Superparamagnetikus vasrészecske MR kontrasztanyagként való alkalmazási lehetősége intracranialis tumorokban PDF Nyomtatás E-mail
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2009. július 03. péntek, 10:48

Possible use of Superparamagnetic Iron Particle as MR Contrast Agent in Intracranial Tumors

Várallyay Péter 1, Bagó Attila 1,
Edward A. Neuwelt 2

1. National Institute of Neurosurgery, Budapest, Hungary
2. Oregon Health & Sciences University, Portland, OR, USA



Response to external field

  • Ferromagnetic - Fe, Co
    very large induced magnetization - residual strength
  • Superparamagnetic - iron oxide particle
    large induced magnetization - soon loses strength
  • Paramagnetic - Gd-ion, Mn, Al, deoxi-Hb
    Small induced magnetization - no residual strength
  • Diamagnetic - Zn, Au, water, most organic compound, oxi-Hb
    Very weak magnetization opposes the external field



  • Strong paramagnetic
  • 7 unpaired electron/atom
  • Electron magnetic field 650x > proton
  • Shorten T1 and T2
  • Enhancement on T1 sequences


Magnevist TM, Omniscan TM

  • Diffusion - fast extracellular distribution
  • Plasma half-life ~70 min
  • Enhancement is seen ~45 min
  • 0.1 mmol/Kg
  • almost complete renal elimination < 24 h


Gd-DTPA enhancement


  • Ultrasmall Superparamagnetic Iron Oxide
    • Ferumoxtran-10 (CombidexŽ, SineremTM)
    • Ferumoxide (FeridexŽ, EndoremTM)
  • Very effective in shortening T1 and T2

    Increased T1 and decreased T2 signal


Ability of changing the signal intensity (Relaxivity; R)

Iron oxide particles >> Gd DTPA
- R1 5x
- R2 10-20x

Intracerebral injection of MION 26


Preclinical studies (rats)

direct inoculation of MION
BBBD with I.A. of MION
Toxicity: - no demyelination
- no inflammation
- no gliosis
- no progressive damage



  • Mean particle size: 29.5 nm
  • Monocrystalline iron cores
  • Complete, thick dextran coat
  • No rapid opsonization
  • Long plasma half-life: 25-30 hours

Jung C et al., Magnetic resonance Imaging, Vol 13, No 5, 1995



  • Combidex as MR contrast agent in intracranial tumors
  • Correlation of Combidex MR and Histology



n=15, each with Gd enhancing areas
Anaplastic glioma, low grade glioma, GBM, Medulloblastoma, Hamartoma, Meningioma, Pituitary macroadenoma

Combidex administration
2.6 mgFe/kg diluted in 50 ml normal saline, infused at 4 ml/min

MR imaging
with Gd <28 days
with Combidex 6 h and 24 h
SE T1, fast SE T2, GRE T2*


Results Progressive signal change with Combidex (oligo. III)

Várallyay et al. American Journal of Neuroradiology 23:510-519, 2002.


Combidex Signal Change versus Gadolinium Enhancement n=15

  • 13 different types of tumor -> Combidex +
    Anaplastic glioma, GBM, Medulloblastoma, Hamartoma, Meningioma, Pituitary macroadenoma
    • 3 / 13 additional Combidex enh. areas
  • 2 low grade gliomas -> Combidex -


Combidex can be used in imaging brain tumors with the following differences:

  • + Gd / - Combidex
  • - Gd / +Combidex
  • + Gd / + Combidex but less intense
  • + Gd / + Combidex but more intense


+Gd / + Combidex- Gd / + Combidex in the middle (oligo. III.)


+Gd / + Combidex (GBM)


+ Gd / - Combidex (oligo. II.)


+ Gd / + Combidex with more and less intense areas
(meningioma after rad. Tx)


+Gd / + Combidex but less intense
(hypophysis macroadenoma)


+ Gd / + Combidex (less intense tumoral)
- Gd / + Combidex (BAT)


Possible explanation for
+ Gd / - or less Combidex

  • Larger Combidex particles are unable to cross the incompetent BBB that is leaky for Gd
  • Amount of cells capable of accumulating the iron particles
  • Metabolic activity


Possible explanation for- Gd / + Combidex

  • Long plasma half life
  • Accumulation mechanism exists for Combidex but not for Gd
  • Separate mechanism to cross the BBB
  • Diffusion, convection, intracellular transport


Perl`s stain iron
staining at the tumor (T) / reactive brain (RB) interface


Perl`s stain
Iron staining at the tumor (T) / reactive brain interface



  • Combidex can be used in brain tumor imaging
  • Accumulation is primarily at the tumor-brain interface
  • MR can be compared with histology showing cellular location of iron



  • Evaluate Combidex in assessing residual tumor



  • Surgically induced intra- and postop "benign" Gd enhancement.
    • Early: contrast leakage, luxury perfusion, BBB damage
    • Late: granulation tissue
  • Long lasting enhancement with Combidex



  • n=7 with malignant tumor (anaplastic glioma, GBM, Metastasis)
  • Gd-enhanced MR (<28 days)
  • Preop. Combidex-enhanced MR
  • (24 h after Combidex infusion; surgery within four hours)
  • Postop. Combidex-enhanced MR (at an average of 22 h after preop. MR, average 18 h after surgery


Comparison of Combidex versus Gadolinium on pre- and postop. MR

  • Preop. MR
    • n=7 each tumor with Gd and Combidex enhancement
    • 5 / 7 additional Combidex enhancing area
  • Postop. MR
    • 4 / 7 residual Combidex enhancement
    • 3 / 7 indeterminate for residual Combidex

Várallyay et al. ASNR/poster/2003


Reason for 3 / 7 indeterminate cases

Hemostasis materials (H2O2, Surgicel)

early, rapid oxidation of oxihemoglobin


Spiller et al. Journal of Neurosurgery 95:687-693, 2001.


GBM, new lesion


GBM, postop residual Combidex or blood ?


GBM, postop residual Combidex or blood ?


GBM, postop residual Combidex area


GBM, new lesion = new tumor foci ?


GBM, intraop. 0.15 T Odin scanner


Conclusion / 1

  • Combidex may show additional enhancing areas near or even at a distance from the Gd-enhancing tumor
  • Residual Combidex-enhancing areas identified at about 2 days after Combidex inf., 1 day after surgery
  • Potential to assess residual tumor without re-administaring a contrast during postop. MR


Conclusion / 2

  • Single dose contrast agent for pre-, intra- and postop. MR
  • Intraop. hemostasis, which result in MR signal change different than Combidex may be needed.
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