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PET-CT Beyond FDG A Quick Guide To Image Interpretation-3540939083 PDF
PET-CT Beyond FDG A Quick Guide To Image Interpretation-3540939083 PDF
13
Stefano Fanti, Prof. Luigi Mansi, Prof. Dr.
University of Bologna Universit Napoli
Policlinico S.Orsola-Malpighi Ist. Scienze Radiologiche
Medicina Nucleare Piazza Miraglia, 2
PAD 30-Via Massarenti 9 80138 Napoli
40138 Bologna Italy
Italy luigi.mansi@unina2.it
stefano.fanti@aosp.bo.it
DOI: 10.1007/978-3-540-93909-2
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protective laws and regulations and therefore free for general use.
Product liability: The publishers cannot guarantee the accuracy of any information about dosage and
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consulting the relevant literature.
The present book was made possible by the efforts of the entire scientific community of
nuclear medicine and radiopharmacy that in last 30 years has pursued the research in the
field of molecular imaging. The authors in particular want to mention the outstanding
contribution of great scientists as Michael Phelps and Markus Schwaiger to the present
development of PET imaging.
Stefano Fanti owes thanks again to all his colleagues, and in particular to Dr. Mario
Marengo, whose vision in planning Bolognas PET site was determinant for every result
obtained, Dr. Stefano Boschi for patiently providing all the required tracers with great
professionality, and to Dr. Paolo Castellucci, Dr. Cristina Nanni, and Dr. Arturo Chiti for
their invaluable capabilities and friendship.
Mohsen Farsad wishes to record, with appreciation, the support and commitment
offered by the staff of nuclear medicine of Bolzano Hospital and want to thank the follow-
ing individuals who have assisted him in various ways: Dr. Patrizia Pernter, Dr. Alessandro
Imondi, Dr. Federica Ferro, and especially Dr. Luzian Osele. Finally thanks are extended
to Rosanna who graciously encouraged him to continue working on realization of this
atlas.
Luigi Mansi dedicates his contribution to Nagia, his wife, and to his son David, to fur-
ther stimulate the realization of his dream: become one of us, a molecular imager search-
ing for the keys opening the mind and the eyes to the knowledge.
Contents
Franca Chierichetti U.O. Medicina Nucleare Centro PET, P.O. Castelfranco Veneto
(ULSS 8 Regione Veneto), Castelfranco Veneto (TV), Italy
Rodney J. Hicks Centre for Molecular Imaging, Peter MacCallum Cancer Centre,
Melbourne, Victoria, Australia
Heikki Minn Turku PET Centre and Department of Oncology and Radiotherapy,
Turku University Hospital, Turku, Finland
Diagnostic imaging is based on two different approaches How to Improve Diagnostic Accuracy
acting as two separate monocular visions: (a) morpho- with PETFDG
structural imaging, analyzing anatomy (structure and
morphology) and using pathology as the golden stan- False Negative and False Positive Results
dard; (b) functional imaging, analyzing physiology (func- of PET-FDG
tion) and using pathophysiology as a reference to define
the disease. In oncology, the results concerning neoplastic lesions not
Traditionally, when multiple diagnostic contributions detected by the procedure are called false negative results
are available, the final diagnosis is achieved through a of FDG. Conversely, false positive results are those con-
visual comparison of the different studies. The computer nected with benign lesions, showing FDG uptake.
revolution, permitting work on digital matrixes, has cre- It has to be pointed out that false negative and false
ated the option to fuse images together. In this way, it is positive results can also be the consequence of pitfalls and
possible to overlap two different images, separately artifacts. For a deeper understanding of these problems
acquired, in a new fused image, including both mor- we suggest a reading of the Atlas of PET-CT: A Quick
phostructural and functional information, for a patient. Guide to Image Interpretation (Springer, 2009).
A major improvement in fusion imaging is the advent A hybrid PET-CT scanner permits higher accuracy
of the so-called hybrid machines, i.e., of scanners hav- with respect to PET alone, because of the added morpho-
ing the capacity to produce two studies simultaneously. structural information and the anatomical location of the
Today, while Positron Emission Tomography-Magnetic FDG activity allowed by CT. This advantage is particu-
Resonance (PET-MR) is still in the prototype phase, the larly significant in evaluating areas with a complex anat-
Single Photon Emission Tomography Computed omy, e.g. the head and neck, or partially covered by the
Tomography (SPET-CT) is already in clinical practice. emunctory system, e.g. along the ureteral course; a major
But among hybrid machines, the leading position is cer- diagnostic improvement is obtained in the case of small
tainly occupied by PET-CT, by now a primary tool in the lesions, such as the evaluation of a lymph node neoplastic
whole diagnostic scenario. involvement. Despite using PET-CT, false negative and
It has to be pointed out that when a PET-CT is used, false positive results are, however, present. An improve-
while the CT information remains the same, the PET ment in sensitivity and specificity with the use of PET
component can give various diagnostic contributions, radiotracers other than FDG, can therefore significantly
depending on the radiotracer used. increase overall diagnostic accuracy.
At present, more than 95% of PET studies worldwide With respect to methodology, many causes can affect
are performed in oncologic patients, using F-18 Fluoro- glucose kinetics, creating difficulties in FDG utilization.
deoxyglucose (FDG). But, despite its high diagnostic The major problem is high glucose serum levels, as
accuracy in determining the pivotal role in the restaging observed, in particular, in diabetes; but many other con-
(and staging) of the neoplasm, FDG is handicapped by ditions can determine an unfavorable physiological and/
false negative and positive results, creating limitations in or para physiological distribution, creating pitfalls and
the differential diagnosis of cancer. Moreover, PET- FDG artifacts decreasing PET-FDG accuracy. For example, it is
shares with all the other diagnostic techniques the inabil- well known that determining a nonspecific FDG uptake
ity to answer all the questions of the oncologist, the sur- requires correct timing for a reliable evaluation of patients
2 who have undergone surgery, radiotherapy, or chemo-
geon, and the radiotherapist. It cannot function alone,
either in the diagnostic field, or in giving all the informa- therapy. Therefore, the availability of radiotracers not
tion connected with prognosis and pursue a tailored affected by conditions such as high glucose levels, inflam-
strategy for each patient. Therefore, despite its primary mation, altered permeability or vascularity, can help in
role, there is a wide range of indications in oncologic finding a rationale to choose an alternative to FDG. Thus,
patients that other radiotracers may be useful, and in this a more effective clinical value can be reached, for exam-
chapter we shall try to understand them. ple, in diabetic patients, or when the clinical history of
Importance of Radiotracers Other than FDG in Oncology 1
the patient suggests that the analysis obtained by using follow up of patients affected with neuroendocrine
FDG is not reliable. tumors and thyroid carcinomas, the presence of FDG
uptake, which is an expression of de-differentiation, is a
negative prognostic factor.
How to Increase Sensitivity Another possibility of increasing overall sensitivity
with Respect to FDG with respect to FDG is the use of radiotracers allowing a
higher L/B ratio on the basis of a more favorable uptake
False negative results of PET-FDG are mainly due to mechanism. An example (see Chap. 5) is the detection
lesions that are too small to be PETs spatial resolution, of bone metastases, where a mismatch can be observed
which is usually above 5 mm. It has to be pointed out that between FDG, concentrating on the pathological skele-
the positive indicators as FDG, i.e., radiotracers with a tal content, and F-18 fluoride, becoming part of the
higher uptake in lesions than in the surrounding normal mineral bone matrix. As a consequence, radio-fluoride
tissue, can also occasionally detect lesions that are less can detect a higher number of skeletal metastases in
than the spatial resolution value. As the image is the result patients affected by tumors, metastasizing through a
of differences in concentration, the detectability of the neoplastic involvement determining early osteobastic
lesion depends mainly on the lesion/background (L/B) response (as it frequently happens in prostate, breast
ratio. To use a simile, it is easier to see an ant on white and lung cancer). Conversely, FDG can detect a higher
marble on a sunny day than a black cat on a dark night. number of malignant lesions in patients with myeloma
As a result, as demonstrated by bone scans, it is possible because of the late involvement of a periosteal reaction
to detect lesions many months before they attain the in the subjects. Therefore, radio-fluoride can find a clin-
theoretically minimum detectable size. This favorable ical indication during follow up (and/or staging) of
condition, creating a premise for an early diagnosis, hap- patients with cancer with a high prevalence of bone
pens when a high L/B ratio is achieved. It depends more metastases, when there is an early osteoblastic reaction.
on the uptake mechanism of the radiotracer than on the Moreover, in some cases, the complementary informa-
PET scanner. With respect to FDG, a higher L/B can be tion provided by fluoride about FDG can be utilized to
achieved by different radiotracers allowing a higher better evaluate the skeletal involvement to adjacent
tumor uptake and/or a lower background activity. malignant lesions.
Independent of the size, not all tumors present a higher Analysis of the normal FDG distribution in humans
FDG uptake with respect to normal tissues. Therefore, shows that the highest uptake is at the level of the brain,
false negative results can be observed even in patients the only organ to use glucose exclusively as carburant.
with tumors of 1 cm or more, characterized by a normal Therefore, although PET-FDG is born evaluate brain dis-
or reduced glucose metabolism. It can happen under eases, the high activity in the normal gray matter creates
many conditions, in differentiated types of tumors, in the difficulties in tumor detection. Therefore, although an
3
presence of slow tumor growth, and in cystic and/or important role in dementia and in prognostic evaluation
mucinous lesions. For example, many false negative of primary cancer, PET-FDG cannot be considered a reli-
results are observed in patients with prostate cancer or able procedure in detecting brain metastases. Moreover,
well-differentiated neuroendocrine tumors. In the follow- despite the added value of CT (or MRI) in precisely local-
ing chapters of this Atlas, the ability of radiotracers such izing FDG uptake and anatomical structures, diagnosis of
as choline, somatostatin analogues, acetate, DOPA and recurrence can be difficult both because of the possible
tryptophan to significantly improve sensitivity in these presence of faint nonspecific uptakes and the confusion
patients is demonstrated. However, it is interesting to note caused by normal tissue, due to the partial volume effect.
that, despite the low sensitivity in patients with well-dif- To avoid these limitations, the use of radiotracers with a
ferentiated tumors, FDG plays an important prognostic minimal uptake in the normal brain has been proposed.
role in the follow up of these subjects. For example, in the The best results achievable for a clinical use are provided
1 Importance of Radiotracers Other than FDG in Oncology
Brain cancer. To improve diagnostic accuracy in brain better accuracy is permitted by the simultaneous CT
cancer, the main strategy is to use radiocompounds not acquisition, acting mainly through a significant reduc-
concentrated in the normal brain. The ideal radiotracer tion of false positive results.
could also have a specific uptake mechanism, permitting a
differential diagnosis between benign and malignant
lesions. At present, the main category of tracers already in Why and When to Use Different Radiotracers
clinical practice is that of amino-acids, having as clinical
with Respect to FDG: To Answer Different
prototype methionine and thyrosine. Amino-acids present
Questions
an increased uptake in tumors, but not in the normal brain
and in inflammatory lesions. Therefore they can improve
In modern medicine, tumor detection is certainly the
accuracy with respect to FDG (and CT and MRI) in the
major request of the clinician, but it does not provide all
diagnosis of tumor recurrence, acting both on sensitivity
the information needed for a diagnostic and therapeutic
and specificity. Conversely, because of their presence in
strategy tailored for each single patient. Therefore, a
both benign and malignant tumors, they are not reliable
wide field of applications for radiotracers other than FDG
for a prognostic evaluation. A less significant clinical inter-
is available, to give more information, and answer many
est is seen with the use of radio-choline and acetate.
questions not answered by FDG, especially those con-
Whole body cancer. To improve the diagnostic accu-
nected with prognosis and therapy.
racy of FDG in patients with whole body cancer, one of
Some of the most interesting possibilities already
the main strategies is to choose radiocompounds concen-
available in the clinical field in humans are considered
trating through an uptake mechanism present in the dif-
here, with a deeper analysis of the clinical aspects in spe-
ferentiated tumors.
cific chapters.
a. A favorable result can be obtained using radiotracers Prognostic information. A promising approach to add a
concentrating through an oxygen dependent mecha- relevant clinical improvement to FDG in prognostic eval-
nism. This is typical of the differentiated tumors with uation and in better defining the tumor response is related
a substantially conserved regular vascular support and to the use of radiocompounds tracing the growth rate.
a not significant neo-angiogenesis. This rationale has The best proposal, already in clinical practice, is linked to
been used for proposing radiotracers such as acetate the use of radiolabeled thymidine (see Chap. 9), a marker
and choline, both defining an increased metabolic ac- of the DNA multiplication rate. This information,
tivity not depending on anaerobiosis. Because of the although nonspecific, is different from that obtained by
lack of vesical concentration, the use of these radio- FDG, because it is not significantly influenced by anaero-
compounds has found clinical value in tumors such as biosis and the presence of inflammatory cells. FLT could
prostate cancer, finding a possible clinical role also in also be important in the near future for a reliable evalua-
hepatomas, renal cancer and brain tumors. tion of tumor response. In fact, FDG plays a significant
b. A more specific approach is utilizing the peculiar role in this field, but with an uptake mechanism not
characteristics of some tumors. A very effective clini- strictly related to the growth rate. Although its contribu-
cal application is the use of somatostin analogues in tion will certainly remain important for this application,
neuroendocrine tumors, or the use of cathecolamine FLT could occupy a clinical role in better defining an
early response. 5
analogues in pheocromocytoma and other tumors
showing increased metabolism. Similarly, a higher
Hypoxia. The presence or absence of hypoxia is relevant
accuracy in restaging differentiated thyroid cancer is
in predicting therapeutic efficacy. These data can create
obtained with I-124 iodide, which has the advantage
an important diagnostic premise, mainly in the evalua-
of also permitting a more rigorous quantitative evalu-
tion of patients undergoing radiotherapy.
ation of the corresponding gamma emitters.
c. As previously described, an increased sensitivity in Receptor state. It is well known that the presence of recep-
detecting bone metastases can be obtained with F-18 tors is crucial, both in defining prognosis and in better
fluoride. It has to be pointed out that this radiotrac- deciding a therapeutic strategy. In this sense, clinical
er presents a nonspecific, although sensitive, uptake improvement can be obtained, for example, using radio-
mechanism, i.e., increased osteoblastic activity. A compounds tracing hormone receptors (estradiol and
1 Importance of Radiotracers Other than FDG in Oncology
6
Chapter 2 Considerations About
PET Isotopes
Nuclear Medicine and Molecular Imaging phy because radioiodines concentration in normal and
differentiated malignant cells has become a matter of
Human beings, like all living organisms, are made of bio- importance for the molecular biologist; in fact, through
molecules. Health can be considered as the expression of the molecular thyroid scintigraphy, it is possible to dem-
homeostasis, i.e., the ability of a system to regulate its onstrate the in vivo presence of the iodine symporter gene
internal environment, thereby tending to maintain a sta- both in normal and in neoplastic cells.
ble and normal condition. In this sense, the real essence Therefore, NM is and has ever been Molecular
of life is the phenomenon in which multiple dynamic Imaging; if this term sounds new, born in the third mil-
equilibrium and regulation mechanisms are needed to lennium, it is only because we have recently entered the
make homeostasis possible. Many diseases result from Genome era, with gene and bio-molecules at the center of
disturbances in homeostasis and are characterized by a the diagnostic universe; a further impulse to the diffusion
condition known as homeostatic imbalance, where a of this term has been given by the incredible technologi-
molecular system goes out of equilibrium. cal evolution: it is possible today to study bio-phenomena
Based on this premise, one of the most effective with a very high spatial and temporal resolution, enabling
approaches to diagnose and treat diseases is to follow bio- to detect and characterize lesions sub-millimeters (in ani-
molecular kinetics in the normal state (physiology) and mal imaging). The best instrument to image bio-mole-
in illness (pathophysiology). This can become a reality cules in humans is PETCT, which gives standard
when tracers for that specific molecule are available. To morpho-structural information with CT and a variegated
follow the bio-molecular kinetics, without interfering spectrum of functional solutions through the PET
with the native molecule, tracers need to be detected by scanner.
an outside scanner to become a diagnostic tool. As described in the previous chapter, although F-18
We call this Molecular Imaging, a new term that has to Fluorodeoxyglucose (FDG) in oncology represents, at
be well understood to avoid confusion. If we want to present, more than 95% of clinical indications, there is a
image a normal or altered molecular system, i.e., an envi- wide field of new applications, both for FDG in the non-
ronment where specific molecules are connected through oncologic area and, using other radiotracers, FDG in
a dynamic interaction, we do not have to modify it. In oncology.
other words, a molecular process can be studied, without The goal of this Atlas being the presentation of the
being disturbed, using tracing molecules, the number of capabilities of positron emitter radiotracers other than
which will be relatively low when compared to the total FDG in the oncologic clinical practice, the following
number of native molecules involved in the system. chapters provide a wider discussion of each specific radio-
Interference and/or effects on the kinetics that are to be compound, analyzing general problems and common
analyzed can be avoided by using tracing molecules. issues.
Starting from this premise, it is possible to obtain a true
molecular imaging today, in the large majority of the sys-
tems (and/or diseases),only by nuclear medicine (NM) Radiotracers, Radioisotopes,
and optical imaging (OI). In fact, only NM and OI can and in vivo Distribution of Radioactivity
produce images with pico/nanomolar amounts of tracers,
while CT and MRI need micro/millimoles, too high to A radiotracer is a radio-compound, constituted by a radi-
8
permit a rigorous and harmless functional evaluation. onuclide (radioisotope) labeling a vector molecule (cell),
Although it plays a pivotal role in basic research, OI is determining the in vivo distribution. In the radio-com-
not yet ready for clinical use because of its incapability to pound, the radionuclide acts as a label permitting the
analyze deep structures. Therefore, molecular imaging in detection of the tracer by an external scanner. From a the-
humans can be almost identified with NM today. oretical point of view, all imaged radioactivity would cor-
It is important to note that NM is born and can exist respond only to the radiotracer and its distribution would
only as Molecular Imaging or therapy. For example,since be dependent only on specific uptake mechanisms.
the 40s, Iodine-131 has been a diagnostic (and therapeu- Practically, after in vivo administration, radioactivity
tic) tool in patients with thyroid diseases because of its can image both the injected radiotracer (with a distribu-
molecular uptake mechanism. Todays molecular imaging tion determined by specific and nonspecific mechanisms,
of thyroid can be identified with the old thyroid scintigra- or by its presence in the vascular pool or in the
Considerations About PET Isotopes 2
emunctories) and other radiochemical forms such as radioactivity and, preferably, of a PET scanner allowing a
metabolites, complexes, and free radionuclides. high count rate, and also a very fast or a very slow achieve-
The goal of this chapter is to discuss the main issues ment of a satisfactory tumor/background ratio. As a con-
regarding PET radiotracers from the radiochemical and sequence, radiotracers labeled with C-11, N-13, or O-15
pharmacological points of view. are almost exclusively used today by institutions which
own a cyclotron. In these secondary PET centers, the uti-
lization of these radiotracers, but for N-13 ammonia,
Radioisotopes: Most Diuse Positron Emitters which is very easily produced, is mainly limited to groups
including professional radio-chemists, who also stimu-
The most diffuse positron emitters are those that can be late research of/with new radiotracers.
produced with a small cyclotron. In this series are included As a consequence, the diffusion of radio-compounds
Carbon-11 (C-11), Nitrogen (N-13), Oxygen (O-15), and labeled with C-11, N-13, or O-15 is not too wide at pres-
Fluorine (F-18). While the first three permit radiolabeling ent. In particular, the interest evinced by industries for
through an isotopic radiochemical substitution of atoms the distribution of the easiest and cheapest radio-com-
present in the large majority of bio-molecules, F-18 is a pound strongly stimulated the development of a
halogen, i.e.,it can substitute hydrogen by halogenation. radiochemistry based on F-18, generators products, and
Leaving the deeper analysis of radiochemistry and radio- other radio-nuclides with a slower decay. In fact, these
pharmacology to other books and specific papers, this radioisotopes permit to produce, distribute, and reliably
work focuses on the half life (HL) of positron emitters use a large number of radiotracers other than FDG in
which is the primary physical characteristic to be known PET centers without cyclotrons which are the majority. A
before their in vivo use in humans. In fact, to reliably use routine use of C-11, N-13, and O-15 radiotracers,on the
a radiotracer, we have to first consider the total time other hand, is feasible only for well organized, complex
needed for the various steps such as radiochemistry, qual- PET centers. The use of the radiotracers is therefore
ity control, time of arrival of the dose to the patient, and mainly of interest for research purposes.
pharmacokinetics after the administration of the
radiotracer. It is clear that too short an HL can create
problems in its clinical use. Radio-Fluorine (F-18)
metabolites and of free fluorine have to be considered in of radiotracers ready for clinical practice in humans are
a rigorous pharmacokinetic evaluation. presented in the following chapters of this Atlas.
Historically, starting from old experiences based on The pivotal role in the development of medicine carried out
I-131 and I-125, radio-iodination has a pivotal position by generators and, in particular, by the Mo-99/Tc-99m sys-
in radiochemistry. At present, there is a wide use of the tem is well known to nuclear physicians. This technology is,
pure gamma emitter I-123 for diagnostic purposes. The since many years, available also for positron emitters,
positron emitter isotope I-124 is characterized by a very mainly with reference to the Ge-68/Ga-68 generator.
long HL (6019.2 minutes, almost 5 days). This condition Germanium 68 has an HL of 271 days, permitting a rela-
is advantageous for the worldwide shipment of high tively cheap routine availability of positron emitters for
amounts of radioactivity, ready for use. Conversely, as many days, without needing a cyclotron. Gallium - 68 has a
negative consequence, dosimetry (for the patient, the favorable HL of 68.0 min and is very promising and already
personnel, the relatives and the environment) can reach in clinical use. The main utilization is in labeling peptides
unjustified values when compared with the I-123 corre- and, among them, somatostatin analogues. A strong and
sponding radiotracers, permitting, however, to achieve stable radiochemical bond is obtained through chelation. It
satisfactory clinical results. Another major disadvantage has to be pointed out that a similar radiochemistry is uti-
is the expense and danger involved in the treatment of lized for labeling the same molecules using gamma emit-
radioactive wastes. Moreover, although radiochemistry ters, as Indium-111, or beta minus emitters, as Yttrium-90
of radioiodine makes the synthesis of a large series of or Lutetium-177. With respect to In-111 radio-compounds,
radiotracers, of targets such as antibodies, peptides, and radiotracers labeled with Ga-68 permit a higher diagnostic
many other molecules, possible, the in vivo presence of accuracy mainly because of the use of the PET technique.
a significant de-iodination can create problems both in The similarity with the corresponding radiochemical forms
dosimetry and in rigorous pharmacokinetic analysis. As labeled Y-90 and Lu-177, used for radionuclide therapy,
consequence, the only diffuse and the one already used stimulated the clinical use of Ga-68 radiotracers for the
in clinical practice, the compound labeled with I-124, is recruitment of patients to be treated; moreover, it is possi-
the simplest and that is iodide. Also in competition with ble to calculate the dosimetry pretherapeutically, permit-
I-123 and I-131, on the basis of being most cost/effec- ting a better definition of the dose to be administered. It has
tive, I-124 had better clinical diagnostic value for to be pointed out, as a minor limitation, that for a rigorous
patients with thyroid cancer; it helps both in permitting dosimetry, Ga-68 is characterized by a relatively too short
a rigorous pretherapeutic individual dosimetry and in HL to calculate the pharmacokinetic analysis of the in vivo
the follow up. distribution up to 2448 h and longer.
It has to be reported that some researchers, on the
basis of some similarities with the Tc-99m radiochemis-
Radio-Copper (Cu-64) try, are working on the possible use of Ga-68 for labeling
instant kits. At present, this is more a perspective, but it is
10
Copper by 64 (Cu-64) is a positron emitter produced in a already evident that there is keen interest in developing
large majority by reactors today, although the develop- the highest number of radiochemical syntheses involving
ment of syntheses by cyclotrons have already been avail- Ga-68.
able. From the physical point of view, Cu-64 is
characterized by the simultaneous emission of positron
and beta minus radiations, with an HL of 12.8 h. Therefore, General Considerations About Radiotracers
tracers labeled with this radionuclide can be used, clearly
at different dosages, both for diagnostic and therapeutic Although radio-compounds can trace bio-molecules, fol-
purposes. This prerogative created significant interest in lowing their functional pathways, the pharmacokinetics
developing new radio-compounds, with the main focus of these compounds do not completely overlap as they are
on those used for radionuclide therapies also. Examples conditioned by radio-labeling. In other words, the same
Considerations About PET Isotopes 2
molecule can present some differences in the in vivo dis- kingdom. In this Atlas, you will learn that, to detect
tribution, if labeled with different radio-nuclides, with prostate cancer it is better to choose a radiotracer, which
different activities of the same radionuclide, with a differ- is not eliminated through the urine, to detect brain
ent specific activity (i.e., with a different amount of the recurrence an amino-acid is better than FDG because of
vector molecule). The reason, as already explained above, the lack of uptake by normal cells, and to diagnose dif-
is that after the in vivo administration, the image is the ferentiated neuroendocrine tumors, radiopeptides have
resultant of a radioactivitys distribution which is depen- a higher accuracy than FDG. You will also understand
dent not only on the injected radiotracer (specific and that it is possible to acquire important prognostic infor-
nonspecific uptake, presence in the vascular pool or in mation, connected to the growing rate, through radiola-
the emunctories), but also on all the other in vivo pro- beled thymidine, or that you can decide a better
duced radiochemical forms such as, metabolites, com- therapeutic strategy for women with breast cancer, start-
plexes, and free radionuclide. ing from the knowledge of in vivo distribution of estro-
This is a major risk in using new radiotracers in clin- gen receptors. In this scenario, you will understand how
ical practice. A reliable use can be obtained only when the oncologists, surgeons, radiotherapists, and all the other
molecular imager has a deep and wide knowledge of clinicians can acquire further advantage in addition to
pathophysiological premises; he/she has to learn uptake the pivotal role already played by FDG. The first area of
and distribution mechanisms determined by physiology, interest can be found in fields where FDG has limita-
para-physiological conditions, pathological events; he/ tions because of the presence of false negative or false
she has to know normal patterns, pitfalls and artifacts; he/ positive results. But a further relevant indication for the
she has to predict the behavior in benign and malignant use of PET radiotracers other than FDG is the formers
diseases. incapability, shared with all the diagnostic procedures,
Therefore, a thorough but fascinating study is required to answer alone all the possible questions concerning
to become an expert in PETCT. In particular, it is neces- diagnosis, prognosis, and those connected with the
sary to learn the functional premises, pathophysiology, therapy.
radiochemistry, and pharmacology to avoid the major We conclude this chapter with a final major remark: as
mistake, that is, to think that PET CT is simply indicat- far as PETCT is concerned, while CT always gives the
ing a colored spot on an anatomical structure. same morpho-structural information, it is PET that per-
In this Atlas, we want to open your mind to the wid- mits this hybrid machine to declare its primacy in
ening field of the clinical use of PET outside the FDG Molecular Imaging in humans.
11
Chapter 3 Choline PET-CT
Case 1 Biodistribution . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Case 15 Biodistribution . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Radiolabeled Choline (labeled to 11C or 18F) is one of the ment, and detection of lymph node micrometastases. This
most applied and promising PET tracers for cancer imag- is mainly due to the limited spatial resolution of PET-CT
ing. Choline is a substrate for the synthesis of phosphati- devices. However, Choline PET may have a role in selected
dylcholine, which is a major phospholipid in the cell cases: in patients with high-risk prostate cancer, it may
membrane. It has been hypothesized that uptake of radio- assist the clinicians in the decision of aborting surgical
labeled Choline reflects proliferative activity by estimat- treatment in presence of lymph node or distant metasta-
ing membrane lipid synthesis. However, the exact uptake sis. In addition, Choline PET imaging could be helpful by
mechanism has to be established. showing lymph node metastasis outside the generally rec-
Choline was first labeled to 11Carbon for cancer imag- ommended surgery regions, which could have an impact
ing in 1997. 11C-Choline is cleared very rapidly from the on extent of lymphadenectomy and on survival after radi-
blood, and optimal tumor-to-background contrast is cal prostatectomy. However, at present, the use of Choline
reached within 57 min after administration of tracer. PET imaging in predicting stage at presentation cannot be
This allows for imaging as early as 35 min after tracer recommended for a routine clinical use.
injection and provides images of good diagnostic quality. Choline PET imaging plays a more relevant role in the
Physiologically increased tracer uptake is noted in sali- detection of prostate cancer relapse. Choline PET shows
vary glands, liver, kidney parenchyma and pancreas and higher specificity and consequently higher accuracy com-
faint uptake in spleen, bone marrow and muscles. Bowel pared to all conventional imaging methods together for
activity is variable and occasionally urinary bladder activ- detection of prostate cancer recurrence. Choline PET
ity can be observed. 11Carbon has, however, a short half- imaging, supplying a whole body tomography exam, has
life time (20 min) and must be used rapidly after the major advantage of detecting local and distant metas-
production; it requires a local cyclotron and is therefore tasis within a single session with a good accuracy.
not a widely available option. However, patient referral criteria still have to be defined.
For these reasons, F-labeled Choline tracers like At present, no definite data exist with regard to the thresh-
Fluoro-ethyl-choline (FEC) and Fluoromethl-dimethyl- olds of serum PSA level under which radiolabeled Choline
hydroxyethylammonium (FCH) were proposed. Both should not be used. Moreover, the influence of medication
compounds show similar properties (rapid blood clear- (e.g., testosterone deprivation) and PSA kinetics on
ance and uptake in prostate tissue) with minor differences PET-CT detection rate has to be clarified. Despite these
(later peak uptake for FEC). The main contrast with limitations, the use of PET-CT with Choline in patients
11
C-Choline is the early urinary appearance of 18F-Choline, with biochemical failure has shown a significantly better
probably caused by incomplete tubular reabsorption. detection rate, when compared to CT or bone scan.
Although Choline PET has been used for identifica- Therefore, in absence of general patient referral crite-
tion of various tumor tissues, the main application field of ria for Choline PET Imaging in detection of prostate can-
Choline PET is prostate Imaging. PET imaging has been cer recurrence, it seems reasonable to use PET imaging in
proposed for early detection of primary prostate cancer, individual cases, where a satisfactory sensitivity is to be
for staging of tumor and identification of nodal involve- expected and imaging findings will have a therapeutic
ment, and finally for detection of tumor recurrence. relevance. In particular, patients with high risk of distant
Choline uptake seems to be similar in patients with metastases or those susceptible to surgery and/or radia-
benign prostatic diseases (prostatitis, prostatic hypertro- tion therapy could benefit the most from early identifica-
14
phy) and proven prostate cancer. This finding, in addition tion of the site of recurrence.
to the limited spatial resolution of PET-CT devices, clearly Besides prostate cancer imaging, Choline PET has also
represents the major limits for the use of this tracer for been used for other minor aims. The minimal background
identification of primary tumor. Despite a tendency activity of 11C-Choline in the pelvis, due to the low level of
towards a higher uptake of Choline in prostate cancer excretion via the urinary tract has permitted the use of
foci, taking all preliminary results into account, Choline this tracer in various tumors of urogenital tract other
PET cannot be recommended for diagnosing primary than prostate cancer (bladder and uterine cancer).
prostate cancer. Diagnostic accuracy of Choline PET for detection of
With regard to prostate staging, Choline PET imaging residual bladder cancer after TURB seems to be compa-
seems not to be accurate enough to be proposed for eval- rable to CT, but Choline PET appears to be superior to
uation of extracapsular extension, seminal vesicle involve- CT for the evaluation of potential additional lymph node
Choline PET-CT 3
metastases. However, only few studies are present in lit- nonneoplastic lesions. Despite these good preliminary
erature on this issue and there is, therefore, a weak ratio- results, in the absence of data from large series of patients,
nale for Choline PET imaging in these cancers. the clinical role of Choline PET for the evaluation of
Radiolabeled Choline also seems to be a suitable PET brain tumors is not fully established, and MET PET
tracer for brain tumor imaging. Choline PET shows a low remains the metabolic tracer of choice for brain tumor
accumulation in normal brain tissue and allows for the imaging.
detection of brain tumors with a high tumor/background Choline PET was also used for identification of
ratio. Choline PET has been applied successfully for char- myelomatous lesions. Choline PET appeared to be more
acterization of brain lesions and seems to be in conjunc- sensitive than FDG PET for the detection of bony
tion to MR imaging as an accurate diagnostic tool for myelomatous lesions, and surprisingly, the SUVmax
identification and detection of high-grade gliomas and turned out higher with Choline compared to FDG.
meningiomas. On the other hand, Choline PET does not However, these data have to be confirmed in a larger
allow one to differentiate low-grade gliomas from series of patients.
15
3 Case 1 Biodistribution
11
C-Choline
16
Case 2 Physiologic Uptake 3
Administration route
Salivary glands
Liver
Kidney parenchima
Bowel
Bladder
11
C-choline nding 17
Teaching point
18
Case 4 Prostate Cancer: Restaging 3
Male 59 years
19
11
C-choline nding
11
Pathologic increased C-choline uptake in iliac
lymph node.
3 Case 5 Prostate Cancer: Restaging
Male 71 years
20 11
C-choline nding
Teaching point
Pathologic uptake in pelvic lymph node
Patient PSA was 1.3 but with a short doubling
time (<3 months).
Case 6 Prostate Cancer: Restaging 3
Male 66 years
21
11
C-choline nding
11
C-choline nding
22
11
C-choline nding 23
Teaching point
Pathologic uptake at bone level.
CT and bone scintigraphy were negative;
choline PET-CT may reveal bone lesions
before other imaging methods.
3 Case 9 Prostate Cancer: Staging
Male 71 year
11
C-choline nding
Teaching point
Pathologic uptake at primary tumor and at two
lymph nodes. Choline PET-CT is not routinely used for
staging purposes.
24
Case 10 Prostate Cancer: Staging 3
Male 60 year
11
C-choline nding
25
Teaching point
Pathologic uptake at several obturatory lymph
nodes. Choline PET-CT may occasionally be useful for
staging purposes in patients at high risk of
nodal spread, to guide a correct surgical
approach.
3 Case 11 Prostate Cancer: Response to Therapy
Before After
11
C-choline nding
Before
After 27
Teaching point
Before After
11
C-choline nding
29
11
C-choline nding
11
C-choline nding
Teaching point
Pathologic uptake at pulmonary primary lesion.
30 Choline PET-CT may occasionally be useful for
other tumors when FDG PET-CT is known to
lack sensitivity.
Case 15 Biodistribution 3
18
F-Choline
31
3 Case 16 Physiologic Uptake
18
F-choline nding
32
Liver uptake
Spleen uptake
Bone marrow
uptake
18
F-choline nding
33
3 Case 16 Physiologic Uptake
Pancreas uptake
18
F-choline nding
35
Teaching point
36
18
F-choline nding
Teaching point
18
Pathologic increased F-choline uptake in pelvic
18
lymph nodes. F-choline PET-CT allows to identify
secondary lymph nodes not easily detectable
on conventional CT scan (<10 mm).
Case 19 Prostate Cancer: Restaging 3
Male 73 years
37
18
F-choline nding
Teaching point
18
Pathologic increased F-choline uptake in right ver-
18
tebral pedicle of D5. F-choline PET-CT allows to identify
secondary lesions that are not easily
detectable on conventional bone scan.
3 Case 20 Prostate Cancer: Bone Lesion
Male 63 years
18
F-choline nding
Teaching point
18
Pathologic increased F-choline uptake in the body
38 of a lumbar vertebra. 18
F-choline PET-CT allows to detect early stage
bone metastasis.
Case 21 Prostate Cancer: Restaging 3
Male 68 years
39
18
F-choline nding
Teaching point
18
Increased F-choline uptake in presacral lymph
18
nodes. F-choline PET-CT allows to identify
secondary lymph node lesions in regions that
are usually not included in limited pelvic
lymph node dissection.
3 Case 22 Pitfall: Inguinal nodes uptake
Male 69 years
18
F-choline nding
40
Case 22 Pitfall: Inguinal nodes uptake 3
Teaching point
41
3 Case 23 Pitfall: Missed bone lesions
Male 66 years
18
F-choline nding
42
Case 23 Pitfall: Missed bone lesions 3
Teaching point
43
3 Case 24 Pitfall: Mediastinal nodes uptake
Male 75 years
18
F-choline nding
Teaching point
45
3 Case 25 Pitfall: Residual urethral uptake
Male 69 years
18
F-choline nding
46
Case 25 Pitfall: Residual urethral uptake 3
Teaching point
47
Chapter 4 Methionine PET-CT
11
C-Methionine (11C-METH) is an aminoacidic PET and benign response to therapy (negative 11C-METH
tracer whose main employment regards the diagnosis of PET) can be done with a very good accuracy.
central nervous system tumors. Methionine is, in fact, This good reliability of PET is based on the fact that
one of the five essential amino acids that can be involved the tracer uptake is not present in enhancing necrosis, is
in different metabolic pathways at a cellular level. The not influenced by corticosteroid therapy (that can be
main destiny of this molecule is the proteic synthesis administrated for reducing edema), and is proportional
within ribosomes, but it can also be converted to enter to the grade of the disease (even low-grade brain tumors
the citric-acid cycle (to produce energy) and as a cofactor are positive). The false positive results are due to recog-
for transferring monocarbon units. nizable clinical events (very recent biopsy, acute inflam-
The uptake mechanism of 11C-METH within brain mations, hematoma, acute stroke with reperfusion)
tumors is still uncertain, but the most probable theories causing an aspecific leakage of the tracer within the inter-
are based on the combination of a passive diffusion cellular space related to a vascular damage or an increased
through the damaged brain blood barrier (BBB) and an vascular permeability (Methionine is a very small mole-
active tumor uptake mediated by a carrier due to an cule). It is important to point out that 11C-METH PET
increased proteic synthesis (related to the active presents less false positive (post RT inflammation is nega-
proliferation). tive at 11C-METH PET) and less false negative results
One of the great advantages of using 11C-METH for compared to 18F-FDG brain PET.
the diagnosis of brain tumors is the very low background The main limitation of this technique is the spatial
that is found in healthy brain. Normal brain tissue, in resolution (approximately 5 mm) and the low availability
fact, recognizes only glucose as metabolic substrate and of the tracer. In fact, the short half-life of 11C prevents the
therefore does not present any significant 11C-METH distribution of tracer on the territory and requires a
uptake. On the other hand, brain tumors present an cyclotron-based PET center with particular skills on
11
increased tracer uptake, and therefore the tumor-to- C-based molecules.
background ratio is really favorable, making the Despite the main clinical application of 11C-METH
11
C-METH PET quite easy to read and interpret. PET-CT in brain tumors with regard to the diagnosis of
From a practical point of view, a PET-CT with disease relapse of low- and high-grade tumors, this exam
11
C-METH is easy and fast to perform. Usually 370740 has been used for other minor aims. In fact, studies from
MBq of tracer are injected intravenously and, because of literature have proved that 11C-METH PET-CT can be
the short half-life of 11C-labeled molecules (20 min), the successfully used for guiding the tumor biopsy by indi-
uptake time ranges from only 20 to 30 min. Then, a seg- cating the most active area inside the mass and can be
mental static image acquisition is performed on brain for used as a prognostic index, since its uptake is propor-
1015 min. No fasting is usually required and no collat- tional to the malignancy of the tumor and its cellular pro-
eral effects have never been described. liferative index. In fact, the proportionality between
The role of 11C-METH PET-CT in clinical practice is tracer uptake and tumor grade may be used to show early,
limited to those patients with brain tumors with an incon- a change in tumor grade without requiring any invasive
clusive MRI (or CT). It is well-known, in fact, that after procedure. This is not always possible with MRI as many
treatment (surgery, chemotherapy or radiotherapy) para- high-grade tumors do not have any significant enhance-
physiological phenomena like fibrosis, necrosis or edema ment. The tumor grade is a prognostic index, and there-
50
may occur as a consequence of therapy. Those phenom- fore a correlation between 11C-METH uptake and survival
ena may present with morphological characteristics very was found. Patients with hypermetabolic tumors have a
similar to a disease relapse, making the interpretation of significantly worse prognosis, while patients with hypo or
conventional imaging equivocal. However, the early iden- isometabolic tumors have a better life expectation.
tification of disease relapse may be very important in the Furthermore, 11C-METH PET-CT may also be used
clinical history of those patients, since an early second for the early diagnosis of a response to both chemo and
line therapy can improve their survival. radiation therapies.
Since fibrosis, necrosis or edema are not cellular pro- The role of 11C-METH PET for the diagnosis of unbi-
liferating processes, they do not present any significant opsied brain masses is controversial. Few studies are pres-
increase in the tracer uptake and so a differential diagno- ent in literature since the major part of brain masses,
sis between disease relapse (positive 11C-METH PET) despite being negative at 11C-METH PET, are biopsied for
Methionine PET-CT 4
histopathological confirmation anyway. There is, there- cally removed), the higher spatial resolution compared to
fore, a weak rationale for the execution of the exam in conventional scintigraphy, and the much shorter time
newlydiagnosed brain masses. needed to complete the entire procedure. According to
A possible advantage of 11C-METH PET in the early recent literature, it was preliminary proved that 11C-METH
evaluation of brain tumors relies on the fact that MRI PET-CT is accurate both for primary and secondary
may fail to identify tumor infiltrated margins, and this hyperparathyroidism, with a true positive rate of approxi-
could be a disadvantage during tumor resection, resulting mately 85%. Of course, further studies are needed to con-
in a margin to be indiscriminately added to radiotherapy firm these preliminary encouraging data.
treatment volumes to account for these infiltrating cells. Other clinical applications of 11C-METH PET were
As this margin includes normal brain, the total dose used explored in the past years. Some interesting published
has to be reduced to reduce the risk of radiation necrosis. protocols were designed on the theory that 11C-METH
As a consequence, gliomas recur within the treatment does not present any significant uptake in enlarged
volume in the majority of patients. Though other PET inflammatory lymph nodes (or at least a much lower
tracers were tried for the diagnostics of brain tumors (in uptake compared to the standard FDG), and this was
particular 18F-FDG and 11C-Choline), 11C-METH turned thought to be somehow useful for the staging of mediasti-
out to be the most accurate and is therefore recognized nal lymph nodes in patients affected by lung cancer before
now as the PET tracer of choice in this field. surgery. The low 11C-METH uptake in post radiotherapy
Besides brain tumors, other minor applications of inflammation suggested some protocols in oncological
11
C-METH PET-CT were analyzed in literature with patients (mainly affected by sarcomas or head and neck
equivocal results. A possible role of this tracer was found cancer) for the early evaluation of post radiotherapy
in the diagnosis of hyperparathyroidism, and this field response to treatment, in order to identify a possible con-
deserves a particular explanation in consideration of the tribution of this tracer to reduce false positive results
good preliminary results, despite not being a routine clin- obtained with FDG.
ical application as yet. Furthermore, the normal increased uptake of
The principle of 11C-METH uptake in hyperfunction- 11
C-METH in salivary glands and pancreas suggested
ing parathyroids relies on the fact that this tracer is an some groups to evaluate it as a tracer for the functional
aminoacid that can be incorporated into parathormone, evaluation of those glands.
which is largely produced in those glands. The advantages All these studies gave equivocal results remaining
over MIBI-SPECT are, of course, the lower dose delivered purely speculative, and no clinical applications were rec-
to the patient, the much higher anatomical detail given by ognized for 11C-METH PET, besides the evaluation of
the CT (which is very important for the correct localiza- central nervous system tumors and a minor application
tion of the hyperfunctioning glands that should be surgi- in hyperparathyroidism.
51
4 Case 1 Physiologic Uptake
a b
11
C-Methionine nding
Teaching point
Physiological biodistribution of 11C-METH: (a) total
body; (b) brain. (a) Note the normal increased uptake in the
liver and pancreas associated to a lower
uptake in the spleen.
(b) The brain does not present any signicant
uptake of the tracer except for the
pituitary gland (white arrow).
52
Case 2 Glioblastoma: Re-Staging 4
MR
11C-METH PET
11
C-Methionine nding
Teaching point
At MR gliosis and edema. 53
11
C-METH PET highlights an area of increased uptake After treatment (surgery, chemotherapy, or
consistent with disease relapse, close to the margin radiotherapy), paraphysiological phenomena
of surgical resection. like brosis, necrosis, or edema may occur as a
consequence of therapy. Those phenomena
may be similar to a disease relapse, making
the interpretation of conventional imaging
equivocal. 11C-METH PET helps in identifying
disease relapse in case of unclear
conventional imaging, leading to an early
therapy onset.
4 Case 3 Glioma: Re-Staging Inconclusive MR
11C-METH
MR PET
11
C-Methionine nding
Teaching point
PET demonstrates an area of focal increased uptake
showing a disease relapse that was unrecognized at Sometimes a small area of disease relapse
MR. may be somehow hidden within
paraphysiological reactions to surgery and
radiotherapy. MR pathological ndings may
appear, therefore, uniform in morphology but
combined begign and malignant processes
may be present at the same time.
54
Case 4 Glioma: Re-Staging Suspect MR 4
MR 11C-METH PET
11
C-Methionine nding
Teaching point
PET is negative demonstrating posttherapy benign
changes. Since brosis, necrosis, or edema are not
cellular proliferating processes, they do not
present any signicant increase in the tracer
uptake and so a dierential diagnosis
between disease relapse (positive 11C-METH
PET) and benign response to therapy
(negative 11C-METH PET) can be done with a
very good accuracy.
55
4 Case 5 Astrocyma: Re-Staging Inconclusive MR
MR
11C-METH PET
56
11
C-Methionine nding
Teaching point
PET demonstrates an area of persistent increased
uptake showing an incomplete response to An early identication of persistent active
therapy. disease may lead to a prolonged
chemotherapy, in order to better control the
unresectable disease.
Case 6 Astrocyma: Suspect Relapse 4
18F-FDG 11C-METH
PET PET
PET nding
Teaching point
18
F-FDG PET fails to demonstrate disease relapse
11
because of the increased normal brain uptake. C-METH PET is more sensitive than FDG for
11
C-METH PET highlights an area of mild increased the identication of disease relapse because
uptake, which is consistent with disease relapse. of the better contrast resolution of images.
Normal brain, in fact, does not present a 57
signicantly increased tracer uptake since
amino acids are not a metabolic substrate of
grey and white matter, while FDG is
physiologically picked up by normal brain,
possibly masking areas of disease relapse.
4 Case 7 MR Suspect for Astrocytoma
MR 11C-METH PET
11
C-Methionine nding
Teaching point
PET is positive, conrming the diagnosis.
In this case a positivity of 11C-METH PET leads
to a prosecution of diagnostic follow-up,
despite the very dicult site to biopsy, since
the probability of malignancy is very high.
58
Case 8 MR Suspect for CNS tumour 4
MR 11C-METH PET
11
C-Methionine nding
Teaching point
PET is negative, conrming a subsequent diagnosis
of displasia. Black arrows indicate normal uptake of In this case, a negative 11C-METH PET excludes
lacrimal glands. with high probability the presence of a
malignant disease, leading to a conventional
imaging follow up and making an invasive
diagnostic procedure not required.
59
4 Case 9 MR Suspect for CSN tumour
MR
11C-METH PET
60
11
C-Methionine nding
18F-FDG PET
11C-METH PET
61
PET nding
Teaching point
18
F-FDG PET fails in identifying the hyperfunctioning
gland. In this case, 11C-METH PET identied an
11
C-METH PET identies an increased tracer uptake ectopic adenoma, which is very dicult to
in the hyperfunctionig parathyroid gland. detect with standard scintigraphy due to its
very small size. The support of corresponding
CT can be used to guide the surgeon in
nding the adenoma during intervention.
Chapter 5 Fluoride PET-CT
Case 3 Metastases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
[18F]fluoride was first introduced in 1962, and rapidly background activity ratio. The uptake time ranges from
proposed as a radiotracer for bone exploration. The com- 30 to 60 min, and the injected activity is usually around
plex [18F]NaF is injected intravenously, and it dissociates 185200 MBq. With the advent of faster and more sensi-
in the blood into Na + and [18F]fluoride ion. The uptake of tive PET devices coupled with high-end CT scanners,
[18F]fluoride results from ionic exchanges between there has been renewed interest in [18F]NaF imaging,
hydroxyl groups of hydroxylapatite to form fluoroapatite especially in the oncology setting.
and is thus directly related to bone metabolism. Both the Schirrmeister et al. reported remarkably impressive
blood flow and the osteoblastic activity influence the [18F] results with [18F]NaF PET in a series of prospective stud-
fluoride accumulation, in proportions that are still dis- ies. They first showed that [18F]NaF PET was significantly
cussed. [18F]NaF-PET imaging, using appropriate model- more sensitive than planar BS for detecting bone metas-
ing, can thus noninvasively assess bone metabolism. The tases from various cancers, mainly prostate and thyroid,
advantage of [18F]fluoride compared to other PET tracers and that it remained highly sensitive regardless of the
is the synthesis, which is extremely simple and relatively location of the lesions, in contrast with BS. [18F]NaF PET
inexpensive: [18F]fluoride is rendered isotonic with a correctly evaluated the skeletal status in 27/28 breast can-
NaCl solution to form [18F]NaF. Since the early sixties, the cer patients, without known bone metastases, as com-
mechanism of uptake of [18F]fluoride has been extensively pared to 16/28 with BS. Although in this study, SPECT
studied. The accumulation of [18F]fluoride in osteoform- did not improve the detection rate, further evaluation in
ing areas of bone metastases was demonstrated in autopsy lung cancer patients showed similar diagnostic perfor-
series and in rabbit experimental models. In mice, [18F] mances for [18F]NaF PET and SPECT, both being more
NaF-PET clearly identified fractures as increased uptake accurate than planar BS. Recent studies performed using
foci up to 7 weeks after the initial trauma, human bone PET-CT yielded further improved results. The group in
grafts 2 months after the implantation, and osteoblastic Tel Aviv reported 85% sensitivity (99% when inconclu-
lesions induced by human prostate cancer cells. Lytic sive foci were considered as positive) and 97% specificity
lesions from human prostate cancer cells (CL-1 et PC-3) in a series of 44 patients with various cancers, compared
were visualized either as foci of globally increased activity with 72% (90%) and 72% for PET alone, respectively. In
or, most frequently, as rim-like foci, surrounding the edge another series of patients with prostate cancer and high
of the lesions. Quantitative uptake, measured as cps/ risk of bone spread, PET-CT showed 100% sensitivity and
pixel/min, was fairly reproducible in femoral and humeral 100% specificity, as compared with 61 and 87%, respec-
ROIs drawn on four studies over a period of 4 weeks. The tively, for BS with SPECT. These Authors considered sus-
relationship between [18F]NaF uptake and bone forma- picious foci on the [18F]NaF PET images as positive, when
tion was clearly established using quantitative modeling there was no CT anomaly that could explain the PET
in mini pigs, showing correlations of bone blood flow and lesions. Such perfect results are unlikely to be reproduced
metabolic activity, with histomorphometric indices of in the routine clinical setting and may be explained by the
bone formation in the normal bone tissue. Furthermore, absence of a gold standard in these studies. Nevertheless,
in patients with secondary hyperparathyroidism, the [18F] it clearly appears that low-dose CT improves the diagnos-
NaF incorporation rate was correlated with the plasma tic accuracy, in particular by evidencing benign condi-
parathormone level and with the bone formation rate. tions that are responsible for nonspecific foci of increased
Bone scintigraphy (BS) with 99mTc methylate diphos- [18F]NaF uptake. Furthermore, all data conclude to a sig-
64
phonate (99mTc-MDP) remains the most widely used nificantly higher sensitivity of [18F]NaF PET for detecting
imaging method for detecting bone metastases. The lytic metastases as compared to bone scintigraphy. The
reported sensitivity and specificity figures range from 62 combination of anatomical and structural information
to 100% and from 78 to 100%, respectively. Although with better tracer properties and improved spatial resolu-
bone scanning has proven highly valuable, the pharma- tion of PET appears extremely potent, enhancing both
cokinetic properties of [18F]NaF appear more favorable the sensitivity and the specificity of the test. Although
than those shown by 99mTc-labeled compounds. In par- PET-CT with [18F]NaF appears to be intrinsically supe-
ticular, the bone tissue first-pass retention is significantly rior toBS, several drawbacks need to be overcome before
higher and the blood clearance faster with [18F]NaF than reaching acceptable clinical performance. There is a steep
with 99mTc-MDP. As a result, the image acquisition can be learning curve for nuclear medicine physicians switching
started earlier after tracer injection, with higher bone to from BS to PET-CT. In addition, the collaboration of
Fluoride PET-CT 5
radiologists with a large experience in bone imaging effectiveness of the analysis. Such analysis should also
enhances both the diagnostic accuracy and the confi- take into account the recurrent shortage in molybde-
dence with which the report is released. num-99 supply in both Europe and USA. Also, up to
Several question marks remain considering a wide- date PET-CT technology should be compared with the
spread use of [18F]NaF PET-CT in oncology. The cost- most recent monophotonic technology, i.e., SPECT/CT.
effectiveness is yet to be appropriately evaluated, even Such studies are currently inexistent. Finally, radiation
though a report published in 2003 concluded to better dose to the patient is not really an issue, as the effective
ratios for BS compared to PET in lung cancer patients. doses (for an adult) of the commonly injected activities
PET imaging in general cannot be considered as inex- of [18F]NaF and 99mTc-MDP are very similar. The low-
pensive, but [18F]NaF is much cheaper than other tracers dose CT procedure of PET-CT increases the dose but
such as FDG, and the increased availability of both similarly, it will probably be increasingly performed with
PET-CT and cyclotrons also influences the cost- new SPECT/CT systems.
65
5 Case 1 Breast Cancer: Follow Up
99mTc-MDP 18F-NaF
99m
Tc-MDP nding 18
F-NaF nding
Bone scan performed as part of the systematic The hot spot is precisely located near the L1/L2
follow-up demonstrates a new hot spot in the supe- disk.
rior lumbar spine.
66
Case 1 Breast Cancer: Follow Up 5
99mTc-MDP 18F-NAF
T1 TSE T2 TSE
Teaching point
18
F-NaF PET has a better bone to background 67
ratio and a higher spatial resolution than bone
scan. It thus allows a better delineation and
location of the lesion. In this case, the
peridiscal location of the hot spot with the
narrowing of the disk space excludes with a
high probability a bone metastasis, as
conrmed by MRI demonstrating L1/L2
degenerative disk disease with corporeal
posterior edema. As a result, 5 years after the
onset of the disease, the patient is considered
in clinical remission and the follow-up will be
performed annually by the GP (CA 15.3 and
mammography).
5 Case 2 Renal Carcinoma: Back Pain
18
F-NaF nding
68
Case 2 Renal Carcinoma: Back Pain 5
Teaching point
69
5 Case 3 Metastases
18
F-NaF nding
Teaching point
Hot spot in (a) a very small pubic osteoblastic metas-
70 18
tasis of a SCLC, (b) a large sacral osteolytic metastasis F-NaF is preferentially deposited at sites of
of a renal cell carcinoma, and (c) an ischiatic mixed high bone turnover and remodeling, and
metastasis of a breast cancer. bone metastases are seen indirectly because
uptake depends on surrounding bone
reaction to the tumor. Metastases may be
predominantly lytic, blastic, or mixed. Most
are associated with increased 18F-NaF uptake.
Changes may be very subtle though and
careful examination of all data sets is required,
as shown in this case (c).
Case 4 Renal Carcinoma: Staging 5
18
F-NaF nding
71
5 Case 4 Renal Carcinoma: Staging
CT a b c
CT nding
Teaching point
Low-dose CT with (a) 5 mm-thick reconstructed
slices; (b) 3 mm-thick reconstructed slices, and (c) In renal cell carcinoma as in squamous cell
diagnostic CT with isotropic 0.6 mm-thick slices lung carcinoma, breast and thyroid cancers,
(transaxial and coronal slices in all three cases). There bone metastases are usually lytic and may
is a low-density lesion with coarsened vertical trabe- appear as a cold spot on the 18F NaF PET
culae surrounded by fat with normal cortex and sur- images. In many cases, the low-dose CT
rounding soft tissues, which is a characteristic provides useful information as regards to the
pattern of hemangioma. nature of the lesion although it must be kept
in mind that a 5 or 3 mm-thick CT does not
provide the spatial resolution and wealth of
structural details provided by a dedicated CT
study, as shown by the various CT sections in
72 this case. Here, the cold spot corresponds to
an hemangioma, which is the more frequent
benign lesion with decreased uptake.
Case 5 Breast Cancer: Follow Up 5
18
F-NaF nding
Teaching point
18F-NaF
18F-FDG
PET nding
75
5 Case 6 Breast Cancer: Follow Up
18F-NaF
18F-FDG
PET nding
Teaching point
In addition, there is a sclerotic lesion of the left side
of the sacrum with increased 18F-NaF uptake (rst The osteoblastic lesions are sometimes earlier
row, arrow) but negative on the FDG scan. These detected by the 18F-NaF PET scan than with
ndings are consistent with bone metastases. the FDG PET as shown on the left sacral ala.
The progressive metastatic disease led to
therapeutic changes (rst line chemotherapy).
76
Case 7 Renal Carcinoma: Restaging 5
99m
Tc-MDP nding
99mTc-MDP
18
F-NaF nding
77
Several additional hot spots are visualized
(arrows). The lesion at the top of the skull
takes the typical rosette-like uptake pattern
of a lytic metastasis, which was conrmed by
18F-NaF the low-dose CT.
5 Case 7 Renal Carcinoma: Restaging
Teaching point
Case 1 Biodistribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Radiolabeled amino acids are attracting increasing inter- evaluation, the most common method is to calculate a
est in nuclear medicine over the past years mainly because tumor to background ratio in a static image (about 2040
amino acid tracers appear to be more specific than FDG min p.i.).
for brain tumor imaging. The uptake of amino acids, The main application field of FET PET is brain tumor
especially of O-(2-[F-18]fluoroethyl)-l-tyrosine (FET) imaging. In the absence of data from a large series of
(less of MET) in macrophages and other inflammatory patients, FET PET seems to have a few emerging useful
cells seems to be lower than FDG. clinical applications for patients with brain tumors. The
FET is used as a tumor imaging tracer since 1999. FET most common clinical indication for FET PET brain
accumulates in malignant transformed cells probably, imaging is the identification of tumor recurrence and dif-
mainly due to increased expression of amino acid trans- ferentiation from delayed radiation-induced lesions in
porters and amino acid transport. There is no relevant patients with unclear findings on morphological imaging.
participation of FET in protein synthesis or any other An earliest possible and reliable differentiation is neces-
metabolic pathway. FET uptake is considered to be sary to determine the most appropriate further treatment.
slightly higher in tumor tissues with than in those with- While radiation necrosis may be treated by steroids, or in
out a disrupted blood-brain barrier. Therefore, probably extensive cases, by debulking surgery, recurrent tumor
an additional passive influx of FET contributes to the requires continuation of therapy, change of ineffective
higher FET uptake. treatment or palliative care only. Conventional structural
FET is one of the first F-18-labeled amino acids with imaging methods are of limited value in this setting, since
high radiochemical yields which can be produced in large recurrent tumor and posttherapeutic lesions may both
amounts. Therefore FET is not restricted, unlike the most appear as mass lesion coming along with edema and con-
commonly used amino acid PET tracer C-11-labeled trast enhancement due to a breakdown of the blood brain
methionine, to a few PET centers with a cyclotron on site barrier. FET PET shows a high diagnostic accuracy in this
and can be distributed in a satellite concept similar to the setting (due to a higher specificity compared to conven-
widely used FDG. tional MRI) and helps to shorten the time of diagnosis in
FET shows the highest activities in the urinary tract. these patients. Therefore, inclusion of FET PET in the
All other organs with visible F-18 accumulation have only diagnostic workup improves patient management and
moderate FET uptake with low standardized uptake val- avoids undertreatment and overtreatment.
ues (SUVs). Noticeable is a faint accumulation in the An important role has also been suggested for biopsy
pancreas, skeletal muscles, and the heart which is in the target definition. Implementation of FET PET in biopsy
range of the liver uptake. No increased radioactivity planning reduces the number of required trajectories in
uptake is seen in the bones, the bone marrow, the lung patients with brain tumors, especially in those patients
parenchyma and the biliary tract. Similar distribution of with widespread abnormalities in MRI or lesions located
the tracer can be seen in all organs in late acquisitions in high risk or functional areas. Metabolic FET PET
(after 3 h post injection). Following tracer injection, nor- imaging with fusion techniques enhances the diagnostic
mal brain tissue shows a very faint FET uptake which yield to assess the metabolically most active and most
steadily increases up to 1 h. In contrast, high-grade representative area within the tumor.
gliomas show an early peak of FET uptake between 5 and Concerning brain tumor delineation which is espe-
15 min after tracer injection followed by slightly decreas- cially relevant for treatment planning, amino acid tracers
80
ing values up to 40 min after injection. Less aggressive are also very helpful and are clearly superior over FDG.
low-grade tumors as well as radiation induced changes Amino acid PET helps to define the optimal volume for
behave more like normal brain tissue with increasing FET percutaneous or stereotactic radiation therapy. Early
uptake over time. Therefore, it can be recommended to studies have shown significantly longer survival times fol-
acquire a series of static limited field tomographic images lowing a combined treatment planning concept including
of 10 min duration each in a time period between 10 and functional and morphological information, compared to
40 min after injection of FET (180370 MBq). For the treatment planning based on morphological data alone.
evaluation of time-activity curves, the single time frames FET PET seems also to be sensitive enough to assess
may be evaluated, or alternatively dynamic acquisition therapeutic effects early on and to distinguish between
(list mode) may be performed after injection of the tracer harmless reactive lesions induced by different treatment
for a time period of 40 min. For semiquantitative modalities (intralesional radioimmunotherapy, radiation
Tyrosine PET-CT 6
therapy and systemic chemotherapy) and tumor regrowth. Slightly increased and homogeneous FET uptake sur-
Furthermore, decreasing metabolic activity of brain rounding the tumor cavity following treatment (surgery
tumors during chemotherapy rather points to a success of and/or radiation therapy) should be attributed to a passive
therapy while increasing uptake values suggest tumor influx of FET. This uptake is usually less intense and more
progression. However, because of few and small-sized homogeneous compared with the FET uptake in tumor
studies, the diagnostic reliability of FET PET remains tissue and it is probably caused by benign posttherapeutic
unknown in this setting and deserves further prospective changes. This has been attributed mainly to the disruption
evaluation. of the blood-brain barrier induced by benign changes
The differential diagnosis of solitary intracerebral which corresponds, in most cases, to more or less intense
lesions with FET PET seems to be less reliable. Some contrast enhancement on MRI or CT scans.
benign lesions such as brain abscesses and demyelinating FET PET has been also used in other cancers than
lesions may show pathological FET accumulation. brain tumors. However, the available preliminary data
Moreover, one third of patients with low-grade gliomas do indicate that the diagnostic performance of FET PET in
not show increased FET uptake. Therefore, a negative FET peripheral tumors is not high enough. In contrast to most
PET scan does not exclude a tumor. However, FET PET cerebral lymphoma or metastases, surprisingly, periph-
may depict some high-grade gliomas in unclear lesions eral lymphoma and also most peripheral adenocarcino-
with widespread T2 abnormalities in MRI, which based mas do not show any FET PET uptake. This might be
on MRI are classified as low-grade gliomas with the dif- caused by expression of different subtypes of the amino
ferential diagnosis of an encephalitis/encephalomyelitis. acid transporter in the brain compared to peripheral
To avoid potential pitfalls, some uptake characteristics organs. Only some head and neck cancers show increased
of FET-PET brain imaging should be mentioned. FET FET accumulation with a somewhat higher specificity,
concentration in the blood compartment, especially in compared to FDG which showed some false-positive
the early phase but also in the later phase, may be rela- results in patients with inflammation. However, the diag-
tively high. Therefore, the visualization of large vessels in nostic sensitivity of FET PET in these patients is lower
the brain, for example, the large venous sinus should not compared to FDG PET, and therefore, FET PET is not
be misinterpreted as pathologic uptake. useful for the management of these patients.
81
6 Case 1 Biodistribution
82
Case 2 Physiologic Uptake 6
Heart uptake
83
6 Case 2 Physiologic Uptake
Pancreas uptake
84
Case 3 Urinary Excretion 6
85
6 Case 4 Physiologic Uptake in CNS
86
Case 4 Physiologic Uptake in CNS 6
Sinus transversus
87
Teaching point
Female 61 years
T1 with Gd DTPA T2
MRI nding 18
F-ET nding
18
MRI conrms low-grade glioma but do not allow to F-ET PET shows a focal area of hypermetabolism
identify any focus transformed to high-grade tumor. (SUVmax/BG = 4). This area was conrmed as anaplas-
tic transformation with a relatively higher prolifera-
tive index (Ki-67 index = 20%) at stereotactic
biopsy.
Case 5 Low Grade Glioma: Follow-Up 6
Female 61 years
89
Teaching point
T2 T1 with Gd DTPA
90
MR nding
91
Low dose - CT Fused PET - CT
18
F-ET nding
Teaching point
18
F-ET PET shows a focal area of hypermetabolism
18
(SUVmax/BG = 3.2). This area was conrmed as tumor F-ET PET is applied for the identication of
recurrence at surgery. tumor recurrence in patients with unclear
ndings on morphological imaging. 18F-ET PET
imaging allows to shorten the time to
diagnosis in these patients.
6 Case 7 Dierential Diagnosis: Recurrence vs. Radiation Necrosis
MR nding 18
F-ET nding
18
MR shows an irregular contrast enhancement with F-ET PET shows only a slight and homogeneous
perifocal edema in both cases of glioblastoma fol- uptake surrounding the necrotic area caused by a
lowing percutaneous radiation therapy. passive inux of F-ET via the disrupted blood brain
barrier in case of radiation necrosis (SUVmax/BGmean:
1.7). In contrast the histologically conrmed recur-
rent glioblastoma on the right side shows an intense
F-ET uptake (SUVmax/BGmean: 3.8).
Teaching point
18
F-ET PET is applied for the identication of
tumor recurrence and dierentiation from
radiation induced benign changes in patients
with unclear contrast enhancement in MRI
following radiation therapy. 18F-ET PET
Imaging allows to determine the most
appropriate treatment in these patients.
92
Case 8 Biopsy Target Denition 6
Male 67 years
T1 with Gd DTPA
MR nding
93
6 Case 8 Biopsy Target Denition
Male 67 years
94
18
F-ET nding
Teaching point
18
F-ET PET shows a focal area of pathologic uptake.
18
Metabolic guided biopsy revealed high grade F-ET PET is very helpful to identify the tumor
glioma. tissue in diuse gliomas with widespread
abnormalities in MR. To enhance the
diagnostic yield, metabolic imaging with
fusion techniques may be useful for biopsy
target denition.
Case 9 Dierential Diagnosis 6
Male 32 years
MR nding 18
F-ET nding
18
MR shows widespread and diuse T2 abnormalities F-ET PET shows slightly increased uptake within
in the left hemisphere without showing a solid lesion the widespread lesion with a clear metabolic focus.
or any contrast enhancement pointing to a malig- PET guided biopsy taken from this area revealed an
nant tumor. Findings were rated unclear with dier- anaplastic astrocytoma in this area.
ential diagnosis of encephalomyelitis (ADEM) vs.
diuse low grade astrocytoma.
Teaching point
18
F-ET PET is very helpful to identify tumor
tissue within widespread diuse lesions
showing only T2 hyperintensites in MRI. In this
case F-ET PET was clearly superior to
conventional MRI to establish the diagnosis of
a brain tumor and to dene the most reliable
target volume. 95
6 Case 10 High Grade Glioma: Restaging
Female 54 years
18
F-ET nding
Teaching point
96
Case 11 Assessment of Brain Lesion 6
Male 47 years
T2 T1 with Gd DTPA
TIRM TIRM
97
MR nding
Male 47 years
98 18
F-ET nding
Teaching point
18
F-ET PET shows only one focal area of hyperme-
18
tabolism in the left frontal region conrmed at sur- F-ET PET may be helpful to clarify doubtful
gery as glioblastoma. The other regions turned out ndings at conventional Imaging. Areas with
to be postencephalitic alterations. intense 18F-ET uptake result to be highly
suspicious for malignant lesions and need to
be further investigated.
Chapter 7 Somatostatin Receptor
PET-CT
Somatostatin receptor PET-CT employs positron emit- min (30180 min). DOTA-peptides are primarily excreted
ting tracers (68Ga-DOTA-peptides) that specifically bind through the kidneys. 68Ga-DOTA-NOC physiologic
to somatostatin receptors (ssr) expressed on tumor cell uptake areas include the pituitary gland, the spleen, the
surface and has been used mainly for the assessment of liver, the adrenal glands, the head of the pancreas, the
neuroendocrine tumors (NETs). NETs derive from neu- thyroid (very mild uptake), and the urinary tract (kid-
roendocrine cells widely dispersed in the human body neys and urinary bladder). Some centers require soma-
and present an increased expression of ssr, particularly of tostatin analogue treatments to be interrupted before
ssr2. 68Ga-DOTA-peptides are very accurate for the PET. A better visualization of gastro-entero-pancreatic
assessment of well-differentiated NETs, since being slow- tumors can be achieved by oral pre-medication with
growing tumors, they are not clearly visualized on 18F- gastrografin.
FDG PET-CT scans. A 68Ga-DOTA-peptides PET-CT scan is a single-day
Several different somatostatin analogues derived from examination that can be performed in a couple of hours,
octreotide, lanreotide, or vapreotide (DOTA-TOC, being more patient friendly than SRS.
DOTA-TATE, DOTA-NOC) have been employed in the Another advantage of 68Ga-peptides is that they directly
clinic. The most relevant difference among the various bind to ssr and provide an indirect measure of tumor cell
compounds is the variable binding affinity to ssr-subtypes. differentiation (ssr are expressed in well-differentiated
Although DOTA-TOC, DOTA-TATE, and DOTA-NOC forms), offering data not only on disease extension but also
can bind to ssr2, the predominant receptor-type in NET, on tumor cell receptor expression status, particularly rele-
and to ssr5, only 68Ga-DOTA-NOC presents also a good vant before starting targeted nuclide therapy.
affinity for ssr3. Indications to perform 68Ga-DOTA-peptides PET-CT
At present, there are no published studies directly in NET cases include disease staging/re-staging, detec-
comparing 68Ga-DOTA-peptides for the assessment of tion of unknown primary tumor sites, selection of patients
NET or papers investigating if ssr-subtypes expression candidated to nuclide therapy and evaluation of treat-
differences on tumor cells are related to any specific clini- ment response.
cal setting. However, considering the more favorable
dosimetry and the wider ssr-subtypes spectrum affinity,
68Ga-DOTA-NOC seems to be the most promising tracer NET Staging and Re-Staging
for NET imaging.
68Ga-peptides present several technical and biologi- 68Ga-DOTA-TOC was the first compound to be used to
cal advantages for NET PET imaging, compared to other assess NET patients: in 2001 Hofmann reported a higher
commonly used tracers (such as 18F-FDG and 18F-DOPA) detection rate for DOTA-TOC as compared to
and to SRS (somatostatin receptor scintigraphy). 111In-octreotide-scinitgraphy.
First of all, the synthesis and labeling process is quite The largest patient population studied by 68Ga-DOTA-
easy and economic. Gallium can be easily eluted from a TOC PET was reported by Gabriel et al. in 2006: 84
commercially available Ge-68/Ga-68 generator, therefore patients with NET were studied with PET, SRS, and CT.
not requiring an on-site cyclotron. 68Gallium (t1/2 = 68 Sensitivity and specificity for the different imaging
min) presents an 89% positron emission and negligible modalities were compared with each other and clinical
gamma emission (1,077 keV) of 3.2%. The long half life of follow up and histology were used as standard of refer-
100 ence. PET sensitivity was significantly higher than SRS
the mother radionuclide 68Ge (270.8 days) makes it pos-
sible to use the generator for approximately 912 months and CT (97 vs. 52 vs. 61% respectively) with an overall
depending upon the requirement, rendering the whole accuracy of 96% for PET, 58% for SRS, and 63% for CT. In
procedure relatively economic. In particular, for particular, PET with 68Ga-DOTA-TOC was superior to
68Ga-DOTA-NOC, a radio-labeling yields of >95% can the other imaging modalities for the detection of NET
usually be achieved within 15 min and 300700 MBq of lesions at bone and node level.
68Ga DOTA-NOC can be obtained within 20 min. In the same year, in a limited population of 15 cases,
68Ga-DOTA-peptides PET-CT technical procedure PET with 68Ga-DOTA-TOC was used to select patients
consists of the intravenous administration of approxi- with tumors expressing ssr that were therefore initiated to
mately 100 MBq (75250 MBq) of the radiolabeled pep- nuclide therapy.
tide (such as 68Ga-DOTA-NOC, DOTA-TOC, etc). Although the experience with 68Ga-DOTA-NOC
Image acquisition usually starts after an uptake time of 60 PET-CT is less extensive, recent studies on limited
Somatostatin Receptor PET-CT 7
populations report its higher sensitivity compared to CT Until today, no studies addressing this issue have been
and its relevant impact on patient management. In a published, due to the very recent introduction of PET-CT
series of 11 patients with bronchial carcinoid, studied for for the detection of NET.
staging and re-staging, PET-CT findings were concordant Considering the very good results obtained using
with c.e. CT in only 3/11 cases; of the remaining 8 cases, PET-CT for NET staging/restaging with 68Ga-DOTA-
PET-CT detected a higher number of lesions in 5/8, and peptides and the good accuracy documented for PET
excluded malignancy at sites reported as positive on c.e. with FDG for the detection of primary tumors of other
CT in 3 patients. In the majority of cases, 68Ga-DOTA- histologies, PET-CT with 68Ga-peptides seems to be a
NOC PET allowed the detection of a higher number (37 potentially useful tool for the detection of the primary
vs. 21) of tumor lesions, in particular at lymph nodes, site in patients bearing NE metastasis.
liver, and bone level. The authors concluded that PET
contributed to a better evaluation of disease extent, and to
a change in the clinical management of 3 patients. Evaluation of the Response to Therapy
In the literature, there is only one paper directly com-
paring 68Ga-DOTA-NOC and 18F-DOPA findings in 18F-FDG PET is routinely used for the assessment of
NET patients: although the studied population was small, patients during and after therapy for the early detection
68Ga-DOTA-NOC identified more lesions than of therapy response.
18F-DOPA (71 vs. 45), especially at liver, lung, and lymph Regarding NET, although good results have been
node level. 68Ga-DOTA-NOC was also more sensitive obtained using cold or targeted somatostatin analogues
for the detection of lesions at pancreatic/peripancreatic for treatment, the studies published until now used clini-
level, known sites of increased 18F-DOPA uptake. cal parameters as standard of reference to assess therapy
A more recent paper, published online ahead of print, response. To our knowledge, there are no studies evaluat-
compared 68Ga-DOTA-TATE PET with 18F-DOPA PET. ing the role of PET in this particular clinical setting.
Also using 68Ga-DOTA-TATE, PET detected a higher However, considering the high accuracy of PET for
number of metastatic lesions (54 of 55 positive metastatic the detection of NET and for the selection of patients
tumor regions) than 18F-DOPA (29 of 55). candidate for targeted therapy, PET will be more and
Overall, 68Ga-DOTA-peptides are accurate for stag- more used with this indication.
ing and restaging of well-differentiated NETs or forms
presenting a high ssr-expression. In this clinical setting,
68Ga-DOTA-NOC seems to be the most interesting Patients Selection to Targeted Therapies
tracer for the wider ssr affinity range, the favorable dosim-
etry, and the easy and economic synthesis process. Surgical resection and cold somatostatin analogues rep-
resent the main stain treatment for NET, while targeted
radionuclide therapies have been increasingly used as a
Detection of the Site of the Unknown third-line treatment option.
Primary Tumor As stated before, 68Ga-DOTA-peptides PET-CT scan
provides not only information on the disease extension
The identification of the unknown primary tumor site but also indicates patients who present a high ssr expres-
(CUP) is another indication to perform 68Ga-DOTA- sion on tumor cells; therefore, PET is crucial to identify 101
peptide PET-CT. In fact, conventional imaging procedures patients who will more likely respond to targeted therapy
fail to detect the primary tumor site in almost one third of (either with cold somatostatin analogues or with peptide
cases (2027%). Therefore patients with biopsy-proven sec- radionuclide targeted therapy).
ondary NET lesions and negative physical examination, Moreover, the semi-quantitative and visual interpreta-
laboratory tests and conventional imaging procedures tion of the uptake of 68Ga-DOTA-NOC measured by
(including chest X-ray, abdominal and pelvic CT, mammog- PET-CT is used to guide the quantity of radiation and the
raphy in women, etc.) should be addressed to 68Ga-DOTA- timing for targeted radionuclide therapy (using 177Lu or
peptides PET-CT. From a clinical point of view, the 90YDOTA-TOC). In this setting, 68Ga-DOTA-NOC
identification of the primary tumor site is crucial to choose represents an indispensable procedure before planning-
the most appropriate line of therapy intervention. targeted treatment.
7 Case 1 Physiologic Uptake
PITUITARY GLAND
SPLEEN
ADRENAL GLANDS
BLADDER
Teaching point
102
a b
68
Ga-DOTA-NOC nding 103
Teaching point
Mild 68Ga-DOTA-NOC uptake can occur in accessory
spleen (a) and pancreatic head and should not be Some evident uptake in the pancreatic head
interpreted falsely as secondary uptake. can be observed in 2050% of cases, it has to
be considered when a mass is known or
suspected at this level. The physiologic uptake
is less intense and not focal.
7 Case 3 Pitfall: Sarcoidosis
a b c
18 68
F-FGG Ga-DOTA-NOC
PET ndings
Teaching point
Patient with sarcoidosis studied with 68Ga-DOTA-
NOC PET (a: transaxial, b: MIP) and with 18F-FDG PET/ Teaching point: activated lymphocytes
CT (c). Increased tracer uptake is present in both present an increased 68Ga-DOTA-NOC uptake
scans. due to ssr expression. Therefore, chronic
inammation may interfere with correct
68
Ga-DOTA-NOC image interpretation.
104
Case 4 Neuroendocrine Tumor 7
68
Ga-DOTA-NOC nding
a d
b e
c f
106
Teaching point
68
Ga-DOTA-NOC nding
Teaching point
PET-CT shows the primary NET and some secondary
peripancreatic lymph nodes. Somatostatin receptor PET has a high
sensitivity also for small primary lesions.
107
7 Case 6 Neuroendocrine Tumor: Staging
68
Ga-DOTA-NOC nding
68
Ga-DOTA-NOC nding
Teaching point
PET scan performed one year after the last radioim-
munotherapy cycle shows a pathologic uptake at D7 Somatostatin receptor PET has a high
and smaller lesions at the fth right rib and at the sensitivity for demonstrating disease relapse.
fourth liver segment.
109
7 Case 8 Neuroendocrine Tumor: Restaging
68
Ga-DOTA-NOC nding
MR showed a suspicious liver lesion while 18F-FDG PET-CT conrmed the presence of relapse at pancre-
PET identied only a suspicious uptake at pancreas atic level (head and body) and ve small liver
level. lesions.
111
7 Case 10 Neuroendocrine Tumor: Suspect Relapse
112
Patient with metastatic atypical lung carcinoid PET-CT scan conrms liver lesions and identies one
already treated; at follow-up CT shows liver lesions adenopathy at the pulmonary-aortic window, one at
and suspect lung nodules. the heart apex and bone involvement (left femur
and sternum).
Case 11 Paraganglioma: Suspect Relapse 7
68
Ga-DOTA-NOC nding
113
PET-CT shows a lesion close to the cava superior.
Surgery conrmed the PET nding to be recurrent
paraganglioma.
7 Case 12 Paraganglioma: Restaging
114
68
Ga-DOTA-NOC nding
Patient with biopsy-proven NET liver lesions and PET-CT conrmed liver involvement and demon-
unknown primary tumor. CT positive at liver; nega- strated a pathologic uptake at ileum, then conrmed
tive other imaging methods. to be the primary tumor.
115
7 Case 14 Neuroendocrine Tumor: Primary Unknoen
18 68
F-FDG Ga-DOTA-NOC
PET nding
18
F-FDG PET/CT was negative, while 68Ga-DOTA-NOC
PET/CT conrmed liver involvement and demon-
116
strated a pathologic uptake at left lung level (pri-
mary tumor), as well as secondary lesions at bone
level (vertebrae, right iliac, homerus) and one
abdominal adenopathy.
Case 14 Neuroendocrine Tumor: Primary Unknoen 7
18
F-FDG
68
Ga-DOTA-NOC
Teaching point
117
7 Case 15 Neuroendocrine Tumor: Staging
INJECTION SITE
SUSPECT FINDING
LIVER LESION
LIVER LESION
SPECT nding
118
Case 15 Neuroendocrine Tumor: Staging 7
68
Ga-DOTA-NOC nding
Teaching point
PET-CT conrmed liver metastasis and showed two
additional abdominal areas of pathologic tracer Better spatial resolution of PET over SPECT
uptake at mesogastric level: one lesion in close prox- allows better lesion localization.
imity to small bowel and the other just below the
kidney vessels. 119
7 Case 16 Neuroendocrine Tumor: Follow-Up
68
Ga-DOTA-NOC nding
120
Case 17 Neuroendocrine Tumor: Response to Therapy 7
before after
68
Ga-DOTA-NOC nding
121
7 Case 17 Neuroendocrine Tumor: Response to Therapy
before
Teaching point
122
Chapter 8 Acetate PET-CT
Acetate is a metabolic substrate of b-oxidation and pre- PSA value is not sensitive to differentiate patients with
cursor of amino acid and sterol. 11Carbon labeled Acetate local relapse or diffuse disease, while ACE PET seems
(ACE) was first used in the early 1980s for the evaluation useful to decide the proper treatment.
of the myocardial oxidative metabolism. 11C-Acetate is A minor role of ACE PET has been suggested for
rapidly taken up in the myocardium and subsequently diagnosis of hepatocellular carcinoma. Some authors
metabolized to CO2 via the Krebs cycle. Therefore, kinetic report the complementary role of ACE PET to FDG PET
analysis of accumulation and washout curves of radiola- in the detection of hepatocellular carcinoma. The well-
beled acetate allows to analyze myocardial oxygen con- differentiated hepatocellular carcinomas demonstrate a
sumption and myocardial blood flow. high ACE and a low FDG uptake, while poorly differenti-
The use of ACE PET in tumor imaging has been sug- ated ones have a low ACE and a high FDG uptake. In
gested in various malignancies (brain, nasopharyngeal, those tumors that are both ACE and FDG positive, authors
ovarian, liver and prostate tumors). It should be pointed suggest that these tracers are taken up by different parts of
out that the mechanism of tumor uptake is different from a moderately differentiated tumor. However, ACE PET is
that of myocardium, in which 11C-Acetate is channeled not a specific tracer for hepatocellular carcinoma. Benign
mainly to the Krebs cycle. The participation in free fatty liver lesions, like hepatic adenoma and focal nodular
acid synthesis is believed to be the dominant method of hyperplasia also show increased 11C-Acetate uptake.
11
incorporation in tumors. However, the metabolic path- C-Acetate has also been used for detection and char-
ways of Acetate are different in various tumor types. acterization of brain tumors. ACE PET shows, despite the
11
C-Acetate like 11C-Choline is the most studied PET low background activity of normal brain, low sensitivity
tracer suitable for prostate cancer imaging. The value of for detection of high-grade gliomas. Furthermore, ACE
these two appears nearly identical and none of them can PET seems not to be useful in differentiating high-grade
be favored. It is hypothesized that the anabolic pathways from low-grade brain tumors. In order to establish the
in fatty acid and sterol synthesis may account for the clinical role of ACE for brain tumor imaging and for dif-
retention of Acetate in prostate cancer. Like Choline, the ferentiation of recurrent brain tumor from radiation
Acetate uptake of normal prostate and benign hyperpla- necrosis, more studies are needed. An interesting applica-
sia overlap significantly with those for prostate cancer tion in brain lesions seems to be the power of ACE PET in
and therefore, ACE PET has a limited value for identifica- identifying meningial tumors with respect to other lesions
tion of primary prostate tumors. At present, the only as neuromas. In our experience, ACE PET was positive in
clinical indication for ACE PET in prostate cancer imag- all meningial tumors and negative in a case of lymphoma
ing is the evaluation of suspected recurrence after first- and in patients with fibrillary neuromas.
line treatment. Available data indicate the successful use Other oncological applications of ACE PET were
of ACE PET in identifying both local and distant metas- explored with equivocal results. The diagnostic accuracy
tasis in patients with prostate cancer relapse. Although of ACE PET for detection of well-differentiated lung
not the perfect radiotracer for prostate cancer imaging, tumors and head and neck cancers is still to be
nevertheless, ACE PET generally shows more sites of dis- addressed.
ease compared to all conventional imaging methods Like Choline, labeling of Acetate with a longerlived
together. In more than half of patients with rising PSA positron emitter such as 18F has been investigated for
after surgery or radiation therapy, ACE PET detects the prostate and brain cancer imaging. Methods for safe and
124
site of disease recurrence, even in the presence of low efficient synthesis for a routine clinical use are still under
PSA values. Moreover, in our experience, it seems that investigation.
Case 1 Biodistribution 8
11
C-Acetate
125
8 Case 2 Pancreatic Uptake
a b
Teaching point
126
Case 3 Prostate Cancer: Restaging 8
11
C-acetate nding
127
8 Case 4 Prostate Cancer: Relapse
11
C-acetate nding
128
Case 5 Prostate Cancer: Relapse 8
11
C-acetate nding
129
8 Case 6 Prostate Cancer: Restaging
11
C-acetate nding
Teaching point
After prostatectomy, pathologic increased uptake in
11
right obturatory lymph node. C-acetate has a high sensitivity also for small
nodal lesions.
130
Case 7 Prostate Cancer: Restaging 8
11
C-acetate nding
132
11
C-acetate nding
Teaching point
After brachitherapy, pathologic increased uptake in
11
several bones. C-acetate can frequently be positive before
CT.
Case 9 Prostate Cancer: Restaging 8
11
C-acetate nding
Teaching point
Pathologic increased uptake in prostate bed and
several bones. PSA was 1.6; PSA values do not necessarily
correlate with the number and the sites of
relapse.
133
8 Case 10 Prostate Cancer: Restaging
11
C-acetate nding
Teaching point
134 Pathologic increased uptake in a lymph node and
several bones. PSA was 19; PSA values do not necessarily
correlate with the number and the sites of
relapse.
Case 11 Hepatocellular Carcinoma: Restaging 8
11
C-acetate nding
Teaching point
11
C-acetate nding
136
Case 12 Hepatocellular Carcinoma: Relapse 8
137
Teaching point
11
C-acetate nding
138
Case 14 Liver Adenoma 8
11C-ACE
18F-FDG
PET nding
Both 11C-acetate and 18F-FDG show increased uptake
in the liver mass.
139
8 Case 14 Liver Adenoma
11
C-ACE
140
18
F-FDG
Case 15 Focal Nodular Hyperplasia 8
11
C-ACE
18
F-FDG
PET nding
141
8 Case 15 Focal Nodular Hyperplasia
11
C-ACE
142
18
F-FDG
Case 16 Hepatocellular Carcinoma 8
11
C-ACE
PET nding
18
F-FDG
143
Teaching point
As previously shown, deregulated cell cycle progression is also been observed in a series of nonsmall cell lung can-
a hallmark of cancer. Accordingly, the majority of thera- cer (mean SUV-values 3.7 and 6.0, respectively).
peutic drugs has been designed to inhibit cell prolifera- [18F]FLT is not or only marginally incorporated into
tion and/or to induce apoptosis. Metabolic imaging with DNA (<2%) and is therefore not a direct measure of pro-
PET and the glucose analog 2-[18F]fluoro-2-deoxyglucose liferation (17). In vitro studies indicated that [18F]FLT
(FDG) has been demonstrated to sensitively detect malig- uptake is closely related to thymidine kinase 1 (TK1)
nant tumors and to identify responding tumors early in activity and respective protein levels. [18F]FLT is therefore
the course of anticancer treatment. [18F]FDG PET is also considered to reflect TK1 activity and, hence, S-phase
a valuable clinical tool for predicting tumor response to fraction rather than DNA synthesis. Although being a
therapy and patient survival. poor substrate for type 1 equilibrative nucleoside trans-
However, tumoral uptake of FDG reflects prolifera- porters (ENT), cellular uptake of [18F]FLT is further facil-
tion only in part and is associated with false positive find- itated by redistribution of nucleoside transporters to the
ings due to unspecific tracer retention in inflammatory cellular membrane after inhibition of endogenous syn-
processes. Therefore, to increase specificity for malignant thesis of thymidylate (TMP) (de novo synthesis of TMP).
lesions, other tracers that complement the information However, the detailed uptake mechanism of [18F]FLT is
provided by [18F]FDG are required. Measurement of yet unknown and the influence of membrane transport-
tumor growth and DNA synthesis might be appropriate ers and various nucleoside metabolizing enzymes remains
for assessment of proliferative activity in malignant to be determined.
tumors. So far, several DNA precursors have been inves- [18F]FLT PET produces images of high contrast, of
tigated including [11C]thymidine which represents the both malignant tumors and proliferating tissues. Because
native pyrimidine base used for DNA-synthesis in vivo. of high physiologic tracer uptake in proliferating bone
Due to the short half-life of 11C and rapid degradation of marrow, the sensitivity of [18F]FLT for detecting tumor
[11C]thymidine, this tracer was considered less suitable manifestations in bone marrow may be reduced. [18F]FLT
for clinical use. undergoes glucoronisation leading to enhanced liver
Recently, the thymidine analog 3-deoxy-3-[18F]fluo- uptake. Decreased sensitivity rates were described for
rothymidine ([18F]FLT) was suggested for noninvasive liver metastases from various solid tumors. Due to negli-
assessment of proliferation and more specific tumor gible background uptake of [18F]FLT in the brain, specific
imaging. The effort to synthesize [18F]FLT is similar to imaging of proliferation may be appropriate for detection
that of the standard radiotracer [18F] FDG. [18F]FLT which of tumors or metastases in the central nervous system.
is derived from the cytostatic drug azidovudine (AZT) Recently, [18F]FLT was suggested for therapeutic
has been reported to be stable in vitro and to accumulate monitoring using various experimental settings. In an
in proliferating tissues and malignant tumors. Thymidine animal model of fibrosarcoma it was reported that [18F]
kinase 1 was revealed as key enzyme responsible for the FLT uptake decreased early after antiproliferative treat-
intracellular trapping of [18F]FLT. Recently, a significant ment with 5-fluorouracil or cisplatin. In a mouse lym-
correlation of tumoral proliferation and [18F]FLT uptake phoma xenotransplant model, significant decrease of
in various malignant tumors has been described, includ- [18F]FLT uptake was already observed 48 h after chemo-
ing breast cancer, colorectal cancer, lung cancer, gliomas, therapy with cyclophosphamide. An early reduction of
sarcoma and lymphomas. In a pilot study comprising 34 tumoral [18F]FLT uptake was further demonstrated, 48 h
146
patients with malignant lymphomas, linear regression after treatment with tyrosine kinase inhibitors in a lung
analysis indicated a significant correlation of tumoral cancer xenograft model. However, data are preliminary
[18F]FLT uptake and proliferation fraction in biopsied tis- and clinical trials are needed to further validate [18F]FLT
sues, as indicated by Ki-67 immunohistochemsitry (r = as marker for therapy response. Moreover, the lower
0.84, P < 0.0001). All patients with indolent or aggressive uptake of [18F]FLT compared to [18F]FDG may result in a
lymphomas exhibited focal [18F]FLT-uptake in lesions reduced sensitivity to detect residual disease after treat-
also described by routine staging procedures indicating a ment. As previously reported for the standard radiotracer
sensitivity of 100%. [18F]FLT uptake in lymphomas was [18F]FDG, false positive findings may also occur at
significantly lower compared to respective [18F]FDG [18F]-FLT PET, because an increased proliferation rate is
uptake (mean SUV-values 4.6 and 5.1, respectively). A not specific for malignant tumors. Recently, reports from
reduced uptake of [18F]FLT compared to [18F]-FDG has Troost and Yap indicated false positive findings
Thymidine PET-CT 9
originating from reactive cervical lymph nodes and histology. However, a significantly reduced tracer uptake
benign lung nodules. compared to the standard radiotracer [18F]FDG has been
In conclusion, specific imaging of proliferative activity observed in a variety of solid neoplasms indicating that
with [18F]FLT is feasible. The use of [18F]FLT as PET tracer [18F]FDG is superior to [18F]FLT regarding detection of
showed advantages for detection of lymphomas in the tumor manifestation sites. [18F]FLT PET has a potential,
central nervous system and the mediastinum. [18F]FLT especially for early assessment of therapy response, which
PET was suitable to differentiate indolent and aggressive has to be validated in further experimental and clinical
tumors and to indicate progression to a more aggressive studies.
147
9 Case 1 Hepatocellular Carcinoma
Male 58 years
a c d
b e
18
F-FLT nding
148
Case 2 Pancreatic Cancer 9
Male 61 years
FLT
FDG
18
F-FLT nding
149
Intense focal FLT uptake (red arrows). In the corre-
sponding FDG PET-CT, there is also an intense uptake
in the pancreatic head. Histology revealed a pT2pN1
adenocarcinoma of the pancreatic head.
9 Case 3 Diuse Large B Cell Lymphoma
Male 47 years
FLT FDG
150
PET nding
FLT
FDG
18
F-FDG nding 18
F-FLT nding
PET-CT scan shows intense focal uptake in the FLT PET also shows intense uptake of the tracer.
antrum region.
151
9 Case 5 Diuse Large B Cell Lymphoma
Female 71 years
FDG FLT
18
F-FDG nding 18
F-FLT nding
PET scan shows intense focal uptake in the iliac bone FLT PET also shows intense uptake of the tracer.
152 and in the left femur (red arrow).
Case 6 Lymphoma: Response to Therapy 9
Female 65 years
BEFORE AFTER
18
F-FLT nding
BEFORE AFTER
154
Case 7 Lung Nodule 9
18
F-FLT nding
FDG FLT
156 18
F-FDG and other ndings 18
F-FLT nding
A patient with suspicion of lung cancer underwent No pathologically increased uptake; biopsy led to
FDG PET showing focal tracer uptake in the right the diagnosis of laryngotracheitis.
lung lobe as well as around the trachea and medi-
astinal lymph nodes (red arrows).
Case 9 High Grade Sarcoma 9
18
F-FLT nding
157
9 Case 10 Acute Myeloid Leukemia
18
F-FLT nding
159
9 Case 11 Breast Cancer
18
F-FLT nding
18
AADC activity in neuroendocrine tumor types and dif- F-DOPA: patient-based sensitivity of 100 vs. 89%,
ferences in metabolic handling of these PET tracers by respectively. Also, 11C-5-HTP seems to be the tracer of
exocrine and endocrine pancreatic tissue. Because of the choice compared to 18F-DOPA, when imaging other
likely strong similarities between 11C-5-HTP and foregut (e.g., bronchial) neuroendocrine tumors.
18
F-DOPA tracer handling in patients with gastrointesti- Also in medullary thyroid carcinoma, and pheochro-
nal neuroendocrine tumors, carbidopa pretreatment is mocytoma and paragangliomas, 18F-DOPA PET imaging
also advocated for 18F-DOPA PET imaging in this patient has been reported to perform well or better than the ref-
group to improve image quality especially in the region of erence imaging techniques. However, this seems to be
the kidneys and bladder, and to improve lesion detect- also dependent on the differentiation grade of the tumor.
ability via further increased SUV of lesions. Indeed, high In patients with more aggressive, and fast growing tumors,
18
accuracy rates for the detection of (metastatic) neuroen- F-FDG PET performs better than 18F-DOPA PET, and
docrine tumors have been reported by the institutes that vice versa. In medullary thyroid carcinoma, there is a sus-
do use carbidopa pretreatment. However, pancreatic islet picion that one may have to rely on the calcitonine dou-
cell tumors may be an exception to the rule. This should bling-time to select the optimal PET tracer for a given
be further investigated. patient, while in malignant pheochromocytoma and
In the last decade, 18F-DOPA PET-CT imaging has paraganglioma this seems to particularly depend on the
been most tested in patients with mid-gut well-differentiated underlying germline mutation.
neuroendocrine carcinomas (carcinoids), other gastroen- It is expected that the reported high detection rates of
18
teropancreatic neuroendocrine tumors, such as (non) F-DOPA PET for various types of neuroendocrine
functioning pancreatic islet cell tumors, pheochromocy- tumor lesions will be lower in clinically more difficult
tomas and paragangliomas, and medullary thyroid carci- cases, such as when a diagnosis is only suspected and not
nomas. In these studies, most patients had proven pathologically confirmed. A recent study seems to con-
(recurrent) disease and 18F-DOPA PET-CT has been firm this finding. In patients (n = 32) with only biochemi-
compared with current anatomical imaging techniques, cal proof of the disease, various types of neuroendocrine
mostly CT and/or MRI, and other functional imaging tumors, the diagnostic accuracy of 18F-DOPA PET-CT
techniques, such as somatostatine receptor scintigraphy was 88%, whereas in patients (n = 61) that were restaged,
with 111In-octreotide (SRS), 123/131I-labeled metaiodoben- the overall accuracy was 92%. Likewise, specificity of the
zylguanidine (MIBG), 18F-FDG PET, and more recently, 18
F-DOPA tracer in the various tumor types has not been
also with 68Ga-labeled PET based variants of octreotide. structurally studied. Furthermore, changes in therapeutic
Regarding the anatomical imaging techniques, they are management due to initial and follow-up 18F-DOPA
frequently found to be complementary to the functional PET-CT scans has not been documented systematically.
imaging techniques under study in these patient series. In Also, its role as a prognosticator or parameter for early
carcinoids, patient based reported sensitivities for response monitoring in the various neuroendocrine
18
F-DOPA PET-CT are very high, ranging from 65100% tumor types has not been studied to date. These are all
and seems to be an excellent staging method. However, in areas in which more research is warranted.
direct comparison to 11C-5-HTP PET, on a patient based Although 18F-DOPA uptake has been reported in both
analysis, the 11C-5-HTP tracer outperformed 18F-DOPA functioning and nonfunctioning neuroendocrine tumors,
(sensitivity of 100 vs. 96%, respectively), whereas per- and also independently from the type of substance pro-
163
lesion analysis showed the opposite (sensitivity of 78% for duced (e.g., serotonin or catecholamine), in theory a rela-
11
C-5-HTP and 87% for 18F-DOPA). In two smaller PET tionship between 18F-DOPA uptake and metabolic activity
studies with mixed-type neuroendocrine tumors, the seems obvious. In a retrospective study analyzing the per-
68
Ga-labeled analogues of somatostatine also did better formance of 18F-DOPA PET and PET-CT in patients with
than 18F-DOPA PET. This can be partly explained by the known or suspected feochromocytomas, no significant
inferior imaging results of 18F-DOPA in patients with correlation was found between SUVmax of the lesions and
(non) functioning islet cell tumors in these studies. This is plasma or urinary biochemical measurements (n = 15
in line with the study that directly compared 18F-DOPA patients available for this analysis). In a prospective analy-
and 11C-5-HTP PET, both in carcinoid and islet cell tumor sis in feochromocytoma patients, both with benign and
patients. Metastatic tumor lesions of islet cell tumors were malignant behavior, also this relationship was studied
visualized much better with 11C-5-HTP compared to using a PET image derived index for overall tumor
10 Dopa PET-CT
activity per patient. Per patient the whole-body metabolic an ectopic ACTH producing tumor, 18F-DOPA PET has
burden was calculated, consisting of the total sum of met- been reported to be helpful.
abolic burden of lesions in one patient. Metabolic burden In conclusion, 18F-DOPA PET is a excellent functional
per lesion was calculated as SUV mean lesion x PET imaging technique in patients with proven neuroendo-
derived volume of the lesion, 40% isodensity contour. crine tumors, especially in carcinoids. Performance also
When not only SUVmax of one lesion but overall tumor seems to be good in feochromocytomas and medullary
activity per patient (n = 43) was taken into account, sig- thyroid carcinomas, depending on the clinical context. In
nificant correlations were found with 24 h urinary excre- contrast, pancreatic islet cell tumors and more generally,
tion of total (free + conjugated) normetanephrine (r = foregut neuroendocrine tumors seem to perform less well
0.84, P < 0.001), metanephrine (r = 0.57, P < 0.01), and compared to other functional imaging methods, e.g.,
3-methoxytyramine (r = 0.65, P < 0.01), as well as plasma somatostatine receptor based scintigraphy (SPECT and
free levels of normetanephrine (r = 0.82, P < 0.001), PET) and 11C-5-HTP PET. Adding CT improves the detec-
3-methoxytyramine (r = 0.51, P = 0.01) and chromogra- tion rate even more, thus combining the 18F-DOPA tech-
nin A (r = 0.49, P < 0.01). This finding needs further con- nique in dedicated PET-CT scanners is likely more
firmation in other patient groups, as well as analyzing this optimal. The imaging characteristics of 18F-DOPA PET-CT
relationship in other situations, e.g., after therapy has been in complex clinical cases or in less advanced clinical stages,
initiated, or the meaning of such a possible relationship, e.g., when there is only a suspicion of a neuroendocrine
e.g., for prognosis and monitoring therapy response. tumor, needs to be further determined. Furthermore, its
18
F-DOPA PET has been tried in other tumor types, role for monitoring response to therapy and predicting
such as small cell lung cancer, melanoma, Merkel cell response to therapy needs to be further investigated. Also,
tumor, prostate cancer with neuroendocrine differentia- how this imaging technique performs in relation to other
tion, neuroblastoma and brain tumors. Patient numbers new functional PET imaging techniques, especially the
68
in these reports were often small and the performance of Ga-labeled somatostatine analogues in neuroendocrine
the 18F-DOPA imaging method, compared to other ana- tumors, needs to be further elucidated. Potential advan-
tomically or functionally imaging methods differed tages of the latter technique are that the labeling technique
widely. of the somatostatine analogues with 68Ga is relatively easy
Furthermore, 18F-DOPA whole-body PET has been to perform, and one does not need a cyclotron, since 68Ga
tested as a tracer in various nononcological settings. In can be eluted from a commercially available generator. On
infants and children with hyperinsulinism, 18F-DOPA the other hand, 18F-DOPA PET may have a broader clini-
PET has been reported to be quite successful to distin- cal applicability, e.g., for studying the dopaminergic sys-
guish the histological focal from the diffuse form. In these tem of the human brain, oncological tumors that do not
situations, carbidopa pretreatment should not be given. usually express somatostatine receptors, nononcological
Visualization of parathyroid adenomas with 18F-DOPA settings, such as infants with hyperinsulinism, and the
PET does not seem to be possible. However, in search for well-known neurological setting.
164
Case 1 Physiologic Uptake 10
165
Teaching point
Teaching point
SRS
18
F-DOPA
18
F-DOPA nding
167
PET shows multiple lesions in the liver, abdomen,
and groin, and also a faint lesion in the myocardial
region. Metastatic carcinoid in the heart was later
conrmed by MRI of the heart.
10 Case 3 Metastatic Carcinoma: Follow-Up
18
F-DOPA PET CT fusion
Teaching point
168
Case 4 Metastatic Carcinoma and Rectal Carcinoma 10
Male 65 years
18 18
F-DOPA F-FDG
PET ndings
Teaching point
The abdominal mass and liver lesions corresponding
to carcinoid lesions are clearly visible on the 18F-DOPA These scans demonstrate that glucose
scan, while the 18F-FDG PET scan shows the rectal metabolism in well-dierentiated, slowly
carcinoma (and a lot of physiological gut uptake). progressive neuroendocrine tumors is usually
not increased. Therefore, these tumors often
show almost no 18F-FDG uptake.
169
10 Case 5 MEN2a: Medullary Thyroid Cancer
Female 52 years
170
18
F-DOPA nding
Teaching point
PET shows the primary tumor in the thyroid region
on the right side. Also (metastatic) medullary thyroid carcinoma
is often visualized with 18F-DOPA. Visualization
may depend on the growth pattern, and
rapidly progressive patients may be better
imaged with 18F-FDG PET.
Case 6 MEN2a: Medullary Thyroid Cancer 10
Male 37 years
MIBG
123
I-MIBG and other ndings
171
10 Case 6 MEN2a: Medullary Thyroid Cancer
Male 37 years
172
18
F-DOPA nding
Teaching point
18
F-DOPA PET shows slightly increased bilateral adre-
nal uptake, corresponding to both adrenals. Sensitivity of 18F-DOPA for both benign and
malignant pheochromocytoma has been
reported to be better compared to 123I-MIBG.
Case 7 Congenital Hyperinsulinism 10
1.5 months old
18
F-DOPA nding
Teaching point
PET scan shows a focal lesion in the region of the tail
of the pancreas. In congenital hyperinsulinism, the 18F-DOPA
PET scan can be very helpful in distinguishing 173
a focal from a diuse form of hyperinsulinism.
If a focal lesion can be demonstrated, only a
partial resection of the pancreas is necessary
to cure the patient.
10 Case 8 Neuroendocrine Tumor
Male 58 years
174 18
F-DOPA nding
c
GALLBLADDER
PANCREAS
175
Teaching point
18
F-DOPA nding
176
Case 9 Metastatic Carcinoid 10
Teaching point
18
F-DOPA nding
18
F-DOPA nding
179
Chapter 11 Imaging of Hypoxia
with PET-CT
For a number of tumors, including head and neck clearance of unbound tracer should be fast in order to
squamous cell carcinoma (HNSCC) and cervical carci- discriminate between specific and nonspecific uptake.
noma, radiotherapy (RT) may fail to achieve local control For the latter, greater hydrophilicity is desirable because
due to the presence of tumor hypoxia (pO2 < 10 mmHg), this increases blood clearance through more rapid renal
which decreases the availability of the oxygen free radi- excretion. In reality, all these criteria are seldom fulfilled.
cals necessary to induce sufficient DNA damage to cause Hypoxia imaging with PET is for the most part based
cell death. The role of hypoxia in increasing tumor resis- on 18F-labeled 2-nitroimidazole compounds, which cova-
tance to radiation therapy was first recognized a century lently bind to cellular macromolecules in hypoxic condi-
ago, but it was not until 1953 that the crucial role of oxy- tions, as a result of multistep intracellular electron reduction
gen in radiation response was fully acknowledged and of the parent compound. When oxygen is present, the
described as the oxygen enhancement effect. There is a reoxidized reactive species exits the cell. Conversely, in
great variability in the oxygen availability to cancer cells, hypoxia, further reductive metabolism gives rise to more
and most human malignancies show microscopic hypoxic or less stable intracellular hydroxylamine derivatives,
regions that are heterogeneously distributed within the which are trapped intracellularly and can be detected with
tumor mass and may be located within an apparently PET. Most 2-nitromidazole tracers are freely diffusible and
well-vascularized lesion. Hypoxic cells are about 3 times no active tissue uptake mechanism is present. The lipophi-
more radioresistant than well-oxygenated cells and their licity and peripheral metabolic properties vary amongst
presence in tumors contributes to failure of local control these tracers and lead to differences in the pharmacoki-
in RT. There is also evidence that hypoxia increases resis- netic properties of the various 2-nitroimidazoles. These
tance to chemotherapy. This may be because hypoxia properties are mainly determined by the chemical compo-
induces a decrease in proliferating cells, which constitute sition of the side chain that is attached to the imidazole
to target cell population of most chemotherapeutic drugs. ring moiety. One common feature and a clear limitation of
18
Cells further away from a functional blood vessel may F-labeled 2-nitroimidazoles is that they accumulate quite
also receive a decreased concentration of drug. slowly in hypoxic tissues, showing no hypoxia-specific sig-
Several papers have shown a clear correlation between nal until 1.54 h postinjection. Most, if not all, of the
tumor oxygenation, as measured by oxygen probes, and a 2-nitroimidazole tracers evaluated so far also show an early
poor tumor response to RT. Intratumoral hypoxia cannot blood flow-dependent distribution. Although they are pri-
be predicted by commonly used clinical prognostic vari- marily excreted via the urinary system, leading to the blad-
ables, such as size, grade, or histology of tumor. Tumors der being the most common dose limiting organ,
that appear identical by clinical and radiological criteria elimination by the hepatobiliary pathway occurs to a vari-
can vary greatly in the extent of hypoxia. Thus, if tumor able degree and can limit evaluation of the abdomen.
oxygenation is to be employed as a predictor of treatment Enhanced tracer binding under hypoxic conditions
resistance, it will have to be individually measured for has been convincingly shown in preclinical settings for
each tumor and potentially at each tumor site. several compounds, including [18F]FMISO, [18F]FETA,
Since the discovery that nitroimidazole based com- [18F]FETNIM, [18F]FAZA, [18F]EF1, [18F]EF3 and [18F]
pounds bind to macromolecules in hypoxic cells, attempts EF5. In addition to [18F]FMISO, which was the first
have been made to find radiolabeled agents that could be hypoxic PET tracer to be used in humans, clinical trials
used noninvasively with PET for assessment of hypoxia. have also more recently been reported using [18F]FAZA,
182
To obtain high-contrast images, an ideal hypoxia tracer [18F]FETNIM, [18F]EF3 and [18F]EF5. In addition to these,
64
should have high affinity and specificity for cellular Cu-labeled ATSM has also been intensively evaluated in
hypoxia and low nonspecific binding in nonhypoxic cells. both preclinical and clinical settings.
Metabolic degradation of the tracer is undesirable, since In this chapter, the use of [18F]FMISO, [18F]FAZA, and
18
the resulting labeled metabolites could bind to nontarget [ F]EF5 in human cancer patients will be discussed with
molecules or take part in biochemical processes unrelated examples given in an image format.
to hypoxia, reducing specificity. One important property
of the tracer is lipophilicity, which determines the ability
of the molecule to cross cell membranes. While this capa- [18F]FMISO
bility is important to allow intra-cellular uptake, high
lipophilicity increases nonspecific activity in nonhypoxic Fluorine-18 fluoromisonidazole ([18F]FMISO) has been
cells, particularly early after tracer administration. Finally, the most widely evaluated hypoxia tracer both in
Imaging of Hypoxia with PET-CT 11
preclinical and human studies up to this point in time. results obtained with a sugar-coupled 2-nitroimidazole
Results of [18F]FMISO PET for evaluation of tumor derivative [123I]IAZA developed for SPECT imaging, ini-
hypoxia in humans have been reported by several institu- tiated the development of fluorine-18 labeled 1-a-D-(5-
tions across a range of malignancies, including head and fluoro-5-deoxy-arabinofuranosyl)-2-nitroimidazole)
neck, cervical, nonsmall cell lung, and renal cell cancers, ([18F]FAZA). This agent was first used in human subjects
glioma and soft-tissue sarcoma. Most importantly, the at the Peter MacCallum Cancer Center and the Technical
ability of [18F]FMISO to stratify prognosis in patients University of Munich for the evaluation of head and neck
receiving conventional radiotherapy and targeted therapy cancer. Additional studies are ongoing in lung cancer and
of hypoxia has been demonstrated. These data suggest sarcoma. Even more clearly than observed with [18F]
that the imaging signal may provide a noninvasive prog- FMISO, [18F]FAZA demonstrates heterogeneity of
nostic and predictive biomarker in patients receiving RT. hypoxic signal between and within lesions in the same
Despite foci hypoxia being almost universal within individual. The Cross Cancer Institute group, which
tumors, sites of viable malignancy, as identified on [18F] developed the tracer, recently published their own initial
FDG PET scanning, have variable uptake of hypoxia trac- experience with this agent in a range of tumor types
ers like [18F]FMISO. This variation occurs both between including lymphoma.
and within lesions. The extent of hypoxia-related trap-
ping apparent on PET imaging is typically less than that
of viable tumor. It is recognized that necrotic tumor areas [18F]EF5
having low reductase activity may not show retention of
[18F]FMISO. EF5 (2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-penta-
Despite encouraging results with ([18f]fmiso, its high fluoropropyl)-acetamide) has been extensively studied as
lipophilicity results in slow clearance kinetics, which a hypoxia marker using intravenous administration fol-
necessitates a delay in imaging for 46 h post injection to lowed by tumor biopsy and immunohistochemical analy-
obtain optimal contrast between hypoxic and nonhypoxic sis. Monoclonal antibodies conjugated with fluorescent
tissue. By this time, count statistics are degraded by the dyes, which recognize cellular adducts of the marker have
relatively rapid decay of fluorine-18 and hence hypoxia- been found to be highly specific. MISO and ETA (pre-
specific retention is typically evaluated 2 h post injection cursors for FMISO and FETA) were originally developed
in clinical cases. However, the substantial background as radiosensitizers, and later adapted as hypoxia tracers
activity even 4 h after tracer administration interferes by incorporating an 18F-label into the molecule. In con-
with the quality of the images, and generally, low contrast trast, EF5 was developed specifically for the detection of
between putatively hypoxic tissue and normal structures hypoxia using immunohistochemical methods, and the
makes these scans difficult to read qualitatively. It may 18
F-labeled compound is identical to unlabeled EF5. EF5
also make it difficult to assign regions-of-interest (ROI) has been shown to have quite a uniform biodistribution
for lesion quantification or radiotherapy planning, in both rodents and humans, which probably is due to the
although initial experience suggest feasibility of [18F] high lipophilicity of the compound. No 18F-labeled
FMISO PET for dose escalation beyond 80 Gy in head metabolites have been detected in rats or humans.
and neck cancer. Noninvasive imaging of tumor hypoxia in rats using [18F]
EF5 was in accordance with data on EF5. The highest
183
uptakes of the tracer were seen in the kidney, liver and in
[18F]FAZA the gastrointestinal tract.
[18F]EF5 has been introduced to clinical PET-CT imag-
The low target-to-background ratios typically observed ing only recently. The development of an electrophilic
with [18F]FMISO raise questions regarding its suitability labeling of [18F]EF5 from [18F]F2 using a post target
as a widely applicable PET hypoxia tracer and have justi- method has enabled high-yield tracer synthesis suitable
fied the development of related tracers that are more for patient studies. Thus far, the experience is limited to
hydrophilic. Such tracers should allow shorter waiting head and neck cancer and glioma, with a growing interest
time for imaging after tracer administration, potentially to study other neoplasms where hypoxia is known to have
lower radiation exposure and greater lesion contrast, importance, such as cervical cancer.
assuming similar binding to hypoxic cells. There are a Human HNSCC is FDG-avid but uptake of [18F]EF5
number of promising agents in this regard. Encouraging in line with other radiolabeled nitroimidazole analogues
11 Imaging of Hypoxia with PET-CT
is variable. This is seen in patients presenting with locally correlation with immunohistochemical examination of
advanced disease who may show differential uptake of the same lesions ex vivo.
[18F]EF5 in primary tumor and lymph node metastases in
the neck. For instance, one patient with multiple neck
metastases from oropharyngeal carcinoma had one large Summary
[18F]EF5-positive lymph node, while the other slightly
smaller ipsilateral node was [18F]EF5-negative. No corre- It is important for readers to acknowledge that imaging of
lation between uptake of FDG and [18F]EF5 in head and hypoxia in a diagnostic setting has not yet emerged into
neck cancer could be demonstrated, while tumors with routine patient management. Until now, all imaging data
the highest uptake of the hypoxia marker showed invari- from human studies have been collected from research
ably low perfusion, measured with [15O]H2O PET-CT. protocols in academic centers, and availability of tracers
[18F]EF5 imaging is performed 3-h from tracer injection, is very limited elsewhere. However, the Trans-Tasmanian
and Figures x-y show representative cases of patients chemoradiotherapy study 98.02 is an excellent example
imaged with [18F]EF5 and FDG PET-CT to demonstrate on how hypoxia imaging may change the outcome of can-
variability in uptake believed to represent hypoxia. cer patients. This study showed that hypoxia, as detected
Generally [18F]EF5 shows similar pattern of uptake in with [18F]FMISO PET is associated with locoregional fail-
head and neck cancer in comparison to related com- ure in patients with head and neck cancer who did not
pounds such as [18F]FMISO or [18F]FAZA. Direct com- receive the hypoxia-activated drug tirapazamine. Other
parison between the three labeled nitroimidazole applications such as dose painting of hypoxic tumor sub-
analogues has not been performed in human tumors nor volumes detected on PET in radiotherapy planning await
is there any knowledge about relationship between uptake confirmation of clinical impact. Furthermore, which
of [18F]EF5 in tumor and outcome to treatment. One of patients have most benefit from hypoxia imaging and
the potential advantages of using [18F]EF5 will be the how variable the regional tracer uptake is in the short
potential to validate the in vivo imaging data by direct term should be clarified.
184
Case 1 Head and Neck Tumour 11
18
F-FMISO nding
Teaching point
Low tracer uptake in this patient with a primary
tumor of the pyriform sinus and bilateral cervical [18F]FMISO typically has low tumor-to-
lymph nodes. background activity ratios as demonstrated by
the comparison of coronal [18F]FDG performed
at 1 h following tracer administration and [18F]
FMISO PET scans obtained 4 h after radiotracer
administration. The high lipophilicity of [18F]
FMISO leads to relatively high non-specic
uptake in muscle and the brain.
185
11 Case 2 Head and Neck Tumour
18
FAZA nding
Teaching point
Moderate tracer uptake.
[18F]FAZA has lower lipophilicity than [18F]FMISO
and generally provides lower background
activity. In particular, little brain uptake is
apparent. This leads to good quality images
within 2 h of radiotracer administration as
demonstrated in this comparison of [18F]FDG
and [18F]FAZA.
186
Case 3 Head and Neck Tumor 11
PET ndings
187
11 Case 4 Lung Cancer
PET ndings
188
Case 5 Sarcome 11
18
FAZA nding
CT
Fused
190
PET
18
F-EF5 nding
FDG [18F]EF5
PET ndings
191
Considerable hypoxia is seen in the large primary
tumor invading the adjacent bony structures (49%
of FDG-avid voxels had [18F]EF5 tumor-to-muscle
uptake ratio 1.5 at 3-h).
11 Case 8 Metastatic Oropharyngeal Carcinoma
Male 68 years
PET ndings
192
Case 9 Metastatic Oropharyngeal Carcinoma 11
Male 57 years
PET ndings
193
Chapter 12 Angiogenesis PET Using
Radiolabeled RGD Peptides
Angiogenesis, the process of developing a new vessel, is developed for PET and SPECT imaging. Both compounds
an essential feature of the growth of solid tumors. For demonstrated improved pharmacokinetics with predom-
decades, the targeting of tumor angiogenesis has evolved inantly renal tracer elimination and increased uptake and
into one of the most widely pursued therapeutic strate- retention in a murine tumor model, compared with the
gies in cancer research. Antiangiogenic drugs like bevaci- first generation peptides. Extensive preclinical evalua-
zumab, sunitinib, or sorafenib, were proved to be effective tions concerning monomeric compounds were carried
in many solid cancers such as colorectal cancer, renal cell out using [*I]Gluco-RGD and [18F]Galacto-RGD. Initial
carcinoma, hepatocelluar carcinoma, etc. But, these kinds in vivo evaluation was carried out using the human mela-
of molecular targeted therapy are responsive only in noma M21 model, which is well characterized concern-
selected patient population. ing avb3 expression. Using this model, [18F]Galacto-RGD
Integrin avb3 plays an important role in tumor angio- and [125I]Gluco-RGD uptake in the tumor 120 min p.i.
genesis and is overexpressed on endothelial cells of newly was 1.5 and 1.8% ID/g, respectively. Blocking experi-
developed vessel induced by tumors or ischemic tissues. ments injecting 6 mg c(RGDfV) per kg mouse 10 min
Integrin avb3 is a receptor for the ligand, vitronectin, and prior to tracer injection reduced tumor accumulation to
arginine-glysine-aspartic acid (RGD) tripeptide is known approximately 15% of control for [125I]Gluco-RGD and
to be active binding moiety to the receptor. Molecular 35% of control for [18F]Galacto-RGD, which demon-
imaging tracers containing RGD peptide have been eval- strates receptor specific accumulation. Furthermore,
uated for monitoring avb3 expression noninvasively imaging studies with mice bearing melanoma tumors
using PET, SPECT, MRI, optical imaging and US. For with increasing amounts of avb3-positive cells (produced
nuclear molecular imaging, studies were done based on by mixing M21 and M21-L cells) showed that there is a
cyclic RGD peptides radiolabeled with 18F, 64Cu, 68Ga for correlation between integrin expression and tracer accu-
PET, or 99mTc for SPECT. mulation. These data demonstrate that noninvasive deter-
[18F] Galacto-RGD has shown high tumor-to-back- mination of avb3 expression and quantification with
ground ratios preclinically and has been evaluated in a radiolabelled RGD peptides is feasible with static emis-
number of clinical studies. To improve targeting effi- sion scans. Moreover, animal PET study with increasing
ciency, multimeric constructs were reported revealing amounts of c(RGDfV) were obtained, that indicated that
improved targeting properties in preclinical models. the dose-dependent blocking of tracer uptake in the
Noninvasive determination of avb3 expression poten- receptor positive tumor could be monitored.
tially can be used to monitor treatment response to anti- Until now, the only approach of imaging avb3 expres-
angiogenic drugs or to select patients likely to respond to sion which has made the transition into the clinic is the
treatment with antiangiogenic drugs. radiotracer approach. [18F]Galacto-RGD was the first
PET tracer applied in patients and could successfully
image avb3 expression in human tumors with good
[18F]Galacto-RGD PET tumor/background ratios. In all patients, rapid, predomi-
nantly renal tracer elimination was observed, resulting in
Kessler and coworkers developed the pentapeptide cyclo low background activity in most regions of the body.
(-Arg-Gly-Asp-dPhe-Val-), which shows high affinity High inter and intraindividual variance in tracer accu-
and selectivity for avb3. For the first evaluation of this mulation in tumor lesions was noted, suggesting great
196
approach, Haubner et al. have synthesized radioiodinated diversity of avb3 expression. These findings emphasize
RGD peptides which showed comparable affinity and the potential value of noninvasive techniques for appro-
selectivity to the lead structure. Several strategies to priate selection of patients entering clinical trials with
improve the pharmacokinetics of radiohalogenated pep- avb3-targeted therapies. Further biodistribution and
tides have been developed. The glycosylation approach is dosimetry studies confirmed rapid clearance of [18F]
based on the introduction of sugar derivatives which are Galacto-RGD from the blood pool and primarily renal
conjugated to the e-amino function of a corresponding excretion. Background activity in lung and muscle tissue
lysine in the peptide sequence. By conjugating the RGD was low and the calculated effective dose found was
containing cyclic pentapeptide cyclo(-Arg-Gly-Asp- approximately 19 mSv/MBq, which is very similar to an
dPhe-Val-) with glucose- or galactose-based sugar amino [18F]FDG scan. We also studied, if [18F]Galacto-RGD
acids, [*I]Gluco-RGD and [18F]Galacto-RGD have been uptake correlates with avb3 expression. 19 patients with
Angiogenesis PET Using Radiolabeled RGD Peptides 12
solid tumors (musculoskeletal system n = 10, melanoma AH111585 with 418F-fluorobenzaldehyde at pH 3.5 to
n = 4, head and neck cancer n = 2, glioblastoma n = 2, form the oxime [18F]AH111585. The specific activity of
breast cancer n = 1) were examined with PET using [18] the injectate, determined by high-performance liquid
Galacto-RGD before surgical removal of the lesions. chromatography (HPLC), ranged between 76 and 170
SUVs and tumor/blood ratios were found to correlate sig- GBq/mmol, which is substantially less compared to [18F]
nificantly with the intensity of immunohistochemical Galacto-RGD.
staining as well as with the microvessel density. Moreover,
immunohistochemistry confirmed lack of avb3 expres-
sion in normal tissue and in the two tumors without [68Ga]NOTA-RGD PET
tracer uptake. We are now systematically examining dif-
68
ferent tumor entities with respect to their avb3 expres- Ga is a positron emitter with a short half-life of 68 min
sion patterns as shown by [18F]Galacto-RGD PET. In and its hydrophilic nature is adequate for the labeling of
squamous cell carcinoma of the head and neck (SCCHN), small peptides with rapid renal clearance for PET. 68Ga
we could demonstrate good tumor/background ratios has a great advantage for PET over other cyclotron-pro-
with [18F]Galacto-RGD PET, but again also a widely vary- duced positron emitters because it can be obtained eco-
ing intensity of tracer uptake. Immunohistochemistry nomically by use of a commercially available 68Ge/68Ga
demonstrated predominantly vascular avb3 expression, generator. The parent nuclide 68Ge has a long half-life of
thus in SCCHN, [18F]Galacto-RGD PET might be used as 271 days, allowing its use as a generator for more than 1
a surrogate parameter of angiogenesis. We have also com- year.
pared the tracer uptake of [18F]FDG and [18F]Galacto- Cyclic Arg-Gly-Asp-D-Tyr-Lys [c(RGDyK)] was con-
RGD in patients with non small cell lung cancer (NSCLC, jugated with 2-(p-isothiocyanatobenzyl)-1,4,7-triazacy-
n = 10) and various other tumors (n = 8), because in case clononane-1,4,7-triacetic acid (SCN-Bz-NOTA), then
of a close correlation of the two tracers, there would prob- labeled with 68Ga and finally 68Ga-NOTA-RGD was
ably be no need for a specific tracer like [18F]Galacto- produced.
RGD. The results showed no correlation between the two Six patients with liver metastasis from colorectal can-
tracers concerning all lesions (r = 0.157). For the sub- cer were enrolled. [18F] FDG and 68Ga-NOTA-RGD
group of [18F]FDG-avid lesions and lesions in patients PET-CT studies were done before combination therapy
with NSCLC, there was a slight trend toward a higher with FOLFOX and bevacizumab. About 5 mCi of
68
[18F]Galacto-RGD uptake in more [18F]FDG-avid lesions Ga-NOTA-RGD was injected to the patients intrave-
(r = 0.337). However, the correlation coefficient was very nously and PET images were acquired 30 min later. There
low. Our results suggest that avb3 expression and glucose is 1 day interval between [18F] FDG and 68Ga-NOTA-
metabolism are not closely correlated in tumor lesions, RGD PET-CT.
and that consequently [18F]FDG cannot provide similar All six patients showed hypermetabolic primary and
information as [18F]Galacto-RGD. Recently, the SPECT metastatic lesions on [18F]FDG PET-CT. In three patients,
tracer [99mTc]NC100692 was introduced by GE healthcare the hypermetabolic lesions on [18F] FDG PET-CT also
for imaging avb3 expression in humans and was first showed mild 68Ga-NOTA-RGD uptakes. However, the
evaluated in breast cancer. Nineteen of twenty two tumors other three had no 68Ga-NOTA-RGD uptakes. The lesions
could be detected with this agent, which was safe and well with 68Ga-NOTA-RGD uptakes showed partial response
197
tolerated by the patients. An avb3 and avb5 specific PET to combination therapy with bevacizumab, while the
radiotracer which has recently been used in clinical trials lesions without 68Ga-NOTA-RGD uptake showed no
named [18F]AH111585. The chemical synthesis of the response or progression of disease.
68
precursor for 18F-AH111585 has previously been Ga-NOTA-RGD PET had the potential to predict the
described. Radiosynthesis was performed on an auto- response to combination chemotherapy with bevaci-
mated module (TRACERlab FX F-N; GE Healthcare) by zumab and might help to select appropriate patients for
coupling an aminooxy-functionalized precursor of [18F] antiangiogenic therapy.
12 Case 1 Squamous Cell Carcinoma
18
F-RGD nding
198
PET-CT shows heterogeneous moderate to focally
intense tracer uptake in the osteolytic lesion with
good tumor to background contrast.
Case 2 Hepatocellular Carcinoma 12
199
18
F-RGD nding
Teaching point
The large tumor shows contrast enhancement in the
CT scan (red arrow); however, it can hardly be This case demonstrates that imaging of liver
detected in the [18F]Galacto-RGD PET (black arrow) lesions is problematic with [18F]Galacto-RGD,
due to the high physiological liver activity. unless there is very high uptake.
12 Case 3 Prostate Cancer: Bone Metastases
99mTc-HDP 18F-RGD
99m
Tc-HDP nding
Teaching point
200 Multiple areas with intense tracer uptake in the
whole skeleton, predominantly in the right scapula Note that normally the skeleton is only very
and in the pelvis (arrows). faintly visualized with [18F]Galacto-RGD, which
means that all parts of the skeleton visible in
this MIP show elevated tracer uptake. Note
18
F-RGD nding also physiological tracer excretion via the
gallbladder and urinary tract.
Multiple foci of moderate to intense tracer uptake in
the whole skeleton.
Case 4 Pelvic Chondrosarcoma 12
18
F-RGD nding
201
12 Case 5 Femural Osteosarcoma
MR 18F-RGD
MR nding
18
F-RGD nding
MR
18F-RGD
203
12 Case 6 Femural Liposarcoma
MR 18F-RGD
MR nding
18
F-RGD nding
204
Case 6 Femural Liposarcoma 12
MR
205
18F-RGD
12 Case 7 Breast Cancer: Staging
a b
18
F-RGD nding
Teaching point
PET scan allow to visualize primary tumor on the left
206 side with heterogeneous tracer uptake (a), multiple This case demonstrates that in the lungs, the
axillary lymph node metastases on the left side with review of nonattenuation corrected images
intense tracer uptake (b) and a single lung metasta- can provide additional information, as with
sis on the right side (c, non attenuation corrected conventional [18F]FDG PET.
image).
Case 8 Non-Small Cell Lung Cancer 12
99mTc-HDP
18F-FGD
207
208
68Ga-NOTA-RGD
Case 10 Physiologic Uptake 12
209
68
Ga-NOTA-RGD
68
Ga-NOTA-RGD is rapidly excreted through kidney.
PET-CT images show high uptake in kidney, ureters,
and urinary bladder. Mild uptake is notied in liver,
spleen, large vessels, and bowel. Mild uptake in the
ventricle is supposed to be choroid plexus.
12 Case 11 Sigmoid Colon Adenocarcinoma
Female 67 years
18F-FDG 68Ga-NOTA-RGD
210
Case 11 Sigmoid Colon Adenocarcinoma 12
18F-FDG
68Ga-NOTA-RGD
211
Chapter 13 Hormonal Receptors PET-CT
Sex hormones play an important role in the development In the literature, several acquisition protocols for [18F]
and growth of cancer, especially in breast and prostate can- FES PET have been described. For research applications,
cer. The mode of action of these sex hormones is activation dynamic imaging protocols with arterial blood sampling
of the corresponding hormone receptor in tumor cells. The and metabolite analysis have been described, but for rou-
hormone-bound receptor acts as a transcription factor and tine clinical applications, a whole body data acquisition
activates signaling pathways that induce proliferation and protocol comparable to that of [18F]FDG can be used.
tumor growth. Because of the pivotal role of the sex hor- Although fasting of the patient prior to the procedure is
mones and their receptors in disease progression of breast not required, the use of medication that binds to the
cancer and prostate cancer, endocrine therapies are devel- active site of the ER (e.g., tamoxifen, fulvestrant) should
oped, that aim to interfere with hormone receptor-medi- be stopped. The use of aromatase inhibitors can be con-
ated pathways by either reducing the level of the hormone tinued. Usually, a dose of 220 MBq [18F]FES is adminis-
or blocking of the hormone receptor. The most important tered to the patient, but acceptable images can still be
hormone receptors involved in tumor progression are obtained when only 100 MBq of the tracer is injected.
estrogen and progesterone receptors in breast cancer and Data acquisition can already be performed as soon as 30
androgen receptors (ARs) in prostate cancer. PET allows min after tracer injection, but a waiting period of 60 or 90
noninvasive monitoring of receptor expression in patients min is preferred to allow clearance of nonspecific uptake.
with hormone-responsive tumors, and thus could poten- Physiological distribution: Normal physiological
tially provide information that can support therapy man- expression of ER is mainly located in epididymes, testes,
agement in patients. Since 1980s, many radiolabeled pituitary gland, ovaries, uterus, kidneys and adrenals, but
steroids have been evaluated as PET tracers for imaging of to a lesser extent also in prostate gland, bladder, liver, thy-
the hormone receptors, but most of these tracers failed in mus and heart. The normal distribution of [18F]FES, how-
preclinical or early-clinical evaluation. So far, only 16a-[18F] ever, is dominated by the hepatic and renal clearance of
fluoro-17b-estradiol ([18F]FES) seems to be an interesting the tracer. Consequently, [18F]FES PET images show
PET tracer for estrogen receptor (ER) imaging in breast highest tracer uptake in liver, gallbladder, intestine, kid-
cancer patients and potentially also for endometrial cancer neys and bladder. Early clearance of [18F]FES from blood
patients. The first clinical studies in patients with prostate is rapid and total blood activity remains almost constant
cancer indicate that PET imaging of the androgen receptor after 1015 min. [18F]FES is rapidly converted into sulfate
(AR) with 16b-[18F]fluorodihydrotestosterone ([18F]FDHT) and glucuronide metabolites by the liver. Twenty minutes
is feasible. Clinically useful PET tracers for progesterone after injection, the intact tracer comprises only 20% of the
receptor imaging are currently not available. Here, we will total radioactivity in blood. The concentration of metab-
describe the current experience with [18F]FES PET and olites in blood remains almost constant between 20 and
[18F]FDHT PET for imaging the ER and AR, respectively. 120 min after tracer injection, because the rate of release
of metabolites from the liver into the blood stream is sim-
ilar to the renal clearance rate of these metabolites.
[18F]FES PET Clinical practice: The main role of [18F]FES PET in clini-
cal practice is related to detection of ER-positive breast
Methodology: [18F]FES can reliably be prepared in two tumors and may have also a role in endometrial carcinoma.
steps from a commercially available precursor. Practical Several studies have demonstrated that [18F]FES PET can
214
radiochemical yields are high (several GBq) and conse- successfully detect the ER status of primary breast tumors,
quently, doses for multiple patients can be obtained from lymph node and distant metastases in humans. Because of
a single preparation. [18F]FES was shown to be stable in the high physiological uptake of [18F]FES in liver and kid-
aqueous solution for at least 24 h. The use of [18F]FES as a neys, however, detection of lesions in these organs is diffi-
PET tracer was found to be safe. The radiation burden of cult. Correlations between quantitative [18F]FES uptake and
[18F]FES is 0.022 mSv/MBq, which is comparable to the in-vitro tests of ER density were found to be 0.96 and 0.73 in
radiation dose associated with other nuclear medicine two relatively small clinical PET studies in 10 and 17 patients,
procedures. The highest radiation dose is received by the respectively. By itself, [18F]FES PET is not ideal for diagnosis
liver and gall bladder. The recommended dose for [18F] and staging, because ER-negative tumors cannot be detected
FES is 220 MBq (6 mCi), which typically corresponds to by this method and liver metastases often remain obscured.
<5 mg of FES per injection. To date, no adverse events for In patients with advanced ER-positive disease, how-
a tracer dose of [18F]FES have been reported. ever, [18F]FES PET could be a useful tool for
Hormonal Receptors PET-CT 13
Other nding
18
F-FES nding
Teaching point
PET showed no pathological uptake.
Notice the very high uptake in the liver,
216
gallbladder, and intestine, which is normal
physiological uptake.
Case 2 Metastatic Breast Cancer 13
Other nding
Teaching point
Patient experienced heavy low back pain located at
the sacroiliac joint on the left side. The bone scan Notice the physiological uptake in liver,
showed no bone metastases and MRI detected two gallbladder, intestine, kidneys, ureters and
bone metastases in vertebras Th 7 and Th 12, but not bladder. High activity in the left wrist is due to
at the location of the pain complaints. the tracer injection. Diuse uptake in the
bone marrow.
217
18
F-FES nding
18
F-FES nding
Teaching point
218
Normal physiological uptake in the liver (enlarged),
gallbladder, intestine, kidneys, and bladder. Notice Patient with bone metastases of breast cancer
the multiple ER-positive bone lesions, including a with progression on third-line hormonal
focal lesion in the skull, in the periorbital region, in treatment. It was unknown whether the ER was
both shoulders (right more than left), multiple still available in order to justify treatment with
lesions in the vertebral column and in the pelvis. estrogen. Biopsy to determine the ER status
was not easy due to the localization of the
metastases. In such cases, PET was performed
to determine the ER status of the lesions.
Case 4 Endometrial Stroma Cell Tumor 13
219
18
F-FES nding
Teaching point
Normal uptake in liver, stomach, intestine, excretion
by kidneys, and bladder. Pathological uptake in Patient with an ER positive tumor, developed
almost the whole right lung with focal regions with lung metastases that responded well to
very intense uptake. Focal uptake apicomedial in the hormonal treatment. When CT showed
left lung. progression, [18F]FES PET was performed to
decide whether a second-line hormonal
treatment could be a useful treatment. This
case illustrates that FES PET could also be useful
in patients with endometrium carcinoma.
Chapter 14 HTP PET-CT
b-[11C]-5-hydroxy-L-tryptophan (11C-5-HTP) is a PET The 11C-5-HTP tracer has been developed during the
tracer used for imaging neuroendocrine tumors which are eighties of the last century in Uppsala, Sweden. Their first
derived from neuroendocrine cells. Neuroendocrine cells clinical results with neuroendocrine tumors were pub-
regulate a variety of body functions through paracrine lished in 1993. Nowadays, 11C-5-HTP PET scanning is
stimulation. This is achieved via the production of a large typically performed 1020 min after injection of 140521
variety of hormones, of which serotonin and cate- MBq 11C-5-HTP with carbidopa pretreatment, 2 mg/kg
cholamines are examples. The production of these hor- body weight or with a fixed dose of 200 mg, 1 h prior to
mones is accomplished via amine precursor uptake and injection. The estimated mean radiation dose is 0.34 mSv
decarboxylation. In many differentiated neuroendocrine per 100 MBq 11C-5-HTP. Patients are requested to fast for
tumors, the capability to synthesize hormonal products 24 h with free intake of fluids. Thus far, as an endoge-
has remained. This makes imaging with amine precursors nous compound, no adverse reactions after tracer injec-
interesting in these tumors. The serotonine pathway is tion have been reported.
active in many neuroendocrine tumors. In this pathway, In earlier days, PET scans were made without carbi-
the naturally occurring amino acid tryptophan and 5-HTP dopa. However, this resulted in lower image quality due
are both precursors. Serotonin is most abundantly present to streaky image reconstruction artefacts caused by high
in blood platelets and the intestinal wall. In the brain sero- physiological excretion of the radiotracer via kidneys and
tonin acts as a neurotransmitter. Both tryptophan and urinary bladder. Carbidopa, a peripheral inhibitor of
5-HTP are taken up via system L large amino acid trans- AADC enzyme activity was tested for its capacity to
porters (LAT). After entering the cell, decarboxylation to decrease urinary activity concentration. Patients with
serotonin takes place via the enzyme aromatic amino acid mid-gut carcinoids (well-differentiated neuroendocrine
decarboxylase (AADC). The resulting end-product sero- carcinomas) were scanned with and without carbidopa
tonin is then transported into storage vesicles through the pretreatment 1 h before 11C-5-HTP injection. Carbidopa
vesicular monoamine transporter (VMAT). From these pretreatment significantly reduced the radioactivity con-
vesicles, serotonin can be released in the extracellular centration in the urinary collecting system, from a mean
environment. Serotonine is thereafter degraded and even- SUV of the renal pelvis of 155 19539 14 SD. As a
tually excreted as urinary 5-hydroxyindole acetic acid secondary effect, tumor uptake of 11C-5-HTP was signifi-
(5-HIAA). In the catecholamine pathway, the same LAT cantly increased after carbidopa administration, increas-
and VMAT transporter systems, and the enzyme AADC ing from a mean SUV of 11 314 3 SD, and improving
play a crucial role, resulting in the end-products, dop- visual image interpretation. With carbidopa pretreat-
amine, adrenaline and noradrenaline. Although the exact ment in normal liver and pancreas tissue, the mean SUV
uptake mechanism and intracellular fate of these amines was significantly increased or decreased, respectively.
and their metabolites are not precisely understood, it However, in these normal background tissues mean SUV
appears that increased LAT activity plays a role to satisfy a was overall still low with mean liver SUV of 3.6 0.8 and
high precursor turnover due to an increased metabolic mean pancreas SUV of 4.4 0.8 SD.
pathway, e.g., serotonin or catecholamine, or at least So far, three patient series with a reasonable number of
increased AADC activity in neuroendocrine tumors. patients have been published. In the first study, the follow-
11
C-5-HTP is only produced in a few centers world- ing 18 patients with histopathologically verified neuroen-
wide. The use of this tracer is limited due to two major docrine tumors who were referred for evaluation and
222
drawbacks. First, an on-site cyclotron is needed for the medical treatment were included: mid-gut (n = 14),
production of the 11C isotope, which has a half-life of 20 foregut (n = 1), hindgut carcinoid (n = 1), and endocrine
min. Furthermore, the tracer synthesis is very complex pancreatic tumors (n = 2). 11C-5-HTP was compared to
since it relies on two complex multienzyme steps. CT. Additionally, 10 of 18 patients were monitored with
However, quantities up to 1,000 MBq can be prepared PET at different intervals during treatment. Patients were
reliably. Major advantages of this technique is that in one not pretreated with carbidopa and fasted 4 h before start
examination the whole body can be assessed for disease of study. Directly after injection of 110700 MBq 11C-5-
activity, and scans are often easy to interpret due to high HTP dynamic imaging was performed with the abdomen
uptake in tumor lesions and low background activity in in the field of view, and plasma samples were taken during
normal organs. Altogether, the published clinical results 45 min. Thereafter, in most patients, an additional 10 min
using 11C-5-HTP justify the use of this tracer. static image with another portion of the abdomen in the
HTP PET-CT 14
field of view was recorded. All 18 patients showed six mm. The main conclusion of this study was that PET
increased 11C-5-HTP uptake in tumor tissue; interestingly imaging with 11C-5-HTP can be universally applied in
this was also the case in two patients with normal urinary neuroendocrine tumors, also in patients without elevated
5-HIAA levels (hindgut carcinoid and a nonfunctioning 5-HIAA excretion in urine, as long as the tumor is not
endocrine pancreatic tumor). Fifteen baseline PET scans highly proliferating and/or dedifferentiating.
could be compared with contrast-enhanced CT scans. Another study confirmed that the information obtained
11
C-5-HTP PET detected more tumor lesions than CT in with 11C-5-HTP PET considerably contributes to the
ten patients, and was equal in five patients (four mid-gut, information regarding tumor status in patients with neu-
one foregut), with missing data in three patients with mid- roendocrine tumors. In this study, carcinoid (n = 24) or
gut neuroendocrine tumors. In the ten patients that were pancreatic islet cell tumor (n = 23) patients with at least
on treatment (interferon-a octreotide, or somatostatin one lesion visible on conventional imaging (e.g., CT, SRS)
analog only), a close correlation between the changes in underwent a 11C-5-HTP and a 6-[F-18]- fluoro-L-dihy-
11
C-5-HTP transport rate constant in the tumors and uri- droxy-phenylalanin (18F-DOPA) PET scan. 18F-DOPA
nary 5-HIAA was noted. It was suggested that 11C-5-HTP PET images the catecholamine metabolic pathway. Whole-
PET may serve as a means to monitor therapy. However, it body PET images with carbidopa pre-treatment were
is still unknown whether these biochemical changes in the recorded 10 min after intravenous injection of 200 50
tumor, while on medical treatment, reflect changes in SD MBq 11C-5-HTP, or 60 min after i.v. administration of
tumor metabolism or primarily amine processing. 180 50 SD MBq 18F-DOPA. The PET findings were com-
In another patient series 38 patients were evaluated, pared, per-patient and per-lesion, with a composite refer-
again with a variety of neuroendocrine tumors, but ence standard derived from all available imaging data
among others, consisting of mid-gut carcinoids (n = 13), along with clinical and cytological/histological informa-
lung carcinoids (n = 7), and nonfunctioning endocrine tion. Results indicated that indeed, 11C-5-HTP PET can be
pancreatic tumors (n = 5). Whole-body 11C-5-HTP PET seen as a universal imaging agent for carcinoid and pan-
imaging was compared to both CT and the functional creatic islet cell tumor patients. It was the only imaging
imaging technique, somatostatin receptor scintigraphy modality that was positive in all patients (100% sensitiv-
(SRS), which is often used in clinical routine in neuroen- ity). Especially in islet cell tumor patients, more tumor-
docrine tumors, and more widely available. Whole-body positive patients and lesions were found with 11C-5-HTP
PET scanning with a mean dose of 381 MBq 11C-5-HTP (100 and 67%) compared to 18F-DOPA (89 and 41%), and
was started 20 min after tracer injection in carbidopa pre- SRS (78 and 46%), and CT (87 and 68%). In carcinoid
treated patients. 11C-5-HTP PET detected tumor lesions patients, the per-lesion analysis showed that 18F-DOPA
in 36 of 38 (95%) patients. In 84% of patients SRS was PET outperformed all other imaging techniques. Adding
positive, whereas CT was positive in 79%. More lesions CT to both imaging techniques resulted in a further
were detected with 11C-5-HTP PET in 22 of 38 (58%) improvement in sensitivity in a per-lesion analysis, since
patients compared to SRS and CT, whereas the imaging both types of imaging techniques were complementary to
modalities showed equal number of lesions in 13 of 38 each other. Therefore, for pancreatic islet cell patients,
11
patients (34%). In three patients, SRS or CT showed more C-5-HTP PET-CT was considered the optimal imaging
lesions; patients with a nonfunctioning endocrine pan- technique, whereas for carcinoid patients, it was 18F-DOPA
creatic tumor, and a pancreatic carcinoma with some PET-CT. Furthermore, it was stated that in carcinoid
endocrine differentiation on immunohistochemistry patients SRS scanning can be omitted without missing any 223
were PET negative. A patient with metastasized thymus lesions. However, in a minority of islet cell patients, (8%)
carcinoma only showed the primary tumor on 11C-5-HTP SRS performed better than both PET techniques and
PET and SRS, while CT scan also detected metastases. therefore remains of additional value. In this regard, direct
From these patients, it was speculated that in case of high comparison of 11C-5-HTP (and 18F-DOPA) to the recently
proliferation rate and dedifferentiation of neuroendo- developed 68Ga-labeled somatostatin analogs for PET
crine tumors, 18FDG PET is probably the imaging modal- imaging in various subtypes of neuroendocrine tumors
ity of choice. In the 17 patients who had their primary would be much of interest.
tumor still in situ, 11C-5-HTP PET was positive in 16, Besides application in neuroendocrine tumors, 11C-5-
compared to SRS in nine, and CT in eight patients. PET HTP has also been tested in a few patients with hormone-
could detect surgically removed lesions as small as refractory prostate cancer, after it became known that
14 HTP PET-CT
hormone-refractory prostate cancer may undergo neu- to therapy and predicting response to therapy needs to be
roendocrine differentiation. In nononcological studies further investigated. Also, how this imaging technique
11
C-5-HTP uptake has been studied in brains of healthy vol- performs in relation to other new functional PET imag-
unteers and patients with major depression. Also, another ing techniques in neuroendocrine tumors needs to be
labeled variant of tryptophan, a-[11C]methyl-L-trypto- further elucidated. 11C-5-HTP PET has also been proven
phan (a-[11C]MTrp), has been tested in the normal and useful in neuroendocrine tumors that do not produce
diseased brains, both neurologically and psychiatrically. bioactive amines and metabolites of the serotonine or cat-
In conclusion, 11C-5-HTP PET is a excellent functional echolamine pathways. More research should be directed
imaging technique in patients with proven neuroendo- in elucidating the exact uptake mechanisms and intracel-
crine tumors, especially in pancreatic islet cell tumors and lular fate of these amines and their metabolites, since
carcinoids. Adding CT improves the detection rate even these are not precisely understood. The major drawback
more; thus, combining these techniques in dedicated of 11C-5-HTP PET is the difficult and laborious synthesis
PET-CT scanners is likely more optimal. The imaging of 11C-5-HTP, and the need for a cyclotron to produce 11C
characteristics of 11C-5-HTP PET-CT in complex clinical on-site. Thus, the development of a more straightforward
cases or in less advanced clinical stages, e.g., when there is synthesis of 18F-labeled 5-HTP could be much helpful,
only a suspicion of a neuroendocrine tumor, needs to be provided this newly developed tracer has the same imag-
determined. Furthermore, its role in monitoring response ing capacities as 11C-5-HTP.
224
Case 1 Biodistribution 14
11C-HTP
225
14 Case 2 Physiologic Uptake
Salivary glands
Pancreas
Kidney
Bladder
Teaching point
11C-5-HTP 18F-DOPA
PET ndings
Teaching point
11 18
Both C-5-HTP PET and F-DOPA PET show increased
tracer uptake in the left > right carotid region, and Although both scans show intense uptake in
also in the hilar region of the left lung, due to the paragangliomas, these lesions show a
paragangliomas. slightly better 18F-DOPA uptake. This could be
related to the active catecholamine pathway
in these tumors. Furthermore, note the 227
physiologic 18F-DOPA uptake in the gall
bladder, which is a potential pitfall as it can be
mistaken for a tumor lesion.
14 Case 4 Neuroendocrine Tumor: Staging
Female 59 years
228
SRS and other ndings
11C-HTP 18F-DOPA
PET ndings
Teaching point
The 11C-5-HTP PET and 18F-DOPA PET show a large
mass in the region of the pancreatic tail, consistent Neuroendocrine tumors of the pancreas are
with the SRS scintigraphy. However, 11C-5-HTP PET very heterogeneous in their biochemical
shows numerous lesions in the liver and abdomen, behavior. In these patients, often a 229
which were not present on either 18F-DOPA PET or combination of several imaging types
the octreotide scintigraphy. (anatomical imaging, PET, somatostatin
receptor scintigraphy) will reveal the true
extent of the disease.
Chapter 15 References
Choline Methionine
Breeuwsma AJ, Pruim J, Jongen MM. In vivo uptake of [11C] Galldiks N, Kracht LW, Burghaus L, et al Use of 11C-methionine
choline does not correlate with cell proliferation in human PET to monitor the effects of temozolomide chemotherapy
prostate cancer. Eur J Nucl Med Mol Imaging. 32(6):66873 in malignant gliomas. Eur J Nucl Med Mol Imaging.
DeGrado TR, Coleman RE, Wang S. Synthesis and evaluation of 2006;33(5):51624
18F-labeled choline as an oncologic tracer for positron emis- Kato T, Shinoda J, Nakayama N, et al Metabolic assessment of
sion tomography: initial findings in prostate cancer. Cancer gliomas using 11C-methionine, [18F] fluorodeoxyglucose,
Res. 2001;61:1107 and 11C-choline positron-emission tomography. AJNR Am
Giovacchini G, Fallanca F, Landoni C, et al F. C-11 choline ver- J Neuroradiol. 2008;29(6):117682
sus F-18 fluorodeoxyglucose for imaging meningiomas: an Kracht LW, Friese M, Herholz K, et al Methyl-[11C]- l-methionine
initial experience. Clin Nucl Med. 2009;34(1):710 uptake as measured by positron emission tomography cor-
Hara T. 11C-choline and 2-deoxy-2-[18F]fluoro-D-glucose in relates to microvessel density in patients with glioma. Eur
tumor imaging with positron emission tomography. Mol J Nucl Med Mol Imaging. 2003;30(6):86873
Imaging Biol. 2002;4(4):26773 Moulin-Romse G, D'Hondt E, de Groot T, et al Non-invasive
Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer grading of brain tumours using dynamic amino acid PET
using carbon-11-choline. J Nucl Med. 1998;39:9905 imaging: does it work for 11C-methionine? Eur J Nucl Med
Husarik DB, Miralbell R, Dubs M, et al Evaluation of [(18)F]- Mol Imaging. 2007;34(12):20827
choline PET/CT for staging and restaging of prostate cancer. Price SJ. The role of advanced MR imaging in understanding
Eur J Nucl Med Mol Imaging. 2008;35(2):25363 brain tumour pathology. Br J Neurosurg. 2007;21(6):56275
Kwee SA, Ko JP, Jiang CS, Watters MR, Coel MN. Solitary brain Pirotte B, Goldman S, Massager N, et al Comparison of 18F-
lesions enhancing at MR imaging: evaluation with fluorine FDG and 11C-methionine for PET-guided stereotactic brain
18 fluorocholine PET. Radiology. 2007;244(2):55765 biopsy of gliomas. J Nucl Med. 2004;45(8):12938
Nanni C, Zamagni E, Cavo M, et al 11C-choline vs. 18F-FDG Scott JN, Brasher PMA, Sevick RJ, Rewcastle NB, Forsyth PA.
PET/CT in assessing bone involvement in patients with How often are nonenhancing supratentorial gliomas malig-
multiple myeloma. World J Surg Oncol. 2007;5:68 nant? A population study. Neurology. 2002;59:9479
Picchio M, Messa C, Bandoni C, et al Value of [11C]coline posi- Sundin A, Johansson C, Hellman P, et al PET and parathyroid
tron emission tomography for re-staging prostate cancer: a L-[carbon-11]methionine accumulation in hyperparathy-
comparison with [18F]fluorodeoxyglucose positron emis- roidism. J Nucl Med. 1996;37(11):176670
sion tomography. J Urol. 2003;169:133740
Picchio M, Treiber U, Beer AJ, et al Value of 11C-choline PET
and contrast-enhanced CT for staging of bladder cancer:
correlation with histopathologic findings. J Nucl Med. Fluoride
2006;47(6):93844
Schiavina R, Scattoni V, Castellucci P, et al 11C-choline positron
emission tomography/computerized tomography for preop- Berger F, Lee YP, Loening AM, et al Whole-body skeletal imag-
erative lymph-node staging in intermediate-risk and high- ing in mice utilizing microPET: optimization of reproduc-
risk prostate cancer: comparison with clinical staging ibility and applications in animal models of bone disease.
nomograms. Eur Urol. 2008;54(2):392401 Eur J Nucl Med Mol Imaging. 2002;29:122536
Sofue K, Tateishi U, Sawada M, et al Role of carbon-11 choline Blake GM, Park-Holohan SJ, Cook GJ, Fogelman I. Quantitative
PET/CT in the management of uterine carcinoma: initial studies of bone with the use of 18F-fluoride and 99mTc-
experience. Ann Nucl Med. 2009;23(3):23543 methylene diphosphonate. Semin Nucl Med. 2001;31:2849
15 References
Blau M, Nagler W, Bender MA. Fluorine-18: a new isotope for Grosu AL, Weber WA, Riedel E, et al L-(methyl-11C) methion-
bone scanning. J Nucl Med. 1962;3:3324 ine positron emission tomography for target delineation in
Even-Sapir E, Metser U, Flusser G, et al Assessment of malignant resected high-grade gliomas before radiotherapy. Int J Radiat
skeletal disease: initial experience with 18F-fluoride PET/ Oncol Biol Phys. 2005;63(1):6474
CT and comparison between 18F-fluoride PET and Langen KJ, Hamacher K, Weckesser M, et al O-(2-[18F]
18F-fluoride PET/CT. J Nucl Med. 2004;45:2728 fluoroethyl)-L-tyrosine: uptake mechanisms and clinical
Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, applications. Nucl Med Biol. 2006;33(3):28794
Leibovitch I. The detection of bone metastases in patients Mehrkens JH, Ppperl G, Rachinger W, et al The positive predic-
with high-risk prostate cancer: 99mTc-MDP Planar bone tive value of O(2[18F]fluoroethyl)-L-tyrosine (FET) PET
scintigraphy, single- and multi-field-of-view SPECT, in the diagnosis of a glioma recurrence after multimodal
18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. treatment. J Neurooncol. 2008;88(1):2735
2006;47:28797 Pauleit D, Stoffels G, Schaden W, et al PET with O-(218F-
Galasko CS. The pathological basis for skeletal scintigraphy. fluoroethyl)-L-tyrosine in peripheral tumors: first clinical
J Bone Joint Surg Br. 1975;57:3539 results. J Nucl Med. 2005;46(3):4116
Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST. Ppperl G, Kreth FW, Mehrkens JH, et al FET PET for the evalu-
Skeletal PET with 18F-fluoride: applying new technology to ation of untreated gliomas: correlation of FET uptake and
an old tracer. J Nucl Med. 2008;49:6878 uptake kinetics with tumour grading. Eur J Nucl Med Mol
Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Imaging. 2007;34(12):193342
Ueno NT. Bone imaging in metastatic breast cancer. J Clin Ppperl G, Gtz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K.
Oncol. 2004;22:294253 Value of O(2[18F]fluoroethyl)- L-tyrosine PET for the
Hetzel M, Arslandemir C, Konig HH, et al F-18 NaF PET for diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging.
detection of bone metastases in lung cancer: accuracy, cost- 2004;31(11):146470
effectiveness, and impact on patient management. J Bone Stber B, Tanase U, Herz M, Seidl C, Schwaiger M, Senekowitsch
Miner Res. 2003;18:220614 Schmidtke R. Differentiation of tumour and inflammation:
Hoh CK, Hawkins RA, Dahlbom M, et al Whole body skeletal characterisation of [methyl-3H]methionine (MET) and
imaging with [18F]fluoride ion and PET. J Comput Assist O(2[18F]fluoroethyl)-L-tyrosine (FET) uptake in human
Tomogr. 1993;17:3441 tumour and inflammatory cells. Eur J Nucl Med Mol
Messa C, Goodman WG, Hoh CK, et al Bone metabolic activity Imaging. 2006;33(8):9329
measured with positron emission tomography and [18F] Weber WA, Wester HJ, Grosu AL, et al O-(2-[18F]fluoroethyl)-
fluoride ion in renal osteodystrophy: correlation with bone L-tyrosine and L-[methyl-11C]methionine uptake in brain
histomorphometry. J Clin Endocrinol Metab. 1993;77: tumours: initial results of a comparative study. Eur J Nucl
94955 Med. 2000;27(5):5429
Piert M, Zittel TT, Becker GA, et al Assessment of porcine bone
metabolism by dynamic. J Nucl Med. 2001;42:1091100
Schirrmeister H, Guhlmann A, Elsner K, et al Sensitivity in
detecting osseous lesions depends on anatomic localization:
planar bone scintigraphy versus 18F PET. J Nucl Med.
Somatostatin Receptors
1999;40:16239
Schirrmeister H, Glatting G, Hetzel J, et al Prospective evalua- Adams S, Baum R, Rink T, Schumm-Drger PM, Usadel KH,
tion of the clinical value of planar bone scans, SPECT, and Hr G. Limited value of fluorine-18 fluorodeoxyglucose
(18)F-labeled NaF PET in newly diagnosed lung cancer. positron emission tomography for the imaging of neuroen-
J Nucl Med. 2001;42:18004 docrine tumors. Eur J Nucl Med. 1998;25:7983
Schirrmeister H, Guhlmann A, Kotzerke J, et al Early detection Ambrosini V, Castellucci P, Rubello D, et al 68Ga-DOTA-NOC:
and accurate description of extent of metastatic bone disease a new PET tracer for evaluating patients with bronchial car-
in breast cancer with fluoride ion and positron emission cinoid. Nucl Med Commun. 2009;30(4):2816
232 tomography. J Clin Oncol. 1999;17:23819 Ambrosini V, Tomassetti P, Castellucci P, et al Comparison between
68Ga-DOTA-NOC and 18F-DOPA PET for the detection of
gastro-entero-pancreatic and lung neuro-endocrine tumours.
Eur J Nucl Med Mol Imaging. 2008;35(8):14318
Tyrosine Antunes P, Ginj M, Zhang H, et al Are radiogallium-labelled
DOTA-conjugated somatostatin analogues superior to those
labelled with other radiometals? Eur J Nucl Med Mol
Balogova S, Pri S, Kerrou K, et al Prospective comparison of Imaging. 2007;34(7):98293
FDG and FET PET/CT in patients with head and neck Gabriel M, Decristoforo C, Kendler D, et al 68Ga-DOTA-Tyr3-
squamous cell carcinoma. Mol Imaging Biol. 2008;10(6): octreotide PET in neuroendocrine tumors: comparison with
36473 somatostatin receptor scintigraphy and CT. J Nucl Med.
Floeth FW, Pauleit D, Sabel M, et al 18F-FET PET differentiation 2007;48(4):50818
of ring-enhancing brain lesions. J Nucl Med. 2006;47(5): Haug A, Auernhammer CJ, Wngler B, et al Intraindividual
77682 comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in
References 15
patients with well-differentiated metastatic neuroendocrine Ponde DE, Dence CS, Oyama N, et al 18F-fluoroacetate: a poten-
tumours. Eur J Nucl Med Mol Imaging. 2009;36(5):76570. tial acetate analog for prostate tumor imagingin vivo eval-
Epub 2009 Jan 10 uation of 18Ffluoroacetate versus 11C-acetate. J Nucl Med.
Hofmann M, Maecke H, Brner R, et al Biokinetics and imaging 2007;48(3):4208
with the somatostatin receptor PET radioligand (68) Sun A, Srensen J, Karlsson M, et al [11C]-acetate PET imaging
Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001; in head and neck cancera comparison with 18FFDGPET:
28(12):17517 implications for staging and radiotherapy planning. Eur J
Koukouraki S, Strauss LG, Georgoulias V, Eisenhut M, Nucl Med Mol Imaging. 2007;34(5):6517
Haberkorn U, Dimitrakopoulou-Strauss A. Comparison of Yoshimoto M, Waki A, Yonekura Y, et al Characterization of
the pharmacokinetics of 68Ga-DOTATOC and [18F]FDG acetate metabolism in tumor cells in relation to cell prolif-
in patients with metastatic neuroendocrine tumours sched- eration: acetate metabolism in tumor cells. Nucl Med Biol.
uled for 90Y-DOTATOC therapy. Eur J Nucl Med Mol 2001;28(2):11722
Imaging. 2006;33(10):111522
Pettinato C, Sarnelli A, Di Donna M, et al (68)Ga-DOTANOC:
biodistribution and dosimetry in patients affected by neu-
roendocrine tumors. Eur J Nucl Med Mol Imaging. 2008;
35(1):729
Thymidine
Reubi JC, Waser B. Concomitant expression of several peptide
receptors in neuroendocrine tumours: molecular basis for in Barthel H, Perumal M, Latigo J, et al The uptake of 3'-deoxy-3'-
vivo multireceptor tumour targeting. Eur J Nucl Med Mol [18F]fluorothymidine into L5178Y tumours in vivo is
Imaging. 2003;30(5):78193 dependent on thymidine kinase 1 protein levels. Eur J Nucl
Med Mol Imaging. 2005;32(3):25763
Buck AK, Bommer M, Stilgenbauer S, et al Molecular imaging of
proliferation in malignant lymphoma. Cancer Res.
Acetate 2006;66(22):1105561
Buck AK, Herrmann K, Buschenfelde CM, et al Imaging bone and
soft tissue tumors with the proliferation marker [18F]fluoro-
Albrecht S, Buchegger F, Soloviev D, et al (11)C-Acetate PET in deoxythymidine. Clin Cancer Res. 2008;14(10): 29707
the early evaluation of prostate cancer recurrence. Eur J Nucl Buck AK, Hetzel M, Schirrmeister H, et al Clinical relevance of
Med Mol Imaging. 2007;34:18596 imaging proliferative activity in lung nodules. Eur J Nucl
Delbeke D, Pinson CW. 11C-Acetate: a new tracer for the evalu- Med Mol Imaging. 2005;32(5):52533
ation of hepatocellular carcinoma J Nucl Med. 2003;44: Buck AK, Schirrmeister H, Hetzel M, et al 3-deoxy-3-[(18)F]
2223 fluorothymidine-positron emission tomography for nonin-
Dienel GA, Popp D, Drew PD, Ball K, Krisht A, Cruz NF. vasive assessment of proliferation in pulmonary nodules.
Preferential labelling of glial and meningeal brain tumours Cancer Res. 2002;62(12):33314
with [214C]acetate. J Nucl Med. 2001;42:124350 Buck AK, Vogg ATJ, Glatting G. [18F]FLT for monitoring
Ho CL, Yu SC, Yeung DW. 11C-acetate PET imaging in hepato- response to antiproliferative therapy in a mouse lymphoma
cellular carcinoma and other liver masses. J Nucl Med. xenotransplant model. [abstract]. J Nucl Med. 2004;45
2003;44(2):21321 Suppl:154P.
Ho C-L, Chen S, Yeung DWC, Cheng TKC. Dual-tracer PET/ Chen W, Cloughesy T, Kamdar N, et al Imaging proliferation in
CT imaging in evaluation of metastatic hepatocellular carci- brain tumors with 18F-FLT PET: comparison with 18F-
noma. J Nucl Med. 2007;48:9029 FDG. J Nucl Med. 2005;46(6):94552
Kaji M, Nomori H, Watanabe K, et al 11C-acetate and Choi SJ, Kim JS, Kim JH, et al [18F]3'-deoxy-3'-fluorothymidine
18Ffluorodeoxyglucose positron emission tomography of PET for the diagnosis and grading of brain tumors. Eur J
pulmonary adenocarcinoma. Ann Thorac Surg. 2007;83(1): Nucl Med Mol Imaging. 2005;32(6):6539
3124 Francis DL, Visvikis D, Costa DC, et al Potential impact of 233
Kotzerke J, Volkmer BG, Glatting G. Intraindividual compari- [18F]3'-deoxy-3'-fluorothymidine versus [18F]fluoro-2-de-
son of [11C]acetate and [11C]choline PET for detection of oxy-D-glucose in positron emission tomography for col-
metastases of prostate cancer. Nuklearmedizin. 2003;42(1): orectal cancer. Eur J Nucl Med Mol Imaging. 2003;30(7):
2530 98894
Nomori H, Shibata H, Uno K, et al 11Cacetate can be used in Kenny LM, Vigushin DM, Al-Nahhas A, et al Quantification of
place of 18Ffluorodeoxyglucose for positron emission cellular proliferation in tumor and normal tissues of patients
tomography imaging of non-small cell lung cancer with with breast cancer by [18F]fluorothymidine-positron emis-
higher sensitivity for well-differentiated adenocarcinoma. sion tomography imaging: evaluation of analytical methods.
J Thorac Oncol. 2008;3(12):142732 Cancer Res. 2005;65(21):1010412
Oyama N, Akino H, Kanamaru H, et al 11C-acetate PET imag- Leyton J, Latigo JR, Perumal M, Dhaliwal H, He Q, Aboagye EO.
ing of prostate cancer. J Nucl Med. 2002;43(2):1816 Early detection of tumor response to chemotherapy by
Pike VW, Eakins MN, Allan RM, Selwyn AP. Preparation of 3'-deoxy-3'-[18F]fluorothymidine positron emission tomog-
[11C] acetatean agent for the study of myocardial metabo- raphy: the effect of cisplatin on a fibrosarcoma tumor model
lism by PET. Int J Appl Radiat Isot. 1982;33:50512 in vivo. Cancer Res. 2005;65(10):420210
15 References
Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson J. Becherer A, Szab M, Karanikas G, et al Imaging of advanced
Simplified labeling approach for synthesizing 3'-deoxy-3'- neuroendocrine tumors with 18F-FDOPA PET. J Nucl Med.
[18F]fluorothymidine ([18F]FLT). J Radioanal Nucl Chem. 2004;45:11617
2000;243(3):8436 Beheshti M, Pcher S, Vali R, et al The value of 18F-DOPA
Perumal M, Pillai RG, Barthel H, et al Redistribution of nucleo- PET-CT in patients with medullary thyroid carcinoma:
side transporters to the cell membrane provides a novel comparison with 18F-FDG PET-CT. Eur Radiol. 2009;19(6):
approach for imaging thymidylate synthase inhibition by 142534
positron emission tomography. Cancer Res. 2006;66(17): Beuthien-Baumann B, Strumpf A, Zessin J, Bredow J, Kotzerke J.
855864 Diagnostic impact of PET with 18F-FDG, 18F-DOPA and
Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. 3-O-methyl-6-[18F]fluoro-DOPA in recurrent or metastatic
Validation of FLT uptake as a measure of thymidine kinase-1 medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging.
activity in A549 carcinoma cells. J Nucl Med. 2002;43(9): 2007;34:16049
12107 Brown WD, Oakes TR, DeJesus OT, et al Fluorine-18-Fluoro-L-
Shields AF, Grierson JR, Dohmen BM, et al Imaging prolifera- DOPA dosimetry with carbidopa pretreatment. J Nucl Med.
tion in vivo with [F-18]FLT and positron emission tomogra- 1998;39:188491
phy. Nat Med. 1998;4(11):13346 Fiebrich HB, Brouwers AH, Kerstens MN, et al 18F-DOPA PET
Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis is superior to conventional imaging in localizing tumors
with FDG PET imaging: physiologic and benign variants. causing catecholamine excess. J Clin Endocrinol Metab
Radiographics. 1999;19(1):6177 2009; 94 (10): 392230
Troost EG, Vogel WV, Merkx MA, et al 18F-FLT PET does not Fiebrich HB, Brouwers AH, Van Bergeijk L, Van den Berg G.
discriminate between reactive and metastatic lymph nodes Localization of an adrenocarticotropin-producing pheo-
in primary head and neck cancer patients. J Nucl Med. chromocytoma using 18F-dihydroxyphenylalanine positron
2007;48(5):72635 emission tomography. J Clin Endocrinol Metab. 2009;94:
Wagner M, Seitz U, Buck A, et al 3'-[18F]fluoro-3'-deoxythymi- 7489
dine ([18F]-FLT) as positron emission tomography tracer Garnett ES, Firnau G, Hahmias C. Dopamine visualized in the
for imaging proliferation in a murine B-Cell lymphoma basal ganglia of living man. Nature. 1983;305:1378
model and in the human disease. Cancer Res. Haug A, Auernhammer CJ, Wngler B, et al Intraindividual
2003;63(10):26817 comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in
Waldherr C, Mellinghoff IK, Tran C, et al Monitoring antiprolif- patients with well-differentiated metastatic neuroendocrine
erative responses to kinase inhibitor therapy in mice with tumours. Eur J Nucl Med Mol Imaging. 2009;36:76570
3'-deoxy-3'-18F-fluorothymidine PET. J Nucl Med. 2005; Hoegerle S, Ghanem N, Althehoefer C, et al 18F-DOPA positron
46(1):11420 emission tomography for the detection of glomus tumours.
Wells P, Gunn RN, Alison M, et al Assessment of proliferation in Eur J Nucl Med Mol Imaging. 2003;30:68994
vivo using 2-[(11)C]thymidine positron emission tomogra- Hoegerle S, Nitzsche E, Altehoefer C, et al Pheochromocytomas:
phy in advanced intra-abdominal malignancies. Cancer Res. detection with 18F DOPA whole-body PET initial results.
2002;62(20):5698702 Radiology. 2002;222:50712
Yap CS, Czernin J, Fishbein MC, et al Evaluation of thoracic Hoegerle S, Schneider B, Fraft A, Moser E, Nitzsche EU. Imaging
tumors with 18F-fluorothymidine and 18F-fluoro- of a metastatic gastrointestinal carcinoid by F-18-DOPA
deoxyglucose-positron emission tomography. Chest. 2006; positron emission tomography. Nuklearmedizin. 1999;38:
129(2):393401 12730
Imani F, Agopian VG, Auerbach MS, et al 18F-FDOPA PET and
PET/CT accurately localize pheochromocytomas. J Nucl
Med. 2009;50:5139
DOPA Jager PL, Chirakal R, Marriott CJ, Brouwers AH, Koopmans KP,
Gulenchyn KY. 6L18Ffluorodihydroxyphenylalanine PET
234 in neuroendocrine tumors: basic aspects and emerging clin-
Ahlstrm H, Eriksson B, Bergstrm M, Bjurling P, Lngstrm B, ical applications. J Nucl Med. 2008;49:57386
berg K. Pancreatic neuroendocrine tumors: diagnosis with Kauhanen S, Seppnen M, Nuutila P. Premedication with carbi-
PET. Radiology. 1995;195:3337 dopa masks positive finding of insulinoma and b-cell-hyper-
Ambrosini V, Tomassett P, Castellucci P, et al Comparison plasia in [18F]-dihydroxy-phenyl-alanine positron emission
between 68Ga-DOTA-NOC and 18F-DOPA PET for the tomography. J Clin Oncol. 2008;26:53078
detection of gastro-entero-pancreatic and lung neuro-endo- Kauhanen S, Seppnen M, Ovaska J, et al The clinical value of [18F]
crine tumours. Eur J Nucl Med Mol Imaging. 2008;35: fluoro-dihydroxyphenylalanine positron emission tomogra-
14318 phy in primary diagnosis, staging, and restaging of neuroendo-
Ambrosini V, Tomassetti P, Rubello D, et al Role of 18F-dopa crine tumors. Endocr Relat Cancer. 2009;16: 25565
PET/CT imaging in the management of patients with Kema IP, Koopmans KP, Elsinga PH, Brouwers AH, Jager PL, De
111
In-pentetreotide negative GEP tumours. Nucl Med Vries EGE. In reply. Premedication with carbidopa masks
Commun. 2007;28:1599606 positive finding of insulinoma and b-cell hyperplasia in
References 15
[18F]-dihydroxy-phenyl-alanine postitron emission tomog- tumour hypoxia with positron emission tomography. Br J
raphy. J Clin Oncol. 2008;26:53089 Cancer. 2004;90:223242
Koopmans KP, Brouwers AH, De Hooge MN, et al Carcinoid Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer
crisis after injection of 18F-DOPA in a patient with metastatic treatment. Nat Rev Cancer. 2004;4:43747
carcinoid. J Nucl Med. 2005;46:12403 Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation
Koopmans KP, De Groot JW, Plukker JT, et al 18F-dihydroxy- of head and neck cancer: changes during radiotherapy and
phenylalanine PET in patietns with biochemical evidence of impact on treatment outcome. Radiother Oncol. 1999;53:
medullary thyroid cancer: relation to tumor differentiation. 1137
J Nucl Med. 2008;49:52431 Chapman JD. Hypoxic sensitizers-implications for radiation
Koopmans KP, De Vries EGE, Kema IP, et al Staging of carcinoid therapy. N Engl J Med. 1979;301:142932
tumours with 18F-DOPA PET: a prospective, diagnostic Dolbier WR, Li AR, Koch CJ, Shiue CY, Kachur AV. [18F]-EF5,
accuracy study. Lancet Oncol. 2006;7:72834 a marker for PET detection of hypoxia: synthesis of precur-
Koopmans KP, Neels OC, Kema IP, et al Improved staging of sor and a new fluorination procedure. Appl Radiat Isot.
patients with carcinoid and islet cell tumors with 2001;54: 7380
18
F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan Eschmann SM, Paulsen F, Reimold M, et al Prognostic impact of
positron emission tomography. J Clin Oncol. 2008;26: hypoxia imaging with 18F-misonidazole PET in non-small
148995 cell lung cancer and head and neck cancer before radiother-
Koopmans KP, Neels ON, Kema IP, et al Molecular imaging in apy. J Nucl Med. 2005;46(2):25360
neuroendocrine tumors: molecular uptake mechanisms and Evans SM, Jenkins WT, Joiner B, Lord EM, Koch CJ.
clinical results. In press, Crit Rev Oncol Hematol. 2009;doi: 2-Nitroimidazole (EF5) binding predicts radiation resis-
10.1016/j.critrevonc.2009.02.009. 2009;71(3):199213 tance in individual 9L s.c. tumors. Cancer Res. 1996;56:
Lemaire C, Damhaut P, Plenevaux A, Comar D. Enantioselective 40511
synthesis of 6-[fluorine-18]-fluoro-L-dopa from no-carrier- Evans SM, Joiner B, Jenkins WT, Laughlin KM, Lord EM, Koch CJ.
added fluorine-18-fluoride. J Nucl Med. 1994;35:19962002 Identification of hypoxia in cells and tissues of epigastric 9L
Mackenzie IS, Gurnell M, Balan KK, Simpson H, Chatterjee K, rat glioma using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-
Brown MJ. The use of 18-fluoro-dihydroxyphenylalanine (2,2,3,3,3-pentafluoropropyl) acetamide]. Br J Cancer. 1995;
and 18-fluorodeoxyglucose positron emission tomography 72:87582
scanning in the assessment of metaiodobenzylguanidine- Evans SM, Kachur AV, Shiue CY, et al Noninvasive detection of
negative phaeochromocytoma. Eur J Endo. 2007;157:5337 tumor hypoxia using the 2-nitroimidazole [18F]EF1. J Nucl
Mohnike K, Blankenstein O, Christesen HT, et al Proposal for a Med. 2000;41:32736
standardized protocol for 18F-DOPA-PET (PET/CT) in con- Gatenby RA, Kessler HB, Rosenblum JS, et al Oxygen distribu-
genital hyperinsulinism. Horm Res. 2006;66:402 tion in squamous cell carcinoma metastases and its relation-
Mohnike K, Blankenstein O, Minn H, Mohnike W, Fuchtner F, ship to outcome of radiation therapy. Int J Radiat Oncol Biol
Otonkoski T. [18F]-DOPA positron emission tomography for Phys. 1988;14:8318
preoperative localization in congenital hyperinsulinism. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The con-
Horm Res. 2008;70:6572 centration of oxygen dissolved in tissues at the time of irra-
rlefors H, Sundin A, Lu L, et al Carbidopa pre-treatment diation as a factor in radiotherapy. Br J Radiol. 1953;26:
improves images interpretation and visualisation of carci- 63848
noid tumours with 11C-5-hydroxytrypthophan positron Grnroos T, Bentzen L, Marjamki P, et al Comparison of the
emission tomography. Eur J Nucl Med Mol Imaging. 2006;33: biodistribution of two hypoxia markers [18F]FETNIM and
605 [18F]FMISO in an experimental mammary carcinoma. Eur J
Timmers HJLM, Hadi M, Carrasquillo JA, et al The effects of Nucl Med Mol Imaging. 2004;31:51320
carbidopa on uptake of 618F-Fluoro-L-DOPA in PET of Grosu AL, Souvatzoglou M, Rper B, Dobritz M, Wiedenmann N,
pheochromocytoma and extraadrenal abdominal paragan- Jacob V, Wester HJ, Reischl G, Machulla HJ, Schwaiger M,
glioma. J Nucl Med. 2007;48:1599606 Molls M, Piert M. Hypoxia imaging with FAZA-PET and
Timmers HJLM, Kozupa A, Chen CC, et al Superiority of fluo- theoretical considerations with regard to dose painting for
rodeoxyglucose positron emission tomography to other individualization of radiotherapy in patients with head and 235
functional imaging techniques in the evaluation of meta- neck cancer. Int J Radiat Oncol Biol Phys. 2007;69(2):
static SDHB-associated pheochromocytoma and paragan- 54151
glioma. J Clin Oncol. 2007;25:22629 Hall EJ. Radiobiology for the radiologist. 5th ed. Philadelphia:
Lipponcott; 1998
Hicks RJ, Rischin D, Fisher R, Binns D, Scott AM, Peters LJ.
Utility of FMISO PET in advanced head and neck cancer
Hypoxia treated with chemoradiation incorporating a hypoxia-
targeting chemotherapy agent. Eur J Nucl Med Mol Imaging.
2005;32:138491
Barthel H, Wilson H, Collingridge DR, et al In vivo evaluation Hicks RJ, Dorow D, Roselt P. Review: PET tracer development a
of [18F]fluoroetanidazole as a new marker for imaging tale of mice and men. Cancer Imaging. 2006;6:S11822
15 References
Koch CJ, Evans SM, Lord EM. Oxygen dependence of cellular cer randomly assigned to chemoradiation with or without tira-
uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3- pazamine: a substudy of Trans-Tasman Radiation Oncology
pentafluoropropyl)acetamide]: analysis of drug adducts by Group Study 98.02. J Clin Oncol. 2006;24:2098104
fluorescent antibodies vs bound radioactivity. Br J Cancer. Sakata K, Wok TT, Murphy, Laderoute KR, et al Hypoxia induced
1995;72:86974 drug resistance: comparison to P-glycoprotein associated
Komar G, Seppnen M, Eskola O, et al 18F-EF5: a new PET tracer drug resistance. Br J Cancer. 1991;64:80914
for imaging hypoxia in head and neck cancer. J Nucl Med. Schwarz G. Uber desensibilisierung gegen rntgen- und radi-
2008;49:194451 umstrahlen. Munchener Med Wochenschr. 1909;24:12
Krohn KA, Link JM, Mason RP. Molecular imaging of hypoxia. Stypinski D, McQuarrie SA, Wiebe LI, Tam YK, Mercer JR,
J Nucl Med. 2008;49:129S48S. McEwan AJ. Dosimetry estimations for 123I-IAZA in healthy
Kumar P, Stypinski D, Xia H, McEwan AJ, Machulla HJ, Wiebe LI. volunteers. J Nucl Med. 2001;42:141823
Fluoroazomycin arabinoside (FAZA): synthesis, 2H and Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant
3H-labelling and prelimary biological evaluation of a novel tumors: pathogenesis of hypoxia and significance for tumor
2-nitroimidazole marker of tissue hypoxia. J Labelled therapy. Semin Oncol. 2001;28:2935
Compd Radiopharm. 1999;42:316 Ziemer LS, Evans SM, Kachur AV, et al Noninvasive imaging of
Laughlin KM, Evans SM, Jenkins WT, et al Biodistribution of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5.
the nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N- Eur J Nucl Med Mol Imaging. 2003;30:25966
(2,2,3,3,3-pentafluoropropyl) acetamide) in mice bearing
subcutaneous EMT6 tumors. J Pharmacol Exp Ther.
1996;277:104957
Lee ST, Scott AM. Hypoxia positron emission tomography Angiogenesis
imaging with 18F-fluoromisonidazole. Semin Nucl Med.
2007;37:45161
Lewis JS, Laforest R, Dehdashi F, Grigsby PW, Welch MJ, Siegel BA. Beer AJ, Haubner R, Goebel M, et al Biodistribution and phar-
An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in macokinetics of the alphavbeta3-selective tracer 18F-galacto-
cancer of the uterine cervix. J Nucl Med. 2008;49:18628 RGD in cancer patients. J Nucl Med. 2005;46(8):133341
Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Beer AJ, Haubner R, Sarbia M, et al Positron emission tomogra-
Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic phy using [18F]Galacto-RGD identifies the level of integrin
tumor model. J Nucl Med. 1999;40:17783 alpha(v)beta3 expression in man. Clin Cancer Res. 2006;
Mahy P, De Bast M, Gillart J, Labar D, Gregoire V. Detection of 12(13):39429
tumour hypoxia: comparison between EF5 adducts and [18F] Beer AJ, Haubner R, Wolf I, et al PET-based human dosimetry
EF3 uptake on an individual mouse tumour basis. Eur J Nucl of 18F-galacto-RGD, a new radiotracer for imaging alpha v
Med Mol Imaging. 2006;33:5536 beta3 expression. J Nucl Med. 2006;47(5):7639
Minn H, Grnroos TJ, Komar G, et al Imaging of tumor hypoxia Beer AJ, Lorenzen S, Metz S, et al Comparison of integrin alphaV-
to predict treatment sensitivity. Curr Pharm Des. 2008;14: beta3 expression and glucose metabolism in primary and
293242 metastatic lesions in cancer patients: a PET study using
Nordsmark M, Bentzen SM, Rudat V, et al Prognostic value of 18F-galacto-RGD and 18F-FDG. J Nucl Med. 2008;49(1): 229
tumor oxygenation in 397 head and neck tumors after pri- Brooks PC, Clark RA, Cheresh DA. Requirement of vascular
mary radiation therapy. An international multi-center study. integrin alpha v beta 3 for angiogenesis. Science. 1994;
Radiother Oncol. 2005;77:1824 264(5158):56971
Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxy- Dijkgraaf I, Beer AJ, Wester HJ. Application of RGD-containing
genation predicts radiation response in advanced squamous peptides as imaging probes for alphavbeta3 expression.
cell carcinoma of the head and neck. Radiother Oncol. Front Biosci. 2009;14:88799
1996;41:319 Folkman J. Angiogenesis: an organizing principle for drug dis-
Piert M, Machulla HJ, Picchio M, et al Hypoxia-specific tumor covery? Nat Rev Drug Discov. 2007;6(4):27386
236 imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. Haubner R, Decristoforo C. Radiolabelled RGD peptides and
2005;46:10613 peptidomimetics for tumour targeting. Front Biosci. 2009;14:
Postema EJ, McEwan AJ, Riauka TA, Kumar P, Richmond DA, 87286
Abrams DN, Wiebe LI. Initial results of hypoxia imaging Haubner R, Kuhnast B, Mang C, et al [18F]Galacto-RGD: syn-
using 1-alpha-D:-(5-deoxy-5-[(18)F]-fluoroarabinofuranosyl)- thesis, radiolabeling, metabolic stability, and radiation dose
2-nitroimidazole ((18)F-FAZA). Eur J Nucl Med Mol Imaging. estimates. Bioconjug Chem. 2004;15(1):619
2009;36 (10):156573 Hurwitz H, Fehrenbacher L, Novotny W, et al Bevacizumab plus
Rasey JS, Casciari JJ, Hofstrand PD, Muzi M, Graham MM, irinotecan, fluorouracil, and leucovorin for metastatic col-
Chin LK. Determining hypoxic fraction in a rat glioma by orectal cancer. N Engl J Med. 2004;350(23):233542
uptake of radiolabeled fluoromisonidazole. Radiat Res. Jeong JM, Hong MK, Chang YS, et al Preparation of a promising
2000;153:8492 angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-
Rischin D, Hicks RJ, Fisher R, et al Prognostic significance of isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-tri-
[18F]-misonidazole positron emission tomography-detected acetic acid and feasibility studies in mice. J Nucl Med.
tumor hypoxia in patients with advanced head and neck can- 2008;49(5):8306
References 15
Li ZB, Cai W, Cao Q, et al (64)Cu-labeled tetrameric and octa- Mankoff DA, Tewson TJ, Eary JF. Analysis of blood clearance
meric RGD peptides for small-animal PET of tumor alpha(v) and labeled metabolites for the estrogen receptor tracer
beta(3) integrin expression. J Nucl Med. 2007;48(7): [F-18]-16 alpha-fluoroestradiol (FES). Nucl Med Biol.
116271 1997;24(4):3418
Li ZB, Chen K, Chen X. (68)Ga-labeled multimeric RGD pep- Mintun MA, Welch MJ, Siegel BA, et al Breast cancer: PET
tides for microPET imaging of integrin alpha(v)beta (3) imaging of estrogen receptors. Radiology. 1988;169(1):458
expression. Eur J Nucl Med Mol Imaging. 2008;35(6):11008 Mortimer JE, Dehdashti F, Siegel BA, Katzenellenbogen JA,
Motzer RJ, Hutson TE, Tomczak P, et al Sunitinib versus inter- Fracasso P, Welch MJ. Positron emission tomography with
feron alfa in metastatic renal-cell carcinoma. N Engl J Med. 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]flu-
2007;356(2):11524 oro-17beta-estradiol in breast cancer: correlation with estro-
Murase S, Horwitz AF. Deleted in colorectal carcinoma and dif- gen receptor status and response to systemic therapy. Clin
ferentially expressed integrins mediate the directional Cancer Res. 1996;2(6):9339
migration of neural precursors in the rostral migratory Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K, Katzenel-
stream. J Neurosci. 2002;22(9):356879 lenbogen JA, Welch MJ. Metabolic flare: indicator of hor-
Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocel- mone responsiveness in advanced breast cancer. J Clin
lular carcinoma: the SHARP trial. Expert Rev Anticancer Oncol. 2001;19(11):2797803
Ther. 2009;9(6):73945 Peterson LM, Mankoff DA, Lawton T, et al Quantitative imaging
Smith JW, Cheresh DA. Integrin (alpha v beta 3)-ligand interac- of estrogen receptor expression in breast cancer with PET
tion. Identification of a heterodimeric RGD binding site on and 18F-fluoroestradiol. J Nucl Med. 2008;49(3):36774
the vitronectin receptor. J Biol Chem. 1990;265(4):216872 Pearce ST, Jordan VC. The biological role of estrogen receptors
alpha and beta in cancer. Crit Rev Oncol Hematol.
2004;50(1):322
Romer J, Fuchtner F, Steinbach J, Johanssen B. Automated pro-
duction of 16 alpha-[F-18]fluoroestradiol for breast cancer
Hormonal Receptors imaging. Nucl Med Biol. 1999;26(4):4739
Shie P, Cardarelli R, Brandon D, Erdman W, Abdulrahim N.
Dehdashti F, Mortimer JE, Siegel BA, et al Positron tomographic Meta-analysis: comparison of F-18 Fluorodeoxyglucose-
assessment of estrogen receptors in breast cancer: compari- positron emission tomography and bone scintigraphy in the
son with FDG-PET and in vitro receptor assays. J Nucl Med. detection of bone metastases in patients with breast cancer.
1995;36(10):176674 Clin Nucl Med. 2008;33(2):97101
Dehdashti F, Mortimer JE, Trinkaus K, et al PET-based estradiol Sundararajan L, Linden HM, Link JM, Krohn KA, Mankoff DA.
challenge as a predictive biomarker of response to endocrine 18F-Fluoroestradiol. Semin Nucl Med. 2007;37(6):4706
therapy in women with estrogen-receptor-positive breast Tsujikawa T, Yoshida Y, Mori T, et al Uterine tumors: pathophys-
cancer. Breast Cancer Res Treat. 2009;113(3):50917 iologic imaging with 16alpha-[18F]fluoro-17beta-estradiol
Dehdashti F, Picus J, Michalski JM, et al Positron tomographic and 18F fluorodeoxyglucose PET-initial experience.
assessment of androgen receptors in prostatic carcinoma. Radiology. 2008;248(2):599605
Eur J Nucl Med Mol Imaging. 2005;32(3):34450 Zanzonico PB, Finn R, Pentlow KS, et al PET-based radiation
Hospers GA, Helmond FA, de Vries EG, Dierckx RA, de Vries EF. dosimetry in man of 18F-fluorodihydrotestosterone, a new
PET imaging of steroid receptor expression in breast and radiotracer for imaging prostate cancer. J Nucl Med. 2004;
prostate cancer. Curr Pharm Des. 2008;14(28):302032 45(11):196671
Kumar P, Mercer J, Doerkson C, Tonkin K, McEwan AJ. Clinical
production, stability studies and PET imaging with 16-alpha-
[18F]fluoroestradiol ([18F]FES) in ER positive breast cancer
patients. J Pharm Pharm Sci. 2007;10(2):256s65s HTP
Larson SM, Morris M, Gunther I, et al Tumor localization of
16beta-18F-fluoro-5alpha-dihydrotestosterone versus 18F- 237
FDG in patients with progressive, metastatic prostate cancer. Agren H, Reibring L, Hartvig P, et al Low brain uptake of
J Nucl Med. 2004;45(3):36673 L-[11C]5-hydroxytryptophan in major depression: a posi-
Linden HM, Stekhova SA, Link JM, et al Quantitative fluo- tron emission tomography study on patients and healthy
roestradiol positron emission tomography imaging predicts volunteers. Acta Psychiatr Scand. 1991;83:44955
response to endocrine treatment in breast cancer. J Clin Bjurling P, Watanabe Y, Tokushige M, Oda T, Lngstrm B.
Oncol. 2006;24(18):27939 Synthesis of b-II-L-tryptophan and 5-hydroxy-L-tryptophan
Liu A, Dence CS, Welch MJ, Katzenellenbogen JA. Fluorine-18- using a multi-enzymatic reaction route. J Chem Soc Perkin
labeled androgens: radiochemical synthesis and tissue dis- Trans I. 1989;13314
tribution studies on six fluorine-substituted androgens, Eriksson B, Bergstrm M, Anders L, Ahlstrm H, Lngstrm B,
potential imaging agents for prostatic cancer. J Nucl Med. berg K. Positron emission tomography (PET) in neuroen-
1992;33(5):72434 docrine gastrointestinal tumors. Acta Oncol. 1993;32:
Mankoff DA, Peterson LM, Tewson TJ, et al [18F]fluoroestradiol 18996
radiation dosimetry in human PET studies. J Nucl Med. Klkner K, Ginman C, Nilsson S, et al Positron emission tomog-
2001;42(4):67984 raphy (PET) with 11C-5-hydroxytryptophan (5-HTP) in
15 References
patients with metastatic hormone-refractory prostatic ande- comparison with somatostatin receptor scintigraphy and
nocarcinoma. Nucl Med Biol. 1997;24:31925 computed tomography. J Clin Endocrinol Metab. 2005;90:
Koopmans KP, Neels OC, Kema IP, et al Improved staging of 3392400
patients with carcinoid and islet cell tumors with rlefors H, Sundin A, Lu L, berg K, Lngstrm B, Eriksson B,
18
F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan Bergstrm M. Carbidopa pre-treatment improves images
positron emission tomography. J Clin Oncol. 2008;26: interpretation and visualisation of carcinoid tumours with
11
148995 C-5-hydroxytrypthophan positron emission tomography.
Koopmans KP, Neels ON, Kema IP, et al Molecular imaging in Eur J Nucl Med Mol Imaging. 2006;33:605
neuroendocrine tumors: molecular uptake mechanisms and Reibring L, Agren H, Hartvig P, et al Uptake and utilization of
clinical results. Accepted for publication in Crit Rev Oncol [beta-11C]5-hydroxytryptophan in human brain studied by
Hematol, 2009 positron emission tomography. Psychiatry Res. 1992;45:
Neels OC, Jager PL, Koopmans KP, et al Development of a reli- 21525
able remote-controlled synthesis of b-[11C]-5-hydroxy-L- Rosa-Neto P, Benkelfat C, Sakai Y, Leyton M, Morais JA, Diksic M.
tryptophan on a Zymark robotic system. J Label Compd Brain regional a-[11C]methyl-L-tryptophan trapping, used
Radiopharm. 2006;49:88995 as an index of 5-HT synthesis, in healthy adults: absence of
rlefors H, Sundin A, Ahlstrm H, et al Positron emission an age effect. Eur J Nucl Med Mol Imaging. 2007;34:
tomography with 5-hydroxytryptophan in neuroendocrine 125464
tumors. J Clin Oncol. 1998;16:253441 Sundin A, Eriksson B, Bergstrm M, et al Demonstration of
Orlefors H, Sundin A, Garske U, et al Whole-body 11C-5- [11C] 5-hydroxy-L-tryptophan uptake and decarboxylation
hydroxytryptophan positron emission tomography as a uni- in carcinoid tumors by specific positioning labelling in posi-
versal imaging technique for neuroendocrine tumors: tron emission tomography. Nucl Med Biol. 2000;27:3341
238
Subject Index
A bone marrow 14, 33, 80, 105, 146, 158, 179, 217
accuracy 26, 10, 11, 14, 50, 55, 64, 65, 80, 100, bone metabolism 64
101, 124, 163 bone metastasis 35, 38, 64, 67, 70, 72, 74, 76, 77, 200,
acetate 35, 123144 215, 217, 218
ACTH producing tumor 164 bone scintigraphy 23, 64, 100
acute inflammation 50 bone tissue 64
acute stroke 50 brain blood barrier (BBB) 50
adrenaline 22, 162, 222 brain cancer 5, 124
a-Adrenergic receptors 162 brain metastases 3, 146
b-Adrenergic receptors 162 brain tumor 4, 5, 15, 50, 51, 8081, 87, 95, 124, 164
amine precursor 162, 222 breast cancer 4, 11, 66, 67, 70, 7376, 146, 160,
amino acid 4, 5, 11, 50, 51, 57, 80, 81, 124, 162, 197, 206, 214218
196, 222, 226
tracers 4, 51, 57, 80, 226 C
transport 80 calcitonine 163
trasporters 80, 222 cancer 26, 10, 1215, 1929, 3639, 43, 51, 6467, 7276,
androgen receptors (ARs) 214 81, 124, 127134, 146, 149, 156, 160, 164, 170172,
angiogenesis 5, 6, 195211 182184, 188, 196, 197, 200, 206, 207, 214218, 223, 224
antiangiogenic therapy 197 carbidopa 162164, 175, 178, 222223, 226
apoptosis 146 carbon-11, 4, 9, 18
arginine-glysine-aspartic acid (RGD) tripeptide 196 carcinoids 101, 105, 112, 162164, 167169, 176,
aromatase inhibitors 214, 215 177, 222224
aromatic amino acid decarboxylase (AADC) 162163, 222 cathecolamine 5, 6
azidovudine (AZT) 146 analogues 5
precursors 6
B 11
C-choline 14, 1626, 28, 51, 124
benign liver lesions 124 11
C-DOPA 162
beta-minus emitters 10 cell death 182
beta-minus radiations 10 cell membrane 14, 146, 182
bevacizumab 197 cell proliferation 55, 146, 182
biopsy 50, 58, 80, 88, 9395, 101, 115, 156, 183, 216, central nervous system tumors 50, 51, 146
218, 228 cerebral lymphoma 81
biopsy target definition 80, 93, 94 cervical carcinoma 182
bladder cancer 14, 29 chemotherapy 50, 53, 56, 76, 81, 182, 197
blood-brain barrier 80, 81, 92 choline 35, 1349, 51, 124, 126
blood clearance 64, 182, 196, 214 chromogranin A 164
bone formation 64 11
C-5-hydroxy-L-tryptophan (11C-5-HTP) 162164, 166,
bone grafts 64 222224, 227, 229
Subject Index
243