Therapy Operating Characteristic (TOC) Curves and their Application to the Evaluation of Segmentation Algorithms.

This paper presents a general framework for assessing imaging systems and image-analysis methods on the basis of therapeutic rather than diagnostic efficacy. By analogy to receiver operating characteristic (ROC) curves, it utilizes the Therapy Operating Characteristic or TOC curve, which is a plot of the probability of tumor control vs. the probability of normal-tissue complications as the overall level of a radiotherapy treatment beam is varied. The proposed figure of merit is the area under the TOC, denoted AUTOC. If the treatment planning algorithm is held constant, AUTOC is a metric for the imaging and image-analysis components, and in particular for segmentation algorithms that are used to delineate tumors and normal tissues. On the other hand, for a given set of segmented images, AUTOC can also be used as a metric for the treatment plan itself. A general mathematical theory of TOC and AUTOC is presented and then specialized to segmentation problems. Practical approaches to implementation of the theory in both simulation and clinical studies are presented. The method is illustrated with a a brief study of segmentation methods for prostate cancer.

Multi-pinhole SPECT Imaging with Silicon Strip Detectors.

Silicon double-sided strip detectors offer outstanding instrinsic spatial resolution with reasonable detection efficiency for iodine-125 emissions. This spatial resolution allows for multiple-pinhole imaging at low magnification, minimizing the problem of multiplexing. We have conducted imaging studies using a prototype system that utilizes a detector of 300-micrometer thickness and 50-micrometer strip pitch together with a 23-pinhole collimator. These studies include an investigation of the synthetic-collimator imaging approach, which combines multiple-pinhole projections acquired at multiple magnifications to obtain tomographic reconstructions from limited-angle data using the ML-EM algorithm. Sub-millimeter spatial resolution was obtained, demonstrating the basic validity of this approach.

Direct Charged-Particle Imaging System Using an Ultra-Thin Phosphor: Physical Characterization and Dynamic Applications.

Imaging ß rays in vivo will help to advance microdosimetry and radiopharmaceutical development. In an earlier paper [1], we reported a newly developed system capable of directly imaging high-energy electron emissions in small animals in vivo. In this paper, we have thoroughly characterized the performance of the system. We have measured the sensitivity and detectability and the spatial resolution at various magnifications, as well as the linearity of the system. The system has also demonstrated the capability of directly detecting conversion electrons and positrons as well as ß rays. The system has been applied to dynamically image spatiotemporal (18)F-Fluorodeoxyglucose (FDG) uptake distributions in xenograft small tumors in dorsal window chambers on mice in vivo. Heterogeneity in FDG uptake in millimeter-sized tumors has been observed.

A prototype instrument for single pinhole small animal adaptive SPECT imaging.

The authors have designed and constructed a small-animal adaptive SPECT imaging system as a prototype for quantifying the potential benefit of adaptive SPECT imaging over the traditional fixed geometry approach. The optical design of the system is based on filling the detector with the region of interest for each viewing angle, maximizing the sensitivity, and optimizing the resolution in the projection images. Additional feedback rules for determining the optimal geometry of the system can be easily added to the existing control software. Preliminary data have been taken of a phantom with a small, hot, offset lesion in a flat background in both adaptive and fixed geometry modes. Comparison of the predicted system behavior with the actual system behavior is presented, along with recommendations for system improvements.

Adaptive SPECT for Tumor Necrosis Detection.

In this paper, we consider a prototype of an adaptive SPECT system, and we use simulation to objectively assess the system's performance with respect to a conventional, non-adaptive SPECT system. Objective performance assessment is investigated for a clinically relevant task: the detection of tumor necrosis at a known location and in a random lumpy background. The iterative maximum-likelihood expectation-maximization (MLEM) algorithm is used to perform image reconstruction. We carried out human observer studies on the reconstructed images and compared the probability of correct detection when the data are generated with the adaptive system as opposed to the non-adaptive system. Task performance is also assessed by using a channelized Hotelling observer, and the area under the receiver operating characteristic curve is the figure of merit for the detection task. Our results show a large performance improvement of adaptive systems versus non-adaptive systems and motivate further research in adaptive medical imaging.

The multi-module, multi-resolution system (M3R): a novel small-animal SPECT system.

We have designed and built an inexpensive, high-resolution, tomographic imaging system, dubbed the multi-module, multi-resolution system, or M3R. Slots machined into the system shielding allow for the interchange of pinhole plates, enabling the system to operate over a wide range of magnifications and with virtually any desired pinhole configuration. The flexibility of the system allows system optimization for specific imaging tasks and also allows for modifications necessary due to improved detectors, electronics, and knowledge of system construction (e.g., system sensitivity optimization). We provide an overview of M3R, focusing primarily on system design and construction, aperture construction, and calibration methods. Reconstruction algorithms will be described and reconstructed images presented.

Evaluation of hardware in a small-animal SPECT system using reconstructed images.

Evaluation of imaging hardware represents a vital component of system design. In small-animal SPECT imaging, this evaluation has become increasingly difficult with the emergence of multi-pinhole apertures and adaptive, or patient-specific, imaging. This paper will describe two methods for hardware evaluation using reconstructed images. The first method is a rapid technique incorporating a system-specific non-linear, three-dimensional point response. This point response is easily computed and offers qualitative insight into an aperture's resolution and artifact characteristics. The second method is an objective assessment of signal detection in lumpy backgrounds using the channelized Hotelling observer (CHO) with 3D Laguerre-Gauss and difference-of-Gaussian channels to calculate area under the receiver-operating characteristic curve (AUC). Previous work presented at this meeting described a unique, small-animal SPECT system (M(3)R) capable of operating under a myriad of hardware configurations and ideally suited for image quality studies. Measured system matrices were collected for several hardware configurations of M(3)R. The data used to implement these two methods was then generated by taking simulated objects through the measured system matrices. The results of these two methods comprise a combination of qualitative and quantitative analysis that is well-suited for hardware assessment.

A Silicon SPECT System for Molecular Imaging of the Mouse Brain.

We previously demonstrated the feasibility of using silicon double-sided strip detectors (DSSDs) for SPECT imaging of the activity distribution of iodine-125 using a 300-micrometer thick detector. Based on this experience, we now have developed fully customized silicon DSSDs and associated readout electronics with the intent of developing a multi-pinhole SPECT system. Each DSSD has a 60.4 mm × 60.4 mm active area and is 1 mm thick. The strip pitch is 59 micrometers, and the readout of the 1024 strips on each side gives rise to a detector with over one million pixels. Combining four high-resolution DSSDs into a SPECT system offers an unprecedented space-bandwidth product for the imaging of single-photon emitters. The system consists of two camera heads with two silicon detectors stacked one behind the other in each head. The collimator has a focused pinhole system with cylindrical-shaped pinholes that are laser-drilled in a 250 µm tungsten plate. The unique ability to collect projection data at two magnifications simultaneously allows for multiplexed data at high resolution to be combined with lower magnification data with little or no multiplexing. With the current multi-pinhole collimator design, our SPECT system will be capable of offering high spatial resolution, sensitivity and angular sampling for small field-of-view applications, such as molecular imaging of the mouse brain.

SemiSPECT: a small-animal single-photon emission computed tomography (SPECT) imager based on eight cadmium zinc telluride (CZT) detector arrays.

The first full single-photon emission computed tomography (SPECT) imager to exploit eight compact high-intrinsic-resolution cadmium zinc telluride (CZT) detectors, called SemiSPECT, has been completed. Each detector consists of a CZT crystal and a customized application-specific integrated circuit (ASIC). The CZT crystal is a 2.7 cm x 2.7 cm x -0.2 cm slab with a continuous top electrode and a bottom electrode patterned into a 64 x 64 pixel array by photolithography. The ASIC is attached to the bottom of the CZT crystal by indium-bump bonding. A bias voltage of -180 V is applied to the continuous electrode. The eight detectors are arranged in an octagonal lead-shielded ring. Each pinhole in the eight-pinhole aperture placed at the center of the ring is matched to each individual detector array. An object is imaged onto each detector through a pinhole, and each detector is operated independently with list-mode acquisition. The imaging subject can be rotated about a vertical axis to obtain additional angular projections. The performance of SemiSPECT was characterized using 99mTc. When a 0.5 mm diameter pinhole is used, the spatial resolution on each axis is about 1.4 mm as estimated by the Fourier crosstalk matrix, which provides an algorithm-independent average resolution over the field of view. The energy resolution achieved by summing neighboring pixel signals in a 3 x 3 window is about 10% full-width-at-half-maximum of the photopeak. The overall system sensitivity is about 0.5 x 10(-4) with the energy window of +/-10% from the photopeak. Line-phantom images are presented to visualize the spatial resolution provided by SemiSPECT, and images of bone, myocardium, and human tumor xenografts in mice demonstrate the feasibility of preclinical small-animal studies with SemiSPECT.

Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin.

BACKGROUND: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TF) are avid transport substrates recognized by the multidrug resistance (MDR) P-glycoprotein (Pgp). This study was designed to compare the properties of MIBI and TF in assessing the inhibition of Pgp by PSC833 in severe combined immunodeficient mice bearing MCF7 human breast tumors using SPECT imaging. METHODS: Animals with drug-sensitive (MCF/WT) and drug-resistant (MCF7/AdrR) tumors were treated by PSC833 and by carrier vehicle 1 h before imaging, respectively. Dynamic images were acquired for 30 min after intravenous injection of MIBI/TF using a SPECT system, FastSPECT. The biodistribution of MIBI and TF was determined at the end of the imaging session. RESULTS: MCF7/WT in the absence and presence of PSC833 could be visualized by MIBI and TF imaging within 5 min and remained detectable for 30 min postinjection. MCF7/AdrR could be visualized only 2-5 min without PSC833 treatment but could be detected for 30 min with PSC833, very similar to MCF7/WT. MCF7/AdrR without PSC833 showed significantly greater radioactive washout than MCF7/WT and MCF7/AdrR with PSC833 treatment. PSC833 increased the accumulation (%ID/g) in MCF7/AdrR 3.0-fold (1.62+/-0.15 vs. 0.55+/-0.05, P<.05) for TF and 1.9-fold (1.21+/-0.04 vs. 0.64+/-0.05, P<.05) for MIBI but did not affect MCF7/WT. CONCLUSIONS: The feasibility of MIBI and TF for assessment of MDR expression and inhibition was demonstrated in mice through FastSPECT imaging. The results indicate that TF may be at least comparable with MIBI in recognizing Pgp expression and modulation.

Experimental task-based optimization of a four-camera variable-pinhole small-animal SPECT system.

We have previously utilized lumpy object models and simulated imaging systems in conjunction with the ideal observer to compute figures of merit for hardware optimization. In this paper, we describe the development of methods and phantoms necessary to validate or experimentally carry out these optimizations. Our study was conducted on a four-camera small-animal SPECT system that employs interchangeable pinhole plates to operate under a variety of pinhole configurations and magnifications (representing optimizable system parameters). We developed a small-animal phantom capable of producing random backgrounds for each image sequence. The task chosen for the study was the detection of a 2mm diameter sphere within the phantom-generated random background. A total of 138 projection images were used, half of which included the signal. As our observer, we employed the channelized Hotelling observer (CHO) with Laguerre-Gauss channels. The signal-to-noise (SNR) of this observer was used to compare different system configurations. Results indicate agreement between experimental and simulated data with higher detectability rates found for multiple-camera, multiple-pinhole, and high-magnification systems, although it was found that mixtures of magnifications often outperform systems employing a single magnification. This work will serve as a basis for future studies pertaining to system hardware optimization.

High-resolution imaging with (99m)Tc-glucarate for assessing myocardial injury in rat heart models exposed to different durations of ischemia with reperfusion.

UNLABELLED: (99m)Tc-Glucarate ((99m)Tc-GLA) is a novel infarct-avid imaging agent. The aim of this study was to evaluate the role of (99m)Tc-GLA for assessing the severity of myocardial ischemia-reperfusion injury in rat heart models exposed to varied durations of left coronary artery (LCA) occlusion with reperfusion using a high-resolution SPECT system, FASTSPECT. We also wanted to clarify whether a rapid sequence of 3-dimensional imaging with FASTSPECT can quantify uptake and washout kinetics of cardiovascular imaging agents in small-animal heart models. METHODS: The ischemic-reperfused rat heart models were created by ligating the LCA for 30 min (IR30, n = 12) or 90 min (IR90, n = 6) (IR = ischemia-reperfusion) and releasing the ligature for 30 min. Dynamic images were acquired over a 2-h period after (99m)Tc-GLA was intravenously injected. The ischemic area at risk (IAR) was determined by Evans blue staining. Necrosis was assessed with triphenyltetrazolium chloride (TTC) staining and a transmission electron microscope (TEM). RESULTS: The infarct size of the left ventricle (% IAR) on TTC staining was smaller in IR30 (49.2 +/- 4.3) than in IR90 (73.4 +/- 4.7, P < 0.05), which exhibited evidence of more severe irreversible injury than the IR30 heart on TEM. FASTSPECT images demonstrated hot spot accumulations of (99m)Tc-GLA in all hearts. The washout of (99m)Tc-GLA from the ischemic-reperfused area in IR90 was significantly slower than that in IR30. The ratio of the hot spot to normal myocardial activity was 4.1 +/- 0.3 in IR30 and 7.1 +/- 1.1 in IR90 (P < 0.05). The hot spot size (% IAR) (58.4 +/- 2.7 in IR30 vs. 75.9 +/- 2.7 in IR90, P < 0.05) related significantly to the infarct size. CONCLUSION: The severity of myocardial injury induced by ischemia-reperfusion can be assessed by FASTSPECT imaging with (99m)Tc-GLA. The results suggest that (99m)Tc-GLA will be clinically useful in detecting and quantifying acute necrotic myocardium. The FASTSPECT imaging with the rat heart models provides a solution-specific approach with high-resolution and fast dynamic acquisition for kinetic studies of new myocardial imaging agents.

99mTc glucarate high-resolution imaging of drug sensitive and drug resistant human breast cancer xenografts in SCID mice.

BACKGROUND AND AIM: Previous studies have showed that 99mTc labelled glucarate (GLA) might be an agent for non-invasive detection of breast tumours. In xenografted BT20 breast tumours, GLA was found to have higher uptake than 99mTc sestamibi (MIBI). It is unclear whether GLA can localize in all cell line breast cancer xenografts, as well as breast tumours with multidrug resistance (MDR). The present study aimed to investigate the properties of GLA in detecting drug sensitive and drug resistant MCF7 breast cancer xenografts in mice by using dynamic single photon emission computed tomography (SPECT) imaging. METHODS: MCF7/S cells are drug sensitive breast carcinoma cells. MCF7/D40 cells are 40-fold more resistant to doxorubicin compared to MCF7/S. Subcutaneous tumours were grown in SCID mice for 10-14 days after injection of 1 x 10(6) cells into the right thigh. Anaesthetized mice with MCF7/S (MIBI, n=9; GLA, n=8) and MCF7/D40 (MIBI, n=6; GLA, n=5) tumours were imaged using a high-resolution SPECT system called FASTSPECT. Dynamic images were acquired for 2 h after intravenous injection of GLA or MIBI. Expression of MDR P-glycoprotein (Pgp) in the tumours was demonstrated in the MCF7/D40 tumours by western blotting, not in the MCF7/S tumours. RESULTS: The xenografted tumours were visualized unequivocally within 10-30 min in GLA images and remained detectable for at least 2 h after injection. Drug resistant tumours, from which MIBI was rapidly expelled, retained GLA as readily as did drug sensitive tumours. The biodistribution data of GLA demonstrated significantly higher accumulation (%ID/g) compared to MIBI. CONCLUSION: MCF7 tumour xenografts can be detected by 99mTc glucarate imaging. More importantly, 99mTc glucarate can potentially localize drug resistant breast tumours.

Imaging recognition of multidrug resistance in human breast tumors using 99mTc-labeled monocationic agents and a high-resolution stationary SPECT system.

Imaging recognition of multidrug-resistance by 99mTc-labeled sestamibi, tetrofosmin and furifosmin in mice bearing human breast tumors was evaluated using a high-resolution SPECT, FASTSPECT. Imaging results showed that the washout rates in drug-resistant MCF7/D40 tumors were significantly greater than that in drug-sensitive MCF7/S tumors. Furifosmin exhibited greater washout from both MCF7/S and MCF7/D40 than sestamibi, while tetrofosmin washout was greater than sestamibi in MCF7/D40 only. Feasibility of the monocationic agents for characterizing MDR expression was well clarified with FASTSPECT imaging.

Compact CT/SPECT Small-Animal Imaging System.

We have developed a dual-modality CT/SPECT imaging system for small-animal imaging applications. The X-ray system comprises a commercially available micro-focus X-ray tube and a CCD-based X-ray camera. X-ray transmission measurements are performed based on cone-beam geometry. Individual projections are acquired by rotating the animal about a vertical axis in front of the CCD detector. A high-resolution CT image is obtained after reconstruction using an ordered subsets-expectation maximization (OS-EM) reconstruction algorithm. The SPECT system utilizes a compact semiconductor camera module previously developed in our group. The module is mounted perpendicular to the X-ray tube/CCD combination. It consists of a 64×64 pixellated CdZnTe detector and a parallel-hole tungsten collimator. The field of view is 1 square inch. Planar projections for SPECT reconstruction are obtained by rotating the animal in front of the detector. Gamma-ray and X-ray images are presented of phantoms and mice. Procedures for merging the anatomical and functional images are discussed.

A new PET system for small-animal imaging.

We outline the design of a new small-animal PET system. This system employs modular scintillation cameras composed of nine PMTs coupled by a light guide to a monolithic NaI(Tl) scintillation crystal. The basic principles of the PET system are presented along with an overview of the electronics and position-estimation scheme. The potential advantages of this design are discussed and preliminary reconstructed images are presented.

FastSPECT II: A Second-Generation High-Resolution Dynamic SPECT Imager.

FastSPECT II is a recently commissioned 16-camera small-animal SPECT imager built with modular scintillation cameras and list-mode data-acquisition electronics. The instrument is housed in a lead-shielded enclosure and has exchangeable aperture assemblies and adjustable camera positions for selection of magnification, pinhole size, and field of view. The calibration of individual cameras and measurement of an overall system imaging matrix (1 mm(3) voxels) are supported via a five-axis motion-control system.Details of the system integration and results of characterization and performance measurements are presented along with first tomographic images. The dynamic imaging capabilities of the instrument are explored and discussed.

Evaluating Estimation Techniques in Medical Imaging Without a Gold Standard: Experimental Validation.

Imaging is often used for the purpose of estimating the value of some parameter of interest. For example, a cardiologist may measure the ejection fraction (EF) of the heart to quantify how much blood is being pumped out of the heart on each stroke. In clinical practice, however, it is difficult to evaluate an estimation method because the gold standard is not known, e.g., a cardiologist does not know the true EF of a patient. An estimation method is typically evaluated by plotting its results against the results of another (more accepted) estimation method. This approach results in the use of one set of estimates as the pseudo-gold standard. We have developed a maximum-likelihood approach for comparing different estimation methods to the gold standard without the use of the gold standard. In previous works we have displayed the results of numerous simulation studies indicating the method can precisely and accurately estimate the parameters of a regression line without a gold standard, i.e., without the x-axis. In an attempt to further validate our method we have designed an experiment performing volume estimation using a physical phantom and two imaging systems (SPECT,CT).

Quantitative analysis of acute myocardial infarct in rat hearts with ischemia-reperfusion using a high-resolution stationary SPECT system.

UNLABELLED: The purpose of this study was to develop an in vivo imaging protocol for a high-resolution stationary SPECT system, called FASTSPECT, in a rat heart model of ischemia-reperfusion (IR) and to compare 99mTc-sestamibi imaging and triphenyltetrazolium chloride (TTC) staining for reliability and accuracy in the measurement of myocardial infarcts. METHODS: FASTSPECT consists of 24 modular cameras and a 24-pinhole aperture with 1.5-mm spatial resolution and 13.3 cps/microCi (0.359 cps/kBq) sensitivity. The IR heart model was created by ligating the left coronary artery for 90 min and then releasing the ligature for 30 min. Two hours after 99mTc-sestamibi injection (5-10 mCi [185-370 MBq]), images were acquired for 5-10 min for 5 control rats and 11 IR rats. The hearts were excised, and the left ventricle was sectioned into 4 slices for TTC staining. RESULTS: Left and right ventricular myocardium in control rats was shown clearly, with uniform 99mTc-sestamibi distribution and 100% TTC staining for viable myocardium. Nine of 11 rats with IR survived throughout imaging and exhibited 50.8% +/- 2.7% ischemic area and 37.9% +/- 3.9% infarct in the left ventricle on TTC staining. The infarct size measured by FASTSPECT imaging was 37.6% +/- 3.6%, which correlated significantly with that measured by TTC staining (r = 0.974; P < 0.01). CONCLUSION: The results confirmed the accuracy of FASTSPECT imaging for measurement of acute myocardial infarcts in rat hearts. Application of FASTSPECT imaging in small animals may be feasible for investigating myocardial IR injury and the effects of revascularization.

SemiSPECT: A Small-animal Imaging System Based on Eight CdZnTe Pixel Detectors.

We have constructed a SPECT system for small animals that utilizes eight CdZnTe pixel detectors. The eight detectors are arranged in a single octagonal ring, where each views the object to be imaged through a single pinhole. Additional projections are obtained via rotation of the animal. Each CdZnTe detector is approximately 2 mm in thickness and is patterned on one surface into a 64×64 array of pixels with 380 micron pitch. We have designed an electronic readout system capable of collecting data from the eight detectors in listmode. In this scheme each event entry for a gamma-ray hit includes the pulse height of the pixel with the largest signal and the pulse height for each of its eight nearest neighbors. We present details of the overall design, the electronics, and system performance.