Michael J. DeLeo

Carotid artery brain aneurysm model: in vivo molecular enzyme-specific MR imaging of active inflammation in a pilot study

PURPOSE To demonstrate the feasibility of using a myeloperoxidase (MPO)-specific paramagnetic magnetic resonance (MR) contrast agent to identify active inflammation in an animal model of common carotid artery (CCA) aneurysm. MATERIALS AND METHODS All animal experiments were approved by the institutional animal care and use committee. Elastase-induced saccular aneurysms were created at the root of the right CCA in 16 New Zealand white rabbits. Intramural and perivascular injection of Escherichia coli lipopolysaccharide (LPS) was performed with an endovascular approach to induce aneurysm inflammation. After intraarterial injection of an MPO-specific (di-5-hydroxytryptamide of gadopentetate dimeglumine, 0.1 mmol per kilogram of bodyweight) or a non-MPO-specific (di-tyrosine of gadopentetate dimeglumine, 0.1 mmol/kg) contrast agent, animals underwent 3-T MR imaging. Intramural presence of MPO in aneurysms in which LPS had been injected was confirmed at immunohistologic analysis. Active MPO activity was verified by measuring the spectrophotometric oxidation of guaiacol. RESULTS Endovascular injection of LPS resulted in inflammatory cell infiltration into the aneurysm wall, and there was a difference in active MPO expression between aneurysms in which LPS had been injected and control aneurysms (20.3 ng of MPO per milligram of tissue vs 0.12 ng of MPO per milligram of tissue, respectively; P < .002). MR imaging with di-5-hydroxytryptamide of gadopentetate dimeglumine revealed a difference in enhancement ratio between inflamed aneurysms in which LPS had been injected and control aneurysms (1.55 +/- 0.05 vs 1.16 +/- 0.10, respectively; P < .02). In inflamed aneurysms, di-5-hydroxytryptamide of gadopentetate dimeglumine exhibited delayed washout kinetics compared with the kinetics of di-tyrosine of gadopentetate dimeglumine. This finding enabled the verification of MPO specificity. CONCLUSION The findings of this pilot study established the feasibility of an animal model of saccular aneurysm inflammation that can be seen with clinical-field-strength MR imaging and use of the enzyme-sensitive MR contrast agent di-5-hydroxytryptamide of gadopentetate dimeglumine, which is a paramagnetic MPO substrate that specifically enhances MR signal.

Cerecyte versus platinum coils in the treatment of intracranial aneurysms: packing attenuation and clinical and angiographic midterm results

BACKGROUND AND PURPOSE: As modifications are made to coils, monitoring the safety profile, ability to achieve high packing attenuation, and durability of occlusion as compared to the standard bare platinum coils is of paramount importance. We compared packing attenuation, initial occlusion, and recanalization rates between Cerecyte and bare platinum coils in the treatment of ruptured and unruptured cerebral aneurysms. MATERIALS AND METHODS: We compared 63 patients (67 aneurysms) treated with Cerecyte coils with 65 patients (70 aneurysms) treated by using bare platinum coils. Results were classified by the Raymond score. Clinical outcomes were assessed by using a modified Rankin Scale. Angiographic and clinical follow-ups were performed routinely at 6 and 12 months after the intervention. RESULTS: In the Cerecyte group, complete occlusion of the aneurysm (grade 1) was accomplished in 49% (33/67), a small residual neck (grade 2) was seen in 21% (14/67), and dome filling (grade 3) was seen in 30% (20/67). In the platinum group, 41% (29/70) were grade 1, 39% (27/70) were grade 2, and 20% (14/70) were grade 3 immediately postembolization. Mean packing attenuation was 43 ± 28% in the Cerecyte group and 40 ± 23% in the bare platinum group (P = .68). Twelve-month follow-up data were available for 54% (36/67) of the Cerecyte population and 43% (30/70) of the bare platinum population. There were 5 cases of neck recanalization (11%) in the Cerecyte group and 11 cases (23%) in the bare platinum group (P = .17). No rebleeds were noted in the follow-up period. CONCLUSIONS: Cerecyte coils have a satisfactory safety profile. We were able to achieve high packing attenuations and initial occlusion rates similar to those obtainable with platinum coils.

Targeted Signal-Amplifying Enzymes Enhance MRI of EGFR Expression in an Orthotopic Model of Human Glioma

Epidermal growth factor receptor (EGFR) imaging in brain tumors is essential to visualize overexpression of EGFRvIII variants as a signature of highly aggressive gliomas and to identify patients that would benefit from anti-EGFR therapy. Seeking imaging improvements, we tested a novel pretargeting approach that relies on initial administration of enzyme-linked anti-EGFR monoclonal antibodies (mAb; EMD72000) followed by administration of a low-molecular-weight paramagnetic molecule (diTyr-GdDTPA) retained at the site of EGFR mAb accumulation. We hypothesized that diTyr-GdDTPA would become enzyme activated and retained on cells due to binding to tissue proteins. In support of this hypothesis, mAb-enzyme conjugates reacted with both membrane-isolated wild-type (wt) EGFR and EGFRvIII, but they bound primarily to EGFRvIII-expressing cells and not to EGFRwt-expressing cells. In vivo analysis of magnetic resonance (MR) tumor signal revealed differences in MR signal decay following diTyr-GdDTPA substrate administration. These differences were significant in that they suggested differences in substrate elimination from the tissue which relied on the specificity of the initial mAb binding: a biexponential signal decay was observed in tumors only upon preinjection with EGFR-targeted conjugates. Endpoint MRI in this setting revealed detailed images of tumors which correlated with immunohistochemical detection of EGFR expression. Together, our findings suggest an improved method to identify EGFRvIII-expressing gliomas in vivo that are best suited for treatment with therapeutic EGFR antibodies.

021 Cerecyte coils in the treatment of intracranial aneurysms; midterm angiographic and clinical follow-up

Purpose: The Cerecyte Coil System (Micrus Endovascular, San Jose, California, USA) is a polyglycolic acid loaded coil that can deliver a stable aneurysm framing while delivering a bioactive copolymer. Here we report our mid-term results on the use of this coil system for the treatment of intracranial aneurysms. Materials and Methods: From July 2005 to August 2008, 62 patients with 67 aneurysms were treated using Cerecyte coils exclusively or in combination with bare platinum coils. We compared this cohort with 65 patients with …

002 Treatment of wide necked intracranial aneurysms using the Enterprise stent: mid-term clinical and angiographic results

Purpose: Stent assisted coiling techniques have improved the endovascular treatment of wide necked (neck >4 mm or dome-to-neck ratio <2) saccular and fusiform/dissecting intracranial aneurysms. The Enterprise stent (Cordis Endovascular; Miami Lakes, Florida, USA) is the first commercially available closed cell nitinol stent approved for the treatment of wide necked intracranial aneurysms in the USA. Here we seek to evaluate the safety and efficacy of the Enterprise stent in the treatment of such aneurysms. Materials and Methods: Between June 2007 and March 2009, 56 wide necked saccular and fusiform/dissecting intracranial aneurysms in 52 patients were treated endovascularly using the Enterprise stent. The aneurysms were in …

005 DeltaPaq coils in the treatment of intracranial aneurysms: packing density, clinical and angiographic results

Purpose: Recanalization of the aneurysm sac is a major drawback of endovascular embolization that often necessitates retreatment. Recent evidence suggests that increased packing density of coils within the aneurysm sac may lower recanalization rates. The DeltaPaq microcoil system (Micrus Endovascular, San Jose, California, USA), designed to increase aneurysm packing density, features an initial wind design with a triangular profile and microscopic rotating rings which provides the coil with a low moment of inertia and the ability to easily change the coils angular motion. Here, we performed safety and packing density analysis of DeltaPaq coils in the treatment of ruptured …

Validation of Di-5-HT-Gd-DTPA, an Enzyme-Specific MR Contrast Agent for Myeloperoxidase, in the Rabbit Elastase Model of Cerebrovascular Aneurysm

Characterization of molecular imaging probes in multiple animal models of disease is essential to increase their diagnostic potential. For example, we recently demonstrated visualization of active inflammation in a rabbit model saccular aneurysm using clinical field strength MRI and the paramagnetic MR contrast agent di-5-HT-GdDTPA, which has been shown in vitro to be sensitive and specific for the enzyme myeloperoxidase (MPO). While the use of transgenic mice (MPO−/−) has demonstrated specificity of di-5-HT-GdDTPA for MPO in a model of myocardial infarction [1], MPO-deficient rabbits are not available. Therefore, in this study, we sought to validate di-5-HT-GdDTPA MPO specificity in the New Zealand white rabbit by comparing serial enhancement ratios of di-5-HT-GdDTPA to a structurally similar MR contrast agent, di-Tyr-GdDTPA, which is activated by peroxidases but not by MPO. Structural diagrams of the synthesis of the two agents are demonstrated in Figure 1 [2].Copyright

Targeted Enzyme-Specific Molecular MR Imaging of Focal Catheter-Induced Vacscular Injury

Catheter-induced vascular injury is a complication of endovascular neurosurgery that may have serious consequences. Other than gross vessel dissection and / or perforation, vessel damage is not visible using standard digital biplane fluoroscopy. Furthermore, the molecular environment in the damaged vessel wall is largely unknown. Recent studies have implicated inflammatory changes in the damaged vessel wall, including upregulation of the key inflammatory mediator NF-kappa-B [1]. Other mediators of inflammation, such as tissue inhibitors of matrix metalloproteinases, are upregulated following arterial de-endothelialization [2]. The enzyme myeloperoxidase (MPO) is known to play significant roles in the progression of vascular pathologies such as atherosclerosis. However, it is unknown whether MPO is involved in catheter-induced vascular injury. In this study, we performed feasibility experiments in an attempt to detect areas of vascular injury using the paramagnetic MR MPO-specific contrast agent, di-5-HT-GdDTPA, which has been shown to be sensitive and specific for MPO both in vitro and in vivo.Copyright

Magnetic resonance detection of inflammation in elastase-induced aneurysms

Intracranial aneurysm rupture is the leading cause of subarachnoid hemorrhage in the United States and is associated with higher fatality rates than ischemic stroke. There is currently no objective diagnostic means to identify aneurysms that are at high risk for rupture despite significant improvements in treatment. Often with no warning signs prior to aneurysm rupture such as the transient ischemic attack in ischemic stroke, the need to develop a method for detecting aneurysm instability is necessary.Copyright