Single Contrast Agent Research Articles

Novel algorithm for qualitative and quantitative material analysis by the K-edges for photon-counting computed tomography

The use of photon-counting detectors (PCD) in X-ray computed tomography (CT) allows for obtaining specific spectral information about the materials present in the studied object. This provides the capability to detect contrast agents (CAs) based on elements with high atomic numbers, which opens up significant prospects for diagnostics and preclinical trials. This work presents a criterion for the extraction of a contrast agent and the determination of its concentration based on the K-edge absorption. The criterion is built on the study of the spectral characteristics of CAs. It considers scenarios where more than two contrast agents are simultaneously used in a wide range of concentrations in the study. The experiment was conducted using a laboratory microtomographic system based on the Medipix3RX detector family. The criterion utilizes five energy thresholds for the identification of a single contrast agent. Lanthanides were used as contrast agents.

Sentinel lymph node mapping in patients with breast cancer using a photoacoustic/ultrasound dual-modality imaging system with carbon nanoparticles as the contrast agent: a pilot study.

Assessing the metastatic status of axillary lymph nodes is a common clinical practice in the staging of early breast cancers. Yet sentinel lymph nodes (SLNs) are the regional lymph nodes believed to be the first stop along the lymphatic drainage path of the metastasizing cancer cells. Compared to axillary lymph node dissection, sentinel lymph node biopsy (SLNB) helps reduce morbidity and side effects. Current SLNB methods, however, still have suboptimum properties, such as restrictions due to nuclide accessibility and a relatively low therapeutic efficacy when only a single contrast agent is used. To overcome these limitations, researchers have been motivated to develop a non-radioactive SLN mapping method to replace or supplement radionuclide mapping. We proposed and demonstrated a clinical procedure using a dual-modality photoacoustic (PA)/ultrasound (US) imaging system to locate the SLNs to offer surgical guidance. In our work, the high contrast of PA imaging and its specificity to SLNs were based on the accumulation of carbon nanoparticles (CNPs) in the SLNs. A machine-learning model was also trained and validated to distinguish stained SLNs based on single-wavelength PA images. In the pilot study, we imaged 11 patients in vivo, and the specimens from 13 patients were studied ex vivo. PA/US imaging identified stained SLNs in vivo without a single false positive (23 SLNs), yielding 100% specificity and 52.6% sensitivity based on the current PA imaging system. Our machine-learning model can automatically detect SLNs in real time. In the new procedure, single-wavelength PA/US imaging uses CNPs as the contrast agent. The new system can, with that contrast agent, noninvasively image SLNs with high specificity in real time based on the unique features of the SLNs in the PA images. Ultimately, we aim to use our systems and approach to substitute or supplement nuclide tracers for a non-radioactive, less invasive SLN mapping method in SLNB for the axillary staging of breast cancer.

Phosphotungstic acid (PTA) preferentially binds to collagen- rich regions of porcine carotid arteries and human atherosclerotic plaques observed using contrast enhanced micro-computed tomography (CE-µCT).

Background and aims: Atherosclerotic plaque rupture in the carotid artery can cause small emboli to travel to cerebral arteries, causing blockages and preventing blood flow leading to stroke. Contrast enhanced micro computed tomography (CEμCT) using a novel stain, phosphotungstic acid (PTA) can provide insights into the microstructure of the vessel wall and atherosclerotic plaque, and hence their likelihood to rupture. Furthermore, it has been suggested that collagen content and orientation can be related to mechanical integrity. This study aims to build on existing literature and establish a robust and reproducible staining and imaging technique to non-destructively quantify the collagen content within arteries and plaques as an alternative to routine histology. Methods: Porcine carotid arteries and human atherosclerotic plaques were stained with a concentration of 1% PTA staining solution and imaged using MicroCT to establish the in situ architecture of the tissue and measure collagen content. A histological assessment of the collagen content was also performed from picrosirius red (PSR) staining. Results: PTA stained arterial samples highlight the reproducibility of the PTA staining and MicroCT imaging technique used with a quantitative analysis showing a positive correlation between the collagen content measured from CEμCT and histology. Furthermore, collagen-rich areas can be clearly visualised in both the vessel wall and atherosclerotic plaque. 3D reconstruction was also performed showing that different layers of the vessel wall and various atherosclerotic plaque components can be differentiated using Hounsfield Unit (HU) values. Conclusion: The work presented here is unique as it offers a quantitative method of segmenting the vessel wall into its individual components and non-destructively quantifying the collagen content within these tissues, whilst also delivering a visual representation of the fibrous structure using a single contrast agent.

Long-Duration and Non-Invasive Photoacoustic Imaging of Multiple Anatomical Structures in a Live Mouse Using a Single Contrast Agent.

Long‐duration in vivo simultaneous imaging of multiple anatomical structures is useful for understanding physiological aspects of diseases, informative for molecular optimization in preclinical models, and has potential applications in surgical settings to improve clinical outcomes. Previous studies involving simultaneous imaging of multiple anatomical structures, for example, blood and lymphatic vessels as well as peripheral nerves and sebaceous glands, have used genetically engineered mice, which require expensive and time‐consuming methods. Here, an IgG4 isotype control antibody is labeled with a near‐infrared dye and injected into a mouse ear to enable simultaneous visualization of blood and lymphatic vessels, peripheral nerves, and sebaceous glands for up to 3 h using photoacoustic microscopy. For multiple anatomical structure imaging, peripheral nerves and sebaceous glands are imaged inside the injected dye‐labeled antibody mass while the lymphatic vessels are visualized outside the mass. The efficacy of the contrast agent to label and localize deep medial lymphatic vessels and lymph nodes using photoacoustic computed tomography is demonstrated. The capability of a single injectable contrast agent to image multiple structures for several hours will potentially improve preclinical therapeutic optimization, shorten discovery timelines, and enable clinical treatments.

Initial experience with a novel, modular, minimalistic approach for transfemoral aortic valve implantation

ObjectivesWe introduce a novel approach that involves a single arterial access and low contrast agent volume (SLIM). BackgroundTranscatheter aortic valve implantation (TAVI) is subject to an ongoing process of refinement and simplification. MethodsBetween January 2019 and November 2020, a total 888 patients with severe aortic stenosis underwent transfemoral TAVI using balloon-expandable or specific self-expanding devices. The study cohort comprised patients with attempted SLIM approach (n = 291). A matched cohort of patients who were treated in a standard fashion served as control group (n = 291). ResultsThe SLIM approach was successful in 92.4% of attempted cases. In the SLIM group, utilization of contrast agent (23 [19–37] vs. 75 [52–100] ml; p < 0.001), rates of any acute kidney injury (5.5% vs. 12.7%; p = 0.002), complications at the secondary access (0.3% vs. 3.1%; p = 0.011) and length of hospital stay (7 [5–8] vs. 7 [6–9]) days; p = 0.039) were significantly reduced. All other procedural outcomes were similar between groups. ConclusionsInitial results of this novel, minimalistic approach demonstrate its feasibility and potential beneficial effects without compromising procedural safety. Further refinement of this approach is warranted.

Contrast-enhanced mammography

Early detection is of great importance for the successful treatment of breast cancer and for a good prognosis. Contrast-enhanced mammography and especially contrast-enhanced spectral mammography (CESM) show promising initial results and are a valuable addition to currently available methods. The advantage of these methods is that imaging of both breasts can be performed in a single examination with a single contrast agent application. The accuracy of CESM is similar to that of magnetic resonance imaging (MRI), easily available at low costs, which is why this procedure is increasingly used in the diagnostic work up of breast cancer. CESM is also a good alternative to MRI if this cannot be performed due to contraindications.

Structurally symmetric near-infrared fluorophore IRDye78-protein complex enables multimodal cancer imaging.

Rationale: Most contemporary cancer therapeutic paradigms involve initial imaging as a treatment roadmap, followed by the active engagement of surgical operations. Current approved intraoperative contrast agents exemplified by indocyanine green (ICG) have a few drawbacks including the inability of pre-surgical localization. Alternative near-infrared (NIR) dyes including IRDye800cw are being explored in advanced clinical trials but often encounter low chemical yields and complex purifications owing to the asymmetric synthesis. A single contrast agent with ease of synthesis that works in multiple cancer types and simultaneously allows presurgical imaging, intraoperative deep-tissue three-dimensional visualization, and high-speed microscopic visualization of tumor margins via spatiotemporally complementary modalities would be beneficial.Methods: Due to the lack of commercial availability and the absence of detailed synthesis and characterization, we proposed a facile and scalable synthesis pathway for the symmetric NIR water-soluble heptamethine sulfoindocyanine IRDye78. The synthesis can be accomplished in four steps from commercially-available building blocks. Its symmetric resonant structure avoided asymmetric synthesis problems while still preserving the benefits of analogous IRDye800cw with commensurable optical properties. Next, we introduced a low-molecular-weight protein alpha-lactalbumin (α-LA) as the carrier that effectively modulates the hepatic clearance of IRDye78 into the preferred renal excretion pathway. We further implemented 89Zr radiolabeling onto the protein scaffold for positron emission tomography (PET). The multimodal imaging capability of the fluorophore-protein complex was validated in breast cancer and glioblastoma.Results: The scalable synthesis resulted in high chemical yields, typically 95% yield in the final step of the chloro dye. Chemical structures of intermediates and the final fluorophore were confirmed. Asymmetric IRDye78 exhibited comparable optical features as symmetric IRDye800cw. Its well-balanced quantum yield affords concurrent dual fluorescence and optoacoustic contrast without self-quenching nor concentration-dependent absorption. The NHS ester functionality modulates efficient covalent coupling to reactive side-chain amines to the protein carrier, along with desferrioxamine (DFO) for stable radiolabeling of 89Zr. The fluorophore-protein complex advantageously shifted the biodistribution and can be effectively cleared through the urinary pathway. The agent accumulates in tumors and enables triple-modal visualization in mouse xenograft models of both breast and brain cancers.Conclusion: This study described in detail a generalized strategic modulation of clearance routes towards the favorable renal clearance, via the introduction of α-LA. IRDye78 as a feasible alternative of IRDye800cw currently in clinical phases was proposed with a facile synthesis and fully characterized for the first time. This fluorophore-protein complex with stable radiolabeling should have great potential for clinical translation where it could enable an elegant workflow from preoperative planning to intraoperative deep tissue and high-resolution image-guided resection.

Synthetic generation of DSC-MRI-derived relative CBV maps from DCE MRI of brain tumors.

Perfusion MRI with gadolinium-based contrast agents is useful for diagnosis and treatment response evaluation of brain tumors. Dynamic susceptibility contrast (DSC) MRI and dynamic contrast enhanced (DCE) MRI are two gadolinium-based contrast agent perfusion imaging techniques that provide complementary information about the tumor vasculature. However, each requires a separate administration of a gadolinium-based contrast agent. The purpose of this retrospective study was to determine the feasibility of synthesizing relative cerebral blood volume (rCBV) maps, as computed from DSC MRI, from DCE MRI of brain tumors. One hundred nine brain-tumor patients underwent both DCE and DSC MRI. Relative CBV maps were computed from the DSC MRI, and blood plasma volume fraction maps were computed from the DCE MRIs. Conditional generative adversarial networks were developed to synthesize rCBV maps from the DCE MRIs. Tumor-to-white matter ratios were calculated from real rCBV, synthetic rCBV, and plasma volume fraction maps and compared using correlation analysis. Real and synthetic rCBV in white and gray matter regions were also compared. Pearson correlation analysis showed that both the tumor rCBV and tumor-to-white matter ratios in the synthetic and real rCBV maps were strongly correlated (ρ = 0.87, P < .05 and ρ = 0.86, P < .05, respectively). Tumor plasma volume fraction and real rCBV were not strongly correlated (ρ = 0.47). Bland-Altman analysis showed a mean difference between the synthetic and real rCBV tumor-to-white matter ratios of 0.20 with a 95% confidence interval of ±0.47. Realistic rCBV maps can be synthesized from DCE MRI and contain quantitative information, enabling robust brain-tumor perfusion imaging of DSC and DCE parameters with a single gadolinium-based contrast agent administration.

MRI Visualization of Whole Brain Macro- and Microvascular Remodeling in a Rat Model of Ischemic Stroke: A Pilot Study

Using superparamagnetic iron oxide nanoparticles (SPION) as a single contrast agent, we investigated dual contrast cerebrovascular magnetic resonance imaging (MRI) for simultaneously monitoring macro- and microvasculature and their association with ischemic edema status (via apparent diffusion coefficient [ADC]) in transient middle cerebral artery occlusion (tMCAO) rat models. High-resolution T1-contrast based ultra-short echo time MR angiography (UTE-MRA) visualized size remodeling of pial arteries and veins whose mutual association with cortical ischemic edema status is rarely reported. ΔR2–ΔR2*-MRI-derived vessel size index (VSI) and density indices (Q and MVD) mapped morphological changes of microvessels occurring in subcortical ischemic edema lesions. In cortical ischemic edema lesions, significantly dilated pial veins (p = 0.0051) and thinned pial arteries (p = 0.0096) of ipsilateral brains compared to those of contralateral brains were observed from UTE-MRAs. In subcortical regions, ischemic edema lesions had a significantly decreased Q and MVD values (p < 0.001), as well as increased VSI values (p < 0.001) than normal subcortical tissues in contralateral brains. This pilot study suggests that MR-based morphological vessel changes, including but not limited to venous blood vessels, are directly related to corresponding tissue edema status in ischemic stroke rat models.

Dual assessment of kidney perfusion and pH by exploiting a dynamic CEST-MRI approach in an acute kidney ischemia-reperfusion injury murine model.

Several factors can lead to acute kidney injury, but damage following ischemia and reperfusion injuries is the main risk factor and usually develops into chronic disease. MRI has often been proposed as a method with which to assess renal function. It does so by measuring the renal perfusion of an injected Gd-based contrast agent. The use of pH-responsive agents as part of the CEST (chemical exchange saturation transfer)-MRI technique has recently shown that pH homeostasis is also an important indicator of kidney functionality. However, there is still a need for methods that can provide more than one type of information following the injection of a single contrast agent for the characterization of renal function. Herein we propose, for the first time, dynamic CEST acquisition following iopamidol injection to quantify renal function by assessing both perfusion and pH homeostasis. The aim of this study is to assess renal functionality in a murine unilateral ischemia-reperfusion injury model at two time points (3 and 7 days) after acute kidney injury. The renal-perfusion estimates measured with iopamidol were compared with those obtained with a gadolinium-based agent, via a dynamic contrast enhanced (DCE)-MRI approach, to validate the proposed method. Compared with the contralateral kidneys, the clamped ones showed a significant decrease in renal perfusion, as measured using the DCE-MRI approach, which is consistent with reduced filtration capability. Dynamic CEST-MRI findings provided similar results, indicating that the clamped kidneys displayed significantly reduced renal filtration that persisted up to 7 days after the damage. In addition, CEST-MRI pH imaging showed that the clamped kidneys displayed significantly increased pH values, reflecting the disturbance to pH homeostasis. Our results demonstrate that a single CEST-MRI contrast agent can provide multiple types of information related to renal function and can discern healthy kidneys from pathological ones by combining perfusion measurements with renal pH mapping.

Decreased native renal T1 up to one week after gadobutrol administration in healthy volunteers.

BackgroundGadolinium‐based contrast agents (GBCAs) are widely used in MRI, despite safety concerns regarding deposition in brain and other organs. In animal studies gadolinium was detected for weeks after administration in the kidneys, but this has not yet been demonstrated in humans.PurposeTo find evidence for the prolonged presence of gadobutrol in the kidneys in healthy volunteers.Study TypeCombined retrospective and prospective analysis of a repeatability study.PopulationTwenty‐three healthy volunteers with normal renal function (12 women, age range 40–76 years), of whom 21 were used for analysis.Field Strength/SequenceInversion recovery‐based T1 map at 3T.AssessmentT1 maps were obtained twice with a median interval of 7 (range: 4–16) days. The T1 difference (ΔT1) between both scans was compared between the gadolinium group (n = 16, 0.05 mmol/kg gadobutrol administered after T1 mapping during both scan sessions) and the control group (n = 5, no gadobutrol). T1 maps were analyzed separately for cortex and medulla.Statistical TestsMann–Whitney U‐tests to detect differences in ΔT1 between groups and linear regression to relate time between scans and estimated glomerular filtration rate (eGFR) to ΔT1.ResultsΔT1 differed significantly between the gadolinium and control group: median ΔT1 cortex –98 vs. 7 msec (P < 0.001) and medulla –68 msec vs. 19 msec (P = 0.001), respectively. The bias corresponds to renal gadobutrol concentrations of 8 nmol/g tissue (cortex) and 4 nmol/g tissue (medulla), ie, ~2.4 μmol for both kidneys (0.05% of original dose). ΔT1 correlated in the gadolinium group with duration between acquisitions for both cortex (regression coefficient (β) 16.5 msec/day, R2 0.50, P < 0.001) and medulla (β 11.5 msec/day, R2 0.32, P < 0.001). Medullary ΔT1 correlated with eGFR (β 1.13 msec/(ml/min) R2 0.25, P = 0.008).Data ConclusionWe found evidence of delayed renal gadobutrol excretion after a single contrast agent administration in subjects with normal renal function. Even within this healthy population, elimination delay increased with decreasing kidney function. Level of Evidence: 3 Technical Efficacy: Stage 3J. Magn. Reson. Imaging 2020;52:622–631.

Development of multifunctional Overhauser-enhanced magnetic resonance imaging for concurrent in vivo mapping of tumor interstitial oxygenation, acidosis and inorganic phosphate concentration

Tumor oxygenation (pO2), acidosis (pH) and interstitial inorganic phosphate concentration (Pi) are important parameters of the malignant behavior of cancer. A noninvasive procedure that enables visualization of these parameters may provide unique information about mechanisms of tumor pathophysiology and provide clues to new treatment targets. In this research, we present a multiparametric imaging method allowing for concurrent mapping of pH, spin probe concentration, pO2, and Pi using a single contrast agent and Overhauser-enhanced magnetic resonance imaging technique. The developed approach was applied to concurrent multifunctional imaging in phantom samples and in vivo in a mouse model of breast cancer. Tumor tissues showed higher heterogeneity of the distributions of the parameters compared with normal mammary gland and demonstrated the areas of significant acidosis, hypoxia, and elevated Pi content.

The potential of photon-counting CT for quantitative contrast-enhanced imaging in radiotherapy

The aim of this study is to use a simulation environment to evaluate the potential of using photon-counting CT (PCCT) against dual-energy CT (DECT) in the context of quantitative contrast-enhanced CT for radiotherapy. An adaptation of Bayesian eigentissue decomposition by Lalonde et al (2017 Med. Phys. 44 5293–302) that incorporates the estimation of contrast agent fractions and virtual non-contrast (VNC) parameters is proposed, and its performance is validated against conventional maximum likelihood material decomposition methods for single and multiple contrast agents. PCCT and DECT are compared using two simulation frameworks: one including ideal CT numbers with image-based Gaussian noise and another defined as a virtual patient with projection-based Poisson noise and beam hardening artifacts, with both scenarios considering spectral distortion for PCCT. The modalities are compared for their accuracy in estimating four key physical parameters: (1) the contrast agent fraction, as well as VNC parameters relevant to radiotherapy such as the (2) electron density, (3) proton stopping power and (4) photon linear attenuation coefficient. Considering both simulation frameworks, a reduction of root mean square (RMS) errors with PCCT is noted for all physical parameters evaluated, with the exception of the error on the contrast agent fraction being about constant through modalities in the virtual patient. Notably, for the virtual patient, RMS errors on VNC electron density and stopping power are respectively reduced from 2.0% to 1.4% and 2.7% to 1.4% when going from DECT to PCCT with four energy bins. The increase in accuracy is comparable to the differences between contrast-enhanced and non-contrast DECT. This study suggests that in a realistic simulation environment, the overall accuracy of radiotherapy-related parameters can be increased when using PCCT with four energy bins instead of DECT. This confirms the potential of PCCT to provide robust and quantitative tissue parameters for contrast-enhanced CT required in radiotherapy applications.

Single-Irradiation Simultaneous Dual-Modal Bioimaging Using Nanostructure Scintillators as Single Contrast Agent.

The rising demand for clinical diagnosis tools has led to extensive research on multimodal bioimaging systems. Unlike single-modal detection, multimodal imaging not only can provide both function and structure information but also can address the issue of sensitivity, depth, and cost. Despite enormous efforts, conventional step-by-step procedures for obtaining multimodal imaging pose a significant constraint on their practical applications. In this work, X-rays as highly penetrating radiation is proposed as a single-irradiation resource, while lanthanide-based nanostructure scintillators are employed as the single contrast agent to attenuate and convert X-rays, achieving computer tomography (CT) and optical dual-modal imaging at the same time. In other words, CT and optical dual-modal imaging are simultaneously produced via single radiation combined with single contrast agent. The function and structure information of targeted tumors in a mouse model can be clearly provided with large penetration and high sensitivity, indicating that this strategy is a simple but promising route for multimodal imaging of molecular disease and preclinical applications.

Magnetite- and Iodine-Containing Nanoemulsion as a Dual Modal Contrast Agent for X-ray/Magnetic Resonance Imaging.

Noninvasive diagnostic by imaging combined with a contrast agent (CA) is by now the most used technique to get insight into human bodies. X-ray and magnetic resonance imaging (MRI) are widely used technologies providing complementary results. Nowadays, it seems clear that bimodal CAs could be an emerging approach to increase the patient compliance, accessing different imaging modalities with a single CA injection. Owing to versatile designs, targeting properties, and high payload capacity, nanocarriers are considered as a viable solution to reach this goal. In this study, we investigated efficient superparamagnetic iron oxide nanoparticle (SPION)-loaded iodinated nano-emulsions (NEs) as dual modal injectable CAs for X-ray imaging and MRI. The strength of this new CA lies not only in its dual modal contrasting properties and biocompatibility, but also in the simplicity of the nanoparticulate assembling: iodinated oily core was synthesized by the triiodo-benzene group grafting on vitamin E (41.7% of iodine) via esterification, and SPIONs were produced by thermal decomposition during 2, 4, and 6 h to generate SPIONs with different morphologies and magnetic properties. SPIONs with most anisotropic shape and characterized by the highest r2/ r1 ratio once encapsulated into iodinated NE were used for animal experimentation. The in vivo investigation showed an excellent contrast modification because of the presence of the selected NEs, for both imaging techniques explored, that is, MRI and X-ray imaging. This work provides the description and in vivo application of a simple and efficient nanoparticulate system capable of enhancing contrast for both preclinical imaging modalities, MRI, and computed tomography.

Effect of contrast agent dosage on longitudinal relaxation time, signal and apparent tumor volume in glioblastoma at 9.4 T

IntroductionGlioblastoma multiforme is the most frequent innate brain tumor and still yields an unfavorable prognosis of 15 months of survival after diagnosis. Animal models play an important role in the investigation of therapeutic strategies of brain tumors. Thereby, MRI is substantial to individual follow-up examination for therapeutic response. Contrast agent dosage at 1.5 and 3T MRI has been thoroughly tested, while there is hardly any data for 9.4T. Therefore, the aim of this study was to find the optimal contrast agent dosage at 9.4T for examination of T1 relaxation time and apparent tumor volume in an animal model. Material and methodsSix animals with a U-87 glioblastoma were part of this study. Scans were performed on a 9.4T MRI. The MRI protocol contained a standard T1w sequence, which was employed for tumor volumetry and signal intensity measurement after single, double and triple contrast agent dosage injections and a T2w sequence for volumetry of tumor and edema. From a T1 map, T1 relaxation times and tumor area were measured. Histologic tumor size measurements were also performed for two animals. ResultsThe mean apparent tumor volume in T1w MRI increased significantly with each additional contrast agent injection, mainly due to the increase of the hyperintense tumor rim. Volumetry based on T2w MRI resulted in a higher tumor volume than in T1w volumetry, whereas the tumor volume in T1w MRI approached the volume in T2w MRI with increasing contrast agent dosage. Histology revealed an apparent tumor volume that corresponded to the volume of the hypointense center in T1w MRI. In contrast, T1 time decrease and T1w signal increase occurred mainly in the tumor rim. ConclusionIncreasing the contrast agent dosage led to an increase in apparent tumor volume. High-dose T1 MRI, however, overestimated the tumor volume that was determined by histology. Thereby, it can be concluded that standard contrast agent dosage is sufficient to visualize the core tumor volume in T1w MRI. Measurement of tumor volume after increasing contrast agent dosage depicts tumor core and edema, which can be due to diffusion or accumulation or both. Tumor core and edema, however, can be visualized by T2w MRI without need of additional contrast agent.

An overview of nanoscale radionuclides and radiolabeled nanomaterials commonly used for nuclear molecular imaging and therapeutic functions.

Recent advances in the field of nanotechnology applications in nuclear medicine offer the promise of better diagnostic and therapeutic options. In recent years, increasing efforts have been focused on developing nanoconstructs that can be used as core platforms for attaching medical radionuclides with different strategies for the purposes of molecular imaging and targeted drug delivery. This review article presents an introduction to some commonly used nanomaterials with zero-dimensional, one-dimensional, two-dimensional, and three-dimensional structures, describes the various methods applied to radiolabeling of nanomaterials, and provides illustrative examples of application of the nanoscale radionuclides or radiolabeled nanocarriers in nuclear nanomedicine. Especially, the passive and active nanotargeting delivery of radionuclides with illustrating examples for tumor imaging and therapy was reviewed and summarized. The accurate and early diagnosis of cancer can lead to increased survival rates for different types of this disease. Although, the conventional single-modality diagnostic methods such as positron emission tomography/single photon emission computed tomography or MRI used for such purposes are powerful means; most of these are limited by sensitivity or resolution. By integrating complementary signal reporters into a single nanoparticulate contrast agent, multimodal molecular imaging can be performed as scalable images with high sensitivity, resolution, and specificity. The advent of radiolabeled nanocarriers or radioisotope-loaded nanomaterials with magnetic, plasmonic, or fluorescent properties has stimulated growing interest in the developing multimodality imaging probes. These new developments in nuclear nanomedicine are expected to introduce a paradigm shift in multimodal molecular imaging and thereby opening up an era of new diagnostic medical imaging agents. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 251-285, 2019.

Consistency of normalized cerebral blood volume values in glioblastoma using different leakage correction algorithms on dynamic susceptibility contrast magnetic resonance imaging data without and with preload

Background and purposeSeveral leakage correction algorithms for dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI)-based cerebral blood volume (CBV) measurement have been proposed, and combination with a preload of contrast agent is generally recommended. A single bolus application scheme would largely simplify and facilitate standardized clinical applications, while reducing contrast agent (CA) dose. The aim of this study was, therefore, to investigate whether appropriate leakage correction redundantizes prebolus application by comparing normalized DSC-based CBV (nCBV) measures of two consecutive CA boli. Materials and methodsTwenty-seven patients with suspected glioblastoma (WHO-grade-IV) underwent DSC-MRI during two consecutive boli of Gd-based CA. Four variants of two post-processing leakage correction techniques were compared with respect to nCBV in contrast enhancing tumor tissue. First, a reference curve approach with first pass and full integration of corrected ΔR2*(t), and second, a deconvolution-based approach using singular value decomposition (SVD) with a standard noise-dependent cutoff or Tikhonov regularization. ResultsCompared to respective uncorrected values, all leakage correction techniques increased nCBV for data acquired without prebolus, while there was no consistent trend for data acquired with prebolus. The best agreement between corrected nCBV values in contrast enhancing tumor, obtained in the same patients without and with prebolus, respectively, was obtained for the reference curve-based correction approach with either first pass or full integration. ConclusionThe reference curve-based leakage correction approach with integration-based nCBV calculation yielded a high accordance between nCBV values without and with prebolus, respectively. Thus, it appears possible to obtain valid nCBV in glioblastoma with a single CA injection.

Knee dGEMRIC at 7\xa0T: comparison against 1.5\xa0T and evaluation of T1-mapping methods

BackgrounddGEMRIC (delayed Gadolinium Enhanced Magnetic Resonance Image of Cartilage) is a well-established technique for cartilage quality assessment in osteoarthritis at clinical field strengths. The method is robust, but requires injection of contrast agent and a cumbersome examination procedure. New non-contrast-agent-based techniques for cartilage quality assessment are currently being developed at 7 T. However, dGEMRIC remains an important reference technique during this development. The aim of this work was to compare T1 mapping for dGEMRIC at 7 T and 1.5 T, and to evaluate three T1-mapping methods at 7 T.MethodsThe knee of 10 healthy volunteers and 9 patients with early signs of cartilage degradation were examined at 1.5 T and 7 T after a single (one) contrast agent injection (Gd-(DTPA)2−). Inversion recovery (IR) sequences were acquired at both field strengths, and at 7 T variable flip angle (VFA) and Look-Locker (LL) sequences were additionally acquired. T1 maps were calculated and average T1 values were estimated within superficial and deep regions-of-interest (ROIs) in the lateral and medial condyles, respectively.ResultsT1 values were 1.8 (1.4–2.3) times longer at 7 T. A strong correlation was detected between 1.5 T and 7 T T1 values (r = 0.80). For IR, an additional inversion time was required to avoid underestimation (bias±limits of agreement − 127 ± 234 ms) due to the longer T1 values at 7 T. Out of the two 3D sequences tested, LL resulted in more accurate and precise T1 estimation compared to VFA (average bias±limits of agreement LL: 12 ± 202 ms compared to VFA: 25 ± 622 ms). For both, B1 correction improved agreement to IR.ConclusionWith an adapted sampling scheme, dGEMRIC T1 mapping is feasible at 7 T and correlates well to 1.5 T. If 3D is to be used for T1 mapping of the knee at 7 T, LL is preferred and VFA is not recommended. For VFA and LL, B1 correction is necessary for accurate T1 estimation.

Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF): A Platform for Simultaneous Quantification of Multiple MRI Contrast Agents

Injectable Magnetic Resonance Imaging (MRI) contrast agents have been widely used to provide critical assessments of disease for both clinical and basic science imaging research studies. The scope of available MRI contrast agents has expanded over the years with the emergence of molecular imaging contrast agents specifically targeted to biological markers. Unfortunately, synergistic application of more than a single molecular contrast agent has been limited by MRI’s ability to only dynamically measure a single agent at a time. In this study, a new Dual Contrast - Magnetic Resonance Fingerprinting (DC – MRF) methodology is described that can detect and independently quantify the local concentration of multiple MRI contrast agents following simultaneous administration. This “multi-color” MRI methodology provides the opportunity to monitor multiple molecular species simultaneously and provides a practical, quantitative imaging framework for the eventual clinical translation of molecular imaging contrast agents.