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¹⁸F-Fluoro-L-Thymidine and ¹¹C-Methylmethionine as Markers of Increased Transport and Proliferation in Brain Tumors

¹ Max Planck Institute for Neurological Research, Cologne, Germany
² Department of Neurology, University of Cologne, Cologne, Germany
³ Center for Molecular Medicine, University of Cologne, Cologne, Germany

View larger version (58K): [in a new window]   FIGURE 1. Two patients with highly intense 18F-FLT accumulation that was found mainly in areas of breakdown of blood–brain barrier as depicted by gadolinium-enhanced MRI. A 64-y-old man with newly diagnosed glioblastoma (A) and 26-y-old woman with newly diagnosed WHO grade I astrocytoma (B). In both patients, 11C-MET PET is suggestive of a larger extent of tumor as depicted by gadolinium MRI.

View larger version (77K): [in a new window]   FIGURE 2. False-negative findings on 18F-FLT PET in 50-y-old woman with WHO grade II astrocytoma that had been resected at primary diagnosis. At a regular follow-up, MRI depicted signal changes within large parts of left hemisphere with only minor gadolinium enhancement (volume, 1.2 cm3) and area of mildly increased 11C-MET uptake (volume, 5.7 cm3; factor, 1.6). Mucosa and cranial bone marrow show intense 18F-FLT uptake, whereas 18F-FLT background in normal brain is low.

View larger version (68K): [in a new window]   FIGURE 3. Two examples of complementary information on activity and extent of tumor as depicted by multimodal imaging. (A) A 49-y-old woman with recurrent glioblastoma that had been treated by operation, radiation, and 5 cycles of temozolomide. 18F-FLT seems to depict some extension of tumor toward internal capsule and thalamus that was not clearly depicted by gadolinium MRI and 11C-MET PET. Contours on MRI depict tumor extent as measured by 18F-FLT PET; contours on 11C-MET and 18F-FLT PET depict tumor extent as measured by gadolinium enhancement. (B) A 58-y-old woman with WHO grade III ganglioglioma. High tumor activity is depicted by high 18F-FLT uptake (uptake ratio, 13.0; SUV, 3.0), which exceeds involvement shown by gadolinium enhancement to lateral side (volume, 40 cm3 vs. 14.4 cm3). 11C-MET PET shows even further extension of tumor toward pole of temporal lobe. Contours on MRI depict tumor extent as measured by 18F-FLT PET; contours on 18F-FLT PET depict tumor extent as measured by gadolinium enhancement.

View larger version (65K): [in a new window]   FIGURE 4. Complementary information on tumor activity and extent as depicted by multimodal imaging in 2 patients with tumors near midline. (A) A 57-y-old woman with recurrent WHO grade III oligoastrocytoma in thalamus. Whereas area of gadolinium enhancement is small, 11C-MET and 18F-FLT PET are suggestive of gross involvement of thalami on both sides. (B) A 39-y-old woman with recurrent astrocytoma within vermis and extension into midbrain and thalamus. Gadolinium enhancement is mainly restricted to vermis, whereas 11C-MET and 18F-FLT uptake show clear involvement of left-sided midbrain and thalamus.

View larger version (12K): [in a new window]   FIGURE 5. Relationship between tumor volumes as measured by gadolinium-enhanced MRI in comparison to 11C-MET PET (•) and 18F-FLT PET (). In most cases, tumor is larger when measured by PET than when measured by MRI.

View larger version (12K): [in a new window]   FIGURE 6. Comparison of uptake ratios for 18F-FLT (A) and 11C-MET (B) in treated and untreated astrocytomas and glioblastomas. Uptake ratios of untreated tumors tend to increase with WHO grade. Uptake ratios vary more in treated tumors, most probably because of tissue alterations in response to therapy. NT = no therapy before study inclusion; T = therapy before study inclusion.

View larger version (14K): [in a new window]   FIGURE 7. Representative measured and fitted time–activity curves from patient 7 (Figs. 1A and Tables 3 and 4). (A) Time–activity curve from tumor region with increased 18F-FLT uptake; simple mean reduced 2 value for fit without k4 is 241.1 and with k4 is 250.6. (B) Time–activity curve from blood. (C) Time–activity curve from contralateral control region; simple mean reduced 2 value for fit without k4 is 130.3 and with k4 is 134.9. Fifteen minutes or more after radiotracer administration, tumor-to-blood ratio is significantly higher than 1, supporting hypothesis that 18F-FLT uptake is at least partly determined by 18F-FLT trapping and TK1 activity.

View larger version (10K): [in a new window]   FIGURE 8. Correlation of K1 and k3 with 18F-FLT uptake ratio. Spearman rank correlation coefficients are r = 0.85 for K1 (P < 0.001) and r = 0.65 for k3 (P = 0.011).