mmc1 (2) - Digital [email protected]

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mmc1 (2) - Digital [email protected]
SUPPLEMENTAL INFORMATION
PET/CT Protocols
In order to qualify the sites for the [124I]FIAU study, images of a phantom study were
performed. A water-fillable phantom was used with ~37 MBq (~1mCi) of 124I. The
phantoms were imaged at two contiguous bed positions for 5 minutes for each bed
position for a total of 10 minutes. The CT portion of the study was performed with kVp
and mAs values used for a typical patient study. Special attention was focused on
calibration of the site dose calibrator since the study tracer was not a common PET tracer
in most community hospitals. The commercial core laboratory assessed the phantom data
and ensured the SUVavg was within a range of 0.9 and 1.1.
Subjects were instructed to be well hydrated and have an empty bladder prior to the
imaging session. Adequate oral intake and frequent voiding were encouraged to limit
radiation exposure.
For the phase 1 dosimetry study, PET/CT scans were acquired on a GE Discovery ST
(Dimension Console) or a Siemens Biograph 16 scanner. Emission scan time was 5
minutes per bed position. For the phase 2 study, scans were acquired on various models
of GE Discovery, Siemens Biograph and Philips Gemini scanners. Emission scan time
was 20 minutes per bed position.
A low dose CT scan protocol was used for attenuation correction in both trials, at 110140 kVp and mA as low as reasonably achievable.
Definition of Prosthetic Joint Infection
A patient will be considered as having an infected prosthetic joint if any of the following
criteria are met:
1.
2.
3.
4.
5.
A sinus tract is present overlying the painful suspect prosthetic joint OR
Prosthetic joint material is visible in the area of tissue breakdown OR
A single intra-operative culture grows the same organism as a pre-operative joint
aspirate OR
Two separate joint aspirates grow the same organism OR
4 or more of the following 6 criteria (a-f) are met
a.
Evidence of an inflammatory process as evidenced by
i.
An elevated leukocyte count with increased neutrophils OR
ii. An increase neutrophil% with a normal leukocyte count OR
iii. Increased erythrocyte sedimentation rate OR
iv. Increased C-reactive protein
b.
Positive pre-operative joint aspirate defined as
i.
Increased leukocyte count in aspirate OR
ii. Increased neutrophil% in aspirate OR
iii. Aspirate grows an organism typical of prosthetic joint infection
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c.
6.
Histology is positive as defined by
i.
Type II or III peri-prosthetic membrane is present OR
ii. > 5 neutrophils are present in each of 5 high power fields (HPFs) OR
iii. ≥ 23 neutrophils are present in 10 HPF’s
d.
Single positive intra-operative culture
e.
Purulence present in the joint space at time of surgery
f.
Positive intra-operative frozen section (there are two options here: Feldman 5
neutrophils in 5 fields vs. Athansou: at least 1 neutrophil per HPF in 10 HPFs)
Culture of the same organism from 2 or more intra-operative samples.
Murine Collagen-Induced Arthritis (CIA) Model and [124I]FIAU PET Imaging
The mouse CIA model was established at Molecular Imaging (Ann Arbor, MI). All
procedures carried out in this experiment were conducted in compliance with all the laws,
regulations and guidelines of the National Institutes of Health (NIH) and with the
approval of Molecular Imaging’s Animal Care and Use Committee. The diseased-group
mice (n=10) were monitored for disease until the time of imaging (Day 40). Footpad
thickness, clinical score, and body weight measurements were made twice weekly
through Day 39.
The naïve-group animals (n=5) were imaged along with the diseased group and used as a
non-diseased comparator. PET was performed using a Siemens lnveon small animaldedicated PET scanner. The animals were anesthetized with 1-2% isoflurane and placed
onto the PET imaging bed. An injection of [124I]FIAU (350 µCi) was administered at the
start of the 90 min dynamic scans. Body temperature was maintained with a
thermostat-regulated recirculating water-heated pad during injection and imaging
procedures. Animals were again imaged at 24 h and 48 h post injection with 20 min
static scans. PET image analysis was performed using the Amira 5.5.0 analysis software
package.
After the final PET imaging time point, the mice were euthanized via CO2. Whole blood
and tissues were taken for gamma counting and weighed.
The mice in the collagen-treated (diseased) group, but not the untreated (naïve) group,
experienced a progressive increase in total footpad swelling (Figure S1A) and clinical
score (15 per paw, max score =60; Figure S1B), indicative of successful induction of
arthritis. Dynamic 90-minute micro-PET scans were acquired along with static
acquisitions at 24 and 48 h post injection. Percent injected dose (%ID) was calculated by
normalizing the total counts in each tissue of interest at each time point, to the wholebody counts calculated over 1 minute from the whole-body maximum uptake time point,
for each animal, during the first 90 minutes after [124I]FIAU administration.
Peak hind limb %ID for naïve animals was 0.66% at 56 minutes, while for diseased
animals, the peak occurred at 13 minutes and was 1.85% (Figure S1D). For fore limbs,
average %ID for naïve animals peaked at 13 minutes at 0.69%, whereas for diseased
animals it peaked at 13 minutes at 1.13% (Figure S1E). At 24 hours, less than 0.1%
injected dose remained in hind or fore limbs for both naïve and diseased groups, having
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decreased to almost background levels. Comparisons of gamma counting and PET
imaging results were similar.
A
B
Total Footpad Swelling
C
Whole Body
D
Total Clinical Score
Average Hindlimb
E
Average Forelimb
Figure S1. Targeted distribution of [124I]FIAU in a murine collagen-induced arthritis
(CIA) model. CIA model development: total footpad swelling comparison between naïve
and diseased groups (A); total clinical score group comparison (B). [124I]FIAU PET
image analysis indicating percent injected dose in whole body (C), average hindlimb (D)
and average forelimb (E).
Table S1. Participating Institutions and Their Principal Investigators
Study
Institution
Phase 1
Sinai Hospital, Baltimore, MD
Michael A. Mont, MD
University of Arkansas for Medical Sciences,
Little Rock, AK
James E. McDonald, MD
Phoenix Clinical Research, Tamarac, FL
Richard D. Berkowitz, MD
Washington University School of Medicine, St.
Louis, MO
Barry A. Siegel, MD
University of Arkansas for Medical Sciences,
Little Rock, AK
James E. McDonald, MD
Gulfcoast Research Institute, Sarasota, FL
Edward J. Stolarski, MD
Phase 2
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Principal Investigator
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Hospital of the University of Pennsylvania,
Philadelphia, PA
Abass Alavi, MD
Clinical Trials of Texas, San Antonio, TX
Douglas S. Denham, MD
Mission Hospital, Ashville, NC
T. Marc Barnett, MD
Coastal Clinical Research, Mobile, AL
Michael L. Granberry, MD
Table S2. Phase 2 PJI Study Patient Profile – Subject 04-001
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Table S3. Phase 2 PJI Study Patient Profile – Subject 04-009
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