Who Will Benefit from Charged-Particle Therapy?
Ontology highlight
ABSTRACT:
SUBMITTER: Kim KS
PROVIDER: S-EPMC8291184 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Solid tumours often present regions with severe oxygen deprivation (hypoxia), which are resistant to both chemotherapy and radiotherapy. Increased radiosensitivity as a function of the oxygen concentration is well described for X-rays. It has also been demonstrated that radioresistance in anoxia is reduced using high-LET radiation rather than conventional X-rays. However, the dependence of the oxygen enhancement ratio (OER) on radiation quality in the regions of intermediate oxygen concentrations, those normally found in tumours, had never been measured and biophysical models were based on extrapolations. Here we present a complete survival dataset of mammalian cells exposed to different ions in oxygen concentration ranging from normoxia (21%) to anoxia (0%). The data were used to generate a model of the dependence of the OER on oxygen concentration and particle energy. The model was implemented in the ion beam treatment planning system to prescribe uniform cell killing across volumes with heterogeneous radiosensitivity. The adaptive treatment plans have been validated in two different accelerator facilities, using a biological phantom where cells can be irradiated simultaneously at three different oxygen concentrations. We thus realized a hypoxia-adapted treatment plan, which will be used for painting by voxel of hypoxic tumours visualized by functional imaging.
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Project description:Radiogenomics is the study of genomic factors that are associated with response to radiation therapy. In recent years, progress has been made toward identifying genetic risk factors linked with late radiation-induced adverse effects. These advances have been underpinned by the establishment of an international Radiogenomics Consortium with collaborative studies that expand cohort sizes to increase statistical power and efforts to improve methodologic approaches for radiogenomic research. Published studies have predominantly reported the results of research involving patients treated with photons using external beam radiation therapy. These studies demonstrate our ability to pool international cohorts to identify common single nucleotide polymorphisms associated with risk for developing normal tissue toxicities. Progress has also been achieved toward the discovery of genetic variants associated with radiation therapy-related subsequent malignancies. With the increasing use of charged particle therapy (CPT), there is a need to establish cohorts for patients treated with these advanced technology forms of radiation therapy and to create biorepositories with linked clinical data. While some genetic variants are likely to impact toxicity and second malignancy risks for both photons and charged particles, it is plausible that others may be specific to the radiation modality due to differences in their biological effects, including the complexity of DNA damage produced. In recognition that the formation of patient cohorts treated with CPT for radiogenomic studies is a high priority, efforts are underway to establish collaborations involving institutions treating cancer patients with protons and/or carbon ions as well as consortia, including the Proton Collaborative Group, the Particle Therapy Cooperative Group, and the Pediatric Proton Consortium Registry. These important radiogenomic CPT initiatives need to be expanded internationally to build on experience gained from the Radiogenomics Consortium and epidemiologists investigating normal tissue toxicities and second cancer risk.
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Project description:PurposeConventional charged-particle imaging techniques - such as autoradiography - provide only two-dimensional (2D) black ex vivo images of thin tissue slices. In order to get volumetric information, images of multiple thin slices are stacked. This process is time consuming and prone to distortions, as registration of 2D images is required. We propose a direct three-dimensional (3D) autoradiography technique, which we call charged-particle emission tomography (CPET). This 3D imaging technique enables imaging of thick tissue sections, thus increasing laboratory throughput and eliminating distortions due to registration. CPET also has the potential to enable in vivo charged-particle imaging with a window chamber or an endoscope.MethodsOur approach to charged-particle emission tomography uses particle-processing detectors (PPDs) to estimate attributes of each detected particle. The attributes we estimate include location, direction of propagation, and/or the energy deposited in the detector. Estimated attributes are then fed into a reconstruction algorithm to reconstruct the 3D distribution of charged-particle-emitting radionuclides. Several setups to realize PPDs are designed. Reconstruction algorithms for CPET are developed.ResultsReconstruction results from simulated data showed that a PPD enables CPET if the PPD measures more attributes than just the position from each detected particle. Experiments showed that a two-foil charged-particle detector is able to measure the position and direction of incident alpha particles.ConclusionsWe proposed a new volumetric imaging technique for charged-particle-emitting radionuclides, which we have called charged-particle emission tomography (CPET). We also proposed a new class of charged-particle detectors, which we have called particle-processing detectors (PPDs). When a PPD is used to measure the direction and/or energy attributes along with the position attributes, CPET is feasible.
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Project description:Charged particles, such as carbon ions, bear the promise of a more effective cancer therapy. In human spaceflight, exposure to charged particles represents an important risk factor for chronic and late effects such as cancer. Biological effects elicited by charged particle exposure depend on their characteristics, e.g., on linear energy transfer (LET). For diverse outcomes (cell death, mutation, transformation, and cell-cycle arrest), an LET dependency of the effect size was observed. These outcomes result from activation of a complex network of signaling pathways in the DNA damage response, which result in cell-protective (DNA repair and cell-cycle arrest) or cell-destructive (cell death) reactions. Triggering of these pathways converges among others in the activation of transcription factors, such as p53, nuclear factor ?B (NF-?B), activated protein 1 (AP-1), nuclear erythroid-derived 2-related factor 2 (Nrf2), and cAMP responsive element binding protein (CREB). Depending on dose, radiation quality, and tissue, p53 induces apoptosis or cell-cycle arrest. In low LET radiation therapy, p53 mutations are often associated with therapy resistance, while the outcome of carbon ion therapy seems to be independent of the tumor's p53 status. NF-?B is a central transcription factor in the immune system and exhibits pro-survival effects. Both p53 and NF-?B are activated after ionizing radiation exposure in an ataxia telangiectasia mutated (ATM)-dependent manner. The NF-?B activation was shown to strongly depend on charged particles' LET, with a maximal activation in the LET range of 90-300?keV/?m. AP-1 controls proliferation, senescence, differentiation, and apoptosis. Nrf2 can induce cellular antioxidant defense systems, CREB might also be involved in survival responses. The extent of activation of these transcription factors by charged particles and their interaction in the cellular radiation response greatly influences the destiny of the irradiated and also neighboring cells in the bystander effect.
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