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Rolando F. Del Maestro

✓ The human race has always contemplated the question of the anatomical location of the soul. During the Renaissance the controversy crystallized into those individuals who supported the heart (“cardiocentric soul”) and others who supported the brain (“cephalocentric soul”) as the abode for this elusive entity. Leonardo da Vinci (1452–1519) joined a long list of other explorers in the “search for the soul.” The method he used to resolve this anatomical problem involved the accumulation of information from ancient and contemporary sources, careful notetaking, discussions with acknowledged experts, and his own personal search for the truth. Leonardo used a myriad of innovative methods acquired from his knowledge of painting, sculpture, and architecture to define more clearly the site of the “senso comune”—the soul. In this review the author examines the sources of this ancient question, the knowledge base tapped by Leonardo for his personal search for the soul, and the views of key individuals who followed him.

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Rolando F. Del Maestro

✓ The development of the Drake fenestrated aneurysm clip is a study in the history of ideas. This communication outlines the conception and solution of a surgical problem involved with the clipping of large basilar tip aneurysms. Dr. Charles G. Drake's ability to modify old ideas and experiment with new ones was instrumental to the conceptual idea of a fenestrated clip. Dr. Frank H. Mayfield and Mr. George Kees, Jr. played essential roles in bringing the idea to a reality. The development of the fenestrated clip has added substantially to the armamentarium of the aneurysm surgeon in dealing with large and complex aneurysms.

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Howard R. Reichman, Catherine L. Farrell and Rolando F. Del Maestro

✓ Cerebral edema produced by brain tumors is clinically and experimentally reduced by steroid therapy. Nonsteroid anti-inflammatory drugs (NSAID's) which have been used to treat non-neural inflammation and swelling have not been evaluated for their ability to affect edema produced by brain tumors. The authors have used the rat C6 glioma spheroid implantation model to compare the effects of two steroids (dexamethasone and methylprednisolone) and two NSAID's (ibuprofen and indomethacin) on protein extravasation caused by intracranial gliomas. Evans blue dye was used as a marker for serum albumin extravasation. The concentration of Evans blue dye was measured in the tumor and peritumoral and contralateral brain tissue 1 hour after intravenous injection.

Extravasation of Evans blue dye within the tumor was decreased in all treatment groups when compared to placebo-injected control animals. The differences between the control specimens and those treated with dexamethasone, methylprednisolone, and indomethacin were highly significant (p < 0.005). The Evans blue staining was also decreased in the peritumoral and contralateral brain. These results indicate that NSAID's compare favorably with steroids in diminishing tumor-induced protein extravasation. It is suggested that NSAID's may prove to be beneficial in clinical instances used either in conjunction with steroid therapy or alone when steroids are contraindicated.

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Meric A. Altinoz, Carlo Santaguida, Marie-Christine Guiot and Rolando F. Del Maestro

✓ The authors describe the case of a patient with von Hippel—Lindau (VHL) disease in which a spinal hemangioblastoma contained metastatic renal cell carcinoma (RCC). The literature on tumor-to-tumor metastasis associated with VHL disease of the central nervous system (CNS) is reviewed.

Midthoracic back pain developed in this 43-year-old man with a left-sided radicular component 2 years after he underwent resection of a left RCC. Radiological findings demonstrated a T6–7 intradural intramedullary lesion. A T5–8 laminectomy and gross-total resection of the spinal cord mass were performed. Light and electron microscopic examination showed features of hemangioblastoma, which contained metastatic foci of RCC. Genetic analysis demonstrated the presence of a deleting mutation in the first exon (nt. 394–406) of the VHL locus, truncating 16 amino acids (N61–77) from the first beta sheet in the VHL protein. A review of the literature revealed that RCC-to-CNS hemangioblastoma is the second most common donor—recipient tumor association among the tumor-to-tumor metastases.

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Catherine L. Farrell, Joseph Megyesi and Rolando F. Del Maestro

✓ The effects of long-term low- and high-dose ibuprofen on tumor growth and permeability were assessed in a glioma model in rats. The rats were treated with ibuprofen (24 mg/kg/day or 96 mg/kg/day) for 24 hours before implantation of C6 astrocytoma spheroids and then for 13 days following implantation. The wet and dry weight of the tumors and protein extravasation were measured by an Evans blue dye technique. Protein extravasation did not appear to be reduced by the treatments when assessed on the basis of tumor dry weight. The treatment significantly reduced the wet weight of the tumors in rats treated with high-dose and low-dose ibuprofen when compared to tumor wet weights in untreated rats. High-dose ibuprofen treatment significantly decreased the dry weight of the tumors compared to that of tumors in untreated control animals. It is hypothesized that the ibuprofen treatment regimen employed inhibits prostaglandin-associated angiogenesis induced by the C6 tumor cell growth and/or the implantation technique, thereby interfering with the ability of the tumors to grow.

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Mahmoud Al-Yamany and Rolando F. Del Maestro

Object. Subdural fluid collections following transcortical intraventricular and/or paraventricular neurosurgical procedures for tumors are common and can be difficult to treat. The authors prospectively studied the efficacy of a fibrin adhesive (Tisseel) in closing cortical and ependymal defects following intraventricular and/or paraventricular lesion resection and in preventing the development of subdural fluid collections.

Methods. Twenty-five patients who underwent 29 transcortical approaches for the resection of intraventricular and/or paraventricular lesions were studied. No patient developed a symptomatic subdural fluid collection and no new seizure or progression of a preexisting seizure disorder was encountered during a median follow-up time of 29 months (range 1–57 months). The incidence of preoperative hydrocephalus was 72% and four (22%) of these patients required postoperative shunt placement.

Conclusions. The use of a fibrin adhesive to seal cortical and ependymal defects after transcortical procedures appears to prevent the development of subdural fluid collections.

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Masashi Tamaki, Warren McDonald and Rolando F. Del Maestro

✓ Type IV collagen is a major protein component of the vascular basement membrane and its degradation is crucial to the initiation of tumor-associated angiogenesis. The authors have investigated the influence of cell density on the release of collagen type IV degrading activity by C6 astrocytoma cells in monolayer culture. The release of collagen type IV degrading activity was assessed biochemically, immunocytochemically, and by Western blot analysis. The results demonstrate that increasing plating density and increasing cell density are associated with decreased collagen type IV degrading activity released per tumor cell. These findings indicate the existence of regulatory mechanisms dependent on cell—cell communication, which modulate release of collagen type IV degrading activity. The extrapolation of these results to the in vivo tumor microenvironment would suggest that individual and/or small groups of invading tumor cells, distant from the main tumor mass, would release substantial collagen type IV degrading activity, which may be crucial to their continued invasion and to angiogenesis.

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Carl D. Lordo, Eric C. Stroude and Rolando F. Del Maestro

✓ Brain-tumor patients often undergo radiation therapy while receiving corticosteroids for the treatment of cerebral edema. Studies have demonstrated that dexamethasone is radioprotective in a number of cell lines. The C6 astrocytoma cell line is well established in vitro and is modulated by dexamethasone treatment. It has therefore been hypothesized that dexamethasone-treated C6 astrocytoma cells would be more resistant to radiation-induced damage.

The present study was carried out to assess this hypothesis using both the in vitro C6 astrocytoma monolayer and three-dimensional multicellular spheroid models. Dexamethasone was inhibitory to the C6 astrocytoma cells in the monolayer preparation, increasing their doubling time by 13%. In the spheroid cultures, dexamethasone treatment decreased the number of cells per spheroid by 46%. Dexamethasone did not affect the plating efficiency of either the cells from the monolayer experiment or those dissociated from spheroids, however, suggesting that the inhibitory effect was not tumoricidal. At a clinical concentration (1.94 × 10−5 M), dexamethasone did not significantly influence plating efficiency of irradiated C6 astrocytoma cells in monolayer or three-dimensional spheroid cultures.

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Patricia A. Stewart, Kay Hayakawa, Catherine L. Farrell and Rolando F. Del Maestro

✓ The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment.

Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.