Faculty Bibliography

The expression of the extracellular matrix glycoprotein tenascin-C (TN) is enhanced in human astrocytomas and correlates with angiogenesis. To determine whether vascular cells are able to synthesize TN, we investigated the expression of TN protein and mRNA in nine astrocytomas. Immunogold electron microscopy in two glioblastomas multiforme detected the presence of TN in an extracellular perivascular location and to a lesser extent among tumor cells, confirming light microscopy immunohistochemical findings. In situ hybridization of astrocytomas using a digoxigenin-labeled antisense riboprobe detected strong staining for TN mRNA in vascular cells, especially in hyperplastic vessels, including those at the invasive edge of the tumors but not in vessels of normal brains. We observed weaker staining in tumor cells indicating a higher level of TN mRNA in vascular than in tumor cells. No staining was detected with the sense probe. Moreover, we investigated the ability of human brain microvessel endothelial cells (HBMECs) in primary culture to synthesize TN in vitro. Western blot analysis of the culture supernatants from HBMECs detected large amounts of TN. Immunogold silver staining demonstrated the presence of TN on the surface of HBMECs and in the subendothelial matrix. The distribution of TN mRNA in vascular cells of astrocytomas and the ability of HBMECs to synthesize TN in vitro demonstrate that vascular cells, including endothelial cells, are a major source of TN associated with angiogenesis. Furthermore, our results suggest that TN expression may be associated with endothelial cell activation and may play an important role in angiogenesis

A consecutive series of six patients underwent operative resection of intramedullary spinal cord subependymomas between January 1981 and August 1993. Three men and three women between the ages of 26 and 66 years experienced symptoms for a mean of 50 months preceding diagnosis. The locations of the tumors were predominantly cervical or cervicothoracic, except in one patient. At operation, a complete extirpation was achieved in each patient. No patient received further adjunct therapy. There has been no tumor recurrence in any patient after a mean follow-up period of 39 months. Most of the intramedullary spinal cord tumors are either ependymomas or astrocytomas. Clinical histories, physical examinations, and radiographic investigations are not conclusive for absolute diagnosis of subependymomas; however, intraoperative gross observations have shown these well-demarcated tumors to be located eccentrically within the spinal cord. Pathological examinations demonstrate tumors with sparse cellularity, clustering of cells, and dense fibrillary stroma. Proliferation studies with the mouse monoclonal antibody MIB-1 reconfirm the slow growth potential of these benign tumors

An important contributor to the malignancy of brain tumors is their ability to infiltrate the brain. Extracellular matrix molecules and cell adhesion molecules on cell surfaces play key roles in cell migration. In the present study, we used reaggregates of dissociated cells from freshly excised human brain tumors to analyze the migration of cells from human brain tumors of different types and grades on many different adhesion proteins adsorbed to glass substrates. Proteins were chosen based on their presence in normal or neoplastic nervous tissue, and included the extra-cellular matrix molecules fibronectin, collagens, fibrinogen, laminin, tenascin-C, thrombospondin, and the neuron-glia cell adhesion molecule, Ng-CAM. Cells from astrocytomas (n = 24) migrated on a variety of substrates, in contrast to cells from primitive neuroectodermal tumors cells (n=6), which only migrated well on laminin, fibronectin, or type IV collagen but not on the other substrates. Typically, migrating cells from astrocytomas of all grades had long, slender processes, were usually bipolar, and their cell bodies did not spread well on any substrate. Although there was variability in the migration of cells from astrocytomas of the same grade, cells from high-grade astrocytomas tended to migrate more extensively (42.3 +/- 4.7 micrometers/16 h: n = 16) than cells from lower grade astrocytomas (28.9 +/- 3.9 micrometers/16 h; P = 0.07; n = 8); the most striking differences were observed for collagen substrates, on which cells from lower grade astrocytomas migrated at very low levels (7.6 +/- 2 .6 micrometers/16 h) and cells from high-grade astrocytomas at higher levels (24.4 +/- 5.2 micrometers;P = 0.01). In contrast to primary cells from glioblastomas (n = 13), glioblastoma cell lines (n = 10) consistently spread on various substrates and migrated at high levels (69.5 +/- 7.6 versus 46.4 +/-5.7 micrometers/16 h; P = 0.03), in particular, on collagens (108.4 +/- 20.2 versus 28.0 +/- 6.1 micrometers/16 h; P= 0.001). Specific monoclonal antibodies to alphaV and beta1 integrin monomers completely inhibited the migration of astrocytoma cells on most substrates, suggesting that alphaV and beta1 integrins play a crucial role in brain tumor infiltration. These studies also suggest that although a large number of extracellular matrix molecules may promote tumor cell migration, disrupting the function of only a few tumor cell receptors may be critical for tumor infiltration in the brain

'Blood vessels have the power to increase within themselves which is according to the necessity whether natural or diseased. As a further proof that this is a general principle, we find that all growing parts are much more vascular than those that are come to their full growth; because growth is an operation beyond the simple support of the part. This is the reason why young animals are more vascular than those that are full grown. This is not peculiar to the natural operation of growth, but applies also to disease and restoration.'

We investigated the expression and distribution of the extracellular matrix protein tenascin (TN) in 59 astrocytomas and 11 samples of normal brain by Western blot analysis and immunohistochemistry using antibodies against human TN. The tumors included 14 juvenile pilocytic astrocytomas (grade 1), 13 low grade fibrillary astrocytomas (grade II), 8 anaplastic astrocytomas (grade III), and 24 glioblastomas multiforme (grade IV). Proliferation indices were calculated by computer-based image analysis after immunostaining with the MIB-1 antibody against the Ki-67 proliferation-associated antigen. Western blot analysis for TN on fresh frozen tumor tissue from 23 of the 59 astrocytomas indicated up to 4-fold higher TN expression in glioblastomas multiforme than in nontumorous control tissues. Enhanced intercellular expression of TN was observed by immunohistochemistry in glioblastomas multiforme. More-over, TN immunostaining was consistently greater within and around the walls of hyperplastic blood vessels than nonhyperplastic vessels of both high grade tumors and juvenile pilocytic astrocytomas. Juvenile pilocytic astrocytomas with increased TN expression by Western blot analysis had vascular hyperplasia by light microscopy. Proliferation indices moderately correlated with tumor grade. Enhanced immunohistochemical expression of TN was associated with higher tumor grade with higher proliferation indices. The strong association of TN and vascular hyperplasia, regardless of tumor grade, suggests that TN may play a crucial role in angiogenesis

A rare case of frontonasal encephalocele associated with a congenital brain tumor is presented. We describe our combined extracranial and intracranial approach to correction of frontonasal encephaloceles. A discussion of frontonasal encephaloceles and neonatal brain tumors follows, with a discussion of embryopathogenesis and surgical correction

Pathological and clinical data from 56 patients operated on for craniopharyngioma since 1981 were analyzed to determine the utility of dividing patients with this tumor into distinct clinical groups based on recognized pathological type and to determine the prognostic import of brain invasion. Of the tumors in the 30 adult patients, 66% were adamantinomatous, 28% were squamous papillary, and the remainder were mixed. However, of the tumors in the 26 children, 96% were adamantinomatous and none were pure squamous papillary (P < 0.01). Forty-six percent of the children compared with 17% of the adults had brain invasion (P < 0.01). Brain invasion was present in 37% of the adamantinomatous but in only 13% of the squamous papillary tumors. Seventy-seven percent of the children underwent gross total resection (GTR) compared with 27% of the adults (P < 0.01). Sixty-three percent of the squamous papillary tumors underwent GTR compared with 54% of the adamantinomatous and mixed tumors. Follow-up ranged from 7 to 187 months (mean, 49 mo). After subtotal resection, with or without radiation therapy, 58% of the tumors recurred compared with 17% recurrence after GTR (P < 0.01), with a mean time to recurrence of 34 months. In both tumor histological types, subtotal resection was associated with a higher rate of tumor recurrence compared with gross total resection. Among the subtotally resected craniopharyngiomas, 2 of the 3 (67%) squamous papillary and 11 of the 21 (52%) adamantinomatous and mixed tumors recurred. In contrast, among the totally resected tumors, none of the 5 squamous papillary and only 5 of the 25 (20%) adamantinomatous and mixed tumors recurred. There were no significant differences in Karnofsky performance status score, mortality rate, or visual and endocrine outcomes when comparing patients based on histological tumor type. When controlling for age and extent of resection, we found that brain invasion had no significant effect on recurrence rate in totally resected tumors. Based on the limited number of patients in this series, we conclude as follows. 1) Contrary to previous reports, squamous papillary craniopharyngiomas, like adamantinomatous tumors, may recur when subtotally resected. 2) For both tumor variants, the most significant factor associated with craniopharyngioma recurrence is the extent of surgical resection rather than histopathological subtype. 3) Contrary to prior hypotheses, brain invasion in totally resected tumors does not predict higher recurrence. 4) GTR is associated with a significantly lower recurrence rate and can be achieved without sacrificing functional outcome