Semaphorin 3A mediated brain tumor stem cell proliferation and invasion in EGFRviii mutant gliomas.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, with a median survival of approximately 15 months. Semaphorin 3A (Sema3A), known for its axon guidance and antiangiogenic properties, has been implicated in GBM growth. We hypothesized that Sema3A directly inhibits brain tumor stem cell (BTSC) proliferation and drives invasion via Neuropilin 1 (Nrp1) and Plexin A1 (PlxnA1) receptors. METHODS: GBM BTSC cell lines were assayed by immunostaining and PCR for levels of Semaphorin 3A (Sema3A) and its receptors Nrp1 and PlxnA1. Quantitative BrdU, cell cycle and propidium iodide labeling assays were performed following exogenous Sema3A treatment. Quantitative functional 2-D and 3-D invasion assays along with shRNA lentiviral knockdown of Nrp1 and PlxnA1 are also shown. In vivo flank studies comparing tumor growth of knockdown versus control BTSCs were performed. Statistics were performed using GraphPad Prism v7. RESULTS: Immunostaining and PCR analysis revealed that BTSCs highly express Sema3A and its receptors Nrp1 and PlxnA1, with expression of Nrp1 in the CD133 positive BTSCs, and absence in differentiated tumor cells. Treatment with exogenous Sema3A in quantitative BrdU, cell cycle, and propidium iodide labeling assays demonstrated that Sema3A significantly inhibited BTSC proliferation without inducing cell death. Quantitative functional 2-D and 3-D invasion assays showed that treatment with Sema3A resulted in increased invasion. Using shRNA lentiviruses, knockdown of either NRP1 or PlxnA1 receptors abrogated Sema3A antiproliferative and pro-invasive effects. Interestingly, loss of the receptors mimicked Sema3A effects, inhibiting BTSC proliferation and driving invasion. Furthermore, in vivo studies comparing tumor growth of knockdown and control infected BTSCs implanted into the flanks of nude mice confirmed the decrease in proliferation with receptor KD. CONCLUSIONS: These findings demonstrate the importance of Sema3A signaling in GBM BTSC proliferation and invasion, and its potential as a therapeutic target.

In-hospital neurologic deterioration following fractures of the ankylosed spine: a single-institution experience.

OBJECTIVE: To determine the rate and severity of in-hospital neurologic deterioration following vertebral fractures of spinal hyperostosis. METHODS: A retrospective review of 92 fractures in 81 patients with diffuse idiopathic skeletal hyperostosis (42%) or ankylosing spondylitis (58%) was performed. Data on demographics, comorbidities, and fracture and treatment characteristics were recorded. Neurologic presentation and outcomes were categorized using American Spinal Injury Association grades and the modified Rankin Scale. Univariate and multivariate analyses were used to identify risk factors for neurologic deterioration or poor outcome (modified Rankin Scale 4-6). RESULTS: Most fractures (66%) occurred after falls of standing height or less. Presentation was delayed in 41% of patients (median 7 days), and diagnosis was delayed in 21% (median 8 days). Most fractures were extension (60%) or distraction (78%) injuries involving all 3 spinal columns. Median Subaxial Cervical Spine Injury Classification and Thoracolumbar Injury Severity Scale scores were 6 (interquartile range 5-7) and 7 (interquartile range 6-8), respectively. Of patients, 62% underwent open operative fusion either as initial therapy or after failed conservative treatment, 20% had percutaneous instrumentation, and 27% were treated in an external orthosis (52% required open fusion). Neurologic deterioration after presentation occurred in 7 patients (8.6%); 5 of these patients deteriorated after surgical treatment, constituting a 7.6% surgical risk. The presenting American Spinal Injury Association grade and patient age predicted poor outcome at 1-year outcome (P < 0.001). Death occurred in 17 patients within 1 year of injury (23%). CONCLUSIONS: Neurologic deterioration during the initial hospitalization after spinal fractures in the setting of diffuse idiopathic skeletal hyperostosis or ankylosing spondylitis is common, and 1-year mortality is high.

Long-term tumor control and cranial nerve outcomes following γ knife surgery for larger-volume vestibular schwannomas.

OBJECT: γ knife surgery (GKS) for vestibular schwannoma (VS) is an accepted treatment for small- to medium-sized tumors, generally smaller than 2.5 cm in the maximum posterior fossa dimension. The purpose of this study was to evaluate the efficacy and toxicity of GKS for larger tumors. METHODS: Prospectively collected data were analyzed for 22 patients who had undergone GKS for VSs larger than 2.5 cm in the posterior fossa diameter between 1997 and 2006. No patient had symptomatic brainstem compression at the time of GKS. The median treated tumor volume was 9.4 cm(3) (range 5.3-19.1 cm(3)). The median maximum posterior fossa diameter was 2.8 cm (range 2.5-3.8 cm). The median tumor margin dose was 12 Gy (range 12-14 Gy). Serial imaging, audiometry (10 patients with serviceable hearing pre-GKS), and clinical follow-up were available for a median of 66 months (range 26-121 months). Tumor control failure was defined as either a progressive increase in tumor diameter of at least 2 mm in any dimension or a later resection. RESULTS: Four patients met the criteria for GKS failure, including 1 patient who demonstrated sarcomatous degeneration more than 7 years after GKS and died 3 months after microsurgical debulking. An enlarging cystic component was the surgical indication in 1 of the 2 patients who required resection, although 27% of tumors (6 lesions) were cystic before GKS. The 3-year actuarial rate of tumor control, freedom from new facial neuropathy, and preservation of functional hearing were 86%, 92%, and 47%, respectively. At 5 years post-GKS, these rates decreased to 82%, 85%, and 28%, respectively. At the most recent follow-up, 91% of tumors were smaller than at the time of GKS and the median maximum posterior fossa diameter reduction was 26%. On multivariate analysis, none of the following factors was associated with GKS failure, new facial weakness, new trigeminal neuropathy, or loss of serviceable hearing: patient age, tumor volume, tumor margin dose, and preoperative cranial nerve dysfunction. CONCLUSIONS: Single-session radiosurgery is a successful treatment for the majority of patients with larger VSs. Although tumor control rates are lower than those for smaller VSs managed with GKS, the cranial nerve morbidity of GKS is significantly lower than that typically achieved via resection of larger VSs.

"Real time" angiographic evidence of "pseudoaneurysm" formation after aneurysm rebleeding.

BACKGROUND: Pseudoaneurysms occur at the rupture site of true aneurysms and appear as irregularly shaped and partially thrombosed outpouchings of the main sac. Recanalization of thrombi inside pseudoaneurysmal sac is one of the putative mechanisms of rebleeding of unsecured aneurysms and of coil migration after endovascular treatment. We document "real time" pseudoaneurysm formation after rerupture of an anterior communicating artery aneurysm. METHODS: Case report. RESULTS: A 55-year-old man with aneurysmal subarachnoid hemorrhage from an anterior communicating aneurysm underwent catheter angiography. After the diagnostic angiogram while awaiting for the anesthesia team to proceed with endotracheal general anesthesia, a seizure occurred. Rebleeding was suspected and confirmed by a dynamic CT in the angio suite. A repeat angiogram showed a pseudoaneurysm arising from the previously ruptured aneurysm which had not been present on the original angiogram a few minutes earlier. Uneventful coiling of the aneurysm was undertaken and the patient was discharged home a week later. CONCLUSIONS: We document angiographic formation of a "pseudoaneurysm" at the site of rupture of an anterior communicating artery aneurysm. "Pseudoaneurysm" formation occurs after rupture of an intracranial aneurysm. They represent a weak spot in the aneurysm sac at the site of rupture and probably the result of persistent flow within the clot forming at the site of rupture. Presence of a pseudoaneurysm with characteristic angiographic features like the one herein described represents an unstable area within the aneurysm. This case also highlights the observation that, in patient harboring unsecured ruptured aneurysms, seizures or seizures-like phenomena are the clinical expression of rebleeding unless proven otherwise.

Morbidity of transcallosal and transcortical approaches to lesions in and around the lateral and third ventricles: a single-institution experience.

BACKGROUND: Resection of an intraventricular mass can result in life-altering complications. Many advocate transcallosal rather than transcortical approaches to these lesions, citing differential postoperative seizure risk. OBJECTIVE: To test the hypothesis that the complication rates and patient outcomes are no different between these ventricular approaches. METHODS: The medical records of 127 patients (93 adults and 34 children) operated on for intraventricular lesions between 1996 and 2007 were retrospectively analyzed. Risk factors for specific postoperative complications and outcome were assessed by multivariate analysis. RESULTS: The transcallosal (59%) or transcortical (41%) approach was used. Gross or nearly total resection was achieved in 87% of cases. The permanent neurological complication rate determined by a staff neurologist was 23.6%. Seizure attributable to surgery occurred after 8% of transcortical and 25% of transcallosal operations (P=.01). After controlling for a variety of factors, the transcallosal approach carried a 4.4-fold increased risk of seizure (95% confidence interval, 1.3-18.9). The operative approach was not a risk factor for any other postoperative complication. One year after surgery, 72% of patients had excellent functional outcome (Karnofsky Performance Score≥70 and Glasgow Outcome Score=5). High tumor grade and impaired preoperative Karnofsky Performance Score predicted poor outcome. More than 90% of patients operated on for symptomatic colloid cysts (n=34) had an excellent outcome. CONCLUSION: Although the 2 traditional approaches to the ventricular system had similar major complication rates, the transcallosal approach was associated with significantly increased seizure risk. Accordingly, the chosen operative corridor should optimize tumor access and the protection of vulnerable neurovascular structures.

Ganglioglioma in the cerebellopontine angle in a child. Case report and review of the literature.

The authors report a case of a posterior fossa ganglioglioma centered in the cerebellopontine angle occurring in a child. As with cortically based gangliogliomas, the primary therapy is resection. When the tumor presents in the posterior fossa, often only partial resection can be accomplished without significant neurological deficit. The role of adjuvant chemotherapy and radiation therapy remains controversial, although these are usually reserved for high-grade lesions or progressive growth. The literature regarding the natural history, surgical outcomes, and indications for adjuvant therapy is reviewed. Although it occurs rarely, ganglioglioma should be included in the differential diagnosis of a posterior fossa mass in a child or young adult.