Gage Redler

Principal component analysis enhances SNR for dynamic electron paramagnetic resonance oxygen imaging of cycling hypoxia in vivo

Low oxygen concentration (hypoxia) in tumors strongly affects their malignant state and resistance to therapy. These effects may be more deleterious in regions undergoing cycling hypoxia. Electron paramagnetic resonance imaging (EPRI) has provided a noninvasive, quantitative imaging modality to investigate static pO2 in vivo. However, to image changing hypoxia, EPRI images with better temporal resolution may be required. The tradeoff between temporal resolution and signal‐to‐noise ratio (SNR) results in lower SNR for EPRI images with imaging time short enough to resolve cycling hypoxia.

In vivo electron paramagnetic resonance imaging of differential tumor targeting using cis-3,4-di(acetoxymethoxycarbonyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl

Electron paramagnetic resonance spectroscopy promises quantitative images of important physiologic markers of animal tumors and normal tissues, such as pO2, pH, and thiol redox status. These parameters of tissue function are conveniently reported by tailored nitroxides. For defining tumor physiology, it is vital that nitroxides are selectively localized in tumors relative to normal tissue. Furthermore, these paramagnetic species should be specifically taken up by cells of the tumor, thereby reporting on both the site of tumor formation and the physiological status of the tissue. This study investigates the tumor localization of the novel nitroxide, cis‐3,4‐di(acetoxymethoxycarbonyl)‐2,2,5,5‐tetramethyl‐1‐pyrrolidin‐yloxyl 3 relative to the corresponding di‐acid 4.

Approaching Oxygen-Guided Intensity-Modulated Radiation Therapy

The outcome of cancer radiation treatment is strongly correlated with tumor oxygenation. The aim of this study is to use oxygen tension distributions in tumors obtained using Electron Paramagnetic Resonance (EPR) imaging to devise better tumor radiation treatment. The proposed radiation plan is delivered in two steps. In the first step, a uniform 50% tumor control dose (TCD50) is delivered to the whole tumor. For the second step an additional dose boost is delivered to radioresistant, hypoxic tumor regions. FSa fibrosarcomas grown in the gastrocnemius of the legs of C3H mice were used. Oxygen tension images were obtained using a 250 MHz pulse imager and injectable partially deuterated trityl OX63 (OX71) spin probe. Radiation was delivered with a novel animal intensity modulated radiation therapy (IMRT) XRAD225Cx microCT/radiation therapy delivery system. In a simplified scheme for boost dose delivery, the boost area is approximated by a sphere, whose radius and position are determined using an EPR O2 image. The sphere that irradiates the largest fraction of hypoxic voxels in the tumor was chosen using an algorithm based on Receiver Operator Characteristic (ROC) analysis. We used the fraction of irradiated hypoxic volume as the true positive determinant and the fraction of irradiated normoxic volume as the false positive determinant in the terms of that analysis. The most efficient treatment is the one that demonstrates the shortest distance from the ROC curve to the upper left corner of the ROC plot. The boost dose corresponds to the difference between TCD90 and TCD50 values. For the control experiment an identical radiation dose to the normoxic tumor area is delivered.

Towards Human Oxygen Images with Electron Paramagnetic Resonance Imaging

Electron paramagnetic resonance imaging (EPRI) has been used to noninvasively provide 3D images of absolute oxygen concentration (pO2) in small animals. These oxygen images are well resolved both spatially (~1 mm) and in pO2 (1-3 mmHg). EPRI preclinical images of pO2 have demonstrated extremely promising results for various applications investigating oxygen related physiologic and biologic processes as well as the dependence of various disease states on pO2, such as the role of hypoxia in cancer. Recent developments have been made that help to progress EPRI towards the eventual goal of human application. For example, a bimodal crossed-wire surface coil has been developed. Very preliminary tests demonstrated a 20 dB isolation between transmit and receive for this coil, with an anticipated additional 20 dB achievable. This could potentially be used to image local pO2 in human subjects with superficial tumors with EPRI. Local excitation and detection will reduce the specific absorption rate limitations on images and eliminate any possible power deposition concerns. Additionally, a large 9 mT EPRI magnet has been constructed which can fit and provide static main and gradient fields for imaging local anatomy in an entire human. One potential obstacle that must be overcome in order to use EPRI to image humans is the approved use of the requisite EPRI spin probe imaging agent (trityl). While nontoxic, EPRI trityl spin probes have been injected intravenously when imaging small animals, and require relatively high total body injection doses that would not be suitable for human imaging applications. Work has been done demonstrating the alternative use of intratumoral (IT) injections, which can reduce the amount of trityl required for imaging by a factor of 2000- relative to a whole body intravenous injection. The development of a large magnet that can accommodate human subjects, the design of a surface coil for imaging of superficial pO2, and the reduction of required spin probe using IT injections all are crucial steps towards the eventual use of EPRI to image pO2 in human subjects. In the future this can help investigate the oxygenation status of superficial tumors (e.g., breast tumors). The ability to image pO2 in humans has many other potential applications to diseases such as peripheral vascular disease, heart disease, and stroke.

3D pulse EPR imaging from sparse-view projections via constrained, total variation minimization

Tumors and tumor portions with low oxygen concentrations (pO2) have been shown to be resistant to radiation therapy. As such, radiation therapy efficacy may be enhanced if delivered radiation dose is tailored based on the spatial distribution of pO2 within the tumor. A technique for accurate imaging of tumor oxygenation is critically important to guide radiation treatment that accounts for the effects of local pO2. Electron paramagnetic resonance imaging (EPRI) has been considered one of the leading methods for quantitatively imaging pO2 within tumors in vivo. However, current EPRI techniques require relatively long imaging times. Reducing the number of projection scan considerably reduce the imaging time. Conventional image reconstruction algorithms, such as filtered back projection (FBP), may produce severe artifacts in images reconstructed from sparse-view projections. This can lower the utility of these reconstructed images. In this work, an optimization based image reconstruction algorithm using constrained, total variation (TV) minimization, subject to data consistency, is developed and evaluated. The algorithm was evaluated using simulated phantom, physical phantom and pre-clinical EPRI data. The TV algorithm is compared with FBP using subjective and objective metrics. The results demonstrate the merits of the proposed reconstruction algorithm.

How In Vivo EPR Measures and Images Oxygen

The partial pressure of oxygen (pO₂) in tissues plays an important role in the pathophysiology of many diseases and influences outcome of cancer therapy, ischemic heart and cerebrovascular disease treatments and wound healing. Over the years a suite of EPR techniques for reliable oxygen measurements has been developed. This is a mini-review of pulse EPR in vivo oxygen imaging methods that utilize soluble spin probes. Recent developments in pulse EPR imaging technology have brought an order of magnitude increase in image acquisition speed, enhancement of sensitivity and considerable improvement in the precision and accuracy of oxygen measurements.

Comparison of parabolic filtration methods for 3D filtered back projection in pulsed EPR imaging

Pulse electron paramagnetic resonance imaging (Pulse EPRI) is a robust method for noninvasively measuring local oxygen concentrations in vivo. For 3D tomographic EPRI, the most commonly used reconstruction algorithm is filtered back projection (FBP), in which the parabolic filtration process strongly influences image quality. In this work, we designed and compared 7 parabolic filtration methods to reconstruct both simulated and real phantoms. To evaluate these methods, we designed 3 error criteria and 1 spatial resolution criterion. It was determined that the 2 point derivative filtration method and the two-ramp-filter method have unavoidable negative effects resulting in diminished spatial resolution and increased artifacts respectively. For the noiseless phantom the rectangular-window parabolic filtration method and sinc-window parabolic filtration method were found to be optimal, providing high spatial resolution and small errors. In the presence of noise, the 3 point derivative method and Hamming-window parabolic filtration method resulted in the best compromise between low image noise and high spatial resolution. The 3 point derivative method is faster than Hamming-window parabolic filtration method, so we conclude that the 3 point derivative method is optimal for 3D FBP.

EPR image based oxygen movies for transient hypoxia.

Chronic hypoxia strongly affects the malignant state and resistance to therapy for tumors. Transient hypoxia has been hypothesized, but not proven to be more deleterious. Electron paramagnetic resonance imaging (EPRI) provides non-invasive, quantitative imaging of static pO₂ in vivo. Dynamic EPRI produces pO₂ movies, enabling non-invasive assessment of in vivo pO₂ changes, such as transient hypoxia. Recent developments have been made to enable Dynamic EPRI. Maximally spaced projection sequencing has been implemented to allow for more accurate and versatile acquisition of EPRI data when studying dynamic systems. Principal component analysis filtering has been employed to enhance SNR. Dynamic EPRI studies will provide temporally resolved oxygen movies necessary to perform in vivo studies of physiologically relevant pO₂ changes in tumors. These oxygen movies will allow for the localization/quantification of transient hypoxia and will therefore help to disentangle the relationship between chronic and transient hypoxia, in order to better understand their roles in therapeutic optimization and outcome.

MO-AB-BRA-02: A Novel Scatter Imaging Modality for Real-Time Image Guidance During Lung SBRT

Purpose: A novel scatter imaging modality is developed and its feasibility for image-guided radiation therapy (IGRT) during stereotactic body radiation therapy (SBRT) for lung cancer patients is assessed using analytic and Monte Carlo models as well as experimental testing. Methods: During treatment, incident radiation interacts and scatters from within the patient. The presented methodology forms an image of patient anatomy from the scattered radiation for real-time localization of the treatment target. A radiographic flat panel-based pinhole camera provides spatial information regarding the origin of detected scattered radiation. An analytical model is developed, which provides a mathematical formalism for describing the scatter imaging system. Experimental scatter images are acquired by irradiating an object using a Varian TrueBeam accelerator. The differentiation between tissue types is investigated by imaging simple objects of known compositions (water, lung, and cortical bone equivalent). A lung tumor phantom, simulating materials and geometry encountered during lung SBRT treatments, is fabricated and imaged to investigate image quality for various quantities of delivered radiation. Monte Carlo N-Particle (MCNP) code is used for validation and testing by simulating scatter image formation using the experimental pinhole camera setup. Results: Analytical calculations, MCNP simulations, and experimental results when imaging the water, lung, and cortical bone equivalent objects show close agreement, thus validating the proposed models and demonstrating that scatter imaging differentiates these materials well. Lung tumor phantom images have sufficient contrast-to-noise ratio (CNR) to clearly distinguish tumor from surrounding lung tissue. CNR=4.1 and CNR=29.1 for 10MU and 5000MU images (equivalent to 0.5 and 250 second images), respectively. Conclusion: Lung SBRT provides favorable treatment outcomes, but depends on accurate target localization. A comprehensive approach, employing multiple simulation techniques and experiments, is taken to demonstrate the feasibility of a novel scatter imaging modality for the necessary real-time image guidance.

Characterization of Compton-scatter imaging with an analytical simulation method

By collimating the photons scattered when a megavoltage therapy beam interacts with the patient, a Compton-scatter image may be formed without the delivery of an extra dose. To characterize and assess the potential of the technique, an analytical model for simulating scatter images was developed and validated against Monte Carlo (MC). For three phantoms, the scatter images collected during irradiation with a 6 MV flattening-filter-free therapy beam were simulated. Images, profiles, and spectra were compared for different phantoms and different irradiation angles. The proposed analytical method simulates accurate scatter images up to 1000 times faster than MC. Minor differences between MC and analytical simulated images are attributed to limitations in the isotropic superposition/convolution algorithm used to analytically model multiple-order scattering. For a detector placed at 90° relative to the treatment beam, the simulated scattered photon energy spectrum peaks at 140-220 keV, and 40-50% of the photons are the result of multiple scattering. The high energy photons originate at the beam entrance. Increasing the angle between source and detector increases the average energy of the collected photons and decreases the relative contribution of multiple scattered photons. Multiple scattered photons cause blurring in the image. For an ideal 5 mm diameter pinhole collimator placed 18.5 cm from the isocenter, 10 cGy of deposited dose (2 Hz imaging rate for 1200 MU min-1 treatment delivery) is expected to generate an average 1000 photons per mm2 at the detector. For the considered lung tumor CT phantom, the contrast is high enough to clearly identify the lung tumor in the scatter image. Increasing the treatment beam size perpendicular to the detector plane decreases the contrast, although the scatter subject contrast is expected to be greater than the megavoltage transmission image contrast. With the analytical method, real-time tumor tracking may be possible through comparison of simulated and acquired patient images.