[18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species.

Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n = 1), rats (n = 4), rabbits (n = 4) and non-human primates (n = 3), via carotid artery in rats (n = 4) and non-human primates (n = 3), and via intra-myocardial injection in rats (n = 5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.

Magnetic resonance imaging of umbilical cord stem cells labeled with superparamagnetic iron oxide nanoparticles: effects of labelling and transplantation parameters.

Cell tracking with magnetic resonance imaging (MRI) is important for evaluating the biodistribution of transplanted cells. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have emerged as a promising therapeutic tool in regenerative medicine. We examined the UC-MSCs labeled with superparamagnetic (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) in terms of cell functioning and imaging efficiency in vitro and in vivo. The UC-MSCs were co-incubated with SPIO or USPIO at a concentration of 50 or 100 µg/mL of label. Viability and proliferation were assessed by Trypan blue dye exclusion and MTT assay, respectively. Differentiation (chondrogenesis, osteogenesis, and adipogenesis) was induced to examine the impact of labelling on stemness. For in vitro experiments, we used 7-T MRI to assess the T2 values of phantoms containing various concentrations of cell suspensions. For in vivo experiments, nine neonatal rats were divided into the control, SPIO, and USPIO groups. The UC-MSCs were injected directly into the rat brains. MRI images were obtained immediately and at 7 and 14 days post injection. The UC-MSCs were successfully labeled with SPIO and USPIO after 24 h of incubation. Cell viability was not changed by labelling. Nevertheless, labelling with 100 µg/mL USPIO led to a significant decrease in proliferation. The capacity for differentiation into cartilage was influenced by 100 µg/mL of SPIO. MRI showed that labeled cells exhibited clear hypointense signals, unlike unlabeled control cells. In the USPIO-labeled cells, a significant (P < 0.05) decrease in T2 values (= improved contrast) was observed when compared with the controls and between phantoms containing the fewest and the most cells (0.5 × 106 versus 2.0 × 106 cells/mL). In vivo, the labeled cells were discernible on T2-weighted images at days 0, 7, and 14. The presence of SPIO and USPIO particles at day 14 was confirmed by Prussian blue staining. Microscopy also suggested that the regions occupied by the particles were not as large as the corresponding hypointense areas observed on MRI. Both labels were readily taken up by the UC-MSCs and identified well on MRI. While SPIO and USPIO provide improved results in MRI studies, care must be taken while labelling cells with high concentrations of these agents.

Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer.

BACKGROUND: Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. METHODS: 99mTc-MIBI and 99mTc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. RESULTS: In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized, whereas 99mTc-TF had high stability. CONCLUSION: 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

Imaging of the thyroid and parathyroid using a cardiac cadmium zinc telluride camera: Phantom studies.

Purpose: Cadmium zinc telluride (CZT) detectors have recently been introduced to the field of clinical nuclear cardiology. However, the feasibility of using them for organs other than the heart remains unclear. The aim of this study was to evaluate the potential of a cardiac CZT camera to acquire thyroid and parathyroid images. We used custom-made phantoms and the currently available standard protocols for CZT, instead of a sodium-iodine scintillation (NaI) camera. Materials and Methods: Thyroid phantoms with or without parathyroid adenomas were made from agar using radiopharmaceuticals (99mTc or 123I) and imaged using CZT and NaI cameras. Using the CZT camera data, we prepared maximum intensity projection (MIP) images and planar equivalent (PE) images. Image counts were compared to those from the NaI camera, and the radioactivity of the phantoms was measured. For parathyroid imaging, three different protocols with the NaI camera were tested using MIP images. Results: For thyroid imaging, MIP could provide images as clear as those obtained from the NaI camera. The radioactivity and image counts correlated better for the PE images than the MIP images, especially for 123I images. We succeeded in obtaining clear parathyroid adenoma images from MIP images using all three protocols. Conclusion: A cardiac CZT camera can effectively perform qualitative and quantitative assessments of the thyroid and parathyroid organs.

Optimal injected dose ratio of a very rapid 1-day protocol of myocardial perfusion imaging with cadmium-zinc-telluride single-photon emission tomography: simulation and phantom study.

OBJECTIVE: Cadmium-zinc-telluride detectors enable shorter acquisition durations in myocardial perfusion imaging (MPI), but the time interval of sequential scanning is still unchanged in clinical practice. We designed a very rapid 1-day protocol of MPI using cadmium-zinc-telluride single-photon emission tomography and evaluated the optimal dose ratio between two scanning acquisitions by means of simulations and phantom experiments. METHODS: We intended to perform a 1-day MPI within 140 min and simulate radioactivities in the second scan under various injected dose ratios. To apply this, a cardiac phantom was scanned with various radioactivities and scans were compared with a reference scan with the ideal tracer concentrations. RESULTS: In the stress-first protocol, the dose ratio 1 : 5 was enough to show the same regional percentage uptake compared with the reference. However, in the rest-first protocol, the regional percentage uptakes were higher than those of the reference image even with a 1 : 6 dose ratio. CONCLUSION: The injected dose ratio 1 : 5 is optimal in a stress-first rapid 1-day protocol. The rest-first protocol is not appropriate because a dose ratio greater than 1 : 6 is required to withdraw shine-through artifacts.

Current status of stress myocardial perfusion imaging pharmaceuticals and radiation exposure in Japan: Results from a nationwide survey.

BACKGROUND: Ionizing radiation generated during medical imaging procedures is a matter of concern. However, the current status of radiopharmaceutical use in stress myocardial perfusion imaging (MPI) and the radiation exposure from these radiopharmaceuticals is unknown in Japan. METHODS AND RESULTS: A nationwide survey was conducted from June through July 2016. The questionnaires on the radiopharmaceuticals used and their administered doses during stress MPI were sent to 641 nuclear medicine facilities. The responses were collected from 431 facilities and the effective dose (ED) for an adult with standard body weight was calculated. Forty-three percent of the facilities used only 201TlCl, 35% used only 99mTc radiopharmaceuticals, and the remaining 22% used both. The two main reasons for using 201TlCl instead of 99mTc radiopharmaceuticals were "more familiarity with the usage of 201TlCl than 99mTc radiopharmaceuticals" and "apprehension about increasing the burden of physicians performing tracer injection twice." The mean ED was 14.0 ± 5.5 mSv (range, 3.9 to 25.2 mSv), which was higher than that reported in other countries. CONCLUSIONS: The ED of stress MPI radiopharmaceuticals in Japan is probably higher than the world standard because more than 50% of the facilities still use 201TlCl. We recommend revising the routine stress MPI protocol to reduce the effects of ionizing radiation.

Differences in accumulation and the transport mechanism of l- and d-methionine in high- and low-grade human glioma cells.

INTRODUCTION: Although [S-methyl-11C]-labeled L-methionine and D-methionine (11C-L-MET and 11C-D-MET) are useful radiotracers for positron emission tomography imaging of brain tumors, it is not known whether the accumulation and transport mechanisms underlying uptake of 11C-D-MET and 11C-L-MET are the same. 11C-L-MET is mainly taken up by the amino acid transport system L. We evaluated accumulation and the transport mechanism of D-MET in high- and low-grade human glioma cells in vitro. METHODS: The expression of transport system genes in high- (A172 and T98G) and low-grade (SW1088 and Hs683) glioma cells was quantitatively analyzed. Accumulation of [S-methyl-3H]-L-MET (3H-L-MET) and [S-methyl-3H]-D-MET (3H-D-MET) in these cells was compared during 60min of incubation. The transport mechanism of 3H-L-MET and 3H-D-MET was investigated by incubating the cells with these compounds and examining the effect of the inhibitors 2-amino-2-norbornane-carboxylic acid or α-(methylamino) isobutyric acid. RESULTS: Absolute expression levels of system L and system alanine-serine-cysteine (ASC) in high-grade glioma cells were higher than in low-grade cells. In high-grade glioma cells, expression of system ASC genes was higher than that of system L genes. 3H-D-MET, which is transported by systems L and ASC, accumulated at higher levels than 3H-L-MET at all incubation times because 3H-D-MET is more sensitive to system ASC than 3H-L-MET. Conversely, in low-grade glioma cells with lower expression of system L and ASC, 3H-D-MET accumulated at higher levels than 3H-L-MET in early incubation times because 3H-D-MET may be more sensitive to system ASC than system L. CONCLUSION: 3H-D-MET was mainly transported by systems L and ASC and sensitive to system ASC, whereas 3H-L-MET was transported by system L in human glioma cells. In vitro, the accumulation of 3H-D-MET was significantly higher than that of 3H-L-MET during the entire incubation time in high-grade glioma cells, and in early incubation times in low-grade glioma cells.

Unusually increased metaiodobenzylguanidine uptake in a gastrointestinal stromal tumor of the stomach.

A 70-year-old woman with a submucosal gastric tumor was referred to our hospital for surgical treatment. Upon examination, it was found that she had hypertension, and abdominal computed tomography revealed swelling on both adrenal glands. The patient was examined with gamma camera imaging and iodine-123 metaiodobenzylguanidine (MIBG), because her hypertension was thought to be due to a suspected adrenomedullary tumor. The planar image showed an unexpected abnormal uptake of MIBG in the upper abdomen. On single-photon emission computed tomographic images, the area of abnormal tracer uptake was thought to correspond to the known gastric tumor. The surgical procedure and histological assessments revealed that the gastric tumor was a gastrointestinal stromal tumor (GIST). MIBG can accumulate in GISTs as well as in neuroendocrine tumors of the medulla of the adrenal glands. Although the cause of radiolabeled MIBG uptake in GISTs is uncertain, further studies are necessary to establish the significance of MIBG scintigraphy in GIST imaging.

[Granular cell tumor in the mediastinum; report of a case].

Granular cell tumor is found in various organs but is rare in the mediastinum. We report a case of 21-year-old woman with a granular cell tumor in the left upper mediastinum. Chest computed tomography (CT) showed a 30 x 20 mm well circumscribed tumor in the left upper mediastinum. Tumor resection was performed. It was found that the tumor involved the sympathetic nerve. Histopathologically, the tumor consisted of cells with eosinophilic granules and diagnosed as a granular cell tumor.

The cutoff value of aldosterone-to-renin ratio for the diagnosis of primary aldosteronism in patients taking antihypertensive medicine.

BACKGROUND: Primary aldosteronism (PA) may account for as much as 6-20% of cases of refractory hypertension referred to hypertension clinics. Because antihypertensive agents affect the physiologic renin-angiotensin-aldosterone system, screening diagnostic tests for PA are generally performed after antihypertensive agents are discontinued. However, such tests can be dangerous for patients with severe hypertension or other cardiovascular complications. However, a reliable cutoff value for the aldosterone-to-renin ratio (ARR) has not been established, especially for Asians, including the Japanese. METHOD: Fifty-five consecutive patients with clinically suspected PA were evaluated from July 10, 2001, to March 1, 2005, at the National Cardiovascular Center in Japan. Every referred patient was screened prospectively for PA with the ARR at the outpatient clinic. The patients tested continued to be treated with a variety of antihypertensive agents. We reviewed the sensitivity, specificity, and accuracy of the ARR without modifying the antihypertensive agents. The diagnosis of PA was established with the results of both abdominal computed tomography and adrenal scintigraphy. RESULTS: Of the 55 patients, 27 were found to have PA, including adrenal adenoma (n = 18) and bilateral adrenal hyperplasia (n = 9). The mean ARR of patients with PA was significantly higher than that of patients without PA. By assuming a cutoff value of the ARR >or= 69 calculated from the receiver operating characteristics curve, the highest sensitivity (81%), specificity (82%), positive-predictive value (81%), and negative-predictive value (81%) were obtained. CONCLUSION: The data suggest that an ARR >or= 69 strongly indicates PA in Japanese patients with hypertension being treated with antihypertensive agents.

A case of malignant pheochromocytoma with early intense uptake and immediate rapid washout of 99mTc-tetrofosmin characterizing the overexpression of anti-apoptotic Bcl-2.

Defective apoptotic program due to the overexpression of the anti-apoptotic Bcl-2 protein of the outer mitochondrial membrane may be a cause of the poor response of malignant pheochromocytoma to 131I-MIBG therapy. We report a case of malignant pheochromocytoma which showed early intense uptake and immediate rapid washout of 99mTc-tetrofosmin characterizing the overexpression of anti-apoptotic Bcl-2 and which was refractory to 131I-MIBG therapy.

Renal function in patients with abdominal aortic aneurysm. Comparison with hypertensive patients.

AIMS: Renal dysfunction occurs occasionally after the repair of abdominal aortic aneurysm (AAA), and preoperative renal function is considered as one of the potential causes. The present study was designed to evaluate and compare renal function and risk factors of AAA patients with those of hypertensive patients. METHODS: We prospectively examined 95 patients with AAA and 72 patients with essential hypertension (HT) without other cardiovascular diseases (CVD). Renal function, urinary albumin excretion (UAE) and renal scintigraphy were compared. Kidney size was calculated using ultrasonography. RESULTS: Serum creatinine and creatinine clearance in AAA patients was worse than in HT patients. Smoking status was more apparent in AAA patients. Renal artery stenosis occurred in 8 patients with AAA. Renal scintigraphy showed normal function in 19%, hypofunction in 69% and severe dysfunction in 12% of the AAA patients, and normal function in 42% and hypofunction in 58% of the HT patients (p < 0.0001). Multivariate linear regression analysis showed that renal function was related to age, UAE, CVD, smoking status and kidney size for all patients, UAE, CVD, smoking status and kidney size for AAA patients, and age and kidney size for HT patients. CONCLUSION: Renal function of AAA patients was worse than HT patients without other CVD. The risk factors for renal dysfunction were different between AAA and HT patients. These preoperative conditions may relate to the postoperative renal dysfunction seen in AAA patients.

Detection of aortic graft infection by fluorodeoxyglucose positron emission tomography: comparison with computed tomographic findings.

OBJECTIVE: Radionuclide imaging with fluorodeoxyglucose (FDG) and positron emission tomography (PET) has been proposed for the identification of vascular graft infection; however, its accuracy has not been determined. We performed this prospective study to compare the usefulness of FDG-PET in the assessment of vascular graft infection relative to computed tomography (CT). METHODS: FDG-PET was performed for 33 consecutive patients with a suspected arterial prosthetic graft infection. The PET images were then assessed visually in terms of the density of uptake. In cases with positive uptake, the pattern of accumulation was also defined, such as focal or diffuse uptake. We compared the diagnostic efficiency of PET with contemporaneous CT in detection of infection of the arterial prosthetic graft. RESULTS: On the basis of the surgical, microbiological, and clinical follow-up findings, the aortic grafts were considered infected in 11 patients and not infected in 22 patients. Although the sensitivity of PET (91%) was higher than that of CT (64%), its specificity (64%) was lower than that of CT (86%). When focal uptake was set as the positive criterion in FDG, the specificity and positive predictive value of PET for the diagnosis of aortic graft infection improved significantly to 95% (P < .05 for both). CONCLUSIONS: Although both techniques are useful in evaluation of patients with suspected aortic graft infection, using the characteristic FDG uptake pattern described previously as a diagnostic criterion made the efficacy of FDG superior to that of CT in the diagnostic assessment of patients with suspected aortic graft infection.

Cardiac tumor as an initial manifestation of acquired immunodeficiency syndrome.

A cardiac tumor was the first manifestation of acquired immunodeficiency syndrome (AIDS) in a female patient in a state of severe immunodeficiency caused by human immunodeficiency virus (HIV) infection. The extensive cardiac and extracardiac involvement shown by various imaging modalities, including echocardiography and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), suggested that she was in the critical stage of non-Hodgkin's lymphoma (NHL). AIDS was treated by highly active-antiretroviral therapy and the NHL was treated by a combination of rituximab-cyclophosphamide-vincristine-doxorubicine-predonisolone. After 6 cycles of chemotherapy, she was in complete remission. Her cardiac tumor dramatically reduced in size and FDG-PET showed no positive uptake on whole body imaging. Generally, an AIDS-related cardiac tumor tends to be diagnosed at the late stage of the disease because of its nonspecific clinical findings, resulting in an extremely poor prognosis. In the present case, the cardiac tumor was detected by echocardiography and treated with appropriate chemotherapy. Early diagnosis and prompt treatment may improve a patient's prognosis.

Visualization of interscapular brown adipose tissue using (99m)Tc-tetrofosmin in pediatric patients.

UNLABELLED: Brown adipose tissue (BAT) is a site of nonshivering thermogenesis in mammals. The mitochondria of BAT operate in an uncoupled mode and increase fatty acid oxidation to produce heat at birth. Thus, the BAT of human infants and children contains more active mitochondria than that of adults. We surmised that because (99m)Tc-tetrofosmin can be absorbed by functional mitochondria in the myocardium and in tumor cells, it could reveal mitochondrial function in BAT. METHODS: Between January 1999 and December 2002, we retrospectively analyzed 385 consecutive studies of (99m)Tc-tetrofosmin uptake in pediatric patients with cardiac disorders. All patients with symmetric (99m)Tc-tetrofosmin accumulation within the neck and shoulder region according to planar images were selected, and the features of the uptake were analyzed. RESULTS: Increased symmetric (99m)Tc-tetrofosmin uptake in the interscapular BAT was a typical profile of 65 of the 385 patients (17%). The frequency of (99m)Tc-tetrofosmin uptake was significantly higher in winter than in spring or summer (P < 0.05) and prominent in newborns. The frequency peaked between 0 and 2 y of age and then declined with age. CONCLUSION: Gamma-camera imaging with (99m)Tc-tetrofosmin can reveal interscapular BAT distribution in infants and children in terms of mitochondrial activity.

Efficacy of screening for primary aldosteronism by adrenocortical scintigraphy without discontinuing antihypertensive medication.

BACKGROUND: Recently, it has been proposed that discontinuation of antihypertensive medications is not necessarily essential for the measurement of plasma aldosterone-to-renin ratios. We examined the efficacy of adrenocortical scintigraphy performed without modification of antihypertensive medications. METHODS: A retrospective study was conducted on 119 patients, in whom functional tests, anatomic studies, and adrenocortical scintigraphy were replete. Interrelationship among these was studied. The patients tested were being treated with antihypertensive medications from several classes including angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers, diuretics, and spironolactone. RESULTS: Significantly higher percentage of scintigraphy positive patients had plasma aldosterone-to-renin ratio of greater than 25:1. Positive rate for adrenal nodules by anatomic studies was significantly higher in the scintigraphy positive patients than in the scintigraphy negative patients. Finally, the percentage of patients who underwent adrenalectomy was higher in the scintigraphy positive patients than in the scintigraphy negative patients. CONCLUSIONS: We conclude that adrenocortical scintigraphy is a valid evaluation tool for primary aldosteronism and that the discontinuation of antihypertensive medications is not a requirement for this test.

Clinical significance of iodine-123-15-(p-iodophenyl)-3-R, S-methylpentadecanoic acid myocardial scintigraphy in patients with aortic valve disease.

The present study sought to determine whether myocardial fatty acid metabolism as assessed with iodine-123-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) scintigraphy is impaired in patients with aortic valve disease (AVD) and whether the degree of the metabolic abnormality reflects the severity of AVD. BMIPP scintigraphy was performed in 12 patients with aortic stenosis (AS), 14 patients with aortic regurgitation (AR), and 9 healthy volunteers, and from that the heart-mediastinum uptake ratio (H/M ratio) corrected by the left ventricular (LV) mass (U/Mass ratio) and the myocardial washout rate (WR) were obtained. The H/M ratio tended to be higher in patients than in healthy volunteers (3.3 +/- 0.7 for AS, 3.5 +/- 0.5 for AR, 3.0 +/- 0.3 for healthy volunteers), and the WR was significantly higher in patients than in healthy volunteers (42.8 +/- 9.1% for AS, 35.7 +/- 6.5% for AR, 19.6 +/- 9.1% for healthy volunteers, p<0.01). In the AS patients, the U/Mass ratio showed significant negative correlations (r=-0.79 to -0.90, all p<0.01) and the WR showed significant positive correlations (r=0.61 to 0.82, all p<0.01) with transaortic pressure gradient, LV wall thickness, and LV mass. Similarly, in AR patients these BMIPP parameters showed proportional changes to the LV volumes and LV mass (r=-0.79 to -0.83, all p<0.01 for U/Mass ratio, r=0.55 to 0.70, p<0.05 to <0.01 for WR). In the 9 patients who underwent aortic valve replacement, the BMIPP parameters tended to normalize with increasing U/Mass ratio (0.90 +/- 0.41 x 10(-2)/g to 1.34 +/- 0.59 x 10(-2)/g, p<0.05) and decreasing WR (41.9 +/- 8.8% to 35.4 +/- 9.2%, p<0.01) after surgery. Myocardial fatty acid metabolism as assessed with BMIPP scintigraphy was impaired in patients with aortic valve disease and the U/Mass ratio and WR reflect the severity. These parameters may be useful for the noninvasive assessment of the myocardial metabolic abnormalities caused by hemodynamic overload.