Pediatric brain stem gliomas: A review

doi:10.1016/S0360-3016(97)00572-5

International Journal of Radiation OncologyBiologyPhysics

Volume 40, Issue 2, 15 January 1998, Pages 265-271

https://doi.org/10.1016/S0360-3016(97)00572-5 Get rights and content

Abstract

Tumors arsing in the brain stem, comprising the midbrain, pons, and medulla oblongata, are now recognized as distinct clinico-pathological entities. Advances in neurosurgical techniques have made surgery not only feasible but the treatment of choice for some of these tumor types. Previously the mainstay of treatment, radiotherapy is now used more selectively. This article reviews the current state of knowledge with regard to tumors arising in the brain stem, the therapeutic options available for each, and provides recommendations with regard to management.

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Citation Excerpt :
Diffuse intrinsic pontine glioma (DIPG) accounts for approximately 10% of all central nervous system tumors and 80% of all pediatric brain stem tumors. Around 300 children are diagnosed with DIPG annually in the United States,1 but it represents the most common cause of death in pediatric patients with a brain tumor. It is estimated that DIPG is responsible for approximately 24,000 years of potential life lost in the United States.2
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The median OS for the HF1, HF2, and CF were 9.6, 8.2, and 8.7 months, respectively. The 1-, 1.5-, and 2-year OS were 34.6%, 17.9%, and 10.7% for HF1; 26.2%, 13.1%, and 4.8% for HF2; and 25.3%, 12.1%, and 8.4% for CF, respectively (P = .3). The hazard ratio was 0.776 and 1.124 for HF1 and HF2, respectively. Considering the noninferiority margin (Δ) of 15% and a power of 90%, the lower inferiority confidence interval for HF1 was –14.34% and for HF2 it was 11.37% (both below Δ), confirming its noninferiority at 18-months OS. Younger patients (2-5 years of age) had better median OS in the whole cohort (11.6 months), HF1 (13.5), and CF (12.1) but not HF2 (6.2) (P = .003). Furthermore, the OS rates at 1, 1.5, and 2 years for children 2 to 5 years of age in the HF2 arm were lower than those in the HF1 and CF arms. However, similar acute and late side effects were reported in the 3 arms.
Two hypofractionated radiation therapy proved to be noninferior to conventional fractionation. Young age (2-5 years) is the only prognostic factor determining both OS and PFS. The young age superiority was lost with a higher hypofractionated radiation therapy dose, necessitating more caution in applying 45 Gy in 15 fractions in younger children (2-5 years of age).
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As an intractable central nervous system (CNS) tumor, brainstem glioma (BG) is one of the leading causes of pediatric death by brain tumors. Owing to the risk of surgical resection and the little improvement in survival time after radiotherapy and chemotherapy, there is an urgent need to find reliable model systems to better understand the regional pathogenesis of the brainstem and improve treatment strategies. In this review, we outline the evolution of BG murine models, and discuss both their advantages and limitations in drug discovery.
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Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.
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Critical reviewPediatric brain stem gliomas: A review

Abstract

Neurosurg. Clin. of North Am

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Neurosurg. Clin. North Am.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Surg. Neurol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Intrinsic tumors of the medulla: Predicting outcome after surgery

Pediatr. Neurosurg.

Prognostic factors in pediatric brain-stem gliomas

J. Neurosurg.

Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: A report from the Children's Cancer Group

Neurosurgery

Contemporary chemotherapy issues for children with brainstem gliomas

Pediatr. Neurosurg.

Brain stem gliomas: A classification system based on magnetic resonance imaging

Pediatr. Neurosurg.

Gliomas of the tectum and periaqueductal region of the mesencephalon

Pediatr. Neurosurg.

Direct surgery for brainstem tumors

Acta. Neurochir. Suppl.

Hyperfractionated radiotherapy for brain-stem glioma: A phase-I-II trial

J. Neurosurg.

Brain-stem glioma growth patterns

J. Neurosurg.

Intrinsic brain-stem tumors of childhood: Surgical indications

J. Neurosurg.

Hyperfractionated radiotherapy for diffuse intrinsic brain stem tumors in children

Pediatr. Neurosurg.

Long term survivors of childhood brain stem gliomas of childhood brain stem gliomas treated with hyperfractionated radiotherapy. Clinical characteristics and treatment related toxicities

Cancer

Hyperfractionated radiotherapy for brain-stem tumors. Results at the 7020 cGy dose level of Pediatric Oncology Group Study #8495

Cancer

Critical review
Pediatric brain stem gliomas: A review