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The Nuclear Medicine Department (NMD) provides traditional Nuclear Medicine
clinical tests (approximately 4,500 per yr) for all NIH patients enrolled
in active protocols. The department is completely equipped with six state-of-the-art
SPECT (single photon emission computerized tomography) gamma cameras interfaced
to modern computer systems
that are used to process and display the studies. The images are centrally
stored and can be assesed by institute investigators. A wide-ranging research
program pertinent to the field
is carried out by the department's senior investigators.
A summary of this past year's clinical research accomplishments follows:
Showed that depression is associated with a significant reduction in bone mineral density. The mechanism of this reduced bone mass is unknown; however, a signi-
ficant proportion of patients with depression produce larger than normal amounts
of cortisol.Showed that prepubertal African American girls had significantly more lean body mass than age, height and weight matched Caucasian girls as determined by dual energy x-ray absorptiometry.
Showed that treatment of filiariasis in its early stages is accompanied by normal-
ization of lymphatic flow abnormalities as shown with lymphoscintigraphy.Showed that somatostatin receptor radiopharmaceuticals do not significantly
accumulate in hemangiomas whereas they do accumulate in a significant propor-
tion of gastrinoma hepatic metastases; and that this radiopharmaceutical can be
used to locate bronchial carcinoid tumors with ectopic ACTH production.Described a simplified method for determining adequate I-131 uptake prior to treatment of thyroid cancer metastases, and that cholecystitis can cause a false-positive accumulation of radioiodine in the gallbladder that could be mistaken for recurrent thyroid cancer.
Showed that glycophorin A red cell antigen levels and estimates of accumulated
bone marrow radiation from I-131 therapy were related in patients with thyroid cancer. Measurement of glycophorin A levels may be useful in determining
cumulated bone marrow exposure in patients who receive I-131 therapy.·Reported a potential new method for analyzing gated tomographic cardiac studies, mimicking M.-mode echocardiography.
Demonstrated that global ejection fraction, a measure of cardiac function, can be easily measured using reprojected SPECT gated blood pool images. The results further suggest that the SPECT data may be more accurate than the planar equivalent test.
Work done in the research division of the Nuclear Medicine Department accomplished the following:
--In in vitro studies we have demonstrated that triplex forming oligonucleotides (TFOs) are able to deliver Auger electron emitters to specific targets in cellular DNA in order to inactivate genes and/or kill the cells containing the targe sequences. Decay of 125I in TFOs results in strand breaks in both strands of the target DNA with an efficiency from 0.4 - 0.8 break/decay. Higher efficiency can be achieved with radionuclide multiple labeling. Breaks are confined to the triplex target sequence, and 90% of the sequence specific breaks are located within 10 bp around the decay site. Specificity of TOFs was shown to be high enough to specifically break genomic DNA in a target located in a single copy gene. A liposome delivery system has been developed to effectively deliver radiolabeled TFOs into the cell nucleus.
In addition, studies have been initiated to investigate the mechanisms
of Auger electron-induced DNA strand break repair in human cells. The aim
of these studies
is to identify methods by which human repair processes may be manipulated
to augment the radiotherapeutic effects of Auger electron emitting TFOs.
The goal of this project is the development of gene-specific therapeutic
radiopharmaceuticals based on targeting the decay of Auger electron emitting
radioisotopes to specific sequences in DNA (genes) using triplex forming
oligonucleotides as delivery vehicles.
--The Imaging Physics group continued development work on several novel,
high performance PET imaging systems intended for small animal use. The
ultimate goal of these projects is to provide the NIH community with the
capability of assessing
in vivo organ function in small laboratory animals such as mice and
rats. Such a capability should be of substantial value in assessing the
effects of treatment in
small animal models of cancer and other human disease, as well as in quantifying
the effects of genetic manipulations on organ function. A prototype imaging
systemnow in use has achieved a spatial resolution better than 1 mm, a factor
of five better than the best human scanner. Work is continuing to create
a "production" system
with this resolution.
--We have collaborated in three Phase 1 radioantibody therapy trials.
Two trials are using Y-90 humanized anti-Tac for therapy of adult T-cell
leukemia or cutaneous
T-cell malignancies (collaboration with Dr. Thomas Waldmann of NCI). One
trial uses Y-90 labeled B3 for therapy of various adenocarcinomas (collaboration
with
Dr. Ira Pastan, NCI).
We have further refined the strategies to block renal accumulation of radiolabeled antibody fragments. One strategy uses a commercially available amino acid solution. The other strategy developed by Dr. Chang Paik, Head of Radiochemistry in NMD relies on changing the pI by conjugating glycolate to an Fab antibody fragment.
We have characterized the detrimental effects of circulating sIL-2Ra receptor on the biodistribution of radiolabeled anti-Tac dsFv directed at IL-2Ra. We have identified strategies based on presaturating sIL-2Ra that will block the detrimental effects.
We have also started a comparative imaging study in colorectal cancer
in collaboration with Dr. S. Libutti, Surgery Branch NCI. In this study
we compare the utility
of anti-CEA Fab antibody scans versus [F-18] Fluorodeoxyglucose positron
emission tomography in patients with elevated CEA but no clear evidence
of tumor recurrence by conventional radiographic evaluation.
--We are developing several new methods of computer analysis to extract
new and additional information from several types of experimental and conventional
imaging tests. These include the measurement of global heart ventricular
function from EKG-gated tomographic blood pool images, measurement of myocardial
thickening by tracking endo- and epicardial wall borders on thallium and
sestamibi heart studies, alignment of functional nuclear medicine studies
with anatomic radiographic studies over time when repetitive examinations
are done on the same patient, development
of better quantitative measures of tumor glucose uptake, and development
of better methods for MRI tissue characterization in patients with polymyocitis.
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Questions about the Clinical Center? OCCC@nih.gov Or call: (301) 496-2563 National Institutes of Health, Warren Grant Magnuson Clinical Center, Bethesda, Maryland 20892. Last Modified 3/98 |