Bone healing during lower limb lengthening by distraction epiphysiolysis

A study of limb lengthening by distraction epiphysiolysis in the rabbit tibia is presented. A special external distraction device was developed that allowed 10 mm lengthening of the leg. Bone formation in the elongated zone was studied by computed tomography and [99mTc] methylene diphosphonate (MDP) scintigraphy. Computed tomography showed bone formation proceeding for several weeks after the end of the distraction period, followed by a decrease in the amount of bone during a remodeling phase leading to the formation of a solid cortical structure. The uptake of [99mTc]MDP increased parallel to, but preceeding the actual accretion of bone, followed by a decrease during the bone remodeling phase. Uptake of the tracer will partly reflect bone metabolism, but other factors, like trauma, determine much of the uptake.     

Comparison of 85Sr, 87mSr, 18F, and 99mTc-labeled phosphates for bone scanning.

The observation by Subramanian and his co-workers that a 99mTc-labeled polyphosphate had excellent affinity for bone has led to widespread use of 99mTc-labeled phosphates as bone scanning agents. Initially, only polyphosphate was employed, but because of somewhat inconstant results and difficulty in preparation of this product, other phosphate compounds were sought. We soon discovered that an inorganic compound, pyrophosphate, appeared to have certain advantages over polyphosphate. Other workers formulated diphosphonates (organic phosphates) which also demonstrated advantages over polyphosphates. Comparison studies in rabbits utilizing 85Sr, 87mSr, 18F, and several phosphates (inorganic and organic) proved the 99mTc-labeled phosphates to be clearly superior in delineating normal skeletal anatomy. Studies in humans confirmed that excellent visualization of bone was obtained with 99mTc-labeled phosphates using either a gamma camera or a rectilinear scanner. What was not known, however, was just how reliable this class of agents would prove to be in detecting bone disease when compared to bone-seeking radiopharmaceuticals such as 85Sr, 87mSr, and 18F. Further comparative analyses have clearly demonstrated that both inorganic and organic 99mTc phosphate complexes are extremely sensitive in revealing more bone disease than the older bone scanning agents.     

Electrophoretic analysis of different technetium-99m (SnCl2) methylene diphosphonate complexes

Technetium-99m MDP was prepared from MDP kits from several different sources. The resulting [99mTc]MDP preparations were analyzed by electrophoresis. The results demonstrated the presence of at least four different 99mTc complexes in these preparations. Modified kit preparations were analyzed to show the effects of concentration and pH on formation of the impurities. The electrophoresis results were correlated with scintillation camera imaging studies in rabbits and suggest that hydrolysis of MDP to phosphate and methylphosphate results in formation of 99mTc complexes with poor biological behavior as bone scanning agents.     

Technetium-99m-labeled phosphonic acid analog of serine: bone uptake

A phosphonic acid analog of serine (PAAS), its P-methyl derivative, and an allied compound were labeled with 99mTc, and evaluated in experimental animals. These molecules were able to bind 99mTc in the presence of stannous ions, but the biologic behavior of the later two labeled compounds was quite different from that of the first one. Technetium-99m-labeled PAAS behaved like 99mTc-labeled methylene diphosphonate, but its P-methyl derivative and the third agent showed little bone accumulation. It appears that both hydroxyl groups attached to the phosphorus atom are essential for uptake in bone, but that only one is required for binding 99mTc.     

Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety, and preliminary comparison to thallium-201 for myocardial perfusion imaging

The biodistribution, dosimetry, and safety of a new myocardial imaging agent, 99mTc-hexakis-2-methoxyisobutyl isonitrile (HEXAMIBI), was evaluated in 17 normal volunteers at rest and exercise (Phase I studies). Technetium-99m HEXAMIBI clears rapidly from the blood with good myocardial uptake and favorable myocardial-to-background ratios for myocardial imaging. Dosimetry allows for administration of up to 30 mCi (1, 110 Bq) of [99mTc]HEXAMIBI. The myocardial images were of good quality and appeared less granular with sharper myocardial walls compared to 201T1 images. The clinical efficacy of [99mTc]HEXAMIBI planar stress and rest imaging was evaluated in a multicenter Phase II clinical trial involving 38 patients. Of 36 patients with significant coronary artery disease, 35 patients (97%) had abnormal 201T1 stress images, and 32 (89%) had abnormal [99mTc]HEXAMIBI stress images (P = N.S.). Technetium-99m HEXAMIBI images correlated in 31/35 patients (86%) who had either scar or ischemia on 201T1 images. By segmental myocardial analysis, exact concordance was obtained in 463/570 myocardial segments (81%). This multicenter Phase I and II study indicates that planar [99mTc]HEXAMIBI stress imaging is safe and compares well with 201T1 stress imaging for detection of coronary artery disease.     

Use of technetium-99m(V)thiocyanate to measure gastric emptying of fat

Technetium-99m(V)thiocyanate was evaluated as a radio-pharmaceutical for measuring gastric emptying of fat. Olive oil was labeled with 99mTc(V)thiocyanate by direct extraction from acidic thiocyanate solution. After incubation with dilute HCl (pH 1.4) at 37 degrees C for 3 hr, approximately 5% of the total radioactivity eluted into the aqueous phase. When incubated with human gastric juice (pH 1.8 and 2.2), approximately 8% of the activity was detected in the aqueous phase at 3 hr. Scintigraphic studies performed in two rabbits showed that olive oil labeled with 99mTc(V)thiocyanate emptied slowly from the stomach, with a gastric half-emptying time (T50) of more than 3 hr. A low-nutrient soup labeled with 113mIn-DTPA and mixed with 99mTc(V)thiocyanate labeled oil was consumed by six human volunteers. The oil emptied much more slowly (p less than 0.02) (median T50 = 198 min) than the aqueous component (median T50 = 30 min). These observations indicate that 99mTc(V)thiocyanate is a suitable pharmaceutical to measure gastric emptying of extracellular fat.     

Technetium-99m-pyrophosphate: studies in vivo and in vitro.

In rats with induced rickets, the uptake of 99mTcO4 and 99mTc-pyrophosphate per gram of bone was increased as compared with weight-matched controls. However, the uptake of radioactive calcium and 32P-pyrophosphate was similar in both rachitic and control animals, suggesting that the 99mTc label conferred specificity and favored the rachitic lesions. Employing the rat tibia in an in vitro system, 99mTcO4 uptake was predominantly in the organic bone matrix; radioactive calcium, 32P-pyrophosphate, or 14C-diphosphonate uptake was mainly in the bone mineral; and 99mTc-pyrophosphate, 99mTc-diphosphonate, and 99mTc-polyphosphate were found in both mineral and organic phases. By removal of both mineral and polysaccharide and by using agents that altered the degree of collagen fibril cross-linking, evidence was obtained suggesting the 99mTcO4 and 99mTc-pyrophosphate are preferentially bound by immature collagen.     

Uptake of myocardial imaging agents by rejecting and nonrejecting cardiac transplants. A comparative clinical study of thallium-201, technetium-99m, and gallium-67

To study the scintigraphic detectability of cardiac rejection, we performed 135 planar myocardial scans ([99mTc]pyrophosphate, 85; 201Tl, 36; 67Ga, 14) together with endomyocardial biopsies in ten patients for a (mean) 17-mo postoperative period. Specificity of each agent exceeded 89%. Technetium-99m pyrophosphate showed results that significantly correlated with the severity of rejection (p = 0.03), as shown by biopsy, but neither 201Tl nor 67Ga did so (p = 0.63 and 0.81, respectively). Technetium-99m pyrophosphate showed better diagnostic accuracy (85%) than 201Tl (69%) and 67Ga (64%). Technetium-99m pyrophosphate also showed higher negative predictive value (91%) than thallium (76%) and gallium (69%). Thus, a normal 99mTc pyrophosphate scan was usually associated with absence of cardiac rejection. However, all three agents showed unacceptably poor sensitivity (0% to 30%) and thus were not useful as a screening test for cardiac rejection, even when the same agent was used serially in imaging a given patient.     

Technetium-99m HM-PAO-labeled leukocytes in detection of inflammatory lesions: comparison with gallium-67 citrate

Forty-three patients with suspected benign, inflammatory, or infectious diseases were imaged with [99mTc]HM-PAO-labeled leukocytes and [67Ga]citrate. Technetium-99m leukocytes showed 22 true-positive, no false-positive, 19 true-negative, and two false-negative findings and [67Ga]citrate 23, 7, 12 and 1, respectively. The sensitivity, specificity, and accuracy values with 99mTc leukocytes were 92%, 100%, and 95%, and with [67Ga]citrate 96%, 63%, and 81%. Technetium-99m leukocyte scintigraphy has a promising future in comparison with [67Ga]citrate because of the ready availability of [99mTc]HM-PAO, the good image quality, more rapid results (within few hours), and the lower radiation exposure to the patient with 99mTc leukocytes. The usefulness of 99mTc leukocytes in chronic osteomyelitis needs further evaluation.     

Abdominal masses in children: multiorgan imaging with 99mTc methylene diphosphonate

Technetium-99m methylene diphosphonate (99mTc MDP) imaging was performed in 29 consecutive children with abdominal masses. Dynamic images of the inferior vena cava were obtained by injecting the radiotracer in the feet. Serial renal images were obtained for the next 30 min. Routine bone imaging was performed at about 3 hr. The radionuclide studies of the inferior vena cava accurately diagnosed total obstruction and displacement to the left but not partial obstruction and displacement to the right. The abnormalities on early renal imaging included displacement (14), distortion (seven), obstruction (eight), and nonvisualization (one). All patients with Wilms tumor (eight) had either nonvisualized or distorted renal parenchyma. Patients with neuroblastoma (17) and other tumors (four) had displacement and obstruction. Soft-tissue accumulation of 99mTc MDP was noted in two Wilms tumors and 12 neuroblastomas.     

Relative accretion of 99mTc-polyphosphate by forming and resorbing bone systems in rats: its significance in the pathologic basis of bone scanning.

The relative roles of osteogenesis andd osteolysis in the production of positive radionuclide images of skeletal lesions were investigated. The uptake of 99mTc-polyphosphate (Tc-PP) by each process was measured in an animal model that permitted bone formation and resorption to be studied independently. Ten rats received intramuscular implants of bone-forming demineralized matrix (DM) and resorbing devitalized bone (DV). Radiographs and Tc-PP scintiscans were made each week thereafter. At 6-10 weeks, the implants and normal bone samples were removed, counted for 99mTc, and examined histologically. The uptake of Tc-PP BY DM implants was first detected on images made 3 weeks after implanatation, and by DV implants, 1-2 weeks later. Serial radiography showed progressive calcification of DM an resorption of DV implants. Microscopic examinations of undecalcified sections, stained with a modified Goldner preparation, revealed vital-bone formation in the DM implants and osteoclastic resorption in the DV. Activity counts per gram of DM and DV implants were, respectively, 200% and 90% that of normal bone. Since only the bone-forming system (DM) accumulated Tc-PP at greater than normal concentrations, this study indicates that positive bone images of osteolytic lesions solely reflect compensatory osteogenic responses.     

Biodistribution, dosimetry, and clinical evaluation of technetium-99m ethyl cysteinate dimer in normal subjects and in patients with chronic cerebral infarction

Technetium-99m ethyl cysteinate dimer (ECD) has high initial cerebral uptake with slow clearance in nonhuman primates suggesting ideal characteristics for single photon emission computer tomography (SPECT) imaging. We evaluated the biodistribution, dosimetry and scintigraphic pattern of [99mTc]ECD in normal subjects and the accuracy of SPECT imaging in patients with chronic cerebral infarction. Sixteen normal subjects were injected with approximately 10 mCi of [99mTc]ECD. Anterior and posterior single-pass whole-body images were obtained at multiple times after injection. Blood clearance of the radiotracer was rapid, falling to 10.0 +/- 6.6% and 4.9 +/- 1.1% of the injected dose at 2 and 60 min, respectively. Brain uptake was 6.4 +/- 2.1% of the injected dose 5 min after injection. The critical organ was the urinary bladder. Technetium-99m ECD SPECT was performed with a rotating gamma camera in ten of the 16 normal subjects and 34 patients with clinical and CT evidence of chronic stroke. Thirty-three of the thirty-four patients had focal [99mTc]ECD abnormalities on SPECT (97.1%) based on visual inspection of the SPECT images. In summary, we obtained high quality SPECT images as a result of the optimal physical and biologic characteristics of the tracer. Technetium-99m ECD SPECT shows promise for the evaluation of patients with stroke.     

Uptake of 99mTc bone-scanning agent by lungs with metastatic calcification.

Uptake of 99mTc bone-scanning agent into lungs containing metastatic calcification was demonstrated in a patient with a carcinosarcoma of the bladder. This gives further support to the hypothesis that 99mTc bone agents are associated with hydroxyapatite.     

Animal evaluation of technetium-99m triamide mercaptide complexes as potential renal imaging agents

Technetium-99m mercaptoacetylglycylglycylglycine (MAG3), a [99mTc]triamide mercaptide (N3S) compound has been synthesized in an attempt to obviate the stereochemistry problems associated with the diamide dimercaptide (N2S2) ligands. Because initial studies have been promising, the terminal glycine on the MAG3 compound has been varied to create a new series of N3S compounds. Twelve new N3S complexes were initially screened in mice and the more promising complexes, 99mTc mercaptoacetylgylcylglycyl-glycine [( 99mTc]MAG3), 99mTc mercaptoacetylgylcylglycyl-L-alanine [( 99mTc]MAG2-Ala), and both complexes of 99mTc mercaptoeacetylglycylglycyl-L-asparagine [( 99mTc]MAG2-Asn) and 99mTc mercaptoacetylglycylglycyl-L-glutamine [( 99mTc]MAG2-Gln), were further evaluated in rats utilizing constant infusion blood clearances, extraction efficiencies and protein binding assays. The renal excretion of all these complexes compared favorably with simultaneously administered [131I]OIH and [125I]iothalamate. The triamide mercaptide complexes represent a new ligand class for 99mTc, which may provide a variety of complexes for the evaluation of renal tubular function.     

Pentavalent [99mTc]DMSA, [131I]MIBG, and [99mTc]MDP--an evaluation of three imaging techniques in patients with medullary carcinoma of the thyroid

Nine patients with histologically proven medullary carcinoma of the thyroid (MCT) were imaged using pentavalent [99mTc]dimercaptosuccinic acid [(V)DMSA], [131I] metaiodobenzylguanidine (MIBG) and [99mTc]methylene diphosphonate (MDP). Technetium-99m (V)DMSA demonstrated most of the tumor sites in eight patients with proven metastases, with an overall sensitivity of 95% in lesion detection. Iodine-131 MIBG showed definite uptake in some of the tumor sites in three of the nine patients imaged, with equivocal uptake seen in a further one patient, with sensitivity of only 11% for lesion detection. Technetium-99m MDP demonstrated bony metastases only, in four of the patients imaged yielding a sensitivity of 61%. Technetium-99m (V)DMSA has been demonstrated in this study to be a useful imaging agent in patients with MCT, showing uptake in significantly more lesions and with better imaging qualities than [131I]MIBG, and with the ability to detect soft tissue as well as bony metastases.     

A long term scintigraphic bone abnormality after trauma: a pitfall in the survey for metastatic disease

A solitary bone lesion was detected by 99mTc bone scintigraphy during a survey for metastatic disease. A trauma in this region which had occurred 47 years previously, was mentioned by the patient on questioning. This case report emphasizes the need for a precise history of traumatic events, no matter how long has passed, before a survey for metastatic disease or when an atypical lesion is noted on the bone scan.     

Technetium-99m red blood cell venography in patients with clinically suspected deep vein thrombosis: a prospective study

We have compared technetium-99m (99mTc) red blood cell (RBC) venography to serial impedance plethysmography (IPG) in 110 consecutive patients with a first episode of clinically suspected deep vein thrombosis (DVT). IPG was performed at Day 0 and, if abnormal, contrast venography was also performed to rule out a falsely positive result. Patients with an initially normal IPG had the test repeated at Days 1, 3, 5 to 7, and 10 to 14. Contrast venography was not performed and anticoagulant treatment was withheld in all patients who remained normal during repeated IPG testing. Technetium-99m RBC venography was performed at Day 0 in patients with an initially abnormal IPG and during the period of serial IPG testing in those with an initially normal IPG. The sensitivity of [99mTc]RBC venography for proximal DVT was 0.68, with 95% confidence limits (CL) from 0.48 to 0.89. Specificity was 0.88 (95% CL from 0.81 to 0.95). When the findings of [99mTc]RBC venography for the entire lower extremity were compared to the reference method, the sensitivity increased to 0.90 (95% CL from 0.82 to 0.97) but the specificity decreased to 0.56 (95% CL from 0.51 to 0.62). Technetium-99m RBC venography is a sensitive but less specific method for detecting DVT of the entire lower extremity. An abnormal [99mTc]RBC venogram, particularly in the calf region, should always be confirmed by another diagnostic method.     

Effect of reperfusion and hyperemia on the myocardial distribution of technetium-99m t-butylisonitrile

Technetium-99m t-butylisonitrile ([99mTc]TBI) is a promising new radiotracer for myocardial imaging. Its myocardial uptake is sufficiently high in humans to permit planar, tomographic, and gated images of excellent technical quality. We studied the behavior of [99mTc]TBI in the dog at rest and under conditions of hyperemia and reperfusion in order to determine the relationship between [99mTc]TBI myocardial concentration and blood flow. After permanent occlusion of the left anterior descending artery, the correlation between the relative myocardial concentration of [99mTc]TBI and regional myocardial blood flow (RMBF) measured with radiolabeled microspheres was excellent. In a dog model of transient hyperemia, the concentration of [99mTc]TBI was directly related to blood flow but underestimated the degree of hyperemia. Technetium-99m TBI redistributed into transiently ischemic myocardium. The myocardial concentrations of [99mTc]TBI and thallium-201(201TI) in transiently ischemic myocardium were similar at 10 and 30 min following reperfusion and were significantly higher than blood flow prior to reperfusion. When [99mTc]TBI was injected into the left anterior descending artery, the washout was slow, falling to 78% of initial activity at 120 min after injection. In conclusion, [99mTc]TBI reflects regional myocardial blood flow accurately in ischemic and normal resting myocardium and underestimates blood flow at high flows. The rate of myocardial redistribution after reperfusion is similar for [99mTc]TBI and 201TI.     

Comparative uptake of 67Ga and 99mTc MDP in rabbits with a benign noninfected bone lesion (fracture)

Mid-shaft fractures of the radius and ulna were produced in 3 to 4 kg New Zealand white rabbits and quantitative uptake of 99mTc MDP and 67Ga determined at 11, 18, 25, 32, 51, and 78 days following fracture. Two hundred microCi of 67Ga was administered 24 hours prior to sacrifice and 1.5 mCi 99mTc MDP 2 hours prior to sacrifice. Specific activity ratios (SARs) were determined between fracture and control sides for bone, muscle and skin. SARs for bone were surprisingly similar for 99mTc MDP and 67Ga, reaching peak values of 6.07 +/- 0.64 (99mTc 18 days); 6.58 +/- 0.90 (67Ga 32 days), subsequently decreasing to minimum values at 78 days postfracture (99mTc MDP 2.25 +/- 0.14; 67Ga 2.18 +/- 0.08). There was no statistically significant difference in SAR for 99mTc MDP vs. 67Ga in bone at any time after fracture. Whole sections of limb were resected on selected animals and activity ratios determined for these sections as a function of the contribution of activity from the various tissues in the volume of interest. Total activity ratios of 67Ga were lower than bone SARs as a result of the contribution of activity from muscle and skin. Thus the apparent lower activity ratios noted on 67Ga images compared with 99mTc MDP images in this fracture model were not due to differences in bone SARs but rather due to the higher soft tissue background activity contribution in the 67Ga images.     

Kinetic analysis of technetium-99m d,1-HM-PAO decomposition in aqueous media

Technetium-99m-d,1-hexamethylpropyleneamine oxime [99mTc]d,1-HM-PAO) is a neutral-lipophilic chelate formed from a kit in high yield by stannous reduction of Na99mTcO4-. Of three methods used to analyze the purity of the 99mTc complexes, a single strip method using ether as the developing solvent was the most rapid and simple to perform. The lipophilic chelate converts to 99mTcO4- and other hydrophilic products with time and this limits the useful lifetime of the preparations. The rate of decomposition of [99mTc]d,1-HM-PAO increased in the presence of excess stannous ion and at pH greater than 9.