2-[C-11]thymidine imaging of malignant brain tumors

Malignant brain tumors pose diagnostic and therapeutic problems. Despite th e advent of new brain imaging modalities, including magnetic resonance imag ing (MRI) and [F-18]fluorodeoxyglucose (FDG) positron emission tomography ( PET), determination of tumor viability and response to treatment is often d ifficult. Blood-brain barrier disruption can be caused by tumor or nonspeci fic reactions to treatment, making MRI interpretation ambiguous. The high m etabolic background of the normal brain and its regional variability makes it difficult to identify small or less active tumors by FDG imaging of cell ular energetics. We have investigated 2-[C-11]thymidine (dThd) and PET to i mage the rate of brain tumor cellular proliferation. A series of 13 patient s underwent closely spaced dThd PET, FDG PET, and MRI procedures, and the i mage results were compared by standardized visual analysis. The resulting d Thd scans were qualitatively different from the other two scans in approxim ately 50% of the cases, which suggests that dThd provided information disti nct from FDG PET and MRI. In two cases, recurrent tumor was more apparent o n the dThd study than on FDG; in two other patients, tumor dThd uptake was less than FDG uptake, and these patients had slower tumor progression than the three patients with both high dThd and FDG uptake. To better characteri ze tumor proliferation, kinetic modeling was applied to dynamic dThd PET up take data and metabolite-analyzed blood data in a subset of patients. Kinet ic analysis was able to remove the confounding influence of [C-11]CO2, the principal labeled metabolite of 2-[C-11]dThd, and to estimate the flux of d Thd incorporation into DNA, Sequential, same-day [C-11]CO, and [C-11]dThd i maging demonstrated the ability of kinetic analysis to model both dThd and CO2 simultaneously, Images of dThd flux obtained using the model along with the mixture analysis method for pixel-by-pixel parametric imaging signific antly enhanced the contrast of tumor compared with normal brain. Comparison of model estimates of dThd transport versus dThd flux was able to discern increased dThd uptake simply on the basis of blood-brain barrier disruption from retention on the basis of increased cellular proliferation. This prel iminary study demonstrates the potential for imaging brain tumor cellular p roliferation to provide unique information for guiding patient treatment.