Journal of Child Neurology

Central nervous system tumors are the most common solid tumors in children. Many histological subtypes and biological variants exist. The 2007 Neurobiology of Disease in Children Symposium, held in conjunction with the 36th annual meeting of the Child Neurology Society, aimed to define current knowledge in the field and to develop specific aims for future clinical, translational, and fundamental science. Because of advances in structural and metabolic imaging, surgical technique, and combination therapies, the life expectancy of children with some of the most common tumors, such as cerebellar astrocytomas and medulloblastomas, has improved. Other common tumor types, including diffuse pontine gliomas and malignant embryonal tumors, still have a dismal prognosis. As novel therapies are identified for pediatric central nervous system tumors, long-term survival may be associated with considerable disability. A cooperative effort is crucial to early diagnosis and to translating basic research findings into safe, effective new treatments.

The management of childhood brain tumors, which consist of many different histological subtypes, continues to be a challenge. Outcome, measured not only by survival rates but also by the effects of disease and therapy on quality of life, has improved over the past two decades for some tumor types, most notably medulloblastomas. For others, however, there has been little progress, and quality of life for long-term survivors remains suboptimal. Because of advances in our understanding of the biology underlying childhood brain tumors, treatments may change dramatically in the years ahead. Accordingly, survival rates may improve and long-term sequelae lessen.

Magnetic resonance technology is continually improving. Functional imaging techniques such as magnetic resonance spectroscopy, perfusion imaging, diffusion imaging, and diffusion tensor imaging are increasingly used in the diagnosis and treatment of brain tumors in children. However, estimate of tumor size remains the primary imaging endpoint in the evaluation of response to treatment, and validation across institutions and vendor platforms of magnetic resonance imaging functional parameters is necessary given the relatively uncommon occurrence of brain tumors in children. Pediatric neuroimaging can be challenging, and the optimal way to image children with tumors of the central nervous system is not uniformly applied across all centers. Application of proper scanning techniques and validation of functional imaging techniques should lead to improved care of children with central nervous system tumors.

Intracranial tumors are the most common solid tumors in children. The infratentorial compartment will be the primary site for 60% to 70% of these tumors, including astrocytomas, medulloblastomas, and ependymomas. Several technological advancements have increased our knowledge of the cell biology of pediatric brain tumors, facilitated earlier diagnosis, and improved neurosurgical resections while minimizing neurological deficits. These in turn have not only improved the survival of children with brain tumors but also their quality of life. Current management strategies in most cases rely on surgery coupled with adjuvant therapies, including radiation therapy and chemotherapy. The vulnerability of the immature brain to adjuvant therapies creates many challenges for the treating physician. We review current diagnostic and therapeutic approaches and outcome for children harboring the most common pediatric brain tumors: astrocytomas (low-grade and high-grade glioma), ependymoma, medulloblastoma, and craniopharyngioma. The emphasis will be on the neurosurgical management of children with these tumors.

During the past 3 decades, chemotherapeutic agents for the treatment of pediatric brain tumors have been extensively evaluated in a myriad of schedules, doses, and combinations. Remarkable advances in outcome have been achieved for certain children, notably those with medulloblastoma, but with a high cost to quality of life. In addition, the success achieved for medulloblastoma is offset by lack of progress for high-grade glioma. Despite intensive investigation, no single chemotherapeutic regimen stands out for children with high-grade glioma, with most succumbing to their disease. Further treatment intensification using conventional nonspecific chemotherapy is more likely to result in additional toxicity without major advances in survival. Genome-wide analysis using microarray technology has contributed significantly to our understanding of tumor biology, shifting the focus onto novel agents that target molecular changes crucial for tumor proliferation or survival. These selective agents are likely to be less toxic to normal cells and more effective.

Neurocognitive late effects are common sequelae of cancer in children, especially in those who have undergone treatment for brain tumors or in those receiving prophylactic cranial radiation therapy to treat leukemia. Neurocognitive morbidity in attention, executive functioning, processing speed, working memory, and memory frequently occurs and contributes to declines in intellectual and academic abilities. Oncologists are faced with the challenge of using the most effective, often the most intense, therapy to achieve the primary goal of medical success, balanced with the desire to prevent adverse late effects. Not all children with similar diagnoses and treatment have identical neurocognitive outcomes; some do very poorly and some do well. Attention now turns to the reliable prediction of risk for poor outcomes and then, using risk-adapted therapy, to preserve neurocognitive function. Prevention of late effects through rehabilitative strategies, continuation of school, and pharmacotherapy will be explored.

In recent years there has been a flood of interest in the relationship between brain tumors and stem cells. Some investigators have focused on the sensitivity of normal stem cells to transformation, others have described phenotypic or functional similarities between tumor cells and stem cells, and still others have suggested that tumors contain a subpopulation of ``cancer stem cells'' that is crucial for tumor maintenance or propagation. Although all these concepts are interesting and provide insight into the origins and properties of brain tumors, the use of similar terms to describe them has led to confusion. The goal of this review is to sort out some of that confusion and highlight what we know and what we have yet to learn.

Recent advances in the categorization of childhood brain tumors have improved risk-based treatment planning. In several instances, new therapeutic strategies that incorporate these advances have resulted in meaningful improvements in progression-free and overall survival. Current studies are directed at further refining therapy based on clinical, biological, and molecular data; testing the effectiveness of a number of novel therapeutic strategies for high-risk tumors; and examining approaches to reduce sequelae of treatment among more favorable-risk tumor subsets. Because multiple tumor subtypes are individually relatively uncommon, most such studies are being conducted by large co-operative groups, such as the Children's Oncology Group, or by smaller brain tumor-focused consortia, such as the Pediatric Brain Tumor Consortium.

Relatively little is known about the seminal genetic events that trigger the development of low-grade gliomas in children. Genetically engineered mouse models of the neurofibromatosis-1—inherited tumor predisposition syndrome have identified key intracellular growth control pathways, defined the contribution of the tumor microenvironment to glioma growth, and helped researchers understand the genetic basis for glioma susceptibility. In addition, genetically engineered mouse low-grade glioma models have recently been used in preclinical therapeutic studies to evaluate the efficacy of particular biologically based therapies and to define outcome measures.

Embryonal tumors are the most common brain tumors in infants less than 36 months. Histologically characterized as undifferentiated small, round cell tumors with divergent patterns of differentiation, these include medulloblastoma, the most common form of embryonal tumor, as well as supratentorial primitive neuroectodermal tumor, medulloepithelioma, ependymoblastoma, medullomyoblastoma, melanotic medulloblastoma, and atypical teratoid/rhabdoid tumor. All are similarly aggressive and have a tendency to disseminate throughout the central nervous system. Because of efforts to avoid craniospinal irradiation in an attempt to lessen treatment-related neurotoxicity, management of these tumors in infants is unique. Outcomes remain similarly poor among all the tumor types and, therefore, identification of specific molecular targets that have prognostic and therapeutic implications is crucial. The molecular and clinical aspects of the 3 most common aggressive infantile embryonal tumors, medulloblastoma, supratentorial primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor, are the focus of this review.

To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase— associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor— binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor—binding protein-2 protein (P = .027). Insulin-like growth factor— binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1—mediated migration, but not insulin-like growth factor-2—mediated migration. However, insulin-like growth factor—binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor—binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.

Although significant advances have been made in treating malignant pediatric central nervous system tumors such as medulloblastoma, no effective therapy exists for diffuse pontine glioma or intramedullary spinal astrocytoma. Biology of these 2 tumors is poorly understood, in part because diffuse pontine gliomas are not treated surgically, and tumor specimens from intramedullary spinal astrocytomas are rare and minuscule. At the 2007 Neurobiology of Disease in Children Symposium, we presented evidence that malignant glioma behaviors, including antiapoptosis, invasiveness, and treatment resistance, are enhanced by hyaluronan, an extracellular glycosaminoglycan. We review the clinical course of pediatric intramedullary spinal astrocytoma and diffuse pontine glioma, and show expression of membrane proteins that interact with hyaluronan: CD44, extracellular matrix metalloproteinase inducer, and breast cancer resistance protein (BCRP/ABCG2). Furthermore, we describe novel animal models of these tumors for preclinical studies. These findings suggest that hyaluronan antagonism has potential therapeutic value in malignant central nervous system tumors.

Ceruloplasmin (glycosylphosphatidylinositol-linked ferroxidase associated with normal astrocytes) can also be secreted by glioma cells, where its function is unknown. Ceruloplasmin is not only present in glioma cells and in human glioma specimens but also is enriched in highly malignant glioma stem-like cells. Hyaluronan is a large extracellular glycosaminoglycan that enhances malignant glioma behaviors by interacting with CD44 receptors and by downstream activation of signaling proteins and transporters associated with malignancy. We examined the relationship between hyaluronan and ceruloplasmin expression in glioma stem-like cells. Antagonism of hyaluronan interactions with short-fragment hyaluronan oligomers decreased ceruloplasmin expression in parental and stem-like glioma cells in vivo and in cell culture, implying that hyaluronan regulates ceruloplasmin expression. Further gain and loss-of-function studies are needed to fully define the relationship between hyaluronan and ceruloplasmin, and ceruloplasmin's effect on malignant behaviors.

Direct perfusion of specific regions of the central nervous system by convection-enhanced delivery is becoming more widely used for the delivery of compounds in the research and treatment of various neural disorders. In contrast to other currently available central nervous system delivery techniques, convection-enhanced delivery relies on bulk flow for distribution of solute. This allows for safe, targeted, reliable, and homogeneous delivery of small—molecular-weight and large—molecular-weight substances over clinically relevant volumes in a manner that bypasses the blood-central nervous system barrier. Recent studies have also shown that coinfused imaging surrogate tracers can be used to monitor and control the convective distribution of therapeutic agents in vivo. The unique features of convection-enhanced delivery, including the ability to monitor distribution in realtime, provide an opportunity to develop new research and treatment paradigms for pediatric patients with a variety of intrinsic central nervous system disorders.

The authors present a 21-year-old woman who has been receiving rapamycin for 5 months for bilateral subependymal giant cell astrocytomas. The patient was started at a dose of 0.2 mg/kg/day. Levels were maintained between 11 and 13 ng/mL. Magnetic resonance imaging of the brain 2½ months after initiating rapamycin demonstrated a decrease in size of both astrocytomas (11 to 7.5 mm on the right and 8 to 5 mm on the left). Further studies are needed with prolonged observation to confirm these findings, determine the length of necessary treatment, and evaluate recurrence risk after discontinuation of rapamycin.