Pathophysiology and diagnosis of deep venous thrombosis.

Lower-limb deep venous thrombosis (DVT) affects between 1% to 2% of hospitalized patients. These thrombi disrupt the vascular integrity of the lower limbs and are the source of emboli that kill approximately 200,000 patients each year in the United States. The causes of thrombosis include vessel wall damage, stasis or low flow, and hypercoagulability. These factors favor clot formation by disrupting the balance of the opposing coagulative and fibrinolytic systems. The symptoms and signs of venous thrombosis are caused by obstruction to venous outflow, vascular inflammation, or pulmonary embolization. About 70% of patients referred for clinically suspected venous thrombosis, however, do not have the diagnosis confirmed by objective testing. Among the 30% who have venous thrombosis, about 85% have proximal vein thrombosis, and the remainder have thrombosis confined to the calf. Physicians cannot rely on signs and symptoms to make the diagnosis of DVT and must depend on imaging studies to guide treatment. Patients with proximal vein thrombosis who are inadequately treated have a 47% frequency of recurrent venous thromboembolism over 3 months. In contrast, clinically detectable recurrence occurs in less than 2% of patients with proximal vein thrombosis if an adequate anticoagulant response is achieved. Of the diagnostic procedures for DVT, venography is the only invasive test of proven value, and ultrasonographic (US) studies are the most commonly used noninvasive modaity. Other procedures are occasionally used to diagnose DVT, including impedance plethysmography, computed tomography, and magnetic resonance imaging. US examinations are noninvasive, they are rapidly obtained, and they can be performed serially. In symptomatic patients, venous US is sensitive and specific for proximal DVT; however, US is insensitive to calf vein thrombosis and to asymptomatic DVT occurring after surgery. Patients with symptoms of recurrent DVT also can present a difficult diagnostic problem. Only about 20% to 30% of these individuals actually have the disease; the rest have symptoms arising from chronic venous insufficiency or from any of the causes of lower extremity pain. After an acute episode, up to 50% of patients have compression ultrasound abnormalities for 6 months that are indistinguishable from the original findings of DVT. Hence, there are a significant number of patients and clinical circumstances in which the diagnosis of DVT is difficult. 99mTc-radiolabeled peptides that target the molecular biology of thrombosis should aid in the management of the disease, particularly in asymptomatic patients at high risk, in patients with recurrent symptoms, in patients with active DVT in the calf and/or pelvis, and in patients with intermediate- or low-probability lung scans.

Reduction of background activity through radiolabeling of antifibrin Fab' with 99mTc-dextran.

UNLABELLED: Scintigraphic detection of occult disease is limited by background activity in the blood and in the extravascular space that reduces target-specific contrast. To lower nonspecific background activity, we have studied the in vivo biodistribution kinetics of a clot-targeting molecule (MH1 Fab') attached to (99m)Tc-dextran. We tested the hypothesis that the complex will have better background clearance than the directly radiolabeled clot-targeting molecule. METHODS: Fab' fragments of MH1 Fab' antifibrin antibody were coupled to (99m)Tc-sulfhydryl dextran through disulfide exchange, and clot binding bioreactivity was tested in vitro and in vivo in a rabbit jugular vein thrombus model. To assess the background clearance kinetics and extravascular leakage, we studied (99m)Tc-dextran, (99m)Tc-MH1 Fab', and the (99m)Tc-dextran-labeled MH1 Fab' complexes in rats. RESULTS: (99m)Tc-radiolabeled dextran derivatives were radiochemically stable and retained clot-binding bioreactivity in vivo. In the rat model, blood and tissue clearance of the (99m)Tc-dextran MH1 Fab' constructs was substantially improved relative to directly radiolabeled MH1 Fab'. At 1 h, total and extravascular tracer localizations in lung and muscle were significantly lower for 99mTc-dextranradiolabeled MH1 Fab' than for (99m)Tc-MH1 Fab' (P < 0.05). CONCLUSION: The study observations suggest that radiolabeling through a (99m)Tc-dextran moiety may improve the detection of pulmonary emboli and other clinically important fixed intravascular targets by lowering nonspecific background activity.

Clinical production of pharmaceutical grade Tc-99m dextran 70 for lymphoscintigraphy.

Lymphoscintigraphy is an established means to determine the lymphatic drainage patterns from malignant tissues and edematous extremities. Unfortunately, there are no commercially available dedicated radiopharmaceuticals labeled for use in lymphoscintigraphy studies. The authors report a simple way to extemporaneously compound pharmaceutical-grade Tc-99m dextran 70 to meet this need. Pharmaceutical-quality Tc-99m dextran 70 injection is prepared by a simple rapid method from drug intermediates that are marketed as parenteral drug products. The radiolabeling process yields a product of high radiochemical purity, with good in vitro and in vivo stability. The authors illustrate the use of this product in a patient with melanoma to show the lymphatic drainage pattern before surgery. The method described permits rapid compounding of Tc-99m dextran 70 injection from drug components that are intended for parenteral administration. Tc-99m dextran 70 provides the option of performing lymphoscintigraphy in any clinical nuclear medicine setting.

Scintigraphic detection of breast cancer xenografts with Tc-99m natural and recombinant human alpha-fetoprotein.

Because adenocarcinoma of the breast expresses receptors for alpha-fetoprotein (AFP), we studied Tc-99m AFP as a radiopharmaceutical to detect breast cancer. The biodistribution of Tc-99m radiolabeled natural human AFP (full length) and recombinant domain III (DIII) of human AFP was compared to Tc-99m sestamibi and Tl-201 in a murine model of human breast cancer. Estrogen receptor positive (MCF7, T-47D) and estrogen receptor negative (MDA-MB-231, BT-20) human breast cancer xenografts were grown subcutaneously in the lateral thorax region of immunosuppressed mice (ICR SCID). Quantitative comparisons of percent-injected dose per gram of tissue (%ID/gram) and tumor to thigh ratio (T/Th) were performed at 0-60 minutes and at 24 hours following injection. For most tumors, T/Th for AFP and DIII was significantly greater than T/Th for Tc-99m sestamibi and Tl-201. In all breast cancers (BT-20, MCF7, MDA-MB-231, T-47D), Tc-99m AFP T/Th increased from 60 minutes to 24 hours, suggesting good tumor retention of this radiopharmaceutical. DIII and AFP had significantly higher %ID/gram than either Tl-201 or Tc-99m sestamibi when considered across all tumor types at both 60 minutes and 24 hours. The data suggests that localization of Tc-99m AFP in human breast cancer xenografts is initially rapid, increases with time, and is superior to Tc-99m sestamibi and Tl-201. Given its high uptake by breast cancer cells, its low non-tumor localization and its rapid renal excretion, these Tc-99m AFP preparations may be useful agents to detect human breast carcinoma.

Etidronate therapy decreases the sensitivity of bone scanning with methylene diphosphonate labelled with technetium-99m.

OBJECTIVE: To define the nature, incidence and consequence of a possible interaction between etidronate (for the treatment of hypercalcemia) and methylene diphosphonate labelled with technetium-99m (99mTc-MDP) (for bone scanning). MATERIALS AND METHODS: The authors reviewed hospital pharmacy records for a period of 2 years and identified 18 patients who had received etidronate. Of this group, 6 patients (4 men and 2 women, ranging in age from 56 to 76 years) had undergone bone scanning with 99mTc-MDP while receiving etidronate. Five of the patients had hypercalcemia associated with metastatic disease, and the sixth had hyperparathyroidism. RESULTS: All bone scans demonstrated poor uptake of tracer by bone accompanied by high soft-tissue background. There was loss of bone definition below the mid-thigh, and in 5 of the 6 patients there was indistinguishable rib uptake. In 1 of the patients, there was absence of uptake in 2 previously defined metastatic lesions. CONCLUSION: Recent oral or intravenous administration of etidronate is a contraindication to bone scintigraphy, as it markedly decreases sensitivity for bone disease. Bone scintigraphy should be timed so that it is performed before etidronate treatment or, if that is not possible, more than 2 to 4 weeks after the therapy has been completed.

Cardiopulmonary thromboembolism detected by Tc-99m MH-1 antifibrin antibody.

A patient with shortness of breath had a high probability lung scan for pulmonary embolism, but no obvious embolic source. Whole-body scintigraphy using Tc-99m labeled Fab' antifibrin monoclonal antibody showed large central pulmonary emboli as well as tracer uptake in the right atrium and aortic arch. No lower extremity clot was detected. This case shows significant differences in the appearance of pulmonary embolism as assessed by direct clot and ventilation-perfusion scintigraphy. It shows the importance of the heart as the origin of pulmonary emboli and the utility of direct thrombus visualization.

Diagnostic test comparisons in patients with deep venous thrombosis.

UNLABELLED: New diagnostic modalities are often judged relative to accepted standard procedures. These comparisons are influenced by the accuracy of the standard test and the prevalence of disease in the study population. We evaluated the importance of these factors in the assessment of antifibrin scintigraphy when used to detect deep venous thrombosis. METHODS: Scintigraphy is compared to contrast venography in two populations of patients with different disease prevalence. We calculate the sensitivity and specificity by limb site (calf, knee, thigh) and the overall diagnosis for each modality. The sensitivity and specificity results obtained using venography as a gold standard are compared to those obtained using a maximum likelihood statistical procedure that does not require comparison to a standard test. RESULTS: A significant variation in the apparent sensitivity, specificity and accuracy is found for antifibrin scintigraphy as related to limb site, disease prevalence and use of a gold standard. The value of antifibrin scintigraphy sensitivity (84.7%) and specificity (75.8%) predicted by the maximum likelihood analysis are substantially higher than those obtained from the estimates based on the use of venography as a gold standard for both high and low disease prevalence populations. The sensitivities and specificities of antifibrin scintigraphy (84.7% and 75.8%, respectively) and venography (71.7% and 80.7%, respectively) are comparable for the combined study group of 268 patients. CONCLUSION: To obtain unbiased evaluations of a new diagnostic modality, it is essential to take into account the errors of the standard reference test and disease prevalence in the study population. The results of our analysis suggest that it may not be appropriate to use contrast venography as a gold standard in the assessment of new diagnostic imaging procedures for DVT.

Bone scan of advanced polycythemia vera with malignant transformation.

A 69-year-old man with polycythemia vera and myelofibrosis was seen with a 2-week history of increasing arm pain. A bone scan showed diffuse prominence of the long bones, especially in the metaphyseal and epiphyseal regions of the lower extremities. There was relative prominence of the proximal right humerus that suggested the presence of a malignant process in addition to marrow space expansion secondary to myelofibrosis. An MRI of the right upper extremity showed a permeated lesion in the proximal right humerus extending into the adjacent soft tissue with a large soft tissue component. At surgery, a biopsy was followed by placement of a humeral rod. The morphologic features of the tumor together with CD34 positivity were consistent with a granulocytic sarcoma. This is the first reported case of bone scintigraphic findings in advanced p. vera with myelofibrosis and malignant transformation. The case illustrates the scintigraphic appearance of extensive expansion of the marrow and suggests the importance of vigilance for relatively subtle changes of complicating malignancies.

Difference analysis of antifibrin images in the detection of deep venous thrombosis.

UNLABELLED: This study was designed to test the hypothesis that the detection of non-blood-pool localization due to deep venous thrombosis uptake can be enhanced by computer processing. METHODS: Immediate blood-pool and 90-min delay images from 25 patient studies obtained with 99mTc T2G1s antifibrin were paired into 125 image sets (5/pt, including A, P knees, A, P calves and A thighs). After spatially aligning the image pairs, the blood-pool activity obtained from the immediate image was removed from the delayed image to produce a "clot only" image. Unprocessed data (UnP) and computer processed images (CmP) were presented to novice readers as part of a receiver operator characteristic (ROC) comparison study. The image interpreters were asked to provide independent diagnostic assessment at 250 limb sites using both datasets. Image intensity and color scale mappings were freely adjustable. Three readers were presented with images adjusted with optimal image contrast as judged by an observer with knowledge of the correct response. RESULTS: The area under the ROC curve (Az), a measure of the method's accuracy, for these readers was 88.5% (UnP) and 88.8% (CmP) (p = ns). Four readers whose images were not optimized showed Az of 79.1% (UnP) and 90.7% (CmP) (p < 0.05). Average diagnostic decision time for all readers, per limb site, was 18.2 +/- 7.8 sec, m +/- s.e.m., (UnP) and 7.6 +/- 4.6 sec (CmP). CONCLUSION: Novice reader accuracy is improved with computer processed images when image intensity and contrast factors are important. Computer processing can provide "clot" images that minimize nonspecific blood background activity and allow greater interpreter decision speed/confidence.

Preparation of dextran 70 injection labeled with technetium 99m for use as a cardiac blood-pool imaging agent.

A means of compounding dextran 70 injection labeled with technetium Tc 99m by using readily available pharmaceutical components is described, and the compound's biological distribution is evaluated. The radiopharmaceutical was prepared by mixing 10 mg (0.17 mL) of dextran 70 in sodium chloride with 0.33 mL of 0.9% sodium chloride injection in a 1-mL syringe. This solution was added to a sterile, pyrogen-free vial containing stannous chloride, and the steps were repeated until five vials had been prepared. The contents of each vial were mixed by swirling until the solids were dissolved. The mixture was incubated for five minutes at 22 degrees C, then 1.48 gigabecquerels of sodium pertechnetate Tc 99m injection in a volume of 0.5 mL was added to each vial. The final mixture was incubated for 15 minutes at 22 degrees C and then stored at room temperature. Thin-layer chromatography was performed after zero, three, and six hours of storage to assess radiochemical purity. Five more vials were prepared as above, and five male volunteers were given 185 megabecquerels of the radiopharmaceutical by i.v. push, and scintigraphic images of the anterior chest were taken immediately and 1, 2, and 24 hours after injection. Immediately after preparation, a mean +/- S.D. of 99.0 +/- 1.0% of the 99mTc was bound to dextran 70. Mean +/- S.D. binding was 98.1 +/- 3.7% and 95.8 +/- 7.5% at three and six hours, respectively. Scintigraphy in the five volunteers yielded high-contrast images of the cardiac blood pool with little uptake of the radionuclide by the lungs. (ABSTRACT TRUNCATED AT 250 WORDS)

Premortem biodistribution of radioactivity in the rat: measurement of blood and tissue activity of tracers used in clinical imaging studies.

Radioactive tracers are used in nuclear medicine imaging studies to detect sites of human disease. Use of animal models helps to establish tracer biodistribution kinetics and, thus, is critical to the early testing of radiopharmaceuticals. We developed a method to characterize the premortem temporal, spatial, and compartmental biodistribution of tracer molecules in the rat and used this method to study three tracers of potential value in detecting thromboembolic disease. Dynamic gamma scintigraphy was used to determine the spatial and temporal distribution of 99mTc-labeled IgG antifibrin antibody, Fab' fragment of antifibrin, and oxidized human serum albumin (OHSA). The blood pool compartment within each tissue was determined from the biodistribution of 131I-labeled bovine serum albumin injected prior to termination. The biodistribution of the blood compartment was maintained by immediately freezing the rat carcass in isotonic saline. Three-dimensional maps of tracer distribution in the tissue and blood compartments were then constructed from cross sections of the frozen tissue. These maps were used to relate necropsy tissue counts to premortem scintigraphic images. Over a 60-min interval after administration of tracer via a tail vein, significant differences in biodistribution were evident. The IgG remained within the blood pool, but there was rapid blood clearance of the OHSA molecules by the kidney and liver. The Fab' molecules were cleared more slowly by the kidney; Fab' molecules were found in the extravascular spaces, whereas IgG and OHSA were not found. The kinetics of OHSA and Fab' in organ regions paralleled changes in the blood compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphic studies of inflammation in diffuse lung disease.

67Ga lung scintigraphy is an established means to assess alveolar inflammation in a wide variety of diffuse lung diseases. It can be used to monitor the extent and activity of the alveolitis during the course of the disease and as a follow-up evaluation to therapy. Although the mechanism of 67Ga localization is not established firmly, the isotope appears to act as a tracer for disturbed protein and cellular fluxes within the interstitium and alveolar spaces. The radiolabeled aerosol study may also be applied to the study of these fluxes as a reflection of inflammation and injury. Although Tc-DTPA clearance studies are highly sensitive to lung injury, they may be too nonspecific to separate lung injury from other physiologic processes effectively.

Nuclear medicine information management systems.

There are good arguments for considering a computer system to improve timeliness and quality of patient care, enhance the format of clinical reports, and strengthen management controls for the containment of health care costs. A nuclear medicine information management system serves to fill these needs. Receptionists access the system to schedule patient studies, log patient data, and generate examination records. Secretaries transcribe and print clinical reports. Film library staff locate patient films and keep track of borrowed studies. Technologists produce study work sheets, record quality assurance information, and process the examination results. Staff preparing radiopharmaceuticals use the system to receive and inventory tracer stocks, track preparation and dispensing activities, and to keep records for external review. Clinicians use it to look up old study results and record their study impressions. Managers access statistical reports, billing information, and resource utilization data. This review describes an information management system as implemented in a nuclear medicine clinic. Software applications for patient scheduling, radiopharmacy, film management, report generation, quality assurance, and inventory control are described as implemented on a variety of academic and commercial systems. Hardware architectures and the issues surrounding system specification and installation are explored.

Dynamic ventilation scintigraphy: a comparison of parameter estimation gating models.

Two procedures for providing the synchronization of ventilation scintigraphic data to create dynamic displays of the pulmonary cycle are described and compared. These techniques are based on estimating instantaneous lung volume by pneumotachometry and by scintigraphy. Twenty-three patients were studied by these two techniques. The results indicate that the estimation of the times of end-inspiration and end-expiration are equivalent by the two techniques but the morphologies of the two estimated time-volume waveforms are not equivalent. Ventilation cinescintigraphy based on time division gating but not on isovolume division gating can be equivalently generated from list mode acquired data by employing either technique described.

Relationship of end-expiratory pressure, lung volume, and 99mTc-DTPA clearance.

We investigated the dose-response effect of positive end-expiratory pressure (PEEP) and increased lung volume on the pulmonary clearance rate of aerosolized technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Clearance of lung radioactivity was expressed as percent decrease per minute. Base-line clearance was measured while anesthetized sheep (n = 20) were ventilated with 0 cmH2O end-expiratory pressure. Clearance was remeasured during ventilation at 2.5, 5, 10, 15, or 20 cmH2O PEEP. Further studies showed stepwise increases in functional residual capacity (FRC) (P less than 0.05) measured at 0, 2.5, 5, 10, 15, and 20 cmH2O PEEP. At 2.5 cmH2O PEEP, the clearance rate was not different from that at base line (P less than 0.05), although FRC was increased from base line. Clearance rate increased progressively with increasing PEEP at 5, 10, and 15 cmH2O (P less than 0.05). Between 15 and 20 cmH2O PEEP, clearance rate was again unchanged, despite an increase in FRC. The pulmonary clearance of aerosolized 99mTc-DTPA shows a sigmoidal response to increasing FRC and PEEP, having both threshold and maximal effects. This relationship is most consistent with the hypothesis that alveolar epithelial permeability is increased by lung inflation.

Acquisition of gamma camera and physiological data by computer.

We have designed, implemented, and tested a new Research Data Acquisition System (RDAS) that permits a general purpose digital computer to acquire signals from both gamma camera sources and physiological signal sources concurrently. This system overcomes the limited multi-source, high speed data acquisition capabilities found in most clinically oriented nuclear medicine computers. The RDAS can simultaneously input signals from up to four gamma camera sources with a throughput of 200 kHz per source and from up to eight physiological signal sources with an aggregate throughput of 50 kHz. Rigorous testing has found the RDAS to exhibit acceptable linearity and timing characteristics. In addition, flood images obtained by this system were compared with flood images acquired by a commercial nuclear medicine computer system. National Electrical Manufacturers Association performance standards of the flood images were found to be comparable.

Pulmonary epithelial clearance of 99mTc-DTPA after thrombin-induced pulmonary microembolism.

We investigated the effect of thrombin-induced pulmonary microembolism on the pulmonary clearance rate of aerosolized 99mTc diethylenetriamine pentaacetic acid (99mTc-DTPA) in awake, chronically prepared sheep. Chest activity was recorded after administration of a 0.44 micron aerosol of 99mTc-DTPA. Decay-corrected data were fit to an exponential and expressed as percent decrease per min (%/min). Sheep were given alpha-thrombin intravenously (80 U/kg for 10 min) 60 min after the aerosol administration. The clearance rate prior to alpha-thrombin was 0.35 +/- 0.05 %/min (mean +/- SEM). During alpha-thrombin administration, the clearance rate increased to 5.84 +/- 0.70 %/min (p less than 0.001 from baseline), but returned to 0.41 +/- 0.06 %/min within 30 min after the end of the thrombin infusion. The increased clearance rate during alpha-thrombin administration was not due to increased lung volume since alpha-thrombin did not change functional residual capacity. Moreover, the clearance rate was unchanged during gamma-thrombin administration, which does not induce coagulation, or during alpha-thrombin challenge in defibrinogenated animals. alpha-thrombin administration in neutrophil-depleted sheep caused a transient increase in DTPA clearance similar to that in control sheep, suggesting that the increase occurred independently of neutrophils. The results indicate that alpha-thrombin causes a large, transient increase in 99mTc-DTPA clearance, which may be the result of increased epithelial permeability. This response is dependent on the activation of intravascular coagulation.

The alveolitis of pulmonary sarcoidosis. Evaluation of natural history and alveolitis-dependent changes in lung function.

Current concepts of the pathogenesis of pulmonary sarcoidosis suggest that a mononuclear cell alveolitis, comprised of activated T-lymphocytes and activated alveolar macrophages, precedes and modulates the formation of granuloma and fibrosis that characterize the disease. To evaluate the natural history of this alveolitis and determine the relationship it has to subsequent changes in lung function, 19 untreated patients with pulmonary sarcoidosis without extrapulmonary manifestations were studied at 6-month intervals over 10.1 +/- 1.6 months with bronchoalveolar lavage, 67Ga scanning, and pulmonary function tests to evaluate lung T-cells, lung alveolar macrophages, and lung function, respectively. In this group of patients with sarcoidosis, low intensity alveolitis (lung T-cells less than or equal to 28% of all lung effector cells and/or 67Ga scan negative) was much more common (80% of all observations) than high intensity alveolitis (lung T-cells greater than 28% and 67Ga scan positive, 20% of all observations). However, the alveolitis can be unstable; 75% of all episodes of high intensity alveolitis spontaneously reverted to low intensity, whereas 12% of all episodes of low intensity alveolitis spontaneously reverted to high intensity. Furthermore, conventional clinical, roentgenographic, or physiologic studies could not predict the alveolitis status; the low intensity and high intensity groups were indistinguishable by usual criteria (p greater than 0.3, all comparisons). Interestingly, of the 51 alveolitis evaluations in the 19 patients, there were 24 occurrences (47%) where the alveolitis was "split," i.e., 67Ga scans positive and T-cells low (39%) or 67Ga negative and T-cells high (8%). In fact, 79% of all patients had either a positive 67Ga scan and/or high lung T-cells at least once during the study period, suggesting that most untreated patients with sarcoidosis without extrapulmonary symptoms often have some inflammatory processes ongoing in their alveolar structures. Overall, whenever a high intensity alveolitis episode occurred, it was followed by deterioration over the next 6 months in at least one lung function parameter 87% of the time. In contrast, a low intensity alveolitis episode was followed by functional deterioration only 8% of the time. Strikingly, while the alveolitis parameters (lavage and 67Ga scanning) clearly predicted prognosis, clinical, roentgenographic, and physiologic tests could not distinguish those patients who would subsequently deteriorate functionally. These observations should prove useful in understanding the natural history of pulmonary sarcoidosis, in staging patients with this disease, and in making rational therapy decisions.