Paradoxic uptake of Gd-EOB-DTPA by hepatocellular carcinoma in mice: quantitative image analysis.

To determine whether paradoxic uptake of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) occurs only with highly differentiated hepatocellular carcinomas, quantitative image analysis was performed in 37 mice with 133 hepatocellular carcinomas. The results of lesion/ liver signal intensity measurement and relative enhancement calculation indicate that paradoxic positive enhancement occurs independently of cellular differentiation.

Assessment of early radiation effects on the liver. Comparison of SPECT and MR.

PURPOSE: To evaluate the early effects of radiation on the liver using single photon emission CT (SPECT) with 99mTc-phytate combined with a pinhole collimator and MR imaging with superparamagnetic iron oxide (SPIO) and to compare 2 modalities regarding the assessment of the reticuloendothelial cell function. MATERIAL AND METHODS: The right sides of the livers of 12 anesthetized rats were irradiated with X-rays (4000 cGy). On the 3rd and 4th days postirradiation, SPECT and MR imaging pre- and postcontrast were performed. RESULTS: On SPECT, the irradiated areas appeared as areas with reduced 99mTc-phytate uptake in 9 rats. In the remaining 3 rats, irradiated lesions were not evident on SPECT. On the early postcontrast MR images, differential negative enhancement of the irradiated and nonirradiated areas in the same 9 rats as on SPECT was apparent. However, on the later postcontrast images of 3 of these rats, the irradiated areas, which were brighter than the nonirradiated areas, were visually less clear than those on the earlier postcontrast images. In the remaining 3 rats, no radiation damage was evident on MR images. CONCLUSION: SPECT with 99mTc-phytate and early postcontrast MR imaging with SPIO can show early radiation damage of the liver. The serial assessment of the postcontrast MR images provides functional information on the Kupffer cells.

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 mumol/kg) and superparamagnetic iron oxide (SPIO; 10 mumol/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.

Neurotoxicity of gadolinium contrast agents for magnetic resonance imaging in rats with osmotically disrupted blood-brain barrier.

The neurotoxicity of intravenously injected Gadolinium (Gd) complexes to rats with disrupted blood-brain barrier (BBB) was evaluated. After disruption of the BBB by infusion of mannitol solution, one of several contrast agents tested was injected intravenously at a dose of 1 or 3 mmol Gd/kg, and neurological symptoms were graded. The concentrations of Gd in brain and plasma were also measured. Injection of Gd-DTPA at a dose of 3 mmol Gd/kg did not change behavior. On the other hand, Gd-DTPA-BMA, Gd-DO3A-butrol, and Gd-DO3A-HP each induced behavioral impairments, and some animals died within 1 h after injection. Gd-DO3A-HP showed lethal effect even at a dose of 1 mmol/kg. The concentration of Gd in the brain of the animals injected with Gd-DO3A-HP at 3 mmol Gd/kg was essentially the same as that of animals injected with Gd-DTPA at the same dose. The neurotoxicity of the contrast agents tested was graded as follows: Gd-DTPA < or = Gd-DTPA-BMA = Gd-DO3A-butrol < Gd-DO3A-HP.

[Study of anti-tumor effects of hyperthermia combined with hydralazine on experimental tumor].

We analyzed tumor growth delay in experimental tumors after hyperthermia alone, hydralazine (HDZ) injection alone and the combination of these modalities. We also analyzed the energy parameter (ATP/Pi ratio) obtained by 31P-MRS (magnetic resonance spectroscopy). The purpose of this study was to evaluate the usefulness of 31P-MRS as an index of anti-tumor effect. FM3A tumor cells were transplanted subcutaneously in the hind legs of C3H/He mice. We dipped the tumors into a heated circulating water bath. 31P-MRS was performed with a CSI spectrometer. The anti-tumor effect obtained with HDZ alone was insignificant, but combined treatment with hyperthermia and HDZ had a significant synergistic effect. The ATP/Pi ratios for all groups treated separately with HDZ or hyperthermia were not different from the control, but the ATP/Pi ratio decreased after combined use of these agents. There was a significant correlation between the decrease in ATP/Pi ratio and tumor growth delay. We observed a direct relation between the delay in tumor growth and the decline in ATP/Pi ratio after combined treatment with HDZ and hyperthermia. The ATP/Pi ratio 24 hr after treatment may be useful in predicting the efficacy of the combined use of HDZ and hyperthermia.

[19F-MR imaging of transplanted tumor: perfluorochemicals as a fluorine tumor imaging agent].

PURPOSE: The purpose of our study was to detect tumor selectively using 19F-magnetic resonance imaging (MRI) and to assess Fluosol-DA, a perfluorochemical emulsion, as a tumor imaging agent for 19F-MRI. MATERIALS AND METHODS: SCC VII cells were transplanted in the right leg of mice. After 6 days, Fluosol-DA was administrated intravenously (40 ml/kg). 19F-MR imaging was performed on a Bruker CSI Omega 2 at 4.7 Tesla using a homemade volume coil. RESULTS: In vitro, the concentration and 19F signal intensity of FDA showed a very high correlation (r = 0.9997). Detection on MRI was possible at a concentration of 2%. In vivo, images of 19F in SCC VII tumors were achieved in animals 2 days after the administration of FDA. CONCLUSION: Our study confirms the feasibility of 19F-MR in vivo imaging of tumors using the fluorine compound FDA.

Differentiation between dysmyelination and demyelination using magnetic resonance diffusional anisotropy.

Using magnetic resonance (MR) diffusion-weighted method, we examined the optic and the trigeminal nerves of jimpy and twitcher mice, considered to be animal models of Pelizaeus-Merzbacher disease, hypomyelination disorder, and Krabbe disease, demyelination disorder, respectively. In jimpy mice, diffusional anisotropy of optic nerve did not show a significant difference compared to age-matched control mice, suggesting that diffusional anisotropy does exist in absence of multiple layers of myelin sheath. In twitcher mice, diffusional anisotropy was attenuated remarkably in the optic and trigeminal nerves. Loss of axonal straightness on longitudinal section confirmed by electron microscopy appeared to be the principal explanation for it. It is further suggested that this MR diffusion-weighted imaging method enables us to differentiate hypomyelination from demyelination in vivo.

Comparison of iopamidol and ioversol in vitro and in animal studies.

In the present series of studies we investigated differences in vitro and in animal experiments between iopamidol (Iopamiron, CAS 60166-93-0) and ioversol (CAS 87771-40-2). The studies included the in vitro investigations partition coefficient, lysozyme inhibition, coagulation time and erythrocyte morphology as well as the in vivo paradigms acute toxicity, neural toxicity, general behavior/locomotor activity and angiography. Iopamidol was superior to ioversol in most of the tests. In spite of its higher hydrophilicity, ioversol did not show improved tolerance in comparison to iopamidol.

Selective and prolonged MRI enhancement by Mn-TPPS in an experimental rat brain tumour with peripheral benzodiazepine receptors.

Synthesized Mn-TPPS, a paramagnetic metalloporphyrin, is expected to be a tumour specific contrast media for magnetic resonance (MR) imaging. We investigated the enhancing characteristics of Mn-TPPS using a transplanted rat C6 glioma model with peripheral type benzodiazepine (PBD) receptors since porphyrins are thought to possibly be endogenous ligands for PBD receptors. An Mn-TPPS enhancement study was then performed either with or without pretreatment while using peripheral and central type benzodiazepine receptor specific ligands (PK11195 and clonazepam, respectively). A signal intensity analysis disclosed the selective and prolonged enhancement of the brain tumour even at 17 h after the Mn-TPPS injection. This specific enhancement of the tumour, however, was not inhibited nor replaced by benzodiazepines. The tissue concentration of Mn-TPPS was significantly higher in the glioma tissue than the other tissues, while PK11195 pretreatment could not reduce the intratumoural Mn-TPPS concentration. A subcellular distribution study disclosed that Mn-TPPS was readily incorporated into the tumour cells. On the other hand, Mn-TPPS was not specifically distributed in the mitochondrial fraction where PBD receptors exist. The present study therefore indicates that Mn-TPPS could be incorporated into tumour cells and supports the potential use of this agent to improve the diagnostic specificity of MR imaging for brain tumours.

Therapeutic effects of imidapril on cerebral lesions observed by magnetic resonance imaging in malignant stroke-prone spontaneously hypertensive rats.

OBJECTIVE: Magnetic resonance imaging (MRI) was used to investigate the therapeutic effects of imidapril, a newly synthesized angiotensin converting enzyme (ACE) inhibitor, on cerebral stroke lesions. DESIGN: Pretreatment with ACE inhibitors is known to prevent stroke in stroke-prone spontaneously hypertensive rats, prolonging their lifespan. Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) were treated with imidapril after the onset of stroke. METHODS: M-SHRSP with proved stroke were divided into two groups. One group received 40 mg/kg per day imidapril and the other group was used as a control. For 4 weeks, neurological symptoms were scored daily, and MRI images were taken and scored once a week. RESULTS: In the control group the MRI score for cerebral lesions increased during the experiment, and seven out of eight control rats died within 17 days. In rats treated with imidapril the major finding was that imidapril rapidly ameliorated the damage to the blood-brain barrier and resolved brain oedema within 1 week. At the same time the neurological symptoms observed after stroke disappeared. Furthermore, none of the rats treated with imidapril showed recurrence of stroke, and their survival rate was improved. CONCLUSION: These results suggest that imidapril has therapeutic effects on stroke lesions, as well as prophylactic effects on the recurrence of stroke.

Evaluation of thermal damage after hyperthermia on murine experimental tumor by 31P-NMR spectroscopy--correlation between ATP and growth delay.

The usefulness of 31P-MRS (phosphate magnetic resonance spectroscopy) for evaluation of the anti tumor effect of hyperthermic treatment was examined. FM3A, an experimental tumor transplantable to C3H mice, was used. FM3A, transplanted subcutaneously to the femoral region, was subjected to hyperthermic treatment and 31P-MRS were measured at various times. Because the ATP/Pi ratio indicates the energy status of tumor cells, we conducted measurement of its sequential changes after hyperthermic treatment. With a water bath, hyperthermic treatment was performed at 44 degrees C. Twenty four hours after treatment, the ATP/Pi ratio dropped as the heating time was prolonged, showing an obvious converse correlation to the tumor growth curve on heating. Immediately after hyperthermic treatment, the ATP/Pi ratio fell drastically, began to recover after 18 hrs and remained unchanged up to the 24 hrs. The finding that the ATP/Pi ratio obtained in tumor tissue 24 hrs after hyperthermic treatment was correlated with tumor inhibition suggested that the ratio can be a possible parameter for evaluation of the anti tumor effect by heating. The ATP/Pi ratio obtained by 31P-MRS could be used for non-invasive prediction of tumor tissue damage by heating.

In vivo differentiation of edematous changes after stroke in spontaneously hypertensive rats using diffusion weighted MRI.

Apparent diffusion coefficients (ADCs) of tissue water were determined in chronic brain lesions of a rat stroke model, the stroke-prone spontaneously hypertensive rat, and compared with histology. ADCs increased in the order normal < edema < gliosis < cyst. The differences between individual groups were statistically significant. The increase in ADC is thought to mainly reflect a relative increase in the extracellular space in brain tissue. ADC may be a new parameter for tissue characterization.

Differentiation of chronic lesions after stroke in stroke-prone spontaneously hypertensive rats using diffusion weighted MRI.

Apparent diffusion coefficients (ADCs) of tissue water were determined in chronic brain lesions of a rat stroke model, stroke-prone spontaneously hypertensive rats and compared with histology. ADCs increased in the order control < edema < gliosis < cyst. The differences between individual groups were statistically significant. The increase in ADC is thought to mainly reflect a relative increase in the extracellular space in brain tissue. ADC values may be a clinically useful parameter for tissue characterization.

Magnetic resonance imaging in a dog with choroid plexus carcinoma.

Choroid plexus carcinoma was diagnosed in a 10-year-old maltese dog with chief complaint of progressive ataxia and head tilt. No abnormalities was observed on hemogram, radiographs of the skull, and electroencepharograph (EEG). Neurological examination suggested central vestibular lesions. On the magnetic resonance imaging (MRI) examination, images after contrast enhancement with Gadolinium DTPA-dimeglumine showed a rough circular lesion with an increased signal intensity in caudal fossa. This lesion was histopathologically confirmed to be choroid plexus carcinoma.

Cerebral embolization in rats induced by red blood cells treated with hypertonic X-ray contrast medium.

RATIONALE AND OBJECTIVES: Hypertonic X-ray contrast media induce morphologic changes in red blood cells (RBCs) and reduce their deformability when measured in vitro. This study investigated whether RBCs treated with hypertonic contrast media could induce circulatory as well as metabolic disturbances in vivo. METHODS: Autologous blood was mixed with an equal volume of meglumine diatrizoate (306 mgI/mL); 50 microliters of this mixture was infused into the left internal carotid artery of rats 2 minutes after mixing. Five minutes after infusion, the cerebral blood flow was determined using iodo[14C]antipyrine. 31P-magnetic resonance spectroscopy (MRS), 1H-MRS and 1H-magnetic resonance imaging (MRI) of the brain were performed before and after infusion of the mixture to study changes in energy metabolites and the integrity of the blood-brain barrier (BBB), as well as the development of edema. RESULTS: The blood flow decreased by 70% to 80% in the left cerebral cortex and caudate-putamen. 31P-MRS and 1H-MRS demonstrated derangement of oxidative phosphorylation. 1H-MRI demonstrated instant destruction of the BBB and gradual progress of edema in the left hemisphere. CONCLUSIONS: These results indicate that intracarotid infusion of RBCs treated with hypertonic contrast medium can induce embolization and subsequent ischemic damage to the brain.

[Preclinical evaluation of iotrolan as a contrast medium for angiography and urography].

Efficacy and tolerability of iotrolan, a nonionic isotonic dimer, as a contrast medium for angiography and urography were investigated in animals. In the arteriography of rabbit femur, the efficacy of iotrolan 280 mgI/ml was as good as iopamidol 300 mgI/ml and better than meglumine diatrizoate 306 mgI/ml. In rat urography, the efficacy of iotrolan 280 mgI/ml was better than both iopamidol 370 mgI/ml and iohexol 350 mgI/ml. Vascular pain was less with iotrolan 280 mgI/ml than with iohexol 300 mgI/ml in rats. Effect of iotrolan on the pulmo-cardiovascular parameters, arterial pO2, hematocrit and plasma osmolality was less than iopamidol and diatrizoate in rabbits. Iotrolan induced no renal dysfunction and diuresis where iopamidol induced diuresis in rats. Effect of iotrolan on the blood coagulation was similar to nonionic monomers and less than diatrizoate in rabbits. Because of its isotonicity, iotrolan induced little water shift in the blood vessel and urinary tract, which would result in good efficacy and tolerability. These results suggest that iotrolan is superior to ionic and nonionic monomers for angiography and urography.

[Evaluation of US contrast medium (LEVOVIST) to experimental liver cancer].

Enhancement of liver cancer on ultrasonography (US) by injection of new contrast medium (LEVOVIST) was performed in rats with 3'-methyl-4-dimethylaminoazobenzene-induced hepatic carcinoma. Echosignals of cancer nodules increased remarkably after the intrahepatic arterial injection of LEVOVIST (200, 300 mg/ml), and contrast enhancement was observed for at least 15 minutes. Furthermore, US after the intrahepatic arterial injection of LEVOVIST (200 mg/ml) can visualize small nodule, which was not recognizable on plain US. As a result of increased echosignals of normal liver parenchyma after the intra-portal injection of LEVOVIST (300 mg/ml), the cancer nodules were demonstrated as hypoechoic. These results indicate that this new contrast medium for sonography is effective in the diagnosis of liver cancer.