Stefano Fanti, Prof. Dr.

Luigi Mansi, Prof. Dr.

University of Bologna

University of Naples

Policlinico S.Orsola-Malpighi

Ist. Scienze Radiologiche

Dipto. Medicina Nucleare

Piazza Miraglia 2

Via Massarenti

40100 Bologna

80138 Napoli

Italy

fanti@orsola-malpighi.med.unibo.it

luigi.mansi@unina2.it

Mohsen Farsad, MD.

Central Hospital Bozen

Nuclear Medicine

Via Pöhler

39100 Bolzano

Italy

mohsen.farsad@asbz.it

ISBN: 978-3-642-15725-7

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DOI: 10.1007/978-3-642-15726-4

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Contributors

Monica Agostini U. O. Medicina Nucleare, Azienda Sanitaria di Cesena, Cesena, Italy

Carina Mari Aparici Department of Radiology and Biomedical Imaging,

University of California, San Francisco, CA, USA

Anca M. Avram Division of Nuclear Medicine/Radiology, University of Michigan Medical

Center, Ann Arbor, MI, USA

Mirco Bartolomei U. O. Medicina Nucleare, Azienda Sanitaria di Cesena, Cesena, Italy

Chiara Basile Medical Physics, Servizio di Fisica Sanitaria, Azienda Ospedaliera

S. Camillo Forlanini, Roma, Italy

Ambros J. Beer Department of Nuclear Medicine, Klinikum rechts der Isar der

Technischen Universität München, Munich, Germany

Francesca Botta Unità di Fisica Sanitaria, Istituto Europeo di Oncologia, Milano, Italy

Medical Physics and Nuclear Medicine, European Institute of Oncology, Milano, Italy

Andreas K. Buck Department of Nuclear Medicine, Klinikum rechts der Isar der

Technischen Universität München, Munich, Germany

Michela Casi U. O. Medicina Nucleare, Azienda Sanitaria di Cesena, Cesena, Italy

Angel Soriano Castrejón Department of Nuclear Medicine, Universitary General Hospital

of Ciudad Real, Ciudad Real, Spain

Marta Cremonesi Unità di Fisica Sanitaria, Istituto Europeo di Oncologia, Milano, Italy

Medical Physics and Nuclear Medicine, European Institute of Oncology, Milano, Italy

Medical Physics Department, Istituto Europeo di Oncologia, Milano, Italy

Vincenzo Cuccurullo U.O. Medicina Nucleare, Seconda Università di Napoli, Napoli, Italy

Concetta De Cicco Divisione di Medicina Nucleare, Istituto Europeo di Oncologia,

Milano, Italy

Medical Physics and Nuclear Medicine, European Institute of Oncology, Milano, Italy

Francesco De Lauro U. O. Medicina Nucleare, Azienda Sanitaria di Cesena, Cesena, Italy

Amalia Di Dia Unità di Fisica Sanitaria, Istituto Europeo di Oncologia, Milano, Italy

Medical Physics and Nuclear Medicine, European Institute of Oncology, Milano, Italy

Fernando Di Gregorio U.O. Medicina Nucleare, Azienda Ospedaliera Santa Maria della

Misericordia di Udine, Udine, Italy

Nuclear Medicine, University Hospital, Udine, Italy

Contributors

Ryan A. Dvorak Division of Nuclear Medicine/Radiology, University of Michigan Medical

Center, Ann Arbor, MI, USA

Paola Erba U.O. Medicina Nucleare, Azienda Ospedialiero-Universitaria Pisana, Pisa, Italy

Jure Fettich Department of Nuclear Medicine, University Medical Centre of Ljubljana,

Ljubljana, Slovenia

Albert Flotats Department of Nuclear Medicine, Universitat Autònoma de Barcelona,

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

José Manuel Cordero Garcia Department of Nuclear Medicine, Universitary General

Hospital of Ciudad Real, Ciudad Real, Spain

Victor Manuel Poblete García Department of Nuclear Medicine, Universitary General

Hospital of Ciudad Real, Ciudad Real, Spain

Onelio Geatti U.O. Medicina Nucleare, Azienda Ospedaliera Santa Maria della

Misericordia di Udine, Udine, Italy

Nuclear Medicine, University Hospital, Udine, Italy

Andor W. J. M. Glaudemans Department of Nuclear Medicine and Molecular Imaging,

University Medical Center Groningen, Groningen, Te Netherlands

Henrik Gutte Department of Clinical Physiology, Nuclear Medicine and PET,

Copenhagen University Hospital, Copenhagen, Denmark

Randall Hawkins Department of Radiology and Biomedical Imaging,

University of California, San Francisco, CA, USA

Ken Herrmann Department of Nuclear Medicine, Klinikum rechts der Isar der

Technischen Universität München, Munich, Germany

Marina Hodolic Department of Nuclear Medicine, University Medical

Centre of Ljubljana, Ljubljana, Slovenia

Cornelis A. Hoefnagel Department of Nuclear Medicine, Te Netherlands Cancer

Institute and Academical Medical Center, Amsterdam, Te Netherlands

Eugenio Inglese U. O. Medicina Nucleare, Ospedale Maggiore della Carità di Novara,

Novara, Italy

Andreas Kjær Department of Clinical Physiology, Nuclear Medicine and PET,

Copenhagen University Hospital, Copenhagen, Denmark

Marco Krengli U. O. Medicina Nucleare, Ospedale Maggiore della Carità di Novara,

Novara, Italy

Torsten Kuwert Clinic of Nuclear Medicine, University of Erlangen-Nuremberg, Erlangen,

Germany

Contributors

Elena Lazzeri U.O. Medicina Nucleare, Azienda Ospedialiero-Universitaria Pisana,

Pisa, Italy

Gianfranco Loi U. O. Medicina Nucleare, Ospedale Maggiore della Carità di Novara,

Novara, Italy

Lucio Mango Servizio di Fisica Sanitaria, Azienda Ospedaliera S. Camillo Forlanini,

Roma, Italy Medical Physics, Azienda Ospedaliera S. Camillo Forlanini, Roma, Italy

Luigi Mansi University of Naples, Ist. Scienze Radiologiche, Piazza Miraglia 2, Napoli,

Italy

Agustín Ruiz Martínez Department of Nuclear Medicine, Universitat Autònoma de

Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Vincenzo Mattone U. O. Medicina Nucleare, Azienda Sanitaria di Cesena, Cesena, Italy

Jann Mortensen Department of Clinical Physiology, Nuclear Medicine and PET,

Copenhagen University Hospital, Copenhagen, Denmark

Massimiliano Pacilio Servizio di Fisica Sanitaria, Azienda Ospedaliera S. Camillo

Forlanini, Roma, Italy

Medical Physics Department, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy

Giovanni Paganelli Divisione di Medicina Nucleare, Istituto Europeo di Oncologia,

Milano, Italy

Medical Physics and Nuclear Medicine, European Institute of Oncology, Milano, Italy

Pier Francesco Rambaldi U.O. Medicina Nucleare, Seconda Università di Napoli, Napoli,

Italy

Prado Talavera Rubio Department of Nuclear Medicine, Universitary General Hospital

of Ciudad Real, Ciudad Real, Spain

Ivan Santi U. O. Medicina Nucleare, Policlinico S. Orsola-Malpighi, Bologna, Italy

Youngho Seo Department of Radiology and Biomedical Imaging, University of California,

San Francisco, CA, USA

Alberto Signore Nuclear Medicine, 2nd Faculty of Medicine, Università Sapienza di

Roma, Roma, Italy

Department of Nuclear Medicine and Molecular Imaging, University Medical Center

Groningen, University of Groningen, Groningen, Te Netherlands

Ana María García Vicente Department of Nuclear Medicine, Universitary General

Hospital of Ciudad Real, Ciudad Real, Spain

John Patrick Pilkington Woll Department of Nuclear Medicine, Universitary General Hospital

of Ciudad Real, Ciudad Real, Spain

Ka Kit Wong Division of Nuclear Medicine/Radiology, University of Michigan Medical

Center, Ann Arbor, MI, USA

Department of Nuclear Medicine, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA

SPECT-CT: Importance for Clinical Practice

1.1 The Diagnostic World Before

1.2 The Advent of Hybrid Systems

Hybrid Machines

With respect to the post-processing problems present in

Diagnostic imaging in the twentieth century was mainly

fusion imaging, the availability of hybrid machines, i.e., a

based on two separate universes:

(1) the morpho-

CT (or, in the near future, a MR) and a PET (or SPECT)

structural, where information on anatomy and structures

scanner working together, led to a major revolution. Te

is acquired, having pathology as the gold standard, and

main advantage is the highly precise anatomical accuracy

(2) the functional, where normal and altered functions

of the fused image (averaging 1° mm), with the two stud-

are analyzed, with pathophysiology as the reference.

ies being acquired simultaneously with the patient immo-

In the “old medicine,” these universes existed and were

bile on the same bed. Moreover, a reliable attenuation

observed separately, like with mono-ocular vision, only

correction, and therefore an accurate quantitative analy-

capable of seeing half of the whole view; therefore, using

sis, is achievable. All these advantages are obtained with a

a single eye, incomplete information was gathered. To

shorter duration of the whole procedure, allowing an ear-

overcome this handicap, traditional diagnostic imaging

lier diagnosis. It has to be pointed out that some minor

can use information acquired separately by visual com-

technical problems still exist in the hybrid machines,

parison, but this approach is affected by many limitations,

mainly because of the technical differences between CT

mainly because of the subjective nature of the analysis.

and nuclear medicine (NM) procedures. However, many

In the last decades, the incredibly fast development of

solutions, such as respiratory gating, are already being

technology and computers led to a revolution that almost

used in clinical practice, and every day new methods are

killed analogical imaging, creating a new world only

being developed to further improve the whole system in

occupied by digital data. In this scenario, a major improve-

order to optimize the final result.

ment has been obtained with so-called fusion imaging,

allowing the overlap of digital scans acquired using dif-

ferent techniques and/or performed on different days.

1.3 SPECT-CT, Parallels and Divergences

Te main consequence, with the possibility of overlap-

with Respect to PET-CT

ping PET (or SPECT) and CT images, has been achieving

a fused image combining morpho-structural and func-

Te initial commercial development of SPECT-CT was

tional data together. In other words, it has become possi-

based on joining a state-of-the-art SPECT and a low-

ble to obtain information containing the advantages but

resolution standard axial CT. Major applications were

not the disadvantages of the single procedures taken

focused on CT-based attenuation correction in cardiology

alone, allowing higher diagnostic accuracy.

and oncology, with further emphasis, mainly in oncology,

However, despite the advanced level reached by com-

on a better localization of hot spots. Terefore, the first steps

puterized techniques, major problems in the post-processing

in the history of SPECT-CT were parallel to those for

of fusion imaging, i.e., because of the retrospective rigid

PET-CT. Also for PET, the earliest rationale for the use of

registration, still exist. In particular, limited anatomical

hybrid systems was the possibility to obtain a faster mea-

accuracy in the fused image (up to 1 cm and more), mainly

sured attenuation correction with CT. A major improve-

due to the unsatisfactory reproducibility of positioning in

ment was the reduction in the whole body imaging time by

different sessions and to technical issues, is achievable.

replacing the slowly rotating rod source (which took several

Moreover, when CT is acquired separately with respect to

minutes per bed position) with the much faster CT scan,

radionuclide procedures, no measured attenuation correc-

taking typically less than 1-2° min for the entire body.

tion can be reliably obtained for PET and SPECT in a short

However, while today PET-CT, even including a diag-

time, also creating errors in accurate quantitative analysis.

nostic multislice CT

(MSCT), has virtually replaced

Furthermore, acquiring two studies at different times causes

stand-alone PET, the situation is completely different for

a delay in the duration of the whole diagnostic process, hav-

SPECT-CT. Despite evidence that combined modalities,

ing effects on the timeliness of the diagnosis. Tis condition

such as for PET, can improve the reader’s confidence and

can have both medical consequences, because of the possi-

therefore diagnostic accuracy, there are currently rela-

bility of hindering diagnostic and therapeutic strategies,

tively few SPECT-CT machines. Tis discrepancy is based

and economic ones, because of time spent in the hospital,

on many factors. First, a hybrid machine costs more than

waiting lists, and the cost for the full medical treatment.

a SPECT alone, and therefore its cost-effectiveness needs

SPECT-CT: Importance for Clinical Practice

to be demonstrated. Furthermore, the need for a more

of more effective and/or appealing PET procedures, which

space and, considering the X-rays produced by CT, radio-

is growing every day.

protection can eventually create unfavorable conditions

Te situation will certainly develop in institutions that

and/or additional costs. Having recently overcome the

do not have PET scanners that developing optimal condi-

fear of a Tc-99m supply shortage, the major competitors

tions in facilities with a PET scanner but without a cyclo-

concerning more widespread use of SPECT-CT scanners

tron, where at least part of the clinical indications will

are PET and/or other alternative procedures (ultrasound,

continue to be assessed using gamma tracers.

MSCT, magnetic resonance) because of their clinical

In this context, the best situation will involve using pro-

capabilities. In fact, although PET is unquestionably

cedures that allow better cost-effectiveness for gamma emit-

increasing its presence in diagnostics daily, also the other

ters, in the presence of strong and consolidated clinical

radiological alternative procedures with respect to SPECT

indications. Tis condition affects many radionuclide stud-

are reinforcing and/or enlarging their operative field. Tis

ies, such as those in cardiology, inflammation and infection,

means that there are many reasons to support the devel-

neuropsychiatry, orthopedics, nephrology, and endocrinol-

opment of a diagnostic imaging department based on

ogy; many of these are supported by a high diagnostic accu-

radiological techniques and PET-CT, without the need for

racy or prognostic value, in the presence of wider diffusion

“traditional” nuclear medicine based on gamma emitters.

and lower costs with respect to PET. In some cases, as in

dynamic studies (renal scintigraphy, cystoscintigraphy, gas-

trointestinal transits, hepatobiliary scintigraphy, etc.) or as a

1.4 Clinical Role for Gamma Emitters

premise for radioguided surgery, gamma emitters will prob-

in the Third Millennium

ably continue to be a first choice also in the near future.

Further indications could develop or find a wider diffusion,

To determine the clinical role of SPECT-CT, we have to

such as the use of gamma emitters in pre-therapeutic dosim-

include this goal in a more general discourse on the value

etry, where their longer decay time with respect to the cor-

of gamma emitters for diagnostic purposes. Tis is a man-

responding positron tracers may allow more reliable tumor

datory premise because of the certain improvement

and whole body dose calculations. Pre-therapeutic studies

achievable by SPECT-CT, with anatomical localization

could become an important field of interest, as already took

added to functional data to transform unclear medical

place for I-131, giving value to an individual dosimetry cal-

treatment with reliable nuclear medicine. It has to be

culated for I-131 MIBG (using I-123 MIBG), Y-90 oct-

emphasized that the potential added contribution of CT

reotide (In-111 octreotide), Y-90 zevelin (In-111 zevelin),

to SPECT can be even higher than the value of combining

I-131 bexxar (I-123 bexxar), etc.

CT with PET because of the poorer resolution and higher

Further technological improvements could also better

noise of images acquired with gamma emitters.

define a possible clinical role of studies with gamma emit-

Terefore, the main question to be answered in this

ters as a guide to biopsy or interventional therapies; new

chapter is: can we assume that there will be a future for

indications could be derived from the definition of the

SPECT-CT like for PET-CT, defining the hybrid system as

biological target in radiotherapy; applications could

a new standard, starting from a clinical value already verifi-

clearly emerge as a consequence of the development of

able in the present that will continue into the near future?

new tracers, including antibodies, antibiotics, neurotrans-

Considering the chapters that will follow, presenting

mitters, radiomolecules involved in apoptosis or in

some of the most important clinical applications showing

neoangiogenesis, and all radiocompounds existing in new

the role of the hybrid system, we want discuss and report

territories designed by genomics, proteomics, and the

here the general situation, justifying the continued use of

emerging molecular biology. In this direction, we have to

gamma emitters in the PET era.

remember not only the great practical advantages of

Tc-99m, but also the radiochemical value of I-123 to label

innovative biomolecules, or of In-111, when a slow bio-

1.5 Gamma Emitters With or Without SPECT

kinetic has to be studied. New and original indications

could be derived from the diffusion of novel techniques,

To demonstrate the effectiveness of SPECT-CT, first an

such as using multiple energies and dual imaging, allow-

analysis of whether gamma emitters will continue to play

ing, for example, to study metabolism (and/or receptors)

a clinical role will be analyzed, despite the increased use

and perfusion in cardiology simultaneously.

SPECT-CT: Importance for Clinical Practice

To all these indications, implemented applications for

resources, work load, type of required services, and costs,

old radiotracers can be added. We need only remember

including instruments and personnel. Te facility has to

the role of Tc-99m sestamibi in defining drug resistance

be organized as rationally and efficiently as possible.

and apoptosis, or the possibility to acquire original

Terefore, a standard department is traditionally based

pathophysiological information in heart and brain dis-

on the presence of a few machines, able to provide results

eases using cardiac scintigraphy with I-123 MIBG. And

as quickly and cost-effectively as possible for the large

certainly old techniques such as the thyroid scan, Meckel’s

majority of events. Tis means that traditional radiology,

diverticulum detection, testing of bleeding and angiomas

such as ultrasounds and a MSCT, needs to be present. A

using red blood cells, etc., will remain part of the diagnos-

significant improvement can be added by the availability

tic armamentarium.

of angiographic techniques, which can also be interven-

Te continuation of a clinical role for gamma emitters

tional procedures; conversely, they are considered not

will be strongly supported by technological develop-

cost-effective, too complicated, and too slow in answering

ments, introducing new cameras, detectors, sofware, and

the demands of both nuclear medicine and MRI. As a

procedures allowing faster and more effective scans with

vicious circle, being only rarely present in the diagnostic

a sensitivity and resolution increased by five- to ten-fold

imaging services of emergency department, radionuclide

and more. Tis is already happening in nuclear cardiol-

procedures do not demonstrate evidence-based effective-

ogy, but will also evolve in other fields because of the

ness, being too far from the initial clinical request. Te

introduction of dedicated cameras.

problem increases when a 24 h nuclear medicine service

A relevant impulse to the expansion of radionuclide

is not available, causing further delays by adding “unnec-

studies with gamma emitters could also be its introduc-

essary dangerous minutes” because of the time for the

tion as a “major procedure” in emergency departments. In

patient, technician, and physician to arrive at the facility,

the following, we will present a general discussion (since

the time to prepare the radiocompound, etc., all of which

this issue is not specifically treated in the other chapters

make reaching the clinical assessment too slow. A partial

of this book) about how demonstrating the cost-effective-

solution could be given by telenuclear medicine, allowing

ness of gamma emitters in emergency departments can

a remote interpretation of emergency studies by an on-

provide a primary motivation to acquire a SPECT-CT.

call expert, but this does not solve all the problems.

Terefore, nuclear medicine is not considered useful

in emergency situations, although it has major advan-

1.6 Nuclear Medicine in the Emergency

tages, being feasible in all patients without absolute con-

Department (A Useful Location

traindications in the presence of clinical justification.

for a SPECT-CT)

Moreover, radionuclide techniques do not require prepa-

ration or pre-diagnostic examinations, are not operator-

Te clinical role of nuclear medicine is based on its own

dependent, and permit the best functional imaging, whole

capabilities compared to those of alternative procedures.

body, and quantitative analysis, providing unique capa-

Its value can be unique and/or complementary, answering

bilities with respect to all the alternative techniques.

not only diagnostic queries, but also questions related to

Te question at this point is: if we solve all the “practi-

the prognosis and therapy; in this way an individual

cal” problems described above, is there a clinical role for

course and more effective therapeutic strategy can be bet-

nuclear medicine in emergency departments? Te answer

ter defined. But no role is possible when a procedure is

is probably yes, if there is evidence of many strong and

not available.

well-defined indications (Table 1.1).

Terefore, the value of nuclear medicine in emergency

Referring to the literature, and a wider and deeper

departments is negatively conditioned by its absence in

analysis of reasons justifying these applications, we want

first aid stations. With the necessity for speed in emer-

to emphasize here that radionuclide techniques using

gency situations, a role for a procedure not available 24 h

gamma emitters can contribute both when the fastest

a day, 365 days a year, and not located where the emer-

diagnosis and choice of a therapeutic approach are

gency has to be diagnosed and treated, cannot be

requested and when a best diagnosis and therapy are

supported.

achievable because there is no critical urgency. In fact,

If we analyze the main criteria for the organization of a

nuclear medicine can play a relevant role, adding a prog-

diagnostic imaging department for emergencies, we

nostic evaluation, better monitoring, and a more precise

indentify the main constitutive elements as the location of

determination of the time of discharge. Considering

SPECT-CT: Importance for Clinical Practice

Table 1.1 Main indications for nuclear medicine in emergency

As a further indication, it has to be remembered that

departments

gated-SPECT using perfusion tracers is an accurate, reli-

• Chest pain:

able, and easy method to evaluate cardiac perfusion and

Pulmonary embolism, myocardial infarction

function in all circumstances required in emergency.

• Cerebral emergencies:

Cerebrovascular accidents, brain death, head traumas, ictal

epilepsy

1.6.1.2 Pulmonary Embolism

Acute inflammation/infection

•

Although today in many institutions the first-line exami-

• Abdominal bleeding

nation in patients with suspicious pulmonary embolism

• Trauma

is MSCT with contrast media, up to 25% of patients can-

• Transplants

not be recruited using this procedure, which shows toxic-

• Skeletal, hepatobiliary, renal, endocrine emergencies

ity and/or collateral effects, including death. Perfusion

• Acute scrotal pain

lung scintigraphy (PLS), with or without a complemen-

• Pulmonary aspiration

tary ventilatory scan, is feasible in all patients without

absolute contraindications in the presence of a clinical

advantage and does not requires pre-test examinations;

human resources and facilities, nuclear medicine can

the scan is affected by a very high negative predictive

therefore be cost-effective, playing a major role, for exam-

value, also showing good accuracy, mainly in younger

ple, avoiding admission for false emergencies and reduc-

patients. Moreover, it can add complementary informa-

ing the number of quick discharges with related increased

tion to MSCT, better defining the severity and extension

risks, causing deaths and/or future costs because of dam-

of the alveolar-capillary function of each lung; finally PLS

ages and the consequent need for rehabilitation.

reliably defines the efficacy of therapeutic procedures,

In the following, some of the most important informa-

both medical and interventional.

tion for emergency nuclear medicine is reported. At pres-

ent, this information is only “practically” feasible using

gamma emitters, as PET tracers are not immediately

1.6.2 Cerebral Emergencies

available on demand.

1.6.2.1 Cerebrovascular Accidents (CVA)

MSCT is the first-line procedure in these patients, but a

1.6.1 Chest Pain

cerebral blood flow study with gamma tracers (CBF-

SPECT) can be an alternative or complementary study

1.6.1.1 Myocardial Infarct

for an early and accurate diagnosis (also in reversible

It has been clearly demonstrated in facilities with a nuclear

ischemia), for defining the vasodilatory reserve (diamox

medicine division in the emergency department that myo-

test), contributing to the prognostic information based

cardial scintigraphy (MS), because of a higher accuracy

on location, extension, and severity, and for differentiat-

with respect to ECG and ultrasound, can help to better

ing between nutritional reperfusion versus luxury perfu-

define the diagnostic and therapeutic strategies. In particu-

sion; similarly, a better selection and monitoring of

lar, it reduces the number of erroneous admissions for false

patients undergoing interventional approaches can be

emergencies, i.e., for patients without a myocardial infarct

obtained.

(MI); conversely, it increases the number of correct admis-

sions, including up to 50-65% of subjects with a non-diag-

nostic ECG misdiagnosed as having MI. As a further

1.6.2.2 Head Trauma

advantage, MS distinguishes 2-8% of patients at risk for a

CT is also the first-line procedure for head trauma. CBF-

too early discharge, causing a three times higher probabil-

SPECT can be an alternative or complementary proce-

ity of death and significantly higher costs for rehabilitation

dure for early and accurate diagnosis (also for patients

and/or new major events. With respect to savings, it has

with negative CT results); moreover, it can add prognos-

also been calculated that the presence of a nuclear medi-

tic information based on location, extension, and sever-

cine division in the emergency department reduces costs

ity, also providing an explanation for the behavioral and

for false emergencies by 5%. In this way a gain in the order

psychological sequelae present in the large majority of

of tens of millions of Euros per year can be obtained.

patients with brain injuries.

SPECT-CT: Importance for Clinical Practice

1.6.2.3 Brain Death

leakage, and fistula. It can play a role in monitoring

Te role of techniques, also planar, using gamma emitters

patients undergoing bowel surgery, and can also help

to define brain death can be very relevant. CBF radiotrac-

diagnose biliary atresia in pediatric patients and biliary

ers are concentrated only by the living brain, permitting a

colic when negative at ultrasounds. Te most important

reliable confirmatory test of brain death (as a complement

indication in emergency medicine is the reliable diagnosis

or alternative to transcranial Doppler US, somatosensory-

of acute cholecystitis. Tere is strong evidence that choles-

evocated potentials, EEG, and angiography) to shorten

cintigraphy is significantly more accurate than US in the

the clinical observation time. Together with being accu-

diagnosis of acute acalculous cholecystitis.

rate, reproducible, and technically easy, a further advan-

tage compared to angiographic techniques using contrast

media is the absence of toxic effects that can be present

1.6.5 Acute Inflammation Infection

using radiological iodinated compounds, affect kidney

function, which can lead to the need for transplants.

Useful information can be obtained using traditional

studies, such as bone, renal, and biliary scintigraphy.

Te use of radiolabeled white blood cells (WBC) is too

1.6.2.4 Ictal Epilepsy

complex for routine use in emergencies, but can be pro-

CBF-SPECT is a very reliable method to diagnose and

posed in the presence of clinical suspicion, mainly for post-

localize the epileptic focus before surgery. If injected dur-

surgical patients. WBC can detect acute appendicitis in

ing or immediately afer an acute event, a higher uptake

subjects with equivocal clinical findings also in the presence

of the CBF radiotracer is observed at the level of the criti-

of non-typical and/or difficult locations, such as retrocoe-

cal area, allowing a detection sometimes not possible with

cal; moreover, it can show perforation reliably and early.

other procedures.

1.6.6 Abdominal Bleeding

1.6.3 Bone Scan in Emergencies

Te Tc-99m pertechnetate scan is the first-line procedure

A mistake in detecting a bone fracture is one of the most fre-

for abdominal bleeding in pediatric patients because of its

quent causes of legal malpractice trials. Bone scintigraphy can

high accuracy in detecting Meckel’s diverticulum. In

perform a primary role because of its very high sensitivity,

adults, application of radiolabeled red blood cell (RBCs)

mainly in the presence of a mismatch between symptoms

can precede angiography because of the high negative pre-

and treatment, taken as the first-line examination; similarly,

dictive value; this also has a diagnostic potential in patients

incremental information can be acquired in unconscious

with absence of active rapid bleeding, negative or incon-

poly-traumatized patients. Bone scintigraphy can also help

clusive endoscopy for whom invasive procedures are con-

exclude bone involvement or define disease activity in patients

traindicated (as in an immediate post-surgical phase).

affected with conditions such as tendinitis, rheumatoid

arthritis, and sacroileitis, while significant clinical improve-

ment can be achieved in the identification of child abuse.

1.6.7 Transplants

Useful information can be acquired about territory border-

lines with respect to the emergency, such as the differential

Nuclear medicine can play a primary role in transplant units

diagnosis of the age of fractures in traumatized patients, to

to define brain death, to recruit donors, and to evaluate

reliably recognize the “actual damage” as opposed to that

early and complications reliably, and is available for patients

caused by old injuries. An interesting application can also be

undergoing renal, cardiac, hepatic, and pulmonary trans-

found in military medicine to exclude bone pain simulation.

plants using standard examinations. Te possible role of

WBCs to detect infections should also be remembered.

1.6.4 Hepatobiliary Emergencies

1.6.8 Trauma

Hepatobiliary scintigraphy permits reliable functional

evaluation of the hepatobiliary system, today also con-

Being ancillary and/or an alternative to more effective

tributing to the detection of duodenogastric reflux, biliary

procedures, radionuclide techniques in abdominal and

SPECT-CT: Importance for Clinical Practice

pelvic traumas can provide useful data for skeletal pathol-

Our proposal is that the best way to include nuclear

ogies and, as previously reported, head traumas. A com-

medicine in the diagnostic imaging section of emergency

plementary role can be demonstrated in all cases when

departments is to transform MSCTs into SPECT-CTs.

dynamic information can better define the clinical pat-

A gamma camera/SPECT, as part of the hybrid machine,

tern, such as using renal or hepatobiliary scintigraphy to

can significantly increase the diagnostic accuracy, also

define altered function, leakage, and fistula.

providing further original and/or complementary infor-

mation that can reduce the number of mistakes and/or

better define therapeutic strategies.

1.6.9 Post-surgical Emergencies

Nuclear medicine, as previously described, can play an

1.8 Can SPECT-CT Be Cost-Effective?

alternative, original, and/or complementary role in many

post-surgical complications. Using radionuclide proce-

To answer to this question, we first need to have evi-

dures, it is possible to detect and/or evaluate the clinical

dence of the clinical effectiveness, defining a role in

relevance of trauma, fistula, leakage, bleeding, and sepsis.

comparison with alternative procedures, both radiologi-

Moreover, they can reliably define cardiovascular and renal

cal and PET-CT. Similarly, we need to specify when the

complications and diagnose pulmonary embolism. Finally,

hybrid machine should be implemented clinically

as previously reported, CBF radiotracers can be an impor-

instead of a SPECT alone. Together with this evaluation,

tant tool contributing to the definition of brain death.

we have to calculate whether the cost is justifiable and

sustainable.

Evaluation of the clinical usefulness in different fields

1.6.10 Miscellaneous

will be the subject of the next chapters, describing the

most important applications of SPECT-CT. Also the

Radionuclide procedures can play a role in many renal

contribution of the implementation in emergency

emergencies, such as transplants, acute renal failure, non-

medicine has to be taken into account. At the end of this

diagnosed obstructive uropathy, and acute infection.

book, we hope the readers will have sufficient informa-

Important information can be obtained in patients with

tion to evaluate the improvements achievable with a

acute scrotal pain, correctly determining the need for sur-

SPECT-CT in order to make decisions about its

gical therapy.

acquisition.

In pediatrics, unique information can be achieved to

To make a more rational and pragmatic evaluation, a

detect pulmonary aspiration in newborns, evaluating

cost analysis also has to be performed. Concerning the

reflux afer the administration of milk labeled with

necessary costs, that a relevant percentage of the value of

Tc-99m.

hybrid machines is determined by the radiological com-

Also, in strict emergency situations, nuclear medicine

ponent needs to be remembered. Only considering diag-

can contribute to diagnosing diseases such as acute thy-

nostic CT, it has to be pointed out that a more expensive

roiditis and pheocromocytoma.

MSCT, with at least 16 slices (preferably 64) or more, is

only mandatory for research or when angiographic data,

such as for coronary CT, are requested. Tis means that

1.7 Why a SPECT-CT in Emergency

satisfactory and less expensive results (also in terms of

Departments?

radioprotection) can also be obtained routinely in the

large majority of institutions with systems with a MSCT

In the above, the clinical effectiveness of radionuclide

with less than 16 slices.

procedures using gamma radiotracers in urgent situa-

Terefore, to correctly evaluate the cost-effectiveness

tions has been demonstrated. Terefore, the absence of

and to determine the best and most productive techno-

nuclear medicine in emergency departments is not

logical acquisition for SPECT-CT, we have to take into

because it is not useful, but can rather mainly be explained

account the dimension and mission of the institution

by structural, organizational, and economic issues. If we

(general hospital, cardiology, oncology, emergency,

solve these problems without changing the rationale of

research, private practice, pediatrics, etc.). We hope that

emergency departments, we could improve the entire

reading this book will show that SPECT-CT can signifi-

clinical result.

cantly enhance the field of nuclear medicine.

SPECT-CT: Importance for Clinical Practice

Suggested Reading

Barrett JF, Keat N. Artifacts in CT: recognition and avoidance.

RadioGraphics. 2004;24:1679-91.

Fig. 2.5 Incorrect AC due to a misalignment between TC

⊡⊡

de Cabrejas ML, Pérez AM, Giannone CA, Vázquez S, Marrero

and SPECT

G. SPECT. Una guía práctica. Comité de Garantía de Calidad

del Alasbimn. Mayo 1992.

Delbeke D, Coleman RE, Guiberteau MJ, et al. Procedure guide-

Te use of CT data for the AC provides several advan-

line for SPECT/CT imaging 1.0. J Nucl Med. 2009;47:

1227-34.

tages. Te statistical noise associated with the AC is lower

McQuaid SJ, Hutton BF. Source of attenuation-correction arte-

with CT than with other techniques, such as transmission

facts in cardiac PET/CT and SPECT/CT. Eur J Nucl Med

with encapsulated sources, because the photon flux pro-

Mol Imaging. 2008;35:1117-23.

vided by the CT is higher. Te total time to perform the

Nuñez M. Cardiac SPECT. Alasbimn J. 2002;5(18): Article No.

study is significantly reduced because of the fast acquisi-

AJ18-13.

Patton JA, Turkington TG. SPECT/CT physical principles and

tion speed of CT. Te anatomical images acquired with

attenuations correction. J Nucl Med Technol.

2008;

CT can be merged with the emission images to provide

36:1-10.

functional anatomical maps for precise localization of

Puchal Añé R. Filtros de imagen en Medicina Nuclear. Nycomed

radiotracer uptake. Te process of aligning the SPECT

Amersham: Ediciones Eurobook; 1997.

and CT images, in order to fuse them and analyze them,

Sociedad Española de Física Médica, Sociedad Española de

Medicina Nuclear y Sociedad Española de Protección

is called spatial registration.

Radiológica. Protocolo Nacional del Control de Calidad en

SPECT/CT not only has the artifacts generated by

la Instrumentación en Medicina Nuclear. 1999.

each of the two imaging systems, but also has those that

Chapter 3

SPECT-CT for Tumor Imaging

Carina Mari Aparici,

Anca M. Avram, Angel Soriano Castrejón,

Ryan A. Dvorak, Paola Erba, Jure Fettich,

José Manuel Cordero Garcia,

Victor Manuel Poblete García,

Randall Hawkins, Marina Hodolic,

Prado Talavera Rubio, Youngho Seo,

Ana María García Vicente,

John Patrick Pilkington Woll,

and Ka Kit Wong

Contents

3.1

Octreotide SPECT-CT.

3.1.1

Neuroendocrine tumors .

3.1.2

Conclusion.

References.

Case 1

Carcinoid Tumor: Suspected relapse .

Case 2

Carcinoid Tumor: Search

for the Primary Tumor.

Case 3

Gastric Neuroendocrine

Tumor: Follow-up.

Case 4

Carcinoid Tumor: Progression.

Case 5

Neuroendocrine Pancreatic Tumor:

Assessment of Treatment Response.

Case 6

Metastatic Neuroendocrine Tumor.

Case 7

Neuroendocrine Lung Tumor:

Staging of Advanced Disease .

Case 8

Neuroendocrine Pancreatic Tumor:

Staging of Advanced Disease .

Case 9

Carcinoid Tumor: Screening.

Case 10

Neuroendocrine Tumor: Screening.

Case 11

Peritoneal Carcinomatosis Secondary

to Carcinoid Tumor: Treatment Response .

S. Fanti et al., Atlas of SPECT-CT,

DOI: 10.1007/978-3-642-15726-4_3, © Springer-Verlag Berlin Heidelberg 2011

SPECT-CT for Tumor Imaging

Case 12

Neuroendocrine Pancreatic Carcinoma

Case 2

Regional Nodal Metastatic Disease

with Liver Metastases:

in the Neck.

Treatment Response.

Case 3

Physiological Radioiodine Activity

Case 13

Disseminated Carcinoid Tumor: Staging.

Due to Gastric Pull-through Procedure.

Case 14

Gastrinoma: Screening.

Case 4

Pulmonary Metastases on Diagnostic and

Post-therapy Imaging.

Case 15

Pancreatic Neuroendocrine Tumor:

Diagnosis.

Case 5

Osseous Metastases

Case 16

Low Grade Endocrine Carcinoma:

Case 6

Non-iodine Avid Regional Nodal Disease

Staging After Surgery.

in the Neck.

3.2

MIBG SPECT-CT.

3.4

Prostascint SPECT-CT .

References.

Case 1

Metastatic Lymph Node Uptake:

SPECT/low-mA CT.

Case 1

Hypertension: Suspected Adrenal

Involvement.

Case 2

Adrenal Gland Uptake: SPECT/low-mA CT.

Case 2

Hypertension + Adrenal Mass:

Case 3

Metastatic Pararectal Lymph Node:

Functional State .

SPECT/high-mA CT.

Case 3

Bilateral Pheochromocytoma Versus

Case 4

Metastatic Peripancreatic Lymph Node:

Metastasis of Pancreatic Cancer

SPECT/high-mA CT.

Case 4

Pheochromocytoma Versus

3.5

Hynic SPECT-CT.

Paraganglioma .

3.5.1

Radiopharmaceutical Preparation .

Case 5

Hypertension + Adrenal Node + Increased

Catecholamines: Suspect

References.

of Pheochromocytoma.

Case 1

Midgut NET.

3.3

Iodine SPECT-CT.

Case 2

Insulinoma.

3.3.1

Introduction.

Case 3

Lymph node metastasis.

3.3.2

Utility of Iodine SPECT-CT.

Case 4

Bone metastasis .

3.3.3

Limitations of Iodine SPECT-CT

Case 5

Invasive adenoma of the pituitary gland.

3.3.4

Future Directions .

3.6

New Tracers.

References.

104

Case 1

Thyroid Remnant Tissue Following Total

Thyroidectomy.

SPECT-CT for Tumor Imaging

3.1 Octreotide SPECT-CT

Normal scintigraphic features include visualization

of thyroid, spleen, liver, kidneys and, in some patients,

Angel Soriano Castrejón (), José Manuel Cordero

pituitary gland. Te pituitary, spleen and kidney visualiza-

Garcia, Victor Manuel Poblete García, John Patrick

tion is due to receptor binding, while a tubular reabsorp-

Pilkington Woll, and Ana María García Vicente

tion mechanism mainly accounts for the renal uptake. Te

radiopharmaceutical is physiologically eliminated by renal

Somatostatine receptor scintigraphy (SRS) with soma-

clearance, although hepatobiliary clearance is also present,

tostatine analogs is nowadays established as a first-line

which causes the presence of the tracer in the bowel. Te

tool in the detection, staging and evaluation of the

physiological urinary and intestinal elimination is respon-

response of neuroendocrine tumors (NETs) and some

sible for the majority of doubtful or misinterpreted stud-

neural crest tumors, yielding much better results than

ies. Ongoing treatment with somatostatine-receptor

conventional imaging techniques [1] as many subtypes of

blockers may cause a diminished spleen or liver uptake,

these tumors overexpress a high density of somatostatine

but, in the presence of tumor with expression of these

receptors at the cell surface [2, 3]. Tis overexpression of

receptors, even high doses of unlabeled octreotide may

the somatostatin receptors, however, may also be present

not result in complete receptor occupancy [10, 11].

in some other tumors, such as differentiated thyroid car-

Although both conventional scintigraphy and SPECT

cinoma, lung cancer, breast cancer, meningiomas, well-

imaging offer functional information of the greatest

differentiated astrocytomas, pituitary tumors, lymphoma

importance, not achievable by other means, the physical

and several others [4-7]. Some benign conditions, mainly

properties inherent to radionuclide imaging, such as pho-

related to the presence of inflammatory cells, i.e., in thy-

ton attenuation, scattered radiation or partial volume

roidal ofalmopathy [8], may also show an increased

effect, are responsible for its poor spatial resolution. Also,

expression of these surface receptors.

the lack of an adequate anatomical landmark can be a

Six types of somatostatin receptors have been cloned,

potential source of misinterpretation of the images, with

namely sst₁-sst₅, with sst₂ spliced to yield sst_2A y sst-_2B, with

the specificity of the technique being reduced at sites of

all somatostatine analogs having high affinity for the recep-

physiological uptake [12]. All these shortfalls are signifi-

tors sst₂ and sst₅, and varying affinity for types sst₃ and sst₄.

cantly reduced by the use of hybrid SPECT-CT cameras,

Tey are G-protein-coupled receptors on the cell membrane

disposable versions of which have been available in clini-

that recognize the ligand and generate a transmembrane

cal daily practice since 1999. Teir widespread use has

signal. Te hormone-receptor complexes have the ability to

increased slowly but steadily. Te hybrid equipment

be internalized. Te vesicles formed fuse to lysosomes, deg-

improves the quality of the images using the CT as a

radating the hormone and recycling the receptor [9].

source of attenuation correction and at the same time

Te short plasmatic half-life of somatostatine (about

provides useful anatomical information [13, 14]. Te

3 min) has promoted the development of analogs with

improvement achieved in the diagnostic accuracy of SRS

longer half-lives, suited to the clinical use. Te most widely

by the use of SPECT-CT, when compared with the planar

used somatostatine analog for SRS is [¹¹¹In]-diethylene tri-

and SPECT images, has been reported by several groups

amine pentacetate acid [DTPA]-octreotide, a somatosta-

[15-18], mainly reducing the false-positives results espe-

tine-derivated octapeptide coupled to a chelant (DTPA)

cially in areas of physiological uptake or elimination.

that shows a high affinity for receptor subtype 2 and 5,

probably internalized afer its binding to the receptor with

residualization of the ¹¹¹In label, which would account for

3.1.1 Neuroendocrine tumors

the good 24 h tumor-to-background ratio.

Tus, the biomarker analyzed by these somatostatine

Neuroendocrine tumors are rare neoplasms that account

analogs is the overexpression of these receptors, offering

for 2% of all tumors. Tey originate from neuroendocrine

functional information about this particular molecular

cells that are thought to arise from common precursor

characteristic, and evaluating the amount of viable

cells of the embryological neural crest and that can be

tumoral tissue before and afer treatment, or allowing the

found throughout the human body. Each type of cell

selection of those patients that could be candidates for the

produces a characteristic hormone and expresses its

therapeutic use of somatostatine analogs.

own protein markers, and the endocrine effect is mainly

SPECT-CT for Tumor Imaging

¹¹¹In-octreotide

¹²³I-MIBG

¹⁸F-DOPA

¹⁸FDG

Abdominal carcinoid

78% (76-82%, 720)

63% (54-72%, 125)

87% (80-93%, 116)

Pancreatic islet cell carcinoma

67% (56-77%, 99)

41% (36-47%, 22)

Pheochromocytoma

63% (51-73%, 14)

79% (68-82%, 161)

100% (75-100%, 14)

Merkel cell tumors

78% (51-92%, 20)

Medulary thyroid carcinoma

48% (42-57%, 168)

66% (52-80%, 48)

75% (67-82%, 128)

Neuroblastoma

63% (53-72%, 105)

84% (79-89%, 204)

Paraganglioma

94% (85-98%, 77)

69% (58-78%, 87)

100% (76-100%, 10)

Bronchial carcinoids

71% (52-86%, 31)

Small cell lung cancer

56% (38-71%, 40)

95% (88-98%, 96)

paracrine, being involved in the regulation of a large vari-

tumors in children and for which an accurate initial diag-

ety of body functions mainly because of the secretion of

nosis is key for the final result.

the so-called biogenic amines (serotonine, catecholamines,

A broad variety of therapeutic options are possible

adrenocorticotropic hormone, growth hormone, sub-

now for patients with neuroendocrine tumors, including

stance P, prostaglandins, etc.). Tus, neuroendocrine

surgery as the only curative alternative when it can be

tumors can arise almost anywhere, although they are

performed, palliative surgical procedures, chemoembo-

more ofen found in the gastrointestinal (56%) and bron-

lization or systemic treatment using Interferon or chemo-

chopulmonary (12%) tracts [19].

therapy. Non-radioactively labeled somatostatine analogs

Although classically classified according to the embry-

or inclusive, radionuclide therapies with somatostatine

ological organ from which they arise, the most recent

analogs bound to ¹⁷⁷Lu, ⁹⁰Y, ¹³¹I or ¹¹¹In can also be used,

World Health Organization (WHO) classification is based

obtaining stabilization of the disease in around the 40%

on histological characteristics, such as cellular grade, size

of the patients and partial regression in approximately

and location of the primary tumor, local invasiveness and

30% [4, 21]. Knowledge of the receptor expression status

production of biological active substances [20], with the

is of great interest not only for the staging and restaging

term carcinoid being replaced by neuroendocrine tumor.

afer treatment, but also for the possible planning and

Globally, they are divided into well differentiated with a

follow-up of these recent therapies, as the expression of

low grade of malignancy, well differentiated more aggres-

SRS makes these tumors suitable for treatment with

sive tumors, poorly differentiated with a high grade of

somatostatine analogs. However, some tumors may suffer

malignancy and mixed exocrine-endocrine tumors.

a dedifferentiation, with lost of expression of somatosta-

Te most frequent behavior of these tumors is a slow

tine receptors, with a low sensitivity in the SRS that would

growth, with a long survival time in spite of finding metas-

make them not appropriate for treatment [22].

tasis at the time of the diagnosis, but some of the tumors

Different tracers other than somatostatine analogs have

may be more aggressive, leading to a shorter survival.

been used in the investigation of this type of tumor, having

Some clinical symptoms, such as flushing or diarrhea,

shown very good results in specific subtypes [13]. Tus,

may be the initial presentation of the disease, although the

¹²³I-MIBG, an analog of guanetidine that accumulates in

diagnosis is only confirmed by histopathological exami-

the presinaptic vesicles of the sympathomedullary system,

nation, ofen followed by inmunohistochemical staining.

represents a first-choice modality in functioning phaeo-

Although the so-called gastroenteropancreatic tumors

chromocytomas, paragangliomas and neuroblastomas

are more frequently found, neuroendocrine neoplasms

[23]. Moreover, the recent development of PET tracers,

include neural crest tumors such as pheochromocytoma,

including

¹⁸F-FDG

[24,

25],

¹⁸F-FDOPA

[26,

27]or

derived from the cathecolamine-secreting chromafin

⁶⁸Ga-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic

cells of the adrenal medulla, which may be associated

acid]-1-Nal3-octreotide (⁶⁸Ga-DOTA-NOC) [28, 29] have

with inherited syndromes (MEN type II, von Hippel-

broadened the possibilities of studying NETs. Te table

Lindau syndrome, neurofibromatosis) and is metastasic

summarizes the sensitivities obtained from the literature

in 10% of the cases, paraganglioma or neuroblastoma, a

for different types of tumors with the more widely used

mainly pediatric tumor that accounts for 10% of the

SPECT and PET tracers, modified from a recent review by

SPECT-CT for Tumor Imaging

Koopmans et al. [30] (in brackets, the calculated confidence

11. Banzo Marraco J, Prats Rivera E, Pazola Alba P, Tardín

interval and the number of patients included).

Cardoso L, Andres Gracia A, Santapau Traveria A.

Diagnóstico y seguimiento de los tumores neuroendocrnos

del tracto gastrointestinal mediante gammagrafía de recep-

tores de somatostatina. In: Soriano Castrejón A, Martín

3.1.2 Conclusion

Comín J, García Vicente AM, editors. Medicina Nuclear en

la práctica clínica. Madrid: Aula Médica; 2009. p. 667-74.

SRS is the best tool for the detection, initial staging, evaluation

12. Chowdhury FU, Scarsbrook AF. The role of hybrid

SPECT-CT in oncology: current and emerging clinical

of treatment response and even therapy planning of NETs.

applications. Clin Radiol. 2008;63:241-51.

SPECT/CT improves the accuracy significantly, offer-

13. Schilacci O, Danieli R, Manni C, Simonetti G. Is SPECT/CT

ing invaluable anatomical information for a correct inter-

with hybrid cameras useful to improve scintigraphy imaging

pretation of scintigraphic findings, and facilitates

interpretation? Nucl Med Comm. 2004;25:705-10.

performing a better attenuation correction.

14. Lucignani G, Bombardieri E. Progress and challenges in neu-

roendocrine and neural crest tumors: molecular imaging and

therapy. Eur J Nucl Med Mol Imaging. 2009;36:2081-8.

15. Castaldi P, Rufini V, Treglia G, Bruno I, Perotti G, Stifano

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SPECT-CT for Tumor Imaging

3.2 MIBG SPECT-CT

radioiodinated MIBG in other neural crest cell-derived

tumors, such as medullary thyroid carcinoma and carci-

Angel Soriano Castrejón (), Ana María García Vicente,

noid tumors, is more limited, resulting in lower sensitiv-

Prado Talavera Rubio, and John Patrick Pilkington Woll

ity when used for these tumors. ¹³¹I MIBG is a more stable

and readily available isotope than ¹²³I, and has been widely

Today MIBG scintigraphy is considered the best diagnos-

used for the localization of neural crest tumors and the

tic technique for evaluation of the disease activity of

treatment of metastatic disease; however, ¹²³I is the pre-

tumors derived from the sympathetic nervous system,

ferred isotope for imaging because it is a pure gamma-

such as neuroblastomas, pheochromocytomas, ganglion-

emitter with a shorter half-life and greater avidity to

euroblastomas and paragangliomas [31]. Tese tumors

neural crest tumors and, therefore, can be used at a higher

originate from the adrenal gland and sympathetic gangli-

dosage resulting in greater sensitivity and specificity for

ons anywhere from the neck to the pelvis. In the case of

the detection of neural crest tumors [38, 39].

malignant tumors, metastases can be found in sof tissue,

CT and MRI are the morphological imaging modali-

bone and bone marrow. Because of their neuroendocrine

ties of choice in localizing these tumors [40]. Tese tech-

origin, these tumors are able to take up catecholamines

niques provide excellent anatomical details, but although

and related substances. Te diagnosis of these tumors is

their sensitivity is very high, both are lacking in specific-

established biochemically by measuring the level of uri-

ity as difficulties may occur in distinguishing between

nary and plasma catecholamines and their metabolites.

tumors deriving from the sympathetic nervous system

Neuroblastoma and pheochromocytoma are the two

and other tumor entities [35, 41, 42]. Terefore, morpho-

most common tumors of the adrenal medulla and the

logical imaging depicts only morphological abnormali-

sympathetic and parasympathetic systems.Neuroblastoma

ties and cannot functionally characterize adrenal or

is one of the most common childhood solid tumors. Up

extraadrenal masses.

to 55% of neuroblastomas appear in the abdominal cav-

Te major advantages of radionuclide imaging are

ity; about 33% arise in the adrenal medulla, and the rest

high sensitivity, very high specificity and the routinely

occur anywhere along the sympathetic chain, most ofen

performed whole-body scanning. Furthermore, in fol-

in the paravertebral region of the posterior mediastinum

low-up examinations, functional imaging is not affected

and the neck. Pheochromocytoma is an uncommon neo-

by postoperative artifacts, such as scar tissue or metallic

plasm that most ofen occurs in adults and rarely in chil-

clips, and is extremely helpful in the detection of extra-

dren. About 85% of pheochromocytomas arise in the

adrenal tumor sites [35].

medulla of the adrenal glands; the rest come from any of

Widely applied whole-body

¹²³I-MIBG scintigraphy

the extraadrenal paraganglia, more ofen below the dia-

localizes neuroblastoma and pheochromocytoma with a

phragm. About 10% of intraadrenal pheochromocytomas

high sensitivity. However, ¹²³I-MIBG scintigraphy comes

are malignant. Te risk of malignant development is

with some disadvantages, such as limited spatial resolution;

higher in the extraadrenal tumors (20-40%).

limited sensitivity in small lesions; the need for

Meta-iodobenzylguanidine

(MIBG) is a structural

2 or—in the case of SPECT—even more acquisition sessions

and functional analog of norepinephrine and guanethi-

with the consequent delay between the start of the examina-

dine that selectively accumulates in the noradrenergic

tion and result; and the relatively high radiation exposure.

neurosecretory granules of cytoplasmic vesicles found in

Today, MIBG scintigraphy is indeed considered the

the cells of organs with rich adrenergic innervation, such

best diagnostic technique for evaluation of disease activ-

as the heart, salivary glands, spleen, adrenal medulla and

ity, both at presentation and at follow-up. In 5-7% of

tumors of medullary origin [32]. Uptake is proportional

cases, however, MIBG scintigraphy is negative at presen-

to granule density [33]. It can therefore serve as a bio-

tation (there is no MIBG uptake by tumor cells) [43]. In

marker that, appropriately labeled, helps in the detection

such cases, PET using ¹⁸F-FDG, ¹⁸F-DOPA (dihydroxy-

of these tumors and that is also used as a carrier for tar-

phenylalanine) or ⁶⁸Ga-DOTATOC (DOTA-D-Phe[1]-

geted radionuclide therapy [34].

Tyr[3]-octreotide) may be indicated [44, 45 ].

Iodine-labeled MIBG scintigraphy has good sensitiv-

It has been established that MIBG rarely provides addi-

ity for the diagnosis of neuroblastoma and pheochromo-

tional diagnostic information for patients who have a clear

cytoma, between 80% and 100%, and high specificity

biochemical diagnosis of pheochromocytoma and a soli-

close to

100% for both [32, 35-37]. Te uptake of

tary tumor identified on cross-sectional imaging [46-50].

SPECT-CT for Tumor Imaging

Terefore, it has been suggested that MIBG should be

distorted anatomic structure, allowing the accurate anatomic

used selectively for patients with a high risk of recurrent,

localization of pathological MIBG uptake in the follow-up of

multifocal or malignant disease and for patients with a

patients with neuroblastoma and pheochromocytoma,

positive biochemical diagnosis who fail to demonstrate a

whereas both contrast-enhanced CT and CT of SPECT/CT

lesion on CT or magnetic resonance imaging (MRI).

alone were equivocal. In their study, MIBG SPECT/CT

However, few studies have investigated the use of MIBG

greatly contributed to the diagnostic accuracy in 53% of all

SPECT or MIBG SPECT/CT as an imaging tool for pheo-

cases and 89% of discordant cases. Tese results are consis-

chromocytoma, particularly in these situations [31, 51].

tent with other published studies [55, 56].

Te diagnosis of the clinically occult pheochromocy-

Other situations in which MIBG SPECT/CT is benefi-

toma remains a particular challenge to the clinician.

cial is for the confirmation of a small extra-adrenal pheo-

Factors that may hinder diagnosis of the clinically occult

chromocytoma, small metastatic lesions or recurrence at

or recurrent pheochromocytoma include non-functioning

a previous operative site, which may have a non-specific

pheochromocytoma, the size and location of the tumor,

appearance on CT or MRI and are ofen poorly visible on

the presence of multiple or metastatic lesions, recurrence

conventional MIBG imaging [57].

at a site with distorted tissue planes or scarring from previ-

ous surgery, and the presence of an adrenal incidentaloma

or other unrelated intra-abdominal lesions.

References

With the development of new tissue-specific radiop-

harmaceuticals, such as 11C-epinephrine, ¹¹C-hydroxy

31. Rozovsky K, Koplewitz BZ, Krausz Y, Revel-Vilk S,

Weintraub M, Chisin R, et al. Added value of SPECT/CT for

epinephrine,¹⁸F-fluorodopamineand¹⁸F-fluorodihydroxyp

correlation of MIBG scintigraphy and diagnostic CT in neu-

henylalanine, fusion PET/CT may become the new “gold

roblastoma and pheochromocytoma. AJR.

2008;190:

standard” for pheochromocytoma imaging in the future

1085-90.

[52, 53]. However, because of the current cost, limited

32. Freitas JE. Adrenal cortical and medullary imaging. Semin

availability and short half-life of many of the radioisotopes

Nucl Med. 1995;25:235-50.

33. Bomanji J, Levison DA, Flatman WD, et al. Uptake of

used, access to fusion PET/CT for most centers with these

iodine-123 MIBG by pheochromocytomas, paragangliomas,

radiotracers will be limited. Terefore, radioiodinated

and neuroblastomas: a histopathological comparison. J Nucl

MIBG remains the recommended initial agent of choice

Med. 1987;28:973-8.

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34. Garaventa A, Guerra P, Arrighini A, et al. Treatment of

In relation to the differences between planar and

advanced neuroblastoma with I-131 metaiodobenzylguani-

dine. Cancer 1991;67:992-8.

SPECT imaging in a multicenter prospective trial includ-

35. Kushner BH. Neuroblastoma: a disease requiring a multi-

ing 150 patients, SPECT had only a small effect on reader

tude of imaging studies. J Nucl Med. 2004;45:1172-88.

performance, producing a slight increase in sensitivity

36. Merrick MV. Essentials of nuclear medicine. 2nd ed. Berlin:

(82-86%) and a small drop in specificity

(82-75%).

Springer; 1998. p. 171-295.

Although SPECT increased reader confidence, this imag-

37. Van Der Horst-Schrivers AN, Jager PL, Boezen HM,

Schouten JP, Kema IP, Links TP. Iodine-123 metaiodoben-

ing only changed the consensus interpretation for ten

zylguanidine scintigraphy in localizing phaeochromocy-

patients (7%) [49].

tomas: experience and meta-analysis. Anticancer Res.

With respect to SPECT/CT in cases of equivocal diag-

2006;26:1599-604.

nostic CT (mainly distorted anatomy) or of suboptimal

38. Nakatani T, Hayama T, Uchida J, et al. Diagnostic localiza-

localization of MIBG-avid foci, SPECT/CT bridges the

tion of extra-adrenal pheochromocytoma: comparison of

(123)I-MIBG imaging and (131)I-MIBG imaging. Oncol

gap between MIBG scintigraphy and CT, helping to define

Rep. 2002;9:1225-7.

the anatomic location of these foci and to characterize the

39. Anderson GS, Fish S, Nakhoda K, et al. Comparison of I-123

benign or malignant significance of uncertain CT find-

and I-131 for whole-body imaging afer stimulation by

ings. However, some authors describe that low-resolution

recombinant human thyrotropin: a preliminary report. Clin

CT of SPECT/CT does not always allow an optimal inter-

Nucl Med. 2003;28:93-6.

40. Pfluger T, Schmied C, Porn U, et al. Integrated imaging using

pretation of the CT images and should be supplemented—

MRI and I-123- metaiodobenzylguanidine scintigraphy to

at least at presentation—by diagnostic contrast enhanced

improve sensitivity and specificity in the diagnosis of pediat-

CT, providing superior anatomic resolution [31].

ric neuroblastoma. AJR. 2003;181:1115-24.

Rozovsky et al. [31] found that fused images enabled dif-

41. Lenders JW, Eisenhofer G, Mannelli M, Pacak K.

ferentiation between the tumor’s mass and surgically

Pheochromocytoma. Lancet. 2005;366:665-75.

SPECT-CT for Tumor Imaging

42. Ilias I, Pacak K. Current approaches and recommended

scintigraphy in the evaluation of patients with known or sus-

algorithm for the diagnostic localization of pheochromocy-

pected primary or metastatic pheochromocytoma or para-

toma. J Clin Endocrinol Metab. 2004;89:479-91.

ganglioma: results from a prospective multicenter trial. J

43. Pirson AS, Krug B, Tuerlinckx D. Additional value of I-123

Nucl Med. 2009;50:1448-54.

MIBG SPECT in neuroblastoma. Clin Nucl Med.

51. Strobel K, Burger C, Schneider P, et al. MIBG-SPECT/CT

2005;30:100-1.

angiography with 3-D reconstruction of an extra-adrenal

44. Ilias I, Shulkin B, Pacak K. New functional imaging modali-

pheochromocytoma with dissection of an aortic aneurysm.

ties for chromaffin tumors, neuroblastomas and ganglioneu-

Eur J Nucl Med Mol Imaging. 2007;34:150.

romas. Trends Endocrinol Metab 2005;16:66-72.

52. Rufini V, Calcagni ML, Baum RP. Imaging of neuroendo-

45. Scanga DR, Martin WN, Delbeke D. Value of FDG PET

crine tumors. Semin Nucl Med. 2006;36:228-47.

imaging in the management of patients with thyroid, neu-

53. Ilias I, Pacak K. Anatomical and functional imaging of meta-

roendocrine, and neural crest tumors. Clin Nucl Med.

static pheochromocytoma. Ann N Y Acad Sci.

2004;

2004;29:86-90.

1018: 495-504.

46. Greenblatt DY, Shenker Y, Chen H. Te utility of metaiodo-

54. Gross MD, Gauger PG, Djekidel M, Rubello D. Te role of

benzylguanidine

(MIBG) scintigraphy in patients with

PET in the surgical approach to adrenal disease. Eur J Surg

pheochromocytoma. Ann Surg Oncol. 2008;15:900-5.

Oncol. 2009;35(11):1137-45.

47. Miskulin J, Shulkin BL, Doherty GM, et al. Is preoperative

55. Ozer S, Dobrozemsky G, Kienast O. Value of combined XCT/

iodine

123 meta-iodobenzylguanidine scintigraphy rou-

SPECT technology for avoiding false positive planar (123)

tinely necessary before initial adrenalectomy for pheochro-

I-MIBG scintigraphy. Nuklearmedizin 2004;43:164-7.

mocytoma? Surgery 2003;134:918-22; discussion 922-3.

56. Schillaci O, Danieli R, Manni C, Simonetti G. Is SPECT/CT

48. Bhatia KS, Ismail MM, Sahdev A, et al. 123I-Metaiodo

with a hybrid camera useful to improve scintigraphic imaging

benzylguanidine (MIBG) scintigraphy for the detection of

interpretation? Nucl Med Commun. 2004;25:705-10.

adrenal and extra-adrenal pheochromocytomas: CT and

57. Meyer-Rochow G-Y, Schembri GP, Benn DE, Sywak MS,

MRI correlation. Clin Endocrinol (Oxf). 2008;69:181-8.

Delbridge LW, Robinson BG, et al. Te utility of metaiodo-

49. Mihai R, Gleeson F, Roskell D, et al. Routine preoperative

benzylguanidine single photon emission computed tomog-

(123)I-MIBG scintigraphy for patients with pheochromocy-

raphy/computed tomography (MIBG SPECT/CT) for the

toma is not necessary. Langenbecks Arch Surg.

2008;

diagnosis of pheochromocytoma. Ann Surg Oncol.

393:725-7.

2010;17:392-400.

50. Wiseman GA, Pacak K, O’Dorisio MS, Neumann DR,

Waxman AD, Mankoff DA, et al. Usefulness of 123I-MIBG

SPECT-CT for Tumor Imaging

3.3 Iodine SPECT-CT

thyroglobulin biomarker, neck ultrasound, whole

body radioiodine scintigraphy and alternative imag-

Ka Kit Wong (), Ryan A. Dvorak, and Anca M. Avram

ing modalities including ¹⁸F-fluorodeoxyglucose PET

when there is non-iodine avid disease. Comprehensive

guidelines have been published regarding management

of WDTC [68, 69].

3.3.1 Introduction

Hybrid SPECT-CT has been reported to be a power-

ful diagnostic tool when combined with iodine scintigra-

phy. Radionuclide imaging with I-131 has poor spatial

Tyroid carcinoma is the most common endocrine malig-

resolution, and image quality is further degraded by sep-

nancy in adults with 37,200 (10,000M:27,200F) newly

tal penetration of energetic 364 keV gamma emissions. A

diagnosed cases in the United States in 2009 [58]. Te

paucity of anatomical information on radioiodine scans

incidence of thyroid carcinoma has been increasing over

means interpretation of SPECT images is difficult and

the last three decades partially due to earlier detection of

not used routinely. At the same time diagnostic CT has

small (<1.0 cm) tumors, although other factors may be

had a limited role in the evaluation of WDTC due to the

involved [59-60]. Tis section focuses on the utility of

need to avoid iodinated contrast and the frequency of

hybrid SPECT-CT imaging performed with iodine scin-

nodal metastases in neck lymph nodes of normal size.

tigraphy for staging and management of well-differenti-

Despite this, the synergistic combination of functional

ated thyroid cancers (WDTC), consisting of papillary and

and anatomical information provided by SPECT-CT has

follicular types, and their variants, which have character-

been found to have many advantages over traditional

istic expression of the sodium iodide symporter.

planar imaging in different clinical settings. Optimal co-

Medullary and anaplastic thyroid cancers do not concen-

registration of tomographic volumes of data obtained by

trate iodine and are not discussed further.

gamma cameras with inline CT, with the patient in the

Te prognosis for the majority of patients with

same bed position, allows precise localization of radioac-

WDTC is excellent with a cancer-specific mortality of

tivity foci. Additional benefits include CT-based attenua-

1% at 20 years in low-risk groups (TNM stage I); how-

tion correction and morphological information from a

ever, this increases to between 25% to 45% at 10 years

non-contrast CT with reduced mAs and kV. Several

in high-risk patients (TNM stage III/IV) [61-63]. Risk

excellent reviews of the clinical applications of hybrid

stratification by tumor staging provides important

SPECT-CT provide context and outline the advantages

prognostic information and guides management. Two

of SPECT-CT imaging [70-74].

examples of widely used staging systems are the AJCC

TNM (7th edition) and MACIS classifications, both of

which use patient age (<45 years) as a major determi-

nant of low risk and better outcome. Radioisotopes of

3.3.2 Utility of Iodine SPECT-CT

iodine have been used for over four decades for detec-

tion and treatment of WDTC. Usually following diag-

Te use of iodine SPECT-CT in patients with thyroid can-

nosis of WDTC total or near-total thyroidectomy is

cer was first reported by Even-Sapir and colleagues in a

performed, with or without cervical lymph node dis-

subgroup of 4 patients out of 27 in whom SPECT-CT

section, which removes the primary cancer, allows his-

imaging was performed to evaluate endocrine neoplasms

topathological staging and removes normal thyroid

[75]. Subsequent studies reported the incremental diag-

tissue that concentrates radioiodine more avidly than

nostic value of SPECT-CT in groups comprised entirely of

thyroid carcinoma. Iodine-131 (I-131) with beta emis-

patients with WDTC. In a study evaluating co-registration

sion is then administered under endogenous or exoge-

of separately acquired SPECT and CT data with the aid of

nous TSH stimulation with the goals of radioablation

external fiducial markers, combined SPECT-CT improved

of remnant thyroid tissue, and to treat microscopic and

diagnostic evaluation compared to SPECT alone in 15/17

macroscopic disease, although there is controversy

(88%) patients [76]. In 25 patients with post-therapy I-131

regarding its role in very low risk patients [64-67].

scans, it was reported that SPECT-CT improved diagnos-

Long-term surveillance uses a combination of

tic interpretation compared to planar images in 17/41

SPECT-CT for Tumor Imaging

(41%) of radioactivity foci resulting in change to manage-

lymph node metastases or contamination. Chen and

ment in 6/24 (24%) patients [77]. In a large, bicenter study

colleagues reported that of 81 inconclusive planar foci

71 patients, of whom

54 had post-therapy and

(36 neck, 45 distant), SPECT-CT could clarify 69/81

17 had diagnostic I-131 imaging, Tarp and colleagues

(85%) of these [77]. Aide and colleagues reported that

reported incremental diagnostic value of SPECT-CT over

in 55 patients there were 29% indeterminate scans on

planar imaging in

41/71

(57%) of patients

[78].

planar imaging and only 7% with SPECT-CT. Of the

Tey observed that the anatomical information from

16 patients with indeterminate planar scans, reclas-

low-resolution CT images allowed characterization of

sification with SPECT-CT as positive or negative for

equivocal neck lesions on planar images. In 36 patients

disease correlated more closely with success or failure

with SPECT-CT to evaluate foci distant from the neck,

of radioiodine treatment at follow-up [79].

integrated SPECT-CT characterized equivocal foci as

Patterns of unusual radioiodine bio-distributions that

benign in 9/36 patients and precisely localized malignant

could potentially mimic disease are well recognized and

lesions to the skeleton (12 patients) and lungs (5 patients).

have been extensively reported [91-94]. Physiological

Information derived from SPECT-CT was found to alter

radioiodine activity is seen in salivary glands, mucosa,

patient management.

breast, thymus, stomach, bowel, kidneys and bladder.

Te utility of iodine SPECT-CT described in these

Salivary and urinary contamination should be considered

early studies has been confirmed by investigators in a

when unexpected bio-distribution occurs. SPECT-CT is a

range of clinical settings [79-89]. Table 1 summarizes

powerful diagnostic tool for rapid evaluation of suspected

the published studies on iodine SPECT-CT to date.

benign physiological radioactivity and can indicate dis-

I-131 SPECT-CT has been performed with diagnostic

tribution related to salivary glands, dental fillings, esoph-

scans using activities between

37 MBq-187 MBq

ageal secretions, airway secretions, diverticuli, breast,

(1 mCi-10 mCi) and post-therapy activities 1.1 GBq-

thymus, hiatal hernia, bowel, skin contamination and

8.1+ GBq (30 mCi-220+ mCi) with both endogenous

benign uptake related to cysts. SPECT-CT is also useful

and exogenous TSH stimulation. To date there has

for evaluation of distant metastatic disease [70-72, 76-

been only a single report on I-123 SPECT-CT [80].

79]. SPECT-CT can confirm osseous and pulmonary sites

Investigators have reported usefulness of iodine

of metastases, providing additional anatomical diagnos-

SPECT-CT for surveillance diagnostic imaging or fol-

tic information to guide management decisions. In the

lowing I-131 therapies [78, 80, 82, 86] and also in the

thorax SPECT-CT can precisely localize malignancy to

post-surgical setting at the time of first radioiodine

bone (ribs or spine), lung or mediastinal lymph nodes.

ablation either on diagnostic [88, 89] or post-therapy

Tere have been several reports of the value of SPECT-CT

imaging [79, 81-85, 87].

in difficult cases including unusual sites of metastases to

Common to all studies in the literature is the ability

the liver, kidney, muscle and trachea, and also benign

of SPECT-CT to allow precise localization of radioac-

uptake in the thymus, struma ovarii, menstruating uterus

tivity foci, which can then be characterized as benign,

and simple renal cysts [96-103].

in remnant thyroid tissue or physiological distribu-

Te sensitivity of diagnostic I-131 planar imaging

tion in normal structures, or as malignant in cervi-

ranges between 45% and 75% and the specificity between

cal nodal or distant metastases. In the neck region

90% and 100% [72, 78, 86]. Iodine SPECT-CT increases

Wong and colleagues found an incremental value of

the accuracy of interpretation, although reports of sensi-

SPECT-CT over planar imaging in 53/130 (41%) of

tivity and specificity are currently lacking for I-131

neck foci, and described typical appearances of thy-

SPECT-CT. Tis is because foci of radioactivity are usu-

roglossal duct remnant and thyroid bed remnant,

ally treated with I-131 without biopsy confirmation, and

which have long been recognized on planar imaging

when successful it is not possible to be sure if the uptake

but are ofen difficult to distinguish from neck nodal

was due to thyroid carcinoma or normal residual thyroid

metastases with confidence [88, 90]. Indeed, one of

tissue. Barwick and colleagues have reported on I-123

the strengths of iodine SPECT-CT is to substantially

SPECT-CT test parameters and found sensitivity, speci-

reduce the number of equivocal foci on planar imag-

ficity and accuracy for planar (41%, 68%, 61%), SPECT

ing alone. In

15 indeterminate planar neck lesions

(45%, 89%, 78%) and SPECT-CT (50%, 100%, 87%)

[86] and in 17 unclear neck foci [87], SPECT-CT was

imaging [80]. Terefore, the value of I-123 SPECT-CT is

reported to reclassify all of them as thyroid remnant,

to increase the specificity to imaging, and this may be

SPECT-CT for Tumor Imaging

expected to apply to I-131, although the authors acknowl-

positive post-therapy SPECT-CT (17/20 patients) still had

edge that biopsy proof was not possible in the majority of

negative diagnostic scan [84]. Te authors identified a neck

patients and that SPECT-CT was an integral component

nodal volume of <0.9 ml on SPECT-CT to be highly likely

of the ‘gold standard.’ Tis limitation is inherent to all

to respond to I-131 therapy and commented that surgical

studies reported in the literature.

resection of these lymph nodes would be excessive man-

Te use of iodine SPECT-CT has been reported to

agement. Te positivity or negativity for disease as deter-

change clinical management in significant numbers of

mined by post-therapy SPECT-CT correlated more closely

patients, both when utilized routinely on all consecutive

to success or failure of radioiodine treatment than the pla-

patients and on selected patients with inconclusive pla-

nar imaging findings

[79]. Te use of post-therapy

nar images. Proposed changes in management include

SPECT-CT at the first radioablation has also extended our

the decision to give or withhold radioiodine treatment,

knowledge regarding incidence of nodal metastases for

indicating and guiding the extent of surgery, selecting

patients with T1 tumors. Using a combination of pN1 (sur-

patients for external beam radiation therapy and indicat-

gical neck dissection) and sN1 (SPECT-CT), a large, bicen-

ing the need for alternative imaging strategies such as

tric study of 151 patients found that lymph node metastases

FDG PET. Change in management has been reported in

occurred in 26% of T1 (≤2.0 cm) tumors and 22% of

25% [77], 41% [79], 47% [82], 23% [88], 36% [87], 24%

microcarcinomas (≤1.0 cm), with implications for patient

[82], 58% [89]and 11% of patients [80]. Risk stratifica-

risk stratification and management [83].

tion of patients following surgery is important to deter-

mine the prognosis and to guide decisions regarding

management and surveillance. SPECT-CT has been

3.3.3 Limitations of Iodine SPECT-CT

found useful in staging of WDTC particularly using the

AJCC TNM staging system. Precise localization with

Iodine SPECT-CT is a powerful addition to the diagnos-

characterization of radioactivity foci using SPECT-CT

tic armamentarium; however, limitations of the modality

lends itself well to N and M scoring. Schmidt and col-

have been recognized. Te spatial resolution of SPECT is

leagues first reported the utility of post-therapy

limited by a partial volume effect in small lesions, and

SPECT-CT at the first radioiodine ablation to complete

although intense activity in normal size neck lymph

N staging, changing the N score in 20/57 (35%) patients

nodes is frequently detected, the modality could not be

and the TNM stage in 14/57 (24.5%) patients, both

expected to resolve radioactivity related to micrometasta-

upstaging and downstaging [85]. Kohlfuerst and col-

ses in the central compartment or even lateral neck lymph

leagues found post-therapy SPECT-CT changed N scores

nodes. Similarly, SPECT-CT is insensitive to residual

in 12/33 (36.4%) patients and M scores in 4/19 (21.1%)

local invasive thyroid cancer afer surgery unless there is

patients [82]. Wong and colleagues found the use of

gross residual tumor volume or anatomical findings of

iodine SPECT-CT with diagnostic scans prior to the first

invasion. Staging therefore relies on the histopathological

radioiodine ablation changed TNM staging in 10/48

description of extra-thyroidal extension and the presence

(21%) patients, and changed selection of proposed I-131

of positive surgical margins for the assignment of T score

activity in 28/48 (58%), to allow confident prescription

and central lymph node dissection for N score. SPECT-CT

of lower activities 1.1 GBq (30 mCi) for radioablation in

may also have limited sensitivity for pulmonary

low-risk patients and higher doses 3.7 GBq - 7.7+ GBq

micronodular disease, although it is more sensitive than

(100 mCi-200+ mCi) for therapeutic purposes [89].

chest radiographs and more specific than diagnostic CT.

Tey reported that SPECT-CT revealed unsuspected

Patient preparation with a low iodine diet prior to imag-

metastatic disease in 4/48 (8%) patients, similar to Wang

ing and avoidance of iodine sources such as iodinated con-

and colleagues in 7/94 (7%) patients [87].

trast remains important prior to iodine SPECT-CT. Faint

Iodine SPECT-CT also provides prognostic informa-

radioiodine uptake seen on planar and pinhole imaging

tion regarding the success of radioiodine treatment as

using diagnostic I-131 activities may occasionally be unre-

determined by clinical follow-up and surveillance I-131

solved on SPECT using 3D OSEM reconstruction parame-

whole-body imaging. Schmidt and colleagues using short-

ters, and filtered back projection may be required [88].

term follow-up reported that almost all patients with nega-

Post-therapy images ofen have intense activity with septal

tive post-therapy SPECT-CT (60/61 patients) had negative

penetration causing a star artifact that may interfere with

5-month diagnostic I-131 scan, and even the majority with

evaluation of nearby tissues, making SPECT-CT

SPECT-CT for Tumor Imaging

interpretation more difficult; however, the availability of

3.3.4 Future Directions

anatomical localization can mitigate this effect. Terefore,

planar images remain valuable for providing an overview of

Tere is interest in the value of diagnostic I-131 SPECT-CT

radioiodine distribution throughout the body and identify-

being used to perform lesion-specific dosimetry. Infor

ing radioactive foci requiring anatomical correlation through

mation regarding lesion uptake and retention, and also

the use of SPECT-CT. Misregistration between functional

tumor volume derived from the CT component could be

and anatomical datasets may still occur because of patient

used to calculate individualized I-131 activities and also

movement or even related to viewing sofware (when SPECT

determine therapeutic responses. An example of this

and CT volumes of coverage differ). Terefore, plausibility

approach in a patient with a large skull metastasis causing

assessment of the fused images is required as a quality con-

infringement of the brain has been reported [107]. It is

trol step such as ensuring good co-registration of radioactiv-

worthwhile to briefly discuss I-124 scintigraphy using

ity to salivary glands in the head and neck region.

hybrid PET/CT technology. Several papers have been

Non-iodine avid disease due to lack or subsequent loss of

published reporting the use of I-124 PET/CT in patients

sodium iodide symporter expression may be a cause of

with WDTC [108-111]. I-124 has a half-life of 4.2 days

reduced sensitivity of iodine SPECT-CT. Tis has been

and a complex decay scheme including a high energy

reported to occur in 30% of WDTC at time of diagnosis [48]

(602 keV) cascade gamma with 60% abundance that

and occurs more frequently with Hurthle cell thyroid cancer,

requires corrective modeling for dosimetry purposes and

papillary subtypes with unfavourable features (e.g., tall cell,

23% positron emission allowing PET imaging. Preliminary

columnar, cribiform) and with poorly differentiated (insular)

data show that I-124 PET/CT has equivalent sensitivity to

thyroid cancer. Barwick and colleagues reported false-negative

post-therapy I-131 scans, and to date thyroid stunning

I-123 SPECT-CT in 11 patients with non-iodine avid disease

has not been reported. Terefore, 124-I PET-CT imaging,

[80]; however, their study used a Millenium VG Hawkeye, GE

considered an ‘older cousin’ to I-131/123 SPECT-CT, has

Amersham, UK, which is a first generation hybrid SPECT-CT

the advantages of hybrid imaging with superior spatial

camera with non-diagnostic quality CT images. Modern

resolution, permits true whole body tomographic

hybrid gamma cameras can detect non-iodine avid lymph

image acquisition and allows quantitative evaluation of

node metastases in enlarged lymph nodes, which would oth-

radioiodine distribution over many days for dosimetry

erwise require neck ultrasound to identify. Detection of non-

calculations.

iodine avid residual or recurrent disease on diagnostic 131-I

In summary, iodine SPECT-CT is a powerful diagnos-

significantly impacts clinical management directing treat-

tic tool that allows precise localization of radioiodine

ment to surgical excision or external beam radiation therapy

foci, superior characterization of benign and malignant

for patients who will no longer benefit from therapeutic 131-I

radioactivity distributions compared to planar imaging,

administration. It may also indicate the need for alternative

completion of TNM staging impacting on management

imaging strategies such as FDG PET.

in significant numbers of patients and providing prog-

SPECT-CT has an axial field of view limited to 40 cm

nostic information that may lead to reassessment of cur-

in the current imaging systems; therefore, evaluation of

rent WDTC management protocols.

both neck and distant radioactivity foci may require two

SPECT-CT acquisitions. Although the CT component is

Acknowledgements Te authors would like to thank Carol

usually deployed in low dose, non-diagnostic mode, there

Kruise for her assistance with assembling the figures for this

is an additional 1-4 mSv radiation exposure to the patient

chapter.

with each acquisition [71]. Analysis of benefit and poten-

tial risk should be performed on an individual basis in

the young female and particularly the pediatric popula-

tion [106].

SPECT-CT for Tumor Imaging

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Eur J Nucl Med Mol Imaging. 2008;35(5):958-965.

Case 6 Non-iodine Avid Regional Nodal Disease in the Neck

Teaching point

Non-iodine avid

disease may be

detected on the

CT component of

the SPECT-CT.

Early detection

may change

management

towards surgical

or radiation

therapy approach,

or prompt use of

FDG PET for

staging.

131-I scan in a 48-year-old woman status post-total

extra-thyroidal extension and positive surgical resec-

thyroidectomy with resection of multifocal, bilateral

tion margins; 6+/13 metastatic lymph nodes with

papillary thyroid carcinoma with tall cell features (1.2

extra-nodal extension resected in bilateral neck and

and 2.3 cm tumors) with capsular and vascular inva-

central neck compartments.

sion into the right internal jugular vein, displaying

⊡⊡

¹³¹Iodine findings

residual tumor at this site cannot be excluded.

SPECT-CT coronal (b) and transaxial (c) images reveal

the presence of an enlarged (1.4 × 1.4 cm.) non-iodine

Planar anterior view (a) demonstrates intensely focal

avid right cervical level IIB lymph node (arrowhead),

activity in the left thyroidectomy bed consistent with

which on US-guided FNA biopsy produced cells of

thyroid remnant tissue in the left thyroid bed (arrow);

papillary thyroid carcinoma

given the positive surgical margins, a component of

SPECT-CT for Tumor Imaging

3.4 Prostascint SPECT-CT

optimal target-to-background contrast. Tus, it has been

recommended that ProstaScint scans be combined either

Carina Mari Aparici, Randall Hawkins, and

with blood-pool imaging such as dual-isotope scans

Youngho Seo (),

(99mTc-labeled red blood cells injected at the time of the

72-96 postinjection ¹¹¹In-ProstaScint scan) or with a

¹¹¹In-Capromab pendetide, better known as ProstaScint, is

structural imaging technique such as computed tomogra-

a murine monoclonal antibody (7E11C5.3) radiolabeled

phy

(CT) or magnetic resonance imaging

(MRI).

with indium-111 that targets the intracellular epitope of

Although the red blood cell scan is a practical solution

prostate-specific membrane antigen (PSMA) and therefore

performed simultaneously with the

¹¹¹In-ProstaScint

can be used for staging and restaging of prostate cancer.

scan, it only outlines the vasculature, therefore providing

Since full-length monoclonal antibody imaging requires at

very limited anatomical information.

least 2-4 days for target accumulation and background

Te advent of the combined dual-modality SPECT/CT

clearance,

¹¹¹In-ProstaScint, with a physical half-life of

scanner in the early 2000s led to a gain in popularity for the

2.83 days, possesses a favorable pharmacokinetic behavior

combined functional-structural imaging procedure as the

for diagnostic imaging. ¹¹¹In-ProstaScint scans are gener-

imaging modality for ¹¹¹In-ProstaScint scans. Te delivery

ally indicated for prostate cancer patients with suspicion of

of anatomical details from CT scans outperforms the blood

recurrent or residual disease following definitive treatment,

pool images provided by 99mTc-labeled red blood cell

or for patients with elevated prostate-specific antigen (PSA)

scans. A hypothetical SPECT/MRI scanner could even

levels and suspected metastatic disease outside the prostate

provide better details of sof tissue contrast. Unlike SPECT/

gland. Te most commonly used ¹¹¹In-ProstaScint imaging

MRI as a whole-body imager, SPECT/CT does not need

protocol is a combination of a 2-dimensional two-view

RF coils that must be placed close to the imaging object

(anterior-posterior) scintigraphy followed by a single pho-

and provides a photon attenuation map that is a desirable

ton emission computed tomography (SPECT) so that both

feature to correct attenuation errors in SPECT reconstruc-

the whole-body distribution of ¹¹¹In-ProstaScint and the

tion using a direct conversion method from CT images.

tomographic cross-sectional views are reviewed for the

For these reasons, SPECT/CT scanners are becoming more

diagnosis of prostate cancer spread.

available as a dual-modality hybrid imaging system for

Immunohistochemistry

(IHC) studies using the

oncological studies such as ¹¹¹In-ProstaScint.

7E11C5.3 monoclonal antibody have shown that PSMA is

Currently, SPECT/CT scanners are offered as either

expressed by all prostate cancers and that the level of PSMA

SPECT with low-mA (limited resolution) CT or SPECT

expression in the primary tumor can be correlated with the

with high-mA diagnostic multislice CT. Both of the

tumor grade. Radiolabeled 7E11C5.3, ProstaScint, provides

SPECT/CT types have capabilities with regard to anatom-

a noninvasive mapping of PSMA expression by using an

ical localization of SPECT uptake and CT-derived attenu-

in vivo imaging method that detects radioactive photons.

ation map generation for SPECT reconstruction. However,

Combined with a therapeutic radionuclide (e.g., 90Y or

the SPECT with low-mA CT does not provide sufficiently

177Lu), the antibody (7E11C5.3) itself is also a good candi-

high spatial resolution to localize small structures, such as

date for targeted radioimmunotherapy, potentially effective

<10-mm size lymph nodes, where ¹¹¹In-ProstaScint accu-

in killing cancer cells that express high levels of PSMA.

mulates. In contrary, the high-mA diagnostic multislice

In spite of that, the value of ¹¹¹In-ProstaScint scans in

CT provides greater anatomical details of most small

prostate cancer evaluation is currently somewhat limited.

lymph nodes in which ¹¹¹In-ProstaScint uptake—seen by

One of the reasons may be that no method to effectively

SPECT—can be correlated. In the following pictorial

use the information provided by ¹¹¹In-ProstaScint scans

examples of

¹¹¹In-ProstaScint SPECT/CT, we present

in the clinical management of prostate cancer has been

SPECT, hybrid SPECT/CT and CT images from both

found. However, a more compeling issue seems to be that

types of scanners, and show distinguishable features with

¹¹¹In-ProstaScint scans are difficult to interpret, even for

annotations corresponding to the specific examples.

specialized nuclear medicine physicians. Te primary

A typical imaging protocol for ¹¹¹In-ProstaScint with

reason for this is widespread nonspecific uptake of

SPECT/CT (without 99mTc-labeled red blood cell imag-

ProstaScint in bowel and bone marrow, and the trace of

ing) would be: (1) dose: 185 MBq of ¹¹¹In-ProstaScint,

ProstaScint that is not cleared completely from the blood

intravenously,

(2) two-view anterior-posterior whole-

stream. Tis nonspecific biodistribution obscures the

body scintigraphy at 72-96 h postinjection and (3) SPECT/

specific areas of ProstaScint uptake, resulting in far from

CT (CT followed by SPECT) scan of the abdomen-pelvis.

SPECT-CT for Tumor Imaging

3.5 Hynic SPECT-CT

gamma probe detection. It can be prepared via EDDA/

tricine coligand exchange labeling [112]; 20 mg HYNIC-

Jure Fettich (), and Marina Hodolic

TOC is heated with 10 mg ethylenediamine N,N’ diacetic

acid (EDDA), 20 mg tricine, 10 mg stannous chloride

dihydrate and 2 GBq of ^99mTc-pertechnetate in 2 ml

Scintigraphy with ¹¹¹In- or ^99mTc-labeled somatostatin ana-

0.05 M phosphate buffer at pH 6 at 100°C for 10 min. Te

logs has become the main imaging technique for neuroen-

solution is purified using a Sep-Pak Light C18 cartridge

docrine tumors (NET), particularly those expressing a

eluted with 70% ethanol and diluted with 5 ml saline.

high density of somatostatin receptors. Combined with

Radiochemical purity above 95% is determined in all

SPECT, it is currently the first choice imaging technique

cases using high-performance liquid chromatography.

for these tumors. Somatostatin receptor scintigraphy not

Te purified radiopharmaceutical is sterilized by filtra-

only has a crucial role in the diagnosis and staging of NET,

tion, and 550-650 MBq of the resulting solution can be

but also in assessing suitability for treatment with cold and

used for the patient study.

radiolabeled somatostatin analogs as well as in monitoring

Because of the advantages of ^99mTc-labeled radiophar-

response to treatment and detecting recurrent disease.

maceuticals, we examined the feasibility of producing

Somatostatin analogs can be radiolabeled not only

^99mTc-octreotide in our laboratory, its quality and clinical

with ¹¹¹In (e.g., Octreoscan®), but also with ^99mTc, e.g.,

utility following modification of the technique suggested

^99mTc-EDDA/HYNIC-TOC ([^99mTc-EDDA/HYNIC-D-Phe 1,

by E. von Guggenberg et al. [112] and compared our

Tyr 3] octreotide).

results with those using

¹¹¹In-octreotide in the same

patients (Figs. 1 and 2).

3.5.1 Radiopharmaceutical Preparation

¹¹¹In-octreotide is commercially available and has a

long half-life, which allows for repeated imaging up to

[99mTc-EDDA-HYNIC-D-Phe1,Tyr3]octreotide

(^99mTc-

72 h post injection. Extensive experience with this radio-

EDDA-HYNIC-TOC) can be used for imaging and

pharmaceutical has been accumulated over the past

⊡⊡Fig. 1 Physiological ¹¹¹In octreotide

uptake in spleen, liver, kidneys and thyroid.

Pathological tracer uptake in primary and

metastatic NET (carcinoid)

SPECT-CT for Tumor Imaging

years. It has suboptimal energy for imaging, a high

¹¹¹In-DTPA-octreotide (4-24 h) [114]. Its advantages are

absorbed dose for the patients, is expensive and is not

availability, low cost, decreased absorbed dose for the

readily available. Te three-dimensional structure of

patients and high quality of scintigraphic images [115].

^99mTc-octreotide is not exactly the same as the ¹¹¹In-labeled

one. ^99mTc-octreotide profits from nearly ideal imaging

References

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able if produced locally, but allows imaging maximally

112. Von Guggenberg, Sarg E, Lindtner H, et al. Preparation via

24 h post-injection. Tis does not appear to be an impor-

coligand exchange and characterization of 99m-Tc-EDDA-

tant disadvantage since tracer uptake by NET is very

HYNIC-D-Phe1, Tyr3-octreotide (99m-Tc-EDDA/HYNIC-

rapid, seen already in the first minutes afer injection

TOC). J Label Compd Radiopharm. 2003;46:07-18.

(Fig. 3). An appropriate low amount of the octreotide can

113. Gabriel M, Decrisoforo C, Donnemiller E, et al. An intra-

be labeled with high enough ^99mTc activity to allow good

patient comparison of

^99mTc-EDDA/HYNIC-TOC with

¹¹¹In-DTPA-octreotide for diagnosis of somatostatin recep-

image resolution, also using SPECT up to 24 h post injec-

tor-expressing tumors. J Nucl Med. 2003;44:708-16.

tion. From the quality of the images obtained, 24 h post-

114. Bangard M, Behe M, Guhlke S, et al. Detection of soma-

injection it appears that labeling of the peptide is stable

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patients and comparison with

¹¹¹In-DTPA-D-Phe¹-

octreotide. Eur J Nucl Med. 2000;27:628-37.

tostatine-expressing tumor spread can be determined

115. Kolenc P, Fettich J, Slodnjak I, et al. Comparison of ^99mTc-

with higher sensitivity using ^99mTc-EDDA/HYNIC-TOC

EDDA/HYNIC-TOC and ¹¹¹In-DTPA-octreotide uptake in

than

¹¹¹In-octreotide

[113]; also

^99mTc-EDDA/HYNIC-

patients without know pathology. Eur J Nucl Med Mol

TOC allows earlier diagnosis (10 min-4 h) compared with

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SPECT-CT for Tumor Imaging

3.6 New Tracers

absorbed by the tumor lesions and all major organs.

Whenever the radiation dose in at least one tumor lesion

Paola A. Erba ()

is found to be appropriate (at least ten-fold higher com-

pared to the dose delivered to the bone marrow, the rate-

Te human recombinant mini-antibody L19 selectively

limiting organ for phase I study, and four-fold higher

binds the angiogenesis-related, alternatively spliced

compared to the dose delivered to normal muscle in the

extra-domain B (ED-B) of fibronectin, one to three a

phase I/II dose finding), the patient became eligible for a

tumor-stroma-associated antigen widely expressed in a

treatment with a single dose of 5 mg L19SIP radiolabeled

variety of normal tissues and body fluids [116-123] Tis

with up to 7,400 MBq (200 mCi) of iodine-131 (“thera-

antigen is virtually undetectable in normal adult tissues,

peutic phase”).

but is strongly expressed around neovascular structures

Te following images demonstrate some examples of

in the majority of malignancies [124, 125].

¹³¹I-L19SIP selective uptake in a series of patients with

Te ¹³¹I-labeled L19 antibody in SIP format has been

both hematological malignancies and solid cancers

shown in three different independent studies to be supe-

enrolled in the phase I and phase I/II trials and studied at

rior compared to the scFv and IgG format for radioimmu-

the Regional Center of Nuclear Medicine of the University

notherapeutic applications

[118,

126,

127]. Indeed,

of Pisa Medical School, Italy (Figs. 1-5).

¹³¹I-labeled L19SIP has displayed an impressive ability to

F16 antibody in the same SIP format has been intro-

target a variety of experimental tumor models in rodents

duced more recently to target the extra-domain A1 of tena-

and to stain a large variety of human tumor specimens,

scin-C, another very interesting component of the modified

thus making it a potentially suitable candidate for radio-

extracellular matrix, which is strongly overexpressed at

immunotherapeutic applications. Te dosimetries dis-

tumor sites, with a prominent perivascular pattern of

played by ¹³¹I-L19SIP in murine models of cancer are

expression [116, 117]. Te F16 antibody recognizes the

among the best reported so far in the field of radioimmu-

alternatively spliced domain A1 of tenascin, one of the best

notherapy [128, 129]. Furthermore, ¹³¹I-L19SIP has dis-

characterized markers of angiogenesis [133]. Tenascin-C is

played a therapeutic benefit in rodent models of human

an extracellular matrix component that is widely expressed

cancer.

in a variety of normal tissues and body fluids. Different

Tus, the mini-antibody L19 has been evaluated in a

Tenascin-C isoforms can be generated by alternative splic-

phase I and a subsequent phase I/II dose finding and effi-

ing of the Ten-C pre-mRNA, a process that is modulated

cacy study in patients with a variety of advanced cancers

by cytokines and extracellular pH. Te domains A1 to D

where ¹³¹I-L19SIP has shown a selective uptake to tumor

may be included or omitted in the Ten-C molecule. Te

tissues and an excellent tolerability at radioactive doses as

Ten-C isoform containing the domain A1 is undetectable

high as 7,400 MBq (200 mCi), and therapeutic benefit for

immunohistochemically in normal adult tissues, with the

some patients enrolled in the study [130-133]. At this

exception of tissues undergoing physiological remodeling

stage, it is in a two-phase I/II trial in combination with

(e.g., endometrium and ovary) and during wound healing.

external beam radiotherapy and concurrent chemotherapy

By contrast, its expression in tumors and fetal tissues is

in patients with inoperable, locally advanced (stage III)

high; A1(+)-tenascin-C is strongly expressed in multiple

NSCLC and with whole brain radiation therapy in patients

cancers at levels as high as L19, but there are certain human

with multiple brain metastases from solid tumors.

tumors where its expression is predominant (i.e., breast

All the studies are designed to obtain a first dose of

cancer and some lung cancers) [126, 132, 134]. Te possi-

¹³¹I-L19SIP radiolabeled with up to 185 MBq (5 mCi) for

bility of selectively targeting tumoral vasculature using the

dosimetric purposes (“dosimetric phase”). Following i.v.

human recombinant antibody fragment scFv (F16), spe-

administration, whole body, planar images and SPECT-CT

cific to the domain A1 of Tenascin-C, has been reported in

are recorded at several time points (typically including

animal models of cancer, and a murine monoclonal anti-

30 min, 2-6 h, 24 h, 48 h, 72 h and >90 h). Additionally,

body to the same antigen has been shown to be able to

blood samples are collected for PK determination. Te

selectively accumulate at tumor sites in patients with

resulting images are used to calculate the radiation doses

cancer [135]. Tese investigations have paved the way for

SPECT-CT for Tumor Imaging

⊡⊡Fig. 1 Selective uptake of ¹³¹I-L19SIP in a patient with HD.

of ¹³¹I-L19-SIP imaging for diagnostic (185 MBq) and thera-

[¹⁸F]FDG PET/CT scans on left column show intense glucose

peutic (5,550 MBq) purposes. SPECT/CT transaxial images of

metabolism in multiple enlarged supraclavicular, axillary and

the thorax are shown, demonstrating selective uptake of

mediastinal lymph-nodes (a) as well as in intrapulmonary

¹³¹I-L19-SIP into the ¹⁸F-FDG avid lymphomatous lesions (right

lesions (b, c). The same patient received intravenous injection

column)

the construction of several therapeutic derivatives of

Similarly to ¹³¹I-L19, iodine-131 radiolabeled F16 has

scFv(F16), which have been extensively tested in animal

been recently evaluated in a phase I/II dose finding and

models of cancer. Importantly, F16 fused to human inter-

efficacy study in patients with a variety of advanced can-

leukin-2 has entered multicenter clinical trials in Europe in

cers (same protocol design of L19).

combination with doxorubicin or taxol for the therapy of

Figure 6 reports an illustrative example of ¹³¹I-F16

breast, lung and ovarian cancer.

accumulation in a patient with MALT-B nHL.

SPECT-CT for Tumor Imaging

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104

Bone Imaging with SPECT-CT

In 2004, skeletal scintigraphy was the most frequently

Te SPECT examination of SPECT/CT is not per-

performed nuclear medical in vivo examination in Europe

formed differently from that of a stand-alone system. For

and can thus also be considered the most frequently per-

skeletal CT, the intravenous injection of contrast medium

formed procedure worldwide. Te quantification of bone

is usually not necessary. With the hybrid systems featur-

metabolism was also among the first applications of trac-

ing a multi-slice spiral CT, a CT examination of the skel-

ers in biology. Te Letter to Nature published in 1935 by

eton in full diagnostic quality is, at least in principle,

George de Hevesy, which earned him the Nobel Prize in

possible. However, since the indication for this CT exam-

1943, described the use of radioactive strontium to inves-

ination is to elucidate unclear scintigraphic findings, low-

tigate bone metabolism in rats.

dose CT examinations with a field of view restricted to

Te ^99mTc-labeled polyphosphonates that are used

the scintigraphic abnormalities are advocated by most

today were introduced into the field approximately

authorities in the field. Te mAs products reported in the

30 years ago; since then, the procedure has, in principle,

literature range between 15 and 60 mAs, also depending

not changed much. Scintigraphic images acquired early

on the indication. With this so-called SPECT-guided CT,

afer intravenous injection of these tracers provide infor-

the radiation doses delivered to the patient come down to

mation on the perfusion and floridity of skeletal lesions.

average values between 2 and 3 mSv in most cases and

Scintigraphy performed several hours afer tracer injec-

thus correspond to doses caused by planar radiographs.

tion allows insight into bone metabolism or, more specifi-

Te advantage of SPECT/CT compared to side-by-

cally, osteoblastic activity, since the polyphosphonates are

side evaluation of data sets acquired independently from

adsorbed on freshly built bone tissue. Initially, bone scin-

each other is the possibility for pixel-wise integration of

tigrams were planar images, acquired either as spot views

the information from both modalities. As patient move-

or as whole-body images. Because of the sensitivity of this

ments between the two independently performed exami-

examination in detecting osseous lesions, skeletal scintig-

nations are minor, the average anatomical accuracy of

raphy has been widely used as a screening tool, e.g., for

alignment between both sets of images is usually better

staging malignant disease. In the late 1980s, single-photon

than 5 mm. Tis variable can also be improved by addi-

emission computed tomography (SPECT) became widely

tionally applying image fusion sofware to the preregis-

available. SPECT allows three-dimensional visualization

tered images.

of the distribution of radioactivity within the human

Based on the CT information on tissue absorption, the

body. Tis technology has considerably improved the

SPECT images of SPECT/CT can be attenuation-cor-

diagnostic accuracy of bone scintigraphy by allowing a

rected and a more realistic and homogeneous image of

better localization of areas exhibiting pathological tracer

tracer distribution obtained. An important prerequisite

uptake. Nevertheless, because of the limitations in spatial

to using this option, however, is that the alignment

resolution of skeletal SPECT, still being in the range of

between CT and SPECT images is well below SPECT

8-10 mm in the reconstructed images, the specificity of

pixel width; otherwise, gross attenuation artifacts may

skeletal scintigraphy is limited. Tis is true particularly

lead to false interpretation of the images.

when compared to radiological techniques such as X-ray

For image interpretation, both image data sets are dis-

computerized tomography (CT) or magnetic resonance

played on one computer workstation. As is also the case

imaging (MRI).

when interpreting stand-alone SPECT images, some

Approximately 8 years ago, the first hybrid camera

attention should be given to standardizing SPECT win-

106

integrating a SPECT camera with a CT scanner into one

dowing. We usually use tracer uptake in the iliac crest as

gantry became commercially available. Te CT compo-

the reference value for evaluating tracer uptake in patho-

nent of this system was a low-dose non-spiral CT. Te CT

logical lesions. CT images should be viewed in the bone

images provided by this camera were without diagnostic

window centered on 500 Hounsfield units (HU) with a

quality, but allowed a fairly exact localization of SPECT

window width of 1,500 HU. We also routinely evaluate

foci of abnormal tracer uptake and the attenuation cor-

the CT scans in the lung and sof-tissue windows,

rection of the SPECT images. Since then, technology has

although the image quality of the low-dose CT scans may

advanced considerably. Currently, SPECT/CT cameras

not be fully sufficient for these purposes.

with a wide array of multislice spiral CT scanners are

One of the major indications for performing skeletal

available, and evidence of their diagnostic performance is

scintigraphy is staging of malignant disease, as osseous

accumulating quickly.

metastases frequently lead to focally increased uptake of

Bone Imaging with SPECT-CT

the ^99mTc-polyphosphonates. Skeletal scintigraphy has a

skeletal scintigraphy can be quite low and is much

high sensitivity to detect osseous metastases of breast and

improved by SPECT/CT coregistration. It has, in fact,

prostate cancer as well as those of primary bone tumors

been shown that SPECT/CT increases diagnostic accu-

such as Ewing’s or osteogenic sarcoma. Its sensitivity is

racy by roughly 30% in orthopedic patients when com-

fairly high in several other neoplasms, such as bronchial

pared to stand-alone radionuclide imaging. Te

or thyroid carcinoma. Several benign lesions of the skele-

molecular/functional information obtained by SPECT

ton may also have increased uptake of the ^99mTc-polyphos-

complements structural information provided by CT. It

phonates, which deteriorates the specificity of scintigraphy

may, in particular, help determine the floridity of lesions,

for staging malignancies. Tis is in particular the case for

such as osteoarthritis or vertebral fractures, as this infor-

degenerative conditions, such as those of the spine involv-

mation can usually not be inferred from the morphologi-

ing osteochondrosis and facet arthritis. Te incidence of

cal appearance of these lesions alone.

spinal degeneration increases sharply with age: virtually

Loosening or infection of prostheses and other metal-

absent in the young, it may affect nearly 50% of individu-

lic implants are difficult to diagnose by CT or MRI.

als older than 60 years. Another frequent condition occur-

Whereas on CT images streak artifacts may compromise

ring in the elderly is vertebral fractures due to osteoporosis,

image quality, MRI is practically of no value for this indi-

which are found in nearly 25% of postmenopausal women.

cation. Bone scintigraphy, therefore, is of particular inter-

Further fairly frequent differential diagnoses of skeletal

est in this clinical setting. Despite the occurrence of streak

hot spots are osteomyelitis and benign bone tumors, such

artifacts on the CT images, areas of abnormal tracer

as enchondroma. Most of these conditions can be diag-

uptake may still be localized on SPECT/CT fusion images,

nosed on CT scans because of their specific morphologi-

improving the diagnostic accuracy of scintigraphy.

cal appearance. Terefore, SPECT/CT is very helpful in

staging tumors as it reduces the frequency of indetermi-

nate readings from roughly 30% to less than 5%. As both

Suggested Reading

examinations are performed directly afer another in a

one-stop shop, patients are spared further examinations,

Bockisch A, Freudenberg LS, Schmidt D, et al. Hybrid imaging

and the time to definite diagnosis is considerably short-

by SPECT/CT and PET/CT: proven outcomes in cancer

ened compared to the traditional approach.

imaging. Semin Nucl Med. 2009;39:276-89.

Purely lytic metastases caused by, e.g., renal carcinoma

Even-Sapir E, Flusser G, Lerman H, et al. SPECT/multislice low-

dose CT: a clinically relevant constituent in the imaging

or plasmocytoma, are frequently not accompanied by

algorithm of non oncologic patients referred for bone scin-

increases in osteoblastic activity and can be easily missed

tigraphy. J Nucl Med. 2007;48:319-24.

on bone scintigrams. However, they may lead to so-called

Gnanasegaran G, Barwick T, Adamson K, et al. Multislice

cold lesions that have reduced tracer uptake compared to

SPECT/CT in benign and malignant bone disease: when the

normal bone. Te differential diagnosis of cold lesions

ordinary turns into the extraordinary. Semin Nucl Med.

2009;39:431-42.

also includes benign lesions such as hemangioma, again

Linke R, Kuwert T, Uder M, et al. Skeletal SPECT/CT of the

presenting with typical phenomenology on CT. Terefore,

peripheral extremities. AJR Am J Roentgenol. 2010;194(4):

also in cold lesions, SPECT/CT may increase the specific-

W329-35.

ity of skeletal scintigraphy.

Mohan HK, Gnanasegaran G, Vijayanathan S, et al. SPECT/CT

Skeletal pain is the leading symptom in orthopedic

in imaging foot and ankle pathology - the demise of other

coregistration techniques. Semin Nucl Med.

2010;40:

107

patients. It has a wide range of differential diagnoses,

41-51.

including osteoarthritis, trauma, inflammation and bone

Römer W, Nömayr A, Uder M, et al. SPECT-guided CT for eval-

tumors. Most of these diseases exhibit increased tracer

uating unclear foci of increased bone metabolism in cancer

uptake. Here, as in staging, the specificity of stand-alone

patients. J Nucl Med. 2006;47:1382-8.

Brain Imaging with SPECT-CT

Overexpression of somatostatin receptors has been dem-

to be administered soon afer surgery, especially in

onstrated in various brain tumours such as meningiomas

atypical and malignant histotypes.

or glia-derived tumours. Tis evidence, following the

For many decades, glia-derived tumour cells have been

clinical experience on neuroendocrine tumours, suggests

studied “in vitro” to assess the presence of specific receptor

that somatostatin analogues may also be of value for the

panels on their surface. Tese investigations are aimed to

imaging and treatment of the above-mentioned brain

develop needed alternative modalities of treatment, accord-

neoplasms.

ing to the “targeted therapy” concept. High-grade gliomas,

Close to 100% of meningiomas express somatostatin

despite the aggressive traditional modalities of treatment,

receptors, especially subtype 2 (sst2), and usually do so at

present an extremely poor prognosis, with a median sur-

high density. As a result, the approach of specifically tar-

vival time of 6-12 and 15-27 months for glioblastoma and

geting receptors on meningioma cells by radiolabelled

anaplastic astrocytoma, respectively. Low-grade gliomas

somatostatin analogues has been developed over the past

show an initial better prognosis (median survival time of

2 decades. Tracer doses of somatostatin analogues, radio-

5-7 years), but, because of their further genetic alterations,

labelled with ¹¹¹In or ⁶⁸Ga via linking moieties, have been

constantly change into high-grade forms. A few trials have

administered for diagnostic imaging, post-surgical

focused on the presence of somatostatin receptors in glia-

follow-up and making the differential diagnosis against

derived tumours. Although these studies have reported

neurofibromas and neurinomas. Moreover, radiodetec-

contradictory results, there is evidence that somatostatin

tion of somatostatin receptors with a hand-held gamma

receptors (especially subtype 2) are present in a large per-

probe has been employed to improve the surgical radical-

centage of low-grade gliomas, and may be expressed by

ization of somatostatin receptor-expressing meningiomas.

anaplastic astrocytomas, but are rarely detectable in undif-

Following these diagnostic experiences, the further obvi-

ferentiated glioblastomas. At present, the use of radiola-

ous step was to employ radiolabelled somatostatin ana-

belled somatostatin analogues in glioma patients (both for

logues for therapeutic purposes. Meningiomas are

diagnostic and therapeutic purposes) represents only an

generally benign and, in most cases, surgery is curative.

experimental approach, and no large series are reported in

However, for high-grade histotypes or partially resected

the literature. A pilot study performed in a group of glioma

tumours, recurrence is fairly common. External beam

patients has proposed the use of radiolabelled somatostatin

radiation therapy is usually given in such cases, but is not

analogues with a locoregional approach [2].

always effective. Bartolomei et al. [1] have assessed pep-

Despite the expanding role of novel PET radiotracers

tide receptor radionuclide therapy

(PRRT) using

(68Ga-DOTATOC/DOTANOC), somatostatin receptor

⁹⁰Y-DOTATOC in a group of patients with meningioma

scintigraphy with ¹¹¹In-DTPA-Octreotide (Octreoscan®)

recurring afer standard treatments in all of whom soma-

remains the standard method to study neuroendocrine

tostatin receptors were strongly expressed on cell surfaces.

tumours and others tumours expressing somatostatin

In particular, 29 patients with scintigraphically proven

receptors. Planar and single-photon-emission computed

somatostatin subtype 2 receptor-positive meningiomas

tomography (SPECT) imaging is commonly performed

were enrolled: 14 had benign (grade I), 9 had atypical

in most nuclear medicine centres, but this technique ofen

(grade II) and 6 had malignant (grade III) disease. Patients

does not provide clear anatomical localisation. Te avail-

received intravenous injections of ⁹⁰Y-DOTATOC, for

ability of a modern dual-head gamma cameras equipped

two to six cycles, for a cumulative dose in the range of

with an integrated X-ray transmission system (SPECT-CT)

122

5-15 GBq. Te treatment was well tolerated in all patients,

offers the opportunity to fuse the functional and morpho-

and magnetic resonance controls, performed 3 months

logical imaging, resulting in greatly increased diagnostic

afer treatment completion, showed disease stabilisation

accuracy.

in 66% of cases. Te authors concluded that PRRT with

Herein the authors report on some SPECT-CT studies

⁹⁰Y-DOTATOC could interfere with the growth of men-

of brain lesions obtained afer diagnostic and therapeutic

ingiomas, supporting the adjuvant role of this treatment,

injection of radiolabelled somatostatin analogues.

Cardiac Imaging with SPECT-CT

Single-photon emission tomography (SPECT) combined

with computed tomography (CT) aims to provide an accu-

rate spatial alignment between the two separate data sets

into one fused image. Te resultant information goes beyond

that achievable with either stand-alone or side-by-side inter-

pretation of the data sets, and beyond the information

derived from attenuation correction (AC), with an equal

contribution of both data sets to the image information.

Cardiac hybrid SPECT/CT imaging depicts anatomic

abnormalities along with their physiologic consequences

in a single setting, resulting in a decreased number of

equivocal results in a patient-friendly image acquisition

(only one visit to the imaging department). In addition,

hybrid SPECT/CT requires fewer personnel compared

with two stand-alone scanners, which may result in

reduced health care costs and saves time. However,

SPECT/CT has also generated controversy with regard to

which patients should undergo such integrated examina-

tion for clinical effectiveness and minimization of costs

and radiation dose, and whether sofware-based fusion of

images obtained separately is a useful alternative.

SPECT myocardial perfusion imaging (MPI) and car-

diac-computed tomographic angiography (CCTA) per-

formed in one session have been proposed for dual-system

scanners equipped with multidetector computed CT

(MDCT). However, cardiac hybrid imaging is not used

⊡⊡Fig. 6.1

Anterior view of stress SPECT/CT. Although mas-

routinely because of the difficulty in predicting a priori

sive coronary tortuosity can be observed, the culprit lesion is

localized in the left anterior descending artery (arrow), which

which patients would benefit from the dual scanning.

induces apical ischemia

(purple area).

(Courtesy of P.A.

Terefore, a sequential diagnostic approach is ofen

Kaufmann, Cardiac Imaging, University Hospital Zurich,

applied in clinical practice, with additional scans (CCTA

Switzerland)

or MPI) performed only if the results of the initial modal-

ity are equivocal. However, when CCTA is performed

first, about 50% of the patients will need MPI.

Hybrid MPI and CCTA with reliable image co-regis-

Teaching point

tration and fusion of three-dimensional information of

myocardial territories onto their subtending coronary

Reliable image co-registration and fusion of

arteries can accurately allocate the culprit lesion in multi-

3D information of myocardial territories onto

vessel coronary artery disease (CAD) (Fig. 6.1), which is

134

their subtending coronary arteries can

particularly important because the so-called standard

accurately indicate the culprit lesion.

distribution of myocardial perfusion territories does not

correspond with the real world of coronary anatomy in

more than half of the cases (Fig. 6.2). Combining ana-

tomical with perfusion data also helps to identify and

assessment of regional myocardial perfusion and viability

correctly register possible subtle irregularities in myocar-

together with the coronary artery tree eliminates uncer-

dial perfusion. Te reduced sensitivity of CCTA in distal

tainties in the relationship of perfusion defects, scar

coronary segments and side branches can be compen-

regions and diseased coronary arteries in watershed

sated by the MPI information. On the other hand, CCTA

regions, which may be particularly helpful in patients

improves the detection of multivessel CAD, which is

with multiple perfusion abnormalities and multivessel

one of the main pitfalls of SPECT MPI. Finally, the

CAD, including previous revascularization procedures.

Cardiac Imaging with SPECT-CT

resolution of SPECT. Te alignment of emission and

Teaching point

transmission data is usually performed manually, a pro-

cess that contributes to certain variability. However, auto-

mated methods for quality control are under investigation.

The specificity and positive predictive value of

It is relevant that even low-quality CT scans for AC can

stand-alone CCTA are particularly suboptimal

provide clinically useful extra-cardiac information that

in the presence of severe coronary

should be taken into account.

calcifications. The so-called standard

distribution of myocardial perfusion territories

does not correspond with the real world of

coronary anatomy in more than half of the

6.2 Integration of Coronary Artery Calcium

cases.

(CAC) with MPI

Imaging of CAC can be a surrogate marker of atheroscle-

rosis in hybrid systems with low- and medium-quality

6.1 CT for MPI Attenuation Correction

CT devices, as opposed to high-end MDCT suitable for

the anatomic assessment of the coronary tree.

Heterogeneous photon attenuation in the thorax is one of

Detection of CAC has been shown to provide incre-

the most important problems of MPI, reducing the diag-

mental value to MPI. Specifically, when MPI is normal,

nostic accuracy, interpretive confidence, quantification

the addition of a CAC score can improve the detection of

and laboratory efficiency. On one hand, attenuation arti-

CAD, particularly severe multivessel CAD. For patients

facts may reduce MPI specificity, since non-uniform,

with normal stress MPI, higher major adverse cardiac

regional perfusion distribution can be misinterpreted as a

event rates are associated with higher CAC scores, espe-

perfusion defect. On the other hand, attenuation artifacts

cially in patients with known CAD or with greater

may also reduce MPI sensitivity when images are improp-

comorbidity.

erly scaled to regions suppressed by attenuation, potentially

masking true perfusion defects. To overcome this problem,

MPI images are corrected by determination of photon

6.3 Integration of CCTA with MPI

attenuation from intervening tissue in the volume of inter-

est. Unfortunately, cardiac imaging poses a particular dif-

CCTA, despite having an excellent negative predictive

ficulty for AC because of respiratory and cardiac motion.

value (NPV) to exclude CAD, is not reliable for the exclu-

AC using the integration of CT components has repre-

sion of myocardial ischemia. CCTA tends to overestimate

sented a major step forward for SPECT MPI, improving

coronary stenoses, and the combination with SPECT MPI

the diagnostic accuracy and interpretive confidence

allows identification of many false-positive CCTA find-

(Figs. 6.3 and 6.4). It may also improve the laboratory effi-

ings. Te specificity and positive predictive value (PPV)

ciency by enabling the omission of the rest study when

of stand-alone CCTA are particularly suboptimal in the

the stress study is normal, which may also be useful in the

presence of motion artifacts or severe coronary calcifica-

emergency department (i.e., single acquisition of images

tions (Fig. 6.2). Non-evaluable, severely calcified vessels

in the acute phase of chest pain).

especially benefit from further testing because of their

136

Low-dose CT acquisitions are feasible for AC.

relatively high likelihood of obstructive disease, whereas

However, a potential misalignment between emission

non-evaluable vessels with motion artifacts [particularly

and transmission data involves the risk of incomplete

in the right coronary artery (RCA) territory] do not usu-

correction, and thus artificial perfusion defects, and

ally have hemodynamic significance. Image fusion is of

requires careful quality control to avoid reconstruction

particular value in lesions of the distal segments, diagonal

artifacts (Fig. 6.5). SPECT/CT studies have shown that

braches, RCA and lef circumflex artery.

the frequency of misalignment is quite high and the con-

On the other hand, a normal stress SPECT MPI is a

sequences clinically significant if not corrected (Fig. 6.5).

poor discriminator of patients with subclinical or “not

Te effects of misalignment are less severe for SPECT/CT

flow-limiting” CAD. Integration of both MPI and CCTA

than for PET/CT, mainly because of the reduced spatial

thus have a complementary role in the evaluation of

Cardiac Imaging with SPECT-CT

rather than ²⁰¹Tl. Furthermore, the SPECT radiation

a CAC scan. For CCTA, the dose tends to be higher with

dose can be markedly reduced with the combination of

lower slice thickness since the radiation dosage must be

new iterative reconstruction methods, and dedicated

increased to obtain the same signal-to-noise ratio.

detectors and collimators optimized specifically for

Implementation of modern acquisition protocols, such as

MPI. In addition, the omission of the rest study when

prospective

(step-and-shoot) ECG triggering, ECG-

the stress study is normal considerably reduces the

controlled current modulation (reduction of the tube

radiation dose.

current by 80% during systole) and body mass adapted

Te effective patient radiation dose from cardiac CT

tube voltage (reduction of the tube voltage to 100 kV in

also varies widely depending on the protocol, instrumen-

patients <90 kg of weight), allows reduction of the radia-

tation and patient size. Te radiation dose is minimal for

tion dose from CCTA by 60-80%.

139

⊡⊡Fig. 6.4 Stress/rest slices and polar maps of ^99mTc-tetro-

ing the CT attenuation map into a statistically based, iterative

fosmin SPECT of a man with suspected coronary artery dis-

reconstruction algorithm. The mild fixed defect in the inferior

ease. FBP filtered back projection reconstruction without

wall present in the FBP images disappears in the IRACSC

attenuation correction (AC). IRACSC iterative reconstruction

images, which confirms its artificial origin due to diaphrag-

with AC and scatter correction. AC was performed incorporat-

matic attenuation

Parathyroid Imaging with SPECT-CT

Hyperparathyroidism (HPT) is a common endocrine dis-

³90% for detection of solitary adenomas by ^99mTc-sesta-

order affecting approximately 1 in 500 women and 1 in

mibi SPECT [12-15]. However, also more critical reports

2,000 men. Te clinical or chemical diagnosis is com-

have been published suggesting that the sensitivity of

monly seen in the 5th through 7th decades of life [1].

parathyroid scintigraphy without SPECT could be signifi-

Primary hyperparathyroidism (pHPT) is caused by a soli-

cantly lower than expected from the literature

[16].

tary parathyroid adenoma in approximately 85% of cases,

Gotthardt et al. conclude that apart from different trial

whereas the remaining cases are ofen secondary HPT

designs (e.g., retrospective vs. prospective, varying defi-

due to glandular hyperplasia, multiple adenomas and,

nitions of a true positive result) and a possible bias by

very rarely, also parathyroid carcinomas [2].

reevaluation of parathyroid scans by specialized physi-

HPT is characterized by an increased secretion of

cians, the experience and routine of the reporting physi-

parathyroid hormone (PTH) leading to hypercalcemia by

cian play an important role.

promoting the renal tubular absorption of calcium,

decreasing tubular reabsorption of phosphate, and stimu-

Recently, integrated SPECT/CT scanners have been

lating osteoclasts and vitamin D production. Te stan-

introduced into clinical routine. With SPECT/CT, lesions

dard curative treatment approach is surgical resection,

visualized by functional imaging can be correlated with

but also percutaneous ethanol injection has been reported.

anatomic structures (Fig. 7.2). Te addition of anatomic

Terapeutic procedures are ofen demanding for highly

information increases sensitivity as well as specificity of

accurate pre-therapeutic imaging, allowing detection and

scintigraphic findings in a widespread number of indica-

localization of abnormal parathyroid gland tissue accu-

tions [17]. SPECT/CT has also been studied for presurgical

rately. Especially the recently developed minimally inva-

imaging and precise localization of parathyroid adenomas

sive surgical techniques require reliable preoperative

(Figs. 7.3 and 7.4). Presurgical localization is critical espe-

disease localization [3, 4].

cially in patients intending to have minimally invasive

Preoperative imaging modalities comprise sonogra-

parathyroidectomy. Lavely et al. compared the diagnostic

phy, scintigraphy including tomographic imaging

performance of planar imaging, SPECT, SPECT/CT, and

(SPECT), CT, MRI and PET. In daily clinical practice,

single- and dual-phase 99mTc-MIBI parathyroid scintigra-

sonography and scintigraphy have emerged as the pri-

phy in 110 patients [18]. Reported sensitivities ranged from

mary means for HPT detection and localization of para-

34% for single-phase planar imaging to 73% for dual-phase

thyroid adenomas [1]. Regarding preoperative sonography

studies, including an early SPECT/CT scan. Lavely et al.

for the detection of solitary parathyroid adenomas, sensi-

concluded that early SPECT/CT in combination with any

tivity values ranging between 72% and 89% have been

delayed imaging method was significantly more accurate

reported [1, 5-8]. In a meta-analysis by Ruda et al. encom-

for parathyroid adenoma localization than any single- or

passing 54 studies performed between 1995 and 2003, the

dual-phase planar or SPECT study. CT coregistration was

sensitivity of ultrasound for detection of primary hyper-

revealed to be a valuable tool for the precise delineation of

parathyroidism prior to surgery was calculated

[2].

parathyroid adenomas. Furthermore, it was stated that

Respective sensitivity values were 79% [95% confidence

localization with dual-phase acquisition protocols was

interval (CI), 77-80%], 35% (95% CI, 30-40%) and 16%

more accurate than with single-phase ^99mTc-sestamibi scin-

(95% CI, 4-28%) for detecting solitary adenoma, hyper-

tigraphy for planar imaging, SPECT and SPECT/CT.

plasia or double adenoma, respectively. Ruda et al. also

Superior localization of parathyroid adenomas was also

144

investigated the value of 99mTc-sestamibi planar scintig-

reported by Harris et al. [19]. In a series of 23 patients,

raphy in their meta-analysis. Published sensitivities for

SPECT/CT performed well for the detection and localiza-

detection of solitary adenomas, hyperplasia and double

tion of solitary adenomas (89%), but performance for the

adenomas were 88% (95% CI, 87-89%), 44% (95% CI,

detection of multifocal disease was limited. Less exciting

41-48%) and 30% (95% CI, 2-62%), respectively [2].

conclusions were drawn in the studies by Ruf et al. [20] and

Introduction of subtraction techniques (administra-

Gayed et al. [21]. Ruf et al. performed low-dose CT for

tion of a second radiotracer taken up only by the thyroid

attenuation correction in 26 patients and reported that the

gland) and SPECT of the neck using a pinhole collimator

sensitivity of attenuation-corrected ^99mTc-MIBI SPECT/CT

resulted in higher sensitivities by improved separation of

was only slightly higher than that of non-attenuation-

parathyroid activity and activity of the overlying thyroid

corrected SPECT [20]. In the publication by Gayed et al.,

[9-11] (Fig. 7.1). Some studies reported sensitivities of

SPECT/CT was assumed to be only of limited additional

Parathyroid Imaging with SPECT-CT

value (8% of patients) [21]. Interestingly, in a retrospective

9. Lorberboym M, Minski I, Macadziob S, Nikolov G, Schachter

P. Incremental diagnostic value of preoperative 99mTc-MIBI

study, Krausz et al. reported a change in therapeutic man-

SPECT in patients with a parathyroid adenoma. J Nucl Med.

agement in

39% of patients

(14/36), mainly due to

2003;44(6):904-8.

localization of ectopic parathyroid adenomas or accurate

10. Slater A, Gleeson FV. Increased sensitivity and confidence of

localization in patients with distorted neck anatomy [22].

SPECT over planar imaging in dual-phase sestamibi for para-

Tese inconsistent results do not allow claiming a definite

thyroid adenoma detection. Clin Nucl Med. 2005;30(1):1-3.

11. Spanu A, Falchi A, Manca A, et al. Te usefulness of neck

role of SPECT/CT in the imaging of parathyroid adenomas

pinhole SPECT as a complementary tool to planar scintigra-

so far, and as previously suggested by Gotthardt and

phy in primary and secondary hyperparathyroidism. J Nucl

co-workers, it is still necessary to conduct well-designed

Med. 2004;45(1):40-8.

prospective multi-center trials to reassess the true clinical

12. Blanco I, Carril JM, Banzo I, et al. Double-phase Tc-99m sesta-

potential of ^99mTc-MIBI SPECT and ^99mTc-MIBI SPECT/

mibi scintigraphy in the preoperative location of lesions causing

hyperparathyroidism. Clin Nucl Med. 1998;23(5):291-7.

CT, especially in endemic goiter areas and in comparison

13. Chen CC, Holder LE, Scovill WA, Tehan AM, Gann DS.

with other imaging modalities, comprising US, MRI

Comparison of parathyroid imaging with technetium-99m-

and potentially PET using radiolabeled amino acids

pertechnetate/sestamibi subtraction, double-phase techne-

(¹¹C-methionine, ¹⁸F- fluoro-ethyl-thyrosine).

tium-99m-sestamibi and technetium-99m-sestamibi SPECT. J

Nucl Med. 1997;38(6):834-9.

14. Pinero A, Rodriguez JM, Ortiz S, et al. Relation of biochemi-

cal, cytologic, and morphologic parameters to the result of

gammagraphy with technetium 99m sestamibi in primary

References

hyperparathyroidism. Otolaryngol Head Neck Surg.

1. Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging:

2000;122(6):851-5.

technique and role in the preoperative evaluation of primary

15. Song AU, Phillips TE, Edmond CV, Moore DW, Clark SK.

hyperparathyroidism. AJR. 2007;188(6):1706-15.

Success of preoperative imaging and unilateral neck explo-

2. Ruda JM, Hollenbeak CS, Stack Jr BC. A systematic review

ration for primary hyperparathyroidism. Otolaryngol Head

of the diagnosis and treatment of primary hyperparathy-

Neck Surg. 1999;121(4):393-7.

roidism from 1995 to 2003. Otolaryngol Head Neck Surg.

16. Gotthardt M, Lohmann B, Behr TM, et al. Clinical value of

2005;132(3):359-72.

parathyroid scintigraphy with technetium-99m methoxy-

3. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral

isobutylisonitrile: discrepancies in clinical data and a sys-

versus bilateral neck exploration for primary hyperparathy-

tematic metaanalysis of the literature. World J Surg.

roidism: a prospective randomized controlled trial. Ann

2004;28(1):100-7.

Surg. 2002;236(5):543-51.

17. Buck AK, Nekolla S, Ziegler S, et al. Spect/Ct. J Nucl Med.

4. Lorenz K, Miccoli P, Monchik JM, Duren M, Dralle H.

2008;49(8):1305-19.

Minimally invasive video-assisted parathyroidectomy: mul-

18. Lavely WC, Goetze S, Friedman KP, et al. Comparison of

tiinstitutional study. World J Surg. 2001;25(6):704-7.

SPECT/CT, SPECT, and planar imaging with single- and

5. Haber RS, Kim CK, Inabnet WB. Ultrasonography for pre-

dual-phase

(99m)Tc-sestamibi parathyroid scintigraphy.

operative localization of enlarged parathyroid glands in pri-

J Nucl Med. 2007;48(7):1084-9.

mary hyperparathyroidism: comparison with

(99 m)

19. Harris L, Yoo J, Driedger A, et al. Accuracy of technetium-

technetium sestamibi scintigraphy. Clin Endocrinol (Oxf).

99m SPECT-CT hybrid images in predicting the precise

2002;57(2):241-9.

intraoperative anatomical location of parathyroid adenomas.

6. Rickes S, Sitzy J, Neye H, Ocran KW, Wermke W. High-

Head Neck. 2008;30(4):509-17.

resolution ultrasound in combination with colour-Doppler

20. Ruf J, Seehofer D, Denecke T, et al. Impact of image fusion

sonography for preoperative localization of parathyroid

and attenuation correction by SPECT-CT on the scinti-

adenomas in patients with primary hyperparathyroidism.

graphic detection of parathyroid adenomas. Nuklearmedizin.

145

Ultraschall Med. 2003;24(2):85-9.

2007;46(1):15-21.

7. Solorzano CC, Carneiro-Pla DM, Irvin 3rd GL. Surgeon-

21. Gayed IW, Kim EE, Broussard WF, et al. Te value of 99mTc-

performed ultrasonography as the initial and only localizing

sestamibi SPECT/CT over conventional SPECT in the eval-

study in sporadic primary hyperparathyroidism. J Am Coll

uation of parathyroid adenomas or hyperplasia.

Surg. 2006;202(1):18-24.

J Nucl Med. 2005;46(2):248-52.

8. Stephen AE, Chen KT, Milas M, Siperstein AE. Te coming

22. Krausz Y, Bettman L, Guralnik L, et al. Technetium-99m-

of age of radiation-induced hyperparathyroidism: evolving

MIBI SPECT/CT in primary hyperparathyroidism. World

patterns of thyroid and parathyroid disease afer head and

J Surg. 2006;30(1):76-83.

neck irradiation. Surgery. 2004;136(6):1143-53.

Case 1 Parathyroid Adenoma

⊡⊡

^99mTc-pertechnetate and ^99mTc-sestamibi

findings

Dual-tracer planar scintigraphy and SPECT/CT in a

patient with hyperparathyroidism. Normal findings

in ^99mTc planar scintigraphy (a). Note that in early

^99mTc-sestamibi planar scintigraphy (b) there is a

larger area of radiotracer uptake visible at the upper

half of the left thyroid lobe compared to the previ-

ous image. In the late ^99mTc-sestamibi planar scintig-

raphy (c) a focal but faint radiotracer uptake is

present in the projection on the upper half of the left

thyroid lobe, though not perfectly distinguishable.

These findings however lead to the diagnosis of an

upper left solitary parathyroid adenoma (arrow). The

patient also underwent early acquisition SPECT/CT.

The fused images in transaxial (d) and coronal (e)

146

sections demonstrate the presence of the solitary

parathyroid adenoma posterior to the left thyroid

lobe (arrows), providing much more precise anatom-

ical details than planar scintigraphy. CT alone in cor-

onal view (f) shows the anatomical position of the

adenoma (arrow) allowing exact measurements (6.9

and 20.9 mm) and precise anatomical localization

for planning of surgery.

Sentinel Node Imaging with SPECT-CT

8.1 Introduction

radical lymphadenectomy will follow in case of metasta-

ses or may be refrained from, when the sentinel node(s)

Te sentinel lymph node biopsy (SLNB) procedure has

is/are normal. Tis procedure represents a sensitive stag-

become an important tool in surgical oncology for stag-

ing method.

ing of operable tumors at the nodal level. If the first drain-

Literature shows that the combined use of lymphos-

ing node(s) is/are found to be free of tumor cells, more

cintigraphy, intraoperative probe and blue dye is the most

extensive nodal surgery, which may be associated with

reliable approach, with a detection rate varying from 93%

additional morbidity and complications, e.g., lymphoe-

to 100%, versus 66-82% for blue dye only and 84-93% for

dema, can be avoided.

using the probe without lymphoscintigraphy. Te num-

However, in order to base the entire treatment policy

ber of false-negative results is inversely related.

on the analysis of a single node or few nodes, it is impera-

In order to make this procedure as successful and reli-

tive that the correct lymph node is identified as the senti-

able as possible, the lymphoscintigraphic studies must

nel node. Nuclear medicine plays an essential role in the

meet the highest quality criteria, which can be achieved

preoperative mapping of sentinel nodes, which can then

by using the right radiopharmaceutical

(generally

be selectively approached and resected, guided by an

Technetium-99m-labeled microcolloids with a diameter

intraoperative gamma probe.

ranging from 5 to 75 nm are preferred), meticulous tracer

Afer this technique was introduced for melanoma

administration (depending on the indication), the use of

and breast carcinoma in the early 1990s, the number of

a modern gamma camera, performing imaging at several

clinical indications has expanded significantly, and the

time intervals both in the anterior and lateral projection

sentinel lymph node biopsy is currently used in a great

(and for breast carcinoma in prone position), defining the

variety of tumor types, including penile carcinoma, vul-

body contour by means of transmission scanning using a

var carcinoma, testicular cancer, cervical carcinoma, pro-

⁵⁷Co-flood source, and identifying and localizing the sen-

static cancer, bladder cancer, head and neck cancer,

tinel node(s) with the aid of a marker source or pen,

thyroid carcinoma, lung cancer, esophageal, gastric and

marking its site on the skin with non-erasable ink in the

colorectal cancers, anal carcinoma and Merkel cell

position in which the patient will be operated.

tumors.

Te major success determining factors for the sentinel

node biopsy procedure are: the administered dose, col-

loid size, number of colloid particles (concentration),

8.2 Sentinel Lymph Node Imaging

route of administration, protocol and quality of the lym-

and Biopsy

phoscintigram. As there is a distinct learning curve for

nuclear medicine physicians, technologists and surgeons,

Te sentinel node biopsy procedure in surgical oncology

experience is an equally important factor, as is teamwork

was introduced in early stage melanoma by Morton in

between nuclear medicine, surgery and pathology depart-

1992, although the term sentinel node had already been

ments. Te yield of this procedure may be significantly

used by Cabanas in 1977, when he reported his approach

enhanced by introducing new tools and three-dimen-

to the management of penile carcinoma.

sional orientation.

Te procedure is based upon the concept of an orderly

progression of lymph node metastases: the tumor drains

152

directly to one or a few first lymph nodes, called sentinel

8.3 New Tools

node(s), from which further connections with so-called

second-echelon nodes exist.

For some of the more recent indications for sentinel

First, the lymphatic drainage pathways from the tumor

lymph node biopsy, the procedure as described above will

are mapped, and the sentinel node(s) is/are identified by

not suffice. To locate and access sentinel nodes in more

lymphoscintigraphy, so that, subsequently, these can be

difficult locations, new technologies have been developed.

localized more easily during surgery, both by using an

For instance, to dissect an intraabdominal sentinel node,

intraoperative probe and by injection of patent blue dye,

laparoscopic probes have become available. But for this

and then selectively removed. Depending on the outcome

approach, it makes no sense to mark the location of the

of histological examination

(including hematoxyline-

sentinel node on the abdominal skin; the surgeon requires

eosine and immunohistochemical staining), subsequently

more accurate anatomical localization of the sentinel

Sentinel Node Imaging with SPECT-CT

node, which can be provided by adding SPECT/CT to the

missed in 20% of all patients, even with the performance

scintigraphic node mapping.

of extended pelvic lymphadectomy.

An additional improvement is the use of a portable

In case of positive sentinel nodes, postoperative radio-

mini gamma camera in the surgical theater. Tis portable

therapy may be indicated, and also here the SPECT/CT

camera can be positioned above the patient undergoing

images can serve as guidance to determine the correct

surgery and can be set to display both the Technetium-

radiotherapy target volume.

99m signal from the sentinel node and the signal from an

Another complex area for sentinel node detection

Iodine-125 seed on the tip of the laparoscopic probe. Tis

and localization is the head and neck region. Again,

way the laparoscopic probe can be guided to the sentinel

SPECT/CT will detect more sentinel nodes than planar

node, and the effective resection of this node can be mon-

lymphoscintigraphy and provides better anatomical

itored real-time.

localization.

More recently, also the use of 3D mini gamma cam-

Also in selected patients with melanoma or breast car-

eras has been investigated and sofware for 3D display of

cinoma, there is additional value of SPECT/CT. For mel-

SPECT/CT images utilized.

anoma, this may be particularly true for head and neck

and truncal locations of the primary tumor. In breast car-

cinoma, SPECT/CT may be very helpful to detect and

8.4 Why SPECT/CT?

localize non-axillary sentinel nodes, e.g., internal mam-

mary, intramammary, interpectoral and subpectoral

For some of the more traditional indications (melanoma,

nodes, and to exclude false-positive findings due no non-

breast cancer, penile and vulvar carcinoma) planar lym-

nodal tracer accumulation (e.g., intralymphatic or con-

phoscintigraphy, both in anterior/posterior and lateral

tamination). Moreover, in case of nonvisualization of a

projections and at several time intervals afer administra-

sentinel node on the planar lymphoscintigram, SPECT/

tion of ^99mTc-nanocolloid, ofen suffices to locate the sen-

CT may still reveal and localize the sentinel node, espe-

tinel node and mark its position on the skin.

cially when it is not so active and/or deeply located.

However, for tumors or lymphatics located in anatom-

Nevertheless, sequential images of planar lymphoscin-

ically more challenging regions, e.g., the head and neck,

tigraphy will remain important to identify lymph nodes

abdominal and pelvic areas, more advanced technologies,

appearing early as sentinel nodes. However the anatomi-

such as SPECT/CT and intraoperative mini gamma cam-

cal localization of these sentinel nodes is better achieved

era are required to provide surgeons with more detailed

by SPECT/CT. It may provide new insight into the lym-

information about the location of the sentinel node(s).

phatic spread of tumors, such as cervical, prostatic and

In prostate cancer, for instance, the tumor generally

testicular cancer, bladder and renal cell carcinoma.

drains to pelvic lymph nodes, but drainage outside the

area of the extended pelvic lymphadenectomy (e.g., to the

aortic-iliac junction, paraaortic lymph nodes, abdominal

8.5 Three-Dimensional Imaging

wall) may also be observed. It is relevant to know the

exact location in relation to other structures (in particu-

Taking the SPECT/CT study one step further, it is possi-

lar, to the large vessels), in order to be able to locate and

ble to display the SPECT/CT fusion images in a two-

identify the sentinel node successfully and to remove it

dimensional way

(transaxial, coronal and/or sagittal

153

safely during operation.

sections) or in a three-dimensional way. For the latter,

In this respect, SPECT/CT has significant value to

SPECT/CT fusion images are stacked and displayed in a

localize the sentinel node(s) preoperatively and guide the

volume-rendered way. Te sofware allows choosing from

surgeon during surgery. Evaluating the role of SPECT/CT

a variety of parameters, by which the sentinel node(s) can

in a series of patients with prostatic carcinoma

[1],

be displayed within its surrounding environment, high-

SPECT/CT was found to reveal additional sentinel nodes

lighting anatomical structures, such as bone, muscle and/

in 63% of the patients, and sentinel nodes located outside

or skin. Although the 3D volume-rendered images (either

the area of extended pelvic lymphadenectomy were

displayed in a static, rotational or tilted mode) contain

detected in 35% of the patients. In 56% of the cases, these

essentially the same information as the 2D tomographic

were only detected by SPECT/CT. In other words, with-

fusion images, the 3D volume-rendered display provides

out the addition of SPECT/CT, sentinel nodes would be

the surgeon with a three-dimensional roadmap, which is

Sentinel Node Imaging with SPECT-CT

attractive and more easily interpretable. Improved ana-

scintigraphy in a variety of tumor types will be demonstrated,

tomical information to the surgeon may influence the

showing how the SPECT/CT fusion image and 3D volume

surgical approach with the aim of preserving important

rendering can highlight the exact location of the sentinel

and fragile normal anatomical structures.

node, which would ofen be difficult to mark on the skin,

Evaluating the use of combined 2D SPECT/CT and

in relation to essential anatomical structures relevant to the

3D volume-rendered images in 30 consecutive patients,

surgeon.

the anatomical localization of the sentinel node was

improved in 77% and the surgical approach was altered in

50% of the patients.

It is concluded that SPECT/CT is more sensitive and

Reference

accurate than planar lymphoscintigraphy in locating the

sentinel node(s), in particular in tumors of the head and

1. Vermeeren L, Valdés Olmos RA, Meinhardt W, Bex A,

van der Poel HG, Vogel WV, Sivro F, Hoefnagel CA,

neck, abdomen and pelvis, as well as in the localization of

Horenblas S. Value of SPECT/CT for detection and anatomic

non-axillary sentinel nodes in breast carcinoma.

localization of sentinel lymph nodes before laparoscopic

By several cases presented in this chapter, the com

sentinel node lymphadenectomy in prostate cancer. J Nucl

plementary role of SPECT/CT in sentinel node lympho

Med. 2009;50:865-870.

154

Infection Imaging Using SPECT-CT

9.1 White Blood Cell SPECT-CT

^99mTc-HMPAO kit preparations have been commercially

available since 1988. Tis lypophilic complex can freely

Onelio Geatti, Andor W.J.M. Glaudemans,

cross the cell membrane of WBCs and is subsequently

Fernando Di Gregorio, and Alberto Signore ()

trapped inside the cell by two mechanisms: (1) conversion

into a hydrophilic complex by reducing agents, such as

Te clinical use of radiolabelled white blood cells (WBC)

glutathione, and (2) binding to nondiffusible proteins and

is of invaluable importance for the diagnosis and follow-

cell organelles. Afer reinjection in the patients, some

up of many diseases and for research purposes. In the

release of ^99mTc-HMPAO from the WBCs is observed,

field of inflammation and infection imaging, radiola-

resulting in accumulation of radioactivity in the gastroin-

belled white blood cell scintigraphy (WBC-S) is the gold

testinal and urinary tracts

[6]. Normal physiological

standard technique for infection detection [1-4]. Te

uptake is seen in the spleen, liver, bone marrow, lungs (in

body of evidence accumulated so far about the use of

early images) and, as mentioned above, the bowel, kid-

WBC-S all over the world makes this technique the

neys and bladder.

method of choice, and it will be the standard technique

Te common clinical indications for WBC-S (both

for many years to come. Over the past 30 years, there has

^99mTc-HMPAO and ¹¹¹In-oxine, the latter being preferable

been phenomenal growth in the use of this technique to

for the detection of inflammatory sites in the abdomen)

satisfy clinical demands.

include osteomyelitis of the appendicular skeleton,

In the mid 1970s, ¹¹¹In-oxine was introduced as a non-

infected joint and vascular prosthesis, inflammatory

selective labelling for WBC-S. Tis complex is a nonspe-

bowel disease, intra-abdominal infections, diabetic foot,

cific agent, as it is neutral and lipid-soluble, which enables

fever of unknown origin, postoperative abscesses, lung

it to penetrate through the bilayer cell membrane. Within

infections, endocarditis, neurological infections, and

the cell, indium becomes firmly attached to cytoplasmic

infected central venous catheters or other devices [5, 6].

components, such as lactoferrin. Afer injection, about

Regardless of which tracer is used, uptake of labelled

60% of the radioactivity is immediately taken up by the

WBCs depends on intact chemotaxis, the number and

liver, spleen, bone marrow and other tissues. Tere is only

types of cells labelled, and the cellular component of a

a very short transient hold-up in the bowel. Te remain-

particular inflammatory response. Labelling of WBCs

der shows exponential clearance from the circulation

does not affect their chemotactic response. A total white

with a half-life between 5 and 10 h, resulting in a final

blood cell count of at least 2,000/ml is needed to obtain

uptake of 20% in the liver, 25% in the spleen, 30% in the

satisfactory images. In most clinical settings, a mixed leu-

bone marrow and 25% in other organs. Clearance of

kocyte population is labelled. Hence, the majority of cells

activity from the liver and spleen is very slow, resulting in

labelled are neutrophils, and therefore the procedure is

a very low excretion of activity in both the urine and fae-

most useful for identifying neutrophil-mediated inflam-

ces. Te advantages of ¹¹¹In-oxine-labelled WBCs are the

matory processes, such as bacterial infections. Te proce-

high labelling efficiency (LE), the low efflux of activity

dure is less useful for those diseases in which the

from the labelled WBCs, and - if a bone marrow scan is

predominant cellular response is not neutrophilic, i.e.,

required at 24 h - that they do not interfere with imaging,

opportunistic infections, tuberculosis and sarcoidosis.

because different energy windows can be used.

Te whole labelling procedure has some major disad-

¹¹¹In-labelled WBCs are preferentially indicated for imag-

vantages. It is laborious and time-consuming, relatively

168

ing abdominal infections and inflammatory bowel dis-

expensive, and exposes the patient and the operator to

eases because of the low intestinal excretion. Disadvantages

several potential risks. Waterproof gloves should be worn

however are the low quality of the planar and SPECT

throughout the procedure, and special caution should be

images, the need to order ¹¹¹In in advance, and the high

taken when handling needles. Strict aseptic conditions

radiation exposure of labelled cells, critical organs (spleen)

are required, with only sterile reagents and disposable

and the whole body [5].

plastic ware used. Tis implies that the whole procedure

Although

¹¹¹In-oxine-labelled WBCs have been

should be performed by trained personnel under strict

successfully used in the field of infection/inflammation,

regulations in a class A laminar flow cabinet in a class B or

over the years the labelling agent has been largely replaced

class C environment [7]. Recently, guidelines from the

by ^99mTc-HMPAO because of the favourable physical char-

EANM for the whole labelling procedure (both with

acteristics, availability, costs and lower radiation burden.

^99mTc-HMPAO and ¹¹¹In-oxine) became available to guide

Infection Imaging Using SPECT-CT

the labelling of WBCs in accordance with currently effec-

Accurate interpretation of WBC-S requires knowledge

tive European Union regulations [5, 6]. Te whole proce-

of the normal and abnormal variants of WBC localisa-

dure and precautions can be read there.

tions. Te diagnosis of an infection is made by comparing

To overcome the disadvantages of the labelling proce-

early and delayed images. Visually images are classified as

dure, a sterile single-use closed disposable device was

negative when no uptake is seen at all or when a decrease

developed

(Leukokit®; GIpharma, Italy) and recently

in uptake is seen from the early to delayed image, and clas-

became available; it is easier to use compared to the stan-

sified positive when the uptake increases with time.

dard techniques and will make WBC labelling available

Quantitative evaluation may also be performed. A region

for more clinical centres and patients [8]. Tis is a licensed

of interest (ROI) is drawn over the suspected region (target

medical device distributed worldwide that may allow sim-

ROI) and over the same region contralateral or in pre-

plification of the required infrastructure, although to date

sumed normal reference tissue, e.g. the iliac bone (back-

there is no defined legislation for the use of this type of

ground ROI). Te target-to-background (T/B) ratio can be

product in a different way from that of open systems. Te

calculated in early and in delayed images. When the T/B

kit includes a sterile GMP-produced vial of anticoagulant

ratio increases with time, the scan is considered positive

agent (ACD-A), a vial of 10% HES and a vial of PBS for

for an infection; when it decreases, it is classified negative.

cell washing and resuspension, thus avoiding possible

Te recent development of the SPECT-CT camera also

causes of contamination of the labelled product [5, 6].

is a major push forward in the imaging of inflammation/

At the time of sampling, patients should preferably be

infection. Using a combined system, one can now sequen-

fasting. A careful history must be obtained from the refer-

tially acquire both anatomic and functional information

ring physician to ensure that the correct procedure will be

that is accurately fused in a single examination. For imag-

applied, e.g. the use of ¹¹¹In-oxine- or ^99mTc-HMPAO-

ing infection, early reports indicate that SPECT-CT

labelled WBCs, and the type and time of acquisition. Te

increases specificity and may significantly affect disease

blood results of the patient have to be checked to deter-

management. Fusion of the WBC images with the CT

mine if infection parameters in the blood are elevated and

images may be helpful for a more accurate localisation of

enough white blood cells are available for labelling. Te

the WBC uptake, particularly for differentiating sof tis-

possible interaction of high levels of cholesterol and glu-

sue uptake from bone uptake, e.g. in the diabetic foot.

cose in the blood has to be taken into account. Further on,

Another important feature is the ability to correct the

the possible interference of some drugs and antibiotics

nuclear emission images for attenuation and scatter to

has to be checked [9].

obtain more accurate image data. Te benefits of using

For the image acquisition a large-field-of-view camera

CT for attenuation correction as opposed to a radionu-

with a low-energy high-resolution collimator for ^99mTc-

clide transmission source include less noise, faster acqui-

HMPAO and medium-energy high-resolution collimator

sition, no influence on CT data by the SPECT radionuclide,

for

¹¹¹In-oxine is usually preferred. Te recommended

and no need to replace decayed transmission sources

injection dose is 10-18.5 MBq ¹¹¹In-oxine-labelled WBCs

[10]. In case of prosthesis, both attenuated and non-atten-

and 370-740 MBq ^99mTc-HMPAO-labelled WBCs. Planar

uated images must be carefully analysed in order to avoid

whole body images should include anterior and posterior

false positives.

views of the head, chest, abdomen and pelvis, and when

Radionuclide imaging procedures are routinely per-

clinically indicated also the extremities. In some cases (e.g.

formed as part of the diagnostic workup in musculoskel-

169

vascular grafs) oblique views may help to differentiate

etal infections. Bone scintigraphy is sensitive with

between uptake in the graf itself and surrounding tissue.

accuracy in unviolated bone. In the setting of underlying

Images are performed 30 min-1 h afer injection (diffuse

osseous abnormalities, however, the specificity of the test

and intense lung uptake should be seen to check if the label-

decreases [11]. Currently, WBC-S is the radionuclide pro-

ling was satisfactory), 3-4 h afer injection (early image) and

cedure of choice for diagnosing osteomyelitis, ofen per-

20-24 h afer injection (delayed image). Early and delayed

formed in conjunction with bone marrow imaging to

images should be acquired in time mode and corrected for

maximise accuracy. Te overall accuracy of combined

the radioisotope half-life. SPECT imaging of the suspected

WBC/bone marrow scintigraphy is approximately 90%

area is recommended, and for some indications (e.g. endo-

[12]. WBC-S is especially useful in the evaluation of pros-

carditis) even obligatory. Usually 20-30 s per step is used

thetic joint infections, neuropathic joint infections and

for early images and 40-50 s per step for delayed images.

infections of the diabetic foot. In suspected joint

Infection Imaging Using SPECT-CT

replacement infections, the accuracy ranges from 88% to

perianal disease [15]. Compared with spiral CT, both

98%. Although inflammation may be present in both the

WBC-S and CT are valuable non-invasive diagnostic

infected and aseptically loosened device, neutrophils are

methods in cases involving severe, active CD. WBC-S

usually absent in aseptic loosening. Tis critical differ-

seems better for the detection of segmental inflammatory

ence between infection and aseptic loosening accounts

activity, whereas CT displayed excellent suitability for the

for the high sensitivity and specificity of WBC-S for diag-

recognition of complications such as abscesses, stenosis

nosing prosthetic joint infection.

and fistula. Using the combined SPECT-CT camera may

Recent publications confirm also the incremental

provide better sensitivity and specificity, but no reports

value of SPECT/CT-labelled WBC imaging. WBC-S with

can be found in the literature yet.

and without SPECT/CT was performed in 26 patients

Fever of unknown origin (FUO) is an illness of at least

with suspicion of musculoskeletal infections. SPECT/CT

3-week duration with several episodes of fever exceeding

significantly changed the interpretation of the study in

38.3°C and no diagnosis afer an appropriate evaluation.

ten patients, excluded osteomyelitis in seven and pro-

Underlying causes are numerous and include infections,

vided a more precise delineation of the extent of infection

malignancies, granulomatous diseases and collagen vas-

in three [13]. In contrast to other sites in the skeleton,

cular diseases. Both ¹¹¹In- or ^99mTc-labelled WBC have

WBC-S is of limited value for detecting spinal osteomy-

been successfully used in patients with FUO. A study

elitis or spondylodiscitis. Although increased uptake is

already performed in the early 1990s with ¹¹¹In-labelled

virtually diagnostic of the disease, 50% or more of all

WBCs in 68 patients with FUO demonstrated an accuracy

cases present as areas of decreased, or absent, activity.

of 76% and was helpful in reaching a final diagnosis in

However photopenia is not specific for vertebral osteo-

28% of these patients [16]. Other studies found a some-

myelitis; it can also be associated with tumours, infarction

what lower overall accuracy. In the recent years, ¹⁸F-FDG-

and previously treat osteomyelitis [11].

PET is increasingly considered the best radionuclide

High sensitivity and specificity values were also

imaging method for FUO; however, a study from Kjaer

reported for WBC-S with ^99mTc-HMPAO for the assess-

et al. in 19 FUO patients showed that ¹¹¹In-labelled WBC-S

ment of activity in inflammatory bowel diseases (Crohn’s

was 71% sensitive and 92% specific, which was signifi-

disease and colitis ulcerosa) [14]. Some discussion has

cantly higher than ¹⁸F-FDG-PET (50% and 46% sensitiv-

been raised about the best imaging time. Te overall ten-

ity and specificity, respectively). Te authors concluded

dency is a high sensitivity and specificity if imaging is per-

that ¹¹¹In-WBC-S has a superior diagnostic performance

formed within 3 h. Moreover, scanning afer 1 and 3 h

compared to ¹⁸F-FDG-PET for the diagnosis of a localised

may be helpful as the pathological accumulation in

infectious/inflammatory or neoplastic cause of FUO [17].

actively inflamed segments becomes more pronounced.

WBC-S plays also an important role in various vascu-

On the other hand, false-positive findings may occur afer

lar diseases. Several studies demonstrated the use of

3 h because of excretion of ^99mTc-HMPAO into the bowel.

WBC-S for the detection of myocardial abscesses in infec-

WBC labelled with ¹¹¹In-oxine has also been used for

tive endocarditis patients. In a recent study, 78 patients

inflammatory bowel diseases and has been shown suitable

with suspected endocarditis or infection of cardiac

for the assessment of presence and location of active

devices were evaluated with ^99mTc-labelled WBC SPECT/

inflammation. In children, WBC-S is a useful tool in the

CT, and this study concluded that the SPECT/CT allows

diagnosis and therapeutic strategy of CD, and provides

an accurate diagnosis of cardiac and additional unsus-

170

information on the presence, intensity and extent of the

pected extra-cardiac infection sites. WBC-S also demon-

disease, particularly in the terminal ileum [14]. Very few

strated high sensitivity (ranging from 82% to 100%) and

studies investigated the role of SPECT in inflammatory

specificity (ranging from 75% to 100%) for the diagnosis

bowel diseases. One study compared SPECT images afer

of vascular graf infection [10].

2 h with planar images afer 30 min and 2 h. Both planar

Te recent availability of radiolabelled anti-granulo-

and SPECT images were comparable in terms of detecting

cyte antibodies (Scintimun®, CIS bio, France) allows fast

the presence of an active inflammation, but SPECT images

and accurate detection of infection. Particularly for

showed a higher uptake and provided more detailed visu-

peripheral osteomyelitis, the diagnostic accuracy is com-

alisation of lesions. SPECT may better discriminate

parable to that of WBCs, and all acquisition and interpre-

between intestinal and bone marrow uptake, and thus is

tation criteria mentioned above can also be applied,

useful for assessing lesions within the pelvis, including

including the use of SPECT/CT techniques.

Infection Imaging Using SPECT-CT

In the examples of WBC-S, the normal body distri-

8. Signore A, Glaudemans AWJM, Lazzeri E, Prandini N,

bution and the qualitative and quantitative evaluation

Viglietti AL, Devicienti A, De Vries EFJ, Dierckx RAJO.

Development and testing of a new disposable sterile device

will be explained. Tis will be followed by some exam-

for labelling white blood cells. Submitted

ples of a positive WBC-S. Te advantages of the use of

9. IAEA Guidelines Radiolabelled autologous cells.

SPECT and SPECT-CT will be demonstrated with some

10. Signore A, Mather SJ, Paiggio G, Malviya G, Dierckx RA.

examples.

Molecular imaging of inflammation/infection: nuclear med-

icine and optical imaging agents and methods. Chem Rev.

2010;110:3112-45.

11. Palestro CJ, Love C, Bhargava KK. Labeled leukocyte

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171

Infection Imaging Using SPECT-CT

9.2 Other Tracers for Infection

findings [22]. Magnetic resonance imaging (MRI) and

other radiopharmaceuticals proposed to complement the

Elena Lazzeri

diagnostic value of MRI, such as bone scintigraphy with

^99mTc-MDP and ⁶⁷Ga-citrate [33, 34] and ¹⁸F-FDG PET

In this chapter we describe the use of a new radioactive

[35-41], have shown high sensitivity but variable specific-

tracer of infection with SPECT/CT acquisition in patients

ity (ranging from 35.8% to 87.9%), especially in cases in

with infective spinal disease and the use of PET/CT dur-

that require differentiating vertebral infection from benign

ing scintigraphic imaging.

pathologies or septic and aseptic SD in the early post-sur-

gical phase [40-45].

Te labelling of biotin with ¹¹¹In is an easy and fast

9.2.1 ¹¹¹In-Biotin SPECT/CT

procedure, and shows high efficiency and stability (>98%

until 24 h).

Biotin, also called vitamin H, is a water-soluble vitamin of

Te scintigraphic acquisition protocol is based on pla-

the B-complex group of vitamins. Biotin (molecular weight

nar and SPECT/CT images of the suspected vertebral

about 224 Da) is a growth factor for the majority of bacte-

region 4-6 h afer i.v. injection of ¹¹¹In-biotin (111 MBq).

ria. In particular, pyruvate carboxylase, a key metabolic

Te main advantage of using ¹¹¹In-biotin is the absence

pathway for producing energy by ATP cleavage, is biotin-

of uptake of healthy bone marrow of the spine, so it is

dependent, and bacterial acetyl-coA carboxylase is a bio-

quite simple to read SPECT/CT images when, in case of

tin-dependent enzyme utilised in the first step of fatty acid

spine infection, they show a focal uptake of the tracer in

synthesis [18, 19]. Tis vitamin can be labelled and utilised

the region of interest (Fig. 1a, b). Another advantage of

for diagnosis of infection, in particular in those infections

this scintigraphic procedure is the possibility to study the

where the conventional radioactive tracers are limited.

patients in follow-up during antibiotic treatment without

Nowadays the gold standard of nuclear medicine imaging

any suspension of the therapy [46, 47].

for infection is represented by labelled leukocyte scintigra-

Rarely false-positive results can be found when a large

phy because of its high sensitivity (95%) and specificity in

inflammatory process leads to leakage of the tracer

many infectious processes (90%) [20, 21]. In case of verte-

because of the altered capillary permeability. When a

bral infection, however, labelled leukocyte scans present

false-positive result is present, it can be resolved by com-

considerable limits: in the majority of cases we can find a

paring early images (4-6 h post injection) with late images

photopenic area in the corresponding infected vertebra,

(18-20 h post injection).

which is not specific for infection [22]; many other pathol-

False-negative results can be found if the infective

ogies, in fact, such as vertebral crush, Paget’s disease or

pathologies of the spine are caused by microorganisms

tumors, show a decrease of leukocyte uptake in nuclear

that do not utilise biotin for their own growth or if the

medicine imaging [23-32]. More rarely, an increased

microrganisms have a low rate metabolism

(e.g.

uptake of labelled leukocytes can be found in the site of

Mycobacterium tubercolosis).

vertebral infection that has been correlated to the duration

Te main limit of ¹¹¹In-biotin scintigraphy is the com-

of symptoms: less than 25% of patients who were symp-

plete urinary excretion of ¹¹¹In that results in a relatively

tomatic for more than 2 weeks showed presented such

high dosimetry for the kidneys.

182

Infection Imaging Using SPECT-CT

33. Stumpe KD, Dazzi H, Schaffner A, von Schulthess GK.

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Red Blood Cell Imaging with SPECT-CT

10.1 Introduction

unknown origin for which endoscopy and angiography

had a negative result. Te greatest chance of success is

In patients suspected to have an acute bleeding, accurate

when there is a need for transfusions of more than 500 mL

localization of the bleeding site and assessment of the

per 24 h. Te aim is to find a bleeding site to direct angiog-

severity of blood loss are essential for the proper manage-

raphy or endoscopy to more specific areas. Rarely, the

ment of the condition.

scintigraphy alone suffices to guide the surgeon.

In gastrointestinal bleeding, a distinction is made

between upper and lower gastrointestinal bleeding. Te

most frequent causes of bleeding in the upper gastroin-

10.3 Procedure

testinal are: duodenal ulcer, gastric ulcer, gastric erosions,

varices and Mallory-Weiss tears. Lower gastrointestinal

For scintigraphic imaging of bleeding, the radiopharma-

bleeding is most commonly caused by angiodysplasia,

ceutical of choice is Technetium-99m-labeled autologous

diverticula, polyps or bowel cancer.

erythrocytes. Afer pretinning, a blood sample is drawn

Both endoscopy and angiography are mostly used to

for ex-vivo labeling with a yield of 90-95%. Tis is pre-

detect, localize and possibly control the bleeding if it is

ferred over the in-vivo labeling technique, which may

active at the time these procedures are performed. It has

result in varying amounts of free pertechnetate, which,

been reported that endoscopy of the upper gastrointesti-

due to uptake in the gastric mucosa, passing into the

nal tract is accurate in more than 90% of the cases of

upper gastrointestinal tract and by excretion via the kid-

upper GI bleeding, and that coloscopy can detect or

neys, may lead to false-positive results.

exclude a colonic bleeding site in 70% of the cases.

Following i.v. administration of 740 MBq ^99mTc-labeled

Nevertheless, because of the ofen intermittent nature of

erythrocytes, a dynamic study of 1 frame/s during the first

gastrointestinal bleeding, both methods may fail to find

minute is acquired, and subsequently either a dynamic

the bleeding.

image sequence of 15-s frames for the next 15 or 30 min, or

It is in these circumstances that scintigraphy with

1-min frames for the next 60 min is recorded, which can be

radiolabeled red blood cells can have a complementary

displayed in cine mode. Tereafer, a series of static anterior

role. Te advantages of this technique are the fact that no

view images of the abdomen is made, initially frequently,

patient preparation is required, its noninvasiveness and

and subsequently at greater intervals for up to 24 h.

easiness to perform, even in acutely ill patients, and its

X-ray contrast from gastric and bowel imaging may

sensitivity at low bleeding rates. In this respect, the great-

interfere with detection of extravasations and should

est advantage of red blood cell scintigraphy is its ability to

therefore be avoided.

detect intermittent bleeding by monitoring the abdomen

over a period of time (up to 24 h). Although angiography

is successful in localizing the site in 65% of active bleed-

10.4 Interpretation

ings with a bleeding rate of >1 mL/min, the handicap is

that the bleeding must be active during the 20-30 s of a

Te aim of the procedure is to detect and localize extrava-

contrast injection.

sation of blood into the bowel, preferably at its earliest

Experimentally in dogs, bleeding rates as low as 0.05-

appearance. Viewing images in cine mode can be of help

0.1 mL/min have been reported to be detected by scintig-

in this respect. In subsequent images, extravasation may

188

raphy. Although in patients generally a bleeding rate of

be seen to be transported both in the distal and proximal

0.4 mL/min is required to produce an intense focus of

direction. Extravasations shown on late images may be

extravasation in the early scintigrams, detection of foci

more difficult to localize because of the movement of

with a lower bleeding rate is possible, especially if, in

activity within the bowel.

addition, SPECT/CT can be performed.

Accumulation of activity that does not move on subse-

quent images is more likely to be due to vascular abnor-

malities than to bleeding, although a clot remaining in

10.2 Indication

the bowel can also cause such a finding.

A negative scintigraphic study does not rule out an

Te main indication for red blood cell scintigraphy is

intermittent bleeding, but does indicate that during the

recurrent intermittent

(gastrointestinal) bleeding of

past 24 h the patient had no or hardly any bleeding.

Ventilation/Perfusion Imaging with SPECT-CT

Acute pulmonary embolism (PE) is a severe and poten-

Rb-Kr generator by oxygen and flows directly to the lungs.

tially fatal disease with a mortality rate of approximately

By the patient’s continuous inhalation of ^81mKr, the scinti-

30% if untreated. Te incidence is 2 per 1,000 person years

gram illustrates the distribution of air flow/ventilation.

in the Western countries. PE is a blockage of the main pul-

Te perfusion scan shows how blood circulates within

monary artery or one of its branches by a thrombus, typi-

the lungs and is most commonly performed in order to

cally a blood clot from the deep veins of the lower

check for the presence of decreased perfusion because of

extremities. PE reduces the cross-sectional area of the pul-

an embolism or abnormal blood flow inside the lungs.

monary blood vessels, resulting in an increase in total pul-

Perfusion lung scanning is performed afer intravenous

monary vascular resistance and pulmonary hypertension.

(i.v.) injection of radiolabeled microparticles

(^99mTc-

Te clinical presentation of PE is highly variable, and

MAA; macroaggregated albumin) that are trapped in the

many of its associated symptoms are non-specific, which

pulmonary precapillaries on a first pass transit. Te prin-

makes diagnosis difficult. Te diagnosis of PE is usually

ciple underlying the diagnosis of PE is that whereas pul-

established by a combination of clinical assessment,

monary perfusion is abnormal, the pulmonary alveolar

D-dimer test and imaging with either lung scintigraphy

ventilation usually remains intact as a result of its bron-

or multidetector computer tomography (MDCT) angiog-

chial ventilation supply. On the V/Q scan, it is seen as a

raphy. Other indications for lung scintigraphy are preop-

mismatch defect.

erative regional function before lung cancer surgery, lung

Among the weaknesses of traditional two-dimensional

volume reduction surgery and cases of pulmonary

(2D) planar V/Q scintigraphy when using the Prospective

hypertension.

Investigation of Pulmonary Embolism Diagnosis (PIOPED)

Pulmonary MDCT angiography has a higher diagnos-

interpretation criteria are high proportions of equivocal

tic accuracy and specificity than conventional planar venti-

studies [4, 7] as well as only moderate interobserver agree-

lation/perfusion (V/Q) scintigraphy [1]. Tus, in many

ment [1]. Accordingly, in recent years V/Q scintigraphy has

institutions MDCT is the first-line imaging test in daily

had a diminished role in the diagnosis of PE.

clinical routine in patients suspected of having PE [2-4]. In

At present, many centers use only pulmonary MDCT,

addition, MDCT has the ability to yield an alternative diag-

but this might not be optimal because of a possible lower

nosis and has a high degree of interobserver agreement

sensitivity and higher radiation dose compared with lung

[1, 2, 5, 6]. Several studies have demonstrated that MDCT

scintigraphy. Reasons for extensive use of MDCT may

angiography is sensitive with a high specificity [1, 5].

also include its around-the-clock availability, lower cost

However, the positive predictive value for pulmonary

and high frequency of conclusive results, as well as staff

MDCT angiography declines when thrombi are located in

inexperience with V/Q-SPECT. Recently, some proposed

smaller pulmonary vessels. Positive predictive values have

algorithms for evaluation of patients suspected of having

been reported to be 97% (116 of 120 patients) for PE in a

PE have totally omitted the use of lung scintigraphy in the

main or lobar artery, 68% (32 of 47 patients) for a segmen-

diagnostic workup. Some guidelines only include lung

tal vessel and 25% (2 of 8 patients) for a subsegmental

scintigraphy as an alternative imaging technique when

branch [2, 3]. However, data are sparse in the subsegmental

patients cannot have a MDCT performed because of

group. Predictive values vary substantially when clinical

severe renal insufficiency or allergy to intravenous con-

probability of PE is taken into account. In patients with

trast agents, or when a CT-based strategy is inconclusive.

high or intermediate clinical probability, the positive pre-

However, the introduction of 3D V/Q-SPECT tech-

196

dictive value of MDCT is high, but decreases in the case of

nology instead of 2D planar V/Q-scintigraphy suggests

low clinical probability. Te negative predictive value of

an improvement in the diagnostic performance of scin-

MDCT is high in patients with low or intermediate clinical

tigraphy [8-11]. Te main advantage of using the SPECT

probability (96% and 89%, respectively), but is lower in

technique compared to planar imaging in relation to V/Q

patients with high clinical probability (60%) [2, 3].

scanning is a higher image “contrast” because superim-

A V/Q lung scan involves imaging and evaluation of

posing of surrounding normal activity onto lesions is

the distribution of pulmonary blood flow and alveolar

eliminated [12], and the images can then be viewed in

ventilation. Te ventilation scan can be performed with

sagittal, axial and coronal views.

radioaerosols, Technegas and Krypton (^81mKr), to assess

V/Q-SPECT examinations can be obtained in less

the ability of air to reach all parts of the lungs. ^81mKr is an

than 20 min if ventilation is performed with Technegas

ultra-short-lived (T½: 13 s) isotope that is eluted from the

(13 min), immediately followed by a perfusion SPECT

Ventilation/Perfusion Imaging with SPECT-CT

(6 min). Alternatively, V/Q-SPECT can be performed as

report V/Q-SPECT has not been clarified. However, there

we do simultaneously in 72 steps of 20 s through a 180°

seems to be consensus about a more simplified reporting

projection on a dual-headed gamma camera. Accordingly,

scheme in V/Q-SPECT reading [15-18].

the total V/Q-SPECT acquisition time is 13 min. Te per-

Te use of the SPECT technique involves a much lower

fusion study can be performed afer, i.e., injection of ~150

frequency of equivocal tests than is known from tradi-

MBq of ^99mTc-MAA. Te ventilation study can be per-

tional planar lung scans, which in previous studies have

formed when inhaling ^81mKr; however, other tracers for

been reported to result in up to 73% non-conclusive

ventilation, e.g., Technegas, can also be used. At our

examinations [7]. Tis is in accordance with previous

department, both studies are performed simultaneously

studies that demonstrated that the use of SPECT in V/Q

with low-energy general-purpose collimators and

scintigraphy reduces the frequency of equivocal tests

acquired in a 128 × 128 matrix.

markedly [15, 19, 20].

Recently, hybrid gamma camera/MDCT systems have

In one study, the addition of low-dose CT without a

been introduced that allow for simultaneous lung V/Q-

contrast agent to the V/Q-SPECT resulted in an even

SPECT and MDCT angiography, and can be used for

higher confidence of the reading with a reduction of

diagnosing PE [9, 13]. However, very limited data directly

inconclusive studies from 5% with SPECT alone to 0%

comparing these two 3D modalities are available [10, 14],

with SPECT + low-dose CT. In addition, the specificity

and a head-to-head comparison of simultaneous V/Q-

was improved with fewer false-positive interpretations

SPECT and pulmonary MDCT angiography for the

(from 18% to 0%). Tis was mainly due to findings on the

detection of PE is warranted.

low-dose CT scan that gave alternative explanations for

In our recently performed study, V/Q-SPECT, pulmo-

subtle perfusion defects that otherwise would have been

nary MDCT angiography and low-dose CT were per-

interpreted as PE on SPECT alone. Although a low dose

formed in 100 patients suspected of having PE. Te first

CT scan without a contrast agent is inherently inferior to

CT acquisition in the study consisted of a low-dose CT

those acquired by a diagnostic CT scan with a contrast

scan without contrast enhancement (140 kV, 20 mAs/

agent, the low-dose CT scan can satisfactorily provide rel-

slice, collimator 16 × 1.5 mm, rotation time 0.5 s and pitch

evant diagnostic information to determine the origin of

0.813, 512 × 512 matrix) and was obtained during tidal

the V/Q-SPECT lesions. When assessing the V/Q-SPECT

breathing. Te low-dose CT was used for attenuation cor-

datasets alone, mismatched defects on the V/Q-SPECT

rection of the V/Q SPECT data and for fusion with the

scans due to interlobar fissures, paraseptal emphysema,

V/Q-SPECT images [11].

pneumonic infiltration, atelectasis and pleural fluid could

V/Q-SPECT alone had a sensitivity of 97% and a spec-

be well demonstrated on the low-dose CT [11].

ificity of 88%. When adding the information of a low-dose

Te fact that that there is no independent gold stan-

CT scan, the sensitivity was still 97%, but the specificity

dard for establishing the PE diagnosis poses difficulties

increased to 100%. A MDCT angiography alone had a

for the evaluation and comparison of the diagnostic accu-

sensitivity of 68% and a specificity of 100% [11].

racy of different modalities in PE. In order to compare the

Tis is in agreement with regard to sensitivity, speci-

diagnostic performance of the tested modalities, a combi-

ficity and accuracy to a previous retrospective study that

nation of composite and head-to-head consensus reading

found values of 97%, 91% and 94%, respectively, for V/Q-

as the criterion standard has been used [11]. Te use of

SPECT alone and values of 86%, 98% and 93%, respec-

this combined method, which includes all tested modali-

197

tively, for MDCT [10]. Another study found that the

ties to classify PE patients, raises methodological and

observed percentage of agreement between SPECT V/Q

conceptual problems and is controversial. However, this

scintigraphy and CTPA data for the diagnosis of PE was

reference is the best currently available. Nevertheless, it is

95%. When calculated against the respiratory physicians’

important to keep in mind the possibility that some

reference diagnosis, V/Q-SPECT alone had a sensitivity

patients being studied may be incorrectly assigned to a

of 83% and a specificity of 98% [14].

disease category by the examination, which can lead to

We find that using the PIOPED criteria is inappropri-

exaggerated or underestimated accuracies.

ate when classifying PE patients using the SPECT tech-

With the use of hybrid scanners, V/Q-SPECT in com-

nique, since these criteria were derived from single view

bination with low-dose CT without contrast enhancement

¹³³Xe ventilation and planar perfusion imaging, which is

has “revitalized” lung scintigraphy and should probably be

very different from V/Q-SPECT [7]. Te best way to

considered the first-line imaging test in diagnosing PE.

Ventilation/Perfusion Imaging with SPECT-CT

References

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198

Radiation Therapy Planning Using SPECT-CT

Up to date image-guided radiotherapy extensively

2. Deformable model based, where an extracted

involves radiology, nuclear medicine and medical phys-

structure from one image is elastically deformed

ics for accurate delineation of the volumes of interest

to fit the same on the other image

(VOIs) and assists physicians to extract the most rele-

3. Voxel property methods, where intensity-based

vant clinical information. Te aim is to precisely iden-

values in different images are aligned.

tify the gross tumor volume (GTV) and to use the

Te low-resolution nuclear medicine image is the major

available information to delineate the clinical target vol-

limitation of these registration techniques.

ume (CTV) that represents the microscopic invasion of

the tumor. Te ever-increasing amount of image data

acquired (CT, MRI, SPECT and PET) requires the devel-

opment of a robust image registration process for pre-

12.1.1 Non-image-Based Registration

cise image alignment. Tis is a prerequisite for obtaining

Methods (Dual-Modality Devices)

imaging useful for precise target identification that

employs multiple modalities with morphological, func-

A non-image-based registration is possible if the imaging

tional and biological information. Te integration of

coordinate systems of the two scanners involved are cali-

these multiple images may allow identifying target and

brated to each other. Tis usually requires the scanners to

non-target structures better than using each single

be brought into the same physical location, with the

imaging modality [1-3].

assumption that the patient will remain motionless

between both acquisitions [7].

Tis method forms the basis for the development of

multi-modality devices combining structural and func-

12.1 Image Fusion (Co-registration)

tional measurements.

of Functional and Anatomical Data

Tese new devices, combining PET and SPECT with

CT, are able to acquire data in the same session and there-

Tese can simply be divided into image-based and non-

fore limit the fusion accuracy problems (positioning and

image based co-registration methods.

movement of patients) of anatomical modalities outside

Image-based registration includes:

of the brain, without the need for fiducial markers and

• Extrinsic method: based on external fiducial markers

complicated mathematical algorithms.

attached to the body surface, designed to be accurately

A hybrid imaging device composed of a dual-head

detectable in all the different imaging modalities. Te

variable angle SPECT combined with a CT scanner is

now the standard equipment proposed by the industry

co-registration of different images is easy and fast, and

for cross-sectional fusion imaging and systematic scatter

can usually be automated without the need of complex

and attenuation correction of gamma ray emission [6, 7].

algorithms. Unfortunately, this method is not suitable

Tis hybrid imaging system was used with In-111 pen-

for retrospective co-registration tasks and not practi-

tetreotide scintigraphy to evaluate 73 patients with neu-

cal for routine clinical use, especially if patients are

roendocrine tumors. In 40% of the patients with abnormal

studied on different days [4].

scintigraphic findings, SPECT/CT improved the accuracy

• Intrinsic methods: the information for the co-registra-

of nuclear medicine studies by providing better localiza-

204

tion process is derived from a set of identified land-

tion of SPECT-detected lesions; in particular, in 21 patients,

marks and on the alignment of segmented binary

it precisely defined the organ involved and the relationship

structures (segmentation-based methods), or directly

of lesions to adjacent structures, in 4 patients, it showed

onto measures computed from the image gray values

unsuspected bone involvement, and in 4 patients, it differ-

(voxel property-based method). Landmarks can be

entiated physiological from tumor uptake [8, 9].

anatomical (points identified by the operator) or geo-

In-111 pentetreotide can also be used to identify the

metric (shapes automatically localized) [5].

precise location and the tumor extension of other neo-

• Segmentation based methods can be:

plasms such as meningioma. Tese images are very suit-

1. Rigid model based, where extracted anatomical

able for use for radiotherapy treatment planning,

structures are co- registered as the only input for

especially when the tumor is located in close proximity to

the alignment procedure

critical structures (Figs. 12.2 and 12.3).

Radiation Therapy Planning Using SPECT-CT

12.1.2 The Mask Approach

Stereotactic techniques are widely used in neurosurgery,

radiosurgery and fractionated radiotherapy. For these

treatments, the patient is fixed to a stereotactic frame that

defines a coordinate system within the patient. Using

tomographic imaging, the positions and shapes of the

clinical target volume (CTV) and the organs at risk can be

located by special localizers. Tese tomographic images

serve as the basis for the three-dimensional treatment

planning process (Fig. 12.1).

In special cases of treatment planning, CT and MRI

are co-registered to PET or SPECT for specific reasons:

the CT data set reflects the electron density of the tissue

and is needed to calculate dose distribution within the

patient. When available, MRI provides superior sof tis-

⊡⊡Fig. 12.1 A customized-shape conformed heat deform-

sue contrast and is used to delineate the tumor and the

able mask positioned on the head and neck of a patient

affected by oropharyngeal carcinoma, lying on the rigid table organs at risk. PET and SPECT images can additionally

of an hybrid machine (SPECT/CT). External anatomical land-

be used to measure the relative metabolic activity for

marks, exactly coincident with laser beams, are adopted to

detecting differences in tumor regions or differentiating

facilitate the accuracy of repositioning

tumor from necrosis.

205

MRI

SPECT-CT

⊡⊡Fig. 12.2 In-111 pentetreotide SPECT-CT images showing tumor relapse in a case of operated meningioma

Radiation Therapy Planning Using SPECT-CT

Tese complementary aspects can be integrated into

12.3 Brain High-Grade Glioma

treatment planning by stereotactic correlation of the

images from different modalities. Te accuracy of the ste-

Despite recent progress in biological knowledge, the

reotactic correlation depends on:

prognosis of patients with high-grade glioma remains

poor, with a median survival time of about 10-14 months

1. Distortions of the imaging process itself

afer multimodality treatment, including surgery, radio-

2. Mechanical errors of the localization hardware

therapy and chemotherapy [11-14].

(e.g., the localizers)

Te identification of the target volume for radiother-

3. Errors in the sofware that calculates the stereotac-

apy of high-grade glioma is still an unsolved problem, as

tic coordinates from the positions of the fiducials.

demonstrated in clinical practice by the high recurrence

A commissioning test by the customer is part of a QC

rate in the marginal region surrounding the volume irra-

program prior to the first application to patients.

diated to the highest dose [15, 16].

For PET, the localization accuracy was found by

Although a number of recent studies have described

Karger et al. [10] to be device dependent, ranging from

the use of PET imaging with ¹⁸F and ¹¹C compounds, the

1.1 to 2.4 mm. For SPECT, the mean deviations in space

role of SPECT is still under investigation, thanks to the

were found to be 1.6 and 2.0 mm. No dependence on

variety of molecules and the wide availability of this tech-

device type was observed, and the deviations were well

nique [17-19].

below the physical resolution of SPECT. Terefore, uncer-

Among the SPECT radiotracers for brain studies,

tainties due to image distortion can be neglected.

^99mTc-methoxy-isobutyl-isonitrile (^99mTc-SestaMIBI) has

With respect to image distortions, CT is less depen-

shown a favorable tumor-to-background uptake related

dent on target point position, and for MRI the errors may

to its accumulation in tumor cells [20, 21].

be larger because of larger inhomogeneities of the basic

Several studies investigated the use of

^99mTc-MIBI

magnet in the off-center region of this device. Te physi-

imaging for detecting the biological characteristics of

cal resolution worsens towards the border of PET and

brain tumors, distinguishing between tumor tissue and

towards the center of SPECT; therefore, different errors

radiation-induced signal alteration predicting the

can be expected for different modalities. It is therefore of

response to radiotherapy and chemotherapy, and the

paramount importance to localize errors for each modal-

prognosis as well [22-26].

ity and target point position.

Major drawbacks of ^99mTc-MIBI, that is, poor morpho-

logical resolution and disturbing sites of physiological

uptake, can be overcome by dual-modality, integrated

12.2 Stereotactic Radiotherapy

systems. In fact, SPECT/CT can distinguish tumor from

the skull and other sites of physiological uptake better

When images of different modalities are to be stereotac-

than SPECT alone (as confirmed by MRI in all cases) and

tically correlated for radiotherapy, the combined uncer-

affords a morphological map.

tainty of stereotactic localization, patient fixation as

Te delineation of gross tumor volume (GTV) by

well as possible organ movements has to be considered

^99mTc-SestaMIBI SPECT imaging for conformal radio-

in the definition of the planning target volume. In frac-

therapy of high-grade glioma is based on the characteris-

tionated radiotherapy, this uncertainty may be signifi-

tics of this radiotracer, which is a small lipophilic

207

cant. Methods registering anatomical structures have

radioligand that enters cells by diffusion, being preferen-

the advantage that the anatomical structures are

tially trapped in mitochondria. As a result of the high

matched directly, which may compensate for different

mitochondrial activity in tumor cells, ^99mTc-SestaMIBI

patient positions within the mask. For radiotherapy

accumulates more in tumor rather than in normal tissue.

purposes, if external markers are placed on the body

In brain tumors, its accumulation is facilitated by dis-

surface for this purpose, the determined accuracy may

ruption of the blood-brain barrier. Te role of ^99mTc-Ses-

not apply for regions within the body where no markers

taMIBI SPECT in the diagnosis and follow-up of brain

can be fixed.

glioma was investigated during the last decade in several

For stereotactic radiotherapy, it appears more reason-

studies [22, 24-28].

able to use stereotactic imaging with known uncertainty

Tese results showed that ^99mTc-SestaMIBI uptake cor-

and consider patient and organ movements separately.

relates with histological grade and prognosis, and can

Radiation Therapy Planning Using SPECT-CT

allow distinguishing tumor recurrence from post-

was actually 33% larger than the average volume on MRI,

treatment necrosis with a sensitivity of 73-88% and a

with greater difference for operated than for inoperable

specificity of 75-100% [27, 29, 30].

cases. Tis kind of information can really be of substan-

Another study correlating

^99mTc-SestaMIBI SPECT

tial help to focus the high irradiation dose on the tumor

and stereotactic biopsy for the detection of tumor recur-

area and to spare normal brain tissue in a similar way as

rence found 90% sensitivity, 91.5% specificity and 90.5%

the more specific, but more expensive, tracer ¹²³I-a-

accuracy [31].

methyl-tyrosine (IMT-SPECT/CT).

We investigated the use of this radiotracer in 21

Te future of brain glioma imaging for treatment plan-

patients diagnosed with high-grade supratentorial glioma

ning of high-precision radiotherapy is most likely related

afer surgery or stereotactic biopsy. We demonstrated that

to the integration of multiple biological imaging modali-

the fusion of ^99mTc-SestaMIBI SPECT imaging with CT

ties allowing the highlighting of the various tumor char-

and MRI is useful for target volume delineation in con-

acteristics, following and developing the concept of

formal radiotherapy of high-grade glioma, since ^99mTc-

biological target volume as already proposed by Ling et al.

SestaMIBI SPECT imaging significantly affected the

[34]. Tis concept would include information about

delineation of the target volume identified by CT and

metabolism, proliferation, hypoxia, apoptosis and loca-

MRI alone [32].

tion of tumor stem cells in order to use radiation in such

Image registration was obtained by an interactive

a way as to deliver different dose levels with different frac-

method based on three-dimensional rigid body transfor-

tionation schedules realizing a kind of dose deposition

mation using the sofware of the treatment-planning sys-

(dose painting) to optimize the control of the various

tem Pinnacle® (Philips, Adac Laboratories, Milpitas, CA).

tumor components. In this effort, imaging techniques

CT images were selected as the reference data set, and MRI

based on biological tumor characteristics, such as non-

and ^99mTc-SestaMIBI SPECT images as floating data sets.

conventional MRI sequences, MR spectroscopy, PET and

Image registration was obtained by translating and

also SPECT images, may find their ideal place.

rotating the floating images according to CT images. Te

accuracy of the procedure was verified by several ana-

tomic landmarks. A previous analysis by Jaszczak phan-

12.4 Lymph Nodes in Prostate Cancer

tom had shown that the registration error of this

interactive procedure was less than 2 mm, according to

Te precise identification of the pathway of lymphatic

other literature data [33].

drainage is a very relevant issue when treating prostate

Our study confirmed the high sensitivity of ^99mTc-Ses-

cancer with high risk of lymph node involvement by

taMIBI SPECT for high-grade gliomas, which is compa-

radiotherapy. Typically, internal and external iliac nodes

rable or even higher than that of MRI in detecting

are included in the treatment volume, which is identified

remnant tumor tissue. Adding ^99mTc-SestaMIBI SPECT to

more on the basis of anatomical landmarks than on func-

MRI, it was possible to identify a larger size and to rede-

tional information on the real pathway in the single

fine the spatial distribution of GTV, as defined by MRI

patient. Such information is greatly relevant because

alone.

nowadays it is possible to optimize the treatment by using

Based on these considerations and waiting for a

intensity-modulated radiation therapy (IMRT), which

non-Cyclotron-dependent PET brain imaging, SPECT

allows precise shaping of the isodose curves to conform

208

functional images of the brain deserve to be studied more

to the delineated target [35]. A quite recent study investi-

in depth for the treatment planning of gliomas with the

gated the anatomic mapping of nodal disease in prostate

purpose of making new imaging modalities available,

cancer by using a magnetic resonance lymphangiographic

such as

¹²³I-a-methyl-tyrosine

(IMT-SPECT), which

technique [36]. Interestingly, the authors found that nodal

could be able to identify the presence, location and pos-

metastases tightly mapped relative to the large pelvic ves-

sibly the biological features of tumor tissue in order to

sels leading to a clinical target volume around not only

optimize the delivery of high-dose precision radiother-

the proximal external and internal iliac, but also the distal

apy [19].

common iliac vessels.

Our findings on ^99mTc-SestaMIBI SPECT imaging

Te technique of the sentinel node (SN) via ^99mTc-

demonstrated that the target volumes for radiotherapy

nanocolloid scintigraphy has been studied in prostate

planning of gliomas can be substantially modified

cancer in several surgical series with high sensitivity up to

(Figs. 12.4 and 12.5). Te average target volume on SPECT

93-96% [37].

Radiation Therapy Planning Using SPECT-CT

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tumor and regional lymph nodes were outlined

ing with 111In-pentetreotide in assessment of neuroendo-

crine tumours. Clin Endocrinol (Oxf). 2003;59:565-73.

10. Karger CP, Hipp P, Henze M, et al. Stereotactic imaging for

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phatic spread by using the SN technique and SPECT-CT

image fusion to identify the location of the potentially

involved nodes and to study the impact that such anatomic

information can have on conformal pelvic irradiation [38].

Brain

Twenty-three prostate cancer patients, candidates for

radical prostatectomy, were studied by CT and SPECT

11. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy

plus concomitant and adjuvant temozolomide for glioblas-

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toma. N Engl J Med. 2005;352:987-96.

nanocolloid. Te SN and other pelvic lymph nodes were

12. Van Meir EG, Hadjipanayis CG, Norden AD, et al. Exciting

clearly identified, and target and non-target structures

new advances in neuro-oncology: the avenue to a cure for

were drawn on SPECT-CT fusion images (Fig. 12.6).

malignant glioma. CA Cancer J Clin. 2010;60:166-93.

Subsequently, a three-dimensional conformal treatment

13. Combs SE, Gutwein S, Schulz-Ertner D, et al. Temozolomide

combined with irradiation as postoperative treatment of pri-

plan was performed for each patient.

mary glioblastoma multiforme. Phase I/II study. Strahlenther

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Onkol. 2005;181:372-7.

210

patients. Te SN was inside the pelvic CTV in 80.0% of

14. Schillaci O, Filippi L, Manni C, Santoni R. Single-photon

patients and received no less than the prescribed dose in

emission computed tomography/computed tomography in

85% of patients. Te most frequent locations of SN outside

brain tumors. Semin Nucl Med. 2007;37:34-47.

15. Aydin H, Sillenberg I, Von Lieven H. Patterns of failure fol-

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lowing CT-based 3-D irradiation for malignant glioma.

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Strahlenther Onkol. 2001;177:424-31.

identified by SPECT were found outside the CTV and

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211

Dosimetry Using SPECT-CT

13.1 For Targeted Radionuclide Therapy

from patient measurements. Tis information embodies

the input data for dose processing, while the other data

Marta Cremonesi (), Francesca Botta,

needed for dose calculation, namely the parameters

Amalia Di Dia, and Giovanni Paganelli

describing the physical properties of tissues and radionu-

clides, are incorporated in computation systems.

13.1.1 Introduction

A skilled analysis with such a task has to take into account

that: (1) a radiotracer is needed that suitably simulates ther-

Te role of dosimetry for radiation therapy is to guide the

apy, and not every radiopharmaceutical used for diagnostic

selection of the optimal treatment design, depending on

purposes is adequate for dosimetry; (2) a sufficient number

radiation modality, parameter setting, and clinical needs

of serial images should be acquired over a time period and at

of the single patient. Te best balance between the irra-

time intervals that entail all the kinetic phases of the thera-

diation of healthy tissues and target tissues allows improv-

peutic agent; (3) the more correct the activity quantification

ing the therapeutic ratio.

and the spatial association of activity to target/non-target

Dealing with targeted radionuclide therapy (TRT),

organs are, the more refined the dosimetry estimate.

external beam radiotherapy (EBRT), or brachytherapy,

Hybrid SPECT/CT imaging allows fulfilling the above

the common effort is to evaluate the absorbed dose dis-

requisites.

tribution as accurately as possible. Tis effort requires

Te array of radiopharmaceuticals for consolidated and

more or less complex calculations about the interaction

more recently developed TRT is summarized in Table 1

of particles with matter, and proper characterization and

along with the corresponding radiotracers useful for dosim-

localization of the tissues involved in the radiation

etry and the possible acquisition modality. Remarkably, the

field.

dosimetry can be determined based on SPECT/CT images

Te development of multimodality imaging combin-

for all therapeutic applications, but this is not the case for

ing functional and anatomic information allows more

PET/CT. In fact, options to mimic therapy include the use

accurate identification and spatial localization of uptak-

of low activities of the same radiocompound, if also a g- or

ing areas. Tis has been leading to important steps for-

b+-emitter (e.g., ¹³¹I, ¹⁷⁷Lu, and ⁶⁴Cu), or of the same thera-

ward in the last years, not only in diagnosis, but also in

peutic molecule labeled with a g- or b⁺-emitter isotope of

the dosimetry for treatment planning.

the same radionuclide (e.g., ¹²⁴I or ¹²³I for ¹³¹I), or of a radio-

Te contribution of PET/CT to the identification of

nuclide with similar chemical behavior (e.g., ¹¹¹In for ⁹⁰Y).

biological target volumes of EBRT is acknowledged.

Moreover, the tracer T_1/2,phys has to be compatible with the

Complementarily to PET/CT, the role of SPECT/CT,

biological half-life of the therapeutic agent. Tus, besides

offering better attenuation correction, increased specific-

the less widespread availability b⁺-emitters, the too short

ity, and accurate localization of disease than SPECT alone,

T_1/2,phys of some candidates (e.g., ⁶⁸Ga) makes SPECT g imag-

is swifly gaining relevance to tailor treatments [1, 2].

ing and also bremsstrahlung more valuable (e.g., with ¹³¹I,

Tere are in fact many applications - several of which are

¹¹¹In, ¹⁵³Sm, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ⁹⁰Y, etc).

described in the previous chapters - that can retrieve cru-

Te impact of image registration of SPECT and CT on

cial information for dosimetry from g-emitting radiotrac-

dosimetry accuracy is palpable, especially when dealing

ers. Tis chapter illustrates the contribution of SPECT/

with a time-sequential SPECT dataset. Dedicated studies

CT to dosimetry for TRT, EBRT, and brachytherapy.

have shown that even small mis-registrations might con-

214

sistently affect absorbed dose estimates, especially for

tumors of certain sizes and sites [5]. Tus, the inherent reg-

13.1.2 Dosimetry for TRT Using SPECT/CT

istration of the anatomical and the functional information

in SPECT-CT has consistently improved dosimetry, sim-

Te SPECT/CT features can be richly exploited in the

plifying the mass delineation in each 3D SPECT-CT data

field of dosimetry for TRT [3, 4].

set and allowing the generation of registered time-SPECT-

TRT consists of the systemic or locoregional adminis-

CT (4D) datasets based on CT-CT registration [2, 5, 6].

tration of a radiolabelled agent that specifically dis-

In addition, the quantitative images obtained by CT-

tributes depending on its own pharmacokinetics and

based attenuation correction are more accurate than those

metabolism.

obtained using conventional SPECT attenuation maps.

Dosimetry studies in TRT require the quantification

Further, the integration of the data collected by multi-

of the radiopharmaceutical uptake and its variation over

modality imaging may significantly improve the accuracy

time in all tissues of interest, as experimentally derived

of dose distribution calculation in organs at risk and

Dosimetry Using SPECT-CT

Table 1 Radiopharmaceuticals for dosimetry in the principle targeted radionuclide therapies

Radiopharmaceuticals

Corresponding radionuclides

3D acquisition for dosimetry

for targeted radionuclide therapy

for dosimetry

SPECT/CT

PET/CT

¹³¹I-Chloride; MoAbs; MIBG

¹³¹I

Yes

¹²³I

Yes

¹²⁴I^a

Yes

⁹⁰Y-MoAbs; peptides

¹¹¹In

Yes

(c)

⁹⁰Y^b

Yes

⁸⁶Y^d

Yes

⁹⁰Y-microspheres

^99mTc^e

Yes

(c)

⁹⁰Y^b

Yes

⁸⁶Y^d

Yes

¹⁷⁷Lu-peptides

¹⁷⁷Lu

Yes

¹⁵³Sm-EDTMP

¹⁵³Sm

^99mTc^f

Yes

¹⁸⁶Re-HEDP

¹⁸⁶Re

Yes

¹⁸⁸Re-HEDP; MoAbs; peptides

¹⁸⁸Re

Yes

^a124I: high costs, limited availability

^b90Y-Bremsstrahlung SPECT to confirm the predicted distribution: complex image corrections

^c90Y-PET imaging: feasibility under evaluation

^d86Y: short half-life, complex image corrections

^e99mTc-MAA used to mimic therapy

^f99mTc-MDP used to mimic therapy

tumor targets: whereas SPECT images alone allow 3D

vs. treatment efficacy [12-15]. Chapter 4 illustrates a

dose calculation only in homogeneous tissues, the avail-

few examples.

ability of combined SPECT and CT images allows 3D

•

Radiopeptide therapy of neuroendocrine and other

dose calculation also in inhomogeneous tissues, provided

tumors overexpressing somatostatin receptors with

computational methods are developed based on direct

⁹⁰Y- and

¹⁷⁷Lu-peptides.

¹¹¹In-pentetreotide images

Monte Carlo simulations [7, 8].

allow evaluating patients for recruitment and rough

Te assessment of the absorbed dose delivered during

prevision of therapy, but are not adequate for dosime-

any radionuclide therapy should be mandatory, as is cur-

try. In case of ⁹⁰Y-peptides, ¹¹¹In- or ⁸⁶Y-surrogates are

rently the case for EBRT. Tis is to rationally plan the

helpful (Table 1), although the latter are more critical

administered activity and/or to determine the need for

because of the complex corrections required and short

additional therapeutic approaches. In addition, such an

time available for data collection [16]. Radiopeptide

attitude would help to correlate the absorbed doses to

therapy needs to be divided into multiple cycles, this

biological effects (toxicity, response) [9], having finally

being a peculiar advantage: dosimetry evaluations

the safety and efficacy of TRT as the future goal.

can be performed before or during the first course of

Among the TRT applications that could benefit dosim-

therapy, or even repeated to follow possible dose

215

etry with SPECT/CT are:

variations at each cycle (especially in responsive

• Radioiodine treatment of metastatic thyroid cancer. Te

tumors). Tis has been done with ¹⁷⁷Lu-peptides using

contribution of dosimetry and of SPECT/CT has been

SPECT/CT [16, 17]. Moreover, the technical advances

published in several studies [10, 11], and interesting

of hybrid equipments and the improvements in

images are shown in Chap. 3.5.

image correction methods have shown the possibility

• Radioimmunotherapy of lymphoma and other cancers

of achieving reasonably accurate activity estimates also

with ⁹⁰Y-, ¹³¹I-, and ¹⁸⁸Re-radiolabelled monoclonal anti

from ⁹⁰Y-bremsstrahlung SPECT/CT [18-20]. Figure 1

bodies (e.g., ⁹⁰Y-ibritumomab tiuxetan, ¹³¹I-anti-CD20

illustrates the case of a patient with a pancreatic

rituximab, and ¹³¹I-L19SIP), given at standard adminis-

lesion (red arrow) with a diagnostic SPECT-CT from

tered activities or in myeloablative settings. Especially

¹¹¹In-pentetreotide and the corresponding bremsstrahl-

in the latter case, other critical organs other than bone

ung images acquired during therapy with ⁹⁰Y-DOTA-

marrow impose special efforts to minimize side effects

TATE for dosimetric purposes. Te different uptakes

Dosimetry Using SPECT-CT

⊡⊡Fig. 1 Dosimetry with SPECT-CT applied to radionuclide

injection of

¹¹¹In-pentetreotide;

(b) bremsstrahlung image

therapy. Transaxial and coronal slices of fused SPECT-CT show-

obtained during therapy, 24 h after the injection of ⁹⁰Y-DOTATATE

ing uptake in a pancreatic lesion (red arrow), the kidneys

(1.7 GBq) (Reproduced with permission of Ecancermedical

and the spleen: (a) Diagnostic image obtained 24 h after the science www.ecancermedicalscience.com/tv [19]

216

(lower in the tumor and higher in the kidneys) of

choice of radionuclide and activity to be administered.

¹¹¹In-pentetreotide vs.

⁹⁰Y-DOTA-TATE because of

Chapter 5 and Fig. 1 of Chap. 13.2 report a few exam-

their different receptor specificities are worth noting.

ples of radionuclide therapy for the treatment of men-

• Locoregional and systemic therapy of unresectable and/

ingiomas and high-grade gliomas [21].

or recurrent brain tumors, given as a further boost afer

• Terapy with ¹³¹I-MIBG addressed to neuroblastoma.

EBRT or adjuvant setting. Especially in patients already

Chapter

3.2 offers clarifying SPECT/CT images.

pre-irradiated, the higher dosimetry accuracy with

Dosimetry, which can be performed using +¹³¹I- or

SPECT/CT can direct the decision-making for a better

¹²³I-MIBG as tracers, has special importance in

Dosimetry Using SPECT-CT

CT image of the liver obtained before liver radioem-

significantly increase the accuracy of dose distribution

bolization showing hepatic metastasis (Fig. 2a) and a

calculation in organs at risk and tumor targets.

SPECT image acquired afer the intrahepatic admin-

Whereas SPECT images alone allow 3D dose calcula-

istration of ^99mTc-MAA for pre-therapeutic evaluation

tion only in homogeneous tissues, the availability of

(Fig. 2b). Te 3D absorbed dose distribution calcu-

combined SPECT and CT images allow 3D dose cal-

lated on the basis of SPECT/CT images is also reported

culation also in non homogeneous tissues, provided

(Fig.

2c). Te results obtained on bremsstrahlung

developing computational methods based on direct

image corrections have also encouraged the acquisi-

Monte Carlo simulations [30, 31]. For example, the

tion of ⁹⁰Y- SPECT/CT to ultimately assess dosimetry

comparison between the dose distribution maps

estimates [20] based on the microsphere distribution

derived by the same 3D activity distribution in bony

afer radioembolization.

lesions, combined with either a uniform water density,

•

Treatment of skeletal metastases. Te improved bone

or instead the CT-derived spatial tissue density distri-

lesion characterization by SPECT/CT (Chap. 5) may

bution, has evidenced moderate differences between

lead to revising the therapeutic activity of curative

radiation doses. Absorbed doses derived for a patient

or palliative TRT, including, e.g.,

¹³¹I,

¹³¹I-MIBG,

administered with ⁹⁰Y-peptides, showed an overesti-

⁹⁰Y/¹⁷⁷Lu-peptides, ¹⁵³Sm-EDTMP, etc. [29-31]. With

mate around 10% when neglecting the real density in

the aim to enhance efficacy while keeping red marrow

favor of uniform water density approximation

doses acceptable, a refined dose evaluation of bony

(Fig 3a-b). Although such difference could be consid-

lesions based on SPECT/CT can make a difference.

ered as negligible within the overall uncertainties typi-

Te possibility to associate the punctual uptake of a

cal of internal dosimetry, they deserve to be taken into

therapeutical agent to the anatomical and density

account and better investigated. Further analyses

information becomes very important. Whether, or in

might deepen the impact from various radionuclides

which extent, the tissue density information from CT

and maybe different skeletal composition, lesion

is relevant for dosimetry is an issue of interest. In prin-

dimensions and localization. Conversely, preliminary

ciple, sites with variable density or at interfaces might

results in a patient treated with

⁹⁰Y-peptides have

heavily impact on the dose distribution computation,

shown underestimate in lesions at the lung-tissue

as compared to uniformity. Tus, the integration of

interface when the hypothesis of uniform density was

the data collected by multimodality imaging may

accepted (Fig 3c-e).

218

Dosimetry Using SPECT-CT

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Dosimetry Using SPECT-CT

30. Bianchi L, Baroli A, Marzoli L, Verusio C, Chiesa C, Pozzi L.

on management in 43% of patients [38]. Figure 1 illus-

Prospective dosimetry with

99mTc-MDP in metabolic

trates an example of a SPECT/CT acquisition of a glio-

radiotherapy of bone metastases with 153Sm-EDTMP. Eur J

blastoma multiforme grade IV astrocytoma.

Nucl Med Mol Imaging. 2009;36:122-9.

31. Loeb DM, Hobbs RF, Okoli A, et al. Tandem dosing of

•

Prostate cancer treatment. Among patients undergoing

samarium-153 ethylenediamine tetramethylene phosphoric

radiotherapy, pre-treatment ProstaScint^® SPECT/CT of

acid with stem cell support for patients with high-risk osteo-

extra-periprostatic metastatic prostate cancer indepen-

sarcoma. Cancer. 2010;116(23):5470-8.

dently and significantly predicted an increased risk of

biochemical failure in those presenting a clinical diag-

nosis of localized adenocarcinoma of the prostate [40].

13.2 For External Beam Radiation

Furthermore, ProstaScint^® SPECT/CT was reported to

Therapy and Brachytherapy

accurately identify biological target volumes for treat-

ment planning in brachytherapy seed implants: in a

Massimiliano Pacilio (), Chiara Basile,

dose-escalation study in patients with T1c-T3b N× M0

Concetta De Cicco, and Lucio Mango

prostate adenocarcinoma, pretreatment SPECT/CT

permitted achieving dose intensification to occult

Te role of SPECT/CT in treatment planning procedures

tumor targets, without increasing rectal toxicity [41].

for EBRT and brachytherapy has grown considerably in

Also, a significant impact of ProstaScint^® SPECT/CT

the last few years (see also Chap. 12). Te contribution of

imaging has been demonstrated to modify the delinea-

SPECT/CT is greatly appreciated for some well-defined

tion of the prostate fossa clinical target volume (CTV)

radiation therapy applications with external sources; a

in patients scheduled for external beam radiation ther-

brief overview is reported here, with mention of some

apy afer prostatectomy [42].

specific problems concerning tumor and organ delinea-

•

Functioning organ sparing in lung cancer treatment.

tion on SPECT/CT images.

SPECT/CT-guided intensity-modulated radiation

•

High-grade brain gliomas and other cerebral mass treat-

therapy (IMRT) for lung cancer is currently under

ments. Even though contrast-enhanced CT and

investigation to establish a methodology for selecting

T1-weighted MRI allow accurate delineation of brain

the beam arrangement able to reduce the dose to the

tumor margins, anatomical imaging can fail in differen-

SPECT-defined functioning lung [43-45]. In a recent

tiating residual tumor infiltration versus surrounding

study, the influence of the number of beams used in

edema, as well as recurrent tumor versus radiation

the IMRT plan on V5, V15, V20 and V30 for the lungs

necrosis and gliosis, afer surgery and/or radiotherapy

(the percent functional lung volume receiving a dose

treatments [32]. In some cases PET with [¹⁸F]FDG may

greater or equal to 5, 15, 20 and 30 Gy, respectively)

not be adequate, but several PET tracers are now avail-

has been quantified. A sensible reduction of V5 and

able, such as ¹¹C-choline, ¹⁸F-FDOPA, ¹¹C-methionine,

V15 (recently associated with radiation pneumonia)

¹⁸F-fluoroethyl-L-tyrosine and ¹⁸F-fluorocholine [33-

has been reported when using fewer beams in IMRT

36]. Nevertheless, when the availability of PET/CT is

planning

[43]. Preplanning SPECT scanning may

limited, as reported in Chap. 12, SPECT/CT can be

contribute to assessing the ventilated lung volume

employed for these clinical indications using various

included in PTV, and thus to estimating the dose

221

radiopharmaceuticals, such as ²⁰¹Tl-chloride, ^99mTc-tet-

delivered to the functional lung, and possibly to opti-

rofosmin,^99mTc-sestamibiandL-3-¹²³I-a-methyltyrosine.

mizing the treatment depending on the patient’s case

Several studies have demonstrated the usefulness of

history [44]. Figure 2 reports an example of the differ-

SPECT/CT for accurate preoperative detection and

ences in the treatment planning strategy considering

localization, and for radiotherapy planning and treat-

functioning lung sparing [44]. Te CT images from a

ment monitoring [37]. SPECT/CT allows good accu-

hybrid SPECT/CT system are useful for localization

racy in the anatomical localization of viable tumor

and attenuation correction, but treatment planning

lesions versus adjacent sites with physiological tracer

must be performed on the images obtained from a CT

uptake, such as the ventricles, choroid plexus and

system commissioned for RT treatments. Proper

venous sinuses [38-39], with a proven clinical impact

co-registration methods of the functional images on

Dosimetry Using SPECT-CT

⊡⊡Fig. 1 SPECT/CT for biological target volume contouring

glioblastoma multiforme grade IV astrocytoma

(images

(automatic segmentation) in radiotherapy of brain lesions: obtained with a GE Infinia Hawkeye 4 SPECT/CT system)

222

the CT images used for RT planning are currently

• Follow-up for cardiac complications from thoracic EBRT

under study. CT images from a hybrid SPECT/CT

treatments. In some cases, SPECT/CT can be also

scanner have to be registered to the planning CT, and

employed for follow-up studies of radiation-induced

then the same transformation has to be applied to the

toxicity effects, helping to better define dose con-

SPECT images. However, new problems are emerging:

straints for treatment planning. For instance, the inci-

it has been reported that the application of non-rigid

dence and prevalence of radiation-induced cardiac

registration methods

(which generally provide a

complications could be better established, including:

higher degree of accuracy than rigid methods) may

acute and chronic pericardia, coronary artery disease

result in unacceptable changes to the SPECT intensity

(CAD), conduction abnormalities, valvular insuffi-

distribution that would preclude its use in RT plan-

ciency and cardiomyopathy. Most of the follow-up

ning [46].

data are referred to the older RT techniques. In the last

Dosimetry Using SPECT-CT

tion-induced cardiac complications with each of these

RT techniques have not yet been investigated ade-

quately [47-49]. SPECT/CT-gated myocardial perfu-

sion imaging (see Chap. 6) has great relevance for

investigations on the prevalence, pattern and location

of myocardial perfusion abnormalities.

•

Delineation of biological target volume (BTV) and/or

functioning organs on SPECT/CT. Te capability to

identify tumors based on functional characteristics,

including metabolism, proliferation, hypoxia, and the

concentration of specific antigens and metabolites, is

highly important for radiation therapy. To this aim,

accurate segmentation may help to better customize

the radiotherapy treatments, improving radiation tar-

geting. Moreover, better tissue differentiation allows

providing more correct dosimetry data, which is asso-

ciated with eventual response and/or side effects. Tumor

volume estimations and segmentations are also impor-

tant for treatment monitoring. Furthermore, as men-

tioned above, in some cases delineation of functioning

parts of critical organs is of great importance for

SPECT/CT-guided radiation therapy. Delineation on

CT or MRI images is usually based on visual contour

assessments. Conversely, the utilization of PET or

SPECT for accurate quantitative measurements of

uptake distribution can be more critical because of the

high noise and low spatial resolution of these images.

Even though a good signal-to-noise ratio is present,

when the observed volume is less than twofold the spa-

tial resolution of the scanner, the uptake measurements

can be very inaccurate because of partial volume effects.

Tis might compromise the use of SPECT systems in

some cases, since the spatial resolution is known to be

Fig. 2 SPECT/CT for lung perfusion for tissue sparing in

⊡⊡

relatively poor. In any case, new processing algorithms

radiotherapy. Isodose distributions on an axial CT image of the

nine-field IMRT plan with no ventilated lung avoidance (a), nine-

and methods may help to recover information. Studies

field IMRT plan with ventilated lung avoidance (b) and a three-

on PET images have led to the development of different

field IMRT plan with ventilated lung avoidance (c): the 66.5 Gy

segmentation methods. Teir use also for SPECT needs

223

isodose line (95% of prescription dose, blue line) conforms to

to be carefully evaluated since the source of errors and

the PTV (purple) on this slice for all three plans; ventilation vol-

umes segmented with SPECT/CT by 50% (green) and 70% iso-

limitations is more emphasized for SPECT images

count curve (brown) are also represented (Reproduced with

compared to PET.

permission of Munawar et al. [44])

Visual segmentation using different window level

settings and look-up tables is the most common and

decades, several improvements have been made to

widely used technique for PET images, but the method

EBRT techniques from the 3-dimensional conformal

has low reproducibility and is highly operator-depen-

RT (3DCRT) to IMRT and proton therapy, also includ-

dent [50-51]. Segmentation adopting a fixed threshold

ing respiratory gating. For thoracic irradiations (such

(i.e., the use of a given percentage of the maximal

as lef-side breast cancer, esophageal cancer, lym-

activity) is also widespread; however, a fixed threshold

phoma, etc.), the incidence and prevalence of radia-

value in the range of 40-50% (as in most applications

Dosimetry Using SPECT-CT

reported in the literature) might lead to significant

39. Schillaci O, Filippi L, Manni C, Santoni R. Single-photon

emission computed tomography/computed tomography in

errors in the volume estimation, depending on the

brain tumors. Semin Nucl Med. 2007;37:34-47.

lesion size and the lesion-to-background contrast

40. Ellis RJ, Zhou EH, Fu P, et al. Single photon emission

[52-54]. In the last few years, additional image seg-

computerized tomography with capromab pendetide

mentation approaches have been proposed. Tese

plus computerized tomography image set co-registra-

tion independently predicts biochemical failure. J Urol.

include adaptive thresholding, region growing, classi-

2008;179:1768-73.

fiers, clustering, edge detection, Markov random field

41. Ellis RJ, Zhou H, Kaminsky DA, et al. Rectal morbidity afer

models, artificial neural networks, deformable models,

permanent prostate brachytherapy with dose escalation to

atlas-guided, and many other approaches [51, 55-61].

biologic target volumes identified by SPECT/CT fusion.

Brachytherapy. 2007;6:149-56.

Despite the remarkable progress that automated image

42. Jani AB, Spelbring D, Hamilton R, et al. Impact of radioim-

segmentation has made, performance validation in the

munoscintigraphy on definition of clinical target volume for

clinical setting remains the most challenging issue

radiotherapy afer prostatectomy. J Nucl Med.

2004;

[51, 62]. Adaptive thresholding is considered the most

45:238-46.

43. McGuire SM, Marks LB, Yin FF, Das SK. A methodology for

accurate, and it has also been validated thoroughly

selecting the beam arrangement to reduce the intensity-

using histological data for PET segmentation [51, 57,

modulated radiation therapy (IMRT) dose to the SPECT-

63]. For SPECT/CT, a new adaptive thresholding

defined functioning lung. Phys Med Biol. 2010;55:403-16.

method based also on recovery coefficients has been

44. Munawar I, Yaremko BP, Craig J, et al. Intensity modulated

radiotherapy of non-small-cell lung cancer incorporating

proposed and is currently under study for clinical vali-

SPECT ventilation imaging. Med Phys. 2010;37:1863-72.

dation [64-65]. Figure 1 illustrates an example of high-

45. Bates EL, Bragg CM, Wild JM, Hatton MQ, Ireland RH.

grade glioma contours obtained with an iterative

Functional image-based radiotherapy planning for non-

thresholding method (ITM, bottom right of figure).

small cell lung cancer: a simulation study. Radiother Oncol.

2009;93:32-6.

46. Yin LS, Tang L, Hamarneh G, et al. Complexity and accuracy

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225

Index

¹¹C-methionine, 145

Coronary calcifications, 136

Abdominal and pelvic traumas, 6-7

Crohn’s disease and colitis ulcerosa, 170

Abdominal bleeding, 5, 6

Abdominal infections, 168

Absorbed dose, 214, 215, 217-219

Acute appendicitis, 6

Diabetic foot, 168, 169

Acute bleeding, 188

[111In]-Diethylene triamine pentacetate acid [DTPA]-

Acute cholecystitis, 6

octreotide, 17, 88

Acute pulmonary embolism, 196

Dosimetry, 214-219, 221-224

Adrenal gland, 52, 56, 63, 64, 82-83

Duodenogastric reflux, biliary, 6

Anti-granulocyte antibodies, 170

Artifacts, 10-13

Astrocytomas, 122, 124, 125

Emergency, 4-7

Attenuation correction, 10, 12, 13

Endocarditis, 168-170, 176

Epileptic focus, 6

External beam radiotherapy (EBRT), 214-216,

Biliary atresia, 6

221-223

Biliary colic, 6

Biological target volume (BTV), 214, 221-223

Bleeding, 4-7

Blue dye, 152

F16 antibody, 96

Bone fracture, 6

¹⁸F-DOPA, 18, 52

Bone pain, 6

Fever of unknown origin, 168, 170

Bone scintigraphy, 6, 106, 107, 114

Fistula, 6, 7

Brain death, 5-7

Fusion imaging, 2

Brain tumors, 216, 221

Breast carcinoma, 152-154

⁶⁸Ga-DOTA-NOC, 18

Gamma camera, 10-12

Carcinoid tumors, 18, 21-23, 26-27, 36-37, 40-41, 44-45,

Gamma emitters, 3-6

52, 86, 89

Ganglioneuroblastomas, 52

Cardiac perfusion, 5

Gastrointestinal bleeding, 188, 190-193

CBF-SPECT, 5, 6

Glia-derived tumours, 122

Cerebral blood flow, 5

Glioblastomas, 122

Child abuse, 6

Glioma(s), 122, 124-127, 207-208, 216, 221, 224

Clinical target volume (CTV), 204, 205, 208, 210

Gross tumor volume (GTV), 204, 207

227

S. Fanti et al., Atlas of SPECT-CT,

Index

Microcolloids, 152

Misalignment, 136, 141

Head trauma, 5, 7

Multi-vessel coronary artery disease, 134, 136

Hepatobiliary scintigraphy, 3, 6, 7

Musculoskeletal infections, 169, 170

Hurthle cell thyroid cancer, 70

Myocardial abscesses, 170

Hybrid machines, 2, 7

Myocardial infarct (MI), 5

Hyperparathyroidism (HPT), 144-148

Myocardial ischemia, 136

Myocardial perfusion and viability, 134

Myocardial perfusion imaging (MPI), 134, 136-140

¹²³I-a-methyl-tyrosine, 208

Myocardial scintigraphy (MS), 5

¹³¹I-anti-CD20 rituximab, 215

¹³¹I-F16, 97, 103

¹³¹I-L19SIP, 96-98, 100, 101, 215

Neural crest tumors, 17, 18, 52

Image-guided radiotherapy, 204

Neuroblastoma(s), 18, 52, 53, 216

¹²³I-MIBG, 18, 52, 56, 58, 62, 64

Neuroendocrine, 215

¹¹¹In-biotin, 182-184

Neuroendocrine tumors (NETs), 17-19, 24-25, 28-31,

¹¹¹In-Capromab pendetide, 80

38-39, 47-49, 60, 86, 88-90, 95

Infected joint and vascular prosthesis, 168

Neurological infections, 168

Infection imaging, 167-184

Inflammation, 168-170, 175

Inflammatory bowel disease(s), 168, 170

¹¹¹In-oxine, 168-170

Osseous metastases, 106, 107, 110-117

¹¹¹In-oxine-labelled WBCs, 168, 169

Osteomyelitis, 168-170, 178, 181

Intraoperative gamma probe, 152

Iodine, 52, 65-70, 96, 97

I-124 PET/CT, 70

Paragangliomas, 18, 52, 61-62

Parathyroid adenoma, 144-146, 148

Parathyroid gland, 144, 147

^81mKr, 196, 197, 199-202

Parathyroid hormone (PTH), 144

Krypton, 196

Perfusion lung scintigraphy (PLS), 5

Pheochromocytomas, 18, 52, 53, 59-64

Poly-traumatized, 6

L19 antibody, 96

Postoperative abscesses, 168

Leakage, and fistula, 6, 7

Primary hyperparathyroidism (pHPT), 144

Liver cancer, 217

ProstaScint, 80-85

Lung cancer, 221

Prostate cancer, 36, 37, 80, 81, 83, 153, 208,

Lung infections, 168

210, 221

Lung scintigraphy, 196, 197

Pulmonary embolism, 5, 7

228

Lymphoma, 215, 223

Pulmonary hypertension, 196

Lymphoscintigraphy, 152-154

Radiation dose, 134, 138, 139

Macroaggregated albumin, 196

Radioimmunotherapy, 80, 96, 100-103

MDCT angiography, 196, 197

Radioiodine, 65-70, 75, 78

Meckel’s diverticulum, 4, 6

Radioiodine ablation, 66, 69

Medullary thyroid carcinoma, 52

Radiolabeled red blood cell, 6

Melanoma, 152, 153, 155, 156

Radiolabelled white blood cell scintigraphy, 168

Meningiomas, 122, 128-132

Radionuclide therapies, 18, 52

MIBG scintigraphy, 52, 53

Rheumatoid arthritis, 6