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  1. 1. 1 Welcome to Cleveland! We hope our program will provide you with information useful in your work as nuclear medicine professionals. Topics include PET and coincidence imaging for cardiac and oncologic applications, lymphoscintigraphy for melanoma and breast imaging as well as scintimammography. Information about antibodies and peptides, including their role in new radiopharmaceuticals for diagnosing acute venous thrombosis and infection, will also be presented. We will be brought up to date on reimbursement in nuclear medicine and learn about new technology in imaging systems, from a corporate viewpoint. Our goal is to broaden your horizons and enable you to practice state-of-the-art nuclear medicine at your facility. We hope this program excites you and keeps your interest! Sincerely, James K. O’Donnell, MD, and Jennifer Nelson, CNMT Co-Chairs, CCSNM 1999 Spring Program Committee
  2. 2. 2 SOCIETY OF NUCLEAR MEDICINE CENTRAL CHAPTER, SPRING MEETING CLEVELAND, OHIO—APRIL 9–11, 1999 FRIDAY, APRIL 9, 1999 Session I Moderator: D. Bruce Sodee, MD 8:15 James L. Quinn III, MD, Memorial Lecture Historical Highlights in the Development of Positron Emission Tomography Floro D. Miraldi, MD, DSc 9:00 PET Radiopharmaceuticals: Present and Future Marc S. Berridge, PhD 9:30 Assessing Myocardial Perfusion and Viability with PET Richard C. Brunken, MD 10:15 COFFEE BREAK IN EXHIBIT HALL Moderator: Michael J. Blend, DO, PhD 10:30 PET Imaging of Lung Carcinoma Paul D. Shreve, MD 11:15 Combined PET/CT Imaging David W. Townsend, PhD 11:45 LUNCH IN THE EXHBIT HALL Session II Moderator: Shirley Garrett, CNMT PROFFERED PAPERS—1:00–2:00 p.m. 1:00 Evaluation of Cerebral Perfusion and Metabolism in Chronic Closed Head Injury (CHI) by PET Paul W. Schneider, DO 1:10 The Clinical Usefulness of Performing Same-Day Sequential 18 FDG and Combined 18 F/18 FDG Regional Oncologic PET Maximo Bleza, DO 1:20 Two SPECT/CT Registration Programs for Imaging the Pelvis Using ProstaScint. Michael J. Blend, PhD, DO 1:30 PET Coincident Experience in Community-Based, Non-Hospital Setting Larry McNamee, MD 1:40 Evaluation of Radioaerosol Delivery Efficiency of Commercial Radioaerosol Kits Peter Cutrera, BA, CNMT 1:50 Reduction of Star Artifact from Excess Gallbladder Activity in SPECT Myocardial Perfusion Imaging James A. Gleba, CNMT
  3. 3. 3 Session II—continued Moderator: Shirley Garrett, CNMT 2:00 Importance of Patient Preparation in PET Imaging Gregory Leisure, CNMT, MBA 2:30 Importance of Image Fusion in Oncologic Imaging A. Dennis Nelson, PhD 3:00 PET Imaging of Abdominal and Pelvic Neoplasms Peter F. Faulhaber, PhD 3:30 SODA BREAK IN EXHIBIT HALL Moderator: Mary Yeomans, CNMT 3:50 Coincidence Detection Gamma Camera Imaging James K. O’Donnell, MD 4:25 Technical Considerations in Gamma Camera Coincidence Detection Imaging Patricia R. Devlin, CNMT 5:00 Central Chapter Business Meeting
  4. 4. 4 SOCIETY OF NUCLEAR MEDICINE CENTRAL CHAPTER, SPRING MEETING CLEVELAND, OHIO—APRIL 9–11, 1999 continued SATURDAY, APRIL 10, 1999 Session III Moderator: Rebecca McGoun, CNMT 8:15 Radiopharmaceuticals for Lymphoscintigraphy Gopal B. Saha, PhD 8:45 Optimizing Protocols for Lymphoscintigraphy Jennifer L. Nelson, CNMT 9:35 Lymphoscintigraphy for Breast Carcinoma and Malignant Melanoma Donald R. Neumann, MD, PhD 10:15 COFFEE BREAK IN EXHIBIT HALL Moderator: Derek Fuerbringer, CNMT 10:30 Sestamibi Scintimammography Douglas Van Nostrand, MD 11:15 Panel Discussion on Breast Imaging Speakers 11:45 LUNCH ON YOUR OWN Session IV Moderator: Ridgely Conant, CNMT 1:00 Clinical Immunoscintigraphy in Oncology Hani A. Nabi, MD 1:45 Imaging of Acute Venous Thrombosis Robert F. Carretta, MD 2:35 Antibodies and Peptides: The Basics Timothy Carroll, PhD 3:25 SODA BREAK IN THE EXHIBIT HALL Moderator: Cathy Herman, NMT 3:45 Infection Imaging with an Anti-Granulocyte Monoclonal Antibody Anthony M. Passalaqua, MD 4:30 CCSNM-Technologist Section Business Meeting
  5. 5. 5 SOCIETY OF NUCLEAR MEDICINE CENTRAL CHAPTER, SPRING MEETING CLEVELAND, OHIO—APRIL 9–11, 1999 continued SUNDAY APRIL 11, 1999 Session V Moderator: David Wang, MD 9:00 Nuclear Medicine Reimbursement—1999 Robert E. Henkin, MD State-of-the-Art in Nuclear Medicine I—Corporate Viewpoint 9:30 Siemens Medical Systems Paul Ottoson, CNMT, MBA 9:50 Picker International Karl Kellar, CNMT, BS 10:10 ADAC Laboratories Steve Atkinson, PhD 10:30 COFFEE BREAK IN THE FOYER State-of-the-Art in Nuclear Medicine II—Corporate Viewpoint 10:45 GE Medical Systems Raffi Kayayan, PhD 11:05 SMV Lonnie Mixon, CNMT 11:25 Hitachi Medical Corporation of America Gary Enos, CNMT State-of-the-Art in Nuclear Medicine III 11:45 Summary D. Bruce Sodee, MD 12:00 ADJOURNMENT NOTE: The sessions beginning at 9:30 and again at 10:45 are short presentations on the latest developments by the instrumentation companies.
  6. 6. 6 HISTORICAL HIGHLIGHTS IN THE DEVELOPMENT OF POSITRON EMISSION TOMOGRAPHY Floro D. Miraldi, MD, DSc Unlike other imaging modalities, positron imaging has taken nearly a half century to progress from concept to clinical experience. Reflecting on the question, “why did it take so long?” provides a perspective for examining the development of PET. What soon becomes apparent is the necessity for the synergistic development of several technologies. Several early investigators demonstrated the advantage of positron imaging using coincidence-counting techniques. The first, and perhaps most prominent, was the work of Brownell and co-workers at Massachusetts General Hospitals. Their early work reported in 1951 [1] used a rectilinear scanning technique, but by 1960 [2] they had developed a clinically usable positron camera. Their camera produced planar images but did provide some mild tomographic capabilities. Meanwhile, tomography with single photon emitters was being studied by Kuhl at the University of Pennsylvania [3]. By late 1959, Kuhl had successfully accomplished transaxial emission tomography and by the late 1960s he had developed his Mark II scanner [ 4]. Kuhl was quite successful at producing useful clinical images by employing an analog method of back projection. He also used his system to produce transmission images, thus predating Hounsfield, and had advanced to the point of performing simultaneous transmission–emission studies. Again in the early 1960s, the Brookhaven National Laboratory group produced a true transaxial positron tomograph utilizing a ring system of detectors that is highly reminiscent of modern tomographs [5]. The system suffered poor results, however, because of a lack of adequate reconstruction methods. Unfortunately, the early work of Radon, Cormack and the Russian researchers on reconstruction methods were unknown to these pioneers. The further development of PET thus did not proceed rapidly until after the elucidation of the advanced reconstruction techniques that came with the development of X-ray CT. The more modern version of positron emission computed tomography then became possible, and was first implemented by the St. Louis group of Phelps and Terpegosian in the mid 1970s [6]. It must be recognized that the driving force behind the use of positron emitters centered on the availability of the radionuclides C-11, N-13, Oj-15, and F-18. Although these nuclides were used in metabolic studies through the 1930s and 1940s, their half-lives were considered a major disadvantage and interest dwindled. In the late 1950s and 1960s, interest was rekindled by the workers at Washington University in St. Louis and in London at Hammersmith Hospital. The renewed scientific interest and recognition of the extensive possibilities of applying these isotopes to physiologic processes stimulated a number of institutions to invest considerable time and money in what has become PET. The successful synthesis and application of F-18 deoxyglucose by Wolf et al. at Brookhaven National Laboratories [7] in the mid 1970s provided another impetus for the advancement of PET. This, in addition to the many clinical studies it spurred, excited the medical community. Finally, PET could not advance without the entrance of commercial enterprises into the field. The manufacturer of sophisticated equipment for routine use demands major involvement if a modality is to gain widespread acceptance in use. That this has occurred is a tribute to the pioneers, the giants upon whose shoulders the present industry is built.
  7. 7. 7 References: 1. Brownell GL and Sweet WH: Nucleonics, Nov. 1953. 2. Brownell GL and Burnham CA: MGH Positron Camera in Tomographic Imaging, ed. Gerald S. Freedman, September 1972. 3. Kuhl DE and Edwards RQ: Radiology, Vol.80: pp. 653-61 [no year]. 4. Kuhl D: Letter to S. Webb in From the Watching of Shadows by Steve Webb. 5. Robertson J et al: Tomographic Imaging in Nuclear Medicine, ed. Gerald S. Freedman, 1973, pp. 151-153. 6. Phelps et al: Journal of Nuclear Medicine, Vol.16, pp. 210-224, 1975. 7. Reivich M et al: Circulation Research, Vol. 44, pp. 127-137, 1979.
  8. 8. 8 PET RADIOPHARMACEUTICALS: PRESENT AND FUTURE Marc S. Berridge, PhD Case Western Reserve University Medical School In PET, radiopharmaceutical has become nearly synonymous with “fluorodeoxyglucose” or simply “FDG.” PET is now truly a clinical technique in addition to being a useful research tool. Fluorodeoxyglucose provides by far the widest range of clinical utility among PET radiopharmaceuticals. Indeed, it is the only one of the basic repertoire that has any degree of formal regulatory approval. The rapid expansion of PET through dedicated clinical PET centers, dual-use coincidence scanners, and limited FDG-manufacturing sites has created a new and relatively narrow prevailing view of the ability of PET. This is a temporary condition. Techniques in SPECT, MRI, and CT are constantly being improved. It is not unreasonable to think that at least some of the more basic jobs that are now done only by FDG-PET, even if it does a significantly better job, will in the future also be served by other methods. Cerebral perfusion measurements are a good example. So what is the true state at the present and where is the future of PET? Certainly fluoroglucose will remain with us for a long time to come. It is a very good general metabolic indicator and so it is very widely useful. But there is more. There are many other useful radiopharmaceuticals being developed and used for a variety of purposes (1–3). For measurement of metabolism, there are other radiopharmaceuticals that are more specific for certain tasks, and they are just as easily available. By being less general, they are often more suited to their niche. For some quick examples: For myocardial metabolism, acetate is an old but very useful tracer that does not present the same difficulties in viability interpretation as FDG. Hypoxia tracers may be able to do a viability determination better and faster than FDG, and they have neurologic and oncologic applications as well. In oncology, there are labeled amino acids [4], nucleic acids, and their derivatives, which give very good contrast and less interference from infections and other sources of non-tumor “hot spots.” [F-18]FLT (3l -deoxy-3l -fluorothymidine) (5) is a very good example of a new radiopharmaceutical that outperforms FDG in producing quantitative research and diagnostic information. Fluoroestradiol and related steroids give excellent sensitivity and specificity in finding estrogen-positive tumors and metastases. But PET at its best goes beyond metabolism and detection of tumors. It gets to the basic biochemistry that underlies metabolism and disease. Receptor binding tracers for receptor assessment have found a large role in research, but application to the clinical setting is still developing. Radiopharmaceuticals are being developed in connection with gene therapy, for assessment of the underlying biochemistry and of the success of genetic manipulations. The characteristics of the dual use coincidence cameras place different priorities on properties of a radiopharmaceutical, and some materials may be developed soon specifically for use in such cameras and in their setting in remote imaging facilities. There are exciting advances being made to provide technetium labeled radiopharmaceuticals with more specific mechanisms of uptake. And the use of PET for assessment of drug action and distribution is a new area of research, which has much to contribute to the drug industry, but also has direct clinical implications. The present of PET is that some useful radiopharmaceuticals are underused due to lack of attention and the inhibitory effect of regulatory and reimbursement mechanisms. The future of clinical PET will necessarily include a more varied menu of radiopharmaceuticals with a wider range of uses and greater effectiveness for each use. Reference List 1. Tewson TJ and Krohn KA (1998) Semin Nucl Med 28, 221-234. 2. Jonson SD and Welch MJ (1998) J Nucl Med 42, 8-17. 3. Saha GB, Macintyre WJ, and Go RT (1992) Semin Nucl Med 22,150-161. 4. Shoup TM, Olson J, Hoffman JM, Votaw JR, Eshima D, Eshima L, Camp VM, Stabin M, Votaw D, and Goodman MM. Synthesis and evaluation of [18 F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. (2-12-1999) J Nucl Med 40, 331-338. 5. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff, JC, Lawhorn CJ, Obradovich JE, Muzik O, and Mangner TJ (1998) Nat Med 4, 1334-1336.
  9. 9. 9 ASSESSING MYOCARDIAL PERFUSION AND VIABILITY WITH PET IMAGING Richard C. Brunken, MD, FACC Director of Nuclear Cardiology The Department of Nuclear Medicine The Cleveland Clinic Foundation Cardiac positron emission tomography (PET) has evolved over the last two decades from an exciting research tool into an affordable and clinically useful noninvasive imaging technique. As the number of clinical imaging centers increases, cardiac PET imaging will be accessible to even greater numbers of patients. The goals of this presentation are: (1) to discuss the role of PET imaging for detecting coronary artery disease, (2) to examine the utility of metabolic PET imaging for identifying myocardial viability in CAD patients with left ventricular dysfunction, and (3) to review the prognostic implications of the identification of viable but jeopardized tissue depicted by PET metabolic imaging in patients with chronic CAD. I. PET Perfusion Imaging for CAD Detection There are important differences between SPECT and PET imaging that are advantageous for the detection of coronary artery disease. Current PET tomographs have in-plane spatial resolutions on the order of 6 to 8 mm (FWHM) in the center of the field of view, as compared with the 12 to 15 mm FWHM achievable with conventional SPECT cameras. In addition, PET images are less affected by tissue attenuation than SPECT images, due to the use of individually measured attenuation coefficients and the higher energies of the photons used for imaging. In clinical practice, this is probably most important for the inferior region of the heart (where diaphragmatic attenuation is frequently a problem for SPECT myocardial images) and for the anteroseptal region in female patients (where breast attenuation may also be problematic). Offsetting the advantages of the PET imaging technique are the higher instrumentation costs as well as the costs associated with an on-site cyclotron for the production of some PET radiopharmaceuticals. Because of the improved contrast resolution and the ability to provide accurate correction for soft tissue attenuation, cardiac PET has a higher sensitivity (93%) and specificity (82%) for detection of CAD than SPECT thallium-201 scintigraphy (85% and 67%, respectively). Although the cost for PET perfusion imaging is somewhat higher than for SPECT thallium-201 scintigraphy, the total costs ultimately borne by the health care system will reflect not only the costs of the clinical tests themselves, but also the costs associated with establishing (or missing) the diagnosis of CAD. Using an economic model incorporating four diagnostic strategies, Patterson and his colleagues have indicated that PET perfusion imaging is the most cost effective means of testing for CAD in symptomatic patients with an intermediate pre-test probability of disease. In patients with a high pre-test likelihood of disease, their model indicates that proceeding directly to coronary angiography is the most cost-efficient means of establishing the diagnosis. II. Assessing Myocardial Viability with PET Imaging Accumulating clinical reports indicate that the identification of residual tissue glucose metabolism in hypoperfused ventricular segments on PET metabolic imaging with FDG in patients with ischemic heart disease is a reliable marker of important myocardial viability. This is manifest clinically by improvement in regional contractile function in metabolically active myocardial segments following interventional restoration of blood flow. Ultimately, the observed improvement in global left ventricular ejection fraction as well as the functional capacity of the patient is related to the anatomic extent and severity of the mismatch between perfusion and glucose metabolism on the pre-operative positron emission tomographic images. Those individuals with the most extensive perfusion-metabolism mismatches derive
  10. 10. 10 the most benefit from revascularization. Clinical studies also suggest that the recovery of both myocardial function and metabolism may be delayed following interventional restoration of blood flow, perhaps indicating that a period of cellular repair is necessary before full contractile function can be achieved. The findings on positron emission tomography have directly been related to their histopathologic correlates in human myocardium in clinical studies involving patients with coronary artery disease. In individuals with left ventricular dysfunction and perfusion-metabolism mismatches, viable but abnormal- appearing myocytes can be identified in affected myocardial regions. The abnormal myocytes are characterized histologically by sarcomere depletion (particularly in the perinuclear region), by an increase in cellular glycogen content, by a reduction in the numbers of mitochondria present, and by ultrastructural changes in the mitochondria. A variety of noninvasive imaging techniques have been considered useful for identifying tissue viability in dysfunctional myocardium. The study of Baumgartner and his colleagues, performed in end-stage hearts removed at the time of cardiac transplantation, suggests that both PET and thallium-201 SPECT are sensitive for identifying viable myocytes, and can produce a positive signal even in segments with <25% viable myocytes. This investigation also suggested that at least 50% of myocytes in a segment had to be viable in order for contractile reserve to be observed with low dose dobutamine echocardiography. In a meta-analysis of the various noninvasive tests used to identify myocardial viability, as defined by improvement in segmental wall motion, Bax and his colleagues reported the following: Method Patients (# studies) Sensitivity Specificity Tc-99m sestamibi SPECT 207 (10) 83% 69% Dobutamine echocardiography 448 (16) 84% 81% Tl-201 SPECT stress/redist 209 (7) 86% 47% PET with FDG 327 (12) 88% 73% Tl-201 SPECT rest/redist 145 (8) 90% 54% Although sensitive, thallium-201 SPECT perfusion imaging has a lower specificity than the other imaging techniques. PET FDG imaging is somewhat more sensitive but appears less specific than dobutamine echocardiography; this may reflect inclusion of PET studies in which patients were imaged in the fasted state or were studied post-exercise. III. Clinical PET Imaging for Prognosis in CAD PET metabolic imaging frequently identifies viable tissue in hypoperfused myocardium in coronary heart disease patients with impaired left ventricular function. Tissue viability was identified in 230 (54%) of the 423 patients in whom clinical outcomes have been correlated with the findings on initial perfusion and metabolic images. The presence of perfusion-metabolism mismatches on positron emission tomographic imaging has profound prognostic and therapeutic implications for patients with ischemic left ventricular dysfunction. In addition, the studies of Tamaki and Lee indicate that stress perfusion imaging provides little additional prognostic information beyond that afforded by a rest perfusion and FDG metabolic study alone. Medically treated patients with perfusion-metabolism mismatches have a significant (41%) and threefold higher risk for all adverse cardiac events than individuals with comparable degrees of left ventricular dysfunction who do not exhibit this scintigraphic finding. The incidence of cardiac death in medically treated patients with mismatches is about twice as high as in patients with mismatches who are revascularized (16.5% versus 8.3%). Patients with the largest perfusion-metabolism mismatches on positron emission tomographic imaging appear to have the highest risk for adverse cardiac events. In the initial report of Di Carli and his co-investigators, the relative risk of death increased by 3.5% for each 1% increase in the extent of the left ventricle with a perfusion-metabolism mismatch. In contrast, coronary revascularization was associated with a 28% reduction in cardiac mortality risk. Patients with mismatches
  11. 11. 11 who are successfully revascularized have adverse cardiac event rates that are similar to those of individuals with matching defects treated either medically or surgically, suggesting that restoration of blood flow favorably benefits both ventricular function and prognosis in individuals with this scintigraphic pattern. References Fundamentals of Cardiac PET Imaging 1. Huang SC and Phelps ME: Principles of tracer kinetic modeling in positron emission tomography and autoradiography. In Phelps ME, Mazziotta JC and Schelbert HR (eds): Positron Emission Tomography and Autoradiography. Principles and Applications for the Brain and Heart. Raven Press, New York, 1986, pp. 287-346. 2. Schelbert HR: Principles of Positron Emission Tomography. In Skorton DJ, Schelbert HR, Wolf GL, Brundage BH, Braunwald E (eds): Marcus Cardiac Imaging (2nd ed). A Companion to Braunwald's Heart Disease. W. B. Saunders Company, Philadelphia, 1996: 1063-1092. 3. Schelbert HR: The usefulness of positron emission tomography. Current Problems in Cardiology 1998; 23: 69-120. Cardiac PET for CAD Detection 1. Go RT, MacIntyre WJ, Chen EQ, et al: Current status of the clinical applications of cardiac positron emission tomography. Radiologic Clinics of North America 1994; 32: 501-519. 2. Go RT, Marwick TH, MacIntyre WJ, et al: A prospective comparison of rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging utilizing a single dipyridamole stress in the diagnosis of coronary artery disease. J Nucl Med 1990; 31: 1899-1905. 3. Maddahi J: Myocardial perfusion imaging for the detection and evaluation of coronary artery disease. In Skorton DJ, Schelbert HR, Wolf GL, Brundage BH, Braunwald E (eds): Marcus Cardiac Imaging (2nd ed). A Companion to Braunwald's Heart Disease. W. B. Saunders Company, Philadelphia, 1996: 971-995. 4. Patterson RE and Eisner RL: Cost analysis of noninvasive testing. In Marwick TH (ed): Cardiac Stress Testing and Imaging. A Clinician’s Guide. Churchill Livingstone, New York, 1996: 113-124. 5. Patterson RE, Eisner RL, Horowitz SF: Comparison of cost-effectiveness and utility of exercise ECG, single photon emission computed tomography, positron emission tomography, and coronary angiography for diagnosis of coronary artery disease. Circulation 1995; 91: 54-65. 6. Stewart RE, Schwaiger M, Molina E, et al: Comparison of rubidium-82 positron emission tomography and thallium-201 SPECT imaging for detection of coronary artery disease. Am J Cardiol 1991; 67: 1303-1310. 7. Tamaki N, Yonekura Y, Senda M, et al: Value and limitation of stress thallium-201 single photon emission computed tomography: Comparison with nitrogen-13 ammonia positron tomography. J Nucl Med 1988; 29: 1181-1188. PET Metabolic Imaging for Myocardial Viability 1. Baer FM, Voth E, Deutsch HJ, et al: Predictive value of low dose dobutamine transesophageal echocardiography and fluorine-18 fluorodeoxyglucose positron emission tomography for recovery of regional left ventricular function after successful revascularization. J Am Coll Cardiol 1996; 28: 60- 69. 2. Bax JJ, Wijns W, Cornel JH, Visser FC, Boersma E, Fioretti PM: Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: comparison of pooled data. J Am Coll Cardiol 1997; 30: 1451-1460. 3. Beanlands RSB, et al: F-18-Fluorodeoxyglucose PET imaging alters clinical decision making in patients with impaired ventricular function. Am J Cardiol 1997; 79: 1092-1095.
  12. 12. 12 4. Carrel T, Jenni R, Haubold-Reuter S, et al: Improvement of severely reduced left ventricular function after surgical revascularization in patients with preoperative myocardial infarction. Eur J Cardio- Thorac Surg 1992; 6: 479-484. 5. Gerber BL, Vanoverschelde JLJ, Bol A, et al: Myocardial blood flow, glucose uptake, and recruitment of inotropic reserve in chronic left ventricular dysfunction. Implications for the pathophysiology of chronic myocardial hibernation. Circulation 1996; 94: 651-659. 6. Grandin C, Wijns W, Melin JA, et al: Delineation of myocardial viability with PET. J Nucl Med 1995; 36: 1543-1552. 7. Gropler RJ, Geltman EM, Sampathkumaran K, et al: Functional recovery after coronary revascularization for chronic coronary artery disease is dependent on maintenance of oxidative metabolism. J Am Coll Cardiol 1992; 20: 569-577. 8. Gropler RJ, Geltman EM, Sampathkumaran K, et al: Comparison of carbon-11-acetate with fluorine- 18-fluorodeoxyglucose for delineating viable myocardium by positron emission tomography. J Am Coll Cardiol 1993; 22: 1587-1597. 9. Knuuti MJ, Saraste M, Nuutila P, et al: Myocardial viability: Fluorine-18-deoxyglucose positron emission tomography in prediction of wall motion recovery after revascularization. Am Heart J 1994; 127: 785-796. 10. Lucignani G, Paolini G, Landoni C, et al: Presurgical identification of hibernating myocardium by combined use of technetium-99m hexakis 2-methoxyisobutylisonitrile single photon emission tomography and fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography in patients with coronary artery disease. Eur J Nucl Med 1992; 19: 874-881. 11. Marinho NVS, Keogh BE, Costa DC, et al: Pathophysiology of chronic left ventricular dysfunction. New insights from the measurement of absolute myocardial blood flow and glucose utilization. Circulation 1996; 93: 737-744. 12. Marshall RC, Tillisch JH, Phelps ME, et al: Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18 F-labeled fluorodeoxyglucose and N-13 ammonia. Circulation 1983; 67: 766-778. 13. Marwick TH, MacIntyre WJ, Lafont A, Nemec JJ, Salcedo EE: Metabolic responses of hibernating and infarcted myocardium to revascularization. A follow-up study of regional perfusion, function and metabolism. Circulation 1992; 85: 1347-1353. 14. Nienaber CA, Brunken RC, Sherman CT, et al: Metabolic and functional recovery of ischemic human myocardium after coronary angioplasty. J Am Coll Cardiol 1991; 18: 966-978, 15. Pagano D, Townend JN, Littler WA, Horton R, Camici PG, Bonser RS: Coronary artery bypass surgery as treatment for ischemic heart failure: the predictive value of viability assessment with quantitative positron emission tomography for symptomatic and functional outcome. J Thorac Cardiovasc Surg 1998; 115: 791-799. 16. Tamaki N, Kawamoto M, Tadamura E, et al: Prediction of reversible ischemia after revascularization. Perfusion and metabolic studies with positron emission tomography. Circulation 1995; 91: 1697- 1705. 17. Tamaki N, Ohtani H, Yamashita K, et al: Metabolic activity in the areas of new fill-in after thallium- 201 reinjection: comparison with positron emission tomography using fluorine-18 deoxyglucose. J Nucl Med 1991; 32: 673-678. 18. Tamaki N, Yonekura Y, Yamashita K, et al: Positron emission tomography using fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting. Am J Cardiol 1989; 64: 860-865. 19. Tillisch J, Brunken R, Marshall R, et al: Reversibility of cardiac wall motion abnormalities predicted by positron tomography. N Engl J Med 1986; 314: 884-888. 20. vom Dahl J, Eitzman DT, Al-Aouar ZR, et al: Relation of regional function, perfusion, and metabolism in patients with advanced coronary artery disease undergoing surgical revascularization. Circulation 1994; 90: 2356-2366. 21. Wijns W, Vatner S, Camici PG: Hibernating myocardium. N Engl J Med 1998; 339: 173-181.
  13. 13. 13 Histopathologic Correlation in Human Myocardium 1. Baumgartner H, Porenta G, Lau YK, et al: Assessment of myocardial viability by dobutamine echocardiography, positron emission tomography and thallium-201 SPECT. Correlation with histopathology in explanted hearts. J Am Coll Cardiol 1998; 32: 1701-1708. 2. Berry JJ, Hoffman JM, Steenbergen C, et al: Human pathologic correlation with PET in ischemic and nonischemic cardiomyopathy. J Nucl Med 1993; 34: 39-47. 3. Depre C, Vanoverschelde JLJ, Melin J, et al: Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am J Physiol 1995; 268 (Heart Circ Physiol 37): H1265-1275. 4. Maes A, Flameng W, Nuyts J, et al: Histologic alterations in chronically hypoperfused myocardium. Correlation with PET findings. Circulation 1994; 90: 735-745. 5. Parodi O, De Maria R, Oltrona L, et al: Myocardial blood flow distribution in patients with ischemic heart disease or dilated cardiomyopathy undergoing heart transplantation. Circulation 1993; 88: 509- 522. 6. Schwarz ER, Schaper J, vom Dahl J, et al: Myocyte degeneration and cell death in hibernating human myocardium. J Am Coll Cardiol 1997: 27: 1577-1585. 7. Schwarz ER, Schoendube FA, Kostin S, et al: Prolonged myocardial hibernation exacerbates cardiomyocyte degeneration and impairs recovery of function after revascularization. J Am Coll Cardiol 1998; 31: 1018-1026. 8. Shivalkar B, Maes A, Borgers M, et al: Only hibernating myocardium invariably shows early recovery after coronary revascularization. Circulation 1996; 94: 308-315. 9. Vanoverschelde JLJ, Wijns W, Depre C, et al: Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 1993; 87: 1513-1523. Cardiac PET for Prognosis in CAD Patients 1. Beanlands RSB, Hendry PJ, Masters RG, deKemp RA, Woodend K, Ruddy TD: Delay in revascularization is associated with increased mortality in rate in patients with severe left ventricular dysfunction and viable myocardium on fluorine 18-fluorodeoxyglucose positron emission tomography imaging. Circulation 1998; 98: II-51–II-56. 2. Di Carli MF, Davidson M, Little R, et al: Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction. Am J Cardiol , 1994; 73: 527-533. 3. Di Carli M, Maddahi J, Rokhsar S, et al: Long-term survival of patients with coronary artery disease and left ventricular dysfunction: Implications for the role of myocardial viability assessment in management decisions. J Thorac Cardiovasc Surg 1998; 116:997-1004. 4. Eitzman D, Al-Aouar Z, Kanter HL, et al: Clinical outcome of patients with advanced coronary artery disease after viability studies with positron emission tomography. J Am Coll Cardiol 1992; 20: 559- 565. 5. Fragasso G, Chierchia SL, Lucignani G, et al: Time dependence of residual tissue viability after myocardial infarction assessed by [ 18 F]fluorodeoxyglucose and positron emission tomography. Am J Cardiol 72: 131G-139G, 1993. 6. Lee KS, Marwick TH, Cook SA, et al: Prognosis of patients with left ventricular dysfunction, with and without viable myocardium after myocardial infarction. Relative efficacy of medical therapy and revascularization. Circulation 1994; 90: 2687-2694. 7. Yoshida K and Gould KL: Quantitative relation of myocardial infarct size and myocardial viability by positron emission tomography to left ventricular ejection fraction and 3-year mortality with and without revascularization. J Am Coll Cardiol 1993; 22: 984-997.
  14. 14. 14 Cardiac PET for Predicting Improvement in Functional Capacity after CABG 1. Di Carli MF, Asgarzadie F, Schelbert HR, Brunken RC, Laks H, Phelps ME, Maddahi J: Quantitative relation between myocardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation 1995; 92: 3436-3444. 2. Marwick TH, Zuchowshi C, Lauer MS, Secknus MA, William MJ, Lytle B: Functional status and quality of life in patients with heart failure undergoing coronary bypass surgery after assessment of myocardial viability. J Am Coll Cardiol 1999; 33: 750-758. 3. Pagano D, Townend JN, Littler WA, Horton R, Camici PG, Bonser RS: Coronary artery bypass surgery as treatment for ischemic heart failure: The predictive value of viability assessment with quantitative positron emission tomography for symptomatic and functional outcome. J Thorac Cardiovasc Surg 1998; 115:791-799.
  15. 15. 15 COMBINED PET/CT IMAGING D.W. Townsend Ph.D. Department of Radiology, University of Pittsburgh Work supported by NIH Grants CA65856 and CA74135 The concept of combining a PET scanner with a CT scanner represents a synergy between two complementary imaging modalities: PET, which provides functional information, and CT, which provides anatomical information. The advantages of having coregistered images from complementary modalities has been widely recognized, although most attempts have been limited to post hoc realignment of images acquired on different scanners. Automated realignment procedures based on computer algorithms achieve good success in the brain, whereas in other parts of the body such procedures are more problematic owing to the movement of internal organs. Nevertheless, image fusion techniques in the abdomen and thorax have been explored, although all require some level of operator interaction. To address this issue, a combined prototype PET and CT scanner has been designed and built, and has recently become operational [1]. Dual-modality imaging range 60 cm CT PET 100 cm Width: 170 cm Height: 168 cm Length: 110 cm Rotation: 30 rpm 110 cm 168 cm 90 cm Figure 1. Schematic of the combined PET/CT design The design is based on combining a spiral CT scanner (Somatom AR.SP) with the PET components from a rotating partial ring tomograph, the ECAT ART [2]. The PET components are mounted on the reverse side of the rotating aluminum support of the CT scanner. The device is housed inside a single gantry 170 cm wide, 168 cm high, and 110 cm deep (Figure 1). The centers of the two tomographs are axially offset
  16. 16. 16 by 60 cm. A common patient handling system (bed) is installed at the front of the combined gantry. Dual- modality PET and CT images can be acquired for an axial extent of 100 cm, sufficient to cover the range for most patients from chin to lower thigh. The CT image is also used to provide PET attenuation correction factors [3], thus replacing the PET transmission sources, and to provide an anatomical image for the model-based scatter correction [4]. The prototype is currently under evaluation and has already demonstrated the importance and added-value of having combined (fused) anatomical and functional images when making a clinical diagnosis. Case Report 1: Lung cancer: A 77-year-old woman with primary squamous cell lung cancer was imaged on the PET/CT scanner. The PET emission scan was acquired for 8 min. The images shown in Figure 2 demonstrate a large lesion in the upper quadrant of the right lung. Although the lesion appears as a uniformly attenuating, isodense mass on CT (Figure 2a), the PET scan (Figure 2b) reveals heterogeneous uptake consistent with a necrotic center and a rim of intense uptake representing high metabolic activity. The fused image (Figure 2c) shows good alignment despite small differences due to respiratory motion. Involvement of a paratrachial lymph node, also seen on CT, was confirmed. (a) CT image (b) PET image (c) Fused PET and CT image Figure 2. A case of primary lung cancer imaged in the PET/CT scanner demonstrating a large lesion with a necrotic center in the posterior of the right lung.
  17. 17. 17 Case Report 2: Pancreatic cancer: A 38-year-old woman with confirmed pancreatic cancer was evaluated following placement of a bleary stent. A contrast-enhanced CT scan (not performed on the PET/CT scanner) revealed the presence of a large, 5 cm by 3 cm, hypodense pancreatic mass. The PET scan was acquired for 10 min, and revealed a region of focally increased uptake in the head of the pancreas (Figure 3b) with an SUV of 5.3. The location of the increased uptake was consistent with the hypodense mass seen on CT (Figure 3c). In addition to the focal uptake in the pancreas, the whole-body PET/CT scan also revealed focally increased 18 F-FDG uptake in a right dorsal rib and in a mediastinal lymph node (not shown here) suggesting spread of the disease. (a) CT image (b) PET image (c) Fused PET and CT image Figure 3. A 38-year-old woman with primary pancreatic cancer referred for post-stent placement evaluation References 1. Bailey DL, Young H, Bloomfield PM, et al. “ECAT ART—a continuously rotating PET camera: performance characteristics, initial clinical studies and installation considerations in a nuclear medicine department”, Eur J Nuc Med 24:6-15, 1997. 2. Kinahan PE, Townsend DW, Beyer T, Sashin D. Attenuation correction for a combined 3D PET/CT scanner, Med Phys 25:2046-2053, 1998. 3. Townsend DW, Beyer T, Kinahan PE, Brun T, Roddy R, Nutt R, Byars LG. The SMART scanner: a combined PET/CT tomograph for clinical oncology. IEEE Medical Imaging Conference Record, 1998. CD-ROM. 4. Watson CC, Newport D, Casey ME. A single scatter simulation technique for scatter correction in 3D PET, in Computational imaging and vision, P Grangeat and J-L Amans, eds. Kluwer Academic, 1996, 255-268.
  18. 18. 18 PROFERRED PAPERS Please see table of contents for page number of submitted abstracts
  19. 19. 19 COINCIDENCE DETECTION GAMMA CAMERA IMAGING James K. O’Donnell, MD University Hospitals of Cleveland Slide 1 POSITRON EMISSION TOMOGRAPHY Dedicated PET vs Gamma Camera Coincidence Imaging ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 2 FDG 2-[fluorine-18] fluoro-2-deoxy-D- glucose ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  20. 20. 20 Slide 3 18 18 + F ---> O + B + Ve 9 9 8 10 . T1/2 = 110 mins ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 4 FDG • Glucose utilization in: BRAIN HEART NEOPLASMS • A powerful imaging tool ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 5 Hi Energy Collimation • Less spatial resolution than LEHRP • Less sensitivity than LEHRP • “Hot” lesion limit: 1.5 cm at 5:1 t:b 1.3 cm at 10:1 t:b ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  21. 21. 21 Slide 6 511 keV Collimator Limitations • Sensitivity and Resolution • Weight (thick septa) • Core length (limits imaging volume) • Septal penetration ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 7 Camera modifications for CD • Thicker NaI(Tl) Crystal • PHA linear energy range to 511 keV • More shielding • Significant electronics modifications ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 8 NaI(Tl) Crystal Photopeak Detection Efficiency • for 3/8” crystal: 84% at 140 keV 13% at 511 kev • at 511 keV: 3/8” 13% 1/2” 31% 5/8” 62% 3/4” 85% (But decreasing RES) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  22. 22. 22 Slide 9 Count Rates PET 350k cps (trues) CD 12k cps ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 10 Count Rates for CD Function of: crystal thickness energy window source geometry singles rate ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 11 Coincidence Detection • Hi Photon Flux…..BUT 0.15 % (2D) of events are TRUES 0.45 % (3D) of events are TRUES • Most of events are: Scatter Singles Randoms ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  23. 23. 23 Slide 12 Axial Filters • Widely spaced slat “collimator” • Slats perpendicular to table axis • Reduce scatter by 30- 40% (“bad” coincidence events) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 13 Clinical Applications 511 UHE E.CD HEART Yes Yes BRAIN No ? ONCOLOGY No Maybe ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 14 CD Clinical - CARDIAC • FDG myocardial viability (with Tc-99m perfusion SPECT) • Rb-82 perfusion NO! (T1/2 = 2 mins) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  24. 24. 24 Slide 15 CD Clinical - BRAIN • Dementias • Seizure disorders • Tumors - especially recurrence or residual after Rad Rx ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 16 CD Clinical - ONCOLOGY • Currently reimbursed for : - solitary pulmonary nodules - lung cancer staging • Many other indications pending ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 17 Current PET “Recipe” • Give FDG i.v. • Wait 60 mins • Scan until done ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  25. 25. 25 Slide 18 Unanswered Questions for PET/CD • When is best T:B ratio achieved ? - is later always better ? • When is best T:B ratio for different tumors ? - maximum accumulation in tumor - lowest background • When is maximal count rate achieved ? - x mCi in field of view ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 19 Unanswered Questions for PET/CD For a given neoplasm and a given organ, how much FDG should be administered to ultimately image x mCi in that field of view when the T:B ratio is expected to be highest ? ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 20 Non- NaI(Tl) Crystal (LSO) lutetium oxyorthosilicate ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  26. 26. 26 RADIOPHARMACEUTICALS FOR LYMPHOSCINTIGRAPHY Gopal B. Saha, PhD Department of Nuclear Medicine Cleveland Clinic Foundation Cleveland, OH The primary requirement for a radiopharmaceutical suitable for lymphoscintigraphy is that it clears rapidly from the injection site after subcutaneous administration, flows with the lymph, and accumulates in the lymph node. Based on these criteria, two major categories of radiopharmaceuticals for lymphoscintigraphy are: (a) colloids and (b) macromolecules such as albumin, dextran, and antibodies. After subcutaneous administration, colloids of smaller size clear from the injection site rapidly, flow through the lymphatic vessels, and accumulate in the lymph nodes where they are phagocytosed by macrophages. Larger colloids cannot cross the endothelium of the cells of the lymphatic vessel and hence are not useful for lymphoscintigraphy. Colloids of size 10–30 nm appear to be the most suitable radiopharmaceutical for lymphoscintigraphy. Among the different colloids used for lymphoscintigraphy, 99m Tc-Sb2S3 (antimony sulfide) colloid, 99m Tc-rhenium colloid, and 99m Tc-nanocolloid having the size of 10–30 nm seem to be the best agents, but none of these is commercially available in the USA. In contrast, the normal 99m Tc2S7 (sulfur colloid) contains large particles (~200 nm) and is not suitable for lymphoscintigraphy. To remove these large particles, the 99m Tc2S7 preparations are filtered through a 0.1 µm membrane filter, whereby only smaller particles of size <100 nm appropriate for lymphoscintigraphy are obtained in the filtrate. Among the macromolecules for lymphoscintigraphy, albumin, dextran, and a selected few antibodies have gained prominence for this use. 99m Tc-albumin and 99m Tc-dextran are vascular agents, flow with the lymph, and accumulate in the lymph nodes, but give higher blood background. Their clearance from the lymphatic system is rapid and hence their use is limited. 131 I-labeled antibodies against melanoma, breast cancer, and T-cell lymphoma have been used for lymphoscintigraphy and their uptake is prompted by antigen-antibody complex formation in the lymph node. Other agents such as 99m Tc-polyethylene starch, 99m Tc-Haemaccel, 111 In-labeled lymphocytes have been used for lymphoscintigraphy, but with limited success. References 1. Bergquist L, Strand SE, Persson BRR. Particle sizing and biokinetics, of interstitial lympho- scintigraphic agents. Semin Nucl Med 1983; 13:9-19. 2. Eshima E, Eshima LA, Gotti NM, et al. Technetium-99m sulfur colloid for lymphoscintigraphy: Effects of preparation parameters. J Nucl Med 1996; 37:1575-1578. 3. Henze E, Schelbert HR, Collins JD, et al. Lymphoscintigraphy with 99m Tc-labeled dextran. J Nucl Med 1982; 23:923-929. 4. Hung JC, Wiseman GA, Wahner HW, et al. Filtered technetium-99m sulfur colloid evaluated for lymphoscintigraphy. J Nucl Med 1995; 36:1895-1901. 5. Kramer EL. Lymphoscintigraphy: Radiopharmaceutical selection and methods. Nucl Med Biol 1990; 17:57-63. 6. Wahl RL, Geatti O, Liebert M, et al. Kinetics of interstitially administered monoclonal antibodies for purposes of lymphoscintigraphy. J Nucl Med 1987; 28:1376-1744.
  27. 27. 27 LYMPHOSCINTIGRAPHY FOR BREAST CARCINOMA AND MALIGNANT MELANOMA Donald R. Neumann, MD, PhD The Cleveland Clinic Foundation I. Sentinel lymph node concept II. Lymphatic mapping techniques a) Scintigraphic b) Vital dyes c) Handheld gamma probe III. Radiopharmaceuticals IV. Techniques for scintigraphy a) Cutaneous b) Breast c) Localization methods d) Pitfalls/Artifacts V. Intraoperative techniques
  28. 28. 28 SESTAMIBI SCINTIMAMMOGRAPHY Douglas Van Nostrand, MD, FACP, FACNP Director of Nuclear Medicine, Good Samaritan Hospital Clinical Professor of Radiology and Nuclear Medicine Uniformed Services University of Health Sciences I. Introduction A. Extent of the problem of breast cancer B. General evaluation of breast cancer C. Why is there a need for Sestamibi scintimammography? II Procedure A. Radiopharmaceuticals B. Mechanism of Sestamibi localization C. Imaging technique III. Normal Scintimammographic Images A. Intensities B. Orientation C. Normal findings IV. Review of Literature A. Sensitivity B. Specificity C. Positive predictive value D. Negative predictive value E. Editorial V. Cases A. Indications with available statistics. 1. Difficult to interpret mammograms (indeterminate mammograms) 2. Selected patients with dense breasts. 3. Selected patients with breast prostheses. 4. Evaluation of multi-focal disease. 5. Evaluation of patients with possible recurrent disease after previous surgery/radiotherapy. B. Pits and Pearls VI. Diagnostic Algorithms VII. Summary
  29. 29. 29 CLINICAL IMMUNOSCINTIGRAPHY IN ONCOLOGY Hani A. Nabi, MD State University of New York at Buffalo Radiolabeled monoclonal antibodies against a variety of solid tumors and hematological malignancies have been developed over the past 2–3 decades. Several have been introduced to the clinics, while many others are still being developed. The most common current applications of the FDA approved MoAbs such as satumomab pendetide, capromab pendetide, arcitumornab, and Verluma, include detection and localization of recurrent colorectal and ovarian cancers, searching for the presence of extrahepatic tumor sites in patients with resectable liver metastases, determining the status of lymph nodes preoperatively in patients with newly diagnosed prostate cancer as well as searching for recurrent/metastatic disease in patients with rising PSA, and finally staging newly diagnosed small cell lung carcinoma. Clinical scenarios of the utility of these agents will be presented and, whenever applicable, compare immunoscintigraphy to other imaging modalities, particularly 18 F FDG Positron Emission Tomography.
  30. 30. 30 IMAGING OF ACUTE VENOUS THROMBOSIS Robert F. Carretta, MD Roseville Community Hospital, Roseville, CA Slide 1 1d.1 ™™ Indication the scintigraphic imaging of acute venous thrombosis in the lower extremities in patients who have signs and symptoms of acute venous thrombosis ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 2 1d.2 Prevalence (USA) ofPrevalence (USA) of Venous ThromboembolismVenous Thromboembolism Deep Vein Thrombosis ➤ 2,000,000 - 5,000,000 cases per year1,2 Pulmonary Embolism ➤ 500,000 - 600,000 cases per year2,3 1. Hirsh J et al. Circulation 1996; 93:2212-2245. 2. Moser KM. Am Rev Respir Dis 1990; 141:235-249. 3. Dalen JE et al. Prog Cardiovasc Dis 1975; 17:259-270. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  31. 31. 31 Slide 3 1d.3 Conditions Associated with Acute DVTConditions Associated with Acute DVT ➤ Cancer ➤ Major surgery ➤ Immobilization ➤ Prior history of DVT ➤ Trauma ➤ Oral contraceptives, obesity, heart disease, pregnancy, advanced age ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 4 1d.4 Complications of Acute DVTComplications of Acute DVT ➤Pulmonary Embolism ➤Post-Phlebitic Syndrome ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 5 1d.5 Pulmonary EmbolismPulmonary Embolism ➤ 50,000 -100,000 deaths per year in USA1,2 ➤ The most common cause of death associated with child-birth3 ➤ 30% fatal if untreated, 10% fatal in spite of treatment2 ➤ 70-90% of PE arise from acute DVT in the legs1,4 1. Moser KM. Am Rev Respir Dis 1990; 141:235-249. 2. Dalen JE et al. Prog Cardiovasc Dis 1975; 17:259-270. 3. Kaunitz AM et al. Obstet Gynecol 1985; 65:605-612. 4. Hull RD et al. Ann Intern Med 1983; 98:891-899 ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  32. 32. 32 Slide 6 1d.6 Post-Phlebitic SyndromePost-Phlebitic Syndrome ➤ 25-65% of cases of acute DVT develop post- phlebitic syndrome1,2 ➤ painful ➤ debilitating 1. Strandness DE et al. JAMA 1983; 250:1289-1292. 2. Prandoni P et al. Ann Intern Med 1996; 125: 1-7. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 7 1d.7 Acute DVTAcute DVT ➤ Originates in the deep veins of the lower extremities ➤ As many as 90% originate in the calves1 ➤ Signs and symptoms are non-specific ➤ Only 20-50% of symptomatic patients have confirmed acute DVT2,3 ➤ 25% develop recurrent DVT4 1. Nicolaides AN et al. Br J Radiol 1971; 44:653-663. 2. Wells RD et al. Lancet 1995; 345:1326-1330. 3. Stamatakis JD et al. Br J Radiol 1978; 65:449-451. 4. Prandoni P et al. Ann Intern Med 1996; 125: 1-7. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 8 1d.8 Treatment of PE and DVTTreatment of PE and DVT Anticoagulation ➤ heparin ➤ warfarin (coumadin) Risk ➤ major bleeding(5%1) ➤ thrombocytopenia (1%1) 1. Hirsh J et al. Chest 1995; 108:258S-275S ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  33. 33. 33 Slide 9 1d.9 Contrast VenographyContrast Venography ➤ “Gold Standard” but: ➤ painful ➤ technically inadequate/difficult to interpret in 10-30% of cases1,2 ➤ cannot reliably differentiate acute from non-acute DVT 1. Hirsh J et al. Circulation 1996; 93:2212-2245. 2. Anand SS et al. JAMA 1998; 279:1094-1099. 3. Lensing AWA et al. Radiology 1990; 177:503-505. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 10 1d.10 UltrasoundUltrasound ➤ high sensitivity for proximal DVT in symptomatic pts but: ➤ low sensitivity below knee1 ➤ low sensitivity (40-60%) in asymptomatic, high risk pts2,3 ➤ may miss duplicate veins4 ➤ technically difficult/equivocal in up to 25% of cases ➤ cannot reliably differentiate acute from non-acute DVT 1. Rose SC et al. Radiology 1990; 175:639-644. 2. Davidson BR et al. Ann Intern Med 1992; 117:735-738. 3. Lensing AWA et al. Arch Intern Med 1997; 157:765-768. 4. Screaton NJ et al.Radiology 1998; 206:397-401. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 11 1d.11 Current Diagnostic ModalitiesCurrent Diagnostic Modalities Contrast Venography and Ultrasound are ➤ not specific for acute DVT ➤ not accurate for the diagnosis of recurrent DVT ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  34. 34. 34 Slide 12 1d.12 Unmet Medical NeedUnmet Medical Need An imaging agent for acute venous thrombosis characterized by: ➤ rapid detection ➤ ease of administration ➤ total body evaluation ➤ non-invasive ➤ safe and effective ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 13 1d.13 Why is NeededWhy is Needed ➤ Clinical signs and symptoms are non-specific ➤ Old, non-acute DVT may confound diagnosis by venography or ultrasound ➤ In some patients, venography and ultrasound are difficult to perform and to interpret ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 14 1d.14 ™™ ➤ Clinical Importance of Acute DVT ➤ Mechanism of Action ➤ Clinical Results ➤ Summary ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  35. 35. 35 Slide 15 1d.15 Deep Vein ThrombosisDeep Vein Thrombosis Natural HistoryNatural History platelets thrombus propagation embolization organization acute non-acute or activated platelets - present in acute but not non-acute thrombi ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 16 1d.16 Platelet AggregationPlatelet Aggregation = Fibrinogen Extracellular Matrix Endothelial Cell Tc-99m apcitide ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 17 1d.17 Binding to Platelet GPIIb/IIIa ReceptorsBinding to Platelet GPIIb/IIIa Receptors fibrinogen PlateletPlatelet RGD sites 99mTc Tc-99m apcitide GPIIb/IIIa 99mTc GPIIb/IIIa 99mTc Activated PlateletActivated Platelet GPIIb/IIIa Tc-99m apcitide and fibrinogen bind to the GPIIb/IIIa receptors on activated platelets ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  36. 36. 36 Slide 18 1d.18 GPIIb/IIIa ReceptorGPIIb/IIIa Receptor ➤expressed only on platelets ➤not expressed on endothelial cells ➤key in platelet aggregation q mediates the binding of fibrinogen to platelets q only binds fibrinogen when platelets are activated ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 19 1d.19 Technetium Tc 99m ApcitideTechnetium Tc 99m Apcitide ➤apcitide, a small synthetic peptide ➤binding region for the platelet GPIIb/IIIa receptor ➤radiolabeled with Tc-99m (D-Tyr)- Apc-Gly-Asp Gly-Gly-Cys(Acm)-Gly-Cys(Acm)C H2C O C O CHNH CH2 S -1 N NH2 O O O N S N Tc O ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 20 1d.20 Active Binding RegionActive Binding Region apcitideRGD NH NH NH O O O S NH3 O O NH NH NH O O O NH NH3 O O HN ➤Fibrinogen contains the RGD (arginine-glycine-aspartic acid) sequence ➤Apcitide contains an analog of the RGD sequence in which arginine is replaced by a synthetic amino acid (Apc) arginine Apc ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  37. 37. 37 Slide 21 1d.21 ™™ How It Works ➤ Activated platelets are present in acute thrombi ➤ The GPIIb/IIIa receptor is expressed on activated platelets ➤ Tc-99m apcitide binds to the GPIIb/IIIa receptor ➤ Unbound Tc-99m apcitide clears rapidly ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 22 1d.22 ™™ ➤ Clinical Importance of Acute DVT ➤ Mechanism of Action ➤ Clinical Results ➤ Summary ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 23 1d.23 Imaging Acute DVT withImaging Acute DVT with Standard Procedure ➤ 20 mCi Tc-99m, 100 µg peptide ➤ Antecubital vein injection ➤ Standard nuclear medicine gamma camera ➤ Planar images at 10 min and 60-90 min ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  38. 38. 38 Slide 24 1d.24 Imaging Acute DVT withImaging Acute DVT with Image Interpretation Criteria ➤ asymmetric, linear uptake ➤ in a deep vein segment ➤ that persists ➤ or becomes apparent on late images ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 25 1d.25 GammaGamma CameraCamera © 1998, ImEngine, Inc. ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 26 1d.26 Normal BiodistributionNormal Biodistribution 10 min 60 min 240 min R anterior L L posterior R R anterior L L posterior R R anterior L L posterior R 41 year old female ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  39. 39. 39 Slide 27 1d.27 Technetium Tc 99m ApcitideTechnetium Tc 99m Apcitide Biodistribution and Dosimetry ➤ rapid urinary excretion over 24 hours (84-99%) ➤ hepatobiliary excretion = 6% over 24 h ➤ blood pool approx. 10% ID at 60 min ➤ mean effective dose equivalent = 0.034 rem/mCi ➤ maximum absorbed radiation dose (to urinary bladder wall) = 0.22 rad/mCi ➤ estimated biological half-life = 1.9 h ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 28 1d.28 Negative CaseNegative Case 10 min 60 min 120 min R anterior L L posterior R R anterior L L posterior R R anterior L L posterior R Patient History: 34y female, no prior history of DVT or PE, 2 days from onset of signs and symptoms in right calf, knee and thigh; venogram negative Findings: negative for acute DVT 2395 ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 29 1d.29 Positive CasePositive Case 10 min 60 min 120 min R anterior L L posterior R R anterior L L posterior R R anterior L L posterior R Patient History: 66y male, prior history of DVT and PE, 5 days from onset of signs and symptoms in right calf and knee, on heparin and warfarin; venogram positive right calf and popliteal veins Findings: acute DVT in right calf, knee and (distal) thigh 4370 ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  40. 40. 40 Slide 30 1d.30 Positive CasePositive Case 60 min images R anterior L Patient History: 23y male, no history of DVT or PE, 8 days post gunshot wound to left thigh, 3 days from onset of signs and symptoms in left leg, on heparin and warfarin; ultrasound positive left femoral and popliteal veins Findings: acute DVT in left calf, knee and thigh R anterior L ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 31 1d.31 Pivotal Clinical ResultsPivotal Clinical Results ➤ 2 Independent and well, controlled clinical trials ➤ Identical protocol ➤ Technetium Tc 99m apcitide - a functional test… ➤ …compared to contrast venography, the “gold standard” - an anatomical test ➤ 34 Centers in North America and Europe ➤ 280 Patients enrolled ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 32 1d.32 SAFETY Treatment-Related Adverse Events in Pivotal Trials AcuTect™ Venography n=278 n=272 Body Pain 0 3 Asthenia 0 1 Injection site edema 0 1 Injection site reaction 0 1 Cardiovascular Hypotension 1 0 Syncope 0 1 Digestive Nausea 0 2 Vomit 0 1 Nervous Hypesthesia 0 1 Skin Rash 0 1 TOTAL 1 12* *p < 0.001 significantly safer than venography in this study ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  41. 41. 41 Slide 33 1d.33 PIVOTAL CLINICAL TRIALPIVOTAL CLINICAL TRIAL DEMOGRAPHICSDEMOGRAPHICS Sites 34 Evaluable Patients 243 Age (mean ± s.d.) 59.6 ± 15.7 years Weight (mean ± s.d.) 78.5 ± 18.7 kg Gender Female 123 Male 120 Race Asian 4 Black 7 Caucasian 222 East Indian 5 Hispanic 4 Native American 1 ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 34 1d.34 PIVOTAL CLINICAL TRIALPIVOTAL CLINICAL TRIAL DESIGNDESIGN Entry Criteria ➤ Within 10 days of onset of signs/symptoms of acute DVT ➤ Or within 10 days of high risk surgery Diagnostic Tests ➤ Contrast Venography and ™ to be performed within 3 days of each other ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 35 1d.35 PIVOTAL CLINICAL TRIAL DATAPIVOTAL CLINICAL TRIAL DATA Presenting Signs and Symptoms Total Evaluable Patients 243 Signs and Symptoms Pain/tenderness/Homans’ sign 210 (86%) Swelling 202 (83%) Increased warmth 100 (41%) Erythema 92 (33%) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  42. 42. 42 Slide 36 1d.36 Time from onset of signs and symptoms to first test and prior history of DVT or PE PIVOTAL CLINICAL TRIAL DATAPIVOTAL CLINICAL TRIAL DATA < 1 Days 43 (18%) < 3 Days 104 (43%) < 5 Days 157 (65%) < 7 Days 206 (85%) Total (< 10 Days) 243 Prior History of DVT or PE 58 (24%) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 37 1d.37 Anticoagulant/antiplatelet medication PIVOTAL CLINICAL TRIAL DATAPIVOTAL CLINICAL TRIAL DATA Total Evaluable Patients 243 Anticoagulants Heparin Group 150 (62%) Vitamin K Antagonists 74 (31%) Antiplatelet medication 72 (30%) At least one antiplatelet/anticoagulant 171 (70%) ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 38 1d.38 PHASE 3 EFFICACY RESULTSPHASE 3 EFFICACY RESULTS Blind-Read Vs Blind-Read Venography Sensitivity 73.4% Specificity 67.5% Agreement Rate 69.1% Institutional-read Vs Blind-read Venography Sensitivity 81.3% Specificity 65.0% Agreement Rate 69.6% ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  43. 43. 43 Slide 39 1d.39 PATIENTS (n=60) PRESENTING WITHIN 3 DAYS OFPATIENTS (n=60) PRESENTING WITHIN 3 DAYS OF ONSET OF SIGNS AND SYMPTOMSONSET OF SIGNS AND SYMPTOMS AND WHO HAD NO PRIOR HISTORYAND WHO HAD NO PRIOR HISTORY Blind-Read Vs Blind-Read Venography Sensitivity 83.3% Specificity 73.8% Agreement Rate 76.7% Institutional-read Vs Blind-read Venography Sensitivity 100 % Specificity 69.0% Agreement Rate 78.3% ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 40 1d.40 ™™ ➤ Clinical Importance of Acute DVT ➤ Mechanism of Action ➤ Clinical Results ➤ Summary ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 41 1d.41 NDANDA ➤ Fast Track review by FDA: q submitted 19 August 1997 q approvable letter 20 Feb 1998 q approved 14 September 1998 ➤ Indicated for: the scintigraphic imaging of acute venous thrombosis in the lower extremities in patients who have signs and symptoms of acute venous thrombosis ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  44. 44. 44 Slide 42 1d.42 Particularly Useful in These Cases ➤ negative or equivocal US but suspected acute DVT ➤ recurrent DVT ➤ contrast venography is contraindicated or technically difficult ➤ calf-vein thrombus ➤ obese patient ➤ duplicate veins ➤ non-compliant patient ➤ trauma ➤ orthopedic casts ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________ Slide 43 1d.43 CONCLUSIONCONCLUSION ™ (Technetium Tc 99m Apcitide) is safe and effective for the scintigraphic imaging of acute venous thrombosis in the lower extremities in patients who have signs and symptoms of acute venous thrombosis ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ ____________________________ _____________________
  45. 45. 45 ANTIBODIES AND PEPTIDES: THE BASICS Timothy Carroll, PhD DuPont Pharmaceuticals Company This presentation will cover the fundamental properties of both antibodies and peptides. The audience will gain an appreciation for what antibodies and peptides are, how they are used by the body, and how we can exploit these properties for use in Radiopharmaceuticals Antibodies are large, molecular “locks,” which are very specific for a particular "key" or antigen to which it will bind. These proteins typically have a very long half-life in the body, high affinity for the target, but generally poor target-to-background ratios. There are some approaches to get around this, which will be discussed. Radiolabelling of antibodies has been performed by a number of strategies, which will be briefly reviewed. In spite of significant visibility of these molecules in the literature and even popular press for the last twenty years, there have been very few new products introduced. Issues relating to the manufacture of these products will also be discussed. Peptides are small, molecular “keys,” which are very specific for a particular "lock" or receptor to which it will bind. Peptides generally have a very short half-life in the body, high affinity for the target, and generally better target to background ratios. The issues with peptides have to do with radiolabelling in such a way as to not impact receptor binding, and finding appropriate ligand-receptor pairs to use that will be relevant to an unmet medical need. Many of the current new developments in the radiopharmaceutical literature are based on peptide or peptidomimetic systems. Peptidomimetics are nonpeptide compounds that bind to receptors in a similar fashion to a peptide. This brief presentation will only serve as an introduction of these topics, but the attendee should gain an appreciation for these interesting materials and how they are being used in our field.
  46. 46. 46 INFECTION IMAGING WITH AN ANTI-GRANULOCYTE MONOCLONAL ANTIBODY: EXPERIENCE WITH NON-CLASSIC ACUTE APPENDICITIS Anthony M. Passalaqua, MD Children's Hospital Medical Center of Akron Introduction There are 250,000 appendectomies for acute appendicitis in the United States each year. Most patients present with classic acute appendicitis, which is readily diagnosed from the history and physical examination. When the presentation is not classic, acute appendicitis can present a diagnostic challenge. In an ambulatory care setting, the incidence of acute appendicitis in children with abdominal pain significant enough to seek medical care is 2.3%. This increases to 32% for children admitted to the hospital for acute abdominal pain. With appropriate treatment, the overall mortality rate for appendicitis is very low (less than 0.3%) although mortality is more frequent in children and the elderly and approaches 5% for patients over the age of 65 years. The mortality and morbidity of appendicitis are predominately related to appendiceal rupture. The incidence of appendiceal rupture is reported to range from 17% to 40% with a median of 20% and, because of delays in seeking medical care, rupture occurs more frequently in children and the elderly. In acute appendicitis, appendiceal rupture occurs in 50% of patients over the age of 65 years. There is significant morbidity associated with the removal of a normal appendix. In most series, the negative laparotomy rate for suspected acute appendicitis ranges from 15% to 35% with a median also of 20%. In young women of childbearing age, the negative laparotomy rate can range as high as 52% since pelvic inflammatory disease and other gynecological disorders may mimic acute appendicitis. Various techniques and imaging modalities have been used in the attempt to effectively separate patients with equivocal findings for acute appendicitis into surgical and nonsurgical categories in order to reduce the negative laparotomy rate and the incidence of appendiceal rupture. These have included various predictive scoring systems, a period of extended observation, and the utilization of diagnostic imaging modalities such as plain radiographs of the abdomen, barium enemas, graded compression ultrasonography, computed tomography, and scintigraphy with ex vivo-labeled leukocytes. These methods have had some success, but each has its limitations and there is an unmet need for a sensitive and timely method to evaluate patients with suspected nonclassic appendicitis. Scintigraphy with in vivo-labeled WBCs White blood cell scintigraphy using in vivo labeling of granulocytes with a Tc99m-labeled anti- granulocyte murine monoclonal antibody Fab' fragment (LeukoScan , Immunomedics Inc., Morris Plains, New Jersey) avoids the limitations and risks of ex vivo labeling of WBCs. When infused intravenously, the antibody labels the granulocytes in vivo since it recognizes and binds to an antigenic surface glycoprotein (NCA-90) on the granulocyte cell wall. Advantages The advantages of in vivo labeling with an antigranulocyte monoclonal antibody fragment are ! WBC scintigraphy is immediately available 24 hours/day. ! Simple preparation, no special skills or equipment. ! Bypasses the need for a 30 to 60 ml aliquot of the patient's blood in the labeling process, which eliminates the associated risk of exposure of the technologist and the patient to the drawing and handling of blood and blood products.
  47. 47. 47 ! Labeling of the granulocytes occurs rapidly and imaging can begin immediately after injection. ! Antibody fragment is rapidly cleared from the blood pool by the kidneys, bone marrow, and liver, providing a good target to background ratio. ! Use of an antibody fragment is not associated with an immune response and the development of human antimouse antibody (HAMA). Preparation of Antibody The anti-granulocyte antibody Fab' fragment is labeled using a kit supplied by Immunomedics, Inc. The kit consists of a 3 ml vial containing 0.31 mg of the anti-granulocyte monoclonal antibody fragment in lyophilized powder. For preparation, 0.5 ml of normal saline is added to the vial and the vial contents are dissolved by swirling, followed by the addition of 20–30 mCi of Tc99m sodium pertechnetate. The labeling reaction is complete in 5 minutes. Patient Dose Patients are given the Tc99m-labeled anti-granulocyte antibody fragment intravenously and the patient's granulocytes are tagged in vivo. The amount of tracer administered is based on the four age ranges: 5 years 10 mCi 6–10 years 15 mCi 11–15 years 21 mCi 16 years or older 25 mCi Patient Imaging Imaging sequence ! Sequential 1-minute images of the abdomen/pelvis for initial 15 minutes post tracer injection. ! Planar images of the abdomen/pelvis or whole body images at 1/2 hour. ! SPECT images of the abdomen/pelvis at 1 hour. matrix size 128x128 120 images (3 deg) 30 sec/image Continue with planar and SPECT images of the abdomen at approximately 1-hour intervals until a positive focus of tracer accumulation is definitely identified in the right lower quadrant of the abdomen or for at least 3 hours in patients deemed normal. Scan Interpretation A scan is abnormal if a focus of tracer accumulation is demonstrated in the right lower quadrant of the abdomen on the planar or SPECT images. Below are typical normal and abnormal planar images of the abdomen and pelvis and abnormal cross-sectional SPECT images.
  48. 48. 48 Planar Images Normal Acute Appendicitis Ruptured Appendix SPECT Images
  49. 49. 49 Potential Pitfalls A pelvic appendix may be obscured by tracer accumulation in the urinary bladder on the planar images and SPECT reconstruction artifacts around the bladder on cross sectional images. The initial one-minute sequential images of the abdomen/pelvis will allow transient visualization of the pelvic region before the bladder begins to fill. On later images, the patient may void between images or, if necessary, the bladder may be drained via a catheter. Tracer may be noted in the bowel lumen on delayed imaging at 3 or more hours and should not be confused with granulocyte accumulation due to infection. Occasionally a prominent focus of tracer is demonstrated in the right lower quadrant due to holdup of the tracer in the distal right ureter as it crosses the iliac vessels. This is located medially and adjacent to the spine on the cross sectional images and should not be confused with the appendix. Diagnostic Results Accuracy In evaluating 32 patients with suspected nonclassic appendicitis, 30 patients had SPECT imaging. SPECT studies had a much greater sensitivity when compared to planar studies. SPECT detected 16 of the 17 patients with nonclassic appendicitis for a sensitivity of 94%. Planar imaging was obtained in 32 patients and detected 10 of the 19 patients with nonclassic appendicitis for a sensitivity of 53%. The combined planar and SPECT imaging results for 32 patients are: Sensitivity 18/19 95% Specificity 12/13 92% Positive Predictive Value 18/19 95% Negative Predictive Value 12/13 92% Accuracy 30/32 94% True Positive =18, True Negative =12, False Positive =1, False Negative =1 WBC imaging with in vivo-labeled granulocytes and SPECT imaging fulfills the unmet need for evaluating patients with suspected non-classic acute appendicitis.
  50. 50. 50 Timeliness The accumulation of tracer in the RLQ of the abdomen was identified relatively early on the scans of patients who had acute appendicitis. Five studies were positive on the ½-hour images, ten studies were positive on the one-hour images, and the remaining three studies were positive on the two-hour images. The data are summarized below: The Antigranulocyte Antibody WBC Scan Sensitivity with Time for 19 Patients with Acute Nonclassic Appendicitis. Time 1/2 hour 1 hour 2 hour Positive Scans 5/19 15/19 18/19 % Sensitivity 26% 79% 95% WBC imaging with in vivo–labeled granulocytes avoids the typical 3–4 hour delay of ex vivo labeling of WBC. When combined with SPECT imaging, suspected nonclassic appendicitis can be evaluated in a timely manner avoiding a delayed or missed diagnosis and increased likelihood of appendiceal rupture. Summary Patients with the classic findings of acute appendicitis should undergo prompt surgical exploration without diagnostic testing, which can delay treatment and increase the likelihood of appendiceal rupture. However, in patients with nonclassic appendicitis, the clinical diagnosis of acute appendicitis is unclear. In vivo–labeled WBC scintigraphy with an antigranulocyte monoclonal antibody (LeukoScan) is a superior method for the evaluation of patients with suspected nonclassic appendicitis. References 1. Addiss DG, Shaffer N, Fowler BS, et al: The epidemiology of appendicitis and appendectomy in the United States Am J Epidemiol 1990; 132:910-925. 2. Balthazar EJ, Birnbaum BA, Yee J, Megibow AJ, Roshkow J, Gray C: Acute appendicitis: CT and US correlation in 100 patients. Radiology 1994; 190:31-35. 3. Becker W, Goldenberg DM, Wolf F: The use of monoclonal antibodies and antibody fragments in the imaging of infectious lesions. Sem in Nucl Med 1994; 24:142-153. 4. Henneman PL, Marcus CS, Inkelis SH, Butler JA, Baumgartner FJ: Evaluation of children with possible appendicitis using Tc99m leukocyte scan. Pediatrics 1990; 85:838-843. 5. Jerman RP: Removal of the normal appendix: the cause of serious complications. Br J Clin Pract 1969; 23:466-467. 6. Kanegaye JT, Vance CW, Parisi M, Miller JH, Mahour GH, Chan LS, Schonfeld N: Failure of technetium-99m hexamethylpropylene amine oxime leukocyte scintigraphy in the evaluation of children with suspected appendicitis. Pediatric Emergency Care 1995; 11:285-290. 7. Lewis FR, Holcroft JW, Boey J, et al: Appendicitis: a critical review of diagnosis and treatment in 1000 cases. Arch Surg 1975; 110:677-684. 8. Ramirez JM, Deus J: Practical score to aid decision making in doubtful cases of appendicitis. British Journal of Surgery 1994; 81:680-683. 9. Rao PM, Rhea JT,Novelline RA, McCabe CJ, Lawrason JN, Berger DL, Sacknoff R: Helical CT technique for the diagnosis of appendicitis: Prospective evaluation of a focused appendix CT examination. Radiology 1997; 202:139-144. 10. Wagner JM, McKinney WP, Carpenter JL: Does this patient have appendicitis? JAMA 1996; 276: 1589-1594. 11. White JJ, Santillana M, Haller JA: Intensive in-hospital observation: a safe way to decrease unnecessary appendectomies. Am Surg 1975; 41:793-798.
  51. 51. 51 NUCLEAR MEDICINE REIMBURSEMENT—1999 Robert E. Henkin, MD, FACNP, FACR Loyola University Medical Center Maywood, IL Background Information Below is an outline of the recent and ongoing reimbursement issues. You will note that most of these issues continue as ongoing items rather than resolved issues. This is the nature of reimbursement and probably will be so for the foreseeable future. 1. Practice Expense Reimbursement Until recently the Healthcare Financing Administration (HCFA) based a portion of physician reimbursement due to practice expenses on data submitted by the American Medical Association. All involved parties acknowledged that these data were inaccurate. Over the last several years, HCFA has engaged in a process to determine exactly what the correct components of the physician practice expense are. It is no surprise that for radiology and nuclear medicine, HCFA has decided that they are overpaying. The panel consensus (CPEP) approach was used to judge practice expenses. Dr. Ken McKusick participated in these panels and tried to negotiate the fairest possible arrangement for practice expenses. The first published version of physician practice expenses information indicated that radiology (including nuclear medicine) may see a one-time readjustment downward of about 15%. This number represented a global value, and depending upon the breakout of case types in your practice, this number might have been higher or lower. There were and are ongoing negotiations with HCFA to attempt to adjust certain nuclear medicine codes and, all codes as a whole, due to levels of intensity that deal with the use of radioactive materials in humans. On November 2, 1998, HCFA issued its final revision of practice expenses. These went into effect on January 1, 1999. In this version, practice expenses decreased only 3% for 1999 in professional fees. However, there will continue to be a refinement of this process throughout 1999. This is for professional component figures only. In general, one could expect to see a reduction of about 10% in professional revenue over the next four years if this system is implemented without further change. Because of other changes implemented by HCFA, after the professional societies intervened, the change in global reimbursement will actually result in a 1% to 5% increase in the technical component now rather than the 24% proposed decrease. A proposed further reduction of 2% over four years is anticipated. 2. Conversion Factors Previously, Medicare had two conversion factors. The first factor was for surgical services and the second for all other services. Nuclear medicine was covered in the all-other-services category. As of January 1, 1999, there is a single conversion factor of $34.73. This is 5.3% less than in the 1998 year. However, the impact on individual practices is somewhat difficult to anticipate since in some situations, practice expenses will be increased based on malpractice relative value units. It seems most likely that practices will see a reduction from the introduction of revised practice expenses and changes in the conversion factor. Reductions on the order of 10% to 15% in Medicare-related revenue are anticipated over several years, as noted above. 3. Direct Supervision Nuclear medicine procedures are one of the areas proposed by Medicare requiring direct physician supervision. Treadmill exercise testing is another such area. There has been controversial comment on the issues of what direct supervision means and how electronic supervision may relate to direct supervision. Currently, direct supervision is required for hospital-based physicians when they have
  52. 52. 52 resident training programs. That is, if a resident performs a procedure, the attending physician must be present for the procedure or he/she cannot bill for the procedure. However, outside the academic setting, these rules have not been placed into force. Because of the volume and complexity of comments that HCFA received on the issue of supervision, it has delayed implementation of its proposed rules. 4. Coding Issues The nuclear medicine community has been active in the issues of coding and reimbursement. There are several new codes this year, most of which combine existing codes into single procedures or describe new services. There is a dispute as to what the future coding system will be. CPT 5 is currently under development by the American Medical Association. However, HCFA may choose to use another coding system in which it has invested a great deal of effort, and it is not CPT 4 or 5 compatible. The ultimate outcome of this effort is uncertain. 5. Carrier Advisory Committees More and more power is being delegated to the local carrier advisory committees. These committees are often given discretionary authority by Medicare for local practice coverage decisions. In the absence of national coverage decisions (where Medicare itself has not made a national decision), the local committee may choose to approve a given medical procedure for reimbursement. The Corporate Committee of ACNP funded a project designed to increase nuclear medicine representation on these committees and to keep our representatives informed as to what the College’s policies and views were. To date, a listing of nuclear medicine and non-nuclear medicine members of carrier advisory committees has been developed. A list of the carrier medical directors has also been developed. 6. Ambulatory Payment Classes Over the last year, the majority of effort has been conducted by the Ambulatory Payment Class (APC) Task Force, which consists of the Society of Nuclear Medicine, The American College of Nuclear Physicians, The American Society of Nuclear Cardiology, CORAR, and ICP. The ambulatory payment classification system is intended to be a resource-based prospective payment system similar to the DRGs in concept. From our perspective the major fault in this system is that it bundles radiopharmaceutical reimbursement in with the technical components for nuclear medicine procedures. It should be noted that this only occurs in the hospital outpatient setting and does not occur in the private practice setting. Private practices continue to be able to bill independently for radiopharmaceuticals. On reviewing the publication from HCFA in the Federal Register of September 8, 1998, a number of inequities were discovered in the proposed reimbursements. Under the APC system, all existing nuclear medicine codes will be lumped into one of nine new APC codes (originally only five APC codes had been proposed, but the APC Task Force was able to convince HCFA to go to 9 codes). We are requesting a 10th code to cover PET MPI imaging. Each APC code has an RVU value assigned and there will be a conversion factor to determine payment. With over 100 nuclear medicine CPT codes reduced to nine payments, inequities are bound to occur. We have had a great deal of difficulty extracting data from HCFA on how radiopharmaceuticals were actually factored into the expenses. However, from the information we did obtain, it appears that the work values or technical component values of the proposed RVUs are logical, if one excludes radiopharmaceutical cost. Independent survey data developed by the APC Task Force show wide variation in radiopharmaceutical cost between institutions. The case mix, size of institution and volume affect radiopharmaceutical costs. We have been discussing the concept with HCFA that radiopharmaceuticals continue to be reimbursed separately. HCFA is not anxious to do this in part because it sets a precedent of paying for drugs, and further that it creates a system outside the standard APC system.
  53. 53. 53 The possibility exists that radiopharmaceuticals could be reimbursed under a separate set of APCs specifically for radiopharmaceuticals. However, at this writing it is uncertain what HCFA’s final approach is going to be to correct the problem. Numerous meetings have been held with HCFA staff to explain the issue and we believe they understand them in depth. However, there are mechanistic and political problems within HCFA that may prevent an easy solution. The APCs were scheduled to be introduced on January 1, 2000. It was to be a four-year phase in period until they were fully in place. It is now likely that the APCs will not be introduced prior to the second quarter of 2000, and perhaps even later than that. This results from Y2K compatibility issues within HCFA as well as difficulties in responding to questions that are being raised about the integration of radiopharmaceuticals and other drugs into the APC system. 7. PET Reimbursement In January 1998, HCFA issued a coverage decision involving the use of coincidence imaging (PET and gamma camera) in solitary pulmonary nodules and intra-thoracic staging of non-small lung cancer. It approved reimbursement for these two diagnoses. However, this reimbursement mechanism is somewhat cumbersome, since it involves the use of “G” codes and submission of additional data beyond those derived from the images. The number of claims received by HCFA so far is small in this category. We believe a problem exists at the carrier level in not being able to follow HCFA’s directions as to how to process the claims. The approved claim amount of $1,980 for the technical component for the procedure includes the cost of the radiopharmaceutical. The physician fee ranges between about $85 and $100. There are over 200 private insurers that are known to reimburse for PET studies. Of importance is the distinction that HCFA made that all coincidence imaging technology is the same: that dedicated PET scanners and coincidence cameras are treated the same under HCFA’s rulings. In January 1999, HCFA held a “Town Meeting” at its Baltimore office. They invited specialists in various areas of the PET community and oncologists to present data on malignant melanoma, lymphoma, recurrent brain tumor, head and neck cancer, and colorectal cancer for review. The result of this meeting was seen in March 1999 when HCFA issued a positive coverage decision for recurrent colon cancer, with rising CEA, malignant lymphoma, and malignant melanoma FDG coincidence imaging. The exact codes and reimbursement for these procedures is yet to be released. 8. Managed Care Managed care itself is in disarray at the moment. Double-digit increases in premiums are occurring as well as reduction of some benefits available to members. This was expected based on the growing enrollment in managed care organizations. Many managed care contracts are pegged to the RBRVS. Since this is the case, changes occurring in the RBRVS due to practice expenses and code realignments become of critical importance. Indirectly, the RBRVS may increase or decrease the managed care payments depending on what happens to each code. Summary Overall, there is a great deal of activity going on in the reimbursement/practice management world. This short document tries to highlight some of the initiatives we have seen during the past year. The next year will have equally interesting “issues” for us to work with. It is important to note that we have received strong support from our corporate colleagues in dealing with these issues. Legal, lobbying, and technical support have been made available to the community from the corporate community to help in formulating responses and dealing with these issues.
  54. 54. 54 DISCLOSURES The following faculty have declared a potentially significant relationship with companies/organizations (a.) whose products or services will be discussed or (b.) who are supporting this activity. Marc S. Berridge, PhD None None Richard C. Brunken None None Robert F. Carretta, MD Diatide Grants/Research Support/Consultant Nycomed Amersham Honorarium Timothy R. Carroll, PhD DuPont Pharmaceuticals Employees Patrick R. Devlin None None Peter F. Faulhaber, PhD None None Robert E. Henkin, MD ADAC Laboratories Consultant Gregory Leisure, CNMT, MBA Siemens Honorarium (Not for this lecture) Floro D. Miraldi, MD, DSc None None Hani A. Nabi, MD Immunomedics, Cytogen Grants/Research Support A. Dennis Nelson, PhD None None Jennifer L. Nelson, CNMT None None Donald R. Neumann, MD, PhD None None James K. O’Donnell, MD None None Anthony M. Passalaqua, MD Immunomedics Grants/Research Support/Stockholder Gopal B. Saha, PhD None None Paul D. Shreve, MD Siemens Honorarium (Not for this lecture) D. Bruce Sodee, MD None None David W. Townsend, PhD CTI PET Systems Consultant Douglas Van Nostrand, MD DuPont Pharmaceuticals Grants/Research Report/Consultant/ Honorarium