N Mistry

A High-Precision Contrast Injector for Small Animal X-Ray Digital Subtraction Angiography

The availability of genetically altered animal models of human disease for basic research has generated great interest in new imaging methodologies. Digital subtraction angiography (DSA) offers an appealing approach to functional imaging in small animals because of the high spatial and temporal resolution, and the ability to visualize and measure blood flow. The micro-injector described here meets crucial performance parameters to ensure optimal vessel enhancement without significantly increasing the total blood volume or producing overlap of enhanced structures. The micro-injector can inject small, reproducible volumes of contrast agent at high flow rates with computer-controlled timing synchronized to cardiopulmonary activity. Iterative bench-top and live animal experiments with both rat and mouse have been conducted to evaluate the performance of this computer-controlled micro-injector, a first demonstration of a new device designed explicitly for the unique requirements of DSA in small animals. Injection protocols were optimized and screened for potential physiological impact. For the optimized protocols, we found that changes in the time-density curves for representative regions of interest in the thorax were due primarily to physiological changes, independent of micro-injector parameters.

Evaluation of template matching for tumor motion management with cine-MR images in lung cancer patients

PURPOSE Accurate determination of tumor position is crucial for successful application of motion compensated radiotherapy in lung cancer patients. This study tested the performance of an automated template matching algorithm in tracking the tumor position on cine-MR images by examining the tracking error and further comparing the tracking error to the interoperator variability of three human reviewers. METHODS Cine-MR images of 12 lung cancer patients were analyzed. Tumor positions were determined both automatically with template matching and manually by a radiation oncologist and two additional reviewers trained by the radiation oncologist. Performance of the automated template matching was compared against the ground truth established by the radiation oncologist. Additionally, the tracking error of template matching, defined as the difference in the tumor positions determined with template matching and the ground truth, was investigated and compared to the interoperator variability for all patients in the anterior-posterior (AP) and superior-inferior (SI) directions, respectively. RESULTS The median tracking error for ten out of the 12 patients studied in both the AP and SI directions was less than 1 pixel (= 1.95 mm). Furthermore, the median tracking error for seven patients in the AP direction and nine patients in the SI direction was less than half a pixel (= 0.975 mm). The median tracking error was positively correlated with the tumor motion magnitude in both the AP (R = 0.55, p = 0.06) and SI (R = 0.67, p = 0.02) directions. Also, a strong correlation was observed between tracking error and interoperator variability (y = 0.26 + 1.25x, R = 0.84, p < 0.001) with the latter larger. CONCLUSIONS Results from this study indicate that the performance of template matching is comparable with or better than that of manual tumor localization. This study serves as preliminary investigations towards developing online motion tracking techniques for hybrid MRI-Linac systems. Accuracy of template matching makes it a suitable candidate to replace the labor intensive manual tumor localization for obtaining the ground truth when testing other motion management techniques.

Nitrite induces the extravasation of iron oxide nanoparticles in hypoxic tumor tissue

Nitrite undergoes reconversion to nitric oxide under conditions characteristic of the tumor microenvironment, such as hypoxia and low pH. This selective conversion of nitrite into nitric oxide in tumor tissue has led to the possibility of using nitrite to enhance drug delivery and the radiation response. In this work, we propose to serially characterize the vascular response of brain tumor‐bearing rats to nitrite using contrast‐enhanced R2* mapping. Imaging is performed using a multi‐echo gradient echo sequence at baseline, post iron oxide nanoparticle injection and post‐nitrite injection, whilst the animal is breathing air. The results indicate that nitrite sufficiently increases the vascular permeability in C6 gliomas, such that the iron oxide nanoparticles accumulate within the tumor tissue. When animals breathed 100% oxygen, the contrast agent remained within the vasculature, indicating that the conversion of nitrite to nitric oxide occurs in the presence of hypoxia within the tumor. The hypoxia‐dependent, nitrite‐induced extravasation of iron oxide nanoparticles observed herein has implications for the enhancement of conventional and nanotherapeutic drug delivery. Copyright

SU-D-12A-05: Iterative Reconstruction Techniques to Enable Intrinsic Respiratory Gated CT in Mice

PURPOSE Longitudinal studies of lung function in mice need the ability to image different phases of ventilation in free-breathing mice using retrospective gating. However, retrospective gating often produces under-sampled and uneven angular samples, resulting in severe reconstruction artifacts when using traditional FDK based reconstruction algorithms. We wanted to demonstrate the utility of iterative reconstruction method to enable intrinsic respiratory gating in small-animal CT. METHODS Free-breathing mice were imaged using a Siemens Inveon PET/micro-CT system. Evenly distributed projection images were acquired at 360 angles. Retrospective respiratory gating was performed using an intrinsic marker based on the average intensity in a region covering the diaphragm. Projections were classified into 4 and 6 phases (finer temporal resolution) resulting in 138 and 67 projections respectively. Reconstruction was carried out using 3 Methods: conventional FDK, iterative penalized least-square (PWLS) with total variation (TV), and PWLS with edge-preserving penalty. The performance of the methods was compared using contrast-to-noise (CNR) in a region of interest (ROI). Line profile through a specific region was plotted to evaluate the preserving of edges. RESULTS In both the cases with 4 and 6 phases, inadequate and non-uniform angular sampling results in artifacts using conventional FDK. However, such artifacts are minimized using both the iterative methods. Using both 4 and 6 phases, the iterative techniques outperformed FDK in terms of CNR and maintaining sharp edges. This is further evidenced especially with increased artifacts using FDK for 6 phases. CONCLUSION This work indicates fewer artifacts and better image details can be achieved with iterative reconstruction methods in non-uniform under-sampled reconstruction. Using iterative methods can enable free-breathing intrinsic respiratory gating in small-animal CT. Further studies are needed to compare the computational complexity for large datasets.

TH‐C‐141‐10: Error of Template Matching for Tracking Tumor Motion Is No Larger Than Inter‐Operator Variability

PURPOSE Recently, template matching has been proposed to track tumor motion using cine-MRI images. However, the technique has been tested primarily on blood vessels in healthy subjects. In this work, we demonstrate the utility of automated template matching in patients with thoracic tumors. We also compare the variability in predicting tumor position using template matching and 3 human operators. METHODS Five patients with non-small cell lung cancer (NSCLC) were recruited in a prospective study. Cine-MRI imaging was performed while the patients were instructed to breathe normally. True FISP (fast imaging in steady state) cine-images were obtained in the sagittal plane. The centroids of the tumors were determined manually by 3 operators and also by the automatic template matching technique. The differences both in the AP and SI directions between the automatic and manual methods and the inter-operator variability were calculated respectively and compared. RESULTS For all patients the variability between automatic and human operators in the SI direction was less than the inter-operator variability. For 4 out of 5 patients the variability between automatic and human operators in the AP direction was less than the inter-operator variability. However, the variability in 1 patient was higher by 14%. This is attributed to out-of-plane motion that currently is not captured using the cine-MRI imaging. CONCLUSION The effectiveness of template matching to estimate tumor position during respiratory motion was tested in patients with lung cancer. Results show that, the difference between the automatic and manual methods was comparable to the inter-operator variability. Future efforts to integrate on-board MRI imaging with linear accelerators can benefit from automated tumor tracking with template matching. Furthermore, the technique can also be utilized to replace the laborious manual tracking process necessary to establish the ground-truth when evaluating external surrogates of tumor motion. NIH/NCICA 122403.

WE-G-17A-02: MRI-Based Lung Tumor Tracking with Navigator Echo Pulses

PURPOSE To evaluate the feasibility of directly tracking the displacement of lung tumors in MRI using navigator echo pulses, and to compare the navigator-derived tumor positions with manually-identified tumor positions. METHODS Twelve patients with lung tumors underwent free-breathing sagittal MR scans under an IRB-approved protocol for 8-12 min. We used a multi-slice 2D TruFISP pulse sequence on a 1.5T Siemens Avanto scanner. Scan parameters were as follows: TE=1.29ms, TR=2.57ms, flip angle=60°, pixel matrix=176×256, resolution=1.95mm × 1.95 mm × (9-16) mm, acquisition time=2.5s. One-dimensional profiles of the images in the SI and AP directions that passed through the center of the tumor were selected for analysis as simulated navigator echo profiles. The tumor position was identified through edge detection and tracked throughout the temporally varying images in each direction. The navigator-tracked direct tumor positions were compared with tumor centroid positions manually identified by an expert physician on the full images (200 acquisitions per scan). The correlation coefficient and pixel distance between the two tumor positions were calculated. In addition, respiratory surrogate navigator positions of the diaphragm and chest wall were also evaluated for correlation with the manually-identified tumor positions. RESULTS Direct tracking of the lung tumor position with navigator echoes was more highly correlated to the manual tumor positions than surrogate tracking in 72% of cases with significant correlations (p<0.005). Only four patients exhibited strong linear correlations (R2 >0.6). The average distance between the navigator tumor positions and the manually-identified tumor positions was 0.99±0.74 pixels (1.93±1.44 mm). CONCLUSIONS Lung tumor displacement can be tracked using navigator echoes to within 2 mm (1 pixel) of manually identified tumor positions. This work was supported in part by Grant No. CA124766 from the NIH/NCI, and Varian Medical Systems (Palo Alto, CA).

SU-E-J-149: Establishing the Relationship Between Pre-Treatment Lung Ventilation, Dose, and Toxicity Outcome.

PURPOSE Recently, there has been an interest in incorporating functional information in treatment planning especially in thoracic tumors. The rationale is that healthy lung regions need to be spared from radiation if possible to help achieve better control on toxicity. However, it is still unclear whether high functioning regions need to be spared or have more capacity to deal with the excessive radiation as compared to the compromised regions of the lung. Our goal with this work is to establish the tools by which we can establish a relationship between pre-treatment lung function, dose, and radiographic outcomes of lung toxicity. METHODS Treatment planning was performed using a single phase of a 4DCT scan, and follow-up anatomical CT scans were performed every 3 months for most patients. In this study, we developed the pipeline of tools needed to analyze such a large dataset, while trying to establish a relationship between function, dose, and outcome. Pre-treatment lung function was evaluated using a recently published technique that evaluates Fractional Regional Ventilation (FRV). All images including the FRV map and the individual follow-up anatomical CT images were all spatially matched to the planning CT using a diffusion based Demons image registration algorithm. Change in HU value was used as a metric to capture the effects of lung toxicity. To validate the findings, a radiologist evaluated the follow-up anatomical CT images and scored lung toxicity. RESULTS Initial experience in 1 patient shows a relationship between the pre-treatment lung function, dose and toxicity outcome. The results are also correlated to the findings by the radiologist who was blinded to the analysis or dose. CONCLUSION The pipeline we have established to study this enables future studies in large retrospective studies. However, the tools are dependent on the fidelity of 4DCT reconstruction for accurate evaluation of regional ventilation. Patent Pending for the technique presented in this work to evaluate FRV incorporating mass correction.

SU-E-J-108: Template Matching Based On Multiple Templates Can Improve the Tumor Tracking Performance When There Is Large Tumor Deformation

PURPOSE Recently, template matching has been shown to be able to track tumor motion on cine-MRI images. However, artifacts such as deformation, rotation, and/or out-of-plane movement could seriously degrade the performance of this technique. In this work, we demonstrate the utility of multiple templates derived from different phases of tumor motion in reducing the negative effects of artifacts and improving the accuracy of template matching methods. METHODS Data from 2 patients with large tumors and significant tumor deformation were analyzed from a group of 12 patients from an earlier study. Cine-MRI (200 frames) imaging was performed while the patients were instructed to breathe normally. Ground truth tumor position was established on each frame manually by a radiation oncologist. Tumor positions were also automatically determined using template matching with either single or multiple (5) templates. The tracking errors, defined as the absolute differences in tumor positions determined by the manual and automated methods, when using either single or multiple templates were compared in both the AP and SI directions, respectively. RESULTS Using multiple templates reduced the tracking error of template matching. In the SI direction where the tumor movement and deformation were significant, the mean tracking error decreased from 1.94 mm to 0.91 mm (Patient 1) and from 6.61 mm to 2.06 mm (Patient 2). In the AP direction where the tumor movement was small, the reduction of the mean tracking error was significant in Patient 1 (from 3.36 mm to 1.04 mm), but not in Patient 2 (from 3.86 mm to 3.80 mm). CONCLUSION This study shows the effectiveness of using multiple templates in improving the performance of template matching when artifacts like large tumor deformation or out-of-plane motion exists. Accurate tumor tracking capabilities can be integrated with MRI guided radiation therapy systems. This work was supported in part by grants from NIH/NCI CA 124766 and Varian Medical Systems, Palo Alto, CA.

SU-E-T-217: Intrinsic Respiratory Gating in Small Animal CT.

PURPOSE Preclinical animal models of lung cancer can provide a controlled test-bed for testing dose escalation or function-based-treatment-planning studies. However, to extract lung function, i.e. ventilation, one needs to be able to image the lung at different phases of ventilation (in-hale / ex-hale). Most respiratory-gated imaging using micro-CT involves using an external ventilator and surgical intervention limiting the utility in longitudinal studies. A new intrinsic respiratory retrospective gating method was developed and tested in mice. METHODS A fixed region of interest (ROI) that covers the diaphragm was selected on all projection images to estimate the mean intensity (M). The mean intensity depends on the projection angle and diaphragm position. A 3-point moving average (A) of consecutive M values: Mpre, Mcurrent and Mpost, was calculated to be subtracted from Mcurrent. A fixed threshold was used to enable amplitude based sorting into 4 different phases of respiration. Images at full-inhale and end-exhale phases of respiration were reconstructed using the open source OSCaR. Lung volumes estimated at the 2 phases of respiration were validated against literature values. RESULTS Intrinsic retrospective gating was accomplished without the use of any external breathing waveform. While projection images were acquired at 360 different angles. Only 138 and 104 projections were used to reconstruct images at full-inhale and end-exhale. This often results in non-uniform under-sampled angular projections leading to some minor streaking artifacts. The calculated expiratory, inspiratory and tidal lung volumes correlated well with the values known from the literature. CONCLUSION Our initial result demonstrates an intrinsic gating method that is suitable for flat panel cone beam small animal CT systems. Reduction in streaking artifacts can be accomplished by oversampling the data or using iterative reconstruction methods. This initial experience will enable freebreathing small animal micro-CT imaging to fuel longitudinal studies of lung function.

SU‐E‐J‐163: Suppressing Motion Related Artifacts in 4D‐CT Or 4D‐CBCT Reconstruction Using Projections and Digitally Reconstructed Projections: Proof of Principle

PURPOSE It has been always challenging to reconstruct good quality 4D-CT or 4D-CBCT when the data are under-sampled for each individual phase. For example, CBCT data is often acquired with limited number of projections and while it is sufficient to reconstruct decent motion averaged images; reconstructing a 4D image from this limited data leads to motion induced artifacts. However, inherent in the projection data are both components that capture the moving and non-moving parts of the image. In this work, we test the feasibility of using such a dataset to separate out the moving and non-moving components and then reconstruct individual phase images to acquire a complete 4D reconstruction with reduced artifacts. METHODS To test our theory, we simulated a simple 2D+time respiratory phantom, and demonstrated the feasibility using a simple filtered backprojection algorithm along with the proposed motion suppression technique to reconstruct 2D+time images. However, the concepts can be expanded to 3D+time (i.e. 4D) datasets both using conventional CT or CBCT acquisition. The core of the technique rests on separating out the motion components from individual projection data by selecting the minimum intensity between projections and digitally reconstructed projections. This information is then later added back into the final images reconstructed at each individual phase to suppress motion artifacts. RESULTS Initial results on a 2D+time simulated phantom proves that severe under-sampling artifacts can be eliminated and individual phase images can be reconstructed with high fidelity when compared to standard under-sampled filtered backprojection. CONCLUSION The technique is successfully demonstrated using simple backprojection, and hence computational complexity is comparable to standard backprojection (for CT) or FDK (for CBCT). Computational complexity will be significantly better when compared to traditional iterative methods that use regularization and penalty functions. NIH R01CA133539.