The potential of biology-guided radiation therapy in thoracic cancer: A preliminary treatment planning study.

Purpose: We investigated the feasibility of biology-guided radiotherapy (BgRT), a technique that utilizes real-time positron emission imaging to minimize tumor motion uncertainties, to spare nearby organs at risk. Methods: Volumetric modulated arc therapy (VMAT), intensity-modulated proton (IMPT) therapy, and BgRT plans were created for a paratracheal node recurrence (case 1; 60 Gy in 10 fractions) and a primary peripheral left upper lobe adenocarcinoma (case 2; 50 Gy in four fractions). Results: For case 1, BgRT produced lower bronchus V40 values compared to VMAT and IMPT. For case 2, total lung V20 was lower in the BgRT case compared to VMAT and IMPT. Conclusions: BgRT has the potential to reduce the radiation dose to proximal critical structures but requires further detailed investigation.

The technical design and concept of a PET/CT linac for biology-guided radiotherapy.

This is a summary of the design and concept of the RefleXion X1, a system for biology-guided radiotherapy (BgRT). This system is a multi-modal tomography (PET, fan-beam kVCT, and MVD) treatment machine that utilizes imaging and therapy planes for optimized beam delivery of IMRT, SBRT, SRS, and BgRT radiotherapy regimens. For BgRT delivery specifically, annihilation photons emanating outward from a PET-avid tumor are used to guide the delivery of beamlets of radiation to the tumor at sub-second latency. With the integration of PET detectors, rapid beam-station delivery, real-time tracking, and high-frequency multi-leaf collimation, the BgRT system has the potential to deliver a highly conformal treatment to malignant lesions while minimizing dose to surrounding healthy tissues. Furthermore, the potential use of a single radiotracer injection to guide radiotherapy to multiple targets opens avenues for debulking in advanced and metastatic disease states.

Biology-guided radiotherapy: redefining the role of radiotherapy in metastatic cancer.

The emerging biological understanding of metastatic cancer and proof-of-concept clinical trials suggest that debulking all gross disease holds great promise for improving patient outcomes. However, ablation of multiple targets with conventional external beam radiotherapy systems is burdensome, which limits investigation and utilization of complete metastatic ablation in the majority of patients with advanced disease. To overcome this logistical hurdle, technical innovation is necessary. Biology-guided radiotherapy (BgRT) is a new external beam radiotherapy delivery modality combining positron emission tomography-computed tomography (PET-CT) with a 6 MV linear accelerator. The key innovation is continuous response of the linear accelerator to outgoing tumor PET emissions with beamlets of radiotherapy at subsecond latency. This allows the deposited dose to track tumors in real time. Multiple new hardware and algorithmic advances further facilitate this low-latency feedback process. By transforming tumors into their own fiducials after intravenous injection of a radiotracer, BgRT has the potential to enable complete metastatic ablation in a manner efficient for a single patient and scalable to entire populations with metastatic disease. Future trends may further enhance the utility of BgRT in the clinic as this technology dovetails with other innovations in radiotherapy, including novel dose painting and fractionation schemes, radiomics, and new radiotracers.

Gray: a ray tracing-based Monte Carlo simulator for PET.

Monte Carlo simulation software plays a critical role in PET system design. Performing complex, repeated Monte Carlo simulations can be computationally prohibitive, as even a single simulation can require a large amount of time and a computing cluster to complete. Here we introduce Gray, a Monte Carlo simulation software for PET systems. Gray exploits ray tracing methods used in the computer graphics community to greatly accelerate simulations of PET systems with complex geometries. We demonstrate the implementation of models for positron range, annihilation acolinearity, photoelectric absorption, Compton scatter, and Rayleigh scatter. For validation, we simulate the GATE PET benchmark, and compare energy, distribution of hits, coincidences, and run time. We show a [Formula: see text] speedup using Gray, compared to GATE for the same simulation, while demonstrating nearly identical results. We additionally simulate the Siemens Biograph mCT system with both the NEMA NU-2 scatter phantom and sensitivity phantom. We estimate the total sensitivity within [Formula: see text]% when accounting for differences in peak NECR. We also estimate the peak NECR to be [Formula: see text] kcps, or within [Formula: see text]% of published experimental data. The activity concentration of the peak is also estimated within 1.3%.

The lower timing resolution bound for scintillators with non-negligible optical photon transport time in time-of-flight PET.

In this work, a method is presented that can calculate the lower bound of the timing resolution for large scintillation crystals with non-negligible photon transport. Hereby, the timing resolution bound can directly be calculated from Monte Carlo generated arrival times of the scintillation photons. This method extends timing resolution bound calculations based on analytical equations, as crystal geometries can be evaluated that do not have closed form solutions of arrival time distributions. The timing resolution bounds are calculated for an exemplary 3 mm × 3 mm × 20 mm LYSO crystal geometry, with scintillation centers exponentially spread along the crystal length as well as with scintillation centers at fixed distances from the photosensor. Pulse shape simulations further show that analog photosensors intrinsically operate near the timing resolution bound, which can be attributed to the finite single photoelectron pulse rise time.

Sparse signal recovery methods for multiplexing PET detector readout.

Nuclear medicine imaging detectors are commonly multiplexed to reduce the number of readout channels. Because the underlying detector signals have a sparse representation, sparse recovery methods such as compressed sensing may be used to develop new multiplexing schemes. Random methods may be used to create sensing matrices that satisfy the restricted isometry property. However, the restricted isometry property provides little guidance for developing multiplexing networks with good signal-to-noise recovery capability. In this work, we describe compressed sensing using a maximum likelihood framework and develop a new method for constructing multiplexing (sensing) matrices that can recover signals more accurately in a mean square error sense compared to sensing matrices constructed by random construction methods. Signals can then be recovered by maximum likelihood estimation constrained to the support recovered by either greedy l0 iterative algorithms or l1-norm minimization techniques. We show that this new method for constructing and decoding sensing matrices recovers signals with 4%-110% higher SNR than random Gaussian sensing matrices, up to 100% higher SNR than partial DCT sensing matrices 50%-2400% higher SNR than cross-strip multiplexing, and 22%-210% higher SNR than Anger multiplexing for photoelectric events.

Radioluminescence microscopy: measuring the heterogeneous uptake of radiotracers in single living cells.

Radiotracers play an important role in interrogating molecular processes both in vitro and in vivo. However, current methods are limited to measuring average radiotracer uptake in large cell populations and, as a result, lack the ability to quantify cell-to-cell variations. Here we apply a new technique, termed radioluminescence microscopy, to visualize radiotracer uptake in single living cells, in a standard fluorescence microscopy environment. In this technique, live cells are cultured sparsely on a thin scintillator plate and incubated with a radiotracer. Light produced following beta decay is measured using a highly sensitive microscope. Radioluminescence microscopy revealed strong heterogeneity in the uptake of [(18)F]fluoro-deoxyglucose (FDG) in single cells, which was found consistent with fluorescence imaging of a glucose analog. We also verified that dynamic uptake of FDG in single cells followed the standard two-tissue compartmental model. Last, we transfected cells with a fusion PET/fluorescence reporter gene and found that uptake of FHBG (a PET radiotracer for transgene expression) coincided with expression of the fluorescent protein. Together, these results indicate that radioluminescence microscopy can visualize radiotracer uptake with single-cell resolution, which may find a use in the precise characterization of radiotracers.

Investigation of a clinical PET detector module design that employs large-area avalanche photodetectors.

We investigated the feasibility of designing an Anger-logic PET detector module using large-area high-gain avalanche photodiodes (APDs) for a brain-dedicated PET/MRI system. Using Monte Carlo simulations, we systematically optimized the detector design with regard to the scintillation crystal, optical diffuser, surface treatment, layout of large-area APDs, and signal-to-noise ratio (SNR, defined as the 511 keV photopeak position divided by the standard deviation of noise floor in an energy spectrum) of the APD devices. A detector prototype was built comprising an 8 × 8 array of 2.75 × 3.00 × 20.0 mm3 LYSO (lutetium-yttrium-oxyorthosilicate) crystals and a 22.0 × 24.0 × 9.0 mm3 optical diffuser. From the four designs of the optical diffuser tested, two designs employing a slotted diffuser are able to resolve all 64 crystals within the block with good uniformity and peak-to-valley ratio. Good agreement was found between the simulation and experimental results. For the detector employing a slotted optical diffuser, the energy resolution of the global energy spectrum after normalization is 13.4 ± 0.4%. The energy resolution of individual crystals varies between 11.3 ± 0.3% and 17.3 ± 0.4%. The time resolution varies between 4.85 ± 0.04 (center crystal), 5.17 ± 0.06 (edge crystal), and 5.18 ± 0.07 ns (corner crystal). The generalized framework proposed in this work helps to guide the design of detector modules for selected PET system configurations, including scaling the design down to a preclinical PET system, scaling up to a whole-body clinical scanner, as well as replacing APDs with other novel photodetectors that have higher gain or SNR such as silicon photomultipliers.

Convex optimization of coincidence time resolution for a high-resolution PET system.

We are developing a dual panel breast-dedicated positron emission tomography (PET) system using LSO scintillators coupled to position sensitive avalanche photodiodes (PSAPD). The charge output is amplified and read using NOVA RENA-3 ASICs. This paper shows that the coincidence timing resolution of the RENA-3 ASIC can be improved using certain list-mode calibrations. We treat the calibration problem as a convex optimization problem and use the RENA-3's analog-based timing system to correct the measured data for time dispersion effects from correlated noise, PSAPD signal delays and varying signal amplitudes. The direct solution to the optimization problem involves a matrix inversion that grows order (n(3)) with the number of parameters. An iterative method using single-coordinate descent to approximate the inversion grows order (n). The inversion does not need to run to convergence, since any gains at high iteration number will be low compared to noise amplification. The system calibration method is demonstrated with measured pulser data as well as with two LSO-PSAPD detectors in electronic coincidence. After applying the algorithm, the 511 keV photopeak paired coincidence time resolution from the LSO-PSAPD detectors under study improved by 57%, from the raw value of 16.3 ±0.07 ns full-width at half-maximum (FWHM) to 6.92 ±0.02 ns FWHM ( 11.52 ±0.05 ns to 4.89 ±0.02 ns for unpaired photons).

Analog signal multiplexing for PSAPD-based PET detectors: simulation and experimental validation.

A 1 mm(3) resolution clinical positron emission tomography (PET) system employing 4608 position-sensitive avalanche photodiodes (PSAPDs) is under development. This paper describes a detector multiplexing technique that simplifies the readout electronics and reduces the density of the circuit board design. The multiplexing scheme was validated using a simulation framework that models the PSAPDs and front-end multiplexing circuits to predict the signal-to-noise ratio and flood histogram performance. Two independent experimental setups measured the energy resolution, time resolution, crystal identification ability and count rate both with and without multiplexing. With multiplexing, there was no significant degradation in energy resolution, time resolution and count rate. There was a relative 6.9 ± 1.0% and 9.4 ± 1.0% degradation in the figure of merit that characterizes the crystal identification ability observed in the measured and simulated ceramic-mounted PSAPD module flood histograms, respectively.

Novel electro-optical coupling technique for magnetic resonance-compatible positron emission tomography detectors.

A new magnetic resonance imaging (MRI)-compatible positron emission tomography (PET) detector design is being developed that uses electro-optical coupling to bring the amplitude and arrival time information of high-speed PET detector scintillation pulses out of an MRI system. The electro-optical coupling technology consists of a magnetically insensitive photodetector output signal connected to a nonmagnetic vertical cavity surface emitting laser (VCSEL) diode that is coupled to a multimode optical fiber. This scheme essentially acts as an optical wire with no influence on the MRI system. To test the feasibility of this approach, a lutetium-yttrium oxyorthosilicate crystal coupled to a single pixel of a solid-state photomultiplier array was placed in coincidence with a lutetium oxyorthosilicate crystal coupled to a fast photomultiplier tube with both the new nonmagnetic VCSEL coupling and the standard coaxial cable signal transmission scheme. No significant change was observed in 511 keV photopeak energy resolution and coincidence time resolution. This electro-optical coupling technology enables an MRI-compatible PET block detector to have a reduced electromagnetic footprint compared with the signal transmission schemes deployed in the current MRI/PET designs.

Fast, accurate and shift-varying line projections for iterative reconstruction using the GPU.

List-mode processing provides an efficient way to deal with sparse projections in iterative image reconstruction for emission tomography. An issue often reported is the tremendous amount of computation required by such algorithm. Each recorded event requires several back- and forward line projections. We investigated the use of the programmable graphics processing unit (GPU) to accelerate the line-projection operations and implement fully-3D list-mode ordered-subsets expectation-maximization for positron emission tomography (PET). We designed a reconstruction approach that incorporates resolution kernels, which model the spatially-varying physical processes associated with photon emission, transport and detection. Our development is particularly suitable for applications where the projection data is sparse, such as high-resolution, dynamic, and time-of-flight PET reconstruction. The GPU approach runs more than 50 times faster than an equivalent CPU implementation while image quality and accuracy are virtually identical. This paper describes in details how the GPU can be used to accelerate the line projection operations, even when the lines-of-response have arbitrary endpoint locations and shift-varying resolution kernels are used. A quantitative evaluation is included to validate the correctness of this new approach.

Study of the performance of a novel 1 mm resolution dual-panel PET camera design dedicated to breast cancer imaging using Monte Carlo simulation.

We studied the performance of a dual-panel positron emission tomography (PET) camera dedicated to breast cancer imaging using Monte Carlo simulation. The PET camera under development has two 10x 15 cm(2) plates that are constructed from arrays of I X 1 X 3 mm(3) LSO crystals coupled to novel ultra-thin (<200 Am) silicon position-sensitive avalanche photodiodes (PSAPD). In this design the photodetectors are configured "edge-on" with respect to incoming photons which encounter a minimum of 2 cm thick of LSO with directly measured photon interaction depth. Simulations predict that this camera will have 10-15% photon sensitivity, for an 8-4 cm panel separation. Detector measurements show approximately 1 mm(3) intrinsic spatial resolution, <12% energy resolution, and approximately 2 ns coincidence time resolution. By performing simulated dual-panel PET studies using a phantom comprising active breast, heart, and torso tissue, count performance was studied as a function of coincident time and energy windows. We also studied visualization of hot spheres of 2.5-4.0 mm diameter and various locations within the simulated breast tissue for 1 X 1 X 3 mm(3), 2 x 2 x 10 mm(3), 3 x 3 x 30 mm(3), and 4 X 4 X 20 mm(3) LSO crystal resolutions and different panel separations. Images were reconstructed by focal plane tomography with attenuation and normalization corrections applied. Simulation results indicate that with an activity concentration ratio of tumor:breast:heart:torso of 10:1:10:1 and 30 s of acquisition time, only the dual-plate PET camera comprising 1 X 1 X 3 mm(3) crystals could resolve 2.5 mm diameter spheres with an average peak-to-valley ratio of 1.3.

A New Positioning Algorithm for Position-Sensitive Avalanche Photodiodes.

We are using a novel position sensitive avalanche photodiode (PSAPD) for the construction of a high resolution positron emission tomography (PET) camera. Up to now most researchers working with PSAPDs have been using an Anger-like positioning algorithm involving the four corner readout signals of the PSAPD. This algorithm yields a significant non-linear spatial "pin-cushion" distortion in raw crystal positioning histograms. In this paper, we report an improved positioning algorithm, which combines two diagonal corner signals of the PSAPD followed by a 45° rotation to determine the X or Y position of the interaction. We present flood positioning histogram data generated with the old and new positioning algorithms using a 3 × 4 array of 2 × 2 × 3 mm3 and a 3 × 8 array of 1 × 1 × 3 mm3 of LSO crystals coupled to 8 × 8 mm2 PSAPDs. This new algorithm significantly reduces the pin-cushion distortion in raw flood histogram image.

Image processing algorithms to facilitate and enhance sentinel node detection using a hand-held gamma ray camera in surgical breast cancer staging.

We have developed a miniature scintillation camera to be used in surgical cancer staging. The availability of such a compact hand-held gamma camera may in certain cases improve localization of the sentinel lymph node and reduce the duration of a surgical breast cancer staging procedure. We have investigated image processing algorithms applied to planar images that may improve node detection capabilities for breast cancer staging. We have also studied contrast enhancement methods that may be able to identify nodes that would otherwise be missed. Exposure duration for a given camera position can be adaptively shortened or increased by using an optical flow algorithm to estimate camera motion with respect to the current frame. By determining if the camera is in motion or not, the exposure time may be increased to allow more image counts to accumulate at a given camera position. Adaptive exposure time may improve the ease of use of the hand-held camera, and allow regions of interest to be imaged more effectively. We feel that these image processing techniques can improve the utility of a hand-held gamma ray imager for sentinel lymph node detection during breast cancer staging.