Evaluation of histamine induced acute inflammation by 67Ga-citrate in conscious rats

Radioactivity of ⁶⁷Ga in the paw edema and the edema rate were measured after subcutaneous injection of histamine into the paw of the conscious rat. The radioactivity increased almost parallel with the edema rate following the injection of histamine. The increase in the radioactivity and edema were almost completely prevented by pretreatment with a 10 mg/kg dose of chlorpheniramine, an antihistaminic agent. A good correlation between the edema rate and the radioactivity was demonstrated. These results suggest that ⁶⁷Ga-citrate is useful for monitoring the process of acute inflammation in the pharmacological evaluation of anti inflammatory drugs. Moreover, there is also a possibility that ⁶⁷Ga-citrate may be useful in measuring vascular permeability.     

Comparison of delayed hepatobiliary imaging using 99mTc-Sn-N-pyridoxyl-5-methyltryptophan and 67Ga-citrate imaging for diagnosis of hepatocellular carcinoma

Images were obtained both with a biliary agent, ^99mTc-Sn-N-pyridoxyl-5-methyltryptophan (^99mTc-PMT), and with ⁶⁷Ga-citrate in 40 cases of hepatocellular carcinoma and in 43 cases of other hepatic diseases and results were compared. Positive results were obtained by delayed ^99mTc-PMT imaging in 25 (63%) of 40 cases of hepatoma: the hepatic tumor showed increased uptake in 18 cases (45%) and equilibrated uptake in 7 cases (18%). Positive ⁶⁷Ga-citrate imaging was found in 28 (70%) of the 40 cases of hepatoma: increased uptake was seen in 24 cases (60%) and equilibrated uptake in 4 cases (10%). Of 15 cases of hepatoma giving negative results in the ^99mTc-PMT study, 7 cases (47%) took up ⁶⁷Ga-citrate, and 6 of these showed increased ⁶⁷Ga-citrate uptake by the hepatic tumors. A certain relation existed between the degree of histological differentiation of hepatomas and the intensity of ^99mTc-PMT uptake by those tumors, while such a histological correlation was denied for ⁶⁷Ga-citrate uptake by the tumors. Delayed ^99mTc-PMT imaging is preferable to ⁶⁷Ga-citrate imaging for increasing the specificity of diagnosis of hepatoma. ⁶⁷Ga-citrate should be used in those cases that do not give positive results with ^99mTc-PMT.     

Better visualization of a lung tumour with 99mTc-DPD than with 99mTc-glucoheptonate or 67Ga-citrate

A case of a squamous cell lung carcinoma detected with ^99mTc-DPD, ⁶⁷Ga-citrate and ^99mTc-glucoheptonate (GH) is reported. The highest uptake was seen with DPD and the lowest with ⁶⁷Ga. Emission-computed tomography was very useful in DPD imaging but gave less new information in GH and ⁶⁷Ga studies in comparison to traditional planar imaging. The patient had been given both irradiation and chemotherapy, which might be the cause of good accumulation of DPD and rather poor accumulation of GH and ⁶⁷Ga.     

Thyroid uptake of <Superscript>67</Superscript>Ga-citrate is associated with thyroid autoimmunity and hypothyroidism in patients with sarcoidosis

Purpose  To evaluate the association of gallium-67 (⁶⁷Ga)-citrate thyroid uptake with the presence of thyroid disorders in patients with sarcoidosis (S patients). Methods  Eighty-four S patients were evaluated by a complete thyroid work-up (neck ultrasound, circulating thyroid hormones and anti-thyroid antibodies, fine-needle aspiration). Results  In S patients with ⁶⁷Ga thyroid uptake (respect those without): serum thyroid-stimulating hormone, the titre of anti-thyroid peroxidase (AbTPO) and/or anti-thyroglobulin antibodies (AbTg), and the prevalence of S patients with hypothyroidism or with positive AbTg or AbTPO was significantly higher; a thyroid hypoechoic pattern was more frequent. The prevalence of thyroid nodules was not significantly different between the two groups. Two cases of papillary thyroid cancer were observed in S patients without ⁶⁷Ga thyroid uptake, whilst no case in those with ⁶⁷Ga thyroid uptake. Conclusions   ⁶⁷Ga thyroid uptake is associated with the presence of aggressive autoimmune thyroiditis and hypothyroidism in S patients; thyroid function and ultrasonography should be performed in the presence of ⁶⁷Ga thyroid uptake.     

Non Hodgkins lymphoma of the breast,unusual presentation: Detection by 67Ga scintigraphy

Lymphomatous involvement of the breast is an uncommon cause of breast masses. A case is presented of a patient with bilateral breast involvement revealed by intense ⁶⁷Ga uptake. Other foci of involvement were also detected scintigraphically, and confirmed by other imaging modalities. Multiagent chemotherapy resulted in significant clinical and scintigraphic regression of tumor, demonstrating the potential utility of ⁶⁷Ga imaging in the followup of these patients.     

Placenta,embryo, and tumor uptake of 67Ga-citrate and 59Fe-citrate

The uptake of gallium citrate Ga⁶⁷ and ferrous citrate Fe⁵⁹ was studied in pregnant rats with or without a 4-dimethylamino-stilben (DS)-induced sarcoma tumor. The liver and placenta of the mother concentrated ⁶⁷Ga, while the uptake of ⁶⁷Ga in the embryo was minimal. However, the embryo showed higher concentrations of ⁵⁹Fe. Preloading with iron did not affect the ⁶⁷Ga uptake of the placenta, but increased the uptake in the blood and liver of the mother. With regard to ⁵⁹Fe uptake, iron loading only affected the embryo liver. Tumors and the placenta showed a similar ⁶⁷Ga uptake but a different incorporation of ⁵⁹Fe. The probable mechanisms involved are discussed.     

The complementary role of sequential 99mTc-MDP and 67Ga-citrate scanning in the diagnosis and follow-up of neuroblastoma

Fourteen children with histopathologically confirmed neuroblastoma underwent 38 studies using ^99mTc-methylene-diphosphonate (MDP) and galliumcitrate Ga67 whole-body scintigraphy during various stages of the disease. Ten patients (71%) showed ^99mTc-MDP accumulation in the primary tumoral site, whereas 11 patients (78.6%) showed ⁶⁷Ga concentration. In 12 patients (86%), at least one of these two radiopharmaceuticals concentrated in the primary tumor. Nine patients had osseous or extraosseous metastases. All of these metastases (100%) were positive on ^99mTc-MDP sctintigraphy. No ⁶⁷Ga-citrate uptake was demonstrable in osseous metastases; only one extraosseous lung metastasis concentrated this radiopharmaceutical. ⁶⁷Ga-citrate was superior to ^99mTc-MDP with regard to accurately demonstrating the extent of primary tumors. Only ^99mTc-MDP indicated the relationship of the tumor to the kidneys and neighbouring osseous structures, prividing early screening of kidney compression and possible damage caused by the tumor. From these results, we found these two methods to be complementary for the diagnosis and follow-up of neuroblastoma; their combined use resulted in high diagnostic accuracy and a considerable gain of information. We therefore recommend sequential ^99mTc-MDP and ⁶⁷Ga-citrate scans for the diagnosis and evaluation of the primary tumor; periodic ^99mTc-MDP wholebody scans should be used in the follow-up of treatment, and for discovering disease exacerbations and metastases.Presented in part in the European Congress of Nuclear Medicine, London, England, September 1985     

Potential radiopharmaceuticals for the detection of ocular melanoma

The uptake and distribution of several 4-(substituted amino)-iodoquinolines, ¹³¹I-labelled, and of ⁶⁷Ga-citrate were investigated in Syrian golden hamsters with Greene melanomas. Because of its uptake in the melanoma (tumour/eye ratio 8.9), 4-(dimethylamino-ethylamino)-7-iodoquinoline (NM113) was selected for further investigations as a possible radiopharmaceutical for ocular scintigraphy when labelled with ¹²³I. High uptake of NM113 turned out to be incidental and could not be favourably influenced by several pharmacological pretreatments. Affinity for melanin, as shown in in vitro experiments, unfavourably influences NM113 tumour-to-eye ratios. In comparison with ⁶⁷Ga-citrate, the latter, with a high tumour-to-eye ratio (44.8 after 24 h) is more promising in patient studies in which NM113 ¹²³I was not.     

Gallium-67 scintigraphy in acute pancreatitis

Acute pancreatitis is a serious surgical problem with a high incidence of mortality. Both ultrasound and X-ray CT have problems in identifying the extent and severity of the disease and the response to therapy. ⁶⁷Ga-citrate has been used in 21 patients with clinically diagnosed acute pancreatitis:9 patients had X-ray CT and 15 had US examination. Gallium scans were more sensitive than X-ray CT and US in detecting the extent and severity of acute pancreatitis. In addition, gallium was helpful to monitor the response to therapy when the scan was repeated at various intervals in three patients. A subtraction technique using ^99mTc-tin colloid and ⁶⁷Ga-citrate was helpful to mask the liver uptake of gallium and clearly identify the extent of acute pancreatitis.     

Tumor uptake of 67Ga-carrying liposomes

The in vivo distribution, excretion, and tumor localization of liposome-encapsulated ⁶⁷Ga in normal and Ehrlich tumor (solid form)-bearing mice were studied. In normal mice, multilamellar vesicles (MLVs) were taken up mainly by the liver and spleen, whereas small unilamellar vesicles (SUVs) exhibited a broader tissue distribution. When ⁶⁷Ga was encapsulated in MLVs or SUVs, the excretion of the radiotracer in the urine and feces was less than that observed for free tracer at 72 h after i.v. administration. In tumor-bearing mice, SUVs were found to accumulate preferentially in tumors. The tumor uptake of neutral, positive, and negative SUVs was 10%–13% of the administered dose per gram of tumor tissue at 24 h after their injection. These values were about three times higher than those found for free ⁶⁷Ga-nitrilotriacetic acid (⁶⁷Ga-NTA) or ⁶⁷Ga-citrate. Significant differences in tumor uptake due to different surface charges of liposomes were not observed. Enhanced tumor-to-blood and tumor-to-muscle ratios were also observed at 24 h after injection. These results suggest that ⁶⁷Ga-carrying liposomes may be a useful for tumor imaging.     

Early detection of infantile endocarditis by gallium — 67 scintigraphy

An infant with suspected soft tissue infection of the knee was studied by ⁶⁷Ga-scintigraphy. In addition to knee and hip joint increased activity, heart uptake was also demonstrated prior to the development of clinical signs of endocarditis. The early detection and treatment resulted in satisfactory clinical resolution.     

99mTc-methylene diphosphonate and 67Ga-uptake in myositis ossificans

A histologically proven case of myositis ossificans is presented. Both ^99mTc-MDP and ⁶⁷Ga imaging demonstrated extensive uptake of radiotracers in the lesion.     

Gallium-67 imaging in the diagnosis of blastomycosis

⁶⁷Ga imaging was used in a group of 13 untreated patients with documented South American blastomycosis in an attempt to obtain additional information on the site and extent of the lesions. All diagnoses were confirmed by demonstration of the fungi in the lesions or body fluids. Serologic tests were performed on all patients. ⁶⁷Ga imaging was correlated with X-ray in all patients, and with bone imaging when bony lesions were suspected. ⁶⁷Ga imaging was positive for all lesions detected on chest X-ray and by clinical evaluation. More importantly, lesions clinically unsuspected and missed by other diagnostic techniques were shown on ⁶⁷Ga imaging: bony and hepatic lesions in three patients; a brain lesion in one patient and parotid gland involvement in five patients. There was good agreement between ⁶⁷Ga imaging and clinical and laboratory data, scintigraphy being more sensitive. Follow-up studies after specific therapy demonstrated decreased uptake in the lungs and other sites. ⁶⁷Ga imaging is a useful tool for detection of suspected and unsuspected lesions of blastomycosis and to evaluate the response of the disease to specific therapy.     

Molecular structures involved in 67Ga and 59Fe binding by placenta and tumors

The binding of ⁶⁷Ga and ⁵⁹Fe by placenta and tumors was compared. After sonification, about 50% of the total radioactivity was present in the insoluble fraction consisting of heavy subcellular particles (mitochondria, fragments of membranes, nuclei, etc.) and known to be rich in lipo- and glycoproteins. Heat denaturation and gel filtration were used to study transferrin and ferritin distribution in the supernatant. The differences between ⁵⁹Fe and ⁶⁷Ga uptake in this supernatant seemed to indicate that the transferrin-ferritin system plays a less important role in ⁶⁷Ga binding than in ⁵⁹Fe binding.     

Tumor and liver uptake models of 67Ga-citrate

After administration ⁶⁷Ga concentrates with time in lysosomes from the cytoplasm of liver cells. The lysosomal role in the accumulation of ⁶⁷Ga in the liver cell is weakened upon transformation of the liver cell into a malignant tumor cell. In malignant tumors (except for hepatoma) the lysosome does not play a major role in the tumor concentration of ⁶⁷Ga. ⁶⁷Ga is bound to acid mucopolysaccharides (keratan polysulfate, etc.) in both tumor and liver. In liver cells, large amounts of ⁶⁷Ga are transported into lysosomes with these acid mucopolysaccharides, and in hepatoma cells, quite large amounts of ⁶⁷Ga are transported into lysosomes with these acid mucopolysaccharides. In malignant tumor cells (except for hepatoma) the effect is much smaller, the acid mucopolysaccharides transporting very little ⁶⁷Ga into lysosome.The ⁶⁷Ga is concentrated in viable tumor tissue within malignant tissue but hardly at all in necrotic tumor tissue, and concentrates avidly in inflammatory infiltration around tumor cells. Plenty of ⁶⁷Ga is found in liver but very little in connective tissue associated with the liver.     

67Ga scan for evaluating response to therapy in malignant lymphoma

⁶⁷Ga scintigrams in a patient with malignant lymphoma before and after chemotherapy are presented. ⁶⁷Ga did not accumulate in the mostly necrotic mass with some viable cells. Negative uptake of ⁶⁷Ga might reflect necrosis of the tumor; however, it is difficult to detect some residual tumor cells. Therefore, negative uptake of ⁶⁷Ga in the mass seen in X-ray CT may not be totally reliable evidence of eradication of viable tumor cells.     

67Ga uptake and heparan sulfate content of Ehrlich solid tumor in mice

The relationship between ⁶⁷Ga uptake and heparan sulfate (HS) content in Ehrlich solid tumor (EST) of mice was investigated, and the effect of cyanomethylamine, papain, streptozotocin, or bleomycin pretreatment on ⁶⁷Ga uptake in EST was studied. ⁶⁷Ga uptakes in EST and kidney were much higher than other tissues, and these tissues also contained large amounts of HS. ⁶⁷Ga uptakes and HS synthesis in the EST were inhibited by pretreatment with cyanomethylamine or papain (inhibitors of fibrosis). Parallel reductions of ⁶⁷Ga uptake and HS synthesis in EST were observed in EST transplanted into streptozotocin-induced diabetic mice. The weight of EST in the bleomycin-injected group was decreased to less than half of the control, but no effect was observed on ⁶⁷Ga uptake per gram of EST. These results suggest that ⁶⁷Ga uptake in the tumor and inflammatory lesions are related to the quantity of HS in these tissues, and the correlation between the uptake of ⁶⁷Ga and the rate of cellular proliferation is secondary.     

The relationship between Ga-67 accumulation and cell cycle in malignant tumor cells in vitro

Previously we reported that the deposition of ⁶⁷Ga into malignant tumor may be a sensitive index of proliferative activity in tumor cells. For the purpose of elucidation of this hypothesis, we investigated the relationship between the accumulation of ⁶⁷Ga into malignant tumor cells and the cell cycle in vitro. We discovered that the uptake of both ⁶⁷Ga and ⁵⁹Fe into synchronized mouse tumor cells reaches a peak at the G2 stage which precedes cellular proliferation. Both iron and transferrin are specifically required by cells in culture for cell division, and the fact that ⁶⁷Ga and ⁵⁹Fe uptake into tumor cells peaks at the G2 stage of the cell cycle suggests that there is a correlation between ⁶⁷Ga uptake and the rate of cellular proliferation in malignant tumor cells.     

Experimental evidence for the probable involvement of calcium ion transport in 67Ga uptake by tumour cells

The study of ⁶⁷Ga-citrate uptake and calcium transport in Ehrlich ascites tumour cells seems to indicate that their peculiar characteristic of increased permeability to extracellular calcium ion might be responsible for their ⁶⁷Ga accumulation. Experiments performed under different conditions of extracellular calcium, temperature, and presence of ionophore and other plasma membrane modifying agents such as lanthanum appear to corroborate this hypothesis.     

Study on the usefulness of whole body SPECT coronal image,MIP image in<Superscript>67</Superscript>Ga scintigraphy

In this study, we examined the usefulness of whole body coronal images and whole body cine display MIP images (CMIP) upon which image processing was carried out after whole body SPECT in comparison to the usefulness of whole body images (WB/SC) compensated by scattered radiation in tumor/inflammation scintigraphy with 67Ga-citrate (67Ga). Image interpretation was performed for the 120 patients with confirmed diagnoses, and the accuracy of their diagnoses was studied by three nuclear medical physicians and two clinical radiological technologists by means of sensitivity, specificity and ROC analysis. The resultant data show that sensitivity, specificity, accuracy and the area under the ROC curve Az in the WB/SC were approximately 65%, 86%, 74% and 0.724, respectively, whereas sensitivity, specificity, accuracy and Az of the image reading system in which CMIP is combined with whole body coronal images reconstructed by the OS-EM method were approximately 93%, 95%, 94% and 0.860, respectively. Furthermore, coronal images reconstructed by the OS-EM method tended to be superior to those produced by the FBP method in both diagnostic accuracy and ROC analysis. In conclusion, the image reading system in which CMIP is combined with whole body coronal images reconstructed by the OS-EM method was shown to be superior in diagnostic accuracy and ROC analysis. Our data suggest that whole body SPECT is an excellent technique as an alternative to WB/SC.