Evaluation of MR-derived CT-like images and simulated radiographs compared to conventional radiography in patients with benign and malignant bone tumors.

OBJECTIVES: To evaluate the diagnostic value of MR-derived CT-like images and simulated radiographs compared with conventional radiographs in patients with benign and malignant bone tumors. METHODS: In 32 patients with a benign or malignant bone lesion (mean age 33.9 ± 18.5 years, 17 females), 3-T MR imaging was performed including a 3D T1-weighted gradient echo sequence as the basis for the CT-like images. From these, intensity-inverted MR image volumes were converted into 2D images via a forward projection to obtain simulated radiographs. Two radiologists assessed these images as well as conventional radiographs for the type of periosteal reaction, matrix mineralization and destruction pattern. Agreement between the modalities was calculated using Cohen's κ. RESULTS: The agreement between conventional radiographs and MR-derived CT-like images in combination with simulated radiographs was substantial (periosteal reaction, κ = 0.67; destruction pattern, κ = 0.75), and the sensitivity of both modalities for the final diagnosis of the lesion (aggressive vs. nonaggressive) was high (MR-derived CT-like images, 86.2% vs. conventional radiographs, 90.0%). Additional information on soft tissue extension (MR-derived CT-like images, 21.9% vs. conventional radiographs, 12.5%; p = 0.009) and lobulation (9.4% vs. 0%; p < 0.001) was significantly more often found on MR-derived CT-like images compared with conventional radiographs. CONCLUSIONS: The assessment of the destruction patterns, periosteal reaction and distinction between aggressive and nonaggressive tumors was feasible using MR-derived CT-like images and simulated radiographs and is comparable to that of conventional radiographs. Moreover, MR-derived CT-like images provided additional information on soft tissue extension and tumor architecture. KEY POINTS: • CT-like images and simulated radiographs can be generated from 3D MRI. • Evaluation of bone tumors is feasible with MR-derived images. • CT-like images and simulated radiographs provide additional information on bone tumors.

Cardiac MOLLI T1 mapping at 3.0 T: comparison of patient-adaptive dual-source RF and conventional RF transmission.

To prospectively compare image quality and myocardial T1 relaxation times of modified Look-Locker inversion recovery (MOLLI) imaging at 3.0 T (T) acquired with patient-adaptive dual-source (DS) and conventional single-source (SS) radiofrequency (RF) transmission. Pre- and post-contrast MOLLI T1 mapping using SS and DS was acquired in 27 patients. Patient wise and segment wise analysis of T1 times was performed. The correlation of DS MOLLI measurements with a reference spin echo sequence was analysed in phantom experiments. DS MOLLI imaging reduced T1 standard deviation in 14 out of 16 myocardial segments (87.5%). Significant reduction of T1 variance could be obtained in 7 segments (43.8%). DS significantly reduced myocardial T1 variance in 16 out of 25 patients (64.0%). With conventional RF transmission, dielectric shading artefacts occurred in six patients causing diagnostic uncertainty. No according artefacts were found on DS images. DS image findings were in accordance with conventional T1 mapping and late gadolinium enhancement (LGE) imaging. Phantom experiments demonstrated good correlation of myocardial T1 time between DS MOLLI and spin echo imaging. Dual-source RF transmission enhances myocardial T1 homogeneity in MOLLI imaging at 3.0 T. The reduction of signal inhomogeneities and artefacts due to dielectric shading is likely to enhance diagnostic confidence.

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer.

Purpose: Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter.Experimental design: PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients.Results: Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAClow = 21.93 months vs. PDACmed = 12.7 months; log-rank P < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker (P = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine (r = -0.84; CI, -0.90- -0.75) and human (r = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADChigh = 41.7 months; ADClow = 14.77 months; log rank, P = 0.040) in PDAC patients.Conclusions: This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. Clin Cancer Res; 23(6); 1461-70. ©2016 AACR.

3D non-contrast-enhanced ECG-gated MR angiography of the lower extremities with dual-source radiofrequency transmission at 3.0 T: Intraindividual comparison with contrast-enhanced MR angiography in PAOD patients.

OBJECTIVE: To compare prospectively image quality and diagnostic confidence of flow-sensitive 3D turbo spin echo (TSE)-based non-contrast-enhanced MR angiography (NE-MRA) at 3.0 T using dual-source radiofrequency (RF) transmission with contrast-enhanced MRA (CE-MRA) in patients with peripheral arterial occlusive disease (PAOD). METHODS: After consent was obtained, 35 patients (mean age 69.1 ± 10.6 years) with PAOD stage II-IV underwent NE-MRA followed by CE-MRA. Signal-to-noise ratio and contrast-to-noise ratio were calculated. Subjective image quality was independently assessed by two radiologists and stenosis scoring was performed in 875 arterial segments. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for stenosis classification were calculated using CE-MRA as a reference method. Diagnostic agreement with CE-MRA was evaluated with Cohen's kappa statistics. RESULTS: NE-MRA provided high objective and subjective image quality at all levels of the arterial tree. Sensitivity and specificity for the detection of relevant stenosis was 91 % and 89 %, respectively; the NPV was 96 % and the PPV 78 %. There was good concordance between CE-MRA and NE-MRA in stenosis scoring. CONCLUSIONS: 3D electrocardiography (ECG)-gated TSE NE-MRA with patient-adaptive dual-source RF transmission at 3.0 T is a promising alternative for PAOD patients with contraindications for gadolinium-based contrast agents. It offers high sensitivity and NPV values in the detection of clinically relevant arterial stenosis. KEY POINTS: • Flow-sensitive TSE NE-MRA is a promising technique for PAOD evaluation. • Diagnostic accuracy is comparable to contrast-enhanced MRA. • NE-MRA eliminates the risk of NSF in patients with renal insufficiency. • Costs arising from the use of contrast agents can be avoided.

Imaging of the lumbar plexus: Optimized refocusing flip angle train design for 3D TSE.

PURPOSE: To study the effects of refocusing angle modulation with 3D turbo spin echo (TSE) on signal and sharpness of small oblique nerves embedded in muscle and suppressed fat in the lumbar plexus. MATERIALS AND METHODS: Flip angle trains were generated with extended phase graphs (EPG) for a sequence parameter subspace. Signal loss and width broadening were simulated for a single-pixel nerve embedded in muscle and suppressed fat to prescribe a flip angle modulation that gives the best compromise between signal and sharpness of small nerves. Two flip angle trains were defined based on the simulations of small embedded nerves: design denoted A, predicting maximum global signal, and design denoted B, predicting maximum signal for minimum width broadening. In vivo data of the lumbar plexus in 10 healthy volunteers was acquired at 3.0T with 3D TSE employing flip angle trains A and B. Quantitative and qualitative analyses of the acquired data were made to assess changes in width and signal intensity. RESULTS: Changing flip angle modulation from A to B resulted in: 1) average signal losses of 23% in (larger) L5 nerves and 9% in (smaller) L3 nerves; 2) average width reductions of 4% in L5 nerves and of 16% in L3 nerves; and 3) statistically significant sharpness improvement (P = 0.005) in L3 nerves. CONCLUSION: An optimized flip angle train in 3D TSE imaging of the lumbar plexus considering geometry-specific blurring effects from both the nerve and the surrounding tissue can improve the delineation of small nerves.

Diffusion-weighted stimulated echo acquisition mode (DW-STEAM) MR spectroscopy to measure fat unsaturation in regions with low proton-density fat fraction.

PURPOSE: To propose and optimize diffusion-weighted stimulated echo acquisition mode (DW-STEAM) for measuring fat unsaturation in the presence of a strong water signal by suppressing the water signal based on a shorter T2 and higher diffusivity of water relative to fat. METHODS: A parameter study for point-resolved spectroscopy (PRESS) and STEAM using oil phantoms was performed and correlated with gas chromatography (GC). Simulations of muscle tissue signal behavior using DW-STEAM and long-echo time (TE) PRESS and a parameter optimization for DW-STEAM were conducted. DW-STEAM and long-TE PRESS were applied in the gastrocnemius muscles of nine healthy subjects. RESULTS: STEAM with TE and mixing time (TM) up to 45 ms exhibited R(2) correlations above 0.98 with GC and little T2 -weighting and J-modulation for the quantified olefinic/methylene peak ratio. The optimal parameters for muscle tissue using DW-STEAM were b-value = 1800 s/mm(2), TE = 33 ms, TM = 30 ms, and repetition time = 2300 ms. In vivo measured mean olefinic signal-to-noise ratios were 72 and 40, mean apparent olefinic water fractions were 0.19 and 0.11 for DW-STEAM and long-TE PRESS, respectively. CONCLUSION: Optimized DW-STEAM MR spectroscopy is superior to long-TE PRESS for measuring fat unsaturation, if a strong water peak prevents the olefinic fat signal's quantification at shorter TEs and water's tissue specific ADC is substantially higher than fat.

Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib.

PURPOSE: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models. EXPERIMENTAL DESIGN: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors. RESULTS: Histologically and biochemically confirmed liver damage resulted in increased (18)F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only. CONCLUSIONS: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.

Characterization of magnetic viral complexes for targeted delivery in oncology.

Oncolytic viruses are promising new agents in cancer therapy. Success of tumor lysis is often hampered by low intra-tumoral titers due to a strong anti-viral host immune response and insufficient tumor targeting. Previous work on the co-assembly of oncolytic virus particles (VPs) with magnetic nanoparticles (MNPs) was shown to provide shielding from inactivating immune response and improve targeting by external field gradients. In addition, MNPs are detected by magnet resonance imaging (MRI) enabling non-invasive therapy monitoring. In this study two selected core-shell type iron oxide MNPs were assembled with adenovirus (Ad) or vesicular stomatitis virus (VSV). The selected MNPs were characterized by high r2 and r2(*) relaxivities and thus could be quantified non-invasively by 1.5 and 3.0 tesla MRI with a detection limit below 0.001 mM iron in tissue-mimicking phantoms. Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2(*) compared to free MNPs. The relaxivity changes could be attributed to the clusterization of particles and complexes shown by transmission electron microscopy (TEM). In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model. In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies. Furthermore, our study provides first evidence of the in vivo applicability of selected MNP-VPs in cancer therapy.

MR-detected changes in liver fat, abdominal fat, and vertebral bone marrow fat after a four-week calorie restriction in obese women.

PURPOSE: To determine changes in the bone marrow fat fraction (BMFF) in obesity after dietary intervention in comparison with changes in abdominal fat, liver fat, and serum lipids. MATERIALS AND METHODS: Twenty obese (BMI 34.92 ± 3.8 kg/m(2) ) women participated in a 4-week dietary intervention of 800 kcal/d plus additional vegetables. They underwent anthropometric and blood value measurements before and after the intervention. Abdominal 3T MRI was performed to measure changes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volume and single-voxel magnetic resonance spectroscopy (MRS) to measure fat content changes in the liver and L5 vertebral body. RESULTS: The greatest relative change after dietary intervention was found in the liver (-40.3%), followed by VAT volume (-15.1%), serum lipids (-12.6 to -14.5%), and SAT volume (-8.5%). There were no statistically significant changes in BMFF after dietary intervention (P = 0.39), but absolute changes in the BMFF were positively associated with SAT volume (r = 0.489) and negatively associated with nonadipose tissue volume (r = -0.493) before dietary intervention. CONCLUSION: Bone marrow behaves differently compared to SAT volume, VAT volume, liver fat, and serum lipids after a 4-week dietary intervention in obesity and BMFF changes depend on abdominal tissue volumes before intervention.

Dual-source RF transmission in cardiac SSFP imaging at 3 T: systematic spatial evaluation of image quality improvement compared to conventional RF transmission.

The purpose of this investigation was to systematically evaluate the spatial distribution of image quality improvement with dual-source radiofrequency (RF) transmission in cardiac steady-state free precession sequences at 3.0 T. Imaging with and without dual-source RF transmission was performed in 30 patients. Contrast-to-noise ratio for the left ventricular myocardium was significantly higher using dual-source RF transmission, but improvement was not uniformly distributed. The posterior myocardium showed significantly less contrast-to-noise ratio gain than all other cardiac regions. Signal-to-noise ratio increase was higher in the right than in the left ventricle. Subjective image quality was significantly enhanced by parallel RF transmission.

Assessment of myocardial infarction and postinfarction scar remodeling with an elastin-specific magnetic resonance agent.

BACKGROUND: To prospectively evaluate an elastin-specific MR contrast agent (ESMA) for in vivo targeting of elastic fibers in myocardial infarction (MI) and postinfarction scar remodeling. METHODS AND RESULTS: MI was induced in C57BL/6J mice (n=40) by permanent ligation of the left anterior descending coronary artery. MRI was performed at 7 and 21 days after MI. The merits of gadolinium-based ESMA (Gd-ESMA) were compared with gadopentetic acid (Gd-DTPA) for infarct size determination, contrast-to-noise ratio (CNR), and enhancement kinetics. Specific binding in vivo was evaluated by blocking the molecular target using nonparamagnetic lanthanum-ESMA. In vivo imaging results were confirmed by postmortem triphenyltetrazolium chloride staining, elastica van Gieson staining, and Western blotting. Delayed enhancement MRI revealed prolonged enhancement of Gd-ESMA in the postischemic scar compared with Gd-DTPA. Infarct size measurements showed good agreement between Gd-ESMA and Gd-DTPA and were confirmed by ex vivo triphenyltetrazolium chloride staining. Preinjection of the blocking lanthanum-ESMA resulted in significantly lower CNR of Gd-ESMA at the infarct site (P=0.0019). Although no significant differences in CNR were observed between delayed enhancement imaging and Gd-DTPA between days 7 and 21 (1.8± versus 3.8; P=ns), Gd-ESMA showed markedly higher CNR on day 21 after MI (14.1 versus 4.9; P=0.0032), which correlated with increased synthesis of tropoelastin detected by Western blot analysis and histology. Higher CNR values for Gd-ESMA further correlated with improved ejection fraction of the mice on day 21 after MI. CONCLUSIONS: Gd-ESMA enables targeting of elastin within the infarct scar in a mouse model of MI. The imaging properties of Gd-ESMA allow quantification of intrascar elastin content in vivo and thereby provide potential for noninvasive characterization of postinfarction scar remodeling.

Three-dimensional magnetic resonance imaging using single breath-hold k-t BLAST for assessment of global left ventricular functional parameters.

OBJECTIVES: To determine the accuracy of three-dimensional k-t broad-use linear acquisition speed-up technique (k-t BLAST) accelerated magnetic resonance imaging (MRI) for the assessment of left ventricular (LV) parameters compared to segmented multiple breath-hold cine imaging. METHODS: A multislice cine (steady state free precession [SSFP]) sequence was performed with complete ventricular coverage during multiple breath-holds (temporal resolution 47 ms, voxel size 1.25 × 1.25 × 8 mm(3)). In addition, two k-t BLAST sequences with complete coverage were acquired, KT1 (temporal resolution 57 ms, voxel size 1.25 × 1.25 × 4 mm(3)) and k-t2 (temporal resolution 57 ms, voxel size 1.25 × 1.25 × 8 mm(3)), during a single breath-hold. For comparison of SSFP and k-t BLAST, LV parameters were determined: ejection fraction (EF), end-diastolic volume, end-systolic volume, and LV mass. RESULTS: EF was underestimated by KT1 (47%) and KT2 (48%) compared to the SSFP sequence (53%). All parameters showed high correlation with the k-t BLAST sequences and the SSFP sequence (r = 0.88-0.98, P < .001). The mean relative difference for KT1/KT2 compared to the SSFP sequence was -0.11/-0.09 for the EF, -0.073/-0.086 for the EDV, 0.044/0.051 for the ESV, and 0.085/0.12 for the LV mass. CONCLUSIONS: The use of three-dimensional k-t BLAST enabled a determination of the LV parameters with high correlation compared to the SSFP sequence. EF was slightly underestimated, and LV mass was slightly overestimated.

Evaluation of the potential of phase-contrast computed tomography for improved visualization of cancerous human liver tissue.

PURPOSE: Phase-contrast X-ray computed tomography (PCCT) is currently investigated and developed as a potentially very interesting extension of conventional CT, and can offer several advantages for specific indications in diagnostic imaging. Current absorption-based computed tomography (CT) without the application of contrast material is limited in the detection of minor density differences in soft-tissue. The purpose of this study is to test whether PCCT can improve soft tissue contrast in healthy and tumorous human liver specimens. MATERIALS AND METHODS: Two specimens of human liver (one healthy and one metastasized liver sample) were imaged with brilliant X-ray beam at the synchrotron radiation source ESRF in Grenoble, France. For correlation the same specimens were imaged with a magnetic resonance imaging system at 1.5 T. The histopathology confirmed our findings in the corresponding sections of the specimens. RESULTS: In the phase-contrast CT images we observed a significantly enhanced soft-tissue contrast when compared to simultaneously recorded standard absorption CT measurements. Further, we found that the pathological and morphological information in the PCCT reconstructions show significant improvement when compared to those performed on MRI. Based on matching of prominent features, a good correlation between PCCT and the histological section is demonstrated; especially the tumor capsule and the surrounding vascular structures are visible in PCCT. In addition, our study revealed the ability of PCCT to visualize the blood vessels structure in the tumorous liver without the need of any contrast agents. CONCLUSION: Grating-based PCCT significantly improves the soft-tissue contrast in ex-vivo liver specimens and holds the potential to overcome the need of contrast materials for visualization of the tumor vascularization.

X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

To explore the potential of grating-based x-ray phase-contrast computed tomography (CT) for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i) high-resolution synchrotron radiation (SR) imaging and ii) dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i) high-performance imaging for virtual microscopy applications and ii) biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI) were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR) of selected regions of interest (ROI) in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

B1+-mapping with the transient phase of unbalanced steady-state free precession.

PURPOSE: A novel B1+-mapping technique (B1-TRAP) is presented, which derives the actual flip angle from the frequency of signal oscillations, observed in the transient phase of unbalanced steady-state free precession sequences. THEORY: For short repetition times (TR), the angular frequency of distinct oscillations in the transient phase of steady-state free precession sequences is proven to be approximately proportional to the actual flip angle: ω⋅TR≈α. The result is not influenced by off-resonance and it can be shown that deviations are only of second order in the small parameter TR/T2. METHODS: B1-TRAP makes use of this effect through a frequency analysis of the transient phase of a train of steady-state free precession signals. RESULTS: In terms of reliability and time efficiency, a two-dimensional multislice implementation was found to be optimal. Unlike many steady-state B1+-mapping methods, the accuracy of B1-TRAP was not impaired by imperfect slice profiles. CONCLUSION: Simulations, phantom, and in vivo measurements showed that B1-TRAP offers a good compromise with respect to speed, robustness, and accuracy.

Evaluation of phase-sensitive versus magnitude reconstructed inversion recovery imaging for the assessment of myocardial infarction in mice with a clinical magnetic resonance scanner.

PURPOSE: To evaluate phase-sensitive inversion-recovery (PSIR) imaging at 1.5 T in a mouse model of permanent coronary artery ligation as a potentially rapid and robust alternative for the accurate assessment of myocardial infarction (MI) by cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: PSIR late gadolinium enhancement (LGE) imaging was compared to conventional 2D segmented inversion-recovery imaging for the assessment of murine MI. RESULTS: PSIR images provided comparable contrast and kinetics of intravenously injected gadopentetate dimeglumine (Gd-DTPA). At the mid-ventricular level there was good agreement between conventional IR and PSIR for infarct size assessment. After intravenous injection a limited time window of ∼6 minutes is available for delayed enhancement imaging in mice. Whole-heart infarct imaging with 1 mm thick slices was only possible in this restricted time frame when the PSIR method is applied, avoiding the need for repetitively adapting the correct inversion time. Infarct size determined by PSIR MRI demonstrated good agreement with postmortem histology. Infarct size determined by PSIR LGE MRI inversely correlates with left-ventricular function on day 7 after MI. CONCLUSION: The PSIR technique provides stable and consistent contrast between hyperenhanced and remote myocardium independent of the selected inversion time (TI) and proved to be a robust, fast, and accurate tool for the assessment of MI in mice.

Silica-iron oxide magnetic nanoparticles modified for gene delivery: a search for optimum and quantitative criteria.

PURPOSE: To optimize silica-iron oxide magnetic nanoparticles with surface phosphonate groups decorated with 25-kD branched polyethylenimine (PEI) for gene delivery. METHODS: Surface composition, charge, colloidal stabilities, associations with adenovirus, magneto-tranduction efficiencies, cell internalizations, in vitro toxicities and MRI relaxivities were tested for the particles decorated with varying amounts of PEI. RESULTS: Moderate PEI-decoration of MNPs results in charge reversal and destabilization. Analysis of space and time resolved concentration changes during centrifugation clearly revealed that at >5% PEI loading flocculation gradually decreases and sufficient stabilization is achieved at >10%. The association with adenovirus occurred efficiently at levels over 5% PEI, resulting in the complexes stable in 50% FCS at a PEI-to-iron w/w ratio of ≥7%; the maximum magneto-transduction efficiency was achieved at 9-12% PEI. Primary silica iron oxide nanoparticles and those with 11.5% PEI demonstrated excellent r(2)* relaxivity values (>600 s(-1)(mM Fe)(-1)) for the free and cell-internalized particles. CONCLUSIONS: Surface decoration of the silica-iron oxide nanoparticles with a PEI-to-iron w/w ratio of 10-12% yields stable aqueous suspensions, allows for efficient viral gene delivery and labeled cell detection by MRI.

Different capacity of monocyte subsets to phagocytose iron-oxide nanoparticles.

OBJECTIVE: To explore the capacity of human CD1⁺CD16⁺⁺ and CD14⁺⁺CD16⁻ monocytes to phagocyte iron-oxide nanoparticles in vitro. METHODS: Human monocytes were labeled with four different magnetic nanoparticle preparations (Ferumoxides, SHU 555C, CLIO-680, MION-48) exhibiting distinct properties and cellular uptake was quantitatively assessed by flow cytometry, fluorescence microscopy, atomic absorption spectrometry and Magnetic Resonance Imaging (MRI). Additionally we determined whether cellular uptake of the nanoparticles resulted in phenotypic changes of cell surface markers. RESULTS: Cellular uptake differed between the four nanoparticle preparations. However for each nanoparticle tested, CD14⁺⁺CD16⁻ monocytes displayed a significantly higher uptake compared to CD14⁺CD16⁺⁺ monocytes, this resulted in significantly lower T1 and T2 relaxation times of these cells. The uptake of iron-oxide nanoparticles further resulted in a remarkable shift of expression of cell surface proteins indicating that the labeling procedure affects the phenotype of CD14⁺CD16⁺⁺ and CD14⁺⁺CD16⁻ monocytes differently. CONCLUSION: Human monocyte subsets internalize different magnetic nanoparticle preparations differently, resulting in variable loading capacities, imaging phenotypes and likely biological properties.

Validation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization.

BACKGROUND & AIMS: The hepatocellular carcinoma (HCC) exhibits varying degrees of vascularization with more poorly differentiated carcinoma commonly exhibiting high amounts of vascularization. Transcatheter arterial embolization (TAE) of HCC tumor nodules results in varying amounts of tumor necrosis. Reliable quantification of necrosis after TAE, would aid in treatment planning and testing of novel combinatorial treatment regimen. The aim of this work was to validate different imaging parameters as individual or combined predictors of tumor necrosis after TAE in an orthotopic rat HCC tumor model. METHODS: Unifocal rat HCC was imaged by T(2)-weighted MRI, quantitative dynamic contrast enhanced (DCE) MRI, diffusion weighted MRI (DWI) and [(18)F]-FDG PET imaging before (day-1) and after (days 1 and 3) TAE. Univariate and multivariate regression analyses were carried out to analyze the ability of each imaging parameter to predict the percent residual vital tumor (vtu) and vital tissue (vti) as determined by quantitative histopathology. RESULTS: TAE induced a wide range of tumor necrosis. Tumor volume was the only parameter showing a correlation with vti (r(2) = 0.63) before TAE. After TAE, moderate correlations were found for FDG tracer uptake (r(2) = 0.56) and plasma tissue transfer constant (r(2) = 0.55). Correlations were higher for the extravascular extracellular volume fraction (v(e), r(2) = 0.68) and highest for the apparent diffusion coefficient (ADC, r(2) = 0.86). Multivariate analyses confirmed highest correlation of ADC and v(e) with vtu and vti. CONCLUSIONS: DWI and DCE-MRI with the respective parameters ADC (day 3) and v(e) (day 1) were identified as the most promising imaging techniques for the prediction of necrosis. This study validates a preclinical platform allowing for the improved tumor stratification after TAE and thus the testing of novel combinatorial therapy approaches in HCC.

Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability.

To evaluate ultra small superparamagnetic iron oxide particles (USPIO) enhanced magnetic resonance (MR) imaging for characterization of atherosclerotic carotid plaques by assessing vascularity and plaque inflammation, besides contrast-enhanced MR angiography (CE-MRA) of the carotid artery stenosis. Twelve patients with severe carotid artery stenosis, scheduled for endarterectomy, underwent MRI of the carotid artery bifurcation using SHU 555 C at a dose of 40 µmol Fe/kg BW. The MR imaging protocol comprised pre- and post-contrast T2*-w, a first-pass CE-MRA and dynamic T1-w sequences. For quantitative data analysis, the signal intensities (SI) were measured and SNR-data (SNR = SI(blood/plaque/bone marrow)/standard deviation(noise)) as well as ΔSI-data (SNR(post)-SNR(pre)) were calculated. In addition, two radiologists rated the diagnostic performance of first-pass MRA according to a four level decision scale. Staining of anti-dextran (SHU 555 C) and anti-CD68 (macrophages) was performed for immunohistological confirmation. Plaque sections with a T2*-w signal decline (intracellular USPIO accumulation in macrophages) showed significantly changes (mean -14%, 95% CI, -5 to -20%; P < 0.01) and corresponding plaque regions had significantly higher (15.15 ± 1.76 vs. 5.22 ± 1.50; P < 0.01) T1-w enhancement data (global estimation of vascularity). The first-pass MRA of the supra-aortal vessels provided images of diagnostic quality. Representative immunohistology sections revealed colocalization of dextran- and CD68-immunoreactive cells. USPIO-enhanced MRI is feasible for in vivo assessment of vascularity and macrophage content in atherosclerotic carotid plaques, determining an association of these potential imaging biomarkers of plaque vulnerability. Diagnostic MRA of the supra-aortal vessels can be imaged additionally with a single administration of SHU 555 C.