Intracerebral administration of heat-inactivated Staphylococcus epidermidis enhances oncolysis and prolongs survival in a 9L orthotopic gliosarcoma model.

BACKGROUND/AIMS: The association between postoperative infection and prolonged survival in high-grade glioma is still a matter of debate. Previously we demonstrated that the intracerebral (i.c.) injection of heat-inactivated staphylococcal epitopes (HISE) resulted in a well-defined infux of immunocompetent cells across the blood-brain barrier. The present study investigated the potential antitumoral effect of HISE-immunostimulation in an experimental glioma model. METHODS: Wistar rats were intracerebrally implanted with 9L gliosarcoma cells (n=6), 9L cells mixed with HISE (n=12), or phosphate buffered saline (n=4). Tumor growth was measured by serial magnetic resonance imaging (MRI). After death due to the tumor burden, the brains were histopathologically assessed for inflammation and oncolysis. A toxicity assay was performed to quantify potential impairment of HISE on tumor cell growth in vitro. RESULTS: Animals treated by HISE showed a significant increase in average survival and even complete regression of an already established mass in one case. Naïve 9L gliosarcomas failed to recruit significant numbers of systemic immune cells. In contrast, concomitant intracerebral HISE inoculation lead to a oncolysis and a distinct peri- and intratumoral infiltration of macrophages, CD8 and CD4 co-expressing T-lymphocytes in two thirds of the tumor-bearing animals. The toxicity screening showed HISE-mediated oncolysis to be ineffective ex vivo. CONCLUSION: This study describes a novel approach for combatting malignant glioma using inactivated staphylococci as potent immunomodulators. Our results provide an outline for investigating the strategic potential of bacteria as emerging future therapeutics.

Evaluation of an active vena cava filter for MR imaging in a swine model.

PURPOSE: To evaluate the feasibility of magnetic resonance (MR) imaging-guided placement of an active vena cava filter (AVCF) in a swine model, the effectiveness of the system in filtering thrombi, and the detection of thrombi with MR imaging. MATERIALS AND METHODS: This study was approved by the government committee on animal investigations. An AVCF tuned to the Larmor frequency of a 1.5-T MR unit was placed in the inferior vena cava (IVC) of seven pigs under real-time MR imaging guidance. Steady-state free precession sequences with four different flip angles (90°, 40°, 25°, and 15°), T1-weighted turbo spin-echo sequences with two flip angles (90° and 15°), and black-blood proton-density-weighted sequences with a flip angle of 90° were performed before and after filter placement. In six cases, extracorporeally produced thrombi were injected through the femoral access to test filter function. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were assessed before and after filter deployment and compared by using the signed-rank test. RESULTS: All AVCFs were successfully deployed. Significant differences (P < .05) in the SNR and CNR of the IVC were found before and after AVCF placement and between sequences with different flip angles. Intravenous thrombi were caught in all cases and clearly depicted with MR imaging. On black-blood proton-density-weighted images, high-signal-intensity thrombi inside the filter were clearly detectable without any overlaying artifacts. CONCLUSION: MR imaging-guided deployment and monitoring of an AVCF is feasible. The AVCF enhances the SNR and CNR, resulting in clear depiction of thrombi inside the filter without the need for contrast material. Design modifications for improved intracaval fixation and retrieval of the prototype AVCF will be required.

Combined interventional stroke therapy using intracranial stent and local intraarterial thrombolysis (LIT).

INTRODUCTION: Supported by results of the ECASS III study, intravenous rt-PA thrombolysis is considered a standard therapy for acute stroke within 4.5 h. Still under debate is the use of a more aggressive treatment as that of local intraarterial thrombolysis (LIT) or combining intravenous administration of recombinant tissue plasminogen activator (rt-PA) followed by LIT (bridging concept). Mechanical thrombus removal devices and effective flow achievement by stenting are reported to increase the recanalization rate and patient outcome. Newer reports showed the use of intracranial stents as the latest trend-setting technique. A combined approach hereby appears to achieve the best results consisting of pharmacologic thrombolysis, manual aspiration devices and stenting. We employed a novel removable stent as a new approach in acute stroke, aiming to make the intraarterial thrombolysis through an enhanced thrombus contact surface more effective and to reduce the effective revascularisation time with the possibility of stent removal after re-opening the occluded vessel. METHODS: We describe four cases with acute stroke in the anterior and posterior circulation using a newer self-expandable removable stent (Solitaire™ AB) combined with LIT performed in the 'bridging technique', occasionally supported by additional thrombus aspiration. RESULTS: In all cases, we directly achieved after stenting an effective revascularization with fast recanalization time when using stent implantation first. Stenting was always technically successful without complications. CONCLUSION: The easy handling of a removable stent in stent-assisted revascularization combined with thrombolysis (i.v./i.a.) is a newly described technique for acute stroke treatment, which join immediate mechanical recanalization, postulated improved thrombolysis and the possibility of stent removing.

Molecular magnetic resonance imaging of myocardial perfusion with EP-3600, a collagen-specific contrast agent: initial feasibility study in a swine model.

BACKGROUND: Cardiac magnetic resonance (MR) perfusion imaging during the first pass after intravenous administration of extracellular contrast agents is hampered by the spatial and temporal resolution achievable and by the artifacts seen in ultrafast MR imaging. Furthermore, time-consuming quantitative data analysis is often added. The use of molecular MR imaging with a target-specific contrast agent with perfusion-dependent binding to myocardium may enable prolonged visualization of perfusion defects and thus may help to overcome limitations of currently used first-pass extracellular MR imaging. EP-3600 is a new gadolinium-containing molecular contrast agent that binds reversibly to myocardial collagen. METHODS AND RESULTS: A significant but nonocclusive coronary artery stenosis was modeled in 7 domestic swine with an undersized MR-compatible balloon positioned in the left anterior descending artery as verified by x-ray angiography. Two animals died before contrast injection as a result of arrhythmias. In 5 swine, high-spatial-resolution gradient echo imaging (approximately 1 x 1 mm(2) in-plane resolution) was performed before and 5, 20, 40, and 60 minutes after intravenous administration of 12.3 micromol/kg EP-3600. Contrast was administered during stress induced by an infusion of 250 mumol x kg(-1) x min(-1) adenosine. Yb-DTPA was administered simultaneously for comparison of myocardium-to-plasma ratios. Images were assessed subjectively by 2 investigators, and signal-to-noise and contrast-to-noise ratios over time were calculated. Normal myocardium showed a significant signal-to-noise ratio increase during the entire examination time. In all animals (n=5), the perfusion defect in the left anterior descending artery territory could be visualized with a high contrast-to-noise ratio for at least 20 minutes after contrast injection. A significantly higher myocardium-to-plasma ratio was found for EP-3600 compared with the control agent Yb-DTPA (0.85+/-0.26 versus 0.22+/-0.08, respectively; P<0.01). CONCLUSIONS: EP-3600 is a new molecular MR imaging contrast agent that binds to the myocardium and enables prolonged, high-contrast, high-spatial-resolution visualization of myocardial perfusion defects.

Registration of coronary venous anatomy to the site of the latest mechanical contraction.

OBJECTIVE: Cardiac resynchronization therapy (CRT) provides a therapeutic option for patients with congestive heart failure (CHF). There is evidence that the optimal pacing site (OIS) is vicinal to the region of the latest contraction (RLC). However, the RLC is not identified routinely to guide lead implantation to the coronary venous system (CVS). The aim of this study was: (i) to develop a software over-imposing CVS-anatomy on parametric images of left ventricular dyssynchrony in a 3D-format obtained from computed tomography (CT) and cardiac magnetic resonance imaging (MRI); and (ii) to apply this 3D-software for analysing the possible correlation between functional/ clinical improvement and the distance between final implantation site (FIS) and RLC. METHODS AND RESULTS: In 20 CHF-patients (11 men, 65.6 +/- 6.8 y, ejection fraction (EF): 27.5 +/- 6.1%) CRT-leads were implanted; follow-up included echocardiographic and exercise evaluation. The OIS and the FIS were noted on 3D-registrations and the distances OIS-RLC and FIS-RLC measured.The target vessel was reached in 14 cases. NYHA class and EF improved significantly with a low rate of non-responders of 3 (15%) (EF) and 4 (20%) (NYHA). Image registration was possible in all patients. Post-process 3D-analysis revealed no correlation between the distance FIS-RLC and functional or echocardiographic improvements.There was a trend towards a shorter distance FIS-RLC in patients classified as responders (EF). NYHA class improved significantly better in patients with target vessel implantation. CONCLUSIONS: Registration of CT/MRI-images enables efforts to reach the RLC by preoperative identification of corresponding veins. Larger randomized trials must define the definite therapeutic benefit.

An MR guidewire based on micropultruded fiber-reinforced material.

A novel fiber-reinforced material for the realization of MR guidewires, made using a newly-developed production process, is presented. The MR-safe artificial material provides a high stiffness and torque and allows the production, in a large range of sizes, of nonmetallic MR guidewires with similar mechanical properties as conventional metallic guidewires. Based on this material, a passively visualized MR guidewire has been developed, and was found to conform to existing standards on mechanical stability. Handling and steerability were evaluated in animal studies and were found to be comparable with conventional metallic guidewires. X-ray visibility is provided by a BaSO(4)- and tungsten-doped jacket. A hydrophilic coating improves sliding properties and hemocompatibility.

Time-resolved 3D MR angiography of the foot at 3 T in patients with peripheral arterial disease.

OBJECTIVE: The objective of our study was to prove the feasibility and clinical relevance of fast contrast-enhanced time-resolved 3D MR angiography (MRA) with submillimeter spatial resolution at a high magnetic field strength. SUBJECTS AND METHODS: Twenty-one patients (five women, 16 men; mean age +/- SD, 65 +/- 14 years) were examined on a 3-T whole-body MR system with an 8-element phasedarray coil for preoperative evaluation of the pedal arterial system and assessment of the visualized vessels to serve as a graft touch-down site in pedal bypass surgery. Time-resolved 3D MRA of the foot was performed after automatic injection of 0.2 mmol/kg of gadobenate dimeglumine using a sagittal gradient-echo T1-weighted sequence (TR/TE, 4.2/1.6; flip angle, 30 degrees ; field of view, 290 mm; matrix, 352; 120 slices; slice thickness, 0.8 mm) with a spatial resolution of 0.8 x 0.8 x 1.6 mm reconstructed to 0.6 x 0.6 x 0.8 mm and a temporal resolution of 3.9 seconds using keyhole and sensitivity-encoding (SENSE) technology (SENSE factors: 4 in anteroposterior direction and 2 in right-left direction). Dynamic subtractions and rotating maximum intensity projections were calculated. The original image data sets were transferred to a dedicated workstation for objective signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) analysis of the arteries. Subjective image analysis regarding image quality and diagnostic findings was performed by two radiologists in consensus. RESULTS: In all patients, images of diagnostic quality were obtained. Despite the known limitations regarding signal intensity measurements in images acquired with the use of parallel imaging technique, SNR and CNR proved to be excellent, with mean +/- SD values of 294 +/- 158 and 248 +/- 144, respectively. Although most of the patients had diabetic foot syndrome with arteriovenous shunting, the arteries and the potential vessel for bypassing could be clearly separated from the veins in each case due to the temporal information given by our study. The ability to reliably discriminate arteries from veins is of high clinical relevance in planning pedal bypass surgery. CONCLUSION: Fast contrast-enhanced time-resolved 3D MRA of the foot at 3 T is feasible and of high clinical value for the preoperative evaluation of the arterial supply of the foot.

A porcine deep vein thrombosis model for magnetic resonance-guided monitoring of different thrombectomy procedures.

PURPOSE: To establish a porcine model of deep iliac vein thrombosis, which allows monitoring of thrombectomy and thrombolytic procedures by magnetic resonance imaging (MRI). MATERIALS AND METHODS: Deep iliac vein thrombosis was induced in 12 domestic swine using an occlusion-balloon catheter and subsequent injection of thrombin distal to the occluded vessel site. Thrombosis induction was successfully achieved in all animals after 1 hour as verified by MRI. In addition, x-ray fluoroscopy was performed for comparison. Subsequently, thrombectomy was performed using a Fogarty catheter, an Arrow-Trerotola percutaneous thrombolytic device as well as electrical discharge-induced shock waves. The latter procedure was carried out with and without additional administration of Actilyse. MRI and x-ray fluoroscopy were repeated to monitor therapy. RESULTS: After successful thrombosis induction within the deep iliac veins in all cases, thrombus material could be completely removed using the Fogarty catheter and the Arrow-Trerotola percutaneous thrombolytic device, whereas electrical discharge-induced shock wave failed to recanalize the occluded vessel even if additional Actilyse was administered. The actual burden of thrombotic material could be reliably visualized using MRI. CONCLUSIONS: A porcine model of deep iliac vein thrombosis model is presented, which permits reliable visualization of thrombotic material. This model might be a useful tool to compare different thrombectomy devices or to evaluate the effectiveness of new thrombolytic approaches.

Molecular MR imaging of human thrombi in a swine model of pulmonary embolism using a fibrin-specific contrast agent.

OBJECTIVE: Molecular targeted MR imaging of human clots material in a model of pulmonary embolism using a fibrin-specific magnetic resonance imaging contrast agent (EP-2104R, EPIX Pharmaceuticals, Cambridge, MA). MATERIAL AND METHODS: Fresh ex vivo engineered thrombi (human blood) and human clots removed from patients were delivered in 11 swine. Molecular MR imaging with a 3D gradient-echo [3D fast field echo (3DFFE)] sequence and a navigator-gated and cardiac-triggered 3D inversion-recovery black-blood gradient-echo sequence (IR) was performed before thrombus delivery, after thrombus delivery but before contrast media application, and 2 hours after i.v. administration of 4 micromol/kg EP-2104R. MR images were analyzed by 2 investigators and contrast-to-noise ratio (CNR) was assessed. Thrombi were removed for assessment of gadolinium (Gd) concentration. RESULTS: Only after contrast media application were pulmonary emboli [freshly engineered thrombi (n = 23) and human clot material removed from patients (n = 25)] visualized as white foci on MR images. CNR was 13 +/- 3 (ex vivo engineered clot) and 22 +/- 9 (patient clot material) for the fast field echo (FFE)-sequence and 29 +/- 9 (ex vivo engineered clot) and 43 +/- 18 (patient clot material) for the IR-sequence, respectively. A high Gd concentration in the clots was found (82 +/- 43 microM for the freshly engineered and 247 +/- 44 microM for the clots removed from patients, respectively). CONCLUSIONS: EP-2104R allows for molecular MR imaging of human clot material in the pulmonary vessels of a swine model.

Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent.

BACKGROUND: Coronary in-stent restenosis cannot be directly assessed by magnetic resonance angiography (MRA) because of the local signal void of currently used stainless steel stents. The aim of this study was to investigate the potential of a new, dedicated, coronary MR imaging (MRI) stent for artifact-free, coronary MRA and in-stent lumen and vessel wall visualization. METHODS AND RESULTS: Fifteen prototype stents were deployed in coronary arteries of 15 healthy swine and investigated with a double-oblique, navigator-gated, free-breathing, T2-prepared, 3D cartesian gradient-echo sequence; a T2-prepared, 3D spiral gradient-echo sequence; and a T2-prepared, 3D steady-state, free-precession coronary MRA sequence. Furthermore, black-blood vessel wall imaging by a dual-inversion-recovery, turbo spin-echo sequence was performed. Artifacts of the stented vessel segment and signal intensities of the coronary vessel lumen inside and outside the stent were assessed. With all investigated sequences, the vessel lumen and wall could be visualized without artifacts, including the stented vessel segment. No signal intensity alterations inside the stent when compared with the vessel lumen outside the stent were found. CONCLUSIONS: The new, coronary MRI stent allows for completely artifact-free coronary MRA and vessel wall imaging.

Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent.

BACKGROUND: The differential diagnosis of acute chest pain is challenging, especially in patients with normal ECG findings, and may include coronary thrombosis or pulmonary emboli. The aim of this study was to investigate the novel fibrin-specific contrast agent EP-2104R for molecular targeted MR imaging of coronary thrombosis and pulmonary emboli. METHODS AND RESULTS: Fresh clots were engineered ex vivo from human blood and delivered in the lungs and coronary arteries of 7 swine. Subsequent molecular MR imaging was performed with a navigator-gated free-breathing and cardiac-triggered 3D inversion-recovery black-blood gradient-echo sequence before and after systemic administration of 7.5 micromol/kg EP-2104R. Two swine served as the control group. MR images were analyzed by 2 investigators, and contrast-to-noise ratio and gadolinium concentration in the clots were assessed. Before contrast media application, no thrombi were visible. After contrast administration, all 32 pulmonary emboli, 3 emboli in the right heart, and 5 coronary thrombi were selectively visualized as white spots with a mean contrast-to-noise ratio of 32+/-19. The average gadolinium concentration from all 3 types of thrombi was 144+/-79 micromol/L. CONCLUSIONS: Molecular MR imaging with the fibrin-targeted contrast-agent EP-2104R allows selective visualization of acute coronary, cardiac, and pulmonary thrombi.

Molecular magnetic resonance imaging of atrial clots in a swine model.

BACKGROUND: The detection and differentiation of intracardiac masses is still challenging and may include neoplasms and thrombi. The aim of this study was the investigation of a targeted, fibrin-specific contrast agent (EP-2104R) for molecular targeted magnetic resonance imaging (MRI) of left atrial clots. METHODS AND RESULTS: Chronic human thrombi were surgically implanted in the left atrial appendage of 5 swine. Molecular MRI was performed with a navigator-gated, free-breathing, cardiac-triggered 3D inversion-recovery, black-blood, gradient-echo sequence before and after systemic administration of 4 micromol/kg EP-2104R. MR images were analyzed by 2 investigators, and the contrast-to-noise ratio was calculated. Location of clots was confirmed by autopsy, and the gadolinium concentration in the clots was assessed. Before contrast agent administration, thrombi were not visible on black-blood MR images. After contrast administration, all atrial clots (n=5) were selectively visualized as white spots with a high contrast-to-noise ratio (clot/blood, 29.7+/-8.0). The gadolinium concentration in the clots averaged 74+/-45 micromol/L. CONCLUSIONS: The fibrin-specific MR contrast agent EP-2104R allows for selective and high-contrast visualization of left atrial clots by means of molecular targeted MRI.

Assessment of myocardial viability in reperfused acute myocardial infarction using 16-slice computed tomography in comparison to magnetic resonance imaging.

OBJECTIVES: The aim of this study was to examine if contrast-enhanced multislice spiral computed tomography (MSCT) is comparable to contrast-enhanced magnetic resonance imaging (MRI) for depiction of acute myocardial infarction (MI). BACKGROUND: Delayed-enhancement MRI of MI is well established, but there are no clinical reports about MSCT for this indication. Early perfusion deficit on MSCT has been reported to correlate with the presence of MI. METHODS: A total of 28 consecutive patients (23 men; 55.9 +/- 11.4 years) with reperfused MI underwent contrast-enhanced cardiac 16-slice MSCT. Images were acquired in the arterial phase and the late phase 15 min after administration of 120 ml contrast material. Within 5 days, patients underwent MRI after administration of 0.2 mmol Gd-dimeglumine/kg/bodyweight. All examinations were completed within two weeks after MI. The area of MI was compared between the different imaging techniques using Bland-Altman method and multivariate analysis. Agreement of the contrast enhancement patterns was evaluated with a weighted kappa test. RESULTS: Mean infarct size on MRI was 31.2 +/- 22.5% per slice compared with 33.3 +/- 23.8% per slice for late-enhancement MSCT and 24.5 +/- 18.3% per slice for early-perfusion-deficit MSCT. Bland-Altman data showed a good agreement between late-enhancement MRI and late-enhancement MSCT. Contrast enhancement patterns demonstrated an excellent agreement between late-enhancement MRI and late-enhancement MSCT (kappa = 0.878). The results were worse comparing MRI and early-phase MSCT (kappa = 0.635). CONCLUSIONS: Multislice spiral computed tomography allows for the assessment of acute MI. Late-enhancement MSCT appears to be as reliable as delayed contrast-enhanced MRI in assessing infarct size and myocardial viability in acute MI.

Semi-automated 3-dimensional intracardiac echocardiography: development and initial clinical experience of a new system to guide ablation procedures.

BACKGROUND: Pre-interventional three-dimensional (3D) reconstruction of the heart by CT or MRI provides important information on cardiac anatomy for electrophysiological interventions. However, updates of 3D-imaging modalities with high soft-tissue contrast are not available during ablation procedures. OBJECTIVE: We describe the development and first clinical testing of a close to real-time visualization of cardiac anatomy by intracardiac echocardiography (ICE). METHODS: An electronic phased-array 5-10 MHz ICE-catheter (AcuNav/Siemens/64 elements) was inserted via a straightened femoral vein sheath (12F) and placed in the right atrium in 5 pigs. A custom-made prototype stepper motor allowed automatic rotation around the longitudinal axis from 90 degrees to 360 degrees in 2-5 degrees steps. For every plane 2D images of a complete cardiac cycle were acquired, triggered by respiration and ECG. The ultrasound images were digitized and 3D-reconstruction was performed by a prototype software. After experimental validation the system was tested in 6 patients during electrophysiological studies. RESULTS: From a single location in the right atrium, 3D-acquisition and reconstruction of both atria and ventricles with good image quality were achieved within 3-5 minutes. Doppler-mode facilitated identification of the great vessels including the pulmonary veins and their entry into the heart. 3D-visualization of ablation catheters was also possible in all patients and pigs. CONCLUSION: Semi-automated 3D intracardiac echocardiography from a single site inside the right atrium provides the electrophysiologist with a detailed image of both atria and ventricles with repeated updates of the cardiac anatomy.

MRI of coronary vessel walls using radial k-space sampling and steady-state free precession imaging.

OBJECTIVE: The objective of our study was to investigate the impact of radial k-space sampling and steady-state free precession (SSFP) imaging on image quality in MRI of coronary vessel walls. SUBJECTS AND METHODS: Eleven subjects were examined on a 1.5-T MR system using three high-resolution navigator-gated and cardiac-triggered 3D black blood sequences (cartesian gradient-echo [GRE], radial GRE, and radial SSFP) with identical spatial resolution (0.9 x 0.9 x 2.4 mm3). The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel wall sharpness, and motion artifacts were analyzed. RESULTS: The mean SNR and CNR of the coronary vessel wall were improved using radial imaging and were best using radial k-space sampling combined with SSFP imaging. Vessel border definition was similar for all three sequences. Radial k-space sampling was found to be less sensitive to motion. Consistently good image quality was seen with the radial GRE sequence. CONCLUSION: Radial k-space sampling in MRI of coronary vessel walls resulted in fewer motion artifacts and improved SNR and CNR. The use of SSFP imaging, however, did not result in improved coronary vessel wall visualization.

Artifact-free in-stent lumen visualization by standard magnetic resonance angiography using a new metallic magnetic resonance imaging stent.

BACKGROUND: Metallic stents cause susceptibility and radiofrequency artifacts on MR images, which, up to now, have not allowed for complete visualization of the stent lumen by MR angiography. The aim of this study was to investigate the potential of a new dedicated renal MRI stent for artifact-free in-stent lumen visualization in vitro and in a swine model. METHODS AND RESULTS: In vitro investigations were performed with prototypes of balloon-expandable Aachen Resonance Renal MRI Stents dilated to diameters of 3 to 6 mm and placed in an aqueous gadolinium solution (1:25). Phase-contrast and contrast-enhanced T1-weighted gradient echo images were acquired. Renal MRI stents (n=12) were deployed in the renal arteries of 6 pigs. Renal arteries were examined with phase-contrast angiography and with flow measurements before and after stent placement in the stented area, respectively. Additionally, a contrast-enhanced, T1-weighted, spoiled-gradient echo sequence after administration of 0.2 mmol gadolinium-DTPA/kg body weight was performed after stent placement. The visibility of artifacts was analyzed on in vitro and in vivo images by two investigators who knew the stent positions. Stent positions were determined visually (in vitro) or by x-ray angiography (animal experiments). No artifacts were detected independent of the applied imaging sequence and the stent orientation to the main magnetic field. CONCLUSION: The examined prototypes of fully MR-compatible MRI stents allow artifact-free visualization of the stent lumen with phase-contrast and contrast-enhanced T1-weighted angiography, as well as phase-contrast flow measurements in the stented area.