Stephan Metz

Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG.

The expression of αvβ3 and glucose metabolism are upregulated in many malignant lesions, and both are known to correlate with an aggressive phenotype. We evaluated whether assessment of αvβ3 expression and of glucose metabolism with PET using 18F-galacto-RGD and 18F-FDG provides complementary information in cancer patients. Methods: Eighteen patients with primary or metastatic cancer (non–small cell lung cancer [NSCLC], n = 10; renal cell carcinoma, n = 2; rectal cancer, n = 2; others, n = 4) were examined with PET using 18F-galacto-RGD and 18F-FDG. Standardized uptake values (SUVs) were derived by volume-of-interest analysis. 18F-Galacto-RGD and 18F-FDG PET results were compared using linear regression analysis for all lesions (n = 59; NSCLC, n = 39) and for primaries (n = 14) and metastases to bone (n = 11), liver (n = 10), and other organs (n = 24) separately. Results: The sensitivity of 18F-galacto-RGD PET compared with clinical staging was 76%. SUVs for 18F-FDG ranged from 1.3 to 23.2 (mean ± SD, 7.6 ± 4.9) and were significantly higher than SUVs for 18F-galacto-RGD (range, 0.3–6.8; mean ± SD, 2.7 ± 1.5; P < 0.001). There was no significant correlation between the SUVs for 18F-FDG and 18F-galacto-RGD for all lesions (r = 0.157; P = 0.235) or for primaries, osseous or soft-tissue metastases separately (P > 0.05). For the subgroup of lesions in NSCLC, there was a weak correlation between 18F-FDG and 18F-galacto-RGD uptake (r = 0.353; P = 0.028). Conclusion: Tracer uptake of 18F-galacto-RGD and 18F-FDG does not correlate closely in malignant lesions. Whereas 18F-FDG PET is more sensitive for tumor staging, 18F-galacto-RGD PET warrants further evaluation for planning and response evaluation of targeted molecular therapies with antiangiogenic or αvβ3-targeted drugs.

PET/CT Imaging of Integrin αvβ3 Expression in Human Carotid Atherosclerosis

OBJECTIVES The goal of this study was to evaluate the feasibility of [(18)F]Galacto-RGD positron emission tomography (PET)/computed tomography (CT) imaging of αvβ3 expression in human carotid plaques. BACKGROUND The integrin αvβ3 is expressed by macrophages and angiogenic endothelial cells in atherosclerotic lesions and thus is a marker of plaque inflammation and, potentially, of plaque vulnerability. [(18)F]Galacto-RGD is a PET tracer binding specifically to αvβ3. Therefore, [(18)F]Galacto-RGD PET/CT imaging of αvβ3 expression in human carotid plaques might provide a novel noninvasive biomarker of plaque vulnerability. METHODS [(18)F]Galacto-RGD PET/CT imaging was performed in 10 patients with high-grade carotid artery stenosis scheduled for carotid endarterectomy. Tracer uptake was measured in the stenotic areas of the carotid arteries, as well as on the contralateral side, and was corrected for blood pool activity, measured in the distal common carotid artery (target-to-background [TB] ratio). TB ratio was correlated with immunohistochemistry of αvβ3 expression (LM609), macrophage density (CD68), and microvessel density (CD31) of the surgical specimen. In addition, ex vivo autoradiography of the surgical specimen with [(18)F]Galacto-RGD and competition experiments with an unlabeled αvβ3-specific RGD peptide were performed. RESULTS [(18)F]Galacto-RGD PET/CT showed significantly higher TB ratios in stenotic areas compared with nonstenotic areas (p = 0.01). TB ratios correlated significantly with αvβ3 expression (R = 0.787, p = 0.026) and intensity of ex vivo autoradiography (R = 0.733, p = 0.038). Binding to atherosclerotic plaques was efficiently blocked in ex vivo competition experiments. A weak-to-moderate correlation was found with macrophage density (R = 0.367, p = 0.299) and microvessel density (R = 0.479, p = 0.176), which did not reach statistical significance. CONCLUSIONS [(18)F]Galacto-RGD PET/CT shows specific tracer accumulation in human atherosclerotic carotid plaques, which correlates with αvβ3 expression. Based on these initial data, larger prospective studies are now warranted to evaluate the potential of molecular imaging of αvβ3 expression for assessment of plaque inflammation in patients.

Whole‐body MRI including diffusion‐weighted imaging (DWI) for patients with recurring prostate cancer: Technical feasibility and assessment of lesion conspicuity in DWI

To evaluate the principal methodological aspects of whole‐body magnetic resonance imaging (MRI) including diffusion‐weighted imaging (DWI) with background suppression using a time‐optimized protocol for restaging of prostate cancer patients in a technical feasibility study.

Detection and quantification of breast tumor necrosis with MR imaging: Value of the necrosis-avid contrast agent Gadophrin-3

RATIONALE AND OBJECTIVES The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

Phenotyping of tumor biology in patients by multimodality multiparametric imaging: relationship of microcirculation, alphavbeta3 expression, and glucose metabolism.

Both dynamic contrast-enhanced (DCE) MRI and PET provide quantitative information on tumor biology in living organisms. However, imaging biomarkers often neglect tissue heterogeneity by focusing on distributional summary statistics. We analyzed the spatial relationship of αvβ3 expression, glucose metabolism, and perfusion by PET and DCE MRI, focusing on tumor heterogeneity. Methods: Thirteen patients with primary or metastasized cancer (non–small cell lung cancer, n = 9; others, n = 4) were examined with DCE MRI and with PET using 18F-galacto-RGD and 18F-FDG. Twenty-three different regions of interest were defined by cluster analysis based on the heterogeneity of tracer uptake. In these regions, the initial area under the gadopentetate dimeglumine concentration–time curve (IAUGC), as well as the regional blood volume (rBV) and regional blood flow (rBF), were estimated from DCE MRI and correlated with standardized uptake values from PET. Results: Regions with simultaneously high uptake of 18F-galacto-RGD and 18F-FDG showed higher functional MRI data (IAUGC, 0.35 ± 0.04 mM·s; rBF, 70.2 ± 12.7 mL/min/100 g; rBV, 23.3 ± 2.7 mL/100 g) than did areas with low uptake of both tracers (IAUGC, 0.15 ± 0.04 mM·s [P < 0.01]; rBF, 28.3 ± 10.8 mL/min/100 g; rBV, 9.9 ± 1.9 mL/100 g [P < 0.01]). There was a weak to moderate correlation between the functional MRI parameters and 18F-galacto-RGD (r = 0.30–0.62) and also 18F-FDG (r = 0.44–0.52); these correlations were significant (P < 0.05), except for 18F-galacto-RGD versus rBF (P = 0.17). Conclusion: These data show that multiparametric assessment of tumor heterogeneity is feasible by combining PET and MRI. Perfusion is highest in tumor areas with simultaneously high αvβ3 expression and high glucose metabolism and restricted in areas with both low αvβ3 expression and low glucose metabolism. The current limitations resulting from imaging with separate scanners might be overcome by future hybrid PET/MRI scanners.

Multispectral Optoacoustic Tomography (MSOT) of Human Breast Cancer

Purpose: In a pilot study, we introduce fast handheld multispectral optoacoustic tomography (MSOT) of the breast at 28 wavelengths, aiming to identify high-resolution optoacoustic (photoacoustic) patterns of breast cancer and noncancerous breast tissue. Experimental Design: We imaged 10 female patients ages 48–81 years with malignant nonspecific breast cancer or invasive lobular carcinoma. Three healthy volunteers ages 31–36 years were also imaged. Fast-MSOT was based on unique single-frame-per-pulse (SFPP) image acquisition employed to improve the accuracy of spectral differentiation over using a small number of wavelengths. Breast tissue was illuminated at the 700–970 nm spectral range over 0.56 seconds total scan time. MSOT data were guided by ultrasonography and X-ray mammography or MRI. Results: The extended spectral range allowed the computation of oxygenated hemoglobin (HBO2), deoxygenated hemoglobin (HB), total blood volume (TBV), lipid, and water contributions, allowing first insights into in vivo high-resolution breast tissue MSOT cancer patterns. TBV and Hb/HBO2 images resolved marked differences between cancer and control tissue, manifested as a vessel-rich tumor periphery with highly heterogeneous spatial appearance compared with healthy tissue. We observe significant TBV variations between different tumors and between tumors over healthy tissues. Water and fat lipid layers appear disrupted in cancer versus healthy tissue; however, offer weaker contrast compared with TBV images. Conclusions: In contrast to optical methods, MSOT resolves physiologic cancer features with high resolution and revealed patterns not offered by other radiologic modalities. The new features relate to personalized and precision medicine potential. Clin Cancer Res; 23(22); 6912–22. ©2017 AACR.

Cholesterol diet and effect of long-term withdrawal on plaque development and composition in the thoracic aorta of New Zealand White rabbits

AIMS Experimental study on plaque progression, regression and composition in atherosclerotic thoracic aorta of hypercholesterolemic rabbits after long-term withdrawal of cholesterol-enriched diet (CED). METHODS Rabbits were fed 2% cholesterol for 6 weeks followed by withdrawal periods for 15, 23, 34, 68, or 78 weeks. Cholesterol, triglyceride, and phospholipids levels in blood and cholesterol concentrations in aorta were quantified. Plaque size and cellularity, phenotype of macrophages and smooth muscle cells were (immuno)histomorphometrically analyzed in segments of the thoracic aorta. RESULTS After 6 weeks of CED, blood cholesterol levels were about 80-fold higher, whereas atherosclerosis and cholesterol content in the thoracic aorta were only minimally increased. However, the latter significantly increased within 15 weeks after cholesterol withdrawal, while serum cholesterol level was still 10-fold increased. Thereafter plaque area and cholesterol content remained almost unchanged until the end of the study despite a long-term normalization of serum cholesterol level after withdrawal of CED. Directly after 6 weeks of CED the densities of macrophages and apoptotic cells within plaques were highest, decreasing after cholesterol withdrawal, whereas, vice versa the density of smooth muscle cells (SMCs) significantly increased. CONCLUSION We suggest that atherosclerotic plaques respond to long-term withdrawal of CED by decrease in number and phenotype of macrophages and increase of SMCs without regression of the lesion size. The cellular changes are suggested to considerably contribute to higher plaque stability.

Multiparametric MR and PET Imaging of Intratumoral Biological Heterogeneity in Patients with Metastatic Lung Cancer Using Voxel-by-Voxel Analysis

Objectives Diffusion-weighted magnetic resonance imaging (DW-MRI) and imaging of glucose metabolism by positron emission tomography (FDG-PET) provide quantitative information on tissue characteristics. Combining the two methods might provide novel insights into tumor heterogeneity and biology. Here, we present a solution to analyze and visualize the relationship between the apparent diffusion coefficient (ADC) and glucose metabolism on a spatially resolved voxel-by-voxel basis using dedicated quantitative software. Materials and Methods In 12 patients with non small cell lung cancer (NSCLC), the primary tumor or metastases were examined with DW-MRI and PET using 18F-fluorodeoxyglucose (FDG). The ADC’s from DW-MRI were correlated with standardized-uptake-values on a voxel-by-voxel basis using custom made software (Anima M3P). For cluster analysis, we used prospectively defined thresholds for 18F-FDG and ADC to define tumor areas of different biological activity. Results Combined analysis and visualization of ADC maps and PET data was feasible in all patients. Spatial analysis showed relatively homogeneous ADC values over the entire tumor area, whereas FDG showed a decreasing uptake towards the tumor center. As expected, restricted water diffusivity was notable in areas with high glucose metabolism but was also found in areas with lower glucose metabolism. In detail, 72% of all voxels showed low ADC values (<1.5x10-3 mm2/s) and high tracer uptake of 18F-FDG (SUV>3.6). However, 83% of the voxels with low FDG uptake also showed low ADC values, increasingly towards the tumor center. Conclusions Multiparametric analysis and visualization of DW-MRI and FDG-PET is feasible on a spatially resolved voxel-by-voxel respectively cluster basis using dedicated imaging software. Our preliminary data suggest that water diffusivity and glucose metabolism in metastatic NSCLC are not necessarily correlated in all tumor areas.

Comparison of different radiography systems in an experimental study for detection of forearm fractures and evaluation of the Müller-AO and Frykman classification for distal radius fractures

Objectives:We sought to compare the diagnostic performance of screen-film radiography, storage-phosphor radiography, and a flat-panel detector system in detecting forearm fractures and to classify distal radius fractures according to the Müller-AO and Frykman classifications compared with the true extent, depicted by anatomic preparation. Materials and Methods:A total of 71 cadaver arms were fractured in a material testing machine creating different fractures of the radius and ulna as well as of the carpal bones. Radiographs of the complete forearm were evaluated by 3 radiologists, and anatomic preparation was used as standard of reference in a receiver operating curve analysis. Results:The highest diagnostic performance was obtained for the detection of distal radius fractures with area under the receiver operating curve (AUC) values of 0.959 for screen-film radiography, 0.966 for storage-phosphor radiography, and 0.971 for the flat-panel detector system (P > 0.05). Exact classification was slightly better for the Frykman (kappa values of 0.457–0.478) compared with the Müller-AO classification (kappa values of 0.404–0.447), but agreement can be considered as moderate for both classifications. Conclusions:The 3 imaging systems showed a comparable diagnostic performance in detecting forearm fractures. A high diagnostic performance was demonstrated for distal radius fractures and conventional radiography can be routinely performed for fracture detection. However, compared with anatomic preparation, depiction of the true extent of distal radius fractures was limited and the severity of distal radius fractures tends to be underestimated.