Proliferation imaging has been a focus of this program since it started, initially with [2-[11]C]-thymidine (TdR) which is incorporated into DNA;later with our introduction of [[18]F]-FLT (FLT). The rate of DNA synthesis via the salvage pathway provides a robust approach for estimating growth rate of tumors and changes in response to treatment. A simple FLT{suv} does not reliably indicate cellular proliferation. Further work is essential to validate how well FLT measures cellular proliferation compared to TdR. Our application of these two tracers requires dynamic imaging with blood sampling and mathematical modeling to separate flux (retention) of the tracers from transport. It is also worthwhile to explore simpler ways to acquire the important parametric data more simply with image-based arterial input functions and a minimal number of venous samples for calibrating the input functions and assaying for metabolites. Generalize: We have published analytical approaches for TdR and FLT in brain tumors and will now generalize this to other tumor sites, directly comparing TdR and FLT to determine whether flux and transport of FLT provides measures as accurately indicative of cellular proliferation as those of TdR. Specifically, we will compare these two tracers in patients with glioma, leukemia, sarcoma, renal, and Gl carcinomas before and after therapy. Our hypothesis is that FLT with appropriate data analysis can be as accurate as TdR for reporting tumor proliferation and response to therapy. Simplify: Our approach to simplifying the PET procedure will evaluate with minimal venous sampling to identify labeled metabolites. Our hypothesis is that the accuracy of flux and transport estimates can be maintained using simplified procedures. Progression or not? Standard therapy for newly diagnosed glioblastoma multiforme is 60 Gy RT plus concurrent temozolomide (TMZ) chemotherapy. From 9 to 45% of patients who complete therapy show MRI changes consistent with tumor progression yet they improve on continued chemotherapy with TMZ. This pseudoprogression is an important problem;clinicians armed with MRI alone wrongly conclude that standard treatment is failing in 9-45% of cases. Wrongly diagnosing tumor progression could risk entering patients into phase II trials of new agents, leading to falsely positive outcomes. Our hypothesis is that FLT PET plus MRI can distinguish between true tumor progression and pseudoprogression in patients with GBM that finish initial therapy with external beam RT plus concurrent TMZ.
The rate of DNA synthesJs provides a robust approach for estimating growth of tumors and changes in response to treatment. It may be the most defensible way to image a cytostatic response. This new work is essential to validate how well FLT measures proliferation compared to TdR. It is also worthwhile to explore simpler ways to acquire the data with image-based arterial input functions and a minimal number of venous samples for calibrating the input function and assaying for metabolites. Lastly, distinguishing pseudoprogression is an exceedingly important clinical problem. Our hypothesis is that FLT PET plus MRI can distinguish between true tumor progression and pseudoprogression in brain tumors.
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