Explore the vast range of titles available.

Contrast-enhanced ultrasound (CEUS) is a specialized form of ultrasound (US) performed with an intravenous injection of microbubble contrast agents. It has been successfully used for a variety of applications including characterization of liver tumors. In April 2014, the American College of Radiology (ACR) convened a working group of international experts to develop ACR CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS). An initial version of CEUS LI-RADS was published in August 2016. Although the CEUS LI-RADS concept and principles for liver lesion characterization, using dynamic contrast enhancement features, are similar to those for CT or MRI, there are significant differences between CT/MRI and CEUS LI-RADS. Therefore, CEUS LI-RADS has different diagnostic features and a unique characterization algorithm. The size of a lesion, the type and degree of arterial phase enhancement, the presence of washout, and the timing and degree of washout are the major features used for categorization. This paper describes key differences between CT/MRI and CEUS, and provides a diagnostic algorithm of CEUS LI-RADS with detailed, step-by-step instructions and imaging examples of CEUS LI-RADS categories.

Key Points Drug development is a costly, time-intensive and high-risk endeavour, with only two to three approvals for novel therapeutics in new drug classes per year eventually making it to market. New strategies are required to identify promising new drug candidates early on and, likewise, to terminate those candidates that are unlikely to be successful, thus allowing a more rapid and efficient move to pivotal trials. Molecular imaging attempts to characterize and quantify biological processes at the cellular and subcellular level in intact living subjects. It exploits specific molecular probes and intrinsic tissue characteristics as the source of image contrast, providing the potential for understanding of integrative biology, earlier detection and characterization of disease, and evaluation of treatment. As most molecular imaging techniques are routine in clinical radiology departments and have counterparts in the experimental research setting, it is possible to design preclinical experiments that not only predict clinical imaging observations but also provide a mechanistic understanding of the observed biological response. Molecular imaging has the potential to have a significant impact on different phases of drug development, including target expression, compound screening and optimization, as well as Phases I to III clinical studies. Examples are detailed in the text of the article. The option of an exploratory IND (eIND) initiated by the US Food and Drug Administration enables first-in-human molecular imaging studies to be performed with reduced preclinical support as compared to that required for a full IND. Consortia such as the Alzheimer's Disease Neuroimaging Initiative, the American College of Radiology Imaging Network and the High-Risk Plaque Initiative seek to correlate a number of imaging biomarkers with the clinical manifestations of diseases and, if successful, will greatly increase the inclusion of these imaging techniques in exploratory clinical development of novel therapeutics. Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility. Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.

Contrast-enhanced ultrasound (CEUS) is a specific form of ultrasound imaging performed with intravenous administration of microbubble contrast agents. It has been extensively used for liver tumor characterization and was recently added to the American College of Radiology Liver Imaging Reporting and Data System (CEUS LI-RADS). This paper describes technical recommendations for successful liver CEUS lesion characterization, and provides imaging protocol and Lexicon of imaging findings.

Medical imaging plays an important role in the diagnosis and management of hepatocellular carcinoma (HCC). The Liver Imaging Reporting and Data System (LI-RADS) was initially created to standardize the reporting and data collection of CT and MR imaging for patients at risk for HCC. As contrast-enhanced ultrasound (CEUS) has been widely used in clinical practice, it has recently been added to the LI-RADS. While CEUS LI-RADS shares fundamental concepts with CT/MRI LI-RADS, there are key differences between the modalities reflecting dissimilarities in the underlying methods of image acquisition and types of contrast material. This review introduces a recent update of CEUS LI-RADS and explains the key differences from CT/MRI LI-RADS.

Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden. Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment. This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.

PurposeMagneto-endosymbionts (MEs) show promise as living magnetic resonance imaging (MRI) contrast agents for in vivo cell tracking. Here we characterize the biomedical imaging properties of ME contrast agents, in vitro and in vivo.ProceduresBy adapting and engineering magnetotactic bacteria to the intracellular niche, we are creating magneto-endosymbionts (MEs) that offer advantages relative to passive iron-based contrast agents (superparamagnetic iron oxides, SPIOs) for cell tracking. This work presents a biomedical imaging characterization of MEs including: MRI transverse relaxivity (r2) for MEs and ME-labeled cells (compared to a commercially available iron oxide nanoparticle); microscopic validation of labeling efficiency and subcellular locations; and in vivo imaging of a MDA-MB-231BR (231BR) human breast cancer cells in a mouse brain.ResultsAt 7T, r2 relaxivity of bare MEs was higher (250 s−1 mM−1) than that of conventional SPIO (178 s−1 mM−1). Optimized in vitro loading of MEs into 231BR cells yielded 1–4 pg iron/cell (compared to 5–10 pg iron/cell for conventional SPIO). r2 relaxivity dropped by a factor of ~3 upon loading into cells, and was on the same order of magnitude for ME-loaded cells compared to SPIO-loaded cells. In vivo, ME-labeled cells exhibited strong MR contrast, allowing as few as 100 cells to be detected in mice using an optimized 3D SPGR gradient-echo sequence.ConclusionsOur results demonstrate the potential of magneto-endosymbionts as living MR contrast agents. They have r2 relaxivity values comparable to traditional iron oxide nanoparticle contrast agents, and provide strong MR contrast when loaded into cells and implanted in tissue.

Objective To identify CT findings predictive of surgical management in non-emergency small bowel obstruction (SBO). Methods Contrast-enhanced abdominal CT of 129 patients with non-emergency SBO were evaluated for small bowel luminal diameter, wall thickness, presence of the small bowel faeces sign (intraluminal particulate matter in a dilated small bowel) and length, transition point, submucosal oedema, mesenteric stranding, ascites and degree of obstruction (low grade partial, high grade partial and complete obstruction). Medical records were reviewed for age, gender, management and history of abdominal surgery, abdominal malignancy, or SBO. Statistical analyses were performed with Stata Release 9.2. Results Degree of obstruction was the only predictor of need for surgery. Whereas 18.0% of patients with low-grade partial obstruction ( n  = 50) underwent surgery, 32.5% of patients with high-grade partial obstruction ( n  = 77) and 100% of patients with complete obstruction ( n  = 2) required surgery ( P  = 0.004). The small bowel faeces sign was inversely predictive of surgery ( P  = 0.018). Conclusion In non-emergency SBO patients with contrast-enhanced CT imaging, grade of obstruction predicts surgery, while the small bowel faeces sign inversely predicts need for surgery.

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.

Purpose In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively. Procedures Rats ( n  = 31) underwent an intramyocardial injection of cardiomyoblasts (2 × 10 6 ) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 μg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis. Results BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (≥16 days) and persistent MR signal (≥42 days). Conclusions Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.

Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.