Michael R. Chicoine

Clinical Features and Outcome in North American Adults With Moyamoya Phenomenon

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 (n=17, 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 (P=0.02) 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.

Integrative Genomic Analysis Identifies NDRG2 as a Candidate Tumor Suppressor Gene Frequently Inactivated in Clinically Aggressive Meningioma

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 down-regulated 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.

Preoperative Sensorimotor Mapping in Brain Tumor Patients Using Spontaneous Fluctuations in Neuronal Activity Imaged With Functional Magnetic Resonance Imaging: Initial Experience

OBJECTIVE To describe initial experience with resting-state correlation mapping as a potential aid for presurgical planning of brain tumor resection. METHODS Resting-state blood oxygenation-dependent functional magnetic resonance imaging (fMRI) scans were acquired in 17 healthy young adults and 4 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 blood oxygenation-dependent data. Resting-state functional mapping localized sensorimotor areas consistent with cortical stimulation mapping and in all patients performed as well as or better than task-based fMRI. CONCLUSION Resting-state correlation mapping is a promising tool for reliable functional localization of eloquent cortex. This method compares well with “gold standard” cortical stimulation mapping and offers several advantages compared with conventional motor mapping fMRI.

CRANIAL DURAL ARTERIOVENOUS FISTULAE: ASYMPTOMATIC CORTICAL VENOUS DRAINAGE PORTENDS LESS AGGRESSIVE CLINICAL COURSE

OBJECTIVECranial dural arteriovenous fistulae (dAVF) with cortical venous drainage (CVD) (Borden Types 2 and 3) are reported to carry a 15% annual risk of intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit (NHND). The purpose of this study was to compare the clinical course of Type 2 and 3 dAVFs that present with ICH or NHND with those that do not. METHODSTwenty-eight 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 Fishers exact test. Cumulative, event-free survival was compared using Kaplan-Meier analysis with log-rank testing. RESULTSOf 17 patients with aCVD, 1 (5.9%) developed ICH and none experienced NHND or death during the median 31.4-month follow-up period. Of 11 patients with sCVD, 2 (18.2%) developed ICH and 3 (27.3%) experienced new or worsened NHND over the median 9.7-month follow-up period. 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.

Molecular Characterization of Human Meningiomas by Gene Expression Profiling Using High-Density Oligonucleotide Microarrays

Meningiomas are common central nervous system neoplasms that exhibit remarkably diverse histopathology and biological behavior. Compared to astrocytomas, the most common central nervous system tumor, little is known about the molecular pathways critical for meningioma tumor formation and malignant progression. As an initial step toward characterizing the genetic basis of meningioma pathogenesis, we assessed cancer-related gene expression profiles of nonneoplastic leptomeningeal specimens and human meningiomas of varying World Health Organization (WHO) grade using high-density oligonucleotide microarrays. Although expression profile differences between nonneoplastic and meningioma specimens were readily discernible, the expression profile of a subset of genes could also distinguish WHO grade I from WHO grades II and III tumors. Altered expression levels of several genes identified in this study have been previously noted in meningiomas (eg, growth hormone receptor, IGFBP-7, endothelin receptor A, IGF2). However, we also identified a number of novel genes whose expression was associated with WHO grade and was confirmed by reverse transcriptase-polymerase chain reaction in a larger, independent set of meningeal tumors (n = 47). This report represents the first gene expression profiling studies of meningiomas and identifies some initial candidate genes that may provide further insights into the genetic basis for meningioma pathogenesis.

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

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 3β (GSK-3β), 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-N′-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 transferase–mediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas.

Comparing indocyanine green videoangiography to the gold standard of intraoperative digital subtraction angiography used in aneurysm surgery

OBJECT The purpose of aneurysm surgery is complete aneurysm obliteration while sparing associated arteries. Indocyanine green (ICG) videoangiography is a new technique that allows for real-time evaluation of blood flow in the aneurysm and vessels. The authors performed a retrospective study to compare the accuracy of ICG videoangiography with intraoperative angiography (IA), and determine if ICG videoangiography can be used without follow-up IA. METHODS From June 2007 through September 2009, 155 patients underwent craniotomies for clipping of aneurysms. Operative summaries, angiograms, and operative and ICG videoangiography videos were reviewed. The number, size, and location of aneurysms, the ICG videoangiography and IA findings, and the need for clip adjustment after ICG videoangiography and IA were recorded. Discordance between ICG videoangiography and IA was defined as ICG videoangiography demonstrating aneurysm obliteration and normal vessel flow, but post-IA showing either an aneurysmal remnant and/or vessel occlusion requiring clip adjustment. RESULTS Thirty-two percent of patients (49 of 155) underwent both ICG videoangiography and IA. The post-ICG videoangiography clip adjustment rate was 4.1% (2 of 49). The overall rate of ICG videoangiography-IA agreement was 75.5% (37 of 49) and the ICG videoangiography-IA discordance rate requiring post-IA clip adjustment was 14.3% (7 of 49). Adjustments were due to 3 aneurysmal remnants and 4 vessel occlusions. These adjustments were attributed to obscuration of the residual aneurysm or the affected vessel from the field of view and the presence of dye in the affected vessel via collateral flow. Although not statistically significant, there was a trend for ICG videoangiography-IA discordance requiring clip adjustment to occur in cases involving the anterior communicating artery complex, with an odds ratio of 3.3 for ICG videoangiography-IA discordance in these cases. CONCLUSIONS These results suggest that care should be taken when considering ICG videoangiography as the sole means for intraoperative evaluation of aneurysm clip application. The authors further conclude that IA should remain the gold standard for evaluation during aneurysm surgery. However, a combination of ICG videoangiography and IA may ultimately prove to be the most effective strategy for maximizing the safety and efficacy of aneurysm surgery.

The Kawase Approach to Retrosellar and Upper Clival Basilar Aneurysms

OBJECTIVE: Fifteen basilar aneurysms approached via Kawases anterior petrosectomy were analyzed to determine parameters that could reliably predict the applicability of this approach to specific basilar aneurysms on the basis of existing imaging. METHODS: Anatomic data were gathered by studying 40 dry skulls in which measurements were taken to define the limits of the surgical window. Clinical data were obtained from the review of charts and radiographic images of 15 patients surgically treated with the Kawase approach. The data were combined to categorize basilar aneurysms according to their position in relation to bony anatomy as seen on preoperative angiograms. RESULTS: Two relevant measurements were determined on lateral angiograms that were predictive of the applicability of operative approach. The K1 line determined the caudal extent of exposure of the Kawase approach to be 18 mm below the floor of the sella turcica and represented the distance to the floor of the internal auditory meatus. The K2 line determined the caudal extent of exposure of the posterior petrosectomy approach to be 24 mm below the floor of the sella turcica and represented the distance to the upper aspect of the jugular tubercle. Basilar aneurysms below the posterior clinoid process could be categorized in relationship to the regional bony anatomy in a manner that is predictive of the appropriate surgical approach as 1) retrosellar, 2) upper clival, 3) midclival, and 4) lower clival. Glasgow outcome data in 15 patients surgically treated with the Kawase approach demonstrated results comparable to those reported for ruptured basilar aneurysms. CONCLUSION: Individual basilar artery aneurysms can be categorized according to their relationship to bony anatomy on lateral view preoperative angiograms without bone subtraction. Anatomic parameters, the K1 and K2 lines, from these angiograms enable the neurosurgeon to predict the most appropriate approach for each type of basilar artery aneurysm.

Mitogens as motogens

Numerous in vivo methodologies have documented the invasivebehavior of glioma cells through normal brain parenchyma.Glioma cell locomotion has also been assessed witha number of in vitro assays including theBoyden chamber and other chemotaxis assays, colloidal goldcell tracking, analysis of migration of cells tumorcells from spheroids, confrontation cultures of glioma cellswith aggregates of non-neoplastic tissue, time-lapse video microscopy,electron microscopic examination of the cytomorphologic correlates ofcell motility, the radial dish assay, and quantitativeenzyme immunoassay of proteins associated with invasion (e.g.laminin). Several of these techniques have been specificallymodified to assess the effects of cytokines onglioma cell motility in vitro. Cytokines studied utilizingthese methods include: epidermal growth factor (EGF), basicfibroblast growth factor (bFGF), the bb dimer ofplatelet-derived growth factor (PDGFbb), nerve growth factor (NGF),interleukin 2 (IL-2), transforming growth factors alpha andbeta 1 (TGFα and TGFstraat1), and tumor necrosisfactor alpha (TNFα). This review summarizes the investigationalmethods used to evaluate random and directional gliomacell motility and invasion in vivo and invitro. The roles of specific mitogens as motogens,as evaluated with these methods are then presented.

The in vitro motility of human gliomas increases with increasing grade of malignancy

Background. Malignant gliomas are a highly invasive disease with a dismal prognosis despite aggressive therapeutic interventions.