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Figure 1. (A) A coin lesion inthe rightlung.(B) The highlevelsofglucoseutilizationindicatethatthe lesionismalignant,andthatthere isa metastaticlymphnodeonthe sameside(298).

Diseases such as cancer ofthe colon develop because of mutational inactivation ofone growth suppressor gene after another,these genes expressing growth suppressor substances, such assomatostatin. These suppressor genes and their products haveevolved as primitive cells became more differentiated. Theirfailure results first in adenomas and eventually in undifferentiated cancer. Throughout the lives ofsusceptible individuals, aseries of somatic cell mutations result in dissonant messagesbeing sent to colon cells, and the cells become cancerous. A person may be predisposed to somatic mutations because of afailure ofthe genes that control mutations. Periodic examination ofsuch patients with whole body FDG scans might revealwhen and where colon cancer develops, an example of thesynergism ofhuman genetics and nuclear medicine.

Cell membrane and intracellular receptors have become amaj or domain of nuclear medicine, involving neurotransmitters, hormones, growth factors, and cytokines controlling cellular behavior. Measuring these receptors in different parts ofthe body with radiotracers makes it possible tocharacterize diseases as failures in communication-―diseaseas dissonance.―

Disease results when mutations change the molecular structure ofmolecular messengers. Cancer is not something thatinvades the body like a germ but is rather a failure ofthe molecular processes that keep us all from getting cancer. Mutationsofsuppressor genes cause the cells in certain parts ofthe bodyto return to a more primitive, undifferentiated, uncontrolled statethat is cancer.

Orlando Meeting Underscores “MolecularMedicine―Among the highlights ofthe 41st Annual Meeting were many

examples ofthe safe and effective use ofradioactive tracers incharacterizing disease at the molecularlevel. Forexample, Guptaand colleagues from Creighton University reported a predictiveaccuracy of 92% in differentiating benign from malignantsolitary pulmonary nodules and lymph nodes (298).* Figure1A is an example ofan anatomical study ofa “coin―lesion withinthe lung. Figure 1B is a “glucoseutilization― image, per

*Numbers in parentheses indicate abstract number, Supplement,JNucl Med (May) 1994.

13NNewsline

DISEASE AS DISSONANCE

The Society ofNuclear Medicine celebrated its 41st anniver

sary at the annualmeeting in Orlando, Florida, in June. For the

seventeenth consecutive year, Henry N. Wagner, Jr., MD, pro

Iessorofmedicine,radiologyandenvironmentalsciencesattheThe Johns Hopkins Medical Institutions, presented his view of

the scientific highlights at thefinalsession ofthe meeting.

T HE FIRST STEPS TOWARDmodem medicine were takenin 1543 with the publication of

the exquisite atlas ofhuman anatomy,entitledDeFabrica Humani Corporis,

byAndreasVesaliusoftheUniversityofPadua. Two centuries later, anothergreatltalian physician, Giovanni Morgagni, developed the “anatomicalconcept ofdisease,― in which he relatedthe clinical manifestations of diseaseto specific organs ofthe body. In hisbookDeSedibus, Morgagni formulated

the basic principles that are at the core ofmodem clinical medicine. In 1894, the German pathologist, RudolfVirchow, tookthenextimportantstepofrelatingdiseasestohistopathologicalabnormalities ofthe cells within organs.

The greatest physicians have been identified as those whowere best at predicting the gross and histopathological findingsat autopsy from the clinical and laboratory manifestations of apatient's clinical illness.

The New Nuclear MedicineThe modem physician must not only “makethe diagno

sis―but select the most effective therapy and monitor its effectiveness.

As John Maynard Keynes pointed out, “Thedifficulty lies notin new ideas, but in escaping the old ones.―And although thepractice ofmedicine is still based largely on attempts to attributediseasesto specificorgans,modemmedicineis increasinglymoving beyond gross anatomy and histopathology into thedomain ofmolecular medicine, and no specialty is better ableto contribute to the transition.

Nuclearmedicinecanprovidenewimagesofdisease,notjustnew tests for old diagnoses. Many patients with the samediagnosis, such as cancer, or even Parkinsonism, can beshowntodifferintheirregionalbiochemicalandphysiologicalmanifestations ofdisease. Even cancers with similar histopathological characteristics, such as islet cell tumors of the pancreas, can be differentiated according to whether they do or donot express somatostatin receptors.

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Outcomes ResearchJust as diagnosis can be based on regional physiology and

biochemistry, so can the effectiveness oftreatment be measuredby the same procedures. Such measurements of effectivenessare not only objective and quantitative but can be made mimediately after treatment is started. In a Harvard study of patientswith lung cancer, glucose utilization within the lesions fell from0.44to 0.06micromol/min/gmin responseto chemotherapy(141). Knopp et al from Heidelberg reported that PET FDGstudies made it possible to predict the response of small celllung cancer to chemotherapy with an accuracy ofbetween 83%and 90% (297).

Multidrug Resistance in CancerThe marriage ofgenetics and nuclear medicine is also illus

trated by studies ofmultidrug resistance that develops in patientsreceiving cancer chemotherapy. Resistance to one cancerchemotherapeuticagent,suchas adriamycin,often leadsto crossresistance to other chemotherapeutic drugs due to the overexpression of a p-glycoprotein (pgp), called multidrug resistance factor (MDR) (891). This p-glycoprotein is involved inthe excretion offoreign chemicals from cells. Piwnica-Wormsand colleagues first reported this phenomenon in studies with

@Tcsestamibi and have subsequently developed a new @“Tcisonitrile useful not only for imaging the transport process butalso in modulating it (66).

Figure 2 illustrates the mechanism ofaction ofthe transporter. The administration of chemotherapy agents resultsin the increased expression ofthe p-glycoprotein in the cancer cell membrane. This protein facilitates the pumping of thechemotherapeutic drug out ofthe cytosol ofthe cancer cellinto the extracellular fluid, thereby preventing its cidal actionon the cell. The p-glycoprotein-mediated cellular excretionprocess rids the cell ofthe foreign drugs, including adriamycinor 99mTcsestamibi. Measuring this excretory mechanismwith @“Tcsestamibi provides a possible means of developingdrugs that will modulate or decrease the transport process, andmake chemotherapy more effective, a whole new approach tocancer chemotherapy. Ifone can block this excretion ofchemotherapeutic agents from the cancer cells, resistancewould not develop and the cancer cells would continue to bekilled. Illustrating the synergism between SPECT and PET,Elsinga et al from Groningen developed “Cdaunorubicin asa positron-emitting radiotracer for study of multidrug resistance (328).

The human genome can be thought of as a reference dictionary ofnucleotide words that bring about the production of peptides, proteins, and other molecules that make up the structureand control the biochemical processes ofthe body. Only a fewofthe messages carried by these genetic words are known.Nuclear medicine can play a major role in deciphering the meanings ofthese nucleotidic words, as they form the sentencesand paragraphs that control life processes. Excellent examples include radiolabeled somatostatin (55) and vasoactiveintestinalpeptide (VIP).Vasoactiveintestinalpeptide (VIP) hasbeen successfully labeled with 1231(384).

Figure2.‘@‘Tcsestamibiis transported by p-glycoprotein which pumpschemotherapeutic andother foreign drugs out ofcancercellsand reducestheir cidal effects. Sestamibi accumulation can beusedto developagentstomodulatethistransportprocess (66).

formed in the same patient with “Fdeoxyglucose (FDG). Notonly did it indicate that the lesion is metabolically very active,and therefore probably malignant, but there was anothermetabolically active lesion in the hilar region on the same sideof the thorax. Since the patient did not have any evidence ofan involved metabolically active lymph node on the oppositeside ofthe thorax, the decision was made to attempt cure by thoracotomy. Ifthere had been bilateral hilarlymph node involvement, the patient would have been treated immediately bychemotherapy and thoracotomy avoided.

Last year there were 2 17 presentations in oncology; this yearthere were 308, a 42% increase (Figure 3). One quarter of thepresentations, from both the United States and abroad, were inoncology; with nearly equal numbers in cardiology and neurosciences.

Seventeen presentations described the results of “FFDGimaging in patients with lung cancer. One was from investigators at the Northem Califomia PET Imaging Center, whosecyclotron is operated by the radiopharmaceutical industry,which is another important trend in nuclear medicine (299).PET imaging with FDG was more accurate than CT in identifying patients who would not benefit from pulmonary resection (94% vs 79%). Mediastinal or hilar node involvement bycancer could be predicted with a positive predictive value of90% anda negativepredictivevalueof97%. Thesehighvalues exemplify how medicine is moving into a “neweraofcertainty,― where decisions will be made and proceduresperformed only in those patients who can clearly benefit. Uncertainty is what makes medicine expensive today. Eighty percent accuracy does not permit cost-effective decision-making. Being wrong 20% ofthe time is not only medically, buteconomically, unacceptable. The goal is to eliminate surgeryor other complex procedures that do not help the patient butare performed only to assure that the lesions are inoperable.Ifsuch surgery can be avoided, hospitalization and surgicalcomplications can be avoided.

Pounds et al showed that FDG studies changed the stagingin 33% of the patients with metastatic cancer of the lung (299).Glucose metabolic rate of the lesions was then used subsequentlyto determine the response to chemotherapy.

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Tc-99m 360 F-18 1661-123 81 C-lI 731-131 46 0-15 541-125 32 N-13 21In-ill 68

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ABSTRACTS

: ONCOLOGY220200

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_______________________________________pharmaceuticals.

@Tclabeled analogue of somatostatin (P587) is now undergoing clinical trials (1057).

Nuclear Medicine Reduces CostsAs medicine becomes more competitive, the time has come

for nuclear medicine to demonstrate its cost-effectiveness inpatient care, demonstrating economic benefits as well as thecontributions to patient care. Results presented at this meetingshowed how nuclear medicine procedures can decrease surgical costs. Both the costs of surgery and the necessary costs ofhospitalization and occasional complications are high. Betterselection ofpatients and more accurate pre-operative information can decrease costs.

Presentations at the meeting indicate that nuclear medicinestudies can reduce costs in the following ways:

(1) Coloncancer:Detectingoccultcarcinomaofthecolonin the early stages in patients who are shown by genetic studies to be at exceedingly high risks can reduce costs. In patientsat later stages ofcolon cancer, fruitless surgical attempts at curecan be avoided.

Many patients with advanced colon cancer are operated uponwith the hope that they can be helped. If what was found atsurgery were known pre-operatively, operation could be avoided.FDG accumulation in recurrentrectal cancer is related to tumorsize and cellularity (471). The increase in deoxyglucose utilization in cancer is due to increased expression ofglucose transport proteins and hexokinase synthesis (894). A MCumonoclonal antibody was more accurate than CT in detecting smallcolorectal cancers after radiation therapy (38).

(2) Braintumors:231methyltyrosine(IMT) isaseffectiveas “Cmethionine in characterizing brain tumors (23). Accumulation ofthe tracers indicates a poorprognosis, regardless ofthe histological diagnosis(24). Malignant meningiomas can bedetected with @‘TlSPECT imaging(27). In patients with gliomas,20'Tl and “Cmethionine gave similar results (165). FDGaccumulation was helpful in prognosis in pediatric primaiy braintumors (169). In patients with brain lesions characterized byvery low levels ofdeoxyglucose or methionine accumulation,surgery can be avoided, especially ifthe lesions are in difficultlocations. In patients with operable brain tumors, exact localization ofthe lesion can decrease operative time and the complications ofbrain tumor surgery. Ofparticularvalue is the ability to distinguish between the lesion and surrounding edema, orfrom radiation necrosis. Radiation therapy does not decreaseglucose utilization in normal irradiated brain, but does so inbrain tumors (867).

5

8283848586878809a091929394 82@38485868788899O9i929394

YEARS YEARS

Figure 3. Presentationsinnuclearoncologyincreased42% from1993to 1994.

PET versus SPECT: Time to End the CompetitionSome persist in viewing PET and SPECT as competitive.

This is unfortunateand unwarranted.Becauseof “C,the chemical power of PET will always be great. On the other hand, ifa patient or research problem can be solved with SPECT,the longer half-life of 231and @mTcprovide important advantages. PET will always be more sensitive than SPECT, andmathematical modeling in quantification will be more accurate.

The synergism ofPET and SPECT is illustrated by the imaging of somatostatin receptors with a single photon-emittingradiotracer, indium-In, while glucose utilization and manyother receptor-imaging radioligands have involved PET. Thetransfer of SPECT to PET is illustrated by the development of“Cdaunorubicin to permit study ofmultidrug resistance bymeans ofPET (328).

PeptidesThe development ofthe somatostatin analogue, “Inoctre

oscan, recently approved by the FDA in the United States, illustrates how basic science advances are translated into health carebenefits. The message carried by somatostatin to cells is to stopsecreting, which in tum results in diminution ofcell division.Vasoactive intestinal peptide (VIP) carries the message to thecells to start secreting. Certain tumor cells express somatostatinreceptors, while others express vasoactive intestinal peptide(VIP) receptors. Investigators from the University of Viennalabeled vasoactive intestinal protein with ‘9,and showed thatmany tumors including adenocarcinoma ofthe pancreas expressVIP receptors (384). The latter do not express somatostatinreceptors, unlike functioning and non-functioning islet celltumors ofthe pancreas.

The roles ofboth PET and SPECT are documented by the 166presentations involving “F;73 involving “C;81 involving BI;and 32 involving ‘251(Figure4). The increasing role of “In,bothin the study of cancer and infectious diseases, adds anothersingle photon-emitting agent to the nuclear medicine armamentarium.

Octreotide labeled with a positron-emitting tracer hasbeen developed at Washington University (422). Such labeledmolecules may be useful in the future for peptide therapy. A

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PHASICHEATPAIN(lt.for.a@a) fluoroestradiol (FES) for detecting malignant breast lesions(569). PET imaging with FDG was highly specific in evaluating axillary metastases (57 1). Negative estrogen receptorsand low grade 20'Tluptake in breast lesions was a sign ofa poorprognosis, presumably related to the degree of undifferentiation ofthe lesions (929). SPECT imaging is more sensitivethan planar scintigraphy in detecting non-palpable breast cancer (933, 934).

In the diagnosis ofbreast cancer, “FFDG had a 94% specificity (571). Ifthere is some doubt about whether a lesion inthe breast is or is not malignant— ifit accumulates FDG abovea certain quantitative threshold level— the lesion should beremoved because it is almost certainly malignant. On the otherhand, ifthe lesion has low levels ofglucose utilization, itcan be watched, possibly after performing a needle biopsy.

Ongoing, carefully designed, multi-institutional “Tcsestamibi studies will better define the role ofthis tracer in breastcancer diagnosis (935). It is possible that a combination oftracers will be used to achieve both high sensitivity and specificity. As many as 75% of 52 breast tumors accumulated“Inoctreoscan (77). This tracer, used in combination with a““Tcsestamibi or FDG study, might bring about absolute certainty in determining whether a lesion is benign. Combiningtracer studies may be needed in some cases to achieve absolutecertainty.

Other tracers used in breast cancer include “Ffluorotamoxifen, an estrogen receptor antagonist, as well as radioiodinated tamoxifen ( 105 1). High doses of ‘@‘Itamoxifen maybe useful in treating primary and metastatic estrogen-positivebreast cancer.

(6) Lymphoma: Bares and colleagues from Aachen foundthat FDG studies assessed tissue viability in assessing patientsfor relapse after treatment (526). Somatostatin receptor imaging detected active lymphomatous disease in 30% ofcases notrevealed by conventional staging methods (529). In nonHodgkin's lymphoma, radioimmunotherapy without bone marrow transplant cured many patients (402).

(7) Ovariancancer:EveryyearintheUnitedStates5,000“second-look―abdominal operations are performed in patientswith ovarian cancer to assure that the patient does not have persistent disease. With FDG, the question was whether one canbe sufficiently certain that no disease persists without surgery.This question was addressed by Holdeman et al from the University ofNebraska, who found that although FDG studies werenot sensitive enough to replace 2nd look laparotomy, the studies were helpful in patients with elevated CA-125 and negative CT (470).

(8) Pancreatic cancer: To identifythenatureoflesions withinthe pancreas, “Inoctreoscan detected not only functioningtumors that produce hypoglycemia but also non-functioningislet cell tumors, thereby avoiding complex and expensivesurgery in the beliefthat the patient is suffering from adenocarcinoma ofthe pancreas. Islet cell tumors are more benignthan adenocarcinomas and can be treated without radical Whippie procedures.

In studies ofpancreatic cancer with FDG, both sensitivity and

Figure5.Astudyperformed with

‘soH20 indicatesthatthe corticalareasofthe brainwhichinitiallyrespondto apainful stimulusdifferfromthosethatshowincreaseactivitywithprolongedpain (122).

(3) Lung cancer: Nuclearmedicineprocedurescanhelpelimmate the 25,000 thoracotomies performed every year in theUnited States in patients subsequently proven to have benignsolitary pulmonary nodules. Studies from Omaha (298) andDuke(932)described the high positive and negativepredictivevalue ofFDG studies in these patients.

Thirtythousandthoracotomiesareperfomied mthe United Statesevery year in patients found at the time ofsurgety to be inoperable because ofpleural or extensive mediastinal and hilar nodeinvolvement.Thiscan be determinedpre-operatively(301,932).

(4) Prostate cancer: Prostatectomies are performed onlywhen the lesion is confined to the prostate. In 50,000 prostatectomies performed every year in the United States, the lesionsare found to extend beyond the prostate. This can be determinedpre-operatively with “InCYT-356, a monoclonal antibody(878). The Washington University group continues their studies of―Flabeledtestosterone tracers inpatients with carcinomaofthe prostate (204). The FDA recently approved the use of ‘@Srfortreatment ofbone pain in patients with metastatic carcinomaofthe prostate. Many at the meeting had the opportunity to heara patient describe how he had been chair-ridden for one yearbecause ofpain, and had spent $ 12,000 for medications. Afterreceiving “Srtherapy,he got up from his wheelchairand resumedhis hobby ofdancing, taking no medications for the followingyear. Another agent under evaluation for the reliefofbone painis ‘@‘Re(965).

In studies ofthe regions ofthe brain activated by experimentalproduction ofpain, it was found that the cortical areas initiallyinvolved in response to pain were different from those involvedlater as the pain persisted ( 122) (Figure 5).

(5) Breast cancer: In the United States, 400,000 of the600,000breastlesionsremovedatsurgeryeveryyearproveto be benign. The patients are operated upon because of therisk ofmalignancy. Ifone can determine with a 98% certaintythat the lesions are benign, surgery could be avoided and thepatient followed by periodic examinations. Most surgeons willnot rely on needle biopsy because ofthe sampling problem;cancer may be present when most ofthe lesion is benign. @Tcsestamibi diagnosed primary breast cancer in lesions less than1 cm in size, as well as detected involved nodes (78, 79).The negative predictive value was 97% (80). 99mTcMDPwas also effective (81). FDG-PET was more sensitive than “F

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Figure 6. FOGPET imaging ofcancer of thepancreas (911).

Figure7.lic acetate

failing to accumulate in carcinoma of thepancreas,unlikeFOGwhichaccumulatesavidlyinthelesions(430).

specificity were more than 90% (904). In 45 patients withpancreatic cancer, 43 were positive. In chronic pancreatitis, only4 out of 3 1 were positive (91 1). Figure 6 is an example of anFDG study in a patient with carcinoma ofthe pancreas.

A most interesting finding was that cancer ofthe pancreas hasa high level ofglucose utilization, but a low metabolism of―Cacetate (430) (Figure 7). The cancerous lesions functionanaerobically.

@°‘T1was also investigated in the detection ofpancreatic tumors(904). In comparisons ofFDG PET with thallium SPECT, FDGPET had a sensitivity of92%, while 20'TlSPECT had a sensitivity of 67%.

(9)Melanoma: InvestigatorsfromtheNetherlandsused handheld probes at surgery to detect sentinel nodes with ““Tccolbid in patients with skin melanomas(914). This is but one exampie ofthe increasing use ofprobe detectors at surgery.

(10) Uterine cancer: “Cmethionine was found to be better than FDG in distinguishing cancerous lesions from surrounding structures (469) (Figure 8).

New InstrumentationTownsend and colleagues described the results obtained

with a rotating positron tomographic camera, which representsa lower-cost instrument than more widely used ring detectorPET scanners ( 155). Another innovative nuclear imager wasdescribed by Barrett and colleagues (102, 367). This device isbased on the use of multiple pinhole collimators, and takesadvantage of the new high-resolution detectors that can beplaced very close to the pinhole to simplify the design. The

FIgure8.Utennecancer is successfully imagedwith“Cmethionme (469). The

contrast is higherthanwithFDG.

scanner has no moving parts, which facilitates temporalstudies with high spatial resolution.

A word ofcaution must be stated with respect to imagingpositron-emitting tracers such as FDG with SPECT instrumentsfitted with high-energy collimators. Investigators from the University ofMichigan compared FDG SPECT and PET studies inthe same patients (19). SPECT imaging ofFDG had a lowsensitivity(36%)in tumors less than 3 cm in size, which is unacceptably low. Sensitivitywas 75% in the case oflarger tumors.The investigators concluded that FDG SPECT is not a satisfactory alternative to PET in cancer imaging.

Cost-EffectivenessMany presentations were directly concerned with cost effec

tiveness. In the staging ofpatients with malignant melanoma,the total cost ofwhole body PET imaging ofall 33 patientswas $62,700. Priorto the PET imaging, $132,000 had been spentin diagnostic imaging studies that didnot solve the problem (20)(Figure 9). Chemicalcharacterization oftheselesions was muchmore accurate. One must also consider the high cost of unhelpflu surgery when performedwith uncertain knowledge of whetherthe lesions are operable.

Thirty percent ofa thousand patients with hypertension werefound to have renal artery stenosis (1091). Ifone depends onarteriography to make the diagnosis, one can rule out renal arterystenosis in 700 patients at a cost of $1.2 million. Ifyou makethe diagnosis with radiotracer renography with captopril, thediagnosis can be excluded in the same number ofpatients at acost of $540,000.

Investigation into the pathogenesis ofrenovascular hypertension may be aided by the successful imaging of angiotensinII receptors (497) (Figure 10).

Nuclear NeurosciencesStudies ofregional cerebral blood flow with single photon

tracers increased dramatically since last year—from 59 to 71,compared to an increase from 23 to 39 in the case ofPET. Therewere 54 presentations of ‘SO,in some cases produced by adedicated, relatively inexpensive tandem cascade accelerator(1021). Fazio and his colleagues from Milan compared the areasofthe brain that were activated when a subject moves a handto those regions activated when the subject imagined movingthe hand(426). In patients with Wernicke's aphasia, Wernicke's

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(CCD)than in olivopontocerebellar atropy(OPCA), but the latter involves the striatum as well, as indicated by ‘8FL-DOPAstudies (854) (Figure 13 A and B).

Another important Japanese presentation pointed out the useofradiotracer studies in patients with transient blindness (amaurosis fugax) (823).

Misonidizole AnaloguesMisonidizole analogues and technetium PNAO derivatives

were described in studies ofregional hypoxia, not only hypoxiaofthe brain but also hypoxic focal infections and myocardialinfarction. Yeh and colleagues from Taiwan illustrated theischemic penumbra in acute stroke demonstrated with ‘8Fmisonidazole (830) (Figure 14). There were 8 PET and 8 SPECTpapers involving misonidizole analogues.

EpilepsyIn focal epilepsy, Mountz et al from the University of Alabama

illustrated the importance offusion ofanatomical and functionalimaging(l 12). They emphasized ictal studies. In another study,there was excellent correlation between PET FDG studies andinvasive EEG studies ( 113). The positive predictive value ofpostsurgical improvement was 94%. Benzodiazepine receptorsin focal epilepsy were examined with “Cflumazenil (839) (Figure 15). lodomazenil is another tracer used in studies of patientswith epilepsy (63).

NeurotransmissionThere were 102 papers on neurotransmission, 52 of them

involving the dopaminergic system. Others included a presentation of imaging cholecystokinin receptors (1016); anotherconcerning substance P receptors (1042). Tasch et al examinedpatients with schizophrenia who were receiving typical neuroleptics, such as haloperidol, and those receiving atypical neuroleptics (291 ) (Figure 16). Those patients treated with atypi

Whole Body PET Compared to Convention@,I ImagingFor Cost Effective Staging of MaIign@@iit Melanoma

(n = 33 patients)

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thanwithotherimaging modali

ties (20).

area was not activated when the patient generated a verb to matcha noun that had been spoken to the patient (120, 123). Therewas activation ofBroca's area.

It was possible to distinguish the areas ofthe brain activatedin patients with simple phobias from those activated in patientswith obsessive-compulsive behaviors (295).

DementiaOne ofthe best illustrations ofthe “newera of certainty―

was the study from Oxford University in which HMPAOSPECT studies were combined with CT (72)(Figure 11). Thinning ofthe medial temporal lobe, when found together withSPECT regional cerebral blood flow abnormalities, were veryspecific in the diagnosis ofAlzheimer's disease, confirmed atautopsy in a large series ofpatients. In the clinical examination ofthe patient by a neurologist or neuropsychologist, therewere 35% false positives; 20% false positives when DSMIII criteria were used; 13% false positives with SPECT alone;7% false positives with CT alone; but only 3% when bothCT and SPECT were used. This means that when a patientis classified as having Alzheimer's disease, the error ratewill be only 3%. The importance ofthese findings in selecting patients for clinical trials of the drug treatment ofAlzheimer's disease is clear. The Michigan group used statistical criteria in establishing ROC curves in the diagnosis ofAlzheimer's disease with FDG (476).

The Michigan group also presented the results oftheir studies ofpre-synaptic acetylcholine neurons, using 1231iodobenzovesamicol (265)(Figure 12). In the cortex ofnormal persons,there were many more presynaptic acetylcholine neuronal vesides than in patients with Alzheimer's disease.

PET FDG studies were more accurate than SPECT bloodflow studies in distinguishing Alzheimer's disease from vascular dementia (477). One can use ‘@Owater perfusion studiesto obtain objective evidence ofthe beneficial effect of high-doseaspirin treatment ofvascular dementia (835). Camargo and colleagues from Brazil used SPECT to illustrate the improvement ofpatients with an unusual form ofaphasia when treatedwith steroids (856).

Many studies illustrated the importance ofusing radiotracerstudies to homogenize the groups of patients examined inclinical trials ofdrug therapy. For example, in spinocerebellardegeneration (SCD), the degree of involvement ofthe cerebellum might be greater in cerebellar cortical degeneration

Provisional comparison of AChE and neuroimaging tests for@willi clinical crileria

30

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Figure 10.Angiotensinll/AT1 receptorsimagedwithanew@ compound in the

kidneys andadrenal(497).

Figure11. Falsepositive rateswithvariousdiagnostictestsin Alzheimer's

disease(72).

Sensitivity i 5

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ofthe acetyl

cholinetransporter on presy

napticvesiclesina normalperson(top) and a

patient withAlzheimersdisease(AO)(265).

Figure 13. (A)In patientswithcerebellarcortical degeneration,(CCO) thedegree of

involvementofthe cerebellumisgreaterthaninpatients with

olivopontocerebellaratropy(OPCA).(B)OPCAinvolvesthe striatum,asdocumentedby“FL-OOPA(854).

cal neuroleptics did not have a degree ofreceptor blockadethat was different from the normal subjects. In those patientstreated with typical neuroleptic drugs, such as haloperidol, therewas a greater degree ofblockade in those patients who developed tardive dyskinesia, or extrapyramidal complications, thanin those who did not.

Endogenous Dopamine Release‘@Iiodobenzofuran was used to measure endogenous dopamine

release, stimulated by administration ofamphetamine (332).Endogenous dopamine release competes with the binding of thetracer by D2 dopamine receptors. The investigators related thedegree ofendogenous dopamine release to the subjective sensations ofalertness and cheerfulness produced by the amphetamine (Figure 17). To me, this was the most interesting presentation ofthe meeting.

Parkinson DiseasePostsynaptic dopaminergic receptors are normal in patients

with classical Parkinson disease, but it is clear that presynap

Figure 14. The ischemicpenumbrainacutestrokeisdemonstratedwith'8Fmisonidazole, a hypoxia imagingagent(830).

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Figure 15. “Cflumazenil imaging of benzodiazepine receptors infocaltemporallobeepilepsy.(839).

tic terminals are deficient, when examined with tracers that bindto dopamine transporters on presynaptic nerve terminals inthe caudate nucleus and putamen. The UCLA group developeda “Ftracer for studying dopamine reuptake sites on the presynaptic neurons (327). The Yale group synthesized several presynaptic transported tracers and selected 1231beta CIT forimaging the dopamine transporter (5 16). They found a striking decrease in presynaptic neuronal transporter in aging persons, comparable to the known decrease in post-synaptic D2dopamine receptors (33) (Figure 18). Since the rate of synthesis ofdopamine does not fall with age, it is likely that the synthesis ofdopamine increases per residual neuron. Beta CITlabeled with 1231is a marker for early Parkinson disease, whichwillgreatly facilitate clinicaltrials ofpotential therapeutic agents.The decrease in pre-synaptic transporters inpatients with Parkinson disease is greater than that observed in normal aging (28;30). Figure 19 indicates that the decrease in transporterbindingis correlated with the severity ofthe disease, as estimated by theHoehn-Yahr scale.

Serotonin TransporterA major advance was the report of the imaging in human

beings ofthe pre-synaptic serotonin transporter (337) (Figure20). The tracer @i-CITis not specific forthe dopamine transporterbecause it binds to both the dopamine and serotonin transporter.The tracer developed by Suehiro and colleagues is more spe

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Figure 18. SPECT and 12312f3-carbomethoxy-3@3-(4-iodophenyl)tropane, @3-ClT,show the decline in binding to the presynaptic dopamine transporter in the human striatum as a function of

age (33).

Figure 19. Thedecreaseinpresynapticdopamine transporters correlatedwith the severityof clinical symp

0 , , , , I toms as graded

on the Hoehn

____________________________________Yahrscale(30).filling was abnormal even in the normotensive acromegalicpatients.

Outcome StudiesVentricular function studies help predict persons susceptible

to cardiac deaths (233) (Figure 2 1). In patients whose globalleft ventricular ejection fraction fell 7 - 8% after exercise,there was improved survival in patients treated by coronaryartery bypass surgery (233).

In patients with ventricular aneurysm detected by simpleobservation ofwhether or not the walls ofthe left ventriclediverged from base to apex, survival was poor (505). SPECTmyocardial perfusion studies that did not reveal ischemia inwomen with chest pain was a good prognostic sign (235). Thechance of subsequent death from myocardial infarction wasonly 0.2% per year (Figure 22). Angiography need not be performed in such patients—a great economic saving.

Peripheral vascular disease is another area where radiotracerstudies are cost-effective. Amputation has a very high mortality, as great as 18%, because ofthe severity of the underlyingdisease. 52Rbis useful in measuring muscle blood flow (622).FDG can be used as an indicator ofmusculoskeletal inflam

it) 90

was the same innormalsandschizophrenicpatientstreatedwithatypical neuroleptics (AN). Schizophrenic patients treated withtypicalneuroleptics(TN), suchas haloperidol,showa greaterdegreeof blockade,whichwasevengreaterinpatientswhodevelopedtardivedyskinesiaor extrapyramidalsymptoms(EPMS) (291).

13-CIT BINDING IN PARKINSON'S DISEASE:CORRELATIONWITHCLINICALSTAGE

0

y = 6.0121 - 0.63069x R = 0.7361 p=0.0001

Relationship between behavioral activation anddecrease in specific (1231]IBZMbinding to D2 receptorsafter 0.3 mg/kg amphetamine i.v. in 5 healthy subjects

24Bhavloralctlvatlon 20

aftr

ampt*tamlne(s&fratlngby16 .Visual an&og•ciIes) 12

8

4

010% 15% 20% 25%

Striatal [1231]IBZM decrsae aftr amphtamlr* (% baseline)

E

0

0C)

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(0

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Hoehn and Yahr

Figure 17. Afterestablishingan equilibriumwith @llodobenzofuran, d-amphetamine was injected to induce endogenous dopaminerelease.The degreeof subjectivesensationsofalertnessandcheerfulness was directly related to the degree of dopamine release(332).

cific ( 1040). There was a very good correlation between tracerbinding and the number of nerve endings of the serotoninergic neurons (262).

Nuclear CardiologyAn 23!fatty acid tracer has been approved for clinical use in

Japan and is useful in risk stratification ofpatients with myocardial infarction (23 1). The relative size ofthe defects seen byfatty acid imaging and the size ofthe defect in regional bloodflow imaged by 20Tl was ofprognostic significance.

“Cacetate, “FFDG and the fatty acid tracer were able todifferentiate patients with hypertrophic cardiomyopathiesinto those with asymmetric septal hypertrophy and those withapical hypertrophic cardiomyopathy (439).

Left ventricular function studies were used to show that patientswith acromegaly have intrinsic myocardial abnormalities, notjust dysfunction secondary to hypertension (662). Ventriuclar

24N The Journal of Nuclear Medicine •Vol. 35 •No 8 •August 1994

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‘4 1@*;@

fteedom F@@mcardIac Events(N—922FemaIesWIthaNoni.chimkorEqulvocdSPECIScan)

that if 2. II did not show evidence of ischemia, the chance of deathwas only 0.2% per year (235).

Figure 23. FDG PET was usedto detectand localizeactivemusculoskeletal inflammatory lesions in the legs and was found to be moresensitive and specific than99@TCantigranulocyte antibody imaging(451).

betic patients were abnormal (612). In coronary heart disease,the defects in MIBG accumulation are far greater than the perfusion defects. In both groups ofpatients, it is important to identify such patients because they are at great risk ofcardiac arrhythmias. A Japanese study related MIBG defects to increasedelectrical excitability ofthe myocardium (3 18) (Figure 24).

This tracerwith a single photon-emittinglabelled to the development of ‘8Flabeled MIBG ( 101 7). While most neuroblastomas can be detected using FDG, the use of MIBG is valuable in patients who fail to accumulate MIBG. FDG can also beused in monitoring treatment (542).

ConclusionAfter several years ofplanning and painstaking execution,

the Hubble telescope was still found to possess flaws in itsdelicately ground mirrors, dissonances in the way the instrument processed images. Thus, even the most finely tuned scientific instruments and techniques, like the body itself, can experience such dissonances.

So it is with medicine. In nuclear medicine today, it has neverbeen more important to develop a strong, highly expert cadreoffull-time nuclear medicine physicians and scientists, who candevelop strong coordination with organ-oriented specialists,

Figure 21. Whena patient'sejectionfractiondecreased7 -8% withexercise, surgical rather than medical therapy resulted in a longersurvival (233).

mation (45 1). Figure 23 shows foci of inflammation in thelegs imaged with FDG PET.

Metaiodobenzylguanidine (MIBG)Everyone at the meeting was delighted that Don Wieland from

the University ofMichigan received the Paul Aebersoldaward for his major accomplishments in the basic sciences ofnuclear medicine. Included among them was the developmentof MIBG, involved in 18 presentations at the meeting. Everyone was also pleased that ‘@‘IMIBG had been approved recentlyby the Food and Drug Administration. 231MIBG, which is moreuseful for imaging studies, is approved for use in Japan, and wehope this will soon be true in the United States as well, andthat it will be available for study, not only forpatients with neuroblastoma, but also for patients with coronary heart disease.Patients with diabetes often have autonomic neuropathy. 20'Tlmyocardial perfusion imaging is normal in most ofthese patients,but MIBG myocardial uptake is reduced, as well as the rate ofwashout ofthe tracer(6l3). Measurements in non-insulin-dependent diabetic patients could be distinguished from those innormal persons, while the results in insulin-dependent dia

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Figure 24. Patientswithidiopathicdilatedcardiomyopathywhohave defects in the sympathetic innervation ofthe myocardiumwhenimagedwith‘@@lMIBGare morelikelyto developventriculartachycardia and sudden death (318).

such as cardiologists and neuroscientists, and other holistic specialists, such as nuclear oncologists and infectious diseasespecialists. This consonance with other fields ofmedicine resembles the smooth growth of healthy branches from a commonvine (Figure 25).

One mainstay ofU.S. medicine—as crucial as recognizingthe relation ofclinical manifestations ofdisease to specific organsor to histopathological abnormalities ofcells—has been peerreview, a major quality-control mechanism, ensuring consonance in scientific findings. Now peer review must be extended

Figure25.Molecularnuclearmedicine,regionalphysiology,andregional biochemistry are the vine from which other medical specialties branch.

to public view. Members ofprofessional societies must workwith persons in industry to perform and document cost-effectiveness studies and preach what we practice. The effectivenessofnuclear medicine procedures is among the best kept secretsin medicine. We must educate decision-makers, not justphysicians, but also patients and third party payers.

Henry N. Wagner, Jr. M.D.

ofGraduate Medical Education (COGME) recommendations, proposed Congressional legislation has set a goal for the generalist/specialistratio that varies from 50/50 to 55/45. Major reformmeasures, notably the Clinton plan, would achievethis goal through regulation—throughCOGME'slimiting the number ofannual residency positionsin each medical field. The prospect of a government agency thus regulating nuclear medicine asjust one ofa set ofspecialties has practitioners inthe field alarmed.

“Adecrease of 5 1% in Nuclear Medicine residency positions would result in serious shortagesofnuclear physicians by preventing the trainingofnew practitioners that are needed to replenishthe aging cadre in the field,―wrote William H.McCartney, MD, ACNP president, and RichardC. Reba, MD, SNM president (at that time), in aMarch 29 letter to COGME. Though the numberofphysicians in the “otherspecialties―grew variously between 10% and 37.2% from 1985-1992,

26N The Journal of Nuclear Medicine •Vol. 35 •No 8 •August 1994

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VISIONS AND REVISIONS:VIEWPOINTSOF NUCLEAR MEDICINEAND HEALTH CARE REFoi@iAs reformerspushforspecialistrationing,aleveling-offof nuclearmedicineworkforcemaymeandecreasesin trainingslots—orthe specialtymaydefinea newidentity

A CENTRAL TENET IN THE MAJORhealth care reform measures now emerging in Washington is that every citizen has

the right to basic health care. An adjunct assumption holds that general practitioners offer the bestroute to such universal access. Not only are generalists supposedly less costly on average than specialists, reformers hold them up as symbols of thesort ofback-to-basics approach that health careallegedly needs. Basing its numbers on Council

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1994;35:13N-26N.J Nucl Med.   Henry N. Wagner, Jr.  Disease as Dissonance

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