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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] Related Publications

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 Related Publications

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.

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 Related Publications

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.

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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] Related Publications

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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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] Related Publications

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] Related Publications

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.

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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] Related Publications

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.

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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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] Related Publications

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.

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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] Related Publications

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.

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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] Related Publications

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.

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Edwards MS, Wara WM, Ciricillo SF, Barkovich AJ
Focal brain-stem astrocytomas causing symptoms of involvement of the facial nerve nucleus: long-term survival in six pediatric cases.
J Neurosurg. 1994; 80(1):20-5 [PubMed] Related Publications

Six children with a history of isolated facial nerve dysfunction or dizziness and nausea were treated for brain-stem glioma between 1984 and 1992. Computerized tomography and/or magnetic resonance (MR) imaging showed a focal, uniformly enhancing mass involving the facial nerve nucleus of the pons. All patients underwent biopsy; the histological diagnosis was juvenile pilocytic astrocytoma in five cases. In the remaining case the biopsy was nondiagnostic, although the surgeon believed that the lesion was a glioma. Postoperatively, five patients underwent conventional focal megavoltage radiation therapy (180 to 200 cGy/day) over a period of 5 1/2 weeks to a total dose of approximately 5400 cGy. One child's family refused radiation therapy; she remained well and stable for 4 years, despite persistent facial weakness, and was eventually lost to follow-up review. Four irradiation-treated patients had complete resolution of their tumors on MR images and have had no evidence of neuropsychological or neuroendocrinological deficits during 4 1/2 to 8 years of follow-up evaluation. Patients whose neuroradiological studies show a lesion resembling those in this series should undergo biopsy and, if the histology of a low-grade tumor (in particular, a juvenile pilocytic astrocytoma) is confirmed, should then receive focal radiation therapy with conventional megavoltage dosages.

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Mulhern RK, Heideman RL, Khatib ZA, et al.
Quality of survival among children treated for brain stem glioma.
Pediatr Neurosurg. 1994; 20(4):226-32 [PubMed] Related Publications

In order to describe the status of long-term survivors of brain stem glioma, neuropsychological and behavioral measures were obtained a median of 2.5 (range 1.5-5.6) years after diagnosis from 16 survivors of 51 consecutively diagnosed children with brain stem glioma between 1983 and 1991. Among 11 children with dorsally exophytic tumors, 7 were treated with surgery alone (SRG) and 4 received conventionally fractionated local cranial radiation therapy (CFRT; 54-56 Gy) to the brain stem following surgery, 3 of these because of recurrent disease. Five others with diffusely infiltrative brain stem tumors received hyperfractionated radiation therapy (HFRT; 70.2 Gy) to the brain stem; 4 following biopsy or limited resection and 1 without prior surgery. IQs of children in the CFRT (mean 89, SD 24.4) and HFRT (mean 85, SD 12.7) groups were not significantly different. Children in the SRG group had significantly higher IQs (mean 100, SD 11.0) and fewer neurologic deficits than those who had received CFRT or HFRT. However, after statistically controlling for severity of neurologic deficits, treatment had no effect on IQ. The severity of residual neurologic deficits accounted for 42% of the variance in IQ scores; children with fewer neurologic problems scored higher. Additional studies are required to evaluate the potential neuropsychological benefits of equivalent total doses of HFRT compared to CFRT.

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Freeman CR, Krischer JP, Sanford RA, et al.
Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study.
Int J Radiat Oncol Biol Phys. 1993; 27(2):197-206 [PubMed] Related Publications

PURPOSE: In September 1984, the Pediatric Oncology Group began accrual to a Phase I/II study designed to assess the efficacy and toxicity of sequentially escalated doses of hyperfractionated (twice daily) radiotherapy in children with poor-prognosis brain stem tumors. Pediatric Oncology Group Study #8495 closed in June 1990 with a total of 136 patients on study. We report here the outcome of patients treated at the third and final dose level (75.6 Gy), and compare the results to those obtained at the 66 and 70.2 Gy dose levels.
METHODS AND MATERIALS: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the midbrain, pons or medulla. Histological confirmation of diagnosis was not mandatory provided that the clinical and radiological findings were typical for brain stem glioma. Treatment consisted of radiotherapy delivered to local fields. At the third dose level, fraction sizes of 1.26 Gy were given twice daily, with a minimum interfraction interval of 6 hr to a dose of 75.6 Gy in 60 fractions over 6 weeks. Between 5/89 and 6/90, 41 patients were accrued to the study. Two were excluded from analysis leaving 39 evaluable patients, 21 male and 19 female, whose ages ranged from 3 to 15 years (median 7.5 years).
RESULTS: Following treatment, neurological improvement was reported in 30/39 (77%) of the patients. On central review of imaging studies in 29 patients, one patient was found to have had a complete response to radiotherapy, five a partial (> 50% response), and only three had non-responding or progressive disease. The median time to disease progression was 7 months; median survival time was 10 months; survival at 1 year was 39.9% (SE 8.3%) and at 2 years, 7% (SE 4.8%). The pattern of failure was local in all patients; in addition six had evidence of leptomeningeal seeding. Morbidity of treatment included an enhanced skin reaction (21%), otitis media and/or externa (26%), and steroid use > 3 months (62%). Intralesional necrosis was a frequent finding (45%) on imaging studies performed at a median time of 6 weeks post treatment.
CONCLUSION: The results of treatment in terms of progression-free survival and overall survival are not significantly different (at p = .55 and p = .46, respectively) from those obtained at the two previous dose levels. There is no evidence that higher doses of hyperfractionated radiotherapy given as in this study improve the outlook of patients with poor-risk brain stem gliomas.

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Tamura M, Ono N, Zama A, et al.
Delayed brain hemorrhage associated with prophylactic whole brain irradiation for pediatric malignant brain tumor: a case report.
Childs Nerv Syst. 1993; 9(5):300-1 [PubMed] Related Publications

Intraparenchymal hemorrhage in the left frontal lobe suddenly occurred in a 7-year-old girl who had undergone partial removal of an undifferentiated brain stem glioma and received craniospinal (30 Gy) and posterior fossa booster (20 Gy) irradiation at the age of 20 months. The brain hemorrhage was thought to be delayed irradiation effect. Follow-up neuro-imaging at age 9 years showed two more small occult chronic and subacute hemorrhages in the brain. The possibility of repeated hemorrhage as a delayed reaction to brain irradiation is emphasized.

Hibi T, Shitara N, Genka S, et al.
Radiotherapy for pediatric brain stem glioma: radiation dose, response, and survival.
Neurosurgery. 1992; 31(4):643-50; discussion 650-1 [PubMed] Related Publications

An analysis of 39 patients under 20 years of age with brain stem glioma treated with radiotherapy between 1977 and 1991 was undertaken. Twenty-eight (71.2%) of the patients responded well to initial radiotherapy, and 11 (28.8%) responded poorly. Median survival for the total patient population was 10 months. Response rates and median survivals were influenced by radiation dose: 45.5% and 9 months at doses less than 4499 cGy (n = 11), 83.3% and 13 months at doses between 4500 and 5499 cGy (n = 12), 66.7% and 11.5 months at doses between 5500 and 6499 cGy (n = 9), and 100% and 10 months at doses more than 6500 cGy (n = 7). Multivariate analysis revealed the response to initial radiotherapy was the only predictor of survival with radiation doses up to 6499 cGy. Four of the patients who responded well demonstrated radiological and/or histological calcification within or around the tumor at the time of clinical deterioration. Radiation injury was confirmed in two autopsy cases. The possibility that intratumoral radiation injury causes clinical deterioration is suggested.

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Mulligan CM, Wittman BK
Nursing care of the child with a brain stem glioma.
J Pediatr Nurs. 1990; 5(6):375-86 [PubMed] Related Publications

The nursing care of the child with a brain stem tumor focuses on supporting the family and the child's adaptation to the physical and emotional problems of an illness with a variable and often fatal course. With the advent of magnetic resonance imaging and stereotaxic biopsy, a more accurate assessment of tumor type, location, and size can be made. Advances in surgery, radiotherapy, and multidrug chemotherapy have affected the course of brain stem tumors even though outcome may remain the same.

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Raffel C, McComb JG, Bodner S, Gilles FE
Benign brain stem lesions in pediatric patients with neurofibromatosis: case reports.
Neurosurgery. 1989; 25(6):959-64 [PubMed] Related Publications

The symptoms and clinical courses of 4 patients with neurofibromatosis and lesions of the brain stem identifiable on computed tomographic and/or magnetic resonance imaging scans are described. Two patients underwent biopsy and both had low-grade astrocytomas with no evidence of anaplasia. Both received radiation and chemotherapy. The other 2 patients have been monitored without biopsy or treatment. Three patients are alive and clinically stable, having been followed up for an average of 4 years; neuroimaging studies have shown no change in their tumors. The fourth patient died of a supratentorial primitive neuroectodermal tumor. Imaging studies had shown no change in his brain stem lesion, which at autopsy was found to be a focal collection of fibrillary astrocytes. These data suggest that some patients with brain stem lesions and neurofibromatosis may have a prognosis distinctly different from that of the typical patient with a brain stem glioma. We recommend caution against aggressive operative and adjuvant therapy for brain stem lesions in patients with neurofibromatosis, unless progression of the lesion is documented clinically and/or by imaging.

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Stroink AR, Hoffman HJ, Hendrick EB, Humphreys RP
Diagnosis and management of pediatric brain-stem gliomas.
J Neurosurg. 1986; 65(6):745-50 [PubMed] Related Publications

The authors reviewed the cases of 49 children, ranging in age from 9 months to 15 years, who were diagnosed by computerized tomography (CT) as having brain-stem glioma. Four distinct groups of brain-stem gliomas were identified based on CT scan characteristics: Group I included isodense contrast-enhancing tumors that were dorsally exophytic into the fourth ventricle; Group II(a) included hypodense nonenhancing intrinsic tumors of the brain stem; Group II(b) included intrinsic tumors of the brain stem with hyperdense exophytic components extending ventrally and laterally into the cerebellopontine and prepontine cisterns; Group III included intrinsic cystic tumors with contrast-enhancing capsules; and Group IV included focally intrinsic tumors of the brain stem that were isodense and enhanced brightly on administration of contrast medium. The clinical presentation, efficacy of surgical intervention, pathology, and prognosis of these tumors were correlated within these groupings. Eleven patients had Group I tumors, all of which were surgically resected; 10 of the 11 lesions were proven to be low-grade gliomas. These patients had an excellent prognosis; 10 of the 11 survived, with a mean follow-up period of 4.5 years. There were 18 patients with Group II(a) tumors; although tumor biopsy was attempted on eight of these, pathological diagnosis at the time of surgery was made in only one case. These patients did poorly; the mean survival time was 6.2 months. The seven Group II(b) tumor patients demonstrated a similarly poor prognosis: all of them died within 23 months of diagnosis, with a mean survival time of 12 months. Only two of six patients undergoing biopsy had sufficient tissue for histological verification. Three of the four patients with Group III tumors died; their mean survival time was 11.5 months. Successful histological examination was carried out in all four cases. The nine Group IV tumor patients did reasonably well; seven of these patients remain alive, with a mean follow-up period of 2.3 years. Histological diagnosis was obtained in three of the seven patients who were explored in this group. This classification system has proven to be of value in determining prognosis and efficacy of surgical intervention.

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Tomita T, McLone DG, Naidich TP
Brain stem gliomas in childhood. Rational approach and treatment.
J Neurooncol. 1984; 2(2):117-22 [PubMed] Related Publications

Thirty-six infants and children with brain stem glioma diagnosed between 1967 and 1980 were reviewed. Posterior fossa craniotomy was performed in 25, with biopsy or partial resection in 18, cyst aspiration in 2, and exploration alone in 5. The 19 surgical specimens obtained revealed neoplastic cells in 15 but only gliosis or blood clot in 4. There was a significant discrepancy in pathological spectrum between autopsy and surgical specimens. The review of the literature shows that 51.6% of autopsy confirmed tumors were malignant while 26.8% of surgically biopsied tumors were benign. Since biopsy specimens often misrepresent the true pathology, we felt that surgery undertaken to obtain precise histological verification of brain stem gliomas is futile. Rather, we employ computed tomography (CT) with high-resolution metrizamide CT cisternography to distinguish surgically resectable extra-axial tumors adjacent to the brain stem from the unresectable intrinsic brain stem gliomas. Radiation therapy is the choice of treatment should CT indicate clear evidence of intrinsic brain stem tumor. However, posterior fossa craniotomy should be undertaken only for aspiration of cystic intrinsic stem tumors, resection of extra-axial juxtastem tumors and, although rare, in instances when CT is unable to definitively distinguish extra-axial from intra-axial mass for verification of lesion location.

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Berger MS, Edwards MS, LaMasters D, et al.
Pediatric brain stem tumors: radiographic, pathological, and clinical correlations.
Neurosurgery. 1983; 12(3):298-302 [PubMed] Related Publications

A retrospective analysis of the case histories of 21 pediatric patients (ages, 2.5 to 18 years) with a histologically proven diagnosis of brain stem glioma was performed to determine whether patterns of radiographic appearance could be correlated with pathology. Based on the computed tomographic or pneumoencephalographic appearance of the tumor at the time of clinical diagnosis, tumors were divided into four types: central intrinsic (Type I), central exophytic expansion into the 4th ventricle (Type II), eccentric exophytic expansion not involving the 4th ventricle (Type III), and both eccentric and central exophytic expansion (Type IV). Regardless of the radiographic classification, all patients except one, who harbored a well-differentiated astrocytoma in the area of the pons, had an anaplastic astrocytoma (n = 14) or a glioblastoma multiforme (n = 6). There was no appreciable difference in survival between patients with either tumor histology. The presence of a cystic component did not affect survival. High resolution computed tomographic scans, with reconstructed images of the posterior fossa, can predict the presence and location of brain stem tumors and associated cysts and probably the histological nature of the tumor.

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Rothman SJ, Olanow CW
Brain stem glioma in childhood: acute hemiplegic onset.
Can J Neurol Sci. 1981; 8(3):263-4 [PubMed] Related Publications

Two children, age seven and 16 years, are described with the abrupt onset of a pure motor hemiplegia as the initial manifestation of a brain stem neoplasm. Subsequent rapid neurological deterioration localized the lesion to the brain stem and glioblastoma multiforme was diagnosed by surgical biopsy. It is suggested that brain stem gliomas with this unusual presentation are likely to be highly malignant and prone to rapid bulbar deterioration.

Related: Childhood Brain Tumours Childhood Brain Tumors

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