Browsing by Author "Turkington, Timothy G"

The main objective of this dissertation research is to develop measurement and data-analysis tools for improving the quantitative accuracy of radiotracer studies of small plants, e.g., grasses in their early growth stages and tree seedlings. Improved accuracy is needed due to the thin nature of plant organs, e.g., leafs and stem. In addition, the methods developed in this thesis are applied to study the plant-environment interface of barley. Some of the approaches explored have potential to increase the statistical accuracy of counting data using PET imaging techniques. Improving the statistical precision of radionuclide tracking data will add to the analysis options. Another important goal is to measure the absolute photosynthetic rate. The standard approach in plant radiotracer experiments is to perform measurements of the relative distribution of radioactivity in various parts of the plant being studied. A limitation of this approach is that it does not take into account differences in the amount of radioisotope assimilated that are available for transport and allocation to the various sinks, that is, absolute CO2 uptake and photosynthetic rates are important factors in understanding the holistic physiological responses of plants to external conditions. For example, monitoring the movement of carbon-11 (11C) tagged carbohydrates in a plant requires an estimate of the average photosynthetic rate to determine the actual quantity of carbohydrates in each plant region (e.g. leaf, shoot, and root).

Radiotracing provides a method for real-time measurements of substance absorption, allocation and metabolic consumption and production in living organisms. Application of radioactive labelling in plants enables measurements associated with core physiological processes, e.g., photosynthesis, water uptake and nitrogen absorption and utilization. Plant uptake of radiotracers allows for tracking spatial and temporal distribution of substances, which enables studies of the plant-environment interface and the mechanisms involved in the allocation of resources (e.g., sugars, nutrients, and water). As such, these techniques are increasingly becoming an important tool for investigating the processes involved in the physiological responses of plants to changes in their local environmental conditions.

This dissertation has two major components: (1) development of experiment techniques for absolute photosynthetic rate measurements in plants using radio-isotope labeling, and (2) application of radioisotope tracing techniques to study the plant-environment interface in barley. The first component is covered in chapters one through three. The second component is presented in chapter four. An introduction into radio-tracing techniques is provided in chapter one. Chapter two describes radio-isotope production, radio-labelled compound preparation and delivery of labels to plant measurements. Chapter three outlines methods that can be employed to measure the absolute photosynthetic rate (µmol/m2/s) for a closed-loop system with [CO2] monitoring capabilities. Chapter four describes the background and results of our study on changing environmental conditions on a model system, barley seedlings. Chapter 5 will introduce the use of Monte-Carlo modeling for scaling the collected data to adjust the detected coincidence counts for losses due to positron escape from plant tissue. Chapter 6 describes the development of a novel imaging technique using direct positron detection that takes advantage of the high fraction of positrons escaping thin plant tissue.

In this dissertation, we have performed the most extensive measurements of carbohydrate allocation and translocation in a plant species using radio-isotope tracing techniques. A major practical limitation of studies based on radio-isotope labeling is the number of samples that can be measured in a single project. Our study on barley (Hordeum distichum) includes measurements on more than 30 plants. The short-lived radionuclide, 11C, was used to determine the real-time response to metabolite transport in barley. Sugars are photosynthesized and tagged with a positron-emitting radioisotope by flowing carbon dioxide (11CO2) tagged air over an active leaf. Data analysis of measurements taken in this dissertation indicates that the fraction of carbohydrates allocated to below ground sinks decreased, by 31% ± 9% in ambient [CO2] and by 37% ± 14% in elevated [CO2], when the nutrient conditions were rapidly changed from high to low nutrient.

Head motion during a Positron Emission Tomography (PET) brain scan can considerably degrade image quality. External motion-tracking devices have proven successful in minimizing this effect, but the associated time, maintenance, and workflow changes inhibit their widespread clinical use. List-mode PET acquisition allows for the retroactive analysis of coincidence events on any time scale throughout a scan, and therefore potentially offers a data-driven motion detection and characterization technique. An algorithm was developed to parse list-mode data, divide the full acquisition into short scan intervals, and calculate the line-of-response (LOR) midpoint average for each interval. These LOR midpoint averages, known as “radioactivity centroids,” were presumed to represent the center of the radioactivity distribution in the scanner, and it was thought that changes in this metric over time would correspond to intra-scan motion.

Several scans were taken of the 3D Hoffman brain phantom on a GE Discovery IQ PET/CT scanner to test the ability of the radioactivity to indicate intra-scan motion. Each scan incrementally surveyed motion in a different degree of freedom (2 translational and 2 rotational). The radioactivity centroids calculated from these scans correlated linearly to phantom positions/orientations. Centroid measurements over 1-second intervals performed on scans with ~1mCi of activity in the center of the field of view had standard deviations of 0.026 cm in the x- and y-dimensions and 0.020 cm in the z-dimension, which demonstrates high precision and repeatability in this metric. Radioactivity centroids are thus shown to successfully represent discrete motions on the submillimeter scale. It is also shown that while the radioactivity centroid can precisely indicate the amount of motion during an acquisition, it fails to distinguish what type of motion occurred.

Coincidence Timing Calibration (CTC) is an essential part of ensuring proper PET scanner function. The purpose of CTC is to account for timing differences in detector modules. The importance and precision in which this calibration needs to work is even more stringent for Time-of-Flight (TOF) PET. In this work, we looked to investigate the CTC process by which the TOF capable GE PET/CT Discovery-690 (D690) operates. Currently, it uses a 68Ge rotating pin source (RPS) to perform the calibration. The purpose of this work was to investigate the use of a centrally located source to perform the calibration. The timing resolution of the D690 was determined and used as a metric to evaluate both methods.

Two cylindrical 18F filled phantoms of 7.5 and 10 cm diameter were used to perform the CTC. The RPS and system table motion had to be disabled in order to use the centrally located sources in the CTC. All CTCs started with the default calibration file in place. Iterations of the CTC were performed until convergence of the calibration was observed on the review screen. Even after convergence, more iterations were performed for further analysis. At the end of the CTC with the centrally located sources, a follow-up iteration with the RPS was performed to see what adjustments would be made. Next, the timing resolution of the system was measured using a 68Ge line source. An apparatus with known locations to support the source allowed for the evaluation of the timing resolution off the central axis. The importance of this was that it allowed for non-centrally located lines of response to be evaluated. Furthermore, the timing resolution was measured with specific calibration files enabled that corresponded to particular iterations. In addition, a novel way of measuring the timing resolution (propagated method) for a particular calibration result without an actual measurement with that calibration enabled was developed and implemented. This greatly reduced the number of resolution measurements needed, which was particularly helpful for evaluating the improvement for each iteration.

The timing resolution of the system improved as more iterations were done. The difference between the propagated and measured timing resolution was under 2% most of the time. The cases in which the discrepancy was larger than 2% corresponded to one of the first iterations performed. After 15 iterations were performed for both centrally located scanners, the timing resolution of the system was measured through propagation to be 610 ps. The 15 iterations amounts to 15 minutes of acquisition time. After one iteration for the RPS, the timing resolution was measured to be 585 ps (587 ps in the propagated measurement). The single iteration of the RPS corresponded to 8 minutes of acquisition time. When following up the final iterations of the centrally located sources with the RPS, there was a change observed that improved the timing resolution to that measured after only one iteration of the RPS.

Conclusively, trends in the data showed that the centrally located sources did bring opposing detectors into good timing alignment with one another. These trends also indicated that the current CTC algorithm is not optimized for centrally located sources for the diameters tested. Finally, the method of propagating the change in calibration files illustrated a new CTC process method.

Nuclear resonance fluorescence (NRF) is a highly sensitive technique for measuring the energies and strengths of dipole excitations in nuclei. For incident photon energies below the particle separation threshold, excited nuclear states decay solely through gamma-ray emission, providing a unique de-excitation energy spectrum corresponding to the differences in energy between excited and final states. When excitation cross sections and transition energies are known, the presence (or absence) of a particular isotope within a sample can be determined and quantified. This dissertation describes the use of the NRF technique in two separate areas of active research: nuclear security and medical diagnostics.

In recent years, the nuclear security community has been seeking to develop new photon-beam based technologies for screening cargo for contraband and special nuclear materials (SNM), especially weapons grade material. However, because the current knowledge of dipole excitations in the actinides is highly limited, much greater study of the energy and strengths of dipole excitations in these isotopes is required, with particular focus on isotopes of uranium and plutonium. Nuclear resonance fluorescence studies using mono-energetic gamma-ray beams have previously been conducted at the High Intensity Gamma-Ray Source (HIS) facility at Triangle Universities Nuclear Laboratory (TUNL) on 235U [Kwa11], 238U [Ham12], and 232Th [Ade11]. Additionally, bremsstrahlung surveys below 3 MeV have been conducted at the Massachusetts Institute of Technology’s High Voltage Research Laboratory, examining dipole excited states in 239Pu [Joh07, Ber08] and 240Pu [Qui12].

The first portion of this dissertation provides details of our high-sensitivity measurements of the distribution of dipole excited states observed in 240Pu between 2–3 MeV using the linearly-polarized, quasi-monoenergetic photon beam at the HIS. Measurements were taken at eleven mean beam energies ranging from 1.95 to 2.95 MeV (in 100-keV steps). The target material was powdered plutonium oxide containing 4.65(8) g of 240Pu. Gamma rays corresponding to transitions between excited states in 240Pu were observed using high-purity germanium (HPGe) detectors. The narrow energy resolution of the HIS beam (e.g., E/E ~4% FWHM achieved using a 0.75" lead collimator) greatly reduced background from Compton scattering off the high-Z target material compared to bremsstrahlung measurements, improving the signal-to-noise ratio (SNR) of observed transitions and allowing the observation of low-intensity transitions that would otherwise be below detection threshold. The linear polarization of the HIS beam also allowed the determination of the parity of excited states based on differences in the polar and azimuthal angular distribution of the gamma rays emitted by the target. For each observed transition, the transition energy, partial integrated cross section, partial level width, and reduced transition probability for de-excitation were determined. The excitation energy, spin, parity, total integrated cross section, total level width, reduced transition probability for excitation, and ratio of the reduced transition probabilities (Rexp) were determined for each excited state. A total of 27 discrete transitions were observed from 14 excited states, of which 10 transitions were observed for the first time in the present experiments. Cross sections measured for ground-state decay were higher on average than those previously measured by Quiter et al., while those for 1st excited state decays were largely consistent with the prior measurements. All ground-state transitions were determined to be M1 in character.

The second portion of this dissertation involves measurements made to determine the feasibility of applying the NRF technique to medical diagnostics. Nuclear resonance fluorescence is a potentially valuable new tool for aiding in the diagnosis of medical conditions which cause the natural abundances of elements in the body to be altered. Evidence has been found for statistically significant asymmetries in certain trace element concentrations between healthy (benign) and malignant (cancerous) breast tissue. One of the elements for which a strong (> factor 2) asymmetry has been found is calcium [Riz84, Ng97, Raj06, Sil12]. A likely source of this asymmetry is differences in the calcium concentrations between the two principle forms of calcium containing minerals that comprise breast calcifications, calcium oxalate and calcium phosphate [Hak02]. Calcium oxalate (Type 1) calcifications generally occur in the form of calcium oxalate dihydrate (CaC2O4•2(H2O)) (also called Weddellite) and have been found to always be associated with benign breast tissue. Calcium phosphate (Type 2) calcifications in breast tissue are primarily composed of hydroxylapatite (Ca5(PO4)3(OH)) and are highly associated with malignancy [Win93, Sco17]. While the density of hydroxyapatite containing lesions is typically greater than calcium oxalate, it is not always possible to distinguish them with traditional mammography. A secondary procedure that could determine the isotopic composition of a calcification would be of benefit in reducing the number of biopsies to which patients are subjected.

The experiment was designed to test the feasibility of using the NRF technique to distinguish between calcium oxalate and hydroxylapatite through examination of known strong dipole transitions in calcium and phosphorus. The first part of the experiment involved benchmark measurements of the cross sections of the strongest recorded NRF transitions from excited states in 40Ca (Ex = 10318.8(4) keV) and 31P (Ex = 7141.1(18) keV) using bulk samples of calcium oxide and red phosphorus, respectively. Cross sections for non-ground state transitions from these excited states as well as transitions from additional excited states populated during the experiment were also measured. The cross sections measured for ground-state transitions from the principally targeted states in calcium and phosphorus were consistent with previously published values, and the uncertainty in these cross sections was decreased. Other transition cross sections measured were mostly in agreement with the published values.

For the second part of the experiment, three cylindrical PRESAGE® radiochromic dosimeters, containing either calcium oxide or calcium hydroxylapatite targets were irradiated with the photon beam at the HIS targeting the same transitions in calcium and phosphorus as during the bulk measurements. The goal of these measurements was to determine the ability to distinguish between calcium oxalate and hydroxylapatite calcifications contained in a tissue-simulating medium as well as to determine the corresponding detection limits for calcium and phosphorus. PRESAGE® material was chosen due to its ability to provide 3D depth-dose information as well as effectively mimicking the photon scattering properties of human tissue. The dosimeters were irradiated for sufficient time so as obtain a dose of several grays (Gy) or higher in regions of interest in order to provide a strong signal for post-irradiation optical scanning. Experimentally measured depth-dose curves were then compared to simulated values. The two calcium compounds contained in the PRESAGE® material were able to be clearly distinguished via the strong counting asymmetry observed. The best detection limit for calcium achieved was 99.0(15)(49) mg/cm2 using a single HPGe detector and 73.5(8)(36) mg/cm2 for two HPGe detectors. Likewise, a minimum detection limit (MDL) for phosphorus of 45.6(5)(20) mg/cm2 was achieved using a single HPGe detector and 34.8(3)(15) mg/cm2 for two HPGe detectors. These MDLs were determined to be sufficient for detection of 1 mm hydroxylapatite calcifications in tissue by both calcium and phosphorus detection. The corresponding doses to tissue for photon beams that will likely be available in the near future (e.g., 0.1% FWHM energy resolution) are too high for consideration of NRF-based breast screening in the near term. Minimum detection limits will have to be lowered further and detector system efficiencies increased substantially before in vivo diagnostics becomes viable.

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.

It is well known that PET performance and image quality degrade as body size increases, and epidemiological studies over the past two decades show that the adult US population's body size has increased dramatically and continues to increase. Larger patients have more attenuating material that increases the number of emitted photons that are scattered or absorbed within the body. Thus, for a fixed amount of injected radioactivity and acquisition duration, the number of measured true coincidence events will decrease, and the background fractions will increase. Another size-related factor, independent of attenuation, is the volume throughout which the measured coincidence counts are distributed: for a fixed acquisition duration, as the body size increases, the counts are distributed over a larger area. This is true for both a fixed amount of radioactivity, where the concentration decreases as size increases, and a fixed concentration, where the amount radioactivity increases with size.

Time-of-flight (TOF) PET is a recently commercialized technology that allows the localization, with a certain degree of error, of a positron annihilation using timing differences in the detection of coincidence photons. Both heuristic and analytical evaluations predict that TOF PET will have improved performance and image quality compared to non-TOF PET, and this improvement increases as body size increases. The goal of this dissertation is to parameterize the image quality improvement of TOF PET compared to non-TOF PET as a function of body size. Currently, no standard for comparison exists.

Previous evaluations of TOF PET's improvement have been made with either computer-simulated data or acquired data using a few discrete phantom sizes. A phantom that represents a range of attenuating dimensions, that can have a varying radioactivity distribution, and that can have radioactive inserts positioned throughout its volume would facilitate characterizing PET system performance and image quality as a function of body size. A fillable, tapered phantom, was designed, simulated, and constructed. The phantom has an oval cross-section ranging from 38.5 × 49.5 cm to 6.8 × 17.8 cm, a length of 51.1 cm, a mass of 6 kg (empty), a mass of 42 kg (water filled), and 1.25-cm acrylic walls.

For this dissertation research, PET image quality was measured using multiple, small spheres with diameters near the spatial resolution of clinical whole-body PET systems. Measurements made on a small sphere, which typically include a small number of image voxels, are susceptible to fluctuations over the few voxels, so using multiple spheres improves the statistical power of the measurements that, in turn, reduces the influence of these fluctuations. These spheres were arranged in an array and mounted throughout the tapered phantom's volume to objectively measure image quality as a function of body size. Image quality is measured by placing regions of interest on images and calculating contrast recovery, background variability, and signal to noise ratio.

Image quality as a function of body size was parameterized for TOF compared to non-TOF PET using 46 1.0-cm spheres positioned in six different body sizes in a fillable, tapered phantom. When the TOF and non-TOF PET images were reconstructed for matched contrast, the square of the ratio of the images' signal-to-noise ratios for TOF to non-TOF PET was plotted as a function, f(D), of the radioactivity distribution size, D, in cm. A linear regression was fit to the data: f(D) = 0.108D - 1.36. This was compared to the ratio of D and the localization error, σ_d, based on the system timing resolution, which is approximately 650 ps for the TOF PET system used for this research. With the image quality metrics used in this work, the ratio of TOF to non-TOF PET fits well to a linear relationship and is parallel to D/σ_d. For D < 20 cm, there is no image quality improvement, but for radioactivity distributions D > 20 cm, TOF PET improves image quality over non-TOF PET. PET imaging's clinical use has increased over the past decade, and TOF PET's image quality improvement for large patients makes TOF an important new technology because the occurrence of obesity in the US adult population continues to increase.

Gallium-68 labeled compounds have shown an important role in PET imaging of detecting neuroendocrine tumors and prostate tumors. As the prostate exists near the bladder, image quality of prostate tumors can be challenged by radioactivity concentration accumulated in the bladder. Previous studies have shown that activity measurements within 4 cm distal to the bladder were more affected by its higher 〖^18〗F concentration and improved with time of flight (TOF) technique. The aim of this research is to understand and compare the effects of 〖^68〗Ga and 〖^18〗F activity concentration on evaluation of structures closer to the bladder, and compare it for different scanners, acquisition modes and reconstruction techniques.

Methods: A bladder insert was placed in the center of an oval phantom with radioactivity at three different bladder-to-background ratios: 1:1, 40:1 and 80:1. Twelve 1-cm spheres representing 8:1 small lesions were symmetrically located in two axial planes, all with 1.2 cm distance to the bladder surface. The whole phantom was scanned on both the GE Discovery 690 and GE Discovery IQ, filled with 〖^18〗F and 〖^68〗Ga separately. In addition to default reconstruction settings, images were also reconstructed with nTOF and TOF modes on D690, and OSEM and REG modes on DIQ. The same ROIs were applied to all these images.

Results: Radioactivity in the bladder resulted in worse visualization and quantitation of the small spheres. The value difference among the 12 spheres became greater, and the lesion-to-background ratio were also affected by high bladder activity. The lesion value could be overestimated to be about three time as much as, or underestimated by 50% at most of its true measurement. The greatest difference was seen when the bladder was filled with 〖^68〗Ga. Both TOF and REG modes provided better lesion value variations compared with nTOF/OSEM reconstruction. Image contrast was significantly improved with more iterations.

Conclusions: Radioactivity of 〖^68〗Ga in the bladder has a similar but more serious effect than 〖^18〗F in the value measurements of surrounding structures. Greater measurement variations occur with higher bladder activity concentration. Iterative reconstruction with TOF information or REG reconstruction can be used to improve image quality, otherwise more iterations are recommended.

The use of Positron Emission Tomography (PET) has been suggested as a tool for quantitative biological measurement to determine outcomes of therapy, diagnosis, and novel drugs, through measures of tumor change from repeated PET scans. However, inherent variability (due to technical and biological effects) results in different measurements even where there is no change in the tumor. This study evaluates the random component of variability due to the limited number of counts acquired in the scans. We have proposed using PET raw list mode data as a way to determine the variability associated with the scanner, including the nonlinear processes like the max standard uptake value (SUVmax) and iterative reconstruction processes. PET simulation (digitally simulated oval phantom), PET list mode whole body (WB) and tapering phantom (TP) data in addition to clinical data (prostate cancer patients) were used to divide a larger acquisition into sequentially smaller half scan durations to compare their variabilities with the ideal Poisson variability in a PET system. Poisson statistics predicts that variability decreases as 1/sqrt(n) of the number of counts (or scan duration).

The WB phantom contained 21 spheres (six 3 cm, six 2 cm, nine 1 cm), the TP contained spheres (thirty-two 1 cm spheres and twenty-four 2 cm spheres) distributed over four levels. Simulated data was used as an ideal scenario with larger statistical power, and showed excellent agreement (<10%) with its Poisson calculation using 4 mm

of smoothing. Through the use of simulation and phantom data variability among measurements using SUVmax have been shown. This data has demonstrated that maximum ROI methodology on iteratively reconstructed images retains the Poisson nature of PET coincidence counts in spite of the potential nonlinearities of both the reconstruction method and the ROI methodology.

In addition to traditional iterative PET reconstruction methods like OSEM, some new algorithms take into account resolution recovery and regularization, has gradually gained attention. Comparing and evaluating these reconstruction methods has become an important issue. The phantom in this research contains a large anthropomorphic chamber and spheres with diameter in 1 cm and 2 cm injected with fluorine-18 radionuclide. To perform the reconstruction, different algorithms are applied from the scanner manufacturer’s software: (1) Time-of-flight (TOF) (2) Non-time-of-flight (NTF) (3) SharpIR (4) Q.Clear. Data is obtained from three PET scanners, and different number of iterations is considered for each algorithm. Three different definitions of noise are measured to assess the quality of the PET images: (1) Image roughness (IR), (2) Background variability (BV) and (3) Ensemble noise (EN). As observed from the noise-contrast plots, images reconstructed with time-of-flight, resolution recovery (SharpIR) and regularization algorithm (Q.Clear) usually lead to better contrast with lower noise. However, for OSEM images without resolution recovery, more iterations (greater than 5) do not necessarily result in higher quality. On the contrary, the image quality will decline because the contrast is almost unchanged, while the noise increases rapidly

The Standardized Uptake Value (SUV) is a method for semiquantitative evaluation of radiotracer accumulation on PET scans. Changes in SUV can be used to determine treatment response. However, SUV measurements are influenced by a variety of biological and technological factors, including image reconstruction parameters.

There are other semiquantitative metrics used in PET that relate to the total metabolic activity of a tumor. Current metrics of this type (e.g., Total Lesion Glycolysis) use a combination of SUV and an object volume. Such concentration-based metrics may not capture all radioactivity of an object. We propose a more direct method to assess total radiotracer uptake (TRU): the total radioactivity in a large VOI is measured and background is subtracted.

Phantom studies were performed to assess the effect of image reconstruction parameters on SUV, and to compare the TRU with concentration-based metrics. Patient images were evaluated to estimate the percent error of the TRU metric in imaging of humans.

Methods:

A whole body phantom with 1 cm hot spheres was scanned with a GE Discovery 690 PET/CT scanner, with time of flight (TOF) capability. Data were reconstructed several different ways to examine the effect of image matrix size, amount of smoothing, field of view (FOV) size, TOF vs. non-TOF reconstruction, iterations of reconstruction algorithm, and image matrix shift on SUV.

An additional whole body phantom was scanned on the same system to compare the accuracy and variability of the new TRU metric with existing measures.

Results:

Reconstruction parameters had substantial effects on SUV for 1 cm spheres. Varying the FOV from 35 to 70 cm produced an 11% change in average normalized SUV. Changing the image matrix size from 128x128 pixels to 256x256 pixels produced an 5.3% difference. Shifting the image matrix produced up to a 12% change in SUV. TOF vs. non-TOF reconstruction resulted in up to a 29% difference in SUV for two iterations.

The TRU method was more accurate than TLG and SUV for all sphere types in images with 0 mm to 10 mm of smoothing. Mean errors of TRU were between 1-12%. The TRU method was less variable than TLG in unsmoothed images with acquisition lengths of 1, 2, and 4 minutes. Coefficients of variation were between from 2-17% for TRU measurements, compared to 5-19% for TLG measurements. Simulation of TRU applied to human images shows potential error from 10-18% for 10:1 lesions 1-4 cm in diameter.

Conclusions:

Changes in image reconstruction parameters could significantly influence the SUV for small, 1 cm lesions. These effects are reduced for larger, 2.5 cm lesions.

TRU can accurately quantify small lesions in a phantom study. In some cases, TRU is less variable than TLG and SUV. Computer simulations of error in TRU when applied to human studies show low percentage errors for realistic tumor contrasts and volumes.

Quantitative measurements in PET imaging have recently become more widespread as a way to diagnose and stage many types of malignant cancer. Currently patients need to have follow-up scans performed on the same PET system due to technical factors. Multi-clinic studies using quantitative PET measurements are also confounded by these technological factors. This work aims to evaluate the use of commonly available phantoms to cross-calibrate processing parameters to equalize small lesion quantitation. The method was verified using an abdomen phantom with small hot sphere inserts, as well as a smaller phantom with small hot sphere inserts.

Methods: A GE Discovery 690 and STE were used. Both time-of-flight (TOF) and non-TOF images were used from the D690. Jaszczak phantoms with hot rod and cold rod inserts were scanned on both systems consecutively for 20 minutes. Images were reconstructed with a range of iterations and post-smoothed (PS) with 2-10 mm of smoothing. Automated analysis of the images used the CT images to find rods and then calculate a rod to background ratio for each rod sector, PET image variant, and scanner. A target rod contrast could then be chosen and parameters determined for both systems separately to equalize rod contrast. Iteration-based resolution control and PS were both evaluated. To verify, an abdomen phantom was filled with a low background activity and ten 10-mm diameter spheres filled with FDG and CT contrast. In order to evaluate any size dependence, six 10-mm diameter spheres filled with FDG and CT contrast were placed inside a Jaszczak container filled with low background activity. An automatic CT-based analysis of the spheres was performed, obtaining mean and maximum values across the spheres.

Results: Small sphere quantitation differed substantially for similar processing between systems. However, sphere quantitation matched well when cross-calibrating the DSTE and non-TOF D690 Jaszczak phantom images by independently limiting iterations. Doing the same process with post-smoothing yielded similar results, with high iteration PS performing slightly better than PS at iterations used clinically at Duke for twenty-minute scans. Equalizing TOF images from the D690 with DSTE images with spheres placed in an abdomen phantom resulted in relatively poor correlation, but correlated well with spheres placed inside the Jaszczak phantom. Shorter scan durations behaved similarly to the twenty-minute scans.

Conclusions: Both Jaszczak phantoms worked well for cross-calibrating processing parameters to equalize quantitation in small lesions for non-TOF imaging. Iterations and PS could both be used to control resolution. It appears the best method is to use PS to fine-tune the resolution. The size dependence of TOF, and PET in general, seems to be an issue.

Positron Emission Tomography with 18F-FDG can be used as a predictor for post-therapeutic tumor response in rectal and gynecologic cancers. An issue with assessing lesions in the vicinity of the bladder is the radioactivity that accumulates in the bladder due to constant filling. SUV analysis is used to discriminate between therapy responders and non-responders based on percentage change/threshold, but it is not yet known how much variability can be attributed to the bladder radioactivity. The purpose of this research is to understand the effects of bladder radioactivity on surrounding concentration measurements with different scanning and image reconstruction techniques.

Methods: ROI analysis was performed on 67 PET scans from DUMC. Typical values of bladder volume, radioactivity, radioactivity concentration and bladder-to-background uptake ratio were determined and incorporated into phantom studies. A bladder phantom insert was created for a 25 L torso phantom to explore effects of a bladder in the center of the FOV, on the edge of the FOV, and outside the FOV on the GE Discovery STE. The bladder insert was also used in a phantom study to assess the effects of different, realistic bladder radioactivity levels on surrounding 1-cm lesions on both the GE Discovery STE and GE Discovery 690. Background activity and in-air environments were explored, as well 2D, 3D and time-of-flight PET acquisitions with different image reconstruction techniques.

Results: The DSTE 2D PET data suffered large void artifacts that worsened as radioactivity in the bladder increased. The DSTE 3D PET data over-estimated background measurements up to 30 slices with the bladder outside the FOV. Concentration measurements within 4 cm distal to the bladder showed great variability and were generally recovered best with TOF PET or 3D PET with an increased number of iterations. Lesions greater than 4 cm distal to the bladder showed consistent recovery in both the 3D and TOF PET data.

Discussion: Radioactivity within the bladder has substantial effects on surrounding radioactivity concentration measurements. There are limits to the measurements of the radioactivity concentration values used in SUV analysis in the vicinity of the bladder.

A general theme is that more accurate results are produced with smaller amounts of radioactivity in the bladder. This validates the DUMC protocol that begins acquisition just below the pelvic area to reduce as much filling as possible and highlights the usefulness of patient voiding prior to scanning.

X-ray computed tomography (CT) forms the basis for attenuation corrected positron emission tomography (PET) using combined PET/CT scanners. With concerns of high radiation exposure to patients through widespread use of CT, the lowest photon flux that will provide uniform attenuation correction for PET to within 5% over a range of body sizes was investigated. Additionally, clinical uniformity measurements are performed on a uniform phantom, but their results may not be applicable as an estimate of error of hot lesions. PET simulations of variability and localized error were performed with and without hot lesions using a tapering phantom. Images were reconstructed using a variety of fixed and modulated tube-current CT scans and various levels of scatter correction. A physical phantom was designed and scanned to augment the simulation results. Attenuation correction of uniform images was within 5% error when using 120 kVp using a noise index of 50 and 140 kVp using a noise index of 50 for all phantom sizes. Variability with hot lesions was within 5% for scans using 120 kVp and greater than 24 mAs for 21.9 cm and 31.7 cm effective diameters and greater than 48 mAs for 38.5 cm effective diameter. Variability was worse in the background than on hot lesions for poor attenuation correction and poor scatter correction cases. Background error overestimates the error in hot lesions when attenuation correction is biased. Variability was within 5% when estimation of scatter magnitude was within 20% of its true value both with and without hot lesions. Errors in background due to under and overcorrected scatter lead to an over and underestimate of hot lesion errors, respectively. Physical phantom uniformity was within 5% when using 120 kVp and 10 mAs, albeit with a much smaller phantom size. The background error and its underestimation of lesion error was also measured in the physical phantom.

Purpose: Our primary goal was to examine the effect of PET image reconstruction parameters on baseline and early-treatment FDG-PET/CT quantitative imaging. Early-treatment changes in tumor metabolism in primary tumor and nodes can potentially determine if the patient is responding to therapy, but this assessment can change based on the reconstruction parameters. We investigated the effect of the following reconstruction parameters: number of Ordered-Subset-Expectation-Maximization (OSEM) iterations, post-reconstruction smoothing, and quantitative metrics (SUV-max, SUV-mean, SUV-peak).

A concurrent investigation explored in detail the sampling parameters of SUV-peak by way of a Monte Carlo digital phantom study. SUV-peak was proposed as a compromise between SUV-max and SUV-mean, in hope to retain key attractive features of these two metrics (inter-physician independence of SUV-max, noise-averaging of SUV-mean) but reduce unwanted errors (noise dependence of SUV-max, contour-dependence of SUV-mean). Sampling parameters have vaguely been defined, in particular, the scanning resolution (i.e. 1 voxel, 1/2 voxel, 1/4 voxel, etc.) of the SUV-peak spherical ROI . We examined the role that partial-voxel scanning plays in tumor SUV recovery in both noise-free and realistic OS-EM noise environments.

Materials and Methods: The response assessment investigation involved 19 patients on an IRB-approved study who underwent 2 baseline PET scans (mean-separation = 11 days) prior to chemoradiotherapy (70 Gy, 2 Gy/fraction). An intra-treatment PET scan was performed early in the course of therapy (10-20 Gy, mean = 14 Gy). The images were reconstructed with varying OS-EM iterations (1-12) and Gaussian post-smoothing (0-7 mm). Patients were analyzed in two separate groups, distinguished by the PET/CT scanner used to acquire data: (1) GE Discovery STE; and (2) Siemens Biograph mCT. For each combination of iterations and smoothing, Bland-Altman analysis was applied to quantitative metrics (SUV-max, SUV-mean, SUV-peak) from the baseline scans to evaluate metabolic variability (repeatability, R = 1.96&sigma). The number and extent of early treatment changes that were significant, i.e., exceeding repeatability, was assessed.

An original SUV-peak algorithm was developed, which measures SUV-max and SUV-peak for as small as 1/32 voxel scanning. Two rounds of digital phantoms were generated for the SUV-peak investigation. First, 10,000 spherical tumors were generated at a random matrix location for each diameter 1-4 cm and smoothed with an isotropic Gaussian, FWHM = 0.8 cm, then evaluated using the SUV-peak algorithm. Next, realistic body-sized phantoms were generated with background activity, and 1,000 spherical tumors of activity 4 time the background for each diameter (1-4cm) were placed inside (8 tumors per phantom, location randomized within certain constraints). These images received realistic corrections in projection space for attenuation, spatial resolution, and noise, were reconstructed with an in-house OS-EM algorithm, and then assessed using the SUV-peak algorithm. The mean recovered activity above background and its coefficient of variation were calculated for all metrics for each tumor size, for both simulations. For the realistic noise simulation, various levels of Gaussian smoothing was applied post-reconstruction, the effects summarized in plots showing coefficient of variation vs. mean recovered activity above background - a comparison of the effectiveness of SUV-max and SUV-peak.

Results: For the GE Discovery STE 2D cases averaged over all metrics (SUV-max, SUV-mean, SUV-peak) and structures (GTV, LN), repeatability, R, improved with increasing smoothing and decreasing iterations. Individually, SUV-mean repeatability was less affected by the number of iterations, but demonstrated the same relationship with smoothing. SUV-mean outperformed SUV-max and SUV-peak with regards to the number of cases exceeding repeatability, N. Considering R, N, and the sum of relative metric change outside repeatability, &Omega, averaged over all metrics and all structures, and normalized, several combinations of reconstruction parameters produced five optimal combinations above set thresholds: 1 iteration with 0.1-3.0 mm smoothing; and 2 iterations with 2.0-3.0 mm smoothing. Current GE 2D reconstruction protocol for HN cases uses 2 iterations and 3.0 mm post-smoothing, which lies on the edge, but within these recommendations.

The relationship between repeatability and number of iterations for the 3D cases was more complex; SUV-max demonstrated the best repeatability with 2 iterations, with both SUV-mean and SUV-peak reaching the best repeatability with 4 iterations. The same dependence on smoothing was noted, i.e. increased smoothing gives lover (desirable) repeatability. SUV-mean once again outperformed SUV-max and SUV-peak with regards to the number of cases exceeding repeatability, N. The calculations of N and &Omega averaged over all metrics were limited severely by the low number of cases, damaging the statistical significance of the following recommendation. Three optimal combinations with averaged and normalized R, N, &Omega, above a set threshold are recommended as most effective reconstruction parameter combinations: 4 iterations with 2.0-4.0 mm smoothing. Current Siemens 3D reconstruction protocol for HN cases uses 4 iterations and 3.0 mm post-smoothing, which lies within these recommended parameters. However, no statistically significant conclusions could be drawn from this analysis for this scanner, and performing similar data analysis on a larger patient pool is proposed.

The minimum spherical tumor diameter required for full recovery was 3.0-3.5 cm for SUV-peak, and 2.5-3.0 cm for SUV-max. SUV-max was found to overestimate the recovered value of tumors by up to 46% (vs. 10% for SUV-peak); above the minimum diameter for full recovery, SUV-peak values were significantly closer to actual tumor activity. Considering only the realistic noise tumors, the coefficient of variation for SUV-max ranged from 5.5-17.7%, whereas for SUV-peak these values were lower, 2.7-13.2%. Partial-voxel scanning did not substantially affect the coefficient of variation (<0.2%). Comparison of coefficient of variation vs. mean recovered value demonstrated that SUV-max with additional Gaussian smoothing outperforms SUV-peak by up to 0.8% for 1 cm tumors and 0.2% for 4 cm tumors. Other tumor sizes showed little difference between the two metrics.

Conclusion: For patients scanned on the GE Discovery STE using the HN protocol (2D acquisition mode), images reconstructed for quantitative analysis may benefit from a low number of OS-EM iterations (≤ 2). Some post-reconstruction smoothing proved to be beneficial (1.0 mm ≤ FWHM ≤ 3.0 mm), however, over-smoothing for the sake of more qualitatively appealing images or improved image quality metric (e.g. SNR, CNR) may prove detrimental to quantitative response assessment analysis. Our results for the Siemens Biograph mCT using the HN protocol (3D acquisition mode) demonstrated favor towards 4 iterations and limited range of smoothing (2.0 mm ≤ FWHM ≤ 4.0 mm). These results are statistically limited, further cases are necessary for any conclusive recommendations on reconstruction parameters.

SUV-peak was shown to reduce uncertainties associated with quantitative PET image analysis when compared directly to SUV-max. Above the minimum tumor diameter required for full recovery, SUV-peak also provides a better estimate of the actual tumor activity. However, initial comparisons of SUV-peak and SUV-max over various levels of additional Gaussian smoothing found SUV-max more favorable. Partial-voxel scanning of SUV-peak did not reduce the metric's coefficient of variation in images with realistic noise. Therefore, a phantom investigation is proposed to compare SUV-peak and SUV-max of real scanned images with various levels of post-smoothing, which may conclusively eliminate the need for SUV-peak.

Positron Emission Tomography is a coincidence-detection-based nuclear imaging modality that has increased in clinical prevalence over the last two decades. Measures have recently been taken to improve the practice, specifically the synergistic combination with CT, and implementation of iterative reconstruction. The time-of- flight (TOF) technique is another improvement theorized early in PET development, which reduces image noise by measuring the difference in coincident photon detection times. It was difficult to implement at the time of inception because of limited technologies, but better detectors and electronics have recently made TOF feasible for clinical use. Its gain in image quality has been measured by various methods, but is difficult to quantify because of tradeoffs inherent in count-based imaging. This work set out to investigate the image quality gained with TOF imaging by determining the effective non-TOF scan time required to achieve equivalent image quality as TOF.

Methods: We used the TOF-capable GE Discovery 690 PET/CT scanner with ~600 ps timing resolution to acquire high-count list-mode data of hot spheres, cold bottles, and a novel low-contrast bead insert housed in three phantoms of increasing diameters. These data were reconstructed with and without TOF information into shorter images of 30 sec, 1, 2, 4 and 8 min, using the OS-EM reconstruction algorithm with 16 subsets and 1, 2, 3, 5 and 10 iterations each. Up to 16 replicates of each image were produced. Regions of interest were drawn on the high-count images and subsequently applied to all images in each set. These data were averaged across the replicate image sets for statistical power and were used to calculate contrast, background variability and replicate variability for regions within each phantom scan. Background variability was measured as the standard deviation of 1 cm ROI means spread throughout the background, while replicate noise was measured as the pixel deviation across replicated images. The contrast for each unique phantom region and scan time were plotted versus the two noise measures, and a unique quantification method was devised to calculate the scan time equivalent for images reconstructed with TOF versus those without.

Results: Visual evaluation showed universal improvement in image quality. Hot spheres were more easily resolved, cold regions were colder, and the low-contrast phantom became clearer overall. Gains were also higher as a function of phantom size. Plotting contrast versus the two variability measures demonstrated greater gains for larger phantoms than small.

The quantification method delivered easily interpretable results that correlated with visual and graphical evaluation. Hot spheres showed between 1.6× and 2.5× scan time gain factor, while cold bottles showed between 3.8× and 4.3× gain, when measuring background variability as the noise component. Three areas of the low- contrast insert were considered, and showed results generally lying between those of the cold and hot inserts, with one exception demonstrating 9.15× and 10.35× gains for the background and replicate variability measures, respectively.

Measuring gains using the replicate noise demonstrated similar quality gain as the background variability.

Conclusions: The results of this work agree with previous studies stating that TOF information contributes significantly to PET image quality when utilized during reconstruction, specifically for hot lesions and cold regions. This was shown visually, graphically, and quantitatively. The unique quantification method devised, which uses image quality plots to generate gain factors in terms of equivalent non-TOF scan time, was successfully implemented and yielded relatively consistent results. The new phantom insert developed to mimic lower-contrast regions present in human abdominal images was successfully imaged, showing a 1.3× to 4.2× overall gain in equivalent scan time across all phantom sizes.

Trends were observed in several aspects of these results that may subjugate TOF quality gain even further. Cold areas recover better than hot lesions, as expected, but low-contrast areas show varying levels of TOF improvement, and tend to lie between those demonstrated for hot and cold regions.

Finally, similar results were found when considering background variability and replicate variability noise measures, which can be considered further validation of the image quality results.