In vivo prostate cancer detection and grading using restriction spectrum imaging-MRI.

BACKGROUND: Magnetic resonance imaging (MRI) is emerging as a robust, noninvasive method for detecting and characterizing prostate cancer (PCa), but limitations remain in its ability to distinguish cancerous from non-cancerous tissue. We evaluated the performance of a novel MRI technique, restriction spectrum imaging (RSI-MRI), to quantitatively detect and grade PCa compared with current standard-of-care MRI. METHODS: In a retrospective evaluation of 33 patients with biopsy-proven PCa who underwent RSI-MRI and standard MRI before radical prostatectomy, receiver-operating characteristic (ROC) curves were performed for RSI-MRI and each quantitative MRI term, with area under the ROC curve (AUC) used to compare each term's ability to differentiate between PCa and normal prostate. Spearman rank-order correlations were performed to assess each term's ability to predict PCa grade in the radical prostatectomy specimens. RESULTS: RSI-MRI demonstrated superior differentiation of PCa from normal tissue, with AUC of 0.94 and 0.85 for RSI-MRI and conventional diffusion MRI, respectively (P=0.04). RSI-MRI also demonstrated superior performance in predicting PCa aggressiveness, with Spearman rank-order correlation coefficients of 0.53 (P=0.002) and -0.42 (P=0.01) for RSI-MRI and conventional diffusion MRI, respectively, with tumor grade. CONCLUSIONS: RSI-MRI significantly improves upon current noninvasive PCa imaging and may potentially enhance its diagnosis and characterization.

Novel technique for characterizing prostate cancer utilizing MRI restriction spectrum imaging: proof of principle and initial clinical experience with extraprostatic extension.

BACKGROUND: Standard magnetic resonance imaging (MRI) of the prostate lacks sensitivity in the diagnosis and staging of prostate cancer (PCa). To improve the operating characteristics of prostate MRI in the detection and characterization of PCa, we developed a novel, enhanced MRI diffusion technique using restriction spectrum imaging (RSI-MRI). METHODS: We compared the efficacy of our novel RSI-MRI technique with standard MRI for detecting extraprostatic extension (EPE) among 28 PCa patients who underwent MRI and RSI-MRI prior to radical prostatectomy, 10 with histologically proven pT3 disease. RSI cellularity maps isolating the restricted isotropic water fraction were reconstructed based on all b-values and then standardized across the sample with z-score maps. Distortion correction of the RSI maps was performed using the alternating phase-encode technique. RESULTS: 27 patients were evaluated, excluding one patient where distortion could not be performed. Preoperative standard MRI correctly identified extraprostatic the extension in two of the nine pT3 (22%) patients, whereas RSI-MRI identified EPE in eight of nine (89%) patients. RSI-MRI correctly identified pT2 disease in the remaining 18 patients. CONCLUSIONS: In this proof of principle study, we conclude that our novel RSI-MRI technology is feasible and shows promise for substantially improving PCa imaging. Further translational studies of prostate RSI-MRI in the diagnosis and staging of PCa are indicated.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Toward absolute quantification of iron oxide nanoparticles as well as cell internalized fraction using multiparametric MRI.

Iron oxide nanoparticles (IONPs) are widely used as MR contrast agents because of their strong magnetic properties and broad range of applications. The contrast induced by IONPs typically depends on concentration, water accessibility, particle size and heterogeneity of IONP distribution within the microenvironment. Although the latter could be a tool to assess local physiological effects at the molecular level, it renders IONP quantification from relaxation measurements challenging. This study aims to quantify IONP concentration using susceptibility measurements. In addition, further analysis of relaxation data is proposed to extract quantitative information about the IONP spatial distribution. Mesenchymal stem cells were labeled with IONPs and the IONP concentration measured by mass spectroscopy. MR relaxation parameters (T(1), T(2), T(2)*) as well as magnetic susceptibility of cylindrical samples containing serial dilutions of mixtures of free and cell-internalized IONPs were measured and correlated with IONP concentration. Unlike relaxation data, magnetic susceptibility was independent of whether IONPs were free or internalized, making it an excellent candidate for IONP quantification. Using IONP concentration derived from mass spectroscopy and measured relaxation times, free and internalized IONP fractions were accurately calculated. Magnetic susceptibility was shown to be a robust technique to measure IONP concentration in this preliminary study. Novel imaging-based susceptibility mapping techniques could prove to be valuable tools to quantify IONP concentration directly by MRI, for samples of arbitrary shape. Combined with relaxation time mapping techniques, especially T(2) and T(2)*, this could be an efficient way to measure both IONP concentration and the internalized IONP fraction in vivo using MRI, to gain insight into tissue function and molecular imaging paradigms.

Optimization of iron oxide nanoparticle detection using ultrashort echo time pulse sequences: comparison of T1, T2*, and synergistic T1- T2* contrast mechanisms.

Iron oxide nanoparticles (IONPs) are used in various MRI applications as negative contrast agents. A major challenge is to distinguish regions of signal void due to IONPs from those due to low signal tissues or susceptibility artifacts. To overcome this limitation, several positive contrast strategies have been proposed. Relying on IONP T(1) shortening effects to generate positive contrast is a particularly appealing strategy because it should provide additional specificity when associated with the usual negative contrast from effective transverse relaxation time (T(2)*) effects. In this article, ultrashort echo time imaging is shown to be a powerful technique which can take full advantage of both contrast mechanisms. Methods of comparing T(1) and T(2)* contrast efficiency are described and general rules that allow optimizing IONP detection sensitivity are derived. Contrary to conventional wisdom, optimizing T(1) contrast is often a good strategy for imaging IONPs. Under certain conditions, subtraction of a later echo signal from the ultrashort echo time signal not only improves IONP specificity by providing long T(2)* background suppression but also increases detection sensitivity, as it enables a synergistic combination of usually antagonist T(1) and T(2)* contrasts. In vitro experiments support our theory, and a molecular imaging application is demonstrated using tumor-targeted IONPs in vivo.

B-mode enhancement of the liver with microbubble contrast agent: a blinded study in rabbits with VX2 tumors.

RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the accuracy of contrast material-enhanced sonography in the detection of liver lesions by using an animal model. MATERIALS AND METHODS: A total of 36 rabbits, 12 normal and 24 with one, two, or more VX2 tumors implanted percutaneously, were imaged on an Acuson 128XP/10 with a 7-MHz sector transducer by a sonographer blinded to the study assignments. The sonographer assigned rabbits to four groups (no, one, two, more than two tumors) based on the number of lesions detected before and then after the intravenous bolus injection of 0.5 mL of AF0150. S-VHS video segments or pre- and postcontrast images were separated, randomized, and evaluated by a blinded reader. Necropsy served as the gold standard. RESULTS: Classification of rabbits as normal or tumor bearing on the precontrast images produced three false-positive results and three false-negative results for the blinded sonographer and six false-positive results and two false-negative results for the blinded reader. On postcontrast images, all rabbits were correctly classified by both observers. The correlation of the classification of whether rabbits had no, one, two, or more tumors relative to the pathologic classification on precontrast images was poor to fair (K = 0.349 +/- 0.099 for the sonographer and 0.274 +/- 0.111 for the reader), whereas the postcontrast correlation was good to excellent (K = 0.924 +/- 0.099 for the sonographer and 0.809 +/- 0.076 for the reader). CONCLUSION: AF0150 markedly increased the ability of the sonographer and the blinded reader to distinguish normal from tumor-bearing animals and improved the classification of rabbits with more than one liver tumor.

A synthetic macromolecule for sentinel node detection: (99m)Tc-DTPA-mannosyl-dextran.

UNLABELLED: We report the synthesis and preliminary biologic testing of a synthetic macromolecule, (99m)Tc-diethylenetriaminepentaacetic acid (DTPA)--mannosyl-dextran, for sentinel node detection. METHODS: Synthesis started with a 2-step process that attaches a high density of amino-terminated leashes to a dextran backbone. Allyl-bromide was reacted with pharmaceutical-grade dextran to yield allyl-dextran. After diafiltration with water, filtration, and lyophilization, the product was reacted with aminoethanethiol and ammonium persulfate. The resulting amino-conjugated dextran was dialyzed, filtered, and lyophilized. The mixed anhydride method was used to attach DTPA; after dialysis, filtration, and lyophilization, 2-imino-2-methoxyethyl-1-D-mannose was used to attach the receptor substrate. The molecular diameter was measured by dynamic light scattering. Amino, mannose, and DTPA densities were measured by trinitrobenzene sulfonate assay, sulfuric acid/phenol assay, and inductively coupled plasma spectroscopy of gadolinium-DTPA-mannosyl-dextran, respectively. Receptor affinity was measured by Scatchard assay of rabbit liver. Axillary, popliteal, and iliac lymph nodes and each injection site were assayed for radioactivity at 1 and 3 h after injection of approximately 3.7 MBq (0.050 mL) (99m)Tc-DTPA-mannosyl-dextran (0.22 nmol) or filtered (99m)Tc-sulfur colloid into the foot pads. Four animals were studied at each time point. RESULTS: DTPA-mannosyl-dextran had a molecular weight of 35,800 g/mol and a molecular diameter of 7.1 nm. The final amine, mannose, and DTPA densities were 23, 55, and 8 mol per dextran. Labeling yields were in excess of 98% and stable for 6 h. Specific activities of 74 x 10(6) GBq/mol were achieved. The equilibrium dissociation constant for binding to the mannose-terminated glycoprotein receptor was 0.12 +/- 0.07 nmol/L. The popliteal extraction at both 1 h and 3 h was significantly (P < 0.05) higher for (99m)Tc-DTPA-mannosyl-dextran (90.1% +/- 10.7% and 97.7% +/- 2.0%, respectively) than for filtered (99m)Tc-sulfur colloid (78.8 +/- 6.5 and 67.4% +/- 26.8%, respectively). (99m)Tc-DTPA-mannosyl-dextran exhibited significantly faster injection site clearance than did filtered (99m)Tc-sulfur colloid. The (99m)Tc-DTPA-mannosyl-dextran percentage injected dose (%ID) for the front and rear paws was 52.6 +/- 10.5 and 52.3 +/- 8.0 at 1 h and 45.7 +/- 8.5 and 43.6 +/- 8.2 at 3 h after administration. The filtered (99m)Tc-sulfur colloid %ID for the front and rear paws was 70.4 +/- 11.0 and 66.3 +/- 15.1 at 1 h and 55.5 +/- 7.8 and 66.9 +/- 8.5 at 3 h. Lymph node accumulation of each agent at either 1 or 3 h was not significantly different. CONCLUSION: (99m)Tc-DTPA-mannosyl-dextran is a receptor-based sentinel node radiotracer that exhibits the desired properties of rapid injection site clearance and low distal node accumulation. This molecule is the first member of a new class of diagnostic agents based on a macromolecular backbone with a high density of sites for the attachment of substrates and imaging reporters.

Initial experience with contrast-enhanced sonography of the prostate.

OBJECTIVE: We investigated the usefulness of contrast-enhanced sonography to depict vascularity in the prostate and improve the detection of prostatic cancer. SUBJECTS AND METHODS: Twenty-six patients with an elevated prostate-specific antigen level (> or = 4 ng/ml) or an abnormal digital rectal examination were enrolled in a phase II study of an i.v. injected sonographic contrast agent. Continuous gray-scale, intermittent gray-scale, phase inversion gray-scale, and power Doppler sonography of the prostate were performed. Sonographic findings were correlated with sextant biopsy results. RESULTS: After the administration of contrast material, gray-scale and Doppler images revealed visible enhancement (p < 0.05). Using intermittent imaging, we found focal enhancement in two isoechoic tumors that were not visible on baseline images. No definite focal area of enhancement was identified in any patient without cancer. Contrast-enhanced images revealed transient hemorrhage in the biopsy tracts of three patients. CONCLUSION: Enhancement of the prostate can be seen on gray-scale and Doppler sonographic images after the administration of an i.v. contrast agent. Contrast-enhanced intermittent sonography of the prostate may be useful for the selective enhancement of malignant prostatic tissue.

Assessment of liver and kidney enhancement with a perfluorocarbon vapor-stabilized US contrast agent.

RATIONALE AND OBJECTIVES: The authors evaluated the time-echogenicity response of liver, kidney, and implanted VX2 tumor after injection of a microbubble contrast medium and assessed use of an avascular lesion as an internal standard. MATERIALS AND METHODS: Twenty-one New Zealand White rabbits were studied. To evaluate use of an internal standard and the dose-response relationship, nine rabbits with 7-day-old avascular liver lesions created by alcohol ablation received 0.1, 0.25, 0.5, and 1.0 mL of AF0145, a microbubble contrast agent. To evaluate tumor echogenicity, 12 rabbits implanted with VX2 tumor in the liver (six also underwent alcohol ablation) received 0.5 mL of AF0145. Videodensitometry was used to analyze echogenicity changes over 10 minutes. RESULTS: Echogenicity of the alcohol-ablated liver was not affected by contrast material administration. Liver and kidney echogenicity relative to ablation increased linearly with dose, peaking 1 minute after injection and decaying to baseline over 9 minutes. Contrast material administration defined the size and margins of VX2 lesions more clearly. In the arterial phase, the tumor rim was hyperechoic relative to surrounding liver, becoming isoechoic during the portal venous phase then hypoechoic during the late phase parenchymal phase. CONCLUSIONS: Lesions created by alcohol ablation can be used as an internal standard for quantitative analysis of adjacent tissues. AF0145 enhances perfused tissues, including vascular tumors, at gray-scale, real-time ultrasonography and enhances the liver.

Liver neoplasms: diagnostic pitfalls in cross-sectional imaging.

The appearances of most common liver neoplasms at computed tomography (CT) and magnetic resonance (MR) imaging have been established. However, there are considerable overlaps in the appearances of various pathologic entities. Certain hepatic lesions, such as hepatic hemangioma, adenoma, focal nodular hyperplasia, intrahepatic cholangiocarcinoma, metastases, hepatocellular carcinoma, regenerative nodules, adenomatous hyperplastic nodules, abscess, and hepatocellular carcinoma treated with transcatheter arterial chemoembolization, can have unusual characteristics at CT and MR imaging that may lead to misinterpretation. Dynamic helical CT and double-phase multisection dynamic MR imaging techniques may be helpful in differentiating between these entities because hemodynamics of the lesion can be evaluated by obtaining both arterial-phase and delayed-phase images. It is important for radiologists to be aware of these uncommon appearances of liver neoplasms. Familiarity with these varied CT and MR imaging features will permit a more accurate diagnosis and aid in avoidance of a false diagnosis.

Renal resistive index in experimental partial and complete ureteral obstruction.

RATIONALE AND OBJECTIVES: Recent clinical work suggests that the Doppler resistive index (RI) may be useful in distinguishing obstructive from nonobstructive hydronephrosis. We evaluated the usefulness of the RI in a rabbit model of hydronephrosis. METHODS: Unilateral partial ureteral obstruction was produced in nine rabbits and complete obstruction in another nine. Three sham operations were performed, and these animals served as control subjects. The RI was measured in all kidneys before and 6 hr after surgery and on days 1, 4, and 7 postoperatively. The RI and the difference in RI (delta RI) between the obstructed and normal kidney were evaluated over time using a two-way analysis of variance. The intravenous urography and Whitaker tests served as gold standards. RESULTS: Hydronephrosis was observed on sonograms in all obstructed kidneys. Comparing groups, there was no significant difference in mean RI or delta RI between the three groups at any time point. Looking at individual groups over time, there was no significant change in mean delta RI, whereas the change in mean RI was significantly elevated above baseline only in the complete obstruction group at 6 hr (p = .002) and on days 4 (p = .008) and 7 (p = .006). In evaluating varying thresholds of RI and delta RI, we could not consistently discriminate between normal and obstructed kidneys. CONCLUSION: Although complete obstruction caused a significant increase in RI, partial obstruction failed to do so. RI and delta RI values proved to be insensitive predictors of obstruction in this rabbit model.

MRI of pelvic neurofibromatosis.

Pelvic neurofibromatosis is a rare disease and rarely involves the prostate. A 19-year-old male presented with irritative and obstructive voiding symptoms. Magnetic resonance imaging showed a large mass extending from the sacral promontory to the perirectal and perivesical spaces and to the proximal root of the penis. The mass also involved the prostate. The characteristics of the mass were highly suggestive for neurofibroma. Prostate biopsy showed neurofibroma, and the immunohistochemistry stain for S-100 protein was positive.

Cystosarcoma phyllodes of the prostate: MRI findings.

Cystosarcoma phyllodes of the prostate is a rare, relatively benign sarcoma of the prostate. We describe the magnetic resonance imaging findings in an unusual case of cystosarcoma phyllodes which resulted in extensive local recurrence and sarcomatous degeneration. Although uncommon, radiologists should be aware of the existence of cystosarcoma phyllodes of the prostate.

Efficacy of Imagent BP at 1.5ml/kg in a rabbit liver tumor model.

We have shown using a Vx2 rabbit model that 3 and 5ml/kg of perflubron emulsion were highly effective in imaging liver tumors. The results from preliminary clinical trials suggested that should the infusion rate be increased, a 1.5ml/kg may be efficacious. This study determined whether 1.5ml/kg given as a bolus IV would be efficacious to image liver tumors using a Vx2 rabbit model. Vx2 tumors were implanted in 5 NZW rabbits, CT of the liver was performed during held expiration at 80kV and 800mAS, before and shortly after 1.5ml/kg Imagent BP (ImBP), again at 30 minutes and 3 days. Regions of interest (ROIs) were drawn over the CT image of the spleen, liver, inferior vena cava, and tumor, CT# obtained and average enhancement of each tissue calculated at each time point. 4 animals had tumors .5cm or greater. Precontrast, tumors were faintly seen on CT. Blood was brighter than liver shortly after infusion and isointense with liver at 30 minutes. Tumors did not enhance following contrast. Except for the liver and spleen, all tissues returned to baseline on the 3rd day. Therefore a clinical trial to determine the efficacy of 1.5ml/kg ImBP to image the liver is warranted.

The use of Imagent BP as a blood pool contrast agent to visualize and quantitate liver tumor burden.

The accurate quantitation of liver tumor burden and visualization of lesions in three dimensions (3D) can assist in treatment planning and can allow monitoring of therapy. Previous attempts have used CT and standard contrast media. Because the iodinated agents rapidly diffuse into tumors, usually effacing, and at time enhancing tumor edges, they decrease accuracy and make image segmentation difficult. CT portography suffers from flow related artifacts and does not allow the distinction of tumors from hemangiomas. Blood pool contrast is ideal in this setting since it enhances liver, liver vessels and hemangiomas, but not tumors, 'physiologically' splitting the image into normal and abnormal tissues. This ongoing study assesses the feasibility of this technique to visualize tumor and presents a scheme to automatically quantitate tumor volume. It utilized a rabbit VX2 liver tumor model and CT scanning shortly after the infusion of 3 ml/kg perflubron emulsion. Cut sections of the frozen carcass served as gross pathologic correlation. Images were imported onto a Sparc workstation, 3D reformatted and tumor and liver volume calculated. Histograms of pixel intensity clearly separated tumors from liver and liver from surrounding structures allowing the easy demarcation of tumor and liver margins.