Ultrasmall Superparamagnetic Iron Oxide Contrast Research Articles

Subnodal Correspondence of PSMA Expression and USPIO-MRI in Metastatic Pelvic Lymph Nodes in Prostate Cancer.

Two advanced imaging modalities used to detect lymph node (LN) metastases in prostate cancer patients are prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography and ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI). As these modalities use different targets, a subnodal comparison is needed to interpret both their correspondence and their differences. The aim of this explorative study was to compare ex vivo 111 In-PSMA μSPECT images with high-resolution 7 T USPIO μMR images and histopathology of resected LN specimens from prostate cancer patients to assess the degree of correspondence at subnodal level. Twenty primary prostate cancer patients who underwent pelvic LN dissection were included and received USPIO contrast and 111 In-PSMA. A total of 41 LNs of interest (LNOIs) were selected for ex vivo imaging based on γ-probe detection or palpation. μSPECT and μMRI acquisition were performed immediately after resection. Overlay of μSPECT images on MR images was performed, and the level of correspondence (LoC) between μSPECT and μMR findings was assessed according to a 4-point Likert classification scheme. Forty-one LNOIs could be matched to an LN on ex vivo μMRI. Coregistration of μSPECT and USPIO-enhanced water-selective multigradient echo MR images was successful for all 41 LNOIs. Ninety percent of the lesions showed excellent correspondence regarding the presence of metastatic tissue and affected subnodal site (LoC 4; 37/41). In only 1 of 41 LNOIs, a small metastasis was misclassified by both techniques. Three LNOIs were classified as LoC 3 (7%) and 1 LNOI as LoC 2. All LoC 2 and LoC 3 lesions had PSMA-expressing metastases on final histopathology. Coregistration of μSPECT and USPIO-μMRI showed excellent subnodal correspondence in the majority (90%) of LNs. Ex vivo imaging may thus help localize small cancer deposits within resected LNs and could contribute to improved interpretation of in vivo imaging of LNs.

Revealing vascular abnormalities and measuring small vessel density in multiple sclerosis lesions using USPIO

Background and PurposeMultiple Sclerosis (MS) is a progressive, inflammatory, neuro-degenerative disease of the central nervous system (CNS) characterized by a wide range of histopathological features including vascular abnormalities. In this study, an ultra-small superparamagnetic iron oxide (USPIO) contrast agent, Ferumoxytol, was administered to induce an increase in susceptibility for both arteries and veins to help better reveal the cerebral microvasculature. The purpose of this work was to examine the presence of vascular abnormalities and vascular density in MS lesions using high-resolution susceptibility weighted imaging (SWI). MethodsSix subjects with relapsing remitting MS (RRMS, age = 47.3 ± 11.8 years with 3 females and 3 males) and fourteen age-matched healthy controls were scanned at 3 T with SWI acquired before and after the infusion of Ferumoxytol. Composite data was generated by registering the FLAIR data to the high resolution SWI data in order to highlight the vascular information in MS lesions. Both the central vein sign (CVS) and, a new measure, the multiple vessel sign (MVS) were identified, along with any vascular abnormalities, in the lesions on pre- and post-contrast SWI-FLAIR fusion data. The small vessel density within the periventricular normal-appearing white matter (NAWM) and the periventricular lesions were compared for all subjects. ResultsAveraged across two independent raters, a total of 530 lesions were identified across all patients. The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM. ConclusionsBy inducing a super-paramagnetic susceptibility in the blood using Ferumoxytol, the vascular abnormalities in the RRMS patients were revealed and small vessel densities were obtained. This approach has the potential to monitor the venous vasculature present in MS lesions, catalogue their characteristics and compare the vascular structures spatially to the presence of lesions. These enhanced vascular features may provide new insight into the pathophysiology of MS.

Histologic Distribution and Characteristics on MR Imaging of Ultrasmall Superparamagnetic Iron Oxide in Ethyl-nitrosourea-induced Endogenous Rat Glioma.

Purpose:(1) To evaluate the enhancement patterns of an ultrasmall superparamagnetic iron oxide contrast agent (USPIO-CA) compared with those of a gadolinium-based contrast agent (Gd-BCA). (2) To compare the histologic distribution of USPIO-related iron particles (USPIO-IPs) with the USPIO-enhancement area in the early vascular and in the cellular imaging phase (E- and L-phase, respectively) after intravenous CA administration.Methods:We performed USPIO-enhanced MRI of N-ethyl-N-nitrosourea (ENU)-induced endogenous rat glioma, including spin-echo (SE) T1-weighted images (T1WIs) and gradient-recalled-echo (GRE) T2-weighted images (T2WIs), before and at 3–6 h after USPIO-CA administration for E-phase images. For L-phase images, MRI was performed at 16–19 and 62–69 h after administration. Two observers determined the USPIO-enhancement area on E-phase images and Gd-enhancement areas. We compared the USPIO-enhancement size (USPIO-ES) and Gd-ES on SE T1WIs, and the hypo-intense USPIO-ES on GRE T2WIs and Gd-ES using the Wilcoxon signed-rank test. In addition, two raters visually evaluated the correspondence between the histologic distribution of USPIO-IPs and the USPIO-enhancement area on corresponding GRE T2WIs at each phase using a 3-rating scale.Results:Significantly smaller hyper-intense, hypo-intense and combined hyper-/hypo-intense areas were observed on USPIO-enhanced SE T1WIs compared with Gd-enhanced images (all P < 0.001). The hypo-intense USPIO-ES on GRE T2WIs was significantly smaller than the Gd-ES (P = 0.001). The distribution of USPIO-IPs on histopathological specimen and USPIO-enhancement on GRE T2WIs exhibited poor agreement in 5 of 9 tumors with enhancement from rats sacrificed early. The distribution of microglia containing USPIO-IPs corresponded with the pattern of USPIO-enhancement in the 2 tumors with late enhancement.Conclusion:The enhancement pattern and size of USPIO-CA in a rat glioma model were statistically different from those of Gd-BCA. Our histological data suggests that USPIO-enhanced MRI offers vascular bed imaging in E-phase and might depict the intra-tumoral distribution of immune effector cells in L-phase.

Simultaneous MRI water-fat separation and quantitative susceptibility mapping of carotid artery plaque pre- and post-ultrasmall superparamagnetic iron oxide-uptake.

Imaging carotid artery plaques to identify features of vulnerability typically requires a multicontrast MRI protocol. The identification of regions of inflammation with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles requires separate pre- and postcontrast scans. We propose a method of joint water-fat separation and quantitative susceptibility mapping (QSM) to aid classification of atherosclerotic plaques and offer a positive contrast mechanism in USPIO-imaging. Ten healthy volunteers (3 women and 7 men; aged, 30.7 ± 10.7 years) were imaged at 1.5T to develop an acquisition and postprocessing protocol. Five patients (1 woman and 4 men; mean age, 71 ± 7.5 years) with moderate to severe luminal stenosis were imaged pre- and postadministration of a USPIO contrast agent. We used a multiecho gradient echo acquisition to perform water/fat separation and subsequently QSM. The results were compared with a conventional multicontrast MRI protocol, CT images, and histopathology data. In the volunteer scans, a multiecho gradient echo acquisition with bipolar readout gradients demonstrated to be a reliable acquisition methodology to produce high-quality susceptibility maps in conjunction with the proposed postprocessing methodology. In the patient study, water/fat separation provided a tool to identify lipid-rich necrotic cores and QSM provided a qualitative and quantitative evaluation of plaque features and positive contrast when evaluating USPIO uptake. Plaque calcification could be identified by strong diamagnetism (-1.27 ± 0.71 ppm), while USPIO uptake demonstrated a strong paramagnetism (1.32 ± 0.61 ppm). QSM was able to identify multiple plaque features in a single acquisition, providing positive contrast for plaques demonstrating USPIO uptake and negative contrast for calcification.

OA31 - Radiotherapy Guided by Ultrasmall Superparamagnetic Iron Oxide Contrast MRI Staging for Patients with High Risk, Clinically Node Positive or Recurrent Prostate Cancer

OA31 - Radiotherapy Guided by Ultrasmall Superparamagnetic Iron Oxide Contrast MRI Staging for Patients with High Risk, Clinically Node Positive or Recurrent Prostate Cancer

A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response.

: Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of α-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2, sO2, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO2 (ΔpO2: 3.1 ± 1.0 mmHg) and was accompanied by decreased sO2 (20%-30% decrease) in SCCVII implants 20-30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation. SIGNIFICANCE: A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response.

Ultra-small superparamagnetic iron oxide contrast agents for lymph node staging of high-risk prostate cancer

Ultrasmall superparamagnetic particles of iron oxide (USPIOs) imaged with magnetic resonance imaging (MRI) have been proposed as an experimental method for visualizing lymph node (LN) metastases. The method does not require ionizing radiation, yet can detect small nodes that are involved with metastases. USPIOs are naturally taken up by macrophages that deposit in the normal LN creating a low signal region in normal areas; areas within the node that do not show this loss of signal are likely involved by tumor although there can be other causes (fibrosis or inflammation). However, the lack of approved USPIOs that are clinically available hinders adoption and larger studies. The proposed indications for USPIO MRI, including specific compounds and imaging methods are discussed.

Imaging Inflammation in Cerebrovascular Disease.

Imaging inflammation in large intracranial artery pathology may play an important role in the diagnosis of and risk stratification for a variety of cerebrovascular diseases. Looking beyond the lumen has already generated widespread excitement in the stroke community, and the potential to unveil molecular processes in the vessel wall is a natural evolution to develop a more comprehensive understanding of the pathogenesis of diseases, such as ICAD and brain aneurysms.

Evaluation of ultrasmall superparamagnetic iron oxide contrast agent labeling of equine cord blood and bone marrow mesenchymal stromal cells.

To evaluate the efficacy and effects of labeling equine umbilical cord blood (UCB)- and bone marrow (BM)-derived multipotent mesenchymal stromal cells (MSCs) with an ultrasmall superparamagnetic iron oxide (SPIO) contrast agent and the detection of labeled MSCs by use of MRI. UCB MSCs from placental tissues of 5 foals and BM MSCs from 5 horses. UCB and BM MSC cultures were seeded in duplicate (5,000 cells/cm(2)). One duplicate was incubated with SPIO (50 μg/mL); the other was processed identically, but without SPIO. Mesenchymal stromal cells were expanded in triplicates for 5 passages and assessed for viability and proliferative capacity, labeling efficacy, and labeled cell proportion. For MRI detection, 5 × 10(6) labeled BM MSCs from passage 1 or 2 were injected into a collagenase-induced superficial digital flexor tendon defect of an equine cadaveric forelimb from 2 horses. For passages 1, 2, and 3, labeling efficacy and cell proportion for UCB MSCs (99.6% [range, 98.8% to 99.9%], 16.6% [range, 6.5% to 36.1%], and 1.0% [range, 0.4% to 2.8%], respectively) were significantly higher than for BM MSCs (99.2% [range, 97.8% to 99.7%], 4.5% [range, 1.6% to 11.8%], and 0.2% [range, 0.1% to 0.6%], respectively). Labeling was not detectable after passage 3. Viability of MSCs was not affected, but cell doubling time increased in labeled MSCs, compared with that of unlabeled MSCs. On MRI 3-D T2*-weighted fast gradient echo sequences, decreased signal intensity was observed for BM passage 1 MSCs. Equine UCB and BM MSCs were labeled with SPIO at high efficiencies.

Diagnostic accuracy of MR imaging to identify and characterize focal liver lesions: comparison between gadolinium and superparamagnetic iron oxide contrast media.

To compare the diagnostic value of gadolinium (Gd) and ultrasmall superparamagnetic iron oxide (SPIO) contrast media for characterization of focal liver lesions (FLL), we retrospectively evaluated the results of magnetic resonance (MR) imaging in 68 patients (40 M, 28 F, age from 22 to 81 yrs) of which 36 with diagnosis of colo-rectal cancer, 26 with hepatic cirrhosis and 6 with incidental imaging detection of FLL. MR (Gyroscan Intera 1.5 T, Philips Medical Systems) study was performed using T1 and T2 fast-field-echo (FFE) and T2 turbo-spin-echo (TSE) sequences in axial and coronal views. Dynamic multi-phases gadolinium Gd-enhanced T1-FFE-Bh images were obtained in arterial, portal and equilibrium phases, followed by SPIO-enhanced T2-FFE scans. A qualitative analysis of pre- and post-contrast MR images to classify FLL as benign or malignant was performed using a 3-point scoring system: 0= benign; 1= suspicious for malignancy; 2= malignant. A total of 118 lesions were evaluated. In particular, histology (n=18), cytology (n=14) or clinical-imaging follow-up data (n=86) demonstrated 4 adenomas, 29 cysts, 3 focal steatosis, 25 hemangiomas, 1 focal vascular abnormality, 5 fibrotic lesions as well as 13 regenerative nodules, 6 dysplastic, 14 hepatocellular carcinomas (HCC), 17 metastasis and 1 cholangiocarcinoma. For MR imaging, diagnostic accuracy, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of Gd vs. SPIO images were respectively 83% vs. 92%, 79% vs. 74%, 85% vs. 99% (P=0.002), 68% vs. 96% (P=0.005) and 91% vs. 90%, respectively. The results suggest that SPIO-MR provides a diagnostic incremental value, as specificity and PPV, particularly to characterize FLL compared to Gd-MR; thus, we strongly recommend the use of SPIO when liver lesion characterization is requested and Gd images are uncertain.

Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL

The study goal was to assess the benefits and potential limitations in the use of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in the MRI diagnosis of CNS inflammatory diseases and primary CNS lymphoma. Twenty patients with presumptive or known CNS lesions underwent MRI study. Eighteen patients received both gadolinium-based contrast agents (GBCAs) and 1 of 2 USPIO contrast agents (ferumoxytol and ferumoxtran-10) 24 hours apart, which allowed direct comparative analysis. The remaining 2 patients had only USPIO-enhanced MRI because of a renal contraindication to GBCA. Conventional T1- and T2-weighted MRI were acquired before and after contrast administration in all patients, and perfusion MRI for relative cerebral blood volume (rCBV) assessment was obtained in all 9 patients receiving ferumoxytol. USPIO-enhanced MRI showed an equal number of enhancing brain lesions in 9 of 18 patients (50%), more enhancing lesions in 2 of 18 patients (11%), and fewer enhancing lesions in 3 of 18 patients (17%) compared with GBCA-enhanced MRI. Four of 18 patients (22%) showed no MRI enhancement. Dynamic susceptibility-weighted contrast-enhanced perfusion MRI using ferumoxytol showed low rCBV (ratio <1.0) in 3 cases of demyelination or inflammation, modestly elevated rCBV in 5 cases of CNS lymphoma or lymphoproliferative disorder (range: 1.3-4.1), and no measurable disease in one case. This study showed that USPIO-enhanced brain MRI can be useful in the diagnosis of CNS inflammatory disorders and lymphoma, and is also useful for patients with renal compromise at risk of nephrogenic systemic fibrosis who are unable to receive GBCA.

Sequential Imaging of Asymptomatic Carotid Atheroma Using Ultrasmall Superparamagnetic Iron Oxide–enhanced Magnetic Resonance Imaging: A Feasibility Study

Inflammation within atheromatous plaques is a known risk factor for plaque vulnerability. This can be detected invivo on high-resolution magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxide (USPIO) contrast medium. The purpose of this study was to assess the feasibility of performing sequential USPIO studies over a 1-year period. Ten patients with moderate asymptomatic carotid stenosis underwent carotid MRI imaging both before and 36 hours after USPIO infusion at 0, 6, and 12 months. Images were manually segmented into quadrants, and the signal change per quadrant was calculated at these time points. A mixed repeated measures statistical model was used to determine signal change attributable to USPIO uptake over time. All patients remained asymptomatic during the study. The mixed model revealed no statistical difference in USPIO uptake between the 3 time points. Intraclass correlation coefficients revealed a good agreement of quadrant signal pre-USPIO infusion between 0 and 6 months (0.70) and 0 and 12 months (0.70). Good agreement of quadrant signal after USPIO infusion was shown between 0 and 6 months (0.68) and moderate agreement was shown between 0 and 12 months (0.33). USPIO-enhanced sequential MRI of atheromatous carotid plaques is clinically feasible. This may have important implications for future longitudinal studies involving pharmacologic intervention in large patient cohorts.

PMD49 The Potential Role of Magnetic Resonance Imaging (MRI) in Axillary Node Assessment of Early Breast Cancer: An Economic Evaluation

THE POTENTIAL ROLE OF MAGNETIC RESONANCE IMAGING (MRI) IN AXILLARY NODE ASSESSMENT OF EARLY BREAST CANCER: AN ECONOMIC EVALUATION Meng Y1, Ward SE1, Cooper K1, Harnan SE1, Wyld L2 1University of Sheffield, Sheffield, UK, 2Royal Hallamshire Hospital, Sheffield, UK OBJECTIVES: Surgical techniques including sentinel lymph node biopsy (SLNB) and 4-node sampling (4-NS) are currently used for axillary nodal assessment of early breast cancer (EBC) in the UK. Such procedures are associated with adverse effects, (AEs), in particular scarring, pain, general anaesthesia and occasional lymphoedema which may impact on long term quality of life. Magnetic resonance imaging (MRI) is a non-invasive technique offering the potential to avoid such AEs. A range of MRI techniques, including USPIO (ultrasmall superparamagnetic iron oxide contrast agent)-enhanced and gadolinium-enhanced MRI exist, however diagnostic accuracy of these techniques may be lower than for surgical techniques. An economic evaluation was undertaken to compare MRI with surgical techniques for assessment of axillary lymph node metastases in patients with EBC. METHODS: The costs and benefits of replacing SLNB or 4-NS with MRI (replacement strategy) or adding MRI before the surgical techniques (addition strategy) were modelled using discrete-event simulation in SIMUL8®. A systematic review was undertaken to obtain effectiveness outcomes of the MRI techniques, whilst resource use data and health related utilities were obtained from the literature. RESULTS: Our results predict that a replacement strategy for MRI, based on the pooled estimate of all MRI techniques, dominates the baseline SLNB and 4-NS strategies, as a result of avoiding AEs from surgical techniques. However this strategy leads to more false-positive and false-negative cases. The MRI addition strategy may also be cost-effective, but is subject to greater uncertainty. USPIO-enhanced MRI produces the most favourable cost effectiveness ratio, but the evidence is based on studies with small patient numbers. CONCLUSIONS: These results suggest that there is a potential role for MRI in axillary node assessment of EBC. Based on current evidence USPIOenhanced MRI offers the most cost effective option, but further large studies are required to obtain high quality evidence on diagnostic accuracy.

Quantitative pharmacologic MRI in mice

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue.

In vitro and in vivo magnetic resonance tracking of Sinerem-labeled human umbilical mesenchymal stromal cell-derived Schwann cells.

Tracking of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles-labeled embryonic stem cells, neural stem cells, or adult mesenchymal stem cells in vitro and in vivo by using magnetic resonance (MR) imaging have been reported. However, whether the transdifferentiated cells can be effectively labeled by USPIO has not yet been investigated. The requirement for nerve donor material evokes additional morbidity and inability to generate a sufficiently large number of cells in a short time to hamper the clinic application of Schwann cells (SCs) transplantation. These limitations may be avoided if SCs can be generated from clinically accessible sources, such as bone marrow and umbilical cord. However, a reliable means of inducing the selective differentiation of human mesenchymal stromal cells isolated from the umbilical cord (HUMSCs) into SCs in vitro has not yet been established. In this study, we induce HUMSCs into Schwann-like cells in terms of morphology, phenotype, and function by an improved protocol basing on our previous studies. Furthermore, HUMSCs-derived SCs are labeled efficiently in vitro with ultrasmall superparamagnetic iron oxide contrast agent (USPIO) Sinerem and poly-L-lysine (PLL) without affecting morphology, cell cycle, proliferation, and differentiation ability of the labeled cells between the concentration of 200 to 800 μg/ml. Importantly, when grafted into the intact cerebral cortex and striatum, the survival and migration of these Sinerem-labeled cells were observed using MRI. Our study suggest the effective concentration field for Sinerem use in tracking transdifferentiated HUMSCs, and Sinerem labeling transdifferentiated HUMSCs is feasible, efficient, and safe for MRI tracing following grafting into nervous system.

Imaging bladder cancer

To review recent developments in imaging for bladder cancer (BCa) diagnosis and staging. Recent technical advances in multidetector computed tomography (CT) and, especially, CT urography make CT the preferred imaging modality for diagnosis and staging of BCa. CT urography combined with cystoscopy is emerging as the diagnostic imaging pathway of choice for investigating haematuria. CT provides information about local, lymph node and distant spread in a single examination. Imaging for BCa should only be performed when it makes a difference to patient management. CT is the preferred imaging modality for diagnosing and staging urothelial cancer. Magnetic resonance (MR) imaging is superior for evaluation of the depth of tumour invasion into the bladder wall, but this knowledge may not ultimately affect treatment as feasibility for radical cystectomy depends on staging by a combination of clinical, histopathological and imaging findings. Radical cystectomy may include resection of adjacent organs and regional lymph nodes. The current purpose of CT or MR imaging is to detect T3b disease or higher and, especially, locoregional lymph node metastases. In the future, MR imaging with ultrasmall superparamagnetic iron oxide contrast agents may detect lymph nodes containing metastatic tumour, which may change treatment from surgery to chemotherapy with or without radiotherapy.

Diagnostic performance of USPIO-enhanced MRI for lymph-node metastases in different body regions: A meta-analysis

Objectives USPIO (ultrasmall superparamagnetic iron oxide contrast agent) MRI was a promising imaging modality in the detection of lymph-node metastases. And this meta-analysis is performed to compare the diagnostic accuracy of USPIO-enhanced MRI with non-enhanced MRI, USPIO-enhanced MRI in various body regions, and postcontrast alone for diagnosis of lymph-node metastases. Methods A comprehensive and systematic search was conducted in PubMed and EMBASE databases. After a systematic review of the studies, sensitivity, specificity, the Q* value and other measures of accuracy of USPIO-enhanced MRI in the diagnosis of lymph-node metastases were summarized. The overall test performance was based on summary receiver operating characteristic curves. Results Summary of ROC curve analysis for per-lymph-node data shows a pooled sensitivity of 0.90 (95% confidential interval [CI]: 0.88–0.91) and overall specificity of 0.96 (95% CI: 0.95–0.97) for USPIO-enhanced MRI, the Q* value for USPIO-enhanced MRI is 0.9195, diagnostic odds ratio (DOR) is 162.28 (95% CI: 91.82–286.81). Non-enhanced MRI had less overall sensitivity 0.39 (95% CI: 0.34–0.43) and specificity 0.90 (95% CI: 0.89–0.91), respectively, the Q* value for USPIO-enhanced MRI was 0.6321, DOR is 5.81 (95% CI: 3.64–9.82). Postcontrast MRI alone had sensitivity 0.85 (95% CI: 0.81–0.88) and specificity 0.93 (95% CI: 0.91–0.95), respectively, the Q* value for USPIO-enhanced MRI was 0.8976, DOR is 76.92 (95% CI: 34.21–172.93). There was significant heterogeneity for studies reporting enhanced MRI and non-enhanced MRI. Conclusions This meta-analysis has shown that USPIO-enhanced MRI offers higher diagnostic performance than conventional MRI, and is sensitive and specific for the detection of lymph-node metastases. Postcontrast images alone can equate diagnostic performance pre- and postcontrast MRI has achieved for lymph-node characterization. And the role of USPIO-enhanced MRI in clinical practice still needs to be investigated in future studies.

Pharmacological Inhibition of C-C Chemokine Receptor 2 Decreases Macrophage Infiltration in the Aortic Root of the Human C-C Chemokine Receptor 2/Apolipoprotein E −/− Mouse: Magnetic Resonance Imaging Assessment

Purpose- This study assessed the pharmacological effect of a novel selective C-C chemokine receptor (CCR) 2 antagonist (GSK1344386B) on monocyte/macrophage infiltration into atherosclerotic plaque using magnetic resonance imaging (MRI) in an atherosclerotic mouse model. Apolipoprotein E(-/-) mice expressing human CCR2 were fed a Western diet (vehicle group) or a Western diet plus10 mg/kg per day of GSK1344386B (GSK1344386B group). After the baseline MRI, mice were implanted with osmotic pumps containing angiotensin II, 1000 ng/kg per minute, to accelerate lesion formation. After five weeks of angiotensin II administration, mice received ultrasmall superparamagnetic iron oxide, an MRI contrast agent for the assessment of monocyte/macrophage infiltration to the plaque, and underwent imaging. After imaging, mice were euthanized, and the heart and aorta were harvested for ex vivo MRI and histopathological examination. After 5 weeks of dietary dosing, there were no significant differences between groups in body or liver weight or plasma cholesterol concentrations. An in vivo MRI reflected a decrease in ultrasmall superparamagnetic iron oxide contrast agent uptake in the aortic arch of the GSK1344386B group (P<0.05). An ex vivo MRI of the aortic root also reflected decreased ultrasmall superparamagnetic iron oxide uptake in the GSK1344386B group and was verified by absolute iron analysis (P<0.05). Although there was no difference in aortic root lesion area between groups, there was a 30% reduction in macrophage area observed in the GSK1344386B group (P<0.05). An MRI was used to noninvasively assess the decreased macrophage content in the atherosclerotic plaque after selective CCR2 inhibition.

Assessment of macrophage infiltration in a Murine model of abdominal aortic aneurysm

To evaluate the use of an ultrasmall superparamagnetic iron oxide (USPIO) contrast agent as a marker for the detection of macrophage in a preclinical abdominal aortic aneurysm animal (AAA) model. Osmotic pumps were implanted subcutaneously in apoE(-/-) mice for continuous infusion of Angiotensin II (Ang-II). Weekly bright-blood gradient echo scans were performed on the suprarenal abdominal aorta to evaluate aneurysm development. Once an AAA was detected, animals were administered 1000 mumol/kg of the USPIO contrast agent ferumoxtran-10 (Combidex) followed by in vivo scanning 24 h post-USPIO administration. After in vivo imaging, aortas were harvested for ex vivo imaging, histology, iron quantification, and gene expression analysis. Reduced signal intensity was evident in the post-USPIO transverse images of the abdominal aorta. The areas of reduced signal were primarily along the aneurysm shoulder and outer perianeurysm areas and corresponded to regions of macrophage infiltration and colocalized USPIO determination by means of histological staining. The absolute iron content measured significantly correlated to the area of signal reduction in the ex vivo images (r = 0.9; P < 0.01). In the AAA tissue, the macrophage-driven cytokine gene expression was up-regulated along with a matrix metalloproteinase known to mediate extracellular matrix breakdown in this disease model. These results demonstrate the feasibility of using an USPIO contrast agent as a surrogate for detecting the acute inflammatory process involved in the development of abdominal aneurysms.

Cardiovascular Molecular Imaging

Series Editor: Zahi Fayad Molecular Imaging of Cardiovascular Disease ATVB In Focus Articles in this series: •Choudhury RP, Fisher EA. Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation. Arterioscler Thromb Vasc Biol . 2009;29:983–991. •Cormode DP, Skajaa T, Fayad ZA, Mulder WJM. Nanotechnology in medical imaging: probe design and applications. Arterioscler Thromb Vasc Biol . 2009;29:992–1000. •Tang TY, Muller KH, Graves MJ, Li ZY, Walsh SR, Young V, Sadat U, Howarth SPS, Gillard JH. Iron oxide particles for atheroma imaging. Arterioscler Thromb Vasc Biol . 2009;29:1001–1008. •Rudd JHF, Hyafil F, Fayad ZA. Inflammation imaging in atherosclerosis. Arterioscler Thromb Vasc Biol . 2009;29:1009–1016. •Jaffer FA, Libby P, Weissleder R. Optical and multimodality molecular imaging: insights into atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29:1017–1024. •Kraitchman DL, Bulte JWM. In vivo imaging of stem cells and beta cells using direct cell labeling and reporter gene methods. Arterioscler Thromb Vasc Biol . 2009;29:1025–1030. •Laufer EM, Winkens MHM, Narula J, Hofstra L. Imaging of cell death in atherosclerosis. Arterioscler Thromb Vasc Biol . 2009;29:1031–1038. Molecular imaging is defined today as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems, and molecular imaging agents are probes …