Novel Gallium 68 Citrate in Orthopedic Infections
Phase: PHASE2
Conditions: Joint Prosthesis
Sponsor: Rutgers, The State University of New Jersey

 
 
Protocol Version 2.0 February 2018 
Nuclear Medicine 
Depatment of Radiology 
Rutgers, The State University of New Jersey 
150 Bergen Street 
Newark, NJ 07103 
p. 973-972-6022 
f. 973-972-6954 
  
 
 
Study Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections.  
 
Principal Investigator: Nasrin Ghesani, MD  
 
Study Site: Rutgers New Jersey Medical School 
 
1. Purpose/Specific Aims:   
 
The purpose of the current study is to demonstrate the feasibility and evaluate the accuracy of 
68Gallium (68Ga)-citrate positron emission tomography/computed tomography (PET/CT) in 
diagnosing prosthetic joint infection and compare it with 18fluorine-fluorodeoxyglucose-positron 
emission tomography/computed tomography (FDG-PET/CT). We expect that 68Ga-citrate PET/CT 
will serve as a novel molecular-based sensitive functional imaging modality superior to FDG-
PET/CT. We intend to translate the results of this preliminary study to fuel larger studies in the 
utility of 68Ga-citrate PET/CT to evaluate prosthesis complications, where current available 
imaging techniques are challenging. 
 
2. Background and Significance 
 
Epidemiology: 
 
A total of 4.5 and 6.7 million people in the United States are currently living with an artificial hip 
or knee. With aging of the population, and increased obesity and longevity, this number is likely to 
increase in the coming decades and will create significant challenges for management of long-term 
complications (1). The local complications of joint replacement include infection, instability and 
dislocation, aseptic loosening and periprosthetic fracture. Periprosthetic infection, the most 
devastating complication of joint replacement, is associated with significant morbidity and cost. 
The infection rates following primary implantation and revision surgery are approximately 1% 
and 3% for hip prostheses and 2% and 5% for knee prostheses, respectively (2, 3). The most 
common complication, on the other hand, is aseptic loosening which is most often caused by wear 
of the prosthetic components. For hip replacement, the risk of aseptic loosening leading to 
revision total hip arthroplasty is about 1 percent per year (4). It is crucial to differentiate 
prosthetic joint infection from aseptic loosening for appropriate patient management. The 
treatment for prosthesis infection generally involves both systemic antibiotics for an extended 
period and exchange arthroplasty in one or two stages, whereas aseptic loosening usually requires 
a single revision arthroplasty (5, 6).  
 
Physical examination, laboratory tests, radiography and joint aspiration used to diagnose 
prosthesis infection are insensitive and/or nonspecific. Evaluation of prosthetic joint with 
morphologic imaging such as CT or MRI has been plagued by poor differentiation between 
infection and aseptic inflammation/loosening. These modalities are also hampered by artifacts 
produced by the prosthetic devices themselves (2). Functional modalities have the ability to detect 
infection when morphologic imaging is nonspecific (2, 7). Of these modalities, promising data exist 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
supporting combined leukocyte–marrow scintigraphy, 67Gallium (67Ga)-citrate imaging and 
18fluorine-fluorodeoxyglucose-positron emission tomography (FDG-PET). 
 
Current Diagnostic Techniques: 
 
Combined leukocyte–marrow scintigraphy: 
Combined 111Indium-labelled leucocyte-99mTechnetium-sulphur colloid marrow scintigraphy 
achieves a high diagnostic accuracy and is currently considered as the imaging modality of choice 
for diagnosing periprosthetic infection. However, combined leukocyte–marrow scintigraphy is 
time-consuming, labor-intensive, not widely available, and potentially hazardous because of direct 
handling of blood products (8).  
 
18F-FDG-PET:  
FDG acts as a glucose analog and is taken up by metabolically active cells, namely leucocytes, 
neutrophilic granulocytes, and macrophages because of increased glucose metabolism and 
expression of glucose transporters in these cells. In the case of infection, it is also taken up by 
bacteria present in the infected tissue (9-12). This increased FDG uptake makes local detection of 
bacterial infections possible. Although FDG PET/CT has high diagnostic sensitivity to detect 
prosthetic joint infection, its specificity is low, that is, it fails to differentiate between prosthesis 
infection and aseptic loosening (7, 8, 10, 13-20). The presence of periprosthetic FDG uptake in a 
non-infected prosthesis can be explained by altered marrow distribution secondary to the 
placement of an orthopaedic prosthesis (15) and an immunological reaction to wear-induced 
polyethylene and metal particles released from the prosthesis inlay (7). 
 
67Ga-citrate Imaging: 
Gallium-67 (67Ga) is a group IIIb transition metal, similar to the ferric ion in terms of its atomic 
radius, charge, and the inorganic complexes it forms. The uptake mechanisms of radiogallium are 
not fully understood (12, 21). The most generally accepted theory is that it may enter the cells by 
means of binding with circulating transferrin and use of transferrin receptors, and locally it may 
bind to lactoferrin produced by leucocytes and siderophores produced by infecting micro-
organisms themselves (22-24). Another uptake mechanism may involve direct uptake of gallium 
by infective organisms, an occurrence that has been proven in vitro. Microorganisms grown in an 
iron-deficient environment produce siderophores that have an extraordinary binding affinity for 
gallium as well as iron. Because of little free iron present in most tissues, it is assumed that 
pathogenic microorganisms produce siderophores, and the siderophore–gallium complex is 
presumably then transported directly into the microorganism (25). Historically, 67Ga has been 
successfully implemented as an infection-detecting tracer in imaging of bone infections (21). 
However, the clinical application of 67Ga scintigraphy has been compromised due to several 
factors. The limited injectable activity (due to the long half-life of 78 hours) and the wide spectrum 
of gammas emitted by 67Ga-citrate reduce image quality and resolution. 67Ga-citrate is a 
cyclotron produced isotope and must be purchased commercially (21). 
 
Novel 68Ga-citrate PET/CT: 
Gallium-68 (68Ga) is a positron-emitting cyclotron-independent radionuclide with a short half-life 
of 68 min. This radionuclide has been previously applied in labelling of oligonucleotides and 
peptides for PET imaging. 68Ga-citrate PET/CT scanning may overcome the shortcomings of 
67Ga-citrate and FDG PET scanning. 68Ga-citrate has a similar mechanism of uptake and 
localization in the human body as 67Ga-citrate.  However, as a different isotope of gallium, 68Ga-

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
citrate isotope presents many advantages over 67Ga-citrate in its use in the diagnostic work-up 
and management of patients with bone infection. First, 68Ga-citrate is a positron emitter, lending 
to higher resolution imaging over gamma emitters like 67Ga-citrate. Second, the half-life of 68Ga is 
much shorter than that of 67Ga (only 68 minutes), allowing patients to be given higher tracer 
doses and to be discharged almost free of the radioactivity. Third, the uptake phase is short, as is 
the whole-body image acquisition, allowing a shorter imaging time. Fourth, due to shorter half-life 
of 68Ga-citrate, there is significantly less radiation burden to patient compared to 67Ga-citrate. 
Recently, one of the commercial radiopharmacy in our area has housed Gallium generator and has 
promised us to deliver Gallium 68 Citrate. We recently received funding from Radiological Society 
of North America to assess utility of Gallium 68 Citrate in hepatocellular carcinoma patients. To 
our knowledge, we will be the only facility in United States pursuing such research.   
 
Preliminary Studies: 
 
Gallium labeled radiotracers are extensively researched in Europe, Asia and Africa. However, 
research in this area in United States is lagging behind due to lack of commercially available 
generator. In preliminary studies, 68Ga-citrate PET/CT has been successful to identify soft tissue 
cellulitis and abscess in humans and osteomyelitis in animal models (21). In animal models of 
Staphylococcus aureus infection, Kumar et al demonstrated avid uptake of 68Ga-citrate at infected 
lesions as early as 5 min following injection. Despite concomitant decrease in cardiac blood pool 
activity, the radiotracer uptake continued to increase for up to 6 h post injection (26). 
68Ga-citrate PET/CT has been shown to be superior to FDG PET in differentiating early bone 
healing from osteomyelitis in rats (12). To the best of our knowledge, there is only a single human 
study from Italy aiming to evaluate the efficacy of 68Ga-citrate PET/CT in patients with acute 
osteomyelitis, chronic osteomyelitis, or diskitis (27). Although a small number of patients (4 of 31) 
were found to have false-positive scans, the authors reported a sensitivity of 100%, a specificity of 
76%, and overall accuracy of 90% in identifying these patients’ sites of infection. However, 
regarding periprosthetic infection, their study was limited due to availability of only 7 patients 
with bone implants (not necessarily prosthesis) and lack of comparison with FDG PET/CT. With 
this background, we aim to demonstrate the feasibility and evaluate the accuracy of 68Ga-citrate 
PET/CT in diagnosing prosthetic joint infection, and compare the results with those of FDG PET 
for the first time. 
 
3. Research Design and Methods: 
 
In the proposed study, our aim is to evaluate the uptake of 68Ga-citrate in patients with failed joint 
prosthesis and compare it with that of conventional 18F-FDG PET/CT scan. To our knowledge, ours 
is the first such study attempting this assessment in human. We will perform PET/CT scan with 
68Galium citrate and 18F-FDG in 17 subjects with failed hip or knee arthroplasty prosthesis.  Both 
68Galium citrate and 18F-FDG scans, done within 24-48 hours from each other, will be performed 
within 4 weeks before surgical evaluation/revision of the hardware. 
 
Rationale for selecting 4-week interval before surgical evaluation is that in the case of 
periprosthetic infection, continued antibiotic therapy may affect the results of tissue 
histology/culture. 
 
Sample Size: 17 subjects 
 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
Subjects: The study subjects will be a sample of patients more than 6 months after knee or hip 
replacement who present with joint pain to our orthopedic and/or infectious disease clinics. 
Seventeen consecutive subjects with radiographic findings concerning for prosthetic joint 
infection or aseptic loosening who will be going under surgical evaluation for a final tissue 
diagnosis within the next 4 weeks will be included in the study. If needed, we may also include 
patients with other forms of orthopedic hardware into the study.  
 
University Hospital and Rutgers New Jersey Medical School (NJMS) serve as a high-volume 
regional care center for patients with complicated bone and joint infections. As a Level 1 Trauma 
Center for northern New Jersey, there is expertise in the management of post-traumatic 
neurosurgical and orthopedic infections, and in particular, chronic osteomyelitis and prosthetic 
device-related infections. Our facility cares for patients through a multidisciplinary approach with 
close collaborations across services including radiology and nuclear medicine, orthopedic and 
infectious diseases. The Division of Infectious Diseases has a designated Orthopedic Infectious 
Diseases Consult Service at University Hospital with two Faculty members specializing in the 
treatment of these infections. They provide in-hospital consultation and management with 
outpatient follow up, including management of patients in subacute care facilities and those 
receiving prolonged home antimicrobials. The service sees approximately 200 new patients 
annually. Therefore, it is expected that the 17 subjects needed for this protocol should be easily 
recruited within 12 months. As we already have resources set up to pursue Gallium 68 Citrate 
research, we believe that our center will be ideal location to pursue utility of this novel radiotracer 
in orthopedic infections.  
 
Inclusion Criteria: 
 
• Non-draining, swollen and painful joint prosthesis 
• At least 6 months after joint replacement. 
• Elevated ESR and CRP levels 
• Pending surgical evaluation and tissue sampling within the next 4 week to differentiate 
between infection and aseptic loosening. 
 
Exclusion Criteria: 
 
• Pregnant or breast-feeding women. 
• Inability to consent. 
• Known or suspected hypersensitivity to metals or gallium. 
• Drainage from the joint 
• Active inflammatory/infectious process at any location other than prosthetic joint. 
• History of HIV, lupus, rheumatoid arthritis and neutropenia 
 
Population characteristics: 
 
Record Selections:  The following data will be obtained from the charts of the index cases: 
 
1. Age 
2. Gender 
3. Race/ethnicity 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
4. Past Medical History 
5. Past surgical history 
6. Current medications 
7. Prior medications 
8. Weight, height and body mass index 
9. History of alcohol abuse 
10. History of intravenous drug use 
11. Evidence of HIV infection (e.g. HIV RNA/DNA PCR, Western blot, viral load) 
12. History of any other joint, connective tissue or systemic inflammatory diseases (e.g. 
systemic lupus erythematosus, sarcoidosis, amyloidosis) 
13. Joint replacement postoperative course 
14. White blood cell count 
15. Erythrocyte sedimentation rate 
16. C-reactive protein level 
17. Histopathology for any biopsied joint/bone tissue 
18. Pre and postoperative CT/MRI 
 
Imaging Protocol: 
 
 The PI, Nasrin Ghesani, MD has obtained investigation new drug license from FDA for the 
investigational compound, 68Ga-citrate.  IBA Molecular, a commercial radiopharmacy, will 
synthesize 18F-FDG and 68Ga-citrate according to the method described in the literature (28) and 
deliver to our facility in unit doses.  Combined PET/CT imaging with both radiotracers will be 
performed using the Discovery LS scanner (GE Medical Systems, Waukesha, WI) within 4 weeks 
before surgical evaluation.  
 
68Gallium Citrate PET/CT scan:  Approximately 5 mCi of 68Ga-citrate will be administered 
intravenously.  Whole body PET/CT scan will be performed after 60 minutes of uptake phase.  
Positron emission data will be acquired for two sets, one starting from vertex to mid-thigh level 
and the second from pelvis to toes. Not being much higher in terms of radiation, we opted to image 
the entire body to include the area of interest, investigate the biodistribution of the radiotracer 
and look for other foci of infection, such as in case of multifocal osteomyelitis.  
 
18FDG PET/CT scan: Subjects will undergo FDG PET/CT scan using the same imaging parameters 
either on the same day or within the next 24-48 hours. The IBA Molecular radiopharmacy will 
synthesize 18F-FDG and deliver to our facility in unit doses. The subjects will be requested to fast 
for a minimum of 4 h prior to PET acquisition. After confirmation of a blood glucose level ≤200 
mg/dl, technologists will establish the intravenous access and the subject will receive 
approximately 10 mCi of 18F-FDG intravenously.  The subject will be placed in uptake room for 60 
minutes to allow for optimal localization of the compound.  The subjects will be requested to void 
prior to administration of 18FDG and again prior to image acquisition. Whole body PET/CT scan 
will be performed after 60 minutes of uptake phase using similar imaging parameters as described 
above.  
 
Consent Procedures: 
 
Written informed consent will be obtained from each subject after explaining the purpose of the 
study, description of experimental procedure (68Ga Citrate PET/CT scan), and risk of radiation 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
exposure and other discomforts. The template of consent form is attached. 
 
Recruitment Process: 
 
We plan to recruit subjects exclusively from Orthopedic clinic or Orthopedic Infectious Diseases 
Consult Service at NJMS.  NJMS orthopedic surgeons and infectious disease specialists will be 
notified to screen for the subjects.  They will be provided with the subject screening log template 
containing eligibility criteria and consent forms.  Subjects will be pre-screened during the office 
visits by orthopedic surgeons and orthopedic infectious disease specialists. 
 
Upon identifying eligible subjects, the principal investigator will be notified.  Subject will be 
screened either by PI or Co-PIs. If all screening data are available and the subject is eligible for the 
study, informed consent will be obtained and documented.   The PI/Co-PIs will notify the staff at 
the Advanced Practice Imaging Center and schedule the subject.  The technologists will contact the 
supplier of investigational radiopharmaceutical compound, IBA molecular, and order the 
compound.   The PI/Co-PIs will contact the subject with date and time of test visit and directions 
to imaging center. 
 
Test Visit:  
 
Upon arrival to imaging center, the PI/Co-PIs will verify the subject’s identity.  The PI/Co-PIs will 
also verify that the consent form is signed.    
 
Pre-imaging evaluation:   
 
Following information will be obtained and documented: 
 
• Current symptoms: 
• Vital Signs: 
• Weight (kg) 
• Height (cm)  
• Blood Pressure 
• Heart rate 
• Respiratory rate 
• Short physical examination 
• Brief review of symptoms 
• Pregnancy test (In women of child bearing age) 
 
Image Acquisition Parameters: 
 
Gallium PET/CT: 68Ga-citrate will be synthesized according to the method described in the 
literature (28). IBA Molecular, a commercial radiopharmacy, will obtain a 68Ge/68Ga generator that 
is produced by ITG Isotope Products. The IBA Molecular radiopharmacy will synthesize 68Ga-
citrate and deliver to our facility in unit doses.  Technologists will establish the intravenous access 
and the subject will receive 5 mCi of 68Ga-citrate intravenously.  The subject will be placed in 
uptake room for 60 minutes to allow for optimal localization of investigational compound. Whole 
body PET/CT scan will be performed after 60 minutes of uptake phase.  

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
 
Combined PET/CT imaging will be performed using the Discovery LS scanner (GE Medical 
Systems, Waukesha, WI).  The CT scanner portion of the Discovery LS consists of a multi-detector 
helical CT (GE Lightspeed Plus, Waukesha, WI).   
 
• Low dose CT scan will be performed followed by positron emission scan. 
• CT imaging parameters will be as follows for a 6 to 7 bed position acquisition: 140 kVp, 80 
mA, 0.8 s per CT rotation, pitch of 6, 22.5 mm/s table speed. CT thickness will be 5 mm.   
• Positron emission data will be acquired for two sets of 6 positions, one starting from vertex 
to mid-thigh level and the second from pelvis to toes. Emission data will be acquired for 5 
minutes for each bed position. 
• PET images will be reconstructed using CT for attenuation correction with the ordered 
subset expectation maximization (OSEM) algorithm.  
 
FDG PET/CT: Subjects will undergo FDG PET/CT scan using the same imaging parameters either on 
the same day or within the next 24-48 hours. The IBA Molecular radiopharmacy will synthesize 18F-
FDG and deliver to our facility in unit doses. The subjects will be requested to fast for a minimum of 4 h 
prior to PET acquisition. After confirmation of a blood glucose level ≤200 mg/dl, technologists will 
establish the intravenous access and the subject will receive approximately 10 mCi of 18F-FDG 
intravenously.  The subject will be placed in uptake room for 60 minutes to allow for optimal 
localization of the compound.  subjects will be requested to void prior to administration of 18FDG and 
again prior to image acquisition. Whole body PET/CT scan will be performed after 60 minutes of uptake 
phase using similar imaging parameters as described above. 
 
Post imaging evaluation:  
 
Upon completion of test procedure, PI/Co-PIs will evaluate the subject and obtain following data: 
 
• Brief review of symptoms including signs of allergic reactions: 
o Rash 
o Itching 
o Difficulty in breathing 
o Swelling of tongue 
• Blood Pressure 
• Heart rate 
• Respiratory rate 
• Short physical examination, including assessment of injection site for swelling, redness, 
discharge and tenderness 
 
Follow-up: 
 
PI/Co-PIs will make a phone call to subject on following day of each scan and on 7th day after 
completion of test procedure and gather following information:  
• Interval development of rash, itching, difficulty in breathing, swelling of tongue, fever, chills 
or any unusual symptoms 
• Injection site for swelling, redness, discharge and tenderness 
 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
If subject experienced any of the above described signs or symptoms, PI/Co-PIs will schedule a 
follow-up visit with referring physicians (NJMS orthopedic surgeons). 
 
Data analysis:  
 
For each subject, we will record the presence and location of abnormal uptake on both Ga and FDG 
PET/CTs. We will then generate a region-of-interest around each area of morphologic abnormality 
to calculate a mean standardized uptake value (SUV), a maximum SUV, and a target-to-background 
ratio. These values will be compared with those of contralateral normal joint. Radiotracer uptake 
pattern on each modality will be classified according to known methods (29). Using the 
macroscopic intraoperative and later tissue histology and culture as the gold standard, sensitivity, 
specificity, and positive and negative predictive values of Ga and FDG PET will be calculated and 
compared with each other. 
 
Chart Review Process:  
 
 
 
 
Electronic databases: PACS, EPIC, Logician (Electronic Medical Database of university hospital, 
affiliate of Rutgers New Jersey Medical School) 
 
Data Manager: Nasrin Ghesani, MD 
Data management service: RedCap 
 
Protected Health Information will be only stored in RedCap. We do not plan to store PHI on 
personal or mobile devices such as laptops and memory sticks. 
 
Coded Identifier List: DOB, MRN, name, dates of services 
 
The file with the link between personal identifiers and the data will be kept for 6 years. 
 
Data Collection Form: Attached 
 
Risks of Harm: 
 
This research study involves exposure to radiation emitted by the injected radioactive metal 
(68Gallium citrate), injected radioactive glucose (18fluorine-fluorodeoxyglucose) and the X-rays 
delivered by the CT scan.  
 
The Human-use subcommittee and full Radiation Safety Committee of Rutgers New Jersey Medical 
School reviewed the dosimetry calculations of 68Ga Citrate and 18F FDG based on ICRP Report # 53 
(30) and utilized updated tissue weighting factors published in ICRP Report # 103 (31) to arrive at 
effective doses (See attached PDF document titled: Dosimetry). Accordingly, from 5 mCi of 68Ga 
Citrate injection, female effective dose was calculated at 3.95 mSv and male effective dose was 
3.89 mSv and from 10 mCi inection of 18F FDG, female effective dose was calculated at 5.82 mSV 
and male effective dose was 5.71 mSv. The study total per annum equivalent doses and effective 
doses per research subject were found to be within FDA diagnostic limits as attached. Accordingly, 
the effective dose is a measure of radiation exposure that is used for calculation of risk.  The unit 
of the effective dose is the millisievert (mSv). The average person in the United States of America 
receives an effective dose of about 3 mSv per year from naturally occurring radioactive materials 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
and cosmic radiation from outer space.  These natural background radiation doses vary 
throughout the country.  In New Jersey, radon gas is the largest source of natural background 
radiation.  Americans also receive radiation exposures from man-made sources such as medical 
procedures and consumer products.  The USA average exposure from all sources is about 6.2 mSv 
per year. 
 
From the participation in the study while undergoing (no. of scans = 2) scans and radionuclide 
injections (no. of injections = 2): 
 
• Total effective dose is calculated at 15.1 mSv for women and 14.9 mSv for men.      
• Total dose to the critical organ, small intestine from injection of 68Ga-citrate is calculated at 21.6 
mSv.  
• Total dose to the critical organ, urinary bladder wall, from injection of 18F FDG, is calculated at 
29.9 mSv. 
 
As a result of each Gallium PET/CT scan: 
 
• Effective dose to the women is calculated at 6.61 mSv; that is 3.95 mSv from radiation 
emitted by the radiogallium injected for the PET scan and 2.66 mSv from X-rays used in the 
CT scan.   
• Effective dose to the men is calculated at 6.55 mSv; that is 3.89 mSv from radiation emitted 
by the radiogallium injected for the PET scan and 2.66 mSv from X-rays used in the CT scan. 
 
As a result of  F18-FDG PET/CT scan: 
 
• Effective dose to the women is calculated at 8.48 mSv; that is 5.82 mSv from radiation 
emitted by the FDG injected for the PET scan and 2.66 mSv from X-rays used in the CT scan. 
• Effective dose to the men is calculated at 8.37 mSv; that is 5.71  mSv from radiation emitted 
by the FDG injected for the PET scan and 2.66 mSv from X-rays used in the CT scan. 
 
The risk associated with this level of radiation exposure is too small to be measured and is small 
when compared with other everyday risks.  It is well below the limit of 50 mSv per study that is 
allowed by the US Food and Drug Administration for experimental studies in humans.  It is also 
well below the limit of 50 mSv per year that can be received by US radiation workers. 
 
Theoretically, radiation exposure can damage sperm and eggs.  About 2000 mSv is required to 
cause temporary sterility in humans. The dose to the testes and ovaries from participation in this 
study is calculated at approximately 11.8 mSv and 13.3 mSv respectively, about 500 times lower 
that the dose that can cause permanent sterility.  The scientists who studied the survivors of the 
atomic bomb in Japan did not demonstrate any increased genetic or reproductive effects in the 
next generation. However, experimentally we know that the ova ovulated in the first few cycles 
after an exposure to radiation have a higher risk of a genetic effect.  The recommendations of the 
Health Physics Society (http://www.hps.org) for the women who have received radiation therapy 
are to wait for three cycles before they attempt to get pregnant.  While participating in the study, 
the subjects will undergo PET/CT scan of the whole body and will have exposure far less then 
someone who is receiving radiation therapy to the abdomen and are not anticipated to be at 
higher risk of radiation exposure to the egg or sperm that could result in birth defects. 
 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
After undergoing PET scan, the subjects will be instructed to drink plenty of water and void 
frequently for the remainder of the day.  They will be also instructed to not to have a close contact 
with pregnant women, babies and young children for at least 6 hours after their scan. 
 
It is possible, but unlikely, that the 68Gallium citrate/18F-FDG injection will miss the vein.  Though 
there is no subjective data available for such an event, there is a theoretical likelihood of 
developing skin cancer at the injection site from local radiation.   
 
Unlikely non-radiation related risks from PET/CT scans include: 
 
• Discomfort from lying still on the enclosed scanning table 
• Bruising or bleeding at the site of injection of radiotracer 
• Infection at the site of injection 
• An allergic type or other adverse reaction to the 68Gallium citrate or 18F-FDG 
 
Potential for Benefit 
 
Our study proposing the 68Ga-citrate PET/CT imaging will aid in management of prosthetic 
infections in many different ways.  Currently, 68Ga-citrate is not approved by Food and Drug 
Administration (FDA).  Data obtained from this pilot study will aid in obtaining extramural 
funding to conduct a large-scale human study that may pave a road for obtaining FDA approval to 
use 68Ga-citrate for clinical purpose.  Routine clinical use of 68Ga-citrate PET/CT imaging will aid in 
differentiating periprosthetic infection from aseptic loosening. As explained above, currently 
available imaging modalities including FDG PET/CT have poor capability for this differentiation. 
68Ga-citrate PET/CT by the mean of its functional nature has the potential to overcome this 
shortage in patient care.  
 
4. Statistical Analysis:   
 
For each subject, we will record the presence and location of abnormal uptake. For the PET/CT 
images, we will generate a region-of-interest (ROI) around each area of morphologic abnormality 
to calculate a mean standardized uptake value (SUV), a maximum SUV, and a target-to-background 
ratio. A target-to-background ratio of at least 2.0 will be used to score a particular ROI as positive.  
These values will be compared quantitatively with those of contralateral normal joint. Radiotracer 
uptake pattern on each modality will be classified according to known methods (29). Then, we will 
descriptively and quantitatively correlate 68Ga-citrate PET/CT findings with those of 18F-FDG 
PET/CT. Using the macroscopic intraoperative and later tissue histology and culture as the gold 
standard, sensitivity, specificity, and positive and negative predictive values of Ga and FDG PET 
will be calculated and compared with each other. We will also review the PET/CT images for 
multifocal involvement, if any. 
 
Statistical Analysis:  
Primarily, all variables will be analyzed and overall, descriptively, as follows:  
• Mean. standard deviation, median and range for continuous variables  
• Median, range and frequency distribution for discrete (ordinal) variations 

Title: Novel Gallium 68 Citrate Imaging in Orthopedic Infections. 
PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
• The results of the imaging modalities (PET, CT and MRI) will be classified as true positive 
(TP), true negative (TN), false positive (FP), or false negative (FN) according to the 
reference standard.  
• The McNemar test of correlated properties will be used to statistically compare the imaging 
results of 68Ga-citrate and 18F-FDG PET with MRI and diagnostic CT.  
• The student t-test will be used to statistically compare the quantitative findings of 68Ga-
citrate and 18F-FDG scans.  
• Analysis will be done on a lesion basis and on a patient basis.  
• All P values, <0.05 will be considered significant.  
• Cohen’s k-statistic with 95% confidence intervals will be calculated to show the degree of 
association between the techniques.   
 
5. Reporting Results 
 
The study was previously supported by the research grant from New Jersey Health Foundation 
(NJHF).  As per the requirement of the NJHF an interim report on the progress of the project and a 
final narrative report have to be submitted to NJHF. In addition, NJHF Vice President of 
Communications should be consulted before any communications activities, including but not 
limited to such media as organization publications, trade publications, newspapers, magazines, 
radio and television. 
 
 
6. Bibliography 
 
1. 
Maradit-Kremers H, Crowson CS, Dirk Larson R, Jiranek WA, Berry DJ, editors. Prevalence of 
Total Hip (THA) and Total Knee (TKA) Arthroplasty in the United States. American Academy of 
Orthopaedic Surgeons Annual Meeting; 2014; New Orleans, LA. 
2. 
Kwee TC, Kwee RM, Alavi A. FDG-PET for diagnosing prosthetic joint infection: systematic 
review and metaanalysis. European journal of nuclear medicine and molecular imaging. 
2008;35(11):2122-32. 
3. 
Hanssen AD, Rand JA. Evaluation and treatment of infection at the site of a total hip or knee 
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PI name: Nasrin Ghesani, MD 
 
Protocol Version 2.0 - 02/6/2018 
 
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