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A. Introduction

  1. Nuclear medicine tests use specific isotopes to evaluate organ function
  2. Thus, while most radiologic tests provide anatomic data, nuclear medicine tests provide physiologic (pathophysiologic) data
  3. Protocol for Nuclear Medicine Tests
    1. Most tests require injection of liquid containing radiolabelled-test substance
    2. Subject is then placed in a radiation counter or other appropriate imaging modality
    3. Images may be read in 60 minutes (99m-Tc) or require longer (111-Indium)
    4. In many cases, computers are required to convert signal to a physiologic image
  4. PET and SPECT are considered in detail elsewhere
  5. Additional topics will be added to this Outline in OCM® Version 8.5 (December 1999)

B. Overview of Nuclear Medicine Uses

  1. Localization of Inflammation
  2. Cardiac Function
  3. Renal Function
  4. Tumor Detection
  5. Brain Function

C. Evaluation of Inflammatory Lesions [1]

  1. Characteristics of Ideal Imaging Agent
    1. Rapid delineation of inflammatory lesion (location and extent)
    2. No significant accumulation of in non-inflamed organs
    3. Rapid washout from background and retention in target lesion
    4. Descrimination between infection and non-microbial inflammation
    5. Low toxicity including absence of immune response
    6. Ease of preparation and low cost
  2. Some Utilities
    1. Demonstration of focus in fever of unknown origin (FUO)
    2. Localization and monitoring of therapy for osteomyelitis
    3. Demonstration of inflammation (vascular permeability) in areas of suspected infection
    4. Assessment of infection around vascular prosthesis and other implanted devices
  3. Agents in Common Use
    1. Ga67-Citrate
    2. Indium-111 labelled leukocytes
    3. 99mTc-HMPAO-leukocytes
    4. 99mTc-antigranulocyte Fab' antibody (Ab)
    5. 18F-deoxyglucose (fluorodeoxyglucose, FDG)
    6. 99mTc-labelled human immunoglobulin (HIG) - experimental
  4. Ga67-Citrate
    1. Gallium (Ga) is handled by iron metabolic pathways
    2. Binds to transferrin in blood and extravasates to inflammatory sites
    3. Binds lactoferrin and other siderophores in inflammed tissues
    4. Physiologic uptake in liver, spleen, bone marrow, kidney
    5. Delayed physiologic uptake in colon
    6. Primarily useful for visualizing inflammation above the diaphragm
    7. Relatively low cost and easy to administer
  5. Indium-111 Labelled Leukocytes
    1. Gold standard nuclear medicine test for inflammation
    2. Blood is removed from patient and labelled with Indium-111
    3. Labelled leukocytes are reinfused
    4. Radionuclide is rapidly cleared from normal lungs and blood pool
    5. High influx in predominantly neutrophilic infiltrates
    6. High physiologic uptake in liver and spleen
    7. No significant uptake by kidneys, bladder, gallbladder, and colon
    8. Optimal for evaluation of mid-abdomen as well as (vascular) prostheses
    9. Requires ~3 hours preparation and requires handling blood
    10. ß-emissions require longer imaging times
  6. 99mTc-HMPAO-Leukocytes
    1. Leukocytes are labelled with technetium-99m, a gamma emitter
    2. Linker is hexamethylpropylene-amine-oxime (HMPAO)
    3. Otherwise, similar issues with this and Indium-111 leukocytes
    4. However, 99mTc is less stable than Indium-111 leukocytes
    5. Therefore, imaging must be done within 3 hours of injection
    6. 99mTc is the preferred agent in children due to low radiation dose
  7. 99mTc-antigranulocyte Fab' antibody (Ab)
    1. Fab' fragment of Ab usually directed against NCA-95 antigen on activated granulocytes
    2. This is a mouse Fab' fragment, but rarely induces human anti-mouse antibodies
    3. Easy administration and good imaging quality
    4. High kidney and bone-marrow uptake
  8. 18F-deoxyglucose (fluorodeoxyglucose, FDG)
    1. Positron emission tomography (PET) with 18FDG is widely used
    2. FDG is taken up by inflammatory cells with increased metabolism
    3. FDG cannot leave cells once it enters them (glucose transporter)
    4. Tumor and inflammatory each take up FDG
    5. Requires PET device for imaging, but these are becoming increasingly available
  9. 99mTc-labelled human immunoglobulin (HIG)
    1. Labelled with 99mTc in hydrazinonicotinylamide chelator
    2. Some bowel excretion and can leak out of target
    3. This is an experimental agent at this time
  10. Experimental Agents in Development
    1. Indium-111 labelled HIG - has little uptake in normal bone marrow, good results
    2. Radiolabelled sterically stabilized liposomes
    3. Radiolabelled E-selectin monoclonal Ab - binds only activated inflammatory cells
    4. anti-CD15 monoclonal Ab -99m-Tc - specific for neutrophils
    5. Radiolabelled chemokines, lymphokines, and peptides
    6. Ciprofloxacin-99mTc- - binds to all bacterial gyrases (including ciprofloxacin resistance)

D. Cardiac Evaluation [2]

  1. Protocols (Common and Experimental)
    1. Radionuclide Ventriculography
    2. Myocardial Perfusion Imaging (SPECT and PET)
    3. Infarct Imaging
    4. Metabolic Imaging
    5. Neuronal Imaging
    6. Atherosclerosis
    7. Thrombus Imaging
    8. Apoptosis Imaging
  2. Radionuclide Ventriculography
    1. Very commonly used methodlogy for assessing ventricular pump function
    2. Radioimaging agent is usually technicium-99m labelled patient's red blood cells
    3. These are reinfused into the patient
    4. ECG triggered data acquired over several hundred heartbeats are summed
    5. Computer programs are used for detailed data interpretation
    6. Probably the most reliable indicator of ventricular function (ejection fraction)
    7. Global and regional ejection fraction and volumes are calculated
    8. Emptying and filling rates of left and right ventricle are also calculated
    9. May be performed at rest or under stress (to assess for reserve)
  3. Myocardial Perfusion Imaging
    1. Radiolabelled agents are retained in myocardial tissue in proportion to blood flow
    2. Radionuclide tracer distributions under stress versus rest can show perfusion problems
    3. Stress is usually physiologic ("exercise stress test") but can be pharmacologic
    4. Analysis using SPECT (single proton emission computerized tomography) is performed
    5. Most commonly used is the potassium (K+) analog Thallium-201 (Tl-201)
    6. Tl-201 is taken up avidly by myocardial cells (slow washout exchange with K+)
    7. Tl-201 is used for evaluating myocardial blood flow due its high extraction rate (85%)
    8. 99mTc-sestamibi or 99mTc-tetrofosmin have less myocardial extraction (60-65%)
    9. These agents are more useful for assessing viable versus non-viable myocardium
    10. Real-time 99mTc-sestamibi scanning can be used to help rule-out myocardial infarction [9]
    11. Novel isotopes for use in PET scanners have been developed
    12. Stress myocardial SPECT imaging has sensitivity 87% and specificity 76%
    13. Stress myocardial PET imaging has sensitivity 92% and specificity 89%
  4. Experimental agents for additional cardiac evaluation are under development

E. Evaluation of Renal Function

  1. 99Tc-DMSA
    1. DMSA undergoes tubular secretion only; it is not filtered
    2. Therefore, this tests evaluates renal tubular function
    3. Also called a nephrogram
  2. 99Tc-DTPA
    1. DTPA is undergoes glomerular filtration only (no tubular secretion)
    2. Therefore, this test is used for evaluation of glomerular filtration
    3. May also be used to assess for renal artery stenosis with captopril dosing
    4. This is called "captopril renogram"
  3. DTPA Renogram with ACE Inhibition [3]
    1. Patient is given 12.5-25mg of captopril1 hour before second DTPA scan
    2. DTPA renal (flow) scan is carried out prior to captopril then 1 hour after it
    3. Affected kidney will show much decreased perfusion following captopril
    4. Sensitivity ~90%, Specificity ~95%

F. Tumor Detection [5,6]

  1. Utility
    1. Cancer Staging and monitoring
    2. Cancer detection - various monoclonal Abs or ligands are used for imaging tumors
    3. Radiolabelled therapeutic antibodies and/or ligands (see below)
  2. Staging
    1. Bone Scan (see below)
    2. Thallium Scan - viable tissue detection, particularly brain tumor, osteosarcoma
    3. Gallium scan - detection of lymphocytes (as above), lymphomas
    4. MIBG Scan - neuroendocrine tumors with norepinephrine uptake (pheochromocytoma)
    5. Somatostatin uptake (see below)
    6. PET Scanning with 2-(18-Fluoro)-2-deoxy-D-glucose (FDG; see below)
  3. Bone Scan
    1. Tumor metasatic to bone generates new reactive bone formation
    2. Does not detect lesions with only osteolytic activity
    3. Uses Tc99m-diphosphonate
    4. Detects prostate, lung, breast, esophageal and other cancers
    5. Does not detect lesions due to multiple myeloma (lytic only)
  4. Somatostatin
    1. Somatostatin receptors are found on a number of tumor types
    2. NeoTect® Tc99-somatostatin can be used to image lung cancers
    3. Octreo-Scan (Indium-111) is also widely used for imaging receptor positive tumors
    4. Octreotide, a stable form of somatostatin, has been very useful
    5. Radiolabelled octreotide or somatostatin binds to most ACTH producing tumors [4]
    6. Also useful for localizing carcinoid tumors
    7. Assessment in melanoma, breast and other cancers is ongoing
  5. Radiolabelled Antibodies
    1. CEA-scan (radiolabelled antibody) is near approval for detection of colon cancer
    2. Radiolabelled prostate specific Abs are being developed for prostate cancer imaging
    3. Oncoscint (monoclonal antibody B72.3) imaged by SPECT 3-6 days after dosing
  6. Sentinel Lymph Node (LN) Analysis [5]
    1. Sentinel LN is the first LN to drain a specific site
    2. Very useful for tumor metastases to LN, avoids full LN dissection
    3. Blue dye with radioactive tracer is injected into region of tumor
    4. Hand held gamma detection probe is used to localize sentinel node
    5. Particularly useful for melanoma and breast cancer
  7. PET-FDG
    1. Semiquantitative measure of tumor metabolism with high sensitivity
    2. Tumors have high rates of aerobic metabolism
    3. FDG accumulates in (especially) tumor cells and is retained there
    4. Can be used for monitoring specific treatment, including chemotherapy or surgery
    5. FDG uptake usually falls after treatment

G. Tumor Treatment [7]

  1. Radioimmunotherapy
    1. Most therapeutics use Iodine-131 (I-131)
    2. However, ß-emissions are therapeutic, not gamma-emissions
    3. Only ~35% of I-131 emissions are ß-rays
    4. Gamma rays contribute to non-specific irradiation to patient and surroundings
    5. Therefore, patients must usually spend several days in a shielded room
    6. More favorable radionuclides are being developed (rhenium-186, -188, curium-57)
    7. Alpha ray emitters are also effective therapeutically (astatine-211, bismuth-213)
  2. Anti-CD20 Monoclonal Antibody (Ab) labelled with I-131
    1. For treatment of Non-Hodgkin's Lymphoma
    2. Unlabelled (non-radioactive) Ab showed 9% complete and 50% partial responses
    3. Radiolabelled Ab showed 50% complete and 79% partial responses
    4. Using myeloablative levels of radiolabelled Ab, 79% complete and 86% partial responses were observed
  3. Other Radiolabelled Monoclonal Abs
    1. Anti-CD22 Radiolabelled Abs
    2. Anti-HLA-DR Radiolabelled Abs
  4. Tumor Ablation
    1. Sodium iodide with Iodine-131 for treatment of differentiated thyroid cancers
    2. Bone-specific radiolabelled compounds for treatment of bone pain

H. Evaluation of Brain Function [8]

  1. SPECT and PET evaluation of brain function gaining in neuropsychiatric disease
  2. Cerebrovascular Disease
    1. Useful for evaluation of ischemic regions (similar to cardiac evaluations)
    2. Tc99m-hexametazime or Tc99m-ethylcysteine reflection at rest cerebral blood flow
    3. Can also evaluate for perfusion reserve using vasodilators (acetazolamide, adenosine)
    4. In addition, intact neurons required for Tc99m- uptake so infarcted regions show loss
  3. Blood-brain barrier can be assessed with Tc99m-technetate
  4. Dopamine Metabolism
    1. Iodine-128 benzamide binds post-synaptic D2 receptor
    2. Iodine-123 fluoropropyl carboxymetoxynortropane bindins presynaptic dopamine transporter
    3. These agents may be useful for monitoring Parkinson's Disease
  5. Serotonin receptor 4 visualized with I-123-SB 207710
  6. Glucose Metabolism
    1. Monitored with SPECT using F-18-deoxyglucose
    2. Useful in epilepsy, dementia
    3. Defects in glucose metabolism found in Alzheimer's Disease
    4. In early AD, bilateral temporal and parietal metabolic defects seen
    5. In more advanced disease, reduced bilateral frontal metabolism seen
    6. Multi-infarct dementia shows more punctate abnormalities

I. Evaluation of Other Organs

  1. Parathyroid Disease
    1. Tc99m-setamibi can be used to localize parathyroid tissue
    2. May be useful for guiding diagnosis and/or surgery
  2. Biliary and Hepatic Disease
    1. Tc99m-HIDA for assessment of biliary flow and function
    2. Excellent for assessment of cholelithiasis, patentcy of bile ducts
  3. Bone Scans
    1. In general, a three-phase bone scan is performed
    2. 99m-Tc-diphosphonate is given intravenously
    3. In very early phase, uptake is greatest in areas of (acute) inflammation
    4. In second phase, 3-24 hours after injection, uptake in areas of soft tissue inflammation
    5. Useful in osteomyelitis, cellulitis, bone metastases (see above), fracture
    6. Specific findings typical for RSDS

References

  1. Corstens FHM and van der Meer JWM. 1999. Lancet. 354(9180):765 abstract
  2. Schwaiger M and Melin J. 1999. Lancet. 354(9179):661 abstract
  3. Erbsloh-Moller B, Dumas A, Roth D, et al. 1991. Am J Med. 90:23 abstract
  4. De Herder WW, Krenning EP, Malchoff CD et al. 1994. Am J Med. 96(4):305 abstract
  5. Krag D and Moffat F. 1999. Lancet. 354(9183):1019 abstract
  6. Eary JF. 1999. Lancet. 354(9181):853 abstract
  7. Chatal JF and Hoefnagel CA. 1999. Lancet. 354(9182):931 abstract
  8. Costa DC, Pilowsky LS, Eli PJ. 1999. Lancet. 354(9184):1107 abstract
  9. Udelson JE, Beshansky JR, Ballin DS, et al. 2002. JAMA. 288(21):2693 abstract