Advertisement

Impact of rs12917 MGMT Polymorphism on [18F]FDG-PET Response in Pediatric Hodgkin Lymphoma (PHL)

  • Stefanie Kewitz-Hempel
  • Lars Kurch
  • Michaela Cepelova
  • Ines Volkmer
  • Axel Sauerbrey
  • Elke Conrad
  • Stephanie Knirsch
  • Gabriele Pöpperl
  • Daniel Steinbach
  • Ambros J. Beer
  • Christof M. Kramm
  • Carsten-Oliver Sahlmann
  • Bernhard Erdlenbruch
  • Wolf-Dieter Reinbold
  • Andreas Odparlik
  • Osama Sabri
  • Regine KlugeEmail author
  • Martin S. StaegeEmail author
Research Article

Abstract

Purpose

The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months.

Procedures

We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status.

Results

We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication.

Conclusion

MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

Key words

Pediatric Hodgkin lymphoma MGMT rs12917 [18F]FDG-PET qPET Deauville score 

Notes

Author Contributions

S.K.-H. and I.V. performed experiments; M.S.S. designed the research; S.K.-H., L.K., M.C., A.S., E.C., S.K., G.P., D.S., A.J.B., C.M.K., C.-O.S., B.E., W.-D.R., A.O., O.S., R.K., and M.S.S analyzed and discussed the data; S.K.-H., L.K., and M.S.S wrote the paper.

Funding Information

This work was supported by a fellowship from the Konrad-Adenauer-Stiftung (S.K.-H.).

Compliance with Ethical Standards

All patients and their guardians gave their written informed consent. The study was approved by the ethical committee of the Medical Faculty of the Martin Luther University Halle-Wittenberg.

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Körholz D, Claviez A, Hasenclever D, Kluge R, Hirsch W, Kamprad F, Dörffel W, Wickmann L, Papsdorf K, Dieckmann K, Kahn T, Mauz-Körholz C, Dannenberg C, Pötter R, Brosteanu O, Schellong G, Sabri O (2004) The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin’s disease: evolution in the tradition of the DAL/GPOH studies. Klin Padiatr 216:150–156CrossRefGoogle Scholar
  2. 2.
    Mauz-Körholz C, Hasenclever D, Dörffel W, Ruschke K, Pelz T, Voigt A, Stiefel M, Winkler M, Vilser C, Dieckmann K, Karlén J, Bergsträsser E, Fosså A, Mann G, Hummel M, Klapper W, Stein H, Vordermark D, Kluge R, Körholz D (2010) Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28:3680–3686CrossRefGoogle Scholar
  3. 3.
    Hasenclever D, Kurch L, Mauz-Körholz C, Elsner A, Georgi T, Wallace H, Landman-Parker J, Moryl-Bujakowska A, Cepelová M, Karlén J, Álvarez Fernández-Teijeiro A, Attarbaschi A, Fosså A, Pears J, Hraskova A, Bergsträsser E, Beishuizen A, Uyttebroeck A, Schomerus E, Sabri O, Körholz D, Kluge R (2014) qPET - a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging 41:1301–1308CrossRefGoogle Scholar
  4. 4.
    Mauz-Körholz C, Metzger ML, Kelly KM, Schwartz CL, Castellanos ME, Dieckmann K, Kluge R, Körholz D (2015) Pediatric Hodgkin lymphoma. J Clin Oncol 33:2975–2985CrossRefGoogle Scholar
  5. 5.
    Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, Johnson NA, Zhao Y, Telenius A, Neriah SB, McPherson A, Meissner B, Okoye UC, Diepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Rimsza LM, Horsman DE, Staudt LM, Steidl U, Marra MA, Gascoyne RD (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471:377–381CrossRefGoogle Scholar
  6. 6.
    Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, Ben-Neriah S, Boyle M, Kridel R, Telenius A, Woolcock BW, Farinha P, Fisher RI, Rimsza LM, Bartlett NL, Cheson BD, Shepherd LE, Advani RH, Connors JM, Kahl BS, Gordon LI, Horning SJ, Steidl C, Gascoyne RD (2013) Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol 31:692–700CrossRefGoogle Scholar
  7. 7.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefGoogle Scholar
  8. 8.
    Karran P, Bignami M (1992) Self-destruction and tolerance in resistance of mammalian cells to alkylation damage. Nucleic Acids Res 20:2933–2940CrossRefGoogle Scholar
  9. 9.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797Google Scholar
  10. 10.
    Kaina B, Fritz G, Coquerelle T (1993) Contribution of O6-alkylguanine and N-alkylpurines to the formation of sister chromatid exchanges, chromosomal aberrations, and gene mutations: new insights gained from studies of genetically engineered mammalian cell lines. Environ Mol Mutagen 22:283–292CrossRefGoogle Scholar
  11. 11.
    Liu L, Gerson SL (2006) Targeted modulation of MGMT: clinical implications. Clin Cancer Res 12:328–331CrossRefGoogle Scholar
  12. 12.
    Ayi TC, Loh KC, Ali RB, Li BF (1992) Intracellular localization of human DNA repair enzyme methylguanine-DNA methyltransferase by antibodies and its importance. Cancer Res 52:6423–6430Google Scholar
  13. 13.
    Kewitz S, Stiefel M, Kramm CM, Staege MS (2014) Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin’s lymphoma cells. Leuk Res 38:138–143CrossRefGoogle Scholar
  14. 14.
    Chekhun VF, Kulik GI, Yurchenko OV, Tryndyak VP, Todor IN, Luniv LS, Tregubova NA, Pryzimirska TV, Montgomery B, Rusetskaya NV, Pogribny IP (2006) Role of DNA hypomethylation in the development of the resistance to doxorubicin in human MCF-7 breast adenocarcinoma cells. Cancer Lett 231:87–93CrossRefGoogle Scholar
  15. 15.
    Drexler HG, Gaedicke G, Lok MS, Diehl V, Minowada J (1986) Hodgkin’s disease derived cell lines HDLM-2 and L-428: comparison of morphology, immunological and isoenzyme profiles. Leuk Res 10:487–500CrossRefGoogle Scholar
  16. 16.
    Kamesaki H, Fukuhara S, Tatsumi E et al (1986) Cytochemical, immunologic, chromosomal, and molecular genetic analysis of a novel cell line derived from Hodgkin’s disease. Blood 68:285–292Google Scholar
  17. 17.
    Wolf J, Kapp U, Bohlen H, Kornacker M, Schoch C, Stahl B, Mücke S, von Kalle C, Fonatsch C, Schaefer HE, Hansmann ML, Diehl V (1996) Peripheral blood mononuclear cells of a patient with advanced Hodgkin’s lymphoma give rise to permanently growing Hodgkin-reed Sternberg cells. Blood 87:3418–3428Google Scholar
  18. 18.
    Schaadt M, Fonatsch C, Kirchner H, Diehl V (1979) Establishment of a malignant, Epstein-Barr-virus (EBV)-negative cell-line from the pleura effusion of a patient with Hodgkin’s disease. Blut 38:185–190CrossRefGoogle Scholar
  19. 19.
    Diehl V, Kirchner HH, Burrichter H, Stein H, Fonatsch C, Gerdes J, Schaadt M, Heit W, Uchanska-Ziegler B, Ziegler A, Heintz F, Sueno K (1982) Characteristics of Hodgkin’s disease-derived cell lines. Cancer Treat Rep 66:615–632Google Scholar
  20. 20.
    Kühnöl CD, Staege MS, Kramm CM (2016) Lenalidomide in an in vitro Dendritic Cell Model for Malignant Gliomas. Anti Cancer Agents Med Chem 16:1468–1473CrossRefGoogle Scholar
  21. 21.
    Kluge R, Körholz D (2011) Role of FDG-PET in staging and therapy of children with Hodgkin lymphoma. Klin Padiatr 223:315–319CrossRefGoogle Scholar
  22. 22.
    Kurch L, Mauz-Körholz C, Bertling S, Wallinder M, Kaminska M, Marwede D, Tchavdarova L, Georgi TW, Elsner A, Barthel A, Stoevesandt D, Hasenclever D, Sattler B, Sabri O, Körholz D, Kluge R (2013) The EuroNet paediatric hodgkin network - modern imaging data management for real time central review in multicentre trials. Klin Padiatr 225:357–361CrossRefGoogle Scholar
  23. 23.
    Stauss J, Franzius C, Pfluger T, Juergens KU, Biassoni L, Begent J, Kluge R, Amthauer H, Voelker T, Højgaard L, Barrington S, Hain S, Lynch T, Hahn K, European Association of Nuclear Medicine (2008) Guidelines for 18F-FDG PET and PET-CT imaging in paediatric oncology. Eur J Nucl Med Mol Imaging 35:1581–1588CrossRefGoogle Scholar
  24. 24.
    Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A, Wiseman GA, Kostakoglu L, Scheidhauer K, Buck A, Naumann R, Spaepen K, Hicks RJ, Weber WA, Reske SN, Schwaiger M, Schwartz LH, Zijlstra JM, Siegel BA, Cheson BD, Imaging Subcommittee of International Harmonization Project in Lymphoma (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25:571–578CrossRefGoogle Scholar
  25. 25.
    Barrington SF, Kluge R (2017) FDG-PET for therapy monitoring in Hodgkin and non-Hodgkin lymphomas. Eur J Nucl Med Mol Imaging 44:97–110CrossRefGoogle Scholar
  26. 26.
    1000 Genomes Project Consortium, Auton A, Brooks LD et al (2015) A global reference for human genetic variation. Nature 526:68–74CrossRefGoogle Scholar
  27. 27.
    Bugni JM, Han J, Tsai MS, Hunter DJ, Samson LD (2007) Genetic association and functional studies of major polymorphic variants of MGMT. DNA Repair (Amst) 6:1116–1126CrossRefGoogle Scholar
  28. 28.
    Altinoz MA, Elmaci I, Bolukbasi FH, Ekmekci CG, Yenmis G, Sari R, Sav A (2017) MGMT gene variants, temozolomide myelotoxicity and glioma risk. A concise literature survey including an illustrative case. J Chemother 29:238–244CrossRefGoogle Scholar
  29. 29.
    Liu K, Jiang Y (2017) Polymorphisms in DNA repair gene and susceptibility to glioma: a systematic review and meta-analysis based on 33 studies with 15 SNPs in 9 genes. Cell Mol Neurobiol 37:263–274CrossRefGoogle Scholar
  30. 30.
    Guo H, Bassig BA, Lan Q, Zhu Y, Zhang Y, Holford TR, Leaderer B, Boyle P, Qin Q, Zhu C, Li N, Rothman N, Zheng T (2014) Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma. Cancer Causes Control 25:1261–1270CrossRefGoogle Scholar
  31. 31.
    Jiao J, Zheng T, Lan Q, Chen Y, Deng Q, Bi X, Kim C, Holford T, Leaderer B, Boyle P, Ba Y, Xia Z, Chanock SJ, Rothman N, Zhang Y (2012) Occupational solvent exposure, genetic variation of DNA repair genes, and the risk of non-Hodgkin’s lymphoma. Eur J Cancer Prev 21:580–584CrossRefGoogle Scholar
  32. 32.
    Wang L, Liu H, Zhang Z, Spitz MR, Wei Q (2006) Association of genetic variants of O6-methylguanine-DNA methyltransferase with risk of lung cancer in non-Hispanic Whites. Cancer Epidemiol Biomark Prev 15:2364–2369CrossRefGoogle Scholar
  33. 33.
    Yang F, Shi JY, Xu L et al (2009) Genetic susceptibility of single nucleotide polymorphism in MGMT to non-Hodgkin lymphoma. Zhonghua Xue Ye Xue Za Zhi 30:622–625Google Scholar
  34. 34.
    Hall J, Hashibe M, Boffetta P, Gaborieau V, Moullan N, Chabrier A, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabiánová E, Holcatova I, Hung RJ, McKay J, Canzian F, Brennan P (2007) The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract. Carcinogenesis 28:665–671CrossRefGoogle Scholar
  35. 35.
    Adel Fahmideh M, Schwartzbaum J, Frumento P, Feychting M (2014) Association between DNA repair gene polymorphisms and risk of glioma: a systematic review and meta-analysis. Neuro-Oncology 16:807–814CrossRefGoogle Scholar
  36. 36.
    Hu Y, Zhou M, Li K, Zhang K, Kong X, Zheng Y, Li J, Liu L (2014) Two DNA repair gene polymorphisms on the risk of gastrointestinal cancers: a meta-analysis. Tumour Biol 35:1715–1725CrossRefGoogle Scholar
  37. 37.
    Bye H, Prescott NJ, Matejcic M, Rose E, Lewis CM, Parker MI, Mathew CG (2011) Population-specific genetic associations with oesophageal squamous cell carcinoma in South Africa. Carcinogenesis 32:1855–1861CrossRefGoogle Scholar
  38. 38.
    Zhang M, Huang WY, Andreotti G, Gao YT, Rashid A, Chen J, Sakoda LC, Shen MC, Wang BS, Chanock S, Hsing AW (2008) Variants of DNA repair genes and the risk of biliary tract cancers and stones: a population-based study in China. Cancer Epidemiol Biomark Prev 17:2123–2127CrossRefGoogle Scholar
  39. 39.
    Remington M, Chtchetinin J, Ancheta K, Nghiemphu PL, Cloughesy T, Lai A (2009) The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity. Neuro-Oncology 11:22–32CrossRefGoogle Scholar
  40. 40.
    Schwarzl SM, Smith JC, Kaina B, Efferth T (2005) Molecular modeling of O6-methylguanine-DNA methyltransferase mutant proteins encoded by single nucleotide polymorphisms. Int J Mol Med 16:553–557Google Scholar
  41. 41.
    Sylvester RK, Steen P, Tate JM, Mehta M, Petrich RJ, Berg A, Kolesar J (2011) Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients. Anti-Cancer Drugs 22:104–110CrossRefGoogle Scholar
  42. 42.
    Fang Q, Loktionova NA, Moschel RC, Javanmard S, Pauly GT, Pegg AE (2008) Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase. Biochem Pharmacol 75:618–626CrossRefGoogle Scholar
  43. 43.
    Ma S, Egyházi S, Ueno T, Lindholm C, Kreklau EL, Stierner U, Ringborg U, Hansson J (2003) O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma. Br J Cancer 89:1517–1523CrossRefGoogle Scholar
  44. 44.
    Molina E, Pérez-Morales R, Rubio J, Petrosyan P, Cadena LH, Arlt VM, Phillips DH, Gonsebatt ME (2013) The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes. Mutat Res 758:62–68CrossRefGoogle Scholar
  45. 45.
    Hill CE, Wickliffe JK, Guerin AT, Kinslow CJ, Wolfe KJ, Ammenheuser MM, Abdel-Rahman SZ (2007) The L84F polymorphism in the O6-Methylguanine-DNA-Methyltransferase (MGMT) gene is associated with increased hypoxanthine phosphoribosyltransferase (HPRT) mutant frequency in lymphocytes of tobacco smokers. Pharmacogenet Genomics 17:743–753CrossRefGoogle Scholar
  46. 46.
    Hill CE, Wickliffe JK, Wolfe KJ, Kinslow CJ, Lopez MS, Abdel-Rahman SZ (2005) The L84F and the I143V polymorphisms in the O6-methylguanine-DNA-methyltransferase (MGMT) gene increase human sensitivity to the genotoxic effects of the tobacco-specific nitrosamine carcinogen NNK. Pharmacogenet Genomics 15:571–578CrossRefGoogle Scholar
  47. 47.
    Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880CrossRefGoogle Scholar
  48. 48.
    Bobustuc GC, Kassam AB, Rovin RA et al (2018) MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide. Oncotarget 9:29727–29742CrossRefGoogle Scholar
  49. 49.
    Niture SK, Doneanu CE, Velu CS, Bailey NI, Srivenugopal KS (2005) Proteomic analysis of human O6-methylguanine-DNA methyltransferase by affinity chromatography and tandem mass spectrometry. Biochem Biophys Res Commun 337:1176–1184CrossRefGoogle Scholar
  50. 50.
    Mostofa AGM, Punganuru SR, Madala HR, Srivenugopal KS (2018) S-phase specific downregulation of human O (6)-Methylguanine DNA Methyltransferase (MGMT) and its serendipitous interactions with PCNA and p21 (cip1) proteins in glioma cells. Neoplasia 20:305–323CrossRefGoogle Scholar
  51. 51.
    Loh YH, Mitrou PN, Wood A, Luben RN, McTaggart A, Khaw KT, Rodwell SA (2011) SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Cancer Epidemiol 35:369–374CrossRefGoogle Scholar
  52. 52.
    Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance, Australasian Leukaemia and Lymphoma Group, Eastern Cooperative Oncology Group, European Mantle Cell Lymphoma Consortium, Italian Lymphoma Foundation, European Organisation for Research, Treatment of Cancer/Dutch Hemato-Oncology Group, Grupo Español de Médula Ósea, German High-Grade Lymphoma Study Group, German Hodgkin's Study Group, Japanese Lymphorra Study Group, Lymphoma Study Association, NCIC Clinical Trials Group, Nordic Lymphoma Study Group, Southwest Oncology Group, United Kingdom National Cancer Research Institute (2014) Recommendations for inital evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. JCO 32:3059–3068CrossRefGoogle Scholar
  53. 53.
    Kurch L, Hasenclever D, Kluge R et al (2018) Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET >/= 2) is prognostic in pediatric Hodgkin lymphoma: results of the GPOH-HD2002 trial. Pediatr Blood Cancer 14:e27539Google Scholar

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  • Stefanie Kewitz-Hempel
    • 1
    • 2
    • 3
  • Lars Kurch
    • 4
  • Michaela Cepelova
    • 5
  • Ines Volkmer
    • 1
  • Axel Sauerbrey
    • 6
  • Elke Conrad
    • 7
  • Stephanie Knirsch
    • 8
  • Gabriele Pöpperl
    • 9
  • Daniel Steinbach
    • 10
  • Ambros J. Beer
    • 11
  • Christof M. Kramm
    • 1
    • 12
  • Carsten-Oliver Sahlmann
    • 13
  • Bernhard Erdlenbruch
    • 14
  • Wolf-Dieter Reinbold
    • 15
  • Andreas Odparlik
    • 16
  • Osama Sabri
    • 4
  • Regine Kluge
    • 4
    Email author
  • Martin S. Staege
    • 1
    Email author
  1. 1.Department of Pediatrics IMartin Luther University Halle-WittenbergHalleGermany
  2. 2.Department of Pediatric Hematology and OncologyJustus Liebig UniversityGiessenGermany
  3. 3.Department of Dermatology and VenereologyMartin Luther University Halle-WittenbergHalleGermany
  4. 4.Department of Nuclear MedicineUniversity Hospital of LeipzigLeipzigGermany
  5. 5.Department of Pediatric Hematology and Oncology, 2nd Faculty of MedicineCharles University in Prague and Motol University HospitalPrahaCzech Republic
  6. 6.Helios Childrens HospitalErfurtGermany
  7. 7.Department of Nuclear MedicineHelios Hospital ErfurtErfurtGermany
  8. 8.Pediatrics 5 (Oncology, Hematology, and Immunology)Klinikum Stuttgart, OlgahospitalStuttgartGermany
  9. 9.Department of Nuclear MedicineKlinikum Stuttgart, OlgahospitalStuttgartGermany
  10. 10.Department of Pediatric Hematology and OncologyUniversity Hospital UlmUlmGermany
  11. 11.Department of Nuclear MedicineUniversity HospitalUlmGermany
  12. 12.Division of Pediatric Hematology and OncologyUniversity Medical Center GöttingenGöttingenGermany
  13. 13.Department of Nuclear MedicineGeorg August UniversityGöttingenGermany
  14. 14.University Hospital for Children and AdolescentsJohannes Wesling Klinikum Minden, Ruhr University HospitalBochumGermany
  15. 15.Universitätsinstitut für Diagnostische Radiologie, Neuroradiologie und Nuklearmedizin, Johannes Wesling Klinikum MindenRuhr University HospitalBochumGermany
  16. 16.Department of Nuclear MedicineMartin Luther University Halle-WittenbergHalleGermany

Personalised recommendations