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TSPO PET, tumour grading and molecular genetics in histologically verified glioma: a correlative 18F-GE-180 PET study

  • M. Unterrainer
  • D. F. Fleischmann
  • F. Vettermann
  • V. Ruf
  • L. Kaiser
  • D. Nelwan
  • S. Lindner
  • M. Brendel
  • V. Wenter
  • S. Stöcklein
  • J. Herms
  • V. M. Milenkovic
  • R. Rupprecht
  • J. C. Tonn
  • C. Belka
  • P. Bartenstein
  • M. Niyazi
  • N. L. AlbertEmail author
Original Article
  • 79 Downloads
Part of the following topical collections:
  1. Neurology

Abstract

Background

The 18-kDa translocator protein (TSPO) is overexpressed in brain tumours and represents an interesting target for glioma imaging. 18F-GE-180, a novel TSPO ligand, has shown improved binding affinity and a high target-to-background contrast in patients with glioblastoma. However, the association of uptake characteristics on TSPO PET using 18F-GE-180 with the histological WHO grade and molecular genetic features so far remains unknown and was evaluated in the current study.

Methods

Fifty-eight patients with histologically validated glioma at initial diagnosis or recurrence were included. All patients underwent 18F-GE-180 PET, and the maximal and mean tumour-to-background ratios (TBRmax, TBRmean) as well as the PET volume were assessed. On MRI, presence/absence of contrast enhancement was evaluated. Imaging characteristics were correlated with neuropathological parameters (i.e. WHO grade, isocitrate dehydrogenase (IDH) mutation, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and telomerase reverse transcriptase (TERT) promoter mutation).

Results

Six of 58 patients presented with WHO grade II, 16/58 grade III and 36/58 grade IV gliomas. An (IDH) mutation was found in 19/58 cases, and 39/58 were classified as IDH-wild type. High 18F-GE-180-uptake was observed in all but 4 cases (being WHO grade II glioma, IDH-mutant). A high association of 18F-GE-180-uptake and WHO grades was seen: WHO grade IV gliomas showed the highest uptake intensity compared with grades III and II gliomas (median TBRmax 5.15 (2.59–8.95) vs. 3.63 (1.85–7.64) vs. 1.63 (1.50–3.43), p < 0.001); this association with WHO grades persisted within the IDH-wild-type and IDH-mutant subgroup analyses (p < 0.05). Uptake intensity was also associated with the IDH mutational status with a trend towards higher 18F-GE-180-uptake in IDH-wild-type gliomas in the overall group (median TBRmax 4.67 (1.56–8.95) vs. 3.60 (1.50–7.64), p = 0.083); however, within each WHO grade, no differences were found (e.g. median TBRmax in WHO grade III glioma 4.05 (1.85–5.39) vs. 3.36 (2.32–7.64), p = 1.000). No association was found between uptake intensity and MGMT or TERT (p > 0.05 each).

Conclusion

Uptake characteristics on 18F-GE-180 PET are highly associated with the histological WHO grades, with the highest 18F-GE-180 uptake in WHO grade IV glioblastomas and a PET-positive rate of 100% among the investigated high-grade gliomas. Conversely, all TSPO-negative cases were WHO grade II gliomas. The observed association of 18F-GE-180 uptake and the IDH mutational status seems to be related to the high inter-correlation of the IDH mutational status and the WHO grades.

Keywords

18F-GE-180 TSPO Glioma Grading Molecular genetics 

Notes

Acknowledgements

We thank Prof. Dr. C. Wetzel for the support regarding polymorphism genotyping. Additionally, we thank Joanne Stevens and GE Healthcare for the support regarding tracer production. N. Albert gratefully acknowledges the Else Kröner-Fresenius-Stiftung for the financial support of her research.

Compliance with ethical standards

Conflict of interest

N.L.A. is a member of the Neuroimaging Committee of the EANM. P.B. has received a speaker honorarium from GE Healthcare. All other authors declare that they have no conflicts of interest.

Ethical approval

The study was authorized by the local ethics committee (IRB 17-769) in accordance with the ICH Guideline for Good Clinical Practice (GCP) and the Declaration of Helsinki.

Informed consent

All patients gave written consent to undergo PET scans.

Supplementary material

259_2019_4491_MOESM1_ESM.docx (5 mb)
ESM 1 (DOCX 4.98 MB)

References

  1. 1.
    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–72.CrossRefGoogle Scholar
  2. 2.
    Galldiks N, Langen KJ, Pope WB. From the clinician’s point of view - what is the status quo of positron emission tomography in patients with brain tumors? Neuro-oncology. 2015.Google Scholar
  3. 3.
    Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, et al. Response assessment in neuro-oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-oncology. 2016.Google Scholar
  4. 4.
    Unterrainer M, Winkelmann I, Suchorska B, Giese A, Wenter V, Kreth FW, et al. Biological tumour volumes of gliomas in early and standard 20–40 min 18F-FET PET images differ according to IDH mutation status. Eur J Nucl Med Mol Imaging. 2018;45(7):1242–9.CrossRefGoogle Scholar
  5. 5.
    Wadsworth H, Jones PA, Chau WF, Durrant C, Fouladi N, Passmore J, et al. [(1)(8)F]GE-180: a novel fluorine-18 labelled PET tracer for imaging translocator protein 18 kDa (TSPO). Bioorg Med Chem Lett. 2012;22(3):1308–13.CrossRefGoogle Scholar
  6. 6.
    Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, et al. 18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015;42(3):503–11.CrossRefGoogle Scholar
  7. 7.
    Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 2014;55(3):466–72.CrossRefGoogle Scholar
  8. 8.
    Sridharan S, Lepelletier F-X, Trigg W, Banister S, Reekie T, Kassiou M, et al. Comparative evaluation of three TSPO PET radiotracers in a LPS-induced model of mild neuroinflammation in rats. Mol Imaging Biol. 2017;19(1):77–89.CrossRefGoogle Scholar
  9. 9.
    Fan Z, Calsolaro V, Atkinson RA, Femminella GD, Waldman A, Buckley C, et al. Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein. J Nucl Med. 2016.Google Scholar
  10. 10.
    Feeney C, Scott G, Raffel J, Roberts S, Coello C, Jolly A, et al. Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain. Eur J Nucl Med Mol Imaging. 2016;43(12):2201–10.CrossRefGoogle Scholar
  11. 11.
    Vomacka L, Albert NL, Lindner S, Unterrainer M, Mahler C, Brendel M, et al. TSPO imaging using the novel PET ligand [18F]GE-180: quantification approaches in patients with multiple sclerosis. EJNMMI Res. 2017;7(1):89.CrossRefGoogle Scholar
  12. 12.
    Unterrainer M, Mahler C, Vomacka L, Lindner S, Havla J, Brendel M, et al. TSPO PET with [18F]GE-180 sensitively detects focal neuro-inflammation in patients with relapsing-remitting multiple sclerosis Eur J Nucl Med Mol Imaging. 2018;Online first.Google Scholar
  13. 13.
    Albert NL, Unterrainer M, Fleischmann D, Lindner S, Vettermann F, Brunegraf A, et al. TSPO PET for glioma imaging using the novel ligand 18F-GE-180: first results in patients with glioblastoma. Eur J Nucl Med Mol Imaging. 2017:1–9.Google Scholar
  14. 14.
    Unterrainer M, Fleischmann DF, Diekmann C, Vomacka L, Lindner S, Vettermann F, et al. Comparison of 18F-GE-180 and dynamic 18F-FET PET in high grade glioma: a double tracer pilot study. European Journal of Nuclear Medicine and Molecular Imaging. 2018;Online first.Google Scholar
  15. 15.
    Unterrainer M, Fleischmann DF, Lindner S, Brendel M, Rupprecht R, Tonn JC, et al. Detection of cerebrospinal fluid dissemination of recurrent glioblastoma using TSPO-PET with 18F-GE-180. Clin Nucl Med. 2018.Google Scholar
  16. 16.
    Miettinen H, Kononen J, Haapasalo H, Helén P, Sallinen P, Harjuntausta T, et al. Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation. Cancer Res. 1995;55(12):2691–5.Google Scholar
  17. 17.
    Roncaroli F, Su Z, Herholz K, Gerhard A, Turkheimer FE. TSPO expression in brain tumours: is TSPO a target for brain tumour imaging? Clin Transl Imaging. 2016;4(2):145–56.CrossRefGoogle Scholar
  18. 18.
    Vlodavsky E, Soustiel JF. Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J Neuro-Oncol. 2007;81(1):1–7.CrossRefGoogle Scholar
  19. 19.
    Su Z, Roncaroli F, Durrenberger PF, Coope DJ, Karabatsou K, Hinz R, et al. The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study. J Nucl Med. 2015;56(4):512–7.CrossRefGoogle Scholar
  20. 20.
    Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.CrossRefGoogle Scholar
  21. 21.
    Suchorska B, Giese A, Biczok A, Unterrainer M, Weller M, Drexler M, et al. Identification of time-to-peak on dynamic 18F-FET-PET as a prognostic marker specifically in IDH1/2 mutant diffuse astrocytoma. Neuro-oncology. 2017.Google Scholar
  22. 22.
    Eigenbrod S, Trabold R, Brucker D, Erös C, Egensperger R, La Fougere C, et al. Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. Acta Neurochir. 2014;156(8):1427–40.CrossRefGoogle Scholar
  23. 23.
    Biczok A, Kraus T, Suchorska B, Terpolilli NA, Thorsteinsdottir J, Giese A, et al. TERT promoter mutation is associated with worse prognosis in WHO grade II and III meningiomas. J Neuro-Oncol. 2018;139(3):671–8.CrossRefGoogle Scholar
  24. 24.
    Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med. 2011;52(1):24–32.CrossRefGoogle Scholar
  25. 25.
    Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32(1):1–5.CrossRefGoogle Scholar
  26. 26.
    Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN. Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. Neuroimage. 2012;60(2):902–10.CrossRefGoogle Scholar
  27. 27.
    Wickstrøm T, Clarke A, Gausemel I, Horn E, Jørgensen K, Khan I, et al. The development of an automated and GMP compliant FASTlab™ synthesis of [18F] GE-180; a radiotracer for imaging translocator protein (TSPO). J Label Compd Radiopharm. 2014;57(1):42–8.CrossRefGoogle Scholar
  28. 28.
    Unterrainer M, Vettermann F, Brendel M, Holzgreve A, Lifschitz M, Zähringer M, et al. Towards standardization of 18 F-FET PET imaging: do we need a consistent method of background activity assessment? EJNMMI Res. 2017;7(1):48.CrossRefGoogle Scholar
  29. 29.
    Zanotti-Fregonara P, Veronese M, Pascual B, Rostomily RC, Turkheimer F, Masdeu JC. The validity of 18 F-GE180 as a TSPO imaging agent. Eur J Nucl Med Mol Imaging. 2019:1–3.Google Scholar
  30. 30.
    Albert NL, Unterrainer M, Brendel M, Kaiser L, Zweckstetter M, Cumming P, et al. In response to: the validity of 18 F-GE180 as a TSPO imaging agent. Eur J Nucl Med Mol Imaging. 2019:1–4.Google Scholar
  31. 31.
    Sridharan S, Raffel J, Nandoskar A, Record C, Brooks DJ, Owen D, et al. Confirmation of specific binding of the 18-kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter. Mol Imaging Biol. 2019.Google Scholar
  32. 32.
    Takaya S, Hashikawa K, Turkheimer FE, Mottram N, Deprez M, Ishizu K, et al. The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas. J Neuro-Oncol. 2007;85(1):95–103.CrossRefGoogle Scholar
  33. 33.
    Usinskiene J, Ulyte A, Bjørnerud A, Venius J, Katsaros VK, Rynkeviciene R, et al. Optimal differentiation of high- and low-grade glioma and metastasis: a meta-analysis of perfusion, diffusion, and spectroscopy metrics. Neuroradiology. 2016;58(4):339–50.CrossRefGoogle Scholar
  34. 34.
    Gutt-Will M, Murek M, Schwarz C, Hewer E, Vulcu S, Beck J, et al. Frequent diagnostic under-grading in isocitrate dehydrogenase wild-type gliomas due to small pathological tissue samples. Neurosurgery. 2018.Google Scholar
  35. 35.
    Muragaki Y, Chernov M, Maruyama T, Ochiai T, Taira T, Kubo O, et al. Low-grade glioma on stereotactic biopsy: how often is the diagnosis accurate? Min-minimally invasive Neurosurgery. 2008;51(05):275–279.Google Scholar
  36. 36.
    Mourik JEM, Lubberink M, Klumpers UMH, Comans EF, Lammertsma AA, Boellaard R. Partial volume corrected image derived input functions for dynamic PET brain studies: methodology and validation for [11C]flumazenil. NeuroImage. 2008;39(3):1041–50.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • M. Unterrainer
    • 1
    • 2
  • D. F. Fleischmann
    • 2
    • 3
  • F. Vettermann
    • 1
  • V. Ruf
    • 4
  • L. Kaiser
    • 1
  • D. Nelwan
    • 1
  • S. Lindner
    • 1
  • M. Brendel
    • 1
  • V. Wenter
    • 1
  • S. Stöcklein
    • 5
  • J. Herms
    • 4
  • V. M. Milenkovic
    • 6
  • R. Rupprecht
    • 6
  • J. C. Tonn
    • 2
    • 7
  • C. Belka
    • 2
    • 3
  • P. Bartenstein
    • 1
    • 2
  • M. Niyazi
    • 2
    • 3
  • N. L. Albert
    • 1
    • 2
    Email author
  1. 1.Department of Nuclear MedicineUniversity Hospital, LMU MunichMunichGermany
  2. 2.German Cancer Consortium (DKTK), Partner Site Munich, and German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of Radiation OncologyUniversity Hospital, LMU MunichMunichGermany
  4. 4.Department of NeuropathologyLMU MunichMunichGermany
  5. 5.Department of RadiologyUniversity Hospital, LMU MunichMunichGermany
  6. 6.Department of Psychiatry and PsychotherapyUniversity of RegensburgRegensburgGermany
  7. 7.Department of NeurosurgeryUniversity Hospital, LMU MunichMunichGermany

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