Parametric images of antibody pharmacokinetics in Bi213-HuM195 therapy of leukemia.

UNLABELLED: Kinetic analysis of gamma camera patient images can provide time-dependent information about antibody behavior. Current region-of-interest-based techniques for the kinetic analysis of these images rely on user selection and drawing of regions to be analyzed. Such analyses do not reveal unexpected kinetic activity outside of the selected regions of interest and do not provide a whole-image assessment regarding the pharmacokinetics of an agent. At Memorial Sloan-Kettering Cancer Center, a method for generating images in which the pixel value represents a kinetic parameter has been developed. This work extends the method into a new application in which whole-body parametric images are used to examine the kinetics of Bi213-HuM195 in patients with leukemia. METHODS: Bi213-HuM195 is typically administered in multiple injections over 2-4 d, yielding a progressive increase in the amount of antibody administered. Patients are injected with individual doses while positioned in a gamma camera, and imaging is initiated at the start of the injection. The acquisition is performed in dynamic mode with images collected at several time intervals over 1 h. Using software developed in-house, images are corrected for patient movement through iterative alignments, decay corrected, and summed to yield a series of images over regular time intervals. Parametric rate images are obtained by fitting a linear expression to the counts in each pixel. In this study, rate images from a patient's first injection were compared with rate images from the last injection. RESULTS: The conventional planar images of antibody distribution showed significant uptake in liver, spleen, and marrow, whereas the generated rate images displayed different patterns, sometimes with negative values in liver and spleen and positive values in marrow, reflecting clearance and uptake rates rather than total accumulation. The impact of the progressive increase in antibody administration was observed by comparing the first with the last rate images. Interpatient comparisons were also made and showed that rate image patterns varied depending on patient-specific conditions such as the amount of disease and previous therapies undergone by the patient. CONCLUSION: Rate images make it possible to succinctly display kinetic information about an agent's behavior over the entire acquired image.

Resistance of [18f]-fluorodeoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine.

Radioactive iodine (131I) is an important therapeutic option for the treatment of metastatic thyroid carcinoma. Survival in patients with metastases that concentrate radioiodine is better than those whose metastatic lesions do not take up radioiodine. Survival is markedly reduced in patients who have metastatic lesions that concentrate 18F-fluorodeoxyglucose (FDG) on positron emission tomography (PET). In this retrospective study, we evaluated the ability of 131I to destroy FDG-avid metastatic lesions in thyroid cancer patients. Twenty-five patients with positive FDG-PET scans received at least one dose of 131I treatment before a second FDG-PET was performed. The average interval between the two PET scans was 12.9 months. The average interval between the 131I treatment and the follow-up FDG-PET was 10.1 months. We measured posttherapy changes in lesional volume, in standard uptake values (SUV) of FDG, and in serum thyroglobulin (Tg) levels. The total volume of FDG-avid metastases rose significantly (p = 0.036) from a mean of 159 mL to 235 mL after 131I therapy, the maximum SUV rose from 9.3 to 11.9, the median Tg at the time of the second PET scan was 132% of that at baseline. Statistical analyses demonstrated no significant changes in maximum SUV, or serum Tg levels after 131I in the FDG-PET-positive group. In a control group of FDG-PET-negative patients, the serum Tg decreased to 38% of baseline after 131I therapy (p < 0.001). We conclude that high-dose 131I therapy appears to have little or no effect on the viability of metastatic FDG-avid thyroid cancer lesions.

Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer.

Poorly differentiated thyroid cancer lesions often lose the ability to concentrate radioactive [131I]iodine (RAI) and exhibit increased metabolic activity, as evidenced by enhanced glucose uptake. We incorporated [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning into the routine follow-up of a cohort of thyroid cancer patients undergoing annual evaluations. One hundred and twenty-five patients who had previous thyroidectomies were included. They had diagnostic RAI whole body scans, serum thyroglobulin measurements, and additional imaging studies as clinically indicated. During 41 months of follow-up, 14 patients died. Univariate analysis demonstrated that survival was reduced in those with age over 45 yr, distant metastases, PET positivity, high rates of FDG uptake, and high volume of the FDG-avid disease (>125 mL). Survival did not correlate with gender, RAI uptake, initial histology, or grade. Multivariate analysis demonstrated that the single strongest predictor of survival was the volume of FDG-avid disease. The 3-yr survival probability of patients with FDG volumes of 125 mL or less was 0.96 (95% confidence interval, 0.91, 1.0) compared with 0.18 (95% confidence interval, 0.04, 0.85) in patients with FDG volume greater than 125 mL. Only 1 death (of leukemia) occurred in the PET-negative group (n = 66). Of the 10 patients with distant metastases and negative PET scans, all were alive and well. Patients over 45 yr with distant metastases that concentrate FDG are at the highest risk. Once distant metastases are discovered in patients with differentiated thyroid carcinoma, FDG-PET can identify high and low risk subsets. Subjects with a FDG volume greater than 125 mL have significantly reduced short term survival.

Overcoming the nephrotoxicity of radiometal-labeled immunoconjugates: improved cancer therapy administered to a nude mouse model in relation to the internal radiation dosimetry.

BACKGROUND: Elevated renal uptake and extended retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. However, cationic amino acids have been shown to reduce renal accretion. The aims of the current study were to evaluate whether this methodology would benefit therapy with yttrium 90 (90Y)-labeled antibody fragments (Fab, F(ab)2), to establish the relationship between radiation dosimetry and observed biologic effects, and to compare the antitumor efficacy of antibody fragments with that of whole immunoglobulin (Ig)G. METHODS: The maximum tolerated dose (MTD) and the dose-limiting organ toxicity of 90Y-labeled anti-carcinoembryonic antigen (CEA) MN-14 monoclonal antibodies (Fab, F(ab)2, and IgG) were determined in nude mice bearing GW-39 human colon carcinoma xenografts. The mice were treated with or without kidney protection by administration of D-lysine, with or without bone marrow transplantation (BMT), or with combinations of each. Toxicity and tumor growth were monitored at weekly intervals after radioimmunotherapy. Dosimetry was calculated from biodistribution studies using 88Y-labeled antibody. Three different dosimetric models were examined: 1) taking solely self-to-self doses into account, using S factors for 90Y in spheroids from 0.1 to 1 g; 2) correcting for cross-organ radiation; and 3) using actual mouse anatomy as represented by nuclear magnetic resonance imaging with a three-dimensional internal dosimetry package (3D-ID). RESULTS: The kidney was the first dose-limiting organ with the use of Fab fragments. Acute radiation nephritis occurred at injected activities > or = 325 microCi, and chronic nephrosis at doses > or = 250 microCi. Activities of 200 microCi were tolerated by 100% of the animals (i.e., the MTD). Application of lysine decreased the renal dose by approximately fivefold, facilitating a 25% increase in the MTD (to 250 microCi), because myelotoxicity became dose-limiting despite red marrow doses of less than 5 gray (Gy). By using BMT and lysine, the MTD could be doubled from 200 to 400 microCi, where no biochemical or histologic evidence of renal damage was observed (kidney dose, < or = 40 Gy). With injected activities of > or = 325 microCi without kidney protection, and with a hepatic self-to-self dose of only 4 Gy, rising liver enzymes were observed, which could be explained only by cross-organ radiation from radioactivity in the kidneys (in the immediate neighborhood of the right kidney up to > or = 150 Gy). The MTD of F(ab)2 fragments could be elevated only by a combination of BMT and lysine. With IgG, the bone marrow alone was dose-limiting. Tumor dosimetry correlated well with antitumor effects; Fab was more effective than F(ab)2, which was consistent with its more favorable dosimetry, and it may also be more effective than IgG due to its higher dose rate and more homogenous distribution. Dosimetry Model 1 was insufficient for predicting biologic effects. Model 2 seemed to be more accurate, accounting for interorgan crossfire. However, Model 3 showed an additional substantial contribution to the red bone marrow dose due to crossfire from the abdominal organs. CONCLUSIONS: These data show that radiation nephrotoxicity is an important effect of cancer therapy with radiometal-conjugated antibody fragments or peptides. However, this effect can be overcome successfully with the application of cationic amino acids, which substantially increase the anti-tumor efficacy of radiometal-labeled immunoconjugates. For understanding the biologic effects (e.g., liver toxicity) of 90Y in a mouse model, accounting for cross-organ radiation is essential. Further studies with radiometal-conjugated monoclonal antibody fragments and peptides are necessary to determine the MTD, dose-limiting organs, antitumor effectiveness, and nephroprotective effects of cationic amino acids in humans.

Implementation of a Monte Carlo dosimetry method for patient-specific internal emitter therapy.

In internal emitter therapy, an accurate description of the absorbed dose distribution is necessary to establish an administered dose-response relationship, as well as to avoid critical organ toxicity. This work describes the implementation of a dosimetry method that accounts for the radionuclide decay spectrum, and patient-specific activity and density distributions. The dosimetry algorithm is based on a Monte Carlo procedure that simulates photon and electron transport and scores energy depositions within the patient. The necessary input information may be obtained from a registered set of CT and SPECT or PET images. The algorithm provides the absorbed dose rate for the radioactivity distribution provided by the SPECT or PET image. The algorithm was benchmarked by reproducing dosimetric quantities using the Medical Internal Radionuclide Dose (MIRD) Committee's Standard Man phantom and was used to calculate absorbed dose distributions for representative case studies.

Implementation and evaluation of patient-specific three-dimensional internal dosimetry.

UNLABELLED: Current methods for calculating the absorbed dose in a target region from a source region rely on a standard "reference man" geometry and assume an uniform distribution of radiolabel. While this approach is acceptable at the low levels of radioisotope administered for most diagnostic purposes, the generality of the calculations is not adequate for doses at the higher levels required for therapy and is not easily extendible to tumor dosimetry. METHODS: We have developed an integrated system which utilizes patient anatomy and radionuclide distribution in the calculation of absorbed dose rate or total dose to any user-defined target region. Images of radionuclide distribution (PET/SPECT) are registered to anatomic images (CT/ MRI) and then entered into a three-dimensional internal dosimetry software system (3D-ID) where regions of interest are defined. Dose calculations are performed by the mathematical convolution between a user-specified, dose-point kernel with the activity in the source volume over the target volume. The resulting dose rate distribution may be scaled by cumulated activity to yield absorbed dose. In addition to calculating the mean dose, dose-volume histograms may be generated which plot absorbed dose with respect to percent of volume. The method was evaluated using selected standard man phantom organs. RESULTS: Dose estimates for two patient studies are included to illustrate differences between patient-specific and MIRD-based calculations. The package provides an alternative approach to image display and three-dimensional internal dose calculations. CONCLUSION: The dose-volume histogram representation of absorbed dose to a target volume provides valuable information in assessing tumor control probability and normal tissue toxicity.

Image registration of SPECT and CT images using an external fiduciary band and three-dimensional surface fitting in metastatic thyroid cancer.

Image registration of 131I SPECT with CT scans was performed in a patient with metastatic thyroid carcinoma using an external fiduciary band and a three-dimensional surface-fitting algorithim. Areas of metastatic disease taking up 131I were accurately localized to the liver, lungs and vertebral bodies; providing information that could not be obtained by planar or SPECT images alone. Based on these findings, further invasive diagnostic procedures were not performed, therefore considerably altering management in this patient. This approach to image registration has immediate clinical utility in the registration and interpretation of SPECT studies with corresponding CT or MRI scans.

Government in the examining room: restrictions on the provision of abortion.

Efforts to deter women from deciding to terminate their pregnancies take their toll on both women and health care providers. Unable to overturn Roe v Wade and ban abortion outright, opponents have sought to prevent women from obtaining abortions by imposing restrictions and burdening service providers. Among the most common measures adopted at the state level are mandatory delay, state-scripted information, and parental notification requirements, while both federal and state policy makers have restricted Medicaid coverage for abortion. In its 1992 decision in Planned Parenthood v Casey, the US Supreme Court made clear that states may not criminalize abortion prior to viability or allow anyone to veto a woman's decision to terminate her pregnancy. Nonetheless, the Court adopted a less protective "undue burden" standard for reviewing the constitutionality of restrictions on a woman's right to choose. In the wake of Casey, courts and legislative bodies continue to grapple with the extent to which the abortion choice is protected under federal and state constitutions. Meanwhile, women and health care providers are forced to endure the hardships caused by restrictive laws and policies.