Glial neoplasms (gliomas) are the most common primary neoplasms of the central nervous system.  Current classification systems such as the widely used World Health Organization (WHO) system typically group gliomas as either astrocytic tumors or otigodendrogliomas, a division reflecting the assumption that these tumors are derived from either astrocytes or oligodendrocytes.  Morphologic criteria such as nuclear/cytoplasm ratios, the degree of nuclear atypia, the presence or absence of mitotic activity, the degree of cellularity, vascular/endothelial proliferation and tumor necrosis are then assessed to assign a grade (II to IV under the WHO system).  Although conceptually straightforward, the application and predictive value of these classification systems is hampered by the limitations of current diagnostic techniques.  Reliance on morphologic assessment in hematoxylin and eosin-stained tissue sections is fraught with difficulty as some gliomas demonstrate features of both astrocytic and oligodendroglial differentiation or are frankly unclassifiable.  Dilemmas of this sort are typically difficult to resolve with immunohistochemistry as relatively few immunohistochemical markers are currently available for specific glioma subtypes.  Consequently, assigmnent of a glioma to a presumed cell of origin is frequently highly subjective.  These difficulties are compounded by a lack of consensos among neuropathologists regarding objective grading criteria.  Clearly, a more objective system for classifying and grading glial neoplasms is badly needed.  Ideally, such a system would consider the molecular changes found in each glioma and use this information to augment and complement tradicional histopathologic approaches.

In support of this proposal, a series of studies examining the genetic alterations encountered in gliomas have demonstrated that certain abnormalities are characteristic of astrocytomas and oligodendroglionias and that additional genetic abnormalities accumulate as these neoplasms progress in grade.  Genes whose expression is altered in astrocytic neoplasms include the epidermal growth factor receptor gene, the tumor suppressor gene p53, the p53 binding protein mouse double minute 2 (mdm2), the cell cycle inhibitor gene INK4a-ARF and the tumor suppressor MMAC1/PTEN.  These alterations accumulate within astrocytic tumors as neoplastic progression occurs, with p53 mutations found in anaplastic astrocytomas and additional abnormalities becoming evident as tumors progress to become glioblastomas.  In contrast, oligodendroglial neoplasms demonstrate loss of heterozygosity (LOH) of chromosome regions 1p and 19q.  Identification of this LOH in oligodendrogliomas has recently assumed special importance as these genetic alterations have been found to predict better responsiveness to combination chemotherapy.

The genetic changes noted above undoubtedly represent only a small fraction of the myriad genetic alterations that occur as gliomas develop and progress.  Consequently, as new high throughput techniques such as CDNA microarray analyses are applied to this vexing clinical problem, it is likely that an ever increasing number of genetic abnormalities will be identified in astrocytomas and oligodendrogliomas.  This information will greatly facilitate efforts to more precisely classify these neoplasms and design therapeutic regimens effectively targeting a specific tumor.

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Multiple Sclerosis is an organ-specific, autoimmune disease of the central nervous system (CNS) characterized by inflammatory demyelination and varying degrees of axonal damage.  A polygenic susceptibility in combination with an environmental agent, presumably one of a number of infectious agents, leads to the onset of symptoms characteristically in young adult life and presumably some years after the environmental exposure.  Both cellular and humoral immune factors play a role in the pathogenesis of multiple sclerosis.  The disease itself is characterized by clinical, neuroimaging and pathological heterogeneity.  Recently recognized is the fact that there are four distinct subtypes of the pathological changes in multiple sclerosis which show intra-individual homogeneity throughout the various lesions existing in the CNS of a single patient with multiple sclerosis.  The treatment of multiple sclerosis can be generally divided into relapse management, modification of the natural history of the disease, and symptomatic therapy for a number of problems encountered by the patient with multiple sclerosis.  Relapse management utilizes glucocorticoids given short-term as high-dose intravenous methylprednisolone followed by a brief oral prednisone taper.  There are now five drugs approved for the treatment of multiple sclerosis to alter the natural history of the disease by decreasing the number and severity of relapses, slowing progression, and lessening the damage detected on magnetic resonance imaging.  These are interferon beta-la (Avonex or Rebif), interferon beta-1b (Betaseron), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone).  Current studies are examining the equivalence of the immunomodulatory agents of interferon beta- 1 b, interferon beta- 1 a and glatiramer acetate for their impact on early relapsing-remitting disease.  Mitoxantrone is undergoing further investigation of its approved benefit in slowing progression and suppressing active relapsing disease.  Symptomatic management continues to evolve with mostly off-label use of new drugs such as modafinil (Provigil) for fatigue.  New treatment strategies involve more precise direction of immunomodulatory and immune-based therapy.

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