Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

Background and Purpose-To describe baseline clinical features and outcomes of adults with moyamoya phenomenon treated at a single North American institution. Methods-We identified 34 adults with moyamoya phenomenon by review of angiographic records. Clinical presentation and baseline stroke risk factors were obtained by chart review. Follow-up was obtained prospectively. A 5-year Kaplan-Meier stroke risk was calculated. Results-The median age was 42 (range 20 to 79) years. Twenty-five were women. The initial symptom was ischemia, hemorrhage, or asymptomatic in 24, 7, and 3 patients, respectively. Twenty-two had bilateral involvement and 12 had unilateral moyamoya vessels. Baseline stroke risk factors were similar between groups. The median follow-up in 31 living patients was 5.1 (range 0.2 to 19.6) years. Fourteen patients were treated with surgical revascularization (20 total hemispheres). In medically treated symptomatic hemispheres, the 5-year risk of recurrent ipsilateral stroke was 65% after the initial symptom and 27% after angiographic diagnosis. Patients with bilateral involvement presenting with ischemic symptoms were at the highest risk of subsequent stroke (nϭ17, 5-year risk of stroke with medical treatment after first symptom of 82%). In surgically treated hemispheres, the 5-year risk of perioperative or subsequent ipsilateral stroke or death was 17%. This was significantly different compared with medical treatment after first symptom (Pϭ0.02) but not after angiographic diagnosis. Conclusion-Moyamoya phenomenon in North American adults is associated with a high risk of recurrent stroke, particularly those with bilateral involvement and ischemic symptoms. These data suggest a potential benefit with surgery if diagnosis could be made earlier.

Objective-To describe initial experience with resting state correlation mapping as a potential aid for presurgical planning of brain tumor resections.Methods/Technique-Resting state blood oxygenation dependent (BOLD) fMRI was acquired in seventeen healthy young adults and four patients with brain tumors invading sensorimotor cortex. Conventional fMRI motor mapping (finger tapping protocol) was also performed in the patients. Intraoperatively, motor hand area was mapped using cortical stimulation.Results-Robust and consistent delineation of sensorimotor cortex was obtained using the resting state BOLD data. Resting state functional mapping in patients showed localization to sensorimotor areas consistent with cortical stimulation mapping (CSM) and in all cases performed as well or better than task-based fMRI.Conclusions-Resting state correlation mapping is a promising tool for reliable functional localization of eloquent cortex. This method compares well with "gold standard" CSM and offers several advantages in comparison to conventional motor mapping fMRI.

Although meningiomas are common central nervous system tumors, little is known about the genetic events responsible for malignant progression. In this study, we employed gene expression profiling to identify transcripts whose expression was lost in anaplastic (WHO grade III) versus benign (WHO grade I) meningioma. Approximately 40% of genes downregulated in anaplastic meningioma were localized to chromosomes 1p and 14q. One specific gene located at 14q11.2, NDRG2, was consistently down-regulated in grade III meningioma, a finding which we validated at both the transcript and protein levels in independent sets of clinically and pathologically diverse meningiomas. Loss of NDRG2 expression was also seen in a subset of lower-grade meningiomas, including atypical meningiomas (WHO grade II) with clinically aggressive behavior. Furthermore, we found that the loss of NDRG2 expression was significantly associated with hypermethylation of the NDRG2 promoter. Collectively, these data identify NDRG2 as the first specific candidate tumor suppressor gene on chromosome 14q that is inactivated during meningioma progression. In addition, these findings highlight the utility of combining genomic, epigenetic, and expression data to identify clinically significant tumor biomarkers, and suggest that NDRG2 expression will be a useful and functionally relevant biomarker to predict aggressive behavior in patients with meningioma. (Cancer Res 2005; 65(16): 7121-6)

Brain invasion prevents complete surgical extirpation of malignant gliomas; however, invasive cells from distant, histologically normal brain previously have not been isolated, cultured, and characterized. To evaluate invasive human malignant glioma cells, the authors established cultures from gross tumor and histologically normal brain. Three men and one woman, with a mean age of 67 years, underwent two frontal and two temporal lobectomies for tumors, which yielded specimens of both gross tumor and histologically normal brain. Each specimen was acquired a minimum of 4 cm from the gross tumor. The specimens were split: a portion was sent for neuropathological evaluation (three glioblastomas multiforme and one oligodendroglioma) and a portion was used to establish cell lines. Morphologically, the specimens of gross tumor and histologically normal brain were identical in three of the four cell culture pairs. Histochemical staining characteristics were consistent both within each pair and when compared with the specimens sent for neuropathological evaluation. Cultures demonstrated anchorage-independent growth in soft agarose and neoplastic karyotypes. Growth rates in culture were greater for histologically normal brain than for gross tumor in three of the four culture pairs. Although the observed increases in growth rates of histologically normal brain cultures do not correlate with in vivo behavior, these findings corroborate the previously reported stem cell potential of invasive glioma cells. Using the radial dish assay, no significant differences in motility between cultures of gross tumor and histologically normal brain were found. In summary, tumor cells were cultured from histologically normal brain acquired from a distance greater than 4 cm from the gross tumor, indicating the relative insensitivity of standard histopathological identification of invasive glioma cells (and hence the inadequacy of frozen-section evaluation of resection margins). Cell lines derived from gross tumor and histologically normal brain were usually histologically identical and demonstrated equivalent motility, but had different growth rates.

Brain tumor dispersal far from bulk tumor contributes to and, in some instances, dominates disease progression. Three methods were used to characterize brain tumor cell motility in vivo and in vitro: 1) 2 weeks after implantation in rat cerebral cortex, single C6 cells labeled with a fluorescent tag had migrated to brain sites greater than 16 mm distant from bulk tumor; 2) time-lapse videomicroscopy of human brain tumor cells revealed motility of 12.5 microns/hr. Ruffling leading edges and pseudopod formation were most elaborate in more malignant cells; 3) an in vitro assay was devised to quantitatively evaluate motility from a region of high cell density to one of lower cell density. Human brain tumor cells were plated in the center of a petri dish, washed, and refed, establishing a 2-cm circular zone of cells in the dish center. Motility was determined by counting cells daily at predetermined distances from the central zone perimeter. Cells were found 1 cm from the perimeter by 24 hours and 3 cm from the perimeter by 4 days. Increasing serum concentration increased motility; however, neither fibronectin nor arrest of cells in the G0 phase by hydroxyurea altered motility. The addition of cytochalasin B to block cytoskeletal assembly prevented cell motility. Motility increased with increased malignancy. Subpopulations of cells were created by clonal amplification of cells that had migrated most rapidly to the dish periphery. Although morphologically indistinguishable when compared to the original cell line from which they were derived, these subpopulations demonstrated significantly increased motility.

ObjectiveCranial dural arteriovenous fistulas (dAVFs) with cortical venous drainage (CVD) (Borden type 2 and 3) are reported to carry a 15% annual risk of intracranial hemorrhage (ICH) or non-hemorrhagic neurological deficit (NHND). The purpose of this study is to compare the clinical course of type 2 and 3 dAVFs that present with ICH or NHND versus those that do not.Methods28 patients with type 2 or 3 dAVFs were retrospectively evaluated. CVD was classified as asymptomatic (aCVD) if patients presented incidentally or with pulsatile tinnitus or orbital phenomena. CVD was classified as symptomatic (sCVD) if patients presented with ICH or NHND. Occurrence of new ICH or new or worsening NHND between diagnosis and disconnection of CVD or last follow-up (if not disconnected) was noted. Overall frequency of events was compared using Fisher's exact test. Cumulative event free survival was compared using Kaplan–Meier analysis with log rank testing.ResultsOf 17 patients with aCVD, one (5.9%) developed ICH and none experienced NHND or death during the mean 4.1 years of follow-up. Of 11 patients with sCVD, two (18.2%) developed ICH and three (27.3%) suffered new or worsened NHND over the mean 2.4 years of follow-up. One of these patients subsequently died. Overall frequency of ICH or NHND was significantly lower in patients with aCVD versus sCVD (p=0.022). Respective annual event rates were 1.4% versus 19.0%. aCVD patients had significantly higher cumulative event free survival (p=0.0016).ConclusionCranial dAVFs with aCVD may have a less aggressive clinical course than those with sCVD.

Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3B (GSK-3B), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-NV -bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferasemediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas. [Mol Cancer Ther 2005;4(9):1293 -302]