| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Departments of Radiology (Division of Nuclear Medicine) [H. V., J. G., M. M., J. M. P., L. M. P.], Pathology [R. A. S., P. R.], and Surgery (Division of Thoracic Surgery) [E. V., D. E. W.], University of Washington, Seattle, Washington 98195
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
Experimental Design: Ten patients with 11 biopsy-proven or clinically suspected NSCLC underwent 2-h dynamic PET imaging after i.v. injection of 0.07 mCi/kg FLT. Tumor FLT uptake was quantitated with the maximum pixel standardized uptake value (maxSUV), the partial volume corrected maxSUV (PV-corr-maxSUV), the average SUV over a small region-of-interest (aveSUV) and with Patlak analysis of FLT flux (aveFLTflux). The lesion diameter from computed tomography was used to correct the maxSUV for PV effects using recovery coefficients determined for the General Electric Advance PET scanner. Two of the 11 lesions were benign inflammatory lesions and 9 were NSCLCs. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all 11 tissue specimens (10 resections, 1 NSCLC percutaneous biopsy), and the S-phase fraction (SPF) from flow cytometry could be determined for 10. The specimens were reviewed for histology and cellular differentiation (poor, moderate, well). Lesions ranged from 1.6 to 7.7 cm.
Results: Excellent correlations were found between SUV measures of FLT uptake and Ki-67 scores [percentage of positive cells; maxSUV versus Ki-67: Rho = 0.78, P = 0.0043 (n = 11); PV-corr-maxSUV versus Ki-67: Rho = 0.83, P = 0.0028 (n = 10); aveSUV versus Ki-67: Rho = 0.84, P = 0.0011 (n = 11)]. Correlation between Ki-67 proliferation scores and Patlak measures of FLT uptake were also strong: aveFLTflux versus Ki-67: Rho = 0.94, P < 0.0001 (n = 11). The correlation between the SPF and all indices of FLT uptake was weaker and reached statistical significance for only two uptake indices [maxSUV versus SPF: Rho = 0.69, P = 0.03 (n = 10); PV-corr-maxSUV versus SPF: Rho = 0.36, P = 0.35 (n = 9); aveSUV versus SPF: Rho = 0.67, P = 0.03 (n = 10); aveFLTflux versus SPF: Rho = 0.46, P = 0.18 (n = 10)].
Conclusion: FLT PET may be used to noninvasively assess proliferation rates of lung masses in vivo. Therefore, FLT PET may play a significant role in the evaluation of indeterminate pulmonary lesions, in the prognostic assessment of resectable NSCLC, and possibly in the evaluation of NSCLC response to chemotherapy.
|
Introduction |
|---|
|
TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
Present methods to assess tumor proliferation require a tissue sample and are, thus, limited by potential morbidity and sampling problems. A noninvasive method to assess proliferation might avoid unnecessary diagnostic biopsies of lung lesions and permit serial assessments during cancer therapy. Hence, extensive investigation has been made into evaluating tumor proliferation noninvasively by PET (18, 19, 20, 21, 22, 23, 24) . Besides being noninvasive, PET imaging permits the evaluation of a tumor in its entirety, overcoming issues of heterogeneity and tumor sampling errors, and can easily be repeated at any point during treatment. Extensive work has been done at our institution and at others in the development and characterization of [11C]thymidine for PET imaging (18, 19, 20, 21, 22, 23, 24) . However, the short half-life of the 11C label (20 min) together with the creation of labeled metabolites in the blood, which requires the use of compartment models for image interpretation, have limited the routine use of [11C]thymidine PET imaging. To overcome these limitations, other potential tracers of proliferation such as 2'-[18F]fluoro-5-methyl-1-ß-D-arabinofuranosyluracil and [124I]iododeoxyuridine have been investigated (25, 26, 27, 28) . Our group has investigated the radiotracer FLT (the abbreviation used for "3'-deoxy-3'-[18F]fluorothymidine" in this article; Refs. 29, 30, 31, 32, 33, 34 ). FLT undergoes the same first metabolic step as thymidine and is monophosphorylated by thymidine kinase-1, an enzyme expressed during the DNA synthesis phase of the cell cycle (35, 36, 37, 38, 39) . FLT monophosphate then accumulates in cells and is unable to cross the cell membrane (34) . As a PET imaging tracer, FLT accumulates in cells as though it were incorporated into DNA (31 , 36 , 37 , 40) . Recent tumor cell studies performed at our institution have also demonstrated that when growth-arrested A549 human lung cancer cells were allowed to grow in fresh medium, FLT uptake in these cells increased steadily with times later than 6 h and correlated well with the percentage of cells in S phase (r2 = 0.91; Ref. 32 ). On the basis of this lung cancer cell line evidence, we evaluated [18F]FLT in human lung masses to explore its potential as a proliferation tracer for PET imaging. Our hypothesis was that the proliferation rate of human lung tumors as expressed by their Ki-67 immunohistochemistry score and SPF could be predicted in vivo by the accumulation of the radiolabeled FLT using PET (41) .
|
Patients and Methods |
|---|
|
TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
FLT Synthesis
FLT was prepared according to the method developed by Grierson (29)
. FLT specific activity was greater than 1 Ci/µmol, decay corrected to the end of cyclotron bombardment. FLT was administered to patients by i.v. injection [10-ml solution of isotonic saline containing less than 10% (v/v) ethanol (USP)]. Calculation of doses was based on the patient’s weight (0.07 mCi/kg), with a 5-mCi maximum dose. Before administration of each dose, quality control testing for pH (pH 7 ± 1) and radiochemical purity (>99%, high-performance liquid chromatography, thin-layer chromatography) was insured. All of the doses administered were also shown to be endotoxin free (<0.4 EU/ml, Limulus Amebocpe Lysis, Cape Cod Inc., Woods Hole, MA test). Sterility testing for anaerobic and aerobic bacterial contamination was performed on all of the batch dose samples, after radioactive decay (24 h).
FLT PET Imaging
Imaging.
All of the PET studies were performed on a GE Advance PET Tomograph (GE Medical Systems, Waukesha, WI). FLT imaging was performed to quantitate FLT uptake as a proposed noninvasive measure of the primary tumor proliferation rate. No preparation was asked of the patients before tracer administration. After informed consent was obtained, two i.v. catheters or an i.v. and an intra-arterial catheter were placed in opposite arms. The tracer was administered through the first venous catheter, the other catheter (venous or radial arterial) was used for blood sampling. Arterial sampling was performed with an automated sampler described previously (42)
. Venous sampling was performed manually. Patients were placed supine in the scanner with the lung lesion and at least a portion of the left ventricular blood pool positioned to fit within the 15-cm wide tomograph field-of-view. Imaging started with a 20–25-min long transmission scan, performed over the selected field-of-view. Subsequently, a [F-18]FLT dose of 0.07mCi/kilogram of patient weight (not to exceed 5.0 mCi) was infused i.v. over one min using a Harvard pump (Harvard Clinical Technology, Inc., Boston, MA). A 2-h long dynamic emission scan was performed over the selected thoracic field-of-view starting 1 min before tracer infusion. Two separate dynamic imaging sequences were used: a single-field or a two-fields-of-view sequence. The imaging sequence for a single-field-of-view protocol was as follows: 8 15-s, 4 30-s, 6 1-min, 2 5-min, and 10 10-min imaging intervals. The imaging sequence for a two-fields-of-view (FOV1 and FOV2) protocol was as follows: FOV1: 4 25-s, 3 50-s, 3 2-min, and 10 5-min imaging intervals; FOV2: four 25-s, three 50-s, three 2-min, and nine 5-min imaging intervals. FOV1 and FOV2 imaging was interleaved from the start of imaging, and 15-s intervals were allowed for the table to move between the two fields-of-view. This allowed us to quantitate tracer uptake in the primary tumor (FOV1) and within another selected region (FOV2) for dosimetry studies.
All of the studies were collected in a two-dimensional imaging mode with scatter septae in place. Real-time randoms correction using counts obtained with a delayed coincidence window and deconvolution-based scatter corrections supplied by the manufacturer were applied. The raw PET data were reconstructed using the standard filtered back projection available on the GE Advance PET system. The following reconstruction parameters were used: 12-mm Hanning filter, 55-cm image diameter, and 128 x 128-array size.
Quantitative Imaging Analysis.
Both the SUV and the FLT flux determined by Patlak analysis were used to quantitate tumor FLT uptake.
SUV.
The SUV is defined as the time-averaged tissue activity C (µCi/ml), over an imaging time interval after injection, divided by the injected dose ID (mCi)/kg of patient body weight:
 |
50% of the maximum pixel value (ROI2). An aveSUV was defined by averaging the pixel SUV values within ROI2 for the images acquired between 30 and 60 min. We, therefore, investigated two separate definitions of the SUV: the maximum pixel SUV and an aveSUV over the 30–60 min imaging interval after FLT injection.
The maxSUV data were corrected for partial volume effects, based on the average diameter of the tumor (recovery coefficients). The average diameter of each lesion was calculated by averaging all three of the lesion dimensions measured from the mediastinal windows of the CT scan. The recovery coefficients have been estimated based on lesion diameter from phantom measurements performed in the GE Advance tomograph (43)
. These recovery coefficients (Fig. 1)
have been calculated for the image reconstruction parameters and the filter used in imaging of NSCLC patients. These coefficients have been previously used by our group to correct the maximal pixel FDG-SUV of NSCLCs (44)
. For all of the lesions, these recovery coefficients (RC) were applied to the difference between lesion and normal lung background activities as defined by Eq. B. The aveSUV was not corrected for partial volume effects because of the difficulty in measuring the exact size of the ROI selected for averaging (ROI2) and the resulting inaccuracy in the recovery coefficient to be used.
|
.
 |
Patlak Analysis of FLT Flux.
For each time frame of the dynamic imaging sequence, the pixels within ROI2 over the lesion were averaged, and the resulting set of dynamic values was analyzed by the graphical analysis method of Patlak et al. (45)
to calculate the aveFLTflux. In this analysis, the tissue activity normalized to the FLT blood activity at each time point [Ctis(t)/CbFLT(t)] is plotted against the normalized integral blood activity [
0t Cbtotal/CbFLT(t)]. The slope of the early linear portion of the curve (15–45 min) is an estimation of the flux of FLT.
Surgery and Pathology
Ten of 11 lung lesions were surgically resected after FLT PET imaging. One patient who had undergone a core biopsy of his primary NSCLC did not undergo a primary resection because a microscopic focus of tumor was discovered in a mediastinal lymph node at mediastinoscopy. He was instead administered neo-adjuvant chemoradiotherapy before subsequent resection. One patient had two histologically different primary NSCLCs resected, one from each lung and at two different surgeries. This patient’s two lesions were imaged at the same time within a single PET field-of-view. Eleven histological specimens were available for pathological, immunohistochemical, and flow cytometric evaluation. All of the tumor specimens were reviewed by a pathologist (R. A. S.) to assess tumor type and differentiation (poor, moderate, or well-differentiated).
Ki-67 Immunohistochemistry.
A representative formalin-fixed, paraffin-embedded section from each specimen was labeled using monoclonal antibody MIB-1 (Immunotech, Westbrook, ME; 1:100) after microwave antigen retrieval in citrate buffer. Antibody binding was detected using the Vectra Elite kit with FeCl3 intensification and hematoxylin counterstain. MIB-1 recognizes the Ki-67 antigen, a Mr 345,000 and 395,000 nuclear protein common to proliferating human cells (46)
. The fraction of labeled tumor cells (Ki-67 score) was assessed over a x4 microscopic field (3-mm diameter) in the field that contained the highest average fraction of labeled cells. The pathologist scoring the immunohistochemical data (R. A. S.) was blinded to the FLT PET results. This same immunohistochemistry method was used and reported previously by our group (44)
.
Flow Cytometry.
To provide for a meaningful comparison of SPF and Ki-67 scores, the area of a tumor selected and scored for Ki-67 immunohistochemistry was marked on the MIB-1 stained slide. This mark was then used to orient the paraffin tumor block so that two 60-µm thick slices of the block could be recut for processing by the flow cytometry laboratory (P. R.). This slice thickness was selected to provide enough nuclei for this analysis. The nuclei of the two slices corresponding to the area marked on the immunohistochemistry slide were evaluated by flow cytometry. An attempt was made to stain the sample with a cytokeratin-specific antibody to selectively evaluate the epithelial component of the tumor. The SPF of the lesion was determined by cytokeratin-gated flow cytometry on all cellular components of the sample. All of the flow cytometry data were reviewed by a pathologist specialized in interpreting them (P. R.).
Statistical Analysis
Because the Ki-67 scores and SPFs are values ranging between 0 and 100%, and not normally distributed, the nonparametric Spearman rank test was used to evaluate their correlation with tumor FLT uptake.
|
Results |
|---|
|
TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
. Fig. 2
illustrates the relative uptake at FLT PET imaging of four representative lesions spanning the range of proliferation rates.
|
|
Ki-67 scores, the percentage of cells positive for the MIB-1 antibody, were measured for all 11 lesion specimens. A strong correlation is found between all three SUV-based definitions of FLT uptake (maxSUV, PV-corr-maxSUV, aveSUV) and the Ki-67 score of lesions (Figs. 3
, 4
, and 5
): maxSUV versus Ki-67: Rho = 0.78, P = 0.0043 (n = 11); PV-corr-maxSUV versus Ki-67: Rho = 0.83, P = 0.0028 (n = 10); aveSUV versus Ki-67: Rho = 0.84, P = 0.0011 (n = 11).
|
|
|
.
|
Cytokeratin-gated flow cytometry was attempted on all of the specimens, but only two of them resulted in a positive stain with the ability of gating the SPF calculation on the epithelial population of cells within each lesion. The results reported here represent the SPF of all of the cells within the lung tumors. One specimen obtained by core biopsy provided insufficient material left for flow cytometry after Ki-67 processing of the tissue block. Therefore, only 10 lesions had SPF determination. The correlations between the SPF and all of the indices of FLT uptake were weaker and reached statistical significance for only two uptake indices: maxSUV versus SPF: Rho = 0.69, P = 0.03, (n = 10); PV-corr-maxSUV versus SPF: Rho = 0.36, P = 0.35, (n = 9); aveSUV versus SPF: Rho = 0.67, P = 0.03, (n = 10); aveFLTflux versus SPF: Rho = 0.46, P = 0.18, (n = 10).
A modest correlation that did not reach statistical significance was found between Ki-67 scores and SPFs: Rho = 0.45, P = 0.19, n = 10.
No statistically significant correlation was found between tumor size and Ki-67 score (Rho = 0.07, P = 0.83, n = 11 lesions) or SPF of the tumor (Rho = 0.098, P = 0.79, n = 10 lesions).
|
Discussion |
|---|
|
TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
Static (SUV) and dynamic (Patlak flux) imaging measures of tumor FLT uptake were assessed in this study. These methods differ greatly in the complexity of their data acquisition and analysis. We evaluated tumors with 2-h long dynamic imaging to compare simple static SUV measures of FLT uptake with the more complicated FLT flux determination in their potential correlation with tissue proliferation markers. We evaluated FLT uptake from static imaging data (SUV) for the following reasons: (a) for FLT uptake to have widespread clinical application as a noninvasive means of grading tumor proliferation, it needs to be easy to perform without requiring dynamic imaging; (b) shorter imaging protocols for SUV static imaging help maximize patient enrollment and compliance with the imaging protocol. We also quantitated FLT uptake with a Patlak determination of FLT flux from complete dynamic data to assess the incremental benefit gained from a more extensive imaging and analysis approach.
Tumor proliferative rates may be estimated in human tumor samples by mitotic figure counting, immunohistochemical detection of cell cycle-specific proteins (Ki-67 and PCNA), and the SPF determination from DNA flow cytometry. However, mitotic figure counting is affected by interobserver reproducibility problems, use of mitotic indices versus mitoses per area, time between tumor resection and fixation, and the laborious nature of the analysis. The staining process for proliferating cell nuclear antigen with the PC10 antibody has the disadvantages of being sensitive to variations in the fixation technique, and, moreover, the microwave treatment in the staining process can cause nonproliferating cells to become stained (51 , 52) . In addition, the PCNA protein has a long half-life in cells and can be present after the proliferation phase has been completed (53) . Consequently, quiescent cells can stain positive for PCNA.
Evaluating the expression of the Ki-67 protein in cells can also assess cell proliferation. Ki-67 is a protein expressed only in proliferating cells. The protein is present in the S phase and in G2 and M phases of the cell cycle, as well as in the proliferation-associated part of G1, but not in G0 (54) . Ki-67 has been shown to be required for cellular proliferation (55) , to be synthesized as a cell begins proliferation, and to be efficiently degraded at the end of the proliferative cycle (reviewed in Ref. 56 ). Ki-67 protein expression is strictly correlated with cell proliferation and with the active phases of the cell cycle (56) . Dependent on the cell proliferation cycle phase, the cellular level of the Ki-67 protein varies; however, detection by an antibody to Ki-67 is possible during the entire life of the protein. Cellular proliferation assessment with Ki-67 measures a tumor-growth parameter that is distinct from both PCNA and flow cytometry (57) . Two antibodies against the Ki-67 protein, the Ki-67 antibody and MIB-1, are available for use in immunohistochemical assays. MIB-1 is a more recent discovery and can be used with formalin-fixed paraffin-embedded tissue sections, whereas the Ki-67 antibody can be used only with fresh or frozen tissue (58) . Thus, MIB-1 is more versatile because fresh tissue is not available for retrospective studies and because paraffin embedding is the most common tissue preservation technique used in clinical settings. The selection of the Ki-67 marker as a tissue correlate for tumor FLT uptake was made in consideration of: (a) the versatility of the MIB-1 antibody; (b) the inherent limitations of the mitotic index and PCNA; (c) the ease with which expression of cell cycle-specific proteins, such as the Ki-67-related antigen, can be assessed semiquantitatively. Another argument for selecting the Ki-67 proliferation score is that it has been shown to have prognostic significance in NSCLC and several other tumor types as reviewed by Scholzen and Gerdes (56) . We found excellent correlations between all of the indices of FLT uptake that we calculated and the Ki-67 score of tumors assessed by MIB-1 immunohistochemistry.
DNA flow cytometry is complicated by technical difficulties in obtaining nuclei for analysis, multiple cell populations in the tumor sample in which the cell cycle compartments may be inextricably intermixed, and various methods for calculating SPFs. However, SPF is a well-accepted standard in cell culture experiments, and such experiments performed at our institution have revealed a correlation between FLT uptake and SPF in A549 human lung cancer cells (32) . Another group recently reported a correlation between FLT uptake of several asynchronously growing human tumor cell lines and their SPFs (59) . As stated above, flow cytometry measures a tumor growth parameter that is distinct from Ki-67 (57) . For these reasons, we also evaluated tumor proliferation using flow cytometry. When compared with the strong correlations found between FLT uptake and Ki-67 scores, we found more modest correlations between indices of FLT uptake and the SPF. The lack of statistical significance in the correlation between the SPF and the PV-corr-maxSUV or the FLT flux likely stems from the more limited number of samples. The correlation between SPF and FLT uptake is probably weaker because, contrary to the Ki-67 antigen, the SPF describes cells only in S phase, rather than the total non-G0 compartment. It is known that the uptake of FLT is tightly linked to TK1 enzyme activity (33) . In cycling cells, TK1 expression increases in late G1, then significantly increases throughout S phase and G2, reaching maximum levels during mitosis (60) . Therefore, the SPF is unlikely to be an optimal proliferation index for correlation with TK1 activity or FLT uptake. This is corroborated by the results of Rasey et al. (33) who showed that growth-arrested A549 cells stimulated to grow in fresh medium, demonstrated increased FLT uptake and increased TK1 activity with essentially no movement of cells from G1 into S phase after 12–14 h. This was reported to be consistent with an increase in TK1 activity in late G1 before DNA synthesis and is also consistent with a slightly better correlation of FLT uptake with TK1 activity than with SPF. In their study, FLT uptake, TK1 activity, and SPF peaked by 24–28 h. In other words, in a cell population, FLT uptake may be indicative of cells preparing to divide as well as of cells dividing and of cells synthesizing DNA.
Human solid tumors are composed of asynchronous cell populations, and the determination of an SPF in such cell lines may underestimate the percentage of cells involved in proliferation. In addition, the temporal relationship between TK1 expression and SPF may vary between the different cell lines contributing to a weaker correlation of FLT uptake with SPF.
A modest correlation was found between the Ki-67 score and SPF of the lesions in our series (Rho = 0.45, P = 0.19). This is in keeping with the correlations reported in the literature for different proliferation indices.
With four different methods of evaluating FLT uptake (maxSUV, PV-corr-maxSUV, aveSUV, and aveFLTflux) we found a strong correlation between FLT uptake and the Ki-67 score. This suggests that the correlation between FLT uptake and the Ki-67 proliferative index is robust.
No statistically significant correlation was found in our series between the size of a lesion and its Ki-67 score or SPF. This would be expected because the size of a lesion represents a single time point measurement during its growth and does not reflect its growth rate as a proliferation score can.
In conclusion, this preliminary investigation demonstrates that FLT uptake in lung lesions correlates with the proliferation rate of such lesions assessed by Ki-67 immunohistochemistry and to a lesser extent with their SPF. This was demonstrated after quantifying FLT uptake either with simple static imaging uptake indices, such as SUVs over 30–60 min, or with more elaborate uptake values such as the FLT flux determined from a Patlak analysis of dynamic imaging data.
The correlation between FLT uptake of lung lesions and their proliferation rate has important clinical implications for PET imaging and characterization of lung lesions. FLT PET imaging could be used to differentiate benign from malignant lung lesions on the basis of their FLT uptake and, therefore, growth rate because most benign lung lesions do not proliferate. This will necessitate further validation with a large series of benign lesions. In addition, the prognostic significance of Ki-67 in NSCLC suggests that FLT uptake could be used to refine the prognostic assessment of NSCLCs. Finally, because NSCLCs with high Ki-67 scores are at higher risk for recurrence after resection, preoperative FLT uptake determination could be used to select which patients would benefit from additional therapy such as neo-adjuvant or adjuvant chemotherapy. Moreover, FLT uptake may help to assess the effects on tumors of therapies targeted at the cell cycle. These encouraging results are, therefore, opening the door to further evaluation and validation of FLT PET imaging.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by NIH through National Cancer Institute Grant 1R01 CA80907. 
2 To whom requests for reprints should be addressed, at Department of Radiology, Division of Nuclear Medicine, Box 356113, University of Washington Medical Center, 1959 Northeast Pacific Street, Seattle, WA 98195. Phone: (206) 598-4240; Fax: (206) 598-4496; E-mail: vesselle{at}u.washington.edu
3 The abbreviations used are: NSCLC, non-small cell lung cancer; FLT, 3'deoxy-3'-[18F]fluorothymidine (or radiolabeled FLT); SPF, S-phase fraction; ROI, region(s) of interest; GE, General Electric; SUV, standardized uptake value; maxSUV, maximum SUV; aveSUV, average tumor SUV; PV-corr-maxSUV, partial volume corrected maxSUV; CT, computed tomography; aveFLTflux, average FLT flux (into the tumor); PET, positron emission tomography; FDG, [F-18] fluorodeoxyglucose; TK1, thymidinekinase-1.
Received 12/18/01; revised 6/28/02; accepted 7/19/02.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionPatients and MethodsResultsDiscussionREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  Y. Menda, L. L. Boles Ponto, K. J. Dornfeld, T. J. Tewson, G. L. Watkins, M. K. Schultz, J. J. Sunderland, M. M. Graham, and J. M. Buatti Kinetic Analysis of 3'-Deoxy-3'-18F-Fluorothymidine (18F-FLT) in Head and Neck Cancer Patients Before and Early After Initiation of Chemoradiation Therapy J. Nucl. Med., July 1, 2009; 50(7): 1028 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhao, L. H. Schwartz, and S. M. Larson Imaging Surrogates of Tumor Response to Therapy: Anatomic and Functional Biomarkers J. Nucl. Med., February 1, 2009; 50(2): 239 - 249. [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]
|
|
|
|
|
|
C. von Forstner, J.-H. Egberts, O. Ammerpohl, D. Niedzielska, R. Buchert, P. Mikecz, U. Schumacher, K. Peldschus, G. Adam, C. Pilarsky, et al. Gene Expression Patterns and Tumor Uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an Orthotopic Mouse Xenotransplantation Model of Pancreatic Cancer J. Nucl. Med., August 1, 2008; 49(8): 1362 - 1370. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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. Vesselle, J. D. Freeman, L. Wiens, J. Stern, H. Q. Nguyen, S. E. Hawes, P. Bastian, A. Salskov, E. Vallieres, and D. E. Wood Fluorodeoxyglucose Uptake of Primary Non-Small Cell Lung Cancer at Positron Emission Tomography: New Contrary Data on Prognostic Role Clin. Cancer Res., June 1, 2007; 13(11): 3255 - 3263. [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]
|
|
|
|
|
|
L. B. Been, A. J.H. Suurmeijer, P. H. Elsinga, P. L. Jager, R. J. van Ginkel, and H. J. Hoekstra 18F-Fluorodeoxythymidine PET for Evaluating the Response to Hyperthermic Isolated Limb Perfusion for Locally Advanced Soft-Tissue Sarcomas J. Nucl. Med., March 1, 2007; 48(3): 367 - 372. [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]
|
|
|
|
 |
|
 A. K. Buck, M. Bommer, S. Stilgenbauer, M. Juweid, G. Glatting, H. Schirrmeister, T. Mattfeldt, D. Tepsic, D. Bunjes, F. M. Mottaghy, et al. Molecular Imaging of Proliferation in Malignant Lymphoma. Cancer Res., November 15, 2006; 66(22): 11055 - 11061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Muzi, A. M. Spence, F. O'Sullivan, D. A. Mankoff, J. M. Wells, J. R. Grierson, J. M. Link, and K. A. Krohn Kinetic Analysis of 3'-Deoxy-3'-18F-Fluorothymidine in Patients with Gliomas J. Nucl. Med., October 1, 2006; 47(10): 1612 - 1621. [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]
|
|
|
|
|
|
W. A. Weber Positron Emission Tomography As an Imaging Biomarker J. Clin. Oncol., July 10, 2006; 24(20): 3282 - 3292. [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]
|
|
|
|
|
|
J. R. Tseng, M. Dandekar, M. Subbarayan, Z. Cheng, J. M. Park, S. Louie, and S. S. Gambhir Reproducibility of 3'-Deoxy-3'-18F-Fluorothymidine MicroPET Studies in Tumor Xenografts in Mice J. Nucl. Med., November 1, 2005; 46(11): 1851 - 1857. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. J. Downey, T. Akhurst, M. Gonen, A. Vincent, M. S. Bains, S. Larson, and V. Rusch Preoperative F-18 Fluorodeoxyglucose-Positron Emission Tomography Maximal Standardized Uptake Value Predicts Survival After Lung Cancer Resection J. Clin. Oncol., August 15, 2004; 22(16): 3255 - 3260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. I. Shapiro Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol Clin. Cancer Res., June 15, 2004; 10(12): 4270S - 4275S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. van Waarde, D. C.P. Cobben, A. J.H. Suurmeijer, B. Maas, W. Vaalburg, E. F.J. de Vries, P. L. Jager, H. J. Hoekstra, and P. H. Elsinga Selectivity of 18F-FLT and 18F-FDG for Differentiating Tumor from Inflammation in a Rodent Model J. Nucl. Med., April 1, 2004; 45(4): 695 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Oyama, D. E. Ponde, C. Dence, J. Kim, Y.-C. Tai, and M. J. Welch Monitoring of Therapy in Androgen-Dependent Prostate Tumor Model by Measuring Tumor Proliferation J. Nucl. Med., March 1, 2004; 45(3): 519 - 525. [Abstract] [Full Text]
|
|
|
|
|
|
D. C.P. Cobben, B. F.A.M. van der Laan, B. Maas, W. Vaalburg, A. J.H. Suurmeijer, H. J. Hoekstra, P. L. Jager, and P. H. Elsinga 18F-FLT PET for Visualization of Laryngeal Cancer: Comparison with 18F-FDG PET J. Nucl. Med., February 1, 2004; 45(2): 226 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Barthel, E. Aboagye, and P. Price Reply Cancer Res., December 1, 2003; 63(23): 8560 - 8560. [Full Text] [PDF]
|
|
|
|
|
|
S. H. Britz-Cunningham and S. J. Adelstein Molecular Targeting with Radionuclides: State of the Science J. Nucl. Med., December 1, 2003; 44(12): 1945 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C.P. Cobben, P. H. Elsinga, A. van Waarde, and P. L. Jager Correspondence re: H. Barthel et al., 3'-Deoxy-3'-[18F]fluorothymidine as a New Marker for Monitoring Tumor Response to Antiproliferative Therapy in Vivo with Positron Emission Tomography. Cancer Res., 63: 3791-3798, 2003. Cancer Res., December 1, 2003; 63(23): 8558 - 8559. [Full Text] [PDF]
|
|
|
|
 |
|
 D L Francis, A Freeman, D Visvikis, D C Costa, S K Luthra, M Novelli, I Taylor, and P J Ell In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography Gut, November 1, 2003; 52(11): 1602 - 1606. [Abstract] [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]
|
|
|
|
|
|
H. Vesselle, J. Grierson, L. M. Peterson, M. Muzi, D. A. Mankoff, and K. A. Krohn 18F-Fluorothymidine Radiation Dosimetry in Human PET Imaging Studies J. Nucl. Med., September 1, 2003; 44(9): 1482 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Coleman Linking Radiation Oncology and Imaging through Molecular Biology (or Now That Therapy and Diagnosis Have Separated, It's Time to Get Together Again!) Radiology, July 1, 2003; 228(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Rowinsky Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies J. Clin. Oncol., May 15, 2003; 21(90100): 175s - 186. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
