Moritz Palmowski
Publications
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2.65Impact points
Multiphase CT scanning and different intravenous contrast media concentrations in combined F-18-FDG PET/CT: Effect on quantitative and clinical assessment.
European journal of radiology. 05/2012;
PURPOSE: To evaluate the influence of multiphase CT scanning and different intravenous contrast media on contrast enhancement, attenuation correction and image quality in combined PET/CT. MATERIAL AND METHODS: 140 patients were prospectively enrolled for F-18-FDG-PET/CT including a low-dose unenhanc... [more] PURPOSE: To evaluate the influence of multiphase CT scanning and different intravenous contrast media on contrast enhancement, attenuation correction and image quality in combined PET/CT. MATERIAL AND METHODS: 140 patients were prospectively enrolled for F-18-FDG-PET/CT including a low-dose unenhanced, arterial and venous contrast enhanced CT. The first (second) 70 patients, received contrast medium with 370 (300) mg iodine/ml. The iodine delivery rate (1.3mg/s) and total iodine load (44.4g) were identical for both groups. Contrast enhancement and maximum and mean standardized FDG uptake values (SUVmax and SUVmean) were determined for the un-enhanced, arterial and venous PET/CT at multiple anatomic sites and PET reconstructions were visually evaluated. RESULTS: Arterial contrast enhancement was significantly higher for the 300mg/ml contrast medium compared to 370mgI/ml at all anatomic sites. Venous enhancement was not different between the two contrast media. SUVmean and SUVmax were significantly higher for the contrast enhanced compared to the non-enhanced PET/CT at all anatomic sites (all P<0.001). Tracer uptake was significantly higher in the arterial than in the venous PET/CT in the arteries using both contrast media (all P<0.001). No differences in tracer uptake were found between the contrast media (all P>0.05). Visual assessment revealed no relevant differences between the different PET reconstructions. CONCLUSIONS: There is no relevant qualitative influence on the PET scan from the use of different intravenous contrast media in its various phases in combined multiphase PET/CT. For quantitative analysis of tracer uptake it is required to use an identical PET/CT protocol.
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6.42Impact points
MRI-Based Attenuation Correction for Hybrid PET/MRI Systems: A 4-Class Tissue Segmentation Technique Using a Combined Ultrashort-Echo-Time/Dixon MRI Sequence.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 04/2012;
Accurate γ-photon attenuation correction (AC) is essential for quantitative PET/MRI as there is no simple relation between MR image intensity and attenuation coefficients. Attenuation maps (μ-maps) can be derived by segmenting MR images and assigning attenuation coefficients to the compartments. Ult... [more] Accurate γ-photon attenuation correction (AC) is essential for quantitative PET/MRI as there is no simple relation between MR image intensity and attenuation coefficients. Attenuation maps (μ-maps) can be derived by segmenting MR images and assigning attenuation coefficients to the compartments. Ultrashort-echo-time (UTE) sequences have been used to separate cortical bone and air, and the Dixon technique has enabled differentiation between soft and adipose tissues. Unfortunately, sequential application of these sequences is time-consuming and complicates image registration. METHODS: A UTE triple-echo (UTILE) MRI sequence is proposed, combining UTE sampling for bone detection and gradient echoes for Dixon water-fat separation in a radial 3-dimensional acquisition (repetition time, 4.1 ms; echo times, 0.09/1.09/2.09 ms; field strength, 3 T). Air masks are derived mainly from the phase information of the first echo; cortical bone is segmented using a dual-echo technique. Soft-tissue and adipose-tissue decomposition is achieved using a 3-point Dixon-like decomposition. Predefined linear attenuation coefficients are assigned to classified voxels to generate MRI-based μ-maps. The results of 6 patients are obtained by comparing μ-maps, reciprocal sensitivity maps, reconstructed PET images, and brain region PET activities based on either CT AC, two 3-class MRI AC techniques, or the proposed 4-class UTILE AC. RESULTS: Using the UTILE MRI sequence, an acquisition time of 214 s was achieved for the head-and-neck region with 1.75-mm isotropic resolution, compared with 164 s for a single-echo UTE scan. MRI-based reciprocal sensitivity maps show a high correlation with those derived from CT scans (R(2) = 0.9920). The same is true for PET activities (R(2) = 0.9958). An overall voxel classification accuracy (compared with CT) of 81.1% was reached. Bone segmentation is inaccurate in complex regions such as the paranasal sinuses, but brain region activities in 48 regions across 6 patients show a high correlation after MRI-based and CT-based correction (R(2) = 0.9956), with a regression line slope of 0.960. All overall correlations are higher and brain region PET activities more accurate in terms of mean and maximum deviations for the 4-class technique than for 3-class techniques. CONCLUSION: The UTILE MRI sequence enables the generation of MRI-based 4-class μ-maps without anatomic priors, yielding results more similar to CT-based results than can be obtained with 3-class segmentation only.
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3.59Impact points
Development and validation of an intrinsic landmark-based gating protocol applicable for functional and molecular ultrasound imaging.
European radiology. 03/2012;
OBJECTIVES: To implement a retrospective intrinsic landmark-based (ILB) gating protocol for contrast-enhanced ultrasound (CEUS) and to compare its efficiency to non-gated, manually gated and extrinsically gated CEUS. METHODS: CEUS of the liver was performed in healthy mice (n = 5) and in NEMO knocko... [more] OBJECTIVES: To implement a retrospective intrinsic landmark-based (ILB) gating protocol for contrast-enhanced ultrasound (CEUS) and to compare its efficiency to non-gated, manually gated and extrinsically gated CEUS. METHODS: CEUS of the liver was performed in healthy mice (n = 5) and in NEMO knockout mice with dysplastic livers (n = 5). In healthy animals, first-pass kinetics of non-specific microbubbles was recorded. Knockout mice were analysed regarding retention of VEGFR2-specific microbubbles. For retrospective gating, a landmark which showed respiratory movement was encircled as a region of interest (ROI). During inspiration, the signal intensity within the ROI altered, which served as gating signal. To evaluate the accuracy, non-gated, extrinsically gated and ILB-gated time-intensity curves were created. For each curve, descriptive parameters were calculated and compared to the gold standard (manual frame-by-frame gating). RESULTS: No significant differences in the variation of ILB- and extrinsically gated time-intensity curves from the gold standard were observed. Non-gated data showed significantly higher variations. Also the variation of molecular ultrasound data was significantly lower for ILB-gated compared to non-gated data. CONCLUSION: ILB gating is a robust and easy method to improve data accuracy in functional and molecular ultrasound liver imaging. This technique can presumably be translated to contrast-enhanced ultrasound examinations in humans. KEY POINTS : • Quantitative analysis of the uptake of contrast agents during ultrasound is complex. • Intrinsic landmark-based gating (ILB) offers a simple implementable method for motion correction. • Results using ILB-gating are comparable to extrinsic gating using external biomonitoring devices. • Functional and molecular imaging of mobile organs will benefit from ILB gating.
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4.41Impact points
Targeted ultrasound imaging of cancer: an emerging technology on its way to clinics.
Current pharmaceutical design. 01/2012; 18(15):2184-99.
Ultrasound is one of the workhorses in clinical cancer diagnosis. In particular, it is routinely used to characterize lesions in liver, urogenital tract, head and neck and soft tissues. During the last years image quality steadily improved, which, among others, can be attributed to the development o... [more] Ultrasound is one of the workhorses in clinical cancer diagnosis. In particular, it is routinely used to characterize lesions in liver, urogenital tract, head and neck and soft tissues. During the last years image quality steadily improved, which, among others, can be attributed to the development of harmonic image analysis. Microbubbles were introduced as intravascular contrast agents and can be detected with superb sensitivity and specificity using contrast specific imaging modes. By aid of these unspecific contrast agents tissues can be characterised regarding their vascularity. Antibodies, peptides and other targeting moieties were bound to microbubbles to target sites of angiogenesis and inflammation intending to get more disease-specific information. Indeed, many preclinical studies proved the high potential of targeted ultrasound imaging to better characterize tumors and to more sensitively monitor therapy response. Recently, first targeted microbubbles had been developed that meet the pharmacological demands of a clinical contrast agent. This review articles gives an overview on the history and current status of targeted ultrasound imaging of cancer. Different imaging concepts and contrast agent designs are introduced ranging from the use of experimental nanodroplets to agents undergoing clinical evaluation. Although it is clear that targeted ultrasound imaging works reliably, its broad acceptance is hindered by the user dependency of ultrasound imaging in general. Automated 3D-scanning techniques-like being used for breast diagnosis - and novel 3D transducers will help to make this fascinating method clinical reality.
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3.40Impact points
Imaging in the age of molecular medicine: Monitoring of anti-angiogenic treatments.
Current pharmaceutical biotechnology. 01/2012;
Angiogenesis is a complex multistep process and a crucial pre-requisite for tumor growth, invasion and metastasis. A profound knowledge of the mechanisms including the elucidation of markers for angiogenic vessels is essential for the generation of new anti-angiogenic chemotherapeutic agents and the... [more] Angiogenesis is a complex multistep process and a crucial pre-requisite for tumor growth, invasion and metastasis. A profound knowledge of the mechanisms including the elucidation of markers for angiogenic vessels is essential for the generation of new anti-angiogenic chemotherapeutic agents and the improvement of specific imaging techniques. During the last decades, numerous angiogenesis inhibitors have been developed and some of them have shown promising results in preclinical and clinical trials. However, the response to anti-angiogenic treatment is often delayed and shows high inter-individual variations. In order to improve anti-angiogenic therapy, new specific surrogate markers are necessary that allow the characterization of different angiogenic steps, especially at the early stage. In this respect, non-invasive imaging is a potent tool for characterizing the tumor vascularization and for sensitive and longitudinal treatment monitoring. In particular, new molecular imaging techniques might ultimately improve the characterization of the angiogenic tumor phenotype and stage. This review summarizes the current status of different imaging modalities e.g. MRI, CT, US, nuclear and optical imaging with respect to the imaging of tumor angiogenesis and of anti-angiogenic treatments. It also includes new approaches in molecular imaging, which give deep insight into the tumor stage and the response of tumor vessels to anti-angiogenic therapy. Thus, this may lead to a more personalized cancer therapy in future.
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2.65Impact points
Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment.
European journal of radiology. 11/2011;
PURPOSE: To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles. MATERIALS AND METHODS: Antiangiogenic therapy effe... [more] PURPOSE: To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles. MATERIALS AND METHODS: Antiangiogenic therapy effects (SU11248) on vascularity of subcutaneous epidermoid-carcinoma xenografts (A431) in female CD1 nude mice were investigated longitudinally using non-enhanced and contrast-enhanced 3D Doppler at 25MHz. Additionally, contrast-enhanced 2D and 3D B-mode scans were performed by injecting hard-shell (poly-butyl-cyanoacrylate-based) and soft-shell (phospholipid-based) microbubbles. Suitability of both contrast agents for high frequency imaging and the sensitivity of the different ultrasound methods to assess early antiangiogenic therapy effects were investigated. Ultrasound data were validated by immunohistology. RESULTS: Hard-shell microbubbles induced higher signal intensity changes in tumors than soft-shell microbubbles in 2D B-mode measurements (424±7 vs. 169±8A.U.; p<0.01). In 3D measurements, signals of soft-shell microbubbles were hardly above the background (5.48±4.57 vs. 3.86±2.92A.U.), while signals from hard-shell microbubbles were sufficiently high (30.5±8.06A.U). Using hard-shell microbubbles 2D and 3D B-mode imaging depicted a significant decrease in tumor vascularity during antiangiogenic therapy from day 1 on. Using soft-shell microbubbles significant therapy effects were observed at day 4 after therapy in 2D B-mode imaging but could not be detected in the 3D mode. With non-enhanced and contrast-enhanced Doppler imaging significant differences between treated and untreated tumors were found from day 2 on. CONCLUSION: Hard-shell microbubble-enhanced 2D and 3D B-mode ultrasound achieved highest sensitivity for assessing therapy effects on tumor vascularisation and were superior to B-mode ultrasound with soft-shell microbubbles and to Doppler imaging.
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6.34Impact points
Virtual elastic sphere processing enables reproducible quantification of vessel stenosis at CT and MR angiography.
Radiology. 09/2011; 260(3):709-17.
To develop and evaluate a user-friendly tool to enable efficient, accurate, and reproducible quantification of blood vessel stenosis in computed tomographic (CT) and magnetic resonance (MR) angiographic data sets. All clinical experiments were approved by the institutional review board, and informed... [more] To develop and evaluate a user-friendly tool to enable efficient, accurate, and reproducible quantification of blood vessel stenosis in computed tomographic (CT) and magnetic resonance (MR) angiographic data sets. All clinical experiments were approved by the institutional review board, and informed patient consent was acquired. Animal experiments were approved by the governmental review committee on animal care. A virtual elastic sphere passes through a blood vessel specified by user-provided start and end points, and the adapting diameter over the course of the vessel is recorded. The program was tested in phantoms to determine the accuracy of diameter estimation, and it was applied in micro-CT data sets of mice with induced vessel stenosis. Dual-energy CT angiography and MR angiography were performed in 16 patients with carotid artery stenosis, and reproducibility and required reader time of this automated technique were compared with manual measurements. Additionally, the effect of dual-energy CT-based discrimination between iodine- and calcium-based enhancement was investigated. Differences between carotid artery diameters of mice and between automated and manual measurement durations were assessed with a paired t test. Reproducibility of stenosis scores was evaluated with the Fisher z test. Phantom diameters were determined with an average error of 0.094 mm. Diameters of normal and injured carotid arteries of mice were significantly different (P < .01). For patient data, automated interreader variability was significantly (P < .01) lower than manual intra- and interreader variability, while time efficiency was improved (P < .01). The virtual elastic sphere tool is applicable to CT, dual-energy CT, and MR angiography, and it improves reproducibility and efficiency over that achieved with manual stenosis measurements.
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3.59Impact points
Molecular and functional ultrasound imaging in differently aggressive breast cancer xenografts using two novel ultrasound contrast agents (BR55 and BR38).
European radiology. 05/2011; 21(9):1988-95.
To characterise clinically translatable long-circulating (BR38) and VEGFR2-targeted (BR55) microbubbles (MB) and to assess their ability to discriminate breast cancer models with different aggressiveness. The circulation characteristics of BR38 and BR55 were investigated in healthy mice. The relativ... [more] To characterise clinically translatable long-circulating (BR38) and VEGFR2-targeted (BR55) microbubbles (MB) and to assess their ability to discriminate breast cancer models with different aggressiveness. The circulation characteristics of BR38 and BR55 were investigated in healthy mice. The relative blood volume (rBV) of MDA-MB-231 (n = 5) or MCF-7 (n = 6) tumours was determined using BR38. In the same tumours in-vivo binding specificity of BR55 was tested and VEGFR2 expression assessed. Data validation included quantitative immunohistological analysis. BR38 had a longer blood half-life than BR55 (>600 s vs. 218 s). BR38-enhanced ultrasound showed greater vascularisation in MDA-MB-231 tumours (p = 0.022), which was in line with immunohistology (p = 0.033). In-vivo competitive binding experiments proved the specificity of BR55 to VEGFR2 (p = 0.027). Binding of BR55 was significantly higher in MDA-MB-231 than in MCF-7 tumours (p = 0.049), which corresponded with the VEGFR2 levels found histologically (p = 0.015). However, differences became smaller when normalising the levels of BR55 to the rBV. BR38 and BR55 are well suited to characterising and distinguishing breast cancers with different angiogenesis and aggressiveness. Long-circulating BR38 MB allow extensive 3-dimensional examinations of larger or several organs. BR55 accumulation faithfully reflects the VEGFR2 status in tumours and depicts even small differences in angiogenesis.
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Application of molecular ultrasound for imaging integrin expression.
Theranostics. 01/2011; 1:127-34.
Stabilized microbubbles with a size between 1-5 µm are used as ultrasound contrast agents in the clinical routine. They have shown convincing results for the vascular characterization of tissues as well as in echocardiography. Due to their size, microbubbles strictly remain intravascular where they ... [more] Stabilized microbubbles with a size between 1-5 µm are used as ultrasound contrast agents in the clinical routine. They have shown convincing results for the vascular characterization of tissues as well as in echocardiography. Due to their size, microbubbles strictly remain intravascular where they can be detected with high sensitivity and specificity. This qualifies them for intravascular molecular imaging. Many studies have been published reporting on the successful use of microbubbles conjugated to specific ligands for target identification in vivo. Among them, there are several promising examples on how to use molecular ultrasound for the imaging of integrin expression. This review provides an overview on the composition of ultrasound contrast agents that can be used for molecular imaging and their detection by ultrasound using destructive and non destructive methods. Furthermore, concrete examples are given on the use of molecular ultrasound to characterize integrin expression on vessels. These cover oncological applications where integrin targeted microbubbles were used to identify and characterize tumor angiogenesis and to assess tumor response to antiangiogenic drugs as well as to radiotherapy. In addition, increased accumulation of integrin targeted microbubbles was found during vascular reformation in ischemic tissues as well as in vulnerable atherosclerotic plaques. In summary, there is clear evidence from preclinical studies that integrin targeted ultrasound imaging is a valuable tool for the characterization of a broad spectrum of diseases. Thus, more efforts should be put into translating this promising technology into the clinics.
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Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects.
EJNMMI research. 01/2011; 1(1):26.
ABSTRACT: Molecular apoptosis imaging is frequently discussed to be useful for monitoring cancer therapy. We demonstrate that the sole assessment of therapy effects by apoptosis imaging can be misleading, depending on the therapy effect on the tumor vasculature. Apoptosis was investigated by determi... [more] ABSTRACT: Molecular apoptosis imaging is frequently discussed to be useful for monitoring cancer therapy. We demonstrate that the sole assessment of therapy effects by apoptosis imaging can be misleading, depending on the therapy effect on the tumor vasculature. Apoptosis was investigated by determining the uptake of Annexin Vivo by optical imaging (study part I) and of 99 mTc-6-hydrazinonicotinic [HYNIC]-radiolabeled Annexin V by gamma counting (study part II) in subcutaneous epidermoid carcinoma xenografts (A431) in nude mice after antiangiogenic treatment (SU11248). Optical imaging was performed by optical tomography (3D) and 2D reflectance imaging (control, n = 7; therapy, n = 6). Accumulation of the radioactive tracer was determined ex vivo (control, n = 5; therapy, n = 6). Tumor vascularization was investigated with an optical blood pool marker (study part I) and contrast-enhanced ultrasound (both studies). Data were validated by immunohistology. A significantly higher apoptosis rate was detected in treated tumors by immunohistological terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining (area fraction: control, 0.023 ± 0.015%; therapy, 0.387 ± 0.105%; P < 0.001). However, both 2D reflectance imaging using Annexin Vivo (control, 13 ± 15 FI/cm2; therapy, 11 ± 7 FI/cm2) and gamma counting using 99 mTc-HYNIC-Annexin V (tumor-to-muscle ratio control, 5.66 ± 1.46; therapy, 6.09 ± 1.40) failed in showing higher accumulation in treated tumors. Optical tomography even indicated higher probe accumulation in controls (control, 81.3 ± 73.7 pmol/cm3; therapy, 27.5 ± 34.7 pmol/cm3). Vascularization was strongly reduced after therapy, demonstrated by contrast-enhanced ultrasound, optical imaging, and immunohistology. The failure of annexin-based apoptosis assessment in vivo can be explained by the significant breakdown of the vasculature after therapy, resulting in reduced probe/tracer delivery. This favors annexin-based apoptosis imaging only in therapies that do not severely interfere with the vasculature.
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1.43Impact points
MMP inhibition blocks fibroblast-dependent skin cancer invasion, reduces vascularization and alters VEGF-A and PDGF-BB expression.
Anticancer research. 03/2010; 30(3):703-11.
Tumor invasion requires intense interactions with stromal cells and a profound extracellular matrix remodelling by matrix metalloproteinases (MMPs). Here, we assessed the specific contribution of fibroblasts to tumor invasion, MMPs, tissue inhibitors of MMPs and angiogenesis-related cytokine express... [more] Tumor invasion requires intense interactions with stromal cells and a profound extracellular matrix remodelling by matrix metalloproteinases (MMPs). Here, we assessed the specific contribution of fibroblasts to tumor invasion, MMPs, tissue inhibitors of MMPs and angiogenesis-related cytokine expression in organotypic cultures of highly malignant HaCaT-ras A-5RT3 cells, with and without MMP inhibition. Collagen degradation, the hallmark of tumor invasion, was dependent on fibroblasts and active MMP-2. Additionally, MMP blockade down-regulated VEGF-A and up-regulated PDGF-BB. These results were paralleled in xenotransplants in vivo, demonstrating strong inhibitory effects of MMP blockade on tumor invasion and vascularization, as shown by the almost complete absence of VEGF-A and MMP-14 and by the decrease in relative blood volume. MMP blockade also increased the fraction of mature vessels, as demonstrated by an increased mean tumor vessel diameter and a higher ratio of Ng2-positive vessels. Thus, this study highlights the importance of targeting the tumor stroma to defeat cancer.
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4.02Impact points
Intrarenal artery delineation with ultra high resolution, flat panel based, volume computerized tomography: outer limits of spatial resolution.
The Journal of urology. 12/2009; 182(6):2915-9.
PURPOSE: New methods of noninvasive high resolution imaging may improve the delineation of tumor microvessels and, thus, be of significant help in surgical planning and cost-effective monitoring of novel anti-angiogenic therapy. We determined the maximum delineation of intrarenal microvessels with a... [more] PURPOSE: New methods of noninvasive high resolution imaging may improve the delineation of tumor microvessels and, thus, be of significant help in surgical planning and cost-effective monitoring of novel anti-angiogenic therapy. We determined the maximum delineation of intrarenal microvessels with a novel flat panel based volume computerized tomography system in an experimental setting. MATERIALS AND METHODS: We prospectively evaluated 13 porcine renal specimens for intrarenal vessel delineation using a prototype gantry based, flat panel, cone beam computerized tomography system. The gantry incorporates an array of a 40 x 30 cm(2) CsI amorphous silicon flat panel detector consisting of a 2,048 x 1,536 matrix. After catheterizing the renal artery with a 5Fr end hole catheter a contrast enhanced scan was performed using BaS as contrast medium at a dilution of 200 mg/ml. The diameter of all definable arterial branches was determined using a software tool based on Medical Imaging and Interaction Toolkit, allowing semi-automatic segmentation of the vessel tree. In step 1 the vessel tree is segmented by a 3-dimensional region growing algorithm. Following its medial axis the vessel tree is extracted and converted to a representation, including the diameter of the vessels. RESULTS: In each kidney an average +/- SD of 47,454 +/- 22,382 arterial branches could be delineated. The diameter of the branches was 0.029 (mean 0.032 +/- 0.0025) to 3.444 mm (mean 1.813 +/- 0.6139) with a median of 0.263 mm. Of visible intrarenal arteries 2.7% had a vessel diameter of 0.029 mm. CONCLUSIONS: Flat panel based volume computerized tomography can visualize intrarenal microvessels down to a diameter of 0.03 mm. It may improve the assessment of renal microvessel architecture in healthy patients and in those with pathological conditions.
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2.65Impact points
Comparison of conventional time-intensity curves vs. maximum intensity over time for post-processing of dynamic contrast-enhanced ultrasound.
European journal of radiology. 11/2009;
Our aim was to prospectively compare two post-processing techniques for dynamic contrast-enhanced ultrasound and to evaluate their impact for monitoring antiangiogenic therapy. Thus, mice with epidermoid carcinoma xenografts were examined during administration of polybutylcyanoacrylate-microbubbles ... [more] Our aim was to prospectively compare two post-processing techniques for dynamic contrast-enhanced ultrasound and to evaluate their impact for monitoring antiangiogenic therapy. Thus, mice with epidermoid carcinoma xenografts were examined during administration of polybutylcyanoacrylate-microbubbles using a small animal ultrasound system (40MHz). Cine loops were acquired and analyzed using time-intensity (TI) and maximum intensity over time (MIOT) curves. Influences of fast (50mul/2s) vs. slow (50mul/10s) injection of microbubbles on both types of curves were investigated. Sensitivities of both methods for assessing effects of antiangiogenic treatment (SU11248) were examined. Correlative histological analysis was performed for vessel-density. Mann-Whitney test was used for statistical analysis. Microbubble injection rates significantly influenced upslope, time-to-peak and peak enhancement of conventional TI curves (p<0.05) but had almost no impact on maximum enhancement of MIOT curves (representing relative blood volume). Additionally, maximum enhancement of MIOT curves captured antiangiogenic therapy effects more reliably and earlier (already after 1 day of therapy; p<0.05) than peak enhancement of TI curves. Immunohistochemistry validated the significantly (p<0.01) lower vessel densities in treated tumors and high correlation (R(2)=0.95) between vessel-density and maximum enhancement of MIOT curves was observed. In conclusion, MIOT is less susceptible to variations of the injection's speed. It enables to assess changes of the relative blood volume earlier and with lower standard deviations than conventional TI curves. It can easily be translated into clinical practice and thus may provide a promising tool for cancer therapy monitoring.
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Molecular ultrasound imaging of early vascular response in prostate tumors irradiated with carbon ions.
Neoplasia (New York, N.Y.). 10/2009; 11(9):856-63.
Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. Fo... [more] Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1) and of alpha(v)beta(3)-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy) was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of alpha(v)beta(3)-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of alpha(v)beta(3)-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and alpha(v)beta(3)-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.
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[Molecular imaging in oncology using targeted ultrasound contrast agents]
Praxis. 06/2009; 98(11):597-602.
Molecular imaging enables to assess disease-associated processes at the cellular and molecular level. Nuclear medicine techniques are already available in the clinical routine. Besides these techniques, intensive research has been performed in the field of ultrasound. The development of target-speci... [more] Molecular imaging enables to assess disease-associated processes at the cellular and molecular level. Nuclear medicine techniques are already available in the clinical routine. Besides these techniques, intensive research has been performed in the field of ultrasound. The development of target-specific ultrasound contrast agents in combination with modern imaging systems transformed ultrasound to a capable molecular imaging technique. It has been shown that the expression of disease-associated endothelial receptors can be assessed using targeted microbubbles, demonstrating its high value in the diagnosis of several diseases. The broad availability of suitable ultrasound systems promises a wide utilisation in the clinical routine, once clinically approved contrast agents are available. This review summarizes the basics and the current status of molecular ultrasound imaging.
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2.65Impact points
Tumor perfusion assessed by dynamic contrast-enhanced MRI correlates to the grading of renal cell carcinoma: Initial results.
European journal of radiology. 06/2009;
In this study, we investigated whether assessment of the tumor perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) enables to estimate the morphologic grading of renal cell carcinomas. A total of 21 patients with suspected renal cell cancer were examined using a Gadobutrol-en... [more] In this study, we investigated whether assessment of the tumor perfusion by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) enables to estimate the morphologic grading of renal cell carcinomas. A total of 21 patients with suspected renal cell cancer were examined using a Gadobutrol-enhanced, dynamic saturation-recovery, turbo-fast, low-angle shot sequence. Tumor perfusion and the tissue-blood ratio within the entire tumor and the most highly vascularized part of the tumor were calculated according to the model of Miles. Immediately after examination, patients underwent surgery, and the results from imaging were compared with the morphological analysis of the histologic grading. Fourteen patients had G2 tumors, and seven patients had G3 tumors. Significantly higher perfusion values (p<0.05) were obtained in G3 tumors than in G2 tumors when the entire tumor area was considered (1.59+/-0.44(ml/g/min) vs. 1.08+/-0.38(ml/g/min)) or its most highly vascularized part (2.14+/-0.89(ml/g/min) vs. 1.40+/-0.49(ml/g/min)). By contrast, the tissue-blood ratios did not differ significantly between the two groups. In conclusion, unlike tissue-blood ratio, surrogate parameters of the tumor perfusion determined by DCE MRI seem to allow an estimation of the grading of renal cell carcinoma. However, further studies with high case numbers and including patients with G1 tumors are required to evaluate the full potential and clinical impact.
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2.03Impact points
[High-Resolution Imaging of the Layers of the Gastrointestinal Wall of Pig and Human Specimens Using an Endoluminal MR Receiver Coil: Correlation to Histology.]
RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 05/2009;
PURPOSE: High-resolution MR imaging of the layers of the gastrointestinal wall to provide a foundation for tumor staging based on morphological criteria. MATERIALS AND METHODS: Over a period of 12 months, miscellaneous parts of the gastrointestinal tract of 15 human specimens and 30 porcine specimen... [more] PURPOSE: High-resolution MR imaging of the layers of the gastrointestinal wall to provide a foundation for tumor staging based on morphological criteria. MATERIALS AND METHODS: Over a period of 12 months, miscellaneous parts of the gastrointestinal tract of 15 human specimens and 30 porcine specimens were scanned using a 1.5 Tesla clinical MRI scanner combined with an endoluminal receiver coil. The sequences used were T 1-weighted opposed-phase, T 2-weighted turbo spin echo with fat saturation and fast T 2-weighted inversion recovery. The number of differentiable layers, their width and the signal intensity were documented. Then, the results were compared with histological specimens in order to link the imaged wall layers to the anatomical layers. Spearman's Rank Correlation was used to determine the soundness of the link between the images and their related histology. RESULTS: For both human and animal specimens, the MRI scanning produced 3 to 5, maximum 6 (pig), differentiable layers. The mucosa, submucosa and muscularis could be differentiated with a hyperintense, hypointense and intermediary signal, respectively. The subserosal layer displayed a hypointense signal. CONCLUSION: High-resolution MRI is able to produce differentiable images of the anatomical layers of the gastrointestinal wall in both humans and pigs. Accordingly, it is possible to use MR imaging to diagnose the extent of local tumor infiltration of the gastrointestinal wall.
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4.64Impact points
Onset and Maintenance of Angiogenesis in Biomaterials: In Vivo Assessment by Dynamic Contrast-Enhanced MRI.
Tissue engineering. Part C, Methods. 05/2009;
Objective: To describe dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a practical tool for longitudinal assessment of angiogenesis in biomaterials. Background: There is a lack of suitable methods for in vivo evaluation of the integration of biomaterials in a clinical setting. In o... [more] Objective: To describe dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a practical tool for longitudinal assessment of angiogenesis in biomaterials. Background: There is a lack of suitable methods for in vivo evaluation of the integration of biomaterials in a clinical setting. In oncology, DCE-MRI is used for the longitudinal monitoring of altered tumor angiogenesis during therapy. Thus, we investigated whether DCE-MRI enables to assess the integration of biomaterials over time. Methods: The tested material was bovine bone matrix applied in a bilateral sinus lift procedure in combination with concentrated mononuclear cells, including mesenchymal stem cells and autologous thrombin. To assess the development of new blood vessels inside the biomaterial, DCE-MRI was carried out before and 11, 25, 53, and 104 days after surgery. Perfusionparameters were calculated according to the model of Tofts. Results: Analysis of the data revealed increasing parameters for perfusion and blood supply within the transplant over time. It was possible to determine the values for each transplantation site and each point of time separately. Conclusion: DCE-MRI is appropriate to repetitively survey angiogenesis and integration of biomaterials in patients. It seems appropriate as a valuable indicator of treatment response or failure, with consecutive adaption of the therapy regime.
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2.77Impact points
Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging.
Journal of magnetic resonance imaging : JMRI. 05/2009; 29(5):1125-1133.
PURPOSE: To assess vascular remodeling in tumors during two different antiangiogenic therapies with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging and to evaluate the vessel size index (VSI) as a novel biomarker of therapy response. MATERIALS AND METHODS: In t... [more] PURPOSE: To assess vascular remodeling in tumors during two different antiangiogenic therapies with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and vessel size imaging and to evaluate the vessel size index (VSI) as a novel biomarker of therapy response. MATERIALS AND METHODS: In two independent experiments, nude mice bearing human skin squamous cell carcinoma xenografts were treated with a vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or a multitargeted tyrosine kinase inhibitor (SU11248). Changes in tumor vascularity were assessed by DCE-MRI and vessel size imaging. DCE-MRI data were analyzed applying a two-compartment model (Brix), calculating the parameters Amplitude and k(ep). RESULTS: For both experiments Amplitude decreased significantly in treated tumors while k(ep) did not change significantly. VSI showed controversial results. VSI was significantly increased in SU11248-treated A431 tumors, whereas no changes were found in bevacizumab-treated HaCaT-ras-A-5RT3 tumors. Immunohistology confirmed these results and suggest differences in the maturation of tumor vascularization as a possible explanation. CONCLUSION: DCE-MRI and vessel size imaging provide reliable and supplementing biomarkers of antiangiogenic therapy response. The results of both methods are in excellent agreement with histology. Nevertheless, our results also indicate that vascular remodeling is complex and that a uniform response cannot be expected for different tumors and therapies. J. Magn. Reson. Imaging 2009;29:1125-1133. (c) 2009 Wiley-Liss, Inc.
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4.71Impact points
Functional and molecular ultrasound imaging: concepts and contrast agents.
Current medicinal chemistry. 02/2009; 16(5):627-42.
Contrast-enhanced ultrasound has shown convincing results for monitoring vessel morphology, surrogate markers of vascularization and changes in molecular marker expression in oncological and cardiovascular diseases. Ultrasound contrast agents have the ability to increase the backscattering signal in... [more] Contrast-enhanced ultrasound has shown convincing results for monitoring vessel morphology, surrogate markers of vascularization and changes in molecular marker expression in oncological and cardiovascular diseases. Ultrasound contrast agents have the ability to increase the backscattering signal intensity of an ultrasound pulse. An interesting class of ultrasound contrast agents are gas filled microbubbles, which can be synthesized by external bubble encapsulation using sugar matrices or microspheres consisting of lipids or polymers with or without surfactant and by selecting gases with low blood solubility and diffusion coefficient such as perfluorocarbons or sulphur hexafluoride. Ultrasound contrast agents can be classified according to the rigidity of their shell. Soft-shell microbubbles are coated with a thin monolayer of surfactant molecules such as palmitic acid or phospholipids and are very sensitive to pressure changes. Hard-shell microbubbles have a rigid shell made of polymers such as polycyanoacrylate, which dramatically increases their stability. Depending on the acoustic properties of the microbubbles and on the purpose of the examination either destructive or non destructive methods are preferred for their detection. Microbubbles can be detected by destructive and non-destructive methods. Both soft- and hard-shell microbubbles coated with target-specific molecules can also be used for molecular imaging. Using target-specific approaches, the expression of several angiogenic markers such as VEGFR2, alpha(v)beta(3) Integrins, ICAM, and E-selectin has been investigated in neoplastic and vascular diseases. This article summarizes the synthesis and properties of contrast agents as well as the indications, limitations and future potential of contrast-enhanced functional and molecular ultrasound.
Following (14)
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Wolfhard Semmler
Deutsches Krebsforschungszentrum -
Kersten Peldschus
Universitätsklinikum Hamburg-Eppendorf -
Katrin Faber
Universitätsklinikum Ulm -
Soenke Bartling
German Cancer Research Center / UMC Mannheim
Topics (1)
