Gregory A. Christoforidis

Occurrence and Predictors of Futile Recanalization following Endovascular Treatment among Patients with Acute Ischemic Stroke: A Multicenter Study

BACKGROUND AND PURPOSE: Although recanalization is the goal of thrombolysis, it is well recognized that it fails to improve outcome of acute stroke in a subset of patients. Our aim was to assess the rate of and factors associated with “futile recanalization,” defined by absence of clinical benefit from recanalization, following endovascular treatment of acute ischemic stroke. MATERIALS AND METHODS: Data from 6 studies of acute ischemic stroke treated with mechanical and/or pharmacologic endovascular treatment were analyzed. “Futile recanalization” was defined by the occurrence of unfavorable outcome (mRS score of ≥3 at 1–3 months) despite complete angiographic recanalization (Qureshi grade 0 or TIMI grade 3). RESULTS: Complete recanalization was observed in 96 of 270 patients treated with IA thrombolysis. Futile recanalization was observed in 47 (49%). In univariate analysis, patients with futile recanalization were older (73 ± 11 versus 58 ± 15 years, P < .0001) and had higher median initial NIHSS scores (19 versus 14, P < .0001), more frequent BA occlusion (17% versus 4%, P = .049), less frequent MCA occlusion (53% versus 76%, P = .032), and a nonsignificantly higher rate of symptomatic hemorrhagic complications (2% versus 9%, P = .2). In logistic regression analysis, futile recanalization was positively associated with age >70 years (OR, 4.4; 95% CI, 1.9–10.5; P = .0008) and initial NIHSS score 10–19 (OR, 3.8; 95% CI, 1.7–8.4; P = .001), and initial NIHSS score ≥20 (OR, 64.4; 95% CI, 28.8–144; P < .0001). CONCLUSIONS: Futile recanalization is a relatively common occurrence following endovascular treatment, particularly among elderly patients and those with severe neurologic deficits.

High resolution MRI of the deep brain vascular anatomy at 8 Tesla: susceptibility-based enhancement of the venous structures.

PURPOSE The purpose of this work was to describe the deep vascular anatomy of the human brain using high resolution MR gradient echo imaging at 8 T. METHOD Gradient echo images were acquired from the human head using a transverse electromagnetic resonator operating in quadrature and tuned to 340 MHz. Typical acquisition parameters were as follows: matrix = 1,024 x 1,024, flip angle = 45 degrees, TR = 750 ms, TE = 17 ms, FOV = 20 cm, slice thickness = 2 mm. This resulted in an in-plane resolution of approximately 200 microm. Images were analyzed, and vascular structures were identified on the basis of location and course. RESULTS High resolution ultra high field magnetic resonance imaging (UHFMRI) enabled the visualization of many small vessels deep within the brain. These vessels were typically detected as signal voids, and the majority represented veins. The prevalence of the venous vasculature was attributed largely to the magnetic susceptibility of deoxyhemoglobin. It was possible to identify venous structures expected to measure below 100 microm in size. Perforating venous drainage within the deep gray structures was identified along with their parent vessels. The course of arterial perforators was more difficult to follow and not as readily identified as their venous counterparts. CONCLUSION The application of high resolution gradient echo methods in UHFMRI provides a unique detailed view of particularly the deep venous vasculature of the human brain.

Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab

Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98EGFR. Experimental Design: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection. Results: The amount of boron retained by F98EGFR gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 μg/g, respectively, with normal brain and blood boron values <0.05 μg/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA. Conclusions: The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Predictors of hemorrhage following intra-arterial thrombolysis for acute ischemic stroke: the role of pial collateral formation.

BACKGROUND AND PURPOSE: The extent of pial collateral formation during acute ischemic stroke has been shown to influence outcomes. This study examines whether angiographic assessment of pial collateral formation is predictive of hemorrhagic transformation following intra-arterial thrombolysis (IAT) for acute ischemic stroke. MATERIALS AND METHODS: Rates of any hemorrhage and significant hemorrhage (>25 mL) were reviewed in 104 consecutive patients who underwent IAT following acute ischemic stroke. The influence of the anatomic extent of pial collateral formation on the rates of hemorrhage and significant hemorrhage relative to known predictors for hemorrhagic transformation (presenting systolic blood pressure, blood glucose level, platelet level, and National Institutes of Health Stroke Scale [NIHSS] score, history of diabetes, time to treatment, age, sex, occlusion site, and extent of reperfusion) was analyzed by using logistic regression models. RESULTS: Rates of any hemorrhage and significant hemorrhage were 25.2% (26/104) and 9.7% (10/104), respectively. The rate of significant hemorrhage was 25.0% (8/32) in patients with poor pial collaterals and 2.78% (2/72) in those with good pial collaterals (P = .0004, Pearson correlation). The rate of any hemorrhage was also significantly higher in patients with poor pial collaterals (40.6% versus 18.1%; P = .0142, Pearson correlation). Logistic regression analyses revealed that pial collateral formation (odds ratio [OR] = 3.04), history of diabetes (OR = 4.83), platelets <200,000/μL (OR = 2.95), and time to treatment <3 hours (OR = 12.0) were statistically significant predictors of hemorrhage, whereas pial collateral formation (OR = 13.1) and platelets <200,000/μL (OR = 8.1) were statistically significant predictors of significant hemorrhage. CONCLUSIONS: Poor pial collateral formation is associated with higher incidence and larger size of hemorrhage following IAT.

Spontaneous intracranial hypotension: report of four cases and review of the literature.

Abstract Spontaneous intracranial hypotension is an unusual syndrome of postural headache and low cerebrospinal fluid pressure without an established cause. We present four cases, analyze those previously reported in the literature, examine the MRI, CT, angiographic and cisternographic finding and discuss the clinical picture, proposed pathophysiologic mechanisms and potential treatment.

Stent-induced Intimal Hyperplasia: Are There Fundamental Differences between Flexible and Rigid Stent Designs?

PURPOSE To evaluate possible differences in neointimal development resulting from overdilation of rigid versus flexible vascular stents. MATERIALS AND METHODS Twelve vascular sheaths were placed bilaterally through femoral arteries in six swine. After angiographic measurement, 12 stents (six flexible and six rigid) were balloon expanded to 8-mm diameters in 12 6-mm iliac arteries (approximately 30% overdilation). All stents were similar in surface area, gauge, and type of wire (tantalum). The primary difference was longitudinal flexibility (low hoop strength) versus rigidity (high hoop strength). Stents were studied with angiography and intravascular ultrasound 5 weeks after implantation. The animals were killed, and the stented segments were removed and examined histologically. RESULTS Rigid stents maintained larger diameters than flexible stents: mean, 6.52 mm versus 5.82 mm (mean difference, 0.70; standard deviation [SD], 0.47; confidence interval [CI], +/- 0.49; P < .05). In addition, rigid stents developed a thicker, eccentric neointimal reaction relative to flexible stents: mean 1.08 mm versus 0.74 mm (mean difference, 0.338; SD, 0.315; CI, +/- 0.331; P < .05). CONCLUSION Rigid stents maintain larger diameters over the long term relative to flexible stents when overdilated in normal swine arteries. However, a thicker neointima develops within the lumen of rigid stents at follow-up (greater late loss).

High resolution MRI of the deep gray nuclei at 8 Tesla.

PURPOSE High resolution MR images obtained from a normal human volunteer at 8 T are utilized to describe the appearance of iron-containing deep gray nuclei at this field strength. METHOD High resolution (1,024 x 1,024 matrix) near-axial gradient echo images of the deep gray nuclei were acquired on a human volunteer by using an 8 T scanner. The images were acquired using a transverse electromagnetic resonator operating in quadrature. The following parameters were utilized: TR = 750 ms, TE = 17 ms, flip angle = 45 degrees, receiver bandwidth = 50 kHz, slice thickness = 2 mm, FOV = 20 cm. The 8 T images were reviewed and correlated to the known anatomy of the deep nuclei by comparing them with images observed at lower field strength, published diagrams, and histologic sections. In addition, the appearance of the nuclei was related to the known imaging characteristics of brain iron at lower fields. RESULTS The caudate, globus pallidus, putamen, thalami, substantia nigra, and red nuclei were clearly identified. The structures with the highest levels of iron, the globus pallidus, substantia nigra, and red nuclei, demonstrated significantly decreased signal, providing a map of iron distribution in the human brain. CONCLUSION Preliminary imaging at 8 T demonstrates the ability to acquire ultra high resolution images of the deep nuclei, with signal characteristics believed to represent the distribution of brain iron. This may prove to be important in the early diagnosis of several neurodegenerative disorders.

Human leptomeningeal and cortical vascular anatomy of the cerebral cortex at 8 Tesla.

PURPOSE The purpose of this work was to describe the human leptomeningeal and cortical vascular anatomy as seen at high resolution on an 8 T UHFMRI system. METHOD With a 1024 x 1024 matrix, axial gradient echo images of the cerebral cortex were acquired on a human volunteer at 8 T with TR 500 ms, TE 16 ms, flip angle 22.5 degrees, bandwidth 53 kHz, and slice thickness 2.84 mm. The same subject was evaluated at 1.5 T using similar parameters. The images were then reviewed in detail and compared with known cortical and leptomeningeal vascular anatomy. RESULTS Two hundred forty micron in-plane resolution images of the human brain were acquired at 8 T without evident artifact from susceptibility distortions, RF penetration, or dielectric resonances. The CSF, gray matter, and white matter structures were well discerned. The microscopic leptomeningeal vascular anatomy was well visualized, and the course of small perforating cortical vessels could be followed from the cortical surface to the white matter junction. CONCLUSION Initial 8 T images of the brain demonstrate detailed leptomeningeal and cortical vascular anatomy.

Intra-arterial carboplatin and intravenous etoposide for the treatment of metastatic brain tumors.

Metastatic brain tumors (MBT) are the most frequent complication of systemic cancer and often respond poorly to treatment. Median survival is only 16–24 weeks after conventional radiation therapy. Regional intra-arterial (IA) administration of chemotherapy results in increased tumor uptake of drug and may improve response rates and survival. Twenty-seven patients with MBT who had received prior irradiation were treated with IA carboplatin (200 mg/m2/d) and intravenous (IV) etoposide (100 mg/m2/d) for 2 days every 3–4 weeks. Eighteen patients (67%) had received prior systemic chemotherapy for their primary tumor. Patients ranged in age from 19 to 68 years (mean 48.1). Thirteen of 24 evaluable patients had objective responses (54.2%). There were 6 complete responses (25%), 6 partial responses (25%), 1 minor response (4.2%), 7 stable disease (32%), and 5 progressive disease (20.8%). Some patients with multifocal tumors had a mixture of responses. The median time to progression was 16.0 weeks overall and 30.0 weeks in responders (range 6–118 weeks). Overall median survival from the time of protocol initiation was 20.0 weeks. In six responders, death occurred due to systemic illness unrelated to MBT progression. Therapy was well tolerated, with predominantly hematologic toxicity. Angiographic complications were rare. Although these are preliminary results, IA carboplatin and IV etoposide is safe and well tolerated, appears to be active against brain metastases, and warrants further study.

Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumors: Report of the eleventh annual blood-brain barrier consortium meeting

Although knowledge of molecular biology and cellular physiology has advanced at a rapid pace, much remains to be learned about delivering chemotherapy and antibodies across the blood–brain barrier (BBB) for the diagnosis and treatment of central nervous system (CNS) disease. A meeting, partially funded by an NIH R13 grant, was convened to discuss the state of the science, current knowledge gaps, and future directions in the delivery of drugs and proteins to the CNS, for the treatment of primary and metastatic brain tumors. Meeting topics included CNS metastases and the BBB, and chemoprotection and chemoenhancement in CNS disorders. The discussions regarding CNS metastases generated possibilities of chemoprotection as a means not only to decrease treatment-related toxicity but also to increase chemotherapy dose intensity. The increasing incidence of sanctuary brain metastasis from breast cancer, in part due to the difficulty of monoclonal antibodies (mAbs) such as herceptin to cross the BBB, was one of the most salient “take home” messages of the meeting.