Annals of Nuclear Medicine

, Volume 32, Issue 4, pp 264–271 | Cite as

Prognostic implications of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET/CT in patients with glioma

  • Akira Toriihara
  • Makoto Ohtake
  • Kensuke Tateishi
  • Ayako Hino-Shishikura
  • Tomohiro Yoneyama
  • Yoshio Kitazume
  • Tomio Inoue
  • Nobutaka Kawahara
  • Ukihide Tateishi
Original Article



The potential of positron emission tomography/computed tomography using 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM PET/CT), which was originally developed as a hypoxic tracer, to predict therapeutic resistance and prognosis has been reported in various cancers. Our purpose was to investigate prognostic value of 62Cu-ATSM PET/CT in patients with glioma, compared to PET/CT using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG).


56 patients with glioma of World Health Organization grade 2–4 were enrolled. All participants had undergone both 62Cu-ATSM PET/CT and 18F-FDG PET/CT within mean 33.5 days prior to treatment. Maximum standardized uptake value and tumor/background ratio were calculated within areas of increased radiotracer uptake. The prognostic significance for progression-free survival and overall survival were assessed by log-rank test and Cox’s proportional hazards model.


Disease progression and death were confirmed in 37 and 27 patients in follow-up periods, respectively. In univariate analysis, there was significant difference of both progression-free survival and overall survival in age, tumor grade, history of chemoradiotherapy, maximum standardized uptake value and tumor/background ratio calculated using 62Cu-ATSM PET/CT. Multivariate analysis revealed that maximum standardized uptake value calculated using 62Cu-ATSM PET/CT was an independent predictor of both progression-free survival and overall survival (p < 0.05). In a subgroup analysis including patients of grade 4 glioma, only the maximum standardized uptake values calculated using 62Cu-ATSM PET/CT showed significant difference of progression-free survival (p < 0.05).


62Cu-ATSM PET/CT is a more promising imaging method to predict prognosis of patients with glioma compared to 18F-FDG PET/CT.


62Cu-ATSM PET/CT 18F-FDG PET/CT Glioma Tumor progression Survival 



This work was supported by a Grant-in-Aid for Cancer Research (21-5-2) from the Ministry of Health, Labor and Welfare and was also supported in part by the Ministry of Education, Culture, Sports, Science and Technology, KAKENHI Grant (15K19977 to Makoto Ohtake). In addition, this work was supported in part by grants from Scientific Research Expenses for Health and Welfare Programs, the Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, No. 15K09885, the Scientific Research Expenses for Health and Welfare Programs, No. 29-A-3 (Takashi Terauchi and Ukihide Tateishi: squad leaders), Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs by Japan Agency for Medical Research and Development (AMED).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12149_2018_1241_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 KB)


  1. 1.
    Lopci E, Grassi I, Chiti A, Nanni C, Cicoria G, Toschi L, et al. PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence. Am J Nucl Med Mol Imaging. 2014;4:365–384.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med. 1997;38:1155–60.PubMedGoogle Scholar
  3. 3.
    Obata A, Yoshimi E, Waki A, Lewis JS, Oyama N, Welch MJ, et al. Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis (N 4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med. 2001;15:499–504.CrossRefPubMedGoogle Scholar
  4. 4.
    Tateishi K, Tateishi U, Sato M, Yamanaka S, Kanno H, Murata H, et al. Application of 62Cu-diacetyl-bis (N 4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma. AJNR Am J Neuroradiol. 2013;34:92 – 9.CrossRefPubMedGoogle Scholar
  5. 5.
    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys. 2003;55:1233–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Dehdashti F, Grigsby PW, Lewis JS, Laforest R, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2008;49:201–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging 2003;30:844–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Kinoshita T, Fujii H, Hayashi Y, Kamiyama I, Ohtsuka T, Asamura H. Prognostic significance of hypoxic PET using (18)F-FAZA and (62)Cu-ATSM in non-small-cell lung cancer. Lung Cancer. 2016;91:56–66.CrossRefPubMedGoogle Scholar
  9. 9.
    Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing Neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum. 2008;51:1641–8.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sato Y, Tsujikawa T, Oh M, Mori T, Kiyono Y, Fujieda S, et al. Assessing tumor hypoxia in head and neck cancer by PET with 62Cu-diacetyl-bis(N 4-methylthiosemicarbazone). Clin Nucl Med. 2014;39:1027–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Tateishi K, Tateishi U, Nakanowatari S, Ohtake M, Minamimoto R, Suenaga J, et al. 62Cu-diacetyl-bis (N 4-methylthiosemicarbazone) PET in human gliomas: comparative study with [18F]fluorodeoxyglucose and l-methyl-[11C]methionine PET. AJNR Am J Neuroradiol. 2014;35:278 – 84.CrossRefPubMedGoogle Scholar
  12. 12.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Chiang GC, Galla N, Ferraro R, Kovanlikaya I. The added prognostic value of metabolic tumor size on FDG-PET at first suspected recurrence of glioblastoma multiforme. J Neuroimaging. 2017;27:243–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Leiva-Salinas C, Schiff D, Flors L, Patrie JT, Rehm PK. FDG PET/MR imaging coregistration helps predict survival in patients with glioblastoma and radiologic progression after standard of care treatment. Radiology. 2017;283:508 – 14.CrossRefPubMedGoogle Scholar
  15. 15.
    Colavolpe C, Metellus P, Mancini J, Barrie M, Bequet-Boucard C, Figarella-Branger D, et al. Independent prognostic value of pre-treatment 18-FDG-PET in high-grade gliomas. J Neurooncol. 2012;107:527 – 35.CrossRefPubMedGoogle Scholar
  16. 16.
    Tralins KS, Douglas JG, Stelzer KJ, Mankoff DA, Silbergeld DL, Rostomilly R, et al. Volumetric analysis of 18F-FDG PET in glioblastoma multiforme: prognostic information and possible role in definition of target volumes in radiation dose escalation. J Nucl Med. 2002;42:1667–73.Google Scholar
  17. 17.
    Toyonaga T, Yamaguchi S, Hirata K, Kobayashi K, Manabe O, Watanabe S, et al. Hypoxic glucose metabolism in glioblastoma as a potential prognostic factor. Eur J Nucl Med Mol Imaging. 2017;44:611–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Kawai N, Lin W, Cao WD, Ogawa D, Miyake K, Haba R, et al. Correlation between 18F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas. Eur J Nucl Med Mol Imaging. 2014;41:1870–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Swanson KR, Chakraborty G, Wang CH, Rockne R, Harpold HLP, Muzi M, et al. Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in the assessment of human glioblastomas. J Nucl Med. 2009;50:36–44.CrossRefPubMedGoogle Scholar
  20. 20.
    Spence AM, Muzi M, Swanson KR, O’Sullivan F, Rockhill JK, Rajendran JG, et al. Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res. 2008;14:2623–30.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Carlin S, Zhang H, Reese M, Ramos NN, Chen Q, Ricketts SA. A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med. 2014;55:515 – 21.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    O’Donoghue JA, Zanzonico P, Pugachev A, Wen B, Smith-Jones P, Cai S, et al. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N 4-methylthiosemicarbazone) positron emission tomography: comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys. 2005;61:1493–502.CrossRefPubMedGoogle Scholar
  23. 23.
    Furukawa T, Yuan Q, Jin ZH, Aung W, Yoshii Y, Hasegawa S, et al. A limited overlap between intratumoral distribution of 1-(5-fluoro-5-deoxy-α-d-arabinofuranosyl)-2-nitroimidazole and copper-diacetyl-bis[N(4)-methylthiosemicarbazone]. Oncol Rep. 2015;34:1379–87.CrossRefPubMedGoogle Scholar
  24. 24.
    Troost EG, Laverman P, Kaanders JH, Philippens M, Lok J, Oyen WJ, et al. Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol. 2006;80:157 – 64.CrossRefPubMedGoogle Scholar
  25. 25.
    Busk M, Mortensen LS, Nordsmark M, Overgaard J, Jakobsen S, Hansen KV, et al. PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging. 2013;40:186 – 97.CrossRefPubMedGoogle Scholar
  26. 26.
    Li F, Jorgensen JT, Forman J, Hansen AE, Kjaer A. 64Cu-ATSM reflects pO2 levels in human head and neck cancer xenografts but not in colorectal cancer xenografts: comparison with 64CuCl2. J Nucl Med. 2016;57:437 – 43.CrossRefPubMedGoogle Scholar
  27. 27.
    Colombie M, Gouard S, Frindel M, Vidal A, Cherel M, Kraeber-Bodere F, et al. Focus on the controversial aspects of 64Cu-ATSM in tumoral hypoxia mapping by PET imaging. Front Med (Lausanne). 2015;2:58. Scholar
  28. 28.
    Bonekamp D, Deike K, Wiestler B, Wick W, Bendszus M, Radbruch A, et al. Association of overall survival in patients with newly diagnosed glioblastoma with contrast-enhanced perfusion MRI: comparison of intraindividually matched T1- and T2 *-based bolus techniques. J Magn Reson Imaging. 2015;42:87–96.CrossRefPubMedGoogle Scholar
  29. 29.
    Coban G, Mohan S, Kural F, Wang S, O’Rourke DM, Poptani H. Prognostic value of dynamic susceptibility contrast-enhanced and diffusion-weighted MR imaging in patients with glioblastomas. AJNR Am J Neuroradiol. 2015;36:1247–52.CrossRefPubMedGoogle Scholar
  30. 30.
    Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355:1253–61.CrossRefPubMedGoogle Scholar
  31. 31.
    Yoshii Y, Furukawa T, Kiyono Y, Watanabe R, Waki A, Mori T, et al. Copper-64-diacetyl-bis (N 4-methylthiosemicarbazone) accumulates in rich regions of CD133+ highly tumorigenic cells in mouse colon carcinoma. Nucl Med Biol. 2010;37:395–404.CrossRefPubMedGoogle Scholar
  32. 32.
    Ikawa M, Okazawa H, Tsujikawa T, Matsunaga A, Yamamura O, Mori T, et al. Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. Neurology. 2015;84:2033–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Indo HP, Davidson M, Yen HC, Suenaga S, Tomita K, Nishii T, et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion. 2007;7:106 – 18.CrossRefPubMedGoogle Scholar
  34. 34.
    Okon IS, Zou MH. Mitochondrial ROS and cancer drug resistance: implications for therapy. Phamacol Res. 2015;100:170–4.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2018

Authors and Affiliations

  • Akira Toriihara
    • 1
  • Makoto Ohtake
    • 2
  • Kensuke Tateishi
    • 2
  • Ayako Hino-Shishikura
    • 3
  • Tomohiro Yoneyama
    • 1
  • Yoshio Kitazume
    • 1
  • Tomio Inoue
    • 3
  • Nobutaka Kawahara
    • 2
  • Ukihide Tateishi
    • 1
  1. 1.Department of Diagnostic Radiology and Nuclear MedicineTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Departments of Neurosurgery, Graduate School of MedicineYokohama City UniversityYokohamaJapan
  3. 3.Departments of Radiology, Graduate School of MedicineYokohama City UniversityYokohamaJapan

Personalised recommendations