Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis.

Glioblastoma multiforme (GBM) is a highly lethal brain tumor for which little treatment is available. The epidermal growth factor receptor (EGFR) signaling pathway is thought to play a crucial role in GBM pathogenesis, initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. The importance of this pathway is highlighted in the fact that EGFR is mutationally activated in over 50% of GBM tumors. Consistent with this, we show here that concomitant activation of wild-type and/or mutant (vIII) EGFR and ablation of Ink4A/Arf and PTEN tumor suppressor gene function in the adult mouse central nervous system generates a fully penetrant, rapid-onset high-grade malignant glioma phenotype with prominent pathological and molecular resemblance to GBM in humans. Studies of the activation of signaling events in these GBM tumor cells revealed notable differences between wild-type and vIII EGFR-expressing cells. We show that wild-type EGF receptor signals through its canonical pathways, whereas tumors arising from expression of mutant EGFR(vIII) do not use these same pathways. Our findings provide critical insights into the role of mutant EGFR signaling function in GBM tumor biology and set the stage for testing of targeted therapeutic agents in the preclinical models described herein.

Chronic subdural haematoma associated with nontraumatic CSF rhinorrhea: a management challenge.

We report an unusual case of chronic subdural haematoma (CSH) associated with cerebrospinal fluid (CSF) rhinorrhoea emphasizing the importance of managing both conditions simultaneously. A 59- year-old man presented with watery discharge from the right nostril, of 2 months duration. MRI of the brain showed a CSH in the left fronto-parietal region with significant mass effect. There was an arachnoidocoele with a defect in the planum sphenoidale. He first underwent a burr hole evacuation of the CSH following which the CSF rhinorrhea did not subside, even with bed rest. Transnasal endoscopic closure of the CSF dural fistula was done. On the first post-operative day, he was disoriented and a CT scan showed a recollection of the subdural haematoma that required repeat evacuation. The patient was asymptomatic at discharge. To our knowledge this is the first reported case of CSF rhinorrhoea associated with CSH. Simultaneous closure of the CSF dural fistula at the time of evacuation of a coexisting CSH would be the optimal management.

Endoscope-assisted microsurgery for intracranial aneurysms.

OBJECTIVE: We discuss the role of the endoscope in the microsurgical treatment of intracranial aneurysms, analyzing its benefits, risks, and disadvantages. METHODS: This was a prospective study of 55 patients with 79 aneurysms, treated between July 1998 and June 2001, for whom the endoscope was used as an adjunct in the microsurgical treatment of their lesions. Seventy-one aneurysms were located in the anterior circulation, and eight were located in the posterior circulation. Thirty-seven patients presented with subarachnoid hemorrhage. Eighteen patients had unruptured aneurysms, of whom 5 presented with mass effect, 2 presented with transient ischemic attacks, and 11 were without symptoms. In all cases, the endoscope was used in addition to microsurgical dissection and clipping (sometimes before clipping, sometimes during clipping, and always after clipping), for observation of the neck anatomic features and perforators and verification of the optimal clip position. Intraoperative angiography was performed for all patients after aneurysm clipping. RESULTS: In the majority of cases, the endoscope was very useful for the assessment of regional anatomic features. It allowed better observation of anatomic features, compared with the microscope, for 26 aneurysms; in 15 cases, pertinent anatomic information could be obtained only with the endoscope. The duration of temporary clipping of the parent artery was significantly reduced for two patients. The clip was repositioned because of a residual neck or inclusion of the parent vessel during aneurysm clipping in six cases, and the clip position was readjusted because of compression of the optic nerve in one case. One patient experienced a small aneurysm rupture that was directly related to use of the endoscope, but this was easily controlled, with no sequelae. For many patients, the combination of the neuro-endoscope and the micro-Doppler probe made intraoperative angiography redundant. CONCLUSION: "Endoscope-assisted microsurgery" is a major advance in the microsurgical treatment of intracranial aneurysms; the endoscope allows better observation of regional anatomic features because of its magnification, illumination, and ability to "look around corners."