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

Background

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

Gd-DTPA

• 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

IUSPO

• Ultrasmall Superparamagnetic Iron Oxide
  Particles
  • Ferumoxtran-10 (CombidexŽ, Sinerem^TM)
  • Ferumoxide (FeridexŽ, Endorem^TM)
• 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

 

Combidex

• 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

Purpose

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

Method

Patients
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

Conclusion

• 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

Purpose

• Evaluate Combidex in assessing residual tumor

Background

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

Method

• 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

Results
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

methemoglobin

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.