Kristy Lynn Perez - Investigating Functional Breast Image Quality and Quantification with a Dedicated SPECT-CT System

The overall goal of this work was to utilize the dedicated breast SPECT-CT system to acquire the best possible images. The work presented in this dissertation investigates phantom and subject positioning as well as collecting data with a variety of angular sampling and acquisition trajectories. Further, a large portion of this work was focused on applying corrections to the system for quantitative imaging. The system was shown to provide high quality images with minimal out-of-field signal contribution. Additionally, the quantification procedure was shown to be within 10% of the known activity concentration present at the time of imaging for both simple vertical axis of rotation (VAOR) and complex projected sinusoidal wave (PROJSINE) trajectories.

 

Andrew Stephen Thomas - Quantitative 3D Optical Imaging: Applications in Dosimetry and Biophysics

Optical-CT has been shown to be a potentially useful imaging tool for for the two very different spheres of biologists and radiation therapy physicists, but it has yet to live up to that potential. In radiation therapy, researchers have used optical-CT for the readout of 3D dosimeters, but it is yet to be a clinically relevant tool as the technology is too slow to be considered practical. Biologists have used the technique for structural imaging, but have struggled with emission tomography as the reality of photon attenuation for both excitation and emission have made the images quantitatively irrelevant.

 

Joshua M. Wilson - Parameterizing Image Quality of TOF versus Non-TOF PET as a Function of Body Size

Positron emission tomography (PET) is a nuclear medicine diagnostic imaging exam of metabolic processes in the body. Radiotracers, which consist of positron emitting radioisotopes and a molecular probe, are introduced into the body, emitted radiation is detected, and tomographic images are reconstructed. The primary clinical PET application is in oncology using a glucose analogue radiotracer, which is avidly taken up by some cancers.

 

Vorakarn Chanyavanich - Knowledge-based IMRT Treatment Planning for Prostate Cancer

 

Samuel Loren Brady - Development of Radiochromic Film for Dosimetric Analysis of Indirect Ionizing Radiation Fields

Traditional dosimetric devices are inherently point dose dosimeters (PDDs) and can only measure the magnitude of the radiation exposure; hence, they are onedimensional (1D). To measure the magnitude and spatial location of dose within a volume either several PDDs must be used at one time, or one PDD must be translated from point-to-point. Using PDDs for spatially distributed, two-dimensional (2D), dosimetry is laborious, time consuming, limited in spatial resolution, susceptible to positioning errors, and the currently accepted approach to measuring dose distribution in 2D. This work seeks to expand the current limits of indirectly ionizing radiation dosimetry by using radiochromic film (RCF) for a high-resolution, accurate dosimetry system. Using RCF will extend the current field of radiation dosimetry to spatially quantitative 2D and three-dimensional (3D) measurements.

The RCF dosimetry system was applied to three novel areas from which a benefit could be derived for 2D or 3D dosimetric information. The first area was for a 3D dosimetry of a pendant breast in 3D-CT mammography. The novel method of developing a volumetric image of the breast from a CT acquisition technique was empirically measured for its dosimetry and compared to standard dual field digital mammography. The second area was dose reduction in CT for pediatric and adult scan protocols. In this application, novel methodologies were developed to measure 3D organ dosimetry and characterize a dose reduction scan protocol for pediatric and adult body habitus. The third area was in the field of small animal irradiation for radiobiology purposes and cancer patient treatment verification. Two methods for small animal irradiation were analyzed for their dosimetry. The first technique was within a gamma irradiator environment using a 137Cs source (663 keV), and the second, a novel approach to mouse irradiation, was developed for fast neutron (10 MeV) irradiated by a Tandem Van de Graff accelerator in a 2H(d,n)3He reaction. For the patient cancer treatment, RCF was used to verify a 3D radiochromic plastic, PRESAGETM, using multileaf collimation (MLC) on a medical linear accelerator (LINAC) with 6 MV x-rays. The RCF and PRESAGETM dosimeters were employed to verify a simple respiratory-gated lung treatment for a small nodule; the film was considered the gold standard. In every case, the RCF dosimetry system was verified for accuracy using a traditional PDD as the golden standard. When considering all areas of radiation energy applications, the RCF dosimetry system agreed to better than 7% of the golden standard, and in some cases within better than 1%. In many instances, this work provided vital dosimetric information that otherwise was not captured using the PDD in similar geometry. This work demonstrates the need for RCF to more accurately measure volumetric dose.

 

Sangroh Kim - Cone Beam Computed Tomography (CBCT) Dosimetry: Measurements and Monte Carlo Simulations

Cone beam computed tomography (CBCT) is a 3D x-ray imaging technique in which the x-ray beam is transmitted to an object with wide beam geometry producing a 2D image projection. Due to its fasterimage acquisition time, wide coverage length per scan, and fewer motion artifacts, the CBCT system is rapidly replacing the conventional CT system and becoming popular in diagnostic and therapeutic radiology. However, there are few studies performed in CBCT dosimetry because of the absence of a standard dosimetric protocol for CBCT. Computed tomography dose index (CTDI), a standardized metric in conventional CT dosimetry, or direct organ dose measurements have been limitedly used in CBCT dosimetry.

This dissertation investigated the CBCT dosimetry from the CTDI method to the organ, effective dose, risk estimations with physical measurements and Monte Carlo (MC) simulations.

An On-Board Imager (OBI, Varian Medical Systems, Palo Alto, CA) was used to perform old and new CBCT scan protocols. The new CBCT protocols introduced both partial and full angle scan modes while the old CBCT protocols only used the full angle mode. The BEAMnrc/EGSnrc MC system was used to simulate the BCCT scans; the MC model of the OBI x-ray tube was built into the system and validated by measurements characterizing the cone beam quality in the aspects of the x-ray spectrum, half value layer (HVL) and dose profiles for both full-fan and half-fan modes. Using the validated MC model, CDTICB, dose profile integral (DPI), cone beam dose length product (DLPCB), and organ doses were calculated with voxelized MC CT phantoms or anthropomorphic phantoms. Effective dose and radiation risks were estimated from the organ dose results. The CDTICB of the old protocols were found to be 84 and 45 mGy for standard dose, head and body protocols. The new scan protocols were found to be advantageous in reducing the patient dose while offering acceptable image quality.

The MC method successfully estimated the CDTICB, organ and effective dose despite the heavy calculation time. The point dose method was found to be capable of estimating the CBCT dose with reasonable accuracy in the clinical environment.

 

Xiang Li - Radiation Dose and Diagnostic Accuracy in Pediatric Computed Tomography

Since its inception in the 1970’s, computed tomography (CT) has revolutionized the practice of medicine and evolved into an essential tool for diagnosing numerous diseases not only in adults but also in children. The clinical utility of CT examinations has led to a rapid expansion in CT use and a corresponding increase in the radiation burden to patients. CT radiation is of particular concern to children, whose rapidly growing tissues are more susceptible to radiation-induced cancer and who have longer life spans during which cancerous changes might occur. In recent years, the increasing awareness of CT radiation risk to children has brought about growing efforts to reduce CT dose to the pediatric population. The key element of all dose reduction efforts is to reduce radiation dose while maintaining diagnostic accuracy. Substantiating the tradeoff between the two is the motivation behind this dissertation work.

The research in this dissertation has two important clinical implications. First, the quantitative relationships between patient dose/risk and patient size, between patient dose/risk and scan parameters, between diagnostic accuracy and image quality, and between diagnostic accuracy and radiation dose can guide the design of pediatric CT protocols to achieve the desired diagnostic accuracy at the minimum radiation dose. Second, patient-specific dose and risk information, when included in a patient’s dosimetry and medical records, can inform healthcare providers of prior radiation exposure and aid in decisions for image utilization, including the situation where multiple examinations are being considered.

 

Ashley Anne Manzoor - Drug Delivery and Anti-vascular Effects of Temperature Sensitive Liposomal Doxorubicin

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumor. Relying on the EPR effect (Enhanced Permeability and Retention), a host of nanoparticles (from micelles and dendrimers to liposomes and lipidic nanoparticles) have been developed and tested for passive accumulation into tumor interstitium. Unfortunately, most nanoparticles achieve only suboptimal drug delivery to tumors, due to heterogeneity of tumor vessel permeability, limited nanoparticle penetration, and relatively slow drug release. However, recent developments in nanoparticle technology have occurred with the design and testing of a fast drug-releasing liposome triggered by local heat.

The experiments aimed to investigate two effects: the existence and influence of intravascular drug release on drug delivery and distribution within the tumor, and the effect of drug delivery on subsequent anti-vascular effects. To investigate drug delivery, two mouse models were used. Dorsal window chambers implanted with FaDu human squamous carcinomas were used with real-time intravital confocal microscopy to evaluate time-resolved delivery of doxorubicin and liposome extravasation over the first 20 minutes of treatment. As a complimentary mouse model, flank FaDu tumors were also treated with Dox-TSL or treatment controls (doxorubicin with and without heat and Doxil with heat), and subsequently sectioned and histologicaly imaged to evaluate drug delivery and penetration depth, as well as impact on hypoxia and perfusion parameters. To investigate vascular effects, a GFP-eNos transgenic mouse model was used, also with window chamber confocal microscopy, to evaluate morphological changes occurring in the tumor vasculature following treatment.

The results demonstrate that contrary to the traditional liposome paradigm of extravasation and subsequent drug release, thermally sensitive liposomes release drug inside the tumor vasculature, and that the released free drug diffuses into the tumor interstitium. This work establishes intravascular release as a new paradigm in drug delivery to solid tumors, resulting in improved drug bioavailability, penetration depth, and enhanced delivery of drug to hypoxic regions of tumors.

 

Jacqueline Marie Maurer - Four-Dimensional Imaging of Respiratory Motion in the Radiotherapy Treatment Room Using a Gantry Mounted Flat Panel Imaging Device

Imaging respiratory induced tumor motion in the radiation therapy treatment room could eliminate the necessity for large motion encompassing margins that result in excessive irradiation of healthy tissues. Currently available image guidance technologies are ill-suited for this task. Two-dimensional fluoroscopic images are acquired with sufficient speed to image respiratory motion. However, volume information is not present, and soft tissue structures are often not visible because a large volume is projected onto a single plane. Currently available volumetric imaging modalities are not acquired with sufficient speed to capture full motion trajectory information. Four-dimensional cone-beam computed tomography (4D CBCT) using a gantry mounted 2D flat panel imaging device has been proposed but has been limited by high doses, long scan times and severe under-sampling artifacts. The focus of the work completed in this thesis was to find ways to improve 4D imaging using a gantry mounted 2D kV imaging system. Specifically, the goals were to investigate methods for minimizing imaging dose and scan time while achieving consistent, controllable, high quality 4D images.

The RCF dosimetry system was applied to three novel areas from which a benefit could be derived for 2D or 3D dosimetric information. The first area was for a 3D dosimetry of a pendant breast in 3D-CT mammography. The novel method of developing a volumetric image of the breast from a CT acquisition technique was empirically measured for its dosimetry and compared to standard dual field digital mammography. The second area was dose reduction in CT for pediatric and adult scan protocols. In this application, novel methodologies were developed to measure 3D organ dosimetry and characterize a dose reduction scan protocol for pediatric and adult body habitus. The third area was in the field of small animal irradiation for radiobiology purposes and cancer patient treatment verification. Two methods for small animal irradiation were analyzed for their dosimetry. The first technique was within a gamma irradiator environment using a 137Cs source (663 keV), and the second, a novel approach to mouse irradiation, was developed for fast neutron (10 MeV) irradiated by a Tandem Van de Graff accelerator in a 2H(d,n)3He reaction. For the patient cancer treatment, RCF was used to verify a 3D radiochromic plastic, PRESAGETM, using multileaf collimation (MLC) on a medical linear accelerator (LINAC) with 6 MV x-rays. The RCF and PRESAGETM dosimeters were employed to verify a simple respiratory-gated lung treatment for a small nodule; the film was considered the gold standard. In every case, the RCF dosimetry system was verified for accuracy using a traditional PDD as the golden standard. When considering all areas of radiation energy applications, the RCF dosimetry system agreed to better than 7% of the golden standard, and in some cases within better than 1%. In many instances, this work provided vital dosimetric information that otherwise was not captured using the PDD in similar geometry. This work demonstrates the need for RCF to more accurately measure volumetric dose.

 

Justin R. Roper - On-board Single Photon Emission Computed Tomography (SPECT) for Biological Target Localization

On-board imaging is useful for guiding radiation to patients in the treatment position; however, current treatment-room imaging modalities are not sensitive to physiology – features that may differentiate tumor from nearby tissue or identify biological targets, e.g., hypoxia, high tumor burden, or increased proliferation. Single photon emission computed tomography (SPECT) is sensitive to physiology. We propose on-board SPECT for biological target localization. Localization performance was studied in computer-simulated and scanner acquired parallel-hole SPECT images. Numerical observers were forced to localize hot targets in limited search volumes that account for uncertainties common to radiation therapy delivery.

Localization performance was studied for spherical targets of various diameters, activity ratios, and anatomical locations. Also investigated were the effects of detector response function compensation (DRC) and observer normalization on target localization. Localization performance was optimized as a function of iteration number and degree of post-reconstruction smoothing. Localization error patterns were analyzed for directional dependencies and were related to the detector trajectory. Localization performance and the effect of the detector trajectory were investigated in a hardware study using a whole-body phantom.

In conclusion, the potential performance characteristics of on-board SPECT were investigated using computer-simulation and real-detector studies. Mean localization errors < 2 mm were obtained for proximal, superficial targets with diameters > 14 mm and of 6:1 activity relative to background using scan times of approximately 5 minutes. The observed direction-dependent localization errors are related to the detector trajectory and have important implications for radiation therapy. This works shows that parallel-hole SPECT could be useful for localizing certain biological targets.

Lei Ren - DTS for image guided radiation therapy

Digital tomosynthesis (DTS) is a quasi-three-dimensional (3D) imaging technique which reconstructs images from a limited angle of cone-beam projections with shorter acquisition time, lower imaging dose, and less mechanical constraint than full cone-beam CT (CBCT). However, DTS images reconstructed by the conventional filtered back projection method have low plane-to-plane resolution, and they do not provide full volumetric information for target localization due to the limited angle of the DTS acquisition.

This dissertation presents the optimization and clinical implementation of DTS in image guided radiation therapy.

A hybrid multiresolution rigid-body registration technique was developed to automatically register reference DTS images with on-board DTS images to guide patient positioning in radiation therapy. This hybrid registration technique uses a faster but less accurate static method to achieve an initial registration, followed by a slower but more accurate adaptive method to fine tune the registration. A multiresolution scheme is employed in the registration to further improve the registration accuracy, robustness and efficiency. Normalized mutual information is selected as the criterion for the similarity measure, and the downhill simplex method is used as the search engine. This technique was tested using image data both from an anthropomorphic chest phantom and from head-and-neck cancer patients. The effects of the scan angle and the region-of-interest size on the registration accuracy and robustness were investigated. The average capture ranges in single-axis simulations with a 44° scan angle and a large ROI covering the entire DTS volume were between -31 and +34 deg for rotations and between -89 and +78 mm for translations in the phantom study, and between -38 and +38 deg for rotations and between -58 and +65 mm for translations in the patient study.

Additionally, a novel DTS reconstruction method using a deformation field map was developed to optimally estimate volumetric information of organ deformation for soft tissue alignment in image guided radiation therapy. The deformation field map is solved by using prior information, a deformation model, and new projection data. Patients’ previous CBCT data are used as the prior information, and the new patient volume to be reconstructed is considered as a deformation of the prior patient volume. The deformation field is solved by minimizing bending energy and maintaining new projection data fidelity using a nonlinear conjugate gradient method. The new patient DTS volume is then obtained by deforming the prior patient CBCT volume according to the solution to the deformation field. The method was tested for different scan angles in 2D and 3D cases using simulated and real projections of a Shepp-Logan phantom, liver, prostate and head-and-neck patient data. Hardware acceleration and multiresolution scheme are used to accelerate the 3D reconstruction. The accuracy of the reconstruction was evaluated by comparing organ volume, similarity and pixel value differences between DTS and CBCT images. Results showed that the respiratory motion in the liver patient, rectum volume change in the prostate patient, and the weight loss and airway volume change in the head-and-neck patient were accurately reconstructed in the prior based 60° DTS images. This new reconstruction method is able to optimally estimate the volumetric information in DTS images using 60-degree projections. It is both technically and clinically feasible for image-guidance in radiation therapy.