Accuracy and reproducibility of tumor positioning during prolonged and multi-modality animal imaging studies.

Dedicated small-animal imaging devices, e.g. positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) scanners, are being increasingly used for translational molecular imaging studies. The objective of this work was to determine the positional accuracy and precision with which tumors in situ can be reliably and reproducibly imaged on dedicated small-animal imaging equipment. We designed, fabricated and tested a custom rodent cradle with a stereotactic template to facilitate registration among image sets. To quantify tumor motion during our small-animal imaging protocols, 'gold standard' multi-modality point markers were inserted into tumor masses on the hind limbs of rats. Three types of imaging examination were then performed with the animals continuously anesthetized and immobilized: (i) consecutive microPET and MR images of tumor xenografts in which the animals remained in the same scanner for 2 h duration, (ii) multi-modality imaging studies in which the animals were transported between distant imaging devices and (iii) serial microPET scans in which the animals were repositioned in the same scanner for subsequent images. Our results showed that the animal tumor moved by less than 0.2-0.3 mm over a continuous 2 h microPET or MR imaging session. The process of transporting the animal between instruments introduced additional errors of approximately 0.2 mm. In serial animal imaging studies, the positioning reproducibility within approximately 0.8 mm could be obtained.

Prediction of absorbed dose to normal organs in thyroid cancer patients treated with 131I by use of 124I PET and 3-dimensional internal dosimetry software.

UNLABELLED: The objective of this work was to determine normal organ (131)I dosimetry in patients undergoing radioiodide therapy for thyroid cancer by use of serial scanning with (124)I PET. METHODS: A total of 26 patients who had papillary and follicular metastatic thyroid cancer and who were already enrolled in a Memorial Sloan-Kettering Cancer Center (131)I thyroid cancer protocol were selected for this study. Imaging before (131)I therapy consisted of multiple, whole-body (124)I PET studies over a period of 2-8 d, an (18)F-FDG PET scan and, for some, a diagnostic CT scan. With a set of in-house-developed software tools (3-dimensional internal dosimetry [3D-ID] and Multiple Image Analysis Utility [MIAU]), the following procedures were performed: all PET emission and transmission and CT image sets were aligned; half-life-corrected tomographic images of (131)I activity were integrated voxel by voxel to produce cumulated (131)I activity images; and the latter images were, in turn, convolved with a (131)I electron-photon point kernel to produce images of (131)I dose distribution. Cumulated activity values and calculated residence times obtained from our patient-specific dosimetry software (3D-ID) were used as inputs to OLINDA, and volume difference-adjusted comparisons were made between the mean dose estimates. RESULTS: With 3D-ID, dose volume histograms and mean doses were calculated for 14 organs, and results were expressed in Gy/GBq. The highest mean dose, 0.26 Gy/GBq, was seen in the right submandibular gland, whereas the lowest mean dose, 0.029 Gy/GBq, was seen in the brain. CONCLUSION: This is the first comprehensive study of normal organ dosimetry in patients by use of a quantitative tomographic imaging modality.

Patient-specific dosimetry for 131I thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software.

UNLABELLED: Compared with conventional, whole-organ, S-factor-based dosimetry, 3-dimensional (3D), patient-specific dosimetry better accounts for radionuclide distribution and anatomic patient variability. Its accuracy, however, is limited by the quality of the cumulated activity information that is provided as input. This input has typically been obtained from SPECT and planar imaging studies. The objective was to implement and evaluate PET-based, patient-specific, 3D dosimetry for thyroid cancer patients. METHODS: Three to 4 PET imaging studies were obtained over a 7-d period in 15 patients with metastatic thyroid carcinoma after administration of (124)I-NaI. Subsequently, patients were treated with (131)I on the basis of established clinical parameters. Retrospective dosimetry was performed using registered (124)I PET images that were corrected for the half-life difference between (124)I and (131)I. A voxel-by-voxel integration, over time, of the resulting (131)I-equivalent PET-derived images was performed to provide a single 3D dataset representing the spatial distribution of cumulated activity values for each patient. Image manipulation and registration were performed using Multiple Image Analysis Utility (MIAU), a software package developed previously. The software package, 3D-Internal Dosimetry (3D-ID), was used to obtain absorbed dose maps from the cumulated activity image sets. RESULTS: Spatial distributions of absorbed dose, isodose contours, dose-volume histograms (DVHs), and mean absorbed dose estimates were obtained for a total of 56 tumors. Mean absorbed dose values for individual tumors ranged from 1.2 to 540 Gy. The absorbed dose distribution within individual tumors was widely distributed ranging from a minimum of 0.3 to a maximum of 4,000 Gy. CONCLUSION: (124)I PET-based, patient-specific 3D dosimetry is feasible, and sequential PET can be used to obtain cumulated activity images for 3D dosimetry.

Correction for oral contrast artifacts in CT attenuation-corrected PET images obtained by combined PET/CT.

UNLABELLED: Recent studies have shown increased artifacts in CT attenuation-corrected (CTAC) PET images acquired with oral contrast agents because of misclassification of contrast as bone. We have developed an algorithm, segmented contrast correction (SCC), to properly transform CT numbers in the contrast regions from CT energies (40-140 keV) to PET energy at 511 keV. METHODS: A bilinear transformation, equivalent to that supplied by the PET/CT scanner manufacturer, for the conversion of linear attenuation coefficients of normal tissues from CT to PET energies was optimized for BaSO(4) contrast agent. This transformation was validated by comparison with the linear attenuation coefficients measured for BaSO(4) at concentrations ranging from 0% to 80% at 511 keV for PET transmission images acquired with (68)Ge rod sources. In the CT images, the contrast regions were contoured to exclude bony structures and then segmented on the basis of a minimum threshold CT number (300 Hounsfield units). The CT number in each pixel identified with contrast was transformed into the corresponding effective bone CT number to produce the correct attenuation coefficient when the data were translated by the manufacturer software into PET energy during the process of CT attenuation correction. CT images were then used for attenuation correction of PET emission data. The algorithm was validated with a phantom in which a lesion was simulated within a volume of BaSO(4) contrast and in the presence of a human vertebral bony structure. Regions of interest in the lesion, bone, and contrast on emission PET images reconstructed with and without the SCC algorithm were analyzed. The results were compared with those for images obtained with (68)Ge-based transmission attenuation-corrected PET. RESULTS: The SCC algorithm was able to correct for contrast artifacts in CTAC PET images. In the phantom studies, the use of SCC resulted in an approximate 32% reduction in the apparent activity concentration in the lesion compared with data obtained from PET images without SCC and a <7.6% reduction compared with data obtained from (68)Ge-based attenuation-corrected PET images. In one clinical study, maximum standardized uptake value (SUV(max)) measurements for the lesion, bladder, and bowel were, respectively, 14.52, 13.63, and 13.34 g/mL in CTAC PET images, 59.45, 26.71, and 37.22 g/mL in (68)Ge-based attenuation-corrected PET images, and 11.05, 6.66, and 6.33 g/mL in CTAC PET images with SCC. CONCLUSION: Correction of oral contrast artifacts in PET images obtained by combined PET/CT yielded more accurate quantitation of the lesion and other, normal structures. The algorithm was tested in a clinical case, in which SUV(max) measurements showed discrepancies of 2%, 1.3%, and 5% between (68)Ge-based attenuation-corrected PET images and CTAC PET images with SCC for the lesion, bladder, and bowel, respectively. These values correspond to 6.5%, 62%, and 66% differences between CTAC-based measurements and (68)Ge-based ones.

Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative MicroPET and MRI.

UNLABELLED: Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma. METHODS: Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry. RESULTS: Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm. CONCLUSION: For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.

Murine S factors for liver, spleen, and kidney.

UNLABELLED: Preclinical evaluation of new radiopharmaceuticals is performed in animal systems before testing is started in humans. These studies, often performed in murine or other rodent models, are important in understanding the relationship between absorbed dose and response, which can be translated to preclinical results for humans. In performing such calculations, either electrons are assumed to deposit all of their energy locally or idealized models of mouse anatomy are used to determine absorbed fractions. Photon contributions are generally considered negligible. To improve the accuracy of such absorbed dose calculations, mouse-specific S factors for (131)I, (153)Sm, (32)P, (188)Re, and (90)Y have been generated, and the photon and electron portions have been tabulated separately. Absorbed fractions for 5 monoenergetic electrons, ranging in energy from 0.5 to 2 MeV, are also provided. METHODS: Female athymic mouse MR images were obtained on a 4.7-T MRI device. Fifteen T1-weighted, 1.5-mm-thick slices (0.5-mm gap) were collected. Using a previously developed software package, 3-dimensional Internal Dosimetry (3D-ID), organ contours were drawn to obtain a 3-dimensional representation of liver, kidneys, and spleen. Using a point-kernel convolution, the mean absorbed dose to each organ from the individual contributions of each source organ were calculated. S factor equivalent values were obtained by assuming a uniform distribution of radioactivity in each organ. Results were validated by comparing 3D-ID generated electron S factors for different-sized spheres with published data. Depending on matrix size, sphere size, and radionuclide, 1% (256(2) matrix) to 18% (64(2) matrix) agreement was obtained. RESULTS: S factor values were calculated for liver, spleen, and right and left kidneys. Cross-organ electron-absorbed fractions of up to 0.33 were obtained (e.g., (90)Y right kidney to liver). Comparisons between S factor values and values obtained assuming complete absorption of electron energy yielded differences of more than 190% ((90)Y spleen self-dose). CONCLUSION: The effect of cross-organ and self-absorbed dose is dependent on emission energy and organ geometry and should be considered in murine dose estimates. The approach used to generate these S factors is applicable to other animal systems and also to nonuniform activity distributions that may be obtained by small-animal SPECT or PET imaging or by quantitative autoradiography.

Patient-specific, 3-dimensional dosimetry in non-Hodgkin's lymphoma patients treated with 131I-anti-B1 antibody: assessment of tumor dose-response.

UNLABELLED: A comprehensive, SPECT-based, patient-specific 3-dimensional (3D) dosimetry analysis has been performed using 3D-ID, a previously developed software package. The role of the total-body tumor burden, individual lesion size, tumor absorbed dose, and the spatial distribution of the absorbed dose on response and on the time course of tumor shrinkage has been examined in patients with lymphoma treated by radioimmunotherapy. METHODS: Data from 15 patients participating in a phase II study of (131)I-labeled anti-B1 antibody (tositumomab) were used. Patients were administered a tracer dose of (131)I for imaging and pharmacokinetics. Dose estimates from the tracer studies were used to prescribe the therapeutic administration such that the whole-body absorbed dose did not exceed 75 cGy. All patients received a fixed mass amount of antibody for both the tracer and the therapeutic administrations. SPECT and planar imaging were performed 3-4 d after the therapeutic administration. CT or MRI scans were available on all patients. Total tumor burden was assessed by drawing contours around all lymphoma lesions identified on whole-body CT or MRI. Mean absorbed doses were estimated for selected, index lesions by conventional dosimetry and also by 3D SPECT-based dosimetry. Using a patient-specific dosimetry package, 3D-ID, dose-volume histograms were also generated to assess the spatial distribution of absorbed dose. This approach made it possible to obtain estimates of the minimum and maximum absorbed doses for individual tumors in addition to the mean. RESULTS: Mean absorbed dose estimates obtained by patient-specific SPECT-based dosimetry using 3D-ID were within 2%-5% of estimates obtained by conventional dosimetry. None of the absorbed dose parameters (mean, minimum, maximum, uniformity) were found to have a significant correlation with tumor response. The total-body tumor burden did not impact on overall response or toxicity. CONCLUSION: This analysis represents the first full reported implementation of a patient-specific 3D dosimetry package. The absence of a dose-response relationship for tumors is surprising and suggests that absorbed dose is not the sole determinant of tumor response in these patients. The absence of a correlation between the total-body tumor burden and overall response or toxicity suggests that tailoring the milligram amount of administered antibody to patient tumor burden is not likely to improve response or reduce toxicity.