Molecular MR imaging of melanoma angiogenesis with alphanubeta3-targeted paramagnetic nanoparticles.

Neovascularization is a critical component in the progression of malignant melanoma. The objective of this study was to determine whether alpha(nu)beta(3)-targeted paramagnetic nanoparticles can detect and characterize sparse alpha(nu)beta integrin expression on neovasculature induced by nascent melanoma xenografts ( approximately 30 mm(3)) at 1.5T. Athymic nude mice bearing human melanoma tumors were intravenously injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles, nontargeted paramagnetic nanoparticles, or alpha(v)beta(3)-targeted-nonparamagnetic nanoparticles 2 hr before they were injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles (i.e., in vivo competitive blockade) and imaged with MRI. Contrast enhancement of neovascularity in animals that received alpha(nu)beta(3)-targeted paramagnetic nanoparticles increased 173% by 120 min. Signal contrast with nontargeted paramagnetic nanoparticles was approximately 50% less than that in the targeted group (P < 0.05). Molecular MRI results were corroborated by histology. In a competitive cell adhesion assay, incubation of alpha(nu)beta(3)-expressing cells with targeted nanoparticles significantly inhibited binding to a vitronectin-coated surface, confirming the bioactivity of the targeted nanoparticles. The present study lowers the limit previously reported for detecting sparse biomarkers with molecular MRI in vivo. This technique may be employed to noninvasively detect very small regions of angiogenesis associated with nascent melanoma tumors, and to phenotype and stage early melanoma in a clinical setting.     

Quantification of the expression level of integrin receptor alpha(v)beta3 in cell lines and MR imaging with antibody-coated iron oxide particles.

Targeted imaging requires site-specific accumulation of a contrast agent (CA), and the properties of that agent must be selected according to the abundance of the target to obtain a signal above the detection limit of the instrument. However, numerical estimates of receptors per cell are rarely found in the literature. Integrin receptors would be particularly promising targets because of their accessibility from the blood stream and expression on activated neovascular endothelial cells. We systematically estimated the number of integrin receptors of cell lines and primary cells by flow cytometry analysis. Since integrin receptors are heterodimeric molecules, and alpha(v) forms complexes with various beta subunits, the numbers of alpha(v) and beta(3) subunits are therefore dissimilar. The observed values are 3 . 10(3)-1.4 . 10(4)/cell for alpha(v), and 5.3 . 10(2)-1.1 . 10(4)/cell for beta(3). Despite the low number of exposed receptors, we show that up to single-cell MR visualization can be achieved with the use of iron oxide beads complexed with antibodies as CAs.     

Molecular imaging of angiogenic therapy in peripheral vascular disease with ανβ3‐integrin‐targeted nanoparticles

Noninvasive molecular imaging of angiogenesis could play a critical role in the clinical management of peripheral vascular disease patients. The α_νβ₃‐integrin, a well‐established biomarker of neovascular proliferation, is an ideal target for molecular imaging of angiogenesis. This study investigates whether MR molecular imaging with α_νβ₃‐integrin‐targeted perfluorocarbon nanoparticles can detect the neovascular response to angiogenic therapy. Hypercholesterolemic rabbits underwent femoral artery ligation followed by no treatment or angiogenic therapy with dietary L ‐arginine. MR molecular imaging performed 10 days after vessel ligation revealed increased signal enhancement in L ‐arginine‐treated animals compared to controls. Furthermore, specifically targeted nanoparticles produced two times higher MRI signal enhancement compared to nontargeted particles, demonstrating improved identification of angiogenic vasculature with biomarker targeting. X‐ray angiography performed 40 days postligation revealed that L ‐arginine treatment increased the development of collateral vessels. Histologic staining of muscle capillaries revealed a denser pattern of microvasculature in L ‐arginine‐treated animals, confirming the MR and X‐ray imaging results. The clinical application of noninvasive molecular imaging of angiogenesis could lead to earlier and more accurate detection of therapeutic response in peripheral vascular disease patients, enabling individualized optimization for a variety of treatment strategies. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

(64)Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor alpha(v)beta(3) integrin expression.

Integrin alpha(v)beta(3) plays a critical role in tumor angiogenesis and metastasis. Suitably radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive imaging of alpha(v)beta(3) expression and targeted radionuclide therapy. In this study, we developed (64)Cu-labeled multimeric RGD peptides, E{E[c(RGDyK)](2)}(2) (RGD tetramer) and E(E{E[c(RGDyK)](2)}(2))(2) (RGD octamer), for PET imaging of tumor integrin alpha(v)beta(3) expression. METHODS: Both RGD tetramer and RGD octamer were synthesized with glutamate as the linker. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N',N',N'-tetraacetic acid (DOTA), the peptides were labeled with (64)Cu for biodistribution and small-animal PET imaging studies (U87MG human glioblastoma xenograft model and c-neu oncomouse model). A cell adhesion assay, a cell-binding assay, receptor blocking experiments, and immunohistochemistry were also performed to evaluate the alpha(v)beta(3)-binding affinity/specificity of the RGD peptide-based conjugates in vitro and in vivo. RESULTS: RGD octamer had significantly higher integrin alpha(v)beta(3)-binding affinity and specificity than RGD tetramer analog (inhibitory concentration of 50% was 10 nM for octamer vs. 35 nM for tetramer). (64)Cu-DOTA-RGD octamer had higher tumor uptake and longer tumor retention than (64)Cu-DOTA-RGD tetramer in both tumor models tested. The integrin alpha(v)beta(3) specificity of both tracers was confirmed by successful receptor-blocking experiments. The high uptake and slow clearance of (64)Cu-DOTA-RGD octamer in the kidneys was attributed mainly to the integrin positivity of the kidneys, significantly higher integrin alpha(v)beta(3)-binding affinity, and the larger molecular size of the octamer, as compared with the other RGD analogs. CONCLUSION: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers. The information obtained here may guide the future development of RGD peptide-based imaging and internal radiotherapeutic agents targeting integrin alpha(v)beta(3).     

Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI.

Before molecular imaging with MRI can be applied clinically, certain problems, such as the potential sparseness of molecular epitopes on targeted cell surfaces, and the relative weakness of conventional targeted MR contrast agents, must be overcome. Accordingly, the conditions for diagnostic conspicuity that apply to any paramagnetic MRI contrast agent with known intrinsic relaxivity were examined in this study. A highly potent paramagnetic liquid perfluorocarbon nanoparticle contrast agent ( approximately 250 nm diameter, >90,000 Gd3+/particle) was imaged at 1.5 T and used to successfully predict a range of sparse concentrations in experimental phantoms with the use of standard MR signal models. Additionally, we cultured and targeted the smooth muscle cell (SMC) monolayers that express "tissue factor," a glycoprotein of crucial significance to hemostasis and response to vascular injury, by conjugating an anti-tissue factor antibody fragment to the nanoparticles to effect specific binding. Quantification of the signal from cell monolayers imaged at 1.5 T demonstrated, as predicted via modeling, that only picomolar concentrations of paramagnetic perfluorocarbon nanoparticles were required for the detection and quantification of tissue factor at clinical field strengths. Thus, for targeted paramagnetic agents carrying high payloads of gadolinium, it is possible to quantify molecular epitopes present in picomolar concentrations in single cells with routine MRI.     

Gadobenate dimeglumine (Gd-DTPA) vs gadopentetate dimeglumine (Gd-BOPTA) for contrast-enhanced magnetic resonance angiography (MRA): improvement in intravascular signal intensity and contrast to noise ratio

PURPOSE: The purpose of this study was to compare contrast enhanced MR angiography (MRA) with gadopentetate dimeglumine (Gd-DTPA) to MRA with gadobenate dimeglumine (Gd-BOPTA), a high relaxivity paramagnetic contrast agent. MATERIALS AND METHODS: Twelve patients referred for carotid artery stenosis were examined with MR angiography using a fast spoiled gradient echo sequence. Gd-DTPA and Gd-BOPTA enhanced MR angiography were performed within 48-72 hours using a dose of 0.1 mmol/kg for Gd-BOPTA and 0.2 mmol/kg for Gd-DTPA, at a flow rate of 2 ml/s. Images were evaluated by two blinded radiologists. Qualitative and quantitative evaluations were performed comparing the sets of images from the two examinations. RESULTS: Qualitative evaluation demonstrated superior arterial contrast enhancement and vessel conspicuity with Gd-BOPTA compared with Gd-DTPA. Quantita-tive evaluation showed an improvement in both signal intensity and contrast to noise ratio with Gd-BOPTA. CONCLUSION: The greater relaxivity of Gd-BOPTA, at lower doses, compared with Gd-DTPA, provides higher intravascular signal and signal to noise ratio. Gd-BOPTA appears to be an optimal contrast agent for contrast enhanced MRA.     

Radiolabeled high affinity peptidomimetic antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in mice

OBJECTIVES: The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonists that selectively target integrin alpha(v)beta(3) receptor and clear rapidly from the whole body. METHODS: Integrin alpha(v)beta(3) antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-beta-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-beta-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2-p-isothiocyanatobenzyl-DOTA at the amino terminus and labeled with (111)In. The (111)In labeled IA and IAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts. RESULTS: The (111)In-labeled IA (40%) and -IAC (72%) specifically bound in vitro to alpha(v)beta(3) (0.8 microM) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to alpha(v)beta(3). The higher receptor-binding affinity of the (111)In-labeled IAC was reflected in higher tumor uptake and retention: 5.6+/-1.4 and 4.5+/-0.7 %ID/g vs. 3.8+/-0.9 and 2.0+/-0.3 %ID/g for the (111)In-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 microg of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The (111)In activity retained in the whole body was quite comparable between the (111)In-labeled IA (24% ID) and the (111)In-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the (111)In-labeled IAC at 2 h with 9.7, 2.3, 0.8, 1.9, 7.1, 2.2, 0.9, 3.7 and 9.9 for blood, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively. The imaging studies with the (111)In-labeled IAC also clearly visualized the receptor-positive tumor at 4 h. CONCLUSIONS: The (111)In-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the alpha(v)beta(3) receptor-positive tumor. This together with the rapid whole-body clearance pharmacokinetics warrants further studies on this IAC analog for molecular imaging of tumor-induced angiogenic vessels and various malignant human tumors expressing the receptor.     

Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits

PURPOSE: To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. MATERIALS AND METHODS: The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material-enhanced MR images obtained minutes after sonications and repeated 1-48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. RESULTS: Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power levels used produced blood-brain barrier opening without damage to the surrounding neurons. Contrast enhancement correlated with the focal signal intensity changes in the magnitude fast spoiled gradient-echo MR images. CONCLUSION: The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent. MR imaging signal intensity changes may be useful in the detection of blood-brain barrier opening during sonication.     

The lactating breast: contrast-enhanced MR imaging of normal tissue and cancer

PURPOSE: To retrospectively describe the magnetic resonance (MR) imaging characteristics of normal breast tissue and breast cancer in the setting of lactation. MATERIALS AND METHODS: The HIPAA-compliant study was exempt from institutional approval, and informed consent was not required. Unilateral MR imaging of 10 breasts was performed in seven lactating patients aged 27-42 years. For the three patients in whom both breasts were imaged, each breast was imaged on a separate day. Nonenhanced T1-weighted and fat-saturated T2-weighted images and contrast material-enhanced dynamic three-dimensional (3D) T1-weighted spiral gradient-echo images interleaved with T1-weighted high-spatial-resolution 3D gradient-echo images (2.0 x 1.0 x 0.4-mm voxels) were obtained. Three readers in consensus assessed the glandular density, T2-weighted signal intensity, milk duct appearance, and contrast enhancement in normal and tumor-containing breast regions. The pharmacokinetic contrast enhancement parameters of tumors were compared with those of normal tissue by using Student t and Mann-Whitney tests. RESULTS: MR findings of normal breast tissue in the seven women included increased glandular density in six women, high T2-weighted signal intensity in six, dilated central ducts in seven, and rapid initial glandular contrast enhancement in seven. MR findings of invasive ductal carcinoma in five women, compared with findings of the normal glandular tissue, included lower T2-weighted signal intensity in five women, more avid and rapid contrast enhancement in five, and early contrast enhancement washout in four. One minute after contrast agent injection, tumor signal intensity increased significantly more than normal lactating tissue signal intensity (153% vs 60% from baseline, P = .016). The median two-compartment model K(21) exchange rate in the tumors, 0.078 sec(-1), was significantly faster than the K(21) exchange rate in normal tissue, 0.011 sec(-1) (P = .03). CONCLUSION: Normal lactating glands have increased density, high T2-weighted signal intensity, and rapid moderate contrast enhancement. Breast cancers are visible during lactation owing to their lower signal intensity and more intense initial contrast enhancement with early washout compared with normal breast tissue.     

Gd-DTPA标记单克隆抗体对荷人肝癌裸鼠的MR成像研究

目的评价特异性MR对比剂Gd-DTPA-单克隆抗体HAb18对肿瘤的强化效果.材料与方法制备Gd-DTPA标记的单克隆抗体,并测定每分子抗体所结合的Gd 3数目及其免疫活性.12只荷人肝癌裸鼠分为两组,分别给予Gd-DTPA-McAb和Gd-DTPA后进行MR扫描,测量SE T1WI平扫及增强后10 min、30 min、1 h、3 h、6 h、12 h、24 h、48 h图像内肿瘤的信号强度,绘制信号强度-时间曲线,并计算肿瘤强化率及对比度噪声比.结果 Gd-DTPA-单克隆抗体组在注射MR对比剂后的早期,肿瘤表现为缓慢轻度的强化,在注射对比剂24 h后,肿瘤强化达25%,与其他各时间点有统计学差异.Gd-DTPA对照组内,肿瘤表现为快进快出的强化特点.结论使用Gd-DTPA-单克隆抗体进行靶向显像具有特异性作用,有助于肿瘤的定性诊断.     

Interactions of paramagnetic contrast agents and the spin echo pulse sequence

The theoretical equations for paramagnetic contrast agent effects and the spin echo pulse sequence are combined to graph magnetic resonance (MR) intensity as a function of paramagnetic contrast agent concentration for various tissues. Analysis of the graphs and equations demonstrate several technical and clinical implications. These include: (1) positive enhancement is most likely to occur with short TEs and TRs; (2) changes in machine parameters TE and TR will change the concentration of agent at which the peak enhancing MR intensity will occur; (3) there is an absolute maximum MR intensity that can be reached with contrast enhancement; (4) the maximum MR intensity reached with enhancement is dependent on the tissues' T2 and, to a lesser degree, T1 relaxation times; (5) certain TE and TR combinations will cause no enhancement; (6) if positive enhancement does occur, it will usually occur only over a limited range of agent concentration; and (7) the tissues' T1 relaxation time but not its T2 time determines whether positive enhancement will occur and the relative amount of enhancement.     

MR signal intensity characteristics in Legg-Calvé-Perthes disease. Value of fat-suppressed (STIR) images and contrast-enhanced T1-weighted images

PURPOSE: To evaluate the MR signal intensity characteristics in Legg-Calvé-Perthes disease on fat-suppressed (STIR) images and contrast-enhanced T1-weighted spin-echo images, and to develop criteria for the administration of contrast material. MATERIAL AND METHODS: Twenty children with Legg-Calvé-Perthes disease underwent conventional radiography and MR imaging of the hip utilizing fat-suppressed (STIR) sequences and T1-weighted spin-echo sequences before and after i.v. contrast administration. The signal intensity characteristics of the femoral head and the proximal femoral metaphysis were assessed retrospectively by two pediatric radiologists. RESULTS: Evaluation of the MR images revealed six different signal patterns within the femoral head: 1) isointense signal on all images; 2) complete signal void on all images; 3) hyperintense signal on STIR images with; or 4) without contrast enhancement on T1-weighted spin-echo images; 5) isointense signal on STIR images with; or 6) without contrast enhancement on T1-weighted images. Within the metaphysis three different signal patterns were differentiated. CONCLUSION: Combination of fat-suppressed (STIR) sequences and T1-weighted pre- and post-contrast sequences allows an accurate evaluation of Legg-Calvé-Perthes disease. In patients without signal alterations or complete signal loss on fat-suppressed and T1-weighted spin-echo images, administration of i.v. contrast is not necessary. In case of bone marrow edema on fat-supressed images, contrast-enhanced T1-weighted images are required to identify viable osseous fragments.     

Three-dimensional cardiac cine magnetic resonance imaging with an ultrasmall superparamagnetic iron oxide blood pool agent (NC100150)

The purpose of this study was to assess image quality of three-dimensional (3D) cardiac cine magnetic resonance (MR) imaging before and after administration of a T1-shortening ultrasmall superparamagnetic iron oxide blood pool agent (NC100150). 3D cardiac cine MR imaging was performed in 13 volunteers using a radiofrequency-spoiled cardiac-gated 3D cine gradient-echo sequence with short repetition and echo times. Compared with precontrast images, postcontrast images showed no enhancement in fat and skeletal muscle, moderate enhancement in myocardium, and significant enhancement in ventricular cavity. After contrast injection, the signal ratio of the ventricular chamber to the myocardium significantly increased, and dramatic improvements were seen in the quality of the cineangiographic images and the depiction of cardiac valves. This quantitative study has shown that 3D cardiac cine MR imaging using a blood pool agent provided MR ventriculography and cineangiography with excellent image quality.     

Small (<20 mm) enhancing hepatic nodules seen on arterial phase MR imaging of the cirrhotic liver: clinical implications

OBJECTIVE: To determine the significance in patients with cirrhosis of small (<20 mm) hepatic nodules that show no hyperintensity on T2-weighted MR images but that enhance during arterial phase MR imaging, we reviewed the cases of patients with such nodules. MATERIALS AND METHODS: Our review of radiology reports yielded 68 nodules in 40 patients with cirrhosis that showed no hyperintensity on T2-weighted MR images but had rapid enhancement during arterial phase MR imaging after administration of a gadolinium contrast agent. Thirty-four patients (60 nodules) had multiple follow-up MR imaging examinations (range of length of follow-up, 1-72 months; average length of follow-up, 15 months 2 weeks). The final diagnosis of the nodule was determined by pathology reports or after at least 2 years of follow-up to ensure nodule stability and, therefore, benignity. Two radiologists independently reviewed MR images of the nodules, noting the size, signal intensity on T1- or T2-weighted images, and homogeneity of contrast enhancement. RESULTS: Nine (13%) of the 68 nodules were hepatocellular carcinomas (HCCs). The size of nodules on the first MR examination was between 4 and 20 mm (mean size, 9.5 mm). No significant correlation between the diagnosis of HCC and nodule signal intensity (p = 0.48) or contrast enhancement homogeneity (p = 0.56) on first MR examination was found. Positive predictive value (PPV) and negative predictive value (NPV) for diagnosing HCC on the basis of nodule growth were 100% and 98%, respectively. For diagnosing HCC on the basis of a change in nodule signal intensity, the PPV was 60% and the NPV was 91%. For diagnosing HCC on the basis of a change of enhancement homogeneity, the PPV was 63%, and the NPV was 94%. CONCLUSION: A finding of growth in small, early-enhancing nodules in patients with cirrhosis is highly predictive of HCC. When small nodules are observed on a single examination, close follow-up of the patient appears appropriate.     

microPET imaging of glioma integrin {alpha}v{beta}3 expression using (64)Cu-labeled tetrameric RGD peptide.

Integrin alpha(v)beta(3) plays a critical role in tumor-induced angiogenesis and metastasis and has become a promising diagnostic indicator and therapeutic target for various solid tumors. Radiolabeled RGD peptides that are integrin specific can be used for noninvasive imaging of integrin expression level as well as for integrin-targeted radionuclide therapy. METHODS: In this study we developed a tetrameric RGD peptide tracer (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid) for PET imaging of integrin alpha(v)beta(3) expression in female athymic nude mice bearing the subcutaneous UG87MG glioma xenografts. RESULTS: The RGD tetramer showed significantly higher integrin binding affinity than the corresponding monomeric and dimeric RGD analogs, most likely due to a polyvalency effect. The radiolabeled peptide showed rapid blood clearance (0.61 +/- 0.01 %ID/g at 30 min and 0.21 +/- 0.01 %ID/g at 4 h after injection, respectively [%ID/g is percentage injected dose per gram]) and predominantly renal excretion. Tumor uptake was rapid and high, and the tumor washout was slow (9.93 +/- 1.05 %ID/g at 30 min after injection and 4.56 +/- 0.51 %ID/g at 24 h after injection). The metabolic stability of (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) was determined in mouse blood, urine, and liver and kidney homogenates at different times after tracer injection. The average fractions of intact tracer in these organs at 1 h were approximately 70%, 58%, 51%, and 26%, respectively. Noninvasive microPET studies showed significant tumor uptake and good contrast in the subcutaneous tumor-bearing mice, which agreed well with the biodistribution results. Integrin alpha(v)beta(3) specificity was demonstrated by successful blocking of tumor uptake of (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) in the presence of excess c(RGDyK) at 1 h after injection. The highest absorbed radiation doses determined for the human reference adult were received by the urinary bladder wall (0.262 mGy/MBq), kidneys (0.0296 mGy/MBq), and liver (0.0242 mGy/MBq). The average effective dose resulting from a single (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) injection was estimated to be 0.0164 mSv/MBq. CONCLUSION: The high integrin and avidity and favorable biokinetics make (64)Cu-DOTA-E{E[c(RGDfK)](2)}(2) a promising agent for peptide receptor radionuclide imaging and therapy of integrin-positive tumors.     

Atlantoaxial joints: patterns of gadolinium enhancement with MR imaging in normal subjects

OBJECTIVE: To evaluate normal patterns of enhancement of signal intensity in and about the atlantoaxial joints following intravenous administration of a gadolinium-containing contrast agent. METHODS AND MATERIAL: Fat-suppressed axial T1 weighted SE images were obtained in 12 patients without evidence of inflammmatory arthritis before and immediately after intravenous administration of a gadolinium-containing contrast agent. Patterns of enhancement of signal intensity in and about the atlantoaxial joints were evaluated qualitatively. RESULTS: Four different MR imaging patterns were observed: no enhancement of signal intensity, enhancement in the form of a single punctate region, enhancement in a confluent pattern, and bandlike enhancement. CONCLUSION: Enhancement occurs around the odontoid process in patients without evidence of rheumatoid arthritis (RA). The dividing line between early synovitis and normal enhancement seems broader than expected. The reasons remain unclear and warant further studies.     

颅内表皮样囊肿的MRI表现(32例报告并文献复习)

目的　研究颅内表皮样囊肿的ＭＲ影像特征。方法　经手术病理证实的表皮样囊肿患者３２ 例,男９ 例,女２３ 例,全部行ＭＲ检查。结果　典型表现者２９ 例,占９１％ ;Ｔ１ＷＩ上表现为低信号,有时不均匀。非典型表现者３ 例,占９％ ;Ｔ１ＷＩ上肿瘤实质内为短Ｔ１ 高信号。２０ 例增强扫描中,８例无强化,１１ 例边缘强化,１ 例肿瘤周边和肿瘤内部呈条索样分隔物增强。Ｔ２ＷＩ上,１７ 例肿瘤信号等于脑脊液信号,１ 例明显高于脑脊液信号,１４ 例肿瘤内可见斑点状等信号。结论　典型常见的表皮样囊肿是Ｔ１ 低信号,在Ｔ１ＷＩ上肿瘤质地欠均匀;非典型罕见的表皮样囊肿呈Ｔ１ 高信号,信号形成原因是高浓度蛋白质所致,并非脂类物质。     

Potential of magnetic resonance lymphography with intrapulmonary injection of gadopentetate dimeglumine for visualization of the pulmonary lymphatic basin in dogs: preliminary results

PURPOSE: To evaluate a new approach of magnetic resonance (MR) lymphography with intraalveolar injection of a conventional extracellular contrast agent (gadopentetate dimeglumine) for imaging lymphatic basin draining from specific portions of the lung. METHODS: Three-dimensional T1-weighted spoiled gradient-recalled echo MR sequence images were acquired serially before and for 40 minutes after intraalveolar injection of gadopentetate dimeglumine in a total of 14 anesthetized beagle dogs. Six of these dogs received 1 mL undiluted and low-concentration (75%) contrast agent into the same portion of the right caudal lobe during a 7-day interval. In all dogs, including these 6 dogs, MR lymphography was repeated with injection of the low-concentration contrast agent into different lung regions at 7-day intervals to evaluate the differences of the visualized draining lymphatic station. Lymphatic enhancement was quantified by percent increases of signal intensity against precontrast. Postmortem examination of the lymphatic anatomy was performed in 7 of these animals. RESULTS: In all dogs, the lymphatic station draining from the injection sites was visualized within 5 minutes after contrast injection. The maximum percent increase of signal intensity of the same middle tracheobronchial lymph nodes was significantly greater with a low-concentration (75%) contrast agent than with an undiluted one in the same 6 dogs (n = 6, 247.6 +/- 30.5% vs. 204.2 +/- 33.8%; P < 0.01). Different lymphatic stations draining from the different injection sites were visualized in all dogs. In a total of 12 MR studies that showed extended nodal enhancement after injection of the low-concentration contrast agent, the enhancement peak of the most proximal nodes (n = 12) from the injection sites appeared earlier than that of their distant nodes (n = 12), with a maximum percent increase of signal intensity of 249.8 +/- 42.4%. The visualized lymph nodes were found in the appropriate locations postmortem, with significant correlation for nodal sizes (r = 0.965; P < 0.0001). CONCLUSION: MR lymphography with low-concentration gadopentetate dimeglumine can quickly and sufficiently visualize the drainage lymphatic station from specific lung portions, and may have the potential of sentinel node mapping in lung cancer.     

Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting.

The alpha(v)beta3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective alpha(v)beta3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [1251]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized alphaIIbeta3 and alpha(v)beta3 integrins. Expression of the alphaVbeta3 receptor on the different tumors was validated by immunohistochemical methods using alpha(v) and alpha(v)beta3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. RESULTS: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for alpha(v)beta3. Immunohistochemical staining clearly indicates the presence of the alpha(v)beta3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 +/- 0.32 %ID/g for the melanoma M21 and 3.50 +/- 0.49 %ID/g for the osteosarcoma and decreases to 1.30 +/- 0.13 %ID/g and 2.03 +/- 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 +/- 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [1251]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. CONCLUSION: [125I]P2 exhibits high affinity and selectivity for the alpha(v)beta3 integrin in vitro and in vivo and, thus, represents the first radiolabeled alpha(v)beta3 antagonist for the investigation of angiogenesis and metastasis in vivo.     

Gadolinium-phthalein complexone as a contrast agent for hepatobiliary MR imaging

Gadolinium-phthalein complexone (Gd-PC) was developed as a hepatobiliary magnetic resonance (MR) contrast agent. Phthalein complexone is one of the iminodiacetic acid derivatives and a structural analogue of bromosulfophthalein. Gadolinium-PC substantially enhanced signal intensity of normal functioning livers on T1-weighted MR images. Contrast enhancement of rabbit liver and gradual accumulation of high intensity bile in the gallbladder were observed after intravenous injection of 0.05 and 0.1 mmol/kg Gd-PC. However, 0.1 mmol/kg of Gd-DTPA caused little effect on liver MR.