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

Kenny, Laura; Vigushin, David M.; Al-Nahhas, Adil; Osman, Safiye; Luthra, Sajinder K.; Shousha, Sami; Coombes, R. Charles; Aboagye, Eric O.

doi:10.1158/0008-5472.can-04-4297

Cited by 169 publications

(154 citation statements)

References 33 publications

Supporting

Mentioning

151

Contrasting

Unclassified

Order By: Relevance

“…NLR3k-derived K i , Patlak-derived K i , SUV 41% and SUV max showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively (Table 2). In contrast, NLR3k-derived k 3 , which, at least in theory, selectively reflects TK1 activity, showed poor reproducibility with an ICC of 0.43 and an SD of 38%. As expected from Akaike and Schwarz analyses, inclusion of a fourth rate constant resulted in decreased reproducibility with an ICC of 0.75 and an SD of 25% for NLR4k-derived K i , and an ICC of 0.33 and an SD of 70% for NLR4k-derived k 3 ( Table 2).…”

Section: Resultsmentioning

confidence: 90%

See 1 more Smart Citation

Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography

Langen

Klabbers

Lubberink

et al. 2008

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

Purpose Positron emission tomography (PET) using 18 F-3′-deoxy-3′-fluorothymidine ([ 18 F]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [ 18 F]FLT measurements. Methods Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [ 18 F]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUV max ) and a threshold defined volume (SUV 41% ) were defined for all delineated lesions. The plasma to tumour transfer constant (K i ) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k 3 , which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. Results All primary tumours and >90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived K i , Patlakderived K i , SUV 41% and SUV max showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k 3 with an ICC of 0.43 and SD of 38%. Conclusion Quantitative [ 18 F]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV 41% , 20-25% in SUV max and Patlak-derived K i , and 32% in NLR3k-derived K i are likely to represent treatment effects.

show abstract

Section: Resultsmentioning

confidence: 90%

“…Several studies have shown good correlations between [ 18 F]FLT uptake and other markers of cellular proliferation, including proliferating cell nuclear antigen, flow cytometry and Ki-67 nuclear staining [1][2][3][4][5].…”

mentioning

confidence: 99%

Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography

Langen

Klabbers

Lubberink

et al. 2008

Eur J Nucl Med Mol Imaging

View full text Add to dashboard Cite

show abstract

“…In contrast to thymidine, FLT is poorly incorporated into DNA (Sundseth et al, 1996). 3 0 -deoxy-3 0 -[ 18 F]fluorothymidine uptake is correlated with S-phase (Rasey et al, 2002), Ki67 immunostaining (Kenny et al, 2005) and TK-1 levels (Barthel et al, 2005). As, anticancer treatment can inhibit proliferation it may change FLT uptake, implying a role for FLT as a marker for monitoring response to chemotherapy.…”

mentioning

confidence: 99%

[18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study

et al. 2008

View full text Add to dashboard Cite

Increased 2 0 -deoxy-2 0 -[ 18 F]fluoro-D-glucose (FDG) uptake is the most commonly used marker for positron emission tomography in oncology. However, a proliferation tracer such as 3 0 -deoxy-3 0 -[ 18 F]fluorothymidine (FLT) might be more specific for cancer. 3 0 -deoxy-3 0 -[ 18 F]fluorothymidine uptake is dependent on thymidine kinase 1 (TK) activity, but the effects of chemotherapeutic agents are unknown. The aim of this study was to characterise FDG and FLT uptake mechanisms in vitro before and after exposure to chemotherapeutic agents. The effects of 5-fluorouracil (5-FU), doxorubicin and paclitaxel on FDG and FLT uptake were measured in MDA MB231 human breast cancer cells in relation to cell cycle distribution, expression and enzyme activity of TK-1. At IC 50 concentrations, 5-FU resulted in accumulation in the G1 phase, but doxorubicin and paclitaxel induced a G2/M accumulation. Compared with untreated cells, 5-FU and doxorubicin increased TK-1 levels by 4300. At 72 h, 5-FU decreased FDG uptake by 50% and FLT uptake by 54%, whereas doxorubicin increased FDG and FLT uptake by 71 and 173%, respectively. Paclitaxel increased FDG uptake with 4100% after 48 h, whereas FLT uptake hardly changed. In conclusion, various chemotherapeutic agents, commonly used in the treatment of breast cancer, have different effects on the time course of uptake of both FDG and FLT in vitro. This might have implications for interpretation of clinical findings.

show abstract

“…12 Therefore, FLT is considered to be a proliferation marker and, as such, could be a more specific tracer of tumor "activity". Indeed, correlations between FLT uptake and S-phase, 12 Ki-67 immunostaining 13 and TK-1 levels 14 have been reported.…”

Section: Research Papermentioning

confidence: 98%

A new rat model of human breast cancer for evaluating efficacy of new anti-cancer agents in vivo

Direcks

Gelder²,

Lammertsma

et al. 2008

Cancer Biology & Therapy

View full text Add to dashboard Cite

Purpose: Advanced stage breast cancer patients may benefit from high dose chemotherapy, but only a minority will respond. A method to select non-responders as early as possible is essential for preventing unnecessary toxicity, possibly enabling a switch to an alternative treatment. Positron emission tomography (PET), a noninvasive molecular imaging modality, is able to detect functional changes well before anatomical changes are visible. The purpose of the present study was to develop a rat model of human breast cancer suitable for PET. This model, together with PET, would provide a means for investigating the efficacy of new anti-cancer drugs in an experimental setting.Methods: Human breast cancer cells MDA MB231 were injected subcutaneously into nude rats. Tumor take, tumor doubling time and growth inhibition after treatment with maximum tolerable doses of 5-fluorouracil, doxorubicin, cyclophosphamide and paclitaxel were established. As thymidine competes with 18 FLT and plasma thymidine levels are high in rodents, this could affect 18 FLT uptake. Therefore, use of thymidine phosphorylase to lower plasma thymidine levels was investigated. Finally, as an illustration of the potential use of the model, a pilot PET study was performed using 18 FDG and 18 FLT.Results: Tumor take rate was 68% when matrigel was coinjected. Tumor doubling time was 6 days. Treating animals with anti-cancer drugs resulted in tumor growth inhibition ranging from 7 to 68%, depending on the type of drug. Using thymidine phosphorylase, plasma concentrations of thymidine could be decreased by more than 80% and these reduced levels were stable for more than an hour, i.e., long enough for a PET study. Tumors could clearly be visualised using 18 FDG and 18 FLT PET.Conclusions: A new in vivo breast cancer model was successfully established in nude rats, allowing for quantitative PET studies of anti-cancer agents.

show abstract

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

Cited by 169 publications

References 33 publications

Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography

Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography

[18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study

A new rat model of human breast cancer for evaluating efficacy of new anti-cancer agents in vivo

Contact Info

Product

Resources

About