Positron emission tomography (PET) is now regularly used in the diagnosis and staging of cancer. These uses and its ability to monitor treatment response would be aided by the development of imaging agents that can be used to measure tissue and tumor proliferation. We have developed and tested [F-18]FLT (3'-deoxy-3'-fluorothymidine); it is resistant to degradation, is retained in proliferating tissues by the action of thymidine kinase 1 (TK), and produces high-contrast images of normal marrow and tumors in canine and human subjects.
Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.
BACKGROUND Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with five year survival ranging from 1-5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer. METHODS The objective of the study was to explore the relationship of early treatment response using the 18 F- fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value (SUV) and kinetic parameters were compared to the clinical outcome. RESULTS Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All twenty patients had pre-study PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (≥50% decrease in SUV after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET non-responders (<50% decrease). Two patients did not have the second PET scan due to clinical progression or treatment toxicity. Mean survival was 23.2 months for PET responders and 11.3 months for non-responders (p=0.234). Similar differences in survival were also noted when response was measured using Patlak analysis. CONCLUSION FDG-PET can aid in monitoring the clinical outcome of patients with locally advanced pancreatic cancer treated with neoadjuvant chemo-RT. FDG-PET may be used to aid patients who could have complete surgical resection as well as prognosticate patients’ survival.
Purpose Imaging tumor proliferation with 3′-deoxy-3′-[18F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach. Experimental Design Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days. Reproducibility (that is, error) was measured as the percent difference between the two patient scans. Dynamic imaging was obtained during the first 60 min after injection. Activity in the blood was assessed from aortic images and the fraction of unmetabolized FLT was measured. Regions of interest were drawn on the plane with the highest activity and the adjacent planes to measure standardized uptake value (SUVmean) and kinetic variables of FLT flux. Results We found that the SUVmean obtained from 30 to 60 min had a mean error of 3.6% (range, 0.6–6.9%; SD, 2.3%) and the first and second scans were highly correlated (r2 = 0.99; P < 0.0001). Using shorter imaging times from 25 to 30 min or from 55 to 60 min postinjection also resulted in small error rates; SUVmean mean errors were 8.4% and 5.7%, respectively. Compartmental and graphical kinetic analyses were also fairly reproducible (r2 = 0.59; P = 0.0152 and r2 = 0.58; P = 0.0175 respectively). Conclusion FLT imaging of patients with NSCLC was quite reproducible with a worst case SUVmean error of 21% when using a short imaging time.
The kinetics of 1-(29-deoxy-29-fluoro-b-D-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated. Methods: Ten patients with brain (n 5 4) or prostate (n 5 6) tumors were imaged using 18 F-FMAU PET (mean dose, 369 MBq). Sixty-minute dynamic images were obtained; this was followed by whole-body images. Mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) of each tumor were determined as the mean over 3 planes of each time interval. For kinetic analyses, blood activity was measured in 18 samples over 60 min. Samples were analyzed by high-performance liquid chromatography at 3 selected times to determine tracer metabolites. FMAU kinetics were measured using a 3-compartment model yielding the flux (K1 · k3/(k2 1 k3)) (K1, k2, and k3 are rate constants) and compared with TRR measurements. TRR was calculated as the tumor 18 F-FMAU uptake area under the curve divided by the product of blood 18 F-FMAU AUC and time. A similar analysis was performed using muscle to estimate 18 F-FMAU delivery. Results: SUVmean measurements obtained from 5 to 11 min correlated with those obtained from 30 to 60 min (r 2 5 0.92, P , 0.0001) and 50 to 60 min (r 2 5 0.92, P , 0.0001) due to the rapid clearance of 18 F-FMAU. Similar results were obtained using SUVmax measurements (r 2 5 0.93, P , 0.0001; r 2 5 0.88, P , 0.0001, respectively). The measurement of TRR using either blood or muscle activity over 11 min provided results comparable to those of 60-min dynamic imaging and a 3-compartment model. This analysis required only 5 blood samples drawn at 1, 2, 3, 5, and 11 min without metabolite correction to produce comparable results. Conclusion: Tissue retention ratio measurements obtained over 11 min can replace flux measurements in 18 F-FMAU imaging. The SUVmean and the SUVmax in 5-11 min images correlated well with those of images obtained at 50-60 min. The quality of the images and tissue kinetics in 11 min of imaging makes it a desirable and shorter tumor imaging option.
Purpose-Fluoropyrimidines like 1-(2 -deoxy-2 -fluoro--D-arabinofuranosyl)-thymine (FMAU) and 3 -deoxy-3 -fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study.Methods-Retention of [ 3 H]FLT and [ 3 H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1--D-arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively.Results-FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r 2 = 0.88, p=0.006). FMAU phosphorylation correlated with increased TK2 activity (r 2 =0.87, p=0.0002).Conclusion-FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.
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