MR imaging of pelvic lymph nodes in primary pelvic carcinoma with ultrasmall superparamagnetic iron oxide (combidex): Preliminary observations

The potential of ultrasmall superparamagnetic iron oxide (Combidex)-enhanced MRI of pelvic lymph nodes in patients with primary pelvic carcinoma is evaluated. Fifteen histologically classified lymph nodes in six patients with known primary pelvic cancer (four prostate; one rectum; one uterus) were evaluated with T2-weighted fast spin-echo (FSE) and T2*-weighted gradient-echo (GRE) MRI at 1.5T 12 to 48 hours after intravenous administration of Combidex at a dose of 1.7 mg Fe/kg. Quantitative image evaluation was performed by comparing signal intensity of individual nodes on pre- and postcontrast images. All patients proceeded to pelvic lymph-node biopsy or surgical dissection, where six were found to be benign and nine were malignant. Of the 15 lymph nodes, four nodes showed a decrease in signal intensity. Of these, three, in which signal loss was homogenous were benign, and one, in which the signal-intensity decrease was heterogeneous, was malignant (micrometastases). No signal change was noted in 11 of 15 lymph nodes of which three were benign (inflammatory) and eight were malignant. Combidex is a promising MR contrast agent for evaluating pelvic lymph nodes. Our preliminary observations suggest that the agent is most useful for classifying normal lymph nodes.     

Bone marrow: ultrasmall superparamagnetic iron oxide for MR imaging

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was evaluated as a potential intravenous contrast agent for magnetic resonance (MR) imaging of bone marrow. One hour after administration of USPIO (40, 80, and 160 mumols of iron per kilogram body weight) in rats and rabbits, T1 and T2 relaxation times were, respectively, approximately 30%, 50%, and 65% lower than precontrast relaxation times. Maximum decrease in relaxation times of marrow occurred within 1-24 hours after intravenous administration; thereafter, relaxation times slowly returned to normal within 7 days. In vivo MR imaging of rabbits and rats confirmed that USPIO decreases signal intensity of red and yellow marrow. The decrease was most marked with gradient echo pulse sequences. An animal model of intramedullary tumor demonstrated the potential of USPIO to enable differentiation between tumor and normal red marrow. USPIO-enhanced MR imaging improves detection of smaller tumors and allows differentiation of tumor deposits from islands of hyperplastic or normal red marrow.     

MR angiography with an ultrasmall superparamagnetic iron oxide blood pool agent

The purpose of the study was to investigate the use of a dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) as a blood pool contrast agent for thoracic and abdominal MR angiography. Abdominal and thoracic MR angiography was performed in six healthy volunteers using two-dimensional and three-dimensional spoiled gradient echo (SPGR) sequences before and after intravenous administration of USPIO. Doses ranged from 1.1 to 2.6 mg Fe/kg. Flip angle was varied from 20 to 60°. Subjective image quality, analysis of signal-to-noise ratio (SNR), and blood T1 relaxation times were measured. USPIO significantly lowered the T1 of blood (from 1,210 ms precontrast to 159 ms postcontrast at a dose of 2.6 mg Fe/kg) (P < .01). Image quality on coronal fast three-dimensional breath-hold SPGR images of the abdomen increased with increasing dose and was maximum at the highest dose, producing an aortic SNR of 9.6 compared to 1.8 precontrast. Axial two-dimensional time-of-flight (TOF) aortic SNR was reduced significantly from 13 on precontrast to 6 on the postcontrast images at the highest dose (P < .05) due to T2* shortening effects. There was little flip angle dependence on image quality. Due to the T1 shortening effect and long intravascular half-life, USPIO improved visualization of vascular anatomy using three-dimensional fast SPGR imaging. The echo time must be minimized to minimize signal loss from T2* shortening effects. The blood pool distribution of USPIO is useful for equilibriumphase MR angiography.     

MR imaging with ultrasmall superparamagnetic iron oxide particles in experimental soft-tissue infections in rats

PURPOSE: To investigate the feasibility of macrophage magnetic resonance (MR) imaging in rats by using an experimental soft-tissue infection model. MATERIALS AND METHODS: Thirteen rats with unilateral calf-muscle infection were imaged with a 4.7-T MR imager at an early chronic stage of infection (day 4 before contrast material injection, days 4-7 after injection). Eleven animals were imaged before and 3 and 24 hours after intravenous application of ultrasmall superparamagnetic iron oxide (USPIO), and eight animals were additionally imaged 48 hours and three animals 72 hours after USPIO application. Two infected rats served as controls. T1- and T2-weighted spin-echo and T2*-weighted gradient-echo sequences were applied. All animals were sacrificed, and histopathologic findings were correlated with findings on MR images. Electron microscopy was performed in two rats. For quantitative analysis, signal intensities on T2*-weighted images and T2 values on T2 maps were measured within regions of interest, and the temporal variation was analyzed by using the signed rank test. RESULTS: Visualization of USPIO-loaded macrophages was most sensitive with a T2*-weighted sequence. USPIO distribution pattern and quantitative analysis of T2 and T2* effects 3 hours after USPIO application were significantly different (P <.05) from those at 24 and 48 hours, reflecting the dynamic transit of the particle accumulation from the intravascular to the intracellular compartment by means of macrophage phagocytosis. Local signal intensity alterations could be correlated with iron-loaded macrophages at histopathologic examination. CONCLUSION: Activated macrophages in acute soft-tissue infection can be labeled with USPIOs and detected with MR imaging because of susceptibility effects.     

Use of ultrasmall superparamagnetic iron oxide in lymph node MR imaging in prostate cancer patients

A macrophage-specific magnetic resonance (MR) contrast agent allows the detection of small and otherwise undetectable lymph node metastases in patients with prostate cancer. This has an important clinical impact, as the diagnosis will be more precise and less invasive to obtain. Subsequently, this will reduce morbidity and health care costs. However, thorough knowledge of sequence parameters and planes, lymph node anatomy, appearance of normal and abnormal nodes, is essential when using this technique. This will be elaborated in this review.     

Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall superparamagnetic iron oxide enhancement

PURPOSE: To evaluate magnetic resonance (MR) imaging with ultrasmall superparamagnetic iron oxide (USPIO) enhancement for preoperative axillary lymph node staging in patients with breast cancer by using histopathologic findings as the standard of reference. MATERIALS AND METHODS: MR imaging was performed with a 1.5-T system within 24-36 hours after the start of intravenous slow-drip infusion of USPIO in 20 patients with breast cancer who were scheduled for surgery, followed by gadolinium-enhanced MR imaging. Lymph nodes were staged prospectively by using newly established criteria, and results were correlated with histologic findings. RESULTS: In two patients, preoperative findings led to a change in therapeutic approach, and neoadjuvant chemotherapy was given; both patients were excluded from statistical analysis. Results of axillary staging with USPIO-enhanced MR imaging were true-positive in nine, true-negative in seven, false-positive in zero, and false-negative in two of 18 patients (sensitivity, 82%; specificity, 100%; positive predictive value, 100%; second reader, kappa = 1.0). Four hundred five lymph nodes were detected with MR imaging. For first and second readers, respectively, lymph node-based sensitivity was 83% and 73% and specificity was 96% and 97% (kappa = 0.68). USPIO as the intravascular contrast agent could not replace gadolinium for assessment of the primary tumor; however, no clinically relevant interaction was seen. Thus, an integrated imaging approach was feasible in all patients. CONCLUSION: USPIO-enhanced MR imaging has the potential to become an adjunct to conventional MR imaging of the breast for preoperative assessment of axillary lymph nodes in patients with breast cancer.     

Evaluation of portal MR angiography using superparamagnetic iron oxide

The purpose of our research was to determine the effects of superparamagnetic iron oxide on MR imaging of the portal venous system. Eight piglets were examined in deep anaesthesia and respiratory arrest using a time-of-flight magnetic resonance fast low angle shot, two-dimensional angiography sequence at 1.5T. MR angiograms were acquired precontrast and after intravenous administration of a cumulative dose of 10, 20 and 40 μmol/kg SHU 555A, a superparamagnetic iron oxide contrast agent for MR imaging with a particle size of 60 nm. For each dose, two subsequent sets of scans were obtained and reconstructed by a maximum-intensity-projection algorithm. Hepatic parenchymal and portal venous signal intensities were measured, and portal vein contrast calculated for each set of scans. All examinations were visually rated as to portal vein contrast and homogeneity by two blinded observers. Receiver operating characteristics of both observers were analyzed. The contrast agent reduced hepatic parenchymal signal in a dose-dependent way. After a cumulative dose of 10 μmol iron oxide, hepatic parenchymal signal intensity decreased to 63 ± 6% (average of measurements at 4 and 14 minutes, mean ± standard error of the mean), after 20 μmol to 24 ± 3%, and after 40 μmol to 12 ± 1% of control. Intra-vascular signal in the left main portal vein branch increased to 117 ± 6%, 127 ± 10%, and 133 ± 9% of control, respectively. The contrast-to-noise ratio of the portal vein improved (521 ± 90%, 891 ± 178%, and 995 ± 201% of control in the left portal vein main branch). Intravascular signal intensities increased slightly. The combined effect improved contrast of the portal vein stem and its branches. Receiver operating characteristics analysis documented dose-dependency of contrast medium effects on portal venous contrast and intravascular homogeneity. Visual rating also indicated a positive effect on portal venous contrast. The superparamagnetic iron oxide agent improved portal venous contrast with surrounding hepatic parenchyma in this normal animal model, and could potentially result in more accurate diagnosis of portal venous pathology.     

Functional-morphologic MR imaging with ultrasmall superparamagnetic particles of iron oxide in acute and chronic soft-tissue infection: study in rats

PURPOSE: To investigate the use of magnetic resonance (MR) imaging enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) to identify acute, early chronic, and late chronic abscess formation in an experimental model of soft-tissue abscess. MATERIALS AND METHODS: Experimental soft-tissue infection in 15 rats was imaged with an MR imaging unit on days 1 and 2 (acute), days 5 and 6 (early chronic), and days 8 and 9 (late chronic) after inoculation of the infectious agent. All animals were imaged without contrast enhancement and immediately and 24 hours after USPIO administration. MR and histopathologic findings were compared. The changes in relative signal intensity (SI) and in the extent and pattern of contrast enhancement (macrophage distribution) between the animal groups were analyzed. Statistical testing was performed with Kruskal-Wallis analysis of variance and the chi2 test. RESULTS: At 24 hours after USPIO administration, the relative SI of the abscess wall and the relative macrophage extent were 0.50 (0.33-0.73) and 1.03 (0.90-1.08), respectively, for acute infection; 0.11 (0.10-0.18) and 0.94 (0.93-1.01) for early chronic infection; and 0.53 (0.44-0.58) and 0.80 (0.77-0.83) for late chronic infection. The changes in enhancement pattern (P <.001), relative SI (P <.001), and relative macrophage extent (P <.05) with time were significant. CONCLUSION: The macrophage distribution pattern increases the specificity of MR findings in chronic infection and allows differentiation between areas with active inflammation and areas of reparative granulation tissue.     

MR angiography with superparamagnetic iron oxide: feasibility study.

Magnetic resonance (MR) angiography with blood-pool superparamagnetic iron oxide (SPIO) particles was evaluated in the whole-body vascular system. In 12 adult patients, three-dimensional fast imaging with steady-state precession was performed in successive steps from the lungs to the calves before and after a standard dose for liver imaging (15 mumol of iron per kilogram of body weight) of AMI-25. On SPIO-enhanced MR angiograms, visualization of the pulmonary arterial, whole-body, and lower extremity venous systems was graded as good or sufficient in all patients, and femoral vein thrombosis was clearly demonstrated in one patient.     

Characteristics of ultrasmall superparamagnetic iron oxides in patients with brain tumors

OBJECTIVE: The aim of this study was to evaluate the characteristics of an ultrasmall superparamagnetic iron oxides (USPIO) agent in patients with brain tumors and to correlate changes on MRI with histopathologic data collected systematically in all patients. SUBJECTS AND METHODS: Nine patients with brain tumors were imaged before and 24 hr after administration of a USPIO at a dose of 2.6 mg Fe/kg. Analysis of MR images included qualitative and quantitative comparison of the USPIO and gadolinium enhancement of brain tumors. Brain surgery was performed 25-112 hr after administration of the USPIO. The histopathologic workup included iron histochemistry with diaminobenzidine (DAB)-enhanced Perls stain. RESULTS: In seven of nine patients, USPIO-related changes of signal intensity were observed in gadolinium-enhancing brain tumors on T1- and T2*-weighted sequences. The difference in signal intensity on T1-weighted USPIO series was 40.1% +/- 26.7% (mean +/- SD). On T2*-weighted USPIO series, the difference in signal intensity was -33.1% +/- 18.4% in solid tumor parts. Areas of suspected radiation necrosis did not enhance in three patients with prior radiation therapy. Iron histochemistry revealed the presence of iron deposits in macrophages in two patients. CONCLUSION: USPIO agents will not replace gadolinium in the workup of patients with brain tumors. Our findings suggest that USPIO agents seem to offer complementary information and may help to differentiate between brain tumors and areas of radiation necrosis. Signal intensity changes on T2*-weighted images might be related to the blood pool properties of the agent, possibly reflecting steady-state susceptibility effects.     

超小型超顺磁氧化铁粒子对比剂的应用现状及进展

超小型超顺磁氧化铁粒子作为一种新型的磁共振对比剂,在淋巴结的良、恶性鉴别,肿瘤病灶的显示,提高磁共振血管成像的图像质量,明确动脉粥样硬化性疾病的斑块的稳定性,鉴别软组织急、慢性炎性病变以及MR活体移植细胞示踪等方面已有所应用.随着在基础及临床方面研究的深入,超小型超顺磁氧化铁粒子将会改变现有的影像诊断模式,对一些疾病的现有治疗模式提出挑战并发生革命性的变革.     

Imaging of macrophages in soft-tissue infection in rats: relationship between ultrasmall superparamagnetic iron oxide dose and MR signal characteristics

PURPOSE: To describe dose-dependent signal intensity (SI) characteristics of experimentally induced soft-tissue abscesses on 1.5-T T1- and T2*-weighted magnetic resonance (MR) images obtained 24 hours after administration of ultrasmall superparamagnetic iron oxide (USPIO) and to describe the relationship between SI and amount of USPIO uptake and macrophage iron content. MATERIALS AND METHODS: Local institutional review committee on animal care approved the experiments, which were performed according to the guidelines of the National Institutes of Health and the committee on animal research at our institution. Unilateral calf muscle abscesses were induced in 21 rats with an injection of a Staphylococcus aureus suspension. The rats were divided into three groups of seven animals each: low USPIO dose (50 micromol of iron per kilogram of body weight), high USPIO dose (150 micromol Fe/kg), and control (saline solution). All rats were imaged before and 24 hours after USPIO administration at 1.5 T (transverse T1-weighted spin-echo, T2*-weighted fast gradient-echo, and short inversion time inversion-recovery sequences). Images were analyzed quantitatively and qualitatively with regard to SI and signal pattern. Temporal variation of calculated contrast-to-noise ratios was analyzed with the Wilcoxon signed rank test. MR findings were correlated with histopathologic findings, including those of electron microscopy. RESULTS: Twenty-four hours after USPIO administration in the high-dose group, susceptibility effects were present in abscess periphery on postcontrast T2*-weighted images (P=.04), and SI enhancement was noted on postcontrast T1-weighted images within both abscess wall and abscess center (P=.04 for both). In the low-dose group, SI enhancement was noted in entire abscess on T1-weighted postcontrast images (P=.03). Neither significant SI loss (P=.09) nor susceptibility effects were detected in periphery or center of any abscess on postcontrast T2*-weighted images. There was no obvious difference in total amount of macrophages among the groups, but there was a clear difference with regard to individual iron content of iron-positive macrophages between the USPIO dose groups. CONCLUSION: At 1.5 T, SI characteristics of abscesses on T1- and T2*-weighted images obtained 24 hours after USPIO injection strongly depend on administered dose of the contrast agent. At low doses, T1 effects were stronger than T2* effects.     

Evaluation of axillary lymph nodes by diffusion-weighted MRI using ultrasmall superparamagnetic iron oxide in patients with breast cancer: initial clinical experience

Purpose:

To investigate the diagnostic performance and clinical feasibility of diffusion‐weighted magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxide (USPIO) in the evaluation of axillary lymph nodes (ALNs) in patients with breast cancer.

Materials and Methods:

Sixteen patients with known breast cancer underwent 1.5 T MRI. Axial diffusion‐weighted images (DWIs) and conventional T1‐ and T2*‐weighted images (CIs) were acquired before and 24–36 hours after intravenous administration of USPIO. Detection of ALNs was evaluated on DWIs in comparison with CIs. The apparent diffusion coefficient values (ADCvs) of the nonmetastatic and metastatic nodes in precontrast DWIs were determined. The diagnostic performance of DWI using USPIO was compared with that of CIs using USPIO with pathological correlation.

Results:

Out of a total of 286 ALNs, 216/286 (76%) nodes were detected on DWIs and 238/286 (83%) on CIs. The differences in the ADCvs between metastatic and nonmetastatic nodes were not significant (P = 0.06). Sensitivity of CIs and DWIs using USPIO were respectively 70% and 83%, specificity 98% and 98%, and overall accuracy 93% and 95%.

Conclusion:

Although the detection on DWIs of ALNs in patients with breast cancer was inferior compared to CIs, the sensitivity and accuracy of DWIs using USPIO were superior in the diagnosis of ALNs metastasis. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.     

Enhancement of phase-contrast MR angiography with superparamagnetic iron oxide

The effect of superparamagnetic iron oxide particles (AMI-227) was assessed in three-dimensional (3D) phase-contrast (PC) MR angiography (MRA), with various scanning parameters for rats at 1.5 T. The blood T1 and T2 before and after 20 μmol Fe/kg of AMI-227 injection were measured sequentially at .47 T. The visualization of abdominal aorta, renal artery, inferior vena cava, and portal vein was respectively evaluated before and after AMI-227 injection qualitatively by the four confidence levels and quantitatively by analysis of signal-to-noise ratio (SNR) of vessels. The blood T1 and T2 were sufficiently shortened for at least 1 hour after AMI-227 injection. The visualization of each vessel was improved by AMI-227 at various velocity encoding (VENC) value, suggesting the extended application of PC-MRA in various conditions. The optimal flip angle was increased from 20° to 30° in higher VENC after AMI-227 injection, resulting in higher signal from blood flow. Quantitative analyses showed that the optimal flip angle to achieve the maximum SNR seemed to be 20° in unenhanced images, but the optimal flip angle of the high speed flow was increased by contrast enhancement. The postcontrast PC-MRA provides the increased sensitivity of slow flow components, even with a high VENC gradient. AMI-227 can significantly improve SNR to blood vessels during 3D-PC-MRA with various scanning parameters.     

Multicenter clinical trial of ultrasmall superparamagnetic iron oxide in the evaluation of mediastinal lymph nodes in patients with primary lung carcinoma.

The purpose of this study was to evaluate the clinical efficacy of ultrasmall superparamagnetic iron oxide particles as a magnetic resonance (MR) contrast agent in differentiating metastatic from benign lymph nodes. Eighteen patients with primary lung malignancy and suspected regional lymph node metastases underwent MR imaging before and after Combidex(R) infusion in a multi-institutional study. All MR sequences were interpreted by one or more board-certified radiologists experienced in imaging thoracic malignancy. Each patient was evaluated for the number and location of lymph nodes, homogeneity of nodal signal, and possible change of MR signal post contrast. All patients underwent resection or sampling of the MR-identified lymph node(s) 1-35 day(s) post contrast MR imaging. In all, 27 lymph nodes or nodal groups were available for histopathologic correlation. Combidex had a sensitivity of 92% and a specificity of 80% in identifying pathologically confirmed metastatic mediastinal lymph nodes. Based on our preliminary data, Combidex MR imaging may provide additional functional information useful in the staging of mediastinal lymph nodes.     

MRI of arthritis: comparison of ultrasmall superparamagnetic iron oxide vs. Gd-DTPA

PURPOSE: To compare the ability of the ultrasmall superparamagnetic iron oxide (USPIO) SHU555C vs. gadopentetate dimeglumine (Gd-DTPA) to detect antigen-induced monoarthritis with MRI. MATERIALS AND METHODS: Twelve seven-week-old female rats with an antigen-induced monoarthritis of the right knee were randomly assigned to two groups. Animals in group I (N = 6) underwent MRI using T1-weighted gradient-echo sequences before injection and at 2, 9, 17, 25, 33, 40, 47, 55, and 63 minutes postinjection (p.i.) of Gd-DTPA on day 1, and before injection and at 3, 23, 43, and 123 minutes p.i. of SHU555C on day 2. Animals in group II (N = 6) were imaged before injection and at 3, 23, 43, and 123 minutes p.i. using identical sequences. Signal-to-noise ratios (SNRs) and relative enhancement (DeltaSI%) of arthritic and normal synovium were determined from region-of-interest (ROI) measurements in consensus reading by two experienced radiologists. Data were tested for significant differences between the two agents and between the arthritic and normal knees using a mixed-effect model and F-tests (P < 0.05). Joints were processed for histopathology as the gold standard. RESULTS: USPIO and Gd-DTPA showed significant enhancement differences (P < 0.001). USPIO provided a progressive and persistent enhancement of arthritic joints while Gd-DTPA provided an early and rapidly declining enhancement. Maximal enhancement in synovitis was 400% at 40-120 minutes p.i. of USPIO vs. 300% at two minutes p.i. of Gd-DTPA. USPIO provided a significant higher difference in enhancement between the arthritic and normal synovium than Gd-DTPA (P < 0.001). Histopathology confirmed marked inflammatory synovial changes in all arthritis-induced right knee joints and normal synovium in all left knee joints. CONCLUSION: Both USPIO and Gd-DTPA detect arthritis by positive T1-enhancement. Compared to standard Gd-DTPA, the USPIO SHU555C provides a comparable maximal T1-enhancement (at two minutes p.i for Gd-DTPA and between 43 and 123 minutes p.i. for SHU555C), but in addition it provides a prolonged T1-enhancement of synovitis and a higher difference between the relative enhancement of arthritic and normal synovium.     

MRI study of atherosclerotic plaque progression using ultrasmall superparamagnetic iron oxide in Watanabe heritable hyperlipidemic rabbits

Objective:

The purpose of this study was to evaluate plaque progression by using MRI with ultrasmall superparamagnetic iron oxide (USPIO) and by histopathological studies.

Methods:

We divided 12 Watanabe heritable hyperlipidemic (WHHL) rabbits into 4 groups based on their age (3, 9, 14 and 26 months) and injected them intravenously with 0.8 mmol (Fe) kg⁻¹ of USPIO (size, 32 nm; concentration, 15 mg dl⁻¹). On the fifth post-injection day, they were again given an intravenous injection with 40 μmol kg⁻¹ of the same USPIO, and MR angiography (MRA) was performed. The signal-to-noise ratio (SNR) in regions of interest in the wall of the upper abdominal aorta was calculated on coronal images. Specimens from the same level of the aorta were subjected to iron staining and RAM-11 immunostaining and used for histopathological study. For statistical analysis of the MRA and histopathological findings, we used analysis of variance [Tukey''s honest significant difference (HSD) test].

Results:

In 9-month-old rabbits, the SNR was significantly lower than in rabbits of the other ages (p < 0.01), and the area of RAM-11 (DAKO Corporation, Glostrup, Denmark) and iron uptake in the aortic wall was significantly larger (RAM-11, p < 0.01; iron, p < 0.05). These areas were the smallest in 3-month-old rabbits.

Conclusion:

Histopathologically, the number of macrophages was the greatest in 9-month-old rabbits. Our findings indicate that the SNR on MRI scans reflects the number of macrophages in the aortic wall of WHHL rabbits.

Advances in knowledge:

USPIO-enhanced MRI visualized the accumulation of macrophages in early atherosclerotic plaques of WHHL rabbits in the course of natural progression.