HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buck, A. K. Articles by Hetzel, M. Search for Related Content PubMed PubMed Citation Articles by Buck, A. K. Articles by Hetzel, M.

Imaging Proliferation in Lung Tumors with PET: ¹⁸F-FLT Versus ¹⁸F-FDG

¹ Department of Nuclear Medicine, University of Ulm, Ulm, Germany
² Department of Thoracic Surgery, University of Ulm, Ulm, Germany
³ Department of Pathology, University of Ulm, Ulm, Germany
⁴ Department of Internal Medicine II, University of Ulm, Ulm, Germany

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Recently, the thymidine analog 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT) was suggested for imaging tumoral proliferation. In this prospective study, we examined whether ¹⁸F-FLT better determines proliferative activity in newly diagnosed lung nodules than does ¹⁸F-FDG. Methods: Twenty-six patients with pulmonary nodules on chest CT were examined with PET and the tracers ¹⁸F-FDG and ¹⁸F-FLT. Tumoral uptake was determined by calculation of standardized uptake value (SUV). Within 2 wk, patients underwent resective surgery or had core biopsy. Proliferative activity was estimated by counting nuclei stained with the Ki-67–specific monoclonal antibody MIB-1 per total number of nuclei in representative tissue specimens. The correlation between the percentage of proliferating cells and the SUVs for ¹⁸F-FLT and ¹⁸F-FDG was determined using linear regression analysis. Results: Eighteen patients had malignant tumors (13 with non–small cell lung cancer [NSCLC], 1 with small cell lung cancer, and 4 with pulmonary metastases from extrapulmonary tumors); 8 had benign lesions. In all visible lesions, mean ¹⁸F-FDG uptake was 4.1 (median, 4.4; SD, 3.0; range, 1.0–10.6), and mean ¹⁸F-FLT uptake was 1.8 (median, 1.2; SD, 2.0; range, 0.8–6.4). Statistical analysis revealed a significantly higher uptake of ¹⁸F-FDG than of ¹⁸F-FLT (Mann–Whitney U test, P < 0.05). ¹⁸F-FLT SUV correlated better with proliferation index (P < 0.0001; r = 0.92) than did ¹⁸F-FDG SUV (P < 0.001; r = 0.59). With the exception of 1 carcinoma in situ, all malignant tumors showed increased ¹⁸F-FDG PET uptake. ¹⁸F-FLT PET was false-negative in the carcinoma in situ, in another NSCLC with a low proliferation index, and in a patient with lung metastases from colorectal cancer. Increased ¹⁸F-FLT uptake was related exclusively to malignant tumors. By contrast, ¹⁸F-FDG PET was false-positive in 4 of 8 patients with benign lesions. Conclusion: ¹⁸F-FLT uptake correlates better with proliferation of lung tumors than does uptake of ¹⁸F-FDG and might be more useful as a selective biomarker for tumor proliferation.

Key Words: ¹⁸F-FLT • ¹⁸F-FDG • Ki-67 • proliferation • lung cancer

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
PET using the glucose analog ¹⁸F-FDG enables noninvasive tissue characterization based on metabolic differences between benign and malignant tumors. Several studies have found ¹⁸F-FDG PET to have a high sensitivity for staging lung cancer (1–3). However, ¹⁸F-FDG uptake is not tumor specific, and false-positive findings can occur in inflammatory lesions (4). Therefore, many efforts have been made to develop more selective tracers. In contrast to ¹⁸F-FDG uptake values, proliferative activity as measured by Ki-67 immunostaining has been shown to be a specific sign of malignant tumors (5). Furthermore, immunohistochemical studies using various biomarkers for proliferation showed significantly decreased survival in patients with highly proliferating tumors (6). In clinical studies, ¹⁸F-FDG uptake correlated with proliferative activity (7,8) and survival in non–small cell lung cancer (NSCLC) (9,10).

¹¹C-Thymidine was the first radiotracer for noninvasive imaging of tumor proliferation (11). The short half-life of ¹¹C and rapid metabolism of ¹¹C-thymidine in vivo make the radiotracer less suitable for routine use. Hence, the thymidine analog 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT) was recently introduced as a stable proliferation marker with a suitable nuclide half-life (12). ¹⁸F-FLT is phosphorylated to 3'-fluorothymidine monophosphate by thymidine kinase 1 and reflects thymidine kinase 1 activity in A549 lung cancer cells (13). In a first clinical study, our group demonstrated proliferation-dependent ¹⁸F-FLT uptake in NSCLC (14).

We devised a prospective study to evaluate whether PET with the novel tracer ¹⁸F-FLT better determines tumoral proliferation and better differentiates benign from malignant lung tumors than does PET with ¹⁸F-FDG.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Patients
This prospective study included 26 patients (17 men, 9 women) with a mean age of 62 ± 9.9 y (range, 37–77 y; Table 1). PET with both tracers, ¹⁸F-FDG and ¹⁸F-FLT, was planned for 30 consecutive patients. Four patients had to be excluded from the study because only ¹⁸F-FDG or ¹⁸F-FLT PET was performed. Patients were selected when pulmonary nodules on CT scans strongly suggested a malignant tumor. Sixteen patients underwent resective surgery up to 14 d after ¹⁸F-FLT and ¹⁸F-FDG PET. In the other 10 patients, core-biopsy specimens were used for histopathologic evaluation. All patients gave written consent to participate in this study, which was approved by the local ethical committee.

Immunostaining and Morphometric Analysis
The detailed protocol for immunostaining was published elsewhere (5). Briefly, formalin-fixed and paraffin-embedded sections (5 µm) of resected specimens and biopsy samples were dewaxed, rehydrated, and microwaved in 0.01 mol/L citrate buffer for 30 min. For immunostaining, the monoclonal murine antibody MIB-1 (Dianova), specific for human nuclear antigen Ki-67, was used in a 1:500 dilution. Sections were lightly counterstained with hematoxylin. As a positive control for proliferating cells, sections of human lymph node tissue were used. The primary antibody was omitted on sections used as negative controls. Histopathologic slides were examined by a pathologist who was unaware of the patients’ clinical data.

An area with high cellularity was chosen for the evaluation of MIB-1 immunostaining. All epithelial cells with nuclear staining of any intensity were defined as positive. Proliferative activity was described as the percentage of MIB-1–stained nuclei per total number of nuclei in the sample. With light microscopy, 600 nuclei per slide and 3 slides per case were evaluated for Ki-67 expression to minimize tissue-sampling error. Representative images of each slide were transferred to the computer frame by a video camera using the computer-assisted imaging system OPTIMAS 6.2 (Media Cybernetics, Inc.).

¹⁸F-FLT Synthesis and PET Imaging
In accord with the method of Machulla et al. (15), benzoyl-protected anhydrothymidine was used for ¹⁸F-FLT synthesis. Radiosynthesis was performed in a PET tracer synthesizer from nuclear interface. After nucleophilic introduction of ¹⁸F-fluoride accompanied by an anhydro-ring opening, the benzylated intermediate was cleaved using 1% NaOH solution. ¹⁸F-FLT was purified via preparative high-performance liquid chromatography.

¹⁸F-FLT and ¹⁸F-FDG PET examinations were performed on consecutive days within 2 wk before resective surgery or core biopsy. PET was performed using a high-resolution full-ring scanner (ECAT EXACT or ECAT HR+; Siemens/CTI), which produces 47 or 63 contiguous slices per bed position. Axial field of view is 15.5 cm per bed position. Five bed positions were measured for each patient, covering a total field of view of 77.5 cm. The emission scan included the thorax and abdomen for all patients. Patients fasted for at least 6 h before undergoing PET. Static emission scans were obtained 45 min after injection of 265–370 MBq of ¹⁸F-FLT (mean, 334 MBq) or 345–550 MBq of ¹⁸F-FDG (mean, 391 MBq). The acquisition time was 10 min per bed position. Four-minute transmission scans with a ⁶⁸Ge/⁶⁸Ga ring source were obtained for attenuation correction after tracer application. Images were reconstructed using an iterative reconstruction algorithm described by Schmidlin (16).

All images were evaluated by 2 experienced nuclear medicine physicians. For calculation of standardized uptake value (SUV), circular regions of interest were drawn containing the area with focally increased pulmonary ¹⁸F-FLT and ¹⁸F-FDG uptake (lesional diameter at spiral CT, 4–48 mm).

Data Analysis
Data are presented as mean, median, range, and SD. The amount of Ki-67–positive cells and the SUVs for ¹⁸F-FDG and ¹⁸F-FLT were compared using linear regression analysis. Differences were considered statistically significant at P < 0.05. ¹⁸F-FDG and ¹⁸F-FLT uptakes were compared using the Mann–Whitney U test.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
¹⁸F-FDG PET
All malignant lesions except 1 carcinoma in situ (NSCLC, patient 13) showed focally increased and easily detectable ¹⁸F-FDG uptake (Table 1). The mean ¹⁸F-FDG SUV in all visible lesions was 4.1 (median, 4.4; SD, 3.0; range, 1.0–10.6). The mean maximum ¹⁸F-FDG uptake was 6.9 (median, 7.0; SD, 5.8; range, 1.4–22.7).

The mean ¹⁸F-FDG SUV in the 13 patients with NSCLC was 5.6 (median, 5.5; SD, 2.6; range, 1.0–10.6; Fig. 1), and the mean maximum ¹⁸F-FDG SUV was 9.7 (median, 10.1; SD, 5.5; range, 1.4–22.7). Four of the 8 patients with benign lesions presented with focal ¹⁸F-FDG uptake. The reviewers visually interpreted 2 of 8 nodules as malignant. Histopathologic examination revealed unifocal tuberculoma in one patient (patient 21; mean ¹⁸F-FDG SUV, 1.1; maximum ¹⁸F-FDG SUV, 1.8; Fig. 2) and focal bronchiolitis in another patient (patient 19; mean ¹⁸F-FDG SUV, 6.9; maximum ¹⁸F-FDG SUV, 10.3). Inflammatory lesions were suspected in the other 2 patients. Tissue sampling was not performed because clinical follow-up at 3 mo indicated benign lesions (a 1 x 2 cm nodule disappeared on CT performed at the 3-mo follow-up examination, and a 2 x 3 cm nodule decreased to 1 x 1 cm). Mean ¹⁸F-FDG SUVs in these lesions were 2.2 and 3.0, respectively, and maximum ¹⁸F-FDG SUVs were 2.9 and 4.3, respectively.

View larger version (79K): [in this window] [in a new window]   FIGURE 1. Patient 5, with NSCLC in left upper lobe. (A) Transaxial 18F-FLT PET scan demonstrates high 18F-FLT uptake (arrow) in tumor margin. 18F-FLT uptake in vertebral column, scapula, and ribs represents proliferating bone marrow. (B and C) Corresponding 18F-FDG PET and CT scans show high 18F-FDG uptake in tumor margin and primary lung tumor. (D) On Ki-67 immunohistochemistry, Ki-67–positive nuclei (brown) demonstrate high proliferation rate of 54%, and hematoxylin background staining reveals Ki-67–negative nuclei (blue).

View larger version (65K): [in this window] [in a new window]   FIGURE 2. Patient 21, with history of colorectal cancer and suggestive nodule in right middle lobe, for which histopathology revealed solitary tuberculoma. (A) Transaxial 18F-FDG PET scan demonstrates moderate 18F-FDG uptake (arrow) in tumor. (B) No focal tracer accumulation is seen in corresponding 18F-FLT PET scan. (C) Corresponding CT scan shows pulmonary nodule in right middle lobe. (D) On Ki-67 immunohistochemistry, 5% of nuclei show immunoreactivity to Ki-67 antigen.

In pulmonary metastases, the mean ¹⁸F-FLT SUV was 1.1 (median, 1.3; SD, 0.8; range, 0.8–2.1), and the mean maximum ¹⁸F-FLT SUV was 1.6 (median, 1.9; SD, 1.3; range, 1.0–3.4). In the 1 patient with pulmonary metastases from colorectal cancer (patient 15), the metastases showed no ¹⁸F-FLT uptake (Fig. 3). Another patient, with small cell lung cancer (patient 14), showed weak but easily detectable ¹⁸F-FLT uptake (mean ¹⁸F-FLT SUV, 1.7). No benign tumors showed focal ¹⁸F-FLT uptake. Hence, SUV was not determined for these tumors.

View larger version (64K): [in this window] [in a new window]   FIGURE 3. Patient 15, with pulmonary metastases from colorectal cancer. (A) Transaxial 18F-FDG PET scan demonstrates high 18F-FDG uptake (B) in metastatic nodule in right middle lobe. (B) 18F-FLT PET scan shows no tumoral 18F-FLT accumulation. (C) Corresponding CT scan shows pulmonary nodule in right middle lobe. (D) On Ki-67 immunohistochemistry, 12% of nuclei exhibit immunoreactivity to Ki-67–specific antibody MIB-1, indicating low proliferative activity.

Ki-67 Immunohistochemistry
Regional lymph nodes serving as a positive control showed an intense nuclear staining with Ki-67 antibody. In control sections, for which the primary antibody was omitted, no positive nuclear staining was visible.

All malignant tissue specimens contained Ki-67–positive cells. Stained nuclei belonged mainly to epithelial cells, and a very small portion belonged to inflammatory cells. Ki-67 positivity ranged from 1% to 70% of sampled epithelial nucleus profiles (median, 35%). The mean fraction of Ki-67–positive nuclei was 33% (SD, 6.5%). In 6 cases, more than 40% of nuclei showed immunoreactivity for Ki-67 antigen. In NSCLC, the mean proliferation fraction was 37.8% (median, 40%; SD, 19.1%; range, 10%–70%). In pulmonary metastases, the mean proliferative fraction was lower (11.5%; median, 11%; SD, 9%; range, 1%–23%).

Ki-67–positive cells were present in only 1 specimen with benign disease (patient 21, with tuberculoma; Ki-67 index, 5%). Seven benign tissue specimens showed no immunoreactivity to Ki-67 antigen. The range for Ki-67–positive cells was 0%–5%. Ki-67–positive nuclei belonged mainly to inflammatory cells rather than to epithelial cells. The mean of Ki-67–positive cells in benign lesions was 1% (SD, 1.4).

In all lung tumors, linear regression analysis indicated a highly significant correlation between ¹⁸F-FLT SUV and Ki-67 index (P < 0.0001; r = 0.92; Fig. 4). Between Ki-67 and ¹⁸F-FDG SUV, statistical analysis also revealed a significant correlation (P < 0.001; Fig. 4) but a weak correlation coefficient (r = 0.59).

View larger version (10K): [in this window] [in a new window]   FIGURE 4. Linear regression analysis of mean tumoral SUVs of 18F-FLT and 18F-FDG and proliferation fraction (percentage of Ki-67–positive tumor cells). Mean 18F-FLT SUV: significant correlation for P < 0.0001, r = 0.92. Mean 18F-FDG SUV: significant correlation for P < 0.001, r = 0.59.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

Despite high sensitivity, false-positive findings can occur with ¹⁸F-FDG PET, especially in inflammatory lesions (4). Concordantly, focal ¹⁸F-FDG uptake was present in 4 of our study patients with inflammatory or other benign lesions (1 case of bronchiolitis, 1 of tuberculoma, and 2 of undefined benign lung tumors). The relatively high number of false-positive findings in the present series is related to patient selection. Other studies with more patients found specificities averaging 78% for ¹⁸F-FDG PET in detecting lung cancer (3). Recently, unspecific ¹⁸F-FDG uptake has been reported in inflammatory cells such as macrophages (19). Furthermore, many other factors have been reported to influence ¹⁸F-FDG uptake, such as upregulation of glucose transporter 1 receptors (20,21), number of viable tumor cells (22), microvessel density, or hexokinase expression (23). In pancreatic cancer, we previously demonstrated that proliferation was a specific sign for malignancy (5) and clearly differentiated benign from malignant tumors. Therefore, a marker specific for proliferation could reduce false-positive PET findings.

A significant correlation between ¹⁸F-FDG uptake and proliferative activity was also found for breast cancer (24) and NSCLC (7). However, the low correlation coefficient (r = 0.41–0.73) indicated that ¹⁸F-FDG uptake reflects proliferation only in part. In agreement with these findings, the correlation coefficient was as low as 0.59 (r² = 0.35) in our study. That means that only 35% of ¹⁸F-FDG uptake in lung tumors can be explained by proliferative activity.

Various nucleoside analogs have been assessed for imaging proliferation (25–27), but ¹⁸F-FLT is probably the best approach so far. ¹⁸F-FLT turned out to be stable in vivo (12) and accumulates in lung cancer cells in a proliferation-dependent manner (13). Furthermore, thymidine kinase 1 was revealed as the key enzyme responsible for intracellular trapping of ¹⁸F-FLT (28). However, the detailed uptake mechanism is still unknown, and the influence of other factors, such as expression of nucleoside transporters, remains to be determined.

For patients with pulmonary nodules, our data show a highly significant correlation between tumoral ¹⁸F-FLT uptake and proliferative activity as indicated by Ki-67 immunostaining. The correlation coefficient was 0.92 (r² = 0.85). In contrast to the lower correlation coefficient observed for ¹⁸F-FDG, 85% of tracer uptake can be explained by proliferative activity. In agreement with this finding, no ¹⁸F-FLT uptake was visible in nonproliferating tumors. ¹⁸F-FLT PET may therefore be used for the differentiation of benign from malignant lung tumors.

However, 2 patients with NSCLC (1 case of carcinoma in situ and 1 of large cell carcinoma with low proliferative activity), and another patient with pulmonary metastases from colorectal cancer with a proliferation rate of 12%, showed no ¹⁸F-FLT uptake but clear uptake of ¹⁸F-FDG. Compared with ¹⁸F-FDG, ¹⁸F-FLT seems less sensitive for staging disease in patients with malignant lung tumors. Further studies with larger patient populations are needed to determine the diagnostic accuracy of ¹⁸F-FLT PET in detecting malignant tumors.

Several studies have reported that ¹⁸F-FDG PET can be used to assess therapeutic response in various tumors (29–33). A first in vitro study demonstrated that ¹⁸F-FLT uptake in esophageal cancer cells was modified early after incubation with various cytotoxic drugs (34). Hence, ¹⁸F-FLT may be an alternative for therapeutic monitoring. However, for evaluation of ¹⁸F-FLT as a marker for therapy response, large clinical trials are needed.

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
¹⁸F-FLT correlates significantly better with the proliferative activity of lung tumors than does ¹⁸F-FDG. ¹⁸F-FLT may therefore be the superior PET tracer for assessment of therapy response and outcome. Because of 3 false-negative findings in our preliminary study, ¹⁸F-FLT PET may be less adequate than ¹⁸F-FDG for primary staging in patients with known lung cancer but may be more accurate for differentiation of unclear lung lesions.

	FOOTNOTES

 
Received Nov. 27, 2002; revision accepted Feb. 19, 2003.

For correspondence or reprints contact: Andreas K. Buck, MD, Department of Nuclear Medicine, University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.

E-mail: andreas.buck{at}medizin.uni-ulm.de

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 

1. Hicks RJ, Kalff V, MacManus MP, et al. ¹⁸F-FDG PET provides high-impact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer. J Nucl Med. 2001;42:1596–1604.[Abstract/Free Full Text]
2. Kalff VV, Hicks RJ, MacManus M, et al. Clinical impact of (18)F fluorodeoxy-glucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol. 2001;19:111–118.[Abstract/Free Full Text]
3. Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA. 2001;285:914–924.[Abstract/Free Full Text]
4. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics. 1999;19:61–77.[Abstract/Free Full Text]
5. Buck AC, Schirrmeister HH, Guhlmann CA, et al. Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity? J Nucl Med. 2001;42:721–725.[Abstract/Free Full Text]
6. Dosaka-Akita H, Hommura F, Mishina T, et al. A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis. Cancer Res. 2001;61:2500–2504.[Abstract/Free Full Text]
7. Vesselle H, Schmidt RA, Pugsley JM, et al. Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography. Clin Cancer Res. 2000;6:3837–3844.[Abstract/Free Full Text]
8. Higashi K, Ueda Y, Yagishita M, et al. FDG PET measurement of the proliferative potential of non-small cell lung cancer. J Nucl Med. 2000;41:85–92.[Abstract/Free Full Text]
9. Vansteenkiste JF, Stroobants SG, Dupont PJ, et al. Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol. 1999;17:3201–3206.[Abstract/Free Full Text]
10. Mac Manus MP, Hicks RJ, Ball DL, et al. F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment. Cancer. 2001;92:886–895.[Medline]
11. Shields AF, Grierson JR, Kozawa SM, Zheng M. Development of labeled thymidine analogs for imaging tumor proliferation. Nucl Med Biol. 1996;23:17–22.[Medline]
12. Shields AF, Grierson JR, Dohmen BM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998;4:1334–1336.[Medline]
13. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43:1210–1217.[Abstract/Free Full Text]
14. Buck AK, Schirrmeister H, Hetzel M, et al. 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res. 2002;62:3331–3334.[Abstract/Free Full Text]
15. Machulla HJ, Blocher A, Kuntzsch M, et al. Simplified labeling approach for synthesizing 3'-deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT). J Radioanal Nucl Chem. 2000;24:843–846.
16. Schmidlin P. Iterative algorithms for emission tomography [in German]. Nuklearmedizin. 1990;3:155–158.
17. Marom EM, McAdams HP, Erasmus JJ, et al. Staging non-small cell lung cancer with whole-body PET. Radiology. 1999;212:803–809.[Abstract/Free Full Text]
18. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al. Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol. 1998;16:2142–2149.[Abstract]
19. Kubota R, Kubota K, Yamada S, Tada M, Takahashi T, Iwata R. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–112.[Abstract/Free Full Text]
20. Marom EM, Aloia TA, Moore MB, et al. Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer. Lung Cancer. 2001;33:99–107.[Medline]
21. Brown RS, Leung JY, Kison PV, Zasadny KR, Flint A, Wahl RL. Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer. J Nucl Med. 1999;40:556–565.[Abstract/Free Full Text]
22. Kubota K, Ishiwata K, Kubota R, et al. Tracer feasibility for monitoring tumor radiotherapy: a quadruple tracer study with fluorine-18-fluorodeoxyglucose or fluorine-18-fluorodeoxyuridine, L-[methyl-¹⁴C]methionine, [6-³H]thymidine, and gallium-67. J Nucl Med. 1991;32:2118–2123.[Abstract/Free Full Text]
23. Bos R, van Der Hoeven JJ, van Der Wall E, et al. Biologic correlates of (18)fluoro-deoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol. 2002;20:379–387.[Abstract/Free Full Text]
24. Avril N, Menzel M, Dose J, et al. Glucose metabolism of breast cancer assessed by ¹⁸F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med. 2001;42:9–16.[Abstract/Free Full Text]
25. Eary JF, Mankoff DA, Spence AM, et al. 2-[C-11]thymidine imaging of malignant brain tumors. Cancer Res. 1999;59:615–621.[Abstract/Free Full Text]
26. Conti PS, Alauddin MM, Fissekis JR, Schmall B, Watanabe KA. Synthesis of 2'-fluoro-5-[¹¹C]-methyl-1-beta-D-arabinofuranosyluracil ([¹¹C]-FMAU): a potential nucleoside analog for in vivo study of cellular proliferation with PET. Nucl Med Biol. 1995;22:783–789.[Medline]
27. Blasberg RG, Roelcke U, Weinreich R, et al. Imaging brain tumor proliferative activity with [¹²⁴I]iododeoxyuridine. Cancer Res. 2000;60:624–635.[Abstract/Free Full Text]
28. Mier W, Haberkorn U, Eisenhut M. [¹⁸F]FLT: portrait of a proliferation marker. Eur J Nucl Med Mol Imaging. 2002;29:165–169.[Medline]
29. Hoekstra CJ, Hoekstra OS, Stroobants SG, et al. Methods to monitor response to chemotherapy in non-small cell lung cancer with ¹⁸F-FDG PET. J Nucl Med. 2002;43:1304–1309.[Abstract/Free Full Text]
30. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2002;13:1356–1363.[Abstract/Free Full Text]
31. Flamen P, Van Cutsem E, Lerut A, et al. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 2002;13:361–368.[Abstract/Free Full Text]
32. Spence AM, Muzi M, Graham MM, et al. 2-[(18)F]Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome. Clin Cancer Res. 2002;8:971–979.[Abstract/Free Full Text]
33. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol. 2001;19:3058–3065.[Abstract/Free Full Text]
34. Dittmann H, Dohmen BM, Kehlbach R, et al. Early changes in [(18)F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging. 2002;29:1462–1469.[Medline]

This article has been cited by other articles:

				F. Eckel, K. Herrmann, S. Schmidt, C. Hillerer, H. A. Wieder, B.-J. Krause, T. Schuster, R. Langer, H.-J. Wester, R. M. Schmid, et al. Imaging of Proliferation in Hepatocellular Carcinoma with the In Vivo Marker 18F-Fluorothymidine J. Nucl. Med., September 1, 2009; 50(9): 1441 - 1447. [Abstract] [Full Text] [PDF]

				D. Y. Lee and K. C. P. Li Systems Diagnostics: The Systems Approach to Molecular Imaging Am. J. Roentgenol., August 1, 2009; 193(2): 287 - 294. [Abstract] [Full Text] [PDF]

				L. Brepoels, S. Stroobants, G. Verhoef, T. De Groot, L. Mortelmans, and C. De Wolf-Peeters 18F-FDG and 18F-FLT Uptake Early After Cyclophosphamide and mTOR Inhibition in an Experimental Lymphoma Model J. Nucl. Med., July 1, 2009; 50(7): 1102 - 1109. [Abstract] [Full Text] [PDF]

				H.-J. Sohn, Y.-J. Yang, J.-S. Ryu, S. J. Oh, K. C. Im, D. H. Moon, D. H. Lee, C. Suh, J.-S. Lee, and S.-W. Kim [18F]Fluorothymidine Positron Emission Tomography before and 7 Days after Gefitinib Treatment Predicts Response in Patients with Advanced Adenocarcinoma of the Lung Clin. Cancer Res., November 15, 2008; 14(22): 7423 - 7429. [Abstract] [Full Text] [PDF]

				J. Leyton, G. Smith, M. Lees, M. Perumal, Q.-d. Nguyen, F. I. Aigbirhio, O. Golovko, Q. He, P. Workman, and E. O. Aboagye Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901 Mol. Cancer Ther., September 1, 2008; 7(9): 3112 - 3121. [Abstract] [Full Text] [PDF]

				K. Herrmann, F. Eckel, S. Schmidt, K. Scheidhauer, B. J. Krause, J. Kleeff, T. Schuster, H.-J. Wester, H. Friess, R. M. Schmid, et al. In Vivo Characterization of Proliferation for Discriminating Cancer from Pancreatic Pseudotumors J. Nucl. Med., September 1, 2008; 49(9): 1437 - 1444. [Abstract] [Full Text] [PDF]

				J. R. Bading and A. F. Shields Imaging of Cell Proliferation: Status and Prospects J. Nucl. Med., June 1, 2008; 49(Suppl_2): 64S - 80S. [Abstract] [Full Text] [PDF]

				A. K. Buck, K. Herrmann, C. M. z. Buschenfelde, M. E. Juweid, M. Bischoff, G. Glatting, G. Weirich, P. Moller, H.-J. Wester, K. Scheidhauer, et al. Imaging Bone and Soft Tissue Tumors with the Proliferation Marker [18F]Fluorodeoxythymidine Clin. Cancer Res., May 15, 2008; 14(10): 2970 - 2977. [Abstract] [Full Text] [PDF]

				R. Ullrich, H. Backes, H. Li, L. Kracht, H. Miletic, K. Kesper, B. Neumaier, W.-D. Heiss, K. Wienhard, and A. H. Jacobs Glioma Proliferation as Assessed by 3'-Fluoro-3'-Deoxy-L-Thymidine Positron Emission Tomography in Patients with Newly Diagnosed High-Grade Glioma Clin. Cancer Res., April 1, 2008; 14(7): 2049 - 2055. [Abstract] [Full Text] [PDF]

				J. Tian, X. Yang, L. Yu, P. Chen, J. Xin, L. Ma, H. Feng, Y. Tan, Z. Zhao, and W. Wu A Multicenter Clinical Trial on the Diagnostic Value of Dual-Tracer PET/CT in Pulmonary Lesions Using 3'-Deoxy-3'-18F-Fluorothymidine and 18F-FDG J. Nucl. Med., February 1, 2008; 49(2): 186 - 194. [Abstract] [Full Text] [PDF]

				K. Herrmann, K. Ott, A. K. Buck, F. Lordick, D. Wilhelm, M. Souvatzoglou, K. Becker, T. Schuster, H.-J. Wester, J. R. Siewert, et al. Imaging Gastric Cancer with PET and the Radiotracers 18F-FLT and 18F-FDG: A Comparative Analysis J. Nucl. Med., December 1, 2007; 48(12): 1945 - 1950. [Abstract] [Full Text] [PDF]

				D. J. A. Margolis, J. M. Hoffman, R. J. Herfkens, R. B. Jeffrey, A. Quon, and S. S. Gambhir Molecular Imaging Techniques in Body Imaging Radiology, November 1, 2007; 245(2): 333 - 356. [Abstract] [Full Text] [PDF]

				W. Chen, S. Delaloye, D. H.S. Silverman, C. Geist, J. Czernin, J. Sayre, N. Satyamurthy, W. Pope, A. Lai, M. E. Phelps, et al. Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study J. Clin. Oncol., October 20, 2007; 25(30): 4714 - 4721. [Abstract] [Full Text] [PDF]

				W. Chen Clinical Applications of PET in Brain Tumors J. Nucl. Med., September 1, 2007; 48(9): 1468 - 1481. [Abstract] [Full Text] [PDF]

				H.-J. Wester Nuclear Imaging Probes: from Bench to Bedside Clin. Cancer Res., June 15, 2007; 13(12): 3470 - 3481. [Abstract] [Full Text] [PDF]

				K. Herrmann, H. A. Wieder, A. K. Buck, M. Schoffel, B.-J. Krause, F. Fend, T. Schuster, C. Meyer zum Buschenfelde, H.-J. Wester, J. Duyster, et al. Early Response Assessment Using 3'-Deoxy-3'-[18F]Fluorothymidine-Positron Emission Tomography in High-Grade Non-Hodgkin's Lymphoma Clin. Cancer Res., June 15, 2007; 13(12): 3552 - 3558. [Abstract] [Full Text] [PDF]

				E. G.C. Troost, W. V. Vogel, M. A.W. Merkx, P. J. Slootweg, H. A.M. Marres, W. J.M. Peeters, J. Bussink, A. J. van der Kogel, W. J.G. Oyen, and J. H.A.M. Kaanders 18F-FLT PET Does Not Discriminate Between Reactive and Metastatic Lymph Nodes in Primary Head and Neck Cancer Patients J. Nucl. Med., May 1, 2007; 48(5): 726 - 735. [Abstract] [Full Text] [PDF]

				T. M. Blodgett, C. C. Meltzer, and D. W. Townsend PET/CT: Form and Function Radiology, February 1, 2007; 242(2): 360 - 385. [Abstract] [Full Text] [PDF]

				J. Leyton, J. P. Alao, M. Da Costa, A. V. Stavropoulou, J. R. Latigo, M. Perumal, R. Pillai, Q. He, P. Atadja, E. W.-F. Lam, et al. In vivo Biological Activity of the Histone Deacetylase Inhibitor LAQ824 Is detectable with 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography. Cancer Res., August 1, 2006; 66(15): 7621 - 7629. [Abstract] [Full Text] [PDF]

				S. Apisarnthanarax, M. M. Alauddin, F. Mourtada, H. Ariga, U. Raju, O. Mawlawi, D. Han, W. G. Bornmann, J. A. Ajani, L. Milas, et al. Early Detection of Chemoradioresponse in Esophageal Carcinoma by 3'-Deoxy-3'-3H-Fluorothymidine Using Preclinical Tumor Models Clin. Cancer Res., August 1, 2006; 12(15): 4590 - 4597. [Abstract] [Full Text] [PDF]

				P. Workman, E. O. Aboagye, Y.-L. Chung, J. R. Griffiths, R. Hart, M. O. Leach, R. J. Maxwell, P. M. J. McSheehy, P. M. Price, and J. Zweit Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst, May 3, 2006; 98(9): 580 - 598. [Abstract] [Full Text] [PDF]

				C. S. Yap, J. Czernin, M. C. Fishbein, R. B. Cameron, C. Schiepers, M. E. Phelps, and W. A. Weber Evaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F- Fluorodeoxyglucose-Positron Emission Tomography. Chest, February 1, 2006; 129(2): 393 - 401. [Abstract] [Full Text] [PDF]

				L. M. Kenny, D. M. Vigushin, A. Al-Nahhas, S. Osman, S. K. Luthra, S. Shousha, R. C. Coombes, and E. O. Aboagye Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [18F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods Cancer Res., November 1, 2005; 65(21): 10104 - 10112. [Abstract] [Full Text] [PDF]

				A Saleem Potential of PET in oncology and radiotherapy Br. J. Radiol., November 1, 2005; Supplement_28(1): 6 - 16. [Full Text] [PDF]

				M. E. Juweid and B. D. Cheson Role of Positron Emission Tomography in Lymphoma J. Clin. Oncol., July 20, 2005; 23(21): 4577 - 4580. [Full Text] [PDF]

				W. Chen, T. Cloughesy, N. Kamdar, N. Satyamurthy, M. Bergsneider, L. Liau, P. Mischel, J. Czernin, M. E. Phelps, and D. H.S. Silverman Imaging Proliferation in Brain Tumors with 18F-FLT PET: Comparison with 18F-FDG J. Nucl. Med., June 1, 2005; 46(6): 945 - 952. [Abstract] [Full Text] [PDF]

				D. R. Aberle, C. Chiles, C. Gatsonis, B. J. Hillman, C. D. Johnson, B. L. McClennan, D. G. Mitchell, E. D. Pisano, M. D. Schnall, and A. G. Sorensen Imaging and Cancer: Research Strategy of the American College of Radiology Imaging Network Radiology, June 1, 2005; 235(3): 741 - 751. [Abstract] [Full Text] [PDF]

				J. Leyton, J. R. Latigo, M. Perumal, H. Dhaliwal, Q. He, and E. O. Aboagye Early Detection of Tumor Response to Chemotherapy by 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography: The Effect of Cisplatin on a Fibrosarcoma Tumor Model In vivo Cancer Res., May 15, 2005; 65(10): 4202 - 4210. [Abstract] [Full Text] [PDF]

				H. L. van Westreenen, D. C.P. Cobben, P. L. Jager, H. M. van Dullemen, J. Wesseling, P. H. Elsinga, and J. Th. Plukker Comparison of 18F-FLT PET and 18F-FDG PET in Esophageal Cancer J. Nucl. Med., March 1, 2005; 46(3): 400 - 404. [Abstract] [Full Text] [PDF]

				M. Muzi, H. Vesselle, J. R. Grierson, D. A. Mankoff, R. A. Schmidt, L. Peterson, J. M. Wells, and K. A. Krohn Kinetic Analysis of 3'-Deoxy-3'-Fluorothymidine PET Studies: Validation Studies in Patients with Lung Cancer J. Nucl. Med., February 1, 2005; 46(2): 274 - 282. [Abstract] [Full Text] [PDF]

				C. Waldherr, I. K. Mellinghoff, C. Tran, B. S. Halpern, N. Rozengurt, A. Safaei, W. A. Weber, D. Stout, N. Satyamurthy, J. Barrio, et al. Monitoring Antiproliferative Responses to Kinase Inhibitor Therapy in Mice with 3'-Deoxy-3'-18F-Fluorothymidine PET J. Nucl. Med., January 1, 2005; 46(1): 114 - 120. [Abstract] [Full Text] [PDF]

				F. C. Detterbeck, J. F. Vansteenkiste, D. E. Morris, C. A. Dooms, A. H. Khandani, and M. A. Socinski Seeking a Home for a PET, Part 3: Emerging Applications of Positron Emission Tomography Imaging in the Management of Patients With Lung Cancer Chest, November 1, 2004; 126(5): 1656 - 1666. [Abstract] [Full Text] [PDF]

				L. Schrevens, N. Lorent, C. Dooms, and J. Vansteenkiste The Role of PET Scan in Diagnosis, Staging, and Management of Non-Small Cell Lung Cancer Oncologist, November 1, 2004; 9(6): 633 - 643. [Abstract] [Full Text] [PDF]

				D. C.P. Cobben, P. H. Elsinga, H. J. Hoekstra, A. J.H. Suurmeijer, W. Vaalburg, B. Maas, P. L. Jager, and H. M.J. Groen Is 18F-3'-Fluoro-3'-Deoxy-L-Thymidine Useful for the Staging and Restaging of Non-Small Cell Lung Cancer? J. Nucl. Med., October 1, 2004; 45(10): 1677 - 1682. [Abstract] [Full Text] [PDF]

				M. Sugiyama, H. Sakahara, K. Sato, N. Harada, D. Fukumoto, T. Kakiuchi, T. Hirano, E. Kohno, and H. Tsukada Evaluation of 3'-Deoxy-3'-18F-Fluorothymidine for Monitoring Tumor Response to Radiotherapy and Photodynamic Therapy in Mice J. Nucl. Med., October 1, 2004; 45(10): 1754 - 1758. [Abstract] [Full Text] [PDF]

				M. Torabi, S. L. Aquino, and M. G. Harisinghani Current Concepts in Lymph Node Imaging J. Nucl. Med., September 1, 2004; 45(9): 1509 - 1518. [Abstract] [Full Text] [PDF]

				A. K. Buck, G. Glatting, and S. N. Reske Quantification of 18F-FDG Uptake in Non-Small Cell Lung Cancer: A Feasible Prognostic Marker? J. Nucl. Med., August 1, 2004; 45(8): 1274 - 1276. [Full Text] [PDF]

				G J R Cook Oncological molecular imaging: nuclear medicine techniques Br. J. Radiol., December 1, 2003; 76(suppl_2): S152 - S158. [Full Text] [PDF]

				A. F. Shields PET Imaging with 18F-FLT and Thymidine Analogs: Promise and Pitfalls J. Nucl. Med., September 1, 2003; 44(9): 1432 - 1434. [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buck, A. K. Articles by Hetzel, M. Search for Related Content PubMed PubMed Citation Articles by Buck, A. K. Articles by Hetzel, M.