MULTIMODALITY MOLECULAR IMAGING – AN OVERVIEW WITH SPECIAL FOCUS ON PET/CT

Review Article

Molecular imaging originated from the field of radiopharmacology due to the need to better understand thefundamental molecular pathways inside organisms in anoninvasive manner. It is defined as “the visualrepresentation, characterization, and quantification ofbiological processes at the cellular and sub-cellular levelswithin intact living organisms” [1]. It enables thevisualization of the cellular function and the follow-up of themolecular process in living organisms without perturbingthem. Molecular imaging differs from traditional imaging inthat probes known as biomarkers are used to help imageparticular targets or pathways. Biomarkers interactchemically with their surroundings and in turn alter theimage according to molecular changes occurring within thearea of interest. This process is markedly different fromprevious methods of imaging which primarily imageddifferences in qualities such as density or water content. Thisability to image fine molecular changes opens up anincredible number of exciting possibilities for medicalapplication, including early detection and treatment ofdisease and basic pharmaceutical development. Further-more, molecular imaging allows for quantitative tests,imparting a greater degree of objectivity to the study of theseareas. Many areas of research are being conducted in thefield of molecular imaging. Much research is currentlycentered on detecting what is known as a predisease state ormolecular states that occur before typical symptoms of adisease are detected. Other important veins of research are

the imaging of gene expression and the development ofnovel biomarkers. Recently the term “Molecular Imaging”has been applied to a variety of microscopy and nanoscopytechniques including live-cell microscopy. There are manydifferent modalities that can be used for noninvasivemolecular imaging. Each has their different strengths andweaknesses and some are more adept at imaging multipletargets than others. PET has a special place. Manybiological molecules could be radio-labeled and becomePET tracers. Figure 1 depicts grossly the extent of eachimaging modality based on its widespread use [2].

Multimodality imaging has emerged as a technologythat utilizes the strengths of different modalities and yieldsa hybrid imaging platform with benefits superior to those of

MULTIMODALITY MOLECULAR IMAGING – AN OVERVIEW WITH

SPECIAL FOCUS ON PET/CT

N Savita*, Sudeshna Maitra* and Uma Ravishankar**

*Registrar, **Senior Consultant Department of Nuclear Medicine, Indraprastha Apollo Hospitals, Sarita Vihar,New Delhi 110 076, India.

Correspondence to: Dr.Uma Ravishankar, Senior Consultant,Department of Nuclear Medicine,Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.

E-mail: uma_r@apollohospitals.com

Imaging capabilities have evolved from those that provide anatomical pictures to those that capture functionalinformation and, more recently, molecular information (nuclear medicine, PET, SPECT, PET/CT, SPECT/CT,MRS, contrast-enhanced ultrasound, fluorescence and bioluminescence imaging). Multimodality imaging hasemerged as a technology that utilizes the strengths of different modalities and yields a hybrid imaging platformwith benefits superior to those of any of its individual components, considered alone. Leading edge hybridimaging (combining multiple, complementary imaging technologies such as PET and CT) offer uniqueopportunities to “view” the molecular biology of disease, and the use of this equipment is on the rise.

Key words: Multimodality imaging; PET/CT; PET/MRI; SP.

Fig.1 Extent, over the imaging applications, of the mostpopular medical imaging modalities based on theirwidespread use [2].

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191 Apollo Medicine, Vol. 7, No. 3, September 2010

any of its individual components, considered alone.Molecular imaging, by definition, renders information thatcan not be provided by conventional radiological imaging,but regardless needs integration of anatomy and function tobe fully understood.

POSITRON EMISSION TOMOGRAPHY (PET)

COMBINED WITH OTHER MODALITIES

Principle of PET scanner

Positron emission tomography (PET) is a tomographictechnique that computes the three-dimensional distributionof radioactivity based on the annihilation photons that areemitted by positron emitter labeled radiotracers. PET allowsnon-invasive quantitative assessment of biochemical andfunctional processes.

The system detects pairs of gamma rays emittedindirectly by a positron-emitting radionuclide which isintroduced into the body on a biologically active molecule.The emitted particle a positron rapidly meets an electron anddisappears while two high-energy (511 keV) gamma raysare emitted (Fig. 2). Those two gamma rays are recordedwith a special camera composed of rings (made with a largenumber of tiny crystals) [3]. Using information aboutdetected rays, a computer calculates the spatial distributionof the tracer within the patient. Images can be presented asslices (“Tomography”) or as 3D data.

The computed PET images are quantitative, i.e. they aremeasurements – although not perfectly accurate – of the realconcentration of the tracer in the organ. In clinical practice,a simple index called the Standardized Uptake Value (SUV)

is generally used. It is defined as the ratio of theconcentration of the tracer in a region to the meanconcentration in the body. The general formula is as follows(although there are variations, such as taking in account leanmass or body surface instead of body mass) [4].

tissue concentration (MBq/mL)SUV = injected radioactivity (MBq)/body weight(g)

Tumor SUV is usually over 2 in malignant tissue. TheSUV could be useful in the diagnosis and follow up ofcancer diseases, but there is no cut-off value, whichaccurately separates malignant and non-malignant uptake[5]. Moreover, limitations of SUV are known [6]: manyconfounding factors influence SUV determination andcriticism of SUV methodology has been made [7].Limitations include variability in obese patients, and usinglean mass seems to be appropriate to avoid overestimation[8] in that specific group of patients. The SUV is not alwayspowerful for discrimination between benign and malignanttissue (depending on the type of lesion). Then its usefulnesslies more in the longitudinal follow-up than in informationin a unique examination.

PROCEDURE AND RADIONUCLIDES

To conduct the scan, a short-lived radioactive tracerisotope is injected intra-venously into blood circulation.The tracer is chemically incorporated into a biologicallyactive molecule. There is a waiting period while the activemolecule becomes concentrated in tissues of interest; thenthe patient is placed in the imaging scanner. During the scana record of tissue concentration is made as the tracer decays.

The most commonly used tracer at present is the glucoseanalogue FDG (more than 95% of the molecular imagingprocedures make use of FDG at present) for which thewaiting period is typically an hour. FDG is a glucosemolecule in which one hydroxyl group has been exchangedfor an 18F fluorine atom. This molecule is incorporated inthe cells via the same paths as glucose [9]: the expression ofglucose transport proteins (especially GLUT 1) allows FDGto enter the cell, and FDG, like glucose, is phosphorylated byhexokinase. However its degradation within the cell isstopped at its second step (FDG-6-phosphate, unlikeglucose-6-phosphate, is not metabolized further by glucose-phosphate-isomerase, and can leave the cytosol only byhydrolysis back to FDG, depending on the phosphataseactivity [10], which is usually rather low). Thus, FDGaccumulation in tissue is proportional to the amount ofglucose utilization. Increased consumption of glucose is acharacteristic of most cancers and is in part related to over-expression of the GLUT-1 glucose transporters andincreased hexokinase activity.

Fig. 2. Positron emission followed by the disintegration of apositron-electron couple, which gives two gamma raysemitted in opposite directions; the information is kept iftwo detectors in the ring-shaped detecting devicereceive a gamma ray of selected energy; starting fromall detection lines, the computer calculates the positionof the different radioactive sources in the volume.

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One hour after injection, its distribution within the bodydepicts the distribution of the glucose uptake. It has beenknown for long [11] that the glucose metabolism in most –but not all – neoplastic tissues is higher than in normaltissues: primary tumors, recurrences and metastases ofmany solid tumors can be visualized with FDG-PET as a hotspot amongst low background. The test is performed onfasting (in order to increase the tracer uptake;hyperglycemia has been shown to decrease FDG uptake intumors [12]) and resting (in order to avoid muscular uptake)patients.

Beside the glucose metabolism, many other metabolicpaths, which are disturbed in neoplastic tissues, can beexplored using PET tracers [9]. Table 1 lists some of thesepaths relevant in oncology, which can be explored usingPET, and the corresponding most studied tracers.

Combination of PET with CT

The combination of a so-called functional imagingtechnique (PET) with an efficient anatomical imagingtechnique (CT) is a major breakthrough in modern cancerimaging. Integrated PET/CT combines PET and CT in asingle imaging device and allows morphological andfunctional imaging to be carried out in a single imaging

Table 1. Metabolism or function disturbed in cancer and the PET tracer used for their study [13].

Function/metabolism Tracer

Glucose metabolism 18F-fluoro-deoxy-glucose (FDG)

DNA replication/cellular proliferation 11C-carbon-thymidine

18F-fluoro-thymidine (FLT)

Protein synthesis, amino acid transport 11C-carbon-methionine (MET)

18F-fluoro-ethyl-tyrosine (FET)

18F-fluoro-methyl-tyrosine (FMT)

18F-fluoro-dihydroxyphenylalanine (F-DOPA)

Membrane lipid synthesis 18F-fluoro-acetate

11C-carbon-choline

18F-fluoro-choline (FCH)

Hypoxia 18F-fluoro-misonidazole (FMISO)

64Cu-copper-ATSM

Apoptosis 18F-fluoro-annexin V

Angiogenesis 18F-fluoro-galacto-RDG

Reporter genes 18F-fluoro-deoxyarabinofuranosyl nucleosides

(FEAU, FIAU, FMAU)

Tumor therapy control 18F-fluoro-uracil (FU)

Receptor binding (estrogen) 18F-fluoro-oestradiol (FES)

Receptor binding (somatostatine) 68Ga-gallium- DOTATOC/DOTANOC

procedure, ( Fig.3). Integrated PET/CT has been shown tobe more accurate for lesion localization andcharacterization than PET and CT alone or the resultsobtained from PET and CT separately and interpreted sideby side or following software based fusion of the PET andCT datasets. Since 2003, the majority of new clinical PETdevices have been associated with a CT scanner. Thismultimodality imaging device performs a PET and a CTacquisition while the patient remains on the same bed andprovides fused images [14] (where the CT information isusually coded in gray levels and the tracer uptake incolors). The two images are perfectly registered [15],assuming that the patient does not move and that theorgans do not move, which is true in most parts of the bodybut could generate artifacts in some areas such as thediaphragm region [16,17]. Computer-assisted techniques(so-called gating techniques) are currently being validatedin order to remove or decrease those breathing artifacts[18,19]. The utility of this dual acquisition procedure istwofold. First, in order to calculate the spatial distributionof the tracer, the computer software has to perform somecorrections, which take into account the physicalprocesses of detection, including the correction of thegamma rays attenuation by the patient’s body. This can becorrected if the spatial distribution of the attenuation

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process is known, which is exactly what the CT imagesprovide [20]. Compared to the stand alone PET, whichuses a rotating radioactive source to estimate the gammarays attenuation, the use of CT data for this purpose hasachieved a major reduction in the acquisition time. Thesecond and more visible advantage of multimodalityconcerns the medical interpretation of the images. A tracerlike FDG has some physiological non-specific (i.e. innormal tissues) uptake, which varies from one patient toanother. Non-specific uptake could often be misleading orlead to an undetermined imaging. The fused PET-CTimages are very helpful in localizing the abnormal uptakes(such as neck or mediastinum lymph nodes) and indifferentiating physiologic from abnormal uptake (forexample in urinary tract, bowels, or in the laryngealcavity). Using contrast media for CT even increase theaccuracy of anatomical information. In spite of causingproblems in the correction for attenuation, intravenousiodinated contrast media injection has several potentials:better delineation of tumor, mostly for dosimetric planningof 3D conformal radiotherapy and non-conventionalsurgery [21] or when vascular involvement is suspected;more accurate anatomical localization of tumors in thehead and neck, the abdomen and the pelvis (for instancelocalization of an hepatic segment involved by a lesion).

Combination of PET with MRI

Despite the success and popularity of PET-CT andmore recently of SPECT-CT, there are some shortcomingsin the use of CT as the combined anatomical imagingmodality. Firstly, CT adds radiation dose to the overallexamination, particularly if used in a full diagnostic rolewith contrast enhancement. Second, CT providesrelatively poor soft tissue contrast in the absence of oraland intravenous iodinated contrast, particularly if lowdose acquisition protocols are utilized to minimize

radiation exposure. These two theoretical limitations donot apply to MRI, which does not involve ionizingradiation and provides soft tissue imaging with highspatial resolution and superior contrast compared to CT.MRI can also provide more advanced ‘functional’techniques such as perfusion and diffusion imaging aswell as spectroscopy, which may be additive to functionalinformation obtained by PET. Furthermore, the highsensitivity of PET may also complement the poor signalstrength inherent in current functional MRI imaging. Thecombination of PET and MRI into a single scanner maytherefore be the pioneer hybrid imaging modality,combining the metabolic and molecular information ofPET with the excellent anatomical detail of MRI, whileoffering new potential applications with respect tofunctional MRI technology.

There are, however, a number of technical problemsthat need to be overcome before a clinical hybrid PET-MRscanner can become a reality. Both MRI and PET have thepotential to affect each other’s performance in theircurrent form. One of the main problems is thatphotomultiplier tubes, a fundamental component ofcurrent PET detectors, will not function in a ‘magnet’ asthe high magnetic field causes electrons to deviate fromtheir original trajectory, resulting in loss of gain [22]. Asmall prototype PET-MRI scanner has been developedusing long optical fibres to transport light from thedetector to photomultiplier tubes situated in a low fieldregion [22] The potential of using novel readouttechnologies insensitive to magnetic fields, includingAPDs and Geiger-mode avalanche photodiodes (G-APDs) has been and still is being explored for furtherdevelopment.

The first prototype human PET insert, the Brain PETscanner [23,24], was designed in 2005 usingphotodetectors insensitive to magnetic fields (APDsinstead of PMTs) and non-magnetic detector and frontendelectronic materials to operate within a clinical MRIsystem. The Brain PET (Fig.4) was designed to operate inthe frequency range of interest for MRI at 3T, allowingperfect matching with the most sophisticated MR brainsequences that can be performed at this magnetic fieldstrength. The first patient images were shown late in 2006[25] and the system is currently undergoing a detailedevaluation of mutual interference between the twoimaging modalities and is being used comprehensively toassess its potential using normal subjects and clinicalstudies [26].

Technical limitations

The radioactive half-lives – the period of time over

(a) (b) (c)

Fig.3. (a) CT Scan Organs and bones; (b) PET Scan Cellactivity; (c) PET/CT Scan exact location of high cellactivity.

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which half the radioactive nuclei undergo disintegration –of the positron emitters are often very short (a few minutesin the case of radioactive 11C carbon~20 mins, 15Ooxygen~2 mins and 13Nnitrogen~10 mins, and less than 2h in the case of 18F fluorine [27]). This limitation restrictsclinical PET primarily to the use of tracers labeled withfluorine-18, which has a half life of ~110 minutes and canbe transported a reasonable distance before use.

The spatial resolution of the human PET cameras islow, between 6 and 8mm for most of the commerciallyavailable PET scanners [14,28]. As a consequence, lesionsunder 1 cm could be missed on the images, althoughsmaller lesions can be seen if they highly concentrate thetracer. This is probably the most limiting parameter inmedical practice. As compared to CT and MRI, PETremains a low-resolution technology.

Finally, PET is a very expensive technique. Due to theshort half lives of most radioisotopes, the radiotracersmust be produced using a cyclotron and radiochemistrylaboratory that are in close proximity to the PET imagingfacility. Few hospitals and universities are capable ofmaintaining such systems, and most clinical PET issupported by third-party suppliers of radiotracers whichcan supply many sites simultaneously. The half life offluorine-18 is long enough such that fluorine-18 labeledradiotracers can be manufactured commercially at anoffsite location.

OTHER LIMITATIONS

Normal uptake reduces the usefulness of FDG: thistracer is not efficient for the diagnosis of brain metastases

since there is a high physiological uptake of FDG by thenormal brain.

Another limitation of FDG is the non-specific uptakeby inflammatory and granulomatous lesions. This can leadto overestimate the spread of a malignant disease or todoubtful interpretation.

Finally FDG uptake is influenced by both insulin andblood glucose levels. The performance of the FDG-PETcould then be altered in non compliant patients or indiabetic patients (if the timing between anti-diabetictreatment and the injection of FDG is not carefullyplanned).

Because the radioactive substance decays quickly andis effective for only a short period of time, it is importantfor the patient to be on time for the appointment and toreceive the radioactive material at the scheduled time.Thus, late arrival for an appointment may requirerescheduling the procedure for another day.

A person who is very obese may not fit into theopening of a conventional PET/CT unit.

SAFETY

PET scanning is non-invasive, but it does involveexposure to ionizing radiation. The total dose of radiationis not insignificant, usually around 5-7 mSv. However, inmodern practice, a combined PET/CT scan is almostalways performed, and for PET/CT scanning, theradiation exposure may be substantial - around 23-26 mSv(for a 70 kg person - dose is likely to be higher for higherbody weights) [29].

The radiation dose of FDG is approximately 2 × 10–2mSv/MBq according to ICRP publication 106 [30], i.e.about 3-4 mSv for an administered activity of 185 MBq.The radiation exposure related to a CT performing a PET/CT examination depends on the intention of the CTcarried out and may differ from case to case: the CT can beperformed as a low-dose CT (with lower voltage andcurrent) to be used for attenuation correction andlocalisation of PET lesions [31]. Alternatively (oradditionally) a diagnostic CT can be indicated (in mostcases with intravenous contrast agent application and deepinspiration in case of a chest CT) for a full diagnostic CTexamination. The effective CTdose could range from 1-20mSv and may be even higher for a high resolutiondiagnostic CT scan. Given the variety of CT systems andprotocols the radiation exposure for a PET/CTexamination should be estimated specific to the systemand protocol being used and an expert from radiology orguidelines provided by the European radiological

Fig.4. Brain PET/MRI fusion image

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societies should be consulted regarding effective dosefrom the CT examination.

Indications

Some of the current applications of PET and PET/CTare in:

• Oncology–identifying and determining the extent ofmalignant disease and monitoring therapy ofnumerous cancers

• Cardiology – detecting coronary artery disease andassessing whether dysfunctional myocardial tissue isviable

• Neurology and psychiatry – differentiating betweentumor recurrence and radiation necrosis,differentiating Alzheimer disease from otherdementias, and locating epileptic foci.

Oncology

Primary presentation: diagnosis: unknown primarymalignancy, differentiation of benign and malignant lesionsof e.g. a solitary lung nodule, Fig.5, especially in case ofdiscrepant clinical and radiological estimates of thelikelihood of cancer;

Staging on presentation: non-small-cell lung cancer, T3esophageal cancer, Hodgkin’s disease, non-Hodgkin’slymphoma, locally advanced cervical cancer, ENT tumorswith risk factors and locally advanced breast cancer.

Response evaluation: malignant lymphoma, GIST, atpresent other applications only in a research setting.Application for esophageal, colorectal, lung and breastcancer appear promising.

Restaging in the event of potentially curable relapse (forFDG avid tumors).

Establishing and localizing disease sites as a cause forelevated serum markers (e.g. colorectal, thyroid, ovarian,cervix, melanoma, breast and germ–cell tumors).

Image guided biopsy (e.g. brain tumors) andradiotherapy planning.

RADIATION THERAPY PLANNING

To be cured by radiation therapy, a tumour must beentirely contained within a volume of tissue treated to atumouricidal dose. Patients selected for curative or ‘radical’radiation therapy must have disease confined to a region thatcan be safely treated to the chosen tumouricidal dose. Anoptimum radiation therapy plan will deliver a sufficientlyhigh dose of radiation to attain durable local tumour control

while delivering the least possible dose to the smallestpossible volume of critical normal tissues. To planpotentially curative radiation therapy, the precise locationand extent of the tumour must be known.

Rapid and continuing advances in computer assisted 3Dplanning have resulted in developments such as threedimensional conformal radiotherapy (3DCRT) andintensity modulated radiation therapy (IMRT) [33]. Thesemethods can facilitate the delivery of higher radiation dosesto the tumour [34,35] and allow relative sparing of normaltissues, with potential for higher tumour control rates and/orless toxicity for the patient (Fig.6).

To take full advantage of these dramatic advances inmodern radiotherapy, the most accurate and precisedelineation of the target is needed. In the pre-PET era,definition of tumour volumes and treatment volumes wasbased primarily on structural imaging with contrast CT orMRI, which together with clinical judgement were used toestimate the likely extension of microscopic disease in eachcase and thereby define the CTV. Molecular imaging, usingradioisotope tracers to identify molecular tumour targets, incombination with PET and single photon emissiontomography (SPECT), has allowed a more complexfunctional and biologic evaluation of tumours. In manytumour types, clinicopathological studies have shown thatthe estimate of tumour extent is most accurate whenfunctional and structural imaging data are combined. Withrapid advances in molecular imaging and the increasing

Fig.5 Patient 1: (Left) 1.6-cm right lower lobe pulmonarynodule on CT (yellow arrow). (Right) SuperimposedFDG PET image shows hypermetabolism (biopsy-proven adenocarcinoma). Patient 2: (Left) 1.3-cm rightlower lobe pulmonary nodule (red arrow). (Right) PET/CT does not show increased FDG uptake, which isstable on follow-up CT examinations [32].

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availability of integrated positron emission tomography/X-ray computed tomography (PET/CT) and single photonemission computed tomography/C ray computedtomography (SPECT/CT) systems, it is now possible tointroduce a new dimension to radiation treatment planningbeyond the structural information offered by conventionalimaging techniques [37]. SPECT due to its relatively poorresolution, makes it inferior to PET.

Dedicated PET scanner vs gamma-camera PET

PET imaging is best performed using a dedicated PETscanner. However, it is possible to acquire PET imagesusing a conventional dual-head gamma camera fitted with acoincidence detector. The quality of gamma-camera PET isconsiderably lower, and acquisition is slower. However, forinstitutions with low demand for PET, this may allow on-site imaging, instead of referring patients to another center,or relying on a visit by a mobile scanner.

SPECT-CT imaging

In single-photon emission computed tomography(SPECT), after a radionuclide is injected, single gamma-rayphotons that exit the body are captured by a standardgamma-ray camera. The camera sequentially acquiresimages from multiple projections as it moves over 360- or180-degree arcs about the body. This raw information isthen reconstructed into tomographic image sets. SPECT/

CT systems have the same SPECT component asconventional nuclear medicine systems, the dual-headgamma cameras are generally used for planar andtomographic imaging of single photon emittingradiotracers. The CT component of the first-generationhybrid devices used a low resolution CT detector whilerecently developed, second-generation SPECT/CT systemsincorporate a variety of multi-slice CT scanners. SPECT/CT systems include separate CT and gamma camera devicesusing common or adjacent mechanical gantries, and sharingthe same scanning table. Integration of SPECT and X rayimaging data is performed by a process that is similar to thatof PET/CT. SPECT and CT images are displayed on thesame screen in addition to the fused images, whichrepresent the overlay of a coloured SPECT over a grey-scaleCT image. A 3-D display with triangulation options allowsto locate lesions and sites of interest on the CT image and toredisplay them on the registered SPECT and fused SPECT/CT images.

Applications of SPECT-CT

The superiority of SPECT/CT over planar scintigraphyor SPECT has been clearly demonstrated for the imaging ofthyroid cancer (Fig.7), neural crest and adrenal tumors(Fig. 8), neuroendocrine cancer, benign and malignantskeletal diseases (Fig.9), parathyroid adenoma (Fig.10) andmapping of sentinel lymph nodes (Fig.11) in the head andneck and in the pelvic region.

PET vs conventional SPECT imaging

PET has several advantages over conventional SPECTimaging. Its spatial resolution is about two times better, andit accurately corrects for attenuation (absorption byinterposed tissue) of photons emitted from the organ ofinterest. The attenuation correction process is faster usingthe PET/CT technique. Because PET images are correctedfor attenuation, they more accurately reflect the true activityof the tracer in tissue.

(a) (b)

(c) (d)

Fig.6 NSCLC arising in the left upper lobe. The associatedatelectasis did not show 18FFDG- uptake, and wastherefore excluded from the GTV. Axial (a) and sagittal(b) CT reconstruction fused with 18F-FDG-PETreconstruction. The GTV (red; (c) was designed usinga source/background algorithm. Recruited for theGerman PET-Plan study (pilot-phase), the patientreceived radio-chemotherapy with radiation confinedto the 18F-FDGpositive area (treatment plan; (d))escalated up to 74 Gy (1,8 Gy daily) [36].

Fig.7. I-131 whole body scan. (A) Planar images showingfocal uptake in left thorax (B) SPECT/CT confirms theuptake in right 9th rib posteriorly.

(a) (b)

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Fig.9. Patient with lung cancer and 2 hot spots, in lower lumbarspine and pelvis (os sacrum). (A and B) Planarscintigrams from skeletal scintigraphy (99mTc-hydroxymethylene diphosphonate). (C) Detailed viewof pelvis with 2 hot spots (arrows). (D) Transversesection of upper lesion in lumbar vertebra 5. (E) Smallosteolytic lesion with intense tracer uptake indicatingbone metastasis in lower pelvis. (F) Fused image. (Gand H) Spondylarthrosis of right facet joint with intensetracer uptake indicating degenerative lesion [38].

Fig.8. Diagnosis of pheochromocytoma with 99mTc-MIBGSPECT/CT. (A) Planar image showing mildly intensefocal lesion extending to left suprarenal area. (B–D)Corresponding sections of SPECT (B), CT (C), andfused SPECT/CT (D) images showing focal uptakeextending to enlarged left adrenal gland, indicatingpheochromocytoma. (E–G) Corresponding transversesections of right adrenal gland showing additional hotspot and enlargement of gland, indicating secondpheochromocytoma, which was proven histologically.Lesion may be missed on planar image (A) oroverexposed transaxial SPECT image (B) [38].

Fig.10. Parathyroid scintigraphy with SPECT/CT. (A and B)Planar views of 99mTc-MIBI scintigraphy 60 min (A)and 15 min (B) after 99mTc-MIBI injection. Arrowsindicate lesions. (C) Transverse section of 99mTc-MIBISPECT showing mildly intense focal lesion in rightlower neck region (arrow). (D and E) CorrespondingCT section (D) and fused image (E) indicatingparathyroid adenoma below right thyroid gland(arrows). (F and G) Demonstration of parathyroidadenoma (arrows) in corresponding coronal CT (F) andSPECT/CT (G) images [38].

of image fusion involving a large number of patients hasbeen achievedwith PET/CT. The design properties of PET/MRI are under consideration,and progress has already beenmade in this field with small animal scanners. The nextgeneration of PET/CT technology is likely to make use ofnew radiation detectors and electronics. Discussions arenow focusing, for example, on the reductionof whole-bodyimaging times to less than 15 min and the introduction ofroutine respiratory and cardiac gating for improvement oflesion localization and margin definition. Multiple slicespiral CT scans will open the way for cardiac imaging, andinteresting developments are expected in this field, which,

Future developments

Multimodality imaging is here to stay and image fusionwill become routine. The first truly routine implementation

Fig.11 Sentinel node localization with 99mTc-Scintiscint [38].

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as with nuclearmedicine in general, is heavily dependent onthe emergence of new, clinically useful ligands. There isrealistic hope that these new ligands will lead to novelpractical applications in neurology, cardiology andoncology. As individually tailored medicines begin toimpact on healthcare, these technologies will find specialrelevance in determining patient responseto these therapies.An early indicator of lack of response may be not onlybeneficial but also immensely important in economicterms.The future for PET/CT imaging as a surrogate endpoint fornovel therapeutic interventions is bright. This will imply arethink of traditional criteria for lesion response –conventional RECIST criteria will need to be re-assessed inthe light of the metabolic parameter made available by PET[39,40].

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