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Evaluation of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The thymidine analog 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of 18F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood–brain barrier (BBB) breakdown in human brain gliomas.

Methods

A total of 21 patients with newly diagnosed gliomas were examined by 18F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of 18F-FLT in the tumor and 18F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.

Results

18F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K 1; P = 0.001 and P < 0.001, respectively), but not with the phosphorylation rate constant (k 3). IHC and real-time PCR studies demonstrated a significant correlation between K 1 and TK-1 mRNA expression (P = 0.001), but not between k 3 and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K 1 and the Ki-67 index (P = 0.003), but not between k 3 and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P = 0.009). 18F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P = 0.003 and P = 0.011, respectively).

Conclusion

These results indicate that 18F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k 3 determined by 18F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.

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Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science and Culture of Japan. The authors are grateful for the excellent technical support of the radiological technologist at our institution.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1 Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

    Aya Shinomiya, Nobuyuki Kawai, Masaki Okada, Keisuke Miyake & Takashi Tamiya

  2. Department of Neurobiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan

    Takehiro Nakamura

  3. Department of Diagnostic Pathology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan

    Yoshio Kushida & Reiji Haba

  4. Department of Medical Physics, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan

    Nobuyuki Kudomi

  5. Department of Radiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan

    Yuka Yamamoto

  6. Department of Cell Physiology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan

    Masaaki Tokuda

Authors
  1. Aya Shinomiya
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  2. Nobuyuki Kawai
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  8. Nobuyuki Kudomi
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  9. Yuka Yamamoto
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  11. Takashi Tamiya
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Correspondence to Nobuyuki Kawai.

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Shinomiya, A., Kawai, N., Okada, M. et al. Evaluation of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas. Eur J Nucl Med Mol Imaging 40, 175–185 (2013). https://doi.org/10.1007/s00259-012-2275-9

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  • DOI: https://doi.org/10.1007/s00259-012-2275-9

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