Practical method for radioactivity distribution analysis in small-animal PET cancer studies

Abstract

We present a practical method for radioactivity distribution analysis in small-animal tumors and organs using positron emission tomography imaging with a calibrated source of known activity and size in the field of view. We reconstruct the imaged mouse together with a source under the same conditions, using an iterative method, Maximum likelihood expectation-maximization with system modeling, capable of delivering high-resolution images. Corrections for the ratios of geometrical efficiencies, radioisotope decay in time and photon attenuation are included in the algorithm. We demonstrate reconstruction results for the amount of radioactivity within the scanned mouse in a sample study of osteolytic and osteoblastic bone metastasis from prostate cancer xenografts. Data acquisition was performed on the small-animal PET system, which was tested with different radioactive sources, phantoms and animals to achieve high sensitivity and spatial resolution. Our method uses high-resolution images to determine the volume of organ or tumor and the amount of their radioactivity has the possibility of saving time, effort and the necessity to sacrifice animals. This method has utility for prognosis and quantitative analysis in small-animal cancer studies, and will enhance the assessment of characteristics of tumor growth, identifying metastases, and potentially determining the effectiveness of cancer treatment. The possible application for this technique could be useful for the organ radioactivity dosimetry studies.

Introduction

Complex clinical decisions on treatment are often guided by positron emission tomography (PET) imaging principally using ¹⁸FDG. PET is often used with other imaging techniques (by combining with CT or MRI) to obtain complementary information. Imaging with ¹⁸FDG or other agents often requires quantitative measurements associated with the imaging data.

The factors that affect PET quantitation are resolution, photon attenuation and scattering, random coincidence rate, detector normalization, dead time and noise. It is very difficult to account for these factors for quantitative analysis of 3D reconstructed radioactivity in tumors or mouse organs.

In most PET studies the standardized uptake value (SUV) method is used to quantify tumor radioactivity. As the most widely used semi-quantitative parameter for tumor diagnosis, SUV determination involves measuring activity at a target site, with correction for injected dose, plasma glucose level, uptake period, body weight and, more important, correction for reconstruction method (Di Chiro and Brooks, 1988; Keyes, 1996; Thie et al., 2000; Huang, 2000; Truong et al., 2004; Kok et al., 2005; Popperl et al., 2006). To eliminate the need for body-weight correction, SUV has been calculated on the basis of body weight: tissue concentration (MBq/g)/injected dose (MBq)/body weight (g) (see other SUV determinations in de Boer et al., 2002). However, the SUV method does not correct for any inaccuracy in the measured dose, which may occur with injected dose extravasations, or with an elevated uptake elsewhere in the body. The accuracy of the SUV and the accuracy of relative change during treatment are not well documented and it might be a problem for diagnostic purposes in multicenter studies (Boellaard et al., 2004). Recent studies even find that SUV readings vary on different PET systems (Takahashi et al., 2007), and regions of interest (ROI) can influence quantitative FDG-PET study results (Evilevich et al., 2007).

Thus, the microPET-R4 rodent scanner and ASIPro reconstruction software (both from CTI Concorde Microsystems Inc., Knoxville, TN) were used for semi-quantitative radioactivity analysis in two recent studies: to delineate the stages involved in the development of arthritis (Wipke et al., 2004) and breast cancer metastasis (Liang et al., 2005). In the first study quantitative analysis of ROI was performed over the selected mouse tissues and averaging the radioactive concentration over the contained voxels. In the second study a pixel ROI was outlined in the regions of increased FDG uptake, and after correction for radioactivity decay, the maximum SUV was semi-quantitatively calculated according to the method of Truong et al. (2004).

A more sophisticated method to determine the maximum radioactivity concentration within a tumor or an organ was described in Zhang et al. (2006). In this method, mean pixel values within the multiple ROI volumes were converted to μCi/mL/min by using a calibration constant (Wu et al., 2005). Recently, an analytic semi-automated approach to calculate body distribution of PET tracers using co-registration a digital mouse phantom with small-animal images was proposed in Kesner et al. (2006). The main goal in Di Domenico et al. (2003) was to quantify the activity measured in an ROI within a reconstructed image of a small-animal and compare results with the ones derived from standard biodistribution methods: sacrificing the animal and putting each organ of interest in a calibrated gamma counter. Note that all PET devices are calibrated periodically for detector sensitivity using a calibrated source (generally a syringe filled with a known amount of radioisotope). From this scan, the number of counts per radioactivity detected by each detector pair is recorded. These numbers are used for subsequent scans to normalize the number of counts for detector efficiencies and to determine the amount of activity within the scanned object, but it not possible with high resolution to determine activity in small-animal tumors or organs.

We present a new practical method (Slavine and Antich, 2007) to determine radioactivity distribution in ROI from reconstructed PET images with a source of known activity and size in the field of view (FOV) in an example using osteolytic and osteoblastic bone metastasis from prostate cancer xenografts. Our method is different, more precise and yet simpler than that described above. It is based on a 3D reconstruction method capable of delivering high-resolution images, which has the possibility of saving time, effort and the necessity to sacrifice animals. The 3D high-resolution reconstruction and radioactivity analysis can help to analyze the size and aggressiveness of the tumor, determine its growth in time and the effectiveness of the treatment.