Visual and Quantitative Evaluation of Low-Concentration Bismuth in Dual-Contrast Imaging of Iodine and Bismuth Using Clinical Photon-Counting CT.

Simultaneous dual-contrast imaging of iodine and bismuth has shown promise in prior phantom and animal studies utilizing spectral CT. However, it is noted that in previous studies, Pepto-Bismol has frequently been employed as the source of bismuth, exceeding the recommended levels for human subjects. This investigation sought to assess the feasibility of visually differentiating and precisely quantifying low-concentration bismuth using clinical dual-source photon-counting CT (PCCT) in a scenario involving both iodinated and bismuth-based contrast materials. Four bismuth samples (0.6, 1.3, 2.5, and 5.1 mg/mL) were prepared using Pepto-Bismol, alongside three iodine rods (1, 2, and 5 mg/mL), inserted into multi-energy CT phantoms with three different sizes, and scanned on a PCCT system at three tube potentials (120, 140, and Sn140 kV). A generic image-based three-material decomposition method generated iodine and bismuth maps, with mean mass concentrations and noise levels measured. The root-mean-square errors for iodine and bismuth determined the optimal tube potential. The tube potential of 140 kV demonstrated optimal quantification performance when both iodine and bismuth were considered. Distinct differentiation of iodine rods with all three concentrations and bismuth samples with mass concentrations ≥ 1.3 mg/mL was observed across all phantom sizes at the optimal kV setting.

Evaluating silicone breast implant rupture with photon-counting CT and volumetric silicone maps.

We present a case of an 81-year-old woman who presented to the emergency department with bleeding from a right breast wound. The patient had prior imaging suggestive of bilateral silicone implant rupture and a history of low tolerance for MRI scans. Ultrasound imaging in the emergency setting showed findings in the right breast suggestive of a fistula with free silicone and hematoma. A subsequent photon-counting CT scan with custom silicone-specific segmentation allowed differentiation of silicone from hematoma, provided anatomic assessment and location of the fistula, and revealed bilateral silicone-induced lymphadenopathy.

Differentiating unexpected hyperattenuating intraluminal material from gastrointestinal bleeding on contrast enhanced dual-energy CT.

We present the case of a 24-year-old woman who presented to the emergency department with mid-epigastric pain and nausea. Contrast enhanced dual-energy CT showed high iodine signal in the small bowel lumen concerning for gastrointestinal bleeding since oral contrast was not given. However, overt bleeding symptoms were absent. Further in-house analysis of the dual-energy CT data revealed the hyperattenuating intraluminal material to be oral indigestion medicine containing magnesium, aluminum, or bismuth, and not extravasated iodine.

Investigating new CT contrast agents: a phantom study exploring quantification and differentiation methods for high-Z elements using dual-energy CT.

OBJECTIVES: To develop a dual-energy CT method for differentiating and quantifying high-Z contrast elements and to evaluate the limitations based on element concentration and atomic number by using an anthropomorphic phantom study. METHODS: Mass spectrometry standards for iodine, barium, gadolinium, ytterbium, tantalum, gold, and bismuth were diluted from 10.0 to 0.3 mg/mL, placed inside 7-mL vials, and scanned with dual-energy CT using an abdominal phantom and cylindrical water-filled insert. This procedure was repeated with all seven high-Z elements at six isoattenuating values from 250 to 8 HU. Quantification accuracy was measured using a linear regression model and residual error analysis with 90% limits of agreement. The limit of detection for each element was evaluated using the limit of blank of water. Pairwise differentiation of isoattenuating vials was evaluated using AUC values and the difference in fit angles between the two elements. RESULTS: Each high-Z element had a unique concentration vector in a two-dimensional plot of Compton scattering versus photoelectric effect attenuations. Mean quantification values were within ± 0.1 mg/mL of the true values for each element with no proportional bias. Limits of detection ranged from 0.35 to 0.56 mg/mL. Pairwise differentiations were proportional to the isoattenuating HU and the angle between the linear fits with mean AUC values increasing from 0.61 to 0.98 at 8 to 250 HU, respectively. CONCLUSION: Dual-energy CT can differentiate and quantify isoattenuating high-Z elements. The high-attenuation characteristics and unique concentration vectors of ytterbium, tantalum, gold, and bismuth are well suited for new dual-energy CT contrast agents especially when simultaneously imaged with iodine, barium, or gadolinium. KEY POINTS: • Dual-energy CT can accurately quantify high-Z contrast elements and readily differentiate iodine, barium, and gadolinium from ytterbium, tantalum, gold, and bismuth. • The differentiation and quantification capabilities for high-Z contrast elements are largely unaffected by phantom size and transaxial location within the phantom. • Potential benefits of new CT contrast agents based on these high-Z elements include alternatives for patients with iodine sensitivity, high conspicuity at both 120 and 140 kVp, simultaneous imaging of two contrast agents, and reduced injection volume.

Use of Spectral Detector Computed Tomography to Improve Liver Segmentation and Volumetry.

INTRODUCTION: Liver segmentation and volumetry have traditionally been performed using computed tomography (CT) attenuation to discriminate liver from other tissues. In this project, we evaluated if spectral detector CT (SDCT) can improve liver segmentation over conventional CT on 2 segmentation methods. MATERIALS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant institutional review board-approved retrospective study, 30 contrast-enhanced SDCT scans with healthy livers were selected. The first segmentation method is based on Gaussian mixture models of the SDCT data. The second method is a convolutional neural network-based technique called U-Net. Both methods were compared against equivalent algorithms, which used conventional CT attenuation, with hand segmentation as the reference standard. Agreement to the reference standard was assessed using Dice similarity coefficient. RESULTS: Dice similarity coefficients to the reference standard are 0.93 ± 0.02 for the Gaussian mixture model method and 0.90 ± 0.04 for the CNN-based method (all 2 methods applied on SDCT). These were significantly higher compared with equivalent algorithms applied on conventional CT, with Dice coefficients of 0.90 ± 0.06 (P = 0.007) and 0.86 ± 0.06 (P < 0.001), respectively. CONCLUSION: On both liver segmentation methods tested, we demonstrated higher segmentation performance when the algorithms are applied on SDCT data compared with equivalent algorithms applied on conventional CT data.

A Technique to Identify Isoattenuating Gallstones with Dual-Layer Spectral CT: An ex Vivo Phantom Study.

Background Previously reported dual-energy CT methods for detecting noncalcified gallstones have reduced accuracy for gallstones smaller than 9 mm. Purpose To develop a dual-energy CT method for differentiating isoattenuating gallstones from bile and compare it with previously reported dual-energy CT methods by using a prospective ex vivo phantom reader study. Materials and Methods From May 2017 to May 2018, gallstones were collected from 105 patients (34 men; mean age, 51 years; age range, 18-84 years) undergoing cholecystectomy and placed inside 120-mL vials containing ox bile. The vials were placed inside a water-filled phantom and were scanned with dual-layer dual-energy CT. Thirty isoattenuating gallstones (4.3-24.7 mm in diameter) were evaluated. Conventional CT images, virtual noncontrast images, and monoenergetic images at 200 and 40 keV were created. Segmented images were created by using a two-dimensional histogram of Compton and photoelectric attenuation. Six readers evaluated the presence of isoattenuating gallstones in each image. Intra- and interreader agreement was measured by using percentage agreement, diagnostic performance was evaluated by using mean area under the receiver operating characteristic curve (AUC) estimates and pairwise comparisons, and the agreement of gallstone sizes measured at pathologic examination with those measured on segmented images was compared by using Bland-Altman analysis. Results For all gallstones, segmented images provided the highest mean intrareader (88.1%) and interreader (88.2% and 93.6%) agreements for all readers and reading sessions and the highest overall AUC (0.99; 95% confidence interval [CI]: 0.97, 1.00; adjusted P < .02 for all). For gallstones larger than 9 mm, no significant difference was found between the segmented and monoenergetic AUCs (all P > .94, adjusted P > .05 for all). For gallstones measuring 9 mm or smaller, the segmented images had the highest overall AUC (0.99; 95% CI: 0.97, 1.00; adjusted P < .01 for all). The mean difference in stone sizes was -0.6 mm, with limits of agreement from 2.6 to -3.8 mm. Conclusion Segmented images from Compton and photoelectric attenuation coefficients improve detection of isoattenuating gallstones compared with previously reported dual-energy CT methods. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Matos in this issue.

Separating High-Z Oral Contrast From Intravascular Iodine Contrast in an Animal Model Using Dual-Layer Spectral CT.

RATIONALE AND OBJECTIVES: To show that water and iodine two-material decomposition images from dual-layer dual-energy spectral X-ray computed tomography (DECT) can be used to separate intravascular iodine contrast from simultaneously administered oral tantalum, tungsten, or rhenium contrast in an animal model. MATERIALS AND METHODS: In this Institutional Animal Care and Use Committee approved study, four female Fischer rats were given simultaneous intravenous and oral X-ray computed tomography contrast. Intravenous iodine contrast was administered via tail vein injection. Oral barium, tantalum, tungsten, or rhenium contrast was administered via gavage. The animals were imaged on a dual-layer DECT system at 120 kVp. Water and iodine two-material decomposition images (water equivalent and iodine equivalent images) were used for qualitative analysis. Computer simulations were performed using a customized DECT simulator to better understand why certain high-Z elements disappear in the iodine equivalent images and what is the theoretical range of elements with this property. RESULTS: The iodine and barium contrast appeared only in the iodine equivalent images and could not be differentiated from each other. However, the tantalum, tungsten, and rhenium contrast only appeared in the water equivalent images. This allowed iodine contrast in the bowel wall to be easily segmented from tantalum, tungsten, and rhenium contrast in the bowel lumen. Simulations confirmed that certain high-Z elements will have pixel values of ≤0 mg iodine/mL in the iodine equivalent images due to a K-edge effect associated with DECT systems. CONCLUSIONS: Dual-layer DECT can separate iodine from certain high-Z elements using water equivalent and iodine equivalent images with an increased element range compared to other DECT systems. This K-edge effect could promote the development and approval of new high-Z contrast agents for DECT.

Pseudoenhancement effects on iodine quantification from dual-energy spectral CT systems: A multi-vendor phantom study regarding renal lesion characterization.

PURPOSE: To measure the effect of pseudoenhancement on spectral CT iodine quantification as a function of lesion size, lesion iodine level, background iodine level, helical versus axial scanning, and spectral CT scanner type in a phantom model. MATERIALS AND METHODS: A custom-built water-filled cylindrical phantom contained either six small vials (8 mm diameter) or six large vials (27 mm diameter) of aqueous iopamidol solutions (0, 0.5, 1.0, 2.0, 4.0 and 6.0 mg iodine/mL). The background iodine concentration was 0, 5, or 10 mg iodine/mL. Helical and axial scans were taken on three different dual-energy spectral CT scanners (two image-based and one projection-based) with the scan parameters consistent between the systems. ROIs were used to measure the average iodine concentration of the vials in the 36 individual scans. Linear fits of the true versus measured iodine values were used for pvalue statistical analysis. Having a y-intercept or slope p-value less than 0.05 implied statistically significant iodine quantification errors. RESULTS: Iodine quantification pseudoenhancement effects are inversely proportional to lesion size and lesion enhancement and are directly proportional to background attenuation level. No significant differences between helical and axial scans were observed. 100% and 88% of the slope and y-intercept p-values were below 0.05 for the two image-based systems, while 13% of the slope and y-intercept p-values were below 0.05 for the projection-based system. CONCLUSIONS: Pseudoenhancement can artificially increase spectral CT iodine quantification levels most notably for small low-enhancing lesions (<5.0 mg iodine/mL) surrounded by a high attenuating background (10 mg iodine/mL). In this study we found iodine quantification to be more accurate on projection-based spectral CT systems than image-based systems.

Phantom Validation of Spectral Detector Computed Tomography-Derived Virtual Monoenergetic, Virtual Noncontrast, and Iodine Quantification Images.

PURPOSE: Spectral detector computed tomography (SDCT) is a new CT technology that uses a dual-layer detector to perform energy separation. We aim to assess 3 clinical concepts using a phantom model: noise profile across the virtual monoenergetic (VME) spectrum, accuracy of iodine quantification, and virtual noncontrast (VNC) reconstructions' ability to remove iodine contribution to attenuation. METHODS: Six vials containing varying concentrations of iodinated contrast (0-6 mg/mL) diluted in water were placed in a water bath and scanned on an SDCT scanner. Virtual monoenergetic (40-200 keV at 10-keV increments), iodine-no-water, and VNC reconstructions were created. Attenuation (in Hounsfield units [HU]), VME noise at each energy level, CT-derived iodine concentration, and VNC attenuation were recorded. RESULTS: Virtual monoenergetic noise was improved at all energies compared with conventional images (conventional, 9.8-11.2; VME, 7.5-9.5). Noise profile showed a slightly higher image noise at 40 keV, but was otherwise relatively flat across the energy spectrum. On iodine-no-water reconstructions, measured varied from actual iodine concentration by ±0.1 mg/mL (SD, 0.16-0.36). Virtual noncontrast attenuation was within 5 HU of water attenuation at all iodine concentrations. CONCLUSION: Reconstructions of SDCT show lower VME image noise, accurate iodine quantification, and VNC attenuation values within 5 HU of expected in a phantom model.

Spectral detector CT-derived virtual non-contrast images: comparison of attenuation values with unenhanced CT.

PURPOSE: To assess virtual non-contrast (VNC) images obtained on a detection-based spectral detector CT scanner and determine how attenuation on VNC images derived from various phases of enhanced CT compare to those obtained from true unenhanced images. METHODS: In this HIPAA compliant, IRB approved prospective multi-institutional study, 46 patients underwent pre- and post-contrast imaging on a prototype dual-layer spectral detector CT between October 2013 and November 2015, yielding 84 unenhanced and VNC pairs (25 arterial, 39 portal venous/nephrographic, 20 urographic). Mean attenuation was measured by one of three readers in the liver, spleen, kidneys, psoas muscle, abdominal aorta, and subcutaneous fat. Equivalence testing was used to determine if the mean difference between unenhanced and VNC attenuation was less than 5, 10, or 15 HU. VNC image quality was assessed on a 5 point scale. RESULTS: Mean difference between unenhanced and VNC attenuation was <15 HU in 92.6%, <10 HU in 75.2%, and <5 HU in 44.4% of all measurements. Unenhanced and VNC attenuation were equivalent in all tissues except fat using a threshold of <10 HU difference (p < 0.05). No significant variation was seen between phases. In fat, VNC overestimated the HU relative to unenhanced images. VNC image quality was rated as excellent or good in 84% of arterial phase and 85% of nephrographic phase cases, but only 40% of urographic phase. CONCLUSION: VNC images derived from novel dual layer spectral detector CT demonstrate attenuation values similar to unenhanced images in all tissues evaluated except for subcutaneous fat. Further study is needed to determine if attenuation thresholds currently used clinically for common pathology should be adjusted, particularly for lesions containing fat.

pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent.

PURPOSE: This study explored the feasibility of using a pH responsive paramagnetic chemical exchange saturation transfer (paraCEST) agent to image the pH gradient in kidneys of healthy mice. METHODS: CEST signals were acquired on an Agilent 9.4 Tesla small animal MRI system using a steady-state gradient echo pulse sequence after a bolus injection of agent. The magnetic field inhomogeneity across each kidney was corrected using the WASSR method and pH maps were calculated by measuring the frequency of water exchange signal arising from the agent. RESULTS: Dynamic CEST studies demonstrated that the agent was readily detectable in kidneys only between 4 to 12 min postinjection. The CEST images showed a higher signal intensity in the pelvis and calyx regions and lower signal intensity in the medulla and cortex regions. The pH maps reflected tissue pH values spanning from 6.0 to 7.5 in kidneys of healthy mice. CONCLUSION: This study demonstrated that pH maps of the kidney can be imaged in vivo by measuring the pH-dependent chemical shift of a single water exchange CEST peak without prior knowledge of the agent concentration in vivo. The results demonstrate the potential of using a simple frequency-dependent paraCEST agent for mapping tissue pH in vivo. Magn Reson Med 75:2432-2441, 2016. © 2015 Wiley Periodicals, Inc.

A pH-Responsive MRI Agent that Can Be Activated Beyond the Tissue Magnetization Transfer Window.

A terbium-based complex that displays a water exchange CEST resonance well outside the normal magnetization transfer (MT) frequency range of tissues provides a direct readout of pH values by MRI. Deprotonation of the phenolic proton in this complex results in a frequency shift of 56 ppm in a bound water molecule exchange peak between pH 5 and 8. This allows direct imaging of pH without prior knowledge of the agent concentration and with essentially no interference from the tissue MT signal.

¹H MRS characterization of neurochemical profiles in orthotopic mouse models of human brain tumors.

Glioblastoma (GBM), the most common primary brain tumor, is resistant to currently available treatments. The development of mouse models of human GBM has provided a tool for studying mechanisms involved in tumor initiation and growth as well as a platform for preclinical investigation of new drugs. In this study we used (1) H MR spectroscopy to study the neurochemical profile of a human orthotopic tumor (HOT) mouse model of human GBM. The goal of this study was to evaluate differences in metabolite concentrations in the GBM HOT mice when compared with normal mouse brain in order to determine if MRS could reliably differentiate tumor from normal brain. A TE =19 ms PRESS sequence at 9.4 T was used for measuring metabolite levels in 12 GBM mice and 8 healthy mice. Levels for 12 metabolites and for lipids/macromolecules at 0.9 ppm and at 1.3 ppm were reliably detected in all mouse spectra. The tumors had significantly lower concentrations of total creatine, GABA, glutamate, total N-acetylaspartate, aspartate, lipids/macromolecules at 0.9 ppm, and lipids/macromolecules at 1.3 ppm than did the brains of normal mice. The concentrations of glycine and lactate, however, were significantly higher in tumors than in normal brain.

Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

PURPOSE: The water molecule exchange rates in a series of DyDOTA-(amide)X chelates were fine-tuned to maximize the effects of T2-exchange line broadening and improve T2 contrast. METHODS: Four DyDOTA-(amide)X chelates having a variable number of glycinate side-arms were prepared and characterized as T2-exchange agents. The nonexchanging DyTETA chelate was also used to measure the bulk water T2 reduction due solely to T2*. The total transverse relaxivity (r2tot) at 22, 37, and 52°C for each chelate was measured in vitro at 9.4 Tesla (400 MHz) by fitting plots of total T2 (-1) versus concentration. The water molecule exchange rates for each complex were measured by fitting (17)O line-width versus temperature data taken at 9.4 Tesla (54.3 MHz). RESULTS: The measured transverse relaxivities due to water molecule exchange (r2ex) and bound water lifetimes (τM) were in excellent agreement with Swift-Connick theory, with DyDOTA-(gly)3 giving the largest r2ex = 11.8 s(-1) mM(-1) at 37°C. CONCLUSION: By fine-tuning the water molecule exchange rate at 37°C, the transverse relaxivity has been increased by 2 to 30 times compared with previously studied Dy(3+)-based chelates. Polymerization or dendrimerization of the optimal chelate could yield a highly sensitive, molecule-sized T2 contrast agent for improved molecular imaging applications.

Characterization of lung cancer by amide proton transfer (APT) imaging: an in-vivo study in an orthotopic mouse model.

Amide proton transfer (APT) imaging is one of the chemical exchange saturation transfer (CEST) imaging methods which images the exchange between protons of free tissue water and the amide groups (-NH) of endogenous mobile proteins and peptides. Previous work suggested the ability of APT imaging for characterization of the tumoral grade in the brain tumor. In this study, we tested the feasibility of in-vivo APT imaging of lung tumor and investigated whether the method could differentiate the tumoral types on orthotopic tumor xenografts from two malignant lung cancer cell lines. The results revealed that APT imaging is feasible to quantify lung tumors in the moving lung. The measured APT effect was higher in the tumor which exhibited more active proliferation than the other. The present study demonstrates that APT imaging has the potential to provide a characterization test to differentiate types or grade of lung cancer noninvasively, which may eventually reduce the need invasive needle biopsy or resection for lung cancer.

Modulation of CEST images in vivo by T1 relaxation: a new approach in the design of responsive PARACEST agents.

A novel approach for the design of responsive paramagnetic chemical exchange saturation transfer (PARACEST) magnetic resonance imaging (MRI) agents has been developed where the signal is "turned on" by altering the longitudinal relaxation time (T1) of bulk water protons. To demonstrate this approach, a model Eu(DOTA-tetraamide) complex (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) containing two nitroxide free radical units was synthesized. The nitroxide groups substantially shortened the T1 of the bulk water protons which, in turn, resulted in quenching of the CEST signal. Reduction of paramagnetic nitroxide moieties to a diamagnetic species resulted in the appearance of CEST. The modulation of CEST by T1 relaxation provides a new platform for designing biologically responsive MRI agents.

Advantages of paramagnetic chemical exchange saturation transfer (CEST) complexes having slow to intermediate water exchange properties as responsive MRI agents.

Paramagnetic chemical exchange saturation transfer (PARACEST) complexes are exogenous contrast agents that have great potential to further extend the functional and molecular imaging capabilities of magnetic resonance. As a result of the presence of a central paramagnetic lanthanide ion (Ln(3+) ≠ La(3+) , Gd(3+) , Lu(3+) ) within the chelate, the resonance frequencies of exchangeable protons bound to the PARACEST agent are shifted far away from the bulk water frequency. This large chemical shift, combined with an extreme sensitivity to the chemical exchange rate, make PARACEST agents ideally suited for the reporting of significant biological metrics, such as temperature, pH and the presence of metabolites. In addition, the ability to turn PARACEST agents 'off' and 'on' using a frequency-selective saturation pulse gives them a distinct advantage over Gd(3+) -based contrast agents. A current challenge for PARACEST research is the translation of the promising in vitro results into in vivo systems. This short review article first describes the basic theory behind PARACEST contrast agents, their benefits over other contrast agents and their applications to MRI. It then describes some of the recent PARACEST research results: specifically, pH measurements using water molecule exchange rate modulation, T2 exchange contrast caused by water molecule exchange, the use of ultrashort TEs (TE < 10 µs) to overcome T2 exchange line broadening and the potential application of T2 exchange as a new contrast mechanism for MRI.

A Multi-Camera System for Bioluminescence Tomography in Preclinical Oncology Research.

Bioluminescent imaging (BLI) of cells expressing luciferase is a valuable noninvasive technique for investigating molecular events and tumor dynamics in the living animal. Current usage is often limited to planar imaging, but tomographic imaging can enhance the usefulness of this technique in quantitative biomedical studies by allowing accurate determination of tumor size and attribution of the emitted light to a specific organ or tissue. Bioluminescence tomography based on a single camera with source rotation or mirrors to provide additional views has previously been reported. We report here in vivo studies using a novel approach with multiple rotating cameras that, when combined with image reconstruction software, provides the desired representation of point source metastases and other small lesions. Comparison with MRI validated the ability to detect lung tumor colonization in mouse lung.

pCEST: Positive contrast using Chemical Exchange Saturation Transfer.

Chemical Exchange Saturation Transfer (CEST) contrast utilizes selective pre-saturation of a small pool of exchanging protons and subsequent detection of the decrease in bulk water signal. The CEST contrast is negative and requires detection of small signal change in the presence of a strong background signal. Here we develop a Positive CEST (pCEST) detection scheme utilizing the analogous nature of the CEST and off-resonance T(1)(ρ) experiments and exploring increased apparent relaxation rates in the presence of the selective pre-saturation. pCEST leads to the positive contrast, i.e., increased signal intensity as the result of the presence of the agent and RF pre-saturation. Simultaneously substantial background suppression is achieved. The contrast can be switched "ON" and "OFF", similar to the original CEST.