Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Background: Histotripsy is a non-thermal, non-invasive high-intensity focused ultrasound (HIFU) ablative technique that causes mechanical fragmentation of tissue, resulting in liquefied acellular debris with histologically clear demarcated boundaries between treated and non-treated tissues. The acellular debris may include tumor antigens with preserved immunogenicity and the potential to generate systemic immune response against tumor cells. Soft tissue sarcomas (STS) are a common form of cancer in dogs with biological behavior similar to STS in humans. Long-term tumor control requires complete removal with extensive surgical resection, which in many cases is not feasible. As a result, there is need for alternative therapies. Objectives: The primary objective of this study was to demonstrate safety and feasibility of histotripsy in a small animal model of spontaneous STS. The secondary objective was to characterize the impact of histotripsy on the immunologic response. Materials and methods: Pet dogs diagnosed with spontaneous STS were recruited. CT scan of the chest, abdomen, and the tumor was performed for staging and treatment planning. Pretreatment biopsies were obtained. Safety was monitored with physical examinations, owner reports, and CBC/serum biochemistry. Partial tumor ablation was performed using a 500 kHz prototype histotripsy system. A spherical treatment zone of up to 3 cm diameter in each tumor was treated with histotripsy according to the patient-specific treatment plan using 1-2 cycle pulses applied at a pulse repetition frequency (PRF) of 500 Hz. Anatomical ablation zones were evaluated with contrast CT at 1- and 4-days post-treatment, with tumor resection at 4-6 days post-treatment. Tumor microenvironment (TME) gene expression was evaluated with the Nanostring Canine IO panel, and the systemic immune response was evaluated using multiplex serum cytokine levels. Results: Ten dogs were recruited and treated. Tumor histologies included 3 grade III STS, 4 grade II STS, 2 grade I STS, and 1 malignant mesenchymoma. Six dogs were alive, three dogs were euthanized due to disease progression, and one dog was lost to follow up. Histotripsy-related complications were generally self-limiting, with only one patient having increased cutaneous injury score from 1 to 2 (scale 1-5) post-treatment, likely due to prefocal cavitation at the skin. No significant adverse events impacting patient outcome were noted in any of the patients. Visible histotripsy cavitation bubble clouds were seen on real-time ultrasound imaging in nine of ten treatments. Post-treatment histopathology indicated sharply defined regions of ablation that were clearly identifiable grossly and histologically in all samples. Treatment zones were characterized by loss of cell viability, hyalinization, and acute hemorrhage. Post-treatment contrast-enhanced CT images revealed clear, demarcated regions of histotripsy ablated tissue in seven of ten patients. Differential gene expression analysis identified 79 genes with at least 2-fold change following treatment. Genes associated with inflammation, immune cell migration, and immune cell interactions were the highest upregulated. Amongst the gene set analyses, the myeloid compartment gene sets obtained the highest significance score. There were no statistically significant differences between pre- and post-treatment cytokine concentrations for any of the analytes. Conclusions: Histotripsy can achieve safe and effective tumor ablation in dogs diagnosed with STS. Histotripsy induced pro-inflammatory changes within the tumor microenvironment. Histotripsy as an immunotherapeutic treatment option needs to be further investigated. Histotripsy has a potential to be a precise, non-invasive treatment for canine STS. / Master of Science / Histotripsy is a non-thermal high-intensity focused ultrasound (HIFU) ablative technique that uses controlled acoustic cavitation to cause mechanical fragmentation of tissue. To date, there are no reports investigating histotripsy for the treatment of soft tissue sarcoma (STS). This study aimed to investigate the in vivo feasibility of ablating STS with histotripsy and to characterize the impact of partial histotripsy ablation on the acute immunologic response in canine patients with spontaneous STS. CT of the chest, abdomen, and the tumor was performed for staging and treatment-planning. Pretreatment biopsies were obtained. Safety was monitored with physical examinations, through owner reports, and CBC/serum biochemistry. A custom 500 kHz histotripsy system was used to treat ten dogs with naturally occurring STS. Anatomical ablation zones were evaluated with contrast CT at 1- and 4-days post-treatment, with tumor resection at 4-days post-treatment. Safety was determined by monitoring vital signs during treatment and post-treatment physical examinations, routine lab work, and owners' reports. Ablation was characterized using radiologic and histopathologic analyses. Systemic immunological impact was evaluated by measuring changes in cytokine concentrations, and tumor microenvironment changes were evaluated by characterizing changes in infiltration with tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) using multiplex immunohistochemistry and differential gene expression. Results showed histotripsy ablation can achieve safe and effective tumor ablation in all ten dogs. Immunological results showed histotripsy induced pro-inflammatory changes in the tumor microenvironment. Histotripsy as an immunotherapeutic treatment option needs to be further investigated. Overall, this study demonstrates histotripsy's potential as a precise, non-invasive treatment for STS.

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<p>This thesis presents investigations on ultrafast laser irradiation of silicon towards the goal of hybridizing ultrafast laser processing and conventional semiconductor fabrication techniques to improve device applications. The fundamental sub-threshold damage accumulation mechanisms for potential defect engineering applications were studied through the use of positron annihilation spectroscopy, in situ sample heating during laser irradiation, varying the laser repetition rate, and samples implanted with various ion species at different conditions. Positron annihilation spectroscopy results suggest an increase in the divacancy density at the surface region of silicon following near- and slightly sub-threshold ultrafast laser irradiations. Laser irradiations at increasing sample temperature up to 600°C show a general decreasing trend of single-shot thresholds, and an increase in the suppression of sub-threshold damage accumulation. There is also a temperature dependence on the surface morphology resulting from ultrafast laser irradiation. Ion implantation modified the ablation threshold fluence, and a dependence on the ion implantation conditions was observed. Surface microstructuring of silicon was shown to improve absorption of light with a sub-bandgap wavelength of 1550 nm. An initial attempt with sulfur implantation did not exhibit further improvement in the optical absorption, and first attempts in device fabrication did not provide photoresponsivity at sub-bandgap wavelengths. Ultrafast laser irradiation of SiO₂-on-Si structures yielded different modification thresholds for different thicknesses of the oxide layer. Surface morphologies obtained in the irradiation of these structures can affect potential applications. Selected studies of ultrafast laser irradiation of GaP, metal-SiO₂-Si structures, quartz, diamond, and porcine bone demonstrated similarities in ablation behavior and morphologies, and the potential for a broad range of applications. The results in combination with the proposed future work in this thesis can contribute to potential device applications while providing valuable insights into the ultrafast laser ablation mechanisms.</p> / Doctor of Philosophy (PhD)