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Intraoperative tumor margin detection using nanoparticles: protocol optimization through kinetic modeling
Title
Intraoperative tumor margin detection using nanoparticles: protocol optimization through kinetic modeling
Creator
Xu, Xiaochun
Date
2018
Description
Clear margins (no tumor on the surface of the resected tissues) is essential to minimize tumor recurrence and prolong survival for wide local...
Show moreClear margins (no tumor on the surface of the resected tissues) is essential to minimize tumor recurrence and prolong survival for wide local excision cancer surgeries. However, standard methods of margin assessment cannot be carried out within the time frame of surgery (meaning patients with positive margins are suggested to undergo call-back surgeries). Intraoperative molecular imaging of cell surface receptors can offer a solution; however, substantial nonspecific diffusion and retention of imaging agents in resected tissues remains a significant challenge to identifying cancer reliably. Recently, “paired-agent” methods—which employ co-administration of a control-imaging agent with a targeting agent—have been applied to thick-sample staining and rinsing applications to account for background staining. This dissertation aimed to optimize paired-agent molecular imaging tumor-to-healthy tissue discrimination through mathematical modeling.Two simplified mathematical models—the rinsing paired-agent model (RPAM) and the serial staining model (SSM)—were derived and tested in accurate simulation models (also developed as a component of this dissertation,) and in preclinical cancer models. More specifically, RPAM was demonstrated to be capable of providing more accurate estimates of receptor concentration than more standard “ratiometric” methods (essentially dividing the targeted agent signal by the control agent signal), and the model was insensitive to the variability of rinsing time from one image to the next. Though it was noted in experiments, that regardless of the approach taken, a very large fraction of signal was removed upon the first rinse, leading to large “gaps” in the data that would be available to RPAM. The SSM, on the other hand, provided a model that could be applied to serial staining data, which yielded a more gradual change in signal between imaging.Considering the multidimensional complexity of paired-agent topical tissue molecular imaging (with diffusion, imaging agent chemical/binding properties, tissue staining, rinsing, imaging, and data analysis protocols all being subject to alteration), thorough optimization margin analysis imaging protocols is untractable using experiments alone. Therefore, a salient feature of this dissertation was the development and validation of a “forward” mathematical diffusion and binding model for in silico testing of proposed paired-agent staining and rinsing protocols in thick tissue.
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Quantification of Vascular Permeability in the Retina Using Fluorescein Videoangiography Data as a Biomarker for Early Diabetic Retinopathy
Title
Quantification of Vascular Permeability in the Retina Using Fluorescein Videoangiography Data as a Biomarker for Early Diabetic Retinopathy
Creator
Kayaalp Nalbant, Elif
Date
2023
Description
Diabetic retinopathy, which is the most common reason for blindness in the working-age population, affects over one-third of those who have...
Show moreDiabetic retinopathy, which is the most common reason for blindness in the working-age population, affects over one-third of those who have had diabetes for over ten years. High blood sugar level (hyperglycemia) in the blood damages blood vessels and tight junction at the blood-retinal barrier (BRB). Chronic inflammation leads to changes in vascular health, and over time blood vessels tend to get damaged and exhibit higher “leakage” or permeability. In the late stage of DR, hemorrhages can occur, leading to irreversible damage of neuronal tissue in the retina and vision loss. In the clinic, there are some biomarkers and imaging modalities used to diagnose DR based on some of the more severe products of DR (e.g., hemorrhage), but there is no non-invasive, highly sensitive method to detect diabetic retinopathy before clinical signs occur, when mitigating therapies could be more effective. In this thesis, indicator dilution theory was explored to modeling the temporal dynamics of fluorescein in the retina after intravenous injection, with an aim to quantitatively map subtle changes in retinal blood flow and vascular permeability that could preempt subsequent irreversible damage. Specifically, a simplified version of indicator dilution theory—namely the “adiabatic approximation in tissue homogeneity” (AATH) model—was used to estimate physiological parameters such as the blood flow (F) and the extraction fraction (E: a parameter coupled with vascular permeability) from retinal fluorescein videoangiography data. The AATH fitting protocol was optimized through simulations using a more complex model (the AATH-vascular heterogeneity model, AATH-VH). It was determined that a two-step least square fitting method was more sensitive than a single-step least square fitting of AATH to simulated data to evaluate vascular permeability in early diabetic retinopathy. The optimized data analysis protocol was then evaluated in an initial clinical study comparing healthy control subjects to those with moderate non-proliferative DR. Volumetric blood flow and retinal vascular permeability maps were compared between patient groups with clear increases in extraction fraction observed in the mild NPDR patients compared to control. These promising early data have been the foundation to an ongoing 5 year study tracking 100 Diabetic patients with no DR so see if early changes in vascular permeability can predict which patients are more likely to progress to DR.
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