Trial Information

Pilot Differentiation of Bone Sarcomas and Osteomyelitis With Ferumoxytol-Enhanced MRI

Objective:

1. Establish MR imaging characteristics of bone sarcomas and osteomyelitis based on their
ferumoxytol-enhancement on relatively early postcontrast T1-weighted images.

2. Establish MR imaging characteristics of bone sarcomas and osteomyelitis based on their
ferumoxytol-enhancement on delayed postcontrast T2-weighted images.

Background and Significance:

Sarcomas represent approximately 5-10 % of adult and childhood tumors. Bone sarcomas, such
as osteosarcomas and Ewing sarcomas, occur in approximately 650 new cases annually in
children and adolescents. An accurate diagnosis is essential in order to refer these
patients to appropriate treatment by oncologists and orthopedic surgeons. However,
conventional clinical, laboratory and imaging (MRI, CT and bone scans) signs of bone
sarcomas, especially Ewing sarcomas, can show significant overlap with a subacute
osteomyelitis. As a result, there are numerous reports of misdiagnoses of sarcomas as
inflammations with inappropriate antibiotic treatment leading to tumor progression or
inadequate biopsies leading to limb amputation. Thus, more accurate diagnostic techniques
that can reliably differentiate these different pathologies are critically needed. The
investigators propose to utilize differences in the cellular composition of sarcomas and
inflammations to generate a more specific diagnostic test. Interestingly, 99mTc sulphur
colloid, which is phagocytosed by macrophages, demonstrated a marked uptake in
osteomyelitis, but not malignant tumors, supporting our concept. Sulphur colloid scans are
associated with considerable radiation exposure and low anatomical resolution, thereby
limiting its utility in children. Ultra small superparamagnetic iron oxide nanoparticles
(USPIO) provide a radiation free alternative to sulphur colloid and can be depicted with MR
imaging, which provides 3D information, high soft tissue contrast and sub-millimeter
anatomical resolution. The investigators and others have utilized preclinical USPIO
compounds for MR imaging of inflammations and tumors. However, to the best of our knowledge,
the value of FDA-approved USPIO for the differentiation of malignant bone sarcomas and
osteomyelitis has not been investigated. Ferumoxytol (FerahemeÔ) represents a novel USPIO
compound that has been recently FDA-approved for intravenous treatment of iron deficiencies
in patients with renal failure. Ferumoxytol exerts strong signal effects on MR images, as
quantified by a high r1 relaxivity of 38 L mmol-1 s-1 and a high r2 relaxivity of 83 L
mmol-1 s-1 at 20 mHz. Ferumoxytol has been applied as a contrast agent for MR imaging of
arthritis in an animal model and imaging of glioblastomas in patients . To the best of our
knowledge, ferumoxytol has not been investigated for MR imaging of bone sarcomas or
osteomyelitis.

Realization of our goal to develop an immediately clinically applicable MR imaging test for
non-invasive differentiation of osteomyelitis and bone sarcomas will enable us to provide a
quick and non-invasive diagnosis of these pathologies, accelerate patient referral to
appropriate pediatric subspecialities and prevent inappropriate anti-inflammatory treatment
or delay of cytotoxic treatment of sarcomas.

Research Design and Methods:

The investigators propose an "off label" investigation of ferumoxytol (FerahemeÔ, AMAG) as a
novel contrast agent for the depiction and differentiation of bone sarcomas and
osteomyelitis via a hypothesis driven approach:

Hypothesis:

1. Bone sarcomas and osteomyelitis show a different T1-enhancement at 1 h post injection
(p.i.) of ferumoxytol

2. Bone sarcomas and osteomyelitis demonstrate differences in T2-enhancement at 24 h p.i.
of ferumoxytol

The investigators plan to enroll 20 patients in this study, 10 patients with bone sarcomas
and 10 patients with an osteomyelitis. The sample size has been determined based on our
preliminary data and power calculations. The investigators will screen all patients with
proven or suspected bone sarcoma or osteomyelitis for potential participation in this study.
Inclusion criteria will comprise an age of less than 10-20 (the investigators do not include
younger patients in order to exclude need of sedation) and a suspected or confirmed
diagnosis of a bone sarcoma or osteomyelitis. Exclusion criteria comprise MR-incompatible
metal implants, need of sedation (since an anesthesia is not supported by this),
claustrophobia or hemosiderosis/hemochromatosis. All patients will undergo two subsequent
imaging tests on a 3T MR scanner, using dedicated surface coils for high resolution MR
imaging. During the first MR examination, ferumoxytol will be injected intravenously at a
dose of 5 mg Fe/kg:

(A) MRI before and up to 1 h after injection of ferumoxytol for evaluation of lesion
perfusion, blood volume, microvascular permeability and interstitial retention (enhanced
permeability and retention effect of macromolecules) (B) 24h after (A): Follow up MRI for
evaluation of macrophage phagocytosis

Data Analysis: The signal intensity of the bone lesion, bone marrow, adjacent normal muscle,
and background noise will be measured by operator defined regions of interest (ROI). The
contrast enhancement of the bone lesions will be calculated as (SIpre-SIpost)/SIpre x 100%.
In addition, T2- and T2* relaxation times of the bone lesions will be determined based on
multi-echo sequences and converted to R2 and R2* relaxation rates. Serial signal-to-noise
ratios of the lesion on dynamic postcontrast T1-SPGR sequences will be used to calculate the
blood volume of the lesion and microvascular permeability of ferumoxytol via kinetic
analyses as described previously.

Statistics: Quantitative MR data will be compared between the two experimental groups,
different time points of observation and different pulse sequences, using T-tests and an
analysis of variance (ANOVA). Statistically significant differences will be assigned for a p
value of < 0.05.

Endpoint: Endpoint of these examinations is to define distinctive MR signal characteristics
of bone sarcomas and osteomyelitis, which will be immediately applicable in a clinical
setting.