Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

Prevalence and indication for changing the primary valve opening pressure in ventriculoperitoneal shunts - A single center five years overview.

OBJECTIVE: Serious medical conditions of patients in neurosurgery often require ventriculoperitoneal shunting to normalize the intracranial pressure. Neurosurgeons select a valve opening pressure (VOP), whose exceeding causes the shunt to open to drain cerebrospinal fluid (CSF): In most cases a standard pressure is chosen. Whereas some patients fare well with the primary chosen VOP, others require one to several VOP changes. This study aims to evaluate the prevalence and indication for occurring valve pressure-adjustments. PATIENTS AND METHODS: We obtained information about 343 ventriculoperitoneal shunt implantations in 321 adult patients from 2013 to 2018 in a single center with well-kept electronic health records regarding hydrocephalus types, hydrocephalus etiologies, primary VOP, valve pressure adjustment, time with shunt, time till VOP change, age, sex and shunt type. The data was analyzed using Kaplan-Meier estimator (KME) for the whole patient sample and for subgroups with the primary VOP adjustment defined as event. In the subgroup analysis different types of hydrocephalus, different hydrocephalus etiologies, valve types, both sexes and the patients' age had been compared by applying Peto-Pike's log-rank test and cox-regression. RESULTS: Of the 343 implanted VP shunts in 321 patients, 166 valve pressure adjustments in 101 V P shunts were required during the observed time with a resulting valve pressure-adjustment rate of 0.484 per valve implant. The time till median valve pressure-adjustment was 2.9 years and 38.3% one year after VP shunt placement for the general sample in Kaplan Meier-analysis. The subgroup comparisons between hydrocephalus types, hydrocephalus etiologies, valve types, sexes and the patients' age did not reveal significant differences applying Peto-Pike's log-rank test. But the primary chosen valve-pressure of 5 cmH2O is associated with a lower percentage of valve-pressure adjustments, than other initial valve-pressures (Chi2 = 7.9; df = 1; p = 0.0049). CONCLUSION: This study reveals a valve pressure-adjustment rate of 38.3% after one year for the whole patient collective and similar adjustment rates for different types of hydrocephalus. The primary valve pressure of 5 cmH2O is associated with a lower valve pressure-adjustment rate than other initial valve pressures and therefore 5 cmH2O may be the preferred initial valve pressure for all patients receiving programmable VP shunt insertions with gravitational unit.

Vasospasm of the basilar artery following spontaneous SAH-clinical observations and implications for vascular research.

The basilar artery (BA), as a reference vessel for laboratory investigations of cerebral vasospasm (CVS) in many experimental models, warrants a sufficient blood supply despite hemodynamic changes during CVS. In a prospective evaluation study, we analyzed  patients who were admitted to our department with subarachnoid hemorrhage (SAH) for the occurrence and sequelae of CVS. Specifically, we sought to identify patients with CVS of the BA. As per institutional protocol, all patients with CVS detected in the posterior circulation had magnetic resonance imaging (MRI) examinations instead of CTA. Between January and December 2016, 74 patients were treated for spontaneous SAH. CVS occurred in 45 (61%) patients, and 31 (42%) patients developed associated cerebral infarctions (CI). CVS was significantly associated with CI (p < 0.0001; OR 44). In 18 (24.3%) patients, CVS significantly affected the basilar artery. Poor admission clinical state, younger age, and treatment modalities were significantly associated with BACVS. BACVS was more often detected in patients with severe CVS (p < 0.046; OR 4.4). Patients with BACVS developed cerebral infarction in a frequency comparable to other patients with CVS (61% vs. 70%, p = 0.7), but none of these infarctions occurred in the brain stem or pons even though vessel diameter was dramatically reduced according to CT- and/or MR-angiography. BACVS does not appear to be followed by cerebral infarction in the BA territory, presumably due to a vascular privilege of this vessel and its perforating branches. In contrast, brain ischemia can frequently be observed in the territories of other major arteries affected by CVS.

Comparison of carotid and basilar bifurcation aneurysms versus non-T-angled bifurcations: the geometry is associated with the outcome.

Patients with ruptured aneurysms of carotid bifurcation artery seem to suffer less often from cerebral vasospasm and early brain injury and have a better clinical outcome. Aim of our study was to identify differences in clinical course and outcome in aneurysms of terminus segments (carotid bifurcation artery and basilar tip) compared to aneurysms of other aneurysm locations except carotid bifurcation artery and basilar tip. Patients with SAH were entered into a prospectively collected database (1999 to June 2014). A total of 471 patients ('T-shaped' aneurysms n = 63, 'non-T-shaped' aneurysms n = 408) were selected. Outcome was assessed by modified Rankin Scale (mRS) 6 months after SAH. Mean age was 53.75 years. Statistically, analysis showed a significant better outcome in 'T-shaped' aneurysms (p = 0.0001) and a significant lower mortality rate (p = 0.02) despite higher rates of Fisher 3 bleeding pattern and CVS. In 'T-shaped' aneurysms, no prognostic factors for outcome could be detected. In 'non-T-shaped' aneurysms admission status (p < 0.0001), early hydrocephalus (p < 0.0001), shunt-dependence (p = 0.001), and the occurrence of severe CVS (p = 0.01) statistically were factors influencing patients' outcome. Multivariate analysis showed 'non-T-shaped' aneurysms itself as independent prognostic factor for patients' outcome. Despite same rate of poor admission status, early hydrocephalus and shunt dependence 'T-shaped' aneurysms have a highly significantly better. Pathophysiological mechanism actually is not understood. Further studies are necessary to identify, which factors lead to the decreased outcome in "non-T-shaped"- aneurysms.

Optimization of the Surgical Approach in AVMs Using MRI and 4D DSA Fusion Technique : A technical note.

PURPOSE: Previously published data demonstrated the possibility of displaying the angioarchitecture of intracranial vascular malformations using time-resolved 3D imaging (4D digital subtraction angiography [DSA]). The purpose of our study was to prove the technical feasibility of creating fused images of time-resolved 3D reconstructions and MPRAGE MRI data sets and to check the reliability of the correct anatomical display of the angioma nidus and the venous drainage in the fused images of patients with intracranial arteriovenous malformations (AVM). PATIENTS AND METHODS: In this study 20 patients with intracranial AVM underwent pretherapeutic DSA and time-resolved 3D DSA in addition to MRI including MPRAGE sequences. The images were post-processed with the fusion software tool on a dedicated research workstation. The fusion of both imaging modalities was done semi-automatically with automatic co-registration software followed by a manual co-registration. RESULTS: Co-registered DSA/MRI data sets of 20 untreated AVMs were evaluated independently by two reviewers. Image fusion was successful in all 20 cases with an acceptable additional set-up time. The fused images were highly scored by the two raters in respect to their congruency of the dedicated regions. Precise anatomical localization of the nidus, the feeding arteries and the draining veins were possible with the merged images. CONCLUSION: Creating fused images of time-resolved 3D DSA and contrast-enhanced T1-weighted MPRAGE MR images might be beneficial for the preoperative and intrasurgical workflow in patients with AVMs. This new software tool fulfils the required quality and accuracy of the merged images. The clinical validation has to be proven in further studies.

Decision-making in a patient with cardiac arrest due to venous thromboembolism within 24 h after glioblastoma resection.

In the fulminant VTE form with cardiac arrest, systemic thrombolysis remains the most effective therapy. However, several contraindications restrict the use such as intracranial neoplasm or a recent history of intracranial surgery. Here, we report the case of a 59-year-old man who underwent glioblastoma resection and suffered from a fulminant pulmonary embolism with cardiac arrest. After CPR, continuous tPA infusion via an endovascularly placed pulmonary catheter was maintained over a period of 8 h. In this case, we report on our decision-making process and the use of local thrombolysis as a successful therapy in a patient with multiple contraindications.

Cross-sectional area of the ulnar nerve after decompression at the cubital tunnel.

UNLABELLED: A total of 48 patients undergoing surgical decompression of the ulnar nerve at the cubital tunnel between February 2010 and May 2013 were retrospectively studied to determine changes in the cross-sectional area of the nerve by the technique of neurosonography. The mean follow-up was 46 months. Post-operative follow-up examination of the cross-sectional area of the ulnar nerve showed a slight reduction in the mean value from 13.8 mm(2) (pre-operative) to 12.9 mm(2) (post-operative). Of the 48 patients, 36 showed a reduction in the cross-sectional area. No correlation was detected between the clinical and sonographic outcomes. Ultrasound seems to be of limited value in the post-operative assessment of patients with entrapment neuropathy of the ulnar nerve. LEVEL OF EVIDENCE: IV.

Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome.

BACKGROUND AND PURPOSE: In some patients with subarachnoid hemorrhage (SAH) a bleeding source cannot be identified. Perimesencephalic (PM) SAH is assumed to have an excellent outcome. Our objective was to analyze the long-term physical and psychological outcome of patients after non-aneurysmal SAH. METHODS: One hundred and seventy-three patients met the inclusion criteria. Short-term follow-up 6 months after SAH was assessed according to the modified Rankin Scale (0-2 favorable). A short-form health survey with 36 questions (SF-36) and eight scales was used as questionnaire for long-term follow-up. RESULTS: Thirty-seven answers were received from the two groups, PM and non-perimesencephalic (NPM) SAH, on average 76 months after ictus (range 1.5-14 years). PM- and NPM-SAH without Fisher grade 3 blood pattern have excellent short-term outcomes. The quality of life (QoL) is significantly reduced after non-aneurysmal SAH, especially in NPM-SAH. In particular, patients with a Fisher 3 blood pattern had significantly higher risks for cerebral vasospasm, delayed cerebral ischaemia, unfavorable outcome, reduced QoL and mortality in short- and long-term follow-up. CONCLUSIONS: Excluding rolph, only patients with a PM-SAH have a similar QoL at long-term follow-up compared to the standard population. Patients with NPM-SAH have a significantly decreased QoL in long-term follow-up. Furthermore, the Fisher 3 blood pattern group in particular had a significantly worse outcome - at short-term and long-term follow-up. Therefore the NPM-SAH group was stratified into patients with Fisher 3 blood pattern and patients without Fisher 3 in further investigations.

Differentiated plasma cell myeloma presenting as a solitary spinal amyloidoma: a case report, possible pitfall and review to the literature.

OBJECTIVE: Solitary spinal amyloidoma is a rare entity. Amyloidomas consist of extracellular amyloid deposits with an insoluble beta-pleated proteinaceous material. Although amyloidomas are slow growing lesions, they may lead to a progressive spinal cord or nerve root compression. Moreover amyloidoma results in destruction of bone with consequence of progressive osteolysis. METHOD: This study is a case presentation and review of the literature and should point out the need to explore any underlying diseases to guarantee the best therapy for the affected patient. In this case report we present a female patient with high-level paraparesis and lumbar stenosis in L2-L3 with combined spondylolisthesis (ASIA Impairemet Scale C). Paraparesis increased shortly after lumbar osteosynthesis. Contrast-enhanced MRI of the thoracic spine revealed medullary compression at the D5 level due to an epidural and paraspinal mass with concomitant bone infiltration. Operative decompression followed. Histopathological examination initially revealed amyloidoma. Finally the lesion was classified as a plasma cell myeloma. RESULTS: Plasma cell myeloma may rarely present as a solitary amyloidoma in the initial pathological examination with the potential to cause spinal cord compression associated to osteolytic lesions of the spine. CONCLUSION: A thorough pathological work-up is mandatory in order to rule out differential diagnosis and exclude possible underlying diseases.

S100B, intraoperative neuromonitoring findings and their relation to clinical outcome in surgically treated intradural spinal lesions.

BACKGROUND: Neurophysiological monitoring (IOM) consisting of somatosensory (SEPs), muscle (MEPs) and spinal motor evoked (D-wave; spinal MEPs) potentials is used to indicate injury related to surgical treatment of intradural and intramedullary lesions. Combining spinal and muscle MEPs reliably predicts long-term motor deficit. If spinal MEPs recording is not possible, additional markers-e.g. S100B, a serum marker for glial injury-may be a helpful adjunct. Thus, serial serum S100B measurements were related to both the intraoperative IOM recordings and the long-term neurological outcome in patients surgically treated for cervical and thoracic intradural lesions. METHODS: In 33 patients (9 men, 24 women, 54 ± 17 years) during intramedullary (8) or intradural (25) cervical or thoracic spinal surgeries significant intraoperative SEP-amplitude decrement >50 % or MEP loss and serial S100B serum concentration (perioperative days 0, 1-3, 5) were related to outcome (>1 year after discharge, grouped into improved and unchanged/altered neurological symptoms). RESULTS: Differences in S100B levels between patients with improved and unchanged/altered neurological outcome were significantly on postoperative days 2 (0.085 ± 0.08 µg/l vs 0.206 ± 0.07 µg/l, p = 0.005) and 3 (0.076 ± 0.03 µg/l vs 0.12 ± 0.05 µg/l, p = 0.007). All patients with permanent altered neurological symptoms developed S100B levels >0.08 µg/l (0.09-0.35 µg/l). Eighty-one percent of patients with improved neurological symptoms presented with S100B levels ≤0.08 µg/l (0.02-0.08 µg/l). Nine out of ten patients (90 %) without changes in EP and S100B had an improved long-term outcome, whereas 9/13 patients (69 %) with changes in EP and S100B had altered neurological symptoms in long-term outcome. CONCLUSION: Intraoperative stable EPs and S100B ≤0.08 µg/l may be used as a marker to predict long-term neurological improvement, whereas EP-changes and elevated S100B levels on the 3rd postoperative day may be useful as a marker to predict long-term neurological alteration. In summary, the combined use of S100B and EPs might be helpful in the prediction of the severity of adverse spinal cord affection following surgery and guidance of patients.

Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.

Gamma knife radiosurgery of recurrent atypical neurocytoma. Case report and review of the literature.

BACKGROUND AND PURPOSE: The goal of this work was to demonstrate the efficacy of stereotactic gamma knife radiosurgery (GKRS) for the treatment of neurocytoma by means of a case report and a comprehensive literature review. CASE REPORT: A locally recurrent atypical neurocytoma in the area of the left third ventricle thalamic wall occurring 7 years after primary microsurgical resection in a 59-year old woman was treated by GKRS. A marginal dose of 17 Gy was delivered to the surrounding 50% isodose. At the last follow-up, 82 months after radiosurgery, the tumor was locally controlled. For the literature review, computerized bibliographic searches of Pubmed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. DISCUSSION: The present case confirms the results of the literature analysis. From 1997-2011, a total of 14 series were published providing results of GKRS in 86 patients (89 lesions). The marginal doses, which have been applied, ranged from 9.6-20.0 Gy. With median follow-up intervals between 6 and 185 months, local control was 97.2% and local tumor progression of neurocytoma after GKRS was restricted to only 4 cases. In accordance with our own experience, GKRS was not associated with a relevant early or late toxicity. CONCLUSION: GKRS can be assumed to be a safe and effective treatment modality of recurrent or residual neurocytoma.

Intraoperative 3D fluoroscopy in stereotactic surgery.

BACKGROUND: Intraoperative localisation of a stereotactic probe remains challenging. Stereotactic X-ray, the "gold standard", as well as intraoperative magnetic resonance (MRI) and computed tomography (CT), require a dedicated operating room (OR). Fluoroscopy with crosshairs confirms only grossly the target position. An alternative would be a mobile three-dimensional (3D) fluoroscopy C-arm. To our knowledge, this is the first report on 3D C-arm fluoroscopy to verify stereotactical trajectories. The objective was to assess the feasibility of using a 3D C-arm to verify the intraoperative trajectory and target. METHODS: A total of 12 stereotactic trajectories in 10 patients were analysed, comprising 8 biopsies and 4 electrode trajectories. The fluoroscopic scan was performed after implantation of the deep brain stimulation electrode or after advancing the biopsy needle to the tumour. An image set is acquired during a rotation of the 3D C-arm. The image set is reconstructed and merged to the preoperative CT scan. Calculating the vector error and the deviation assesses target and trajectory accuracy. RESULTS: The mean trajectory deviation was 0.6 mm (±0.54 mm) and the mean vector error was 1.44 mm (±1.43 mm). There was no influence on the surgical time and the mean irradiation dosage was 401.9 cGycm(2). CONCLUSIONS: This target and trajectory verification is feasible. Its accuracy seems comparable with MRI and CT. There is no additional time consumption. Irradiation is comparable with stereotactic X-ray.

Recurrence rate, time to progression and facial nerve function in microsurgery of vestibular schwannoma.

OBJECTIVE: Recurrence rate, time to progression, and facial nerve function were analysed by comparing patients with complete and near total tumor removal after suboccipital craniotomy for vestibular schwannoma surgery. METHODS: From 1996 to 2004, 118 patients with vestibular schwannoma were operated with an interdisciplinary approach. Fifty patients fulfilled the inclusion criteria and were included in the study. Progression was defined as an increase of ⩾2 mm in the largest diameter in the magnetic resonance imaging. Preoperative tumor size, facial nerve function estimated using the House-Brackmann score (HBS), time to progression, and recurrence rate were analysed and related to the extent of resection. RESULTS: In 28 cases (group I), a capsular remnant was left. In 22 cases (group II), tumor removal was complete. In group I, nine patients (32·1%) showed progression. In group II, two patients (9·1%) developed a recurrent tumor, no significance (P = 0·085). In groups I and II, 53·6 and 59·6% had a good function of the facial nerve (HBS I+II), 28·6% in group I and 13·5% in group II had a moderate disturbance (HBS III+IV), and 17·9% in group I and 27·7% in group II had a poor function (HBS V+VI). There was no significant difference between median preoperative tumor size and facial nerve function within patients with HBS III and IV. CONCLUSION: Complete tumor removal may be associated with a risk of functional loss, whereas near total tumor removal may be associated with a higher risk of progression.

[Microneurovascular facial reanimation via the masseteric nerve: reconstruction alternative for long-standing facial palsy]. / Mikroneurovaskuläre Gesichtsreanimation über den N. massetericus : Rekonstruktionsalternative bei lang bestehender Fazialisparese.

BACKGROUND: The aim of the study was to retrospectively analyze the functional outcomes of microneurovascular facial reanimation using the masseteric innervation. PATIENTS AND METHODS: Seventeen patients with irreparable facial paralyses resulting from benign lesions involving the facial nuclei (n=14) or Möbius syndrome (n=3) were treated with free muscle flaps for oral commissural reanimation using ipsilateral masseteric innervation and using temporalis muscle transfer for eyelid reanimation. The results were analyzed by a commissural excursion (CE) index and a patient self-evaluation score. The presence of synkinesis was documented. Follow-up ranged from 8 to 48 months (mean 26.4 months). RESULTS: Normalization of the CE index could be observed in 8 out of 17 patients (47%), an improvement in 7 out of 17 (41%) and failure in 2 out of 17 (12%). A natural smiling response was observed in 10 out of 17 (59%) patients. Patient self-evaluation scores were a level higher than objective indices. CONCLUSIONS: Innervation of free muscle flaps with the masseteric nerve for oral commissure reanimation might play an important role in patients with long-standing facial palsy (as in Möbius syndrome). Synkinesis persists for long periods after surgery. However, most of the patients had learned to express their emotions by overcoming this phenomenon. Despite hypercorrection or inadequate correction, patients evaluate themselves favorably.

Intra-operative subcortical electrical stimulation: a comparison of two methods.

OBJECTIVE: For intra-operative subcortical electrical stimulation of the corticospinal tract, two techniques - originally described for cortical stimulation - have evolved: the 50-Hz-stimulation first described by Penfield in 1937 and the high-frequency multipulse train stimulation technique first described by Taniguchi in 1993. Motor thresholds of both methods in combination with a bipolar and monopolar stimulation technique and their reliability for eliciting motor evoked potentials (MEPs) were studied. METHODS: Data were obtained in 20 patients (50±17 years; 10 females) undergoing tumour resection under general anaesthesia. Both 50-Hz-stimulation of 1-s duration and a multipulse stimulation (5 pulses interstimulus interval 4 ms, 0.5-Hz repetition rate) were applied with a bipolar probe (1.5-mm ball tip, 8-mm interelectrode distance) and a monopolar probe (1.5-mm-diameter tip). MEPs were recorded in muscles contralateral to the stimulated hemisphere. Comparison of different stimulation modalities was performed at the site where monopolar multipulse stimulation technique elicited MEPs with the lowest stimulation intensity (constant current monophasic cathodal stimulation, individual pulse width 0.5 ms, max. 25 mA). RESULTS: MEPs were elicited by monopolar multipulse stimulation with an intensity of 8±3.9 mA (21/21 stimulation sites); monopolar 50-Hz stimulation with 12±5.4 mA (18/21 stimulation sites); bipolar multipulse stimulation with 14±8.1 mA (12/21 stimulation sites) and bipolar 50-Hz stimulation with 15±6.3 mA (11/21 stimulation sites). CONCLUSIONS: Stimulation intensities for eliciting MEPs are significantly lowest for the monopolar multipulse stimulation (p<0.025). Monopolar compared to bipolar stimulation resulted in eliciting MEPs in a higher number of tested patients (Fisher's p<0.0001). SIGNIFICANCE: Subcortical stimulation with a monopolar probe and a multipulse stimulation is most efficient for the purpose of identifying the corticospinal tract. This is explained by the more radiant electric field properties of the monopolar probe compared to the bipolar probe.

The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma.

The main aim of this study was to investigate the influence of perioperative anticoagulation on the clinical course and outcome of 144 patients who underwent surgery for chronic subdural hematoma (CSDH). The outcome was categorized according to the modified Rankin Scale (mRS), Barthel Index and postoperative quality of life (QoL) scale. There was a significant correlation between preoperative aspirin medication and reoperation (Mann-Whitney U-test, p<0.05). Moreover, dosage and duration of postoperative low-molecular-weight heparin (LMWH) administration were associated with a higher risk of reoperation (Mann-Whitney U-test, p<0.01) and a worse outcome on the mRS (Mann-Whitney U-test, p<0.05). Intraoperative treatment with prothrombin complex concentrate led to a poor outcome on the mRS (Craddock-Flood test, p<0.05). Reoperation is the strongest predictive factor of a poor QoL after surgical treatment of CSDH. Both preoperative and postoperative anticoagulation treatment may affect reoperation rate and, thus, postoperative QoL.

Inhibition of tissue factor/protease-activated receptor-2 signaling limits proliferation, migration and invasion of malignant glioma cells.

Tissue factor (TF) is upregulated in several malignant diseases, including gliomas. Here, we demonstrate pronounced differences in the expression of TF and its interactors factor VII and protease-activated receptor 2 (PAR-2) in nine human glioma cell lines (U87, U251, U343, U373, MZ-18, MZ-54, MZ-256, MZ-304, Hs 683) as detected by RT-PCR and Western blot analysis. Inhibition of TF signaling by a neutralizing monoclonal antibody (mAb TF9-10H10) led to significantly reduced proliferation in high-grade astroglial (MZ-18 and MZ-304) and oligodendroglial (Hs 683) cell lines abundantly expressing TF, but not in U373 cells expressing low amounts of TF. Scratch migration assays and Boyden chamber assays indicated that mAb TF9-10H10 and lentiviral knockdown of TF significantly reduced cell migration and invasion of MZ-18, MZ-304 and Hs 683 cells, both under normoxic and hypoxic conditions. Of note, all three cell lines displayed increased cell migration and invasion under hypoxic conditions (1% O(2)), which was associated with enhanced expression of TF and increased phosphorylation of p44/42 mitogen-activated protein kinase (ERK1/2). Silencing of TF blocked activation of the ERK pathway, induction of TF expression and the potentiating effect of hypoxia on cell migration and invasion. RNA interference against PAR-2 abrogated the autocrine effects of TF on cell proliferation, migration and invasion, indicating that TF signals via PAR-2 in glioma cells. Our results suggest an important role for the TF/FVIIa/PAR-2/ERK axis in tumor growth and invasion of glioma and suggest that TF may be a suitable target for the development of novel therapies against high-grade glioma.