2 0 0 8 S N M H I G H L I G H T S L E C T U R E

Advancing a Molecular Theory ofDisease

The Highlights Lecture is presented at the closingsession of each SNM Annual Meeting by Henry N. Wagner,Jr., MD. This year’s lecture was presented on June 18 inNew Orleans, LA. This was the 31st year in which Wagnerdelivered the lecture, and 2008 also marks the 40thanniversary of the publication of his seminal text,Principles of Nuclear Medicine. Past SNM presidentsAlexander McEwan, MD, and Peter Conti, MD, PhD,introduced the lecturer.

As always, this meeting has been absolutely wonder-ful, in no small part because of the combined effortsof many of the organizers and participants. I would

like to begin by thanking Virginia Pappas and the excellentstaff of SNM. Credit also goes to Fred Fahey, DSc, chairof the Scientific Program Committee, and his team inselecting the presentations for this meeting and continuingto ensure that these are of such high quality. Thanks, too, tothe officials and conscientious staff of the New OrleansMorial Convention Center for the tremendous amount ofwork it takes over many days to make the metaphoricaltrains run on time for an event such as this meeting.

Every year I pick a theme for this highlights talk, andthis year I’ve chosen to spotlight the movement in whichwe are all participating in advancing a molecular theory ofdisease. Theories of disease, of course, have been aroundsince before recorded history. In relatively modern times,the cell theory of disease was first proposed in 1858 byRudolph Virchow (1821–1902). The germ theory of diseasewas proposed in 1862 by Louis Pasteur (1822–1895). Thesetheories and their subsequent validation in scientificresearch provided new ways of organizing and understand-ing medical knowledge and applying that knowledge acrossan extraordinarily complex range of health challenges.

Molecular imaging simplifies the mind-boggling com-plexity of the human body. For example, the human bodyhas 100 billion cells with 20,000 different molecularspecies per cell, each cell containing 100 millionmolecules. The human body contains 1011 neurons and1015 synapses that have presynaptic neuronal vesicles, eachvesicle of which contains 5,000 neurotransmitter mole-cules. I believe that many of you are to be congratulated foralready working productively under the general frameworkof a new theory that I think will equal those of Virchow andPasteur by creating the platform for future medicine. This isthe ‘‘molecular theory’’ of disease. Derived from molecularimaging, this theory will provide the infrastructure for

a revolutionary advance in scientificmedicine. When we look at thebillions and billions of molecules inthe human body, we can feel securethat this is a field that will remainvital and productive for centuries.

The essence of life is the recogni-tion of molecules by molecules. Muchof modern nuclear medicine has to dowith labeling molecules that will betargeted at specific molecules or partsof molecules in the body, for imaging or therapy andsometimes for both. One example of molecular labeling wasin the presentation at this meeting by Knešaurek andcolleagues from the Mt. Sinai Medical School (New York,NY) on the use of 111In-white blood cell SPECT/CT and MRimaging in tracking radiolabeled molecules to assessappropriate surgical approaches in the diabetic foot. Theauthors found that the CT study in 111In SPECT/CT can beused to accurately fuse and compare SPECT and MR imagesin these patients. Figure 1 shows a fused image in a 24-y-oldwoman with an infected foot. The image shows osteomyelitisand soft tissue disease and provided valuable informationthat affected surgery and management. I selected this as theSPECT/MR Image of the Year for 2008.

Moving from the cellular into the molecular domain, wecan look at a presentation from Castelluci and colleaguesfrom the Azienda Ospitaliero Universitaria di Bologna (Italy)on the use of 68Ga-DOTA-NOC PET to evaluate unusualneuroendocrine tumors. Figure 2 is a 3D PET/CT image ina 33-y-old man who had been referred for restaging ofa somatostatin receptor–expressing tumor in the left middleear. This precise imaging technique revealed that the tumorwas not confined to the ear and that the pituitary gland andlymph node were also involved. This knowledge helped hisphysicians amend and enhance treatment approaches. Iselected this as the PET/CT Image of the Year for 2008.Together, these images illuminate both the anatomical andfunctional range of molecular imaging ‘‘from head to toe.’’These images represent the state of the art and clearlyindicate that both PET and SPECT are here to stay.

PET, SPECT, and Beyond in Molecular ImagingThe 4 pillars of molecular imaging at the present time

are PET, SPECT, CT, and MR imaging, with a fifth pillar,optical imaging, now making substantial inroads. Figure 3

Henry N. Wagner, Jr.,MD

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shows the growth in numbers of abstracts for presentationson PET (including PET/CT) and SPECT (includingSPECT/CT) at the SNM Annual Meeting from 1982 tothe present. Looking at the percentages of the total

presentations also shown in this figure, it is clear thatPET still dominates. Although SPECT is declining slightlyas a percentage of papers, it has plateaued at a high level inabsolute numbers.

SPECT is alive and well and being used to explore newareas. Wiseman and colleagues from the Mayo Clinic(Rochester, MN), GE Healthcare (Princeton, NJ), theNational Institute of Child Health and Human Development(Bethesda, MD), the University of Iowa (Iowa City), theCleveland Clinic Foundation (OH), Cedars–Sinai MedicalCenter (Los Angeles, CA), and the University of Wash-ington (Seattle) reported on the results of a multicenter trialof 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphyin patients with known or suspected pheochromocytoma.The studies were performed in 150 patients, with resultingsensitivity and specificity for scintigraphy of 85% and 78%,respectively. These results confirmed the clinical utility ofthis approach in managing pheochromocytoma.

Serafini and colleagues from the University of MiamiHospital (FL), GE Healthcare (Princeton, NJ), Mt. SinaiHospital (New York, NY), and Piedmont Hospital (Atlanta,GA) reported on a study assessing the impact of SPECTon the interpretation of 123I-MIBG studies in the evaluationof 200 children and adults with known or suspectedpheochromocytoma or neuroblastoma. They found that123I-MIBG scintigraphy had a sensitivity and specificity of81% and 79%, respectively. The researchers noted thatalthough this technique provided a small improvement inquantitative performance, the use of SPECT assisted thereaders’ interpretation in almost half of patients studied.

Haug and colleagues from the Ludwig-MaximiliansUniversity (Munich, Germany) compared the diagnosticvalue of 68Ga-DOTA-TATE, a positron-emitting tracer thatbinds to somatastatin receptors, with that of 18F-DOPAPET/CT in patients with histologically proven neuroendo-crine tumors. In general diagnosis was better with thegallium tracer, with half of 18F-DOPA studies as false-negatives. However, uptake of 18F-DOPA, because it isa precursor of monoamine, was correlated with increasedserum levels of serotonin. The authors concluded that 68Ga-

FIGURE 1. SPECT/MR Image of the Year. 111In-white bloodcell SPECT and MR imaging revealed osteomyelitis and softtissue disease in this 24-y-old woman.

FIGURE 2. PET/CT Image of the Year. Molecular imaging ofa somatostatin receptor–expressing tumor in a 33-y-old manshowed additional involvement outside the ear.

FIGURE 3. Left, number of PET and SPECT presentations atSNM annual meetings, 1982–2008. Right, PET and SPECTpresentations as percentages of total presentation at eachmeeting, 1982–2008.

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DOTA-TATE PET should be considered as a first-line im-aging modality for well-differentiated neuroendocrine tu-mors, whereas 18F-DOPA might be useful only in serotonin-positive cases with negative 68Ga-DOTA-TATE PET.

As is the case with many agents, therapy follows diag-nosis. Cwikla and colleagues from the Medical Center ofPostgraduate Education and the Hospital Ministry of InternalAffairs and Administration (Warsaw, Poland), the OBRI-Polatom Radioisotope Center (Otwock-Swierk, Poland), andthe Royal Free Hospital (London, UK) reported on thebenefits of 90Y-DOTA-TATE somatastatin-binding therapyin patients with progressive metastatic neuroendocrine tu-mors. The study included 56 patients (26 women, 30 men;mean age, 52 y; range, 23–72 y) with histologically proven,extensive, nonresectable, and progressive neuroendocrinecarcinomas. The patients underwent a total of 168 treatments.Therapy was found to be effective, with standard dosescarrying a low risk of myelotoxicity. Figure 4 shows an ex-ample image of a patient at baseline (before treatment) and at12 m after initiation of treatment.

Important advances are being made in generators. New90Sr/90Y generators for radiotherapeutic applications, de-veloped with funding by the International Atomic EnergyAgency (IAEA) in association with investigators in India,were described by Chakravarty and colleagues from theBhabha Atomic Research Centre in Mumbai and from theIAEA. These generators can produce up to 100 mCi (3.7GBq) levels. Radiochemical separation is effective, andradionuclidic purity is .99.998%, suitable for directlabeling of biomolecules. These generators are simple tooperate and can be scaled up and automated. This type ofcollaborative and beneficial work is an example of what theIAEA continues to do for the field of nuclear medicine,particularly in developing countries.

Scott and Australian colleagues from Austin Hospital,Peter MacCallum Cancer Centre, and the Australian andNew Zealand Association of Physicians in NuclearMedicine (Melbourne); Wesley Hospital (Brisbane); RoyalAdelaide Hospital; Liverpool Hospital (Sydney); and theSir Charles Gardner Hospital (Perth) compared the effectsof 18F-FDG PET and 68Ga scanning in disease staging andmanagement of patients with low-grade non-Hodgkin’s

lymphoma. The study included 74 patients, all of whomunderwent PET scanning and 16 of whom underwentgallium scanning. Gallium detected additional lesions in 6of the 16 patients (38%), but 18F-FDG detected additionallesions in 10 of the 16 patients (63%). Patients withadditional lesions detected by PET had a significantlyinferior disease-free survival and a lower complete re-sponse. Patient treatment was changed in 7 of the 16patients (44%) based on 18F-FDG PET criteria and in only3 of the 16 patients (19%) based on gallium scanningresults. A big difference, however, is that 68Ga is availablefrom a generator, making it an option for those who do nothave cyclotrons or a supply of 18F-FDG.

The utility of molecular-based imaging in screening ofasymptomatic individuals is a topic of growing interestannually at this meeting. Minamimoto and Japanesecolleagues from Yokohama City University, the Instituteof Biomedical Research and Innovation (Kobe), theNishidai Clinic Diagnostic Imaging Center (Tokyo),Atsuchi Memorial Clinic PET Center (Kahoshima), andTohoku University (Sendai) reported on a nationwidesurvey of the performance of 18F-FDG PET and PET/CTfor cancer screening conducted in 2005 and 2006.Researchers at 97 centers completed surveys and respondedwith the results of imaging in 87,057 healthy individualswho had positive PET and/or combined screening tests. Ofthese, 992 (1.14%) were found to have previously un-detected cancers. Among these were colon/rectum (218cases), thyroid (194 cases), lung (173 cases), breast (64cases), prostate (91 cases), and gastric (56 cases) cancers.

Isohashi and colleagues from the Osaka UniversityGraduate School of Medicine (Suita, Japan) compared theaccuracy of 18F-FDG PET with that of CT or MR imagingin staging/restaging in patients with malignant lymphomaand in evaluating therapy response and recurrence. Thestudy included 59 patients who had undergone chemo- orradiation therapy. Serial PET and CT/MR images werecompared. PET and CT/MR imaging accuracies for staging/restaging were 92% and 84%, respectively. The corre-sponding figures were 84% and 50% for evaluation oftreatment and 83% and 72% for screening of recurrence. Inthe 122 pathologic sites with discrepant findings betweenPET and CT/MR imaging, the accuracy of PET (76%) wassignificantly greater than that of CT/MR imaging forevaluation of treatment response.

In addition to monitoring response to drug therapy, wecan also monitor the effects of surgical procedures. Zuo andcolleagues from the Huashan Hospital and Ruijin Hospital(Shanghai, China) and the North Shore–Long Island JewishHealth System (Manhasset, NY) reported on modulation ofmetabolic brain function by bilateral subthalamic nucleusstimulation in the treatment of Parkinson’s disease. Figure 5shows the positioning of the intracranial electrodes for deepbrain stimulation. Researchers found that bilateral sub-thalamic nuclear stimulation increased metabolism in theleft midbrain and pons (Fig. 6) but decreased metabolism in

FIGURE 4. Example images at baseline (A) and at 12 mo (B)after initiation of 90Y-DOTA-TATE somatastatin-binding therapyin a patient with a progressive metastatic neuroendocrinetumor.

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the right lentiform nucleus and cerebellum, as well as in thebilateral thalamus and precuneus. Clinical symptomsshowed some improvement, leading the authors to concludethat deep brain stimulation is more likely to function byregulating the entire neuronetwork than by exciting orinhibiting specific areas.

What is the relationship of blood tests to molecular im-aging in screening? Kong and colleagues from YeungnamUniversity Hospital (Daegu, South Korea) compared thesensitivities of 18F-FDG PET/CT and serum carcinoem-bryonic antigen (CEA) levels in detection of recurrentcolorectal cancer after curative surgical resection. The studyincluded 715 patients who underwent both PET/CTand CEAlevel analyses. A final diagnosis of recurrence was provenhistologically or radiologically in 79 patients (52 men,27 women; mean age 60.7 6 11.8 y). PET/CT detectedsuspicious lesions in 78 patients. Five of these 78 patientswere positive only on CT (lung nodules), with no traceruptake. Forty of the 79 patients (51%) showed increasedserum CEA (.10 ng/mL), meaning that CEA levels werenormal in almost half of these patients in whom PET/CTdetected disease.

Champion and colleagues from the Rene HugueninCancer Research Center (Saint-Cloud, France) reported onthe value of 18F-FDG PET/CT in patients in whom rising

tumor markers lead to a suspicion of recurrent breastcancer. The study included 238 consecutive, asymptomaticpatients who presented with rising tumor markers overa mean follow-up of 34 mo (range, 12–67 mo). Theresearchers found that PET/CT sensitivity, specificity,positive and negative predictive values, and accuracy indetecting recurrence were 94.5%, 85.5%, 97.4%, 72.5%,and 92.5%, respectively. They concluded that 18F-FDGPET/CT should be considered as a ‘‘one-stop shop’’ pro-cedure for breast cancer recurrence, particularly in thesetting of rising tumor markers.

How did 18F-FDG become the tracer molecule of the20th century? Are there lessons to be learned in looking athow FDG has attained this status? We can look at some ofthe successes and advantageous aspects of this tracer. First,FDG measures a key biochemical process (energy metab-olism), and the results of FDG studies have been clearlylinked to the enhancement of surgical decision making.Legislative support led to reimbursement by the Centers forMedicare and Medicaid Services (CMS) in the United States,in part as a result of early clinical adoption and promotion byindustry. For some time, many regional suppliers haveoffered FDG, which is produced through easily automatedchemical synthesis. 18F has an appropriate and manageablehalf-life of 110 min. PET/CT images now appeal to radio-logists and other physicians by relating visually familiarstructure to function and biochemistry. The images we haveto offer with 18F-FDG PET/CT have gone from the old ‘‘un-clear’’ nuclear studies to a more medically accessible clarity.

In my opinion, clinical radiotracer production in the fu-ture will be active at the national, regional, and institutionallevels. The United States had 10 regional FDG distributionsites in 1996 and has 110 today. Japan has 10 FDG pro-duction sites, supplying 50 hospitals.

Hillner et al. reported in the May issue of the Journal ofClinical Oncology (2008;26:2155–2161) on initial resultsfrom the National Oncologic PET Registry (NOPR). NOPRcollected questionnaire data from referring physicians onintended patient management before and after PET andPET/CT over a 1-y period. The results included 22,975 PETstudies (83.7% of which were PET/CT) from 1,178 centers.Results showed that patient management changed in 37.2%of patients after PET or PET/CT. NOPR has now formallyasked CMS to expand reimbursement for the use of 18F-FDGPET for nearly all oncologic applications, with a responseexpected this fall.

I believe that personal acceptance of responsibility by thephysician should be the primary regulatory mechanism ofthe future for imaging procedures––somewhat analogous tothe responsibility that surgeons assume when they decide,with their patients, whether or not to proceed with specifictypes of surgery. The economist William H. Donaldsonrecently said, ‘‘There is a limit to how much regulation cando. In the final analysis, you could write all the rules youwant, but there has to be a philosophy of ethical behavior thatcomes from human beings operating in a professional way.’’

FIGURE 5. Positioning of intracranial electrodes for bilateralsubthalamic nucleus stimulation in the treatment of Parkinson’sdisease.

FIGURE 6. Bilateral subthalamic nucleus stimulation in-creased metabolism in the left midbrain and pons in individualswith Parkinson’s disease.

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Described at this meeting was a global imaging networkthat has been initiated and is already in use that willmanage and archive every imaging study being consideredin clinical use. Connected via the Hermes Solution, thisnetwork will provide secure remote access to users world-wide. This technology is already available. My proposal isthat the U.S. Food and Drug Administration (FDA) approvea relatively small number of studies and make it possiblefor these studies to be carried out with a modified phase 4approach; that is, all the studies must go into a centraldatabase. Such a database could have a server in the UnitedStates and one in Europe on which images could be re-corded and continuously examined to make sure that theimaging procedures are safe and effective.

Shah and Srinivas from the Cleveland Clinic (OH)decribed an innovative reporting scheme for hybrid di-agnostic examinations. Their approach in integrated report-ing of both PET and diagnostic contrast-enhanced CT scanseliminates redundancy in performing separate modality-specific interpretations and provides a single cohesiveanswer to the clinical question. The elimination of discordantreports produces a clearer assessment of pertinent findingsfor the referring physician. Additional benefits includeworkflow efficiency and cost savings.

The Value of the UnexpectedMany studies presented at this meeting showed the

importance of an expert observer in detecting and interpret-ing unexpected findings in PETand SPECT studies. I like theanalogy of a modern airplane where a skilled pilot is stillrequired, despite many automated features that enable theplane to ‘‘fly itself.’’ Han and colleagues from CatholicUniversity of Korea (Seoul, South Korea), for example,reported on the significance of incidental finding of focaluptake of 18F-FDG in the prostate. Among 5,118 PET/CTimages reviewed from a 4-y acquisition period, 62 casesshowed incidental focal tracer uptake in the prostate. Ofthese, 52 had pathologic confirmation, clinical follow-up,radiologic images, or prostate serum antigen levels forinclusion in the final analysis. Among these 52 individuals, 2patients (3.8%) were confirmed to have malignant lesions.The authors concluded that although focal 18F-FDG uptake inthe prostate was incidentally noted in 1.2% of PET/CT scansand that only a small percentage of these were malignant,‘‘further evaluation is necessary when the focal uptake is seendiscretely in the periphery.’’

Wu and colleagues from the Chi Mei Medical Centers(Liouying and YungKang, Taiwan) reported on incidentalfindings of tuberculosis in 2,850 patients undergoing 18F-FDG PET/CT scanning for oncologic indications. Thirty-four patients were found to have tuberculosis in lesions thataccumulated tracer in specific nodular patterns. Figure 7shows an example scan from a 57-y-old man in whomregions of glucose accumulation had a diffuse appearancethat was at first thought to be pneumonia but was describedby these investigators as characteristic of tuberculosis. In

the images acquired after 6 mo of tuberculosis treatment,these lesions had disappeared, although residual accumu-lation can be seen in the cancerous lung lesions.

Incidental thyroid lesions are often detected by PET/CT.Ono and colleagues from the Yotsuya Medical Cube (Tokyo,Japan) reported that in a review of the PET/CT records of2,514 asymptomatic individuals, diffuse thyroid uptakewas observed in 96 (3.8%). Localized thyroid uptake wasseen in 26 (1%) individuals, and thyroid carcinoma wasidentified in 9 (38%) of these. Overall the PET-positive ratewas 4.8%, and the positive predictive value in detectingthyroid lesions was as high as 95%.

Shie and colleagues from the Kaiser PermanenteFontana Medical Center (CA) and the University of NorthTexas Health Science Center (Fort Worth) reported on aneven larger study of the prevalence of malignancy inincidental focal thyroid nodules identified by PET. (I wantto pause here and parenthetically note how impressed I amwith the number of studies at this meeting that includedmany results from patients across geographic and in-stitutional boundaries. For many years we routinely heardpresentations on 4 or 5 patients. Now, with an emphasis onevidence-based medicine and cooperative efforts, we areseeing studies with many thousands of patient records.) Inthis metadata review, published studies on 63,960 patientsfrom 19 institutions were aggregated, and 672 of thesepatients had incidental focal thyroid 18F-FDG uptake. Ofthese 672, 379 patients had associated records of histo-pathologic diagnosis, and 127 (33.51%) of these proved to

FIGURE 7. In this 57-y-old man with lung cancer, incidentalfindings of diffuse tracer uptake (A panel) suggested pneumoniabut were found to be tuberculosis. After 6 mo of tuberculosistreatment (B panel), uptake was reduced.

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be malignant. The authors concluded that the high prevalenceof thyroid malignancy associated with focal hypermetabolicthyroid nodules calls for needle biopsy when accumulationsof 18F-FDG are encountered incidentally.

Grassetto and colleagues from the Santa Maria dellaMisericordia Hospital (Rovigo, Italy) reported on the roleof 18F-FDG PET in the diagnostic work-up of patients withadrenal incidentaloma on conventional (MR/CT/ultra-sound) imaging. The study included 74 patients with suchfindings, of whom 54 had histories of cancer. Significant18F-FDG uptake was found in 32 patients. At surgery,metastases were confirmed in all 28 of these 32 patientswho had histories of cancer. The authors recommendedPET as a ‘‘first-choice examination’’ to be performed in pa-tients with oncologic histories and adrenal incidentalomason conventional imaging.

Kiendys and colleagues from Ghent University Hospital(Belgium) reported on the prevalence and clinical signif-icance of 18F-FDG PET-positive incidentalomas. Theretrospective review included the records of 5,476 whole-body PET/CT scans in patients, among whom 18 (0.3%)were found to have unexpected focal 18F-FDG uptake in theparotid gland. Eight patients underwent surgery. Of these, 4had benign tumors, 2 had infections, and 2 had metastaticdisease. The authors concluded that 18F-FDG PET-positiveparotid incidentalomas are rare and focal uptake in this areacan signal benign tumors, infection, or metastatic disease.

Yamane and colleagues from the Daiyuka General Hos-pital (Aichi, Japan) reported on the frequency of and clinicalfactors associated with incidental increased splenic uptakeobserved in 18F-FDG PET. In a review of 5,577 patient re-cords, increased splenic tracer uptake was observed in 209individuals (3.7%). Uptake patterns were diffuse in 187 ofthese patients and nodular in 22. The group elucidated a rangeof causes for the unexpected uptake, the most common ofwhich (131 patients, 63%) was related to the presence ofpreviously unsuspected malignant lymphoma.

New Instrumentation and RadiopharmaceuticalsMany new instruments were introduced at this meeting.

Among the trends seen is the advancing development ofsemiconductor imaging devices that provide good energyresolution and speed. Among their significant advantages isthe elimination of phototubes, a feature that aids in fusingMR with either PET or SPECT in hybrid imaging. Nuclearimaging fusion with MR imaging, although the topic of atleast a dozen papers at this meeting, is only in its beginningstages, and the use of these semiconductor instruments willbe a tremendous boost in advancing new hybrid and single-modality innovations.

Figure 8 is a prototype brain PET scanner based onsemiconductor detectors, described at this meeting byMorimoto and colleagues from Hitachi Ltd. (Ibaraki,Japan) and Hokkaido University (Japan). The scanner isbased on the use of 18 cadmium telluride detectors, witha port diameter of 35 cm and an axial field of view of 25 cm

without interplane septa. Initial performance evaluationsreported by the developers indicate that the scanner isfeasible for clinical use with high spatial resolution.

From the same research group, Shiga and colleaguesreported on the use of this device in identification ofintratumoral inhomogeneous cell activity. Phantom andclinical tests suggested that the new PET device has thepotential for better differentiation of differing cell activitieswithin tumors because of higher resolution and less scatternoise. Figure 9 indicates that the new device provides betterdefinition of lesions than either whole-body or brainscintillator PET and may provide advantages in treatmentplanning tailored to tumor inhomogeneity.

Lofton and colleagues from the University of TexasM.D. Anderson Cancer Center (Houston) reported on theperformance characteristics of a portable pixilated cad-mium telluride miniature g camera (Fig. 10). The camerahas a 32 · 32 element array, 44.8-mm2 field of view, 1.2 ·1.2 · 5-mm element size, and an application-specificintegrated circuit (128 elements · 8) with standard, high-resolution, and diverging collimators.

FIGURE 8. Prototype PET brain scanner (A) and exampleimages (B) from Hitachi, Ltd., based on semiconductor detectortechnology.

FIGURE 9. Image (right) acquired with the semiconductordevice pictured in Figure 8 provides better definition of lesionsthan either whole-body (left) or brain (middle) scintillator PETimaging and may provide advantages in treatment planningtailored to tumor inhomogeneity.

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O’Connor and colleagues from the Mayo Clinic(Rochester, MI) reported on molecular breast imaging as anadjunct to screening mammography. This is another im-portant area in which molecular imaging techniques are usedincreasingly, with gains being driven by special-purposedevices. In this case, a cadmium zinc telluride g camera (Fig.11) provides excellent spatial resolution of 1.6 mm andenergy resolution of ;4%. Figure 12 compares the conven-tional mammogram with breast molecular imaging, in-dicating that although a 20-mm lesion is seen on bothmodalities, an additional 10-mm lesion is seen only on breastmolecular imaging.

Schilling and colleagues from Boca Raton CommunityHospital (FL) reported on the utility of high-resolutionpositron-emission mammography in presurgical planningfor breast cancer. Imaging results in Figure 13 suggest thevarious ways in which this approach is helpful in determiningthe extent of disease, in evaluating indeterminate lesionsdetected by MR imaging, and particularly in imaging patientswith implants or dense breasts. In addition, excellentpathologic correlations are noted with the results of high-resolution positron-emission mammography.

Spanu and colleagues from the University of Sassari(Italy) reported on the value of preoperative planarscintimammography with a high-resolution dedicatedbreast camera (Fig. 14). The study included 44 patients(4 with bilateral disease, 24 with multifocal/multicentricinvasive disease, and 16 with multifocal/multicentric in situdisease). Planar scintimammography was more accuratethan mammography in 10 patients (22.7%), whereasconventional mammography was more accurate in only 1patient (2.3%). The spatial resolution of this device is 1.6mm, and the energy resolution is ,5%. The imagesincluded in Figure 14 indicate that this allows visualizationof much more detail in a multicentric invasive ductalcarcinoma with an intraductal component, allowing thepatient to be correctly staged and for operative managementto be planned more precisely.

Piert and Guo from the University of Michigan (AnnArbor) reported on a b/g interoperative system designed tolook for small pieces of remaining tumor after resection ofbreast cancer. The probes were developed because so manypatients went to surgery soon (in some cases on the sameafternoon) after 18F-FDG studies. The new system was ableto detect lesions even in the presence of high levels ofresidual background radiation.

FIGURE 10. Portable pixilated cadmium telluride miniature gcamera from AcroRad Co., Ltd.

FIGURE 11. Gains in molecular breast imaging are beingmade with apparatus like this cadmium zinc telluride g camera.

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Menard and colleagues from the Laboratoire IMNC(Orsay, France) and the Centre Hospitalier UniversitaireHenri Mondor (Créteil, France) described a miniaturizedintraoperative multimodal b-probe for brain tumor surgery.This probe is dedicated to real-time localization of residualtumor after the primary lesion has been excised. Directcoupling of the imaging device to the excision tool helps tosimultaneously detect and remove residual tumor (Fig. 15).The ultrasonic aspirator fits inside the b-probe (Fig. 16).The small lesions peripheral to the resection site arelocalized and then immediately aspirated after ultrasonicdestruction into particles.

In addition to new instruments, we need new radio-tracers approved for a range of applications. In my opinion,the following radiotracers are currently ripe for approvaland reimbursement: fluoride, fluorothymidine (FLT), hyp-oxia tracers, acetate, methionine, choline, fluoroethyl-tyrosine, and 18F-DOPA.

Suleiman and colleagues from the U.S. FDA (Bethesda,MD) reported at this meeting that in 2007 75 RadioactiveDrug Research Committees (RDRCs) submitted annualreports, summarizing 308 studies on more than 3,000 humanresearch subjects. Two-thirds of the studies used PET nu-clides. The researchers stated their belief that the FDAcontinues to believe that the RDRC program is an integralpart of essential research for potential candidate drugs.

I want to offer a proposal for obtaining (and hastening)regulatory approval for this multitude of promising tracers.In this schema, physician- or industry-sponsored explor-atory Investigational New Drug (eIND) applications areapproved by the FDA for a small (e.g., 10 or 20) number ofstudies. The agent would then receive conditional approval,requiring cumulative evaluation for safety and effectivenessduring further but indefinite clinical use. Each result froma patient study would be reported and included in a databasethat allows continual monitoring of safety and effectiveness.

FIGURE 12. Although a 20-mm lesion is seen on bothconventional (left) and molecular (right) breast imaging, anadditional 10-mm lesion is seen only on molecular imaging.

FIGURE 13. High-resolution positron-emission mammogra-phy is useful in presurgical planning for breast cancer bydetermining extent of disease (A), evaluating indeterminatelesions detected by MR imaging (B and D), and imagingpatients with implants or dense breasts (C).

FIGURE 14. High-resolution dedicated breast camera fromGamma Medica-Ideas, Inc., used for preoperative planarscintimammography (A). Imaging allowed visualization of muchmore detail in a multicentric invasive ductal carcinoma with anintraductal component (C and E) than conventional imaging(B and D), allowing the patient to be correctly staged and foroperative management to be planned more precisely.

FIGURE 15. Miniaturized intraoperative multimodal b-probefor brain tumor surgery. Direct coupling of the imaging device tothe excision tool helps to simultaneously detect and removeresidual tumor.

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This approach has recently been called ‘‘in-life testing’’ byVisiongain, Ltd. (London, UK), in the development of stabledrugs. The result provides continuous, long-term (evenperpetual) assessment of safety and effectiveness.

Another proposal for obtaining reimbursement for newmolecular imaging biomarkers is to first determine thevalidity of the tracer for measuring a specific chemicalprocess. Initial clinical studies would be performed afterobtaining institutional RDRC or IND approval or anindustry- or physician-sponsored FDA eIND. Hospitals orresearch grants would pay the costs of initial clinicalresearch prior to approval for reimbursemet by CMS andothers payors (I will explain later the economic model thatmight make them willing to do this). The medical andeconomic value of each study would then be assessedcontinually for all subsequent studies, with the resultsrecorded in a national database.

A New Drug Application for radioactive tracers isa request for approval to market a new drug for a specificclinical use. The present requirement for approval is thelegal requirement for ‘‘substantial’’ evidence of efficacydemonstrated through controlled clinical trials, which at thepresent time usually consist of hundreds and hundreds ofpatient studies assessing criteria such as outcomes, whichmay require long periods of time to yield definitive results.This requirement lies at the heart of the regulatory programfor stable drugs but, in my opinion, should not be the basisof regulation of tracers. Tracers, unlike stable drugs,provide information analogous to that provided bymeasurements such as body temperature, blood pressure,or electrocardiographic data. Fewer patient studies shouldbe needed before conditional approval.

CMS is the agency that determines whether a study willbe reimbursed and should be made aware that the economicvalue of molecular imaging is a function of knowledge. Ihave discussed the following equation in previous High-lights Lectures: dV/dt 5 fK*, where V 5 value and K 5knowledge. Correct decision making depends on knowl-edge, and this is different from clinical outcome. Increasingknowledge by molecular imaging is expensive, but makingcorrect decisions decreases the cost of caring for eachpatient. The result may be an overall increase in institu-tional costs, because increasing productivity also increasesdemand for procedures, but ultimately the cost per patientdecreases.

Local synthesis of tracers is a recurring focus at theSNM meetings. A few examples of 18F-labeled tracers thatcould be synthesized within hospitals or regional facilitiesfollowing the simplified regulatory process that I outlinedhere include: 18F-DOPA for dopamine synthesis; 18F-fluo-rouracil for pyrimidine analogs; 18F-fluorotyrosine for largeamino acid transport; 18F-fluorocholine for membranesynthesis; 18F-FLT for DNA synthesis; 18F-fluorestradiolfor estrogen receptors; and 18F-fluoroazomycin arabinoside,18F-misonidazole, and 18F-FRP-170 for hypoxia. Theadvantages of in-house production of radiotracers includeeasier regulatory approval, ever-increasing numbers ofavailable tracers, ready availability, and decreased costsof care per patient. More than 40 y ago in Nucleonics Iwrote that every hospital would have a cyclotron in 30 y.Although the timeline has slipped somewhat, I stand by theessential truth of that prediction.

Tabletop cyclotrons are being developed and commer-cialized. Ronald Nutt, PhD, with Siemens MedicalSolutions (Malvern, PA), has a system with a beam energyof 7.5 MeV, which can produce 50 mCi of 11C or 18F. Itcannot produce 13N or 15O. What they visualize and havealready done in small numbers is ‘‘franchise’’ this bio-marker generator for a $200,000 fee from the institution.Then the institution pays $100.00 per dose, with anagreement to produce a minimum of 8 doses per day. Thisapproach of local production of PET tracers is, in myopinion, analogous historically to the conversion frommainframe to personal computers. I remember that in theearly days, when computers were first introduced, themainframe computers were behind a big glass screen,where it looked as if the computer experts inside were outof The Wizard of Oz. Today, although mainframe computersstill exist, personal computers have become common, withthe functionalities of the original mainframe now availableto all PC users at their desks. Chemical synthesis in thetabletop cyclotron is based on microfluidics with glass-based liquid polytetrafluorethylenes. They are quite fast andhave a high yield and low mass, which aids in making themnontoxic.

Another very important advance makes it possible tolabel almost any kind of peptide. McBride and colleaguesfrom Immunomedics, Inc. (Morris Plains, NJ), and GardenState Cancer Center (Belleville, NJ) reported on a newmethod of 18F labeling of peptides and proteins via a metalligand. The rationale is that 18F labeling usually attaches18F to carbon, a time-consuming and often multistepsynthesis. Metal labeling of ligands is usually fast andcan be carried out in a single step. The hypothesis of theseinvestigators was that chelated 18F-metal complexes mayallow for rapid and efficient labeling of small molecules.They wanted to determine which metal(s) will form stablecomplexes with fluoride and be nontoxic at low doses.Fluorine binds to aluminum to form AlFn complexes, whichcan perform several different functions in vivo. The peptideis labeled and purified in about 1 h, a method that can be

FIGURE 16. An ultrasonic aspirator (A) is coupled with theintraoperative b-probe (B) in the device seen in Figure 15.

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applied to label almost any peptide 18F. The group outlinedinitial work with combining a NOTA complex and Al18F tolabel proteins and peptides in bispecific antibody pretarget-ing for immunoPET. Images from 3D mouse studies (Figs.

17 and 18) show the lesion quite clearly. The pretargetedAl18F IMP 449 showed exceptional targeting in vivo, hightumor uptake, and excellent tumor-to-nontumor ratioswithin 1 h.

Small animal imaging devices have become widespreadin academic chemistry and nuclear medicine departments.The growing availability of radiotracers made possible byin-house production is increasing interest in these studies,but not every department has access to a dedicated smallanimal scanner. Several groups at the meeting focused ondevices for small animal imaging using clinical scanners.DiFilippo, from the Cleveland Clinic (OH), reported ona multipinhole collimation device for small animal micro-SPECT/CT using a clinical scanner (Fig. 19). Figure 20shows some of the images obtained with this modifiedclinical instrument, including 99mTc-MAA lung micro-SPECT slices, coregistered CT, bone microSPECT, andmicro-SPECT/CT.

Beekman and colleagues from University MedicalCenter Utrecht (The Netherlands) described very high-resolution SPECT with a dedicated high-resolution focusedcollimator based on pinholes. Figure 21 shows theUSPECT-II with the 2 collimators, one for brain and onefor whole body. Figure 22 provides an example of thequality of the images that can be obtained with .3 mmresolution compared with conventional CT imaging. Figure23 is an example of 99mTc-HDP imaging with this device ina mouse.

FIGURE 17. Al18F-IMP peptide uptake in a colon tumor–bearing mouse pretargeted with anti-CEA anti-HSG bispecificantibody. Image shows uptake at 30 min in a 6-mm tumor.

FIGURE 18. The in vivo peptide targeting technique shown inFigure 17 demonstrated high tumor uptake and excellenttumor-to-nontumor ratios, here seen in the same mouse at 1 h.

FIGURE 19. Multipinhole collimation device for small animalmicro-SPECT/CT using a clinical scanner.

FIGURE 20. Images obtained with the device shown in Figure19, including 99mTc-MAA lung micro-SPECT slices (C, top),coregistered CT (C, bottom), bone microSPECT (A), and micro-SPECT/CT (B).

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Cadmium telluride semidetector instruments are alsobeing used in small animal PET scanners. Tanizaki andcolleagues from Sumitomo Heavy Industries, Ltd. (Tokyo,Japan), and Tohoku University (Sendai, Japan) havedeveloped a 512-channel detector device (Fig. 24) withbore size of 100 mm and transaxial and axial fields of viewof 77 and 22 mm, respectively. Figure 25 shows imagesacquired with the device.

Kanai and colleagues from the Osaka UniversityGraduate School of Medicine (Japan) and Tohoku Univer-sity (Sendai, Japan) reported on rat brain studies acquiredwith 123I-iomazenil and a semiconductor-based animalPET scanner. Figure 26 is a PET coronal section acquiredwith this in vivo technique and shows that the resolutionis comparable with and superior to that of ex vivoautoradiography.

18F-fluoride, in my opinion, should be first on the listfor CMS approval because of its utility in imaging patientswith bone metastases. Doot and colleagues from theUniversity of Washington (Seattle) and the Seattle Cancer

Care Alliance reported that kinetic analysis of 18F-fluoridePET images can differentiate osteoblastic and osteolyticlesions in breast cancer metastases. The authors concludedthat fluoride flux and transport can be accurately andindependently measured for bone metastases and normalvertebrae (Fig. 27).

A negative 18F-fluoride PET may occur in patients withmalignant sclerotic bone lesions. Behesti and colleaguesfrom the PET-CT Center and St. Vincent’s Hospital (Linz,Austria) and King’s College (London, UK) looked atpossible reasons for 18F-fluoride-negative PET in suchlesions. In a study of 14 patients with known or suspectedbone metastases, 31 malignant sclerotic lesions wereidentified with no 18F-fluoride uptake. The mean densityof these lesions was 1,221 6 560 Hounsfield units, and theyremained 18F-fluoride negative despite disease progressionand new metastatic formations in the other skeletal sites. Inretrospective monitoring, 5 lesions were positive in pre-vious 18F-fluoride PET studies. The authors theorized thatthe lack of uptake could be the result of therapy response orapoptosis. Clearly 18F fluoride is not perfect, but it remainsa very good tool in our armamentarium.

Another example of a study with a large series ofpatients came from military experience at the Walter ReedArmy Medical Center (Washington, DC). Kao andcolleagues assessed the utility of skeletal scintigraphy forosteomyelitis evaluation in patients with amputations or

FIGURE 21. The USPECT-II (A) acquires small animal imageswith dedicated high-resolution focused pinhole collimators forbrain (B) and whole body (C).

FIGURE 22. USPECT-II device 3D rat brain phantom (A) andresolution (D). Right panels compare CT (B and E) withU-SPECT images (C and F).

FIGURE 23. Example of 99mTc-HDP mouse imaging with theUSPECT-II.

FIGURE 24. Ultra-high spatial resolution small animal PETscanner (A) using cadmium telluride semiconductor detectors(B and C).

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orthopedic devices. The investigators retrospectively re-viewed all 3-phase bone scan reports for a 1-y period, witha total of 1,475 individuals. Inclusion criteria were anextremity amputation or current extremity orthopedicdevice and referral for potential osteomyelitis. Of the 29patients who met these criteria, 28 (97%) scans hadincreased activity in the region of interest. Of these 28, 23(82%) showed increased activity on all 3 phases of theexamination. Twenty-seven were referred for 111In-whiteblood cell/99mTc-sulfur colloid imaging to diagnose orexclude osteomyelitis. The investigators concluded that pa-tients who have undergone an amputation or have anorthopedic device in an extremity should proceed directlyto 111In-tagged white blood cell/99mTc-sulfur colloid ex-amination when osteomyelitis is suspected, stating that‘‘skeletal scintigraphy provides little diagnostic benefit andresults in unnecessary radiation exposure for this patientpopulation.’’

Herrmann and colleagues from the Technische Uni-versität München (Germany) reported that 18F-FLT helps inthe characterization of proliferation and thereby indiscriminating cancer from pancreatic pseudotumors. Thestudy included 31 patients with undefined pancreatic

FIGURE 25. Images (A and C) acquired with the small animalPET scanner (B).

FIGURE 26. Coronal section image (A) acquired with 123I-iomazenil and a semiconductor-based animal PET scanner iscomparable with and superior to results from ex vivoautoradiography (B).

FIGURE 27. Kinetic analysis of 18F-fluoride PET images candifferentiate osteoblastic and osteolytic lesions in breast cancermetastases. The authors concluded that fluoride flux andtransport can be accurately and independently measured forbone metastases and normal vertebrae.

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tumors that were suspected to be malignant. All underwent18F-FLT PET, and focal uptake of the tracer was ex-clusively detected in malignant tumors; that is, a specificityof 100%. Fifteen of 21 malignant tumors, however, showedhigh focal uptake, for a sensitivity of 71%. It is important toremember that at any particular time, only about a tenth ofthe cells in even a very malignant tumor are dividing, sothat although the signal with 18F-FDG is 10 times that of18F-FLT, the accumulation of 18F-FLT is more specific inshowing cell division.

Souvatzoglou and colleagues from the same TechnischeUniversität München group reported on the potentialinfluence of 11C-choline PET/CT on radiotherapy treatmentplanning in patients with biochemical recurrence ofprostate cancer. 11C-choline is now fairly widely used tostudy prostate cancer. In a study of 38 patients, theseresearchers found that the use of the labeled choline in anextended PET/CT radiotherapy plan was helpful in 5patients (13%), contributing positively to individualizedtreatment planning and potentially improving the effec-tiveness of salvage radiotherapy. Figure 28 shows theconventional treatment planning and the incrementalinformation provided by the addition of PET/CT data.

Nuclear CardiologyNuclear cardiology continues to advance. We are

reminded with some frequency that the most commonpresenting manifestation of coronary artery disease (CAD)is still sudden death. Identification of those patients who areat significant risk remains extremely important. Piccini andcolleagues from the Duke University Medical Center(Durham, NC) reported on SPECT myocardial perfusionimaging defects as strong predictors of sudden cardiacdeath in patients with CAD. Data they presented froma cohort of 6,383 patients with angiographically docu-mented CAD who had also undergone gated SPECTimaging showed clear cut-off points in assessment oflesions and ejection fraction that predicted survival. When

the summed stress score (SSS; i.e., blood flow as assessedby sestamibi studies) defects were ,6 and the ejectionfraction was .35, then survival rates were good. When theSSS was .6 and the ejection fraction was ,35, thensurvival over the 12-y follow-up period was significantlylower.

Hutton and colleagues from University College (London,UK) and Spectrum Dynamics (Caesaria, Israel) reported onperformance evaluation of the D-SPECT dedicated cardiacscanner (Fig. 29), which has a high sensitivity that facilitateshigh-quality dynamic studies. The improved energy resolu-tion permits dual- or triple-radionuclide imaging, includingthe use of 99mTc, 123I, and 201Tl. The device permits the

FIGURE 28. Conventional radiotherapy planning (A) wasenhanced by data from PET (B) and CT (C) to provide a moreprecise PET/CT radiotherapy plan (D).

FIGURE 29. D-SPECT solid state cardiac SPECT scanner (A)and components (B and C).

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acquisition of a stress study and rest study in a period of about30 min rather than requiring separate rest and exerciseexaminations. Ben Haim and colleagues from the sameresearch group reported on 11 patients in whom simultaneousdual-isotope myocardial perfusion imaging was acquiredwith the D-SPECT. The accuracy and image quality wereequal to those of conventional myocardial perfusion imagingwith separate stress and rest acquisitions.

CAD, as Javadi and colleagues from the Johns HopkinsUniversity (Baltimore, MD) pointed out in a presentation atthis meeting, is a continuum that can be characterized byPET, SPECT, and CT. The continuum begins with pre-clinical disease, which is accompanied by endothelial dys-function and can be assessed by measuring coronary flowreserve. It then progresses to vascular remodeling andplaque formation, which can be measured by CT angio-graphy, assessing the plaque burden. The progression isthen to clinical disease, with flow-limiting stenosis orocclusion of the vessels. PET or SPECT can show regionalischemia or infarction. Our continued aim, of course, is todetect CAD as early along this continuum as possible.

I believe that the most important population thatmolecular imaging should be focusing on in this area isdiabetic patients. A few example studies will explain why.Lautamäki and colleagues from the same Johns HopkinsUniversity group that described the CAD continuumreported on quantification of myocardial blood flow withPET/CT and 82Rb in a canine model of coronary arterystenosis. 82Rb quantification of myocardial blood flowprovides a new way to detect and assess CAD, making itpossible to detect uniformly distributed (so-called ‘‘bal-anced’’) ischemia, which has been problematic. When allvessels are involved, initial distribution may appear normal,because we compare one region with another. Theseinvestigators showed that it is possible to more accuratelymonitor therapy as well as detect CAD with this approachthat measures regional as well as balanced ischemia.

Yoshinaga and colleagues from the Hokkaido Univer-sity Graduate School of Medicine (Japan) and the Uni-versity of Ottawa Heart Institute (Ontario, Canada)compared 82Rb with 15O-water PET in the measurementof coronary endothelial function––the earliest changes thatoccur in the continuum of CAD. 82Rb and 15O-water myo-cardial blood flow estimates were well correlated over awide blood flow range. Both identified altered flowresponse during cold pressor tests in smokers. The authorsconcluded that 82Rb has a potential for wide clinical ap-plication, including the measurement of coronary endothe-lial function in smokers.

Lautamäki and the Johns Hopkins University group alsolooked at multitracer PET characterization of impaired myo-cardial sympathetic innervation in the viable infarct border-zone. Three different tracers were combined to investigatedifferent components of presynaptic nerve biology. Theseincluded 11C-epinephrine, which is normally stored invesicles that protect it from metabolism; 11C-hydroxyephe-

drine, which is avidly taken up but not metabolized; and 11C-phenylephrine, which is not efficiently stored but leaks fromvesicles and is degraded. Impaired neuronal biochemistrywithout complete denervation (the neurons are not com-pletely damaged) contributes to arrhythmogenicity in theinfarct borderzone, and this state may be reversible. Theauthors concluded that tissue heterogeneity and impairedinnervation of viable myocardium are observed in theborderzone of myocardial infarct and show only partialagreement, so that these 2 arrhythmia markers are com-plementary rather than competitive and can be integratedinto a single PET/CT session. Neuronal imaging can helpdevelop novel antiarrhythmic therapies. Every year we seea few papers on sympathetic innervation of the heart, and Ibelieve that these will continue to increase.

Kardan and colleagues from the Massachusetts GeneralHospital (Boston, MA) gave 2 presentations at this meetingon the characteristics of CardioPET, a modified fatty acidclosely resembling naturally occurring fatty acids, asa cardiac PET tracer. As we know, the heart relies on fattyacids for most of its energy and, when stressed, begins tometabolize glucose. Figure 30 shows the CardioPETimages in a healthy individual and a patient with CAD,which the authors noted were superior to myocardialperfusion SPECT in demonstrating coronary perfusion anddetecting abnormalities in the myocardium in both rest andstress. Figure 31 is an example of the changing informationthat can be gathered from serial studies carried out from 3min to 1 h after injection.

I believe that these and other techniques should beemployed in looking for silent CAD in all patients withdiabetes or risk factors as part of a concerted effort to

FIGURE 30. CardioPET, an 18F-fatty acid analog, effectivelydemonstrated coronary perfusion and detected metabolicabnormalities in myocardium. Healthy volunteer (A and C);individual with coronary artery disease (B and D).

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encourage preventive measures. Why? We know that34%244% of patients with type 2 diabetes mellitus havecoronary endothelial dysfunction, a functional precursor ofCAD, without coronary artery calcification or abnormalincreases in carotid intima-media thickness, as determinedby ultrasound and electron beam tomography. Coronaryendothelial dysfunction, which is the earliest sign ofbeginning CAD, can be detected by PET before structuralalterations of the arterial wall can be seen.

Nkoulou and colleagues from the University Hospital ofGeneva (Switzerland) reported on the results of 201TlSPECT screening of stressed-induced perfusion myocardialischemia in a study population of 386 diabetic patients.Forty-four percent of symptomatic patients and 40% ofasymptomatic patients were found to have perfusion defects(Fig. 32). This high percentage of ‘‘silent’’ myocardial

ischemia led the authors to call for further studies toidentify clinical predictors or algorithms that would selectdiabetic patients for myocardial perfusion screening.

Lieberman and colleagues from the University of Penn-sylvania and Avid Radiopharmaceuticals, Inc. (Philadelphia),and the University of Michigan (Ann Arbor) reported on a newPET ligand for directly measuring b-cell mass in the pancreas,a capability of great importance in the diabetic patient. 18F-epoxide FP-DTBZ is a tracer for vesicular monoaminetransporter-2 (VMAT2) with high selective uptake. Figure33 shows the tracer distribution in rats, indicating that thepancreas had the highest level of uptake of all organs or tissues.Figure 34 shows the localization of the tracer in the pancreas.

Ichise and colleagues from Columbia University (NewYork, NY) reported on another VMAT2 tracer, 11C-DTBZ,for PET quantification of b-cell mass in the pancreas indiabetes. The study was conducted in patients withlongstanding type 1 diabetes, a clinical situation in whichb-cell mass may be almost depleted. Figure 35 showsaccumulation of the tracer and binding in the pancreas,although the researchers noted that nonspecific bindingmay be a confounding factor in patients with longstandingdiabetes.

Delbeke and colleagues from Vanderbilt Hospital(Nashville, TN) and Rambam Healthcare (Haifa, Israel)

FIGURE 31. Example of changing information that can begathered from serial studies carried out at 1–3 (left), 15–30(middle), and 30–60 min (right) after injection of fatty acid analogtracer.

FIGURE 32. Percentage prevalence of perfusion abnormalityin diabetic patients. Forty-four percent of symptomatic patients(left) and 42% of asymptomatic patients (right) were found tohave perfusion defects.

FIGURE 33. Distribution in rats of 18F-epoxide FP-DTBZ,a tracer for vesicular monoamine transporter-2 and measure-ment of b-cell mass in the pancreas, indicates that thepancreas had the highest level of uptake of all organs ortissues.

FIGURE 34. PET images of localization of tracer for vesicularmonoamine transporter-2 and measurement of b-cell mass inthe rat pancreas.

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reported on the effect of integrated rest/stress myocardialperfusion SPECT and 64-slice coronary CT angiography(CTA) on the management of symptomatic patients with anintermediate likelihood of CAD. They found that CTA wasmost helpful in decision making in 22% of patients withatypical CAD and 12% of patients with typical CAD. The 2techniques were equally helpful in 47% of patients withatypical CAD and in 12% of patients with typical CAD.Both were important in 25% with atypical CAD and 75%with typical CAD. They concluded that the 2 imagingtechniques are complementary and that the addition ofa second noninvasive test avoided invasive procedures inmore than 20% of patients.

Uebleis and colleagues from the University of Munich(Germany) reported on the value of calcium score andmyocardial perfusion SPECT in the prediction of severecardiac events during long-term follow-up in 260 patientswith known CAD. Calcium score and myocardial perfusionscans were acquired within a 6-mo period. Over an average5-y follow-up period (range, 0.2–10 y), calcium score andcoronary stenosis were found to be strong and independentpredictors of severe cardiac events. A total of 23 severecardiac events (cardiac death or myocardial infarction)were recorded, and the highest annual event rate was inpatients with calcium scores .400.

Inflammation is important in the pathogenesis andclinical outcome of atherosclerosis. Atherosclerotic plaquerupture results from inflammatory cell activity within theplaque. Plaques that contain numerous inflammatory cells(in particular, macrophages) have a high risk of rupture.Imaging techniques in current widespread use provide noindication of plaque inflammation. However, this is an areaof research and investigation that is being explored withgreat success. By detecting regions of plaque instabilitythrough markers for inflammation, patients at risk can betreated to prevent future events. At Hopkins, for example,very few studies are performed in the nuclear medicinedepartment on diabetic patients unless they come in viasome other route or are referred for other reasons. I think

that all of you in your own hospitals should begin to takea look at what molecular imaging can do for the diabeticpopulation, remembering that approximately 40% of thesepatients will have CAD. Procedures that we are able toperform today and are exploring for tomorrow can have aneffect on preventing the advance of disease by earlyidentification and modification of risk factors.

Dresser and colleagues from the Harry S. TrumanMemorial Veterans Administration Hospital and theUniversity of Missouri (Columbia) reported on outcomesin patients with abnormal myocardial perfusion imagingand normal coronary angiography. In a retrospective reviewof 808 patients who had undergone both myocardialperfusion imaging and coronary angiography, 48 patientshad abnormal perfusion imaging and normal coronariesseen in angiography. Sixteen of these patients were found tohave had cardiovascular events over the follow-up period of2–10 y, including 4 pericardial infarctions, 2 myocardialinfarctions, 1 coronary artery bypass graft, 6 cerebrovas-cular events, and 3 peripheral revascularizations. Theresearchers concluded that myocardial perfusion imagingmay predict a higher likelihood for cardiovascular diseasethan suggested by cardiac angiography alone.

NeuroimagingI believe that clinical molecular imaging studies of the

brain will eventually equal the number of studies in oncologyor cardiology. Hwang and colleagues from the SeoulNational University College of Medicine (South Korea)reported on gender differences in age-related decline inregional cerebral glucose metabolism. 18F-FDG PET imageswere obtained in 230 healthy individuals (90 men, 140women; age range, 34–82 y). Each sex was divided into 5groups representing individuals in their 30s, 40s, 50s, 60s,and 70s and older. Imaging and quantitative results (Fig. 36)indicated that both men and women show significant age-related decline in cerebral glucose metabolism in similarregions of the brain. In men, however, the decline is fairlyconstant across the age group studies, whereas women gothrough patterns of steep declines in their 40s and 60s.

Shimosegawa and colleagues from the Osaka Univer-sity Graduate School of Medicine (Saita, Japan) alsostudied gender differences in brain metabolism. The groupreported on quantification of cerebral blood flow, cerebralblood volume, oxygen extraction fraction, and cerebralmetabolic rate of oxygen with 3D high-resolution andhigh-sensitivity PET and 15O. They found that womenmetabolize oxygen in the brain to a greater degree than men.Figure 37 shows images of cerebral oxygen metabolism andcerebral blood flow in women and men. The authors noted theneed for separate normal absolute values for men and women.

Wang and colleagues from the Brookhaven NationalLaboratory (Upton, NY), St. Luke’s–Roosevelt Hospital(New York, NY), and the National Institute on AlcoholAbuse and Alcoholism and the National Institute on DrugAbuse (Bethesda, MD) reported that binge eating is

FIGURE 35. Images of 11C-DTBZ accumulation in (top)patient with diabetes and (bottom) healthy volunteer. Left,summed tissue images; middle, tissue classification images;right, VMAT2 binding potential images.

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associated with dopamine increase during food stimulation.They showed a correlation between caudate dopaminerelease and the severity of binge eating disorder. Psycholo-gists, with whom we work and should be working, have teststhat can assess subjectively the degree of the eating disorder,and molecular imaging is providing quantitative support andvalidation of these tests.

The public has recently become much more aware ofcurrent diagnostic and treatment approaches to braintumors through the well-publicized experience of SenatorTed Kennedy. It is important for us to make sure that thepublic also knows about the advantages that molecularimaging can bring in this disease setting. Wardak andcolleagues from the David Geffen School of Medicine atthe University of California at Los Angeles reported on the

utility of 18F-FLT PET in monitoring brain therapy. Figure38 shows that within 2 and 6 wk after beginning therapy,tracer accumulation changed markedly in the tumor. Whenthey looked at the change in standardized uptake values andperformed kinetic modeling and discriminant analysis, thisaccumulation proved to be a good predictor of whether ornot patients would survive for 1 y (Fig. 39).

Song and colleagues from the Sun Yat-sen University(Guangzhou, China) reported that 13N-NH3 PET is moresensitive and specific than Gd-DTPA MR imaging fordiagnosing brain tumor. These authors compared imagingresults from the 2 modalities in patients with 29 histo-logically confirmed brain tumors. For low-grade gliomas,13N-NH3 PET had a 60% probability of lesion detectioncompared with only 20% for Gd-DTPA MR imaging. MRimaging was superior to PET in lesion detection of extra-axial tumors. Figure 40 shows imaging results in a patientwith a grade 3 astrocytoma. The lesion demonstrateda markedly increased uptake of 13N-NH3 on PET but wasonly faintly enhanced in T1-weighted Gd-DTPA imaging.

In the 19th century, Broca (1861) and Wernicke (1874)related brain structure to function. Today, blood oxygenlevel–dependent (BOLD) functional MR imaging measureschanges in regional brain blood flow and helps selectregions of interest for molecular examination. With PET/CT and SPECT/CT, these approaches can provide a foun-dation for the molecular theory of brain disease, movingagain beyond the cellular level to the molecular level. I

FIGURE 36. Men and women showed age-related declines incerebral glucose metabolism in similar regions of the brain (A).In men, however, the decline is fairly constant across the agegroups studied, whereas women go through patterns of steepdeclines in their 40s and 60s (B).

FIGURE 37. Gender differences in brain metabolism. 15O PETindicates that women (A and C) metabolize oxygen in the brainto a greater degree than men (B and D). Top, cerebral oxygenmetabolic rate; bottom, cerebral blood flow.

FIGURE 38. 18F-FLT PET was useful in monitoring braintherapy. Left, baseline MR and PET. Right, evidence of changeduptake at 2 and 6 wk after initiation of bevacizumab andirinotecan therapy.

FIGURE 39. In the same study seen in Figure 38, percentageof standardized uptake value change at 6 wk after treatment(A) and scores from discriminant function (B) proved to be goodpredictors of whether or not patients would survive for 1 y.

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should note that this is the 25th anniversary of the firstimaging of a neuroreceptor in the human brain. Dopaminereceptors were first imaged on May 25, 1983.

A number of tracers are currently used for molecularimaging in the brain. These include but are not limited to:18F-FDG, 13NH3, and 15O; dopamine receptor agonists andantagonists; serotonin receptor agonists and antagonists;adrenergic receptor agonists and antagonists; monaminetransporters (NE, DA, 5-HT); adenosine receptors andtransporters; vesicular transporters (VMAT2, VAChT),cholinergic receptor agonists and antagonists; GABA/benzodiazapine receptors; opiate (m, k, D, and s) receptors;peripheral benzodiazapine receptors; excitatory aminoacids (glutamate) receptors; NMDA and AMPA receptors;neurotensin receptors; and histamine H3 receptors.

eINDs are a novel regulatory mechanism used toprovide proof of action, evaluate pharmacokinetics, selectthe most promising agent from a group of lead candidates,and determine their biodistribution. eINDs require lesspreclinical support than traditional INDs. The toxicologyrequirements are simpler, as are the dosimetry, pharmaco-kinetics, and metabolism required in animal models, withlow tracer dose and low radiation exposure. eINDapplications to the FDA have been used in the evaluationof 18F-labeled PET amyloid plaque imaging agents, asreported in a multiinstitutional study by Pontecorvo andcolleagues from Avid Radiopharmaceuticals (Philadelphia,PA), Duke University (Durham, NC), University ofMichigan (Ann Arbor), Mayo Clinic (Rochester, MD),Washington University (St. Louis, MO), and Johns HopkinsUniversity (Baltimore, MD). They compared 4 novelimaging agents. Figure 41 shows the striking accumulationof 18F-AV-45, an amyloid imaging agent now in phase 2clinical development.

Villemagne and colleagues from Austin Hospital, theNational Ageing Research Institute, and the University ofMelbourne (Melbourne, Australia) reported on a longitudi-nal study of b-amyloid deposition using 11C-PiB PET topredict conversion to mild cognitive impairment (MCI) or

Alzheimer’s disease (AD). The study included 35 healthycontrols and 28 individuals with MCI or AD who wereobserved over a 21-mo period. Among the 25 healthycontrols who were PiB-negative on PET, only 1 (4%)converted to MCI over the follow-up period. Of the 10healthy controls who were PiB-positive, 3 (30%) convertedto MCI or AD. In the group with MCI or early AD, 13individuals were PiB-negative, and 5 (385) converted todementia. The 15 remaining individuals in this group werePiB-positive, and 12 (89%) converted to AD over thefollow-up period. The overall changes in the amyloid-bburden over 21 mo were small (6.4% in AD). However, asis clear from this and other studies, the amyloid-b de-position occurs well before the onset of AD. PiB-positivehealthy controls are at increased risk for cognitive decline,and most PiB-positive MCI patients convert to AD within2 y. PiB-negative patients with MCI may be more prone todevelop non-AD dementia, such as multiple infarct de-mentia. PiB PET is an excellent predictor of conversion toAD.

Yeung and colleagues from the Hong Kong Sanatoriumand Hospital and the University of Hong Kong (China)reported on a practical method for 3D imaging of cerebrallocalization of 11C-PiB PET in an investigation of AD andcompared the information provided by this technique withthat from 18F-FDG PET. Figure 42 shows avid accumula-tion of the PiB compound in amyoid plaques using theauthors’ subtraction technique.

Deeb and colleagues from the University of PittsburghMedical Center (PA) compared the merits of visual

FIGURE 40. 13N-NH3 PET (B) had a 60% probability of lesiondetection compared with only 20% for Gd-DTPA MR imaging(A). This example is in a patient with a grade 3 astrocytoma.

FIGURE 41. 18F-AV-45 is an amyloid imaging agent in phaseII clinical development. PET imaging in individuals withAlzheimer’s disease (A) and in healthy controls (B).

FIGURE 42. 3D 11C-PiB PET imaging (B) shows avidaccumulation of tracer in amyloid plaques, contrasted with18F-FDG PET imaging (A).

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diagnosis and statistical software analysis of 18F-FDG PETimages to distinguish between normal, MCI, and ADindividuals. The study included 19 elderly normal controls,17 individuals with MCI, and 16 individuals with AD. Theyfound that in general visual assessment provides a fairlyaccurate ability to distinguish between controls and AD, butthat this accuracy significantly increases with the statisticalsoftware.

Forster and colleagues from the Ludwig-MaximiliansUniversity (Munich, Germany) reported on 18F-FDG PETand cortical representation of visual/spatial abilities inpatients with AD. We are all familiar with the increasinglypopular drawing tests to screen for AD, a process that isroughly analogous to stress testing in nuclear medicine. Inthis study, performance on a simpler standardized drawingexercise (Fig. 43A) was correlated with 18F-FDG uptake inthe right hemispheric visual association cortex, whichbelongs to the dorsal visual stream and is involved in theprocessing of localization information. Performance in ananalytically more complex task (Fig. 43B) correlated withuptake in structures of the ventral visual stream, which areinvolved in high-level visual processing and objectrecognition. These regions of the brain become abnormalearly in dementia.

Kendziorra and colleagues from the University ofLeipzig (Germany) and the University of Zurich (Switzer-land) reported on 2FA-PET imaging in elaborating differ-ences in cerebral nicotinic acetylcholine receptors inpatients with stable MCI and in MCI patients convertingto AD. In patients who converted to AD, tracer accumu-lation was markedly diminished in the cingulate cortex,hippocampus, and the temporal cortex. The authors point tothis technique as a potential tool in predicting conversionfrom MCI to AD.

Hattori and colleagues from the University of Wash-ington, Seattle Pacific University, Minor and JamesMedical Center, Veterans Affairs Puget Sound Health CareSystem, and Seattle Nuclear Medicine (all of Seattle)reported on cognitive fatigue after mild traumatic braininjury as an indication of frontocerebellar functionaldissociation. The study included 15 patients who wereimaged with 99mTc-ECD SPECT at rest and after activationwith the Paced Auditory Serial Addition Test (anotherpsychological stress test). Persons with a history of mildtraumatic brain injury had less neuronal activation and

fewer neurons than the control subjects when attempting tocarry out a task. Figure 44 compares results from a normalcontrol and a patient with mild traumatic brain injury.

Prunier-Aesch and colleagues from the CHRU Breton-neau and the University Francxois Rabelais (Tours, France)reported on the use of 123I-IBZM SPECT dopaminereceptor imaging in patients with parkinsonian syndrome.This technique has already found success in differentiatingbetween Parkinson’s disease and so-called Parkinson-plussyndromes (multiple system atrophy and progressivesupranuclear palsy). This group studied 99 patients with123I-IBZM SPECT, automated partial volume correctiontechniques, and a 2-y follow-up. They found that imagingwas able to differentiate between Parkinson’s disease andParkinson-plus syndromes and that the partial volumetechniques increased specificity.

Brašić and colleagues from the Johns Hopkins Schoolof Medicine (Baltimore, MD) reported on the correlationof dopamine release and psychiatric symptoms in in-dividuals with Tourette’s syndrome. The study groupincluded 18 adults with and 10 healthy adults withoutTourette’s syndrome. Psychiatric rating scale assessmentswere performed throughout 2 consecutive PET scans duringwhich each individual received high-specific-activity11C-raclopride after saline and amphetamine challenges.

FIGURE 43. CERAD drawing test (A) and Rey OsterreithComplex Figure drawing test (B) for dementia assessment.

FIGURE 44. 99mTc-ECD SPECT in a person with a history ofmild traumatic brain injury (right) showed less neuronalactivation and fewer neurons than in a control subject (left).

FIGURE 45. 3D view of 11C-GSK 215083 distribution in thehuman brain, with high uptake in striatal regions.

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The researchers found that in adults with Tourette’s, therelease of dopamine in striatal regions correlates stronglywith behavioral changes.

New types of neuroreceptors are being imaged. Martarelloand colleagues from the GSK Clinical Imaging Center andImperal College (London, UK) reported on the first humanevaluation of 11C-GSK 215083, a high-affinity 5-HT6serotonin receptor antagonist with potential useful applica-tions in AD. 5-HT6 serotonin receptors are the latest receptorsto be identified by isolating defined DNA sequences and thenobtaining multiple copies. Figure 45 is a 3D view of tracerdistribution, with high uptake in striatal regions.

Volkow and colleagues from the Brookhaven NationalLaboratory (Upton, NY) and the National Institute on DrugAbuse (Bethesda, MD) provided evidence that modafinil attherapeutic doses blocks the dopamine transporter in thestriatum by 50% and reduces 11C-raclopride binding todopamine receptors by 6%. Modafinil is prescribed to treatnarcolepsy, tiredness, and sleep apnea and is underinvestigation as a treatment for drug addiction. It isfrequently used off-label by persons in jobs demandingwakefulness (military pilots on long missions) and asa cognitive enhancer (Nature. Professor’s little helper.2008;450:1157). The authors found in this study that levelsof dopamine transporter blockade after therapeutic doses ofmodafinil are equivalent to those after therapeutic doses ofmethylphenidate (ritalin), suggesting that synaptic dopa-mine-enhancing mechanisms are relevant in the therapeuticeffects of modafinil. Because drugs that elevate braindopamine have the potential for abuse, these findings raiseconcerns about the possible abuse of modafinil.

One question that is now being asked and that molecularimaging is in a position to explore is: should we try toimprove mental function in normal people? Volkow andcolleagues also looked at the mechanisms by whichmethylphenidate enhances attention. Using 18F-FDG PETthey studied 21 healthy adults tested at baseline and whileperforming a numerical task with and without methylpheni-date pretreatment (Fig. 46). They discovered that withmethylphenidate the brain required ;50% less glucose toperform tasks equally well. One of the mechanisms ofmethylphenidate, then, is to improve the efficiency of thehuman brain.

Final ThoughtsMolecular imaging is now part of the big business of

health care. In 2006, only 13 new drugs were approved byFDA, although $27 billion were spent on research anddevelopment. Pfizer and Johnson and Johnson, for example,spent well more than $7 billion each. Worldwide sales ofprescribed drugs totaled more than $600 billion per year.Laura Wood wrote on the Web resource Research andMarkets that, ‘‘The challenges facing large pharmaceutical

companies are stark: sales are slowing, and research anddevelopment costs are rising. There is an overwhelmingneed to reduce development costs by as much as30%240%, while at the same time significantly shorteningdevelopment cycle times.’’

Molecular imaging is in an increasingly advantageousposition to help develop new drugs at lower cost and todecrease the complexity and invasiveness of manyprocedures. One example can be seen in the work ofMoulin-Romsee and colleagues from the CHU St. Louisand the Institut Curie (Paris, France), who reported that inthe PET era routine bone biopsy is no longer necessary instaging patients for Hodgkin’s disease. The study included14 patients with newly diagnosed Hodgkin’s leukemia whohad undergone both 18F-FDG PET/CT imaging and a bonemarrow biopsy. PET/CT was found to be more sensitivethan biopsy in the detection of lesions as a result of thesampling limitations of biopsy. The authors concluded thatbone marrow biopsy is not justified in patients withpretreatment negative PET/CT.

It takes more than good science to move research fromthe laboratory into medical practice. It is clear from thisyear’s SNM meeting that many people are very activelyinvolved in the molecular imaging movement. Molecularimaging is at a ‘‘tipping point.’’ We need to educate thepublic, press, and our political leaders about the revolu-tionary effect that molecular imaging can have in creatinga medical theory of disease and health care.

FIGURE 46. 18F-FDG PET showed increased regional glucosemetabolism in the parietal cortex, singulate cortex, and striatumwhen individuals performed numerical tasks with methylpheni-date pretreatment.

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