DESKTOP GENERATED MICROPLANAR X-RAY BEAMS AND THEIR BIOLOGICAL EFFECTS

Cancer affects 1 in 2 men and 1 in 3 women in the US and about half of all cancer patients receive some type of radiation therapy sometime during the course of their treatment. Normal tissue toxicity is the most important dose-limiting side effect of radiotherapy. This effect not only occurs after conventional broad beam radiotherapy (BB) but also following new radiation modalities namely, intensity modulated radiotherapy and proton therapy. Microbeam radiotherapy (MRT) is a novel preclinical approach for radiotherapy, which delivers spatially fractionated submillimeter lines of the collimated quasi-parallel of a single high-dose (100Gy<) radiation (peaks), separated by wider nonirradiated regions (valleys). Interestingly, the preclinical studies on animal models have consistently demonstrated the selective tumoricidal effect of MRT with the ability to even cure the aggressive orthotropic tumor models while sparing the normal tissue. Most of the MRT studies have been conducted in spars synchrotron facilities around the world. To make this technology more available for preclinical biomedical studies and facilitate the translation of this promising modality to the clinic, here a desktop approach for applying MRT has been sought. My dissertation goal was to develop a more accessible microbeam approach, study its effectiveness and evaluate some of the hypothetical underlying radiobiological mechanism of the desktop MRT approach. In this work, first, the effect of MRT and BB on normal mouse brain will be evaluated using batteries of neurocognitive tests, up to 8-months post irradiation. Next, a novel method for applying microbeams using an industrial cabinet animal irradiator will be introduced and a detailed description of its final characteristics will be given, including a comprehensive evaluation of the treatment geometry and a full-scale phantom-based quantification of its dosimetric output. Subsequently, the in-vitro and in-vivo efficacy of this new approach will be investigated. Later, the role of the acquired immune system will be evaluated in the tumor response after MRT. Finally, future project directions will be described briefly. Based on the results of this work, the author’s belief that our approach for applying MRT can be easily reproduced in other research facilities for radiobiological research and has definite clinical translation potential.Doctor of Philosoph

Minibeam radiotherapy with small animal irradiators: in-vitro and in-vivo feasibility studies

Minibeam radiation therapy (MBRT) delivers an ultrahigh dose of x-ray (≥100 Gy) in 200–1000 µm beams (peaks), separated by wider non-irradiated regions (valleys) usually as a single temporal fraction. Preclinical studies performed at synchrotron facilities revealed that MBRT is able to ablate tumors while maintaining normal tissue integrity. The main purpose of the present study was to develop an efficient and accessible method to perform MBRT using a conventional x-ray irradiator. We then tested this new method both in vitro and in vivo. Using commercially available lead ribbon and polyethylene sheets, we constructed a collimator that converted the cone beam of an industrial irradiator to 44 identical beams (collimator size ≈ 4 × 10 cm). The dosimetry characteristics of the generated beams were evaluated using two different radiochromic films (beam FWHM = 246 ± 32 µm; center-to-center = 926 ± 23 µm; peak-to-valley dose ratio = 24.35 ± 2.10; collimator relative output factor = 0.84 ± 0.04). Clonogenic assays demonstrated the ability of our method to induce radiobiological cell death in two radioresistant murine tumor cell lines (TRP = glioblastoma; B16-F10 = melanoma). A radiobiological equivalent dose (RBE) was calculated by evaluating the acute skin response to graded doses of MBRT and conventional radiotherapy (CRT). Normal mouse skin demonstrated resistance to doses up to 150 Gy on peak. MBRT significantly extended the survival of mice with flank melanoma tumors compared to CRT when RBE were applied (overall p < 0.001). Loss of spatial resolution deep in the tissue has been a major concern. The beams generated using our collimator maintained their resolution in vivo (mouse brain tissue) and up to 10 cm deep in the radiochromic film. In conclusion, the initial dosimetric, in vitro and in vivo evaluations confirmed the utility of this affordable and easy-to-replicate minibeam collimator for future preclinical studies

Ear Bars

For lab work with mic

Data from: Comparison of cerebral blood volume and plasma volume in untreated intracranial tumors

Purpose: Plasma volume and blood volume are imaging-derived parameters that are often used to evaluation intracranial tumors. Physiologically, these parameters are directly related, but their two different methods of measurements, T1-dynamic contrast enhanced (DCE)- and T2-dynamic susceptibility contrast (DSC)-MR utilize different model assumptions and approaches. This poses the question of whether the interchangeable use of T1-DCE-MRI derived fractionated plasma volume (vp) and relative cerebral blood volume (rCBV) assessed using DSC-MRI, particularly in glioblastoma, is reliable, and if this relationship can be generalized to other types of brain tumors. Our goal was to examine the hypothetical correlation between these parameters in three most common intracranial tumor types. Methods: Twenty-four newly diagnosed, treatment naïve brain tumor patients, who had undergone DCE- and DSC-MRI, were classified in three histologically proven groups: glioblastoma (n=7), meningioma (n=9), and intraparenchymal metastases (n=8). The rCBV was obtained from DSC after normalization with the normal-appearing anatomically symmetrical contralateral white matter. Correlations between these parameters were evaluated using Pearson (r), Spearman's (ρ) and Kendall’s tau-b (τB) rank correlation coefficient. Results: The Pearson, Spearman and Kendall’s correlation between vp with rCBV were r=0.193, ρ=0.253 and τB=0.33 (p-Pearson=0.326, p-Spearman=0.814 and p-Kendall=0.823) in glioblastoma, r=-0.007, ρ=0.051 and τB=0.135 (p-Pearson=0.970, p-Spearman=0.765 and p-Kendall=0.358) in meningiomas, and r= 0.289, ρ=0.228 and τB= 0.239 (p-Pearson=0.109, p-Spearman=0.210 and p-Kendall=0.095) in metastasis. Conclusion: Results indicate that no correlation exists between vp with rCBV in glioblastomas, meningiomas and intraparenchymal metastatic lesions. Consequently, these parameters, as calculated in this study, should not be used interchangeably in either research or clinical practice

Data from: Comparison of cerebral blood volume and plasma volume in untreated intracranial tumors

Purpose: Plasma volume and blood volume are imaging-derived parameters that are often used to evaluation intracranial tumors. Physiologically, these parameters are directly related, but their two different methods of measurements, T1-dynamic contrast enhanced (DCE)- and T2-dynamic susceptibility contrast (DSC)-MR utilize different model assumptions and approaches. This poses the question of whether the interchangeable use of T1-DCE-MRI derived fractionated plasma volume (vp) and relative cerebral blood volume (rCBV) assessed using DSC-MRI, particularly in glioblastoma, is reliable, and if this relationship can be generalized to other types of brain tumors. Our goal was to examine the hypothetical correlation between these parameters in three most common intracranial tumor types. Methods: Twenty-four newly diagnosed, treatment naïve brain tumor patients, who had undergone DCE- and DSC-MRI, were classified in three histologically proven groups: glioblastoma (n=7), meningioma (n=9), and intraparenchymal metastases (n=8). The rCBV was obtained from DSC after normalization with the normal-appearing anatomically symmetrical contralateral white matter. Correlations between these parameters were evaluated using Pearson (r), Spearman's (ρ) and Kendall’s tau-b (τB) rank correlation coefficient. Results: The Pearson, Spearman and Kendall’s correlation between vp with rCBV were r=0.193, ρ=0.253 and τB=0.33 (p-Pearson=0.326, p-Spearman=0.814 and p-Kendall=0.823) in glioblastoma, r=-0.007, ρ=0.051 and τB=0.135 (p-Pearson=0.970, p-Spearman=0.765 and p-Kendall=0.358) in meningiomas, and r= 0.289, ρ=0.228 and τB= 0.239 (p-Pearson=0.109, p-Spearman=0.210 and p-Kendall=0.095) in metastasis. Conclusion: Results indicate that no correlation exists between vp with rCBV in glioblastomas, meningiomas and intraparenchymal metastatic lesions. Consequently, these parameters, as calculated in this study, should not be used interchangeably in either research or clinical practice

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Demographics of study population in the three diagnostic groups.

<p>Demographics of study population in the three diagnostic groups.</p

Graphical relationship between the perfusion parameters in different study groups.

<p>Scatter-plot of fractional plasma volume (vp) (%), fractional blood volume (vb) (%) and relative cerebral blood volume (rCBV) in glioblastoma, meningioma, and intraparenchymal metastatic lesions.</p

Box-and-Whisker plot of permeability and perfusion parameters.

<p>The graph demonstrates median, maximum, minimum and first and third quartile of Ktrans (min^-1), relative cerebral blood volume (rCBV) and fractional plasma volume (VP) (%) in three different types of brain tumor. (**p-value<0.05)</p

Analyze of correlation between perfusion parameters.

<p>Analyze of correlation between perfusion parameters.</p