Stefanie Remmele

Dynamic and simultaneous MR measurement of R1 and R2* changes during respiratory challenges for the assessment of blood and tissue oxygenation

This work presents a novel method for the rapid and simultaneous measurement of R1 and R2* relaxation rates. It is based on a dynamic short repetition time steady‐state spoiled multigradient‐echo sequence and baseline R1 and B1 measurements. The accuracy of the approach was evaluated in simulations and a phantom experiment. The sensitivity and specificity of the method were demonstrated in one volunteer and in four patients with intracranial tumors during carbogen inhalation. We utilized (ΔR2*, ΔR1) scatter plots to analyze the multiparametric response amplitude of each voxel within an area of interest. In normal tissue R2* decreased and R1 increased moderately in response to the elevated blood and tissue oxygenation. A strong negative ΔR2* and ΔR1 response was observed in veins and some tumor areas. Moderate positive ΔR2* and ΔR1 response amplitudes were found in fluid‐rich tissue as in cerebrospinal fluid, peritumoral edema, and necrotic areas. The multiparametric approach was shown to increase the specificity and sensitivity of oxygen‐enhanced MRI compared to measuring ΔR2* or ΔR1 alone. It is thus expected to provide an optimal tool for the identification of tissue areas with low oxygenation, e.g., in tumors with compromised oxygen supply. Magn Reson Med, 2013.

Accelerated T2 Mapping for Characterization of Prostate Cancer

Prostate T2 mapping was performed in 34 consecutive patients using an accelerated multiecho spin‐echo sequence with 4‐fold k‐space undersampling leading to a net acceleration factor of 3.3 on a 3T scanner. The mean T2 values from the accelerated and conventional, unaccelerated sequences demonstrated a very high correlation (r = 0.99). Different prostate segments demonstrated similarly good interscan reproducibility (p = not significant) with slightly larger difference at base: 2.0% ± 1.6% for left base and 2.1% ± 1.1% for right base. In patients with subsequent targeted biopsy, T2 values of histologically proven malignant tumor areas were significantly lower than the suspicious looking but nonmalignant lesions (p < 0.05) and normal areas (p < 0.001): 100 ± 10 ms for malignant tumors, 114 ± 23 ms for suspicious lesions and 149 ± 32 ms for normal tissues. The proposed method can provide an effective approach for accelerated T2 quantification for prostate patients. Magn Reson Med, 2011.

Current limitations of molecular magnetic resonance imaging for tumors as evaluated with high-relaxivity CD105-specific iron oxide nanoparticles.

ObjectiveTumor imaging via molecular magnetic resonance imaging (MRI) that uses specific superparamagnetic iron oxide particles (SPIOs) has been addressed in the literature several times in the last 20 years. To our knowledge, none of the reported approaches is currently used for routine clinical diagnostic evaluation, nor are any in clinical development. This raises questions as to whether SPIO-enhanced molecular MRI is sensitive and specific enough for use in clinical practice. The aim of our preclinical study was to investigate the minimum requirements for obtaining sensitive molecular MRI for use in tumor evaluations under optimal conditions. The well-vascularized F9 teratocarcinoma tumor model, which exhibits high levels of the highly accessible target CD105 (endoglin), was used to compare the accumulation and visualization of target-specific SPIOs by MRI. Material and MethodsSuperparamagnetic iron oxide particles were optimized in the following ways: (a) proton relaxivity was increased for higher imaging sensitivity, (b) a coating material was used for optimal loading density of the &agr;CD105 antibody, and (c) binding activity to the target CD105 was increased. Binding activity and specificity were confirmed in vitro using enzyme-linked immunosorbent assay and in vivo using pharmacokinetic and biodistribution studies of 11 F9 teratoma–bearing mice together with micro-autoradiography. CD105 target expression was determined using immunohistochemistry and quantitative enzyme-linked immunosorbent assay. The transverse relaxation rate R2* was quantified by 3.0-T MRI in the tumors, kidneys, and muscles before and up to 60 minutes after injection in 11 mice. The use of [59Fe]-labeled SPIOs for all in vivo experiments allowed for the direct correlation of the imaging results with SPIO accumulation. ResultsHigh-relaxivity &agr;CD105-polyacrylic acid-SPIOs (r2 up to 440 L mmol−1 Fe s−1) with strong binding activity accumulated specifically in tumors (1.4% injected dose/g) and kidneys (4.1% injected dose/g) in a manner dependent on the target concentration. The accumulation occurred within the first 3 minutes after injection. Visualization of specific SPIOs was accomplished with MRI. In contrast to the successful use of MRI in all examined kidneys (mean ± SEM &Dgr;R2*, 61 ± 11 s−1), only 6 of 11 tumors (mean ± SEM &Dgr;R2*, 15 ± 7 s−1) showed a clear signal when compared with the control even though optimal conditions were used. ConclusionThe accumulation of CD105-specific SPIOs in F9 mouse teratomas was robust. However, visualization of the specifically accumulated SPIOs by MRI was not reliable because of its limited signal detection sensitivity. We postulate that it will be challenging to improve the imaging properties of targeted SPIOs further. Therefore, molecular MRI by targeted SPIOs is currently not suitable for clinical tumor imaging using routinely applicable sequences and field strength.

Tumor Blood Volume Determination by Using Susceptibility-corrected ΔR2* Multiecho MR

PURPOSE To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. MATERIALS AND METHODS All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. RESULTS For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. CONCLUSION Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.

Vessel Size Imaging (VSI) by Robust Magnetic Resonance (MR) Relaxometry: MR-VSI of Solid Tumors in Correlation with Immunohistology and Intravital Microscopy

The aim of this study was to evaluate a robust magnetic resonance (MR) vessel size imaging (VSI) method for the noninvasive assessment of mean vessel size in solid tumors in a clinical dose range of ultrasmall superparamagnetic particles of iron oxide (USPIO). Therefore, USPIO-enhanced MR-VSI was performed on DU-4475, MDA-MB-435, and EOMA tumor–bearing mice xenografts with known differences in angiogenic activity and vessel morphology. MR results were compared to vessel sizes determined by immunohistochemistry (anti-CD31) and by intravital microscopy (IVM). MR-VSI revealed significantly different mean vessel sizes between the xenograft models at both USPIO doses (DU-4475: 20.6 ± 4.9 mm; MDA-MB-435: 37.4 ± 8.8 μm; and EOMA: 60.3 ± 9.6 μm at 80 μmol/kg; p < .05). Immunohistochemistry revealed lower values for all tumor entities, whereas the size distribution was in line with MR-measurements. IVM corroborated the MR results for DU-4475 and MDA-MB435, but showed similar vessel sizes for MDA-MB-435 and EOMA. Our MR-VSI method allowed a noninvasive estimation of the mean vessel size in mice xenograft solid tumors with variable vascularity using a clinically relevant USPIO dose range.

Concurrent MR blood volume and vessel size estimation in tumors by robust and simultaneous ΔR2 and ΔR2* quantification

This work presents a novel method for concurrent estimation of the fractional blood volume and the mean vessel size of tumors based on a multi‐gradient‐echo‐multi‐spin‐echo sequence and the injection of a super‐paramagnetic blood‐pool agent. The approach further comprises a post‐processing technique for simultaneous estimation of changes in the transverse relaxation rates R2 and R  2* , which is robust against global B0 and B1 field inhomogeneities and slice imperfections. The accuracy of the simultaneous ΔR2 and ΔR  2* quantification approach is evaluated in a phantom. The simultaneous blood volume and vessel size estimates, obtained with MR, compare well to the immunohistological findings in a preclinical experiment (HT1080 cells, implanted in nude mice). Clinical translation is achieved in a patient with a pleomorphic sarcoma in the left pubic bone. The latter demonstrates the robustness of the technique against changes in the contrast agent concentration in blood during washout. Magn Reson Med, 2011.

Quantification of the magnetic resonance signal response to dynamic (C)O2‐enhanced imaging in the brain at 3 T: R*2 BOLD vs. balanced SSFP

To compare two magnetic resonance (MR) contrast mechanisms, R*2 BOLD and balanced SSFP, for the dynamic monitoring of the cerebral response to (C)O2 respiratory challenges.

Analysing the response in R2* relaxation rate of intracranial tumours to hyperoxic and hypercapnic respiratory challenges: initial results.

ObjectiveTo investigate the response in R2* relaxation rate of human intracranial tumours during hyperoxic and hypercapnic respiratory challenges.MethodsIn seven patients with different intracranial tumours, cerebral R2* changes during carbogen and CO2/air inhalation were monitored at 3 T using a dynamic multigradient-echo sequence of high temporal and spatial resolution. The R2* time series of each voxel was tested for significant change. Regions of interest were analysed with respect to response amplitude and velocity.ResultsThe tumours showed heterogeneous R2* responses with large interindividual variability. In the ‘contrast-enhancing’ area of five patients and in the ‘non-tumoral’ tissue most voxels showed a decrease in R2* for carbogen. For the ‘contrast-enhancing’ area of two patients hardly any responses were found. In areas of ‘necrosis’ and perifocal ‘oedema’ typically voxels with R2* increase and no response were found for both gases. For tissue responding to CO2/air, the R2* changes were of the same order of magnitude as those for carbogen. The response kinetic was generally attenuated in tumoral tissue.ConclusionThe spatially resolved determination of R2* changes reveals the individual heterogeneous response characteristic of intracranial human tumours during hyperoxic and hypercapnic respiratory challenges.

Changes in the MR relaxation rate R2* induced by respiratory challenges at 3.0 T: a comparison of two quantification methods

The consistent determination of changes in the transverse relaxation rate R2* (ΔR2*) is essential for the mapping of the effect of hyperoxic and hypercapnic respiratory challenges, which enables the noninvasive assessment of blood oxygenation changes and vasoreactivity by MRI. The purpose of this study was to compare the performance of two different methods of ΔR2* quantification from dynamic multigradient‐echo data: (A) subtraction of R2* values calculated from monoexponential decay functions; and (B) computation of ΔR2* echo‐wise from signal intensity ratios. A group of healthy volunteers (n = 12) was investigated at 3.0 T, and the brain tissue response to carbogen and CO2–air inhalation was registered using a dynamic multigradient‐echo sequence with high temporal and spatial resolution. Results of the ΔR2* quantification obtained by the two methods were compared with respect to the quality of the voxel‐wise ΔR2* response, the number of responding voxels and the behaviour of the ‘global’ response of all voxels with significant R2* changes. For the two ΔR2* quantification methods, we found no differences in the temporal variation of the voxel‐wise ΔR2* responses or in the detection sensitivity. The maximum change in the ‘global’ response was slightly smaller when ΔR2* was derived from signal intensity ratios. In conclusion, this first methodological comparison shows that both ΔR2* quantifications, from monoexponential approximation as well as from signal intensity ratios, are applicable for the monitoring of R2* changes during respiratory challenges. Copyright

Intracranial tumor response to respiratory challenges at 3.0 T: Impact of different methods to quantify changes in the MR relaxation rate R2*

To compare two ΔR2* quantification methods for analyzing the response of intracranial tumors to different breathing gases. The determination of changes in the magnetic resonance imaging (MRI) relaxation rate R2* (ΔR2*), induced by hyperoxic and hypercapnic respiratory challenges, enables the noninvasive assessment of blood oxygenation changes and vasoreactivity.