Magnetic resonance lymphography of profundus lymph nodes with liposomal gadolinium-diethylenetriamine pentaacetic acid.

Lymphography, especially imaging of profundus lymph nodes, is a useful tool for diagnosis of cancer metastases in lymph nodes. However, positive enhancement agents for magnetic resonance lymphography (MRL) have not been available, since the positive imaging agents so far introduced are low-molecular-weight materials that are not trapped in lymph nodes. For the purpose of improved positive enhanced MRL, we employed liposomes as carriers of a positive enhancer, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Magnetic resonance (MR) imaging was performed after subcutaneous injection of Gd-liposomes into the hind feet of rabbits which had reactive enlarged retroperitoneal lymph nodes. As a result, not only popliteal but also profundus retroperitoneal lymph nodes were positively enhanced by Gd-liposomes, especially after 20 min massage of the injected sites. Gd-Liposomes containing dipalmitoylphosphatidylglycerol were more effective than Gd-liposomes containing palmityl-D-glucuronide, a type of long-circulating liposomes, suggesting that liposomal accumulation in lymph node is, at least partly, mediated by the trapping of liposomes by macrophages. These data show that liposomes modified with Gd-DTPA are effective for positive enhancement of both regional and profundus lymph nodes in MR lymphography.

Prostate cancer tumor grade differentiation with dynamic contrast-enhanced MR imaging in the rat: comparison of macromolecular and small-molecular contrast media--preliminary experience.

PURPOSE: To differentiate prostate cancers of different histopathologic grades with dynamic gadolinium-enhanced magnetic resonance (MR) imaging. Results with a conventional small-molecular contrast medium (CM) were compared to those with a prototypic macromolecular CM. MATERIALS AND METHODS: High- and low-grade tumors, sublines of the Dunning R3327 rat prostate cancer line, were subcutaneously implanted into the flanks of 12 male Copenhagen rats. Dynamic contrast material-enhanced MR imaging was performed with small-molecular CM and macromolecular CM at an interval of 1 day. Microvascular permeability, as estimated with the endothelial transfer coefficient, and fractional plasma volume were calculated for each tumor and each CM by means of a two-compartmental, bidirectional kinetic model. RESULTS: Mean endothelial transfer coefficient values for both macromolecular CM and small-molecular CM were significantly different between the two tumor sublines (P = .0004 and P = .01, respectively). For the high- and low-grade tumors, no overlap of values was seen with macromolecular CM, but a broad overlap was seen with small-molecular CM despite a significant difference in mean values. CONCLUSION: Dynamic contrast-enhanced MR imaging permits differentiation of histopathologic prostatic tumor types. Quantitative microvascular permeability characteristics estimated from macromolecular CM-enhanced data were significantly superior to those derived from small-molecular CM-enhanced data.

Tumor blood volume assays using contrast-enhanced magnetic resonance imaging: regional heterogeneity and postmortem artifacts.

Tumor blood volume (BV), subject to both morphologic and physiologic influences, can be measured using contrast-enhanced magnetic resonance imaging (MRI). The aims of this study were to determine whether MRI enhanced with a macromolecular contrast medium (MMCM) could resolve differences in BV between different tumor types, between different regions within tumors, and within the same tumor in life and after death. Tumor BV estimates were based on the MRI signal intensity responses in the tumors and in reference venous blood following enhancement with a blood pool MMCM using two mammary adenocarcinoma models. Estimates of BV were made before and immediately following death. An in vitro measurement of tumor gadolinium concentration following death was correlated with MRI enhancement. Statistically significant differences (P < 0.05) were observed in MRI-estimated tumor BV between tumor subtypes, between in vivo and postmortem measurements, and between the tumor periphery and tumor centers. MRI assays enhanced with a macromolecular contrast agent can resolve blood volume differences between tumor types, between regions within the same tumor, and between vital and postmortem states.

Delivery of diagnostic agents for magnetic resonance imaging.

A review of contrast agents used for magnetic resonance imaging was made with regard to methods of drug delivery using published literature. Since the clinical approval of Gd-DTPA in 1988, there has been extensive research towards developing organ- and tissue-specific contrast agents. Targeting strategies have consistently improved along with improvements in nuclear medicine imaging, and a broad spectrum of potential agents has accumulated. Liver, blood-pool targeted, and, due to their inherent convenience of delivery, intraorally administered gastrointestinal agents have been developed or are being developed. For intravenous contrast agents, collective magnetic labels with modifications for some specificities results in the larger-sized agents which can be an obstacle for the agent in accessing the targeted cells. In conclusion, the next step in the development of specific contrast agents for clinical use is to improve non-specific delivery to the extra-capillary space adjacent to targeted cells.

Correlation of dynamic contrast-enhanced MR imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media.

OBJECTIVE: The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic MR imaging were correlated with histopathologic grade in mammary soft-tissue tumors. MATERIALS AND METHODS: A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N-ethyl-N-nitrosourea, a potent carcinogen. Dynamic contrast-enhanced MR imaging was performed using a small-molecular contrast medium (gadopentetate, molecular weight = 0.5 kDa) and a macromolecular contrast medium (albumin-(Gd-DTPA)30, molecular weight = 92 kDa) at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (K(PS)), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bidirectional kinetic model. MR imaging microvascular characteristics were correlated with histopathologic tumor grade. RESULTS: Tumor permeability to macromolecular contrast medium, characterized by K(PS), showed a highly positive correlation with tumor grade (r2 = .76, p < 10(-10)). K(PS) values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r2 = .25, p < .003). No correlation between K(PS) or fPV values and tumor grade was found using gadopentetate (r2 = .01, p > .95 and r2 = .03, p > .15, respectively). CONCLUSION: Quantitative tumor microvascular permeability assays generated with macromolecular MR imaging contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

Quantification of the extraction fraction for gadopentetate across breast cancer capillaries.

To quantify the extraction fraction, E, for gadopentetate across tumor capillaries, R3230 adenocarcinomas were implanted in the mammary fat pads of seven rats. The value of E was determined by using a two-compartment tissue model in which the endothelial transfer coefficient, K(PS) (ml x min(-1) x cc(-1) of tissue), was estimated from the model fitted to changes in R1 relaxation time (deltaR1; s(-1)) measured by dynamic three-dimensional spoiled gradient recalled magnetic resonance imaging after injection of 0.1 mmol x kg(-1) of gadopentetate dimeglumine. The plasma flow rate through the tumor capillaries, Fp, (ml x min(-1) x g(-1) of tissue), was independently measured with fluorescent microspheres. E could be calculated by the relationship, E = K(PS)/Fp. The mean E for gadopentetate in the R3230 tumor was 0.197 +/- 0.118 with a range of 0.123-0.454. The relatively small mean value of E for gadopentetate allows a fair approximation of the permeability surface area product by K(PS) in this R3230 tumor model.

Correlation of dynamic contrast-enhanced magnetic resonance imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media.

BACKGROUND: The endothelial integrity of microvessels is disrupted in malignant tumors. Quantitative assays of tumor microvascular characteristics based on dynamic magnetic resonance imaging (MRI) were correlated with histopathologic grade in mammary soft tissue tumors. MATERIALS AND METHODS: A spectrum of tumors, benign through highly malignant, was induced in 33 female rats by administration of N -ethyl-N -nitrosourea (ENU), a potent carcinogen. Dynamic contrast-enhanced MRI was performed using a small-molecular contrast medium [gadopentetate, MW = 0.5 kDa] and a macromolecular contrast medium [albumin-(Gd-DTPA)30, MW = 92 kDa] at an interval of 1-2 days. Permeability surface area product (PS), as estimated by the corresponding endothelial transfer coefficient (KPS), and fractional plasma volume (fPV) were calculated for each tumor and each contrast agent using a two-compartment bi-directional kinetic model. MRI microvascular characteristics were correlated with histopathologic tumor grade. RESULTS: Tumor permeability to macromolecular contrast medium, characterized by KPS, showed a highly positive correlation with tumor grade (r 2 = 0.76, P < 10(-10)). KPS values were zero for all benign and some low-grade carcinomas, greater than zero in all other carcinomas, and increased in magnitude with higher tumor grade. A considerably smaller but significantly positive correlation was found between fPV and tumor grade using macromolecular contrast medium (r 2 = 0.25, P < 0.003). No correlation between KPS or fPV values and tumor grade was found using gadopentetate (r 2 = 0.01, P > 0.95 and r2 = 0.03, P > 0.15, respectively). CONCLUSION: Quantitative tumor microvascular permeability assays generated with macromolecular MRI contrast medium correlate closely with histologic tumor grade. No significant correlation is found using small-molecular gadopentetate.

Cavernous hemangioma of the adrenal gland: MRI appearance.

We describe a case of cavernous hemangioma of the adrenal gland in which MR imaging showed low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, and dynamic MR imaging using Gd-DTPA showed late and delayed enhancement, allowing definitive diagnosis.

[MR lymphography: first application to human].

First clinical trial of MR lymphography is described. The subjects were two normal volunteers. The contrast agent was cideferron, which was an iron colloid. We obtained MR images of the inguinal lymph nodes before and after subcutaneous injection of the agent in the dorsal feet. As a result, the signal intensities on T2 weighted images remarkably decreased at two hours after injection and kept low until three months after. Although pigmentation around the injection site was observed, it was gradually fading within six months. In conclusion, MR lymphography with cideferron can be applied clinically.

Inhalation MR lymphography: a new method for selective enhancement of the lung hilar and mediastinal lymph nodes.

On MR lymphography, a new approach to the lung hilar and mediastinal nodes was developed in an animal model. Five rabbits were made to inhale iron colloid (cideferron) that was nebulized to aerosol. Two days after inhalation of the agent, the mediastinal lymph nodes decreased in signal on SE 2000/30 and SE 2000/60 images and proved to have iron on histological evaluation, whereas the popliteal nodes did not have any iron. Experimental results indicate that inhalational administration can deliver the agent to the pulmonary lymphatic system and has the potential of lung hilar and mediastinal MR lymphography.

Chronological changes of MRI findings on striatal damage after acute cyanide intoxication: pathogenesis of the damage and its selectivity, and prevention for neurological sequelae: a case report.

A 31-year-old male technician in an electroplating factory, who had been suffering from the temporal lobe epilepsy for 24 years and from hypertension for 2 years, took an unknown amount of potassium cyanide apparently over the lethal dose, in an attempt to commit suicide. He was treated successfully and survived without any neurological sequelae. The electroencephalograms and the nature of the seizures were not different before and after the poisoning. The T2-weighted magnetic resonance images at 9 and 51 days after the poisoning showed bilateral elevation of signals in the caudate nuclei and the putamina. At the 143th and 286th days. T2-weighted high-resonance areas were restricted to the lateral portion of the putamina. The T1-weighted images at the 51st day showed abnormal signal elevations in both putamina, while those of 9th, 143th and 286th days were mainly normal. Selective vulnerability of the putamen and the caudate nucleus may be due to their specific structural properties of high oxygen and glucose utilization, and enzyme distribution. Both chronological changes of striatal damage and the absence of neurological sequelae in this patient suggest the possibility that anti-epileptics and a calcium antagonist played a neuroprotective role in the acute cyanide intoxication.

[An experimental study on MR lymphography with various iron colloid agents].

Magnetic resonance (MR) lymphography with iron colloid agents was evaluated in an animal model. The agents examined were ferric gluconate (FeG), saccharated ferric oxide (SFO), iron chondroitin sulfate (ICS) and cideferron (CiF), which were used as intravenous medication for iron deficiency anemia. The author performed time-dose-response and correlative histologic studies. MR images of the popliteal lymph nodes of rabbits were obtained at 1.5 T with a spin-echo sequence (TR = 300, TE = 30 msec) before and after subcutaneous injection of the agents to dorsal hind-feet. The images were evaluated by signal intensity (SI). Histologic specimens were evaluated for distribution and relative quantity of stained iron with a color image analyzer. The SI with FeG 4 mgFe increased by 50% at 5 to 60 minutes after injection but returned to the pre-contrast level 48 hours after. The SIs with SFO 8 mgFe, ICS 1 mgFe and CiF 1 mgFe decreased to the background level at 60 minutes and 48 hours after. The histologic study in combination with the images indicated that in case of FeG the particles in lymph increased SI while in the other agents those within macrophages decreased SI.

[A preliminary study on MR lymphography with iron chondroitin sulfate colloid].

We investigated MR lymphography with iron chondroitin sulfate colloid, which was an intravenous agent for iron deficiency anemia. MR images (SE350/30) of the medial iliac lymph nodes were obtained before and after subcutaneous++ injection of this agent (2 mg Fe) on dorsal hindfeet bilaterally in five rabbits (3.0 kg weight). Signal intensities of the nodes were increased 5-15 minutes after the injection and the nodes were clearly identified in three of them. In the other two, increase in the signal intensity was not shown and any nodes could not be detected macroscopically at the investigated region on dissection. These results indicated the possibility of positive contrast enhancement of lymph nodes on MR imaging using iron colloid.

[Efficacy of pancreatic scan--comparison among conventional scan, SPECT and X-CT].

We studied the efficacy of pancreas scintigraphy using 75Se-selenomethionine by conventional method and SPECT in 26 patients diagnosed as pancreatic tumor or pancreatitis. X-CT was also performed in all patients and compared its efficacy with that of scintigraphy. In order to evaluate the image quality, 4 doctors analysed the images independently without clinical information and score them according to the possible abnormality. The average score of each film was adopted as an index for sensitivity, and the standard deviation was evaluated as objectiveness of the images. As for the detection of pancreatic tumor, both the sensitivity and the objectiveness of X-CT were superior to those of scintigraphies. However, evaluation by scintigraphy combined with X-CT increased the diagnostic sensitivity of pancreatitis than that of X-CT alone in some cases. These results suggest that the scintigraphy has no indication to suspected pancreatic tumor, but it still has some value in limited cases of pancreatitis. Almost no advantage was noted in SPECT combined with conventional image. Main reason was the artifact of SPECT preventing the accurate interpretation. Only benefits of SPECT were to decrease the false positive rate and to increase the objectiveness of 75Se-selenomethionine scan. When the scan is discussed as the examination, careful considerations should be done on the point of limited advantage on diagnostic efficacy and marked disadvantage of radiation to patients and environment.

[Injuries of the sigmoid colon following radiation therapy of carcinoma of the uterine cervix--a method of estimating the radiation dose to the sigmoid colon].

Grade 2 or 3 injuries of the sigmoid colon were observed in 4 out of 42 patients with carcinoma of the uterine cervix who were treated by radiation therapy. The irradiation was planned as the combination of the external irradiation (whole pelvic 30 Gy and 20 Gy with central shielding by 25 fractions, 5 weeks) and the intracavitary irradiation (RALS, 19 Gy at point A by 3 fractions). To analyze the causes of the radiation sigmoiditis, we have investigated the following factors: age, dose at point A, dose at point C, grade of tandem dislocation, uterine angle, obesity score, evidence of previous surgery to the pelvic cavity and hypertension. The dose at point C and the grade of tandem dislocation were determined from the confirming X-Ps at RALS therapy and external irradiation. The superimposition of these films was performed with corrections for the angle between the projection direction of the X-Ps and the vertical magnification factor of the central shielding area. Point C was defined as a point 2 cm anterior to the intersection of the tandem axis and a curvilinear line 1 cm outside from the margin of central shield on the X-Ps. Grades of tandem disclocation were decided as the number of tandem tips which were outside of the central shielding area on X-Ps. As the results, the doses at point C showed very high statistical significance (p less than 0.001) with the evidence of radiation sigmoiditis. All the cases with radiation sigmoiditis were received over 1290cGy at point C. Age had also some significance (p less than 0.05) with radiation sigmoiditis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Radiotherapy of uterine cervix carcinoma].

Seventy-eight patients with uterine cervix cancer were treated radically with standardized radiation therapy at Teikyo University Hospital in Tokyo from January 1979 to December 1985. The age of these patients ranged from 32 to 88 years old (average age 66.0). The pathology and the stage of them were 71 cases of squamous cell carcinoma (1 in stage I, 11 in stage II, 58 in stage III and 1 in stage IV) and 7 cases of adenocarcinoma (6 in stage III and 1 in stage IV). The cumulative survival rates for 5 years by Kaplan-Meier method were 71.5% for squamous cell carcinoma stage II, 47.4% for squamous cell carcinoma stage III and 0% for adenocarcinoma stage III. Radiation injury was studied by the grading system of Kottmeier-NIRS in Japan. The incidence of the injuries for grade 2 and 3 was 12.8% (10/78), and the items of those were rectal injury 5.1% (4/78) and sigmoidal colonic injury 7.7% (6/78). The results of survival rate were fair for the squamous cell carcinoma compared with the other reports but poor for adenocarcinoma stage III. Concerning the therapy for advanced adenocarcinoma of the uterine cervix, special consideration should be given for irradiation doses or infusion chemotherapy.