<Superscript>99m</Superscript>Tc-Hynic-annexin V imaging to evaluate inflammation and apoptosis in rats with autoimmune myocarditis

Inflammation and cell death are two important components of myocarditis. We evaluated the distribution of inflammation and apoptotic cell death in rats with autoimmune myocarditis using two radiotracers - technetium-99m Hynic-annexin V ((99m)Tc-annexin) as a marker of apoptotic cell death and carbon-14 deoxyglucose ((14)C-DG) as a marker of inflammation - in comparison with histologic findings. Three, 7 and 14 weeks after immunization with porcine cardiac myosin (acute, subacute, and chronic phases, respectively) (99m)Tc-annexin and (14)C-DG were injected. The uptake in the total heart was determined as the percentage of injected dose per gram (% ID/g) by tissue counting. Dual-tracer autoradiography with (99m)Tc-annexin and (14)C-DG was performed. The distribution of each of these agents was compared with the results of hematoxylin and eosin staining to identify areas of inflammation, and TUNEL staining to identify areas of apoptosis. Total cardiac uptake of (99m)Tc-annexin in the acute phase of myocarditis was significantly higher than that in normal rats (1.28%+/-0.30% vs 0.46%+/-0.01%; P<0.0001); it then decreased in the subacute phase and reached normal levels (0.56%+/-0.08% vs 0.60%+/-0.08%; P=NS). Total cardiac uptake of (14)C-DG in the acute phase of myocarditis was significantly higher than that in normal rats (2.78%+/-0.95% vs 1.02%+/-0.25%; P<0.0001); it then decreased in the subacute phase, but still remained higher than in controls (2.06%+/-0.52% vs 1.37%+/-0.46%; P<0.05). Using autoradiography and staining of tissue specimens, it was found that most histologic inflammatory foci corresponded to areas of high (14)C-DG uptake; some also corresponded to areas of high (99m)Tc-annexin uptake in the acute phase of myocarditis. (99m)Tc-annexin localization was strongly correlated with the number of TUNEL-positive cells (P<0.0001, r=0.83), but the uptake of (14)C-DG showed no relationship with it. There is a marked difference in the distribution of inflammation and apoptotic cell death in the myocardium of animals with immune myocarditis. These changes are mirrored by the localization of (14)C-DG and (99m)Tc-annexin. Sites of inflammation and zones of apoptotic cell death change over the course of immune myocarditis.     

A simplified method for preparation of 99mTc-annexin V and its biologic evaluation for in vivo imaging of apoptosis after photodynamic therapy.

Apoptosis is the likely mechanism behind the effects of chemotherapeutic and radiation treatments, rejection of organ transplants, and cell death due to hypoxic-ischemic injury. A simplified method capable of imaging apoptosis in living animals could have many applications leading to understanding of the involvement of apoptosis in biologic and therapeutic processes. To accomplish this goal we developed a method for the preparation of (99m)Tc-annexin V and evaluated its usefulness to detect apoptosis that occurs during tumor shrinkage after photodynamic therapy (PDT). PDT is a cancer treatment modality that leads to rapid induction of apoptosis both in vitro and in in vivo animal models. METHODS: A novel synthesis of (99m)Tc-annexin V was performed in a simple 1-pot procedure. Radiation-induced fibrosarcoma (RIF-1) tumors grown in C(3)H mice were treated with PDT, followed by injection of (99m)Tc-annexin V and measurement of its tumor uptake at 2, 4, and 7 h after PDT by autoradiography. RESULTS: The radiochemical purity of (99m)Tc-annexin V was >95%. At all time points, (99m)Tc-annexin V was clearly imaged in the PDT-treated tumors, whereas the untreated tumors showed no uptake of the radiolabeled compound. Histopathology and immunohistochemistry of PDT-treated tumors confirmed the evidence of apoptosis compared with untreated tumors. CONCLUSION: These data demonstrate the detection of apoptosis using (99m)Tc-annexin V in tumor tissue in living animals after PDT treatment. This novel technique could be used as a noninvasive means to detect and serially image tissues undergoing apoptosis after cancer treatment protocols in humans. Other potential applications of this technique could be the diagnosis of several human disorders, such as myocardial ischemia or infarct, rejection of organ transplantation, and neonatal cerebral ischemia.     

Structural requirements for in vivo detection of cell death with 99mTc-annexin V.

(99m)Tc-Annexin V is used to image cell death in vivo via high-affinity binding to exposed phosphatidylserine. We investigated how changes in membrane-binding affinity, molecular charge, and method of labeling affected its biodistribution in normal mice and its uptake in apoptotic tissues. METHODS: An endogenous Tc chelation site (Ala-Gly-Gly-Cys-Gly-His) was added to the N-terminus of annexin V to create annexin V-128. The membrane-binding affinity of annexin V-128 was then progressively reduced by 1-4 mutations in calcium-binding sites. In addition, mutations were made in other residues that altered molecular charge without altering membrane-binding affinity. All mutant proteins were labeled with (99m)Tc at the same N-terminal endogenous chelation site. Wild-type annexin V was also labeled with (99m)Tc after derivatization with hydrazinonicotinamide (HYNIC). Radiolabeled proteins were tested for biodistribution in normal mice and in mice treated to induce apoptosis of the liver. RESULTS: Comparison of (99m)Tc-annexin V-128 with (99m)Tc-HYNIC-annexin V showed that the protein labeled at the endogenous chelation site had the same or higher uptake in apoptotic tissues, while showing 88% lower renal uptake at 60 min after injection. The blood clearance of annexin V was unaffected by changes in either the membrane-binding affinity or the molecular charge. Kidney uptake was unaffected by changes in binding affinity. In marked contrast, uptake in normal liver and spleen decreased markedly as affinity decreased. The same pattern was observed in animals treated with cycloheximide to induce apoptosis. Control experiments with charge mutants showed that the effects seen with the affinity mutants were not due to the concomitant change in molecular charge that occurs in these mutants. CONCLUSION: (a) All four domains of annexin V are required for optimal uptake in apoptotic tissues; molecules with only 1 or 2 active domains are unlikely to be suitable for imaging of cell death in vivo. (b) Uptake in normal liver and spleen is specific (dependent on phosphatidylserine-binding affinity), whereas renal uptake is nonspecific. (c) (99m)Tc-Annexin V-128 detects cell death as well as (99m)Tc-HYNIC-annexin V, while showing 88% less renal retention of radioactivity due to much more rapid urinary excretion of radioactivity.     

Feasibility of 99mTc-annexin V for repetitive detection of apoptotic tumor response to chemotherapy: an experimental study using a rat tumor model.

Annexin V (annexin A5), a human protein with a high affinity for phosphatidylserine, labeled with (99m)Tc can detect apoptosis in vivo. In the repetitive detection of apoptosis with (99m)Tc-annexin V, however, the specific binding of annexin V to phosphatidylserine might affect the subsequent detection of apoptosis with this compound. To determine whether there is interference with repetitive doses of annexin V, we evaluated the effects of previous administration of cold annexin V on accumulation of (99m)Tc-annexin V in tumors in an experimental tumor model. METHODS: Rats bearing hepatoma received cyclophosphamide (150 mg/kg, intraperitoneally) 11 d after the tumor inoculation. Cold annexin V (20 microg/kg, intravenously) was administered 24 h before or after the cyclophosphamide treatment (n = 7/group). (99m)Tc-Annexin V was injected intravenously (radioactive dose, 5-23 MBq/kg; mass dose, 20 microg/kg), and radioactivity in tissues was determined 6 h later. RESULTS: Accumulation of (99m)Tc-annexin V in tumors was not significantly affected by previous treatment with cold annexin V before or after chemotherapy. CONCLUSION: These results demonstrate the feasibility of (99m)Tc-annexin V imaging for repetitive detection of apoptosis, which is highly required in the clinical setting.     

<Superscript>99m</Superscript>Tc-tetrofosmin or <Superscript>99m</Superscript>Tc-sestamibi for double-phase parathyroid scintigraphy?

Several years ago technetium-99m tetrofosmin was reported to localise parathyroid adenomas. The aim of this study was to compare the sensitivity of this radiopharmaceutical with that of (99m)Tc-sestamibi using a double-phase parathyroid scintigraphy protocol. Scans of 12 patients were evaluated visually and lesion to thyroid ratios were calculated. Nine of the patients were subsequently operated on; a total of eight parathyroid adenomas or hyperplastic glands were histologically confirmed in seven of the patients, while in one patient a parathyroid carcinoma was histologically proven. All of these patients had positive (99m)Tc-sestamibi scintigrams, whereas only two (99m)Tc-tetrofosmin scintigrams were positive. With (99m)Tc-sestamibi there was a significant increase in the lesion to thyroid ratio from 10 min to 90 min and 150 min p.i. which was not seen on scintigraphy with (99m)Tc-tetrofosmin. This makes (99m)Tc-tetrofosmin less suitable for double-phase parathyroid scintigraphy.     

Comparative study of rest technetium-99m sestamibi SPET and low-dose dobutamine stress echocardiography for the early assessment of myocardial viability after acute myocardial infarction: importance of the severity of the infarct-related stenosis

Rest technetium-99m sestamibi single-photon emission tomography (SPET) has been shown to under-estimate viability in some patients with chronic ischaemic myocardial dysfunction. The present study was designed to appraise the value of^99mTc-sestamibi as a viability tracer in patients with a recent myocardial infarction and to determine factors that might influence its accuracy in assessing infarct size. Therefore, rest^99mTc-sestamibi SPET, low-dose dobutamines stress echocardiography and quantitative coronary angiography were performed in 51 patients with a recent myocardial infarction. Perfusion activity and regional wall motion were scored semi-quantitatively using the same segmental division of the left ventricle. Assessment of^99mTc-sestamibi uptake as a marker of viability was performed by comparing a binary uptake score (viable=>50% vs necrotic =50% of the maximal tracer activity) with a binary wall motion classification during low-dose dobutamine infusion (viable=normal/hypokinetic vs necrotic=akinetic/dyskinetic). Infarct size, expressed as the number of segments with evidence of necrotic tissue, was significantly greater in the scintigraphic study than in the echocardiographic study (2.8±1.5 vs 2.2±1.3,P=0.006). This overestimation of infarct size by^99mTc-sestamibi was present only in patients with a severe infarct-related stenosis (% diameter stenosis 65%–100%) and particularly those with late reperfusion therapy (time delay 180 min). In patients without a severe infarct-related stenosis,^99mTc-sestamibi was able to accurately distinguish viable from necrotic segments. Thus, rest^99mTc-sestamibi scintigraphy early after acute myocardial infarction may underestimate residual viability within the infarct region, particularly in patients with low flow state coronary anatomy, as a result of a severe infarct-related stenosis and/or late reperfusion therapy.This paper was presented in part at the European Nuclear Medicine Congress, Brussels, Belgium, August 1995     

Quantification of myocardial infarct size by technetium-99m pyrophosphate single photon emission computed tomography

Myocardial infarct size in 41 patients with the first attack of acute transmural myocardial infarction (MI) was assessed by technetium-99m pyrophosphate single photon emission computed tomography (99mTcPYP-SPECT). A ratio of the number of voxels of 99mTcPYP uptake into the infarct area to that into the thorax was calculated as a parameter of MI size. The ratio was positively correlated with both peak CPK activity (r = 0.53, p less than 0.005, n = 24) and extent score in 201TI-SPECT (r = 0.70, p less than 0.005, n = 14) significantly in patients with anterior MI but not in patients with inferior MI. There was also significant negative correlation between the ratio and the left ventricular ejection fraction (LVEF) measured by RI angiography in both acute (r = -0.67, p less than 0.005, n = 18) and chronic (r = -0.75, p less than 0.005, n = 25) phases in patients with anterior MI. Recovery in LVEF at chronic phase was noted in patients with small anterior MI but not with large anterior MI. 8 of 14 patients with inferior MI had right ventricular MI, that might have affected evaluation of MI size and resulted in no correlation between variables. It was suggested that 99mTcPYP-SPECT was a useful method to evaluate MI size and to predict prognosis of cardiac function in patients with anterior MI but not in patients with inferior MI.     

Monitoring the protective effects of minocycline treatment with radiolabeled annexin V in an experimental model of focal cerebral ischemia.

Minocycline is an antibiotic now recognized to have antiapoptotic and antiinflammatory properties. Because of these properties, minocycline may be of benefit in reducing neuronal apoptosis from ischemia and subsequent postischemic inflammation if administered soon after a stroke. We now explore the feasibility of using (99m)Tc-annexin V, an in vivo marker of apoptosis, with SPECT to monitor the antiapoptotic effects of minocycline therapy. METHODS: CB6/F1 adult male mice underwent unilateral distal middle cerebral artery occlusion (dMCA) occlusion and were imaged and sacrificed at 1, 3, 7, or 30 d after injury. Animals were given minocycline (or vehicle) 30 min and 12 h after dMCA occlusion and then given 22.5 mg/kg twice daily for up to 7 d. Before imaging, behavioral tests were performed to evaluate the neurologic function. After imaging, brains were collected for histology and assessed for the degree of apoptosis and microglial activation. RESULTS: (99m)Tc-Annexin V uptake in injured hemispheres was significantly decreased 2- to 3-fold by minocycline at all time points. Minocyline reduced infarct size as seen histologically and improved behavioral indices as late as 30 d. Infarct volume as seen histologically correlated with radiolabeled annexin V uptake seen by SPECT. In situ fluorescent microscopy demonstrated that annexin V bound primarily to neurons at 1 and 3 d, with a shift toward microglia by 7 and 30 d. CONCLUSION: We found that minocycline significantly reduces neuronal apoptosis and infarct size and improves neurologic outcome in mice after acute focal cortical ischemia.     

Preoperative localization and radioguided parathyroid surgery.

Clinical or subclinical hyperparathyroidism is one of the most common endocrine disorders. Excessive secretion of parathyroid hormone is most frequently caused by an adenoma of >or=1 parathyroid gland. Unsuccessful surgery with persistent hyperparathyroidism, due to inadequate preoperative or intraoperative localization, may be observed in about 10% of patients. The conventional surgical approach is bilateral neck exploration, whereas minimally invasive parathyroidectomy (MIP) has been made possible by the introduction of (99m)Tc-sestamibi scintigraphy for preoperative localization of parathyroid adenomas. In MIP, the incision is small, dissection is minimal, postoperative pain is less, and hospital stay is shorter. Localization imaging techniques include ultrasonography, CT, MRI, and scintigraphy. Parathyroid scintigraphy with (99m)Tc-sestamibi is based on longer retention of the tracer in parathyroid than in thyroid tissue. Because of the frequent association of parathyroid adenomas with nodular goiter, the optimal imaging combination is (99m)Tc-sestamibi scintigraphy and ultrasonography. Different protocols are used for (99m)Tc-sestamibi parathyroid scintigraphy, depending on the institutional logistics and experience (classical dual-phase scintigraphy, various subtraction techniques in combination with radioiodine or (99m)Tc-pertechnetate). MIP is greatly aided by intraoperative guidance with a gamma-probe, based on in vivo radioactivity counting after injection of (99m)Tc-sestamibi. Different protocols used for gamma-probe-guided MIP are based on different timing and doses of tracer injected. Gamma-probe-guided MIP is a very attractive surgical approach to treat patients with primary hyperparathyroidism due to a solitary parathyroid adenoma. The procedure is technically easy, safe, with a low morbidity rate, and has better cosmetic results and lower overall cost than conventional bilateral neck exploration. Specific guidelines should be followed when selecting patients for gamma-probe-guided MIP.     

Combined use of 99mTc-sestamibi and 99mTc-V-DMSA in the assessment of chemotherapy effectiveness in patients with multiple myeloma.

This study determined the role of the combined use of (99m)Tc-sestamibi and (99m)Tc-pentavalent dimercaptosuccinic acid (V-DMSA) scintigraphy in evaluating the effectiveness of chemotherapy in patients with multiple myeloma. METHODS: In 20 patients with multiple myeloma who had received or were receiving chemotherapy, (99m)Tc-sestamibi and (99m)Tc-V-DMSA scanning was performed to evaluate the effectiveness of chemotherapy. RESULTS: In group A (11 patients with active disease), 42 (99m)Tc-sestamibi-positive lesions were found. Thirty-seven of those lesions were also positive for (99m)Tc-V-DMSA uptake, as were 16 additional lesions (nonactive) (NAL). Thus, in group A, the total number of positive lesions (TPL) detected was 58 and the NAL/TPL ratio was 16:58. In group B (9 patients in remission), 5 (99m)Tc-sestamibi-positive lesions were found. A further 22 lesions were also positive for (99m)Tc-V-DMSA uptake. Thus, in group B, the NAL/TPL ratio was 22:27. Therefore, the NAL/TPL ratios considered to represent effectively treated lesions were 27.6% and 81.5% for groups A and B, respectively. CONCLUSION: Combined use of the 2 agents allows the effectiveness of chemotherapy to be evaluated through a comparison of NAL and TPL multiple myeloma lesions even in the absence of a baseline study.     

Efficacy of 99mTc-sestamibi SPECT/CT for minimally invasive parathyroidectomy: comparative study with 99mTc-sestamibi scintigraphy, SPECT, US and CT

Purpose

We evaluated the efficacy of ^99mTc-sestamibi SPECT/CT for planning minimally invasive parathyroidectomy (MIP), comparing with dual phase ^99mTc-sestamibi scintigraphy, ^99mTc-sestamibi SPECT and conventional imaging (US and CT).

Methods

Thirty-one patients (M:F?=?10:21, range 35?C78?years old) who showed high serum parathyroid hormone (intact PTH) level were included. ^99mTc-sestamibi scintigraphy was performed 15 and 150?min after injection of ^99mTc-sestamibi (555?MBq), and ^99mTc-sestamibi SPECT/CT was obtained just after the delayed scan. Comparison study between imaging modalities was done by patient-based and lesion location-based analysis. The location of the lesion was confirmed by the operative finding. An operation was performed in 24 patients. Seven patients had normal ^99mTc-sestamibi SPECT/CT, and followed for more than 6?months after SPECT/CT.

Results

Among 24 patients, parathyroid adenoma was detected in 19 patients and the other 5 had parathyroid hyperplasia (total 35 lesions). ^99mTc-sestamibi scintigraphy detected abnormal uptake in 15 patients with 24 lesions. Conventional imaging identified abnormal findings in 17 patients with 27 lesions. SPECT detected abnormal findings in 18 patients with 27 lesions. SPECT/CT identified abnormal findings in 24 patients with 35 lesions. SPECT/CT demonstrated 100?% sensitivity in a patient-based analysis. SPECT/CT exhibited significantly better sensitivity than ^99mTc-sestamibi scintigraphy, SPECT and conventional imaging (p?<?0.05). All lesion location was correctly identified to perform MIP. The final clinical diagnosis of 7 normal SPECT/CT patients was secondary hyperparathyroidism on 6?months follow-up.

Conclusions

We correctly identified the precise location of parathyroid adenomas or hyperplasia by ^99mTc-sestamibi SPECT/CT which was helpful to perform MIP.     

Technetium-99m sestamibi leg scintigraphy for non-invasive assessment of propionyl-l-carnitine induced changes in skeletal muscle metabolism

Carnitine derivatives, such as propionyl-l-carnitine (PLC), have been shown to improve walking distance in patients with obstructive peripheral artery disease (PAOD). The aim of this study was to ascertain whether technetium-99m sestamibi leg scintigraphy may be a useful tool in the evaluation of changes in skeletal muscle metabolism induced by chronic therapy with PLC. Twenty patients with clinical and instrumental evidence of PAOD were randomly assigned to a 3-month period of therapy with either PLC or placebo. Rest^99mTc-sestamibi leg scintigraphy and echo-Doppler sonography were performed on all subjects immediately before and upon completion of the treatment period. At the end of the protocol the following results were observed in patients who underwent PLC administration: (a) a significant increase in both thigh and calf^99mTc-sestamibi uptake, in comparison with baseline values (P<0.001); (b) the absence of statistically significant modifications of Doppler blood flow indices of the lower limbs. In conclusion, after chronic administration of PLC, a significant increment in skeletal muscle uptake of^99mTc-sestamibi was demonstrated without any apparent change in regional blood flow. This fact, if proven in further studies, may suggest a role for this tracer as a non-invasive probe of tissue bioenergetics.     

99mTc-sestamibi uptake and histological malignancy grade in invasive breast carcinoma

The aim of this study was to investigate whether there is a correlation between (99m)Tc-sestamibi uptake and histological malignancy grade in breast carcinoma. Such a correlation could, prior to surgery and histopathological analysis, facilitate selection of patients who need adjuvant therapy. Ninety-six patients with mammographically determined lesions and/or a palpable tumour suspected for malignancy underwent (99m)Tc-sestamibi scintimammography prior to surgery. The final diagnosis was determined by histopathological examination. Benign lesions, cancer in situ and tumours located medially in the breast were excluded. Fifty-three invasive cancer lesions in 53 patients were finally included in the study. Planar scintigraphic breast imaging included two prone lateral projections and one anterior supine projection taken 10 min after injection of 700 MBq (99m)Tc-sestamibi. Focal (99m)Tc-sestamibi uptake in breast lesions was used as the scintigraphic criterion of abnormality. Tumour to background ratios were calculated with partial volume compensation, and histological malignancy grading was performed according to the Elston classification. A correlation was found between (99m)Tc-sestamibi uptake and histological malignancy grade in invasive breast carcinomas ( P相似文献   

Limited sensitivity of parathyroid imaging with (99m)Tc-sestamibi/(123)I subtraction in an endemic goiter area.

Double-phase single-tracer scintigraphy with (99m)Tc-sestamibi is now generally used for parathyroid imaging but, at least in endemic goiter areas, complementary thyroid scintigraphy is recommended. Although (123)I-sodium iodide is considered to be the optimal thyroid agent, it is hardly ever used because of high costs and logistic difficulties. Our study presents the results of using the (99m)Tc-sestamibi/(123)I subtraction technique in a region with a high goiter prevalence. Special attention was paid to the changes in sensitivity and specificity and their relationship to thyroid volume as well as to autonomous and nodular thyroid disease. METHODS: One hundred three scintigraphic parathyroid examinations on 96 patients were included in this study. Fifty-eight of all patients had concomitant morphologic or functional alterations of the thyroid. Initially, 10 MBq (123)I-sodium iodide were injected. Then, 150 MBq (99m)Tc-sestamibi were administered after 3-5 h, followed by planar scintigraphic imaging of the neck and upper chest region using a double-isotope technique. RESULTS: An area with increased tracer uptake on the subtraction image was found in 44 cases. Forty-three of them proved to be true-positive. No suspicious lesions were detected scintigraphically on the remaining 59 examinations. However, histologic examination revealed a parathyroid adenoma or hyperplasia in 11 of these cases. The mean parathyroid volume of these false-negative patients was 0.9 mL. Secondary hyperparathyroidism with multiple enlarged parathyroid glands was found in 4 of these cases. The sensitivity of the parathyroid scintigraphy was 80% (43/54) and the specificity was 98% (48/49). There was a distinct difference in the sensitivity between the subgroups with thyroid volumes of >15 mL and <15 mL (76% vs. 88%), although the resected parathyroid glands had a similar size in both subgroups. The specificity was 97% and 100%, respectively. No significant difference in the sensitivity and specificity was observed between the subgroups with and without morphologic or functional alterations of the thyroid (80% vs. 79% and 96% vs. 100%, respectively). CONCLUSION: The sensitivity of parathyroid imaging with (99m)Tc-sestamibi/ (123)I subtraction depends mainly on the thyroid and parathyroid volumes rather than on the presence of nodular or autonomous thyroid disease.     

Preoperative parathyroid gland localization with technetium-99m sestamibi in secondary hyperparathyroidism

Technetium-99m sestamibi scintigraphy has become a valuable tool in locating parathyroid glands in patients with primary hyperparathyroidism. The aim of this study was to evaluate its usefulness in secondary hyperparathyroidism. Twenty patients were injected intravenously with 740 MBq of ^99mTc-sestamibi and images were obtained at 15 min and 2 h post injection. All patients underwent parathyroid ultrasonography (US) as well as bilateral surgical neck exploration and 64 parathyroid glands were removed. US revealed at least one enlarged gland in 15/20 patients (75%), while ^99mTc-sestamibi scintigraphy showed focal areas of increased uptake in at least one gland in 17/20 patients (85%). When imaging results for all glands were evaluated according to surgical results, sensitivity was 54% for parathyroid scintigraphy and 41% for US, and specificity was 89% for both imaging techniques. There was a discrepancy between the two imaging modalities in 28 glands (35%). The mean surgical weight of US-positive glands (1492±1436 mg) was significantly higher than that of US-negative glands (775±703 mg) (P<0.05). However, there were no significant differences in weight between sestamibi-positive and sestamibi-negative glands. When only sestamibi-positive glands were considered, a positive correlation between uptake and weight was found (r=0.4, P<0.05). In conclusion, parathyroid US and ^99mTc-sestamibi scintigraphy are complementary imaging techniques in the preoperative localization of abnormal parathyroid glands in patients with secondary hyperparathyroidism. The limited sensitivity of the techniques means that patients will still require bilateral neck exploration; therefore routine preoperative parathyroid scanning in renal patients is not justified. Received 1 June and in revised form 6 August 1997     

Comparison and histopathological correlation of three parathyroid imaging methods in a population with a high prevalence of concomitant thyroid diseases

The aim of this prospective study was to evaluate the diagnostic utility of a technetium-99m sestamibi dual-phase protocol enhanced by single-photon emission tomography (SPET) and semiquantitative analysis in comparison to established preoperative staging procedures in patients with primary hyperparathyroidism. Twenty-eight (50%) out of 56 patients had superimposed thyroid disease, and 12 patients had previously undergone neck surgery. Visual and semiquantitative analysis of planar^99mTc-sestamibi dual-phase imaging, SPET of the delayed phase, ultrasonography, and thallium-201 chloride-technetium-99m pertechnetate subtraction scintigraphy was further correlated with the histopathological examination of the surgical specimens.^99mTc-sestamibi dual-phase imaging achieved the highest sensitivity for side localization and precise localization compared with²⁰¹Tl-^99mTc subtraction scintigraphy and ultrasonography, but the differences reached statistical significance only in comparison to ultrasonography. Semiquantitative analysis did not enhance sensitivity. Adenoma detection by^99mTc-sestamibi dual-phase imaging was only correlated to serum calcium levels and osteocalcin, not to cell density or oxyphil cell count (SPET yielded additional information for the exact topographical localization of the parathyroid tumour in 22 (39%) patients with superimposed thyroid disease or previous neck surgery but did not enhance the overall detection rate.     

Detection of apoptotic tumor response in vivo after a single dose of chemotherapy with 99mTc-annexin V.

Annexin V, a human protein with a high affinity for phosphatidylserine, has been labeled with (99m)Tc to detect apoptosis in vivo. To determine the effectiveness of imaging with this agent as a reflection of the degree of apoptosis after the first dose of chemotherapy, we studied rats with an engrafted hepatoma. METHODS: Annexin V was labeled with (99m)Tc (specific activity, 3.0 MBq/ micro g protein). Eleven days after being inoculated with allogenic hepatoma cells (KDH-8) in the left calf muscle, the rats were randomized to receive a single dose of cyclophosphamide (150 mg/kg intraperitoneally) or to serve as controls. (99m)Tc-annexin V was injected 20 h later. Radioactivity in tissues was determined 6 h after injection of (99m)Tc-annexin V. Tumor uptake of (14)C-iodoanitpyrine was determined as a marker of tumor blood flow. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) of tissue harvested at necropsy was performed to detect apoptosis in the tumor. RESULTS: Cyclophosphamide treatment significantly increased the tumor uptake (percentage activity of injected dose per gram of tissue after normalization to the animal's weight [%ID/g/kg]) of (99m)Tc-annexin V (0.070 +/- 0.007 %ID/g/kg for treated rats and 0.046 +/- 0.009 %ID/g/kg for controls, P < 0.001). (14)C-iodoantipyrine uptake was similar in the treated and untreated groups. The number of TUNEL-positive cells in the tumor was significantly larger in the treated rats (297.70 +/- 50.34 cells/mm(2)) than in the control rats (168.45 +/- 23.60 cells/mm(2), P < 0.001). Tumor uptake of (99m)Tc-annexin V correlated with the number of TUNEL-positive cells in the tumor (r = 0.712; P < 0.001). CONCLUSION: Tumor uptake of (99m)Tc-annexin V was significantly increased by a single dose of cyclophosphamide treatment, and the increase was concordant with the number of TUNEL-positive cells in the tumor. The current results are suggestive of the utility of (99m)Tc-annexin V as a noninvasive means to assess tumor response, although further testing, including clinical evaluation, is required.     

Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure.

Apoptosis, or programmed cell death (PCD), contributes to the decline in ventricular function in heart failure. Because apoptosis comprises a programmed cascade of events, it is potentially reversible, and timely intervention should delay the development of cardiomyopathy. (99m)Tc-Labeled annexin A5 has successfully been used for the noninvasive detection of PCD in myocardial infarction and heart transplant rejection. The present study evaluated the role of annexin A5 imaging for detection of PCD in heart failure patients. METHODS: Annexin A5 imaging was performed on 9 consecutive heart failure patients with advanced nonischemic cardiomyopathy (dilated, n = 8; hypertrophic, n = 1) and in 2 relatives having the same genetic background as the hypertrophic cardiomyopathy patient but no heart failure. RESULTS: Four of the patients with dilated cardiomyopathy and the 1 with hypertrophic cardiomyopathy and heart failure showed focal, multifocal, or global left ventricular uptake of annexin A5. No uptake was visualized in the remaining 4 patients or in the 2 controls. All cases showing annexin A5 uptake within the left ventricle experienced significant reduction in left ventricular function or functional class. In cases with no annexin A5 uptake, left ventricular function and clinical status remained stable. CONCLUSION: These data indicate the feasibility of noninvasive PCD detection with annexin imaging in heart failure patients. Annexin A5 uptake is associated with deterioration in left ventricular function, and this association may lend itself to the development of novel management strategies.     

Technetium-99m sestamibi scintigraphy for the assessment of lower extremity ischaemia in peripheral arterial disease

Technetium-99m sestamibi was used for functional investigation of the muscle perfusion of lower extremities in 35 patients with peripheral vascular disease. The aim was to test what useful information could be obtained by additional imaging of the legs in patients referred for risk stratification with dipyridamole myocardial scanning. Posterior images were acquired over the thighs and calves after postocclusive reactive hyperaemia and at rest. Inter- and intraextremity ratios and differences between the stress and rest data were used for the assessment of abnormal circulation. Arteriography was performed in every case, and surgical procedures or transluminal angioplasty in 31 patients. To estimate diagnostic accuracy, the results of^99mTc-sestamibi scintigraphy were compared with those of angiography and the functional consequences of revascularization procedures. The sensitivity and specificity of^99mTc-sestamibi scintigraphy were 55% and 25%, respectively, with an overall accuracy of 50%. Apparently methodological error was not responsible for these poor results. Instead, a paradoxically high uptake of the radiopharmaceutical in muscles supplied by significantly stenosed vessels was identified as the main source of both false-negative and false-positive results. This phenomenon resembles the findings of a previous study involving delayed administration of thallium-201 after exercise. In conclusion,^99mTc-sestamibi scintigraphy has not proved sufficiently reliable to help in the management strategy for patients with peripheral vascular disease.     

Assessment of contractile response to dobutamine stress by means of ECG-gated myocardial SPECT: Comparison with myocardial perfusion and fatty acid metabolism

The present study assessed left ventricular performance during dobutamine stress measured using gated SPECT, and compared the results to myocardial perfusion and fatty acid metabolism. METHODS: Thirty-six patients with myocardial infarction given (99m)Tc-sestamibi or (99m)Tc-tetrofosmin were examined by gated SPECT at rest and during dobutamine stress (4-20 microg x kg(-1) x min(-1)). After acquiring data at the highest dose, 201TlCl was injected and dual-isotope SPECT was performed to assess myocardial ischemia. Thirty of 36 patients also underwent myocardial SPECT with 123I-BMIPP. Regional wall motion changes during dobutamine infusion were determined from the gated SPECT data and classified as: (1) Improvement, (2) Worsening, (3) No change, and (4) Biphasic response. For myocardial segments of each infarct area, stress 201Tl, rest (99m)Tc and (123)I-BMIPP uptakes were graded on a five-point scoring system of defects from 0 (normal) to 4 (grossly defective). RESULTS: Rest 99mTc defect score index (DSI) in No change area was significantly higher than that in Biphasic area. The ADSI (stress 201Tl - rest (99m)Tc) in Biphasic area was significantly higher than those in Improvement and No change areas. The deltaDSI (BMIPP - (99m)Tc) in Worsening area tended to be higher than that in No Change area. Conclusions: Regional contractile response to dobutamine stress analyzed by gated SPECT showed that the response in-myocardial infarct areas could be classified by rest and stress myocardial perfusion and BMIPP accumulation.