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Positron Emission Tomography.

The 19th century discovery of photographic process marks the genesis of film-based medical imaging.[1] Photography, in combination with the discovery of x-rays by Wilhelm Conrad Roentgen in 1895, not only provided "insight into the unopened living body," but also the means to record and assess patient health. Before these events, surgery and autopsy were the only tools available to physicians and scientists interested in the visual differentiation of health and disease.

Today, a wide range of noninvasive imaging technologies are available to clinicians. However, until recently, diagnostic imaging was limited to the anatomical appearance of tissues and organs. The advent of positron emission tomography (PET) has transformed the clinician's vantage point. PET and sophisticated computational image processing give clinicians the ability to see the effect of physiological changes related to pathology.

Overview

Unlike other medical imaging techniques, PET provides a physiology-based assessment of health and pathology. The movement and accumulation of isotope-tagged, physiologically active biomolecules offers a way to see cell metabolism, perfusion or cell-surface integrity. Often used in combination with magnetic resonance (MR) imaging and computed tomography (CT), PET links physiology to anatomical change.

Historical Development

The science and technology behind PET involves particle physics, the biological and chemical behavior of isotope-labeled molecules, the fabrication of radiopharmaceuticals and the technical ability to convert isotopic disintegrations into information-rich images. PET has emerged as an important medical imaging technique because of the interdisciplinary efforts of physicists, biochemists, chemists, engineers, mathematicians, computer scientists and physicians.

Although PET appears to be a recent innovation, its history can be traced back to the 1930s when cyclotrons first were used to dissect the structure of the atomic nucleus. Then, more than 20 years later, a group of physicists at Washington University in St. Louis found that:

* Metabolic processes occur quickly enough to be traced by cyclotron-produced isotopes.

* Physiologically active molecules could be labeled as tracers.

* Energy released by the annihilation of positrons makes it possible to locate the site of biological activity.

In 1973 Ter-Pogossian and colleagues at Washington University built the first PET scanner. Initially used to study normal brain function, PET imaging now is gaining wide acceptance as a gold standard to diagnose certain cancers, coronary artery disease (CAD) and a limited number of neurological conditions.

Comparison With Other Imaging Techniques

Each imaging technique has unique characteristics and applications. PET and single photon emission computed tomography (SPECT) use nuclear imaging methods to assess tissue function. Although PET has a higher resolution, SPECT is a more affordable technology, making physiology-based images more widely available (M. Hartshorne, M.D., oral communication, March 2001).

Both CT and MR produce anatomic images. CT uses x-radiation, often in combination with contrast media, to produce highly detailed images of bone and the surrounding soft tissues. MR uses a strong magnetic field and radio waves to produce computer-enhanced anatomical images. Unlike CT and PET, MR does not require the use of ionizing radiation. (See Table 1.)
Table 1
Comparison of PET With Selected Imaging Techniques[2]

                PET            SPECT        MR           CT

Measures        Physiology     Physiology   Anatomy      Anatomy

Resolution(*)   4.5-5 mm       8-10 mm      0.5-1 mm     1-1.5 mm

Physical        Positron       Gamma        Nuclear      X-ray
basis           annihilation   emission     magnetic     absorption
                                            resonance

Potential       Radiation      Radiation    None known   Radiation
harmful         exposure       exposure                  exposure
effects

No. of exams    3-6            4-8          10-15        15-20
per day

Use             Research and   Clinical     Research,    Research,
                clinical                    clinical,    clinical,
                                            fused        fused with
                                            with PET     PET

(*) As of 1995.

PET indicates positron emission tomography; SPECT, single photon
emission computed tomography; MR, magnetic resonance imaging,
computed tomography.


PET can be used as a stand-alone method and in combination with CT and MR. A combined image generated by dedicated CT/PET machines or constructed from separate PET, CT or MR data sets, allows clinicians to evaluate PET data in relation to anatomical landmarks. (See Fig. 1.) Clinicians can make well-founded patient-care decisions when they can see the exact location of abnormal physiologic activity.

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HCFA Reimbursement

The Health Care Financing Administration (HCFA), a federal agency within the Department of Health and Human Services, administers Medicare, Medicaid and the State Children's Health Insurance Program. In addition to providing health insurance, HCFA also is involved in activities such as regulating clinical laboratories, improving quality of care and formulating coverage policy.[2] It is in this last capacity that HCFA-regulated reimbursement influences the use of certain medical procedures. In addition to approving payment for specific procedures, HCFA defines the level of payment for services, payment codes and "conditions of participation" for affected institutions (C. Fredman, B.A., R.N., oral communication, February 2001). Private insurance reimbursement for medical procedures often follows HCFA approval.

PET is just beginning to make the transition from research tool to an important diagnostic method. Between 1995 and 1999, HCFA approved coverage of PET imaging for diagnosis, staging or evaluation of 6 narrowly defined oncological conditions and 1 myocardial indication. (See Table 2.)
Table 2
Medicare-approved Uses of PET 1995-1999(20)

Date of    Use                         Radiotracer
Approval

1995       Heart perfusion and          Rubidium
           management of                   82
           patients with known or
           suspected coronary
           artery disease

1998       Staging of non-small-           FDG
           cell lung cancer in
           patients with a con-
           firmed tumor, but extent
           of disease is unknown

1998       Characterization of sus-        FDG
           pected solitary pul-
           monary nodules to
           determine likelihood of
           malignancy

1999       Evaluation of recurrent         FDG
           colorectal cancer in
           patients with rising lev-
           els of carcinoembryonic
           antigen

1999       Substitute for gallium          FDG
           scan in staging
           Hodgkin disease and
           non-Hodgkin lymphoma

1999       Detection of recurrent          FDG
           melanoma

FDG indicates fluorodeoxyglucose


HCFA received a request to consider broad coverage of 22 additional diseases in July 2000. After an in-depth review of the scientific literature and discussion of clinical issues, coverage was approved for 10 new applications of PET technology. (See Table 3.) Jeffery Kang, director of HCFA's Office of Clinical Standards and Quality said, "We expect to expand coverage for additional conditions when we accumulate sufficient scientific evidence."[3]
Table 3
Summary of New Medicare Coverage for FDG PET, 2000[19]

Clinical Condition              Coverage Decision

Non-small-cell lung cancer      Diagnosis, staging and restaging
Esophageal cancer               Diagnosis, staging and restaging
Colorectal cancer               Diagnosis, staging and restaging
Lymphoma                        Diagnosis, staging and restaging
Melanoma                        Diagnosis, staging and restaging;
                                  regional node evaluation not
                                  covered
Head and neck cancers           Diagnosis, staging and restaging
  (excluding CNS and thyroid)
Breast cancer                   Referred to MCAC for review
Myocardial viability            Covered following inconclusive
                                  SPECT exam; referred to MCAC
                                  for review of additional uses
Refractory seizures             Covered for presurgical evaluation
Alzheimer disease/dementia      Referred to MCAC for review

MCAC indicates Medicare Coverage Advisory Committee; CNS, central
nervous system; SPECT, single photon emission computed tomography


Recent expansion in coverage demonstrates PET's acceptance as a valuable diagnostic tool and makes the technique more available to specific populations. Michael Phelps, Ph.D., a coinventor of the PET scanner, underscored the importance of the HCFA ruling, "With this, HCFA is also recognizing that the merging of biology and medicine is changing our understanding, diagnosis and treatment of disease."[3]

According to researchers and clinicians, the benefit and cost-saving potential for PET lie in its ability to:

* Detect disease before anatomical deterioration.

* Stage and track disease progression.

* Limit patient exposure to invasive diagnostic and treatment techniques.

* Eliminate the need for redundant diagnostic tests and surgical procedures.

* Influence the use of the most appropriate and effective treatment protocols.

* Track treatment efficacy.

* Guide surgical procedures.

* Select patients with a high potential for a positive outcome.

Retrospective studies involving lung and breast cancer, colorectal cancer recurrence and myocardial viability suggest that PET is a cost-effective medical imaging technique despite the high cost of equipment.[4] (See Table 4.) These cost-saving estimates do not include costs associated with complications and mortalities inherent in invasive procedures.
Table 4
Estimated Impact of PET Imaging on
Medicare

                             Impact

Total PET studies/y          388 951
No. of invasive procedures   189 162
  eliminated/y
Total savings to Medicare    $1.6 billion/y
Total projected net cost     $1.2 billion/y
  savings to Medicare


Biological Principles

Although PET is a technologically complex procedure, it evaluates what many would claim are the most basic of biological processes -- perfusion, metabolism and biosynthesis. All living cells transport molecules across membranes, produce energy-rich adenosine triphosphate (ATP) molecules and convert building-block nutrients into required biomolecules.

PET takes advantage of cellular needs for glucose, water, and carbon- and nitrogen-containing molecules. By studying the accumulation patterns of special isotopes, PET enables clinicians to assess cell viability, abnormalities in metabolism and nutrient use. Tissues and organs that show elevated accumulations of PET isotopes demonstrate inappropriately high rates of cell metabolism or altered cell transport characteristics. Conversely, diminished uptake indicates loss of cell activity or cell death. Therefore, unlike other medical imaging techniques, PET is a dynamic rather than a static assessment of tissue health and integrity. With PET, clinicians have the opportunity to monitor and treat potentially degenerative pathologies before anatomical manifestation of the disease process.

Biochemical Principles

Isotopes for PET imaging are prepared by incorporating radioactive forms of carbon, oxygen or nitrogen into metabolically relevant or clinically important molecules such as water, carbon monoxide, dopamine-affinity markers or fatty acids. The most commonly used PET isotope is fluorine 18 ([sup.18]F), which is used to make fluorodeoxyglucose (FDG).[5]

Glucose is the starting molecule for glycolysis, a metabolic step common to almost every life form on earth. Literally meaning, "the breaking of glucose," glycolysis splits the 6-carbon glucose molecule into 2, 3-carbon pyruvate molecules and produces a net gain of 2 ATP molecules. Converting nutrients into high-energy ATP molecules enables cells to stockpile or use energy to perform cell functions.

Because of its ubiquitous nature, carbon-labeled glucose disperses quickly throughout the body, thereby making it difficult to differentiate normal from abnormal glucose usage. To solve this problem, [sup.18]F replaces the hydroxyl group attached to the number 2 carbon in the glucose molecule. (See Fig. 2.) The body handles FDG uptake as if it were ordinary glucose molecules. However, once the glucose analog enters cells, glycolysis cannot proceed and [sup.18]F byproducts accumulate in the cell cytoplasm.[6]

Cells with abnormally high metabolic rates take up large amounts of [sup.18]F-labeled glucose. Malignant tumors, which typically demonstrate high rates of cell division, require higher than normal amounts of glucose to meet their metabolic needs. This makes it possible to both identify and stage malignancy in situ without having to resort to invasive biopsy and surgical methods.

Cells compromised by pathology or long-term loss of tissue perfusion are metabolically less active. Therefore, compromised cells and tissues demonstrate diminished uptake of FDG. This characteristic helps distinguish cardiac patients who might benefit from revascularization procedures.

In addition to FDG, there are several other important, though less commonly used, isotope-labeled molecules for PET diagnostic studies.[5] (See Table 5.) Inhaled oxygen 15 is used to map normal cerebral oxygen metabolism, and [sup.15]O-labeled carbon monoxide allows clinicians to assess the corporal blood pool.[6] Water is another [sup.15]O-labeled molecule used for PET studies. Like [sup.15]O-labeled carbon monoxide, [sup.15]O water is used to determine cerebral and myocardial perfusion and oxygenation.
Table 5
Some Cyclotron-produced Isotopes[7]

Target Sample              Isotope Produced

[sup.18]O water               [sup.18]F
water                         [sup.13]N
[N.sub.2] + 1% [O.sub.2]      [sup.15]O


When used in PET analysis, nitrogen 13 is most often chemically linked to ammonia molecules. Nitrogen 13 ammonia is transported into myocardial cells where it is incorporated into nitrogen-containing amino acids, the building-block molecules needed for protein synthesis.[5] Because [sup.13]N ammonia does not readily diffuse out of myocardial tissues, it is an effective marker for myocardial perfusion studies. (See Fig. 3.)

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Carbon 11 generally is used for carbon monoxide blood-pool studies. However, its most effective use is to label compounds that have unique physiologic or pharmacologic properties, such as fatty acids for myocardial viability studies and the antipsychotic drug spiperone to study brain dopamine receptor sites.

Physical Principles

PET radiopharmaceuticals contain proton-enriched elements. Cyclotrons accelerate the protons to speeds at which they combine or react with elemental nuclei. In the process, stable elements are transformed into radioactive elements. PET converts the radioactive energy spontaneously released from isotope-identified organs and tissues into images displayed on a computer monitor or printed on acetate film.

When the radioisotope decays, it emits a positron that almost immediately reacts with an electron. The combined particles undergo an annihilation reaction that releases 2, 511-kV gamma photons.[7] The photons disperse in opposite directions. An array of specialized crystal detectors, positioned directly opposite one another, records the annihilation events. Only coincidental events, those that are recorded within 8 to 12 nanoseconds from each other, count as having resulted from a single annihilation.[6] Complex computational algorithms convert the electronic signal into a tomographic image.

Isotope Production

PET imaging depends on the availability of short-lived isotopes manufactured in cyclotrons. (See Table 6.) The gamma-emitting isotopes used in PET imaging are created by bombarding target elements with high-energy protons stripped from hydrogen ions. Various polarity and magnetic field manipulations cause the protons to travel at high speeds in the acceleration chamber. When high-energy protons hit the sample, some of them react with target nuclei and produce unstable and proton-rich elements. These proton-rich isotopes decay by annihilation and, in the process, emit a positron and gamma radiation.
Table 6
Specific PET Isotopes and Their Medical Uses[8]

Isotope       Half-life   Medical Uses
              (minutes)

Carbon 11         20      Blood-pool tracer studies (carbon
                            11 carbon monoxide)
                          Dopamine receptors and mental
                            disorders (carbon 11 spiperone)
                          Myocardial viability (carbon 11
                            fatty acids)
Fluorine 18      110      Brain activity (FDG)
                          Identification of noninfarcted
                            myocardial tissues (FDG)
                          Location of primary tumors and
                            metastases (FDG)
                          Bone density studies (fluorine 18)
Nitrogen 13       10      Myocardial blood flow (nitrogen 13
                            ammonia)
Oxygen 15          2      Blood flow to the brain and
                            myocardium (oxygen 15 water)

FDG indicates fluorodeoxglucose


To make [sup.18]F for FDG, [sup.18]O water is placed in the target chamber. The collision of high-energy protons with [sup.18]O nuclei converts oxygen to [sup.18]F. The resulting product contains a mixture of unreacted [sup.18]O water and proton-rich [sup.18]F.[8]

Types of Cyclotrons

Isotopes needed for radiopharmaceuticals are made in different types of cyclotrons. Some facilities use a self-contained radioisotope delivery system (RDS) to produce PET radiopharmaceuticals. RDS cyclotrons are relatively small, free-standing units dedicated to producing PET isotopes for imaging purposes. All functions of the RDS are controlled by a personal computer.[9]

Other facilities use research-grade cyclotrons to produce PET isotopes. These cyclotrons require both special protective shielding and building construction to house them. For example, the high-energy cyclotron located at the University of Iowa PET imaging center weighs 22 tons and is located within a cement vault that has 5-foot-thick concrete walls.[10]

PET facilities generate revenue through patient payments, Medicare and insurance reimbursements and research grants to cover the costs of basic and applied research. The expenses associated with isotope production often limit PET technology to urban areas or to major medical centers likely to serve large numbers of patients.

The initial outlay for an RDS capable of producing a full range of PET isotopes is more than $2 million, with an additional $180 000 for annual maintenance. (D. Hunter, M.Sc., oral communication, March 2001.) The University of Iowa's research-grade cyclotron was purchased in 1989 for $1.5 million. The annual cost of repairs and maintenance for this cyclotron, aside from indirect costs, is approximately $80 000 per year (R. Hichwa, Ph.D., e-mail communication, March 2001). A cyclotron has a 30-year lifetime before the unit becomes obsolete and too expensive to maintain.

In addition to the cost of producing isotopes, there are costs associated with the delivery of the product to the PET imaging center. Fluorine 18, which has a half-live of 110 minutes, is the only PET pharmaceutical transported to off-site locations. Private courier services can deliver FDG to PET facilities within 2 hours' travel time of the cyclotron. This can add several hundred dollars to the cost of each unit dose.

PET Radiopharmaceuticals

Because of their short half-lives, PET isotopes are custom-produced for patients. The handling, processing and synthesis of PET radiopharmaceuticals is carried out in a nearby "hot lab" protected by lead walls and 6-inch-thick silicon glass windows. Robots or mechanical arms move the isotopes through the synthesis and compounding processes. PET pharmaceuticals must be made rapidly and with verifiable purity and radioactivity.[6] For example, it takes less than 30 minutes to make the FDG used in metabolic studies. For specialized brain or myocardial studies requiring short-lived carbon, oxygen or nitrogen-labeled pharmaceuticals, the patient and imaging facility must be located close to the source of PET isotopes.

There is considerable regulatory confusion and debate concerning the manufacture of PET isotopes. Unlike other compounded medications, these drugs are custom-compounded by chemists rather than pharmacists. This raises some complicated issues pertaining to the interpretation of federal laws that regulate manufacturing practices and drug safety laws.[11]

The Food and Drug Administration Modernization Act of 1997 (FDAMA) requires the FDA to establish new drug application procedures and manufacturing practices for PET drugs. The complication lies in the difference between the "manufacture" and "compounding" of PET drugs. Because compounding by pharmacists is implied in the FDAMA's section on PET drugs, a costly new drug application (NDA) procedure is required. Although the FDA has waived the NDA fees for 3 PET drugs, the FDAMA must be revised to ensure that PET drugs can continue to be custom produced for patients undergoing PET procedures.[11]

The PET Scanner

Conventional PET imaging systems consist of arrays of photosensitive crystals, most frequently bismuth germinate (BGO) and sodium iodide (NaI). (See Fig. 4.) Crystal size determines PET resolution -- the smaller the crystal, the better the resolution of the scanner. The detector module consists of an arrangement of crystals coupled in an overlapping fashion to photo-multiplier tubes. Coincident gamma-photon events are recorded and converted into an electronic signal that eventually becomes a tomographic image. High numbers of coincident hits directly correlate to physiologic locations of high FDG accumulation.

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Like CT and MR, PET images depend on data acquisition and their computational conversion into film or paper-based images. PET results are represented either as gray-scale or color-scale images. Typically, whole-body scans are gray-scale images with darker areas corresponding to areas of high FDG uptake. (B. Jones, B.S., R.T. (N), oral communication, March 2001) Color-scale is used for regional scans of the brain, chest or abdomen. Hot colors (yellow, orange and red) depict areas of high metabolic activity, while blue, green or purple mark areas of low FDG uptake. Because color assignments are not consistent from one PET facility to another, it is necessary to check the color bar code before interpreting PET images.

PET Facilities

PET scanners usually are located in hospitals, free-standing medical imaging facilities and mobile units. However, unlike many other imaging facilities, their construction and workspaces must accommodate safe use of gamma-emitting sources and safe patient management.

Mobile PET brings new and sophisticated technology to places where it would be otherwise unaffordable. Because of expansion in HCFA coverage, the number of mobile units will increase rapidly over the next few years. Although they represent a large investment for medical imaging companies, mobile PET units generate business by providing service to small or rural health care facilities located within range of the isotope supply. Health care facilities contract with medical imaging companies for the PET isotopes, certified technologists and the medical imaging equipment. Usually the nursing staff are health care facility employees. The mobile unit is ready to serve the first patient about 40 minutes after arrival at the facility (J. Trelsted, oral communication, February, 2001).

FDG Considerations

Because FDG is manufactured and transported from distant locations, facilities must conform to strict rules that regulate the transport and handling of radioactive substances. Lead-sheathed FDG syringes arrive as unit doses enclosed in a lead-lined container. A 3-dose transport container weighs more than 100 pounds. (See Fig. 5.) The syringes are activity calibrated for their scheduled time of use. Unit-dose activities, which are reassessed in the PET facility, must be within 10% of the labeled value (B. Jones, B.S., R.T. (N), oral communication, March 2001). (See Fig. 6.)

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Coordination With Other Medical Procedures

To assure cost-effective and efficient use of the PET facility and the custom-produced radiopharmaceuticals, PET procedures should be coordinated with other aspects of the patient's treatment. Appointments should be scheduled to take into consideration prior surgery, chemotherapy or radiation therapy that may compromise the uptake of PET isotopes and obscure results. It is also important to coordinate the patient's PET session to optimize safety and efficacy of postPET procedures (J. Clark, R.N. oral communication, March 2001).

Patient Preparation

PET is a relatively new technology, and standard protocols for patient preparation still are being refined. Because PET imaging assesses abnormal metabolic activity, a goal of patient preparation is to limit the uptake of PET-labeled molecules into unrelated tissues and spaces and maximize uptake into target tissues. (See Fig. 7.) Typical preprocedure protocols include:

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* Delaying imaging for one month after radiation, chemotherapy or surgery.

* With the exception of water and daily medications, fasting 6 to 12 hours before the examination.

* For certain cardiac procedures, fasting for 12 hours and abstaining from caffeine, theophylline and cigarettes for 24 hours.

* Following special instructions for diabetic patients.

* Screening women of childbearing age for pregnancy.

Before the PET examination, patients need to be told the following:

* An intravenous line will be inserted.

* Scanning time is usually 1 to 2 hours.

* Total time in the PET facility is usually 2 to 3 hours.

* There are no aftereffects from injection or imaging.

* Patients may return to normal activities after leaving the imaging facility.

Glucose Considerations

FDG imaging procedures rely on the differential uptake of glucose into cells. Therefore, blood glucose, a measure of normal carbohydrate metabolism and nutritional status, is an important baseline parameter. At the University of Iowa PET Imaging Center, a blood glucose level of 120 mg/dL or lower is recommended for all patients undergoing imaging procedures (J. Clark, R.N., oral communication, March 2001). A normal adult fasting blood glucose level is 65 to 110 mg/dL.[12] Insulin-dependent diabetic patients taking either "regular" or long-acting insulin require special preprocedural preparation.

PET may not accurately portray physiological conditions if blood glucose is elevated. In this situation, FDG molecules are swamped by large numbers of unlabeled glucose molecules and are less likely to enter cells. For this reason, patients undergoing neurology or oncology scans should not eat or drink anything other than water and daily medications before the procedure.

Glucose uptake also plays an important role in differentiating necrotic from potentially viable myocardium. Unlike oncology and neurology FDG studies, glucose loading discriminates between ischemic, but viable, and normal myocardial tissues. Because of the metabolic demands of myocardial activity, both normal and ischemic tissues demonstrate high glucose uptake levels. However, assessing patients under conditions of glucose loading depresses normal myocardial FDG uptake while ischemic myocardium is still comparatively elevated.[13] This further demonstrates the high level of metabolic stress coronary artery disease imposes on myocardial tissues.

Postinjection Considerations

Depending on the facility's protocol, patients injected with FDG wait from 45 minutes to 1 hour before their PET scan. The waiting period allows the isotope to equilibrate and move into tissues. Placing mobile lead shielding between radiation-emitting patients and the imaging area prevents incidental radiation from compromising image quality. (See Fig. 8.)

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Bladder Management

Before a PET imaging examination, radioactivity must be removed from the bladder. The quality of pelvic area images is compromised and potential sites of pathology are obscured when the bladder contains large amounts of FDG or other radiopharmaceuticals. (See Fig. 1.) Patients who undergo full-body scans, pelvic-area scans or those who are unable to retain urine for the duration of the procedure require bladder irrigation. To encourage efficient bladder irrigation, patients should receive water by mouth or IV following Foley catheter placement. Intravenous injection of a diuretic 30 minutes after FDG injection is recommended for some catheterized patients.[14]

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Postprocedural Management

Patients emit radiation for several hours after being injected with FDG, and precautions must be taken to prevent exposure to medical staff and other patients. The bladder, which receives 629 mrad/mCi (assuming 20% of injected activity is voided post 2 hours), is the critical organ.[15] After a PET study, patients should increase their fluid intake to facilitate clearing the radiopharmaceutical from their systems. Many facilities collect urine via a Foley catheter and store it until it can be safely disposed in the municipal sewer system.

Imaging Challenges

Certain conditions make patients either poor or inappropriate candidates for PET imaging. Patients who have dementia or who are disoriented or fearful may not be able to stay still. A patient's weight and girth can affect whether PET imaging methods can be used. Patients who weigh more than 400 pounds exceed both the table's weight limitations and the fixed gantry diameter.

In other cases, patients may be able to undergo a PET procedure, but their situations or other medical conditions can challenge the technologist's patient management skills. For example, some patients are uncooperative or hostile if they have recently received news of their illness.

Preparing diabetic patients for PET imaging is medically challenging as well. To prevent diabetes-related complications, the patient's insulin requirements and the preprocedure fast must be coordinated with the patient's blood sugar levels and the uptake of FDG. In addition, many diabetic patients have compromised vasculature, thus making it difficult to find a good isotope injection site.

Patients who undergo PET for diagnosing and staging colon cancer also present technical imaging challenges. Because the bladder takes up the FDG not immediately absorbed by other organs, tumors lying near or behind the bladder are obscured by high FDG concentrations. To produce good images, these patients must undergo vigorous bladder irrigation procedures.[16]

Technologist Safety

Nuclear medicine technologists need to limit their exposure to high-energy positron and gamma emissions from fluorine 18. At 511 kV, the energy associated with these photons is 3.65 times the energy released from the decay of technetium Tc 99m (140 kV) and 1.40 times that of iodine 131 (365 kV).[15]

National Regulatory Commission (NRC) guidelines state that whole-body, total effective dose equivalent, exposure may not exceed 50 mSv (5 rem) per year and at the extremities less than 500 mSv (50 rem) per year.[16] PET technologists should wear a ring badge, film badge or pocket dosimeter and should receive instruction in their proper use. (See Fig. 9.) Enforcing the International Commission of Radiation Protection (ICRP) "as low as reasonably achievable" (ALARA) concepts of time, shielding and distance minimizes occupational radiation exposures.

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Radiation dose is directly related to the length of exposure. Although patient care requires that technologists spend time at the patient's side, there are several ways to reduce occupational exposure.[15]

* Limit time spent preparing doses for injection.

* Use unit-dose rather than multidose vials.

* If only multidose vials are available, do all calculations before drawing the radiopharmaceutical.

* Keep the dose shielded.

* Rotate technologists through all PET-related tasks.

* Obtain and maintain IV access.

Typical sources of radiation exposure are the radiopharmaceutical vial, the unit-dose syringe and the patient. (See Fig. 10.) Protection from these sources is based on distance and shielding. Long-handled tongs are used to move the vial from the lead vial shield to the dose calibrator. The postinjection patient is a radiation-emitting source and care must be taken to limit exposure to other patients and staff and to prevent imaging system interference.

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The need for radiation protection and safety can cause problems if PET patients are scheduled for other imaging procedures on the same day. Protection of imaging personnel is of particular importance in ultrasound facilities where sonographers work in close proximity to their patients. In addition, some ultrasound methods require patients to have a full bladder, a situation that is neither practical nor safe immediately following FDG PET procedures because the patient's urine is radioactive. Researchers recommend that ultrasound imaging be performed either before or more than 3 hours after the patient's PET study.[17]

Complications

Positron emission tomography is a safe procedure. In more than 20 years of practice and nearly 100 000 PET studies, there has not been a reported medical complication directly related to the scanner or the use of radiopharmaceuticals.[18] The U.S. Food and Drug Administration's safety criteria covers the use of positron-emitting radiopharmaceuticals. A 3-year retrospective study of 22 PET imaging centers did not reveal any negative effects from using PET radiopharmaceuticals.[19]

The rare incidents of PET-associated complications are not due to the effects of PET isotopes but from a breech of injection or bladder irrigation sites. Inadvertent extravasation invalidates the PET scan because the isotope inappropriately concentrates in lymph nodes. On rare occasions, the use of urinary catheters may introduce bacteria into the bladder and cause a bladder infection.

Clinical Impact and Applications

As a primary diagnostic tool and in combination with other imaging modalities, PET has far-reaching effects on patient care and the medical system. PET technology can reduce the number of invasive procedures needed to diagnose and stage cancer, evaluate CAD and determine appropriate applications of cardiac revascularization, and evaluate and differentiate certain neurological diseases. This not only represents substantial cost savings to the public and health care facilities, but also lowers the morbidity and mortality resulting from invasive procedures.

Although PET imaging potentially has broad applications, clinical uses of PET are limited to specific oncologic, cardiac and neurologic HCFA-reimbursable indications. (See Tables 2 and 3.) The gap between potential use and reimbursable application is particularly great in the diagnosis of behavioral and neurological disorders (See Table 7.)
Table 7
Some Uses of PET Imaging Not Covered by
HCFA

Differentiation of thyroid cancer

Correlation studies between pain tolerance, drug
  addiction and endorphin production

Investigation of language processing

Studies of vulnerability to depression

Effect of antidepressants and other psychoactive
  drugs on brain activity

Diagnosis of bipolar disorder (manic depression),
  obsessive-compulsive disorder, attention deficit
  disorder, schizophrenia

Detection of infections associated with lower limb
  prosthetic implants

Evaluation of prion diseases


Oncology

Recent HCFA rulings permit the use of PET to diagnose, stage or restage lung, esophageal, colorectal cancers, certain head and neck cancers, lymphoma and melanoma. Although other types of cancer are excluded from Medicare reimbursement, PET is useful for detecting, staging and monitoring treatment of many other conditions.

For a cancer to be eligible for reimbursement, PET must be used to avoid or to direct an invasive procedure. For use in staging or restaging malignancies, PET is covered if the stage of the cancer remains uncertain following conventional medical imaging methods and if the clinical management of the patient may differ according to the disease stage.[20]

Because of abnormally high rates of cell division and metabolism, malignant tissues have a higher uptake of FDG than normal tissues. This characteristic permits PET imaging to:

* Differentiate cancerous from noncancerous lesions.

* Locate cancers before they can be observed by other imaging techniques.

* Demonstrate metastases. (See Fig. 11.)

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* Assess cancer treatment progress.

Therefore, PET results often can change a treatment plan or disease prognosis.[21] Some studies demonstrate that from 30% to 50% of patients who undergo PET assessment will have a change in their treatment strategy that may include changes:

* From active to palliative treatment.

* From palliative to active treatment.

* In chemotherapy treatment.

* In radiation therapy.

* In surgical treatment.

For patients with suspected lung cancers, PET is the most sensitive way to get information concerning the location of tumors, metastases and, most importantly, allows clinicians to determine if a lung is free of disease after treatment.[22] In addition to lung cancer, PET is a valuable tool to:

* Stage tumors of the head and neck.

* Detect recurrent tumors of the head and neck.

* Stage malignant melanoma.

* Detect cancer recurrences before they can be observed by other imaging techniques.

* Detect cancer recurrences in response to cancer-specific antigens in blood.

* Find residual disease after chemotherapy or radiation therapy.

* Differentiate between scar tissue and recurrent colorectal cancer.

Cardiology

The first application of PET technology approved for HCFA reimbursement involved heart perfusion and management of patients with known or suspected coronary artery disease. The July 2000 list of approved indications extends the application to include myocardial viability studies as well.

Heart perfusion studies, which assess blood flow, typically use one of the following isotopes: thallium 201, rubidium 82 or nitrogen 13. Myocardial viability studies most commonly use FDG. However, for certain specialized studies, carbon 11 palmitate and carbon 11 acetate are used to assess overall oxidative metabolism.[23]

Myocardial Viability

Normal cardiac contractile function depends on myocardial blood flow and oxygen consumption. Blood flow to the heart is the source of the nutrients and oxygen needed to support the high metabolic activity of the organ. When CAD inhibits or impinges on blood flow, various levels of myocardial dysfunction can occur.

Severe or prolonged ischemia leads to necrosis. However, under less extreme conditions, tissue damage may be reversible or "hibernating." (See Fig. 12.) A variant of the hibernating scenario is "stunned" myocardium. Stunned myocardium develops after an acute ischemic attack. Blood flow is re-established, but it may take several weeks before oxygen consumption returns to normal levels.[24]

[ILLUSTRATION OMITTED]

Because patients with hibernating or stunned myocardium can benefit from coronary angioplasty and coronary bypass graft procedures, it is important to differentiate between nonreversible necrosis and potentially viable myocardium. PET can accurately show improvements after revascularization procedures; therefore, patients who would not benefit from surgical intervention can be treated medically.[25] (See Table 8.)
Table 8
Summary of Myocardial Viability Studies

Condition        Blood Flow   FDG Uptake

Acute ischemia   Decreased    Normal or
                                increased
Hibernating      Decreased    Normal or
                                increased
Stunned          Normal       Decreased
Necrosis         Decreased    Decreased


The availability of PET changes the type and number of invasive procedures performed in coronary units. Research presented at the 1997 meeting of the American Heart Association demonstrated that PET is associated with 50% reductions in the use of coronary arteriography and coronary bypass grafting.[25]

Neurology

Neurological applications of PET include brain mapping and behavioral and neurological disorder research; however, there are few HCFA-covered neurological uses for this technology. PET applications that have been approved for HCFA reimbursement include presurgical evaluation of refractory seizure foci and differentiation of Alzheimer disease from other types of dementia.

Presurgical Evaluation of Seizure Foci

Seizures occur when brain cells suddenly release an unusually large burst of electrical energy. Situations in which this can occur include trauma, stroke, viral infections and difficult labor and delivery. Depending on whether all or part of the brain is involved, a variety of different seizures can result. In some cases, when medication does not control seizures, brain surgery may correct abnormal brain activity.

PET assessment of temporal lobe epilepsy, the most common form of refractory epilepsy, usually demonstrates lower than normal glucose uptake in epileptogenic foci.[26] Therefore, PET imaging reduces the need for invasive electroencephalogram (EEG) monitoring of brain activity and better identifies areas for surgical removal. With PET, more than 31% of refractory epilepsy patients are able to forgo invasive diagnostic testing procedures. Many others, for whom surgical intervention did not appear possible, are able to undergo surgical treatment for their seizures.[27]

Differentiation of Alzheimer Disease

Due to increasing longevity, Alzheimer disease and other dementias are a growing health problem. Alzheimer symptoms, which include confusion, loss of memory and cognitive skill, overlap with symptoms of other dementias, and the lack of a diagnostic laboratory test for this illness often leads clinicians to assume a diagnosis of Alzheimer disease. However, definitive diagnosis at autopsy reveals that nearly 10% of the brains from supposed Alzheimer patients demonstrate some other brain disease.[28]

PET, in Conjunction with structural brain-imaging techniques, enables clinicians to better distinguish between Alzheimer disease and other forms of dementia. Often Alzheimer disease demonstrates bilateral superior parietal hypometabolism (low uptake of FDG) that extends as the disease progresses into the inferior parietal and temporal lobes. (See Fig. 13.) In contrast, dementia due to brain infarction demonstrates multiple asymmetric regions of cortical and subcortical hypometabolism.[26]

[ILLUSTRATION OMITTED]

Combination PET and CT Imaging

Combining PET and CT data into a single image is cutting-edge science. The need for combination imaging stems from the difficulty in interpreting stand-alone PET images because of patient-specific anomalies and a lack of easily recognized anatomical landmarks. (See Fig. 14.) There are 2 approaches to generating combined PET/CT images -- one in which a single machine combines anatomical and physiologic information and another that uses computational methods to fuse data acquired from separate CT and PET units. As with any highly competitive technical area, each technological approach has its supporters.

[ILLUSTRATION OMITTED]

Dedicated PET/CT scanners have demonstrated their ability to identify and locate new cancers. According to David Townsend, Ph.D., one of the inventors of the PET/CT scanner, combining anatomical and functional imaging techniques in one machine produces better information than fusing separately scanned images. He argues that fusing images using computational methods is difficult due to movement of internal organs, differences in patient position and scanner bed profiles.[29] Studies show that PET/CT scanners enable clinicians to respond to a rise in blood cancer markers and identify and locate small metastases before they are visible using CT alone.[29]

Other clinicians believe that it is better to use computationally fused images. Operating separate PET and CT machines allows the use of higher resolution PET scanners and prevents redundant equipment expenditures (M. Hartshorne, M.D., oral communication, March 2001). Rather than investing in a single machine, proponents of fused imaging argue that it is a better use of time and resources to have a stand-alone CT machine available for both CT and fused imaging protocols. They maintain that problems with patient anatomical variation and alignment can be solved using high-powered computational algorithms to match edges and accurately fuse the images taken from the 2 techniques. (See Fig. 15 and 16.)

[ILLUSTRATIONS OMITTED]

With either situation, the effects of combined image technology on patient care are significant. Nearly 30% of the patients who undergo combined image analysis have changes in their diagnosis or their treatment plan (B. Jones, B.S., R.T. (N), oral communication, March, 2001).

Future Applications

In addition to developments in combination imaging and image processing, new isotope-tagged markers will broaden the applicability of PET to situations currently assessed using other methods. Women's imaging is one of several emerging applications of PET technology. At the Palo Alto VA Medical Center, combined PET and CT imaging is used to stage cervical, uterine and ovarian cancer.

Positron emission mammography (PEM) is another new application of PET-based technology. Using [sup.99]Tc and less complicated detection cameras, PEM promises to be a cost-effective method to differentiate between benign and malignant breast lesions. Physiologically specific PET radiopharmaceuticals will improve diagnosis and management of breast cancer. Using 2 tracers, FDG and fluoroestradiol (FES), researchers hope to better identify estrogen-dependent breast tumors and predict and monitor their response to therapy.

With respect to coronary disease, future applications are most likely to be directed toward identifying disease in earlier stages. This will involve the use of specialized cell markers able to distinguish subtle physiological changes before heart pathology is evident. Used in concert with PET imaging, isotope-tagged genetic markers may help predict the likelihood of heart disease in certain people.

Current HCFA-reimbursable PET applications for neurological diseases are limited, but there is hope that coverage will be expanded. Future neurological applications of PET imaging may include methods to:

* Diagnose and treat behavioral and mental illness.

* Treat degenerative neuropathies.

* Treat drug addiction.

* Improve pain management strategies.

Conclusion

Although invented more than 25 years ago, PET is just now emerging as a clinically useful technique. Difficulties in PET's transition from a research tool to a primary imaging technology are due primarily to the costs associated with clinical implementation. However, HCFA coverage for selected PET procedures has made it economically feasible for institutions to include PET in their repertoire of imaging techniques. Unlike many other imaging methods, PET provides information about physiological rather than anatomical abnormalities. Therefore, clinicians can "see" pathology before it is observable on CT or MR images.

Combining PET with CT or MR data links the physiological information to its anatomical site. PET imaging methods help detect, stage and monitor cancers, determine myocardial viability and differentiate between Alzheimer disease and other dementias. Because the results of a PET imaging assessment can impact a patient's treatment protocol, PET plays an important role in assuring that patients receive the best and most appropriate treatment for their medical problems.

Glossary of Terms

adenosine triphosphate The primary energy currency of molecules.

algorithm A systematic process, an ordered series of steps, with each step dependent on the outcome of the previous step.

analog A molecule that resembles another, but is not an isomer of that molecule.

annihilation reaction Positrons emitted during beta decay are annihilated as the result of an interaction with an electron.

biomolecules Protein, carbohydrate, nucleic acid and lipid molecules synthesized and used by living organisms.

epileptogenic Site of origin in the brain for epileptic seizures.

half-value layer The distance of travel through an absorber that decreases the intensity of gamma rays to one half its initial value.

ischemia Local anemia due to mechanical obstruction of the blood supply.

metabolism The collection of biochemical reactions that controls the breakdown and synthesis of biological molecules and the expenditure of energy.

prion A small, infectious proteinaceous particle that causes 4 types of neurodegenerative diseases in humans.

spiperone An antipsychotic drug.

unit dose A premeasured dose.

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Janet Yagoda Shagam, Ph.D., is a microbiologist with more than 25 years of experience teaching college-level biology, medical and environmental microbiology and chemistry. In addition, she is actively engaged in field and laboratory-based microbiology research and medical photography.

Dr. Yagoda Shagam, an award-winning medical and science writer, has written numerous professional articles, peer-reviewed research articles, case studies for BioQuest and made presentations to various clinical, community, national and international professional organizations. Dr. Yagoda Shagam serves on several editorial boards and is the Southwest Regional Director for the American Medical Writer's Association.

The author wishes to thank Michael Hartshorne, M.D., of the University of New Mexico Medical Center and the Veterans Administration Medical Center in Albuquerque, NM and Bradley Jones, R.T. (N), fusion specialist, of the Veterans Administration Medical Center in Albuquerque, NM for their time, PET images and the opportunity to visit the PET facility. The author also wishes to thank Jo Clark, R.N., and Richard Hichwa, Ph.D., both of the University of Iowa Hospitals and Clinics in Iowa City, Iowa, for their time and permission to use their PET images, and Elizabeth Roll, Ph.D., for helpful conversation.

Reprint requests may be sent to the American Society of Radiologic Technologists, Communications Department, 15000 Central Ave. SE, Albuquerque, NM 87123-3917.
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Title Annotation:history, technique, usage
Author:SHAGAM, JANET YAGODA
Publication:Radiologic Technology
Geographic Code:1USA
Date:Jul 1, 2001
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