Single Low-Dose Targeted Bevacizumab Infusion in Adult Patients with Steroid-Refractory Radiation Necrosis of the Brain: A Phase II Open-Label Prospective Clinical Trial

OBJECTIVE There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN. METHODS Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and \u3e 25% decrease in lesion volume. Images were analyzed by a board-certified neuroradiologist blinded to pretrial diagnosis and treatment status. Secondary outcomes included changes in headache, steroid use, and functional status and absence of neurocognitive sequelae. Comparisons were analyzed using the Fisher exact test, Mann-Whitney U-test, linear mixed models, Wilcoxon signed-rank test, and repeated-measures 1-way ANOVA. RESULTS Ten adults (mean ± SD [range] age 35 ± 15 [22-62] years) participated in this study. No patients died or exhibited serious adverse effects of systemic bevacizumab. At 3 months, 80% (95% CI 44%-98%) and 90% (95% CI 56%-100%) of patients demonstrated \u3e 25% decrease in RN and vasogenic edema volume, respectively. At 12 months, RN volume decreased by 74% (median [range] 76% [53%-96%], p = 0.012), edema volume decreased by 50% (median [range] 70% [-11% to 83%], p = 0.086), and headache decreased by 84% (median [range] 92% [58%-100%], p = 0.022) among the 8 patients without RN recurrence. Only 1 (10%) patient was steroid dependent at the end of the trial. Scores on 12 of 16 (75%) neurocognitive indices increased, thereby supporting a pattern of cerebral white matter recovery. Two (20%) patients exhibited RN recurrence that required further treatment at 10 and 11 months, respectively, after bevacizumab infusion. CONCLUSIONS For the first time, to the authors\u27 knowledge, the authors demonstrated that a single low-dose targeted bevacizumab infusion resulted in durable clinical and imaging improvements in 80% of patients at 12 months after treatment without adverse events attributed to bevacizumab alone. These findings highlight that targeted bevacizumab may be an efficient one-time treatment for adults with brain RN. Further confirmation with a randomized controlled trial is needed to compare the intra-arterial approach with the conventional multicycle intravenous regimen

Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke).

BACKGROUND: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. METHODS: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. RESULTS: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( CONCLUSIONS: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239640

Clipping of a Mycotic Basilar Trunk Aneurysm under Cardiac Arrest in a Pregnant AIDS Patient

We present the first case of a coccidioidomycosis mycotic anterior inferior cerebellar artery (AICA) aneurysm that was clipped under hypothermic cardiac standstill in a pregnant acquired immunodeficiency syndrome (AIDS) patient. A 24-year-old pregnant AIDS patient presented with intraventricular hemorrhage and hydrocephalus. Angiography revealed an 8-mm basilar trunk aneurysm with the right AICA protruding from the side wall of the aneurysm. The patient underwent a retrosigmoid craniotomy and direct clipping of the aneurysm under hypothermic cardiac standstill. At presentation, the patient had a poor grade due to subarachnoid and intraventricular hemorrhage. Despite her large posterior circulation aneurysm in the setting of AIDS with extensive coccidioidomycosis meningitis, the lesion was clipped successfully. To do so required the full range of neurosurgical repertoire, including a skull base approach and hypothermic cardiac standstill

Nonsurgical Treatment Options in the Management of Intracranial Meningiomas

Surgical resection is the treatment of choice for most intracranial meningiomas. We review the current state of adjuvant therapies, including radiation and chemotherapy. Conventional external beam radiation and stereotactic radiosurgery remain second-line options for patients unwilling or unable to undergo surgery. Radiation therapy is most useful in the setting of recurrent or residual tumor after surgical resection, where it is associated with a clear increase in the length of progression-free survival. This survival advantage is most pronounced with highgrade meningiomas, which have a much higher recurrence rate than low-grade meningiomas, even after gross total resection. In contrast, the role of chemotherapy in the treatment of meningiomas is limited. This treatment modality is often reserved for inoperable tumors or those refractory to radiation treatment. Furthermore, the choice of chemotherapy agents is limited. Hydroxyurea, a ribonucleotide reductase inhibitor, has modest clinical activity in meningiomas. In recent small clinical trials, somatostatin analogues have been moderately effective in controlling tumor growth

Endovascular Treatment of Intracranial Dural Arteriovenous Fistulae Using Onyx: A Case Series

OBJECTIVE: An endovascular approach is often the first-line treatment of dural arteriovenous fistulae (DAVFs). Information on the use of Onyx (ev3 Neurovascular, Irvine, CA) for treating DAVFs, however, is limited. Therefore, we present our early experience, technical considerations, and complications associated with the use of Onyx for DAVF embolization. METHODS: Twenty-eight patients with 29 DAVFs treated with Onyx embolization were included in this analysis. Hospital records, operative reports, and angiograms were reviewed and analyzed. RESULTS: Forty Onyx procedures, including 39 transarterial and 1 transvenous approaches, were performed. Fifty-one external carotid artery branches, 8 posterior meningeal artery branches, and 3 internal carotid artery branches were used for Onyx embolization. Branches of the middle meningeal artery were embolized 32 times, and the occipital artery was embolized 15 times. Twenty-one fistulae (72%) were cured angiographically with endovascular therapy. Transarterial embolization via the middle meningeal artery cured 12 DAVFs (41%). Four complications (9.7%) were recorded, including 3 transient (7.3%) and 1 permanent neurological deficits (2.4%). Follow-up imaging, which was available for 8 fistulae with angiographic cures, showed no evidence of recurrence. CONCLUSION: Transarterial Onyx embolization of external carotid artery branches, particularly the middle meningeal artery, offers a high likelihood of cure. This technique provides a safe and effective method of embolization with few side effects and complications. However, long-term follow-up is needed to establish its efficacy. © 2009 by the Congress of Neurological Surgeons

Mechanical Thrombectomy as First-Line Treatment for Venous Sinus Thrombosis: Technical Considerations and Preliminary Results Using the Angiojet Device

Background: Cerebral venous sinus thrombosis (CVT) is an uncommon cause of stroke that is usually treated medically with intravenous heparin therapy followed by long-term anticoagulation therapy. A series of patients with CVT who underwent rheolytic thrombectomy with the AngioJet as a first-line adjunctive treatment in addition to standard anticoagulation therapy is presented. Methods: Prospectively maintained endovascular databases at two institutions were retrospectively reviewed. The available clinical and imaging data were compiled at each institution and combined for analysis. Results: Over 18 months, 13 patients (seven women and six men; age range 17-73 years, median age 45 years) with CVT were treated with rheolytic thrombectomy. Immediate (partial or complete) recanalization of the thrombosed intracranial sinuses was achieved in all patients. At a median radiographic follow-up of 7 months there was continued patency of all recanalized sinuses. Clinical follow-up was available on nine patients: modified Rankin score of 0 in four patients, 1 in three patients and 6 in two patients. Conclusion: This series demonstrates the feasibility of performing mechanical thrombectomy as a first-line treatment for acute CVT. This technique facilitates the prompt restoration of intracranial venous outflow, which may result in rapid neurological and symptomatic improvement

Keratinocyte survival, differentiation, and death: many roads lead to mitogen-activated protein kinase

The epidermis is a dynamic and continually renewing surface that provides and maintains a life-sustaining interface with the environment. The epidermal keratinocyte, the major cell type of the epidermis, undergoes a complex and carefully choreographed program of differentiation. This process requires a balance between keratinocyte proliferation, differentiation, and apoptosis. This overview will concentrate on cascades that regulate the balance between keratinocyte cell proliferation and survival, and apoptosis and cell differentiation, with a particular emphasis on the role of the mitogen-activated protein kinase cascades. A summary of the literature suggests that extracellular regulated kinases function to promote keratinocyte proliferation and survival, whereas p38 mitogen-activated protein kinase functions to promote differentiation and apoptosis

Keratinocyte survival, differentiation, and death: many roads lead to mitogen-activated protein kinase

The epidermis is a dynamic and continually renewing surface that provides and maintains a life-sustaining interface with the environment. The epidermal keratinocyte, the major cell type of the epidermis, undergoes a complex and carefully choreographed program of differentiation. This process requires a balance between keratinocyte proliferation, differentiation, and apoptosis. This overview will concentrate on cascades that regulate the balance between keratinocyte cell proliferation and survival, and apoptosis and cell differentiation, with a particular emphasis on the role of the mitogen-activated protein kinase cascades. A summary of the literature suggests that extracellular regulated kinases function to promote keratinocyte proliferation and survival, whereas p38 mitogen-activated protein kinase functions to promote differentiation and apoptosis

Regulation of involucrin gene expression

The epidermis is a dynamic renewing structure that provides life-sustaining protection from the environment. The major cell type of the epidermis, the epidermal keratinocyte, undergoes a carefully choreographed program of differentiation. Alteration of these events results in a variety of debilitating and life-threatening diseases. Understanding how this process is regulated is an important current goal in biology. In this review, we summarize the literature regarding regulation of involucrin, an important marker gene that serves as a model for understanding the mechanisms that regulate the differentiation process. Current knowledge describing the role of transcription factors and signaling cascades in regulating involucrin gene expression are presented. These studies describe a signaling cascade that includes the novel protein kinase C isoforms, Ras, MEKK1, MEK3, and a p38delta-extracellular signal regulated kinase 1/2 complex. This cascade regulates activator protein one, Sp1, and CCATT/enhancer-binding protein transcription factor DNA binding to two discrete involucrin promoter regions, the distal- and proximal-regulatory regions, to regulate involucrin gene expression