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This report examines (99m)Tc-etarfolatide imaging to identify the presence of folate receptor (FR) on tumors of women with recurrent/refractory ovarian or endometrial cancer and correlates expression with response to FR-targeted therapy (vintafolide).In this phase II, single-arm, multicenter study, patients with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before vintafolide treatment. Up to 10 target lesions (TLs) were selected based on Response Evaluation Criteria In Solid Tumors criteria using computed tomography scans. Single-photon emission computed tomography images of TLs were assessed for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%), and FR(0%). Lesion and patient response were correlated with etarfolatide uptake.Forty-nine patients were enrolled; 43 were available for analysis. One hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive and 29 FR negative. Lesion disease control rate (DCR = stable or response) was observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in FR(100%), FR(10%-90%), and FR(0%) patients, respectively.Overall response to FR-targeted therapy and DCR correlate with FR positivity demonstrated by (99m)Tc-etarfolatide imaging.NCT00507741.

The prefrontal cortex is asymmetric in both structure and function. In normal subjects, the right prefrontal cortex is activated more than the left during response inhibition. Patients with attention deficit hyperactivity disorder (ADHD) have impaired response inhibition and altered structural interhemispheric asymmetry. This study was conducted to examine the functional interhemispheric asymmetry during response inhibition in children with ADHD. Subjects were divided into three groups according to the level of motor hyperactivity. Blood flow tracer (99m)Tc-ethyl cysteinate dimer was injected while subjects were performing a response inhibition task (RIT), followed by single photon emission computerized tomography (SPECT). After three-dimensional reconstruction, filtering and smoothing, individual scans were morphed to a template. Three average group images were created from individual scans. Each average group image was subtracted voxel-by-voxel from its mirror image to compare the regional cerebral blood flow (rCBF) in the right and left cerebral hemispheres, yielding images of significant interhemispheric rCBF asymmetry. The severe hyperactivity group exhibited most prefrontal left>right rCBF asymmetry and left>right occipitoparietal asymmetry. Reversal of functional prefrontal asymmetry in boys with severe motor hyperactivity supports the hypothesis of right prefrontal cortex dysfunction in ADHD.

Migration of monocytes into the arterial wall is an early finding of atherosclerosis. Monocytes are attracted to sites of vascular endothelial cell injury, the initiating event in the development of atheromatous disease, by a chemokine known as monocyte chemoattractant protein-1 (MCP-1). Injured vascular endothelial and smooth muscle cells selectively secrete MCP-1. This study was performed to determine if radiolabeled MCP-1 would co-localize at sites of monocyte/macrophage concentration in an experimental model of transplant-induced vasculopathy in diabetic animals. Hearts from 3-month-old male Zucker rats, heterozygote (Lean) or homozygote (Fat) for the diabetes-associated gene fa, were transplanted into the abdomens of genetically matched recipients. Lean and Fat animals were then fed normal or high-fat diets for 90 days. At 90 days significant increases (P < 0.013) of MCP-1 graft uptake were seen at imaging and confirmed on scintillation gamma well counting studies in Lean (n = 5) and Fat (n = 12) animals, regardless of diet, 400 % and 40 %, above control values, respectively. MCP-1 uptake of native and grafted hearts correlated with increased numbers of perivascular macrophages (P < 0.02), as seen by immunostaining with an antibody specific for macrophages (ED 2). Radiolabeled MCP-1 can detect abnormally increased numbers of perivascular mononuclear cells in native and grafted hearts in prediabetic rats. MCP-1 may be useful in the screening of diabetic children for early atherosclerotic disease.

Monocytes/macrophages (Mphis), the predominant cell types in subacute and chronic inflammation, are attracted to and activated by monocyte chemotactic peptide-1 (MCP-1). Mphis promote the resolution of inflammation through the induction of apoptosis and phagocytosis of senescent (spent) and bystander (superfluous) granulocytes. We wished to determine whether MCP-1, which selectively binds to Mphis, could be used to image subacute and chronic inflammation. We also sought to image granulocyte apoptosis within these lesions with technetium-99m labeled annexin V, a marker of apoptotic cells. Sterile inflammation was induced in 45 12-week-old male Sprague-Dawley rats by deep intramuscular injection of turpentine into the right thigh. Groups of four to six animals were then imaged 1 h after tail vein injection of 37-148 MBq (1-4 mCi) of 99mTc-labeled MCP-1 or annexin V 1-14 days after turpentine treatment. Image analysis showed significantly greater activity of both MCP-1 and annexin V in inflamed thighs than in control thighs (165%-290% and 188%-313%, respectively; P0.01) on days 1-5 after turpentine injection. Dual autoradiography in animals co-injected with iodine-125 labeled bovine serum albumin on days 1 and 4 showed specific location of MCP-1 to infiltrating Mphis while annexin V localized to focal zones of apoptosis within granulocytic infiltrates adjacent to abscess cavities. Scintillation well counting on day 5 demonstrated significantly higher (P0.005) ratios of abscess to control thigh specific activities for MCP-1 (5.83+/-2.17) and annexin V (9.24 +/- 2.8) as compared to 125I-labeled bovine serum albumin (3.11 +/- 0.65). No significant increases in uptake were noted at imaging or ex vivo analyses on days 13 and 14, when lesions were predominately fibrotic. It is concluded that 99mTc-labeled MCP-1 and 99mTc-labeled annexin V both localize in zones of subacute inflammation, reflecting the density of Mphis and the incidence of apoptotic granulocytes, respectively. These agents may be useful in the characterization of subacute inflammation.

Apoptosis, also known as programmed cell death, is an indispensable component of normal human growth and development, immunoregulation and homeostasis. Apoptosis is nature's primary opponent of cell proliferation and growth. Strict coordination of these two phenomena is essential not only in normal physiology and regulation but in the prevention of disease. Programmed cell death causes susceptible cells to undergo a series of stereotypical enzymatic and morphologic changes governed by ubiquitous endogenous biologic machinery encoded by the human genome. Many of these changes can be readily exploited to create macroscopic images using existing technologies such as lipid proton magnetic resonance (MR) spectroscopy, diffusion-weighted MR imaging and radionuclide receptor imaging with radiolabeled annexin V. In this review the cellular phenomenon of apoptotic cell death and the imaging methods which can detect the process in vitro and in vivo are first discussed. Thereafter an outline is provided of the role of apoptosis in the pathophysiology of clinical disorders including stroke, neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia and inflammation, myelodysplastic disorders, organ transplantation, and oncology, in which imaging may play a critical role in diagnosis and patient management. Objective imaging markers of apoptosis may soon become measures of therapeutic success or failure in both current and future treatment paradigms. Since apoptosis is a major factor in many diseases, quantification and monitoring the process could become important in clinical decision making.

Cardiac positron emission tomography (PET) is an accurate method for assessing myocardial perfusion and metabolism in the evaluation of coronary heart disease. PET allows more accurate detection of myocardial ischemia than single photon emission tomography (SPECT). In addition, PET has higher spatial resolution and allows attenuation correction and the quantification of various physiologic parameters. PET with 2-(fluorine-18) fluoro-2-deoxy-D-glucose is considered the standard of reference for predicting improvement in regional or global left ventricular function after revascularization by identifying hibernating viable myocardium that shows diminished perfusion and preserved metabolism. Other less commonly used clinical applications of cardiac PET include assessment of myocardial oxygen consumption and fatty acid metabolism. The use of PET in myocardial imaging is expected to increase in the near future with the regional distribution of positron-emitting radiotracers and the emergence of relatively low-cost PET systems.

RATIONALE AND OBJECTIVES The authors demonstrate the feasibility of monitoring renal status continuously and noninvasively at a patient's bedside, avoiding both radioactivity and blood and urine samples. METHODS Gadolinium-153-labeled ProHance and a glomerular filtration rate (GFR) standard technetium-99m-DTPA were coadministered to anesthetized normal and nephrectomized rats with their tails hanging in a PC 20 spin analyzer. Blood samples and T1 measurements were collected and analyzed. RESULTS Log time plots of 153Gd, 99mTc (from blood samples) and T1 of the rat tails were all linear and parallel. Halftimes were 32 +/- 2, 32 +/- 6, and 32 +/- 6 minutes for the decay of the T1, 153Gd and 99mTc, respectively. The halftime of the nephrectomized animal was 2000 +/- 4000 minutes. CONCLUSIONS T1 of an appendage remote from the kidneys reflects the concentration of gadolinium in the blood, which is in rapid equilibrium with tissue interstitial space gadolinium. The decay in T1 of the appendage reflects glomerular filtration. Thus, it is feasible to detect changes in renal status at a patient's bedside by monitoring T1 of a finger or wrist using a small, inexpensive magnet.

Patients with obstructive sleep apnea experience nocturnal hemodynamic oscillations in association with repetitive respiratory events. Apnea termination (recovery) is accompanied by the nadir of arterial O2 saturation (SaO2), changes in intrathoracic pressure, and arousal from sleep. To investigate separately the contributions of hypoxemia and of arousal from sleep to changes in cardiac function, we continuously measured left ventricular stroke volume (LVSV) and mean arterial pressure (MAP) in eight subjects with severe obstructive sleep apnea (apnea-hypopnea index > 30 events/h associated with SaO2 < or = 82%) during two experimental conditions: 1) subjects slept without intervention for 1–2 h and then supplemental O2 was administered to maintain SaO2 > or = 90% (mean SaO2 nadir 92.7%) throughout the apnea-recovery cycle and 2) upper airway obstructions were abolished using nasal continuous positive airway pressure and subjects were aroused from sleep by an auditory signal. Recovery was associated with an increase in MAP and a decrease in LVSV both with and without supplemental O2. Arousal from sleep on nasal continuous positive airway pressure reproduced the postapneic elevation of MAP but not a decrease in cardiac function of the magnitude that occurred at apnea termination. We conclude that elevation of blood pressure and reduction of LVSV that occurred at apnea termination may be due to different physiological mechanisms.

Positron emission tomography (PET) with [18F]fleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with approximately 20 mCi of [18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (> 34), liver (> 25), lung (> 20), myocardium (> 19), and spleen (> 18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (> 10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram +/- standard error of the mean) of drug were as follows: brain, 0.83 +/- 0.032; myocardium, 4.53 +/- 0.24; lung, 5.80 +/- 0.48; liver, 7.31 +/- 0.33; spleen, 6.00 +/- 0.47; bowel, 3.53 +/- 0.74; kidney, 8.85 +/- 0.64; bone, 2.87 +/- 0.29; muscle, 4.60 +/- 0.33; prostate, 4.65 +/- 0.48; uterus, 3.87 +/- 0.39; breast, 2.68 +/- 0.11; and blood, 2.35 +/- 0.09. Concentrations of fleroxacin in tissue were similar in males and females, before and after pretreatment with unlabeled drug.

Myocarditis occasionally masquerades as acute myocardial infarction because patients may present with severe chest pain, electrocardiographic changes, and elevated serum levels of creatine kinase. In patients with normal coronary arteries who presumably died of acute myocardial infarction, myocarditis has been reported as an incidental abnormality at autopsy1–4. Although there have been anecdotal clinical reports of myocarditis mimicking myocardial infarction in patients with normal coronary arteries, this association has almost always relied on a demonstration of diffuse electrocardiographic abnormalities or a preceding viral illness in young patients with few coronary risk factors5–7. In most cases no definitive . . .

Patients with obstructive sleep apnea (OSA) experience repetitive nocturnal oscillations of systemic arterial pressure that occur in association with changes in respiration and changes in sleep state. To investigate cardiac function during the cycle of obstruction (apnea) and resumption of ventilation (recovery), we continuously measured left ventricular stroke volume (LVSV) and mean arterial blood pressure (MAP) during non-rapid-eye-movement sleep in six males with severe OSA (apnea/hypopnea index > or = 30 events/h associated with oxygen saturation < 82%). LVSV was assessed continuously using an ambulatory ventricular function monitor (VEST; Capintec). The apnea-recovery cycle was divided into three phases: 1) early apnea (EA), 2) late apnea (LA), and 3) recovery (Rec). In all subjects recovery was associated with an abrupt decrease in LVSV [54.0 +/- 14.5 (SD) ml] compared with either EA (91.4 +/- 14.7 ml; P < 0.001) or LA (77.1 +/- 15.2 ml; P < 0.005). Although heart rate increased with recovery, the increase was not sufficient to compensate for the decrease in LVSV so that cardiac output (CO) fell (EA: 6,247 +/- 739 ml/min; LA: 5,741 +/- 1,094 ml/min; Rec: 4,601 +/- 1,249 ml/min; EA vs. Rec, P < 0.01; LA vs. Rec, P < 0.025). Recovery was also associated with a significant increase in MAP. We speculate that such abrupt decreases in LVSV and CO at apnea termination, occurring coincident with the nadir of oxygen saturation, may further compromise tissue oxygen delivery.

BACKGROUND Mice with abdominal heterotopic heart transplants were studied to determine whether scintigraphic detection of an increase in major histocompatibility complex (MHC) class II antigen expression could be used as a noninvasive method for diagnosing early rejection. METHODS AND RESULTS Allografts from C3H/He (H2k) donors were transplanted into BALB/c (H2d) recipients (n = 18). Two of the 18 allografted mice were treated with cyclosporine (15 mg/kg/day), and two isografted mice served as controls. Each mouse was injected intravenously with 100 microCi of 111In-labeled anti-MHC class II monoclonal antibodies (10-2-16 and 14-4-4S) 24 hours before scintigraphy. After imaging, the mice were killed for tissue counting and histopathology. Radiotracer uptake in the grafts reflected the severity of rejection as determined by histopathological criteria. The percent injected dose per gram of tissue in excised grafts was 4.8 +/- 1.8 (mean +/- SD) for normal grafts (n = 8), 11.1 +/- 9.7 for grafts with grade IA rejection (n = 3, NS), 18.0 +/- 3.8 for grafts with grade IIIA rejection (n = 4, p less than 0.001 versus normal), 18.7 +/- 3.2 for grafts with grade IIIB rejection (n = 3, p less than 0.001 versus normal), and 22.6 +/- 5.4 for grafts with severe rejection (grade IV) (n = 3, p less than 0.001 versus normal). Rejecting allografts with lymphocyte infiltration but without significant myocyte necrosis could be identified by this scintigraphic method. In the BALB/c donor-C57BL/6 (H2b, IE-) recipient combination, rejecting allografts were visualized by 14-4-4S (anti-IEk,d,p,r) antibody but not by 10-2-16 (anti-IAk,r,s,f) antibody. This difference shows that class II antigens induced on donor hearts are solely responsible for the antibody uptake in positive scintigrams of rejecting allografts. CONCLUSIONS We conclude that 111In-labeled anti-MHC class II antigen antibody imaging is a sensitive and noninvasive method for detecting cardiac allograft rejection.

Patients who cannot be separated from mechanical ventilation (MV) after an episode of acute respiratory failure often have coexisting coronary artery disease. The authors hypothesized that increased left ventricular (LV) wall stress during periods of spontaneous ventilation (SV) could alter myocardial perfusion in these patients. Using thallium-201 (201TI) myocardial scintigraphy, the authors studied the occurrence of myocardial perfusion abnormalities during periods of SV in 15 MV-dependent patients (nine women, six men; aged 71 +/- 7 yr, mean +/- SD). Fourteen of these patients were studied once with 201TI myocardial scintigraphy during intermittent mechanical ventilation (IMV) and again on another day, after at least 10 min of SV through a T-piece. One patient was studied during SV only. Thirteen of 14 of the patients (93%) studied during MV had abnormal patterns of initial myocardial 201TI uptake, but only 1 patient demonstrated redistribution of 201TI on delayed images. The remainder of the abnormalities observed during MV were fixed defects. SV produced significant alterations of myocardial 201TI distribution or transient LV dilation, or both, in 7 of the 15 patients (47%). Four patients demonstrated new regional decreases of LV myocardial thallium concentration with redistribution of the isotope on delayed images. The patient studied only during SV also had myocardial 201TI defects with redistribution. Five patients (3 also having areas of 201TI redistribution) had transient LV dilation during SV.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential changes in the regional distribution of technetium 99m Teboroxime (SQ30217) were evaluated in nine dogs with graded coronary artery stenosis, occlusion and reperfusion of either the left anterior descending or left circumflex arteries. 99mTc-Teboroxime accumulation recorded by planar imaging was compared with directly measured coronary blood flow (Doppler) and regional myocardial perfusion (microspheres). Serial images were recorded beginning at the time of injection and continuing for the next 18 min. The data were summed from minutes 2-3, 3-6, 4-8 and 9-18 after injection for comparison with the other parameters. Myocardial clearance of Teboroxime was analysed at each level of blood flow. There was a linear relationship between the Teboroxime activity ratio (abnormal/normal) and coronary blood flow (r = 0.96) and regional myocardial perfusion (r = 0.99). Zones of diminished perfusion were least apparent in the summed images recorded during minutes 2-3. In later images, the lesions were well visualized. The myocardial clearance half-times at 100%, 75% and 50% flow were not significantly different, while clearance half-time at total occlusion was significantly (P less than 0.01) faster. In the 3-6, 4-8 and 9-18 minutes summed images, the Teboroxime activity ratio increased significantly (P less than 0.01) after reperfusion compared with total occlusion.

Objectives: Vulnerability of atheroma is associated with activated macrophage infiltration and apoptosis of foam cells. Activated macrophages have a high metabolic rate, and utilize exogenous glucose as their energy source. The oxidized lipid content of foam cells, is toxic and often results in apoptosis of these cells. Nuclear imaging provides at least two potential indicators to identify vulnerable plaques: 18 F-FDG as a marker of macrophage metabolism and 99m Tc-annexin A5 ( 99m Tc-AN5) as a marker of apoptosis. This study compared the macrophage infiltration and lesion histology to the uptake of each tracer in apolipoprotein E knockout (ApoE−/−) mice. Methods: Male apoE−/− mice (n=4 –5/group) were maintained on a high-fat diet after the age of 5 wks. At the age of 25 and 35 wks, 14 C-FDG and 99m Tc-AN5 were administered and aortas were harvested. Dual-tracer autoradiography, Movat pentachrome staining and Mac-2 staining were performed on serial cryostat sections (n=5– 6/mouse). Regional tracer uptake levels (ID%×kg/mm 2 ) were evaluated in relation to the morphological lesion characteristics (AHA lesion phenotypes) and degree of macrophage infiltration (Mac-2 positive areas). Results: Plaque size and intimal thickness were increased with lesion progression. Macrophage infiltration was increased from early (type I-II) to atheromatous lesions (type III-IV) but decreased in fibroatheromatous lesions (type V). 99m Tc-AN5 showed higher uptake levels in atheromatous lesions (0.49±0.20 %IDxkg/mm 2 ) than early (0.40±0.17) or fibroatheromatous (0.30±0.13) lesions, being concordant with macrophage infiltration. 14 C-FDG uptake was also the highest in atheromatous lesions (3.1±1.5 in atheromatous, 2.8±1.5 in early, and 2.3±1.4 in fibroatheromatous lesions). The uptakes of both 99m Tc-AN5 (r=0.65, p14 C-FDG (r=0.44, p Conclusion: Each tracer showed a higher uptake in atheromatous lesions (AHA type III-IV) than other more stable lesions, directly corresponding to the degree of macrophage infiltration. Unstable plaques can be imaged utilizing 18 F-FDG and 99m Tc-annexin A5, due to the presence of metabolically active and apoptotic macrophages.

Preoperative dipyridamole-thallium-201 scanning is sensitive in identifying patients prone to ischemic cardiac complications after vascular surgery, but most patients with redistribution do not have an event after surgery. Therefore, its positive predictive value is limited. To determine which patients with thallium redistribution are at highest risk, dipyridamole-thallium-201 images were interpreted semiquantitatively. Sixty-two consecutive patients with redistribution on preoperative dipyridamole-thallium-201 planar imaging studies were identified. Each thallium scan was then analyzed independently by 2 observers for the number of myocardial segments out of 15, the number of thallium views out of 3 and the number of coronary artery territories with redistribution. Seventeen patients (27%) had postoperative ischemic events, including unstable angina pectoris, ischemic pulmonary edema, myocardial infarction and cardiac death. Thallium predictors of ischemic operative complications included thallium redistribution greater than or equal to 4 myocardial segments (p = 0.03), greater than or equal to 2 of the 3 planar views (p = 0.005) and greater than or equal to 2 coronary territories (p = 0.007). No patient with redistribution in only 1 view had an ischemic event (0 of 15). Thus, determining the extent of redistribution by dipyridamole-thallium-201 scanning improves risk stratification before vascular surgery. Patients with greater numbers of myocardial segments and greater numbers of coronary territories showing thallium-201 redistribution are at higher risk for ischemic cardiac complications. In contrast, when the extent of thallium redistribution is limited, there is a lower risk despite the presence of redistribution.

Sodium pertechnetate Tc99m scintigraphy is a valuable technique for the evaluation of acute testicular torsion in postpubescent males. However, in neonates and children with small testicles, the method is less reliable. Since the testicles of adult rats and young children are of similar size, the reliability of testicular imaging for detecting torsion was evaluated in this species. The utility of the radionuclide angiogram (RA) and static images were determined in 17 anesthetized animals before, 2 h after and 20 h after ligation of the left spermatic cord. The preligation RA was asymmetric in 27% of animals, while the static images were abnormal in 18%. Postligation flow and static images were abnormal in 57% and 82% of the animals (localized to the correct side, 38% and 36%), respectively. The animals with vascular occlusion failed to show any statistically significant greater incidence of decreased radionuclide accumulation on the ligated side. To determine the influence of relative perfusion and extracellular fluid space of the scrotum and testicles on the images, additional studies were performed with 201Tl (representing perfusion) and 99mTcO4- (representing ECF space). Perfusion was approximately equal in the testis and epididymis but significantly higher in the scrotum. These results suggest that scrotal scintigraphy is unreliable for detecting acute torsion of small testicles.

Atherosclerosis is an indolent, chronic arterial disease involving inflammation and thickening of the walls of medium- and large-sized vessels, with potentially-lethal sequelae. An atherosclerotic lesion is an accumulation of lipids and inflammatory cells, within the arterial wall, which becomes more complicated and extensive and deforms the involved artery, with time. Clinically-significant lesions of atherosclerosis typically become manifest after decades of growth and transformation; yet, not all lesions become symptomatic and many end by becoming calcified or fibrotic, with no clinical significance. Atherosclerotic lesions of the carotid arteries begin in infancy [19]. The arterial response that initiates atherosclerosis has not been definitively identified [63]. Yet the subsequent natural history of atherosclerosis has been well-characterized. The vascular burden of atherosclerosis increases in volume and extent, over decades, remaining clinically ‘silent’, while progressing through stages of developme with changes in the morphology and composition of lesions.

To compare patients with visualized sentinel lymph nodes (SLNs) and patients with nonvisualized SLNs, with a focus on variables affecting SLN visualization at preoperative lymphoscintigraphy and on nodal drainage basins as related to tumor location.One hundred thirty-six patients who had breast cancer underwent preoperative lymphoscintigraphy before SLN biopsy. Patients with visualized and nonvisualized SLNs were compared for age; tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; interval between biopsy and lymphoscintigraphy; intraoperative identification method; and surgical identification rate. Visualized SLN drainage basins were noted.Ninety-nine patients had visualized and 37 had nonvisualized SLNs, without statistically significant differences in tumor site, size, and histologic findings; injection guidance method; diagnostic biopsy type; and interval between biopsy and lymphoscintigraphy. Ninety-nine (73%) of the 136 SLNs were visualized at lymphoscintigraphy; 30 (81%) of the 37 nonvisualized SLNS were identified at surgery. Of the seven SLNs not identified at surgery, five were mapped with radiocolloid only. Patients with nonvisualized SLNs were older than those with visualized SLNs. Eleven (46%) of 24 tumors with internal mammary drainage were in the outer part of the breast.Patients with and those without visualization differed in age, SLN identification at surgery, and surgical identification method. Nonvisualized status does not preclude axillary metastasis. In older patients with nonvisualized SLNs, blue dye may aid in SLN detection, as compared with isotope-only localization.

Monocyte Chemoattractant Protein 1 (MCP-1) is a chemokine important to the recruitment of perivascular monocytes in transplanted organs. Its expression is associated with the development of chronic rejection as manifested by graft coronary artery disease (GCAD) following cardiac transplantation. This study assesses whether radiolabelled MCP-1 binds to its receptors in chronic cardiac allografts and thereby provides a potential imaging modality to assess GCAD. Methods: Allogeneic (PVG-.ACI, n59) and syngeneic (ACI.ACI, n59) rat heterotopic heart transplants were performed. Allograft recipients were treated with 7.5mg/kg/day of oral Cyclosporin A for ten days until tolerance was achieved. After 90 days, animals were infused intravenously with Tc99m MCP-1 and sacrificed after one hour. Radioactivity of heart tissues was measured in scintillation well counters and expressed as a ratio to that of uptake in the overall blood pool. Autoradiographs were imaged by exposing 50-micron desiccated sections on a phosphoimager overnight. Additional sections were fixed in 10% formalin prior to paraffin embedding and cutting into 5-micron sections for elastin von Gieson staining. Hearts were scored for luminal narrowing and intima to media ratio (I/M) with computerized image analysis. Results: Allografts exhibited significantly more luminal narrowing (22.5610.7% vs. 2.664.6%, p5.0005) and higher I/M (0.17360.151 vs. 0.01560.029, p5.0088) than isografts. The ratio of heart tissue well counts to that of the blood pool demonstrated 1.44 times greater Tc99m MCP-1 uptake in allografts (1.04) compared to isograft controls (0.72) (p50.03). The figure shows representative autoradiograph images of native, isograft, and allograft cross sections. Conclusion: Tc99m bound MCP-1 is higher in allografts vs. isografts which is consistent with a greater degree of vasculopathy. These data provide a foundation for the development of a potentially noninvasive imaging assay of chronic rejection after heart transplantation.

Histological evaluation of the first draining lymph node (sentinel node) in the axilla of patients with breast cancer has dramatically altered the surgical approach to these patients, with sparing of the axilla if no tumour cells are identified. In a fraction of patients imaged after peri-tumoural injection of the breast, there is no visualization of the sentinel node. We retrospectively analysed the status of patients whose nodes were visualized and of patients whose nodes failed to visualize, to define the variables associated with non-visualization of the sentinel node. Seventy-four breast cancer patients were imaged following peri-tumoural injection of filtered 99Tc(m)-sulfur colloid, immediately and up to 5.5 h post-injection. The scintigraphic data were analysed with reference to the patient's age, histology, grade, site and size of tumour, previous diagnostic procedure and time interval to scan, using univariate analysis and a logistic regression model. A sentinel node was visualized in 53 of 74 women (72%). Comparison of patients with non-visualized versus visualized sentinel nodes disclosed no statistically significant univariate relation to age of the patients (P = 0.10), size of tumour (P = 0.46), site (P = 0.26), histology [invasive ductal carcinoma in 16 of 20 (80%) non-visualized cases, and in 43 of 53 (81%) visualized patients], prior excision biopsy (P = 0.36) and time interval to surgery (P = 0.29). Tumour grade was the only significant variable on univariate analysis (P = 0.03), though multivariate analysis showed that none of the independent parameters were statistically significant. In 39 patients with an upper outer quadrant tumour, the location of the sentinel node was not limited to the axilla and even crossed the midline of the breast. Our results show that none of the independent variables is associated with non-visualization of sentinel lymph node on preoperative lymphoscintigraphy of patients with breast cancer, though the tumour grade may have contributed to non-visualization of this node. The non-axillary drainage from upper outer quadrant tumours suggests the routine use of lymphoscintigraphy prior to axillary dissection.

To assess the value of imaging rejection-induced apoptosis with technetium 99m and annexin V, a human protein-based radiopharmaceutical used in the diagnosis of acute rejection of a liver transplant, in a well-characterized rodent model of orthotopic liver transplantation.99mTc-radiolabeled annexin V was intravenously administered to six allografted (immunologically mismatched) and five isografted (immunologically matched) recipient rats on days 2, 4, and 7 after orthotopic liver transplantation. Animals were imaged 1 hour after injection of 0.2-2.0 mCi (8.0-74.0 MBq) of radiolabeled annexin V by use of clinical nuclear scintigraphic equipment.All animals in the allografted group demonstrated marked increases of 55% and 97% above the activity in the isografted group in hepatic uptake of annexin V on days 4 and 7, respectively. Severe acute rejection was histologically detected in all allografted livers on day 7. There was no histologic evidence of acute rejection in isografted animals. Dynamic hepatobiliary imaging with 99mTc and mebrofenin, an iminodiacetic acid derivative, demonstrated no correlation with the presence or absence of acute rejection or with annexin V uptake.Noninvasive imaging with radiolabeled annexin V is more sensitive and specific than imaging with 99mTc-mebrofenin in the diagnosis of acute rejection of a liver transplant.

We report cerebral SPECT studies on two siblings with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Tc-99m HMPAO brain SPECT was performed 8, 19 and 30 days after a stroke-like episode in one case and 10 days after a stroke-like episode, 6 h after a partial seizure and as a follow-up study in the other. Increased blood flow was seen in both these patients with stroke-like episodes due to MELAS. The cause of the increased blood flow is uncertain, but it may be related to the decreased pH created by local increase in lactic acid.

Myocarditis constitutes an important component of rheumatic carditis. Antimyosin scintigraphy, which allows noninvasive assessment of myocyte damage, can be used for documentation of cardiac involvement in patients with rheumatic fever where clinical diagnosis is not unequivocal.

The uptake of radiolabelled colloid or bacteria was compared in normal rats and animals subjected to acute burn trauma. The uptake of colloid by the liver was unaffected by burn trauma, but uptake of the labelled bacteria was reduced. Spleen uptake of both colloid and bacteria was reduced by burn trauma while lung uptake was increased. These data are consistent with the hypothesis that acute burn trauma alters reticuloendothelial system phagocytic activity in the rat towards both inert particles and live bacteria.

99mTc-D-Glucaric acid (99mTcGLA) favourably accumulates in animal models of acute ischemia/early myocardial necrosis and in human tumor xenografts. This study evaluated the biodistribution pharmacokinetics and radiation dosimetry (using the MIRD approach) of 99mTcGLA in 12 cancer patients, based on whole-body scans and blood/urine sampling from 046 hours. The pharmacokinetic pattern showed fast removal from the body (about 10% I.D. retained at 46 hr, almost exclusively in the kidneys). The initial and total distribution volumes corresponded to the extracellular and the total body water, respectively. The main radiation dosimetry estimates (mGy/MBq) were: 0.5488 (kidneys), 0.0208 (bladder), 0.051 (liver), 0.0041 (red marrow), 0.0053 (ovaries), 0.0036 (testes) and 0.0041 (whole-body).

Background We tested the hypotheses that prolonged, demand-induced myocardial ischemia plateaus and that on relief of stress, myocardial function remains depressed, with proportionate reductions in blood flow and oxygen consumption indicative of hibernation. Methods and Results Closed-chest swine (n=20) were prepared with an 80% coronary stenosis. Hemodynamics, myocardial blood flow, oxygen, and lactate metabolism were measured in group 1 (n=9) (1) at baseline, (2) at 10 and 30 minutes of atrial pacing plus intravenous norepinephrine infusion, and (3) in 5 of 9 (group 1a) at ≈50 minutes after stress. Group 1a had ischemia assessed with 99m Tc-labeled BMS 181321. In group 2 (n=11), myocardial function was determined with radionuclide ventriculography (n=8), and myocardial necrosis was looked for with trichlorotetrazolium chloride staining (n=7), histology (n=10), and myocardial creatine kinase concentration (n=4). Baseline stenotic-zone endocardial blood flow was reduced versus the normal zone (0.94±0.33 versus 1.38±0.27 mL·min −1 ·g −1 , mean±SD; P −1 ·g −1 ). Stenotic-zone endocardial flow was unchanged versus baseline at 10 and 30 minutes of stress, whereas epicardial flow increased (1.62±0.53 mL·min −1 ·g −1 at 10 minutes and 1.44±0.51 mL·min −1 ·g −1 at 30 minutes, both P −1 ·100 g −1 ) at 10 and 30 minutes of stress (14.9±5.2 and 13.9±4.5 mL·min −1 ·100 g −1 , both P P Conclusions Myocardial ischemia induced by a sustained increase in oxygen demand may not progress to necrosis but may instead plateau. After relief of stress, myocardial function remains depressed, with a proportionate reduction in blood flow and oxygen consumption consistent with myocardial hibernation.

A series of radiopharmaceuticals that incorporate nitroimidazole moieties have been synthesized to detect decreased local tissue pO2. In contrast to agents that localize in proportion to perfusion, these agents concentrate in hypoxic tissue. Myocardium with an intracellular pO2

Decreased tissue oxygen tension is a component of many diseases. Although hypoxia can be secondary to a low inspired P02 or a variety of lung disorders, the commonest cause is ischemia due to an oxygen demand greater than the local oxygen supply. In tumors, low tissue p02 is often observed, most often due to a blood supply inadequate to meet the tumor's demands. Hypoxic tumor tissue is associated with increased resistance to therapy. In the heart tissue hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. In patients with stroke, hypoxia has been associated with the penumbral region, where an intervention could preserve function. Despite the potential importance of oxygen levels in tissue, difficulty in making this measurement in vivo has limited its role in clinical decision making. A class of compounds known to undergo different intracellular metabolism depending on the availability of oxygen in tissue, the nitroimidazoles, have been advocated for imaging hypoxic tissue. When a nitroimidazole enters a viable cell the molecule undergoes a single electron reduction, to form a potentially reactive species. In the presence of normal oxygen levels the molecule is immediately reoxidized. This futile shuttling takes place for some time, before the molecule diffuses out of the cell. In hypoxic tissue the low oxygen concentration is not able to effectively compete to reoxidize the molecule and further reduction appears to take place, culminating in the association of the reduced nitroimidazole with various intracellular components. The association is not irreversible, since these agents clear from hypoxic tissue over time. Initial development of nitroimidazoles for in vivo imaging used radiohalogenated derivatives of misonidazole, such as fluoromisonidazole, some of which have recently been employed in patients. Two major problems with fluoromisonidazole are its relatively low concentration within the lesion and the need to wait several hours to permit clearance of the agent from the normoxic background tissue (contrast between lesion and background typically

RATIONALE AND OBJECTIVES Little is known about the time-related biologic behavior of radiopharmaceutical misinjections. Such inadvertent tissue infiltration of such injections may not only adversely affect a scheduled test or cause some discomfort, but potentially could produce tissue damage. Radiopharmaceutical infiltrations were assessed in a rat model. METHODS Particulate and nonparticulate radiopharmaceuticals were injected subcutaneously or intradermally into an anesthetized shaved rat model. The rate of release of the nine infiltrations per radiopharmaceutical per injection type were measured from computer data acquired with a gamma camera up to 24 hours after administration. These data were used for dosimetry determinations. RESULTS When injected subcutaneously, the particulate radiopharmaceutical, technetium 99m (99mTc) albumin microspheres, exhibited essentially no movement, and the soluble agents showed a biexponential release pattern. The rate of release was similar for 99mTc methylene diphosphonate (99mTc MDP) and for 67Ga citrate (67Ga), whereas thallous chloride (201Tl) exhibited the slowest release pattern. The average effective half-lives (T1/2 av-eff) were 78.3 minutes, 76.1 minutes, and 268.4 minutes, respectively. When injected intradermally, the nonparticulates exhibited a triexponential release pattern; MDP showed a more rapid release (T1/2 av-eff, 50 minutes) and 201Tl showed the slowest (T1/2 av-eff, 491.2 minutes). Absorbed doses were calculated using conventional medical internal radiation dose (MIRD) methodology for small unit density spheres. The absorbed dose was greatest for a 201Tl infiltration. A 201Tl infiltrate of 1 mCi per gm of tissue is capable of producing radiation-absorbed doses greater than 500 rads. Additional studies were performed with heat, hyaluronidase, and volume dilution in an attempt to accelerate the rate of release of 201Tl. Local heat application proved to be more efficient than volume change or hyaluronidase application. CONCLUSION These data indicate an insignificant skin radiation burden from the majority of nonparticulate infiltrated radiodiagnostic agents. Thallium 201, however, has the potential to produce significant radiation burdens when infiltrated at high specific activity. Actual human infiltration release rates may differ because of variants in blood flow and assumed infiltration volume relative to the animal model.

Tissue accumulation of radiolabeled uridine, a precursor of uracil, reflects ribonucleic acid (RNA) synthesis and may be a marker of viability. To test this hypothesis, myocardial accumulation of H-3 uridine was compared to deoxyglucose uptake and histopathology in an experimental model of myocardial ischemia. In 18 Wistar rats the left coronary artery was occluded for 5, 10 or 60 minutes followed by reperfusion. Five hours later H-3 uridine and C-14 deoxyglucose were administered intravenously and the animals were sacrificed 45 minutes later. The left ventricle of each animal was divided into 12 segments and myocardial tracer accumulation was determined by measurement of tissue radioactivity. From the results of TTC staining, the animals were divided into 3 groups: Group I--ischemia without infarction (n = 9); Group II--non-transmural infarction (n = 4) and transmural infarction (n = 5). Retention of uridine was observed in ischemic zones with enhanced deoxyglucose accumulation in Group I animals. Uridine accumulation was relatively preserved compared to slightly decreased deoxyglucose accumulation in regions of non-transmural infarction in Group II. In Group III, uridine accumulation decreased in parallel with deoxyglucose in zones of infarction. These result suggest that accumulation of radiolabeled uridine may be a useful indicator of viability in ischemic myocardium.

To test the hypothesis that acute subarachnoid hemorrhage is associated with abnormal myocardial perfusion, we assessed myocardial blood flow with thallium scintigraphy in 19 patients with a confirmed subarachnoid hemorrhage and an abnormal electrocardiogram. A thallium scan was performed at the bedside of each patient 3 +/- 2 days (mean +/- SD) after subarachnoid hemorrhage and subsequently was analyzed both qualitatively and quantitatively. Patients averaged 58 +/- 13 yr of age and 68% had one or more cardiac risk factors. The neurologic condition of patients on the day of the scan was II (median; range I-V) on the standard 5-point scale of Botterell. Abnormalities on a standard 12-lead electrocardiogram obtained on the same day as the scan consisted of repolarization changes in most patients; 10 had T wave inversions and 8 had nonspecific ST segment changes. Thirty-two percent (n = 6) of patients had an abnormal thallium scan. There were, however, no features of the clinical history, electrocardiogram pattern, or neurologic condition that were associated with a positive scan. For instance, 2 of 4 patients with diffuse deeply inverted T waves had a normal thallium scan, whereas the scan was abnormal in 2 of 8 patients with minor nonspecific electrocardiographic abnormalities. The thallium scan was also positive in neurologically intact (grade I) as well as severely injured (grade V) patients. Thus, abnormal myocardial perfusion and possibly myocardial ischemia occur frequently following subarachnoid hemorrhage, but no specific electrocardiographic characteristic identifies patients with a perfusion abnormality.

Rationale and objectives Reports published earlier this century suggested that meteorologic factors influence the incidence of pulmonary embolism. These observations were based on few patients and often lacked rigorous standards of evidence. In the current study, the authors evaluate the association between barometric pressure changes and pulmonary embolism using radionuclide ventilation-perfusion (V/Q) scan data. Methods Daily interpretation data for V/Q lung scans were correlated retrospectively with daily local barometric pressure changes over a 7-year period. Results The incidence of pulmonary embolic disease was significantly related to a decrease in barometric pressure during the 3 days preceding clinical presentation. Conclusions Meteorologic factors are less important than better-known risk factors for pulmonary embolism; however, their effect is demonstrable in a large data sample. This work confirms previously published associations between barometric pressure changes and the incidence of pulmonary embolism.

Indium-111-labeled human nonspecific immunoglobulin G (111In-IgG) is a newly developed radiopharmaceutical for imaging infectious and inflammatory foci. This article presents an overview of the literature concerning 111In-IgG scintigraphy. The current theory about the mechanism of accumulation suggests that 111In-IgG accumulates in lesions as a result of enhanced vascular permeability and subsequent entrapment of the radiolabeled protein. Human studies show excellent results in imaging bone and joint, abdominal, and intravascular infection. Of special interest is the ability to depict infectious foci in granulocytopenic patients. The value of 111In-IgG scintigraphy for detection of infection is compared with that of gallium-67, labeled-leukocyte, and technetium-99m (99mTc) nanocolloid scintigraphy. The significance of differences between 111In-IgG scintigraphy and two other new scintigraphic techniques, 99mTc-labeled IgG and 99mTc-labeled murine monoclonal anti-granulocyte antibody BW 250/183, are discussed.

Infection causes remarkable changes in extracellular fluid volume, blood flow and oxygen consumption in the region of the lesion. To determine the sequence and magnitude of these changes, we performed serial scintigraphic measurements in 10 rabbits with experimental Escherichia coli abscesses. Positron emission tomography with C15O2, 15O2 and 11CO was used to measure regional blood flow, oxygen extraction (OEF) and blood volume; extracellular fluid volume was evaluated by single photon scintigraphy with indium-111 immunoglobulin G (IgG). Images were recorded following tracer administration at 1 and 7–10 days after infection. At the first imaging time, blood flow to infected muscle had increased by 40% compared with control sites (7.4±0.6 to 10.8 ± 3.8 ml/min · 100 g), OEF had decreased from 55%±34% to 45%±14%, and the infected-tocontralateral (I/C) ratio of IgG had increased to 3.34±1.85. At the later imaging time, flow had increased by almost threefold compared with day 1 (29.4±9.8 ml/min · 100 g), OEF had decreased to 29%±14%, and the I/C ratio for IgG had remained constant. Although OEF fell,oxygendelivery (OEF × flow) increased from 4.07 ml/min (control value) to 4.86 ml/min on day 1 and 8.64 ml/min on days 7–9. The infected-to-contralateral (IC) ratio of 1502/C15O2 was 0.74±0.15 on day 1 and 0.77±0.10 at 7–9 days. These studies indicate that expansion of the extracellular fluid volume increases early in the evolution of the infection and exceeds changes in regional perfusion and oxygen delivery.

The relative myocardial distribution of 201Tl and modified fatty acid (123I-labelled 3-methyl-p-[iodo]-phenyl pentadecanoic acid, MFA) was determined in eight patients with unstable angina (UA) and six patients with acute myocardial infarction treated with reperfusion therapy within 4.1 h (MI). The results of radionuclide imaging were correlated with coronary angiography and quantitative left ventriculography performed within 10 days of the radionuclide procedures. Zones of injury were identified as areas with diminished 201Tl uptake distal to sites of coronary narrowing. A nearly parallel reduction in regional fatty acid concentration was observed in these areas. Comparison of the regional distributions of the two agents revealed subtle differences in their distributions in the ischaemic zones. Three patterns were recognized: (a) MFA uptake greater than Tl (MFA greater than Tl), (b) matched decrease of MFA and Tl (MFA = Tl), (c) MFA uptake less than Tl (MFA less than Tl). Seven of eight patients with UA had normokinesis or hypokinesis on quantitative left ventriculography. Five of the seven showed the MFA greater than Tl pattern, while one had the MFA less than Tl pattern and one had the MFA = Tl pattern. The eighth patient with UA had akinesis and the MFA = Tl pattern. All six patients with acute infarction had akinesis on ventriculography. One of these patients had the MFA greater than Tl pattern, two had the MFA = Tl pattern and three had the MFA less than Tl pattern. These results suggest that fatty acid and thallium have grossly similar distributions in areas of acute myocardial ischaemia. On careful inspection, zones of slight relative excess fatty acid concentration are observed more often in areas of acute ischaemia with normal wall motion.

The abilities of 99Tcm-labelled monoclonal anti-human granulocyte antibody (AGAb) and 111In-labelled nonspecific polyclonal human immunoglobulin (IgG) to localize at focal sites of inflammation were compared in rats with deep thigh infection due to E. coli. The radiolabelled antibodies were coadministered followed 4-6 and 24 h later by imaging and biodistribution studies. At 4-6 h after injection, the target to background ratio (T/B, lesion to contralateral leg) and percentage residual activity (% RA, counts in the lesion/total body counts) were nearly identical for both antibody preparations. At 24 h, T/B and % RA increased significantly (P less than 0.001) for both proteins but differences between the agents were not significant. In vitro analysis of the binding of AGAb and human polyclonal IgG to rat granulocytes showed a low level of binding with both agents. These results suggest that the primary mechanism of localization, by either antibody preparation in this model, is not antigen related. 111In-labelled nonspecific human IgG and 99Tcm-AGAb are equivalent reagents for the detection of focal sites of infection in the rat.

The relative sensitivity of imaging with 67Ga-citrate (67Ga) and non-specific human polyclonal IgG radiolabelled with 111In (111In-IgG) for the detection of Pneumocystis carinii pneumonia (PCP) was determined in rats. Pneumocystis carinii pneumonia was induced by low protein diet and dexamethasone. The course of the disease was monitored by serial imaging with 111In-IgG and 67Ga. Diffuse accumulation of both radiopharmaceuticals was observed in the lungs of infected animals (infection was verified by histological examination of the lungs), however, accumulation of 111In-IgG was consistently higher. In rats with early PCP, 111In-IgG imaging revealed pulmonary accumulation in animals with normal chest radiographs and 67Ga scans. In animals successfully treated for PCP, decreased pulmonary accumulation of 111In-IgG coincided with histological improvements. Several animals developed superinfection with bacteria or fungi. These animals had striking focal accumulation of 111In-IgG, in addition to the pattern of generalized uptake. Gallium concentration in these animals did not show this focal accumulation. These observations suggest that 111In-IgG may be useful for detecting PCP and pulmonary abscesses in the immunocompromised host.

The application of radioimmune imaging techniques to the evaluation of non-neoplastic disease is largely based on the same principles as tumor imaging; specificity and high affinity of antibodies. Currently the most common non-tumor applications of antibody imaging are the detection of clots (peripheral and pulmonary emboli), myocardial necrosis (myocardial infarction, myocarditis and cardiac transplant rejection) and focal sites of infection/inflammation. In the area of injection imaging, both antigen-specific and non-specific properties of antibodies have been successfully exploited in imaging studies. While the number of non-tumor applications of antibodies are far fewer than the number of tumor studies, in many cases, they appear to be more reliable. The basis for the reliability of antibodies for detecting non-neoplastic lesions is probably related to the availability of abundant antigen, lack of antigen modulation and enhanced permeability at the lesion site. These observations suggest that there will be rapid proliferation of work in this area.

Cardiovascular nuclear medicine procedures are useful to characterize coronary artery disease by measuring changes in perfusion, myocardial metabolism, cellular integrity, and regional or global function. Coronary angiography, while an excellent indicator of anatomic changes in arterial lumenal diameter, is a poor predictor of downstream perfusion, since neither the length of the stenosis nor absolute lumenal diameter is considered. Even if the anatomy is known, perfusion measurements provide information about ischaemia and ventricular dysfunction that is helpful for planning therapy. New technetium 99m-labelled perfusion agents are likely to improve the certainty of diagnosis due to their higher photon flux. The development of techniques for continuous ventricular function monitoring during daily activities provides an opportunity for detecting the impact of silent ischaemia on cardiac function. The role of the radionuclide imaging procedures in classifying patients with coronary disease is discussed in light of the pathophysiology of ischaemia and necrosis.