MRI assessment of experimental gliomas using 17.6 T.

INTRODUCTION: Using ultra-high-field contrast-enhanced magnetic resonance imaging (MRI), an increase of field strength is associated with a decrease of T 1 relaxivity. Yet, the impact of this effect on signal characteristics and contrast-enhanced pathology remains unclear. Hence, we evaluated the potential of a 17.6-T MRI to assess contrast-enhancing parts of experimentally induced rat gliomas compared to 3 T. METHODS: A total of eight tumor-bearing rats were used for MRI assessments either at 17.6 T (four rats) or at 3 T (four rats) at 11 days after stereotactic implantation of F98 glioma cells into the right frontal lobe. T 1-weighted sequences were used to investigate signal-to-noise-ratios, contrast-to-noise-ratios, and relative contrast enhancement up to 16 min after double-dose contrast application. In addition, tumor volumes were calculated and compared to histology. RESULTS: The 17.6-T-derived contrast-enhancing volumes were 31.5 ± 15.4 mm(3) at 4 min, 38.8 ± 12.7 mm(3) at 8 min, 51.1 ± 12.6 mm(3) at 12 min, and 61.5 ± 10.8 mm(3) at 16 min after gadobutrol injection. Corresponding histology-derived volumes were clearly higher (138.8 ± 8.4 mm(3); P < 0.01). At 3 T, contrast-enhancing volumes were 85.2 ± 11.7 mm(3) at 4 min, 107.3 ± 11.0 mm(3) at 8 min, 117.0 ± 10.5 mm(3) at 12 min, and 129.1 ± 10.0 mm(3) at 16 min after contrast agent application. Averaged histology-derived volumes (139.1 ± 13.4 mm(3)) in this group were comparable to the 16-min volume (P ↔16 min = 0.38). Compared to ultra-high-field MRI, all 3-T-derived volumes were significantly higher (P < 0.02). CONCLUSION: Compared to 3-T-derived images and histology, tumor volumes were underestimated by approximately 50 % at 17.6 T. Hence, contrast-enhanced 17.6-T MRI provided no further benefits in tumor measurement compared to 3 T.

Efficient drug-delivery using magnetic nanoparticles--biodistribution and therapeutic effects in tumour bearing rabbits.

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR: This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

Deep treasury management for banks.

Retail banks use Asset Liability Management (ALM) to hedge interest rate risk associated with differences in maturity and predictability of their loan and deposit portfolios. The opposing goals of profiting from maturity transformation and hedging interest rate risk while adhering to numerous regulatory constraints make ALM a challenging problem. We formulate ALM as a high-dimensional stochastic control problem in which monthly investment and financing decisions drive the evolution of the bank's balance sheet. To find strategies that maximize long-term utility in the presence of constraints and stochastic interest rates, we train neural networks that parametrize the decision process. Our experiments provide practical insights and demonstrate that the approach of Deep ALM deduces dynamic strategies that outperform static benchmarks.

Flat-detector computed tomography in the assessment of intracranial stents: comparison with multi detector CT and conventional angiography in a new animal model.

OBJECTIVE: Careful follow up is necessary after intracranial stenting because in-stent restenosis (ISR) or residual stenosis (RS) is not rare. A minimally invasive follow-up imaging technique is desirable. The objective was to compare the visualisation of stents in Flat Detector-CT Angiography (FD-CTA) after intravenous contrast medium injection (i.v.) with Multi Detector Computed Tomography Angiography (MD-CTA) and Digital Subtracted Angiography (DSA) in an animal model. METHODS: Stents were implanted in the carotid artery of 12 rabbits. In 6 a residual stenosis (RS) was surgically created. Imaging was performed using FD-CTA, MD-CTA and DSA. Measurements of the inner and outer diameter and cross-section area of the stents were performed. Stenosis grade was calculated. RESULTS: In subjective evaluation FD-CTA was superior to MD-CTA. FD-CTA was more accurate compared with DSA than MD-CTA. Cross-sectional area of the stent lumen was significantly larger (p < 0.05) in FD-CTA in comparison to MD-CTA. Accurate evaluation of stenosis was impossible in MD-CTA. There was no statistically significant difference in the stenosis grade of DSA and FD-CTA. CONCLUSION: Our results show that visualisation of stent and stenosis using intravenous FD-CTA compares favourably with DSA and may replace DSA in the follow-up of patients treated with intracranial stents.

Reduction of cerebral infarct size by dronedarone.

PURPOSE: In the ATHENA trial, dronedarone reduced the incidence of stroke in patients with atrial fibrillation. Since smaller cerebral infarcts are sometimes asymptomatic, the reduced incidence of stroke might reflect reduction of infarct size (IS) by dronedarone. However, no data on this effect of dronedarone are available. METHODS: In 60 rats, the middle cerebral artery was occluded (MCAO) for 1 h followed by reperfusion. IS was assessed at day 7. Animals were examined using a neurological 5 points score. Twelve animals served as controls (group A), 12 animals received 30 mg/kg (group B) and 100 mg/kg (group C) dronedarone daily starting 3 days before MCAO; 12 animals received 30 mg/kg (group D) starting 2 h after MCAO. In all groups treatment was maintained until day 7. In 12 additional animals (6 controls, 6 pretreated animals) fractional anisotropy (FA) was assessed using magnetic resonance imaging (MRI). RESULTS: IS in group A was 151 ± 45 mm(3) versus 94 ± 42 mm(3) in group B, 79 ± 29 mm(3) in group C, and 127 ± 51 mm(3) in group D, respectively (B,C,D P < 0.05 vs. A). Neuroscores and weight loss (expressed as percent of initial weight) were less in treatment groups: 1.8 ± 0.6 and 91% in group B, 1.4 ± 0.5 and 93% in group C, and 2.1 ± 0.6 and 89% in group D compared to 2.4 ± 0.5 and 83% in controls (B,C,D P < 0.05 vs. A). FA in the ischemic penumbra was significantly higher in treated than in control animals (0.44 ± 0.2 vs. 0.35 ± 0.17; P < 0.05). CONCLUSIONS: Dronedarone administered before and after MCAO reduces IS and improves FA and neurological outcome in transient cerebral ischemia.

Flat-detector computed tomography with intravenous contrast material application in experimental aneurysms: comparison with multislice CT and conventional angiography.

BACKGROUND: Despite limited soft tissue resolution flat-detector computed tomography (FD-CT) provides substantial superior spatial resolution in comparison with multislice computed tomography (MS-CT). This may add value in the visualization of small vascular structures if intravenous contrast application leads to substantial opacification and visibility of intracranial vessels or aneurysms. PURPOSE: To evaluate the feasibility of visualization of vascular structures by FD-CT angiography (FD-CTA) after intravenous contrast injection compared with MS-CTA and intra-arterial digital subtracted angiography (IADSA) in an animal model. MATERIAL AND METHODS: Aneurysms were created in the right common carotid artery in six New Zealand White Rabbits using the elastase technique. Imaging was performed using FD-CTA, MS-CTA (injection of 1 ml/kg body weight) and IADSA. Anonymized volume rendering reconstruction (VRT), maximum intensity projection (MIP), and multiplanar reconstruction (MPR) images were reconstructed and evaluated by two experienced reviewers for aneurysm geometry and vascular structure anatomy using standard tools of a dedicated workstation. RESULTS: Aneurysms could be successfully created in all animals. Measurements of aneurysm geometry (aneurysm height, width, neck width) and vascular structures (brachiocephalic trunk, carotid artery diameter and plane) were nearly identical in all three modalities. Intra- and inter-observer correlations of the different parameters showed high r values between 0.83 and 0.99. CONCLUSION: Our results show the feasibility of FD-CTA in comparison with MS-CTA and IADSA in an animal model. Despite limited soft tissue resolution, opacification of vascular structures with sufficient contrast to the surrounding structures was possible in all animals. Vascular structures appeared better delineated in FD-CTA than in MS-CTA, probably due to the superior spatial resolution.

Cellular characterization of the peritumoral edema zone in malignant brain tumors.

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so-called perifocal edema or brain swelling imposes in T2-weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin-4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2-weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment.

Characterization of the murine orthotopic adamantinomatous craniopharyngioma PDX model by MRI in correlation with histology.

PURPOSE: Adamantinomatous craniopharyngiomas (ACP) as benign sellar brain tumors are challenging to treat. In order to develop robust in vivo drug testing methodology, the murine orthotopic craniopharyngioma model (PDX) was characterized by magnetic resonance imaging (MRI) and histology in xenografts from three patients (ACP1-3). METHODS: In ACP PDX, multiparametric MRI was conducted to assess morphologic characteristics such as contrast-enhancing tumor volume (CETV) as well as functional parameters from dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI) including area-under-the-curve (AUC), peak enhancement (PE), time-to-peak (TTP) and apparent diffusion coefficient (ADC). These MRI parameters evaluated in 27 ACP PDX were correlated to histological features and percentage of vital tumor cell content. RESULTS: Qualitative analysis of MRI and histology from PDX revealed a similar phenotype as seen in patients, although the MRI appearance in mice resulted in a more solid tumor growth than in humans. CETV were significantly higher in ACP2 xenografts relative to ACP1 and ACP3 which correspond to respective average vitality of 41%, <10% and 26% determined histologically. Importantly, CETV prove tumor growth of ACP2 PDX as it significantly increases in longitudinal follow-up of 110 days. Furthermore, xenografts from ACP2 revealed a significantly higher AUC, PE and TTP in comparison to ACP3, and significantly increased ADC relative to ACP1 and ACP3 respectively. Overall, DCE-MRI and DWI can be used to distinguish vital from non-vital grafts, when using a cut off value of 15% for vital tumor cell content. CONCLUSIONS: MRI enables the assessment of craniopharyngioma PDX vitality in vivo as validated histologically.

The power of vertical geolocation of atmospheric profiles from GNSS radio occultation.

High-resolution measurements from Global Navigation Satellite System (GNSS) radio occultation (RO) provide atmospheric profiles with independent information on altitude and pressure. This unique property is of crucial advantage when analyzing atmospheric characteristics that require joint knowledge of altitude and pressure or other thermodynamic atmospheric variables. Here we introduce and demonstrate the utility of this independent information from RO and discuss the computation, uncertainty, and use of RO atmospheric profiles on isohypsic coordinates-mean sea level altitude and geopotential height-as well as on thermodynamic coordinates (pressure and potential temperature). Using geopotential height as vertical grid, we give information on errors of RO-derived temperature, pressure, and potential temperature profiles and provide an empirical error model which accounts for seasonal and latitudinal variations. The observational uncertainty of individual temperature/pressure/potential temperature profiles is about 0.7 K/0.15%/1.4 K in the tropopause region. It gradually increases into the stratosphere and decreases toward the lower troposphere. This decrease is due to the increasing influence of background information. The total climatological error of mean atmospheric fields is, in general, dominated by the systematic error component. We use sampling error-corrected climatological fields to demonstrate the power of having different and accurate vertical coordinates available. As examples we analyze characteristics of the location of the tropopause for geopotential height, pressure, and potential temperature coordinates as well as seasonal variations of the midlatitude jet stream core. This highlights the broad applicability of RO and the utility of its versatile vertical geolocation for investigating the vertical structure of the troposphere and stratosphere.

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging.

Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial-monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

Suppression of proatherogenic leukocyte interactions by MCS-18--Impact on advanced atherosclerosis in ApoE-deficient mice.

OBJECTIVE: Atherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes. APPROACH & RESULTS: ApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 µg, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p < 0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50-200 µg/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p < 0.001). Compared to controls, CD209 (p < 0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p < 0.001) and of phosphorylated NF-κB-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p < 0.001). CONCLUSIONS: MCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.

PRG3 induces Ras-dependent oncogenic cooperation in gliomas.

Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas.

The impact of dietary isoflavonoids on malignant brain tumors.

Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the body's response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose-dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose-response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor-implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor-induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state-of-the-art multimodal treatment approach.

Dynamic contrast enhancement of experimental glioma an intra-individual comparative study to assess the optimal time delay.

RATIONALE AND OBJECTIVES: The aim of this study was to compare tumor signal and contrast media uptake characteristics on contrast-enhanced T1-weighted sequences at 3 Tesla over 30 minutes after double-dose administration of different contrast agents in an animal model of brain glioma. MATERIALS AND METHODS: Nine rats underwent magnetic resonance imaging (MRI) after stereotactic F98 glioma cell implantation before and repetitively for 30 minutes after injection of gadobutrol, gadopentetate, and gadobenate, respectively. Signal-to-noise ratio (SNR) and tumor contrast-to-noise ratio (CNR) were evaluated and MRI-derived tumor volumes were compared to histology. RESULTS: Postcontrast tumor SNR and CNR peaked at 4 minutes after contrast application. While contrast-enhancement within the tumor was fading, tumor volume increased by continuous contrast-uptake of peripheral parts between 4 minutes (137 + or - 29 mm(3), 126 + or - 16 mm(3), 141 + or - 24 mm(3)) and 20 minutes (182 + or - 35 mm(3), 164 + or - 32 mm(3), 191 + or - 25 mm(3)), respectively. At 8 and 12 minutes, 84% and 91% of the tumor volume were definable, respectively. CONCLUSION: Optimal correlation between MRI-derived tumor volume and histology is achieved by imaging up to 20 minutes after contrast application. At 4 minutes (this delay is mostly used in clinical routine), only 75% of the enhancing tumor volume is assessable. A delay of 8 minutes already reveals 84% of the tumor and seems to be a practical clinical compromise.

In vivo micro-CT imaging of rat brain glioma: a comparison with 3T MRI and histology.

The aim of this study was to evaluate the potential of a novel micro-CT system to image in vivo the extent of tumor in a rat model of malignant glioma compared to 3T magnetic resonance imaging (MRI) and histology. Fourteen animals underwent double dose contrast-enhanced imaging with micro-CT and 3T MRI using a clinical machine at day 10 after stereotactic F98 glioma cell implantation. Calculation of the volume of the contrast-uptaking part of the tumor was done by manually outlining the tumor contours by two experienced neuroradiologists. The micro-CT- and MRI-derived tumor volumes were compared to histology as gold standard (hematoxylin and eosin staining and fluorescence staining). There was high interobserver reability regarding the tumor volumes (Crombach's alpha>0.81). Also, there was good correlation of micro-CT- and high-field MRI-derived tumor volumes compared to histology: 72+/-21 mm3 and 69+/-23 mm3 compared to 81+/-14 mm3, respectively (r>0.76). Both the micro-CT- and MRI-derived tumor volumes were not significantly smaller compared to histology (P>0.14). In conclusion, micro-CT allows in vivo imaging of the contrast-enhancing part of experimental gliomas with an accuracy comparable to high-field MRI.