Brain Tumors

CHAPTER 95 Brain Tumors

General Considerations

A century has elapsed since the early publications on the topic of brain tumors and the pioneering work of Harvey Cushing and associates. During that time, progress was recorded in all basic aspects of the diagnosis and management of these disorders. However, the past decade has witnessed the most dramatic advances in several areas. A better understanding of the molecular oncogenesis of several types of brain tumors has resulted in testing more targeted therapies. Dramatic improvement in our imaging capabilities has led to improved anatomic and functional localization of the tumor mass in relation to critical brain matter, improved surgical orientation and outcome, and enhanced delivery of radiation to the tumor with greater sparing of surrounding neural tissues.

In the absence of known risk factors underlying the genesis of the majority of brain tumors, understanding their molecular oncogenesis takes on primary importance. To this end, the development of several animal models has provided specific clues about the formation of gliomas, medulloblastomas, and neurofibromas. Such animal models are also beneficial for testing molecularly targeted small molecules, signal transduction modulators, and other therapies such as those based on immunity and biologic agents (gene, viruses). There has also been the recent discovery that tumors may be composed of a subpopulation of self-renewing progenitor cells (“stem-like” cells) that are the main culprits of resistance to treatment and may perhaps be susceptible to altogether different treatment strategies. Other molecularly based discoveries are improving our ability to classify brain tumors and better predict their clinical course and response to therapy. One example that has entered routine clinical use is that of oligodendrogliomas that harbor deletions at chromosome segments 1p and 19q. Patients with both these deletions respond better and live much longer than those without both deletions.¹ Another advance has been the improved median survivorship of patients with glioblastoma treated with the combination of temozolomide and radiotherapy and the subsequent correlation of hypermethylation of the promoter for the gene encoding methylguanine methyltransferase (MGMT) in glioblastomas with improved response to temozolomide and radiotherapy.^2,3 In fact, almost half of this subpopulation of malignant glioma patients was alive at 2 years, an impressive result considering that previous median survivorships were thought to be less than a year! The significance of knowledge gained by understanding signal transduction pathways related to tumorigenesis is underscored by the finding that only patients whose glioblastoma tumors coexpressed the gene for the variant III form of the epidermal growth factor receptor (EGFRvIII) and the tumor suppressor gene PTEN were responsive to erlotinib, an EGFR kinase inhibitor.⁴ Recent elucidation of the complete anatomy of genetic mutations present in glioblastomas now provides the blueprint not only for further dissecting mechanisms of tumor formation but also for devising improved therapy based on the spectrum of genetic mutations present in tumor.^5–7

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