CNS Drugs

, Volume 32, Issue 3, pp 229–240 | Cite as

Gadolinium-Based Contrast Agent-Related Toxicities

  • Luca Pasquini
  • Antonio Napolitano
  • Emiliano Visconti
  • Daniela Longo
  • Andrea Romano
  • Paolo Tomà
  • Maria Camilla Rossi Espagnet
Review Article
First Online:
  • 161 Downloads

Abstract

In recent years, gadolinium-based contrast agents have been associated with different types of toxicity. In particular, nephrogenic systemic fibrosis, a progressive sclerotic-myxedematous systemic disease of unknown etiology, is related to gadolinium-based contrast agent administration in patients with kidney dysfunction. More recently, evidence of magnetic resonance signal intensity changes on pre-contrast T1-weighted images after multiple gadolinium-based contrast agent administrations resulted in the hypothesis of gadolinium brain accumulation in patients with normal renal function, subsequently confirmed in pathological samples. However, there is limited current data and further investigations are necessary before drawing definite conclusions on the clinical consequences of gadolinium-based contrast agent accumulation in human tissues and particularly in the brain. Gadolinium-based contrast agent-related toxicity appears connected to molecular stability, which varies together with the pharmacokinetic properties of the compound and depends on the individual characteristics of the subject. During a lifetime, the physiological changes occurring in the human body may influence its interaction with gadolinium-based contrast agents: the integrity and developmental stage of the organs has an effect on the dynamics of gadolinium-based contrast agent distribution and excretion, thus leading to different possible mechanisms of deposition and toxicity. Therefore, the aim of this work is to discuss the pharmacokinetics and pharmacodynamics of gadolinium-based contrast agents, with a special focus on the brain, and to explore potential predominant gadolinium-based contrast agent-related toxicity in two cornerstone periods of the human life cycle: fetal/neonatal and adulthood/aged.

This is a preview of subscription content, log in to check access

Notes

Compliance with Ethical Standards

Funding

No sources of funding were received for the preparation of this article.

Conflict of interest

Luca Pasquini, Antonio Napolitano, Emiliano Visconti, Daniela Longo, Andrea Romano, Paolo Tomà, and Maria Camilla Rossi Espagnet have no conflicts of interest directly relevant to the content of this article.

References

  1. 1.
    Idée J, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol. 2006;20:563–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Hao D, Ai T, Goerner F, et al. MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging. 2012;36:1060–71.CrossRefPubMedGoogle Scholar
  3. 3.
    Cowper S, Robin H, Steinberg S, Su L, Gupta S, LeBoit P. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000–1.CrossRefPubMedGoogle Scholar
  4. 4.
    Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology. 2014;270:834–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Kanda T, Fukusato T, Matsuda M, et al. Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology. 2015;276:228–32.CrossRefPubMedGoogle Scholar
  6. 6.
    McDonald R, McDonald J, Kallmes D, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275:772–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Le Mignon MM, Chambon C, Warrington S, et al. Gd-DOTA: pharmacokinetics and tolerability after intravenous injection into healthy volunteers. Invest Radiol. 1990;25:933–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Aime S, Caravan P. Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging. 2009;30:1259–67.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Huckle J, Altun E, Jay M, Semelka R. Gadolinium deposition in humans. Invest Radiol. 2016;51:236–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Prybylski J, Maxwell E, Coste Sanchez C, Jay M. Gadolinium deposition in the brain: lessons learned from other metals known to cross the blood–brain barrier. Magn Reson Imaging. 2016;34:1366–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Maximova N, Gregori M, Zennaro F, Sonzogni A, Simeone R, Zanon D. Hepatic gadolinium deposition and reversibility after contrast agent-enhanced MR imaging of pediatric hematopoietic stem cell transplant recipients. Radiology. 2016;281:418–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Birka M, Wentker K, Lusmöller E, et al. Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis. Anal Chem. 2015;87:3321–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann H. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 °C. Invest Radiol. 2008;43:817–28.CrossRefPubMedGoogle Scholar
  14. 14.
    Prybylski J, Semelka R, Jay M. The stability of gadolinium-based contrast agents in human serum: a reanalysis of literature data and association with clinical outcomes. Magn Reson Imaging. 2017;38:145–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Puttagunta NR, Gibby WA, Smith GT. Human in vivo comparative study of zinc and copper transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol. 1996;31:739–42.CrossRefPubMedGoogle Scholar
  16. 16.
    Kimura J, Ishiguchi T, Matsuda J, et al. Human comparative study of zinc and copper excretion via urine after administration of magnetic resonance imaging contrast agents. Radiat Med. 2005;23:322–6.PubMedGoogle Scholar
  17. 17.
    Fretellier N, Poteau N, Factor C, et al. Analytical interference in serum iron determination reveals iron versus gadolinium transmetallation with linear gadolinium-based contrast agents. Invest Radiol. 2014;49:766–72.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Niendorf HP, Seifert W. Serum iron and serum bilirubin after administration of Gd-DTPA in healthy volunteers. Invest Radiol. 1988;23:275–80.CrossRefGoogle Scholar
  19. 19.
    Swaminathan S. Gadolinium toxicity: iron and ferroportin as central targets. Magn Reson Imaging. 2016;34:1373–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Mühler A, Saeed M, Brasch R, Higgins C. Amelioration of cardiodepressive effects of gadopentetate dimeglumine with addition of ionic calcium. Radiology. 1992;184:159–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Schaer CA, Schoedon G, Imhof A, Kurrer MO, Schaer DJ. Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Circ Res. 2006;99:943–50.CrossRefPubMedGoogle Scholar
  22. 22.
    esur.org. ESUR guidelines. 2016. http://www.esur.org/esur-guidelines/. Accessed 18 Feb 2018.
  23. 23.
    ema.europa.eu. European Medicines Agency. 2016. http://www.ema.europa.eu/ema/. Accessed 18 Feb 2018.
  24. 24.
    Fda.gov. US Food and Drug Administration. 2016. http://www.fda.gov/. Accessed 18 Feb 2018.
  25. 25.
    Webb JA, Thomsen HS, Morcos SK, et al. The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol. 2005;15:1234–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Tirada N, Dreizin D, Khati N, Akin E, Zeman R. Imaging pregnant and lactating patients. Radiographics. 2015;35:1751–65.CrossRefPubMedGoogle Scholar
  27. 27.
    Oh K, Roberts V, Schabel M, Grove K, Woods M, Frias A. Gadolinium chelate contrast material in pregnancy: fetal biodistribution in the nonhuman primate. Radiology. 2015;276:110–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Webb J, Thomsen H. Gadolinium contrast media during pregnancy and lactation. Acta Radiol. 2013;54:599–600.CrossRefPubMedGoogle Scholar
  29. 29.
    Okuda Y, Sagami F, Tirone P, Morisetti A, Bussi S, Masters R. Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (3): study of embryo-fetal toxicity in rabbits by intravenous administration. J Toxicol Sci. 1999;24(Suppl. 1):79–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Khairinisa M, Takatsuru Y, Amano I, et al. The effect of perinatal gadolinium-based contrast agents on adult mice behavior. Invest Radiol. 2018;53(2):110–8.PubMedGoogle Scholar
  31. 31.
    Ray J, Vermeulen M, Bharatha A, Montanera W, Park A. Association between MRI exposure during pregnancy and fetal and childhood outcomes. JAMA. 2016;316:952.CrossRefPubMedGoogle Scholar
  32. 32.
    Fraum T, Ludwig D, Bashir M, Fowler K. Gadolinium-based contrast agents: a comprehensive risk assessment. J Magn Reson Imaging. 2017;46:338–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Kubik-Huch R, Gottstein-Aalame N, Frenzel T, et al. Gadopentetate dimeglumine excretion into human breast milk during lactation. Radiology. 2000;216:555–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Schmiedl U, Maravilla KR, Gerlach R, Dowling CA. Excretion of gadopentetate dimeglumine in human breast milk. AJR. 1990;154:1305–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Rofsky NM, Weinreb JC, Litt AW. Quantitative analysis of gadopentetate dimeglumine excreted in breast milk. J Magn Reson Imaging. 1993;3:131–2.CrossRefPubMedGoogle Scholar
  36. 36.
    Roccatagliata L, Vuolo L, Bonzano L, Pichiecchio A, Mancardi G. Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology. 2009;251:503–10.CrossRefPubMedGoogle Scholar
  37. 37.
    Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology. 2015;275:783–91.CrossRefPubMedGoogle Scholar
  38. 38.
    Kanda T, Osawa M, Oba H, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology. 2015;275:803–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Cao Y, Huang DQ, Shih G, Prince MR. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR. 2016;206:414–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Radbruch A, Weberling LD, Kieslich PJ, et al. Intraindividual analysis of signal intensity changes in the dentate nucleus after consecutive serial applications of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol. 2016;51:683–90.CrossRefPubMedGoogle Scholar
  41. 41.
    Radbruch A. Are some agents less likely to deposit gadolinium in the brain? Magn Reson Imaging. 2016;34:1351–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Radbruch A, Haase R, Kickingereder P, et al. Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast agent. Radiology. 2017;283:828–36.CrossRefPubMedGoogle Scholar
  43. 43.
    Conte G, Preda L, Cocorocchio E, et al. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. Eur Radiol. 2017;27:4372–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Flood T, Stence N, Maloney J, Mirsky D. Pediatric brain: repeated exposure to linear gadolinium-based contrast material is associated with increased signal intensity at unenhanced T1-weighted MR imaging. Radiology. 2017;282:222–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Miller J, Hu H, Pokorney A, Cornejo P, Towbin R. MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics. 2015;136:e1637–40.CrossRefPubMedGoogle Scholar
  46. 46.
    Roberts D, Holden K. Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. Brain Dev. 2016;38:331–6.CrossRefPubMedGoogle Scholar
  47. 47.
    McDonald RJ, McDonald JS, Kallmes DF, et al. Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without intracranial abnormalities. Radiology. 2017;285:546–54.CrossRefPubMedGoogle Scholar
  48. 48.
    Rossi Espagnet M, Bernardi B, Pasquini L, Figà-Talamanca L, Tomà P, Napolitano A. Signal intensity at unenhanced T1-weighted magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children. Pediatr Radiol. 2017;47:1345–52.CrossRefPubMedGoogle Scholar
  49. 49.
    Stojanov D, Aracki-Trenkic A, Benedeto-Stojanov D. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents: current status. Neuroradiology. 2016;58:433–41.CrossRefPubMedGoogle Scholar
  50. 50.
    Bjørnerud A, Vatnehol S, Larsson C, Due-Tønnessen P, Hol P, Groote I. Signal enhancement of the dentate nucleus at unenhanced MR imaging after very high cumulative doses of the macrocyclic gadolinium-based contrast agent gadobutrol: an observational study. Radiology. 2017;285:434–44.CrossRefPubMedGoogle Scholar
  51. 51.
    Tibussek D, Rademacher C, Caspers J, et al. Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology. 2017;285:223–30.CrossRefPubMedGoogle Scholar
  52. 52.
    Murata N, Gonzalez-Cuyar LF, Murata K, et al. Macrocyclic and other non-group 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue: preliminary results from 9 patients with normal renal function. Invest Radiol. 2016;51:447–53.CrossRefPubMedGoogle Scholar
  53. 53.
    Wedeking P, Kumar K, Tweedle M. Dose-dependent biodistribution of [153Gd] Gd(acetate)n in mice. Nucl Med Biol. 1993;20:679–91.CrossRefPubMedGoogle Scholar
  54. 54.
    Robert P, Violas X, Grand S, et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol. 2016;51:73–82.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Adding L, Bannenberg G, Gustafsson L. Basic experimental studies and clinical aspects of gadolinium salts and chelates. Cardiovasc Drug Rev. 2006;19:41–56.CrossRefGoogle Scholar
  56. 56.
    Frenzel T, Apte C, Jost G, Schöckel L, Lohrke J, Pietsch H. Quantification and assessment of the chemical form of residual gadolinium in the brain after repeated administration of gadolinium-based contrast agents: comparative study in rats. Invest Radiol. 2017;52:396–404.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Gianolio E, Bardini P, Arena F, et al. Gadolinium retention in the rat brain: assessment of the amounts of insoluble gadolinium-containing species and intact gadolinium complexes after repeated administration of gadolinium-based contrast agents. Radiology. 2017;285(3):839–49.CrossRefPubMedGoogle Scholar
  58. 58.
    Iliff J, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid b. Sci Transl Med. 2012;4:147ra111.Google Scholar
  59. 59.
    Jessen N, Munk A, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40:2583–99.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Burns E, Dobben G, Kruckeberg TW, Gaetano PK. Blood–brain barrier: morphology, physiology, and effects of contrast media. Adv Neurol. 1981;30:159–65.PubMedGoogle Scholar
  61. 61.
    Chung MC-M. Structure and function of transferrin. J Chem Inf Model. 1989;53:160.Google Scholar
  62. 62.
    Chia W-J, Tan FCK, Ong W-Y, Dawe GS. Expression and localization of brain-type organic cation transporter (BOCT/24p3R/LCN2R) in the normal rat hippocampus and after kainate-induced excitotoxicity. Neurochem Int. 2015;87:43–59.CrossRefPubMedGoogle Scholar
  63. 63.
    Bressler JP, Cheong JH, Kim Y, Maerten A, Bannon D. Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities. Hum Exp Toxicol. 2007;26:221–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Xia D, Davis RL, Crawford J, Abraham JL. Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiol. 2010;51:1126–36.CrossRefPubMedGoogle Scholar
  65. 65.
    Hadaczek P, Yamashita Y, Mirek H, Tamas L, Bohn MC, Noble C, et al. The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther. 2006;14:69–78.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bakker EN, Bacskai BJ, Arbel-Ornath M, et al. Lymphatic clearance of the brain: perivascular, paravascular and significance for neurodegenerative diseases. Cell Mol Neurobiol. 2016;36:181–94.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Naganawa S, Nakane T, Kawai H, Taoka T. Lack of contrast enhancement in a giant perivascular space of the basal ganglion on delayed FLAIR images: implications for the glymphatic system. Magn Reson Med Sci. 2017;16:89–90.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Jost G, Frenzel T, Lohrke J, Lenhard D, Naganawa S, Pietsch H. Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue. Eur Radiol. 2016;27:2877–85.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Öner A, Barutcu B, Aykol Ş, Tali E. Intrathecal contrast-enhanced magnetic resonance imaging-related brain signal changes. Invest Radiol. 2017;52:195–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17:2359–62.CrossRefPubMedGoogle Scholar
  71. 71.
    Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int. 2007;72:260–4.CrossRefPubMedGoogle Scholar
  72. 72.
    Thomsen H, Morcos S, Almén T, et al. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol. 2012;23:307–18.CrossRefPubMedGoogle Scholar
  73. 73.
    Zou Z, Zhang H, Roditi G, Leiner T, Kucharczyk W, Prince M. Nephrogenic systemic fibrosis. JACC Cardiovasc. Imaging. 2011;4:1206–16.Google Scholar
  74. 74.
    Edward M, Quinn JA, Burden AD, Newton BB, Jardine AG. Effect of different classes of gadolinium-based contrast agents on control and nephrogenic systemic fibrosis-derived fibroblast proliferation. Radiology. 2010;256:735–43.CrossRefPubMedGoogle Scholar
  75. 75.
    Varani J, DaSilva M, Warner RL, et al. Effects of gadolinium-based magnetic resonance imaging contrast agents on human skin in organ culture and human skin fibroblasts. Invest Radiol. 2009;44:74–81.CrossRefPubMedGoogle Scholar
  76. 76.
    Steger-Hartmann T, Raschke M, Riefke B, Pietsch H, Sieber MA, Walter J. The involvement of pro-inflammatory cytokines in nephrogenic systemic fibrosis: a mechanistic hypothesis based on preclinical results from a rat model treated with gadodiamide. Exp Toxicol Pathol. 2009;61:537–52.CrossRefPubMedGoogle Scholar
  77. 77.
    Idée JM, Port M, Dencausse A, Lancelot E, Corot C. Involvement of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: an update. Radiol Clin North Am. 2009;47:855–69.CrossRefPubMedGoogle Scholar
  78. 78.
    High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol. 2007;56:21–6.CrossRefPubMedGoogle Scholar
  79. 79.
    Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. 2007;56:27–30.CrossRefPubMedGoogle Scholar
  80. 80.
    Kribben A, Witzke O, Hillen U, Barkhausen J, Daul AE, Erbel R. Nephrogenic systemic fibrosis: pathogenesis, diagnosis, and therapy. J Am Coll Cardiol. 2009;53:1621–8.CrossRefPubMedGoogle Scholar
  81. 81.
    Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology. 2007;243:148–57.CrossRefPubMedGoogle Scholar
  82. 82.
    European Medicines Agency. EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans. 2017. EMA/625317/2017. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/gadolinium_contrast_agents_31/European_Commission_final_decision/WC500240575.pdf. Accessed 18 Feb 2018.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuroradiology UnitSant’Andrea HospitalRomeItaly
  2. 2.Medical Physics Unit, Risk Management EnterpriseBambino Gesù Children’s HospitalRomeItaly
  3. 3.Neuroradiology UnitOspedale M. BufaliniCesenaItaly
  4. 4.Neuroradiology Unit, Imaging DepartmentBambino Gesù Children’s HospitalRomeItaly
  5. 5.Department of Odontostomatological and Maxillo-Facial SciencesSapienza UniversityRomeItaly
  6. 6.Imaging DepartmentBambino Gesù Children’s HospitalRomeItaly

Personalised recommendations