Imaging regional variation of cellular proliferation in gliomas using 3′-deoxy-3′-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study
Introduction
Uncontrolled cellular proliferation is a cardinal feature of neoplasia. The molecular genetic changes involved in transforming a normal cell into a cancerous one typically involve mutations in genes that control the progress of the cell through the cell cycle. The ability to measure the proliferation rate in tumours in patients in vivo will help with tumour grading and staging, targeting biopsies, and assessing the effect of therapy.
Modern imaging techniques enable the investigation of pathological changes in tumours in vivo. Attempts to image cell proliferation have largely involved techniques that exploit the increase in cellular metabolism in these cells. The most commonly used technique for imaging tumours uses 2′-deoxy-2′- [18F]fluoro-d-glucose (FDG) positron emission tomography (PET) to show areas of increased glycolysis. More recently PET has been used to assess proliferation through changes in protein synthesis using labelled amino acids, such as 11C-methionine (MET)1 or, more recently, the fluorine analogue O-2- [18F]fluoroethyl-l-tyrosine (FET).2
Autoradiographic studies of cell proliferation have commonly used labelled thymidine as this is incorporated into DNA and not into RNA. These experiments have shown that thymidine is readily transported across the blood–brain barrier and is taken up into dividing cells. Attempts have been made to use 11C-thymidine PET to image these processes, however, it is extremely difficult to manufacture sufficient labelled thymidine for such clinical studies and it is rapidly broken down to form a number of labelled metabolites that account for a considerable but variable amount of the PET signal.3 Attempts to label thymidine in the 2-ring position still produced labelled metabolites, especially 11CO2, which is widely distributed and slowly but variably excreted.4 Although kinetic modelling of this process is possible, it needs to account for five separate compartments, 10 model parameters, and makes nine assumptions.5 As a result this is unlikely to be acceptable for clinical use.
3′-Deoxy-3′- [18F]fluorothymidine (FLT) was initially developed as an antiviral agent for use against retroviral infections. In trials, however, there was an unacceptably high incidence of haematological toxicity and reports of two cases of fatal hepatic necrosis. As a result it is not used routinely, although it is still licensed for multidrug-resistant human immunodeficiency virus (HIV) infections. However, its fluorine-18-labelled radiotracer used at much lower non-toxic concentrations, is an excellent imaging marker, as it is transported across the blood–brain barrier and is taken up into cells using the same transporter system as thymidine.6 Once in the cell it is phosphorylated by the enzyme thymidine kinase-1 to form the monophosphate. It then undergoes very slow further phosphorylation at a rate 23 times slower than normal thymidine.7 As a result, FLT accumulates in dividing cells8 without producing significant quantities of labelled metabolites. Therefore, kinetic analysis is simpler and more applicable for clinical use.9 FLT retention has been shown to correlate with the percentage of cells in the S-phase of the cell cycle with [3H]-thymidine uptake, both accepted markers of cell proliferation rate.10
FLT PET has been used to study a variety of different tumour types.11, 12, 13, 14, 15, 16 These studies show that accumulation is correlated with histological markers of proliferation and that it provides better contrast to the background ratio than FDG. Similar findings have been found in brain tumours. Chen et al.17 found that the standardized uptake value (SUV) of FLT was more sensitive in the detection of high-grade tumours than FDG and that FLT uptake predicted tumour progression and survival. Choi et al.18 also found that the contrast between tumour and normal brain is better with FLT than FDG, but FLT could not differentiate tumour from non-neoplastic mass lesions. Jacobs et al. have been the only group to use full kinetic modelling and found that FLT accumulation is dominated by transport from blood into tissue rather than thymidine kinase-1 activity.19 They also found that the volume of FLT uptake was larger than that delineated by gadolinium enhancement and differed from that found with methionine PET. All three groups found that the maximum uptake of FLT correlated with the highest MIB-1 labelling index within the tumour. None of these studies, however, attempted to correlate FLT uptake with MIB-1 labelling index in tissue taken from the same region.
The hypothesis of the present study was that regional values of FLT accumulation will correlate with MIB-1 labelling index from tissue samples taken from the same region, and that FLT PET will provide further information on gliomas that is not provided by a conventional magnetic resonance imaging (MRI) study. In addition, by taking uptake values from both high and low-grade gliomas and from normal brain, the determination of the threshold values that could differentiate tumour from normal brain and between tumour grades was attempted.
Section snippets
Patients
Fourteen patients with imaging findings suggesting a supratentorial glioma that required an image-guided brain tumour biopsy were recruited. All patients had not been previously treated. The study group had a mean age of 48.8 years (range 18–79 years) and included six patients with World Health Organization (WHO) grade II gliomas (two astrocytomas and four oligodendrogliomas), three WHO grade III gliomas (all anaplastic oligoastrocytomas) and five WHO grade IV tumours (four glioblastomas and
Comparison of Patlak plot and DEPICT determination of Ki
The Ki values in 14 ROIs (six tumour, eight non-tumour) in seven patients were compared. The Ki values produced by the two methods were highly correlated; using a linear regression method, plotting Kimean (PMOD) as a function of Kimean (DEPICT) gave a linear fit of Kimean (PMOD) = 1.022 × Kimean (DEPICT) + 0.0002; r2 = 0.995. However, the standard deviation on the Ki values within each ROI was significantly lower for DEPICT (mean of the SD 0.0025 versus 0.0018; p < 0.001, using a paired t-test). So Ki
Discussion
In this study it was shown that FLT accumulation is higher in gliomas than in normal brain. For the low-grade gliomas there was frequently little increase in FLT uptake on visual inspection, but Ki values derived from kinetic analysis were significantly higher than that taken from normal brain. For high-grade tumours there was an increase in FLT accumulation, both on visual inspection and quantitative analysis. The present study suggests that a Kimean threshold of 1.8 × 10−3 mlplasma/min/mltissue
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2020, Cancer LettersCitation Excerpt :The advantages of these radiotracers include: 1) high accumulation within tumor cells, which has been linked in part to plasma membrane transporters such as LAT1 [59]; 2) low background activity in normal brain, which facilitates detection of tumoral tissue on imaging [60]; and 3) the ability to cross an intact BBB, which aids evaluation of non-enhancing tumor [61]. While radiotracers such as 18F-FLT (18F-3′-deoxy-3′-fluorothymidine) have shown high correlation with tumor indices such as proliferation and grade [62], 18F-FLT has limited applicability for defining the extent of non-enhancing tumor due to the inability to cross an intact BBB [63]. While PET requires separate image acquisition beyond that for MRI, the additional complementary information on tumor metabolism likely provides an important adjunct to routine clinical imaging.
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