Requirements for a treatment planning system for radioimmunotherapy.

Cancer-seeking antibodies carrying radionuclides can, in theory, be very powerful agents for the radiotherapy of cancer. However, as with all radiotherapy, the undesired dose to critical normal organs is the limiting factor that determines success or failure. The distribution of radiation dose in cancer and noncancer tissue is highly dependent on choices the therapist can make: choices of the antigens to be targeted, choices of the antibodies or antibody fragments to be used, choices of radionuclides, of amounts, of timing, and other electives. New technologies, especially of monoclonal antibody production, make the options myriad. Optimization of this therapy depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, for particular treatment selections. These tracer techniques can now be implemented by advanced equipment for quantitative, tomographic radionuclide imaging and strengthened by dynamic modeling of the physiological parameters which govern radionuclide distribution, and hence radiation dose distribution.

Tc-99m galactosyl-neoglycoalbumin: in vitro characterization of receptor-mediated binding.

Hepatic binding protein (HBP) is a membrane receptor that binds and transports plasma glycoproteins from hepatic blood to hepatocellular lysosomes. We have characterized the in vitro binding of Tc-99m galactosyl-neoglycoalbumin (Tc-NGA), a synthetic HBP ligand, to liver membrane. Structural modifications of NGA resulted in the alteration of the equilibrium constant, KA, and the forward-binding rate constant, kb. Binding was second-order; the relative amount of membrane-bound NGA depended on the initial concentrations of ligand and membrane. Membrane displacement studies, using carrier ligands in contrast to previously bound Tc-NGA or I-NGA, correlated with the binding characteristics of a native HBP ligand, asialo-orosomucoid. We used computer simulation to study the detectability of the changes in HBP concentration at different values of kb. The simulations indicated that radiopharmacokinetic sensitivity to alterations in [HBP] should be possible using a neoglycoalbumin preparation with a carbohydrate density within the range of 15 to 25 galactose units per albumin molecule.

Measurement of receptor concentration and forward-binding rate constant via radiopharmacokinetic modeling of technetium-99m-galactosyl-neoglycoalbumin.

Technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA) is a synthetic ligand to the hepatocyte receptor, hepatic binding protein (HBP). A five-state mathematical model containing a bimolecular chemical reaction was utilized for quantitative estimation of the following physiologic and biochemical parameters: extrahepatic plasma volume Ve; hepatic plasma flow F and volume Vh; receptor-ligand forward-binding rate constant kb and reaction volume Vr; and receptor concentration [R]o. Nine normal subjects were studied. Given (a) liver and heart time-activity data, (b) the patient's weight, height, and hematocrit, (c) the fraction of injected dose in a 3-min blood sample, and (d) the amount and galactose density of the NGA dose, a computer program executed a curve-fit to the kinetic model. Systematic error, as measured by reduced chi-square, ranged from 1.43 to 2.56. Based on the nine imaging studies, the mean and relative error of each parameter were: [R]o, 0.813 +/- (0.11) microM; kb, 2.25 +/- (0.15) microM-1 min-1; F, 0.896 +/- (0.20) liter/min; Ve, 1.67 +/- (0.27) liter; and Vh, 0.228 +/- (0.22) liter. Two unique features of 99mTc-NGA radiopharmacokinetic systems permit the simultaneous estimates of receptor quantity, ligand affinity, and hepatic plasma flow. The first is the ability to administer a quantity of ligand capable of occupying a significant fraction of receptor; and the second is a simple model structure that conserves mass.

Diagnosis of cirrhosis and hepatitis by quantitative hepatic and other reticuloendothelial clearance rates.

Although methods for measuring colloid clearance rates have been described, they are not commonly used. Rather, most clinicians rely on the relative radiocolloid accummulation in the liver and spleen as estimated by visual inspection of liver scans. This method lacks objectivity, however, and only indirectly reflects the rate of radiocolloid clearance. We have developed a noninvasive kinetic technique for measuring radiocolloid clearance by the liver, spleen, and other reticuloendothelial tissues. The clerance-rate constants obtained by this technique appear to differentiate among cirrhosis, fatty metamorphosis, hepatitis, and normal function. In normal subjects, the mean clearance-rate constants for the liver, spleen, and extrahepatosplenic reticuloendothelial system were 16.0, 1.4, and 3.4 ml/min per 100 ml of plasma, respectively. The mean hepatic clearance-rate constant was normal in hepatitis (16.8 ml/min per 100 ml), reduced in cirrhosis (5.7), and slightly reduced in fatty metamorphosis (10.4). Both the hepatic-to-splenic and the hepatic-to-extrahepatosplenic ratios of clearance-rate constants were reduced in cirrhosis and slightly reduced in fatty metamorphosis and hepatitis. Interestingly, the splenic clearance-rate constants were normal in these three diseases.

Multicompartmental analysis of the kinetics of radioiodinated monoclonal antibody in patients with cancer.

A conceptual biologic model was developed and used to analyze the behavior of 123I-Lym-1 monoclonal antibody against African human B cell lymphoma in patients with B cell lymphoma. Originally, the observed data could not be simulated with parameters for homologous immunoglobulins reported in the literature because of a major processor that was capable of distinguishing this murine immunoglobulin from the patient's own immunoglobulins. With a nonlinear parametric model, the data observed in patients could be fitted to the model. The nonlinear parameter determined the transfer of antibody from the intravascular to a processor compartment, primarily the liver. This transfer was a function of the number of free receptors in the processor. Model simulated curves for the time course of concentration of antibody in the blood for different amounts of injected antibody revealed that blood clearance of radiolabeled antibody was profoundly decreased by increased amount of injected antibody. This model provides an explanation for the observations that tumor imaging is improved with injection of larger amounts of antibody, and a basis for modifying the pharmacokinetic behavior of an antibody in order to optimize radioimmunodiagnosis and radioimmunotherapy.

Local identifiability of a receptor-binding radiopharmacokinetic system having measured parameters of known uncertainty.

Local identifiability was determined for a receptor-binding radiopharmacokinetic system that included measured parameters of known uncertainty. Healthy subjects and patients with severe liver disease were studied with [99mTc] galactosylneoglycoalbumin (TcNGA). Measurements during the 30-min dynamic imaging study included the count rate over liver and heart, the quantity of TcNGA injected Lo, and the fraction-of-injected dose per liter of sampled plasma f. Typical relative standard deviations for these measurements were 1, 0.2, and 5 percent, respectively. A four-state nonlinear model describing the hepatic and plasma time-activity data was then used to calculate the standard error se(pj) for model parameters representing receptor concentration [R]o, the TcNGA-receptor forward binding rate constant kb, extrahepatic plasma volume Ve, hepatic plasma volume Vh, and hepatic plasma flow F. Accounting for the measurement uncertainties of Lo and f did not significantly increase the standard errors for parameters [R]o, kb, Ve, Vh and F. When the relative errors of Lo and f were increased to 40%, the change in se(pj) ranged from 10 to 100%, with parameter Vh being the most sensitive. The exception was se(kb), the increase of which was less than 1%. Imaging studies with reduced [R]o, typically associated with patients with liver disease, resulted in greater increases in all estimated parameter errors except se(kb) which had a lower increase. Lastly, the error propagation introduced by direct measurement of the liver observational coefficients sigma 12 and sigma 13 was investigated by simulating changes in the relative standard deviation in parameters sigma 12 and sigma 13 from 0 to 40%. Imaging studies from healthy subjects showed no increase in se(pj).(ABSTRACT TRUNCATED AT 250 WORDS)

Goodness-of-fit and local identifiability of a receptor-binding radiopharmacokinetic system.

A four-state nonlinear model describing a radiopharmacokinetic system for a hepatic receptor-binding radiopharmaceutical, [99mTc]-galactosyl-neoglycoalbumin (TcNGA), was tested for goodness-of-fit and local identifiability using scanning data from nine healthy subjects and seven patients with severe liver disease. Based on standard deviations of liver and heart imaging data at equilibria as a measure of observational error, the reduced chi-square ranged from 0.5 to 2.6. Values above 1.2 occurred when the subject moved during the 30 min study. Relative standard errors for each parameter were: TcNGA-receptor forward binding rate constant kb, 13-54%; extra-hepatic plasma volume Ve, 0.8-15.0%; hepatic plasma volume Vh, 0.2-6.5%; hepatic plasma flow F, 54----greater than 1000%; and receptor concentration [R]o, 0.3-13%. The highest standard errors occurred when the amount of TcNGA injected exceeded the total amount of receptor. Therefore, when TcNGA functional imaging was performed without excess patient motion and receptor saturation, the kinetic model provided data fits of low systematic error and yielded high precision estimates of receptor concentration and forward binding rate constant. In summary, optimal performance of the kinetic model occurred when the amount of injected TcNGA resulted in the nonlinear operation of the pharmacokinetic system.

Noise analysis of a digital radiography system.

The sources of noise in a digital video subtraction angiography system were identified and analyzed. Signal-to-noise ratios of digital radiography systems were measured using the digital image data recorded in the computer. The major sources of noise include quantum noise, TV camera electronic noise, quantization noise from the analog-to-digital converter, time jitter, structure noise in the image intensifier, and video recorder electronic noise. A new noise source was identified, which results from the interplay of fixed pattern noise and the lack of image registration. This type of noise may result from image-intensifier structure noise in combination with TV camera time jitter or recorder time jitter. A similar noise source is generated from the interplay of patient absorption inhomogeneities and patient motion or image re-registration. Signal-to-noise ratios were measured for a variety of experimental conditions using subtracted digital images. The measured signal-to-noise ratios were found to fluctuate on repeat trials with about a 10% standard deviation. Averaging of video frames was found to reduce the noise level by the expected square root N relation, where N is the number of frames averaged. Image-intensifier structure noise was shown to be a dominant noise source in unsubtracted images at medium to high radiation exposure levels. A total-system signal-to-noise ratio (SNR) of 750:1 was measured for an input exposure of 1 mR/frame at the image intensifier input. The effect of scattered radiation on subtracted image SNR was found to be greater than previously reported. The detail SNR was found to vary approximately as one plus the scatter degradation factor. Quantization error noise with 8-bit image processors (signal-to-noise ratio of 890:1) was shown to be of increased importance after recent improvements in TV cameras. The results of the analysis are useful both in the design of future digital radiography systems and the selection of optimum clinical techniques.

Tc-99m-galactosyl-neoglycoalbumin: in vivo characterization of receptor-mediated binding to hepatocytes.

The biodistribution and kinetics of a receptor-binding hepatic radiopharmaceutical, Tc-99m-galactosyl-neoglycoalbumin (Tc-NGA), were investigated using mammalian and avian models. The radiopharmaceutical exhibited four significant features associated with receptor-mediated binding at the hepatocyte membrane in mammals: (a) high tissue specificity, (b) high molecular specificity, (c) affinity-dependent uptake, and (d) dose-dependent uptake. Diminished hepatic uptake by the avian model illustrated low nonspecific binding. The kinetic sensitivity to ligand-receptor affinity and stoichiometry illustrated the principal feature of receptor-binding radio-pharmaceuticals, namely, quantitative assessment of tissue function based upon the biochemical interaction of a ligand and its specific receptor.

Statistical profiles in computed tomography.

A diagnostic console consisting of a high resolution video display coupled to a microcomputer was programmed to enable us to derive a battery of statistical parameters from any area of interest on a CT scan. These statistical parameters enable us to characterize the CT numbers of areas of interest in a more meaningful way than has been possible with most currently available consoles. A combination of statistical parameters enables us to discriminate between certain lesions with similar appearance such as porencephalic cysts, epidermoid tumors and cystic gliomas.

A new constant infusion radioisotopic technique for the noninvasive determination of cardiac output.

A constant infusion radioisotopic method for the noninvasive determination of cardiac output is introduced and validated in a series of 22 patients by comparison with simultaneous dye dilution or Fick measurements. The new bedside radioisotopic technique utilizes peripheral venous infusion of indium-113m, detection by a single external probe, and analysis of the time-concentration curve by a specially designed, multivariate computer model. The technique is entirely atraumatic, requiring neither injection into the central circulation nor intra-arterial cannulation. The correlation coefficient was 0.72 (p less than 0.001) between the radioisotopic and standard methods for cardiac output determinations. In addition, results in five patients with valvular regurgitation or intracardiac shunts support the validity of the constant infusion radioisotopic technique in these clinical settings in which the standard dye dilution methods for determining cardiac output are invalid. The techniques is applicable in a variety of clinical conditions in which the invasive techniques for cardiac output measurement are either impractical or not available.