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Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

ABSTRACT: The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare. In the present work, wildtype zebrafish embryos (Danio rerio) were used to characterize the effects of plateau and mid-SOBP (spread-out Bragg peak) proton radiation relative to that induced by clinical MV photon beam reference. Based on embryonic survival data, RBE values of 1.13 ± 0.08 and of 1.20 ± 0.04 were determined four days after irradiations with 20 Gy plateau and SOBP protons relative to 6 MV photon beams. These RBE values were confirmed by relating the rates of embryos with morphological abnormalities for the respective radiation qualities and doses. Besides survival, the rate of spine bending, as one type of developmental abnormality, and of pericardial edema, as an example for acute radiation effects, were assessed. The results revealed that independent on radiation quality both rates increased with time approaching almost 100% at the 4th day post irradiation with doses higher than 15 Gy. To sum up, the applicability of the zebrafish embryo as a robust and simple alternative model for in vivo characterization of radiobiological effects in normal tissue was validated and the obtained RBE values are comparable to previous finding in animal trials.

SUBMITTER: Szabo ER

PROVIDER: S-EPMC6224071 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

Szabó Emília Rita ER Brand Michael M Hans Stefan S Hideghéty Katalin K Karsch Leonhard L Lessmann Elisabeth E Pawelke Jörg J Schürer Michael M Beyreuther Elke E

PloS one 20181108 11

The increasing use of proton radiotherapy during the last decade and the rising number of long-term survivors has given rise to a vital discussion on potential effects on normal tissue. So far, deviations from clinically applied generic RBE (relative biological effectiveness) of 1.1 were only obtained by in vitro studies, whereas indications from in vivo trials and clinical studies are rare. In the present work, wildtype zebrafish embryos (Danio rerio) were used to characterize the effects of pl ...[more]

PMID: 30408095

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Project description:Currently, the relative biological effectiveness (RBE) is assumed to be constant with a value of 1.1 in proton therapy. Although trends of RBE variations are well known, absolute values in patients are associated with considerable uncertainties. This study aims to evaluate the impact of a variable proton RBE in proton therapy liver trials using different fractionation schemes. Sixteen liver cancer cases were evaluated assuming two clinical schedules of 40 Gy/5 fractions and 58.05 Gy/15 fractions. The linear energy transfer (LET) and physical dose distribution in patients were simulated using Monte Carlo. The variable RBE distribution was calculated using a phenomenological model, considering the influence of the LET, fraction size and ?/? value. Further, models to predict normal tissue complication probability (NTCP) and tumor control probability (TCP) were used to investigate potential RBE effects on outcome predictions. Applying the variable RBE model to the 5 and 15 fractions schedules results in an increase in mean fraction-size equivalent dose (FED) to the normal liver of 5.0% and 9.6% respectively. For patients with a mean FED to the normal liver larger than 29.8 Gy, this results in a non-negligible increase in the predicted NTCP of the normal liver averaging 11.6%, ranging from 2.7% to 25.6%. On the other hand, decrease in TCP was less than 5% for both fractionation regimens for all patients when assuming a variable RBE instead of constant. Consequently, the difference in TCP between the two fractionation schedules did not change significantly assuming a variable RBE while the impact on the NTCP difference was highly case specific. In addition, both the NTCP and TCP decrease with increasing ?/? value for both fractionation schemes, with the decreases being more pronounced when using a variable RBE compared to using RBE??=??1.1. Assuming a constant RBE of 1.1 most likely overestimates the therapeutic ratio in proton therapy for liver cancer, predominantly due to underestimation of the RBE-weighted dose to the normal liver. The impact of applying a variable RBE (as compared to RBE??=??1.1) on the NTCP difference of the two fractionation regimens is case dependent. A variable RBE results in a slight increase in TCP difference. Variations in patient radiosensitivity increase when using a variable RBE.

Project description:BackgroundRecently, much progress has been made in the field of gene-expression in early embryogenesis. However, the dynamic behaviour of transcriptomes in individual embryos has hardly been studied yet and the time points at which pools of embryos are collected are usually still quite far apart. Here, we present a high-resolution gene-expression time series with 180 individual zebrafish embryos, obtained from nine different spawns, developmentally ordered and profiled from late blastula to mid-gastrula stage. On average one embryo per minute was analysed. The focus was on identification and description of the transcriptome dynamics of the expressed genes in this embryonic stage, rather than to biologically interpret profiles in cellular processes and pathways.ResultsIn the late blastula to mid-gastrula stage, we found 6,734 genes being expressed with low variability and rather gradual changes. Ten types of dynamic behaviour were defined, such as genes with continuously increasing or decreasing expression, and all expressed genes were grouped into these types. Also, the exact expression starting and stopping points of several hundred genes during this developmental period could be pinpointed. Although the resolution of the experiment was so high, that we were able to clearly identify four known oscillating genes, no genes were observed with a peaking expression. Additionally, several genes showed expression at two or three distinct levels that strongly related to the spawn an embryo originated from.ConclusionOur unique experimental set-up of whole-transcriptome analysis of 180 individual embryos, provided an unparalleled in-depth insight into the dynamics of early zebrafish embryogenesis. The existence of a tightly regulated embryonic transcriptome program, even between individuals from different spawns is shown. We have made the expression profile of all genes available for domain experts. The fact that we were able to separate the different spawns by their gene-expression variance over all expressed genes, underlines the importance of spawn specificity, as well as the unexpectedly tight gene-expression regulation in early zebrafish embryogenesis.

Project description:BackgroundProton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and β vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE = 1.1.PurposeHere, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters.Methods and materialsWe performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x-rays and 1.2, 2.6, or 9.9 keV/µm protons, and combined our measurements with published survival data (n = 397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF% , (the dose required to achieve survival fraction [SF], e.g., D10% ) varied with proton LET, and calculated the Bayesian information criteria associated with different LET-dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six-parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting.ResultsOur analyses of the trends in the data show that DSF% is linearly correlated between x-rays and protons, regardless of the choice of the survival level (e.g., D10% , D37% , or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%-30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE-weighted doses than the other empirical models, with RBE-weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE-weighted doses (RBE = 1.1) to the tumor.ConclusionsWe established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams.

Project description:IntroductionProton arc therapy (PAT) is an emerging treatment modality that holds promise to improve target volume coverage and reduce linear energy transfer (LET) in organs at risk. We aimed to investigate if pruning the highest energy layers in each beam direction could increase the LET in the target and reduce LET in tissue and organs at risk (OAR) surrounding the target volume, thus reducing the relative biological effectiveness (RBE)-weighted dose and sparing healthy tissue.MethodsPAT plans for a germinoma, an ependymoma and a rhabdomyosarcoma patient were created in the Eclipse treatment planning system with a prescribed dose of 54 Gy(RBE) using a constant RBE of 1.1 (RBE1.1). The PAT plans was pruned for high energy spots, creating several PAT plans with different amounts of pruning while maintaining tumor coverage, denoted PX-PAT plans, where X represents the amount of pruning. All plans were recalculated in the FLUKA Monte Carlo software, and the LET, physical dose, and variable RBE-weighted dose from the phenomenological Rørvik (ROR) model and an LET weighted dose (LWD) model were evaluated.Results and discussionFor the germinoma case, all plans but the P6-PAT reduced the mean RBE-weighted dose to the surrounding healthy tissue compared to the PAT plan. The LET was increasingly higher within the PTV for each pruning iteration, where the mean LET from the P6-PAT plan was 1.5 keV/μm higher than for the PAT plan, while the P4- and P5-PAT plans provided an increase of 0.4 and 0.7 keV/μm, respectively. The other plans increased the LET by a smaller margin compared to the PAT plan. Likewise, the LET values to the healthy tissue were reduced for each degree of pruning. Similar results were found for the ependymoma and the rhabdomyosarcoma case. We demonstrated a PAT pruning technique that can increase both LET and RBE in the target volume and at the same time decreased values in healthy tissue, without affecting the target volume dose coverage.

Project description:Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/β)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/β)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

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Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

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Radiobiological effects and proton RBE determined by wildtype zebrafish embryos.

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