Gallium scans in patients with mediastinal Hodgkin's disease treated with chemotherapy.

PURPOSE: To determine the predictive value of gallium scans in patients with mediastinal Hodgkin's disease treated with chemotherapy or combined modality treatment. PATIENTS AND METHODS: A retrospective study was performed of 48 patients with mediastinal Hodgkin's disease treated with chemotherapy or combined modality therapy. Patients were monitored with whole-body planar scans (34 patients) or chest single-photon-emission computed tomography (SPECT) plus planar abdominal imaging studies (14 patients). Scans were performed at diagnosis, following three to eight cycles of chemotherapy, and after the end of treatment. The value of gallium scans in modifying treatment and predicting outcome was assessed. RESULTS: All patients studied at the time of diagnosis had abnormal gallium accumulation in the mediastinum. After chemotherapy, four patients had residual mediastinal activity; two patients with persistent activity on planar scans failed to enter remission and died of disease; two other patients with abnormal activity only seen on SPECT had therapy modified and remain in remission. After chemotherapy, 44 patients had a normal gallium scan. Twelve patients with negative scans relapsed, including nine patients with recurrence above the diaphragm. CONCLUSION: The use of gallium scans after several courses of chemotherapy resulted in a modification of treatment in four patients, including two patients who are apparently cured. However, after negative scans, 20% of patients relapsed above the diaphragm. These results suggest that gallium imaging, including SPECT, is of limited value in predicting disease sterilization, although the number of patients studied with SPECT was small. At present, the major value of gallium scans is to identify patients who may benefit from a modification of treatment.

Gold-195m for serial first pass radionuclide angiocardiography during upright exercise in patients with coronary artery disease.

Sequential first pass radionuclide angiocardiography can be performed in rapid succession using gold-195m because of its low radiation dose and short half-life (30.5 seconds). In 25 patients with known or suspected coronary artery disease, first pass studies with gold-195m were obtained using a computerized multicrystal gamma camera at rest (n = 29), at the end of each 3 minute stage of exercise (n = 25) and immediately after exercise (n = 23). In 13 patients, assessment of left ventricular function during exercise with gold-195m was combined with thallium-201 stress scintigraphy. Left ventricular ejection fraction at rest assessed with technetium-99m and gold-195m correlated well (r = 0.93). In addition, repeat left ventricular ejection fractions at rest with gold-195m correlated closely (r = 0.96). Comparing peak exercise left ventricular ejection fraction with ejection fraction at rest, abnormal left ventricular reserve was found in 20 of 25 patients. Various abnormal patterns of left ventricular ejection fraction response were noted, showing the diagnostic potential of serial exercise angiocardiography. Thallium-201 myocardial images, obtained on a single crystal gamma camera after multiple gold-195m injections, were all of good diagnostic quality and were abnormal in 10 of 13 patients. Thus, multiple high count rate first pass studies can be obtained with gold-195m during and after exercise, allowing serial study of physiologic changes in left ventricular function during exercise. Thallium-201 myocardial imaging can be performed using the same exercise test, providing direct comparison of myocardial function and perfusion.

Simplified captopril renography in diagnosis and treatment of renal artery stenosis.

To improve the diagnosis and forecast the response to surgery or renal angioplasty in patients with hypertension and renal artery stenosis, we employed a simplified captopril renography protocol in conjunction with renal arteriography in 94 clinically selected patients. Fifty hypertensive patients (group 1) with a high clinical likelihood of renovascular hypertension were evaluated using a simplified captopril renography protocol and renal angiography on the arterial side. Criteria for normal captopril renal scintigrams were established based on this original cohort and validated in an additional 44 clinically comparable patients (group 2). Renal revascularization or nephrectomy was performed in 39 patients, and success of the procedure was determined in the 34 patients for whom 3-month follow-up was available. In the 94 patients, 44 (47%) had renal artery stenosis. Simplified captopril renography was 91% sensitive and 94% specific in identifying or excluding renal artery stenosis in the combined group, with no difference in the diagnostic utility between groups 1 and 2, or in those with renal insufficiency (n = 38) or those with bilateral disease (n = 17). Scintigraphic abnormalities induced by captopril were strongly associated with cure or improvement in blood pressure control following revascularization or nephrectomy (15 of 18), while the lack of captopril-induced changes was associated with failure of such intervention (13 of 16) (p = 0.0004). We conclude that simplified captopril renography is highly sensitive and specific in the diagnosis of renal artery stenosis in a clinically selected high-risk population and that the test accurately predicts the success or failure of therapeutic intervention.

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

Graphical, kinetic, and equilibrium analyses of in vivo [123I] beta-CIT binding to dopamine transporters in healthy human subjects.

The in vivo kinetics of the dopamine (DA) transporter probe 123I-labeled 2 beta-carboxymethoxy-3 beta-(4-iodophenyl) tropane ([123I] beta-CIT) in striatum was investigated with single-photon emission computerized tomography (SPECT) in five healthy human subjects. The aim of this study was to derive an adequate measure of the DA transporter density that would not be affected by regional cerebral blood flow or peripheral clearance of the tracer. SPECT data were acquired on the day of injection (day 1) from 0 to 7 h and on the following day (day 2) from 19 to 25 h. Arterial sampling on day 1 was used to measure the input function. Graphical, kinetic, and equilibrium analyses were evaluated. Graphical analysis of day 1 data, with the assumption of negligible dissociation of the tracer-receptor complex (k4 = 0), was found to be blood flow-dependent. A three-compartment kinetic analysis of day 1 data were performed using a three (k4 = 0)- and a four (k4 > 0)-parameter model. The three-parameter model estimated the konBmax product at 0.886 +/- 0.087 min-1. The four-parameter model gave a binding potential (BP) of 476 ml g-1, a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspecific equilibrium partition coefficient (V3" = k3/k4 = 6.66 +/- 1.54). Results of day 1 kinetic analysis and day 2 equilibrium analysis were well correlated among subjects. Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives > 10 h. We propose the equilibrium analysis on day 2 as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial plasma tracer concentrations.

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: I. Kinetic modeling of single bolus experiments.

The aim of this work was to study the feasibility and reproducibility of in vivo measurement of benzodiazepine receptors with single photon emission computerized tomography (SPECT) in the baboon brain. Arterial and brain regional activities were measured for 420 min in three baboons after single bolus injection of the benzodiazepine antagonist [123I]iomazenil. Data were fit to a three-compartment model to derive the regional binding potential (BP), which corresponds to the product of the receptor density, (Bmax) and affinity (1/KD). Regional BP values (from 114 in striatum to 241 in occipital) were in good agreement with values predicted from in vitro studies. Constraining the regional volume of distribution of the nondisplaceable compartment to the value measured during tracer constant infusion experiments in baboons (Laruelle et al., 1993) improved the identifiability of the rate constants. Each experiment was repeated to investigate the reproducibility of the measurement. The regional average reproducibility was 10 +/- 5%, expressed as coefficient of variation (CV). Results of equilibrium analysis at peak uptake were in good agreement with results of kinetic analysis. Empirical counts ratio methods were found to be poorly sensitive to benzodiazepine receptor density. These studies suggest the feasibility of quantitative measurement of benzodiazepine receptors by kinetic analysis of SPECT data and the inadequacy of empirical methods of analysis, such as counts ratios, to evaluate differences in receptor density.

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: II. Equilibrium analysis of constant infusion experiments and correlation with in vitro parameters.

In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor-ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4-9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 +/- 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37 degrees C on occipital homogenate membranes. In vitro values of Bmax (114 +/- 33 nM) and 37 degrees C KD (0.66 +/- 0.16 nM) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.

Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease.

BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.

"Central" and "peripheral" benzodiazepine receptors: opposite changes in human epileptogenic tissue.

We measured the density of two benzodiazepine (BZ) receptor subtypes in neurosurgically obtained hippocampal tissue from the seizure focus of patients with temporal lobe epilepsy (TLE) showing mesial temporal sclerosis, the most common pathologic finding in TLE. We performed quantitative in vitro receptor autoradiography with [125I]Ro 16-0154, a probe for the central-type BZ receptor and with [3H]PK 11195, a probe for the peripheral-type BZ receptor. In comparison with autopsy and neurosurgical control groups, patients with mesial temporal sclerosis had regionally selective decreased central-type and increased peripheral-type BZ receptors. These changes paralleled regional losses of neurons and proliferation of glia. Decreases of the inhibitory central-type BZ receptor may be a component of the enhanced excitability of the seizure focus and also may allow localization of the focus by in vivo neuroreceptor imaging. Single photon emission computed tomography (SPECT) imaging of two TLE patients with [123I]Ro 16-0154 suggests that this technique may provide a more sensitive means of localizing the seizure focus than current imaging methods relying on changes in blood flow or glucose metabolism.

[123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease.

We have used in vivo single-photon emission computed tomography (SPECT) of the dopamine transporter with 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to investigate striatal dopamine transporter loss in patients with early Parkinson's disease (PD). Striatal uptake of ([123I] beta-CIT was compared in eight early-PD patients with exclusively hemi-parkinsonism and eight age- and sex-matched healthy subjects. [123I] beta-CIT striatal uptake was reduced by approximately 53% contralateral and by 38% ipsilateral to the clinically symptomatic side in the hemi-PD patients, compared with the mean striatal uptake in age- and sex-matched healthy subjects. The relative reduction in [123I] beta-CIT uptake in the hemi-PD patients was greater in the putamen than in the caudate. These data demonstrate that SPECT imaging of the dopamine transporter with [123I] beta-CIT can identify patients with PD at the onset of motor symptoms and suggest that this technique also may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms.

Siderophore-mediated mechanism of gallium uptake demonstrated in the microorganism Ustilago sphaerogena.

The radioactive gallium analog of ferrichrome, Ga-67 deferriferrichrome, has been prepared and compared with ferrichrome in the specific siderophore-transport system of Ustilago sphaerogena. The gallium analog is taken up by the cells in an active transport process indistinguishable from that of ferrichrome. Ga(III) effectively competes with Fe(III) for siderophore ligands both in vitro and in vivo at a rate that is highly dependent upon the chemical nature of the ligand. The findings may explain how Ga(III) mimics Fe(III) in clinical use.

Salivary gland uptake of 67Ga-citrate following radiation therapy.

Radiogallium uptake in the salivary glands is strongly correlated with prior therapeutic radiation which includes the cervical region. Fifteen of 17 patients with increased salivary gland uptake had such a history. An easily identified characteristic pattern of symmetric localization of 67Ga occurs in the parotid and submandibular regions in these patients. This pattern must not be mistaken for recurrent tumor in the cervical region.

Lactoferrin: its role as a Ga-67-binding protein in polymorphonuclear leukocytes.

Gallium-67 bound to lactoferrin--an iron-binding protein found in high concentration in polymorphonuclear leukocytes--has been isolated from PMNs that have previously been incubated with Ga-67 citrate. Although the cell-labeling efficiency was highly variable (0.026-10%), much of the activity that did bind to the PNMs (74.8 +/- 10%) was recovered in the supernatant after sonication and centrifugation. About half (approximately 47%) of the PMN-bound activity was retained after dialysis and was presumably bound to macromolecules in the supernatant. When this retained activity was placed on a column containing immobilized antilactoferrin antibody, almost three quarters of the activity was bound to the column. This bound activity was (36 +/- 17%) of the total activity absorbed by the PMN. The addition to the antilactoferrin column of a known antigen-antibody-dissociating agent caused the disolution of the complex. No significant activity was bound to a control column. The findings indicate that lactoferrin is a major Ga-67-binding protein present in PMNs and suggest that it may play a major role in Ga-67 localization in an abscess. These results support the contention that molecules binding ferric iron have an important effect on Ga-67 distribution in vivo.

The association of Ga-67 and lactoferrin.

Activity was seen in the breasts of a patient with galactorrhea 72 h after intravenous injection of Ga-67 citrate. Differential protein separation of breast secretion, extracted from the breast, revealed that the Ga-67 was contained primarily in the lactoferrin-rich protein fraction. Additional studies on partially purified lactoferrin revealed that lactoferrin binds Ga-67 more avidly than does transferrin. Since lactoferrin is present in high concentration non only in human colostrum and milk, but also in neutrophilic leukocytes, bone marrow, spleen, colon, tears, and in genital, salivary, and nasopharyngeal secretions, binding of Ga-67 to lactoferrin may explain the localization of Ga-67 in certain normal tissues and inflammatory lesions.

Inhibition of gallium-67 uptake in melanoma by an anti-human transferrin receptor monoclonal antibody.

The effect of an anti-human transferrin receptor (anti-TFR) monoclonal antibody (MoAb), designated B3/25, and an anti-melanoma antibody, designated 96.5, on the uptake of gallium-67 (67Ga) by tumor was studied. Three groups of six athymic mice bearing a human melanoma were injected via tail vein with (a) 0.55 mg human serum albumin (HSA) (control group), (b) 0.5 mg MoAb B3/25 + 0.55 mg HSA, and (c) 0.5 mg MoAb 96.5 + 0.55 mg HSA, respectively. Twenty-four hours later, each mouse was given an intravenous dose of 5 microCi [67Ga] citrate. Biodistribution of activity (percent injected dose per gram) determined 48 hr after injection of 67Ga showed a 75% decrease in tumor uptake in the group of mice that received B3/25 (anti-TFR MoAb) compared with the control group. In contrast, MoAb 96.5 did not show any effect on melanoma uptake of 67Ga. Histologic findings suggest that the decreased uptake was not due to cellular damage resulting from binding of B3/25 to TFR. The results of this study strongly suggest the involvement of TFR in the in vivo tumor uptake of 67Ga.

In vitro transfer of Ga-67 from transferrin to ferritin.

Equilibrium dialysis was used to examine the binding of Ga-67 to horse spleen ferritin (HFE), and the ability of this protein to remove Ga-67 originally bound to human transferrin (TF). Seventy hours were required for the HFE to bind 70% of the activity. When HFE was placed in competition with preformed TF-Ga-67 complex, little nuclide was translocated to HFE. Upon the addition of compounds of low molecular weight that occur intracellularly, this transfer was dramatically enhanced. In the presence of 1 mM adenosine triphosphate (ATP), the most effective mediator examined, the final distribution was 17% bound to TF and 62% to HFE, with 16% not protein-bound. In the absence of any mediator, the same distribution was 84, 6, and 3%. Control experiments with ATP showed that little radionuclide was transferred from TF to albumin. These results add support to the previous suggestions of the potential role of ferritin in Ga-67 localization.

Effect of desferoxamine on tissue and tumor retention of gallium-67: concise communication.

Desferoxamine (DEF) was administered intramuscularly (0.25 mg/g body weight) to mice harboring a Cloudman's melanoma S-91 3 hr before, simultaneously with, and 3 hr after i.v. injection of Ga-67 citrate (approximately 1 microCi/g body weight). Relative Ga-67 retention was compared with that in non-DEF controls at 24 hr. The chemical nature of Ga-67 excreted in urine following DEF was also studied in healthy mice. Desferoxamine administered 3 hr before Ga-67 had little effect on radiogallium localization; administration coincident with or 3 hr after radiogallium resulted in decreased retention at 24 hr. The effect was most profound when Ga-67 and DEF were administered simultaneously. In DEF-injected animals Ga-67 was excreted in the urine as a Ga-67-DEF complex. When DEF was administered 3 hr after Ga-67, there was a trend to greater tumor-to-blood activity ratios (.2 > p > .1).

Comparison of 1- and 2-hr delayed brain scans in patients undergoing chemotherapy for primary brain tumors.

Fifty-five patients receiving various forms of chemotherapy for primary brain tumors had brain scans performed at 1 hr and again at 2 hr following injection of the radionuclide. The images were compared for changes in lesion size, lesion intensity, and surgical flap intensity. Sixteen percent (9) of the patients showed a definite increase in size of the lesions and 29% (16) a definite increase in intensity from 1-hr to the 2-hr scan. Fifty-one percent (28) of the patients showed fading in surgical flap intensity. One case of primary neoplasm, one case of meningeal spread of tumor, and one case of subdural hematoma were detected only on the 2-hr view. In addition, changes in the so-called doughnut sign were observed. These findings demonstrate a need for strict adherence to a specified time between injection and imaging in studying brain lesions receiving chemotherapy, and emphasize the superiority of the 2-hr scan for evaluation of these patients.

Demonstration of lactoferrin in tumor tissue from two patients with positive gallium scans.

We have detected lactoferrin in tumor tissue from a patient with Hodgkin's disease and a patient with Burkitt's lymphoma. Both patients had radiogallium scans demonstrating increased uptake in the tumor tissue subsequently found to contain lactoferrin. Tissue assay for lactoferrin was performed by the indirect immunofluorescence method. Control splenic tissue showed either slight lactoferrin content or none.

Improved intrinsic resolution: does it make a difference? Concise communication.

The purpose of this study was to determine what effect further improvement in an Anger camera's intrinsic resolution has on lesion detection. We studied 52 patients undergoing bone imaging and 58 undergoing liver imaging. All patients had images performed in rapid sequence on ZLC -75 and ZLC -37 Anger cameras, both by Siemens. The two imaging systems are virtually identical except for the number of photomultiplier tubes and crystal thickness; these resulted in differences in intrinsic resolution ( ZLC -75 less than 3.8 mm FWHM at 140 keV, ZLC -37 less than 4.9 mm) and sensitivity ( ZLC -75 approximately 0.91 of ZLC -37 at 140 keV). Observer performance, measured by ROC curves, for detection of abnormalities was virtually identical with the two instruments. Subjectively, there was a trend toward preference of the ZLC -75 images, but this was not associated with any significant improvement in lesion detectability even in the subgroup in which a preference for one or the other instrument was noted.