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Open Access Publications from the University of California

Scholarly Works (21 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2012)

Positron Emission Tomography (PET) systems designed specifically for small animal imaging have a unique set of requirements for successful operation. This work investigates a limited angle tomography microPET system, in contrast to conventional cylindrical systems. Initial studies included measurements of spatial resolution, uniformity, contrast-to-noise ratios, resolution recovery coefficients, and detector deadtime.

A subsequent investigation was performed to ascertain the use of Factor Analysis in mitigating artifacts caused by the limited angle tomography. Three separate studies were conducted: a dual-isotope experiment, a semi quantitative study, and mouse models. The results indicate potential use of Factor Analysis with possible limitations due to noise or uptake.

A more rigorous investigation into the limits of Factor Analysis was performed using Principal Component Analysis. Using the definitions of correlation and covariance matrices, the results of uniform phantom studies were used to measure uniformity, signal-to-noise ratio, and noise distribution. This analysis was applied to the limited angle tomographic system and a conventional cylindrical system. The results were insightful and in strong agreement with Poisson statistics.

Multimodality coregistration between systems was also performed using a rigid body least-squares transformation ("Horn's method"). Spherical phantoms were imaged to obtain calibration data within each system. In addition to deriving the transformation between a pair of systems, a metric was computed to estimate the error associated with the coregistration. Once computed, the transformation was applied to independently acquired mice studies from each pair of systems. The method proved fairly successful, and a number of improvements are suggested.

The rigid body nature of the transformation also allowed for a convenient method of measuring spatial linearity. Coregistration between synthetic grid-like images, and actual images of grid-like phantoms, were performed. The least-squares metric produced is used to determine spatial linearity. Grid-like phantoms were created using activity-infused ink in conjunction with a conventional inkjet printer. Each phantom was scanned on the limited angle tomography system. The results indicated a very high degree of spatial linearity.

Although motivated by limited angle PET, most of the methods employed may be used for other imaging modalities as well. These methods are statistical in nature, and may be similarly interpreted within various modalities. While the purpose of each study was different, the underlying mathematical concepts are common amongst most of them.

    Cover page: Performance Characterization, Image Processing, and Multimodality Coregistration of Small Animal Positron Emission Tomography Systems
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2011)
    In the last decade, PET-only systems have been phased out and replaced with PET-CT systems. This merger of a functional and anatomical imaging modality turned out to be extremely useful in clinical practice. Currently, PET-CT is a major diagnostic tool in oncology. At the dawn of the merger of MRI and PET, another breakthrough in clinical imaging is expected. The combination of these imaging modalities is challenging, but has particular features such as imaging biological processes at the same time in specific body locations.
      Cover page: Molecular imaging in oncology: the acceptance of PET/CT and the emergence of MR/PET imaging
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2019)
        Cover page: A good beginning with an uncertain future
        • Thesis
        • Peer Reviewed
        UCLA Electronic Theses and Dissertations (2022)

        One promising treatment option for metastatic castration-resistant prostate cancer is systemic radionuclide therapy targeting prostate-specific membrane antigen (PSMA). PSMA is a highly overexpressed protein on prostate cancer cells, but has low expression in normal organ tissues. Small molecule inhibitors of PSMA specifically bind to PSMA and can therefore be labeled with imaging or therapeutic isotopes to deliver the radiation directly to the site of cancer cells. When labeled with a therapeutic isotope, such as a beta- or alpha-emitter, PSMA ligands acts as a delivery vector for a lethal payload of radiation to cancer cells. This therapy is known as radionuclide therapy (RNT).

        The most commonly used therapeutic isotope in PSMA-targeted RNT is lutetium-177 (177Lu). Treatment response rates to 177Lu-PSMA RNT vary widely across treatment studies and patient cohorts from 30 to 70%. However, actinium-225 (225Ac), an alpha particle emitter, has emerged as a promising alternative isotope with favorable therapeutic decay properties. Alpha particles are of interest in RNT due to higher energy deposition over a shorter tissue penetration range, ostensibly causing more dense ionizations and inducing more DNA damage as compared with beta particles. While fewer clinical studies have been conducted with 225Ac-PSMA RNT, the studies so far report impressive response rates, particularly in chemotherapy-na�ve patients. Despite improved biochemical response in 225Ac-treated patients, this comes at the cost of higher-grade toxicities. Overall, PSMA RNT using either therapeutic isotope is not curative and even in those patients who do respond, the disease almost inevitably relapses. One possible explanation for treatment failure and disease relapse is that the tumor targets are not receiving a sufficiently high radiation dose necessary to kill the cancer cells.

        The current treatment paradigm is to treat with fixed activities for the same number of cycles at fixed intervals. However, treatment with a fixed activity neglects the fact that the mechanism of action of RNT is by radiation, and as such warrants radiation dose evaluation. To move away from a “one size fits all” approach to more individualized treatment, dosimetry can be used to devise safe therapeutic activities to deliver maximal tumor doses while delivering as low as achievable doses to non-target volumes.

        This dissertation addresses two overarching goals: i) to identify clinically relevant differences between 177Lu and 225Ac by incorporating dosimetry in translational RNT research, and ii) to evaluate the clinical dosimetry of imaging and therapy theranostic agents. The first specific aim uses various in vivo murine models of prostate cancer for the optimization of preclinical PSMA RNT exploring the effect of different therapeutic isotopes and targeting ligands relative to intervention time and lesion size. The second specific aim evaluates the clinical radiation dosimetry profile of two new imaging theranostic tracers. Finally, the third specific aim seeks to quantify the patient-specific absorbed doses in tumors and normal organs for therapeutic 177Lu and 225Ac PSMA RNT agents.

          Cover page: Advancements in Prostate-Specific Membrane Antigen Targeted Radionuclide Therapy Through Dosimetry
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2014)

          Unlabelled

          Absolute quantitation of myocardial blood flow (MBF) by PET is an established method of analyzing coronary artery disease (CAD) but subject to the various shortcomings of available radiotracers. Flurpiridaz F 18 is a novel PET radiotracer that exhibits properties of an ideal tracer.

          Methods

          A new absolute perfusion quantitation method with flurpiridaz was developed, taking advantage of the early kinetics and high first-pass extraction by the myocardium of this radiotracer, and the first-in-human measurements of MBF performed in 7 healthy subjects and 8 patients with documented CAD. PET images with time-activity curves were acquired at rest and during adenosine stress.

          Results

          In healthy subjects, regional MBF between coronary artery territories did not differ significantly, leading to a mean global MBF of 0.73 mL/min/g at rest and 2.53 mL/min/g during stress, with a mean global myocardial flow reserve (MFR) of 3.70. CAD vascular territories with <50% stenosis demonstrated a mean MBF of 0.73 at rest and 2.02 during stress, leading to a mean MFR of 2.97. CAD vascular territories with ≥50% stenosis exhibited a mean MBF of 0.86 at rest and 1.43 during stress, leading to a mean MFR of 1.86. Differences in stress MBF and MFR between normal and CAD territories, as well as between <50% and ≥50% stenosis vascular territories, were significant (P < 0.01).

          Conclusion

          Absolute quantitation of MBF in humans with the novel PET radiotracer flurpiridaz is feasible over a wide range of cardiac flow in the presence or absence of stress-inducible myocardial ischemia. The significant decrease in stress MBF and ensuing MFR in CAD territories allows a clear distinction between vascular territories exhibiting stress-inducible myocardial ischemia and those with normal perfusion.
            Cover page: Absolute Quantitation of Myocardial Blood Flow in Human Subjects With or Without Myocardial Ischemia Using Dynamic Flurpiridaz F 18 PET
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2020)
            Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer 68Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of 68Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUVmax/organ SUVmean). Results: At all time points, average SUVmax was highest in the liver. Tumor and organ SUVmean decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Conclusion:68Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.
              Cover page: Radiation Dosimetry and Biodistribution of 68Ga-FAPI-46 PET Imaging in Cancer Patients
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2015)
              Monte Carlo simulation provides a valuable tool in performance assessment and optimization of system design parameters for PET scanners. SimSET is a popular Monte Carlo simulation toolkit that features fast simulation time, as well as variance reduction tools to further enhance computational efficiency. However, SimSET has lacked the ability to simulate block detectors until its most recent release. Our goal is to validate new features of SimSET by developing a simulation model of the Siemens Biograph mCT PET scanner and comparing the results to a simulation model developed in the GATE simulation suite and to experimental results. We used the NEMA NU-2 2007 scatter fraction, count rates, and spatial resolution protocols to validate the SimSET simulation model and its new features. The SimSET model overestimated the experimental results of the count rate tests by 11-23% and the spatial resolution test by 13-28%, which is comparable to previous validation studies of other PET scanners in the literature. The difference between the SimSET and GATE simulation was approximately 4-8% for the count rate test and approximately 3-11% for the spatial resolution test. In terms of computational time, SimSET performed simulations approximately 11 times faster than GATE simulations. The new block detector model in SimSET offers a fast and reasonably accurate simulation toolkit for PET imaging applications.
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (1993)
                Using our recently reported whole body PET imaging technique, we performed whole body PET studies of the skeletal system with [18F]fluoride ion in 19 patients with a range of malignant and benign skeletal conditions and in 19 normal male volunteers. The technique produces two-dimensional projection images of the entire skeletal system ("a PET bone scan"), in addition to coronal, sagittal, and axial tomographic images of the skeletal system. The tomographic images had a 13% higher lesion detection sensitivity than the projection images. Whole body PET skeletal imaging with [18F]fluoride ion is technically feasible, provides images of excellent quality, and may be coupled with more quantitatively precise kinetic PET [18F]fluoride ion studies (over limited regions of the body) when numerical estimates of skeletal [18F]fluoride ion uptake are desired. The method is potentially useful in clinical applications where the high resolution and numerical precision of PET are of particular value (e.g., in accurately defining the anatomic location and extent of lesions and in assessing changes in bone metabolism on serial studies).
                  Cover page: Whole Body Skeletal Imaging with [18F]Fluoride Ion and PET
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2013)

                  Purpose

                  To quantitatively compare the accuracy of tumor volume segmentation in amplitude-based and phase-based respiratory gating algorithms in respiratory-correlated positron emission tomography (PET).

                  Methods and materials

                  List-mode fluorodeoxyglucose-PET data was acquired for 10 patients with a total of 12 fluorodeoxyglucose-avid tumors and 9 lymph nodes. Additionally, a phantom experiment was performed in which 4 plastic butyrate spheres with inner diameters ranging from 1 to 4 cm were imaged as they underwent 1-dimensional motion based on 2 measured patient breathing trajectories. PET list-mode data were gated into 8 bins using 2 amplitude-based (equal amplitude bins [A1] and equal counts per bin [A2]) and 2 temporal phase-based gating algorithms. Gated images were segmented using a commercially available gradient-based technique and a fixed 40% threshold of maximum uptake. Internal target volumes (ITVs) were generated by taking the union of all 8 contours per gated image. Segmented phantom ITVs were compared with their respective ground-truth ITVs, defined as the volume subtended by the tumor model positions covering 99% of breathing amplitude. Superior-inferior distances between sphere centroids in the end-inhale and end-exhale phases were also calculated.

                  Results

                  Tumor ITVs from amplitude-based methods were significantly larger than those from temporal-based techniques (P=.002). For lymph nodes, A2 resulted in ITVs that were significantly larger than either of the temporal-based techniques (P<.0323). A1 produced the largest and most accurate ITVs for spheres with diameters of ≥2 cm (P=.002). No significant difference was shown between algorithms in the 1-cm sphere data set. For phantom spheres, amplitude-based methods recovered an average of 9.5% more motion displacement than temporal-based methods under regular breathing conditions and an average of 45.7% more in the presence of baseline drift (P<.001).

                  Conclusions

                  Target volumes in images generated from amplitude-based gating are larger and more accurate, at levels that are potentially clinically significant, compared with those from temporal phase-based gating.
                    Cover page: A Comparison of Amplitude-Based and Phase-Based Positron Emission Tomography Gating Algorithms for Segmentation of Internal Target Volumes of Tumors Subject to Respiratory Motion
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2010)
                    Subcortical white matter is known to be relatively unaffected by amyloid deposition in Alzheimer’s disease (AD). We investigated the use of subcortical white matter as a reference region to quantify [18F]FDDNP binding in the human brain. Dynamic [18F]FDDNP PET studies were performed on 7 control subjects and 12 AD patients. Population efflux rate constants ( $$ {k\prime_2} $$ ) from subcortical white matter (centrum semiovale) and cerebellar cortex were derived by a simplified reference tissue modeling approach incorporating physiological constraints. Regional distribution volume ratio (DVR) estimates were derived using Logan and simplified reference tissue approaches, with either subcortical white matter or cerebellum as reference input. Discriminant analysis with cross-validation was performed to classify control subjects and AD patients. The population estimates of $$ {k\prime_2} $$ in subcortical white matter did not differ significantly between control subjects and AD patients but the variability of individual estimates of $$ {k\prime_2} $$ determined in white matter was lower than that in cerebellum. Logan DVR showed dependence on the efflux rate constant in white matter. The DVR estimates in the frontal, parietal, posterior cingulate, and temporal cortices were significantly higher in the AD group (p<0.01). Incorporating all these regional DVR estimates as predictor variables in discriminant analysis yielded accurate classification of control subjects and AD patients with high sensitivity and specificity, and the results agreed well with those using the cerebellum as the reference region. Subcortical white matter can be used as a reference region for quantitative analysis of [18F]FDDNP with the Logan method which allows more accurate and less biased binding estimates, but a population efflux rate constant has to be determined a priori.
                      Cover page: Quantitative analysis of [18F]FDDNP PET using subcortical white matter as reference region
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