Detection of colorectal metastases in patients being treated with chemotherapy utilising SPIO-MRI: a radiological–pathological study

Objective

Chemotherapy commonly causes liver injury through sinusoidal obstructive syndrome and steatosis. Chemotherapy-induced liver injury may make it more difficult to detect metastases secondary to reduced contrast between the injured liver and metastases. The aim of this study was to determine the sensitivity of superparamagnetic iron oxide (SPIO) contrast-enhanced imaging in patients who have undergone chemotherapy prior to liver surgery.

Methods

Local ethics committee approval was obtained. Thirty-one patients with hepatic metastases completing preoperative chemotherapy were prospectively recruited. Images were reviewed independently by two blinded observers who identified and localized lesions with a four-point confidence scale. The alternative free-response receiver operator characteristic method was used to analyze the results.

Results

The sensitivity in detecting colorectal metastases following chemotherapy was 78% and 76%, respectively, for observers 1 and 2 (95% confidence interval: 71%–85% and 68%–82%). The areas under the alternative free-response receiver operator curves were 0.73 and 0.80 for observers 1 and 2, respectively.

Conclusion

Compared to previously published work on chemotherapy-naïve patients, it is clear that the sensitivity of SPIO-enhanced magnetic resonance imaging (MRI) in detecting colorectal metastases following chemotherapy is reduced. It is therefore critical that all imaging — pre-, during and postchemotherapy — is reviewed when reporting liver MRI prior to surgery.     

Quantitative evaluation of optimal imaging parameters for single-cell detection in MRI using simulation

Super-paramagnetic iron oxide (SPIO) nanoparticles are actively investigated to enhance disease detection through molecular imaging using magnetic resonance imaging (MRI). Detection of the cells labeled by SPIO depends on the MRI protocols and pulse sequence parameters that can be optimized. To evaluate the sensitivity and specificity of the image acquisition methods and to obtain optimal imaging parameters for single-cell detection, we further developed an MRI simulator. The simulator models an object (tissue) at a microscopic level to evaluate effects of spatial distribution and concentration of nanoparticles on the resulting image. In this study, the simulator was used to evaluate and compare imaging of the labeled cells by the gradient-echo (GE), true-FISP [fast imaging employing steady-state acquisition (FIESTA)] and echo-planar imaging (EPI) pulse sequences. Effects of the imaging and object parameters, such as field strength, imaging protocol and pulse sequence parameters, imaging resolution, cell iron load, position of SPIO within the voxel and cell division within the voxel, were investigated in the work. The results suggest that true-FISP has the highest sensitivity for single-cell detection by MRI.     

Tracking of transplanted mesenchymal stem cells labeled with fluorescent magnetic nanoparticle in liver cirrhosis rat model with 3-T MRI

In vivo visualization of transplanted stem cells with noninvasive technique is essential for the monitoring of cell implantation, homing and differentiation. At present, superparamagnetic iron oxide (SPIO) is most commonly used for cell labeling. However, stem cells lack phagocytic capacity and transfection agent is required for sufficient internalization of SPIO for cellular imaging. However, the potential hazards of transfection agents are not fully investigated. Instead of SPIO, we used commercially available new tagging material, fluorescent magnetic nanoparticle (MNP) containing rhodamine B isothiocyanate within a silica shell (Biterials, Seoul, Korea). This tagging material does not require transfection agents for the cell labeling. In addition to that, the core of this MNP is composed of ferrite and the inner portion of silica shell contains fluorescent materials, therefore, it has both magnetic and optical features. This study was designed to track intrasplenically injected bone marrow mesenchymal stem cells (MSCs) labeled with fluorescent MNP in liver cirrhosis rat model with 3-T magnetic resonance equipment. We compared magnetic resonance imaging (MRI) of livers in rats which were injected with non-labeled stem cells or labeled stem cells with MNP or SPIO. We found that the respective liver-to-muscle contrast-to-noise ratios at 3 and 5 h after MNP or SPIO-labeled stem cell injection was significantly lower than that of pre-injection and non-labeled group. There was no significant difference between MNP-labeled group and SPIO-labeled group. We can effectively detect intrasplenically injected MNP-labeled MSCs in an experimental rat model of liver cirrhosis with 3-T MRI.     

Hypervascular hepatocellular carcinoma in the cirrhotic liver: diffusion-weighted imaging versus superparamagnetic iron oxide-enhanced MRI

Purpose

The purpose of the study was to validate diffusion-weighted imaging (DWI) in the assessment of hypervascular hepatocellular carcinoma (HCC) compared with superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) in the cirrhotic liver.

Material and Methods

Forty-six consecutive patients with 106 hypervascular focal lesions in the cirrhotic liver who underwent DWI using three b factors and gadopentetate dimeglumine-enhanced dynamic MRI followed by SPIO-enhanced MRI were enrolled. Two independent radiologists evaluated two separated image sets (SPIO set, dynamic MRI and SPIO-enhanced T2*-weighted images; DWI set, DWI and dynamic MRI) and assigned confidence levels for diagnosis of HCC using a five-point scale for each lesion. Area under the receiver operating characteristic curve (A_z) was calculated for each image set.

Results

The A_z value of the DWI set was larger than the SPIO set by both readers (reader 1, 0.936 vs. 0.900, P=.050; reader 2, 0.938 vs. 0.905, P=.110). For the sensitivity (reader 1, 93.1% vs. 86.2%, P=.146; reader 2, 95.4% vs. 88.5%, P=.070) and specificity (reader 1, 89.5% vs. 73.7%, P=.250; reader 2, 79.0% vs. 73.7%, P=1.000) of HCC diagnosis, DWI sets were superior to SPIO sets without statistically significant differences.

Conclusion

For assessment of hypervascular HCC, DWI in combination with dynamic MRI provides comparable or slightly better information compared with the combination of dynamic and SPIO-enhanced MRI.     

Multifunctional Hybrids Based on 2D Fluorinated Graphene Oxide and Superparamagnetic Iron Oxide Nanoparticles

Carbon‐based nanomaterials have garnered a lot of attention in the research of yesteryear. Here this study reports a composite based on fluorinated graphene oxide—a multifunctional subsidiary of graphene; and iron oxide nanoparticles as a contrast agent for magnetic resonance imaging (MRI). Extensive structural and functional characterization is carried out to understand composite behavior toward biotoxicity and its performance as a contrast agent. The electron withdrawing fluorine group decreases the charge transfer to iron oxide increasing the magnetic saturation of the composite thus enhancing the contrast. The interaction of paramagnetic and superparamagnetic systems yields a superior contrast agent for MRI and fluorescent imaging.     

Control of the interparticle spacing in superparamagnetic iron oxide nanoparticle clusters by surface ligand engineering

Polymer-mediated self-assembly of superparamagnetic iron oxide(SPIO) nanoparticles allows modulation of the structure of SPIO nanocrystal cluster and their magnetic properties. In this study, dopamine-functionalized polyesters(DApolyester) were used to directly control the magnetic nanoparticle spacing and its effect on magnetic resonance relaxation properties of these clusters was investigated. Monodisperse SPIO nanocrystals with different surface coating materials(poly(ε-caprolactone), poly(lactic acid)) of different molecular weights containing dopamine(DA) structure(DA-PCL2k,DA-PCL1k, DA-PLA1k)) were prepared via ligand exchange reaction, and these nanocrystals were encapsulated inside amphiphilic polymer micelles to modulate the SPIO nanocrystal interparticle spacing. Small-angle x-ray scattering(SAXS)was applied to quantify the interparticle spacing of SPIO clusters. The results demonstrated that the tailored magnetic nanoparticle clusters featured controllable interparticle spacing providing directly by the different surface coating of SPIO nanocrystals. Systematic modulation of SPIO nanocrystal interparticle spacing can regulate the saturation magnetization(Ms) and T_2 relaxation of the aggregation, and lead to increased magnetic resonance(MR) relaxation properties with decreased interparticle spacing.     

GoldMag nanoparticles with core/shell structure: characterization and application in MR molecular imaging

GoldMag is a kind of bi-functional nanoparticle, composed of a gold nanoshell and an iron oxide core. GoldMag combines the antibody immobilization property of gold nanoshell with the superparamagnetic feature of the iron oxide core. Rabbit anti-mouse IgG was immobilized on the surface of GoldMag to synthesize GoldMag-IgG in a single-step process. Transmission electron microscopy, UV/Vis spectrophotometry, zeta potential analysis, dynamic light scattering, enzyme-linked immunosorbent assay, and magnetic resonance imaging (MRI) were employed to characterize the nanostructures and the spectroscopic and magnetic properties of GoldMag and GoldMag-IgG. The antibody encapsulation efficiency of GoldMag was measured as 58.7%, and the antibody loading capacity was 88 μg IgG per milligram of GoldMag. The immunoactivity of GoldMag-IgG was estimated to be 43.3% of that of the original IgG. The cytotoxicity of GoldMag was assessed by MTT assay, which showed that it has only little influence on human dermal lymphatic endothelial cells. MR imaging of different concentrations of ultrasmall superparamagnetic iron oxide, GoldMag, and GoldMag-IgG showed that 3 μg/mL of nanoparticles could significantly affect the MRI signal intensity of GRE T2*WI. The results demonstrate that GoldMag nanoparticles can be effectively conjugated with biomacromolecules and possess great potential for MR molecular imaging.     

SPIO–RGD nanoparticles as a molecular targeting probe for imaging tumor angiogenesis using synchrotron radiation

Angiogenesis, new blood vessels sprouting from pre‐existing vessels, is essential to tumor growth, invasion and metastasis. It can be used as a biomarker for early stage tumor diagnosis and targeted therapy. To visualize angiogenesis many molecular imaging modalities have been used. In this study a novel X‐ray molecular targeting probe using superparamagnetic iron oxide (SPIO) conjugated with arginine–glycine–aspartic acid (SPIO–RGD) has been developed. Based on the extremely high sensitivity to the iron element of synchrotron radiation X‐ray fluorescence and the superior spatial resolution of third‐generation synchrotron radiation, the feasibility of SPIO–RGD as a promising molecular probe for imaging tumor angiogenesis has been demonstrated.     

Visualization of superior mesenteric lymph nodes by the combined oral and intravenous administration of the ultrasmall superparamagnetic iron oxide, AMI-227

Superior mesenteric lymph nodes which lie as a chain near the small intestine are difficult to visualize in the rat with MRI either with or without the use of contrast agents. We previously demonstrated that the oral administration of an ultrasmall superparamagnetic iron oxide (AMI-227) produces a brightening of the lumen of the GI tract with a T₁-weighted spin-echo pulse sequence. We have also shown that AMI-227 darkens abdominal lymph nodes. In the present study we show that the combined oral and intravenous administration of AMI-227 produces a brightening of the lumen of the GI tract and a darkening of the superior mesenteric lymph node chain. As a result of these combined and opposing effects on image signal intensity, a necessary contrast is established to reliably locate the superior mesenteric lymph nodes in vivo, which, to our knowledge, have been elusive by other techniques.     

Evaluation of the prostate by magnetic resonance imaging

Forty-seven male patients with suspected prostatic disease underwent magnetic resonance imaging (MRI) of the pelvis on a Picker resistive magnet operating at 0.15 T; 33 had histologically proved adenocarcinoma, 12 benign prostatic hypertrophy, 1 a transitional cell carcinoma, and 1 a seminoma. Eleven normal subjects also were included in the study. The study attempted to (1) define the MRI characteristics of the normal prostate, benign prostatic hypertrophy, and prostatic adenocarcinoma, (2) evaluate various pulse sequences in imaging the prostate, and (3) compare MRI findings with clinical, pathologic, and computed tomography results. Various pulse sequences, including inversion recovery and spin-echo with short and long TE and TR, were used. MRI was sensitive in detecting intracapsular and extracapsular prostatic disease. The finding of inhomogeneous signal texture throughout the gland was a sensitive but nonspecific finding for adenocarcinoma. A focal nodule with prolonged T1 and T2 relaxation times was the most specific MRI finding for adenocarcinoma. Extracapsular spread of neoplasm was often demonstrated, and because of its superior soft-tissue contrast ability, MRI was more accurate than computed tomography in delineating extracapsular extension.     

Labelling of cultured macrophages with novel magnetic nanoparticles

Magnetic resonance (MR) imaging is capable of demonstrating human anatomy and pathological conditions. Iron oxide magnetic nanoparticles (MNPs) have been used in MR imaging as liver-specific contrast medium, cellular and molecular imaging probes. Because few studies focused on the MNPs other than iron oxides, we developed FeNi alloy MNPs coated with polyethylenimine (PEI). In this study, we demonstrated PEI-coated FeNi MNPs are able to label the cells, which could be detected in MR imaging. For labelling purpose, MNPs were incubated with mouse macrophage cell line (Raw 264.7) for 24 h and these PEI-labelled FeNi alloy MNPs can be uptaken by macrophages efficiently compared with Ferucarbotran, a commercialized superparamagnetic iron oxide (SPIO) under flow cytometry measurement. Besides, these cells labelled with MNPs could be imaged in MR with the identical potency as Ferucarbotran. Further investigation of the cells using Prussian blue staining revealed that FeNi alloy MNPs inside the cells is not oxidized. This phenomenon alleviated the consideration of potential risk of nickel toxicity. We conclude that PEI-coated FeNi MNPs could be candidate for MR contrast medium.     

Abdominal aortic aneurysm evaluation: comparison of US, CT, MRI, and angiography

We studied 26 cases of abdominal aortic aneurysm with magnetic resonance imaging (MRI), computed tomography (CT), ultrasonography (US), and angiography. Data acquired were compared to those obtained at surgery. Diameter of the aneurysm was correctly defined in all cases by CT and MRI, while angiography underestimated the diameter of lesions without peripheral calcifications. Involvement of renal arteries was present in four cases and correctly diagnosed with MRI and angiography in all of them. CT did provide this information in three cases and US were not useful. Also, iliac arteries involvement was depicted by CT, MRI, and angiography in 10 out of 10 patients. Coronal sections of MRI provided comparable images to those of angiography. By comparing these different techniques we verified the good reliability of MRI as investigation tool for an accurate evaluation of aneurysms; its only limit lying in the poor capability of detecting calcifications.     

Medlar (<Emphasis Type="Italic">Achras Sapota</Emphasis> L.) as Oral Contrast Agent for MRI of the Gastrointestinal Tract

Magnetic resonance imaging (MRI) of the gastrointestinal (GI) tract is still limited due to the lack of widely available oral contrast agents (OCA). The availability of OCA for MRI of the GI tract is a necessity; different fruits might be implemented as OCA in order to solve this need throughout the year. The objective of this study is to present an alternative fruit as a clinical OCA for MRI of the GI tract, Achras sapota L. (common medlar). Both physical and chemical characterization of the medlar was performed. It was also tested in situ and in vivo as an OCA for MRI of the GI tract. Results showed that this fruit had a diamagnetic behavior, although it has enough iron, manganese and copper to contrast the GI tract in T ₁- and T ₂-weighted images. Thus we conclude that the medlar fruit has shown a potential as an OCA in GI evaluation by MRI, so it can be considered as an alternative in complementation of natural OCA.     

Preautopsy magnetic resonance imaging: initial experience

To our knowledge, there are no prospective data in the literature investigating the role of magnetic resonance imaging (MRI) in detecting abnormalities in cadavers to determine the feasibility of this concept. We prospectively studied six cadavers (three stillborn infants, one infant, and two adults) with a 0.15 T resistive magnet. The images obtained allowed detection of abnormalities in multiple organs. Although autopsy was superior to MRI in detecting very small abnormalities, MRI was equal to autopsy in detecting gross cranial, pulmonary, abdominal, and vascular pathology in this small series. In addition, MRI was superior to autopsy in detecting air and fluid in potential body spaces. Preautopsy MRI may be an alternate method in restricted or denied autopsies and may provide an additional MRI research and educational tool.     

MRI and diabetic foot infections

The role of magnetic resonance imaging and plain radiographs in evaluating osteomyelitis in the diabetic foot was studied. Fifty patients were prospectively examined by magnetic resonance imaging and plain radiographs to determine the extent of infection. Thirty-seven patients had positive MRI for osteomyelitis and 19 were positive with conventional radiography. Thirteen patients had negative MRI healed with short course of antibiotics. Five patients with positive MRI received four weeks' course of intravenous antibiotics with two still having persistent infection in the six weeks follow-up. Thirty-two patients underwent surgery with favorable results. Sixty-two bone specimens were obtained for histologic evaluation of osteomyelitis. In cases with histologic proof of diagnosis, magnetic resonance sensitivity was 99%, specificity was 81%, and accuracy was 94%. Thus magnetic resonance imaging was shown to have a high sensitivity, specificity, and accuracy in detecting osteomyelitis.     

In vivo fate of superparamagnetic iron oxides during sepsis

The enzymatic generation of nitric oxide (NO) in vivo has been reported to be modulated by ions, such as copper and iron. Superparamagnetic iron oxide (SPIO) or ferumoxides is a liver-specific magnetic resonance contrast agent that is taken up by the Kupffer cells, where NO is generated by inducible nitric oxide synthase (iNOS). Thus, it is important to evaluate SPIO in vivo under conditions, such as infectious disease, where significant amounts of NO are generated by iNOS. In this study, we monitored the pharmacokinetics of SPIO in the liver of septic-shock mice and rats. A significant decrease in the ferric iron EPR signal was observed during NO generation in septic-shock mice compared with control mice doped with only SPIO. These results were also confirmed in a model reaction system consisting of SPIO and the NO donor, S-nitroso-N-acetyl DL penicillamine (SNAP). We compared NO generation quantitatively in the liver of the septic-shock rats, either in the presence or absence of SPIO, and found that the presence of SPIO did not affect the NO-generating activity of NOS expressed in the liver. T2-weighted MR images of an agarose gel phantom containing different SPIO to NO donor (SNAP) ratios clearly demonstrated that the contrast enhancement by SPIO decreased with increasing NO at constant SPIO levels. The reduced contrast is most probably due to the reduction of ferric to ferrous irons, resulting in a decrease in paramagnetic relaxation of water protons. These results show that SPIO can be a versatile NO-sensitive indicator, especially employing MRI as a powerful tool to 'visualize' sites of NO generation.     

Ultrasmall superparamagnetic particles of iron oxide (USPIO) MR imaging of infarcted myocardium in pigs

The purpose of this study is to assess the potential value of ultrasmall superparamagnetic iron oxide (USPIO) for the detection of acute myocardial infarction by magnetic resonance (MR) imaging. Spin-echo magnetic resonance imaging of the heart was performed before, immediately after, and approximately 35 and 90 min after 30 μmol Fe/kg of USPIO administration in seven pigs with surgically induced myocardial infarction. Gradient-echo sequences were used to identify contraction abnormalities at the site of infarction. Myocardial signal intensities were measured using region-of-interest analysis in normal and infarcted myocardium. In addition, liver and lung signal intensities were measured. Pathologic correlation was performed after sacrificing the animals. The infarct area was located with wall-motion analysis. The site of infarction was confirmed at pathologic examination. The signal-intensity ratio between infarcted and normal myocardium was not significantly changed after USPIO administration at equilibrium stages (immediately after injection p = 0.64, at 35 min p = 0.32, at 90 min p = 0.73). The signal intensity of the liver decreased significantly after contrast administration (p < 0.05). For the lung, the change in signal intensity after USPIO administration was not significant. This pig model is well suited to study wall motion abnormalities after induction of acute myocardial infarction. USPIO-enhanced magnetic resonance imaging does not improve the visualization of acute myocardial infarction at equilibrium stage.     

Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles

Stable 30–50 nm polymeric polyethylene glycol–phosphatidylethanolamine (PEG–PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG–PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.     

Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles

Encapsulated microbubbles coupled with magnetic nanoparticles, one kind of hybrid agents that can integrate both ultrasound and magnetic resonance imaging/therapy functions, have attracted increasing interests in both research and clinic communities. However, there is a lack of comprehensive understanding of their dynamic behaviors generated in diagnostic and therapeutic applications. In the present work, a hybrid agent was synthesized by integrating superparamagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles (named as SPIO-albumin microbubbles). Then, both the stable and inertial cavitation thresholds of this hybrid agent were measured at varied SPIO concentrations and ultrasound parameters (e.g., frequency, pressure amplitude, and pulse length). The results show that, at a fixed acoustic driving frequency, both the stable and inertial cavitation thresholds of SPIO-albumin microbubble should decrease with the increasing SPIO concentration and acoustic driving pulse length. The inertial cavitation threshold of SPIO-albumin microbubbles also decreases with the raised driving frequency, while the minimum sub- and ultra-harmonic thresholds appear at twice and two thirds resonance frequency, respectively. It is also noticed that both the stable and inertial cavitation thresholds of SonoVue microbubbles are similar to those measured for hybrid microbubbles with a SPIO concentration of 114.7 μg/ml. The current work could provide better understanding on the impact of the integrated SPIOs on the dynamic responses (especially the cavitation activities) of hybrid microbubbles, and suggest the shell composition of hybrid agents should be appropriately designed to improve their clinical diagnostic and therapeutic performances of hybrid microbubble agents.