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In the United States, 11,900 children and adolescents under the age of 20 were diagnosed with cancer in 2001 and about 2,200 died of the disease. The diagnosis of invasive brain and nervous system cancers accounts for 17 percent of all pediatric cancers, second only to acute lymphocytic leukemia. About half of the diagnosed cases of brain tumors are malignant.

Although there are fifty neuroepithelial pediatric tumor classifications, medulloblastoma, a tumor arising in the lower portion of the brain that can spread to other regions of the brain and spinal cord, is the most common type of malignant childhood central nervous system cancer. Astrocytomas, a malignancy of cells (astrocytes) located throughout the brain, and brain stem gliomas, tumors that grow in the central region of the brain which can involve the spinal cord, are other types of pediatric brain tumors.

Although the annual mortality rate of pediatric cancer has decreased over the past two decades, the proportion of deaths from tumors of the central nervous system in the same population has increased from 18 percent to 30 percent. These figures clearly highlight the lack of positive outcomes in children with central nervous system malignancies compared to other pediatric tumors.

The cause of childhood brain tumors is largely unknown. While radiation exposure is a recognized risk factor for brain tumors, the role of other environmental toxins is unclear in children. "Less than 5 percent of pediatric brain tumors are associated with a known genetic disease, such as neurofibromatosis, a common genetic condition associated with benign tumor growths on nerve tissue," said Katherine Warren, M.D., pediatric neuro-oncologist at the National Cancer Institute. "Although only 1 percent of childhood brain tumors are detected at birth or in the first few months of life, a significant number are diagnosed before age five, suggesting a developmental defect. As a matter of fact, defects in developmental growth signaling pathways have recently been identified in embryonal tumors."

Historically, a diagnosis of brain cancer is provided by a pathologist, who views tissue samples under a microscope. Upon visual inspection of brain cells (histology), pathologists can then classify the tumor type. The limitations of this practice are that many brain tumors have a similar histology when they are actually very different tumors with greatly different prognoses and responses to therapies. "There are some children diagnosed with medulloblastoma who respond well to therapy while others do not,"

Warren explained. "And you can't tell the difference by looking under the microscope." In this new era of genomic analysis, tumor classification is moving toward the use of molecular signatures to more precisely classify and grade tumor tissues. In pediatric oncology, a major issue is the treatment of developing brain tissue where the potential for neurotoxicity is considerable. "If we could divide kids into different groups based on their prognosis, then those who don't need aggressive therapy could be identified and treated less aggressively," said Warren.

In addition to confusing tumor classifications, in the past, pediatric tumors were considered to be similar to tumors in adults. However, recent studies have revealed that pediatric brain tumors are very different biologically than their adult counterparts.

"What's been happening recently is that we are realizing that pediatric tumors are different from adult tumors in many ways. Recent genetic and molecular testing on some pediatric tumors have revealed significant differences," Warren said. "One example is a tumor called fibrillary astrocytoma, a tumor that occurs both in children and adults. Biologically they behave very differently even though they look the same under the microscope. This disease in children rarely will become a high-grade tumor during childhood years, but in adults it can turn into higher grade tumors and nobody knows why." These observations are further supported by recent studies of molecular markers. Mutations in specific genes that cause disease in adults may not be the cause of disease in children. Future studies should provide fertile opportunities for drug target discoveries and related molecularly targeted therapies.

The use of surgery in treatment of pediatric brain tumors is well-established, but more effective treatments are needed. Imaging technologies have been used to non-invasively assess tumor status and treatment in children, thus eliminating the need to obtain repeated biopsies of the same tumor. The gains achieved in improved surgical resection of brain tumors also can be attributed to improved imaging technologies. Surgeons are now better able to locate a tumor and assess the margins, removing less of the normal brain tissue. This is a significant improvement because there is a direct correlation between the extent of tumor resection and survival in some types of brain tumors in pediatric patients.

Improved imaging technologies have also spurred advances in radiation therapy techniques. "For kids we are trying to tone down the radiation -- to just deliver it to the tumor itself using a method called conformal radiation. We follow the outline of the tumor and give a small margin around it. The theory behind this is that normal brain tissue is less likely to be exposed to radiation," Warren said. "All of these advances are possible due to imaging. Everything is tying together. We are doing molecular analyses to see which patients need more intensive therapy and then through the advances in imaging use conformational radiation to treat the tumor."

In addition to providing information about the size and location of a tumor, imaging techniques are also providing data to evaluate the biochemical profile of the tumor,as well. Studies have shown that changes in the ratio of certain biochemical components of a tumor can aid an oncologist in determining if a tumor is actively growing. These results would support the choice of aggressive or less stringent treatment regiments.

Blood flow to tumors and tissues in the brain is also being examined through imaging. Evaluation of changes in the amount of blood flowing to tissues in the brain is essential to assess the effectiveness of anti-angiogenic drugs. These drugs do not target the tumor directly, but attack the cells lining the blood vessels that support tumor growth. The tumor size may not shrink, but a decrease in the number of blood vessels surrounding the tumor is a significant advance.

Warren noted, "Anti-angiogenic drugs will most likely be combined with other agents that target the tumor directly. Currently, these agents are being tested alone for safety. Safety is always a concern when adopting new therapies to the pediatric patient population. So we lag behind the adults. There has been an issue with getting drugs to pediatric patients faster, so NCI has proposed a combined adult and pediatric trial that is still under discussion."

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