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.     

Ultrasmall superparamagnetic iron oxide enhanced MR imaging for lymph node metastases

The presence of a lymph node metastasis is one of the most important factors influencing therapeutic planning and prognosis in patients with malignancy. For example, a single nodal metastasis approximately halves the survival rate in patients with head and neck cancer, regardless of the location or size of the primary tumor. Currently used imaging techniques such as CT or conventional MRI are unreliable in detecting involved nodes accurately. There are few new techniques that have proven to be of value in nodal staging, and one such technique is ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for MRI. Administered intravenously, USPIO are phagocytosed by macrophages within lymph nodes. Homogeneous uptake of iron oxide particles in normal lymph node shortens the T2 and T2*, turning these nodes dark on post contrast images whereas malignant nodes, lacking the normal physiologic uptake, remain hyperintense on T2- and T2*-weighted images. These differences in signal intensity between normal and metastatic nodes are easily detected visually, leading to high sensitivity and specificity regardless of size or morphological features.This article will review the physiologic properties of USPIO, the technical considerations for imaging using USPIO agent, the results of various clinical trials, and other experimental agents, as well asthe future directions.     

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.     

Lymph node metastasis: ultrasmall superparamagnetic iron oxide-enhanced MR imaging versus PET/CT in a rabbit model

PURPOSE: To prospectively compare the diagnostic accuracy of ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging and integrated positron emission tomography-computed tomography (PET/CT) for the depiction of lymph node metastasis in an animal model, with histologic findings as the reference standard. MATERIALS AND METHODS: This experiment was approved by the local animal care committee. VX2 carcinoma was implanted into the thighs of 11 rabbits 4 weeks before the imaging study. T2- and T2*-weighted MR examinations were performed 24 hours after USPIO administration, followed by integrated PET/CT. USPIO-enhanced MR imaging and PET/CT analysis for the evaluation of the presence of metastasis in iliac lymph nodes were performed independently by two radiologists and two nuclear medicine physicians, respectively, without histopathologic knowledge. Results were evaluated by using receiver operating characteristic (ROC) analysis, and sensitivities and specificities were compared by using a Z test. RESULTS: Metastases were histopathologically confirmed in 22 of 62 iliac lymph nodes. USPIO-enhanced MR imaging showed a significantly greater area under the ROC curve than did PET/CT (0.984 vs 0.852; P=.023). The respective sensitivity and specificity for the detection of lymph node metastasis were 91% (20 of 22) and 95% (38 of 40) for USPIO-enhanced MR imaging and 64% (14 of 22) and 98% (39 of 40) for PET/CT. In terms of sensitivity, a significant difference was found between USPIO-enhanced MR imaging and PET/CT, particularly for nodal metastasis of less than 5 mm (86% [six of seven] vs 0% [zero of seven]; P=.031), whereas the specificity of the two imaging modalities was similar (P=.226). CONCLUSION: USPIO-enhanced MR imaging results in higher diagnostic accuracy for depicting lymph node metastasis than does PET/CT.     

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.     

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.     

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.     

Evaluation of lymph node metastases of breast cancer using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging

BACKGROUND: We assessed the utility of enhanced magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxide (USPIO) in the evaluation of axillary lymph node metastases in patients with breast cancer. STUDY DESIGN: MR examination of the axilla was performed before and 24-36 h after USPIO administration for patients with stage II or III breast cancer. Diagnostic performance was compared using size criteria (metastasis was defined when short axis diameter >5 or >10mm) or morphologic criteria on conventional MRI, the combined study of USPIO precontrast and postcontrast images, and USPIO postcontrast study alone. RESULTS: A total of 622 nodes (503 metastatic and 119 nonmetastatic nodes) were dissected from 33 patients. The results of conventional MRI for nodes >5mm were 59.1% sensitivity, 86.7% specificity, and 80.4% overall accuracy. Results for nodes >10mm were 15.7% sensitivity, 99.2% specificity, and 80.2% overall accuracy. Results based on morphology were 36.5% sensitivity, 94.1% specificity, and 81.0% overall accuracy. The results of the combined study of USPIO precontrast and postcontrast images were 86.4% sensitivity, 97.5% specificity, 91.1% positive predictive value, 96.1% negative predictive value, and 95.0% overall accuracy. The results of USPIO postcontrast images alone were 84.7% sensitivity, 96.8% specificity, and 94.0% overall accuracy. Patient-based results of postcontrast USPIO study alone were 100.0% sensitivity, 80.0% specificity, and 93.9% overall accuracy. CONCLUSIONS: USPIO postcontrast study alone was useful in the assessment of axillary lymph node metastases in patients with breast cancer.     

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.     

Pelvic lymph node visualization with MR imaging using local administration of ultra-small superparamagnetic iron oxide contrast

PURPOSE: To determine if interstitial injection of iron oxide particles improves visualization of pelvic lymph nodes at magnetic resonance imaging (MRI) and to determine the effect of injection site on location of visualized nodes. MATERIALS AND METHODS: In nine healthy volunteers, ferumoxtran-10 iron oxide (0.28 mg iron per kg) was injected into the anterior thigh (three subjects) or perianal (three subjects) or periprostatic tissues (three subjects). MRI at 1.5 T was performed before injection and one, three, and seven days after injection. RESULTS: The mean of 30 nodes seen post-injection was greater than the mean of 5.8 seen pre-injection (P < 0.001). After thigh injection, a mean of three internal vs. 36 external nodes were seen. Compared with thigh injection, there was a higher fraction of internal nodes with perianal (mean of nine internal vs. 14 external, P < 0.001) and periprostatic injection (mean of 11 internal vs. five external, P < 0.001). More nodes were seen with gradient-echo sequences than with other sequences (P < 0.001). CONCLUSION: Interstitial injection of iron oxide particles increases visualization of pelvic lymph nodes. Perianal and periprostatic injection increases the number of internal pelvic lymph nodes seen compared with thigh injection.     

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.     

Contrast-enhanced MR imaging of liver and spleen: First experience in humans with a new superparamagnetic iron oxide

The aim of this prospective study was to obtain the first human safety and magnetic resonance (MR) imaging results with a new formulation of superparamagnetic iron oxide (SPIO) (SHU 555 A). The SPIO was tested at four iron doses, from 5 to 40 μmol/kg. Laboratory tests and clinical measurements were done in 32 healthy volunteers for up to 3 weeks after administration. MR imaging at 1.5 T was performed before and 8 hours to 14 days after fast intravenous injection (500 μmol Fe/min) of the SPIO (six subjects per dose). Results of this phase I study demonstrate that SHU 555 A at a concentration of 0.5 mol Fe/L was well tolerated. A dose-dependent minor increase in activated partial thromboplastin time, which remained within the normal range, was seen. All doses of SPIO caused a signal loss in both liver and spleen (P <.05) with a spin-echo sequence (TR = 2,300 msec, TE = 45 msec). The signal losses in the liver 8 hours after contrast agent injection were 58%, 79%, 82%, and 87% for the 5, 10, 20, and 40 μmol Fe/kg doses, respectively. The corresponding signal losses in the spleen were 23%, 45%, 65%, and 78%, respectively. The doses that reduced signal intensity by half were 3.1 μmol Fe/kg for the liver and 12.8 μmol Fe/kg for the spleen. The results suggest that the new SPIO formulation is a safe and efficient MR contrast agent.     

Splenic imaging with ultrasmall superparamagnetic iron oxide ferumoxtran-10 (AMI-7227): preliminary observations

PURPOSE: Ferumoxtran-10 (ultrasmall superparamagnetic iron oxide; Combidex, AMI-7227) is a long-circulating MR contrast agent with reticuloendothelial uptake known to enhance tissue T1 and T2 relaxation rates. The purpose of this study was to assess the effect of ferumoxtran-10-enhanced MRI in evaluating focal splenic lesions. METHOD: Eighteen patients underwent MR evaluation of the spleen. Two of these patients with exophytic normal splenic tissue (splenules) and 13 of these patients with 24 focal splenic lesions (7 cysts, 2 hemangiomas, 7 metastases, 1 infarct, 7 lymphoma) were assessed by T1-weighted gradient echo and T2-weighted fast SE MRI following intravenous administration of ferumoxtran-10 (1.1 mg of Fe/kg). Qualitative analysis involving improved lesion detection and/or characterization, additional information from postcontrast images affecting staging, and patient management was performed. Quantitative measurements of lesion-to-spleen contrast-to-noise ratio were also performed. RESULTS: Additional information was provided by ferumoxtran-10-enhanced images in 15 of 18 patients. In 8 of 15 (53%) patients, improved lesion detection (i.e., number of lesions) was obtained on contrast-enhanced images. Improved lesion visualization (i.e., conspicuity) was noted in 11 of 15 (73%) of patients. In 10 of 15 (67%) patients, postcontrast imaging provided additional information leading to lesion characterization. Staging of disease and patient management were affected in 5 of 15 (33%) and 6 of 15 (40%) patients, respectively. CONCLUSION: Ferumoxtran-10 is a promising contrast agent for the evaluation of focal splenic lesions.     

MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic-pathologic correlation

OBJECTIVE: The purpose of this study was to administer ultrasmall superparamagnetic iron oxide (USPIO) and compare changes in signal intensity of lymph nodes in patients with primary abdominal and pelvic malignancies. Also, we correlated radiographic with pathologic findings. SUBJECTS AND METHODS: Nineteen patients with proven primary abdominal or pelvic cancer (prostatic [n = 10]; colonic [n = 5]; endometrial [n = 1]; Merkel cell tumor [n = 1]; lymphoma [n = 1]; seminoma [n = 1]) were enrolled as part of our phase II and phase III clinical trials. In these patients, 49 lymph nodes (mean size, 1.4 cm) revealed on CT or MR imaging were evaluated on T1-weighted spin-echo, T2-weighted fast spin-echo, and T2*-weighted gradient-echo MR imaging at 1.5 T 24-36 hr after IV administration of USPIO. Quantitative analyses used measurements of unenhanced and enhanced region-of-interest values in lymph nodes. Qualitative assessment used subjective evaluation and classification of changes in signal intensity. All patients underwent lymph node biopsy or surgical dissection followed by histopathologic correlation. RESULTS: Of the 49 lymph nodes that were evaluated, 20 were benign and 29 were malignant. A decrease in nodal signal intensity on enhanced T2-weighted and T2*-weighted gradient-echo images was seen in 20 benign lymph nodes and two malignant lymph nodes. No appreciable signal change was noted in 27 of the 29 malignant lymph nodes. The mean signal intensity on fast spin-echo T2-weighted images for benign lymph nodes changed from 186.48 (unenhanced) to 73.66 (enhanced). Conversely, mean signal intensity for malignant lymph nodes was relatively unchanged from 191.17 (unenhanced) to 183.18 (enhanced). CONCLUSION: USPIO appears to be a useful MR contrast agent for characterizing benign and malignant lymph nodes based on the enhancement criteria evaluated in our study.     

MR receptor imaging: ultrasmall iron oxide particles targeted to asialoglycoprotein receptors

Previously we have reported that ultrasmall superparamagnetic iron oxide (USPIO) particles migrate across capillary endothelium, a prerequisite for the design of particulate pharmaceuticals for MR receptor imaging. In the current study, USPIO particles are directed specifically to asialoglycoprotein (ASG) receptors by coupling galactose terminals in the form of arabinogalactan (AG) to these particles. Biodistribution data showed that ASG-directed, AG-coated USPIO (AG-USPIO) particles selectively accumulate in the liver but not in other organs. Electron microscopy of liver showed electron-dense iron oxide particles bound to hepatocyte cell-surface membranes and in large numbers within intracellular lysosomes. The specificity of AG-USPIO for asialoglycoprotein receptors was confirmed by incubation experiments with and without ASG-blocking agents such as D(+)galactose and asialofetuin. In vivo MR imaging in rats showed a significant decrease in liver signal intensity at low doses (2 mumol Fe/kg); no significant changes were observed in the spleen. This decrease in signal intensity is larger than that observed with conventional iron oxides at equal doses. These initial data suggest that, for the first time, superparamagnetic agents can be directed to specific sites for MR imaging by strategies such as receptor targeting.     

Detection of liver metastases with superparamagnetic iron oxide in 15 patients: results of MR imaging at 1.5 T

The first clinical results of using superparamagnetic ferrite particles as a tissue-specific contrast agent for MR of the liver are reported at high fields (1.5 T). Fifteen patients with proved secondary liver malignancies were studied with plain and contrast-enhanced MR. Superparamagnetic iron oxide was administrated IV in a dose of 20 mumol/kg. Intermediate TR, 820/30, 60 (TR/TE), and long TR, 2200/22, 70, spin-echo sequences were used before and 1 hr after injection of contrast material. Before injection, the largest number of lesions (437) was detected with the T2-weighted sequence. Lesion-to-liver contrast, expressed as the difference between the tumor and liver signal-to-noise, improved after ferrite administration in both sequences from -1 to 20 and from 7 to 15 for the 820/30, 60 sequence and from 9 to 34 and 15 to 21 for the 2200/22, 70 sequence. Despite this significant improvement in terms of the number of lesions detected, contrast-enhanced images did not show significantly more metastases than the unenhanced T2-weighted images did (383, 421, 407, and 407 vs as many as 437, respectively). In this limited study at 1.5 T, the benefit of ferrite enhancement was only marginal when postcontrast images were compared with heavily T2-weighted precontrast scans.