Uptake Of F-FLT Research Articles

Single-Cell Characterization of 18F-FLT Uptake with Radioluminescence Microscopy.

The radiotracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is commonly used to measure cell proliferation in vivo. As a marker of cell proliferation, (18)F-FLT is expected to be differentially taken up by arrested and actively dividing cells, but PET measures only aggregate uptake by tumor cells and therefore the single-cell distribution of (18)F-FLT is unknown. We used a novel in vitro radioluminescence microscopy technique to measure the differential distribution of (18)F-FLT radiotracer with single-cell precision. Using radioluminescence microscopy, we imaged the absolute uptake of (18)F-FLT in live MDA-MB-231 cells grown under different serum conditions. We then compared (18)F-FLT uptake with a standard measure of cell proliferation, using fluorescence microscopy of 5-ethynyl-2'-deoxyuridine incorporation in fixed cells. According to 5-ethynyl-2'-deoxyuridine staining, few cells (1%) actively cycled under serum deprivation whereas most of them (71%) did under 20% serum. The distribution of (18)F-FLT reflected this dynamic. At 0% serum, uptake of (18)F-FLT was heterogeneous but relatively low. At 20% serum, a subpopulation of (18)F-FLT-avid cells, representing 61% of the total population, emerged. Uptake of (18)F-FLT in this population was 5-fold higher than in the remainder of the cells. Such a dichotomous distribution is not typically observed with other radiotracers, such as (18)F-FDG. These results suggest that increased (18)F-FLT uptake by proliferating cells is due to a greater fraction of (18)F-FLT-avid cells rather than a change in (18)F-FLT uptake by individual cells. This finding is consistent with the fact that (18)F-FLT uptake is mediated by thymidine kinase 1 expression, which is higher in actively dividing cells. Overall, these findings suggest that, within the same patient, changes in (18)F-FLT uptake reflect changes in the number of actively dividing cells, provided other parameters remain the same.

DW-MRI and (18) F-FLT PET for early assessment of response to radiation therapy associated with hypoxia-driven interventions. Preclinical studies using manipulation of oxygenation and/or dose escalation.

Early markers of treatment response may help in the management of patients by predicting the outcome of a specific therapeutic intervention. Here, we studied the potential value of diffusion-weighted MRI (DW-MRI) and (18)F-fluorothymidine ((18)F-FLT), markers of cell death and cell proliferation respectively, to predict the response to irradiation. In addition, dose escalation and/or carbogen breathing were used to modulate the response to irradiation. The studies were performed on two hypoxic rat tumor models: rhabdomyosarcoma and 9L-glioma. The rats were imaged using MRI and PET before and two days after the treatment. In both tumor models, changes in ADC (apparent diffusion coefficient) and (18)F-FLT SUV (standardized uptake value) were significantly correlated with the tumor growth delay. For both tumor models, the ADC values increased in all irradiated groups two days after the treatment while they decreased in the untreated groups. At the same time, the uptake of (18)F-FLT increased in the untreated groups and decreased in all treated groups. Yet, ADC values were not sensitive enough to predict the added value of dose escalation or carbogen breathing in either model. Change in (18)F-FLT uptake was able to predict the higher tumor response when using increased dose of irradiation, but not when using a carbogen breathing challenge. Our results also emphasize that the magnitude of change in (18)F-FLT uptake was strongly dependent on the tumor model.

Ex-vivo biodistribution and micro-PET/CT imaging of 18F-FDG, 18F-FLT, 18F-FMISO, and 18F-AlF-NOTA-PRGD2 in a prostate tumor-bearing nude mouse model.

(18)F-Fluorodeoxyglucose ((18)F-FDG), (18)F-fluoro-3'-deoxy-3'-L-fluorothymidine ((18)F-FLT), (18)F-fluoromisonidazole ((18)F-FMISO), and (18)F-AlF-NOTA-PRGD2 ((18)F-RGD) are all commonly used PET tracers for tumor diagnosis based on different mechanisms of tissue uptake. This study compared the ex-vivo biodistribution and PET/computed tomography (CT) imaging studies of these four PET tracers in a xenograft prostate tumor-bearing mouse model. Nude mice were inoculated with 5 × 10 PC-3 cells in the right armpit. The ex-vivo biodistribution of (18)F-FDG, (18)F-FLT, (18)F-FMISO, and (18)F-RGD at 30, 60, 90, and 120 min after injection was compared. Micro-PET/CT images of (18)F-FDG, (18)F-FLT, and (18)F-RGD were acquired at 60 min, whereas (18)F-FMISO images were acquired at 90 min after injection. The tumors were clearly visualized by micro-PET/CT using all four PET tracers. Ex-vivo biodistribution results showed highest tumor accumulation and tumor-to-muscle ratio of (18)F-FDG at each time point, accompanied by physiologically high uptakes in the brain, heart, and intestinal tract. Modest uptake of (18)F-FLT and (18)F-FMISO in tumors was observed at 60 and 90 min after injection, with less interference from other tissues compared with (18)F-FDG. Besides, (18)F-RGD also exhibited high tumor specificity; however, relatively low uptake was observed in the tumor. Our results demonstrated the potential of (18)F-FMISO and (18)F-FLT in the diagnosis of xenograft prostate cancer.

Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of (18) F-FDG-PET and (18) F-FLT-PET.

Inhibition of the V600E mutated BRAF kinase gene (BRAF(V600E) ) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF(V600E) , PLX3603, showed potent melanoma growth-inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of (18) F-FDG and (18) F-FLT-PET to monitor the early effects of the BRAF(V600E) inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF(V600E) , received the BRAF(V600E) inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of (18) F-FDG and (18) F-FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial (18) F-FDG and (18) F-FLT-PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF(V600E) inhibitor. A dose-dependent decrease in (18) F-FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased (18) F-FDG uptake in A375 tumors (41, 35 and 51%, respectively). (18) F-FLT uptake in the A375 tumors was low at baseline and no significant changes in (18) F-FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo (18) F-FDG and (18) F-FLT-PET imaging. These data demonstrate that (18) F-FDG-PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603.

Imaging proliferation in human leukemia-tumor bearing mice with (18)F-FLT: Comparison with (18)F-FDG PET.

Leukemia threatens human life due to its uncontrolled proliferative malignancy. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) has been suggested as a new positron emission tomography (PET) tracer for imaging tumor proliferation. The aim of the study was to investigate the usefulness of (18)F-FLT PET for imaging human leukemia-tumor bearing mice, compared with fluorine-18-fluorodesoxyglucose ((18)F-FDG PET). In vitro the experiments of (18)F-FLT and (18)F-FDG uptake were performed in K562 cell lines at various time points and radioactive tracer uptake was measured in a gamma counter. (18)F-FLT and (18)F-FDG PET imaging were performed both in the same mouse when eight tumor-bearing mice models of human chronic myeloid leukemia were established successfully by injecting K562 cells. Regions of interest were drawn over the tumor, the crossed normal tissue was regarded as background and the ratio of tumor to non-tumor counts (T/NT) in tissues was calculated. A higher uptake of (18)F-FLT (15min, 5.73±0.05%; 30min, 5.90±0.06%; 60min, 6.16±0.19%; 120min, 6.32±0.08%) than that of (18)F-FDG (15min, 1.05±0.10%; 30min, 1.11±0.14%; 60min, 1.14±0.37%; 120 min, 1.36±0.25%) was observed in K562 cells in the tracer uptake experiment. Ratios of T/NT of (18)F-FLT PET (0.5h, 5.39±0.42; 1h, 4.88±0.43; 2h, 3.81±0.38) were higher than those of (18)F-FDG PET/CT (0.5h, 0.34±0.12; 1h, 0.21±0.06; 2h, 0.13±0.05) after injection. Both uptake and T/NT differences of (18)F-FLT versus (18)F-FDG were significant (P>0.05). In conclusion, (18)F-FLT and (18)F-FDG quantitative and semi-quantitative uptake measurements resulting from cell lines and PET imaging respectively suggested a promising potential of (18)F-FLT for metabolic imaging of human chronic myeloid leukemia.

Analysis of the Growth Dynamics of Angiogenesis-Dependent and -Independent Experimental Glioblastomas by Multimodal Small-Animal PET and MRI

The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo. Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using (18)F-FDG, (11)C-methyl-l-methionine ((11)C-MET), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and by MRI at 3-6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis. Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of (11)C-MET and (18)F-FLT and relatively low uptake of (18)F-FDG. (11)C-MET was an early indicator of vessel remodeling and tumor proliferation. (18)F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate (11)C-MET and (18)F-FLT and impaired the (18)F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast. For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and (11)C-MET was more sensitive than (18)F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood-brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative (18)F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.

18F-FLT PET performs better than 18F-FDG PET in differentiating malignant uterine corpus tumors from benign leiomyoma

The aim of this study is to test the hypothesis that positron emission tomography (PET) with 3'-deoxy-3'-[(18)F]-fluorothymidine ((18)F-FLT) can differentiate malignancy from benign leiomyoma better than PET with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), and to evaluate whether (18)F-FLT and (18)F-FDG uptake correlate with immunohistochemical index of cell proliferation. The protocol of this prospective study was approved by the institutional ethics committee, and all patients gave written informed consent. Fifteen patients (aged 26-65 years, median 44 years) with uterine corpus tumor which has the possibility of being leiomyosarcoma underwent (18)F-FLT and (18)F-FDG PET scans. Maximum standard uptake value (SUV(max)) of PET scans and Ki-67 labeling index of surgical specimens were evaluated. Mann-Whitney's U test was used for comparing uptakes between benign and malignant, and linear regression analysis was used for evaluating the correlation between Ki-67 labeling index and SUV(max). Five cases were diagnosed as malignant (leiomyosarcoma for 3 cases, and carcinoma for 2 cases), and the others were benign leiomyoma. Sensitivity and negative predictive value of both tracers for detecting malignancy was 100%. Specificity, positive predictive value and accuracy of (18)F-FLT PET were higher than those of (18)F-FDG PET. Difference in SUV(max) between malignant and benign was significant for (18)F-FLT PET (P < 0.01), but not for (18)F-FDG PET. While all the malignant cases showed positive uptake in both tracers, a case of leiomyosarcoma with huge necrosis showed relatively low uptake. Uptake of (18)F-FLT showed better correlation with Ki-67 labeling index compared with (18)F-FDG (R(2) = 0.91 vs. R(2) = 0.26). Negative findings on additional (18)F-FDG or (18)F-FLT PET may rule out the possibility of malignancy for the patients with suspected leiomyosarcoma diagnosed by conventional methods. (18)F-FLT PET is superior to (18)F-FDG PET in differentiating malignant from benign leiomyoma. Moreover, (18)F-FLT uptake correlated well with the immunohistochemical index of cell proliferation.

Differential 18F-FDG and 3′-Deoxy-3′-18F-Fluorothymidine PET Responses to Pharmacologic Inhibition of the c-MET Receptor in Preclinical Tumor Models

The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling. Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting. Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 μM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.

PET imaging of early response to the tyrosine kinase inhibitor ZD4190.

We evaluated noninvasive positron emission tomography (PET) imaging for monitoring tumor response to the VEGFR-2 tyrosine kinase (TK) inhibitor ZD4190 during cancer therapy. Orthotopic MDA-MB-435 tumor-bearing mice were treated with ZD4190 (100 mg/kg orally per day for three consecutive days). Tumor growth was monitored by caliper measurement. During the therapeutic period, longitudinal PET scans were acquired using (18)F-FDG, (18)F-FLT and (18)F-FPPRGD2 as imaging tracers to evaluate tumor glucose metabolism, tumor cell proliferation, and angiogenesis, respectively. Imaging metrics were validated by immunohistochemical analysis of Ki67, GLUT-1, F4/80, CD31, murine integrin β3, and human integrin αvβ3. Three consecutive daily oral administrations of 100 mg/kg of ZD4190 were effective in delaying MDA-MB-435 tumor growth. A significant difference in tumor volume was observed on day 7 between the treatment group and the control group (p < 0.01). After the final treatment, tumor growth resumed after a short delay. In the control tumors, (18)F-FPPRGD2 uptake was stable between days 0 and 7. In ZD4190-treated tumors, (18)F-FPPRGD2 uptake had decreased significantly relative to baseline by 26.74 ± 8.12% (p < 0.05) on day 1 and by 41.19 ± 6.63% (p < 0.01) on day 3, then had returned to baseline on day 7. Tumor uptake of (18)F-FLT had also decreased on both day 1 and day 3 after initiation of ZD4190 treatment. No significant change in (18)F-FDG uptake in ZD4190-treated tumors was observed, however, compared with the control group. All of the imaging findings were supported by ex vivo analysis of related biomarkers. The longitudinal imaging results demonstrated the usefulness of quantitative (18)F-FLT and (18)F-FPPRGD2 PET imaging in evaluating the early antiproliferative and antiangiogenic effects of ZD4190. The quantification data from the PET imaging were consistent with the pattern of initial growth inhibition with treatment, followed by tumor relapse after treatment cessation.

Early Detection of Response to Experimental Chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in Human Ovary Cancer Xenografts in Mice

Background3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use 18F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET.Methodology/Principal Findings In vivo uptake of 18F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline 18F-FLT scans were made before either Top216 (n = 7–10) or vehicle (n = 5–7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2′-deoxy-2′-[18F]fluoro-D-glucose (18F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). 18F-FLT uptake decreased significantly at 2 hours (−52%; P<0.001), 6 hours (−49%; P = 0.002) and Day 1 (−47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (−21%; P = 0.003), Day 1 (−29%; P<0.001) and Day 5 (−19%; P = 0.05) compared to baseline.Conclusions/SignificanceOne injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by 18F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that 18F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.

Measuring Tumor Cell Proliferation with 18F-FLT PET During Radiotherapy of Esophageal Squamous Cell Carcinoma: A Pilot Clinical Study

The primary aim of this study was to use serial (18)F-3'-deoxy-3'-fluorothymidine (FLT) PET/CT to measure tumor cell proliferation during radiotherapy of squamous cell carcinoma (SCC) of the esophagus. Twenty-one patients with inoperable locally advanced SCC of the esophagus underwent serial (18)F-FLT PET/CT during radiotherapy. Each patient received a pretreatment scan, followed by 1-3 scans after delivery of 2, 6, 10, 20, 30, 40, 50, or 60 Gy to the tumor. Among the 19 patients who completed radiotherapy without interruption, parameters reflecting (18)F-FLT uptake in the tumor (i.e., maximum tumor standardized uptake value [SUVmax] and proliferation target volume) decreased steadily. All patients demonstrated an almost complete absence of proliferating esophageal tumor after 30 Gy and a complete absence after 40 Gy. In the 2 patients whose radiotherapy course was interrupted, (18)F-FLT uptake in the tumor was greater after the interruption than before the interruption. Marked early reduction of (18)F-FLT uptake in irradiated bone marrow was observed in all patients, even after only 2 Gy. All showed a complete absence of proliferating marrow in irradiated regions after 10 Gy. Both patients who underwent scans after completing the entire radiotherapy course showed no tumor uptake on (18)F-FLT PET/CT but high uptake on (18)F-FDG PET/CT. Pathologic examination of these regions revealed inflammatory infiltrates but no residual tumor. (18)F-FLT uptake can be used to monitor the biologic response of esophageal SCC and normal tissue to radiotherapy. Increased uptake of (18)F-FLT after treatment interruptions may reflect accelerated repopulation. (18)F-FLT PET/CT may have an advantage over (18)F-FDG PET/CT in differentiating inflammation from tumor.

Using Dual-Tracer PET to Predict the Biologic Behavior of Human Colorectal Cancer

(18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) have been proven useful in diagnosing and staging many types of cancer but with emphasis on different aspects of tumor biology. The aim of the current study was to evaluate whether (18)F-FDG and (18)F-FLT can be used complementarily in monitoring the biologic characteristics of colorectal cancer (CRC). Human CRC cell lines SW480 and SW620 of the same genetic origin but different metastatic potential were cultured and implanted into nude mice to create CRC models. Uptake of (18)F-FDG and (18)F-FLT in SW480 and SW620 cells in vitro was assessed after incubation with radiotracers for 0, 30, 60, 90, and 120 min. In vivo imaging of SW480 and SW620 tumor-bearing mice was performed using small-animal PET/CT at 60 min after injection of each tracer. A region of interest was drawn over tumor and background to calculate the tumor-to-nontumor ratio (T/NT) using software on reconstructed images. Tumor growth rate, metastatic status, and survival time were assessed in tumor-bearing mice. The relationship between uptake of the tracers, metastatic capability, and tumor marker expression was evaluated using linear regression. SW480 tumors grew more quickly than SW620 tumors (t = 3.332, P = 0.004). A higher incidence of lung and liver metastases was noted for SW480 than for SW620 (P = 0.023). Uptake in SW480 and SW620 cells was significantly different between (18)F-FDG and (18)F-FLT (t = 2.507, P = 0.021, vs. t = 3.497, P = 0.002). In the small-animal PET study, the T/NT of (18)F-FDG did not differ between SW480 and SW620 tumors (2.69 +/- 0.98 vs. 3.09 +/- 1.26, P = 0.524), but the T/NT of (18)F-FLT differed significantly between SW480 and SW620 tumors (3.65 +/- 0.51 vs. 2.22 +/- 0.42, P < 0.001). Heat shock protein 27 (HSP27) expression and integrin beta(3) expression were higher, whereas vascular endothelial growth factor receptor 2 (VEGFR2) expression and Ki67 expression were lower, in SW480 cells than in SW620 cells. For SW480, metastases in lung and liver correlated significantly with (18)F-FLT uptake in tumors (r = 0.763, P = 0.005) and with expression of HSP27 (r = 0.894, P = 0.008) and integrin beta(3) (r = 0.635, P = 0.088). A correlation was also found between (18)F-FLT uptake and expression of HSP27 (r = 0.924, P = 0.004) and integrin beta(3) (r = 0.813, P = 0.025). No correlation was found between (18)F-FDG uptake in tumors and metastasis in lung and liver (r = -0.111, P = 0.388). However, there was a significantly negative correlation between (18)F-FDG uptake and the survival time of tumor-bearing mice (r = -0.500, P = 0.017), to which (18)F-FLT did not relate (r = 0.262, P = 0.182). High uptake of (18)F-FDG and (18)F-FLT may reflect poorer survival and a higher metastatic potential for CRC in mice. Combining (18)F-FDG with (18)F-FLT PET would be helpful in better predicting the biologic behavior of CRC.

Imaging Cellular Proliferation During Chemo-Radiotherapy: A Pilot Study of Serial 18F-FLT Positron Emission Tomography/Computed Tomography Imaging for Non–Small-Cell Lung Cancer

To establish whether (18)F-3'-deoxy-3'-fluoro-L-thymidine ((18)F-FLT) can monitor changes in cellular proliferation of non-small-cell lung cancer (NSCLC) during radical chemo-radiotherapy (chemo-RT). As part of a prospective pilot study, 5 patients with locally advanced NSCLC underwent serial (18)F-FLT positron emission tomography (PET)/computed tomography (CT) scans during treatment. Baseline (18)F-FLT PET/CT scans were compared with routine staging (18)F-FDG PET/CT scans. Two on-treatment (18)F-FLT scans were performed for each patient on Days 2, 8, 15 or 29, providing a range of time points for response assessment. In all 5 patients, baseline lesional uptake of (18)F-FLT on PET/CT corresponded to staging (18)F-FDG PET/CT abnormalities. (18)F-FLT uptake in tumor was observed on five of nine (55%) on-treatment scans, on Days 2, 8 and 29, but not Day 15. A "flare" of (18)F-FLT uptake in the primary tumor of one case was observed after 2 Gy of radiation (1.22 x baseline). The remaining eight on-treatment scans demonstrated a mean reduction in (18)F-FLT tumor uptake of 0.58 x baseline. A marked reduction of (18)F-FLT uptake in irradiated bone marrow was observed for all cases. This reduction was observed even after only 2 Gy, and all patients demonstrated a complete absence of proliferating marrow after 10 Gy. This proof of concept study indicates that (18)F-FLT uptake can monitor the distinctive biologic responses of epithelial cancers and highly radiosensitive normal tissue changes during radical chemo-RT. Further studies of (18)F-FLT PET/CT imaging during therapy may suggest that this tracer is useful in developing response-adapted RT for NSCLC.

In Vivo Characterization of Proliferation for Discriminating Cancer from Pancreatic Pseudotumors

We have determined the ability of PET with the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to detect pancreatic cancer and to differentiate malignant from benign pancreatic lesions. In this prospective study, (18)F-FLT PET was performed on 31 patients with undefined pancreatic lesions. Routine diagnostic procedures included endoscopic ultrasound, MRI, or multislice helical CT of the upper gastrointestinal tract in all patients. Uptake of (18)F-FLT was evaluated semiquantitatively by calculation of mean and maximal standardized uptake values (SUVs). Results were correlated to the reference methods, which were histopathology (23/31) or cytology/clinical follow-up (8/31). All 10 benign pancreatic lesions were negative on (18)F-FLT PET and showed only background activity (specificity, 100%; 90% confidence interval, 74%-100%). On visual interpretation, 15 of 21 malignant tumors presented as focal (18)F-FLT uptake higher than the surrounding background (sensitivity, 71.4%; 90% confidence interval, 52%-89%). (18)F-FLT PET missed 4 well-differentiated and 2 T1 cancers. Mean (18)F-FLT uptake was 3.1 in all malignant tumors (median, 2.8; range, 1.3-8.5), 3.7 in tumors with visual tracer uptake (median, 3.2; range, 2.1-8.5), and significantly higher in malignant than in benign tumors (mean/median, 1.4; range, 1.2-1.7; P<0.001). For discriminating cancer from benign pancreatic lesions, receiver-operating-characteristic analysis indicated a sensitivity of 81% and specificity of 100% (area under the curve, 0.93) using a mean (18)F-FLT SUV cutoff of 1.8 (maximal (18)F-FLT SUV: area under the curve, 0.92; SUV cutoff, 2.1). In this pilot study, focal uptake of the in vivo proliferation marker (18)F-FLT was detected exclusively in malignant tumors. (18)F-FLT PET may therefore be useful as a diagnostic adjunct for differentiating cancer from benign pancreatic lesions.