The emergent role of exosomes in glioma.

Extracellular vesicles (EVs) are known mediators of intercellular communication for both normal and tumour cells. With the capability to transfer nucleic acids, proteins and lipids, EVs are able to influence numerous functional and pathological aspects of both donor and recipient cells. The tumour microenvironment possesses a high level of complex heterogeneity, particularly within the most prominent brain malignancy, glioblastoma multiforme (GBM). This complexity relies on a network-based communication between many different components of the local niche, including the various cell types, stroma, blood vessels, secreted factors and surrounding matrix. Exosomes are one type of EV which facilitates this intercellular communication and cross-talk within the tumour microenvironment. Exosomes secreted by tumour cells are increasingly recognized in a number of processes underlying tumour progression including facilitating the transport of receptors, signalling molecules, oncogenic genes and miRNA. They are emerging as a key component in the biogenesis of glioma, in addition to contributing to the modification of the surrounding microenvironment to support tumour progression. In this review we describe advancements in the understanding of the biology of exosomes, as well as their roles in tumour progression, as a tumour biomarker for tracking cancer progression, and as a potential therapeutic target/delivery system, with a contextual emphasis on GBM.

Use of tissue plasminogen activator in the treatment of shunt blockage secondary to intraventricular haemorrhage.

A 51-year-old woman with a history of idiopathic aqueduct stenosis, treated initially with insertion of a ventriculo peritoneal shunt, presented to our institution with shunt dysfunction. She had previously undergone multiple shunt revisions for shunt infection, shunt blockage and low-pressure symptoms, most recently with conversion to a ventriculo atrial (VA) shunt. Her VA shunt was again revised, with replacement of the ventricular catheter, however surgery was complicated by a large intraventricular haemorrhage (IVH) requiring placement of an external ventricular drain (EVD). Prior to eventual removal of her EVD it was determined that the VA shunt had blocked as a result of the IVH. Subsequently alteplase, a recombinant tissue plasminogen activator (tPA), was administered into the shunt reservoir, resulting in successful return of shunt function, therefore avoiding the need for further shunt revision. This is the first description of the use of tPA to unblock a shunt obstructed by blood.

Glutamate quantification in patients with supratentorial gliomas using chemical shift imaging.

This study aimed to evaluate and validate chemical shift imaging (CSI) for in vivo glutamate (Glu) quantification in patients with supratentorial gliomas. If validated, CSI could become an extremely useful tool to investigate metabolic dysfunction of Glu in excitotoxic neuropathologies. Quantitative CSI estimates of Glu concentrations were compared with known concentrations of Glu in aqueous phantom solutions. Forty-one patients with known or likely supratentorial gliomas underwent preoperative CSI. The spectra obtained were analyzed for Glu concentrations and Glu to creatine (Cr) ratios. These in vivo measurements were correlated against ex vivo Glu content quantified by high performance liquid chromatography (HPLC) measured in 65 resected brain tumor and peritumoral brain specimens. For the phantom solutions the CSI estimates of Glu concentration and the Glu/Cr ratios were highly correlated with known Glu concentration (r² = 0.95, p = 0.002, and r² = 0.97, p < 0.0001, respectively). There was a modest, but statistically significant, correlation between the ex vivo measured Glu and in vivo spectroscopic Glu concentration (r² = 0.22, p = 0.04) and ratios of Glu to Cr (r² = 0.30, p = 0.002). Quantitative measurement of Glu content is feasible in patients with supratentorial gliomas using CSI. The in vitro and in vivo results suggest that this has the potential to be a reliable quantitative imaging assay for brain tumor patients. This may have wide clinical research applications in a number of neurological disorders where Glu excitotoxicity and metabolic dysfunction are known to play a role in pathogenesis, including tumor associated epilepsy, epilepsy, stroke and neurotrauma.

Diagnosis and management of optic nerve sheath meningiomas.

Optic nerve sheath meningiomas account for a third of all intrinsic tumours of the optic nerve. Despite their classification as histologically benign tumours they cause progressive visual loss that often leads to blindness if left untreated. Recent therapeutic advances have increased the treatment options available to clinicians but patient management remains controversial. We systematically review the progress made in the diagnosis and management of optic nerve sheath meningiomas, clarify current best practice, and suggest future avenues for research.

Glycogen synthase kinase-3ß (GSK-3ß) and its dysregulation in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most frequently occurring and devastating human brain malignancy, retaining almost universal mortality and a median survival of only 14 months, even with recent advances in multimodal treatments. Gliomas are characterised as being both highly resistant to chemo- and radiotherapy and highly invasive, rendering conventional interventions palliative. The continual dismal prognosis for GBM patients identifies an urgent need for the evolutionary development of new treatment modalities. This includes molecular targeted therapies as many signaling molecules and associated pathways have been implicated in the development and survival of malignant gliomas including the protein kinase, glycogen synthase kinase 3 beta (GSK-3ß). Here we review the activity and function of GSK-3ß in a number of signaling pathways and its role in gliomagenesis.

Targeting Stat3 and Smad7 to restore TGF-ß cytostatic regulation of tumor cells in vitro and in vivo.

Transforming Growth Factor-ß (TGF-ß) and Epidermal Growth Factor (EGF) signaling pathways are both independently implicated as key regulators in tumor formation and progression. Here, we report that the tumor-associated overexpression of epidermal growth factor receptor (EGFR) desensitizes TGF-ß signaling and its cytostatic regulation through specific and persistent Stat3 activation and Smad7 induction in vivo. In human tumor cell lines, reduction of TGF-ß-mediated Smad2 phosphorylation, nuclear translocation and Smad3 target gene activation were observed when EGFR was overexpressed, but not in cells that expressed EGFR at normal levels. We identified Stat3, which is activated specifically and persistently by overexpressed EGFR, as a key signaling molecule responsible for the reduced TGF-ß sensitivity. Stable knockdown of Stat3 using small hairpin RNA(shRNA) in Head and Neck (HN5) and Epidermoid (A431) tumor cell lines resulted in reduced growth compared with control shRNA-transfected cells when grown as subcutaneous tumor xenografts. Furthermore, xenografts with Stat3 knockdown displayed increased Smad3 transcriptional activity, increased Smad2 phosphorylation and decreased Smad7 expression compared with control xenografts in vivo. Consistently, Smad7 mRNA and protein expression was also significantly reduced when EGFR activity was blocked by a specific tyrosine kinase inhibitor, AG1478, or in Stat3 knockdown tumors. Similarly, Smad7 knockdown also resulted in enhanced Smad3 transcriptional activity in vivo. Importantly, there was no uptake of subcutaneous HN5 xenografts with Smad7 knockdown. Taken together, we demonstrate here that targeting Stat3 or Smad7 for knockdown results in resensitization of TGF-ß's cytostatic regulation in vivo. Overall, these results establish EGFR/Stat3/Smad7/TGF-ß signaling axis driving tumor growth, which can be targeted therapeutically.

Suprasellar meningioma presenting with an altitudinal field defect.

We report a female patient with an unusual suprasellar meningioma presenting with a right-sided inferior altitudinal visual field defect. Two causative factors were identified at surgery: an aberrant ophthalmic artery found lying on the superior aspect of the optic nerve, and marked compression of the nerve superiorly against the falciform ligament.

Diagnosis and management of optic nerve glioma.

Optic nerve gliomas are highly variable tumours with an unpredictable clinical course. Consequently, the diagnosis and management of these tumours remains complex and a standardised management strategy does not exist. In this paper we describe a patient with optic nerve glioma treated at our institution and then review recent advances made in the diagnosis and treatment of these tumours over the past 10 years. Our aim is to clarify current best practice in the management of optic nerve gliomas.

Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg.

Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.

Complex visual hallucinations as a presentation of temporal low-grade glioma.

We report a patient with an unusual presentation of a temporal low-grade glioma with visual symptoms of formed, coloured meaningful images without coexistent psychiatric symptoms or epileptiform activity consistent with a diagnosis of visual hallucinosis. The location and extent of the lesion on the MRI differs from the lesions commonly associated with this diagnosis.

Traumatic brain injury and quality of life: initial Australian validation of the QOLIBRI.

The Quality of Life after Brain Injury (QOLIBRI) is a new international instrument for assessing quality of life after traumatic brain injury (TBI). We report first use and validation. Patients previously admitted with TBI to the Royal Melbourne Hospital, Melbourne, Australia, were randomly sampled (n=66, 61% response rate) and administered the QOLIBRI. Fifty-five re-completed it at 2-week follow-up. QOLIBRI scales (with two exceptions) met standard criteria for internal consistency, homogeneity and test-re-test reliability. Correlations with the Assessment of Quality of Life, Short Form-36 version 2 and the Satisfaction with Life Scale were moderate. The QOLIBRI was sensitive to the Glasgow Outcome Scale - Extended scores, Hospital Anxiety and Depression scale, and measures of social isolation (Friendship Scale). There was evidence that further refinement may improve the QOLIBRI. The QOLIBRI should be considered as an outcome measure by clinicians and researchers conducting treatment trials, rehabilitation studies or epidemiological surveys into the treatment or sequelae of trauma.

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs.

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazin.

Stargazin is membrane bound protein involved in trafficking, synapse anchoring and biophysical modulation of AMPA receptors. A quantitative trait locus in chromosome 7 containing the stargazin gene has been identified as controlling the frequency and duration of absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Furthermore, mutations in this gene result in the Stargazer mouse that displays an absence epilepsy phenotype. GAERS stargazin mRNA expression is increased 1.8 fold in the somatosensory cortex and by 1.3 fold in the thalamus. The changes were present before and after the onset of absence seizures indicating that increases are not a secondary consequence of the seizures. Stargazin protein expression was also significantly increased in the somatosensory cortex after the onset of spontaneous seizures. The results are of significant importance beyond the GAERS model, as they are the first to show that an increase in stargazin expression may be pro-epileptic.

Myelin structure is a key difference in the x-ray scattering signature between meningioma, schwannoma and glioblastoma multiforme.

Small angle x-ray scattering (SAXS) patterns of benign and malignant brain tumour tissue were examined. Independent component analysis was used to find a feature set representing the images collected. A set of coefficients was then used to describe each image, which allowed the use of the statistical technique of flexible discriminant analysis to discover a hidden order in the data set. The key difference was found to be in the intensity and spectral content of the second and fourth order myelin scattering peaks. This has clearly demonstrated that significant differences in the structure of myelin exist in the highly malignant glioblastoma multiforme as opposed to the benign: meningioma and schwannoma.

Venous air embolism and the sitting position: a case series.

Venous air embolism is a potentially serious complication of neurosurgery that occurs more commonly when the patient is in the sitting position. In this study, we aimed to quantify the incidence of venous air embolism during neurosurgical procedures performed with the patient in the sitting position in our institution. We performed a prospective audit of venous air embolism in 100 consecutive patients who underwent neurosurgical procedures in the sitting position, as evidenced by a decrease in end-tidal carbon dioxide partial pressure of 5 mmHg or more within 5 min. The incidence of venous air embolism was 9% (95% confidence interval: 3.3-14.7%). These patients did not have a significantly higher rate of hypotension or desaturation. Our results suggest that the sitting position can be safely used in neurosurgery.

MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome.

Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.

Solitary metastasis to the choroid plexus of the third ventricle mimicking a colloid cyst: a report of two cases.

Cerebral metastasis to the choroid plexus is rare and almost always occurs in the presence of multiple cerebral metastases. We present two cases of a solitary cerebral metastasis to the choroid plexus of the anterior third ventricle mimicking a colloid cyst. There appears to be an increased tendency for renal cell carcinomas to metastasis to the choroid plexus. Metastatic disease is an important differential diagnosis even for solitary lesions of the anterior third ventricle.

Aggressive intracranial fibromatosis: case report.

Fibromatosis is a locally aggressive, proliferative fibroblastic lesion affecting musculoaponeurotic structures, most often in the limbs and trunk. Intracranial fibromatosis is extremely rare and requires aggressive treatment to prevent recurrence. We present the case of a 48 year old woman with aggressive skull base fibromatosis. The lesion extended through the sphenoid sinus, into both pterygoid recesses, destroying the right lateral wall of the sphenoid sinus and invading the cavernous sinus. There was also involvement of the floor of the sella, the clivus, the right petrous temporal bone and the right mastoid. The patient underwent partial resection of the lesion via an extended trans-sphenoidal approach. Postoperative MRI showed residual tissue. A review of the literature shows that intracranial fibromatosis usually appears in the first or second decade. Complete resection is often impossible because of its widely infiltrative nature. Radiotherapy and chemotherapy are often required to improve local control of the lesion.

Sphenoid sinus mucocoele presenting as complete ophthalmoplegia.

Sphenoid sinus mucocoeles represent 1% of all paranasal sinus mucocoeles. We describe a case of a sinus mucocoele with an atypical presentation comprising the sudden onset of a complete ophthalmoplegia. There was good recovery following drainage of the mucocoele.

Idiopathic spinal cord herniation.

Spinal cord herniation is a rare condition that has become increasingly recognised in the last few years. The authors report a case of idiopathic spinal cord herniation in a 33 year old woman who presented with progressive Brown-Sequard syndrome. The diagnosis was made on MR imaging. After repairing the herniation the patient made a gradual improvement. Potential causes are discussed, including the possible role of dural tethering. In conclusion, idiopathic spinal cord herniation is a potentially treat able condition that should be more readily diagnosed with increased awareness and newer imaging techniques such as high resolution MRI.