suggesting efficacy of vincristine and oral VP-16, The Pediatric Oncology Group (POG, now part of the Children's Oncology Group) conducted a study using these agents in combination with standard external beam radiation for children with newly diagnosed brain stem glioma.
METHODS: Children were eligible for the study if they 3-21 years of age, had MRI-evidence of a diffuse intrinsic pontine glioma, and had neurologic deficits of <6 months duration. Patients received local radiotherapy to a dosage of 54 Gy. Chemotherapy consisted of two 28-day cycles of vincristine, 1.5 mg/m(2), days 1, 8, and 15 and oral VP-16, 50 mg/m(2), days 1-21, starting concurrent with radiation, and continuing for ten cycles following radiation.
RESULTS: Of the 31 children enrolled, 30 were eligible and evaluable for survival and toxicity. Their median age was 8 years (range 3-14 years). Seven patients (23%) had a partial response following radiation, 18 (60%) had stable disease, 2 (7%) had progressive disease, and response in 3 patients (10%) was not measured. All 30 children have died. Overall survival at 1 year was 27 +/- 7% and at 2 years, 3 +/- 2%. The median survival was 9 months (range 3-36 months). Hematologic toxicity was significant; other toxicities included constipation, mucositis, emesis, and infection.
CONCLUSION: The addition of vincristine and oral VP-16 to standard external beam radiation causes moderate toxicity and does not improve survival of children with diffuse intrinsic brain stem glioma.

Hargrave DR, Hargrave UA, Bouffet E
Quality of health information on the Internet in pediatric neuro-oncology.
Neuro Oncol. 2006; 8(2):175-82 [PubMed] Free Access to Full Article

The Internet is now the single largest source of health information and is used by many patients and their families who are affected by childhood brain tumors. To assess the quality of pediatric neuro-oncology information on the Internet, we used search engines to look for information on five common tumor types (brain stem glioma, craniopharyngioma, ependymoma, low-grade glioma, and medulloblastoma). The Web sites were evaluated for content quality by using the validated DISCERN rating instrument. Breadth of content and its accuracy were also scored by a checklist tool. Readability statistics were computed on the highest-rated sites. Of 114 evaluated Web sites, the sources were as follows: institutional, 46%; commercial, 35%; charitable, 15%; support group, 2%; and alternative medicine, 2%. Good interobserver correlation was found for both ratings instruments. The DISCERN tool rated Web sites as excellent (4%), good (7%), fair (29%), poor (39%), or very poor (21%). Only 5% of the Web sites provided one or more inaccurate pieces of information. Web sites were found deficient in topics covering etiology, late effects, prognosis, and treatment choices. Few sites offered information in languages other than English, and readability statistics showed an average required reading level of U.S. grade 12+ (the suggested level being grades 6-8 for an adult audience). The Internet is increasingly being used as a source of oncology information for patients and their families. Health care professionals should be actively involved in developing high-quality information for use in the next generation of Web sites.

De Sio L, Milano GM, Castellano A, et al.
Temozolomide in resistant or relapsed pediatric solid tumors.
Pediatr Blood Cancer. 2006; 47(1):30-6 [PubMed]

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT).
PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt.
RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%.
CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

Korones DN, Smith A, Foreman N, Bouffet E
Temozolomide and oral VP-16 for children and young adults with recurrent or treatment-induced malignant gliomas.
Pediatr Blood Cancer. 2006; 47(1):37-41 [PubMed]

BACKGROUND: Children and young adults with recurrent or treatment-induced malignant gliomas have limited responses to temozolomide or oral VP-16 when either is administered as a single agent. We postulated that a combination of these two drugs for patients with recurrent or treatment-induced malignant gliomas might result in better and more prolonged responses. A retrospective analysis was performed on patients treated with the combination of temozolomide and VP-16.
PROCEDURE: Eleven patients with recurrent or treatment-induced malignant gliomas were treated with varying combinations of temozolomide (150-210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4-12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record.
RESULTS: The median age of the 11 patients was 17 years (range 5-23 years). Diagnoses included recurrent brain stem glioma (2), recurrent anaplastic astrocytoma (2), and glioblastoma (7) (3 treatment-induced, 2 malignant transformations of lower grade tumors, 1 recurrence, and 1 second tumor arising 10 months after diagnosis of medulloblastoma). All 11 patients had received radiotherapy (including 4 who received craniospinal radiation), and 7 had prior chemotherapy. Nine patients were treated at first recurrence, two at second recurrence. One patient had a complete response (CR), six had partial responses (PR), and four had progressive disease (PD). The median progression-free survival for the seven responding patients was 6 months (range 4-15+ 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 for children and young adults with recurrent malignant gliomas.

Rose SR, Danish RK, Kearney NS, et al.
ACTH deficiency in childhood cancer survivors.
Pediatr Blood Cancer. 2005; 45(6):808-13 [PubMed]

BACKGROUND: Adrenocorticotropin deficiency (ACTHD) can be clinically subtle, but life-threatening if not recognized. We assessed the prevalence of ACTHD in survivors of childhood cancer according to tumor diagnosis/therapy.
PROCEDURE: Chart review of endocrine/oncology history was performed in 310 childhood cancer survivors. Patients were referred to endocrine clinic because of slow growth, fatigue, or abnormal pubertal timing. Evaluation of growth hormone (GH), thyrotropin (TSH), ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was performed. Low response to metyrapone and/or low dose ACTH test defined ACTHD.
RESULTS: ACTHD was identified in 56 (18%), [44 of 182 (24%) central nervous system (CNS) tumors, 3 of 18 (17%) non-CNS cranial tumors, 9 of 97 (9%) hematologic malignancies]. Of the 56 with ACTHD, 53 (95%) had received cranial irradiation (mean 45.5 Gy, range 14-70 Gy); three had not: one each with craniopharyngioma, hypothalamic astrocytoma, and brain stem glioma. All but one also had GH deficiency and/or central hypothyroidism.
CONCLUSIONS: Childhood cancer survivors with greatest risk for ACTHD had craniopharyngioma, other suprasellar tumor, or medulloblastoma or > or =24 Gy cranial irradiation. We recommend annual testing for ACTHD for 10-15 years and continued lifelong surveillance after CNS tumor or cranial irradiation, in patients with other hypothalamic-pituitary deficiencies or symptoms of ACTHD.

Wolff JE, Finlay JL
High-dose chemotherapy in childhood brain tumors.
Onkologie. 2004; 27(3):239-45 [PubMed]

Early attempts to use high-dose chemotherapy technology in order to improve the effect of nitrosourea on high-grade gliomas resulted in minimal benefit as well as in severe toxicity. Since then, other drugs have been applied in conjunction with either autologous bone marrow or peripheral blood stem cells, including thiotepa, etoposide, melphalan, cyclophosphamide, and busulfan. The data suggest benefit in recurrent primitive neuroectodermal tumors (PNET), in newly diagnosed young children with PNET and possibly in young children with newly diagnosed ependymoma, as a strategy not only to improve tumor-free survival but also to avoid exposure of the young brain to irradiation. In other tumors such as recurrent ependymoma and newly diagnosed or recurrent brain stem glioma, high-dose chemotherapy remains ineffective. New protocols under evaluation include new agents, multiple cycles of high-dose chemotherapy and allogeneic transplantation as immunotherapeutic approach.

Gilbertson RJ, Hill DA, Hernan R, et al.
ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma.
Clin Cancer Res. 2003; 9(10 Pt 1):3620-4 [PubMed]

PURPOSE: This study was conducted to investigate the incidence of ERBB1 amplification and overexpression in samples of diffusely infiltrative (WHO grades II-IV) pediatric brain stem glioma (BSG) and determine the relationship of these abnormalities to expression and mutation of TP53 and tumor grade.
EXPERIMENTAL DESIGN: After central pathology review, the incidence of ERBB1 amplification and overexpression was determined in 28 samples (18 surgical biopsy and 10 postmortem specimens) of BSG using quantitative PCR and immunohistochemistry, respectively. Mutation and expression of TP53 were also determined in these same samples by direct sequence analysis of microdissected tumor material and immunohistochemistry, respectively. All experimental procedures were performed blind to tumor grade.
RESULTS: Twelve, 9, and 7 tumors were classified as WHO grades II, III, and IV, respectively. A significant increase in ERBB1 expression was observed with increasing tumor grade (P < 0.001). Two grade IV tumors displayed intense membranous ERBB1 expression in 90% of tumor cells in association with high-level ERBB1 gene amplification. One grade III tumor also contained low-level amplification of ERBB1. Six tumors demonstrated TP53 nuclear immunoreactivity, and six contained a mutation in TP53. No correlation was observed between abnormalities in TP53 and either tumor grade or amplification and overexpression of ERBB1.
CONCLUSIONS: These data suggest that ERBB1 signaling is important for the development of childhood BSG and is worthy of study as a therapeutic target in this disease. Our data also indicate that the genetics of childhood BSG are complex and include both grade-dependent amplification and overexpression of ERBB1 and grade-independent expression and mutation of TP53.

Amano T, Inamura T, Nakamizo A, et al.
Case management of hydrocephalus associated with the progression of childhood brain stem gliomas.
Childs Nerv Syst. 2002; 18(11):599-604 [PubMed]

OBJECT: Most patients diagnosed with brain stem glioma become bedridden because of deteriorating brain stem function. Many brain stem glioma patients develop hydrocephalus. Both of these outcomes greatly detract from the quality of life of these patients. We have analyzed the occurrence of hydrocephalus in diffuse brain stem gliomas in children, and we discuss the management of advanced cases.
METHODS: Eighteen patients diagnosed with brain stem glioma while under 15 years of age, including 1 with dissemination, were studied retrospectively. The average overall survival was 11.8 +/- 6.5 months (mean +/- SD). Hydrocephalus occurred in 16 (88.9%) of the 18 cases. The patients diagnosed with hydrocephalus all exhibited a rapid decline in consciousness. The average time to onset of hydrocephalus after tumor diagnosis was 5.1 +/- 3.3 months. Twelve of the 16 patients with hydrocephalus were treated with cerebrospinal fluid (CSF) diversion, by means of a Torkildsen shunt, a ventriculoperitoneal shunt, or third ventriculostomy. The level of consciousness and patient performance status improved after CSF diversion except in 2 patients who had received Torkildsen shunts. The patients treated for hydrocephalus survived significantly longer than those patients who did not undergo any intervention for hydrocephalus. CSF diversion may be a therapeutic intervention that significantly improves the quality of life and survival of patients.
CONCLUSION: Our results suggest that patients diagnosed with brain stem glioma should be closely monitored for signs of hydrocephalus and be examined by neuroimaging rapidly when indicated. Our results also suggest that once hydrocephalus is diagnosed CSF diversion should be performed promptly.

Kirton A, Kloiber R, Rigel J, Wolff J
Evaluation of pediatric CNS malignancies with (99m)Tc-methoxyisobutylisonitrile SPECT.
J Nucl Med. 2002; 43(11):1438-43 [PubMed]

UNLABELLED: SPECT has the potential to add valuable information to the diagnosis and management of central nervous system (CNS) malignancy. Radioactive tracers including (99m)Tc-methoxyisobutylisonitrile (MIBI), or sestamibi, have been shown to be sensitive markers for brain tumors; however, their role in imaging children is poorly defined.
METHODS: We undertook a pilot study of 29 pairs of (99m)Tc-MIBI and MRI images from 20 children to explore the clinical usefulness of this tracer in CNS malignancy.
RESULTS: Tumor types that took up (99m)Tc-MIBI included brain stem glioma, fibrillary astrocytoma, other low-grade astrocytomas, and glioblastoma multiforme. Most tumors positive for (99m)Tc-MIBI uptake were astrocytomas, including those in the brain stem, cerebellum, and cortex. This method of nuclear imaging not only was able to identify the presence of a tumor but also could identify changes in the same tumor over time. Some correlation between histologic grade and (99m)Tc-MIBI uptake was observed. Several tumors, including craniopharyngioma, medulloblastoma, and optic glioma, were evident on MRI but not on (99m)Tc-MIBI SPECT.
CONCLUSION: The results suggest that this modality is a potentially useful tool in the diagnosis and management of CNS malignancies, particularly higher-grade astrocytomas, in children.

Benesch M, Lackner H, Moser A, et al.
Outcome and long-term side effects after synchronous radiochemotherapy for childhood brain stem gliomas.
Pediatr Neurosurg. 2001; 35(4):173-80 [PubMed]

Between 1993 and 1999, 11 children with histologically confirmed diffuse and exophytic brain stem glioma (BSG) were treated with intensive induction chemotherapy and simultaneous external beam irradiation. Chemotherapy was performed according to the German/Austrian Pediatric Brain Tumor Study HIT '91 and included two cycles of ifosfamide (days 1-3), etoposide (days 4-6), methotrexate (days 15 and 22), cisplatin (days 29-31) and cytarabine (days 29-31), separated by a 3-week interval. Maintenance chemotherapy with carmustine, carboplatin and vincristine (8 cycles over a 1-year period) was given in those patients who responded clinically or radiographically to induction chemotherapy. Six of 11 patients showed an objective reduction in tumor size on magnetic resonance imaging and 4 of 11 are alive in good general condition >22, >22, >90 and >92 months, respectively, after diagnosis without radiographic evidence of tumor progression (1 complete remission, 2 partial remissions, 1 stable disease), but suffer from moderate to severe long-term side effects. Three patients died due to disease progression after having achieved a partial remission which lasted 5, 6 and 18 months, respectively, whereas only short-term stabilization was observed in 4 patients who died within 1 year after diagnosis. Acute hematologic toxicity was severe but manageable. This intensive combined modality treatment was toxic but yielded objective responses in more than 50% and long-term survivors in one third of childhood BSG patients.

Hurwitz CA, Strauss LC, Kepner J, et al.
Paclitaxel for the treatment of progressive or recurrent childhood brain tumors: a pediatric oncology phase II study.
J Pediatr Hematol Oncol. 2001 Jun-Jul; 23(5):277-81 [PubMed]

PURPOSE: To assess the efficacy and define the toxicity of paclitaxel given at a dosage of 350 mg/m2 every 3 weeks as a 24-hour continuous infusion to children with recurrent or progressive primary brain tumors.
PATIENTS AND METHODS: Seventy-three eligible patients, ages 4 months to 19 years, with progressive or recurrent primary brain tumors were treated according to a Pediatric Oncology Group (POG) phase II protocol with paclitaxel (POG 9330). Tumor histologic strata included: astrocytoma (n = 4), malignant glioma (n = 13), medulloblastoma (n = 16), brain stem glioma (n = 15), ependymoma (n = 13), and miscellaneous histologies (n = 12). All patients had previous histologic confirmation of a primary intracranial or spinal cord tumor with magnetic resonance imaging or computed tomography documentation of unequivocally measurable progressive or recurrent disease. All patients had received previous therapy including surgery, radiation therapy, and/or chemotherapy, but no patient had been previously treated on more than one phase II trial. Paclitaxel was administered as a 24-hour intravenous infusion at a dosage of 350 mg/m2 every 3 weeks. Neurologic and neuroradiologic reevaluations were performed after every second course. Patients were allowed to continue therapy for a total of 18 cycles in the absence of progressive disease or unacceptable toxicity.
RESULTS: Seventy-five patients were enrolled onto the POG 9330 protocol; two ineligible patients were removed from the study before receiving any therapy. Of the 73 eligible patients, 72 were evaluable for toxicity and 70 were either fully or partially evaluable for disease response. There was one complete response and three partial responses (5.7%). Twenty patients had stable disease for more than 2 months. Toxicities included mild nausea, central nervous system toxicity, myelosuppression, and febrile neutropenia, including one septic death. One grade 2 and two grade 3 allergic reactions occurred. No cardiac toxicities or arthralgias were reported.
CONCLUSION: Paclitaxel is well tolerated in children with recurrent or progressive brain tumors at this dosage and schedule and may result in short-term disease stabilization in this patient population. The lack of a significant number of patients with measurable disease regression, however, precludes it from being identified as an active agent when administered as a single agent by 24-hour continuous infusion.

Freeman CR, Kepner J, Kun LE, et al.
A detrimental effect of a combined chemotherapy-radiotherapy approach in children with diffuse intrinsic brain stem gliomas?
Int J Radiat Oncol Biol Phys. 2000; 47(3):561-4 [PubMed]

PURPOSE: To compare the proportion of patients that survive at least 1 year following treatment with hyper-fractionated radiotherapy (HRT) to a dose of 70.2 Gy on Pediatric Oncology Group (POG) study #8495 with that of patients treated with similar radiotherapy plus cisplatinum given by continuous infusion on weeks 1, 3, and 5 of radiotherapy on POG #9239.
METHODS AND MATERIALS: The eligibility criteria for the two studies were identical and included age 3 to 21 years, previously untreated tumor involving the brain stem of which two-thirds was in the pons, history less than 6 months, and clinical findings typical for diffuse intrinsic brain stem glioma, including cranial nerve deficits, long tract signs, and ataxia. The outcome of 57 patients who were treated at the 70.2 Gy dose level of POG #8495 between May 1986 and February 1988 was compared with that of 64 patients treated with identical radiotherapy plus cisplatinum on POG #9239 between June 1992 and March 1996.
RESULTS: The number of patients accrued to POG #9239 was determined to guarantee that the probability was at least 0.80 of correctly detecting that the 1-year survival rate exceeded that of patients on POG #8495 by 0.2. However, the z value for this test was -1.564, giving a p value of 0.9411. That is, there is almost sufficient evidence to conclude that survival for patients receiving HRT plus cisplatinum on POG #9239 was worse than that for patients receiving the same radiotherapy alone on POG #8495.
CONCLUSION: The finding that patients who received cisplatinum given as a radiosensitizing agent concurrent with HRT fared less well than those receiving the same dose of HRT alone was unexpected and is clearly a cause for concern as many current protocols for patients with diffuse intrinsic brain stem gliomas call for use of chemotherapeutic and/or biological agents given concurrent with radiotherapy.

Bowers DC, Georgiades C, Aronson LJ, et al.
Tectal gliomas: natural history of an indolent lesion in pediatric patients.
Pediatr Neurosurg. 2000; 32(1):24-9 [PubMed]

The mesencephalic tectal glioma is a distinctive form of brain stem glioma with an unusually benign clinical course. Periaqueductal location, lack of contrast enhancement, and long periods of stability are classic features. The clinical management of these lesions, especially at the time of radiographic enlargement varies widely in the published literature. It is unclear whether these progressive lesions need to be treated. Accordingly, clinical and radiologic features of 7 patients were reviewed, with attention to the clinical course of the disease after radiologic enlargement. The age at diagnosis ranged from 3.3 to 16.6 years. Six of 7 had MRI tumor enlargement beginning 0.3-5.7 years after initial diagnosis. One of these 6 patients had radiographic progression coupled with a new clinical symptom which was treated with stereotactic radiation therapy. The remaining 5 patients with MRI progression and normal neurological exams were not treated and remain free of new neurologic deficits 1.8-6.9 years after the first radiographic tumor enlargement. The results suggest that pediatric tectal gliomas are a very low-grade lesion. Conservative management in the absence of new clinical symptoms could be argued, reserving radiotherapy or chemotherapy for clinical progression.

Selvapandian S, Rajshekhar V, Chandy MJ
Brainstem glioma: comparative study of clinico-radiological presentation, pathology and outcome in children and adults.
Acta Neurochir (Wien). 1999; 141(7):721-6; discussion 726-7 [PubMed]

Although the clinical and imaging features and behaviour of brain stem gliomas in children are well documented, similar data are not available, for adults. We have carried out a retrospective study, on 101 consecutive patients (71 children and 30 adults) with a histologically verified brain stem glioma. Duration of symptoms, clinical features, imaging characteristics, histopathology and outcome were specifically compared in children and adults with brain stem glioma. Peak incidence was in the first decade in children and in the third and fourth decades in adults. Mean duration of symptoms before admission was 9.7 months in adults and 3.6 months in children (P < 0.001). There were no significant differences in the clinical features between adults and children. Imaging characteristics revealed no major differences except that diffuse hypodense lesions involving the whole brainstem accounted for 41.2% of the lesions in children and only 11.1% of adults (P < 0.001). A stereotactic biopsy was performed in 92 patients and an open biopsy or partial excision in 9 patients. Histopathological examination showed that the majority of gliomas were diagnosed as grade II astrocytomas in both groups. Survival was significantly shorter in children when compared to adults (P < 0.01). While the tumour grade was a significant factor in predicting survival in adults, in children it did not correlate with outcome. Therefore, determination of the grade of a brain stem glioma may be of prognostic significance in adult patients.

Driever PH, Knüpfer MM, Cinatl J, Wolff JE
Valproic acid for the treatment of pediatric malignant glioma.
Klin Padiatr. 1999 Jul-Aug; 211(4):323-8 [PubMed]

Despite surgery and adjuvant cytotoxic therapy anaplastic astrocytoma, glioblastoma and diffuse intrinsic brain stem glioma continue to have dismal prognosis. Differentiation induction is a new approach taking into account that malignant glioma cells share many features with immature glial progenitor cells that are capable of terminal differentiation. The concept of differentiation therapy is currently evaluated for several pediatric malignancies with or without multimodal standard therapy. Valproic acid (VPA) is a branched chain fatty acid that is able to inhibit proliferation of neuroectodermal cells and to induce these cells along neuronal or glial lineage. Preclinical studies have shown that VPA inhibits growth of human and rodent glial tumor cells in vitro and induces a distinct mature glial phenotype. In addition, growth of human neuroblastoma cells is inhibited in vitro and in vivo and exhibits marked evidence of differentiation. Treatment of neuroblastoma and glioma cells with VPA was accompanied by changes of surface molecule expression that enhance immunogenicity and reduce their capability to metastasize. The antitumoral effects observed in preclinical studies were reached at concentrations that are readily achieved in patients treated with VPA for epilepsy. Epilepsy patients receiving VPA have significantly enhanced hemoglobin F levels, supporting the hypothesis that nontoxic levels of VPA can induce cellular differentiation. Broad clinical experience with VPA and its low toxicity encourage the evaluation of VPA in patients that have been submitted to postoperative combined chemo- and radiotherapy for pediatric malignant glioma.

Ghaziuddin N, DeQuardo JR, Ghaziuddin M, King CA
Electroconvulsive treatment of a bipolar adolescent postcraniotomy for brain stem astrocytoma.
J Child Adolesc Psychopharmacol. 1999; 9(1):63-9 [PubMed]

This is the first reported use of electroconvulsive treatment (ECT) in an adolescent with bipolar mania who had been treated with craniectomy for an intracranial neoplasm. The reported case is of a 16-year-old girl with a history of brain stem glioma (pontomesencephalic astrocytoma) diagnosed at 13 years of age. She presented in a psychiatric emergency room with suicidal ideation, depressed mood, irritability, olfactory hallucinations, early insomnia, grandiosity, and guilt. Her symptoms failed to respond to a trial of an antidepressant, mood stabilizer alone, and mood stabilizer in conjunction with a neuroleptic. The decision to use ECT was based on suicidal ideation, extreme disinhibition, and danger to self and others. Significant improvement in mood and remission in psychosis were noted after the eighth treatment. Comparison of 2-week pre-ECT and 3-month post-ECT cognitive testing revealed no change in IQ. This report highlights rapid response and the ability to tolerate ECT in an adolescent diagnosed with bipolar disorder, who had also been treated with radiation and craniotomy.

Chuba PJ, Zamarano L, Hamre M, et al.
Permanent I-125 brain stem implants in children.
Childs Nerv Syst. 1998; 14(10):570-7 [PubMed]

Between 1988 and 1997, 28 children have had iodine-125 implants for CNS tumors performed in our institution. Ten had stereotactic implantation in the brain stem region, and nine had the diagnosis of brain stem glioma (8 diffuse pontine, 1 midbrain tumor). Their ages ranged from 1.8 to 12 years. All patients had histological confirmation of malignancy (7 high-grade glioma, 2 low-grade glioma, 1 PNET). Diffuse pontine glioma patients received external beam radiation (50 Gy) followed by a fractionated stereotactic boost of 3 Gyx4 fractions. After 4-6 weeks, patients were reevaluated for stereotactic interstitial I-125 therapy. The planned implant dose was 82.9 Gy to the enhancing tumor (4 cGy per h). Preliminary results indicated that no surgical complications were associated with the catheter placement. Four patients have died (7-9 months from diagnosis) and four patients remain alive (5-38 months from diagnosis, median 10 months). Two autopsies confirmed the presence of progressive glioblastoma multiforme and intralesional necrosis. In one patient who received an implant alone for midbrain LGA, necrosis without tumor was found on biopsy after 36 months. He was successfully treated with hyperbaric oxygen therapy. The implementation of permanent I-125 implants appears to have a role in the management of pediatric CNS malignancy. This study confirms the results of previous reports regarding the safety of stereotactic interstitial brachytherapy in the brain stem. Tumor control for patients with high-grade brain stem glioma remains poor even with high focal radiation doses.

Chuba PJ, Aronin P, Bhambhani K, et al.
Hyperbaric oxygen therapy for radiation-induced brain injury in children.
Cancer. 1997; 80(10):2005-12 [PubMed]

BACKGROUND: Radiation-induced necrosis (RIN) of the brain is a complication associated with the use of aggressive focal treatments such as radioactive implants and stereotactic radiosurgery. In an attempt to treat patients with central nervous system (CNS) RIN, ten patients received hyperbaric oxygen treatment (HBOT).
METHODS: Patients presented with new or increasing neurologic deficits associated with imaging changes after radiotherapy. Necrosis was proven by biopsy in eight cases. HBOT was comprised of 20-30 sessions at 2.0 to 2.4 atmospheres, for 90 minutes-2 hours. Sites of RIN included the brain stem (n = 2), posterior fossa (n = 1), and supratentorial fossa (n 7). Histologic types included brain stem glioma (n = 2), ependymoma (n = 2), germinoma (n = 2), low grade astrocytoma (n = 1), oligodendroglioma (n = 1), glioblastoma multiforme (n = 1), and arteriovenous malformation (n = 1).
RESULTS: Initial improvement or stabilization of symptoms and/or imaging findings were documented in all ten patients studied and no severe HBOT toxicity was observed. Four patients died, with the cause of death attributed to tumor progression. Five of six surviving patients were improved by clinical and imaging criteria; one patient was alive with tumor present at last follow-up.
CONCLUSIONS: HBOT may prove to be an important adjunct to surgery and steroid therapy for CNS RIN.

Lewis J, Lucraft H, Gholkar A
UKCCSG study of accelerated radiotherapy for pediatric brain stem gliomas. United Kingdom Childhood Cancer Study Group.
Int J Radiat Oncol Biol Phys. 1997; 38(5):925-9 [PubMed]

PURPOSE: Between 1991 and 1994, the United Kingdom Childhood Cancer Study Group (UKCCSG) conducted a multicenter study to assess the efficiency and tolerability of accelerated radiotherapy in children with a diagnosis of poor-prognosis brain stem glioma.
METHODS AND MATERIALS: Patients eligible for study were those aged 3-16 years with tumors arising in the pons, medulla, or midbrain, not previously treated with radiotherapy or chemotherapy. Histologic confirmation was not mandatory, but computed tomography or magnetic resonance imaging and clinical findings had to be typical, and patients were selected with short prediagnosis symptom history (<3 months), cranial nerve palsies or long tract signs, and intrinsic diffuse lesions on scanning. The treatment dose was 48.6 Gy in 27 fractions, increased to 50.4 Gy in 28 fractions in January 1992, delivered twice daily (except weekends) with an interfraction interval of at least 8 h. Between January 1991 and July 1994, 28 available patients were recruited: 15 boys and 13 girls with ages ranging between 3 and 13 years (median 6).
RESULTS: After treatment, neurologic improvement sustained for a period of at least 6 weeks without steroids was reported in 13 children (46%). On central review of postradiotherapy imaging, 50% of children showed evidence of partial response, but none exhibited a complete response. A further six patients (22%) had stable disease. The median survival time was 37 weeks (8.5 months); 1-year survival was 32%, and 2-year survival 11%. The pattern of relapse was local in all 26 patients who died of their disease; 1 patient had evidence of leptomeningeal seeding. Acute radiation morbidity was minimal, with only three patients (11%) exhibiting mild toxicity. No evidence of radiation-induced necrosis was found radiologically or histologically at postmortem. Ability to withdraw steroids following radiotherapy was the single most important prognostic variable in our study.
CONCLUSION: The results of this study are comparable to previous outcomes of studies with conventional and hyperfractionated radiotherapy in poor-prognosis brain stem glioma. The fractionation regimen was shown to be tolerable with an acceptable morbidity profile. However, further research is required to improve the poor prognosis of these unfortunate children.

Ito K, Murofushi T, Mizuno M, Semba T
Pediatric brain stem gliomas with the predominant symptom of sleep apnea.
Int J Pediatr Otorhinolaryngol. 1996; 37(1):53-64 [PubMed]

Two children complaining of sleep apnea presented with brain stem gliomas. In the early stage of their illness, neurological disorders were too subtle to be recognized as significant by the physicians or to be noted by the parents. Case 1 experienced an episode of unsteady gait and weakness in the bilateral arms, at the age of 5. When it recurred after 7 years of remission, the predominant symptom was sleep apnea. Case 2 exhibited nasality of speech as the earliest sign of this illness very early in his life, presumably 5 years before the diagnosis of brain stem glioma. A slight sleep apnea which developed afterwards did not draw attention of the physicians because no neurological signs other than paralyses of the bilateral soft palates were present. MRIs of the both cases revealed diffuse, infiltrating lesions in the pons, the medulla oblongata and the upper cervical spinal cord. Both cases shared some features: (1) diagnostic delay of several years from the first symptom; (2) the main lesion in the medulla oblongata, where important structures for respiratory control are identified; (3) infiltrative growth patterns in the MRI of the tumor, which might account for the uncommon clinical courses.

Zimmerman RA
Neuroimaging of pediatric brain stem diseases other than brain stem glioma.
Pediatr Neurosurg. 1996; 25(2):83-92 [PubMed]

A wide variety of both neoplastic and non-neoplastic lesions affect the pediatric brain stem. Of these, inflammatory and infectious, along with occult vascular malformations produce the greatest concern regarding the interpretation of imaging studies that could lead to inappropriate therapeutic modalities in the treatment of the patient. Awareness of the differential diagnosis and, when appropriate, the judicious use of follow-up examination are warranted.

Blaney SM, Phillips PC, Packer RJ, et al.
Phase II evaluation of topotecan for pediatric central nervous system tumors.
Cancer. 1996; 78(3):527-31 [PubMed]

BACKGROUND: Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors.
METHODS: Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity.
RESULTS: There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation.
CONCLUSIONS: Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors.