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

8 Years
30 Years
Open (Enrolling)
Bone Cancer, Chondrosarcoma, Ewing's Sarcoma, Osteosarcoma, Rhabdomyosarcoma

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Trial Information

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


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

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:


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

Inclusion Criteria:

Inclusion criteria will comprise:

- An age of 8-30 years

- Suspected or confirmed diagnosis of a bone sarcoma or osteomyelitis.

The investigators do not include younger patients (age less than 8 yrs) in order to
exclude need of sedation. There will be no gender/race-ethnic restrictions

In this pediatric & adult study, the participant or parent/guardian is consented, and the
patient when a minor is given an assent form and involved in the discussion as

Exclusion Criteria:

Exclusion criteria will comprise:

- Contraindication to MRI

- Presence of metal implants

- Need for sedation or anesthesia

- Claustrophobia

- Hemosiderosis/hemochromatosis

There will be no restrictions regarding use of other Investigational Agents.

Patients with evidence of iron overload, hemosiderosis/hemochromatosis will be excluded.

History of allergic reactions to similar compounds will be obtained and patients with
positive history of allergic reactions will be excluded from the study.

Pregnancy or nursing patients will be excluded from the study. A pregnancy test will be
done prior to the MR examination for postmenarchal teenage girls, in whom pregnancy may be
possible. Only patients with a negative pregnancy test will be included in the study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Diagnostic

Outcome Measure:

all cause mortality

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Dr. Heike E Daldrup-Link

Investigator Role:

Principal Investigator

Investigator Affiliation:

Stanford University


United States: Institutional Review Board

Study ID:




Start Date:

August 2011

Completion Date:

March 2014

Related Keywords:

  • Bone Cancer
  • Chondrosarcoma
  • Ewing's Sarcoma
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Bone Neoplasms
  • Osteosarcoma
  • Chondrosarcoma
  • Osteomyelitis
  • Rhabdomyosarcoma
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma



Stanford University School of Medicine Stanford, California  94305-5317