Dr. George W. Kabalka
University of Tennessee Medical Center
1924 Alcoa Highway
Knoxville, TN 37920
Phone: 615-544-9670
Fax: 615-544-8883
Email: Kabalka@novell.chem.utk.edu
Projects are approved by an IRB located at: University of Tennessee Medical Center-Knoxville.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1056
Number of Human Subjects Projects reported: 2
Project Identifier: UTMC-92-IRB-0104
Project Title:
A Consortium to Develop the Medical Uses of NMR Imaging, NMR Spectroscopy, and Positron Emission Tomography
Principal Investigator:
Dr. Gary T. Smith
Project started in: 1992
This project ended in Fiscal Year 1998.
Project Funding Information:
Project received funding in Fiscal Year 1998.
Project used human subjects in Fiscal Year 1998.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 03, 1998
IRB Approval Number: 0795
Number of Human Subjects who participated in this project/protocol during
FY 1998 (10/1/97 - 9/30/98): 68
Reported last fiscal period
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
During years one, two and three, this project concentrated on quantifying skeletal muscle blood flow and metabolism for assessment of ischemia. The ultimate goal is to provide a non-invasive method of measuring viability of skeletal muscle following traumatic vascular compromise. The technique involves the use of both dynamic positron emission tomography (PET) coupled with compartmental model analysis of the resulting time activity relationships and nuclear magnetic resonance spectroscopy (NMRS). PET scanning is ideally suited for this project because of the capability to utilize labeled organic compounds. Blood flow will be measured with N-13 ammonia. Metabolism will be assessed with F-18 deoxyglucose (FDG).
Specific aims of the project included: 1) is there a threshold level of muscle perfusion below which there is no chance of metabolic recovery, 2) can the degree of recovery be assessed by PET measurements of skeletal muscle metabolism, in particular, with FDG and BCAA, 3) can PET be used to assist surgeons in choosing the optimal site for muscle debridement in order to minimize the risk of both infection and recurrent tissue death, and maximize the potential for wound healing, and 4) can NMRS be used either in conjunction with PET scanning or independently to provide information about the healing potential of skeletal muscle following acute injury.
The initial study period was divided into two phases. Phase I (year 1) was devoted to developing new methods applicable to skeletal muscle physiology utilizing an isolated gracilis muscle canine model. Twelve animals with induced skeletal muscle ischemia were studied. Models for determination of skeletal muscle blood flow (13N ammonia) and both glucose and BCAA metabolism 18F deoxyglucose, 11C-leucine, were investigated for use with dynamic PET scanning. In Phase II (year 2 and 3), the models were studied in 39 human subjects.
In year 4 of the study, the project turned to the development of the use of PET for staging of multiple soft tissue cancers and infections. The study concentrated on the ability to define increased tissue metabolism with PET for diagnosis of neoplasm. A total of 68 patients with determined or suspected cancers were studied using this protocol. The majority of cancer patients examined were patients with lung cancer, ovarian cancer, breast cancer, colorectal cancer, and lymphomas. The data collected from these studies is being analyzed, and the data from these studies will be included in subsequent publications. Two abstracts using data supported by this study were presented at the 10th Annual International ICP Conference, in Cambridge, Massachusetts on October 28, 1998. "Cost Analysis in Managing Patients with Ovarian Cancer Using FDG PET," and "FDG Accumulation in Dissemination Blastomyces Dermatitidis in a Dog." Both are being published in Clinical PET.
Methodology: All procedures in this study may be performed on an outpatient basis. A transmission scan is done using an external ring source containing 5 mCi of 68Ge for the purpose of attenuation correction. The patient is given 13NH3 or 18FDG. The average dose will be: 13NH3 - 15mCi and 18FDG - 7.5 mCi. PET imaging of affected tissue begins according to the following schedule: 13NH3: upon completion of transmission scan, 18FDG: 1 hour after completion of 13NH3 scan. Each scan continues for approximately 20 minutes. Scans are done with a 15 slice machine 931/08 ECAT PET unit. In the 18FDG scans, glucose loading with 50 gm dextrose will be given by either IV or PO in all trauma patients. In the diabetic patients, glucose loading will only be employed when the initial blood sugar is below 140 mg/dl (milligrams per deciliter). Measurement of blood glucose is obtained in all patients at the time of glucose loading, one hour after oral or IV glucose, and at the end of the study.
Human Subject Involvement: All women of reproductive age have serum HCG analysis for pregnancy prior to the scans. No studies will be performed on patients less than 18 years of age. Each clinical protocol and the use of radioactive tracers has been approved by the UTMCK Human Subject Protection Committee, the Isotope Committee, and the Radiation Protection Committee.
All participants sign a consent form which includes the following: the nature of the procedure, potential benefits and risks, patient's right to refuse any stage of the protocol without jeopardizing their care, provision of any or all medical treatment necessary as a result of participation, and the names and telephone numbers of investigators or UTMCK officials who can be contacted for questions and concerns. All examination results and patient medical records are kept strictly confidential.
Venous punctures are standard procedures and carry a low risk for complications. The radiation doses to the patient are within the radiation exposure considered acceptable for routine diagnostic and nuclear medicine procedures. The risk of low level radiation is explained to the patient.
Safety precautions at UTMCK are employed according to usual practices within the medical center. The PET facility is equipped with standard acute care materials including a crash cart, cardiac monitors, and automated blood pressure monitoring devices. A board certified nuclear medicine physician and a critical care nurse are present during each study to supervise the use of monitoring equipment and the delivery of radioisotopes.
Any information derived from these studies can potentially benefit the patient's care management. Ultimately, data from the first three years of this study is expected to provide a more practical approach to the management of wounds in acute and chronic situations. Information from the fourth year of study will be used to determine if PET is clinically viable and cost effective in the management of cancer.
Project Identifier: UTMC-93-IRB-0555
Project Title:
An Evaluation of Fluorine-18 Labeled BPA-F in Patients with Glioblastoma Multiforme Using Positron Emission Tomography (PET)
Principal Investigator:
Dr. George W. Kabalka
Project started in: 1993
Project Funding Information:
Project received funding in Fiscal Year 1998.
Project used human subjects in Fiscal Year 1998.
Funding Sources:
Four patients with GMB were studied during this reporting period. A total of seven 3F-18-BPA PET scans were performed.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 14, 1998
IRB Approval Number: 0555/0737
Number of Human Subjects who participated in this project/protocol during
03/14/97 - 03/14/98: 4
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
The overall incidence of glioblastoma multiforme (GBM) in the United States has been estimated to be approximately 7,000 new cases per year. The treatment of GBM is problematic. Most patients undergo a surgical "debulking" followed by radiation therapy. A successful surgical approach is improbable in cases with diffuse and infiltrating growth of the tumor. Furthermore, the low tolerance of the normal brain tissue limits the delivery of tumor-effective radiation doses. Chemotherapy has been shown to be ineffective. As a result, the median survival time is less than 12 months. The overall prognosis for a patient suffering from GBM remains dismal.
Boron neutron capture therapy (BNCT) represents a promising alternative for selective radiation therapy of such tumors. The specific aims in this study are: to evaluate 4-Borono-2[18F] Fluoro-D, L-Phenylalanine-Fructose Complex [18F]BPA-F with the use of positron emission tomography (PET); to measure the pharmacokinetics of [18F]BPA-F and to examine if the GBM and/or normal brain accumulation of [18F]BPA-F changes as a result of surgery; to evaluate the accumulation of [18F]BPA-F in the residual tumor for potential BNCT; and to evaluate the use of [18F]BPA-F imaging for measuring the response to BNCT.
All patients will be referred for PET brain scans on the basis of clinical indication with a strong suspicion for GBM. Following the brain scan, a whole body PET scan will also be obtained, if the patient can tolerate it, in order to gather information on the extracranial distribution of the BPA. The patients shall be 18 years of age or older. All patients will have undergone physical, neurologic, fundoscopic, and visual field examinations, as well as x-ray computerized tomography (CT) and/or magnetic resonance imaging (MRI) studies of the brain within one week to ten days of the PET examination. All tumors will be confirmed histologically. The biopsies will be done after the PET scan to avoid non-specific biochemical changes secondary to the surgical procedure. A second PET scan, including brain and whole body, will be done 4 to 6 weeks after the craniotomy, if possible.
A transmission scan will be done using an external ring source containing germanium-68 for the purpose of acquiring data for image attenuation correction. Following the transmission scan, patients will be given fluorine-18 labeled BPA-F by intravenous injection. The average dose to be given is 0.15 millicurie (mCi) per Kilogram (Kg) of body weight. PET imaging of the brain will begin immediately after administration of the radiolabeled BPA-F. Scans will be carried out using the 47 slice tomograph which provides a spatial resolution of approximately 5 millimeters in 7 millimeter slices. Images of the BPA-F utilization will be analyzed quantitatively for selected regions of interest.
Patients will participate with informed consent. All information gathered in this study will be treated confidentially and the privacy of the research subject will be protected. Patients will receive nothing by mouth (NPO) for at least 4 hours prior to the scan. Each patient will have a venous line kept open by a 0.9% Sodium Chloride for Injection, United States Pharmacopeia (U.S.P.) drip through an 18 to 20 gauge needle for adequate bolus administration of the radiotracer. Vital signs will be monitored prior to, during, and after the PET scan.
Participation in the PET study involves exposure to radiation. The estimated total body radiation dose that the patient may receive from 2 x [18F]BPA-F injections (10 mCi/injection) is 0.94 rem or approximately 19% of the annual radiation dose allowed to a radiation worker in the course of his/her normal work activities. This radiation dose is not expected to produce any harmful effects.
Adverse effects with BPA-F have been generally non-complicating. Investigators at Idaho State University have studied the acute toxicity of intravenously administered BPA-F at very high doses. The investigators found that intravenous administration of BPA-F doses up to 3000 mg (BPA)/kg appeared to be well tolerated when delivered over a 1-hour infusion period to minimally stressed rats.
Arterial or venous blood samples not to exceed a total volume of 60 mL may be drawn during a period of 60 to 90 minutes. The patient may have some discomfort in the arm. There is a possibility of the artery being lacerated during cannulation; however, the probability of this occurring is extremely slight. There is also a chance that arterial spasm may occur, which would make the patient's hand become cold and painful. If this occurs, the physician may treat the spasm with lidocaine or stop the procedure. Rarely, a clot may form and require surgical removal. A small collection of blood can occur when the tube is removed, and a bruise may occur. Overall, the complications described are unlikely to occur.
Patients participating in this study may be required to endure up to 4 hours of PET imaging procedures. The PET procedures have been broken into two 2-hour segments, with intermittent ambulation.
The purpose of this preliminary investigation is to evaluate whether PET using [18F]BPA-F can be used to study the biodistribution of [18F]BPA-F. The results of this PET study will not be used to guide the therapy of the involved patients. Hence, involved patients will receive no direct benefit from this study. Their participation may result in an improved understanding of the pharmacokinetics of [18F]BPA-F in patients with GBM and perhaps improve therapy planning.