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We have developed and demonstrated an imaging system that couples an X-ray CT scanner to a scintillation camera for the localization and absolute measurement of radionuclide uptake. We use the registered CT images to provide physical information to overcome the quantitative errors in nuclear imaging due to attenuation, scatter, and limited spatial resolution. The registration accuracy and precision in phantom experiments was 0.0 [+ or -] 0.4 mm. Preliminary patient scans suggest that the registration techniques developed for phantom studies can be used. Conversion of X-ray CT image data to attenuation maps was accomplished by the scaling of calibration data and includes extensions to account for the presence of iodinated contrast agents. Experimental phantom studies with 99mTc show absolute quantitation with less than 10% error for up to 2:1 target:background activity concentration for objects as small as 2.7 ml. We are currently evaluating the imaging methods for the localization and absolute quantitation of 131I-MIBG in neuroblastoma patients.

Purpose: To compare the prediction of therapeutic hepatic radiation-absorbed dose rates from tracer imaging plus a linearity assumption to estimation based on intra-therapy imaging in (131)I metaiodobenzylguanidine (MIBG) therapy of refractory neuroblastoma., Materials and Methods: Conjugate-view images of the liver were obtained before therapy for seven patients at seven times after a tracer infusion of (131)I MIBG and at three times after the therapy infusion. Measured liver activities were converted to dose-rate estimates. Three statistical models of the rates assuming double exponential dependences on time were examined. One of the three models allowed for a multiplicative correction to the therapeutic late-phase dose-rate amplitude. Results from that model: (1) the tracer prediction of the late-phase absorbed-dose-rate amplitude was a factor of 1.75 times the intra-therapy-estimated value, and (2) the difference between tracer prediction of the radiation-absorbed dose and intra-therapy estimation of it was statistically significant, and (3) the liver radiation-absorbed dose did not reach 30 Gy., Conclusions: A statistical modeling analysis finds that the radiation-absorbed dose after therapy appears to be lower than that which is predicted from the linear scaling with administered activity of the tracer radiation-absorbed dose. Hepatocyte toxicity is the most likely reason but it is not high enough to produce clinically observable results.

Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

Unlabelled: High-dose administration of 131I-metaiodobenzylguanidine (131I-MIBG) continues to be a promising treatment for neuroblastoma. However, currently used methods of estimating 131I-MIBG uptake in vivo may be too inaccurate to properly monitor patient radiation exposure doses. To improve localization and uptake measurements over currently practiced techniques, we evaluated different methodologies that take advantage of the correlated patient data available from a combined CT-scintillation camera imaging system., Methods: Serial CT and radionuclide scans of three patients were obtained on a combined imaging system. SPECT images were reconstructed using both filtered backprojection and maximum-likelihood expectation maximization (MLEM). Volumes of interest (VOIs) were defined on anatomic images and automatically correlated to spatial volumes in reconstructed SPECT images. Several radionuclide quantification methods were then compared. First, the mean reconstructed values within coregistered SPECT VOIs were estimated from MLEM reconstructed images. Next, we assumed that reconstructed activity in SPECT voxels were linear combinations of activities present in individual objects, weighted by geometric factors derived from CT images. After calculating the weight factors by modeling the SPECT imaging process with anatomically defined VOIs, least-squares fitting was used to estimate the activities within lesion volumes. We also estimated the lesion activities directly from planar radionuclide images of the patients using similar linearity assumptions. Finally, for comparison, lesion activities were estimated using a standard conjugate view method., Results: Activities were quantified from three patients having a total of six lesions with volumes ranging from 0.67 to 117 mL. Methods that used CT data to quantify lesion activities gave similar results for planar and tomographic radionuclide data. Estimating activity directly from mean VOI values in MLEM-reconstructed images alone consistently provided estimates lower than CT-aided methods because of the limited spatial resolution of SPECT. Values obtained with conjugate views produced differences up to fivefold in comparison with CT-aided methods., Conclusion: These results show that anatomic information available from coregistered CT images may improve in vivo localization and measurement of 131I-MIBG uptake in tumors.

Objectives: The purpose of this study was to measure the accumulation of labeled albumin and to visualize its distribution pattern in reperfused infarcted myocardium as a function of time between onset of reperfusion and administration of the tracer., Background: Myocardial microvascular injury leads to leakage of albumin from the intravascular space. Quantitative measurements of GdDTPA-albumin with inversion recovery echoplanar imaging (IR-EPI) may allow noninvasive monitoring of microvascular injury., Methods: After 1 h of coronary artery occlusion, 56 rats were injected with GdDTPA-albumin or 123I-GdDTPA-albumin either immediately before reperfusion or 1/2, 1 or 24 h after reperfusion. GdDTPA-albumin in blood, normal myocardium and reperfused infarction was dynamically measured with IR-EPI during 1 h postinjection (PI). Autoradiograms were obtained at 15 min PI. Accumulation of labeled albumin in myocardium was expressed as the ratio of myocardial to blood content., Results: In normal myocardium, the ratio of changes of relaxation rate-ratio (deltaR1-ratio) was 0.12+/-0.01 and did not change over 1 h. In reperfused infarction, however, the deltaR1-ratio increased after administration. Animals given GdDTPA-albumin before reperfusion exhibited fastest accumulation (deltaR1-ratio 15 min PI: 0.56+/-0.03) and essentially homogeneous distribution. The accumulation was slower when administered at 1/2, 1 and 24 h after reperfusion (deltaR1-ratios 15 min PI: 0.39+/-0.03; 0.31+/-0.04; 0.16+/-0.01; p < 0.001 compared to administration before reperfusion). Moreover, the tracer accumulated predominantly in the periphery of the injury zone., Conclusions: Amount and distribution pattern of labeled albumin in reperfused infarction are modulated by duration of reperfusion. The accumulation of GdDTPA-albumin can be quantified by IR-EPI. Thus, IR-EPI may be useful to noninvasively monitor myocardial microvascular injury in reperfused infarction.

Background: Metaiodobenzylguanidine (MIBG) labeled with 131I has been used for targeted radiotherapy of neural crest tumors, with bone marrow suppression being the primary dose-limiting toxicity. The purpose of this study was to examine the engraftment and toxicity of higher myeloablative doses of 131I-MIBG with autologous bone marrow support., Procedure: Twelve patients with refractory neuroblastoma were given infusions of their autologous, cryopreserved bone marrow following 1-4 doses of 131I-MIBG. The median cumulative administered activity per kilogram of 131I-MIBG was 18.0 mCi/kg (range 14.1-50.2 mCi/kg), the median total activity was 594 mCi (range 195-1,353 mCi), and the median cumulative whole body irradiation from 131I-MIBG was 426 cGy (range 256-800 cGy). A median of 2.5 x 10(8) viable cells/kg (range 0.9-4.7 x 10(8) cells/kg) was given in the bone marrow infusion., Results: All 12 patients achieved an absolute neutrophil count > 500/microliter with a median of 19 days, but only 5/11 evaluable patients achieved red cell transfusion independence, in a median of 44 days; and 4/11 evaluable patients achieved platelet count > 20,000/microliter without transfusion, in a median of 27 days., Conclusions: Autologous bone marrow transplantation may allow complete hematopoietic reconstitution following ablative 131I-MIBG radiotherapy in patients with neuroblastoma. Risk factors for lack of red cell or platelet recovery include extensive prior chemotherapy, progressive disease at the time of transplant, especially in the bone marrow, and a history of prior myeloablative therapy with stem cell support.

Iodine-131 metaiodobenzylguanidine (MIBG) has shown effectiveness as a systemic radiotherapeutic agent in neuroblastoma. The authors postulated a likely dose-related relationship of MIBG sensitivity when it was administered for neuroblastoma detection. They studied this relationship in neuroblastoma patients who underwent scanning after receiving diagnostic and therapeutic doses of MIBG in temporal proximity. Seven patients with stage IV disease received a total of 14 therapeutic administrations of I-131 MIBG (150-350 mCi [5,550-12,950 MBq]/m2 per treatment). Posttherapy scans were obtained at 3 and at 5-7 days. Diagnostic MIBG scans had been obtained no more than 4 weeks before the start of therapy. Use of diagnostic MIBG scanning led to underestimation of the tumor burden by 50% compared with use of posttherapy scanning. This difference may be an important consideration in selecting therapeutic strategies for individual patients. It further suggests that use of much larger diagnostic doses of MIBG is a rational strategy in histologically confirmed cases of advanced disease.

To further characterize the behavior of metaiodobenzylguanidine (MIBG) in the myocardium and to test the hypothesis that the denervated heart would show normal early uptake on MIBG due to non-neuronal localization, we examined the early and late distribution of 123I-labeled MIBG in normal and globally denervated canine and human hearts. Canine hearts were denervated by intravenous injections of 6-hydroxydopamine, while patients were studied a mean of 4.3 mo following cardiac transplantation. Results in denervated hearts were compared to normal controls. Normal hearts showed prominent MIBG uptake on initial 5-min and 3-hr delayed images. Globally denervated canine hearts showed prominent uptake on initial images and absence of localization on delayed images, indicating complete washout of non-neuronally bound radionuclide. The transplanted human hearts showed no localization of MIBG on either early or delayed images. These results suggest that the non-neuronal uptake mechanism (uptake 2) is not significant in human myocardium. This finding has significant implications for interpreting the myocardial behavior of MIBG in various pathologic situations such as dilated cardiomyopathy.

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.

A simple method to test new gadolinium complexes potentially useful as enhancement agents for magnetic resonance imaging was developed. Healthy rats underwent scintigraphy with two potential hepatobiliary agents, diethyl IDA and diisopropyl IDA complexed with gadolinium-153. Control products included 153Gd DTPA, 153GdCl3 and technetium-99m diethyl IDA. As shown scintigraphically, 153Gd IDA complexes were partially excreted by urinary and hepatobiliary excretion early after administration. These findings paralleled significant reduction in 1H T1 values of excised livers. However, these agents exhibited prolonged 153Gd whole-body retention. The prolonged tissue distribution of 153Gd activity in animals given 153Gd diethyl IDA did not differ significantly from that observed in animals given GdCl3, and could be attributed to chemical instability or reticuloendothelial uptake. The scintigraphic method permits screening of gadolinium complexes in animals by showing mass balance, kinetics, distribution, and effective stability. Biologic effects of tracer or pharmacologic levels can be compared with those of carrier-free and carrier-added pharmaceuticals.

Nonradioactive cesium, as an analogue of potassium, has been used to label autologous red blood cells for determination of the red cell volume in man. The initial and the equilibration concentrations of cesium are assayed by fluorescent excitation analysis (FEA), using a 600 mCi 241Americium source and a Si(Li) detector with a 1024-channel analyzer. Comparative studies with 51Chromium in 13 rabbits showed good correlation, but the intracellular cesium concentration achieved by simple incubation with 2.6 per cent cesium chloride solution was too low to be of practical value in humans. Incubation of the human red blood cells with 50 mug per milliliter of Nystatin in 2.6 per cent cesium chloride opened reversible "pores" in the red cell membrane which permitted high intracellular cesium labeling without demonstrable red cell damage. The cesium red cell volumes in 11 random human subjects differed from the 51Chromium red cell volumes by only 0.2 +/- 4.5 per cent and 2.5 +/- 7.6 per cent at blood sampling times of 10 minutes and 40 minutes, respectively. Blood cesium levels fell with a clearance half-time of 31.5 hours in 4 rabbits, and 2.4 days in 1 normal human. Fluorescent excitation analysis of cesium-labeled autologous red blood cells permits accurate determination of the red cell volume in man without associated patient radiation, thus making the procedure much more acceptable for children, pregnant women, normal volunteers, and for repeated studies in the same individual.

A phase 1 study was conducted using a monoclonal antimelanoma antibody-DTPA conjugate labeled with indium-111, for immunolymphoscintigraphy in patients with metastatic melanoma. The imaging agent, labeled with 1 mCi (37 MBq) In-111, was administered as an interstitial interdigital injection to six patients scheduled to undergo lymph node dissection for suspected metastatic malignant melanoma. No adverse effects were observed in any of the patients either during or after the infusion as determined by clinical and laboratory parameters. Antibodies to the murine immunoglobulin were produced in some patients. Regional lymph nodes were visualized whether tumor-bearing or not, and light microscopic autoradiography showed In-111 activity associated with histiocytes. One of two patients harboring both tumor-bearing and tumor-free lymph nodes exhibited preferential localization in tumor-bearing nodes. The authors conclude that this study demonstrates safety of the radiopharmaceutical and that further study is needed to improve its usefulness for diagnosis of lymph node metastases.

To assess the feasibility of noninvasively imaging the regional distribution of myocardial sympathetic innervation, we evaluated the distribution of sympathetic nerve endings, using 123I metaiodobenzylguanidine (MIBG), and compared this with the distribution of myocardial perfusion, using 201Tl. Twenty dogs were studied: 11 after regional denervation, and nine as controls. Regional denervation was done by left stellate ganglion removal, right stellate ganglion removal, and application of phenol to the epicardial surface. Computer-processed functional maps displayed the relative distribution of MIBG and thallium in multiple projections in vivo and excised heart slices in all animals. In six animals, dual isotope emission computed tomograms were acquired in vivo. Tissue samples taken from innervated and denervated regions of the MIBG images were analyzed for norepinephrine content to validate image findings. Normal controls showed homogeneous and parallel distributions of MIBG and thallium in the major left ventricular mass. In the left stellectomized hearts, MIBG was reduced relative to thallium in the posterior left ventricle; whereas in right stellectomized hearts, reduced MIBG was in the anterior left ventricle. Phenol-painted hearts showed a broad area of decreased MIBG extending beyond the area of phenol application. In both stellectomized and phenol-painted hearts, thallium distribution remained homogeneous and normal. Norepinephrine content was greater in regions showing normal MIBG (550 +/- 223 ng/g) compared with regions showing reduced MIBG (39 +/- 44 ng/g) (p less than 0.001), confirming regional denervation. Combined MIBG-thallium functional maps display the regional distribution of sympathetic innervation. This new ability to noninvasively map the distribution of sympathetic nerves with simultaneous comparison to regional perfusion may provide important new insights into mechanisms, whereby an imbalance in sympathetic activity may relate to clinical disorders.