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W. Thomas Smith and Eric Turner

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Robin I. Davidson, Kathleen Phillips, Joseph Zito and Thomas W. Smith

✓ The spontaneous onset of an acute subgaleal hematoma in a 13-year-old boy is recorded. The underlying lesion causing the hemorrhage was believed to be an anomalous periosteal venous structure, which is briefly illustrated angiographically, grossly, and histologically.

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Thomas W. Smith, Umberto DeGirolami and Robert M. Crowell

✓ The long-term toxic effects of ethyl 2-cyanoacrylate adhesive were evaluated histologically in 25 cats. Fresh medical- or commercial-grade adhesive was introduced transorbitally into the subarachnoid space in the vicinity of the right middle cerebral artery. Three sham-operated animals served as controls. The animals were sacrificed at intervals ranging from 2 days to 6 months. For both medical- and commercial-grade adhesive, neuropathological examination disclosed acute and chronic granulomatous inflammation of the meninges and evidence of severe vascular damage, including vessel wall necrosis, inflammation, thrombosis, and occasionally hemorrhage. Most animals showed cerebral infarcts of variable size in the territories of distribution of the basal arteries which were in contact with adhesive. The results of this study show that ethyl 2-cyanoacrylate is capable of producing severe arterial and parenchymal damage. The risk of its deleterious effects should be weighed against its potential benefits. Clinical experience would suggest that ethyl 2-cyanoacrylate can be used in difficult situations as long as care is taken to protect the brain and local blood vessels.

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Lawrence Recht, Carmen O. Torres, Thomas W. Smith, Vic Raso and Thomas W. Griffin

✓ The distribution of transferrin receptor (TfR) in normal human brain-tissue obtained at autopsy and in brain-tumor biopsy specimens from 27 patients was determined by immunohistochemistry using two specific murine monoclonal antibodies against human TfR. The tumors studied included 10 glioblastomas multiforme (GBM's), nine other glial tumors, and eight meningiomas. In normal brain, TfR was detected primarily in endothelial cells; rare glial cells also contained immunoreactive product. All tumors contained TfR-positive cells, although the intensity (number of cells stained) and pattern (focal vs. diffuse) of staining varied with the histopathological type of the tumor. Among gliomas, the most intense staining was seen in GBM's, especially in areas of pseudopalisading where virtually all cells were stained. A rough correlation between tumor grade, number of positively stained cells, and staining pattern was seen in the other astrocytic tumors. By contrast, all meningiomas demonstrated an identical and characteristic focal staining pattern. Considering the differential immunostaining for TfR between normal and neoplastic tissue, the authors conclude that TfR may be an appropriate target for monoclonal antibody-directed brain-tumor immunotherapy, especially in more malignant tumors such as GBM's.

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Murli Krishna, Thomas W. Smith and Lawrence D. Recht

✓ The bcl-2 protooncogene encodes a 26-kD protein that extends cell survival by blocking apoptosis. This protein has been found to be overexpressed in neoplastic neural cell lines, although its expression in reactive and neoplastic astrocytes in vivo has not been well characterized. The authors hypothesized that bcl-2 oncoprotein expression in gliomas might be positively correlated with the tumor's degree of malignancy. Sixty-three gliomas of various subtypes and histological grades were immunostained by bcl-2 protein and the percentage of positive cells was quantitatively assessed. All tumors contained neoplastic cells that were immunoreactive for the bcl-2 protein (range of cell positivity 1%–53%). It was found that bcl-2 expression did not vary significantly as a function of tumor subtype or grade (p < 0.1, one-way analysis of variance (ANOVA) on ranks) as compared to the cell proliferation marker Ki-67 (MIB-1) in which a very significant correlation with tumor grade was noted (p < 0.0000001, one-way ANOVA on ranks). In fact, the highest percentage of bcl-2 immunoreactive cells was noted in low-grade gliomas, that is, in juvenile pilocytic astrocytomas and oligoastrocytomas. The specificity of bcl-2 overexpression was also assessed in 10 nonneoplastic lesions associated with prominent reactive astrocytosis. In nine of these cases (90%), bcl-2—positive reactive astrocytes were observed, often in large numbers, whereas relatively few Ki-67 immunoreactive cells were noted. The authors conclude that bcl-2 oncoprotein expression as assessed immunohistochemically does not correlate with glial tumor type or grade and its overexpression is not confined only to neoplastic conditions. Instead, the finding of robust bcl-2 expression in low-grade glial tumors and in reactive astrocytes warrants the inference that resistance to apoptosis is a nonspecific finding in astrocytes associated with both reactive and neoplastic conditions.

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Lawrence F. Marshall

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Guy L. Clifton, Sung C. Choi, Emmy R. Miller, Harvey S. Levin, Kenneth R. Smith Jr., J. Paul Muizelaar, Franklin C. Wagner Jr., Donald W. Marion and Thomas G. Luerssen

Object. In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences.

Methods. The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data.

Conclusions. For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.

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Kris A. Smith, Lynn S. Ashby, L. Fernando Gonzalez, David G. Brachman, Terry Thomas, Stephen W. Coons, Matthew Battaglia and Adrienne C. Scheck

Object

The purpose of this study was to determine whether increased local control and improved survival can be achieved in patients with glioblastoma multiformes (GBMs) who undergo aggressive resection, Gliadel wafer implantation, Gamma Knife radiosurgery (GKS), and fractionated radiotherapy (RT) as the initial treatment.

Methods

Thirty patients with radiographically suspected GBMs were screened for enrollment in a Phase I/II prospective clinical trial. Twenty-seven patients were eligible and underwent gross-total resection and Gliadel wafer implantation. Gamma Knife radiosurgery (12 Gy at 50%) was administered to the resection cavity within 2 weeks of surgery. Patients then received standard fractionated RT (total dose 60 Gy over 6 weeks). Temozolomide was prescribed for patients at the time of recurrence. Surveillance MR imaging, neurological examination, and quality-of-life evaluations were performed at 2-month intervals. To estimate the potential effects on the DNA repair mechanism, tumor tissue was analyzed with methylation-specific polymerase chain reaction analysis and immunohistochemical assays for MGMT gene promoter methylation and protein expression.

Results

The median survival for all patients was 50 weeks and the 2-year survival rate was 22%. When stratified into standard and high-risk patient groups, the median survivals were 76 and 33 weeks, respectively. Two patients remain alive at the time of this report with no clinical or radiographic evidence of disease at > 189 and 239 weeks posttreatment and excellent performance status. Local tumor control was achieved in 53% of patients, and local failure occurred in 47%. No acute early toxicity was noted; however, delayed symptomatic radionecrosis occurred in 47% of patients, which required repeated operations 9–24 months after the initial treatment. Delayed hydrocephalus requiring ventriculoperitoneal shunt placement occurred in 47% of patients. There was a significant difference in survival between patients whose tumors contained the methylated and unmethylated MGMT promoter, 103 versus 45 weeks, respectively (p = 0.0009, log-rank test).

Conclusions

The combination of aggressive resection, Gliadel wafer implantation, and GKS in addition to standard fractionated RT in selected patients resulted in increased local control and increased survival compared with a historical control group treated with surgery and involved-field RT alone. Delayed focal radionecrosis was increased to 47% in this series and was managed with steroids and repeated resection. Aggressive local tumor control with these multimodal therapies should be approached judiciously for a select group of high performance patients and the probability of developing symptomatic radionecrosis requiring surgery should be anticipated and fully disclosed to patients who undergo this treatment.

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James T. Rutka

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Oguz Cataltepe, Paul Marshall and Thomas W. Smith

Dysembryoplastic neuroepithelial tumors (DNETs) are frequently seen in children and young adults with intractable epilepsy, and are typically located in the temporal cortex. Extracortical location of DNET is a very rare occurrence. The authors report on a child with a unique extracortical location of DNET with an extensive involvement to the supracallosal cistern and callosum, septum pellucidum, and lateral ventricle ependyma. The authors discuss the radiological and pathological characteristics of the lesion and reiterate the difficulty in differentiating the histological characteristics of central neurocytoma and DNET in extracortical locations and its significance for further management planning.