Adjacent Brain Parenchyma Research Articles

Associated Brain Parenchymal Abnormalities in Developmental Venous Anomalies: Evaluation with Susceptibility-weighted MR Imaging

Developmental venous anomalies (DVAs) of the brain are frequently encountered on contrast-enhanced (CE) CT or MR imaging. They are regarded as normal variants of the cerebral venous development and are usually asymptomatic (1-4). However, it has been reported that MR signal abnormalities in the adjacent brain parenchyma could be This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: July 12, 2015 Revised: August 15, 2015 Accepted: August 18, 2015

Brain metabolic abnormalities associated with developmental venous anomalies.

Developmental venous anomalies are the most common intracranial vascular malformation and are typically regarded as inconsequential, especially when small. While there are data regarding the prevalence of MR imaging findings associated with developmental venous anomalies, FDG-PET findings have not been well-characterized. Clinical information systems were used to retrospectively identify patients with developmental venous anomalies depicted on MR imaging examinations who had also undergone FDG-PET. Both the MR imaging and FDG-PET scans were analyzed to characterize the developmental venous anomalies and associated findings on the structural and functional scans. Qualitative and quantitative assessments were performed, including evaluation of the size of the developmental venous anomaly, associated MR imaging findings, and characterization of the FDG uptake in the region of the developmental venous anomaly. Twenty-five developmental venous anomalies in 22 patients were identified that had been characterized with both MR imaging and FDG-PET, of which 76% (19/25) were associated with significant metabolic abnormality in the adjacent brain parenchyma, most commonly hypometabolism. Patients with moderate and severe hypometabolism were significantly older (moderate: mean age, 65 ± 7.4 years, P = .001; severe: mean age, 61 ± 8.9 years, P = .008) than patients with developmental venous aberrancies that did not have abnormal metabolic activity (none: mean age, 29 ± 14 years). Most (more than three-quarters) developmental venous anomalies in our series of 25 cases were associated with metabolic abnormality in the adjacent brain parenchyma, often in the absence of any other structural abnormality. Consequently, we suggest that developmental venous anomalies may be better regarded as developmental venous aberrancies.

Pregnant woman with an intracranial meningioma – case report and review of the literature

Abstract It is about a 33-year-old female, with a 36 weeks uncomplicated pregnancy and with signs of increased intracranial pressure. Hours after admission and an obstetric evaluation, uterine contraction started and the patient was taken to the delivery room, where she presented a partial motor seizure on the left side with secondary generalization and urine emission. A caesarean section was performed without fetal or maternal complications. The urgent MRI gadolinium-enhanced brain scan revealed a 39/50/54 mm tumoral mass having an aspect of an anterior third falx cerebri meningioma. The patient was transferred to our neurosurgical department and afterwards surgery was performed with gross total removal of the tumoral mass. Histological examination revealed atypical meningioma with direct invasion into the adjacent brain parenchyma. A week later she was discharged from the hospital in good condition. One month after surgery, a contrastenhanced magnetic resonance imaging of the brain did not reveal any signs of tumor recurrence or residual tumor. Our recommendation is for postpartum surgery when is possible. Urgent neurosurgical interventions should be made in case of patients with malignant tumors, active hydrocephalus or benign intracranial tumor such as meningioma associated with signs of impending herniation, progress

Magnetic Resonance Characteristics of Ischemic Brain Infarction in Three Dogs

This case study describes the magnetic resonance characteristics of brain infarction in three dogs. Locations of the brain infarcts were cerebella, thalamus, and multifocal. The infarcts were sharply demarcated from adjacent brain parenchyma, homogeneous, T1-hypointense, T2-hyperintense with/without contrast enhancement, and minimal or no mass effect. Diffusion-weighted imaging (DWI) sequences were available in a dog and the infarcts were hyperintense on DWI and were hypointense on the apparent diffusion coefficient map.

Emerging concepts in Alzheimer's disease.

Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.

P16.28 * INTRAOPERATIVE CEREBRAL GLIOMA CHARACTERIZATION WITH CONTRAST ENHANCED ULTRASOUND (CEUS)

BACKGROUND: Contrast Enhanced Ultrasound (CEUS) is a dynamic and continuous modality that offers a real-time direct view of vascularization and flow distribution patterns of different organs and type of tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and there are no guidelines on this regard. Furthermore a thorugh characterization of cerebral glioma had never been performed. OBJECTIVE: To describe the different patterns of enhancement of cerebral gliomas using the CEUS technique. METHODS: We performed intra-operative CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An on-site and a post-procedural semi-quantitative analysis was performed for each case, evaluating CEUS parameters: timing, degree of CE and contrast distribution. RESULTS: Both low grade glioma (LGG) and high grade glioma (HGG) appear hyper-echoic relative to the adjacent brain parenchyma on B-mode US. Different contrast enhancement patterns were observed according to lesion characteristics: LGG showed a dotted or diffuse appearance with a slower and delayed arterial and venous phase compared with HGG, whereas HGG have a more nodular, non-homogeneous appearance, with faster and major contrast enhancement. CONCLUSION: Our study characterizes for the first time, human brain glioma with CEUS, giving us further insight regarding the biology of these tumors: being a dynamic and continuous modality it offers a real-time direct view of the tumor perfusion and of the afferent and efferent vessels. CEUS is a fast, safe, dynamic, real-time, economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining the surgical strategy.

Imaging genomic mapping of an invasive MRI phenotype predicts patient outcome and metabolic dysfunction: a TCGA glioma phenotype research group project.

BackgroundInvasion of tumor cells into adjacent brain parenchyma is a major cause of treatment failure in glioblastoma. Furthermore, invasive tumors are shown to have a different genomic composition and metabolic abnormalities that allow for a more aggressive GBM phenotype and resistance to therapy. We thus seek to identify those genomic abnormalities associated with a highly aggressive and invasive GBM imaging-phenotype.MethodsWe retrospectively identified 104 treatment-naïve glioblastoma patients from The Cancer Genome Atlas (TCGA) whom had gene expression profiles and corresponding MR imaging available in The Cancer Imaging Archive (TCIA). The standardized VASARI feature-set criteria were used for the qualitative visual assessments of invasion. Patients were assigned to classes based on the presence (Class A) or absence (Class B) of statistically significant invasion parameters to create an invasive imaging signature; imaging genomic analysis was subsequently performed using GenePattern Comparative Marker Selection module (Broad Institute).ResultsOur results show that patients with a combination of deep white matter tracts and ependymal invasion (Class A) on imaging had a significant decrease in overall survival as compared to patients with absence of such invasive imaging features (Class B) (8.7 versus 18.6 months, p < 0.001). Mitochondrial dysfunction was the top canonical pathway associated with Class A gene expression signature. The MYC oncogene was predicted to be the top activation regulator in Class A.ConclusionWe demonstrate that MRI biomarker signatures can identify distinct GBM phenotypes associated with highly significant survival differences and specific molecular pathways. This study identifies mitochondrial dysfunction as the top canonical pathway in a very aggressive GBM phenotype. Thus, imaging-genomic analyses may prove invaluable in detecting novel targetable genomic pathways.

Parkinsonism as an initial manifestation of rheumatoid meningitis

Rheumatoid meningitis (RM) has been considered to be an extremely rare complication of rheumatoid arthritis (RA), which itself is very common [1]. However, due to better access to MRI, RM has been increasingly diagnosed. More than 30 cases diagnosed by MRI and pathology have been reported [2–4]. In most cases, onset occurred after the age of 50 in both sexes. The clinical symptoms and signs and the MRI findings were those of non-specific chronic leptomeningitis [5]. Of interest, there were no associations between the onset and activity of RM, the severity and activity of synovitis, the duration of RA or the way it treated [3]. We have described here for the first time a patient with pathologically proven RM the initial symptom of which was parkinsonism. A 68-year-old Japanese man with a 10-year history of RA treated successfully with prednisolone (6 mg/day) was referred to a regional hospital because of a bilateral resting tremor predominating on the right side, progressive gait instability that began by hesitation and bradykinesia. He was diagnosed as having Parkinson’s disease, but his symptoms did not respond to levodopa. He soon developed a progressive cognitive dysfunction, accompanied by a slight fever, followed 2 months later by urinary incontinence. In spite of more than 3 months of treatment with antibiotics, antiviral agents and antimycotics, his condition gradually deteriorated and he was transferred to our university hospital. On admission, he was apathetic and bedridden. Disuse atrophy was generalized, and he had severe bilateral swanneck deformities of his fingers due to RA. His face was mask-like, and his verbal responses were very slow with muted monotonous voice. His Mini-Mental State Examination (MMSE) score was 11. Bradykinesia was remarkable, and rigidity was seen in the neck and all extremities. Resting tremor was observed intermittently in both hands. Laboratory data suggested inactive RA. Cerebrospinal fluid (CSF), analyzed after lumbar puncture, was clear, and pressure was normal. The cell count was slightly increased (13/mm), but there were no atypical cells. Protein levels were increased (75 mg/dL), but glucose levels were normal. Results of cell cultures performed repeatedly, immunological investigations, a polymerase chain reaction (PCR) to detect microorganisms, and cytological investigations of the CSF were all negative. No malignancy was detected by a whole body CT scan with enhancement. Brain MRI with contrast enhancement (Fig. 1a, b) revealed a diffuse meningeal lesion. Secondary hydrocephalus was also observed (Fig.1c). A biopsy of the leptomeninx together with adjacent brain parenchyma from the right frontal lobe revealed foci of necrotic tissue in the subarachnoid space surrounded by chronic inflammatory cells consisting of numerous lymphocytes, plasma cells, a few neutrophils and scattered giant multinucleated cells (Fig. 1e, f). No inflammation was seen in the dura mater and parenchyma per se. These pathological findings associated with the negative laboratory data were consistent with a diagnosis of RM. Y. Hayashi M. Namekawa (&) Department of Neurology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan e-mail: mnamekaw@jichi.ac.jp

Evaluation of linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) for cerebral cavernous malformations: a 15-year single-center experience

BACKGROUND AND OBJECTIVESSurgery is the principal treatment for safely accessible hemorrhagic and symptomatic cavernous malformations. Nevertheless, the role of linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) in the management of high-risk, symptomatic cavernoma lesions warrants further refinement. In this study, we evaluate the use of LINAC-based SRS for cerebral cavernous malformations (CMs) and report our 15-year single-center experience.DESIGN AND SETTINGSA retrospective study from the Department of Radiation Oncology and the Department of Neurosurgery at Gulhane Military Medical Academy and Medical Faculty, Ankara from April 1998 to June 2013.PATIENTS AND METHODSFifty-two patients (22 females and 30 males) with cerebral CM referred to our department underwent high-precision single-dose SRS using a LINAC with 6-MV photons. All patients had at least 1 bleeding episode prior to radiosurgery along with related symptoms. Median dose prescribed to the 85% to 95% isodose line encompassing the target volume was 15 Gy (range, 10–20).RESULTSOut of the total 52 patients, follow-up data were available for 47 patients (90.4%). Median age was 35 years (range, 19–63). Median follow-up time was 5.17 years (range, 0.08–9.5) after SRS. Three hemorrhages were identified in the post-SRS period. Statistically significant decrease was observed in the annual hemorrhage rate after radiosurgical treatment (pre-SRS 39% vs post-SRS 1.21, P<.0001). Overall, there were no radiosurgery-related complications resulting in mortality.CONCLUSIONLINAC-based SRS may be considered as a treatment option for high-risk, symptomatic cerebral CM of selected patients with prior bleeding from lesions located at surgically inaccessible or eloquent brain areas.

17. Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus

Although the immune system modulates higher functions of the brain under non-inflammatory conditions, how immune cells interact with brain parenchymal cells remains to be determined. Using bone marrow chimeric mice produced by syngeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) with GFP-transgenic mice being as a donor, we examined the distribution, density and differentiation of donor-derived marrow cells in the brain parenchyma 2 weeks and 1, 4 and 8 months after BMT. Marrow-derived cells started to populate discrete brain regions from 1 to 4 months after BMT, exhibited ramified morphology and expressed Iba-1. Most of these discrete regions were adjacent to the attachments of choroid plexus that comprised thinned brain parenchyma consisting of astroglial processes in the narrow channel between the ependyma and pia. These specific portions of astroglial processes expressed fractalkine. In the choroid plexus stroma, not only Iba-1 + myeloid cells but also non-myeloid CXCL12-expressing cells were of bone marrow-origin. Transcripts of fractalkine, CXCL12 and their related molecules such as CX3CR1, ADAM10 and CXCR4 were detected in the tissue consisting of the choroid plexus, the attachments and adjacent brain parenchyma. Thus, bone marrow cells selectively enter the discrete brain regions adjacent to the attachments of choroid plexus and differentiate into ramified myeloid cells. Fractalkine in the attachments of choroid plexus and CXCL12 in the choroid plexus stroma may be involved in these brain–immune interactions.

High-resolution 3-T MR imaging of the temporal part of the caudate tail in children

This study aims to investigate the high-resolution 3-T MRI appearance and morphological variation of the temporal part of the caudate tail in pediatric subjects with normal brain MR examinations. One hundred pediatric patients were retrospectively evaluated using a high-resolution 3-T imaging protocol. Different morphological parameters including shape, size, and symmetry were evaluated. The appearance and shape of the caudate tail were classified into nodular, linear, or imperceptible. The location and relation of the caudate tail to the temporal horn and adjacent brain parenchyma were categorized. Relationships between age, gender, shape, location, side, and the cross-sectional area of the caudate tail were investigated. The caudate tail was imperceptible in 22 %, had a nodular shape in 66.5 %, and was flat in 11.5 %. There was asymmetry of the caudate tail between the two sides in 37 % of subjects. The caudate tail was completely embedded within the temporal lobe parenchyma in 8.3 %, completely protruding into the temporal horn in 27.5 %, or intermediate in 64.1 %. The mean cross-sectional area of the caudate tail was constant across ages despite the varied age range of the subjects. There was no difference in overall mean cross-sectional area of the caudate tail between the two sides. There is a wide variation in the appearance of the caudate tail adjacent to the temporal horn of the lateral ventricle. Identification of anatomical variation of the caudate tail may prevent potential diagnostic pitfalls, especially with respect to subependymal heterotopia.

SU‐E‐T‐486: Evaluation of the Fisher‐Kolmogorov Glioma Growth Model for Radiotherapy Target Delineation

Purpose: Gliomas infiltrate the adjacent brain parenchyma far beyond the tumor mass visible on current imaging modalities. In current clinical practice, an isotropic margin is applied to account for infiltrative disease. However, histopathology suggests that glioma growth is anisotropic: (1) the ventricles and the falx represent barriers for migrating tumor cells; (2) gray matter is infiltrated less than white matter; and (3) glioma cells appear to preferentially spread along white matter fibers. Developing objective and quantitative approaches to account for these growth patterns may improve and automate target delineation for gliomas. Methods: We study the Fisher‐Kolmogorov glioma growth model, which represents a partial differential equation for the tumor cell density and replicates the observed growth characteristics. Via brain segmentation into anatomical barriers, cerebrospinal fluid, and white and gray matter, the model equations are solved on the patient‐specific anatomy. Preferential spread along white matter fibers is incorporated through DTI imaging. The radiotherapy target can be defined as an isoline of the derived tumor cell density. We performed a retrospective study involving 10 glioblastoma patients to (1) identify the anatomical situations for which the model suggests target volumes that differ from the manually drawn targets, and (2) fully understand the capabilities and limitations of the model for target delineation. Results: It was found that tumors located close to the corpus callosum potentially benefited the most from model‐based target delineation because it consistently predicted the contralateral tumor extension across the corpus callosum in addition to easily modeling falx and ventricles as boundaries. Furthermore, for tumors located close to major sulci (Sylvian fissure), modeling reduced gray matter infiltration can potentially reduce the amount of brain tissue targeted for irradiation. Conclusion: The tumor growth model represents a promising tool to objectively create target volumes for radiotherapy of gliomas by consistently account ing for known growth patterns.

Design of Physical Surgical Simulator for Drilling in the Expanded Endonasal Approach to the Skull Base

Drilling of the anterior skull base via the expanded endoscopic endonasal approach is a delicate and complex neurosurgical procedure that may result in mechanical and thermal injuries to adjacent cranial nerves, arteries, venous structures, dura mater, and brain parenchyma. Patients suffering from malignancies of the anterior skull base often require radical surgical resection of the tumor. High-speed drills mounted with miniature diamond burs are typically used to remove the bone to provide exposure for tumor resection. This procedure often includes drilling the bone encasing the optic nerves, cavernous sinuses, internal carotid arteries, and branches of the trigeminal nerve. Two of the most feared complications of this surgical approach are (1) thermal or mechanical injuries to cranial nerves from drilling, and (2) stroke caused by coagulation of blood in the internal carotid arteries because surgeons cannot ascertain the tissue temperature or control the extent of thermal injury during the bone drilling. What is more, this procedure is now commonly performed endoscopically, for which visualization requires skillful manipulation of the endoscope, rather than the open visualization to which surgeons are accustomed. Currently, there is no existing physical anterior skull base simulator available for training and practice. A commercially available virtual reality simulator provides clear visualization, but the haptic feedback for drilling is lacking. Trainees still must practice drilling on cadavers and patients. To provide a better and more accessible training environment, we have developed a low-cost, practical surgical simulator specifically for drilling in the expanded endonasal approach.

Ring-shaped Lateral Ventricular Nodules Detected with Brain MR Imaging

We evaluated the prevalence and imaging characteristics of ring-shaped lateral ventricular nodules (RSLVNs) detected by postcontrast brain magnetic resonance (MR) imaging. We retrospectively reviewed cranial MR images of 1,241 patients who underwent contrast-enhanced brain imaging between January 1, 2008 and March 31, 2011, excluded images of inadequate quality of 130 patients, and ultimately analyzed images of 1,111 patients (544 male, 567 female). We assessed location, shape, and signal intensity of RSLVNs on T₁-weighted (T₁WIs), T₂-weighted (T₂WIs), fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted (DWIs) images and characteristics of contrast enhancement. In 5 patients, we found 6 RSLVNs (0.45%), four in the frontal horn and two in the roof of the body. Three RSLVNs were round, two were oval, and one was lobular on axial images. All 6 RSLVNs were isointense with adjacent brain parenchyma on T₁WI, T₂WI, and DWI but slightly hyperintense on FLAIR images; none showed enhancement on postcontrast MR imaging. Five nodules serially examined (range, 8 to 24 months) showed no interval changes. Our MR imaging findings of a 0.45% prevalence of RSLVNs shows they are not so rare as previously reported. Except for configuration, all nodules had similar intensity, and none showed contrast enhancement. Absence of changes during the follow-up period seemed to indicate that the nodules have no clinical significance. However, their clear differentiation avoids unnecessary surgery.

Selective localization of bone marrow-derived ramified cells in the brain adjacent to the attachments of choroid plexus

Although the immune system modulates higher functions of the brain under non-inflammatory conditions, how immune cells interact with brain parenchymal cells remains to be determined. Using bone marrow chimeric mice in which the recipients' immune system was reconstituted by marrow cells derived from GFP-transgenic mice by syngeneic intra-bone marrow-bone marrow transplantation (IBM-BMT) and by intravenous (IV)-BMT, we examined the distribution, density and differentiation of donor-derived marrow cells in the brain parenchyma 2 weeks and 1, 4 and 8 months after BMT. Marrow-derived cells started to populate discrete brain regions from 1 to 4 months after BMT, exhibited ramified morphology and expressed Iba-1. The ramified marrow-derived cells were distributed in more brain regions and for a longer time after IBM-BMT than IV-BMT. Most of these discrete regions were adjacent to the attachments of choroid plexus that comprised thinned brain parenchyma consisting of astroglial processes in the narrow channel between the ependyma and pia. These specific portions of astroglial processes expressed fractalkine. In the choroid plexus stroma, not only Iba-1+ myeloid cells but also non-myeloid CXCL12-expressing cells were of bone marrow-origin. Transcripts of fractalkine, CXCL12 and their related molecules such as CX3CR1, ADAM10 and CXCR4 were detected in the tissue consisting of the choroid plexus, the attachments and adjacent brain parenchyma. Thus, bone marrow cells selectively enter the discrete brain regions adjacent to the attachments of choroid plexus and differentiate into ramified myeloid cells. Fractalkine in the attachments of choroid plexus and CXCL12 in the choroid plexus stroma may be involved in these brain-immune interactions.

Atypical choroid plexus papilloma: a case report and literature review

Objective To report a rare case of atypical choroid plexus papilloma and explore its clinical presentations and histopathological features, at the same time to take a review of relevant literature. Methods and Results A 1 ⁃ year ⁃ old male patient presented with vomiting for 3 days after a sudden tumbling. Computed Tomography (CT) showed a space⁃occupying lesion located in the left lateral ventricle. The lesion was with slight hyper⁃intensity signal compared to the adjacent brain parenchyma. Left lateral ventricle was enlarged and hydrocephalus was visible. Besides, edema occured in adjacent cerebral tissues. The surgical operation was performed under general anesthesia. During the operation, the tumor tissue was in heterogeneous consistency and rich blood supply, showing grey⁃white color, and attached to the choroid plexus. Microscopically, most tumor cells grew around the fibrovascular axis forming papillary pattern and showed no obvious atypia. However, in some areas, solid and sheet⁃like patterns were identified. Within these areas, increased cell density, mild to moderate cellular atypia and focal necrosis were appreciated. Some cells with acidophilic cytoplasm, few giant tumor cells and accidental mitosis were also seen, and the counting of mitosis was 2/10 HPF. Immunohistochemistry showed positive expression of pancytokeratin (PCK), synaptophysin (Syn), cytokeratin (CK)8/18, vimentin (Vim) and podoplanin (D2⁃40) in tumor cells. Integrase interactor⁃1 (INI⁃1) were also positively and focally expressed. The Ki⁃67 labeling index of tumor cells was 8％ . S ⁃ 100 protein, CK19, neuronal nuclei (Neu ⁃ N), glial fibrillary acidic protein (GFAP), epithelial membrane antigen (EMA), chromogranin A (CgA), CK7 and CK20 were negatively stained. The patient was followed up for 6 months after operation and no recurrence was found. Conclusion Atypical choroid plexus papilloma, the biological behavior of which is between benignancy and malignancy, is one of the rare tumors of central nervous system that occurs in the ventricular system. The incidence is low. It often occurs in the early childhood with atypical histopathological features. Follow up is suggested although patients with complete resection usually have a good long⁃term prognosis. DOI：10.3969/j.issn.1672⁃6731.2012.06.017

Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma

Gliomas display anoikis resistance, enhanced invasion in to the adjacent brain parenchyma and eventually recur despite using the standard therapies. Our studies on increased anoikis sensitization in matrix metalloproteinase-2 (MMP-2)-knockdown 4910 and 5310 human glioma xenograft cells were interestingly correlated with p21-activated kinase 4 (PAK4) inhibition, prompting us to further investigate the role of PAK4 in glioma. Here, we report the PAK4 upregulation in positive correlation with increasing glioma pathological grades. The siRNA-mediated PAK4 knockdown elevated anoikis, and inhibited invasion and migration by downregulating MMP-2, αvβ3-integrin and phospho-epidermal growth factor receptor (phospho-EGFR). The cDNA-PCR arrays revealed a transcriptional suppression of essential proteins involved in cell proliferation and adhesion in PAK4-knockdown cells. Most importantly, glutathione S-transferase pull-down assays demonstrated the MMP-2 as a new PAK4-interacting protein which binds to PAK4 kinase domain. Individual EGFR/ErbB2 inhibitor and αvβ3 antibody treatments in PAK4si-treated cells indicated the regulation of αvβ3/EGFR survival signaling by PAK4. Overexpression of PAK4 significantly reversed the MMP2si-induced cell death in both cell lines. Codepletion of PAK4 and MMP-2 resulted in robust anoikis-mediated cell death, and severely inhibited invasive and migratory properties in these cells. PAK4si inhibited in vivo tumor growth in nude mice by inhibiting MMP-2, β3-integrin and phospho-EGFR levels in tumors. Our findings indicate a physical association between PAK4 and MMP-2, and suggest the future therapeutic potential of PAK4/MMP-2 dual targeting in glioma treatment.

A Shared Vision to Prevent Heart Disease and Stroke Through United Action

Cardiovascular diseases are the second and fourth leading causes of death in North Carolina, and when combined become the leading killers of North Carolinians. A key strategy for reducing this disease burden and saving lives is to focus on prevention through a combined approach of policy change and program implementation.

MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas

High-grade gliomas are some of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in gliomas, paraffin-embedded glioma tissue samples from 193 patients with gradeI, II, III, and IV tumors were analyzed by insitu hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels in each of these compartments. The miR-21 levels correlated significantly with grade [p=0.027, r (s)=0.161, 95% confidence interval (CI), 0.015-0.301] with the highest levels measured in glioblastomas. Only tumor cell miR-21 was associated with poor prognosis when adjusting for known clinical parameters (age, grade, and sex) in a multivariate analysis [p=0.049, hazard ratio (HR)=1.545, 95% CI, 1.002-2.381]. In conclusion, we have shown that miR-21 is located in both tumor cells and tumor blood vessels and that its level in the tumor cell compartment holds unfavorable prognostic value in gliomas.

O-031 Metal artifact reduction for C-arm flat panel CT: preliminary results in neurointerventional applications

PurposeWith the advent of latest generation flat panel detectors, C-arm angiographic systems have the ability to provide high-resolution CT-like images of brain parenchyma, vasculature and deployed devices while the patient...