Kimberly Kicielinski

Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme

PURPOSE We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Phase 1 Clinical Trial of Intratumoral Reovirus Infusion for the Treatment of Recurrent Malignant Gliomas in Adults

Reovirus, an oncolytic RNA virus exhibiting antiglioma activity, was shown in a previous single institution phase 1 study found that the inoculation of the virus to be well tolerated in patients with recurrent malignant glioma (MG). The goals of multicenter study reported herein were to determine the dose-limiting toxicity, maximum tolerated dose, and target lesion response rate when reovirus was administered in a novel fashion via intratumoral infusion for 72 hours in patients with recurrent malignant glioma. Fifteen adult patients were treated in a dose escalation study ranging from 1 × 10(8) to 1 × 10(10) tissue culture infectious dose 50, tentimes the dose achieved in the previous trial. Neurological, functional examinations, and imaging studies were completed pre- and postinfusion. There was one grade 3 adverse event (convulsions) felt to be possibly related to treatment, but no grade 4 adverse events considered probably or definitely related to treatment. Dose-limiting toxicity were not identified and a maximum tolerated dose was not reached. Evidence of antiglioma activity was seen in some patients. This first report of intratumoral infusion of reovirus in patients with recurrent malignant glioma demonstrated the approach to be safe and well tolerated, warranting further studies.

Seizure outcomes after stereotactic radiosurgery for the treatment of cerebral arteriovenous malformations

OBJECTIVE Patients with cerebral arteriovenous malformations (AVMs) commonly present with seizure. Seizure outcomes in patients treated with stereotactic radiosurgery (SRS) are poorly defined. A case series of patients with cerebral AVMs treated with SRS is presented to evaluate long-term seizure outcome. METHODS A retrospective review of the medical record was performed, identifying 204 consecutive patients with AVMs treated with SRS between January 1991 and June 2012. Clinical and radiographic data were evaluated. Seizure outcome was measured using the Engel Epilepsy Surgery Outcome Scale. Mean duration of follow-up was 37.1 months (SD 38.3 months) with a minimum follow-up period of 1 month. RESULTS Of the 204 patients with cerebral AVMs treated with SRS, 78 patients (38.2%) presented with seizures and 49 of those patients were treated with antiepileptic drugs (AEDs). Following SRS, 63 (80.8%) of the 78 patients who had had seizures prior to SRS were seizure-free at a mean follow-up time of 37.2 months (SD 41.3 months). Of the 49 patients who had been treated with AEDs, 17 were still taking AEDs at last follow-up. Of the 126 patients who did not present with seizures prior to treatment with SRS, only 5 patients (4.0%) had seizures in the post-SRS period. There was no significant correlation between post-SRS seizure status and patient demographic features, comorbidities, AVM characteristics, history of operative intervention, pre- or posttreatment hemorrhage, or radiographic degree of AVM resolution. CONCLUSIONS Stereotactic radiosurgery for treatment of cerebral AVMs is effective at providing long-term control of seizures. A substantial number of patients who were treated with SRS were not only seizure free at their last follow-up, but had been successfully weaned from antiepileptic medications.

Carotid and vertebral injury study (CAVIS) technique for characterization of blunt traumatic aneurysms with reliability assessment.

Traumatic aneurysms occur in up to 20% of blunt traumatic extracranial carotid artery injuries. Currently there is no standardized method for characterization of traumatic aneurysms. For the carotid and vertebral injury study (CAVIS), a prospective study of traumatic cerebrovascular injury, we established a method for aneurysm characterization and tested its reliability. Saccular aneurysm size was defined as the greatest linear distance between the expected location of the normal artery wall and the outer edge of the aneurysm lumen (“depth”). Fusiform aneurysm size was defined as the “depth” and longitudinal distance (“length”) paralleling the normal artery. The size of the aneurysm relative to the normal artery was also assessed. Reliability measurements were made using four raters who independently reviewed 15 computed tomographic angiograms (CTAs) and 13 digital subtraction angiograms (DSAs) demonstrating a traumatic aneurysm of the internal carotid artery. Raters categorized the aneurysms as either “saccular” or “fusiform” and made measurements. Five scans of each imaging modality were repeated to evaluate intra-rater reliability. Fleiss’s free-marginal multi-rater kappa (κ), Cohen’s kappa (κ), and interclass correlation coefficient (ICC) determined inter- and intra-rater reliability. Inter-rater agreement as to the aneurysm “shape” was almost perfect for CTA (κ = 0.82) and DSA (κ = 0.897). Agreements on aneurysm “depth,” “length,” “aneurysm plus parent artery,” and “parent artery” for CTA and DSA were excellent (ICC > 0.75). Intra-rater agreement as to aneurysm “shape” was substantial to almost perfect (κ > 0.60). The CAVIS method of traumatic aneurysm characterization has remarkable inter- and intra-rater reliability and will facilitate further studies of the natural history and management of extracranial cerebrovascular traumatic aneurysms.

C5-C6 Cervical Spinal Cord Cavernous Malformation Microsurgical Resection: 2-Dimensional Operative Video

We describe the case of a previously healthy 44-yr-old female patient presenting with a sudden onset of numbness, paresthesias, and decreased sensation in her lower limbs. Physical examination revealed a decreased sensation to vibration and light touch in her lower extremities, primarily in the left limb. Impaired proprioception was also evident primarily in the left toe. Full strength with 2+ reflexes was observed in all extremities. Magnetic resonance imaging demonstrated an exophytic lesion in the posterior aspect of the cervical spinal cord at the C5-C6 level, with a hemosiderin halo, consistent with a cavernous malformation. Given the evidence of past hemorrhage and the location of the lesion, microsurgical intervention was indicated. A midline cervical C5-C6 laminectomy under neurophysiologic monitoring was performed, and complete resection of the lesion was achieved with mild improvement of the sensitive symptoms and no evidence of new motor deficits. Any microsurgical resection of a cervical spinal cord lesion can be technically difficult and adequate patient selection with evaluation of the accessibility to the lesion is key.1 Surgical resection of cavernous malformations in selected patients eliminates the risk of future hemorrhage and may achieve satisfactory outcomes comparable to patients who undergo conservative management.2 In the following video illustration, we narrate this operative case, and highlight the nuances of this approach. Patient consent was obtained for the submission of the video to this journal.

Proposal of a follow-up imaging strategy following Pipeline flow diversion treatment of intracranial aneurysms

OBJECTIVEThere is currently no standardized follow-up imaging strategy for intracranial aneurysms treated with the Pipeline embolization device (PED). Here, the authors use follow-up imaging data for aneurysms treated with the PED to propose a standardizable follow-up imaging strategy.METHODSA retrospective review of all patients who underwent treatment for ruptured or unruptured intracranial aneurysms with the PED between March 2013 and March 2017 at 2 major academic institutions in the US was performed.RESULTSA total of 218 patients underwent treatment for 259 aneurysms with the PED and had undergone at least 1 follow-up imaging session to assess aneurysm occlusion status. There were 235 (90.7%) anterior and 24 posterior (9.3%) circulation aneurysms. On Kaplan-Meier analysis, the cumulative incidences of aneurysm occlusion at 6, 12, 18, and 24 months were 38.2%, 77.8%, 84.2%, and 85.1%, respectively. No differences in the cumulative incidence of aneurysm occlusion according to aneurysm location (p = 0.39) or aneurysm size (p = 0.81) were observed. A trend toward a decreased cumulative incidence of aneurysm occlusion in patients 70 years or older was observed (p = 0.088). No instances of aneurysm rupture after PED treatment or aneurysm recurrence after occlusion were noted. Sixteen (6.2%) aneurysms were re-treated with the PED; 11 of these had imaging follow-up data available, demonstrating occlusion in 3 (27.3%).CONCLUSIONSThe authors propose a follow-up imaging strategy that incorporates 12-month digital subtraction angiography and 24-month MRA for patients younger than 70 years and single-session digital subtraction angiography at 12 months in patients 70 years or older. For recurrent or persistent aneurysms, re-treatment with the PED or use of an alternative treatment modality may be considered.

An anatomic variant causing a previously unreported complication of transcutaneous treatment of trigeminal neuralgia

This case report describes a patient with an anatomic variant of the foramen ovale that was encountered during an attempted glycerol rhizolysis for trigeminal neuralgia. Various complications have been reported during transcutaneous trigeminal neuralgia treatment. We report an adult female on whom transcutaneous cannulation of the foramen ovale was not possible. Subsequent imaging revealed a causative elongation of the spine of the sphenoid that distorted the foramen ovale and effectively blocked it. Variations in bony anatomy may complicate transcutaneous approaches to the foramen ovale for the treatment of trigeminal neuralgia.