Advertisement

Differential diagnosis of solitary pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy

  • Qingjie Ma
  • Bin Ji
  • Bing Jia
  • Shi Gao
  • Tiefeng Ji
  • Xueju Wang
  • Zhenguo HanEmail author
  • Guoqing ZhaoEmail author
Original Article

Abstract

Purpose

Targeting of integrin ανβ3 with molecular imaging agents offers great potential in early detection and monitoring of tumour angiogenesis. Recently, an RGD (Arg-Gly-Asp) tracer, 99mTc-3P4-RGD2, with high affinity to integrin ανβ3 and in vivo tumour uptake was developed. In this study, we evaluate the feasibility of this novel radiotracer in the noninvasive differentiation of solitary pulmonary nodules (SPNs).

Methods

Twenty-one patients with SPNs on CT were studied scintigraphically after administration of 99mTc-3P4-RGD2 with a dose of 939 ± 118 MBq. Image interpretation using a 5-point scale was performed by one thoracic radiologist for CT and three nuclear medicine radiologists for single photon emission computed tomography (SPECT). Scintigraphic images were also analysed semiquantitatively by calculating tumour to normal tissue ratio (T/N). The “gold standard” was based on the histopathological diagnosis of the surgical samples from all recruited patients. A fraction of the samples were analysed immunohistochemically for integrin αvβ3 expression.

Results

Among the 21 SPNs, 15 (71%) were diagnosed as malignant and 6 (29%) were benign. The mean size for SPNs was 2.2 ± 0.6 cm. The sensitivity and specificity for CT interpretation, SPECT visual and semiquantitative analysis were 80/67%, 100/67% and 100/67%, respectively. All SPNs classified as indeterminate by CT were correctly diagnosed by 99mTc-3P4-RGD2 scintigraphy. The empirical receiver-operating characteristic (ROC) areas were 0.811 [95% confidence interval (CI) 58–95%] for CT, 0.833 (95% CI 61–96%) for SPECT and 0.844 (95% CI 62–96%) for T/N ratios, respectively. Immunohistochemistry confirmed ανβ3 expression in malignant and benign nodules with uptake in 99mTc-3P4-RGD2 scintigraphy.

Conclusion

In this first-in-human study, we demonstrated the feasibility of using 99mTc-3P4-RGD2 scintigraphy in differentiating SPNs. This procedure appears to be highly sensitive in detection of malignant SPNs. SPECT visual analysis seems to be sufficient for characterization of SPNs.

Keywords

Integrin ανβ3 99mTc-3P4-RGD2 Solitary pulmonary nodule Scintigraphy 

Notes

Acknowledgments

This work was supported by the Research Fund of Science and Technology Department of Jilin Province (no. 201015185).

Conflicts of interest

None.

References

  1. 1.
    Gould MK, Sanders GD, Barnett PG, Rydzak CE, Maclean CC, McClellan MB, et al. Cost-effectiveness of alternative management strategies for patients with solitary pulmonary nodules. Ann Intern Med 2003;138(9):724–35.PubMedGoogle Scholar
  2. 2.
    Schrevens L, Lorent N, Dooms C, Vansteenkiste J. The role of PET scan in diagnosis, staging, and management of non-small cell lung cancer. Oncologist 2004;9(6):633–43. doi: 10.1634/theoncologist.9-6-633.PubMedGoogle Scholar
  3. 3.
    Rohren EM, Lowe VJ. Update in PET imaging of nonsmall cell lung cancer. Semin Nucl Med 2004;34(2):134–53.PubMedGoogle Scholar
  4. 4.
    Jeong SY, Lee KS, Shin KM, Bae YA, Kim BT, Choe BK, et al. Efficacy of PET/CT in the characterization of solid or partly solid solitary pulmonary nodules. Lung Cancer 2008;61(2):186–94. doi: 10.1016/j.lungcan.2007.12.021.PubMedGoogle Scholar
  5. 5.
    Rebollo AC, Jiménez-Hoyuela JM, Martínez del Valle MD Martinez, Fernández Aguirre C, Soria C, Velasco JL. [Lung scintigraphy with technetium 99m depreotide in the assessment of solitary pulmonary nodules]. Arch Bronconeumol 2004;40(11):534–6.PubMedGoogle Scholar
  6. 6.
    Plachcińska A, Mikołajczak R, Maecke HR, Michalski A, Rzeszutek K, Kozak J, et al. 99mTc-EDDA/HYNIC-TOC scintigraphy in the differential diagnosis of solitary pulmonary nodules. Eur J Nucl Med Mol Imaging 2004;31(7):1005–10. doi: 10.1007/s00259-004-1511-3.PubMedGoogle Scholar
  7. 7.
    Spanu A, Schillaci O, Pirina P, Arru A, Madeddu G, Chessa F, et al. 99mTc-tetrofosmin SPECT in solitary pulmonary nodule evaluation. Oncol Rep 2006;16(4):763–9.PubMedGoogle Scholar
  8. 8.
    Niu G, Chen X. Why integrin as a primary target for imaging and therapy. Theranostics 2011;1:30–47.PubMedGoogle Scholar
  9. 9.
    Chen X, Sievers E, Hou Y, Park R, Tohme M, Bart R, et al. Integrin alpha v beta 3-targeted imaging of lung cancer. Neoplasia 2005;7(3):271–9. doi: 10.1593/neo.04538.PubMedGoogle Scholar
  10. 10.
    Jia B, Liu Z, Zhu Z, Shi J, Jin X, Zhao H, et al. Blood clearance kinetics, biodistribution, and radiation dosimetry of a kit-formulated integrin alpha(v)beta (3)-selective radiotracer (99m)Tc-3PRGD (2) in non-human primates. Mol Imaging Biol 2011;13(4):730–6. doi: 10.1007/s11307-010-0385-y.PubMedGoogle Scholar
  11. 11.
    Wang L, Shi J, Kim YS, Zhai S, Jia B, Zhao H, et al. Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers. Mol Pharm 2009;6(1):231–45. doi: 10.1021/mp800150r.PubMedGoogle Scholar
  12. 12.
    Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, et al. Quantitative PET imaging of tumor integrin alphavbeta3 expression with 18F-FRGD2. J Nucl Med 2006;47(1):113–21.PubMedGoogle Scholar
  13. 13.
    Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F et al. Tumor uptake of the RGD dimeric probe (99m)Tc-G(3)-2P(4)-RGD2 is correlated with integrin alpha(v)beta(3) expressed on both tumor cells and neovasculature. Bioconjug Chem 2010. doi: 10.1021/bc900547d.
  14. 14.
    Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, et al. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res 2006;12(13):3942–9. doi: 10.1158/1078-0432.ccr-06-0266.PubMedGoogle Scholar
  15. 15.
    Bach-Gansmo T, Danielsson R, Saracco A, Wilczek B, Bogsrud TV, Fangberget A, et al. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med 2006;47(9):1434–9.PubMedGoogle Scholar
  16. 16.
    Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 2008;49(6):879–86. doi: 10.2967/jnumed.107.049452.PubMedGoogle Scholar
  17. 17.
    Gottschalk KE, Kessler H. The structures of integrins and integrin-ligand complexes: implications for drug design and signal transduction. Angew Chem Int Ed Engl 2002;41(20):3767–74. doi: 10.1002/1521-3773(20021018)41:20<3767::aid-anie3767>3.0.co;2-t.PubMedGoogle Scholar
  18. 18.
    Liu S. Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjug Chem 2009;20(12):2199–213. doi: 10.1021/bc900167c.PubMedGoogle Scholar
  19. 19.
    Dijkgraaf I, Boerman OC. Molecular imaging of angiogenesis with SPECT. Eur J Nucl Med Mol Imaging 2010;37 Suppl 1:S104–13. doi: 10.1007/s00259-010-1499-9.PubMedGoogle Scholar
  20. 20.
    Viggiano RW, Swensen SJ, Rosenow 3rd EC. Evaluation and management of solitary and multiple pulmonary nodules. Clin Chest Med 1992;13(1):83–95.PubMedGoogle Scholar
  21. 21.
    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(7):914–24.PubMedGoogle Scholar
  22. 22.
    Kim SK, Allen-Auerbach M, Goldin J, Fueger BJ, Dahlbom M, Brown M, et al. Accuracy of PET/CT in characterization of solitary pulmonary lesions. J Nucl Med 2007;48(2):214–20.PubMedGoogle Scholar
  23. 23.
    Beyer T, Townsend DW, Brun T, Kinahan PE, Charron M, Roddy R, et al. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41(8):1369–79.PubMedGoogle Scholar
  24. 24.
    Folkman J. Angiogenesis. Annu Rev Med 2006;57:1–18. doi: 10.1146/annurev.med.57.121304.131306.PubMedGoogle Scholar
  25. 25.
    Higashi K, Ueda Y, Seki H, Yuasa K, Oguchi M, Noguchi T, et al. Fluorine-18-FDG PET imaging is negative in bronchioloalveolar lung carcinoma. J Nucl Med 1998;39(6):1016–20.PubMedGoogle Scholar
  26. 26.
    Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994;264(5158):569–71.PubMedGoogle Scholar
  27. 27.
    Mousa SA. alphav Vitronectin receptors in vascular-mediated disorders. Med Res Rev 2003;23(2):190–9. doi: 10.1002/med.10031.PubMedGoogle Scholar
  28. 28.
    Antonov AS, Antonova GN, Munn DH, Mivechi N, Lucas R, Catravas JD, et al. alphaVbeta3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-kappaB activation. J Cell Physiol 2011;226(2):469–76. doi: 10.1002/jcp.22356.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Nuclear MedicineChina-Japan Union Hospital of Jilin UniversityChangchunChina
  2. 2.Medical Isotopes Research CenterPeking UniversityBeijingChina
  3. 3.Department of PathologyChina-Japan Union Hospital of Jilin UniversityChangchunChina
  4. 4.Department of Thoracic SurgeryChina-Japan Union Hospital of Jilin UniversityChangchunChina

Personalised recommendations