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Necrosis and vascular proliferation are the pathologic features that distinguish the most malignant infiltrative astrocytoma, glioblastoma (GBM), from those of lower grades. In GBM, hypercellular zones called pseudopalisades typically surround necrotic foci. Although these cells are known to secrete high levels of proangiogenic factors that promote tumor growth, their origins are ill defined. We propose that pseudopalisades represent differing stages and histologic samplings of astrocytoma cells migrating away from a hypoxic/anoxic focus, often triggered by a central vaso-occlusive event. This proposition is based on our findings that pseudopalisading cells are 5-50% less proliferative and 6 -20 times more apoptotic than adjacent astrocytoma, indicating that cell accumulation does not result from increased proliferation or resistance to apoptosis. Coexisting inflammatory cells account for <2% of pseudopalisading cells and cannot account for hypercellularity. Pseudopalisading cells show nuclear expression of hypoxia-inducible factor 1␣, consistent with their hypoxic nature, and hypoxia induces a 20 -60% increase in glioma cell migration in vitro. Hypoxic cells in vitro and pseudopalisades in GBM specimens show enhanced gelatinase activity, typical of an invasive phenotype. These results suggest that pseudopalisading cells are migrating at the periphery of a hypoxic center. To uncover a potential source of hypoxia and sequence of structural events leading to pseudopalisade formation, we performed a morphometric analysis of 234 pseudopalisades from 85 pretreatment GBMs. We found distorted, degenerating, or thrombosed blood vessels within the center of more than half the pseudopalisades, suggesting that at least a subset of pseudopalisades are two-dimensional histologic representations of tumor cells migrating away from a vaso-occlusive event.

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Brain Angiogenesis Inhibitor 1 (BAI1) is a putative G protein-coupled receptor with potent anti-angiogenic and anti-tumorigenic properties that is mutated in certain cancers. BAI1 is expressed in normal human brain, but it is frequently silenced in glioblastoma multiforme (GBM). In this study we show this silencing event is regulated by overexpression of methyl-CpG-binding domain protein 2 (MBD2), a key mediator of epigenetic gene regulation, which binds to the hypermethylated BAI1 gene promoter. In glioma cells, treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine (5-Aza-dC) was sufficient to reactivate BAI1 expression. Chromatin immunoprecipitation (ChIP) showed that MBD2 was enriched at the promoter of silenced BAI1 in glioma cells and that MBD2 binding was released by 5-Aza-dC treatment. RNAi-mediated knockdown of MBD2 expression led to reactivation of BAI1 gene expression and restoration of BAI1 functional activity, as indicated by increased anti-angiogenic activity in vitro and in vivo. Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the anti-angiogenic activity of a key tumor suppressor. These findings have therapeutic implications since inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology.

BackgroundVariant Creutzfeldt–Jakob disease (vCJD) is a prion disease thought to be acquired by the consumption of prion-contaminated beef products. To date, over 200 cases have been identified around the world, but mainly in the United Kingdom. Three cases have been identified in the United States; however, these subjects were likely exposed to prion infection elsewhere. Here we report on the first of these subjects.Methodology/Principal FindingsNeuropathological and genetic examinations were carried out using standard procedures. We assessed the presence and characteristics of protease-resistant prion protein (PrPres) in brain and 23 other organs and tissues using immunoblots performed directly on total homogenate or following sodium phosphotungstate precipitation to increase PrPres detectability. The brain showed a lack of typical spongiform degeneration and had large plaques, likely stemming from the extensive neuronal loss caused by the long duration (32 months) of the disease. The PrPres found in the brain had the typical characteristics of the PrPres present in vCJD. In addition to the brain and other organs known to be prion positive in vCJD, such as the lymphoreticular system, pituitary and adrenal glands, and gastrointestinal tract, PrPres was also detected for the first time in the dura mater, liver, pancreas, kidney, ovary, uterus, and skin.Conclusions/SignificanceOur results indicate that the number of organs affected in vCJD is greater than previously realized and further underscore the risk of iatrogenic transmission in vCJD.

Gliomas of the optic nerve, although typically of pilocytic (WHO grade I) histology, can present within the spectrum of astrocytic neoplasia including glioblastoma (WHO grade IV). In certain cases, histologic features alone make the distinction between pilocytic and diffuse astrocytomas difficult. We reviewed 22 cases of optic nerve gliomas, 19 of which were pilocytic astrocytomas (PA), and 3 of which were diffuse, non-pilocytic astrocytomas. The cases were evaluated for their clinical course, radiographic appearance, histologic grade, and proliferation indices as detected by MIB-1 (Ki-67) and p53 antibodies. Of the 19 PA, 14 showed no tumor growth by magnetic resonance imaging, and had Ki-67 and p53 labeling indices (LI) of < 1%. The other 5 PA exhibited aggressive behavior manifest by marked diffuse infiltrative tumor growth causing death in 2 patients, 1 of whom was diagnosed with neurofibromatosis type 1 (immunoperoxidase and radiographs not available), and marked local growth with an average time to growth of 39.3 months, a Ki-67 LI of 2-3%, and a p53 LI of < 1% in three others. Three of the five aggressive PA histologically demonstrated a finely reticulated pattern, a pattern that appears as an exaggeration or expansion of the normal neuroglia of the optic nerve, and may simulate a diffuse low-grade astrocytoma. Two demonstrated the coarsely reticulated pattern, with the biphasic and microcystic pattern typical of PA. Three diffuse astrocytomas (2 anaplastic astrocytomas and 1 glioblastoma) originated clinically and radiographically from the optic nerve, and revealed a Ki-67 LI of 2-12%, a p53 LI of 2-8%, and an average time to growth of 8 months. We conclude that the majority of PA of the optic nerve are non-aggressive, stabilize radiographically, and have Ki-67 and p53 LI < 1%. However, a subpopulation of PA has a propensity for aggressive behavior, and are identified by a Ki-67 LI of 2-3% and a p53 LI of < 1%. Diffuse astrocytomas have both Ki-67 and p53 LI > 2%. Thus, in cases of aggressive optic nerve tumors in which the histologic review of biopsy material cannot confidently confirm the diagnosis of pilocytic or diffuse fibrillary glioma, a p53 LI of > 1% appears to favor the diagnosis of diffuse astrocytoma.

Glioblastoma multiforme (GBM) is the highest-grade infiltrative astrocytoma and also the most common. It is generally associated with a dismal prognosis (mean survival 11 months), yet individual patient survivals vary. Histologic parameters have had limited value in predicting survival among patients with GBM. The current view of GBM as a histopathologic entity consisting of several genetic subtypes raises the possibility that molecular alterations could be predictive of survival. Common genetic alterations in GBM include gene amplification of epidermal growth factor receptor (EGFR), mutations in the tumor suppressors TP53 and PTEN, and genetic losses on chromosome 10. Less common in GBMs is the combined loss of chromosomes 1p and 19q-a combination that has proven prognostically favorable in oligodendrogliomas. A recent article on prognostic factors in a series of 97 GBMs by Schmidt et al. finds that both TP53 mutations and young patient age at presentation are independent factors associated with a long survival. Loss of heterozygosity (LOH) of chromosome 10q was predictive of a poor outcome. Perhaps most intriguing, the finding of combined LOH of 1p and 19q, which was noted in only five GBMs, was associated with a significantly longer survival. Thus, combined losses of 1p and 19 may be associated with a favorable prognosis in a wider range of infiltrative gliomas that includes GBM. While these findings will be debated and need to be confirmed, it is clear that genotyping of infiltrative gliomas will be an important component of neuro-oncology in the future. Not only will genetic alterations offer prognostication, but they will also serve as targets for directed therapies. Treatments directed against tumors with EGFR amplification, TP53, mutations and PTEN mutations are being developed and tested in clinical trials. It remains to be seen if GBMs with 1p and 19q losses are chemosensitive in the same manner as oligodendrogliomas.