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.

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.

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.

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.

A triple suicide gene strategy that improves therapeutic effects and incorporates multimodality molecular imaging for monitoring gene functions.

Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly, all the three genes (thymidine kinase, cytosine deaminase and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron emission tomography, magnetic resonance spectroscopy and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple suicide gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo.

Broad-spectrum multi-modality image registration: from PET, CT, and MRI to autoradiography, microscopy, and beyond.

Image registration and fusion are increasingly important components of both clinical and small-animal imaging and have lead to the development of a variety of pertinent hardware and software tools, including multi-modality, e.g. PET-CT, devices. At the same time, advances in microscopic imaging, including phosphor-plate digital autoradiography and immunohistochemistry, now allow ultra-high (sub-100 microm)-resolution molecular characterization of tissue sections. To date, however, in vivo imaging of intact subjects and ex vivo imaging of harvested tissues sections have remained separate and distinct, making it difficult to reliably inter-compare the former and the latter. The Department of Medical Physics and the Radiation Biophysics Laboratory at Memorial Sloan-Kettering Cancer Center, under the direction of Dr. Clifton Ling, has now designed, fabricated, and tested a stereotactic imaging system for so-called "broad-spectrum" image registration, from coarser-resolution in vivo imaging modalities such as PET, CT, and MRI to ultra-high-resolution ex vivo imaging techniques such as histology, autoradiography, and immunohistochemistry.

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.

A generalized algorithm for determining the time of release and the duration of post-release radiation precautions following radionuclide therapy.

The Nuclear Regulatory Commission has recently amended its regulation concerning patients who have received therapeutic amounts of radioactivity. The amended regulation allows patient release based on a total effective dose equivalent (TEDE) limit of 5 mSv (500 mrem) instead of the activity administered or retained [1,110 MBq (30 mCi)] or the dose rate [0.05 mSv h(-1) (5 mrem h(-1)) at 1 m]. Record-keeping and written post-release radiation safety precautions are required, however. A general algorithm, combining patient-specific kinetics and dose rate measurements, has been developed to systematically determine the actual duration of post-release radiation precautions as well as the time of release post-treatment. This algorithm is based on the maximum permissible effective dose equivalents (MPEDEs) of the respective cohorts exposed, 5 mSv (500 mrem) to non-pregnant adult family members and 1 mSv (100 mrem) to pregnant women, children, and members of the general public. Operational equations to determine the times post-radionuclide treatment of release from medical confinement, of not working, of avoiding pregnant women and children, of limiting holding of children, and of sleeping partners not sleeping together have been derived and illustrated with a hypothetical example. TEDE-based release criteria should be less restrictive than the previous activity-based or dose rate-based release criteria. However, post-release radiation precautions may be more intrusive and longer in duration than those to which most practitioners have grown accustomed. Up to now, however, the duration (typically 1-2 d) of advised post-release precautions had not been rigorously derived from MPEDEs and were generally inappropriately short. Even so, dose-based release criteria should prove more cost-effective overall than hospitalization of patients commonly imposed by activity-based and dose rate-based release criteria.

Effects of time of administration and dietary iodine levels on potassium iodide (KI) blockade of thyroid irradiation by 131I from radioactive fallout.

Radioiodines, particularly 131I, may be released into the environment in breach-of-containment nuclear reactor accidents and localize in and irradiate the thyroid with an attendant risk of neoplastic growth and other adverse health effects. Pharmacologic thyroid blockade by oral potassium iodide (KI) (50-100 mg in adults) can substantially reduce thyroid uptake of and irradiation by internalized radioiodine. In the current analysis, computer modeling of iodine metabolism has been used to systematically elucidate the effects of two practically important but highly variable factors on the radioprotective effect of KI: the time of administration relative to exposure to radioiodine and the dietary level of iodine. In euthyroid adults receiving iodine-sufficient diets (250 microg d(-1) in the current analysis), KI administered up to 48 h before 131I exposure can almost completely block thyroid uptake and therefore greatly reduce the thyroid absorbed dose. However, KI administration 96 h or more before 131I exposure has no significant protective effect. In contrast, KI administration after exposure to radioiodine induces a smaller and rapidly decreasing blockade effect. KI administration 16 h or later after 131I exposure will have little effect on thyroid uptake and absorbed dose and therefore little or no protective effect. The 131I thyroid absorbed dose is two-fold greater with insufficient levels of dietary iodine, 2,900 cGy/37 MBq, than with sufficient levels of dietary iodine, 1,500 cGy/37 MBq. When KI is administered 48 h or less before 131I intake, the thyroid absorbed doses (in cGy/37 MBq) are comparably low with both sufficient and insufficient dietary iodine levels. When KI is administered after 131I intake, however, the protective effect of KI is less and decreases more rapidly with insufficient than with sufficient dietary iodine. For example, KI administration 2 and 8 h after 131I intake yields protective effects of 80 and 40%, respectively, with iodine-sufficient diets, but only 65 and 15% with iodine-deficient diets. In conclusion, whether exposed populations receive sufficient or insufficient dietary iodine, oral KI is an effective means of reducing thyroid irradiation from environmentally dispersed radioiodine but is effective only when administered within 2 d before to approximately 8 h after radioiodine intake.

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.

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.

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.

Age-dependent thyroid absorbed doses for radiobiologically significant radioisotopes of iodine.

In light of the post-Chernobyl increase in pediatric thyroid cancer incidence, among other recent events, there is renewed interest in radioiodine thyroid dosimetry and effects. Among the radioiodines produced in fission of 235U, only 131I [(T1/2)p = 8.04 d], 132I (2.3 h), 133I (20.3 h), and 135I (6.7 h) may undergo significant environmental dispersion. Age-dependent thyroid absorbed dose estimates for these radiobiologically significant radioiodines and for the "medical" radioisotopes 123I (13.2 h) and 125I (60 d) have been derived, incorporating the effect of absorption following inhalation or ingestion. This effect has generally been ignored in previously derived estimates of radioiodine absorbed doses to the thyroid. Based on the latest ICRP lung and gut models, inhaled radioiodine is absorbed at a rate of 0.175 h(-1) and exhaled at 0.101 to 0.118 h(-1) (depending on age) and ingested radioiodine is completely absorbed in the stomach at a rate of 1 h(-1). Whole-body compartmental models (SAAM II) were fit to previously published 24-h thyroid uptakes, thyroid half-times, and 48-h plasma concentration of protein-bound iodine. The resulting fitted models were used to calculate thyroid residence times of radioiodine. The mean thyroid absorbed doses [cGy/37 kBq (rad/microCi) injected intravenously] were then calculated using the age-dependent S(thyroid<--thyroid) factors (MIRDOSE III), with the highest doses (from 0.49 for 123I to 36 for 131I) in newborns and the lowest doses (from 0.014 for 123I to 1.4 for 131I) in adults in inverse relation to the thyroid mass. Although the thyroid absorbed dose for inhalation is substantially (30 to 70%) less than that for injection for all radioiodines and at all ages, it is markedly (25%) less for ingestion only for short-lived 132I.

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.

Thyroid uptake of liquid versus capsule 131I tracers in hyperthyroid patients treated with liquid 131I.

The amount of 131I used to treat hyperthyroid patients is based in part on the 24-hour thyroid uptake of a diagnostic amount of radioiodine (tracer). We compared the 24-hour uptake of an 131I tracer administered in liquid or capsule form to the 24-hour uptake of 131I therapy administered as liquid. Sixty-five hyperthyroid patients with Graves' disease were evaluated and subsequently treated with radioiodine. The liquid group (45 patients) received a liquid 131I tracer (1.85 MBq [0.05 mCi]) and the capsule group (20 patients) received a capsule 131I tracer (1.63 MBq [0.044 mCi]). Probe calibration factors were the same for the liquid and capsule 131I standards. All patients received therapeutic amounts of 131I [114.7-1106.3 MBq [3.1-29.9 mCi]) in liquid form. Therapy uptakes were obtained using the same collimated uptake probe modified with a calibrated lead shield to attenuate the high photon flux. The mean therapeutic uptake was the same for both groups (58%). The mean diagnostic uptake for the capsule group, however, was less than the mean diagnostic uptake for the liquid group (44% vs. 63%). The mean diagnostic uptake for the capsule group was significantly lower than the mean therapeutic uptake for this group (44% vs. 58%), whereas the mean diagnostic and therapeutic uptakes were similar for the group receiving a liquid tracer (63% vs. 58%). In conclusion, diagnostic uptakes performed with a liquid tracer more accurately predicted liquid therapy uptakes than diagnostic uptakes performed with a capsule tracer. This raises concern about the bioavailability of 131I in capsule form and has implications for determining the amount of 131I to administer for therapy. Patients whose 131I therapy was based on the uptake of a capsule tracer received a higher than intended amount of radiation to the thyroid gland.

In vitro evaluation of the relative thrombolytic efficiency of forced intrathrombic injections: saline versus urokinase.

PURPOSE: To compare the rates of thrombolysis produced by forced intrathrombic injections of saline versus urokinase, as well as automated versus manual injections of urokinase, with use of an in vitro model of a vascular occlusion. MATERIALS AND METHODS: The rates of thrombolysis produced by forced intrathrombic injections of saline and urokinase were compared in an in vitro radiometric model utilizing I-125-labeled thrombus. Similar experiments were performed to compare manual and automated injections of urokinase. The dissolution of the thrombus was quantitatively monitored with use of a scintillation detector. Averaged time activity data for each type of experiment were fit to exponential functions and half times of lysis calculated. The differences in the half times for the experiments being compared were evaluated for significance with use of the Student t test. RESULTS: The half times of lysis produced by forced intrathrombic injections of urokinase were substantially and significantly shorter than those produced by forced saline injections. The half time of lysis produced by automated injections was not significantly different than that produced by manual injections. CONCLUSIONS: Forced intrathrombic injections of urokinase produce faster and substantially more thrombolysis when compared with similarly administered saline. Also, for forced intrathrombic injections of lytic agents, an automated injector is an equivalent alternative to manual injections.

Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and transgene expression from adenovirus vectors can provide in vivo delivery of proteins. On the basis of this knowledge, we hypothesized that local administration of a replication-deficient adenovirus vector expressing complementary DNA for VEGF (AdVEGF) would induce collateral vessel formation in the setting of ischemia that could protect against subsequent acute vascular occlusion. METHODS: Hindlimb ischemia was induced in Sprague-Dawley rats by means of unilateral ligation of the common iliac artery immediately followed by administration of 4 x 10(9)-plaque-forming units VEGF, the control vector AdNull, or phosphate-buffered saline solution into the iliofemoral adipose tissue and thigh muscles. Untreated rats with common iliac ligation were used as an additional control group. RESULTS: Local VEGF expression was observed for 5 days in AdVEGF-treated rats but not in controls. Three weeks after ligation and vector administration, the ipsilateral femoral artery was ligated for a model of an acute vascular occlusion in the setting of preexisting ischemia. Blood flow to the ischemic hindlimb relative to the contralateral hindlimb evaluated with color microspheres demonstrated significantly increased blood flow in the AdVEGF-treated rats compared with each control group (p < 0.0001). Relative blood flow assessed by means of 99mTc-sestamibi radionuclide scans also demonstrated increased blood flow to the ligated hindlimb of AdVEGF-treated rats compared with each control group (p < 0.002). AdVEGF-treated rats also demonstrated increased vascularity in the ligated limb compared with each control group as assessed by means of angiography (p < 0.0001) and histologic quantification of blood vessels less than 80 microm diameter in local adipose tissue and capillaries per muscle fiber (p < 0.0002). AdVEGF treatment prevented a rise in femoral venous lactate femoral venous concentrations 1 hour after femoral artery ligation in control rats (p < 0.04). CONCLUSIONS: An adenovirus vector expressing VEGF complementary DNA is capable of stimulating an angiogenic response that protects against acute vascular occlusion in the setting of preexisting ischemia, suggesting that in vivo gene transfer of VEGF complementary DNA might be useful in prophylaxis of advancing arterial occlusive disease.

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.