18F-fluorothymidine PET imaging in gliomas: an update
Ann Nucl Med
18F-fluorothymidine PET imaging in gliomas: an update
Alexandra Nikaki 0 1 2 3 4
George Angelidis 0 1 2 3 4
Roxani Efthimiadou 0 1 2 3 4
Ioannis Tsougos 0 1 2 3 4
Varvara Valotassiou 0 1 2 3 4
Konstantinos Fountas 0 1 2 3 4
Vasileios Prasopoulos 0 1 2 3 4
Panagiotis Georgoulias 0 1 2 3 4
0 PET/CT Department, Hygeia Hospital , 4 Erythrou Stavrou Str., 15123 Athens , Greece
1 Department of Nuclear Medicine, University Hospital of Larissa , Mezourlo, 41110 Larissa , Greece
2 & Panagiotis Georgoulias
3 Department of Nuclear Medicine, Hygeia Hospital , 4 Erythrou Stavrou Str., 15123 Athens , Greece
4 Department of Neurosurgery, University Hospital of Larissa , Mezourlo, 41110 Larissa , Greece
Brain neoplasms constitute a group of tumors with discrete differentiation grades, and therefore, course of disease and prognosis. Magnetic resonance imaging (MRI) remains the gold standard method for the investigation of central nervous system tumors. However, MRI suffers certain limitations, especially if radiation therapy or chemotherapy has been previously applied. On the other hand, given the development of newer radiopharmaceuticals, positron emission tomography (PET) aims to a better investigation of brain tumors, assisting in the clinical management of the patients. In the present review, the potential contribution of radiolabeled fluorothymidine (FLT) imaging for the evaluation of brain tumors will be discussed. In particular, we will present the role of FLTPET imaging in the depiction of well and poorly differentiated lesions, the assessment of patient prognosis and treatment response, and the recognition of disease recurrence. Moreover, related semi-quantitative and kinetic parameters will be discussed.
Department of Clinical Physiology, KHSHP, 20
Ahvenistontie Str., 13530 Ha¨meenlinna, Finland
Brain neoplasms can be classified into two main groups,
primary tumors and metastatic brain lesions which are more
common. Gliomas represent the most frequent type of primary
brain tumors and mainly consist of malignant neoplasms;
more than half of these lesions are glioblastomas [
incidence of malignant gliomas is approximately 3–5/100,000
cases, with slightly higher incidence in males and a peak at the
sixth decade of life [
]. They arise from the glial cells and
constitute a heterogeneous group of neoplasms characterized
by different cell origin and developmental pattern .
According to their malignant potential, they are categorized
into four grades (I–IV). Grade I and II lesions correspond to
non-invasive gliomas, whereas grades III and IV include
invasive tumors with worse outcome and poorer prognosis
]. However, there may be overlaps among the
morphological and diagnostic characteristics used for grading
purposes. Moreover, genetic/epigenetic evidence is taken into
account for the determination of prognosis and in the
therapeutic decision-making, including signaling pathways and
molecular markers such as mitotic marker MIB-1, isocitrate
dehydrogenase 1 (IDH1) mutations, 1p/19q loss for
oligodendrogliomas, epigenetic silencing of
methylguaninmethyltransferase (MGMT) gene promoter, epidermal growth
factor receptor (EGFR) amplification, and microRNAs
]. In general, current treatment management includes
surgical excision of the tumor, radiation treatment and
chemotherapy with alkylating factors (temozolomide).
Magnetic resonance imaging (MRI) with gadolinium
(Gd)—enhancement is the method of choice for the initial
diagnostic investigation of brain lesions, as well as for the
evaluation of treatment response and the early depiction of
disease recurrence [
(18FFDG)—positron emission tomography (PET), the
conventional PET imaging technique in oncology, has been also
used in patients with brain lesions, either at their
presentation, or for the assessment of response to treatment and
detection of recurrence [
]. Notably, despite its
applicability, 18F-FDG is not considered as the most appropriate
radiotracer for the investigation of brain lesions due to the
high background activity. For this reason, several
radiopharmaceuticals have been developed in this field, such as
radiolabeled amino acids, 18F-choline, hypoxia detection
agents and tumor proliferation markers (Table 1).
Radiolabeled analog of fluorothymidine (18F-FLT)
18F-FLT is a radiolabeled analog described initially as a
selective inhibitor of DNA synthesis . It was
introduced by Wilson et al., and in an alternative form, by
Shields and Grierson [
]. Given that thymidine is a
nucleoside encountered only in DNA, the radiolabeled
analog was proposed to reflect tissue proliferation rate .
18F-FDG enters cells by active transport through
nucleoside transporters (salvage thymidine pathway), as well as
by passive diffusion [
]. However, it does not incorporate
into the DNA chains and remains trapped after
phosphorylation by thymidine kinase-1 (TK-1), which is increased
at the S-phase of the cell cycle, reflecting, in this context,
tumor proliferation [
In brain tumors, newer evidence suggests that 18F-FLT
uptake depends mainly on the increased permeability,
intracellular transport and influx after the disruption of the
blood–brain barrier (BBB) or the function of nucleoside
transporters in case of intact BBB, whereas the contribution
of the metabolic trapping through phosphorylation seems
to be less important [
]. These findings became
available using kinetic analysis in animal models and
human series, both in newly diagnosed gliomas and lesions
after treatment. Moreover, it is now recognized that the
major limiting factor of 18F-FLT uptake is the transport
mechanism, while its accumulation is mainly attributed to
the transport and influx rate [
]. Interestingly, an
association has been demonstrated in grade III and IV
gliomas between 18F-FLT uptake and the metabolic rate (as
described by K3 constant), indicating—at least in part—the
contribution of the metabolic factor in radiotracers’
intracellular maintenance in this subgroup of tumors [
Further, in recurrent lesions, a link has been suggested
between radiotracer uptake and the combined influence of
influx and metabolic rate (as described by Ki constant)
]. Consequently, it remains unclear whether 18F-FLT
could actually demonstrate cell proliferation in brain
tumors. There is also a possibility to reflect only BBB
disruption, a characteristic that could lead to controversy
regarding radiotracer specificity in tumor detection. In
particular, the non-specific binding of the radiotracer may
be related to the false positive results, and could impair
proper tumor delineation and characterization.
Tumor detection and grading
Accurate tumor detection and delineation, as well as
grading before surgical resection, are of great importance.
These parameters have influences on the surgical
procedure, the post-surgical treatment management and the
patient prognosis. In addition, it is crucial to identify tumor
grade in inoperable cases. Figure 1 shows a grade IV
glioblastoma as depicted by MRI (A) and 18F-FLT
18F-FLT imaging has been reported to depict accurately
the biopsy site when glioma is suspected [
sensitivity of the method in detecting high-grade gliomas could
reach 100%; however, overall sensitivity is lower (*83%)
due to significant differences in radiotracer uptake between
high- and low-grade tumors [
12, 25, 26
]. Moreover, the
sensitivity and accuracy of the technique in differentiating
high- vs. low-grade tumors is *92% [
]. In high-grade
lesions, its ability to discriminate between grade III vs.
grade IV gliomas is also high, but it is lower when
differentiating grade II vs. grade III tumors [
general, 18F-FLT imaging is considered less valuable for
lowgrade gliomas, as they present no or little radiotracer
uptake . Nevertheless, this characteristic can be used in
tumor grading. Compared to advanced MR techniques and
spectroscopy, 18F-FLT imaging can provide important
evidence in the discrimination of tumors between grades II
and IV and grades III and IV, despite its lower performance
for grade III vs. grade IV differentiation [
In accordance with 11C-methionine (11C-MET) imaging,
the use of 18F-FLT leads to larger volume when delineating
the tumor, compared to Gd-enhanced MRI method.
Possibly, radiotracer accumulation may precede substantial
BBB breakdown, or the radiotracer could be a more
sensitive marker of BBB breakdown. Nevertheless, previous
reports suggested a fairly good agreement in tumor volume
definition between MRI and PET studies. The two
diagnostic methods contribute supplementarily to the
delineation of the tumor burden, even though tumor margins
may be defined less accurately based on FLT uptake
22, 30, 31
Primary or progressive tumors with no or little
enhancement in MRI images were found not to concentrate
18F-FLT, as expected based on the reported strong
association between 18F-FLT uptake and Gd- enhancement
]. Typically, grade II gliomas do not show
Gd-enhancement, 18F-FLT uptake or modifications in cerebral
blood volume (CBV) maps. On the other hand, grade III
gliomas usually demonstrate mild Gd-enhancement and
radiotracer uptake, whereas grade IV gliomas show high
in  by the Society of Nuclear Medicine and Molecular Imaging,
Inc. *FLT fluorothymidine
Gd-enhancement and 18F-FLT uptake. However, a grade
III glioma may demonstrate MRI and magnetic resonance
spectroscopy (MRS) characteristics of glioblastoma
multiform (including apparent diffusion coefficient (ADC)),
despite the presence of mild 18F-FLT uptake, or a grade IV
lesion may present non-profound perfusion changes though
high radiotracer uptake [
]. Moreover, intratumoral
heterogeneity could be apparent in gliomas, and the related
measurements may provide additional information about
tumor characteristics [
]. Finally, in a rat and a mouse
model, 18F-FLT uptake has been related to tumor
development, growth and size [
Notably, the standardized uptake value (SUV)
calculations alone may not be adequate to assess the actual
proliferative cellular activity. Uptake results could be also
associated with non-specific leakage, probably representing
BBB breakdown in high-grade gliomas. Therefore, the
evaluation of compartmental-derived kinetic parameters
has a significant role in this field [
concentration remains constantly low in normal brain tissue
allowing high tumor-to-background ratio, although SUV
values may be low [
]. Chen et al. reported that gliomas
concentrate radiotracer rapidly, reaching the maximum
uptake after 5–10 min and remaining stable for about
75 min [
]. Apparently, kinetic analysis can vary among
studies in one or more of the following points: differences
in the compartmental model, corrections for metabolites,
the K constants (representing intracellular transport and
metabolism of 18F-FLT), as well as in methods used to
discriminate vascular and tissue activity. For high-grade
lesions, no substantial differences have been observed
between blood measurements from arterial blood sampling
and PET derived venous measurements, indicating that
such calculations can be easily applied in the clinical
]. Regarding the circulating metabolites due to FLT
metabolism, even a limited set of blood samples is
adequate in the kinetic analysis of radiotracer retention, and
for metabolic rate calculations [
]. In general, radiotracer
kinetics can provide useful information about the tumor
characteristics and patient prognosis, leading to a better
therapeutic management compared to the semi-quantitative
results alone [
]. However, 18F-FLT PET findings in
previously untreated low-grade gliomas were correlated
with overall survival, not event-free survival, possibly due
to referral bias [
18F-FLT correlations with biomarkers
Given its association with TK-1 at the salvage DNA
synthesis pathway, 18F-FLT was proposed to be correlated
with proliferation markers. After analyzing the results of
previous studies with a total sample of 509 patients,
Chalkidou et al. reported that 18F-FLT kinetic parameters
and SUVmax values were associated with Ki-67
]. Moreover, higher reproducibility was achieved
when mean instead of maximum SUV values were
analyzed, as well as when surgically excised sections (not
biopsy samples) were used [
]. In comparison to
11CMET, the association of 18F-FLT uptake with Ki-67 was
found to be more significant, whereas the highest Ki-67
percentage glioblastoma cases exhibited high 18F-FLT, but
moderate 11C-MET, uptake [
]. Further, 18F-FLT uptake
was significantly associated with Ki-67 both in newly
diagnosed and recurrent brain tumors; however, the
correlation in recurrent lesions was weaker [
]. In a rat
glioblastoma model, a good agreement was confirmed
between 18F-FLT uptake and Ki-67 staining in both
bevacizumab-treated and non-treated groups, suggesting an
association between radiotracer uptake and angiogenesis
]. Moreover, diminished proliferation rate (as
assessed by Ki-67), increased cell death and diminished
18F-FLT uptake were observed after irradiation of
glioblastoma cells in a mouse model [
18F-FLT PET imaging may provide additional information
regarding tumor cell proliferation in radiation-treated
areas. Finally, normal-to-background ratio in 18F-FLT
imaging of newly diagnosed and recurrent tumors was
positively correlated to the expression of a 58-kD
microspherule protein highly produced in grade IV gliomas
]. Furthermore, both radiotracer uptake and the
expression of the above mentioned protein were linked to
Ki-67 expression and overall survival in newly diagnosed
lesions, implying the potential role of these parameters as
targets for proliferation therapy, as well as in therapy
Evaluation of recurrence—residual disease
Pseudo-progression and pseudo-regression may present
about two months after radiation therapy and
temozolomide administration in patients with gliomas.
Pseudo-progression refers to increased Gd-enhancement in MRI
images despite response to treatment, whereas
pseudo-regression corresponds to cases characterized by tumor
progression despite decreased Gd-enhancement. Therefore, in
the clinical setting, the main question is whether patient
symptoms could be attributed to either recurrent disease or
radiation necrosis [
Studies not only in cell lines and animal models but also
in humans have been performed investigating the role of
semi-quantitative and dynamic kinetic 18F-FLT parameters
in disease recurrence and treatment response. Since
18FFLT uptake is mostly attributed to BBB disruption,
imaging findings can be associated with necrosis after radiation
therapy, or the presence of proliferating tissue [
Furthermore, unspecific radiotracer uptake may lead to false
positive results [
]. Figure 2 shows a grade III cerebral
In comparison to 18F-FDG imaging, 18F-FLT was found
to have higher sensitivity and accuracy in the investigation
of disease recurrence, despite similar specificity [
Moreover, 18F-FLT technique has lower ability to
distinguish recurrent lesions according to their grade, than newly
diagnosed tumors [
]. In particular, using SUVmax as a
quantitative parameter in the differential diagnosis between
radiation necrosis and disease recurrence, 18F-FLT
technique yielded high sensitivity but moderate specificity,
limiting its use as only a supplementary tool in this field.
Although treatment-induced changes could be
differentiated from recurrent lesions based on radiotracer uptake, as
well as high- vs. low-grade recurrent lesions, the
accumulation of 18F-FLT in low-grade gliomas is low (Figs. 2,
3). For this reason, 18F-FLT imaging should not be used in
low-grade recurrent brain tumors .
Nevertheless, there is evidence that no 18F-FLT uptake
in MRI enhanced lesions could actually reflect the absence
of recurrence [
]. Notably, tumor-to-background ratio
may be more accurate index in the discrimination between
necrotic vs. malignant tissue, compared to SUVmax [
Further, in residual tumor delineation, 18F-FLT-defined
tumor volume may differ from T2-defined tumor volume
and contrast-enhanced regions, possibly resulting in
modifications in radiation tumor targets (including plan tumor
volume and boost tumor volume) [
molecular information obtained through 18F-FLT imaging
may be useful in radiation treatment planning, both for
dose escalation in residual cancer cells and the protection
of the surrounding normal tissue.
Finally, 18F-FLT kinetic parameters were reported to
perform better than semi-quantitative measurements in the
differentiation between radiation necrosis and recurrent
]. Particularly, Enslow et al. demonstrated the
value of Kimax in tumor 18F-FLT kinetics assessment,
compared to necrotic tissue characteristics due to radiation
]. On the other hand, no significant difference was
observed between necrotic vs. malignant tissue, with
regard to SUVmax parameter [
Treatment response: yielding prognostic information
Depending on the location and differentiation state of each
lesion, the therapeutic management of gliomas may include
surgery, radiation therapy and/or chemotherapy.
Subsequently, the evaluation of treatment response is of great
importance since it is directly related to survival. Contrast
enhancement MRI, with additional T2 and
FLAIR-weighted MRI response assessment after chemotherapy, is the
method of choice to evaluate treatment response, whereas
MRS and radiolabeled amino acids PET imaging may be
also helpful [
]. Regarding 18F-FLT technique, several
uptake and kinetic parameters (such as SUVmax,
tumor-tobackground ratio and proliferative volume—the volume of
the proliferation section of the tumor as described by
18FFLT PET) have been investigated for the evaluation of
treatment response and their ability to provide prognostic
information. In a mouse model, the influence of radiation
on the pattern and degree of radiotracer uptake was studied,
showing important associations with micro-environmental
changes in glioblastoma tumors [
]. Irradiated lesions
appeared with a lower and more uniform uptake pattern,
whereas non-irradiated lesions exhibited peripheral uptake
with a photopenic center. Therefore, 18F-FLT PET imaging
may contribute to radiation therapy response assessment;
however, clinical trials in this area are lacking [
18F-FLT technique has been demonstrated to provide
useful information for the evaluation of response to
chemotherapy, yielding prognostic value in newly
diagnosed high-grade gliomas and recurrent brain tumors. After
enrolling 21 patients with recurrent tumors treated with
irinotecan-bevacizumab, Chen et al. demonstrated the
predictive capability of the technique in depicting
responders vs. non-responders and its correlation with
progression-free and overall survival [
]. These findings
were also confirmed in subsequent studies [
Interestingly, in a study sample of 30 patients treated with
bevacizumab, radiotracer uptake changes at 6th week
posttreatment initiation were found to be the strongest
independent predictor of survival .
In everyday clinical practice, SUV values may be the only
semi-quantitative measurements recorded [
]. Notably, in
previous studies, conflicting prognostic information was
obtained based on SUVmax measurements. However, these
discrepancies may be related to sample differences among
studies. On the other hand, tumor-to-background
measurements seemed to be a more reliable prognostic indicator
fluorothymidine, MRI magnetic resonance imaging, PET positron
emission tomography, SUV standardized uptake value
]. Moreover, Idema et al. enrolled glioma patients
with either untreated or recurrent lesions and found that
18FFLT-derived proliferative volume was significantly
correlated to overall survival . In comparison to Gd-enhanced
MRI method, radiotracer uptake may correspond to larger
areas. However, these areas were found to be related to
relative cerebral blood volume (rCBV) with higher accuracy
]. Further, proliferative uptake volumes were associated
with overall survival in patients with recurrent gliomas, and
the observed association was stronger than that using
MRIderived volume [
Differences in 18F-FLT kinetic parameters in patients
with gliomas can be attributed to either tumor-induced
consequences or changes related to treatment response;
therefore, kinetic analysis may provide important
prognostic information [
]. According to Wardak et al.,
18F-FLT kinetics may be useful in discriminating long-term
vs. short-term survivors with high diagnostic accuracy,
possibly leading to a more individualized therapeutic
management . Moreover, evidence obtained through
18F-FLT kinetic analysis was reported to predict overall
survival more accurately in comparison to 18F-fluorodopa
]. Consequently, if 18F-FLT kinetic data are
obtained early in the treatment of recurrent brain tumors
with bevacizumab and irinotecan, useful prognostic
information can be obtained with reasonable confidence [
Comparison between the available imaging techniques
MRI can offer morphological evidence in glioma patients.
However, its value is limited for the evaluation of more
specific information regarding the biological characteristics
of the lesions. Moreover, MRI has certain limitations,
particularly for the initial evaluation of tumor
aggressiveness. False results have been also described, especially
after radiotherapy or chemotherapy. Although advanced
MRI techniques (Fig. 4) may contribute to the
minimization of MRI pitfalls, certain limitations still exist,
especially regarding the magnetic field inhomogeneity of the
area under investigation [
]. PET imaging may contribute
to the individualization of therapeutic management.
Several molecular processes can be visualized depending on
the radiotracer used (Table 1). Maximal or mean SUV is
commonly used for the semi-quantitative evaluation of the
radioactivity in the target.
18F-FDG PET was initially proposed due to the
increased glucose metabolism in high-grade gliomas, as
well as the positive association between glycolysis rate and
]. 18F-FDG uptake was linked to tumor
grading, showing prognostic value [
]. However, the
utility of 18F-FDG imaging is hampered by the high
glucose metabolism in normal brain areas; both the sensitivity
for tumor detection and specificity for tumor delineation
are significantly limited [
]. Particularly, low-grade
gliomas are characterized by modest radiotracer uptake which
is similar to that of white matter, and decreased uptake in
comparison to gray matter [
]. Moreover, 18F-FDG
accumulation in inflammatory tissue makes the distinction
between malignancy and inflammation often challenging.
Regarding stereotactic biopsy target selection, 18F-FDG
imaging was reported to be superior compared to MRI,
despite its limited value in low-grade gliomas [
Since cell proliferation can be related to higher
metabolism of cell membrane components, radiolabeled choline
was proposed for the assessment of brain lesions,
particularly oligodendroglial tumors [
]. Moreover, the choline
analog 18F-fluorocholine was considered to discriminate
high-grade gliomas, metastatic lesions, and benign tumors.
A main disadvantage is the high radiotracer accumulation
in the choroid plexus, venous sinuses, and pituitary gland,
limiting the value of the technique in the vicinity of these
Rapid tumor growth is associated with lower oxygen
levels in parts of the lesion compared to the surrounding
normal tissue, while hypoxia is linked to tumor progression
and resistance to radiotherapy. Uptake of nitroimidazole
derivative 18F-fluoromisonidazole, a marker of hypoxia,
was observed in high grade but not in low-grade gliomas
]. However, this technique was associated with
suboptimal imaging properties, including low
target-to-background ratio and slow tumor uptake.
Increased cell proliferation in gliomas leads to higher
amino acid utilization [
]. High-contrast images can be
obtained using radiolabeled amino acids in both low- and
high-grade gliomas, given the low normal tissue uptake.
On the other hand, increased uptake due to BBB damage
may be misinterpreted, and differences in amino acid
transport characteristics could result in significant uptake
]. Radiolabeled amino acids can contribute to
the diagnosis of gliomas, while accuracy in biopsy
planning may be significantly increased through the
implementation of combined 18F-FET PET and MRI [
Further, radiolabeled amino acid PET may provide useful
information in surgery and radiotherapy planning [
Finally, since these radiotracers are not taken up by
glycolytic inflammatory cells, a more accurate discrimination
between disease progression (or recurrence) and
therapyrelated effects can be achieved .
18F-FLT imaging focuses on the increased DNA
replication observed in malignant transformation. Radiotracer
uptake is lower in most regions because of the limited
neuronal cell division [
]. 18F-FLT PET imaging can depict
high-grade gliomas and assist in the discrimination between
*CT computed tomography, FLT fluorothymidine, PET positron
emission tomography, SUV standardized uptake value
high- vs. low-grade lesions. Although this technique has been
reported to depict the biopsy site, it cannot accurately identify
tumor margins [
]. On the other hand, 18F-FLT imaging
may assist in the investigation of recurrence after surgical
excision (Fig. 5). Finally, since structural abnormalities occur
after changes in cellular proliferation, 18F-FLT uptake during
treatment can provide valuable prognostic evidence, as well as
information about treatment response.
Kinetic analysis can be performed complementing the
basic 18F-FLT study. Notably, since cellular 18F-FLT
uptake is limited by transport across the BBB, a complete
kinetic model of radiotracer uptake, transport and
metabolism could significantly improve DNA synthesis
quantification. Furthermore, kinetic modeling may also provide
valuable evidence for the discrimination between
recurrence and radiation necrosis.
Radiolabeled FLT can serve as an in vivo marker of cell
proliferation, providing valuable information regarding
brain malignancies in combination with tumor proliferative
biomarkers. However, further prospective cohort studies,
with greater number of participants, are required before
18F-FLT PET imaging would gain its final position in the
diagnostic evaluation and prognostication of glioma
Compliance with ethical standards
Conflict of interest No potential conflicts of interest were disclosed.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
1. Porter KR , McCarthy BJ , Freels S , Kim Y , Davis FG . Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology . Neuro Oncol . 2010 ; 12 : 520 - 7 .
2. Stupp R , Brada M , van den Bent MJ , Tonn JC , Pentheroudakis G , ESMO Guidelines Working Group. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup . Ann Oncol. 2014 ; 25 : iii93 - 101 .
3. Al-Hussaini M . Histology of brain tumors . In: Lichtor T, editor. Clinical management and evolving novel therapeutic strategies for patients with brain tumors . Rijeka: In Tech; 2013 .
4. Goodenberger ML , Jenkins RB . Genetics of adult glioma . Cancer Genet . 2012 ; 205 : 613 - 21 .
5. Takei H , Bhattacharjee MB , Rivera A , Dancer Y , Powell SZ . New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors . Arch Pathol Lab Med . 2007 ; 131 : 234 - 41 .
6. Zalatimo O , Zoccoli CM , Patel A , Weston CL , Glantz M. Impact of genetic targets on primary brain tumor therapy: what's ready for prime time ? Adv Exp Med Biol . 2013 ; 779 : 267 - 89 .
7. Ahmed R , Oborski MJ , Hwang M , Lieberman FS , Mountz JM . Malignant gliomas: current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods . Cancer Manag Res . 2014 ; 6 : 149 - 70 .
8. Chen J , McKay RM , Parada LF . Malignant glioma: lessons from genomics, mouse models, and stem cells . Cell . 2012 ; 149 : 36 - 47 .
9. Nikaki A , Piperi C , Papavassiliou AG . Role of microRNAs in gliomagenesis: targeting miRNAs in glioblastoma multiforme therapy . Expert Opin Investig Drugs . 2012 ; 21 ( 10 ): 1475 - 88 .
10. Tsougos I , Svolos P , Kousi E , Fountas K , Theodorou K , Fezoulidis I , et al. Differentiation of glioblastoma multiforme from metastatic brain tumor using proton magnetic resonance spectroscopy, diffusion and perfusion metrics at 3 T . Cancer Imaging. 2012 ; 12 : 423 - 36 .
11. Wray R , Solnes L , Mena E , Meoded A , Subramaniam RM . (18)Fflourodeoxy-glucose PET/computed tomography in brain tumors: value to patient management and survival outcomes . PET Clin . 2015 ; 10 ( 3 ): 423 - 30 .
12. Choi SJ , Kim JS , Kim JH , Oh SJ , Lee JG , Kim CJ , et al. [18F] 30 - deoxy-30 -fluorothymidine PET for the diagnosis and grading of brain tumors . Eur J Nucl Med Mol Imaging . 2005 ; 32 ( 6 ): 653 - 9 .
13. Barthel H , Cleij MC , Collingridge DR , Hutchinson OC , Osman S , He Q , et al. 30-deoxy-30-[18F] fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography . Cancer Res . 2003 ; 63 : 3791 - 8 .
14. Wilson IK , Chatterjee S , Wolf W. The use of 30-fluoro-30-deoxythymidine and studies of its 18F-labelling, as a tracer for the non-invasive monitoring of the biodistribution of drugs against AIDS . J Fluorine Chem . 1991 ; 55 : 283 - 9 .
15. Grierson JR , Shields AF . Development of a radiosynthesis for 30- [F-18] fluoro -30 -deoxynucleosides . J Label Compd Radiopharm . 1997 ; 40 : 60 - 2 .
16. Salskov A , Tammisetti VS , Grierson J , Vesselle H. FLT : measuring tumor cell proliferation in vivo with positron emission tomography and 30-deoxy-30 -[18F]fluorothymidine. Semin Nucl Med . 2007 ; 37 : 429 - 39 .
17. Idema AJ , Hoffmann AL , Boogaarts HD , Troost EG , Wesseling P , Heerschap A , et al. 30 -Deoxy-30 - 18F -fluorothymidine PETderived proliferative volume predicts overall survival in highgrade glioma patients . J Nucl Med . 2012 ; 53 : 1904 - 10 .
18. Tehrani OS , Shields AF . PET imaging of proliferation with pyrimidines . J Nucl Med . 2013 ; 54 : 903 - 12 .
19. Muzi M , Spence AM , O'Sullivan F , Mankoff DA , Wells JM , Grierson JR , et al. Kinetic analysis of 30-deoxy-30-18F-fluorothymidine in patients with gliomas . J Nucl Med . 2006 ; 47 : 1612 - 21 .
20. Shinomiya A , Kawai N , Okada M . Evaluation of 30-deoxy-30- [18F] -fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas . Eur J Nucl Med Mol Imaging . 2013 ; 40 : 175 - 85 .
21. Dimitrakopoulou-Strauss A , Strauss LG . The role of 18F-FLT in cancer imaging: does it really reflect proliferation? Eur J Nucl Med Mol Imaging . 2008 ; 35 : 523 - 6 .
22. Jacobs AH , Thomas A , Kracht LW , Li H , Dittmar C , Garlip G , et al. 18F-fluoro-L-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors . J Nucl Med . 2005 ; 46 : 1948 - 58 .
23. Schiepers C , Dahlbom M , Chen W . Kinetics of 30-deoxy-30 -18Ffluorothymidine during treatment monitoring of recurrent highgrade glioma . J Nucl Med . 2010 ; 51 : 720 - 7 .
24. Weber MA , Henze M , Tu¨ttenberg J , Stieltjes B , Meissner M , Zimmer F , et al. Biopsy targeting gliomas: do functional imaging techniques identify similar target areas? Invest Radiol . 2010 ; 45 : 755 - 68 .
25. Hatakeyama T , Kawai N , Nishiyama Y , Yamamoto Y , Sasakawa Y , Ichikawa T , et al. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma . Eur J Nucl Med Mol Imaging . 2008 ; 35 : 2009 - 17 .
26. Yamamoto Y , Ono Y , Aga F , Kawai N , Kudomi N , Nishiyama Y. Correlation of 18F-FLT uptake with tumor grade and Ki-67 immunohistochemistry in patients with newly diagnosed and recurrent gliomas . J Nucl Med . 2012 ; 53 : 1911 - 5 .
27. Ferdova ´ E, Ferda J , Baxa J , Tupy´ R, Mracˇek J , Topolcˇan O , et al. Assessment of grading in newly-diagnosed glioma using 18Ffluorothymidine PET/CT . Anticancer Res. 2015 ; 35 : 955 - 9 .
28. Tripathi M , Sharma R , D'Souza M , Jaimini A , Panwar P , Varshney R , et al. Comparative evaluation of F-18 FDOPA , F-18 FDG , and F-18 FLT- PET/CT for metabolic imaging of low grade gliomas . Clin Nucl Med . 2009 ; 34 : 878 - 83 .
29. Collet S , Valable S , Constans JM , Lechapt-Zalcman E , Roussel S , Delcroix N , et al. [ (18)F] -fluoro-L-thymidine PET and advanced MRI for preoperative grading of gliomas . Neuroimage Clin . 2015 ; 29 : 448 - 54 .
30. Yamamoto Y , Wong TZ , Turkington TG , Hawk TC , Reardon DA , Coleman RE . 30 -Deoxy-30 - [F-18] fluorothymidine positron emission tomography in patients with recurrent glioblastoma multiforme: comparison with Gd-DTPA enhanced magnetic resonance imaging . Mol Imaging Biol . 2006 ; 8 : 340 - 7 .
31. Price SJ , Fryer TD , Cleij MC , Dean AF , Joseph J , Salvador R , et al. Imaging regional variation of cellular proliferation in gliomas using 30-deoxy - 30-[18F] fluorothymidine positron-emission tomography: an image-guided biopsy study . Clin Radiol . 2009 ; 64 : 52 - 63 .
32. Nowosielski M , DiFranco MD , Putzer D , Seiz M , Recheis W , Jacobs AH , et al. An intra-individual comparison of MRI , [18F] - FET and [18F] -FLT PET in patients with high-grade gliomas . PLoS One . 2014 ; 9 : e95830 .
33. Mitamura K , Yamamoto Y , Kudomi N , Maeda Y , Norikane T , Miyake K , et al. Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas . Ann Nucl Med . 2017 ; 31 : 46 - 52 .
34. Viel T , Boehm-Sturm P , Rapic S , Monfared P , Neumaier B , Hoehn M , et al. Non-invasive imaging of glioma vessel size and densities in correlation with tumour cell proliferation by small animal PET and MRI . Eur J Nucl Med Mol Imaging . 2013 ; 40 : 1595 - 606 .
35. Chandrasekaran S , Hollander A , Xu X , Benci JL , Davis JJ , Dorsey JF , et al. 18F-fluorothymidine-pet imaging of glioblastoma multiforme: effects of radiation therapy on radiotracer uptake and molecular biomarker patterns . Sci World J . 2013 ; 2013 : 796029 .
36. Ullrich R , Backes H , Li H , Kracht L , Miletic H , Kesper K , et al. Glioma proliferation as assessed by 30-fluoro-30-deoxy-L-thymidine positron emission tomography in patients with newly diagnosed high-grade glioma . Clin Cancer Res . 2008 ; 14 : 2049 - 55 .
37. Chen W , Cloughesy T , Kamdar N , Satyamurthy N , Bergsneider M , Liau L , et al. Imaging proliferation in brain tumors with 18FFLT PET: comparison with 18F-FDG . J Nucl Med . 2005 ; 46 : 945 - 52 .
38. Backes H , Ullrich R , Neumaier B , Kracht L , Wienhard K , Jacobs AH . Noninvasive quantification of 18F-FLT human brain PET for the assessment of tumour proliferation in patients with high-grade glioma . Eur J Nucl Med Mol Imaging . 2009 ; 36 : 1960 - 7 .
39. Shields AF , Briston DA , Chandupatla S , Douglas KA , LawhornCrews J , Collins JM , et al. A simplified analysis of [18F] 30 - deoxy-30 -fluorothymidine metabolism and retention . Eur J Nucl Med Mol Imaging . 2005 ; 32 : 1269 - 75 .
40. Belohlavek O , Fencl P , Majovsky M , Jaruskova M , Benes V . FLT-PET in previously untreated patients with low-grade glioma can predict their overall survival . Nucl Med Rev Cent East Eur . 2014 ; 17 : 7 - 12 .
41. Chalkidou A , Landau DB , Odell EW , Cornelius VR , O'Doherty MJ , Marsden PK . Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: a systematic review and meta-analysis . Eur J Cancer . 2012 ; 48 : 3499 - 513 .
42. Lin W , Dai SH , Chen T , Kawai N , Miyake K , Okada M , et al. Expression of 58-kD microspherule protein (MSP58) is highly correlated with PET imaging of tumor malignancy and cell proliferation in glioma patients . Cell Physiol Biochem . 2016 ; 38 : 635 - 45 .
43. Nihashi T , Dahabreh IJ , Terasawa T. Diagnostic accuracy of PET for recurrent glioma diagnosis: a meta-analysis . AJNR . 2013 ; 34 : 944 - 50 .
44. Li Z , Yu Y , Zhang H , Xu G , Chen L . A meta-analysis comparing 18F-FLT PET with 18F-FDG PET for assessment of brain tumor recurrence . Nucl Med Commun . 2015 ; 36 : 695 - 701 .
45. Jeong SY , Lee TH , Rhee CH , Cho AR , Il Kim B , Cheon GJ , et al. 30 -Deoxy-30-[(18)F] fluorothymidine and O-(2-[(18)F]fluoroethyl)-L-tyrosine PET in Patients with suspicious recurrence of glioma after multimodal treatment: initial results of a retrospective comparative study . Nucl Med Mol Imaging . 2010 ; 44 : 45 - 54 .
46. Hong IK , Kim JH , Ra YS , Kwon DH , Oh SJ , Kim JS . Diagnostic usefulness of 30-deoxy-30-[18F] fluorothymidine positron emission tomography in recurrent brain tumor . J Comput Assist Tomogr . 2011 ; 35 : 679 - 84 .
47. Shishido H , Kawai N , Miyake K , Yamamoto Y , Nishiyama Y , Tamiya T. Diagnostic value of 11C-methionine (MET) and 18Ffluorothymidine (FLT) positron emission tomography in recurrent high-grade gliomas; differentiation from treatment-induced tissue necrosis . Cancers (Basel) . 2012 ; 4 : 244 - 56 .
48. Zhao F , Li M , Wang Z , Fu Z , Cui Y , Chen Z , et al. (18)FFluorothymidine PET-CT for resected malignant gliomas before radiotherapy: tumor extent according to proliferative activity compared with MRI . PLoS One . 2015 ; 10 : e0118769 .
49. Spence AM , Muzi M , Link JM , O'Sullivan F , Eary JF , Hoffman JM , et al. NCI-sponsored trial for the evaluation of safety and preliminary efficacy of 30-deoxy-30-[18F]fluorothymidine (FLT) as a marker of proliferation in patients with recurrent gliomas: preliminary efficacy studies . Mol Imaging Biol . 2009 ; 11 : 343 - 55 .
50. Enslow MS , Zollinger LV , Morton KA , Butterfield RI , Kadrmas DJ , Christian PE , et al. Comparison of F-18 fluorodeoxyglucose and F-18 fluorothymidine positron emission tomography in differentiating radiation necrosis from recurrent glioma . Clin Nucl Med . 2012 ; 37 : 854 - 61 .
51. Tran LB , Bol A , Labar D , Karroum O , Mignion L , Bol V , et al. DW-MRI and (18) F-FLT PET for early assessment of response to radiation therapy associated with hypoxia-driven interventions. Preclinical studies using manipulation of oxygenation and/or dose escalation . Contrast Media Mol Imaging . 2016 ; 11 ( 2 ): 115 - 21 .
52. Chen W , Delaloye S , Silverman DH , Geist C , Czernin J , Sayre J , et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study . J Clin Oncol . 2007 ; 25 : 4714 - 21 .
53. Harris RJ , Cloughesy TF , Pope WB , Nghiemphu PL , Lai A , Zaw T , et al. 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab . Neuro Oncol . 2012 ; 14 : 1079 - 89 .
54. Schwarzenberg J , Czernin J , Cloughesy TF , Ellingson BM , Pope WB , Geist C , et al. 30-deoxy-30 - 18F -fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab . J Nucl Med . 2012 ; 53 : 29 - 36 .
55. Wardak M , Schiepers C , Dahlbom M , Cloughesy T , Chen W , Satyamurthy N , et al. Discriminant analysis of 18F-fluoro-thymidine kinetic parameters to predict survival in patients with recurrent high-grade glioma . Clin Cancer Res . 2011 ; 17 : 6553 - 62 .
56. Zhao F , Cui Y , Li M , Fu Z , Chen Z , Kong L , et al. Prognostic value of 30-deoxy-30 - 18F -fluorothymidine ([(18)F] FLT PET) in patients with recurrent malignant gliomas . Nucl Med Biol . 2014 ; 41 : 710 - 5 .
57. Schiepers C , Chen W , Dahlbom M , Cloughesy T , Hoh CK , Huang SC . 18F-fluorothymidine kinetics of malignant brain tumors . Eur J Nucl Med Mol Imaging . 2007 ; 34 : 1003 - 11 .
58. Wardak M , Schiepers C , Cloughesy TF , Dahlbom M , Phelps ME , Huang SC . 18F-FLT and 18F-FDOPA PET kinetics in recurrent brain tumors . Eur J Nucl Med Mol Imaging . 2014 ; 41 : 1199 - 209 .
59. Di Chiro G. Positron emission tomography using [18F] fluorodeoxyglucose in brain tumors. A powerful diagnostic and prognostic tool . Invest Radiol . 1987 ; 22 : 360 - 71 .
60. la Fouge`re C, Suchorska B , Bartenstein P , Kreth FW , Tonn JC . Molecular imaging of gliomas with PET: opportunities and limitations . Neuro Oncol . 2011 ; 13 : 806 - 19 .
61. Pirotte BJ , Lubansu A , Massager N , Wikler D , Goldman S , Levivier M. Results of positron emission tomography guidance and reassessment of the utility of and indications for stereotactic biopsy in children with infiltrative brainstem tumors . J Neurosurg . 2007 ; 107 : 392 - 9 .
62. Kato T , Shinoda J , Nakayama N , Miwa K , Okumura A , Yano H , et al. Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positron-emission tomography . AJNR . 2008 ; 29 : 1176 - 82 .
63. Ishiwata K , Kubota K , Murakami M , Kubota R , Sasaki T , Ishii S , et al. Re-evaluation of amino acid PET studies: can the protein synthesis rates in brain and tumor tissues be measured in vivo ? J Nucl Med . 1993 ; 34 : 1936 - 43 .
64. Pauleit D , Floeth F , Hamacher K , Riemenschneider MJ , Reifenberger G , Mu¨ller HW , et al. O-( 2 -[18F]fluoroethyl) -L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas . Brain . 2005 ; 128 : 678 - 87 .
65. Tanaka Y , Nariai T , Momose T , Aoyagi M , Maehara T , Tomori T , et al. Glioma surgery using a multimodal navigation system with integrated metabolic images . J Neurosurg . 2009 ; 110 : 163 - 72 .
66. Gambhir SS . Molecular imaging of cancer with positron emission tomography . Nat Rev Cancer . 2002 ; 2 : 683 - 93 .