Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma.

PURPOSE: The analogue 131I-metaiodobenzylguanidine (MIBG), which is specifically targeted to neuroblastoma cells, may provide more effective and less toxic treatment for neuroblastoma than conventional external-beam radiotherapy. We report a dose escalation study of 131I-MIBG to define dose-limiting toxicity without and with autologous bone marrow support. PATIENTS AND METHODS: Thirty patients with relapsed neuroblastoma were treated in groups of six with escalating doses of 3 to 18 mCi/kg of 131I-MIBG. After rapid escalation in the first three patients treated at 3 to 6 mCi/kg, treatment was escalated in 3-mCi/kg increments from 9 to 18 mCi/kg. Autologous tumor-free bone marrow was cryopreserved in all patients receiving 12 mCi/kg and more. Toxicity and response were assessed. RESULTS: Eighty percent of patients who received 12 mC/kg or more experienced grade 4 thrombocytopenia and/or neutropenia. Dose-limiting hematologic toxicity was reached at 15 mCi/kg, at which level two of five assessable patients required bone marrow reinfusion for absolute neutrophil count (ANC) of less than 200/microL for more than 2 weeks, and four of nine at the 18-mCi/kg level. Prolonged thrombocytopenia was common, with failure to become platelet-transfusion independent in nine patients. One patient with extensive prior treatment developed secondary leukemia and three became hypothyroid. Responses were seen in 37% of patients, with one complete response (CR), 10 partial response (PR), three mixed response, 10 stable disease, and six progressive disease. The minimum dose of 131I-MIBG for 10 of the 11 responders was 12 mCi/kg. CONCLUSION: Treatment with 131I-MIBG has mainly hematologic toxicity, which can be abrogated with bone marrow rescue. The high response rate in refractory disease suggests that this agent may be useful in combination with myeloablative chemotherapy and autologous stem-cell rescue to improve outcome in advanced neuroblastoma.

Posterior fossa scintiangiography: documentation of genetic penetrance of von Hippel-Lindau syndrome in a clinically unaffected girl and her father.

The 16-year-old clinically normal daughter of a patient with the von Hippel-Lindau syndrome demonstrated a vascular posterior fossa lesion on scintiangiography that failed detection in delayed images. Contrast arteriography corroborated the presence of a hemangioblastoma. Noninvasive demonstration of the genetic penetrance of this disorder offers its victims an opportunity for low morbidity early surgical cure of the associated brain lesions.

Gallium-67/stable gadolinium antagonism: MRI contrast agent markedly alters the normal biodistribution of gallium-67.

An 11-yr-old patient was scanned 96 hr after the administration of gallium-67 (67Ga). The scan emulated the biodistribution of a typical bone-seeking radipharmaceutical-rather than that of 67Ga. None of the factors previously identified with alteration of the biodistribution of 67Ga were found. However, the patient had been injected with gadopentetate in conjunction with magnetic resonance imaging 4 hr before receiving the 67Ga. Gadolinium appears to cause a strong carrier-like effect in 67Ga scans.

Significance of renewal asymmetry in bone scans: experience in 795 cases.

A retrospective study of 795 consecutive bone scans employing either 18F or 99mTc-pyrophosphate to evaluate the diagnostic value of renal asymmetry in such scans has been carried out. It is concluded that asymmetric renal images in bone scans convey relatively specific information regarding renal pathology, especially in the 99mTc-pyrophosphate studies.

Duration of etidronate effect demonstrated by serial bone scintigraphy.

There have been several reports of etidronate disodium (EHDP) interference upon the biodistribution of 99mTc-methylene diphosphonate (MDP). With the increasing use of etidronate for the treatment of Paget's disease, hypercalcemia, and osteoporosis, nuclear physicians can expect to encounter increasing numbers of cases in which EHDP-induced artifacts impair the diagnostic utility of bone scans. The temporal duration of this effect is unknown yet obviously important. We report serial bone scintigraphy in a patient who received a single dose of EHDP for hypercalcemia. Normal biodistribution of 99mTc-MDP was noted at 15 days, suggesting that 2 wk are sufficient before performing a bone scan after a single intravenous dose of etidronate.

Segmental acute tubular necrosis in kidneys with multiple renal arteries transplanted from living related donors.

Ten patients received kidneys from living, related donors, the transplants having multiple renal arteries; a retrospective analysis of the postoperative Hippuran renograms is presented. All seven kidneys that had the large artery reopened before anastomosis of the smaller, developed scintigram findings suggestive of acute tubular necrosis (ATN) in the region with the more prolonged ischemia. Three similar kidneys with simultaneous recanalization of both renal arteries had normal Hippuran scintiphotos. Electron photomicrographs from upper- and lower-pole biopsies--in one case undergoing sequential revascularization--confirm the development of ischemic changes consistent with ATN in the half of the kidney developing scan findings of ATN.

Differentiation of reversible ischemia from end-stage renal failure in nephrotic children with 131I-hippurate dynamic scintigraphy.

In renal failure associated with the nephrotic syndrome, therapeutic strategy is highly dependent upon the cause of the renal failure. Dynamic hippurate scintigraphy was studied in five pediatric patients. Four had nephrotic syndrome, and of these, three had acute renal failure. The fifth patient had end-stage renal failure. Specific alteration in renal hippurate kinetics offers a noninvasive assessment of renal failure in this clinical setting.

Clinical utility of bone scan features of pleural effusion: sensitivity and specificity for malignancy based on pleural fluid cytopathology.

UNLABELLED: Asymmetric chest activity with malignant and benign pleural effusions has been described in bone scans. However, the clinical utility of this finding is not elucible from the literature. We developed specific scintigraphic criteria for malignant pleural effusion and retrospectively assessed their sensitivity and specificity in a group of patient scans. METHODS: Pleural fluid was submitted for cytopathology from 850 patients over a 5-yr period. Bone scans were done within 2 mo of the thoracentesis in 74 patients. As a consensus panel, we reread the scans and reviewed the cytology. RESULTS: The effusions were cytologically malignant in 25/74 patients (34%), indeterminate in 9/74 (12%) and benign in 40/74 (54%). Based on cytopathology, malignant pleural effusions were detected by bone scans with a sensitivity of 34%-50% and a specificity of 78%-89%; true sensitivity and specificity was somewhere in between averaging 42% (95% confidence interval 24%-60%) and 84% (95% confidence interval 73%-95%), respectively. CONCLUSIONS: The bone scan is frequently the first examination suggesting pleural metastasis, and when it is detected it should be pursued beyond pleural fluid cytology, if negative or indeterminate.

Optimized diagnostic strategy for neuroblastoma in opsoclonus-myoclonus.

Infantile myoclonic encephalopathy (opsoclonus-myoclonus or IME) is a rare clinical syndrome associated with occult neuroblastoma in 20%-50% of all cases. IME is the initial presentation of neuroblastoma in 1%-3% of children. Imaging approaches including chest radiography and abdominal computed tomography (CT) have been proposed to detect neuroblastoma in IME. Metaiodobenzylguanidine (MIBG) is highly effective in the detection of neuroblastoma. These scans can identify both soft-tissue and skeletal lesions anywhere in the body. Our purpose was to attempt to determine the best screening method for detection of occult neuroblastoma in patients with IME. Records of all neuroblastoma patients from 1983 to May 1991 were reviewed. Four cases of IME with neuroblastoma were identified in which imaging studies included an MIBG scan. All four patients had positive MIBG scans (100%) while only two had masses on initial CT (50%). In the three patients initially evaluated by traditional methods, the mean time to diagnosis and the mean number of advanced radiologic studies were 7.5 mo and 7.3 studies respectively. The patient screened with MIBG had only cranial and abdominal CT prior to surgery. Although based on a limited number of patients, results suggest that MIBG may prove to be a useful screening procedure in patients with IME. Traditional imaging modalities can then be directed to evaluate sites of disease identified by MIBG scans.

Analysis of thallium-201 "washout" from parametric color coded images.

We developed a parametric washout image which color codes regional washout, and blindly compared enhanced perfusion images in multiple projections with regional washout graphs and images in 25 patients. Washout images permitted true spatial and anatomic assessment of regions viewed en face as well as those seen in tangent, making possible the exclusion of non-coronary irregularities and permitting evaluation of washout over the apparent cavity. "Cavitary" washout was abnormal in 10 of 12 patients with apparent cavitary dilation on the post stress image, but in none without this finding. The distribution and rotation of washout abnormalities seen over the cavity when viewed en face, and the long delay between the termination of stress and post-exercise image acquisition, suggest that apparent cavitary dilation is often related to improved visibility of the 201T1 deficient blood pool due to relative ischemia of the overlying myocardial wall.

Unique scintigraphic findings of bile extravasation in the presence of ascites: a complication of hepatic transplantation.

A 99mTc-HIDA scan was performed on a 4-mo-old female, six days after hepatic transplantation. Gradually, a diffuse increase in activity was seen over the peritoneal region, consistent with a slow bile leak into ascitic fluid. Although the scintigraphic appearance of a bile leak has been previously described, it is usually seen as a focal area of extrabiliary activity. In this case, we report a pattern identified when the leak occurs in conjunction with ascites.

Intrinsic dual-energy processing of myocardial perfusion images.

UNLABELLED: We have developed a software-based method for processing dual-energy 201TI SPECT emission projection data with the goal of calculating a spatially dependent index of the local impact of gamma-ray attenuation. We refer to this method as intrinsic dual-energy processing (IDEP). METHODS: IDEP exploits the differential attenuation of lower energy emissions (69-83 keV) and higher energy emissions (167 keV) resulting from the decay of 201TI to characterize the relative degree of low-energy gamma-ray attenuation throughout the myocardium. In particular, IDEP can be used to estimate the relative probability that a low-energy gamma-ray emitted from a particular region of the myocardium is detected during the acquisition of SPECT projection data. Studies on phantoms and healthy human volunteers were performed to determine whether the IDEP method yielded detection probability images with systematic structure visible above the noise of these images and whether the systematic structure in the detection probability images could be rationalized physically. In patient studies, the relative regional detection probabilities were applied qualitatively to determine the likely effects of attenuation on the distribution of mapped photon emissions. RESULTS: Measurements of the detection probability in uniform phantoms showed excellent agreement with those obtained from computer simulations for both 180 degrees and 360 degrees acquisitions. Additional simulations with digital phantoms showed good correlation between IDEP-estimated detection probabilities and calculated detection probabilities. In patient studies, the IDEP-derived detection probability maps showed qualitative agreement with known nonuniform attenuation characteristics of the human thorax. When IDEP data were integrated with the findings on the emission scan, the correlation with coronary anatomy (known in 6 patients and hypothesized on the basis of clinical and electrocardiographic parameters in 5 patients) was improved compared with evaluating the mapped emission image alone. CONCLUSION: The IDEP method has the potential to characterize the attenuation properties of an object without use of a separate transmission scan. Coupled with the emission data, it may aid coronary diagnosis.

Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts--implications for clinical studies.

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.

Phase image characterization of ventricular contraction in left and right bundle branch block.

The phase image is a computer-derived functional image, based on the analysis of the time versus radioactivity curve in each pixel location of the multiple gated blood pool scintigram. Within the ventricular regions of interest, the phase angle is roughly equivalent to the time of onset of counts reduction or to the time of onset of ventricular contraction and is expressed in degrees from 0 to 360 degrees. A gray scale-coded image of such a regional phase angle, the phase image, can be looked on as a map of sequential contraction. This method was applied in 33 patients without severe contraction abnormality including 16 patients with normal conduction, 9 with right bundle branch block and 8 with left bundle branch block. In patients with normal conduction the pattern of phase angle distribution, representing the pattern of ventricular contraction, was homogeneous and symmetric in both the left and right ventricles. Analysis in this normal group indicated a slight but significant difference between the mean (+/- standard deviation) phase angle of the left ventricle (8.5 +/- 11.8 degrees) and that of the right ventricle (13.6 +/0 12.9 degrees, p = 0.01). There was a slight, but nonsignificant difference between mean intrapatient left and right ventricular phase angle onset (1.9 +/- 6.5 degrees). The mean phase angle of the right ventricle in patients with right bundle branch block (27.6 +/- 14.2 degrees) and of the left ventricle in those with left bundle branch block (21.9 +/- 14.0 degrees) was delayed compared with that in patients with normal conduction (p less than 0.05 for both). The mean intrapatient difference between left and right ventricular mean phase angles in patients with normal conduction (-5.2 +/- 6.8 degrees) was significantly different from that in patients with right (-21.8 +/- 10.3 degrees, p less than 0.001) or left (21.8 +/- 6.8 degrees, p less than 0.001) bundle branch block. The mean intrapatient difference between onset of left and right ventricular phase angles was also significantly different from normal in patients with right (-10.6 +/- 7.5 degrees, p less than 0.005) or left (18.7 +/- 8.3 degrees, p = 0.01) bundle branch block. Although phase imaging is not without artifactual error, this study demonstrates that the phase image can characterize familiar conduction abnormalities. It presents the potential for application as a general noninvasive tool in the investigation of the timing and sequence of ventricular contraction in patients with normal or abnormal ventricular activation.

An accurate means of detecting and characterizing abnormal patterns of ventricular activation by phase image analysis.

The ability of scintigraphic phase image analysis to characterize patterns of abnormal ventricular activation was investigated. The pattern of phase distribution and sequential phase changes over both right and left ventricular regions of interest were evaluated in 16 patients with normal electrical activation and wall motion and compared with those in 8 patients with an artificial pacemaker and 4 patients with sinus rhythm with the Wolff-Parkinson-White syndrome and delta waves. Normally, the site of earliest phase angle was seen at the base of the interventricular septum, with sequential change affecting the body of the septum and the cardiac apex and then spreading laterally to involve the body of both ventricles. The site of earliest phase angle was located at the apex of the right ventricle in seven patients with a right ventricular endocardial pacemaker and on the lateral left ventricular wall in one patient with a left ventricular epicardial pacemaker. In each case the site corresponded exactly to the position of the pacing electrode as seen on posteroanterior and left lateral chest X-ray films, and sequential phase changes spread from the initial focus to affect both ventricles. In each of the patients with the Wolff-Parkinson-White syndrome, the site of earliest ventricular phase angle was located, and it corresponded exactly to the site of the bypass tract as determined by endocardial mapping. In this way, four bypass pathways, two posterior left paraseptal, one left lateral and one right lateral, were correctly localized scintigraphically. On the basis of the sequence of mechanical contraction, phase image analysis provides an accurate noninvasive method of detecting abnormal foci of ventricular activation.

A consideration of factors affecting the diagnostic accuracy of thallium-201 myocarial perfusion scintigraphy in detecting coronary artery disease.

Several factors influence the ability of TI-201 myocardial perfusion scintigraphy to detect coronary artery disease. Among these are the physiologic effect of the coronary lesion on relative myocardial perfusion and radionuclide distribution; technical and physiologic aspects of the scintigraphic process; and observer interpretation. The diagnostic accuracy of this scintigraphic method is related to: (1) the extent of the hypoperfused myocardium, which will depend on the severity and extent of coronary disease, the presence of collaterals, the exercise method, and the timing of thallium administration and scintigraphy; (2) the scintigraphic process, which depends on the nature of the isotope, the imaging system, and the method of image display; and (3) image interpretation, which depends on the experience of the observer as well as on the area of hypoperfused myocardium and the scintigraphic process. The diagnostic accuracy of scintigraphy for detecting coronary disease can be optimized by computer methods of image enhancement, which maximize differences in image contrast; by electrocardiographic gating; and by emission computer tomography. Other computer methods have been developed to reduce or eliminate observer intervention in interpretation and to increase the objectivity of the method.

Improved immune-specificity in monoclonal radioimmunoimaging using dual radionuclide color functional maps.

Diagnostic radioimmunoimaging is potentially limited by tissue localization of radiolabeled antibody products through mechanisms other than antigen binding. Comparing the distributions of reactive and nonreactive products can distinguish tracer in targeted and nontargeted tissues. To achieve this in a single imaging procedure, dual photopeak scintigraphy was performed using 111In and 67Ga products. Melanoma-bearing athymic mice were coadministered intravenously subtype-matched 111In melanoma-reactive and 67Ga melanoma-nonreactive murine monoclonal antibodies. Paired images from 245 and 93 keV windows were processed with a unique dual parameter color display program. The display algorithm expresses pixel counts from paired photo-peak images in polar coordinates and color-encodes angle as hue and magnitude as intensity. The color functional maps permitted ready distinction of immune from nonimmune uptake. Compared with single tracer imaging methods, this technique better depicts antigen distribution.

Efficacy of metaiodobenzylguanidine as a scintigraphic agent for the detection of neuroblastoma.

RATIONALE AND OBJECTIVES: Metaiodobenzylguanidine (MIBG) has been shown to be both sensitive and highly specific for the detection of neuroblastoma. However, controversy surrounds its sensitivity in detecting neuroblastoma when compared with radionuclide (technetium 99m-methylene diphosphonate [99mTc]-MDP) bone scans. Because a diagnostic test ideally should be easy to interpret in addition to being sensitive and specific, this study aims to determine the most efficacious scintigraphic agent for diagnostic use in neuroblastoma. METHODS: Twenty patients with neuroblastoma had a total of 26 paired MIBG and 99mTc-MDP bone scans obtained less than 4 weeks apart. Each study was evaluated independently of its counterpart by six separate observers (3 experienced and 3 inexperienced in MIBG scintigraphy) to determine the presence or absence of disease and the tumor burden. RESULTS: Inexperienced observers reported more confidence in their interpretations of 99mTc-MDP bone scans; however, seven false-positive bone scans were reported. Using MIBG, all true-positive and true-negative scans, as well as significantly more sites of both primary and metastatic disease, were identified by all observers. CONCLUSION: This study suggests that MIBG is the more efficacious agent for the scintigraphic evaluation of neuroblastoma.

Imaging characteristics of a small germanium camera.

A high purity germanium gamma-camera has been developed and is currently being evaluated. This camera incorporates unique performance parameters such as a 2 mm full-width spatial response function with rejection of multiple-scatter in the detector, a 2.2% FWHM energy resolution for 99 mTc, a 180 nsec paralyzable dead-time, and a 2 mu sec non-paralyzable dead-time. Imaging studies demonstrate the superior capabilities of this instrument.

No gravity-independent gradient of blood flow distribution in dog lung.

The existence of a major gravity-independent gradient of blood flow in lungs has recently been described based on single photon emission computed tomography after intravenous injection of radioactively labeled macroaggregates. We wanted to test this hypothesis of a major gravity-independent gradient in lung blood flow in experiments with direct measurement of macroaggregate distribution in the dog lung. In six anesthetized (4 prone spontaneously breathing, 2 mechanically ventilated) dogs we injected 111In-labeled albumin macroaggregates intravenously. We killed the dogs, removed, inflated, and froze the lower lobes. We sliced the lobes 1 cm thick and made gamma camera images of the slices. We then cut three or four slices in each lobe into two or three concentric layers and measured the radioactivity per gram of tissue in a well-type gamma counter. In three of the dogs we also labeled the red cells (99mTc) so that blood volume in each sample could be determined. The gamma camera images were acquired on a 64 X 64 matrix with 4 X 4 mm pixels. On the numeric printouts from the individual slices we made two or three concentric layers and calculated activity per pixel in each layer. Neither by the well counting nor by the pixel analysis of the gamma scans did we detect any gravity-independent distribution of blood flow. With the well counting the distribution was the same whether macroaggregate activity was expressed per gram of tissue or per gram of blood-free tissue. We conclude that by direct measurements no major gravity-independent gradient of pulmonary blood flow can be detected in dog lungs.