Radioactive seed localization is a safe and effective tool for breast cancer surgery: an evaluation of over 25,000 cases.

Radioactive seed localization (RSL) provides a precise and efficient method for removing non-palpable breast lesions. It has proven to be a valuable addition to breast surgery, improving perioperative logistics and patient satisfaction. This retrospective review examines the lessons learned from a high-volume cancer center's RSL program after 10 years of practice and over 25 000 cases. We provide an updated model for assessing the patient's radiation dose from RSL seed implantation and demonstrate the safety of RSL to staff members. Additionally, we emphasize the importance of various aspects of presurgical evaluation, surgical techniques, post-surgical management, and regulatory compliance for a successful RSL program. Notably, the program has reduced radiation exposure for patients and medical staff.

Correction to: 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

The article 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors written by Laure Michaud, B. J. Beattie, T. Akhurst, M. Dunphy, P. Zanzonico, R. Finn, A. Mauguen, H. Schöder, W. A. Weber, A. B. Lassman, R. Blasberg.

18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

PURPOSE: The aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection. METHODS: Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI. RESULTS: 18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine. CONCLUSION: Tumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

KRAS mutation effects on the 2-[18F]FDG PET uptake of colorectal adenocarcinoma metastases in the liver.

BACKGROUND: Deriving individual tumor genomic characteristics from patient imaging analysis is desirable. We explore the predictive value of 2-[18F]FDG uptake with regard to the KRAS mutational status of colorectal adenocarcinoma liver metastases (CLM). METHODS: 2-[18F]FDG PET/CT images, surgical pathology and molecular diagnostic reports of 37 patients who underwent PET/CT-guided biopsy of CLM were reviewed under an IRB-approved retrospective research protocol. Sixty CLM in 39 interventional PET scans of the 37 patients were segmented using two different auto-segmentation tools implemented in different commercially available software packages. PET standard uptake values (SUV) were corrected for: (1) partial volume effect (PVE) using cold wall-corrected contrast recovery coefficients derived from phantom spheres with variable diameter and (2) variability of arterial tracer supply and variability of uptake time after injection until start of PET scan derived from the tumor-to-blood standard uptake ratio (SUR) approach. The correlations between the KRAS mutational status and the mean, peak and maximum SUV were investigated using Student's t test, Wilcoxon rank sum test with continuity correction, logistic regression and receiver operation characteristic (ROC) analysis. These correlation analyses were also performed for the ratios of the mean, peak and maximum tumor uptake to the mean blood activity concentration at the time of scan: SURMEAN, SURPEAK and SURMAX, respectively. RESULTS: Fifteen patients harbored KRAS missense mutations (KRAS+), while another 3 harbored KRAS gene amplification. For 31 lesions, the mutational status was derived from the PET/CT-guided biopsy. The Student's t test p values for separating KRAS mutant cases decreased after applying PVE correction to all uptake metrics of each lesion and when applying correction for uptake time variability to the SUR metrics. The observed correlations were strongest when both corrections were applied to SURMAX and when the patients harboring gene amplification were grouped with the wild type: p ≤ 0.001; ROC area under the curve = 0.77 and 0.75 for the two different segmentations, respectively, with a mean specificity of 0.69 and sensitivity of 0.85. CONCLUSION: The correlations observed after applying the described corrections show potential for assigning probabilities for the KRAS missense mutation status in CLM using 2-[18F]FDG PET images.

ICRP Publication 140: Radiological Protection in Therapy with Radiopharmaceuticals.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Internal radionuclide radiation dosimetry: a review of basic concepts and recent developments.

Internal dosimetry deals with the determination of the amount and the spatial and temporal distribution of radiation energy deposited in tissue by radionuclides within the body. Nuclear medicine has been largely a diagnostic specialty, and model-derived average organ dose estimates for risk assessment, the traditional application of the MIRD schema, have proven entirely adequate. However, to the extent that specific patients deviate kinetically and anatomically from the model used, such dose estimates will be inaccurate. With the increasing therapeutic application of internal radionuclides and the need for greater accuracy, radiation dosimetry in nuclear medicine is evolving from population- and organ-average to patient- and position-specific dose estimation. Beginning with the relevant quantities and units, this article reviews the historical methods and newly developed concepts and techniques to characterize radionuclide radiation doses. The latter include the 3 principal approaches to the calculation of macroscopic nonuniform dose distributions: dose point-kernel convolution, Monte Carlo simulation, and voxel S factors. Radiation dosimetry in "sensitive" populations, including pregnant women, nursing mothers, and children, also will be reviewed.

Neuroleptic binding sites: specific labeling in mice with [18F]haloperidol, a potential tracer for positron emission tomography.

Haloperidol labeled with fluorine-18 (T 1/2 = 110 min, positron emission 97%), prepared yielding .04 Ci/millimole by the Balz-Schiemann reaction, was evaluated in a murine model as a potential radiotracer for noninvasive determination, by positron-emission tomography, of regional concentrations of brain dopamine receptors in patients. As the haloperidol dose in mice was increased from 0.01 to 1000 micrograms/kg, the relative concentration of [18F]haloperidol (microCi per g specimen/microCi per g of body mass), at one hour after injection decreased from 30 to 1.0 in the striatum and from 8.0 to 1.0 in the cerebellum. The striatal radioactivity, plotted as relative concentration against log of dose, decreased sigmoidally, presumably reflecting competition between labeled and unlabeled haloperidol for a single class of accessible binding sites. Because the cerebellum is relatively deficient in dopamine receptors, the observed decrease in cerebellar radioactivity may reflect a saturable component of haloperidol transport into brain. The high brain concentrations and the unexpectedly high striatum-to-cerebellum concentration ratios (greater than 4 at haloperidol doses less than or equal to 1 microgram/kg) suggest that [18F]haloperidol warrants further investigation as a potential radiotracer for dopamine receptors.

Bremsstrahlung radiation exposure from pure beta-ray emitters.

UNLABELLED: With increasing therapeutic use of radionuclides that emit relatively high-energy (>1 MeV) beta-rays and the production in vivo of bremsstrahlung sufficient for external imaging, the potential external radiation hazard warrants evaluation. METHODS: The exposure from a patient administered beta-ray-emitting radionuclides has been calculated by extending the National Council on Radiation Protection and Measurement model of a point source in air to account for biologic elimination of activity, the probability of bremsstrahlung production in vivo and its mean energy and the absorption by the patient's body of the bremsstrahlung thus produced. To facilitate such calculations, a quantity called the "specific bremsstrahlung constant" (in C/kg-cm2/MBq-h), betaBr, was devised and calculated for several radionuclides. The specific bremsstrahlung constant is the bremsstrahlung exposure rate (in C/kg/h) in air at 1 cm from a 1 MBq beta-ray emitter of a specified maximum beta-ray energy and frequency of emission in a medium of a specified effective atomic number. RESULTS: For pure beta-ray emitters, the retained activities at which patients can be released from medical confinement (i.e., below which the effective dose equivalent at 1 m will not exceed the maximum recommended value of 0.5 cSv for infrequently exposed members of the general public) are extremely large: on the order of hundreds of thousands to millions of megabecquerels. CONCLUSION: Radionuclide therapy with pure beta-ray emitters, even high-energy beta-ray emitters emitted in bone, does not require medical confinement of patients for radiation protection.

Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides.

A calculational approach is described that provides the spatially varying radiation absorbed dose, presented as isodose contours superimposed on CT images, from nonuniform and/or irregular cumulated activity distributions. CT images are read from magnetic tape and are displayed on a high-resolution color graphics display monitor. Source tissue geometries are defined on a series of contiguous CT images automatically (by an edge detection algorithm) or manually (using a trackball), thereby obtaining a three-dimensional representation of the various source volumes of activity. Dose calculations are performed using a radionuclide-specific absorbed dose point kernel in the form of a lookup table. The method described yields the spatially varying dose delivered to tumor and normal tissue volumes from a patient-specific cumulated activity distribution in a clinically implementable manner. This level of accuracy in determining normal tissue and tumor doses may prove valuable in the evaluation and implementation of radionuclides and radiolabeled compounds for therapeutic purposes.

Effect of prior radiopharmaceutical administration on Schilling test performance: analysis and recommendations.

UNLABELLED: Previously administered diagnostic and therapeutic radiopharmaceuticals may interfere with performance of the Schilling test for prolonged periods of time. Additionally, presence of confounding radionuclides in the urine may not be suspected if baseline urine measurements have not been performed before the examination. METHODS: We assumed that a spurious contribution of counts corresponding to 1% of the administered Schilling dose would begin to contribute clinically significant interference. Based on the typical amounts of radiopharmaceuticals administered, spectra of commonly used radionuclides and best available pharmacokinetic models of biodistribution and excretion, we estimated the interval required for 24-hr urinary excretion of diagnostic and therapeutic radiopharmaceuticals to drop below this threshold of significant interference. RESULTS: For previously administered 99mTc-based radiopharmaceuticals and 123I-Nal, the interval required for urinary levels of activity to fall below thresholds of allowable interference are between 2-5 days. For 67Ga-citrate, several 111In compounds, 131I-MIBG and 201Tl-thallous chloride, periods of 12-44 days are estimated. Estimates for 131I-Nal vary greatly between 4 and 115 days, depending on the amount administered, and the degree of thyroid uptake. CONCLUSION: Patients should be interviewed before performing the Schilling test to ensure that interfering radiopharmaceuticals have not been recently administered. The estimates developed in this paper can serve as guidelines for the necessary waiting time between prior radiopharmaceutical administration and the Schilling examination.

Prospective study of simultaneous orthoiodohippurate and diethylenetriaminepentaacetic acid captopril renography. The Einstein/Cornell Collaborative Hypertension Group.

UNLABELLED: Captopril renography (CR) has been established in the past 10 yr as a useful diagnostic test for renovascular hypertension. However, direct comparison of tubular and glomerular tracers, quantitative criteria, comparison of quantitative and qualitative results and the reliability of the results in renal failure have not been described in a systematic, prospective fashion. METHODS: Same-day baseline and CR using 99mTc-labeled diethylenetriaminepentaacetic acid (DTPA) and [131I]orthoiodohippurate (OIH) were simultaneously performed in two groups of hypertensive subjects, one with demographically defined essential hypertension (n = 43) and the other (n = 60) with a high prevalence of renovascular disease, defined with angiograms. Quantitative criteria for abnormal CR were derived from results among the subjects with essential hypertension. Qualitative analysis was performed using widely established criteria. RESULTS: There were no statistically significant differences between quantitative and qualitative accuracy, between OIH and DTPA or among quantitative parameters. The best accuracies for quantitative CR were 56% with DTPA (n = 57) and 60% with OIH (n = 60), in both cases using the relative renal uptake parameter. Qualitative CR (n = 60) had accuracies of 43% (DTPA) and 50% (OIH), both hindered by 29 (DTPA) and 25 (OIH) abnormal but nondiagnostic studies. Two false-positive studies were detected. Twenty-seven of 29 nondiagnostic studies were associated with a glomerular filtration rate of <50 ml/min (n = 17), one small kidney (n = 17) and/or bilateral renal artery stenosis (n = 16). Supplemental measurement of in vitro stimulated plasma renin activity insignificantly (p > 0.10) and improved accuracies to 63% (DTPA) and 70% (OIH), without introducing additional false-positive tests. CONCLUSION: Orthoiodohippurate and DTPA have comparable accuracy in prospective simultaneous evaluation of CR. False-positive studies are fewer than 5%. The accuracies of quantitative and qualitative criteria do not differ significantly but may be improved by supplemental use of the in vitro stimulated plasma renin activity. In individuals with renal insufficiency, small kidneys and/or bilateral renal artery disease, up to 48% of CR studies are abnormal but nondiagnostic.

The intraoperative gamma probe: basic principles and choices available.

By taking advantage of the proximity to radioactive sentinel nodes and occult tumors achievable in an operative setting, intraoperative probes are becoming increasingly important in the surgical management of cancer. This article begins with a discussion of the statistical limitations of radiation detection and measurement and of the key performance parameters (sensitivity, energy resolution, and spatial resolution) that characterize detectors. The basic design and operating principle of radiation detectors used in intraoperative probes, scintillation and semiconductor detectors, are then reviewed. Scintillation detector-based intraoperative probes, generally using a NaI(T1) or a CsI(T1) crystal connected to a photomultiplier tube by a fiberoptic cable, have the advantages of reliability, relatively low cost, and high sensitivity, especially for medium- to high-energy photons. Disadvantages include poor energy resolution and scatter rejection, and bulkiness. Semiconductor (CdZn, CdZnTe, HgI2)-based probes are compact and have excellent energy resolution and scatter rejection, but with complex energy spectra reflecting charge-carrier trapping. Their main disadvantage is lower sensitivity. The performance parameters of various commercially available intraoperative probes are then compared. The article concludes with a discussion of the practical considerations in selecting and using intraoperative probes, including ergonomic and other design features, as well as performance parameters.

Quantitative SPECT in radiation dosimetry.

Accurate and precise radiation dosimetry is critical for the successful therapeutic application of systemically administered radionuclides, including, of course, radionuclides in the form of radiolabeled antibody. This requires determination, based on discrete serial measurements, of the time-dependent concentrations and/or total amounts of radioactivity in situ in order to calculate source region cumulated activities. Based on extensive studies (with clinically realistic numbers of counts and accuracies of the order of 10%) in simple geometric phantoms, in complex anthropomorphic phantoms, in animal models, and in humans, quantitative rotating scintillation camera-based single-photon emission computed tomography (SPECT) now appears to be a practical approach to such measurements. The basis of the quantitative imaging capability of a three-dimensional imaging modality such as SPECT is the elimination in the reconstructed image of counts emanating from activity surrounding the source region. Subject to considerations such as the reconstruction algorithm, attenuation and scatter corrections, and, most importantly, statistical uncertainty, the counts in a pixel in a reconstructed image are therefore directly proportional to the actual counts emanating from the corresponding voxel in situ. Among intrinsic, pre-processing, and post-processing attenuation corrections, post-processing algorithms, the most widely used approach in current commercial SPECT systems, have proven adequate in uniformly attenuating parts of the body (eg, abdomen, pelvis), subject to accurate delineation of the body contour. Although a number of sophisticated scatter correction methods have been developed, the lack of explicit scatter correction has, in practice, not been a major impediment to reasonably accurate quantitative SPECT imaging, despite scattered radiation representing up to 50% of the counts in a large source region (eg, liver). Because of its mathematical propagation in the image reconstruction process, statistical uncertainty (ie, "noise") in SPECT is far greater than would be expected if it were distributed according to Poisson statistics, as in planar imaging. The low "single slice" sensitivity of rotating scintillation camera-based SPECT is therefore the principal limitation of practical quantitative SPECT. Accordingly, absolute quantitation of count-limited clinical images has been accomplished using a judiciously selected "non-ramp" filter function. In summary, reasonable quantitative SPECT imaging is now feasible clinically, even without sophisticated scatter corrections, at least in uniformly attenuating parts of the body.(ABSTRACT TRUNCATED AT 400 WORDS)

Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart.

OBJECTIVES: Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function. METHODS: Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10(8) pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed. RESULTS: SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 animals. CONCLUSIONS: An Ad vector expressing the VEGF121 cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible.

External imaging of atherosclerosis in rabbits using an 123I-labeled synthetic peptide fragment.

The oligopeptide fragment of apolipoprotein B, SP-4, has demonstrated pronounced uptake in the healing edges of balloon-injured rabbit aortic endothelium. To assess 123I-labeled SP-4 for identification of atherosclerotic plaques by gamma camera imaging, 14 Watanabe heritable hyperlipidemic (WHHL) and 5 normal rabbits were imaged 5 minutes and 12 and 24 hours after intravenous injection of 123I-SP-4. In addition, two WHHL and two normal rabbits were injected with 125I-SP-4 for autoradiography. Twelve of the 14 WHHL, but none of the normal, rabbits had visually apparent focal radioiodine accumulation in the region of the aorta. Focus-to-lung and focus-to-heart count ratios were 2.4 +/- 1.3 and 1.0 +/- 0.4, respectively. Five of the visually positive WHHL rabbits were reimaged 4 and 8 weeks later with 123I-NaI and 123I-SP-2 (an apo E peptide), respectively, as negative controls. Perceptible, but faint, aortic localization of 123I-NaI and of 123I-SP-2 was seen in only one animal each. The distributions of atherosclerotic lesions on photographs of the opened WHHL aortas and of film blackening on 125I-SP-4 autoradiograms were identical. In contrast, the two normal rabbit aortas did not exhibit plaques on photographs or film blackening on autoradiograms. Thus, in an animal model closely simulating human atherosclerotic disease, SP-4 localizes specifically in aortic atherosclerotic lesions.

Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121.

BACKGROUND: Adenovirus (Ad) vector-mediated gene therapy strategies have emerged as promising modalities for the "biological revascularization" of tissues. We hypothesized that direct intramyocardial, as opposed to intracoronary, administration of an Ad vector coding for the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic angiogenesis. METHODS: Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and enzyme-linked immunosorbent assay, after intramyocardial Ad(GV)VEGF121.10 in the rat, and either intramyocardial or intracoronary (circumflex territory) vector in Yorkshire swine. Based on these results, we assessed the focal nature of the improved cardiac blood flow in a previously reported porcine myocardial ischemia model. RESULTS: Intramyocardial delivery of Ad(GV)VEGF121.10 in the rat resulted in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks, with peak myocardial VEGF expression 24 to 72 h after vector delivery. After intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pigs, Ad vector genome and VEGF protein levels were more than 1,000-fold and more than 90-fold higher, respectively, in this distribution than in other myocardial regions. In comparison, intracoronary injection yielded maximum myocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days after intramyocardial Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitution via collaterals localized to the region of vector administration. CONCLUSIONS: These studies demonstrate that direct intramyocardial administration of Ad(GV)VEGF121.10 results in focal genome and VEGF levels, including focal angiogenesis, sufficient to normalize blood flow to the ischemic myocardium, findings that are relevant to designing human trials of gene therapy-mediated cardiac angiogenesis.

Pharmacokinetic modeling.

For radiation dosimetry calculations of radiolabeled monoclonal antibodies, (MAB), pharmacokinetics are critical. Specifically, pharmacokinetic modeling is a useful component of estimation of cumulated activity in various source organs in the body. It is thus important to formulate general methods of pharmacokinetic modeling and of pharmacokinetic data reduction, leading to cumulated activities. In this paper different types of models are characterized as "empirical," "analytical," and "compartmental" pharmacokinetic models. There remains a pressing need for quantitative studies in man for a proper understanding of the pharmacokinetics of MAb. Pharmacokinetic modeling of radiolabeled MAb in vivo has relied on relatively limited studies in man and complementary detailed measurements in animals. In either case, any model chosen for analysis of such data is inevitably based on measurements of limited accuracy and precision as well as assumptions regarding human physiology. Very few macroscopic compartmental pharmacokinetic models for MAb, have been tested over a range of conditions to determine their predictive ability. Extracorporeal immunoadsorption represents one approach for drastically altering the biokinetics of antibody distribution, and may serve to validate a given pharmacokinetic model. In addition to macroscopic modeling, the microscopic evaluation of the time-dependent distribution of radiolabeled MAb in tissues is of utmost importance for a proper understanding of the kinetics and radiobiologic effect. Many tumors do not exhibit homogeneous uptake. A mathematical understanding of that distribution is thus essential for accurate tumor dosimetry estimates. This review summarizes methodologies for pharmacokinetic modeling, critically reviews specific pharmacokinetic models and demonstrates the capability of modeling for predictive calculations of altered pharmacokinetics, emphasizing its use in dosimetric calculations.

A stereotactic method for the three-dimensional registration of multi-modality biologic images in animals: NMR, PET, histology, and autoradiography.

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging (MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2 +/- 0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRI images with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy--even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.

Radiation dose to patients and relatives incident to 131I therapy.

Radioiodine long has proven to be a safe and effective treatment for thyroid disease. Nonetheless, persisting concerns regarding radiogenic stochastic risks (e.g., carcinogenesis) to patients, their families, and the general public have led regulators to establish criteria for release of 131I-containing patients from medical confinement, with limits ranging from as low as 2 mCi in some parts of Europe to as high as 30 mCi in the United States. To optimize clinical efficacy and cost-effectiveness of 131I therapy, such regulations should be based on logical dosimetric considerations. The thyroidal absorbed dose, proportional to maximum uptake and effective half-life and inversely proportional to mass, is typically approximately 1,500 rad/mCi of 131I administered to a euthyroid adult (based on a thyroid maximum uptake of 25%, effective half-life equivalent to the physical half-life of 131I (8.04 days), and mass of 20 g). As thyroid uptake increases from 0% to 100%, extrathyroidal absorbed doses range from a minimum of 0.15 to 0.5 rad/mCi for breast and gonads to a maximum of 1.5 to 2 rad/mCi for stomach and salivary glands; the absorbed doses of the urinary bladder wall, in contrast, decrease with increasing thyroid uptake, from 2 to 0.6 rad/mCi. In hyperthyroid patients (approximately 15%) with a small iodine pool (so-called small patients), the short effective half-life of radioiodine in the thyroid and high serum concentrations of long-lived protein-bound 131I result in a standard 7,000-rad absorbed dose for treatment of Graves' disease requiring an administered activity of 28 mCi of 131I and yielding a prohibitively high blood absorbed dose of 150 rad. Importantly, once the fetal thyroid begins to function and accumulate radioiodine at a gestational age of 10-12 weeks, fetal thyroid absorbed doses as large as 5,000 rad/mCi of 131I administered to the mother can result. Thus, pregnancy is an absolute contraindication to administration of 131I because of the risk of radiogenic cretinism. Based on actual measurements of thyroid activity and of external absorbed dose, the total thyroid and mean extrathyroidal absorbed doses to adult family members from immediately released 131I-treated patients are approximately 0.01 and approximately 0.02 rad/mCi administered, respectively, yielding an effective dose of approximately 0.02 rem/mCi. A maximum permissible effective dose of 0.5 rem for adults therefore is consistent with a release criterion of 30 mCi of retained 131I. Lower-activity release criteria therefore may be unnecessarily restrictive.

Potassium iodide for thyroid blockade in a reactor accident: administrative policies that govern its use.

A marked increase in thyroid cancer among young children who were in the vicinity of the Chernobyl nuclear power plant at the time of the 1986 accident strongly suggests a possible causal relationship to the large amounts of radioactive iodine isotopes in the resulting fallout. Although remaining indoors, restricting consumption of locally produced milk and foodstuffs, and evacuation are important strategies in a major breach-of-containment accident, stable potassium iodide (KI) prophylaxis given shortly before or immediately after exposure can reduce greatly the thyroidal accumulation of radioiodines and the resulting radiation dose. Concerns about possible side effects of large-scale, medically unsupervised KI consumption largely have been allayed in light of the favorable experience in Poland following the Chernobyl accident; 16 million persons received single administrations of KI with only rare occurrence of side effects and with a probable 40% reduction in projected thyroid radiation dose. Despite the universal acceptance of KI as an effective thyroid protective agent, supplies of KI in the US are not available for public distribution in the event of a reactor accident largely because government agencies have argued that stockpiling and distribution of KI to other than emergency workers cannot be recommended in light of difficult distribution logistics, problematic administrative issue, and a calculated low cost-effectiveness. However, KI in tablet form is expensive and has a long shelf life, and many countries have largely stockpiles and distribution programs. The World Health Organization recognizes the benefits of stable KI and urges its general availability. At present there are 110 operating nuclear power plants in the US and more than 300 in the rest of the world. These reactors product 17% of the world's electricity and in some countries up to 60-70% of the total electrical energy. Almost all US nuclear power plants have multistage containment structures with large steel and concrete shells and multiple redundancy of core cooling mechanisms. These successfully prevented the release of major amounts of radionuclides in the Three Mile Island partial loss-of-primary coolant accident in 1979. The Chernobyl accident, in a different type of reactor that is common in Eastern Europe, did not have effective outer shell containment and released almost 50 MCi of 131I compared to the 20 Ci of 131I released at Three Mile Island. Such accidents have precipitated extensive re-evaluation of the design and safety devices of all operating reactors. However, a major contributing factor to the accidents was human error and considerable efforts must be made to train plant operators so they have a better understanding of reactor operation and use of safety mechanisms.