Brian W. Miller

Maximum-Likelihood Methods for Processing Signals From Gamma-Ray Detectors

In any gamma-ray detector, each event produces electrical signals on one or more circuit elements. From these signals, we may wish to determine the presence of an interaction; whether multiple interactions occurred; the spatial coordinates in two or three dimensions of at least the primary interaction; or the total energy deposited in that interaction. We may also want to compute listmode probabilities for tomographic reconstruction. Maximum-likelihood methods provide a rigorous and in some senses optimal approach to extracting this information, and the associated Fisher information matrix provides a way of quantifying and optimizing the information conveyed by the detector. This paper will review the principles of likelihood methods as applied to gamma-ray detectors and illustrate their power with recent results from the Center for Gamma-ray Imaging.

Mesenchymal Stem Cell‐Mediated Delivery of the Sodium Iodide Symporter Supports Radionuclide Imaging and Treatment of Breast Cancer

Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor‐targeted delivery of therapeutic agents. This study aimed to introduce MSC‐mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC‐NIS), followed by 99mTechnetium pertechnetate imaging 3–14 days later using a BazookaSPECT γ‐camera. Tissue was harvested for analysis of human NIS (hNIS) expression by relative quantitative‐polymerase chain reaction. Therapy animals received an i.p. injection of 131I or saline 14 days after injection of MSC‐NIS, and tumor volume was monitored for 8 weeks. After injection of MSC‐NIS, BazookaSPECT imaging revealed an image of animal intestines and chest area at day 3, along with a visible weak tumor image. By day 14, the tumor was visible with a significant reduction in radionuclide accumulation in nontarget tissue observed. hNIS gene expression was detected in the intestines, heart, lungs, and tumors at early time points but later depleted in nontarget tissues and persisted at the tumor site. Based on imaging/biodistribution data, animals received a therapeutic dose of 131I 14 days after MSC‐NIS injection. This resulted in a significant reduction in tumor growth (mean ± SEM, 236 ± 62 mm3 vs. 665 ± 204 mm3 in controls). The ability to track MSC migration and transgene expression noninvasively in real time before therapy is a major advantage to this strategy. This promising data supports the feasibility of this approach as a novel therapy for breast cancer. STEM CELLS 2011;29:1149–1157

Single-photon spatial and energy resolution enhancement of a columnar CsI(Tl) / EMCCD gamma-camera using maximum- likelihood estimation

We examined the spatial resolution of a columnar CsI(Tl), single-photon imaging system using an approach that estimates the interaction position to better than the spread of the light distribution. A columnar scintillator was directly coupled to a 512×512 electron multiplying CCD (EMCCD) camera (16 μm pixels) binned at 2×2 to sample at 32 μm pixels. Optical photons from gamma-ray/scintillator interactions are sampled over multiple pixels. Resultant images show clusters of signal at the original interaction site, clusters from Cs and I K x-rays up to several hundred microns away, and clusters from collimator K x-rays. Also evident are depth-of-interaction effects which result in a broadening of the light distribution. These effects result in a degradation of spatial and energy resolution. Cluster pixel data was processed to better estimate the interaction position within the initial interaction cluster. Anger (centroid) estimation of individual gamma-ray events yielded spatial resolutions better than 100 μm; a result previously achievable only with pixellated semiconductor detector arrays. After proper calibration, depth-of-interaction (DOI) effects are corrected by performing maximum-likelihood 3D position and energy estimation of individual gamma-ray interactions.

A Low-Cost Approach to High-Resolution, Single-Photon Imaging Using Columnar Scintillators and Image Intensifiers

Results are presented for a low-cost, ultra-high resolution gamma camera for small-animal SPECT and molecular imaging. The detector, known as Bazooka SPECT, employs a second-generation image intensifier which is directly coupled to a columnar CsI(Tl) scintillator. Operating in photon-counting mode, individual gamma-ray interactions are seen as clusters of signal, and significant improvement in spatial resolution is obtained by estimating the interaction position via Anger (centroid) estimation for individual clusters. Amplification of scintillator light prior to the optical path is advantageous compared to similar, low-light CCD gamma-cameras which solely apply gain in the CCD. With amplification from the image intensifier, the system is no longer limited by light loss from the optical path. This allows for a customizable optical system via lenses in a macro photography configuration and for the use of a low-cost, highspeed CCD. Experimental results show that Bazooka SPECT has an intrinsic resolution of approximately 150mum when the entire 25mm intensifier output screen is imaged onto the CCD. Better than 100mum resolution is attainable with less demagnification from the optical system. Initial indications are that this detector will serve as an attractive, inexpensive modular camera for high-resolution, multiple-pinhole, small-animal SPECT and molecular imaging.

System integration of FastSPECT III, a dedicated SPECT rodent-brain imager based on BazookaSPECT detector technology

FastSPECT III is a stationary, single-photon emission computed tomography (SPECT) imager designed specifically for imaging and studying neurological pathologies in rodent brain, including Alzheimers and Parkinsonss disease. Twenty independent BazookaSPECT [1] gamma-ray detectors acquire projections of a spherical field of view with pinholes selected for desired resolution and sensitivity. Each BazookaSPECT detector comprises a columnar CsI(Tl) scintillator, image-intensifier, optical lens, and fast-frame-rate CCD camera. Data stream back to processing computers via firewire interfaces, and heavy use of graphics processing units (GPUs) ensures that each frame of data is processed in real time to extract the images of individual gamma-ray events. Details of the system design, imaging aperture fabrication methods, and preliminary projection images are presented.

Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model

α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.

Progress in BazookaSPECT: High-resolution, dynamic scintigraphy with large-area imagers

We present recent progress in BazookaSPECT, a high-resolution, photon-counting gamma-ray detector. It is a new class of scintillation detector that combines columnar scintillators, image intensifiers, and CCD (charge- coupled device) or CMOS (complementary metal-oxide semiconductors) sensors for high-resolution imaging. A key feature of the BazookaSPECT paradigm is the capability to easily design custom detectors in terms of the desired intrinsic detector resolution and event detection rate. This capability is possible because scintillation light is optically amplfied by the image intensifier prior to being imaging onto the CCD/CMOS sensor, thereby allowing practically any consumer-grade CCD/CMOS sensor to be used for gamma-ray imaging. Recent efforts have been made to increase the detector area by incorporating fiber-optic tapers between the scintillator and image intensi_er, resulting in a 16x increase in detector area. These large-area BazookaSPECT detectors can be used for full-body imaging and we present preliminary results of their use as dynamic scintigraphy imagers for mice and rats. Also, we discuss ongoing and future developments in BazookaSPECT and the improved event- detection rate capability that is achieved using Graphics Processing Units (GPUs), multi-core processors, and new high-speed, USB 3.0 CMOS cameras.

Novel applications of rapid prototyping in gamma-ray and X-ray imaging

Advances in 3D rapid-prototyping printers, 3D modeling software, and casting techniques allow for the fabrication of cost-effective, custom components in gamma-ray and x-ray imaging systems. Applications extend to new fabrication methods for custom collimators, pinholes, calibration and resolution phantoms, mounting and shielding components, and imaging apertures. Details of the fabrication process for these components are presented, specifically the 3D printing process, cold casting with a tungsten epoxy, and lost-wax casting in platinum.

Development of microcolumnar LaBr3:Ce scintillator

While a wide variety of new scintillators are now available, new cerium-doped lanthanide halide scintillators have shown a strong potential to move beyond their familiar role in conventional gamma ray spectroscopy, toward fulfilling the needs of highly demanding applications such as radioisotope identification at room temperature, homeland security, and quantitative molecular imaging for medical diagnostics, staging and research. Despite their extraordinary advantages, however, issues related to reliable, large volume manufacturing of these high light yield materials in a rapid and economic manner have not been resolved or purposefully addressed. Also, if microcolumnar films of this material could be fabricated, it would find widespread use in a multitude of high-speed imaging/nuclear medicine applications. Here we report on synthesizing LaBr3:Ce scintillators using a thermal evaporation technique, which permits the fabrication of high spatial resolution microcolumnar films and holds a potential to synthesize large volumes of high quality material in a time efficient and cost effective manner. Performance evaluation of the fabricated films and their application for SPECT imaging are also discussed.

A system calibration and fast iterative reconstruction method for next-generation SPECT imagers

Recently, high-resolution gamma cameras have been developed with detectors containing > 105–106 elements. SPECT imagers based on these detectors usually also have a large number of voxel bins and therefore face memory storage issues for the system matrix when performing fast tomographic reconstructions using iterative algorithms. To address these issues, we have developed a method that parameterizes the detector response to a point source and generates the system matrix on the fly during MLEM or OSEM on graphics hardware. The calibration method, interpolation of coefficient data, and reconstruction results are presented in the context of a recently commissioned small-animal SPECT imager, called FastSPECT III.