Stefan Hadlich

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

BackgroundPancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.Methods6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.ResultsMRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/-22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.ConclusionsThis model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.

Ophthalmic Magnetic Resonance Imaging at 7 T Using a 6-Channel Transceiver Radiofrequency Coil Array in Healthy Subjects and Patients With Intraocular Masses

ObjectivesThis study was designed to examine the feasibility of ophthalmic magnetic resonance imaging (MRI) at 7 T using a local 6-channel transmit/receive radiofrequency (RF) coil array in healthy volunteers and patients with intraocular masses. Materials and MethodsA novel 6-element transceiver RF coil array that makes uses of loop elements and that is customized for eye imaging at 7 T is proposed. Considerations influencing the RF coil design and the characteristics of the proposed RF coil array are presented. Numerical electromagnetic field simulations were conducted to enhance the RF coil characteristics. Specific absorption rate simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Phantom experiments were carried out to validate the electromagnetic field simulations and to assess the real performance of the proposed transceiver array. Certified approval for clinical studies was provided by a local notified body before the in vivo studies. The suitability of the RF coil to image the human eye, optical nerve, and orbit was examined in an in vivo feasibility study including (a) 3-dimensional (3D) gradient echo (GRE) imaging, (b) inversion recovery 3D GRE imaging, and (c) 2D T2-weighted fast spin-echo imaging. For this purpose, healthy adult volunteers (n = 17; mean age, 34 ± 11 years) and patients with intraocular masses (uveal melanoma, n = 5; mean age, 57 ± 6 years) were investigated. ResultsAll subjects tolerated all examinations well with no relevant adverse events. The 6-channel coil array supports high-resolution 3D GRE imaging with a spatial resolution as good as 0.2 × 0.2 × 1.0 mm3, which facilitates the depiction of anatomical details of the eye. Rather, uniform signal intensity across the eye was found. A mean signal-to-noise ratio of approximately 35 was found for the lens, whereas the vitreous humor showed a signal-to-noise ratio of approximately 30. The lens-vitreous humor contrast-to-noise ratio was 8, which allows good differentiation between the lens and the vitreous compartment. Inversion recovery prepared 3D GRE imaging using a spatial resolution of 0.4 × 0.4 × 1.0 mm3 was found to be feasible. T2-weighted 2D fast spin-echo imaging with the proposed RF coil afforded a spatial resolution of 0.25 × 0.25 × 0.7 mm3. ConclusionsThis work provides valuable information on the feasibility of ophthalmic MRI at 7 T using a dedicated 6-channel transceiver coil array that supports the acquisition of high-contrast, high–spatial resolution images in healthy volunteers and patients with intraocular masses. The results underscore the challenges of ocular imaging at 7 T and demonstrate that these issues can be offset by using tailored RF coil hardware. The benefits of such improvements would be in positive alignment with explorations that are designed to examine the potential of MRI for the assessment of spatial arrangements of the eye segments and their masses with the ultimate goal to provide imaging means for guiding treatment decisions in ophthalmological diseases.

Automated detection of amyloid-β-related cortical and subcortical signal changes in a transgenic model of Alzheimer's disease using high-field MRI.

In vivo imaging of amyloid-β (Aβ) load as a biomarker of Alzheimers disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AβPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AβPP/PS1 mice present with rapid-onset cerebral β-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aβ-deposition in brain. Data were analyzed with a novel automated voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AβPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aβ plaques and activated microglia. Grey matter density did not differ between wild-type mice and AβPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies.

T1 bias in chemical shift-encoded liver fat-fraction: Role of the flip angle

To investigate flip angle (FA)‐dependent T1 bias in chemical shift‐encoded fat‐fraction (FF) and to evaluate a strategy for correcting this bias to achieve accurate MRI‐based estimates of liver fat with optimized signal‐to‐noise ratio (SNR).

MR Microscopy of the human eye at 7.1 T and correlation with histopathology-proof of principle.

Objective: Magnetic resonance imaging (MRI) at 1.5 and 3.0 Tesla with small surface coils is a well-established procedure in the diagnosis of masses of the eye and orbital cavity. Until now histological examination has been required to obtain definitive information on tumor extent or possible infiltration of surrounding structures. With ultra-high-field MRI, however, it is possible to evaluate tumor morphology as well as possible extension into surrounding structures with submillimeter spatial resolution. Materials and Methods: We present a female patient with a uveal melanoma who underwent a preoperative MRI at 1.5 T (spatial resolution = 0.9 x 0.9 x 4 mm/voxel). Postoperatively, the enucleated specimen was examined in a 7.1 Tesla high-field MRI scanner (slice thickness = 500 µm, matrix size = 512 x 512 pixels, spatial resolution = 78 x 78 x 500 µm/voxel, acquisition time = 8:20 min per plane). Finally, the specimen was examined histologically, and the histological and MRI results were correlated. Results: Ultra-high-field MRI at 7.1 Tesla visualized the uveal melanoma and anatomical structures of the bulb with high resolution, enabling definitive assessment of tumor morphology and extent. Subsequent histological examination confirmed the MRI findings regarding origin, internal structure, and extent of the tumor. Conclusion: MR microscopy correlates strongly with histology, suggesting that this new imaging modality has the potential for noninvasively assessing tumor morphology, extent, and infiltration of surrounding structures. The examination was performed ex vivo and demonstrates that diagnostic assessment of malignant masses is feasible using high-resolution MR microscopy.

Diffusion-sensitized ophthalmic magnetic resonance imaging free of geometric distortion at 3.0 and 7.0 T: a feasibility study in healthy subjects and patients with intraocular masses.

ObjectivesThis study is designed to examine the feasibility of diffusion-sensitized multishot split-echo rapid acquisition with relaxation enhancement (RARE) for diffusion-weighted ophthalmic imaging free of geometric distortions at 3.0 and 7.0 T in healthy volunteers and patients with intraocular masses. Materials and MethodsA diffusion-sensitized multishot split-echo RARE (ms-RARE) variant is proposed as an alternative imaging strategy for diffusion-weighted imaging. It is compared with standard single-shot echo planar imaging (EPI) and readout-segmented EPI in terms of geometric distortions in a structure phantom as well as in vivo at 3.0 and 7.0 T. To quantify geometric distortions, center of gravity analysis was carried out. Apparent diffusion coefficient (ADC) mapping in a diffusion phantom was performed to verify the diffusion sensitization within ms-RARE. An in vivo feasibility study in healthy volunteers (n = 10; mean age, 31 ± 7 years; mean body mass index, 22.6 ± 1.7 kg/m2) was conducted at 3.0 and 7.0 T to evaluate clinical feasibility of ms-RARE. As a precursor to a broader clinical study, patients (n = 6; mean age, 55 ± 12 years; mean body mass index, 27.5 ± 4.7 kg/m2) with an uveal melanoma and/or retinal detachment were examined at 3.0 and 7.0 T. In 1 case, the diseased eye was enucleated as part of the therapy and imaged afterward with magnetic resonance microscopy at 9.4 T. Macrophotography and histological investigation was carried out. For qualitative assessment of the image distortion, 3 independent readers reviewed and scored ms-RARE in vivo images for all subjects in a blinded reading session. Statistical significance in the difference of the scores (a) obtained for the pooled ms-RARE data with b = 0 and 300 s/mm2 and (b) for the 3 readers was analyzed using the nonparametric Mann-Whitney test. ResultsThe assessment of geometric integrity in phantom imaging revealed the ability of ms-RARE to produce distortion-free images. Unlike ms-RARE, modest displacements (2.3 ± 1.4 pixels) from the fast low angle shot imaging reference were observed for readout-segmented EPI, which were aggravated for single-shot EPI (8.3 ± 5.7 pixels). These observations were confirmed in the in vivo feasibility study including distortion-free diffusion-weighted ophthalmic images with a 0.5 × 0.5 × 5 mm3 spatial resolution at 3.0 T and as good as 0.2 × 0.2 × 2 mm3 at 7.0 T. The latter represents a factor of 40 enhancement in spatial resolution versus clinical protocols recently reported for diffusion-weighted imaging of the eye at 1.5 T. Mean ADC values within the vitreous body were (2.91 ± 0.14) × 10−3 mm2/s at 3.0 T and (2.93 ± 0.41) × 10−3 mm2/s at 7.0 T. Patient data showed severe retinal detachment in the anatomical images. Whereas the tumor remained undetected in T1-weighted and T2-weighted imaging at 3.0/7.0 T, in vivo ADC mapping using ms-RARE revealed the presence of a uveal melanoma with a significant contrast versus the surrounding subretinal hemorrhage. This observation was confirmed by high-resolution ex vivo magnetic resonance microscopy and histology. Qualitative analysis of image distortion in ms-RARE images obtained for all subjects yielded a mean ± SD image quality score of 1.06 ± 0.25 for b = 0 s/mm2 and of 1.17 ± 0.49 for b = 300 s/mm2. No significant interreader differences were observed for ms-RARE with a diffusion sensitization of b = 0 s/mm2 and 300 s/mm2. ConclusionsThis work demonstrates the capability of diffusion-sensitized ms-RARE to acquire high-contrast, high–spatial resolution, distortion-free images of the eye and the orbit at 3.0 and 7.0 T. Geometric distortions that are observed for EPI-based imaging approaches even at lower field strengths are offset by fast spin-echo–based imaging techniques. The benefits of this improvement can be translated into the assessment of spatial arrangements of the eye segments and their masses with the ultimate goal to provide guidance during diagnostic treatment of ophthalmological diseases.

Simultaneous magnetic resonance imaging and pharmacokinetic analysis of intramuscular depots

The present pilot study introduces a method that might give novel insights in drug absorption processes from intramuscularly administered depots. An oily suspension or an aqueous solution of paracetamol (6 mg/kg body mass), prednisolone or its hemisuccinate sodium salt for the aqueous solutions (10mg/kg body mass) or diclofenac (10mg/kg body mass) was injected into the muscle tissue of the hind leg of female Lewis-rats (n=47). For the oily suspensions the micronized particles were suspended in medium-chain triglycerides. The aqueous solutions were buffered to a pH of 7.4 ± 0.5. Polyethylene glycol was added as a cosolvent in the formulations containing paracetamol (acetaminophen) and diclofenac and sodium chloride was added to the aqueous solutions of prednisolone hemisuccinate sodium to achieve nearly isotonic formulations. The formed depot was visualized by magnetic resonance imaging (MRI) and characterized with regard to volume and surface area. A 7 T-small animal scanner was used and T1-weighted and T2-weighted sequences including a fat saturation were performed. Simultaneously blood samples were taken and the drugs were quantitatively analyzed. The water based solvent and the oily dispersion agent were visible in the MRI images without the use of contrast agents. Since a free hand injection mostly led to an application directly into the fascia, resulting in a fast removal of the depot, MRI-guided injection was conducted. Comparing pharmacokinetic data with MRI data it was observed that maximal blood levels occurred before the solvent and the dispersion agent were removed from the muscle tissue. Thus, the drug is not absorbed together with the depot. Furthermore, no correlation was found between the shape of the depot and the rate of absorption. Consequently, a higher surface area or volume of the depot did not result in a faster release or absorption of the drugs from the tested formulations. In contrast to the paracetamol and prednisolone formulations the formulations containing diclofenac led to a massive accumulation of interstitial fluid around the injection area being a sign for an acute local reaction. Histological analysis of the muscle tissue revealed a clear correspondence between the amount of interstitial fluid and the extent of infiltrating lymphocytes and granulocytes indicating a tissue response. In conclusion combining MRI with pharmacokinetic data is a suitable method to gain deeper insights into drug absorption processes from intramuscular depots. Furthermore, MRI offers a great possibility detecting local side effects caused by an intramuscularly applied dosage form. This might be very useful in preclinical phases during the development of new intramuscular formulations.

Anatomic and pathological characterization of choroidal melanoma using multimodal imaging: what is practical, what is needed?

Choroidal melanoma is the most frequently occurring intraocular tumor in adults. The aim of this work is to assess the potential of state-of-the art in-vivo and ex-vivo imaging modalities for the characterization of choroidal melanoma. Multimodal imaging of a choroidal melanoma was performed in a 53-year-old male patient. In-vivo ophthalmoscopy, ultrasound microscopy, duplex ultrasound, and 7.0 T MRI were performed. Ex-vivo examination of the enucleated eye included 7.0 and 9.4 T magnetic resonance microscopy as well as histopathology with hematoxylin and eosin staining. Imaging of choroidal melanoma with ultrahigh field MRI and duplex sonography provides detailed morphologic and functional information of the eye. High-spatial-resolution MRI at 9.4 T shows details of the internal texture of melanoma and other structures of the eye with an in-plane spatial resolution of 32 &mgr;m. Ultrahigh field in-vivo MRI at 7.0 T and ex-vivo MRI at 7.0 and 9.4 T correlate well with histologic evaluation. In-vivo ultrahigh field MRI is an emerging technique for the characterization and staging of ocular tumors. The combination of in-vivo ultrahigh-field MRI and duplex sonography has the potential to complement or even substitute complex and invasive biopsies.

Ophthalmologische Bildgebung mit Ultrahochfeld-Magnetresonanztomografie: technische Innovationen und wegweisende Anwendungen

This review documents technical progress in ophthalmic magnetic resonance imaging (MRI) at ultrahigh fields (UHF, B(0) ≥ 7.0 T). The review surveys frontier applications of UHF-MRI tailored for high spatial resolution in vivo imaging of the eye, orbit and optic nerve. Early examples of clinical ophthalmic UHF-MRI including the assessment of melanoma of the choroid membrane and the characterisation of intraocular masses are demonstrated. A concluding section ventures a glance beyond the horizon and explores research promises along with future directions of ophthalmic UHF-MRI.

Morphologic and biometric evaluation of chick embryo eyes in ovo using 7 Tesla MRI

The purposes of this study were (1) to characterize embryonic eye development during incubation in ovo and (2) to analyze the putative influence of repetitive ultrahigh-field MRI (UHF-MRI) measurements on this development. A population of 38 fertilized chicken eggs was divided into two sub-groups: two eggs (Group A) were examined repeatedly during the developmental period from embryonic day 1 (E1) to embryonic day 20 (E20) to evaluate the influence of daily MRI scanning. A second larger group of 36 eggs was examined pairwise on one day only, from E3 to E20, and the embryos were sacrificed immediately after MR imaging (Group B). Fast T2-weighted MR sequences provided biometric data on the eye with an in-plane resolution of 74 μm. The data show rapid growth of the eye with a steep increase in intraocular dimensions in all axis directions and in eyeball volume during initial development up to E10, followed by a phase of reduced growth rate in later developmental stages. Comparison of the two groups revealed no differences in ocular development.