The immune response or inflammation is known to be a key driver of progression and growth in many solid tumours. Inflammatory cells called macrophages are present in high numbers in many brain tumours and these tumour associated macrophages or TAM are thought to have prognosis and treatment implications in these tumours. A key question, however, is how this inflammation or TAM abundance can be detected, measured and monitored in the clinic. A clinically applicable imaging test that can directly and accurately measure tumour macrophage content would be of considerable value and one technique that may provide this is USPIO enhanced magnetic resonance imaging (MRI). Following intravenous injection, USPIO or ultrasmall superparamagnetic iron oxide nanoparticles, circulate in the bloodstream before being taken up by inflammatory cells/macrophages in tumour tissue, wherein they can be detected by MRI. This pilot study is to evaluate if a commercially available USPIO preparation called ferumoxytol (Feraheme ©) can accurately quantify macrophage abundance in brain tumours, with an exploratory focus on vestibular schwannoma (VS) and suspected transforming low-grade glioma (LGG). Patients with both non-growing (static) and growing VS, and patients with suspected transforming LGG will undergo dedicated MRI sequences before, immediately after (\< 2 hours) and at both 24 and 48hrs after ferumoxytol administration. In patients undergoing surgery, acquired imaging will be compared with resected tumour tissue so that markers of inflammation can be compared with USPIO uptake. Through advanced laboratory methods this study will seek to establish within resected VS and LGG specimens: the cellular destination/s of USPIO uptake; the nature of the inflammatory and/or tumour cells containing the USPIO; and the relationship between USPIO uptake and tumour blood vessel permeability or leakiness.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
17
Ferumoxytol (Feraheme©, AMAG pharmaceuticals, US) enhanced MRI
Salford Royal Hospital Northern Care Alliance NHS Foundation Trust
Salford, Greater Manchester, United Kingdom
RECRUITINGEstablish in a cohort of surgically resected sporadic VS if the enhancement pattern of delayed (24-48 hr) USPIO uptake correlates with tissue markers of TAM density and tissue microvascular markers.
Use correlation tests to establish the relationship between delayed (24-48 hr) USPIO related MRI signal intensity changes and tissue markers of TAM density and microvascular markers.
Time frame: Three years
Establish the relationship between enhancement patterns following GBCA administration and the volume, pattern and intensity of early (<2hr) and delayed (24-48 hr) USPIO imaging in these tumours.
Differences in the enhancement pattern between post GBCA T1W images and the delayed (24-48hr) ferumoxytol enhanced T1W images will be compared through visual inspection and use of the structural similarity index
Time frame: Three years
Evaluate the association between microvascular parameters derived from dynamic contrast enhanced (DCE) MRI) and the volume, pattern and intensity of early (<2hr) and delayed (24-48 hr) USPIO imaging in these tumours.
Use voxelwise correlation tests and ROI analysis to establish the relationship between microvascular parameters derived from dynamic contrast enhanced (DCE) MRI) and USPIO related signal intensity changes at early (\<2hr) and delayed (24-48 hr) imaging timepoints in these tumours.
Time frame: Three years
Establish in VS the relationship between the volume, pattern and intensity of early (<2hr) and delayed (24-48 hr) USPIO imaging in these tumours with tumour size and tumour growth status (non-growing or static vs growing).
Evaluate using appropriate parametric and non-parametric statistical tests if there are differences between non-growing and growing VS in USPIO related signal intensity changes on acquired T1, T2 and T2\* weighted imaging at early (\<2hr) and delayed (24-48 hr) imaging timepoints. Evaluate using correlation and regression analyses if there is a relationship between tumour size and USPIO related signal intensity changes on acquired T1, T2 and T2\* weighted imaging at early (\<2hr) and delayed (24-48 hr) imaging timepoints.
Time frame: Three years
Establish within resected VS and transforming low-grade glioma specimens the cellular destination/s of USPIO internalisation and the in vivo relationship between BBB disruption and USPIO extravasation.
Immunohistochemistry (IHC)/ immunofluorescence will be used on both formalin fixed paraffin embedded (FFPE) and frozen tissue samples to map the uptake of USPIO within immune and non-immune cell populations.
Time frame: Three years
Establish if the enhancement pattern of delayed (24-48 hr) USPIO uptake correlates with loco-regional tissue markers of immune cell infiltration and malignant transformation within imaged transforming low grade glioma.
Evaluate using appropriate parametric and non-parametric statistical tests if there are differences in USPIO related signal intensity changes and immune cell infiltration within regions of histologically proven transformation when compared to non-transformed areas.
Time frame: Three years
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