Dissertation
Characterization of normal tissue injury development after 125I-plaque brachytherapy for uveal melanoma: a multimodal image-based approach
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006334
Abstract
Over half a million Americans receive radiation therapy as part of their cancer treatment each year. Within several years of their treatment, many of these patients will present with clinically-significant disorders, such as cardiomyopathy, pulmonary fibrosis, and cognitive decline. These injuries are classified as “normal tissue injury” due to their resulting from radiation exposure to the healthy tissues surrounding the targeted cancer tissue. Acute radiation damage to the microvascular endothelium (termed “radiation microvasculopathy”) is thought to eventually lead to a loss of capillaries, tissue ischemia, and, consequently, a loss of normal tissue function. Portions of this proposed sequence have been observed in vivo in preclinical models like rabbits and miniature pigs; however, to date, clinical data have been limited to descriptive studies of histopathology specimens or indirect indicators of poor perfusion or ischemia. While early perfusion defects and late loss of capillaries have been observed clinically using methods like laser Doppler and single photon emission computed tomography (SPECT), the use of radiotracers and radiographic imaging have made serial measurements within a single individual over time impractical. Furthermore, noninvasive methods capable of visualizing the microvessels with high enough resolution to simultaneously assess changes in both structure and function are currently missing. To effectively understand normal tissue injury development, especially the role of radiation microvasculopathy, new imaging modalities capable of assessing microvascular structure and function are needed. The purpose of this thesis work was to obtain an in-depth characterization of radiation microvasculopathy and its related pathologies in patients treated with radiotherapy for uveal melanoma, the most common primary intraocular cancer in adults. A cross-sectional cohort of 25 patients was assessed to test the hypothesis that radiation damage to the microvasculature precedes a loss of capillaries, neural tissue, and visual function in a dose- and time-dependent manner. Evidence for damage to the microvascular endothelium was identified by detecting vessel leakage and fluid accumulation in the retinal layers within the first 2 years from radiotherapy. During this same time period, decreases in blood flow compared to the contralateral, nonirradiated eye were observed. Importantly, these decreases in flow were observed before a loss of capillaries was detected. These early changes in blood flow and retinal layer thickness were followed by a loss of capillaries, thinning of the retinal tissue, and loss of visual function, indicative of ischemia and loss of normal tissue function.
To enable studies of radiation microvasculopathy in mice, complementary methods for detecting changes in retinal blood flow were established in a C57/Bl6J mouse model, in both normal control mice and in mice with angiotensin-II-induced hypertension. Additionally, methods for measuring blood flow in mice exposed to a light flicker stimulus, used to assess vasodilation during neurovascular coupling, were established to enable the development of a preclinical model of radiation microvasculopathy in mice. Together, these data suggest hemodynamic changes can be detected before a loss of capillaries and normal tissue function, and indicate a need for a longitudinal study to confirm this sequence of normal tissue injury development.
Details
- Title: Subtitle
- Characterization of normal tissue injury development after 125I-plaque brachytherapy for uveal melanoma: a multimodal image-based approach
- Creators
- Michelle Rossa Tamplin
- Contributors
- Isabella M Grumbach (Advisor)Randy H Kardon (Committee Member)John M Buatti (Committee Member)Daniel E Hyer (Committee Member)Douglas R Spitz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Free Radical and Radiation Biology
- Date degree season
- Autumn 2021
- DOI
- 10.17077/etd.006334
- Publisher
- University of Iowa
- Number of pages
- xvi, 155 pages
- Copyright
- Copyright 2021 Michelle Rossa Tamplin
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 138-155).
- Public Abstract (ETD)
After several years, many people treated with radiation for cancer therapy will develop other diseases in the areas surrounding their cancer that significantly reduce their quality of life. These disorders, such as heart disease seen after treatment for left-sided breast cancer, are known as normal tissue injury. Radiation damage to the small blood vessels (“microvessels”) is thought responsible for the development of these disorders. However, because they are so small, it is difficult to see the microvessels, observe how they respond to radiation, and evaluate their role in disease progression. Without this understanding, new strategies for preventing normal tissue injury cannot be developed.
The work of this thesis focuses on applying multiple imaging techniques to observe normal tissue injury development in patients with ocular melanoma. Using light-based, noninvasive imaging methods, we obtain detailed images of the microvessels and neurons responsible for vision in both the irradiated and fellow eyes of each patient. We obtain images in both eyes to account for potential, unrelated changes due to age, diabetes, or high blood pressure. When compared to each patient’s normal eye, we find early changes in blood vessels, such as decreased blood flow and vessel leakage; later on, we observe loss of visual function, neurons, and blood vessels. The techniques and analysis methods described here can be used in future studies to identify the time course for normal tissue injury development, to decide whether a patient needs to be treated with an intervention, and to develop new ways to prevent the damage from occurring.
- Academic Unit
- Free Radical and Radiation Biology Program
- Record Identifier
- 9984210944302771
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