Pharmacokinetic Modeling of Targeted Ultrasound Contrast Agents for Quantitative Assessment of Anti-Angiogenic Therapy: a Longitudinal Case-Control Study in Colon Cancer.

PURPOSE: To evaluate quantitative and semi-quantitative ultrasound molecular imaging (USMI) for antiangiogenic therapy monitoring in human colon cancer xenografts in mice. PROCEDURES: Colon cancer was established in 17 mice by injection of LS174T (Nr = 9) or CT26 (Nn = 8) cancer cells to simulate clinical responders and non-responders, respectively. Antiangiogenic treatment (bevacizumab; Nrt = Nnt = 5) or control treatment (saline; Nrc = 4, Nnc = 3) was administered at days 0, 3, and 7. Three-dimensional USMI was performed by injection at days 0, 1, 3, 7, and 10 of microbubbles targeted to the vascular endothelial growth factor receptor 2 (VEGFR2). Microbubble binding rate (kb), estimated by first-pass binding model fitting, and semi-quantitative parameters late enhancement (LE) and differential targeted enhancement (dTE) were compared at each day to evaluate their ability to assess and predict the response to therapy. Correlation analysis with the ex-vivo immunohistological quantification of VEGFR2 expression and the percentage blood vessel area was also performed. RESULTS: Significant changes in the USMI parameters during treatment were observed only in the responders treated with bevacizumab (p-value < 0.05). Prediction of the response to therapy as early as 1 day after treatment was achieved by the quantitative parameter kb (p-value < 0.01), earlier than possible by tumor volume quantification. USMI parameters could significantly distinguish between clinical responders and non-responders (p-value << 0.01) and correlated well with the ex-vivo quantification of VEGFR2 expression and the percentage blood vessels area (p-value << 0.01). CONCLUSION: USMI (semi)quantitative parameters provide earlier assessment of the response to therapy compared to tumor volume, permit early prediction of non-responders, and correlate well with ex-vivo angiogenesis biomarkers.

Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer.

Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. © RSNA, 2016 Online supplemental material is available for this article.

Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.

Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging.

BACKGROUND: Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background. METHODS: Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology. RESULTS: Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%). CONCLUSIONS: Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.

Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent.

PURPOSE: To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin-targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. MATERIALS AND METHODS: The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin-targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 10(8) MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. RESULTS: Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 10(8) MB/kg and plateaued between a dose of 10 and a dose of 20 × 10(8) MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). CONCLUSION: Quantitative measurements of inflammation obtained by using dual-selectin-targeted US are reproducible and correlate well with the extent of inflammation at histologic examination in a porcine acute ileitis model as a next step toward clinical translation.

Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model.

PURPOSE: To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis. RESULTS: Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images. CONCLUSION: Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging.

PURPOSE: To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system. MATERIALS AND METHODS: The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis. RESULTS: MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 ± 14.6 % compared to non-treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05). CONCLUSION: Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts.

Tumor angiogenic marker expression levels during tumor growth: longitudinal assessment with molecularly targeted microbubbles and US imaging.

PURPOSE: To evaluate the use of molecularly targeted microbubbles (MBs) and ultrasonography (US) in the noninvasive assessment of the level of expression of three angiogenic markers, α(v)ß(3) integrin, endoglin, and vascular endothelial growth factor receptor (VEGFR) 2, on tumor vascular endothelial cells in vivo during tumor growth. MATERIALS AND METHODS: All procedures using laboratory animals were approved by the Institutional Administrative Panel on Laboratory Animal Care. Binding specificity of three types of targeted MBs (MB(Integrin), MB(Endoglin), MB(VEGFR2)) was tested in cell culture under flow shear stress conditions. In vivo targeted contrast material-enhanced US imaging signal using the three MB types was measured at three tumor stages (small, medium, large) in three subcutaneous cancer xenografts (breast, ovarian, pancreatic cancer) in mice (n = 54). In vivo US imaging signal was correlated with ex vivo angiogenic marker expression. Significant differences were evaluated by using the Student t, analysis of variance, Wilcoxon, and Tukey Honest Significant Difference tests. RESULTS: Cell attachment of all three MB types was significantly (P = .016) higher compared with control MBs, and this attachment could be significantly (P = .026) decreased by blocking antibodies. Angiogenic marker-expressing cells bound significantly (P = .003) more targeted MBs than negative control cells, and MB attachment significantly (P < .001) correlated with marker expression levels on cells (ρ = 0.87). In early stage breast and ovarian cancers, in vivo targeted contrast-enhanced US demonstrated significantly (P ≤ .04) higher endoglin expression than both α(v)ß(3) integrin and VEGFR2 expression, whereas in early stage pancreatic cancer, marker expressions were not significantly different (P ≥ .07). There was good correlation (ρ ≥ 0.63; P ≤ .05) between in vivo targeted contrast-enhanced US imaging signals using the three MB types and ex vivo immunoblotting results regarding expression levels of the three angiogenic markers. Immunofluorescence confirmed expression of α(v)ß(3) integrin, endoglin, and VEGFR2 on tumor vascular endothelial cells. CONCLUSION: Targeted contrast-enhanced US imaging allows noninvasive in vivo assessment of the expression levels of α(v)ß(3) integrin, endoglin, and VEGFR2, which vary during tumor growth in subcutaneous cancer xenografts.

Assessment and monitoring tumor vascularity with contrast-enhanced ultrasound maximum intensity persistence imaging.

OBJECTIVES: Contrast-enhanced ultrasound imaging is increasingly being used in the clinic for assessment of tissue vascularity. The purpose of our study was to evaluate the effect of different contrast administration parameters on the in vivo ultrasound imaging signal in tumor-bearing mice using a maximum intensity persistence (MIP) algorithm and to evaluate the reliability of in vivo MIP imaging in assessing tumor vascularity. The potential of in vivo MIP imaging for monitoring tumor vascularity during antiangiogenic cancer treatment was further evaluated. MATERIALS AND METHODS: In intraindividual experiments, varying contrast microbubble concentrations (5 × 105, 5 × 106, 5 × 107, 5 × 108 microbubbles in 100 µL saline) and contrast injection rates (0.6, 1.2, and 2.4 mL/min) in subcutaneous tumor-bearing mice were applied and their effects on in vivo contrast-enhanced ultrasound MIP imaging plateau values were obtained using a dedicated small animal ultrasound imaging system (40 MHz). Reliability of MIP ultrasound imaging was tested following 2 injections of the same microbubble concentration (5 × 107 microbubbles at 1.2 mL/min) in the same tumors. In mice with subcutaneous human colon cancer xenografts, longitudinal contrast-enhanced ultrasound MIP imaging plateau values (baseline and at 48 hours) were compared between mice with and without antiangiogenic treatment (antivascular endothelial growth factor antibody). Ex vivo CD31 immunostaining of tumor tissue was used to correlate in vivo MIP imaging plateau values with microvessel density analysis. RESULTS: In vivo MIP imaging plateau values correlated significantly (P = 0.001) with contrast microbubble doses. At 3 different injection rates of 0.6, 1.2, and 2.4 mL/min, MIP imaging plateau values did not change significantly (P = 0.61). Following 2 injections with the same microbubble dose and injection rate, MIP imaging plateau values were obtained with high reliability with an intraclass correlation coefficient of 0.82 (95% confidence interval: 0.64, 0.94). In addition, in vivo MIP imaging plateau values significantly correlated (P = 0.01; R² = 0.77) with ex vivo microvessel density analysis. Tumor volumes in treated and nontreated mice did not change significantly (P = 0.22) within 48 hours. In contrast, the change of in vivo MIP imaging plateau values from baseline to 48 hours was significantly different (P = 0.01) in treated versus nontreated mice. CONCLUSIONS: Contrast-enhanced ultrasound MIP imaging allows reliable assessment of tumor vascularity and monitoring of antiangiogenic cancer therapy in vivo, provided that a constant microbubble dose is administered.

Molecular ultrasound assessment of tumor angiogenesis.

Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications.

MR angiography with parallel acquisition for assessment of the visceral arteries: comparison with conventional MR angiography and 64-detector-row computed tomography.

The purpose of the study was to retrospectively compare three-dimensional gadolinium-enhanced magnetic resonance angiography (conventional MRA) with MRA accelerated by a parallel acquisition technique (fast MRA) for the assessment of visceral arteries, using 64-detector-row computed tomography angiography (MDCTA) as the reference standard. Eighteen patients underwent fast MRA (imaging time 17 s), conventional MRA (29 s) and MDCTA of the abdomen and pelvis. Two independent readers assessed subjective image quality and the presence of arterial stenosis. Data were analysed on per-patient and per-segment bases. Fast MRA yielded better subjective image quality in all segments compared with conventional MRA (P = 0.012 for reader 1, P = 0.055 for reader 2) because of fewer motion-induced artefacts. Sensitivity and specificity of fast MRA for the detection of arterial stenosis were 100% for both readers. Sensitivity of conventional MRA was 89% for both readers, and specificity was 100% (reader 1) and 99% (reader 2). Differences in sensitivity between the two types of MRA were not significant for either reader. Interobserver agreement for the detection of arterial stenosis was excellent for fast (kappa = 1.00) and good for conventional MRA (kappa = 0.76). Thus, subjective image quality of visceral arteries remains good on fast MRA compared with conventional MRA, and the two techniques do not differ substantially in the grading of arterial stenosis, despite the markedly reduced acquisition time of fast MRA.

Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo.

PURPOSE: To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and alpha(v)beta(3) integrin and to compare the US imaging signal obtained from dual-targeted MBs (MB(D)) with that from single-targeted MBs (MB(S)) in a murine model of tumor angiogenesis. MATERIALS AND METHODS: Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single- and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti-alpha(v)beta(3) integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G-labeled control MBs (MB(C)) and nontargeted nonlabeled MBs (MB(N)) were tested with VEGFR2-positive and alpha(v)beta(3) integrin-positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material-enhanced US by using anti-VEGFR2-targeted MBs (MB(V)), anti-alpha(v)beta(3) integrin-targeted MBs (MB(I)), MB(D), and MB(C) were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, alpha(v)beta(3) integrin, and CD31. RESULTS: Attachment of MB(D) to SVR cells (mean, 0.74 MBs per cell +/- 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 +/- 0.03), and attachment to SVR cells was higher for MB(D) than for MB(V) (mean, 0.58 +/- 0.09), MB(I) (mean, 0.42 +/- 0.21), MB(C) (mean, 0.11 +/- 0.13), and MB(N) (mean, 0.01 +/- 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MB(D) (mean, 16.7 +/- 7.2) than for MB(V) (mean, 11.3 +/- 5.7), MB(I) (mean, 7.8 +/- 5.3), MB(C) (mean, 2.8 +/- 0.9), and MB(N) (mean, 1.1 +/- 0.4). Immunofluorescence confirmed expression of VEGFR2 and alpha(v)beta(3) integrin on tumor vasculature. CONCLUSION: Dual-targeted contrast-enhanced US directed at both VEGFR2 and alpha(v)beta(3) integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/248/3/936/DC1.

Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice.

PURPOSE: To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice. MATERIALS AND METHODS: Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Lipid-shell perfluorocarbon-filled MBs, targeted to VEGFR2 via anti-VEGFR2 antibodies, were radiolabeled by conjugating the radiofluorination agent N-succinimidyl-4-[(18)F]fluorobenzoate (SFB) to the anti-VEGFR2 antibodies. These MBs were then injected intravenously into nude mice (n = 4) bearing angiosarcomas, and the whole-body biodistribution of these probes was assessed for 60 minutes by using dynamic micro-PET. Results were compared with ex vivo gamma counting (n = 6) and immunofluorescence staining (n = 6). Control studies in angiosarcoma-bearing mice were performed with injection of the radiolabeled antibodies alone (n = 3) or free SFB (n = 3). A mixed-effects regression of MB accumulation on fixed effects of time and tissue type (tumor or muscle) and random effect of animal was performed. RESULTS: VEGFR2-targeted MBs rapidly cleared from the blood circulation (50% blood clearance after approximately 3.5 minutes) and accumulated in the liver (mean, 33.4% injected dose [ID]/g +/- 13.7 [standard deviation] at 60 minutes) and spleen (mean, 9.3% ID/g +/- 6.5 at 60 minutes) on the basis of micro-PET imaging. These findings were confirmed with ex vivo gamma counting. Uptake of targeted MBs was significantly higher (P < .0001) in tumor than in adjacent skeletal muscle tissue. Immunofluorescence staining demonstrated accumulation of the targeted MBs within hepatic Kupffer cells and splenic macrophages. Biodistribution of the radiolabeled antibodies and free SFB differed from the distribution of the targeted MBs. CONCLUSION: Dynamic micro-PET allows assessment of in vivo biodistribution of VEGFR2-targeted MBs.

Assessment of aortoiliac and renal arteries: MR angiography with parallel acquisition versus conventional MR angiography and digital subtraction angiography.

PURPOSE: To prospectively compare the image quality, sensitivity, and specificity of three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography accelerated by parallel acquisition (ie, fast MR angiography) with MR angiography not accelerated by parallel acquisition (ie, conventional MR angiography) for assessment of aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the reference standard. MATERIALS AND METHODS: The study was approved by the institutional review board; informed consent was obtained from all patients. Forty consecutive patients (33 men, seven women; mean age, 63 years) suspected of having aortoiliac and renal arterial stenoses and thus examined with DSA underwent both fast (mean imaging time, 17 seconds) and conventional (mean imaging time, 29 seconds) MR angiography. The arterial tree was divided into segments for image analysis. Two readers independently evaluated all MR angiograms for image quality, presence of arterial stenosis, and renal arterial variants. Image quality, sensitivity, and specificity were analyzed on per-patient and per-segment bases for multiple comparisons (with Bonferroni correction) and for dependencies between segments (with patient as the primary sample unit). Interobserver agreement was evaluated by using kappa statistics. RESULTS: Overall, the image quality with fast MR angiography was significantly better (P=.001) than that with conventional MR angiography. At per-segment analysis, the image quality of fast MR angiograms of the distal renal artery tended to be better than that of conventional MR angiograms of these vessels. Differences in sensitivity for the detection of arterial stenosis between the two MR angiography techniques were not significant for either reader. Interobserver agreement in the detection of variant renal artery anatomy was excellent with both conventional and fast MR angiography (kappa=1.00). CONCLUSION: Fast MR angiography and conventional MR angiography do not differ significantly in terms of arterial stenosis grading or renal arterial variant detection.

Assessment of the abdominal aorta and its visceral branches by contrast-enhanced dynamic volumetric hepatic parallel magnetic resonance imaging: feasibility, reliability and accuracy.

The purpose of this study was to evaluate a new three-dimensional gradient-echo (GRE) MR sequence performed with a parallel acquisition technique to shorten breath-hold times (parallel GRE MRI) in the detection of arterial variants and stenosis of the abdominal aorta and its visceral branches. A total of 102 patients underwent dynamic parallel GRE MRI, timed to the arterial phase by a test bolus (mean breath-hold time, 17 s). For both quantitative and qualitative analysis, the abdominal aorta and its visceral branches were divided into 13 arterial segments. In a subanalysis of 55/102 patients, the accuracy of parallel GRE MRI compared to MDCT in the detection arterial variants and stenosis was calculated for two independent readers. Mean SNRs and CNRs were 47.2 and 35.6, respectively. Image quality was rated good or excellent in 1,234/1,326 segments (93%). Hepatic and renal arterial variants were identified with an accuracy of 93 and 95%, respectively (reader 1) and 98 and 100%, respectively (reader 2). Both readers detected arterial stenosis with an accuracy of 98%. Interobserver agreement was good to excellent for the detection of hepatic (kappa=0.69) and renal (kappa=0.92) variants and for the diagnosis of stenosis (kappa=0.96). Dynamic three-dimensional parallel GRE MRI is feasible and allows a reliable and accurate diagnosis of arterial variants and stenosis of the abdominal aorta and its visceral branches in a short breath-hold-time.

Prospective intraindividual comparison between respiratory-triggered balanced steady-state free precession and breath-hold gradient-echo and time-of-flight magnetic resonance imaging for assessment of portal and hepatic veins.

The purpose of this study was to compare respiratory-triggered balanced steady-state free precession (bSSFP) with breath-hold contrast-enhanced dynamic two-dimensional (2D) gradient-echo (GRE) and time-of-flight (TOF) magnetic resonance imaging (MRI) for portal and hepatic vein visualization and assessment of portal and hepatic venous variants. Sixty patients with liver disease underwent nonenhanced bSSFP and contrast-enhanced GRE, bSSFP, and TOF imaging. Contrast-to-noise ratios (CNRs) for portal and hepatic veins were measured. Two readers rated the quality of portal and hepatic vein visualization on a 5-point Likert scale. The diagnostic performance of each MRI series in the detection of portal and hepatic venous variants was assessed in 40/60 patients who also underwent contrast-enhanced multidetector-row computed tomography (MDCT). CNRs for portal and hepatic veins were highest on contrast-enhanced bSSFP images. Image quality of portal and hepatic veins was rated higher for nonenhanced bSSFP than for contrast-enhanced GRE (p<0.03) and TOF (p<0.003) and higher for contrast-enhanced than for nonenhanced bSSFP (p<0.003). Compared with MDCT, portal and hepatic venous variants were identified with an accuracy of 99% on bSSFP images, with an excellent interobserver agreement (kappa=0.97). Compared with MDCT, presence of surgically important portal and hepatic venous anatomical variants can be predicted with high accuracy on bSSFP images.

ECG-gated multi-detector row CT for assessment of mitral valve disease: initial experience.

Our objective was to evaluate applicability and image quality of contrast-enhanced, retrospectively ECG-gated multi-detector row CT (MDCT) for visualization of anatomical details of the mitral valve and its apparatus, and to determine the value of MDCT for diagnosing abnormal findings of the mitral valve. Twenty consecutive patients with mitral valve disease underwent MDCT preoperatively. Two readers assessed visibility of the mitral valve annulus, mitral valve leaflets, tendinous cords, and papillary muscles by using a four-point Likert grading scale. Abnormal mitral valve findings [thickening of the mitral valve leaflets, presence of mitral annulus calcification (MAC), and calcification of the valvular leaflets] were compared with preoperative echocardiography and intraoperative findings. Visibility of the mitral valve annulus and mitral valve leaflets was good or excellent in 15 patients (75%) and in 19 patients (95%) for papillary muscles. The MDCT yielded a 95-100% agreement compared with echocardiography and surgery with regard to the assessment of mitral valve leaflet thickening and the presence of calcifications of the mitral valve annulus or mitral valve leaflets. Intermodality agreement between MDCT and echocardiography was excellent with regard to classification of mitral valve leaflet thickness (kappa=1.00) and good regarding classification of MAC thickness (kappa=0.73). Contrast-enhanced, retrospectively ECG-gated MDCT allows good to excellent visualization of anatomical details of the mitral valve and its apparatus, and demonstrates good agreement with echocardiography and surgery in diagnosing mitral valve abnormalities.

Electrocardiographically gated multi-detector row CT for assessment of valvular morphology and calcification in aortic stenosis.

PURPOSE: To evaluate the applicability and image quality of nonenhanced and contrast material-enhanced multi-detector row computed tomography (CT) combined with retrospective electrocardiographic (ECG) gating for visualization of the aortic valve, determination of aortic valve morphology and diameter of the aortic valve annulus, and assessment of the degree of valvular calcification in patients with aortic valve stenosis, as compared with results of surgery and echocardiography. MATERIALS AND METHODS: Prior to surgical valve replacement, 25 patients with aortic valve stenosis and sinus rhythm underwent nonenhanced (n = 15) and contrast-enhanced (n = 25) retrospectively ECG-gated multi-detector row CT. Two readers working in consensus evaluated image quality and assessed valvular morphology and the degree of valvular calcification. In addition, the diameter of the aortic valve annulus was measured. Results were compared with surgical and echocardiographic findings by using the paired sign test, kappa statistics, and the method of Bland and Altman. RESULTS: The aortic valve could be visualized nearly free of motion artifacts on all multi-detector row CT images. Image quality and diagnostic confidence for classification of aortic valve morphology were significantly superior on contrast-enhanced rather than nonenhanced images (P =.004 and P =.006, respectively). Nonenhanced and contrast-enhanced CT showed good agreement with surgical findings with regard to quantification of the degree of aortic valve calcification (kappa = 0.77 and kappa = 0.74, respectively). Measurement of the diameter of the aortic valve annulus was more reliable on contrast-enhanced images. CONCLUSION: Contrast-enhanced retrospectively ECG-gated multi-detector row CT allows determination of aortic valve morphology, measurement of the diameter of the aortic valve annulus, and assessment of the degree of aortic valve calcification in patients with aortic stenosis.