The LundADose Method for Planar Image Activity Quantification and Absorbed-Dose Assessment in Radionuclide Therapy.

A new method for absorbed-dose assessment in radionuclide therapy is presented in this paper. The method is based on activity quantification by the conjugate-view methodology, applied to serial whole-body, anterior-posterior, scintillation-camera scans. The quantification method is an extension of previous studies, and includes separate corrections for attenuation, scatter, and overlapping organs. Further development has now been undertaken to take into account the capabilities of new dual-head camera systems with a built-in X-ray tube for anatomical imaging. Furthermore, the modeling of time-activity data is included, and dosimetric calculations based on the formalism by the Medical Internal Radiation Dose (MIRD) committee. To streamline absorbed-dose assessments for a large number of patient studies, the programs for quantification, image registration, and absorbed-dose calculations have been embedded in an envelop program termed LundADose, where calculations, to a great extent, are performed automatically. Evaluation of the whole-body activity quantification is performed for patients undergoing radioimmunotherapy by monoclonal antibodies labeled with In-111 or Y-90

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry.

BACKGROUND: The method for red marrow dosimetry in radioimmunotherapy, in the absence of specific activity uptake in red marrow, is based on the activity measured in the blood or plasma. The activity concentration ratio of red marrow to blood is then assumed to be constant. The aim of the current study was to determine whether this ratio varies with time after injection. METHODS: Measurements were carried out with both animals and patients.Tumor-bearing rats were intravenously injected with iodine-131-, iodine-125-, indium-111-, or rhenium-188-labeled BR96, a chimeric immunoglobulin G1 monoclonal antibody. (All were chelate-labeled, except for iodine-131, which was iodogen-labeled.) Measurements were made of the activity concentration in blood and bone marrow at different points in time after injection, and the ratio of activity concentration in red marrow and blood as a function of time postinjection (RMBLR[t)]) was calculated. For patients treated with iodine-131-labeled monoclonal antibody (LL2, Immunomedics Inc., Morris Plains, NJ; anti-CD22; immunoglobulin G2 isotype of mouse origin), blood samples were drawn and scintillation camera images taken at different times after injection. The red marrow activity concentration in the sacrum was determined by activity quantification from regions of interest. The activity concentration in blood was also measured. The RMBLR(t) was calculated based on these data. RESULTS: For both patients and rats, the RMBLR(t) was increased 72 hours after injection. Furthermore, it was found that the use of a constant RMBLR can lead to an over- or underestimation of the absorbed dose in bone marrow. CONCLUSIONS: These data demonstrate the difficulty in using fixed values of the activity concentration ratio of red marrow to blood for dosimetry

Scintigraphic method to quantify the passage from brain parenchyma to the deep cervical lymph nodes in rats

In order to investigate the kinetics of the passage from the brain parenchyma to the lymphatic system in vivo a high resolution scintillation camera technique was developed. Albumin, albumin colloids and dextran labelled with 99mTc were injected into the right side of the thalamus of anesthetized rats. Continuous measurement of the activity distribution in head and neck were performed for 70 min. Rate constants were calculated by means of a computer program for compartment analysis. The animals were killed 10 h postinjection, to measure the activity in tissue samples. For some animals, images were registered up to 24 h after injection. This work presents an in vivo technique to clarify the particle flow paths in the brain and make quantification possible. The method is simple and does not require continuous blood or lymph sampling. Our work shows that there is a substantial flow of injected material from the brain via lamina cribriformis to the lymphatic system. This route is of great interest for the drainage of the interstitial fluid of the brain. We have also shown a difference in flow for dextran particles with different charg

Evaluation of methods for red marrow dosimetry based on patients undergoing radioimmunotherapy.

Evaluation of methods for red marrow dosimetry based on patients undergoing radioimmunotherapy Red marrow dosimetry is essential during radioimmunotherapy and a reliable method is essential in order to find a measure correlated to the toxic effect observed. The aim of this study was to calculate the absorbed dose to red marrow with different methods for the same patients and to compare the results. Patients diagnosed with B-cell lymphoma were treated with I-131-labelled monoclonal antibodies ( LL2, anti-CD22). Blood samples were collected, scintillation camera images were taken and single probe measurements were carried out at different points in time after administration of the radiopharmaceutical. The absorbed dose to red marrow per unit activity administered was calculated using four varieties of the blood method and from activity quantification in the sacrum in the scintillation camera images. The absorbed dose to the total body per unit activity, sometimes used as a measure for determining the toxic effect in red marrow, was calculated from both the scintillation camera images and the single probe measurements. The results from the different methods of calculating the absorbed dose for the same patient and treatment were compared. The ratio of the maximum and the minimum absorbed dose to red marrow calculated using the four variations of the blood method and the sacrum imaging method for one and the same patient varied between 1.8 and 2.8. The correlation coefficients for all the possible combinations of the dosimetry methods, including total body measurements, varied from 0.51 to 0.99. The results show that the variability of the absorbed dose to the bone marrow is dependent on both method and patient

Registration of emission and transmission whole-body scintillation-camera images

In this work, a method for registration of whole-body (WB) scintillation-camera images is presented. The primary motive for the development is to perform activity quantification using the conjugate view method on an image basis. Accurate image registration is required for sequential anterior and posterior scans, for serial emission images for analysis of the biokinetics, and for transmission and emission images for a pixel-based attenuation correction. METHODS: Registration is performed by maximization of the mutual information. The spatial transformation has been tailored for the registration of WB images and is composed of global and local transformations, including rigid, projective, and curved transformations. A coarse registration is first performed using cross-correlation and direct pixel scaling. Optimization is then performed in a sequence, beginning with the 2 legs independently, followed by the upper body and head. Evaluation is performed for clinical images of an (131)I-labeled monoclonal antibody and for Monte Carlo-simulated images. An anthropomorphic WB computer phantom, which has been especially modified to match the patient position during WB scanning, is used for the simulations. RESULTS: For simulated images, registration errors are within 1 pixel (<3.6 mm) for a sufficient image count level. Separate evaluation of the influence of noise shows that the errors increase below a total image count of approximately 10(5) (signal-to-noise ratio, approximately 4). For clinical evaluations, the deviations between point markers are 9 +/- 5 mm. CONCLUSION: An automatic registration method for WB images has been developed, which is applicable to emission-emission and transmission-emission registration. This method has been applied in more than 50 clinical studies and has shown to be robust and reliable

Parametric images of antibody pharmacokinetics based on serial quantitative whole-body imaging and blood sampling

We present a method for pharmacokinetic modeling of distributions of In-111-labeled monoclonal antibodies (mAbs) on individual pixels of planar scintillation-camera images. Methods: The method is applied to 2 sets of clinical whole-body images, each consisting of 6 consecutive images acquired over a week. Quantification is performed on a pixel basis, yielding images in units of Bq/pixel. The images acquired on the different occasions are registered using a nonrigid method, and for each pixel location a time-activity curve is obtained for which kinetic modeling is performed. The In-111-mAb is assumed to be located in either the vascular or the extravascular space. The vascular content is assumed to follow the global blood kinetics as determined from blood samples, together with a model parameter alpha that describes the fraction of the whole-body blood volume present in the particular pixel. The rate of change of the extravascular compartment is described by a linear 1-tissue-compartment model with 2 rate constants, K-1' and k(2), reflecting extravasation and washout, respectively. The model is optimized for each pixel position with regard to the values of the 3 parameters (alpha, K-1', and k(2)), resulting in 3 parametric images. From these, images of the cumulated activity in vascular and extravascular spaces are calculated, as is an image of the rate-constants ratio, which is closely related to the volume of distribution. Results: The resulting parametric images are analyzed in terms of the appearance of the time-activity curves at various locations. Results also include interpretation of the parametric images in their clinical context, and the location of regions that exhibit high extravasation and a low washout rate is compared with confirmed malignant sites. Conclusion: Parametric imaging allows the study and analysis of the spatial and temporal distributions of mAbs simultaneously. Parametric imaging enhances regions where the pharmacokinetics differ from the surrounding tissue and provides a tool to detect and locate unexpected kinetic behavior, which is sometimes characteristic of malignant tissue. For dosimetry in radionuclide therapy, parametric imaging offers a less biased means of analyzing serial mAb images than traditional region-of-interest-based analysis

Single tumor cell uptake and dosimetry of technetium-99m Fab ' anti-CD22 in low-grade B-cell lymphoma

BACKGROUND. A patient with follicular lymphoma was investigated with 0.5 mg Fab' anti-CD22 labeled with 1100 MBq technetium-99m (Tc-99m). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. METHODS. Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with Tc-99m anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell Populations was Measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for die extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. RESULTS. The average number of Tc-99m atoms per CD19+ and CD3 cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). CONCLUSIONS. It seems feasible to assess the mean single tumor cell uptake of Tc-99m targeted by Fab' anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from Tc-99m to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy elCancer 2002;94:1270-4

Development and evaluation of a pharmacokinetic model for prediction of radioimmunotherapy based on pretherapy data.

The aim of this work was to develop a pharmacokinetic model for the analysis of the pharmacokinetics of (111)Inlabeled monoclonal antibodies (mAbs) in B-cell lymphoma patients and to evaluate the model's ability to predict a subsequent radioimmunotherapy by (90)Y-labeled mAbs. Data from quantified scintillation camera images and blood samples were used to fit a compartment model. The modeling included two steps: 1) a two-compartment model describing the total-body kinetics for the estimation of a set of global parameters and 2) a multicompartment model for estimating the model parameters for organs. In both steps, a correction for radiochemical impurity in the form of (111)In-DTPA (diethylene triamine pentaacetic acid) was included. The model was found to describe all patient data with good accuracy. From the model, the time-activity data of all organs could be separated into extravascular and vascular components, where the estimates of the regional vascular volumes were found to be in close agreement with literature data. A significant improvement of the model fit to total-body activity data was obtained by correcting for radiochemical impurity. The therapy kinetics area under the curves (AUCs) predicted from pretherapy data were in good agreement with the measured therapy AUCs. The good correlation between the model estimates and measured data, the accurate prediction of the therapy kinetics, and the good estimates of regional vascular volumes demonstrates the reliability of the model. These findings also indicate that the model can be useful for individual optimization of the amount of activity to be administered with respect to patient dosimetry

Carbohydrate groups of alpha1-microglobulin are important for secretion and tissue localization but not for immunological properties

The role of the carbohydrates for the structure and functions of the plasma and tissue protein alpha1-microglobulin (alpha1m) was investigated by deletion of the sites for N-glycosylation by site-directed mutagenesis (N17,96-->Q). The mutated cDNA was expressed in a baculovirus-insect cell system resulting in a nonglycosylated protein. The biochemical properties of N17,96Q-alpha1m were compared to nonmutated alpha1m, which carries two short non-sialylated N-linked oligosaccharides when expressed in the same system. Both proteins carried a yellow-brown chromophore and were heterogeneous in charge. Circular dichroism spectra and antibody binding indicated a similar overall structure. However, the secretion of N17,96Q-alpha1m was significantly reduced and approximately 75% of the protein were found accumulated intracellularly. The in vitro immunological effects of recombinant nonmutated alpha1m and N17,96Q-alpha1m were compared to the effects of alpha1m isolated from plasma, which is sialylated and carries an additional O-linked oligosaccharide. All three alpha1m variants bound to human peripheral lymphocytes and mouse T cell hybridomas to the same extent. They also inhibited the antigen-stimulated proliferation of peripheral lymphocytes and antigen-stimulated interleukin 2-secretion of T cell hybridomas in a similar manner. After injection of rats intravenously, the blood clearance of recombinant nonmutated and N17,96Q-alpha1m was faster than that of plasma alpha1m. Nonmutated alpha1m was located primarily to the liver, most likely via binding to asialoglycoprotein receptors, and N17,96Q-alpha1m was located mainly to the kidneys. It is concluded that the carbohydrates of alpha1m are important for the secretion and the in vivo turnover of the protein, but not for the structure or immunological properties