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1.
Indium-111-labeled monoclonal antimyosin Fab has been used to image myocardial infarction, myocarditis and cardiac transplant rejection with localization in myocytes that have suffered irreversible loss of cell membrane integrity. Technical factors potentially limiting clinical usefulness of 111In antimyosin include dosimetry (72 hr half-life of 111In), slow blood clearance of antibody proteins delaying optimal imaging to 24 to 48 hr postinjection and nontarget organ uptake. Therefore, two new antimyosin imaging agents experimentally shown to potentially improve dosimetry, shorten time from injection to imaging or decrease nonspecific cell binding were evaluated in a primate cardiac transplant model. The two agents evaluated were polylysine 111In-antimyosin (0.023 mg Fab modified with a 3.3 kd polymer of polylysine and labeled with 111In) and 99mTc-antimyosin (0.5 mg Fab' antimyosin labeled using the RP-1 ligand technique). A total of eight baboons were studied: three with heterotopic (cervical) xenographs, three with orthotopic allographs and two control animals. Each animal was injected first with 12-23 mCi of 99mTc-RP-1 antimyosin and 5-16 hr after completion of imaging, was injected with 0.72-1.88 mCi of 111In-polylysine antimyosin (PIs) and reimaged 12-48 hr later. The imaging results were compared to the histology of the animals. Biexponential curves were fit to the blood sample data and rate constants were determined and expressed as T1/2 values. There were no significant differences between the two agents in either the early fast components or the late slow components. On planar imaging, there was blood-pool activity at 10-12 hr postinjection of both agents, but by 16-24 hr postinjection, blood pool was negligible on the 111In-PIs scans. Both agents were concentrated in the rejected cardiac tissue. The slow blood-pool clearance combined with the 6 hr half-life of 99mTc-RP-1 AMA make this agent less promising for detection of diffuse myocardial uptake than 111In Fab modified with polylysine.  相似文献   

2.
Monoclonal 111In antimyosin Fab is a marker for myocytes which have lost their membrane integrity. Because of the slow blood pool clearance of the radiopharmaceutical, imaging is usually started 24-48 h after intravenous injection of 74 MBq of the tracer. This long postinjection interval restricts its utilization in the primary diagnosis of acute myocardial infarction. However, antimyosin may help to differentiate between necrotic and viable myocardium in the subacute stage of incomplete myocardial infarction. Serial endomyocardial biopsy for early detection of transplant rejection after heart transplantation may be partially replaced or supplemented by antimyosin scintigraphy. The compound may facilitate the diagnosis of myocarditis. Other potential indications may be prognostic assessment of dilated cardiomyopathy, monitoring cardiotoxic side-effects of chemotherapeutics, recognition of cardiac contusion as well as diagnosis of rhabdo- and leiomyosarcoma. In specific clinical situations 111In antimyosin Fab immunoscintigraphy may provide valuable diagnostic information.  相似文献   

3.
Technetium-99m antimyosin (99mTc-AM) antibody imaging may have significant advantages over indium-111 antimyosin in clinical practice. The purpose of this study was to determine the human biodistribution, the safety profile and the sensitivity of99mTc-AM (3–48) imaging in the detection of both Q-wave and non-Q-wave myocardial infarction (MI). Biodistribution and safety parameters were mainly determined in 12 normal healthy volunteers while 40 patients with proven MI (22 Q-wave, 18 non-Q-wave) were injected with99mTc-AM (20–25 mCi) between 5 h and 7 days after the onset of acute chest pain. Three standard planar views were performed at 6 h and at 24 h post injection. Both sets of images were completed in 33 patients while two patients were imaged only at 6 h, three patients only at 18 h and one at 18 and 24 h. One patient was not imaged. Vital signs and ECG were recorded and blood samples for haematology, biochemistry and human antimurine antibodies (HAMA) and urinalysis were obtained in all volunteers and patients. No serious adverse reactions or side-effects attributable to99mTc-AM have been reported. No volunteers or patients developed allergic reactions or significant increases in HAMA titres. Reading of99mTc-AM imaging was performed by two blinded experienced observers. The sensitivity of99mTc-AM in the detection of MI was 100% (21/21) for Q-wave and 83.3% (15/18) for non-Q-wave infarctions. The overall sensitivity was 92.3% (36/39). The three false-negative cases were inferoposterior MI. A certain degree of uptake focalization was seen in 26 out of 35 (74.2%) at 6 h. At 24 h, two patients (5.8%) did not show99mTc-AM uptake while 22 (64.7%) showed intense focal uptake, seven (20.6%) moderate uptake and 3 (8.9%) slight uptake. It is concluded that99mTc-AM (3–48) imaging is safe and shows high sensitivity in the detection of both Q-wave and non-Q-wave MI even with early imaging (6 h post injection). These promising results warrant further clinical investigation.  相似文献   

4.
The current role of infarct avid imaging   总被引:4,自引:0,他引:4  
Tc-99m pyrophosphate is the grandfather of infarct avid agents. Its value is its clinical availability and ease of use. However, its shortcomings are the delay of 2 to 3 days for reliable interpretation in nonreperfused myocardial infarction (MI) and the overarching bone activity. Antimyosin provides exquisite specificity for the detection of myocardial necrosis irrespective of the cause of the injury. Therefore, diagnosis of equivocal MI or confirmation of diffuse myocardial necrosis would benefit from the availability of In-111 labeled antimyosin Fab. The drawback of antimyosin, like that of Tc-99m pyrophosphate, is the delay, in this case because of the protracted blood clearance of the antibody protein macromolecules. Tc-99m glucaric acid, on the other hand, may fulfill the original role envisioned for antimyosin, which was to enable early, rapid diagnosis of acute MI. However, the window for the use of Tc-99m glucaric acid appears to be limited to within the first day of the acute event. Therefore, there is a potential use of both Tc-99m glucaric acid and In-111 antimyosin in tandem with Tc-99m glucaric acid, which would not only facilitate early detection and diagnosis of acute MI and diagnosis of equivocal MI, but also may permit stratification of the infarct age.  相似文献   

5.
Somatostatin receptor scintigraphy (SRS) using 111In-octreotide has proven useful in patients suspected of having meningiomas. Delayed imaging is regularly performed up to 24 h postinjection. However, this procedure is time consuming and expensive. Therefore, we investigated whether 24-h imaging may be omitted in these patients. METHODS: After clinical examination and standard MRI, 71 patients were suspected of having 92 meningioma lesions. Before surgery, all patients underwent SRS after intravenous injection of 200 MBq (5.4 mCi) 111In-octreotide. Planar whole-body images were obtained at 10 min and 1, 4 and 24 h, and SPECT was performed at 4 and 24 h. Results of SRS in all lesions were evaluated with respect to histology and time of image acquisition. RESULTS: SRS yielded 58 true-positive, 20 true-negative and 14 false-negative results, with the false-negatives all less than 5 mL (2.3+/-2.1 mL) in volume. In 52 of 58 true-positive lesions (89.7%), diagnosis could be established by 4-h imaging without further information by 24-h imaging. In 10 of the 52 lesions, SPECT was necessary to confirm planar findings. Imaging at 24 h was necessary in only 6 of 58 true-positive lesions (10.3%): 3 patients who had intracranial relapse of meningioma (volume < 5 mL) and 3 who had spinal meningioma. Thus, a diagnosis of intracranial meningioma could be established in 52 of 55 lesions (95%) using a 4-h imaging protocol. CONCLUSION: With a 4-h acquisition protocol that includes SPECT imaging, SRS yields sufficient information in patients suspected of having intracranial meningiomas. Delayed imaging at 24 h is recommended only for patients who have small meningiomas (volume < 5 mL), spinal localizations or negative SRS at 4 h.  相似文献   

6.
111Indium-monoclonal antimyosin scans were carried out in 21 patients with suspected myocarditis, confirmed by reduced ejection volume, pericardial effusion and clinical follow up in 12 patients. Coronary heart disease was excluded angiographically in all cases. Quantitative evaluation of myocardial 111In-antimyosin accumulation 48 hours after injection showed a pathological uptake in 10/12 patients with increased heart/lung ratios (Q48 greater than 1.58). Ratios were also elevated in 2 patients with cardiomyopathy, 2 suffering from vasculitis and 1 with dermatomyositis. Four patients without proven cardiac disease had normal ratios (Q48 less than or equal to 1.58). Examination after 24 hours was of limited value, depending on the residual blood pool activity. Visual analysis of the scans showed a high interobserver variation despite a positive correlation with quantitative analysis (48 h p.i.: r = 0.72; p less than 0.001), and is not recommended. The results show the value of the 111In-antimyosin scan as a screening method prior to myocardial biopsy. However, scintigraphy cannot definitely elucidate the cause of myocardial damage. Therefore, myocardial biopsy is still recommended after positive antimyosin scans.  相似文献   

7.
The significance of indium-111 antimyosin antibody and thallium-201 dual nuclide single photon emission computed tomography (SPECT) was evaluated in 7 patients with acute myocardial infarction (AMI) who underwent emergency coronary angiography with successful revascularization by intracoronary thrombolysis. Indium-111 antimyosin antibody and thallium-201 dual nuclide SPECT was performed 11 to 36 days after the onset of AMI. Antimyosin SPECT images delineated areas of myocardial necrosis in all 7 patients (100%), but planar images detected necrotic areas in only 4 of 7 patients (57%). Peak CPK-MBs of the 3 patients in which no necrotic area was detected by indium-111 planar image showed a tendency to be smaller. Indium-111 antimyosin antibody/thallium-201 overlap was observed in all patients. The area of overlap was at the center of necrosis in 4 patients (2 anterior infarction, 1 inferior infarction, 1 inferolateral infarction) and at the peripheral portion in 3 patients (all 3 had inferior infarction). Indium-111 antimyosin antibody and thallium-201 dual nuclide SPECT is useful in identifying the localization of myocardial infarction and the overlap of these tracers might reflect the presence of salvaged myocardium adjacent to the necrotic myocardium.  相似文献   

8.
Recently proposed image comparison software is applied to immunoscintigraphy. The software performs geometric and gray level registration of two images and generates an image of the statistically significant differences. It permits the comparison of scintigraphic images recorded at different times. It is used to subtract 113mIn and 111Inphytate colloid liver scans and early (blood pool) images from 131I or 111In-monoclonal Ab images and to compare Ab images recorded at different times. Using the procedures made possible by this software, only images recorded using the same radionuclide or using radionuclides of about the same energy are compared. Anti CEA, 19-9 and OC 125 F(ab)2 fragments labeled with 131I or 111In are used in 32 patients with 47 demonstrated recurrences or metastases of colorectal or ovarian cancers. The overall sensitivities of the unprocessed and processed images are 25/47 and 41/47 respectively. The improvement in sensitivity is particularly high in the liver when In labelled Ab are used. This technique improves the contrast of the images, but the interpretation must take into account the components of the non target activity (kidney, bone marrow, colon...) which are not removed by the image subtraction method.  相似文献   

9.
The relative renal uptake of Tc-99m DMSA was compared with the relative glomerular filtration rate (GFR) in ten patients with serum creatinines ranging from 0.3 to 2.5 mg/dl. Relative GFR was based on the renal uptake of Tc-99m DTPA determined by two methods: 1) integrating the counts from 1 to 3 minutes postinjection and correcting for background. 2) Totalizing the individual renal counts in a single 15-second frame from 2:45 minutes to 3:00 minutes postinjection and correcting for background. The two methods of determining relative DTPA uptake showed excellent correlation, r = 0.98. Relative DMSA uptake determined at 24 hours post-injection using computer-assisted regions of interest showed excellent correlation with the relative GFR determined by either the integral or single-frame method, r = 0.98. The addition of background subtraction for the DMSA images at 24 hours did not improve the correlation.  相似文献   

10.
Indium-111 antimyosin F(ab')2 was used in a series of scintigraphic studies on experimentally induced myocardial infarctions in pigs. Antimyosin distribution recorded by planar images of in vivo pigs and by single photon emission computed tomography (SPECT) of excised hearts delineated areas of myocardial necrosis if infarct volume exceeded 3.3 cm3. Scintigraphic images were compared with magnetic resonance images (MRI) obtained from excised hearts and with photographs of slices of the hearts. Infarct size and localization determined with antimyosin were compared. The MR images, with or without gadolinium-DTPA (Gd-DTPA), of the in vivo pigs were all false-negative; some myocardial wall thinning and high bloodpool signals were visible. Results show that both the antimyosin and the MR technique are specific methods for the visualization of induced myocardial necrosis in this animal model. However, the use of antimyosin is limited to a period ranging from 24 to 72 hours after infarction.  相似文献   

11.
The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.  相似文献   

12.

Introduction

Noninvasive imaging of small animals to measure biodistributions and pharmacokinetics of radiolabeled agents is increasingly seen as an effective alternative to external counting of tissues obtained by sacrifice and dissection. However, we have observed important disagreements in measuring the accumulation of 111In-labeled antibodies in organs such as liver and kidneys when comparing imaging to ex vivo counting in the same animals. This study was conducted to establish whether this discrepancy could be minimized by selecting the region of interest (ROI) in images at the appropriate color threshold and by correcting for the estimated radioactivity within the blood pool of these organs during imaging.

Methods

Vials with known concentrations of 111In as phantoms were imaged on a Bioscan NanoSPECT/CT. Thereafter, an 111In-DTPA-IgG antibody as the test agent was administered intravenously to normal rats, and whole body acquisitions were obtained at 2, 24 or 48 h. Immediately following imaging, the animals were sacrificed, the tissues were removed for ex vivo counting and the radioactivity accumulations were then compared.

Results

The phantom measurements showed that accuracy depended upon setting the correct ROI and that, in turn, depended upon setting the appropriate threshold of the color scale. Under the most unfavorable conditions, this error did not exceed 60%. Compared to the results of ex vivo counting, quantitation by imaging provided high values in liver and kidneys at all three time points by as much as 140%. However, by using the blood radioactivity at the time of sacrifice and the known blood volume in these organs, the disagreement was reduced in all cases to below 25%.

Conclusion

In this study, the discrepancy in quantitating organ radioactivity accumulations between noninvasive imaging and necropsy was primarily due to blood pool radioactivity contributing to the in vivo images. The discrepancy may be minimized by subtracting an estimate of this contribution.  相似文献   

13.
To investigate the clinical implications of 111In-antimyosin antibody scintigraphy in the chronic stage of myocardial infarction, 34 studies were performed in 26 patients with 36 infarcts of various infarct ages. The infarcts were divided into three groups according to time from onset of chest pain to scintigraphy. Positive antimyosin images were obtained in 93% of Group I patients (3 days to 1 mo), 71% of Group II patients (1.5 mo to 1 yr) and none were obtained from Group III patients (1.5-6 yr). A negative correlation was observed between antimyosin uptake and the time after myocardial infarction. In Group II, patients with coronary artery patency and patients showing redistribution on exercise 201TI scintigraphy were more likely to have positive antimyosin images compared to patients without these features. Recurrent angina may also relate to chronic antimyosin uptake. Indium-111-antimyosin antibody scintigraphy may be a useful method in assessing the course of myocardial infarction and for the patient follow-up.  相似文献   

14.
Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiolabeled-biotin is a promising approach to improve absorbed dose ratios and achieve high durable remission rates with diminished systemic toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody. METHODS: Athymic mice bearing Ramos human Burkitt's lymphoma xenografts were injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by (111)In- or (90)Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin. The comparison groups consisted of mice injected with conventional, directly labeled (111)In- or (90)Y-1F5. RESULTS: Rapid tumor uptake of radioactivity within 2 h was observed with the pretargeting approach, resulting in high-contrast tumor images at 24 h with minimal blood-pool radioactivity. Although conventional radiolabeled antibodies produced clear tumor images at 24 h, a large amount of radioactivity was present in the blood pool. The tumor-to-blood ratio was 3.5:1 with pretargeting compared with 0.4:1 with conventional (111)In-1F5. Pretargeted RIT with 29.6 MBq (800 micro Ci) (90)Y-DOTA-biotin cured 100% of mice with tolerable toxicity, whereas conventional RIT with (90)Y-1F5 at a dose of 14.8 MBq (400 micro Ci) produced no cures, induced profound pancytopenia, and was lethal to all mice. CONCLUSION: These results suggest that anti-CD20 pretargeted RIT may be superior to conventional radiolabeled antibodies in terms of radioimmunoscintigraphy, toxicity, and therapeutic efficacy for treatment of B-cell lymphomas.  相似文献   

15.
Preliminary clinical studies have been carried out to determine whether the monoclonal antibody 791T/36 would localize in primary lung cancer to an extent sufficient for external detection by gamma scintigraphy. Radiolabelling of the antibody with 131I permitted visualization of three out of eight (38%) tumours using planar imaging with 99Tcm-labelled blood pool subtraction. Radiolabelling of the same antibody with 111In permitted visualization of tumour uptake in nine out of 13 (69%) tumours, without the need for image subtraction. Single photon emission computed tomography (SPECT) studies of seven patients demonstrated concentration of 111In-labelled antibody at the tumour site in each case, four of which were visualized on the planar images. The present study demonstrates localization of the 791T/36 antibody in primary lung carcinoma and confirms the superiority of 111In over 131I as a radiolabel for antibody imaging, especially when emission tomography is performed. These data indicate that further work will be required to determine whether this antibody will be a suitable carrier for cytotoxic agents in the therapy of lung cancer.  相似文献   

16.
The role of antimyosin antibodies in acute myocardial infarction   总被引:1,自引:0,他引:1  
Antimyosin is an Fab fragment of a monoclonal antibody that binds with human myosin exposed in myocytes irreversibly damaged by an ischemic event. Labeled with 111In, the antibody is taken up into acutely necrotic tissue and can be imaged by planar or single photon emission computed tomography (SPECT) techniques. A large, multicenter clinical trial has demonstrated a high degree of both sensitivity for detecting infarction and specificity for excluding a recent ischemic event in patients admitted with chest pain syndrome. No allergic reactions to antibody injection have occurred, nor have there been documented significant increases in human antimouse antibody titers postinjection. Due to relatively slow blood clearance, the optimal imaging time is 24 to 48 hours post-injection. Between 13% and 21% of 24-hour scans are nondiagnostic due to persistent blood pool activity. In two thirds of these patients, 48-hour scans confirm negative tracer uptake. Moderate to intense cardiac uptake occurs in greater than 80% of scans. Faint tracer uptake, which occurs in a small minority of patients, is associated with inferoposterior infarct location and an occluded infarct vessel. Potential clinical uses include both diagnostic and prognostic areas. A negative scan in a patient with chest pain syndrome and no ECG changes rules out a recent significant ischemic event. The extent of antimyosin uptake (infarct size), measured semiquantitatively from planar scans or quantitatively from SPECT reconstructions, has been shown to correlate with future cardiac events. Relative patterns of distribution of indium-antimyosin and 201TI on simultaneous dual isotope SPECT reconstructions may identify patients with residual myocardium at further ischemic risk.  相似文献   

17.
PURPOSE: To develop and test a delayed-enhancement imaging method for improving the contrast between myocardial infarction (MI) and blood pool. MATERIALS AND METHODS: The T(2) of blood is significantly longer than that of acute or chronic MI. The proposed multi-contrast delayed-enhancement (MCODE) imaging method produces a series of images with both T(1) and T(2) weightings, which provides both excellent contrast between normal and infarcted myocardium, and between blood and MI. RESULTS: The subendocardial border between MI and blood pool was easily discriminated in the T(2)-weighted image. The measured MI-to-blood contrast-to-noise ratio (CNR) was better in the T(2)-weighted image than in the T(1)-weighted image (22.5+/-8.7 vs. 2.9+/-3.1, mean+/-SD, N=11, P<0.001, for True FISP, and 19.4+/-10.8 vs. 3.9+/-2.3, N=11, P<0.001, for Turbo FLASH). CONCLUSION: The MCODE method provides a significant improvement in the ability to easily discriminate subendocardial MI by providing a T(2)-weighted image with high contrast between blood and MI. MCODE should improve both the detection and accurate sizing of MI.  相似文献   

18.
Prognostic significance of myocardial uptake of indium-111 antimyosin antibody was evaluated in 17 patients with idiopathic cardiomyopathy; 10 patients with dilated cardiomyopathy and 7 patients with hypertrophic cardiomyopathy. Seven of 10 patients with dilated cardiomyopathy showed positive images. Three of these 7 patients with strongly positive scans died after scintigraphic examination. Six of 7 patients with hypertrophic cardiomyopathy showed positive images. Three of the patients with dilated left ventricle had prominent positive scans and higher heart to lung ratio. The heart to lung ratio of antimyosin uptake in total patients was correlated with left ventricular end-diastolic dimension and ejection fraction measured by echocardiography. In patients with myocarditis, all three patients showed positive scintigrams within 4 weeks after the onset of the disease and 1 of 6 patients was positive thereafter, who had dilated ventricle and decreased cardiac function. Thus, indium-111 antimyosin antibody imaging may be useful to evaluate prognosis of patients with cardiomyopathy and myocarditis.  相似文献   

19.
To assess the role of 111In antimyosin antibody (AbAm) in the delineation of myocardial damage following coronary bypass surgery, we studied 51 consecutive patients who underwent coronary surgery, 27 of whom had a history of prior myocardial infarction. All patients underwent a diagnostic protocol comprising: (1) 99Tcm pyrophosphate (PYP) and AbAm injection 48 h after surgery (AbAm imaging 24 and 48 h post-injection) (myocardial/background and myocardial/lung ratios were obtained respectively from the computer image); (2) Radioimmunoassay (RIA) serum CK-B levels from samples obtained immediately before surgery, and 24 and 48 h later; (3) clinical and ECG follow-up. Twenty-five patients showed positive AbAm studies, 10 had positive PYP images, and 21 had CK-B levels above normal limits at 24 h. One patient with abnormal AbAm, PYP and CK-B studies had new Q waves on the ECG after surgery. This patient was considered to have sustained a peri-operative myocardial infarction. The large number of positive AbAm studies probably reflects myocardial damage frequently associated with coronary bypass surgery.  相似文献   

20.
Since a 256-slice CT can perform real time observation of the volumetric cine images at multiple angles, volumetric CT angiography can provide much useful clinical information. Conventional CT subtraction angiography is generated by subtracting the non-enhanced CT image (mask CT image) from each contrast-enhanced CT image. Since even conventional CT subtraction angiography takes a few minutes to compute the image, volumetric CT subtraction angiography images require computation of an enormous amount of volumetric cine data (image base CT subtraction angiography: ICTSA) which means an excessively long calculating time. To reduce calculating time, we developed the raw data base CT subtraction angiography (RCTSA) that subtracts raw data instead of the reconstructed four-dimensional image sets. Image quality of the two image processing methods was evaluated in phantom and animal studies. Evaluation items were image noise, CT number uniformity, and subtracting RCTSA from ICTSA. ICTSA calculates the number of volume data; however, RCTSA uses the number of CT rotations. Moreover, since RCTSA can also be started subtraction early in the process of data acquisition, it reduced the number of calculations considerably. As there is a longer CT acquisition time, RCTSA shortens the ratio of the calculating time compared to that of ICTSA. RCTSA is useful image processing to reduce CT subtraction angiography examination time instead of ICTSA.  相似文献   

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