Application of superparamagnetic iron oxide to imaging of hepatocellular carcinoma

Superparamagnetic iron oxide (SPIO) particles are as MR contrast media composed of iron oxide crystals coated with dextran or carboxydextran. These particles are sequestered by phagocytic Kupffer cells in normal reticuloendothelial system (RES), but are not retained in tumor tissue. Consequently, there are significant differences in T2/T2* relaxation between normal RES tissue and tumors, which result in increased lesion conspicuity and detectability. The introduction of SPIO has been expected to substantially increase the detectability of hepatic metastases. For focal hepatocellular lesions, it has been documented that SPIO-enhanced MR imaging exhibits slightly better diagnostic performance than dynamic helical CT in the detection of hypervascular hepatocellular carcinoma (HCC). A combination of dynamic and static MR imaging technique using T1- and T2 imaging criteria appears to provide clinically more useful patterns of enhancement. SPIO-enhanced MR imaging also provides information useful for differential diagnosis, via enhancement of RES-containing tumors. With the exploitation of rapid T2*-sensitive sequences, SPIO-enhanced dynamic MR imaging may become comparable to gadolinium-enhanced dynamic MR imaging and dynamic studies with multidetector-row CT. SPIO-enhanced MR imaging plays an important role in therapeutic decision-making for patients with HCC.     

Contrast enhancement with GD-EOB-DTPA in MR imaging of hepatocellular carcinoma in mice: A comparison with superparamagnetic iron oxide

The purpose of this study was to evaluate the ability of the new liver-specific magnetic resonance contrast agent gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) to detect hepatocellular carcinoma (HCC). Seventeen mice with 66 chemically induced HCCs underwent magnetic resonance imaging with both Gd-EOB-DTPA (30 μmol/kg) and superparamagnetic iron oxide (SPIO; 10 μmol/kg). After enhancement, lesion-to-liver contrast-to-noise ratios (CNRs) of 47 detected HCCs increased negatively from 3.7 ± 10.7 (mean ± SD) to –55.1 ± 25.8 with Gd-EOB-DTPA (P < .001) and increased positively from 10.4 ± 10.4 to 26.1 ± 16.3 with SPIO (P < .001). The improvement of CNR after administration of SPIO was less in smaller lesions (< 4 mm), whereas that after administration of Gd-EOB-DTPA was independent of lesion size. However, Gd-EOB-DTPA positively enhanced four HCCs (8.5%), both highly differentiated (grade 1) and moderately differentiated (grade 2). Gd-EOB-DTPA allows the conspicuous detection of small HCCs; however, moderately differentiated HCCs occasionally may be positively enhanced.     

超顺磁性氧化铁纳米粒子在原发性肝癌诊断与治疗中的研究进展

原发性肝癌(hepatocellular carcinoma,HCC)是我国最常见的恶性肿瘤之一,其发病率居于恶性肿瘤第5位.肝癌患者5年生存率仅有7%,全球每年约有60万以上患者死于肝癌,位居肿瘤相关死亡率的第3位[1].我国是肝癌的高发区,目前发病人数占全球的55%,在肿瘤相关死亡中仅次于肺癌,位居第2.由于HCC早期症状隐匿,合并肝硬化的发生率极高,肝功能储备差,病人就诊时多属中晚期,手术切除率较低,能够手术切除者不足20%,且切除后复发率较高[2].因此,肝癌的早期诊断与治疗面临着巨大的挑战.     

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.     

Perfusion study of liver lesions with superparamagnetic iron oxide: distinguishing hepatocellular carcinoma from focal nodular hyperplasia

We performed a perfusion study with superparamagnetic iron oxide (SPIO) and evaluated the possibility of acquiring hemodynamic imaging in hypervascular hepatocellular nodules. Single-slice computed tomography during arteriography (SCTA) and an SPIO perfusion study were performed and compared. The findings of the direction of blood flow in the lesion and the findings corresponding to the corona enhancement on the SPIO perfusion study agreed well with the findings of SCTA. In conclusion, SPIO perfusion is useful in evaluating the hemodynamics of hypervascular hepatocellular nodules.     

Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles

Experimental data show accumulation of superparamagnetic iron oxide (SPIO) particles in atherosclerotic plaques. SPIO uptake occurred in plaques, suggesting an increased endothelial permeability and macrophage infiltrates as signs of inflammatory plaque activity. We incidentally observed SPIO uptake in aortic and arterial wall segments in patients who had originally received the magnetic resonance (MR) contrast agent for staging lymph node metastases. Twenty patients (19 male, 1 female; mean age, 64; range, 41-78 years) with bladder or prostate cancer underwent MR imaging (MRI) using a T2*-weighted high-resolution gradient-echo sequence prior to and 24-36 hours after intravenous injection of 2.6 mg of Fe/kg of SPIO (Sinerem). The aorta, both common external and internal iliac, as well as both superficial femoral arteries, were retrospectively analyzed for atherosclerotic wall changes. One patient was excluded. A positive finding was defined as an area of pronounced signal loss on postcontrast images clearly confined to the arterial wall, which was absent in the precontrast examination or increased in size. Such a finding was observed in one to three arteries in 7 of the 19 patients. The pronounced signal loss in the wall of the aorta and pelvic arteries seen in part of an elderly patient population after intravenous SPIO administration strongly suggests that this contrast agent accumulates in human atherosclerotic plaques.     

MR imaging detection of superparamagnetic iron oxide loaded tris-acryl embolization microspheres

PURPOSE: To assess by magnetic resonance (MR) imaging the detectability of superparamagnetic iron oxide (SPIO)-labeled microspheres (MSs) in vitro on gelose, ex vivo in kidneys from embolized sheep, and in vivo in kidneys from embolized pigs. MATERIALS AND METHODS: With various sizes of SPIO-labeled MSs, common neck and pelvic spin-echo and gradient-echo sequences were acquired on a 1.5-T MR unit. SPIO-labeled MSs of four sizes were embedded in a hydrogel as single MSs or in multiple units, or multiplets. Detection rate on MR imaging was assessed according to the real size and number of MSs. SPIO-loaded and unloaded MSs of four sizes were injected into eight sheep kidneys, which underwent MR and pathologic examinations. For each size, the location of MSs in renal vasculature was determined and compared according to the technique used. Kidneys were embolized in pigs with various amounts of MSs in three sizes. MR was performed immediately after embolization and SPIO-labeled MS detection was assessed according to size, organ, and amount injected. Results SPIO-labeled MSs provide a low signal intensity on T1-weighted sequences, without distortion. In vitro, 28% of 100-300-microm single MSs were detected and more than 80% were detected for larger sizes. MS multiplets were all detected in all sizes. Ex vivo, all sizes of MSs were detected by MR imaging in kidneys, whereas control MSs were not observed. Histologic analysis showed that there was no difference in vascular distribution between SPIO-labeled MS and control MSs, and therefore for each caliber (P > .05). Arterial location of SPIO-labeled MSs was the same on MR imaging and histologic analysis. In vivo, SPIO-labeled MS were detected in the kidney vasculature when volumes greater than 1 mL of 100-300-microm or 500-700-microm MSs were injected. Volumes lower than 1 mL SPIO-labeled MSs were hardly detected in kidneys, regardless of MS size. Conclusions SPIO-labeled MSs are detected by MR imaging with common gradient-echo sequences in vitro in gelose and ex vivo and in vivo in kidneys. SPIO-labeled MSs could allow better control of embolization and thereby enhance efficacy and safety of the procedure.     

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.     

Local arterial infusion of superparamagnetic iron oxide particles in hepatocellular carcinoma: A feasibility and 3.0 T MRI study

OBJECTIVES: We sought to prove feasibility of selective arterial infusion of superparamagnetic iron oxide (SPIO) particles in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We studied 13 patients with HCC who underwent modified transarterial chemoembolization (TACE). Six patients received concurrent infusion of Ferucarbotran (Resovist, Schering, Berlin, Germany) in tumor-feeding arteries, and another 6 received MFL AS (MagForce, Nanotechnologies, Berlin, Germany). The iron content of both dispersions was 3.92 mg. One patient served as a control. All patients underwent magnetic resonance imaging (MRI) as baseline and immediate follow-up investigation. RESULTS: Selective arterial infusion of both SPIO particles resulted in significant intratumoral signal intensity decrease on T1-weighted sequences (P < 0.0001), which was greater after MagForce infusion compared with Resovist (P = 0.002). Only minimal amounts of dispersed particles were found in adjacent normal liver parenchyma. No change in intratumoral signal intensity was noted when ferromagnetic particles were omitted. CONCLUSIONS: Modified TACE with selective arterial infusion of SPIO particles can be used for precise tumor targeting in patients with HCC, for which MagForce appeared superior to Resovist.     

Perfusion MR imaging with a superparamagnetic iron oxide using T2-weighted and susceptibility-sensitive echoplanar sequences: evaluation of tumor vascularity in hepatocellular carcinoma.

OBJECTIVE: The study purpose was to examine the usefulness of perfusion echoplanar MR imaging with a superparamagnetic iron oxide (SHU-555A) for evaluating the vascularity of hepatocellular carcinomas. SUBJECTS AND METHODS: Twenty-two patients with 32 hepatocellular carcinomas underwent perfusion imaging with bolus injection (0.7-1.1 ml) of SHU-555A. Echoplanar sequences included multishot spin-echo (17 patients) and single-shot gradient-echo (five patients) imaging. Image acquisition was repeated every 30 sec for 3 min with the multishot spin-echo sequence and every 2 sec for 100 sec with the single-shot gradient-echo sequence. Lesion signal intensity versus time curves were created for quantitative analysis. RESULTS: Transient decreases in tumor signal intensity (28.8% with multishot spin-echo and 63.3% with the single-shot gradient-echo) were seen in the perfusion phase. These decreases in signal intensity were statistically significantly (p < .01) different for each histologic type of hepatocellular carcinoma (poorly differentiated, 43.3%; well differentiated, 18.4%; and moderately differentiated, 24.8%). After the perfusion phase, the tumor signal intensities rapidly recovered. The multishot spin-echo sequence could detect some signal changes even in lesions smaller than 1 cm. CONCLUSION: Hepatocellular carcinoma vascularity can be evaluated with perfusion echoplanar imaging with SHU-555A. Because of its excellent temporal resolution, the single-shot gradient-echo echoplanar sequence detects the transient signal decrease in most lesions. The high image quality of the multishot spin-echo echoplanar sequence allows evaluation of the vascularity of even very small lesions.     

大鼠种植型肝癌的超顺磁性的氧化铁磁共振增强实验研究

目的 研究正常大鼠的超顺磁性氧化铁（ＳＰＩＯ）剂量梯度－肝脏信号曲线、大鼠种植地癌ＳＰＩＯ增强前后的对比噪声比和检出率。方法 第１组：７２只正常ＳＤ大鼠随机分成１８个样本组,平扫后以０、２、５……２８０ｕｍｏｌＦｅ／ｋｇ１８个ＳＰＩＯ剂量分别做增强扫描,做剂量梯度－肝脏信号曲线。第２组：３８只种植型肝癌模型鼠,共计生成４３个肿瘤,行平扫及ＳＰＩＯ增强扫描,分析肿瘤磁共振强化特点;测量增强前后Ｔ１及     

Clinical application of superparamagnetic iron oxide to MR imaging of tissue perfusion in vascular liver tumors

Previous studies of AMI-25, a particulate iron oxide magnetic resonance contrast agent, imaged liver tumors 1 or more hours after injection, in the retention phase after complete clearance of AMI-25 from the circulation. In the present study, imaging was performed in the distribution phase, during the first 12 minutes after injection while contrast agent remain in circulation, and these images were compared with those obtained in the retention phase. Nineteen patients with cancer were studied, including 15 imaged during the distribution phase. T2-weighted distribution phase images demonstrated 90% of the lesions detected by means of T2-weighted retention phase images, showed a 3.5-fold increase in contrast-to-noise ratio over images obtained before administration of AMI-25, and increased diagnostic confidence by reducing signal from small intrahepatic blood vessels. Distribution phase images showed little contrast agent uptake by cancer tissue. Both distribution and retention phase images demonstrated greater contrast agent uptake by hemangiomas than by malignant neoplasms (P less than .01). The use of both distribution phase and retention phase AMI-25-enhanced images offers improved diagnostic accuracy in the detection and characterization of focal liver lesions.     

Application of a superparamagnetic iron oxide (Resovis®) for MR imaging of human cerebral blood volume

The authors describe the feasibility of dynamic MRI using a novel superparamagnetic iron oxide contrast agent. Resovist® was injected as a bolus at doses of 4, 8, and 16 μmol Fe/kg bodyweight in three consented patients participating in a Phase 2 clinical multicenter trial for hepatic MRI. Dynamic images of the brain were obtained with a conventional FLASH sequence. Results were analyzed by evaluation of dynamic images, cerebral blood volume maps, and normalized signal intensity time curves. Resovist® enabled rapid injections and a dose-dependent strong reduction in gray and white matter signal intensity. The small injection volume and good tolerability may enable Resovist® to serve as a perfusion agent. Dedicated clinical trials are warranted to assess the potentials of Resovist® for perfusion MRI and fMRI.     

Efficacy of dynamic MRI with superparamagnetic iron oxide (SH U 555 A): vascularity evaluation in hepatocellular carcinoma.

PURPOSE: A study was conducted to determine the possibility of evaluating the blood flow in cases of hypervascular hepatocellular carcinoma (HCC) by employing dynamic MRI with superparamagnetic iron oxide (SH U 555 A), which can be rapidly injected via an intravenous route. METHODS: Six patients with hypervascular HCC (23 nodules) served as the subjects. Dynamic MRI includes images obtained at precontrast and at 10 (perfusion phase), 60, 120, 180, 240, 300 and 600 s after the start of injection of SH U 555 A. CT hepatic arteriography (CTHA) and CT during arterial portography (CTAP) were used as the standards of reference, and these were performed in all patients three days after dynamic MRI. The signal changes were evaluated at each phase, especially at the perfusion phase from the viewpoints of a lesion-to-liver contrast-to-noise ratio (CNR) and visual examination. RESULTS: A total of 23 hypervascular HCC were detected on CTHA and CTAP. Of the 23 lesions, 17 were detected on SH U 555 A enhanced MRI. Incorrect timing during acquisition of the perfusion phase was considered in two cases with three lesions. Of 14 lesions, excluding two cases with incorrect timing, a reduction in the transient signal in the lesions at the perfusion phase was visually recognized in 10 lesions (71%). Significant differences were seen in tumor size between visible and non-visible tumors involving transient signal reduction (p< 0.05). CNR gradually increased after rapidly decreasing in the perfusion phase. CONCLUSION: SH U 555 A enhanced MRI is valuable in limited cases. Evaluation of tumor blood flow employing dynamic MRI with SH U 555 A is affected by tumor size and requires optimal timing of the perfusion phase.     

Efficacy of sequential use of superparamagnetic iron oxide and gadolinium in liver MR imaging

Purpose: To evaluate the efficacy of combined (double contrast) use of superparamagnetic iron particles (SPIOs) and gadolinium (Gd) in liver MR imaging.Material and Methods: Unenhanced, Gd-enhanced, SPIO-enhanced, and both SPIO- and Gd-enhanced images were acquired at 1.5 T. Twenty patients with previously detected liver lesions were included. Fast SE-STIR, and breath-hold true FISP, fat-suppressed T1- and T2-weighted sequences were obtained with all techniques. Lesion count was assessed by consensus reading.Results: Collective evaluation of all MR sequences revealed 61 lesions in 16 patients; SPIO-enhanced MR detected lesions with a sensitivity of 95% (n=58). The sensitivity of unenhanced MR imaging was 90% (n=55). There was no statistical difference between SPIO-enhanced and unenhanced MR images. From single sequences, the greatest number of lesions was detected with the SPIO-enhanced fast SE-STIR sequence (n=56, sensitivity 92%). By using the fat-suppressed T1-weighted sequence, Gd-enhanced and both SPIO- and Gd-enhanced MR images demonstrated sensitivities of 77% (n=47) and 80% (n=49), respectively. Despite the combined use of both contrast media, this sequence was significantly less sensitive in lesion detection when compared to SPIO-enhanced imaging.Conclusion: SPIO-enhanced MR imaging was the most sensitive method in lesion detection. The benefit of the combined use of SPIO and Gd was negligible.     

Hepatocellular carcinoma with marginal superparamagnetic iron oxide uptake on T2*-weighted magnetic resonance imaging: histopathologic correlation

Purpose

To evaluate the characteristics of hepatocellular carcinomas (HCCs) with marginal superparamagnetic iron oxide (SPIO) uptake on T2*-weighted MRI.

Materials and methods

The study group consisted of 73 patients with 83 surgically resected HCCs. Preoperative SPIO-enhanced MRI studies were retrospectively reviewed. Marginal SPIO uptake was considered positive if a rim-like or band-like low intensity area was present on SPIO-enhanced T2*-weighted images. The prevalence of marginal SPIO uptake was evaluated. Pathological specimens with hematoxylin and eosin staining and immunohistochemical staining of CD68 were reviewed in HCCs with marginal SPIO uptake and 33 HCCs without marginal SPIO uptake (control group).

Results

Ten of 83 (12%) HCCs showed marginal SPIO uptake. All HCCs were hypervascular, and only one nodule showed a nodule-in-nodule appearance on imaging findings. The pathology specimens suggested possible causes of marginal SPIO uptake, including marginal macrophage infiltration in moderately or poorly differentiated HCC (n = 4), residual normal hepatic tissue at the marginal area of confluent multinodular or single nodular with extranodular growth type HCC (n = 3), and a well-differentiated HCC component in nodule-in-nodule type HCC (n = 3). Marginal macrophage infiltration was not seen in the control group.

Conclusion

SPIO-enhanced MRI may be able to demonstrate marginal macrophage infiltration in HCC.     

The diagnosis of splenic lymphoma by MR imaging: value of superparamagnetic iron oxide

This study was designed to evaluate superparamagnetic iron oxide (AMI-25) as a contrast agent for MR to distinguish normal spleens from those diffusely infiltrated by lymphoma. As diffuse splenic involvement lacks visible tumor-tissue boundaries, signal-intensity measurements of spleens were used as a diagnostic criterion in 33 patients (lymphoma, n = 8; benign splenomegaly, n = 5; normal subjects, n = 20). Unenhanced MR images were insensitive (four of eight patients) and nonspecific (20 of 25 patients) in the diagnosis of lymphoma. After injection of superparamagnetic iron oxide (40 mumol Fe/kg), lymphomatous spleens showed a significantly higher signal intensity (p less than .05) than did normal spleens or spleens enlarged by benign disease (hepatic cirrhosis, n = 4; spherocytosis, n = 1). Changes in splenic MR signal intensity unambiguously identified eight of eight lymphomatous spleens and 25 of 25 normal or enlarged spleens that did not contain lymphoma. Phagocytosis of superparamagnetic iron oxide in lymphomatous spleens is reduced because of diffuse displacement of splenic macrophages by lymphoma cells and/or by immunologic suppression of macrophage activity. Our results suggest that superparamagnetic iron oxide (AMI-25) can improve the accuracy of MR imaging in the diagnosis of splenic lymphoma. With further development, this noninvasive technique may reduce the need for diagnostic splenectomy in lymphoma patients.     

MR imaging of hydrogel filament embolic devices loaded with superparamagnetic iron oxide or gadolinium

Introduction  

We evaluated hydrogel filaments loaded with barium sulphate and either gadolinium or superparamagnetic iron oxide (SPIO) in an effort to develop an embolic material that is visible with fluoroscopic and magnetic resonance imaging.