Barry L. Engelstad’s research while affiliated with University of California, San Francisco and other places

Iron-dextran (1 mmol Fe/kg) was used as an intravascular, paramagnetic contrast agent in rat and cat brain in conventional spin-echo T2-weighted (TR 2800/TE 100) 1H magnetic resonance imaging. The resulting images displayed differential decreases (30-50%) in intensity whose pattern was similar to that obtained with the superparamagnetic particulate iron oxide AMI-25 (0.18 mmol Fe/kg). Postcontrast images displayed improved anatomic detail, and contrast effects were observed to be greater in cortical and subcortical gray matter than in adjacent white matter. Intravenous injection of acetazolamide after administration of iron-dextran caused a small additional decrease in image intensity. Measurement of whole blood and plasma at 5 min postinjection of either contrast agent revealed significant increases in their volume magnetic susceptibilities. The contrast effect appears to be related to magnetic susceptibility changes brought about by the iron-dextran; it has both blood volume and blood flow components. The static model of magnetic susceptibility effects in brain capillaries is modified to include bolus flow of erythrocytes, providing a mechanism for the observed flow effects.

A method is provided for obtaining in vivo diferentiation of tissues in an animal by nuclear magnetic resonance imaging comprising the steps of introducing into the animal a complex comprising a paramagnetic ferric ion and a chelator. Particular contrast agents, Fe(HBED) and Fe(EHPG), are excretable by a hepatobiliary pathway.

Succinyl (SDF), phenylsuccinyl (PSDF), glutaryl (GDF), and phenylglutaryl (PGDF) derivatives of desferrioxamine B (DF) have been synthesized. In rats given the 59Fe(III) chelates of each these ligands at tracer levels, 82-94% of the 59Fe was eliminated within 1-2 days. 59Fe given as DF, SDF, and GDF chelates was excreted primarily in the urine, while nearly 50% of that given as PSDF and PGDF was excreted in the feces. Correspondingly, Fe-DF, Fe-SDF, and Fe-GDF (0.2 mmol/kg) produced early, marked renal, but no gastrointestinal magnetic resonance imaging (MRI) enhancement. Fe-PSDF and Fe-PGDF (0.2 mmol/kg) produced marked and rapid MRI enhancement of the upper small intestine. In animals with cannulated bile ducts, 59Fe from 59Fe-PGDF (carrier added, 0.1 mmol/kg) appeared rapidly in the collected bile, but not in the intestinal contents, proving that the contrast agent reaches the bowel via the bile. These changes in the excretion and MRI enhancement patterns brought about by the presence of a phenyl substituent apparently were not related to changes in lipophilicity or protein binding.

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative that is selectively concentrated in sympathetic nervous tissue. MIBG labeled with 123I or 131I has proven to be a specific and sensitive tool for detection of primary and metastatic pheochromocytoma and neuroblastoma. Eleven patients, with refractory stage IV neuroblastoma were treated with a total of 23 courses of 131I-MIBG, 100-400 mCi/m2/course. Total activity administered per course ranged from 90-550 mCi; maximum cumulative radioactivity per patient was 1356 mCi. The 131I-MIBG was given as a 2 hour infusion. Total body dose was calculated from whole body activity measurements, ranging from 73-250 cGy. The main toxicity was thrombocytopenia, with platelet nadirs to less than 25,000/microL in 5/23 courses (5 patients), all occurring in patients with greater than 25% replacement by tumor in the bone marrow. Neutropenia to a nadir of less than 500/microL was seen in only 2 patients, both with greater than 50% bone marrow replacement after 2 and 4 courses of 131I-MIBG, respectively. Tumor doses were calculated in patients with an evaluable measurable lesion, and ranged from 312-6329 cGy per course. Two of the eleven patients had partial responses, with one long-term survivor with stage IV neuroblastoma with no evidence of active disease now 4 years off treatment. Two other patients survive with stable disease after 3 treatments, at 3+ and 5+ months. Seven patients died with progressive disease. This study shows that treatment with 131I-MIBG is safe and can be effective in refractory neuroblastoma, particularly in patients who do not have extensive bone and bone marrow involvement.

Volume localization of magnetic resonance signals was achieved by using the regional susceptibility differences produced by superparamagnetic iron oxide particles. In vitro experiments demonstrated a direct linear relationship between the concentration of particulate iron and phosphorus-31 chemical shift or line broadening. In vivo experiments indicated that an intravenous dose of 5-10 mg of iron per kilogram of body weight suppressed P-31 signal from normal liver in healthy rats. In rats with hepatic implants of mammary adenocarcinoma, superparamagnetic iron oxide particles suppressed detectable P-31 or hydrogen-1 signal arising from healthy liver tissue, but not that from tumor. Signal due to surface tissues, which affect surface-coil spectra, could be selectively suppressed with a film-based application of particles to the abdominal wall. Thus, P-31 spectra from simulated or actual lesions could be selectively detected after chemically suppressing signals from neighboring or surrounding tissue.

Twelve Yucatan micropigs (3 controls; 3 sham-operated; 6 with unilateral obstruction) were studied to assess the value of noncontrast and contrast-enhanced (Gadolinium-DTPA) magnetic resonance (MR) imaging in the evaluation of partial ureteral obstruction. MR findings were correlated with findings of quantitative (Tc-99m-DMSA) scintigraphy, and histology. On noncontrast T1-weighted images, the normal porcine kidney demonstrated good corticomedullary contrast (CMC = 16.8% +/- 5.0). Five minutes after administration of Gd-DTPA, there was enhancement of the renal cortex (+24.4% and medulla (+46.2%), and CMC was no longer discernible. Enhancement of the urine within the collecting system (+119.1%) was also observed. The obstructed kidneys demonstrated marked thinning of the renal parenchyma and decreased signal intensity on noncontrast T1- and T2-weighted images (P less than 0.01). Urine in the dilated collecting system did not differ significantly from urine in controls except in the three animals with urinary tract infection (P less than 0.05). Five minutes following injection of Gd-DTPA, there was enhancement of the renal parenchyma in all kidneys. Excretion was seen in three pigs and no excretion in two. Thus, useful information can be obtained in partial ureteral obstruction from both pre-contrast and Gd-DTPA-enhanced MR images of the kidney.

Improved rat liver tumor models with solitary or multiple metastastic tumors were developed for radiological imaging research. Unlike previous studies which employed trocar inoculation of tumor fragments, an enzymatically disaggregated cell suspension of mammary cancer was injected by fine needle either directly into the liver to produce solitary cancer nodules, or indirectly via the spleen or mesenteric vein to produce multiple liver metastases. Tumor size was proportional to the time elapsed after implantation. The operative mortality of direct liver, splenic parenchymal, and mesenteric inoculations were 8%, 4%, and 27%, respectively. MR tissue characteristics, image contrast, and pharmaceutical enhancement of these tumors closely resembles human hepatic metastases. The availability of reproducible, inexpensive animal models of metastatic cancer allows efficient evaluation of new liver imaging techniques.

The value of rapid, contrast-enhanced, diuretic magnetic resonance (MR) imaging (using ferrioxamine B and furosemide) in demonstrating partial unilateral ureteral obstruction and the potential of such MR imaging in differentiating obstructive from nonobstructive hydronephrosis was assessed in six micropigs. MR imaging (0.35 Tesla, partial-flip technique with repetition time [TR] of 125 milliseconds, echo-delay time [TE] of 20 milliseconds, and flip angle of 70 degrees) was performed before, and at 5, 12, and 19 days after partial ureteral obstruction. Additionally, MR images were acquired 5, 12, and 19 days after release of obstruction. The diuretic was injected 10 minutes after the contrast medium. MR findings were correlated with results from nuclear scintigraphy (99mTc-DMSA uptake). MR images provided good morphologic detail from which renal size, parenchymal thickness, and degree of hydronephrosis could be determined. Contrast medium allowed assessment of cortical uptake and urinary excretion. The course of cortical signal enhancement best characterized the difference between obstructive and nonobstructive hydronephrosis. Normal kidneys and kidneys with nonobstructive hydronephrosis showed progressive decrease in cortical signal enhancement (-11.7% within 40 minutes) after furosemide injection. The kidneys with obstructive hydronephrosis demonstrated a plateau of signal enhancement without decrease (-0.7% within 40 minutes). These results demonstrate the utility of rapid contrast-enhancing, diuretic MR imaging in differentiating obstructive from nonobstructive hydronephrosis.

The pharmacokinetics (distribution, metabolism, bioavailability, excretion) and toxicity (acute and subacute toxicity, mutagenicity) of a superparamagnetic iron oxide preparation (AMI-25), currently used in clinical trials, were evaluated by 59Fe radiotracer studies, measurements of relaxation times, the ability to reverse iron deficiency anemia, histologic examination, and laboratory parameters. One hour after administration of AMI-25 to rats (18 mumol Fe/kg; 1 mg Fe/kg), 82.6 +/- 0.3% of the administered dose was sequestered in the liver and 6.2 +/- 7.6% in the spleen. Peak concentrations of 59Fe were found in liver after 2 hr and in the spleen after 4 hr. 59Fe slowly cleared from liver (half-life, 3 days) and spleen (half-life, 4 days) and was incorporated into hemoglobin of erythrocytes in a time-dependent fashion. The half-time of the T2 effect on liver and spleen (24-48 hr) was shorter than the 59Fe clearance, indicating metabolism of AMI-25 into other forms of iron. IV administration of AMI-25 (30 mg Fe/kg) corrected iron-deficiency anemia and showed bioavailability similar to that of commercially available IV iron preparations within 7 days. No acute or subacute toxic effects were detected by histologic or serologic studies in rats or beagle dogs who received a total of 3000 mumol Fe/kg, 150 times the dose proposed for MR imaging of the liver. Our results indicate that AMI-25 is a fully biocompatible potential contrast agent for MR.