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- Schiavo, Filippo, 1994-, et al.
(författare)
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Perfusion-Limited Hypoxia Determines the Outcome of Radiation Therapy of Hypoxic Tumours
- 2022
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Ingår i: Oxygen Transport to Tissue XLIII. - Cham : Springer. - 9783031141898 - 9783031141904 ; 1395, s. 249-254
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Konferensbidrag (refereegranskat)abstract
- Despite advancements in functional imaging, the resolution of modern techniques is still limited with respect to the tumour microenvironment. Radiotherapy strategies to counteract e.g., tumour hypoxia based on functional imaging therefore carry an inherent uncertainty that could compromise the outcome of the treatment. It was the aim of this study to investigate the impact of variations in the radiosensitivity of hypoxic tumours in small regions in comparison to the resolution of current imaging techniques on the probability of obtaining tumour control. A novel in silico model of three-dimensional tumour vasculature and oxygenation was used to model three tumours with different combinations of diffusion-limited, perfusion-limited and anaemic hypoxia. Specifically, cells in the transition region from a tumour core with diffusion-limited hypoxia to the well-oxygenated tumour rim were considered with respect to their differential radiosensitivity depending on the character of the hypoxia. The results showed that if the cells in the transition region were under perfusion-limited hypoxia, the tumour control probability was substantially lower in comparison to the case when the cells were anaemic (or under diffusion-limited hypoxia). This study therefore demonstrates the importance of differentiating between different forms of hypoxia on a scale currently unattainable to functional imaging techniques, lending support to the use and importance of radiobiological modelling of the cellular radiosensitivity and response at microscale.
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| 2. |
- Schiavo, Filippo, 1994-
(författare)
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The virtual tumour - in silico modelling of tumour vasculature, oxygenation and treatment outcome
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Poor tumour oxygenation, namely hypoxia, is one of the major challenges that has been recognised in radiotherapy, yet it is not being accounted for in standard treatments. Hypoxia, resulting from a heterogeneous distribution of vessels (chronic hypoxia) or of a loss in vascular perfusion (acute hypoxia), affects all kinds of solid tumours to different extents. Although over-sustained angiogenesis with vascular remodelling is one of the key hallmarks of cancer, the resulting tumour vasculature is often frail and lacking a clear hierarchical structure, hence incapable of maintaining the same nutrients and oxygen supply standards of healthy vascular networks.It is ascertained that hypoxic cells require an up to three times higher radiation dose than normoxic tissues to achieve the same biological effect. Tumour hypoxia correlates to worse disease prognoses when compared to normoxic tumours. However, many of its biological aspects remain only partially understood. Although from a clinical perspective most of the countermeasures that have been devised to oxygenate or kill hypoxic cells can be evaluated in terms of short- and long-term effects, a clear and pristine understanding of the mechanisms involved in the curative process of hypoxic tumours has not been provided. From this perspective, in silico modelling of the tumour key radiobiological features could instead represent a new frontier: unprecedented computational power and numerical optimisation routines permit to expand virtually the set of possible microenvironmental situations, with simulations of real treatments and concurrent intercomparison of hypothetical scenarios. The fact that the real vascular anatomy of a deep-seated tumour is not fully accessible – and hence not precisely modellable – could be compensated by a large casuistry of heterogeneous oxygenation patterns provided by the model, with inherent best- and worst- case studies. At the same time, in silico modelling would not replace in vivo functional imaging, but would rather act in synergy with that as an additional layer of study: based on the underlying macroscopic information that for instance positron emission tomography (PET) or magnetic resonance imaging (MRI) could offer, the microscopic radiobiological nature of the tumour could be simulated.This thesis consists of papers I-II and an introductory overview of the topics, which provide the background needed for their basic understanding. Starting with an account of tumour hypoxia, its radiobiology and the solutions that have been explored so far to counteract its negative effects are also discussed. Paper I is concerned with the presentation of the novel three-dimensional radiobiological model developed, which is the core of a comprehensive project developed during the PhD work; therefore, it will be introduced in the framework of previously designed models that dealt within this subject in the context of radiotherapy. Since this is probably the first model of its kind designed to be implemented into a treatment planning system (TPS), the subsequent natural steps will consist of the integration of the model in a research version of a TPS and study of the efficacy of various treatment scenarios in terms of underlying tumour oxygenation and treatment choices regarding beam quality, fractionation, and total dose.
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| 3. |
- Schiavo, Filippo, 1994-, et al.
(författare)
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Towards the virtual tumor for optimizing radiotherapy treatments of hypoxic tumors : A novel model of heterogeneous tissue vasculature and oxygenation
- 2022
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Ingår i: Journal of Theoretical Biology. - : Elsevier BV. - 0022-5193 .- 1095-8541. ; 547
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Tumor oxygenation is one of the key features influencing the response of cells to radiation and chemo therapies. This study presents a novel in silico tumor model simulating realistic 3D microvascular structures and related oxygenation maps, featuring regions with different levels and typologies of hypoxia (chronic, acute and anemic). Such model, if integrated into a treatment planning system, could allow evaluations and comparisons of various scenarios when deciding the therapy to administer. Methods and Materials: Spherical tumors between 0.6 and 1.5 cm in diameter encompassed uniformly by vascular trees generated starting from pseudo-fractal principles were simulated with a voxel resolution of 10 µm. The approach ensures a continuous transition from a well-perfused rim to a core with poor vascularization. The oxygen diffusion equation in the tumor is solved by a finite difference method. Several quantities, such as the fractal dimension (FD), the microvascular density (MVD) and the hypoxic fraction (HF) were assessed and compared. Results: Different tumors with various degrees of chronic hypoxia were simulated by varying the tumor size and the number of bifurcations in the vascular networks. The simulations showed that for the case of chronically hypoxic tumors, in well-oxygenated volumes FD = 2.53 ± 0.07, MVD = 3460 ± 2180 vessels/mm3 and HF = 4.0 ± 3.4%, while in hypoxic volumes FD = 2.34 ± 0.09, MVD = 365 ± 156 vessels/mm3, HF = 49.8 ± 18.3%. The superimposition of acute or anemic hypoxia accentuated the oxygen deprivation in the core of the volumes. Conclusions: Tumors varying in diameter and extension of their vasculature were simulated, showing features that define two distinctive subvolumes in terms of oxygenation. The model could be regarded as a testbed for simulations of key radiobiological features governing the tumor response to radio- and chemotherapy and thus for treatment outcome simulations.
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