Mechanism of gadophrin-2 accumulation in tumor necrosis

The molecular mechanism by which gadophrin-2 targets necrotic tumor tissue was investigated. Biodistribution studies and magnetic resonance imaging (MRI) and histologic/autoradiographic correlation were performed in xenograft mouse models bearing human tumors (HT 29, WiDr, LX 1). Binding of gadophrin-2 to DNA, lipids, or proteins was determined by fluorescence spectrophotometry. Protein binding was determined by dialysis and gel electrophoresis. Accumulation of gadophrin-2 was low (<0.7% injected dose/g tissue at 24 hours after injection) in viable tumor but higher in necrotic tumor regions and was readily detectable by MRI. Within a given tumor, the agent preferentially localized in the periphery of necrotic areas. Within these regions gadophrin-2 was bound to interstitial albumin and not other proteins, lipids, or DNA. Tumoral accumulation of gadophrin-2 most likely occurs through its binding to plasma albumin and subsequent slow extravasation into the tumor interstitium.     

Synthesis and preliminary evaluation of MP-2269: A novel,nonaromatic small-molecule blood-pool MR contrast agent

A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugating a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yielded spin-lattice relaxivities (R₁) for MP-2269 of 6.2, 20.0 and 26.1 mM^?1 sec^?1 in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate sig nificant binding of the agent to blood proteins. At a dose of 45 μmol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (～70% in 24 h by this mode). The LD₅₀ value of MP-2269 is ～3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiography.     

MRI contrast enhancement of malignant liver tumours following successful cryoablation

Objectives  

To assess the incidence and degree of MRI contrast enhancement in liver tumours following successful percutaneous cryoablation.     

Perfusion-weighted MRI using gadobutrol as a contrast agent in a rat stroke model

The purpose of this study was to examine the new nonionic contrast agent gadobutrol in MR perfusion-weighted imaging, including the influence of different concentrations and dosages of the agent on the sensitivity to perfusion alterations. Sixteen rats were examined within 35 to 105 minutes after endovascular occlusion of the middle cerebral artery. A fast T2*-weighted fast low-angle shot (FLASH) sequence was used to acquire four images before and 16 images after bolus injection of .1, .2, .3, and .4 mmol/kg gadobutrol as .5 molar and 1.0 molar formulation. From user-defined regions, we obtained the maximum signal decrease, the relative regional cerebral blood volume, and the bolus delay. Contrast between ischemic and nonischemic regions during bolus passage increased with dose and concentration of the contrast agent. For low doses (.1 and .2 mmol/kg), the ischemic lesion could not or could barely be discerned. For higher doses (.3 and .4 mmol/kg), administration of the 1 molar contrast agent yielded a better contrast between ischemic and nonischemic tissue. Our results suggest that administration of gadobutrol at higher dosage and higher concentration increases sensitivity to perfusion alterations. These results are potentially useful for perfusion-weighted imaging of the human brain, because the volume of contrast agent will be reduced if a solution with higher concentration is used. When using contrast agents in higher concentrations for human examinations, a significant signal decrease may be achieved also with the low doses (.1–.15 mmol/kg).     

EVP-ABD-enhanced MRI to evaluate diffuse liver disease in a rat model

PURPOSE: To evaluate the feasibility of using manganese-based MR imaging contrast agent EVP-ABD to detect diffuse liver disease in an established rat hepatitis model. MATERIALS AND METHODS: Hepatitis was induced by administration of CCl(4) in corn oil vehicle to rats intraperitoneally. MR images were acquired on a 3T scanner using a volume coil approximately 36 hours after the administration of CCl(4). EVP-ABD was administered via a tail vein at a dose of 10 mumol/kg. Multi-TI turboflash images were acquired to evaluate liver R1 (=1/T1) values before and after the EVP-ABD administration. Eighteen rats received various doses of CCl(4) and completed pre- and postcontrast MRI scans and liver histologic evaluation. RESULTS: The liver R1 after the EVP-ABD administration and the change of the liver R1 before and after the administration, DeltaR1, show significant correlations with the CCl(4) dose. A significant correlation was also found between the histologic scores and the CCl(4) doses despite known variability in the relationship of CCl(4) dose to histology. A significant correlation was found between the histologic score and DeltaR1. CONCLUSION: Our results indicate that EVP-ABD-enhanced MRI can detect diffuse liver disease generated by CCl(4) based on the significant correlation between proton R1 in liver following EVP-ABD and the CCl(4) doses as well as the histologic scores.     

Dynamic enhancement features of gadophrin-2 on magnetic resonance imaging: an experimental model of VX2 carcinoma and bacterial abscess in rabbit thigh

RATIONALE AND OBJECTIVES: To determine the dynamic enhancement features of malignant tumor and bacterial abscess in rabbits on magnetic resonance imaging (MRI) after injection of gadolinium mesoporphyrin (gadophrin-2) and to correlate them with histopathologic findings. METHODS: Six VX2 carcinomas and six bacterial abscesses were experimentally induced in either thigh of six rabbits. Dynamic T1-weighted MRI was performed before and 1, 3, 5, 10, 30 minutes and 16, 21, 72 hours after intravenous injection of gadophrin-2 (0.05 mmol/kg). The enhancement ratios of lesions were calculated for each time point. All tumors and abscesses were sectioned along the same plane of MR images for a detailed MRI-histopathologic correlation. RESULTS: In tumors and abscesses, peripheral-rim enhancement appeared on MRI at 1, 3, 5, 10, 30 minutes after injection of gadophrin-2. The lesions showed peripheral enhancement with irregular central enhancement or diffuse enhancement after 16 and 21 hours, and there was diffuse enhancement of the entire lesion after 72 hours. Enhancement ratios in tumor-necrosis mixed area and the pure necrotic area in VX2 carcinoma and the central cavity in bacterial abscess were significantly lower than that in the compact cellular portion in VX2 carcinoma and the wall of abscess at early phase (P < 0.01). On delayed phase MRI, there was no statistical significance in enhancement ratio of three histologic parts of VX2 carcinoma (P > 0.05) and two histologic parts of abscess (P > 0.05). Rapid enhancement at early phase with diminishing signal intensity at delayed phase is indicative of viable compact tumor and delayed strong enhancement is indicative of necrosis. CONCLUSION: It is difficult to distinguish an abscess from a tumor on gadophrin-2 enhanced MRI especially when intratumoral necrosis is prominent. However, the trend and degree of enhancement by gadophrin-2 could be helpful in discrimination between viable tumor and tumor necrosis.     

大鼠原位肝癌纤维间质成分与MR延迟强化的关系

目的：探究大鼠原位肝癌纤维间质成分的特点及其与 MR延迟强化的关系。方法4只 Wistar大鼠原位肝癌模型行肝脏 MR扫描及多期延迟增强扫描,取12个肝癌标本行 HE、苦味酸-天狼猩红染色、Verhoeff Van-Gieson染色、Gordon-Sweets 染色及α-SMA免疫组化染色,观察肿瘤内及周边纤维间质特点及 MR延迟强化特点。结果肝细胞癌内胶原纤维分布于病灶内的纤维间隔中;弹力纤维分布于肿瘤内的纤维间隔及动脉血管壁;网状纤维分布于癌灶内、汇管区及假包膜纤维组织中。胶原、弹力、网状纤维的平均面密度值分别为0.102±0.020、0.063±0.018、0.109±0.032,胶原纤维及网状纤维与弹力纤维间有统计学差异(P<0.01),胶原纤维与 MR延迟强化间正相关(P<0.05)。结论大鼠肝癌 MR延迟强化与病灶内胶原纤维关系密切,MR 可对肝癌内胶原纤维进行无创评估。     

MR contrast enhancement in brainstem and deep cerebral infarction.

MR imaging with IV administration of gadopentetate dimeglumine was performed in 89 patients with 100 clinically and radiologically documented brainstem or deep cerebral (basal ganglia/internal capsule) infarctions to determine the patterns and time course of contrast enhancement. By location, there were 61 deep cerebral, eight midbrain, 23 pontine, and eight medullary infarctions. The age of the infarctions ranged from 1 day to 3 1/2 years, with 22% of the patients scanned within 4 days and 43% scanned within 2 weeks of clinical ictus. Abnormalities on T2-weighted images were encountered in every case. Mass effect was seen in 10 infarctions, most commonly noted between days 2 and 6, but persisting to day 20 in a single case. Parenchymal contrast enhancement was seen in 43 cases, occurring predominately between days 2 and 80. By postinfarction day 3 only half the strokes enhanced, although all did after day 6. Intravascular enhancement within the vertebral or basilar arteries was noted in five cases; all were brainstem infarctions imaged during the first week following ictus. Meningeal enhancement adjacent to the infarction was not seen in any case. Our results indicate that MR contrast enhancement of brainstem and deep cerebral infarctions typically occurs over a period from about 3 days to 3 months following ictus. Lack of both parenchymal and intravascular enhancement is thus to be expected for several days after a brainstem or deep cerebral infarction.     

Clinical evaluation of a computer simulated prediction model of contrast enhancement of the liver in spiral CT

OBJECTIVE: A software program was developed simulating a compartmental model of blood circulation based on differential equations. The aim of this study was to compare software-simulated levels of hepatic enhancement with the true values in patients and to test how many patients reach the simulated hepatic enhancement level. METHODS: As software program the CT application software carebolus 2 (Siemens, Forchheim, Germany) was used. Hepatic contrast-enhancement curves were simulated prior to CT examinations to evaluate a patient specific time delay after contrast application. At the time delay, when the simulation curve showed an enhancement threshold of 40 Hounsfield Units (HU), the CT spiral scan was started applying 120 ml contrast media with 2 ml/s. The simulated curves were compared with the empiric curves of each patient. RESULTS: 25 of 28 patients (89%) achieved 40 HU. The mean enhancement of empiric patients curves was 46.32 +/- 11.9 HU, the mean simulated enhancement was 46.62 +/- 4.3 HU S.D. (P= 0.48). 4.4 values per patient liver could be compared with the simulation curve (122 points for 28 patients): 50% of the patient curves were within a range of 5 HU compared with the simulation curve. CONCLUSION: Software simulation of contrast enhancement curves of the liver is a feasible and valuable method to predict individual liver enhancement curves. Improvements concerning the integration of cardiovascular parameters and preexisting liver parenchymal diseases into the simulation software have to be arranged.     

Comparison of methods for quantifying contrast enhancement exemplified by dynamic MRI mammography

AIM: Aim of this study was to demonstrate and compare different quantification techniques to assess contrast enhancement in dynamic MRI studies. The diagnostic potential of dynamic MRI studies is increasingly appreciated and already used in different organ systems. METHOD: A patient population of 314 histologically verified breast lesions (138 malignant, 176 benign) were evaluated using a high temporal resolved dynamic sequence. Different quantification techniques such as the use of a cutoff line, time dependent and pharmacokinetic assessment were comparatively evaluated. RESULTS: Time dependent quantification methods revealed higher diagnostic potential which was further improved by in vivo normalization of the contrast availability in the vascular system. Significant differences in the enhancement characteristics were determined between malignant and benign as well within the different histological entities. CONCLUSION: Time dependent quantification methods enable an angiogenic characterization of lesions to improve diagnostic interpretation as well as monitoring during therapy. They are also the basis for automated, color-coded visualization of dynamic studies.     

Post-radiotherapy contrast enhancement changes in fast dynamic MRI of cervical carcinoma

This pilot study determines fast dynamic gadolinium enhanced MRI contrast enhancement parameters (onset of enhancement and time to peak enhancement) before and after radiotherapy in 10 cervical carcinoma patients. Before radiotherapy, onset of enhancement and time to peak enhancement were early, with a median of 4.5 and 5.2 seconds, respectively. High-grade tumors showed early enhancement, compared with low-grade. After radiotherapy, contrast enhancement patterns differed. In survivors, onset of enhancement after radiotherapy was later than before radiotherapy. In non-survivors, onset of enhancement after radiotherapy was still early. The median difference in onset of enhancement before and after radiotherapy in survivors and non-survivors was an increase of 3.2 and a decrease of 1.1 seconds, respectively. Early onset of enhancement after radiotherapy was a better predictor for survival than a high-signal intensity zone on post radiotherapy unenhanced T1/T2-weighted MRI. It is concluded that enhancement parameters from fast dynamic Gd-enhanced MR images can provide additional functional information with regard to tumor vascularization, and may have prognostic significance. It complements clinical examination and unenhanced MRI in determining the effectiveness of radiotherapy treatment in cervical carcinoma. Future studies will focus on the clinical utility and improvements of the estimation of contrast-enhanced parameters with this new technique.     

MRI及动态增强扫描对鼻腔及鼻窦恶性黑色素瘤的诊断价值

目的:探讨MRI及动态增强扫描对鼻腔及鼻窦恶性黑色素瘤的诊断价值.方法:回顾性分析26例经手术病理证实的鼻腔及鼻窦恶性黑色素瘤的MRI资料.结果:肿瘤位于鼻腔16例,上颌窦3例,筛窦6例,额窦1例,表现为侵袭性、破坏性或膨胀性生长.免疫组化及组织病理学检查示3例肿瘤内未发现黑色素成分,余23例肿瘤内黑色素均呈阳性.与脑灰质比较,肿瘤T1WI呈高信号17例,等信号9例;T2WI呈低信号14例,等信号10例,高信号2例;T2WI信号混杂,20例瘤内见多发线状低信号影.10例肿瘤DWI表现:9例呈高信号,1例呈等信号.26例肿瘤动态增强扫描后21例呈轻-中度强化;14例肿瘤中12例时间信号强度曲线(TIC)呈速升缓降型,1例呈速升速降型,1例呈持续上升型.结论:鼻腔及鼻窦恶性黑色素瘤具有特征性的MRI表现:T1WI上呈高信号,T2WI信号混杂且可见多发纡曲、线状低信号影.TIC及DWI能更好地了解恶性黑色素瘤内部的多形性成分.     

大鼠急性脑梗死后不同区域扩散和灌注成像的变化特点

目的探讨急性脑缺血后不同区域的PWI和DWI随时间变化的规律及其病理基础,确立评估急性脑缺血可逆性梗死的MRI特异指标及标准。方法利用线栓法建立实验大鼠急性脑缺血模型。应用随机数字表法进行随机分组,A组(单纯脑缺血组):①1.5h(3只),②3h(6只),③6h(3只),④9h(5只)。另设立假手术组作对照组(B组,5只,仅分离颈总动脉)。对上述各组大鼠在规定的时间内行MRI检查,重点测量梗死中心区、梗死边缘和皮质区的表观扩散系数(ADC)、相对血流量(rNEI)、相对峰值时间(rTTM)、信号强度时间曲线的相对上升斜率(rMSI)和信号强度时间曲线的相对下降斜率(rMSD)。将结果与TTC染色、光镜、电镜、免疫组化和激光扫描共聚焦显微镜(LSCM)的结果进行对照。结果A组于缺血1.5h后梗死中心区ADC降低(0.29×10-3mm2s),不同时间组间差异无显著性(P>0.05)。梗死边缘区ADC随时间延长进一步降低,其ADC于脑缺血后1.5h与9h、3h与9h之间存在显著差异(P<0.05)。脑缺血后1.5h,梗死中心区、皮质区之间ADC差异显著(P<0.05),ADC位于皮质区与梗死边缘之间差异无显著性(P>0.05)。对照病理结果和LSCM结果,ADC大于0.51×10-3mm2s,rNEI大于70%和rTTM小于120%,提示脑组织的损伤轻微或可逆。结论急性脑缺血后其DWI、PWI参数值随时间、空间变化,DWI、PWI的半定量化分析,可以鉴别脑缺血发生后脑缺血不同区域的变化,为我们鉴别缺血半影区的存在及范围提供新的方法。     

Assessment of liver and kidney enhancement with a perfluorocarbon vapor-stabilized US contrast agent

RATIONALE AND OBJECTIVES: The authors evaluated the time-echogenicity response of liver, kidney, and implanted VX2 tumor after injection of a microbubble contrast medium and assessed use of an avascular lesion as an internal standard. MATERIALS AND METHODS: Twenty-one New Zealand White rabbits were studied. To evaluate use of an internal standard and the dose-response relationship, nine rabbits with 7-day-old avascular liver lesions created by alcohol ablation received 0.1, 0.25, 0.5, and 1.0 mL of AF0145, a microbubble contrast agent. To evaluate tumor echogenicity, 12 rabbits implanted with VX2 tumor in the liver (six also underwent alcohol ablation) received 0.5 mL of AF0145. Videodensitometry was used to analyze echogenicity changes over 10 minutes. RESULTS: Echogenicity of the alcohol-ablated liver was not affected by contrast material administration. Liver and kidney echogenicity relative to ablation increased linearly with dose, peaking 1 minute after injection and decaying to baseline over 9 minutes. Contrast material administration defined the size and margins of VX2 lesions more clearly. In the arterial phase, the tumor rim was hyperechoic relative to surrounding liver, becoming isoechoic during the portal venous phase then hypoechoic during the late phase parenchymal phase. CONCLUSIONS: Lesions created by alcohol ablation can be used as an internal standard for quantitative analysis of adjacent tissues. AF0145 enhances perfused tissues, including vascular tumors, at gray-scale, real-time ultrasonography and enhances the liver.     

Potential role of combined FDG PET/CT & contrast enhancement MRI in a rectal carcinoma model with nodal metastases characterized by a poor FDG-avidity

Purpose

To investigate the additional role of MRI contrast enhancement (CE) in the primary tumor and the FDG uptake at PET in the lymph-node metastases.

Materials and methods

A model of colorectal cancer induced by orthotopic HT-29 cells microinjection, producing pelvic lymph node metastases, was assessed using CE-MRI and FDG-PET. Histology and GLUT-1 immunohistochemistry were performed on primary tumors and iliac lymph nodes.

Results

Primary tumors were characterized by low FDG-uptake but high CE-MRI, particularly at tumor periphery. Undetectable FDG-uptake characterized the metastatic lymph-nodes. Histology revealed large stromal bundles at tumor periphery and a dense network of stromal fibers and neoplastic cells in the inner portion of the tumors. Both primary tumors and positive lymph nodes showed poor GLUT-1 staining.

Conclusion

Our data support the complementary role of MRI-CE and FDG PET in some types of carcinomas characterized by abundant cancer-associated stroma and poor FDG avidity consequent to poor GLUT-1 transported. In these tumors FDG-PET alone may be not completely adequate to obtain an adequate tumor radiotherapy planning, and a combination with dual CE-MRI is strongly recommended.     

Comparison between intravenous and intraarterial contrast injections for dynamic 3D MRI of liver tumors in the VX2 rabbit model

PURPOSE: To test the hypothesis that catheter-directed intraarterial (IA) contrast agent injection increases tumor enhancement and conspicuity compared to intravenous (IV) injection. MATERIALS AND METHODS: Eight VX2 liver tumors were grown in five rabbits. After positioning a catheter in the hepatic artery, we performed 3D inversion recovery GRE MRI after IA and IV gadopentetate-dimeglumine contrast injections at doses of 0.04 and 0.1 mmol/kg, respectively. Peak enhancement (signal-to-noise ratio (SNR)) and conspicuity (contrast-to-noise ratio (CNR)) were measured for each acquisition. RESULTS: The peak SNR and CNR were 21.7 +/- 5.8 and 17.0 +/- 4.8 (mean +/- SD) after IA injection, and 16.9 +/- 10.2 and 6.2 +/- 2.6 after IV injection. The IA CNR was significantly greater than the IV CNR (P < 0.05), with a >60% increase in CNR for each tumor. For six of the eight tumors the IA SNR was greater than the IV SNR, but statistical significance was not achieved due to the small sample size of the study (P = 0.07). CONCLUSION: We demonstrated the feasibility of using IA injection techniques to improve tumor conspicuity. This strategy could be employed to enhance the detection of small liver tumors or to conserve contrast agent in future MRI-guided transcatheter liver therapies.