Benjamin M. Zussman

Outcomes of the ACT III Study: Rindopepimut (CDX-110) Therapy for Glioblastoma.

G lioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Standard therapy, including maximal surgical resection, concomitant chemoradiation therapy, and adjuvant temozolomide, results in a median progression-free survival (PFS) of approximately 8 months and a median overall survival (OS) of 16 to 19 months from diagnosis. Targeted immunotherapy trials are one potential method of improving outcomes for this disease. The most common genetic alteration in GBM is overexpression of epidermal growth factor receptor (EGFR), and the most common EGFR mutation subtype is EGFRvIII. This subtype, which is present in approximately 25% of cases, is associated with poor prognosis in GBM. The mutation results in expression of a unique glioblastoma cell surface receptor that is not expressed in normal brain tissue, making it an excellent immunotherapeutic target. Rindopepimut (CDX-110) is an injectable peptide vaccine that specifically targets this cell surface receptor. A recent multicenter phase II study of this agent has been reported with promising results for GBM (ACT III). The authors enrolled 65 adult patients pooled from 33 study centers with newly diagnosed EGFRvIII1 GBM who had undergone gross total resection and standard radiotherapy and were starting standard temozolomide chemotherapy. EGFRvIII1 status was confirmed with tumor immunohistochemistry and polymerase chain reaction assays. Rindopepimut was administered with intradermal injections, first in an initial priming phase and then at monthly intervals, staggered with temozolomide treatments. Patient clinical status, anti-EGFRvIII antibody titers, PFS, and OS were closely monitored. Radiation Therapy Oncology Group (RTOG) 0525 trial data were queried, and 74 trial participants with EGFRvIII1 GBM and other similar characteristics were selected to act as a historically matched cohort for comparison. For patients treated with rindopepimut, the median PFS was 9.2 months (95% confidence interval, 7.4-11.3) and median OS was 21.8 months (95% confidence interval, 17.9-26.5) from study entry (ie, approximately 3 months after diagnosis; Figure). In comparison, the “matched” RTOG cohort patients showed a median OS of 16.0 months after randomization. The authors found that anti-EGFRvIII antibody titers increased .4-fold over baseline levels in 85% patients treated with rindopepimut, demonstrating robust, specific, and durable immune responses, despite concurrent temozolomide therapy. In general, rindopepimut was well tolerated: There were no fatal adverse events, no cumulative toxicity over time (median duration of rindopepimut treatment was 7.4 months), and primarily mild to moderate injection site reactions, including erythema and pruritus. Finally, a subanalysis of tumor samples taken from 10 rindopepimut patients with tumor recurrence showed that many of these tumors no longer expressed EGFRvIII. The 3 existing phase II trials of rindopepimut (including this study) demonstrate a pooled median PFS of 12.3 to 15.3 months from diagnosis and a median OS of 24 months from diagnosis. We eagerly await the results of the double-blind, phase III trial (ACT IV), which will randomize patients with resected EGFRvIII1 GBM to receive either rindopepimut or a control injection.

Stent Reconstruction of Carotid Tonsillar Loop Dissection Using Telescoping Peripheral Stents

Background: Endovascular treatment options for internal carotid artery (ICA) dissection with tandem intracranial occlusion are evolving. We report 2 cases of stent reconstruction of carotid loop dissections. Methods: Two patients with symptomatic ICA dissections of true 360° tonsillar loops and tandem intracranial occlusions were treated with manual aspiration thrombectomy (MAT) and telescoping Zilver self-expanding peripheral stents. Patient demographics, clinical presentations, endovascular techniques, and clinical outcomes were reviewed. Results: In both cases, MAT achieved modified Treatment in Cerebral Ischemia scale 2B reperfusion, and complete endovascular reconstruction of the dissected extracranial loop was performed. Both patients had improved pre- to postintervention National Institutes of Health Stroke Scale scores (16 to 0 and 14 to 0), and both had modified Rankin scale scores of 1 at 3-month follow-up. Conclusions: Stent reconstruction of complex cerebrovascular anatomy is increasingly feasible with advancements in stent technology and catheter support system design. This technique may be of use to neuroendovascular surgeons who encounter variant ICA anatomy.

Intravenous Drug Use Is Novel Predictor of Infectious Intracranial Aneurysms in Patients with Infective Endocarditis

INTRODUCTION Infectious intracranial aneurysms (IIAs) are a rare but potentially devastating complication of infective endocarditis. The clinical and radiographic findings that predispose patients to IIA remain poorly understood. METHODS We performed a retrospective review of a prospectively maintained database of consecutive endocarditis patients undergoing catheter-based angiography at a single tertiary-level academic center during the period of July 2013-December 2017. Patient records were reviewed for clinical and radiographic characteristics that may be associated with IIA. Multivariate regression models were used to evaluate the relationship between clinical and radiographic characteristics and presence of IIA on invasive imaging. RESULTS Of 92 patients included in this analysis, 12 of them with 19 IIAs were discovered. Univariate analysis identified age, male sex, presence of hemorrhage, and history of IV drug use (IVDU) as predictors of IIA presence. After multivariate analysis, only intracranial hemorrhage and IVDU remained as independent predictors of IIA. CONCLUSIONS Presence of hemorrhage on noninvasive imaging and history of IVDU are independently predictive of IIA presence in patients with infectious endocarditis. Risk stratification using these 2 factors may help identify the most vulnerable populations for IIA formation.

In Reply: A Randomized Trial of Second-Generation Hydrogel Neurovascular Coils

1. Taschner CA. Letter: A randomized trial of second-generation hydrogel neurovascular coils. Neurosurgery. 2019;84(1):E96. 2. Zussman B, Weiner G, Ducruet A. A randomized trial of second-generation hydrogel neurovascular coils. Neurosurgery. 2018;83(1):667-674. 3. Taschner CA, Chapot R, Costalat V, et al. Second-generation hydrogel coils for the endovascular treatment of intracranial aneurysms: A randomized controlled trial. Stroke. 2018;49(3):667-674.

Use of Omnipaque Intraoperative Dye in the Surgical Treatment of Pan-Spinal Epidural Abscesses: Technical Case Report.

BACKGROUND AND IMPORTANCE: Spinal epidural abscesses are difficult to diagnose and could have high morbidity and mortality if left untreated. If patients present with acute neurological deficits and evidence of a multilevel ventral spine abscess on neuroimaging, blood cultures should be taken and the abscess emergently evacuated in patients able to tolerate surgical interventions. CLINICAL PRESENTATION: A 57-year-old man presented with lower back pain, which progressed to include urinary retention and evidence of lumbar discitis/osteomyelitis on magnetic resonance imaging. The patient was started on antibiotic therapy. After the patient developed new cervical pain, interval magnetic resonance imaging showed extension of the abscess to involve the cervical, thoracic, and lumbar spine with intraventricular extension. The decision was made to perform a C4 corpectomy and insert a flexible ventriculoperitoneal catheter to serially flush out the abscess. Omnipaque dye was then used to ensure that the entire abscess was evacuated and no septations existed in the anterior epidural space. CONCLUSION: The patients neurological deficits completely resolved, and he is intact a year after the operation. In selected patients with pan-spinal epidural abscesses associated with acute neurological deficits, a combination of an open approach and a catheter-based procedure in addition to an intraoperative monitoring option to ensure complete evacuation of the abscess and absence of septations in the anterior epidural space is a low-morbidity option in the armamentarium of the surgeon. ABBREVIATION: SEA, spinal epidural abscess

A previously unidentified mechanism of immune evasion in glioblastoma.

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