In vivo dosimetry to narrow down proton range uncertainties

Tese de mestrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2014A dosimetria de verificação in vivo é uma abordagem que tem sido objeto de estudo como um método para diminuir as incertezas associadas ao alcance de feixes de protões em planos dosimétricos. O objetivo do projeto é investigar a viabilidade da utilização de diferentes dosímetros para minimizar o valor da incerteza atualmente estabelecido de ±3%. Medindo a dose resultante de certos campos de protões que atravessam um fantoma (simulação de uma cabeça humana), com dosímetros colocados na sua superfície, e compará-la com a dose calculada pelo sistema de planeamento dosimétrico para o respectivo plano dosimétrico, é possível saber se a dose está a ser sobrestimada ou subestimada. Dois casos podem acontecer: se for medida experimentalmente uma certa quantidade de dose, o plano dosimétrico calculado pelo sistema de planeamento está subestimado. Consequentemente, cenários com uma distribuição de dose subestimada no fantoma podem ser descartados. Por outro lado, se nenhuma dose é medida com os dosímetros, cenários com a distribuição de dose sobrestimada podem ser colocados de lado. Cinco dosímetros com diferentes características foram testados no fantoma de forma a desenvolver um procedimento padrão viável para a dosimetria externa in vivo. Foram realizados dois métodos: no primeiro método TLDs e uma câmara de ionização (IC) (Semiflex (125 mm3) da PTW) foram colocados na superfície do fantoma em 4 pontos diferentes. No segundo método, um detetor planar (“2D array” da PTW) foi colocado perpendicularmente ao feixe, atrás do fantoma, e os TLDs, duas câmaras de ionização (Semiflex e advanced Markus (PTW)) e um detetor de diamante (diamond detector) foram colocados sobre a superfície da 2D array em 2 pontos específicos. No primeiro método dois planos dosimétricos foram utilizados para as medições: um plano nominal e um plano sobrestimado em 3%, isto é, com as unidades de Hounsfield (HU) da tomografia computorizada (TAC) alteradas em +3%, representando o erro máximo possível no alcance. Ambos foram usadas com um campo clínico de protões (110º rotação da gantry, 180º rotação da mesa). No segundo método, juntamente com os últimos planos, um plano sobrestimado em 10% foi adicionado (HU da TAC alteradas em + 10%) e um campo experimental de protões foi utilizado (90º rotação da gantry, 180º rotação da mesa). Depois do processamento dos resultados necessário, foi efetuada a comparação entre as medições obtidas experimentalmente e a dose respetiva prevista pelo sistema de planeamento (PSIplan). Os resultados mostram que a dose medida pelos dosímetros não está dentro da incerteza no alcance utilizada no Paul Scherrer instituto (PSI) devido a erros inerentes aos métodos utilizados. Várias abordagens foram feitas para contornar estes erros metodológicos, no entanto sem melhorias relevantes. Não foi portanto encontrado nenhum dosímetro viável para o método de dosimetria externa in vivo proposto.In Vivo exit dosimetry is an approach that has been under investigation as a tool to narrow down the uncertainties associated to proton beam range of dosimetric distributions. The goal of the project is to investigate the feasibility of different dosimeters to minimize the currently established range uncertainty value of ±3%. Measuring the exit dose of certain fields with dosimeters placed in a head phantom surface and compare it with the dose predicted by the treatment planning system (TPS) for the respective dosimetric plan, one can know whether the dose is being overestimated or underestimated. Two cases can happen: if it is experimentally measured a certain amount of dose, the current dosimetric plan calculated by the TPS is being underestimated. Consequently, undershooting scenarios on the phantom can be discarded. On the other hand, if no dose is measured with the dosimeters, overshooting scenarios can be discarded. Five different dosimeters were tested in the head phantom in order to develop a feasible standard procedure for the external in vivo dosimetry (EIVD) approach. Two different methods were performed: a first method where TLDs and the ionization chamber (IC) Semiflex (125 mm3) (from PTW) were placed on the surface of the phantom in 4 different points; and a second method where the 2D array detector (from PTW) was placed perpendicular to the beam, behind the phantom on the opposite side of the gantry nozzle. TLDs, two ICs (Semiflex and Advanced Markus (PTW)) and a diamond detector were placed on the surface of the 2D array over 2 specific points. In the first method two dosimetric plans were measured: a nominal scenario and a overshooting scenario (characterized by a change of +3% in the Hounsfield units (HU) CT), representing the maximum range error possible. Both were used with a clinical field of protons (110º gantry, 180º couch rotation). In the second method, along with the latter scenarios a 10% overshooting scenario was added (HU of the CT changed by +10%) and a experimental field was used (90º gantry, 180º couch rotation). After the necessary results post-processing, the comparison between the measurements obtained experimentally and the respective dose predicted by the TPS (PSIplan) was done. The results show that the dose measured by the dosimeters is not within the ±3% of uncertainty in the range used at Paul Scherrer Intitut (PSI) due to errors inherent to the methods used. Several approaches were made to overcome this methodological errors, without relevant improvements, however. Therefore, was not found any feasible dosimeter for such EIVD approach

Comparison of 3DCRT and IMRT out-of-field doses in pediatric patients using Monte Carlo simulations with treatment planning system calculations and measurements

Purpose: Out-of-field doses are given to healthy tissues, which may allow the development of second tumors. The use of IMRT in pediatric patients has been discussed, as it leads to a "bath" of low doses to large volumes of out-of-field organs and tissues. This study aims to compare out-of-field doses in pediatric patients comparing IMRT and 3DCRT techniques using measurements, Monte Carlo (MC) simulations, and treatment planning system (TPS) calculations. Materials and methods: A total dose of 54 Gy was prescribed to a PTV in the brain of a pediatric anthropomorphic phantom, for both techniques. To assess the out-of-field organ doses for both techniques, two treatment plans were performed with the 3DCRT and IMRT techniques in TPS. Measurements were carried out in a LINAC using a pediatric anthropomorphic phantom and thermoluminescent dosimeters to recreate the treatment plans, previously performed in the TPS. A computational model of a LINAC, the associated multileaf collimators, and a voxelized pediatric phantom implemented in the Monte Carlo N-Particle 6.1 computer program were also used to perform MC simulations of the out-of-field organ doses, for both techniques. Results: The results obtained by measurements and MC simulations indicate a significant increase in dose using the IMRT technique when compared to the 3DCRT technique. More specifically, measurements show higher doses with IMRT, namely, in the right eye (13,041 vs. 593 mGy), left eye (6,525 vs. 475 mGy), thyroid (79 vs. 70 mGy), right lung (37 vs. 28 mGy), left lung (27 vs. 20 mGy), and heart (31 vs. 25 mGy). The obtained results indicate that out-of-field doses can be seriously underestimated by TPS. Discussion: This study presents, for the first time, out-of-field dose measurements in a realistic scenario and calculations for IMRT, centered on a voxelized pediatric phantom and an MC model of a medical LINAC, including MLC with log file-based simulations. The results pinpoint significant discrepancies in out-of-field doses for the two techniques and are a cause of concern because TPS calculations cannot accurately predict such doses. The obtained doses may presumably increase the risk of the development of second tumors.info:eu-repo/semantics/publishedVersio

The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation

Ajuts: TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, by the German-Israeli Foundation for Scientific Research and Development (GIF), and by a grant from the Niedersachsisches Ministerium fur Wissenschaft und Kultur (MWK). TFO and SV are supported by a grant from Fundación La Marato de TV3 (Ref. 20144330). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset. We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis. We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies. - The online version of this article (doi:10.1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users

Comparison of 3DCRT and IMRT out-of-field doses in pediatric patients using Monte Carlo simulations with treatment planning system calculations and measurements

3DCRT and IMRT out-of-field doses in pediatric patients were compared using Monte Carlo simulations with treatment planning system calculations and measurements.PurposeOut-of-field doses are given to healthy tissues, which may allow the development of second tumors. The use of IMRT in pediatric patients has been discussed, as it leads to a “bath” of low doses to large volumes of out-of-field organs and tissues. This study aims to compare out-of-field doses in pediatric patients comparing IMRT and 3DCRT techniques using measurements, Monte Carlo (MC) simulations, and treatment planning system (TPS) calculations.Materials and methodsA total dose of 54 Gy was prescribed to a PTV in the brain of a pediatric anthropomorphic phantom, for both techniques. To assess the out-of-field organ doses for both techniques, two treatment plans were performed with the 3DCRT and IMRT techniques in TPS. Measurements were carried out in a LINAC using a pediatric anthropomorphic phantom and thermoluminescent dosimeters to recreate the treatment plans, previously performed in the TPS. A computational model of a LINAC, the associated multileaf collimators, and a voxelized pediatric phantom implemented in the Monte Carlo N-Particle 6.1 computer program were also used to perform MC simulations of the out-of-field organ doses, for both techniques.ResultsThe results obtained by measurements and MC simulations indicate a significant increase in dose using the IMRT technique when compared to the 3DCRT technique. More specifically, measurements show higher doses with IMRT, namely, in right eye (13,041 vs. 593 mGy), left eye (6,525 vs. 475 mGy), thyroid (79 vs. 70 mGy), right lung (37 vs. 28 mGy), left lung (27 vs. 20 mGy), and heart (31 vs. 25 mGy). The obtained results indicate that out-of-field doses can be seriously underestimated by TPS.DiscussionThis study presents, for the first time, out-of-field dose measurements in a realistic scenario and calculations for IMRT, centered on a voxelized pediatric phantom and an MC model of a medical LINAC, including MLC with log file-based simulations. The results pinpoint significant discrepancies in out-of-field doses for the two techniques and are a cause of concern because TPS calculations cannot accurately predict such doses. The obtained doses may presumably increase the risk of development of second tumors

The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation

Ajuts: TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, by the German-Israeli Foundation for Scientific Research and Development (GIF), and by a grant from the Niedersachsisches Ministerium fur Wissenschaft und Kultur (MWK). TFO and SV are supported by a grant from Fundación La Marato de TV3 (Ref. 20144330). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset. We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis. We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies. - The online version of this article (doi:10.1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users

Assessment of out-of-field doses in radiotherapy treatments of paediatric patients using Monte Carlo methods and measurements

Purpose: To assess out-of-field doses in radiotherapy treatments of pediatric patients, using Monte Carlo methods to implement a new model of the linear accelerator validated against measurements and developing a voxelized anthropomorphic pediatric phantom. Methods: CT images of a physical anthropomorphic pediatric phantom were acquired and dosimetric planning using a TPS was obtained. The CT images were used to perform the voxelization of the physical phantom using the ImageJ software and later implemented in MCNP. In order to validate the Monte Carlo model, dose measurements of the 6 MV beam and Linac with 120 MLC were made in a clinical setting, using ionization chambers and a water phantom. afterward, TLD measurements in the physical anthropomorphic phantom were performed in order to assess the out-of-field doses in the eyes, thyroid, c-spine, heart, and lungs. Results: The Monte Carlo model was validated for in-field and out-of-field doses with average relative differences below 3%. The average relative differences between TLD measurements and Monte Carlo is 14,3% whilst the average relative differences between TLD and TPS is 55,8%. Moreover, organs up to 22.5 cm from PTV center show TLD and MCNP6 relative differences and TLD and TPS relative differences up to 21.2% and 92.0%, respectively. Conclusions: Our study provides a novel model that could be used in clinical research, namely in dose evaluation outside the treatment fields. This is particularly relevant, especially in pediatric patients, for studying new radiotherapy treatment techniques, since it can be used to estimate the development of secondary tumors.info:eu-repo/semantics/publishedVersio

Combining IMRT and DIBH for the treatment of mediastinal lymphomas: what’s the benefit?

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