64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.
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64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. METHODS: Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. RESULTS: In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. CONCLUSION: The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors. (+info)
Somatostatin receptor scintigraphy in the initial staging of low-grade non-Hodgkin's lymphomas.
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In this prospective study, somatostatin receptor (SS-R) scintigraphy was compared with conventional staging procedures for the initial staging of patients with low-grade non-Hodgkin's lymphoma (NHL). METHODS: Fifty consecutive untreated patients with low-grade NHL underwent SS-R scintigraphy as part of their initial staging. Planar images were obtained 24 and 48 h after intravenous injection of 220 MBq (111)In-pentetreotide. SPECT images of the upper abdomen were obtained from all patients. SS-R scans were evaluated blindly without knowledge of the results of the conventional staging methods. SS-R scintigraphy findings were compared with the results of physical and radiologic examinations. RESULTS: SS-R scintigraphy findings were positive in 42 of 50 patients (84%). In 10 patients (20%), the SS-R scan revealed new lesions that had not been revealed by conventional staging procedures. These 10 patients were all upgraded to a higher stage. Consequently, the treatment plan would have been altered in 5 patients (10%). However, in 19 patients (38%), lesions apparent after conventional staging methods were missed by SS-R scintigraphy. The sensitivity of SS-R scintigraphy varied from 62% for supradiaphragmatic lesions to 44% for infradiaphragmatic lesions. The specificity of SS-R scintigraphy was high (98%-100%). In comparison with CT scanning and sonography, SS-R scintigraphy is inferior for the visualization of NHL lesions in the thorax and abdomen. CONCLUSION: Although SS-R scintigraphy findings are positive in a large proportion of patients with low-grade NHL, in most patients only part of the lesions can be visualized. Because of the limited sensitivity, we recommend SS-R scintigraphy for initial staging of patients with low-grade NHL only in selected conditions and not for the general work-up. (+info)
Evaluation of pulmonary alveolar epithelial integrity by the detection of restriction to diffusion of hydrophilic solutes of different molecular sizes.
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The rate of transfer of a hydrophilic solute from the alveoli to pulmonary blood following inhalation as an aerosol depends on the molecular size of the solute and the permeability of the alveolar epithelium. The value of this measurement for assessing damage to the epithelium in lung disease is compromised by cigarette smoking, which accelerates clearance by unknown mechanisms. The rates of clearance of (99m)Tc-labelled diethylenetriaminepenta-acetic acid (DTPA) (molecular mass 492 Da) and (113m)In-labelled biotinylated DTPA (B-DTPA) (molecular mass 1215 Da) were monitored simultaneously by dynamic gamma-radiation camera imaging following simultaneous inhalation, and compared between eight normal non-smoking subjects and nine habitual cigarette smokers. The clearance rates of DTPA were 0.95 (S.D. 0.39)%/min in non-smokers and 4.13 (1.06) %/min in smokers. These were about twice the clearance rates of B-DTPA, which in the corresponding groups were 0.41 (0.26) and 2.12 (0.72)%/min respectively. The ratio of the B-DTPA/DTPA clearance rates was, in all subjects, less than the ratio (0.74) of the cube roots of the molecular masses of the solutes, assumed to correspond to the ratio of their free diffusion coefficients in water, and was not significantly different between smokers and non-smokers. As alveolar permeability increased, the ratio of clearance rates in the entire population showed a significant trend to increase in a non-linear fashion towards the value corresponding to the ratio of the free diffusion coefficients. We conclude that the diffusion of at least the larger of these two solutes through the pulmonary alveolar epithelium is restricted (i.e. associated with a reflection coefficient greater than zero). Cigarette smoking, however, does not appear to cause a loss of this restriction, and may increase solute clearance by other mechanisms, such as reducing fluid volume within the alveolus, thereby raising the local radiotracer concentration, or increasing the number of pores available for solute exchange without affecting pore size. Conversely, if restriction was lost in lung disease, the ratio of the clearance rates of two solutes of dissimilar sizes could be used to detect disease in smokers as well as non-smokers. (+info)
Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.
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The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck. (+info)
111In platelet scintigraphy for the noninvasive detection of carotid plaque thrombosis.
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BACKGROUND AND PURPOSE: Thrombosis on atherosclerotic lesions in the large extracranial arteries is the main cause of embolization in the distal cerebral circulation and thus is involved in the pathogenesis of ischemic stroke. The assessment of biological characteristics of lesions that are predictive of thrombotic complications might help in stratification of the risk for stroke but is currently imperfect. METHODS: We compared the performance of (111)In-platelet scintigraphy with blood pool subtraction, ultrasound-based tissue texture analyses, and transcranial Doppler techniques in their ability to predict the occurrence of superficial thrombosis or the presence of a lipid pool in carotid artery plaque specimens removed at the time of carotid endarterectomy in 22 patients with unilateral carotid artery stenosis of >70%. RESULTS: Positivity at (111)In-platelet scintigraphy was present in 8 patients and correctly identified the presence of thrombosis superimposed on a complicated plaque. Neither tissue texture analysis nor emboli detection by transcranial Doppler, performed in 12 patients, significantly identified plaque thrombosis. None of the techniques used were able to detect the presence of a significant lipid pool inside the plaque. CONCLUSIONS: Indium-platelet scintigraphy is an accurate noninvasive diagnostic tool to detect thrombotic complications in carotid plaques. Prospective studies should assess its ultimate value in risk stratification, possibly to guide the decision of whether to perform endarterectomy in selected patient categories. (+info)
Involvement of serum mannan binding proteins and mannose receptors in uptake of mannosylated liposomes by macrophages.
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The roles of serum mannan binding protein (MBP) and the mannose receptor in the cellular uptake of mannosylated liposomes (Man-liposomes) by macrophages were studied. Man-liposomes were prepared by incorporating cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol) into small unilamellar long circulating liposomes consisting of cholesterol (Chol) and distearoyl phosphatidylcholine (DSPC). In the in vitro cellular uptake study with cultured mouse peritoneal macrophages, [(3)H]Man-liposomes were taken up to a great extent, whereas no significant uptake was observed for [(3)H]cholesterol and DSPC liposomes without Man-C4-Chol (Bare-liposomes). The uptake of [(3)H]Man-liposomes was dose- and temperature-dependent and inhibited by an excess of mannosylated bovine serum albumin, suggesting their specific uptake via membrane mannose receptor-mediated endocytosis. Furthermore, it was demonstrated that (111)In-MBP binds strongly to Man-liposomes based on the recognition of Man-C4-Chol and markedly enhanced their uptake by macrophages. These results are supported by confocal laser microscopic images. In addition, in vivo hepatic uptake of (111)In-MBP was enhanced by Man-liposomes. On the other hand, the uptake of Man-liposomes was significantly reduced by preincubation with serum and further with MBP-depleted serum suggesting inhibitory effects of serum proteins such as albumin on mannose receptor-mediated endocytosis. The involvement of serum-type MBP and membrane mannose receptors in the uptake of Man-liposomes is thus suggested. (+info)
Eosinophil recruitment into sites of delayed-type hypersensitivity reactions in mice.
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The selective accumulation of eosinophils in tissue is a characteristic feature of allergic diseases where there is a predominance of lymphocytes expressing a Th2 phenotype. In an attempt to define factors determining specific eosinophil accumulation in vivo, we have used a radiolabeled technique to assess the occurrence and the mechanisms underlying (111)In-eosinophil recruitment into Th1- and Th2-predominant, delayed-type hypersensitivity (DTH) reactions. Eosinophils were purified from the blood of IL-5 transgenic mice, labeled with (111)In and injected into nontransgenic CBA/Ca mice. Th1- and Th2-predominant, DTH reactions were induced in mice by immunization with methylated bovine serum albumin (MBSA) in Freund's complete adjuvant or with Schistosoma mansoni eggs, respectively. In these animals, (111)In-eosinophils were recruited in skin sites in an antigen-, time-, and concentration-dependent manner. Depletion of CD4+ lymphocytes abrogated (111)In-eosinophil recruitment in both reactions. Pretreatment of animals with anti-IFN-gamma mAb abrogated (111)In-eosinophil recruitment in MBSA-immunized and -challenged animals, whereas anti-IL-4 inhibited (111)In-eosinophil recruitment in both models. Local pretreatment with an anti-eotaxin polyclonal antibody inhibited the MBSA and SEA reactions by 51% and 39%, respectively. These results demonstrate that, although eosinophilia is not a feature of Th1-predominant, DTH reactions, these reactions produce the necessary chemoattractants and express the necessary cell adhesion molecules for eosinophil migration. The control of the circulating levels of eosinophils appears to be a most important strategy in determining tissue eosinophilia. (+info)
In vivo recognition of mannosylated proteins by hepatic mannose receptors and mannan-binding protein.
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In vivo recognition of mannosylated proteins by hepatic mannose receptors and serum mannan-binding protein (MBP) was investigated in mice. After intravenous administration, all three different (111)In-mannosylated proteins were taken up mainly by liver, and uptake was saturated with increasing doses. (111)In-Man-superoxide dismutases and (111)In-Man(12)- and (111)In-Man(16)-BSA had simple dose-dependent pharmacokinetic profiles, whereas other derivatives ((111)In-Man(25)-, -Man(35)-, and -Man(46)-BSA and (111)In-Man-IgGs) showed slow hepatic uptake at <1 mg/kg. Purified MBP experiments in vitro indicated that these derivatives bind to MBP in serum after injection, which interferes with their hepatic uptake. To quantitatively evaluate these recognition properties in vivo, a pharmacokinetic model-based analysis was performed for (111)In-Man-BSAs, estimating some parameters, including the Michaelis-Menten constant of the hepatic uptake and the dissociation constant of MBP, which correlate to the affinity of Man-BSAs for mannose receptors and MBP, respectively. The dissociation constant of Man-BSA and MBP decreased dramatically with increasing density of mannose, but the Michaelis-Menten constant of hepatic uptake of Man-BSA was not so sensitive to the change in density. This suggests that the in vivo recognition of MBP has a stronger cluster effect than that of mannose receptors. Differences obtained here are due to the unique arrangement of carbohydrate recognition domains on each mannose-specific lectin available for mannosylated ligand recognition. (+info)