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  • 1. Grzanka, Leszek
    et al.
    Ardenfors, Oscar
    Stockholm University, Faculty of Science, Department of Physics.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics. Aarhus University, Denmark.
    MONTE CARLO SIMULATIONS OF SPATIAL LET DISTRIBUTIONS IN CLINICAL PROTON BEAMS2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 296-299Article in journal (Refereed)
    Abstract [en]

    The linear energy transfer (LET) is commonly used as a parameter which describes the quality of the radiation applied in radiation therapy with fast ions. In particular in proton therapy, most models which predict the radiobiological properties of the applied beam, are fitted to the dose-averaged LET, LETd. The related parameter called the fluence-or track-averaged LET, LETt, is less frequently used. Both LETt and in particular LETd depends profoundly on the encountered secondary particle spectrum. For proton beams including all secondary particles, LETd may reach more than 3 keV/um in the entry channel of the proton field. However, typically the charged particle spectrum is only averaged over the primary and secondary protons, which is in the order of 0.5 keV/um for the same region. This is equal to assuming that the secondary particle spectrum from heavier ions is irrelevant for the resulting radiobiology, which is an assertion in the need of closer investigation. Models which rely on LETd should also be clear on what type of LETd is used, which is not always the case. Within this work, we have extended the Monte Carlo particle transport code SHIELD-HIT12A to provide dose-and track-average LET-maps for ion radiation therapy treatment plans.

  • 2. Høye, Ellen Marie
    et al.
    Skyt, Peter S.
    Balling, Peter
    Muren, Ludvig P.
    Taasti, Vicki T.
    Swakoń, Jan
    Mierzwińska, Gabriela
    Rydygier, Marzena
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics. Aarhus University, Denmark.
    Petersen, Jørgen B. B.
    Chemically tuned linear energy transfer dependent quenching in a deformable, radiochromic 3D dosimeter2017In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, no 4, p. N73-N89Article in journal (Refereed)
    Abstract [en]

    Most solid-state detectors, including 3D dosimeters, show lower signal in the Bragg peak than expected, a process termed quenching. The purpose of this study was to investigate how variation in chemical composition of a recently developed radiochromic, silicone-based 3D dosimeter influences the observed quenching in proton beams. The dependency of dose response on linear energy transfer, as calculated through Monte Carlo simulations of the dosimeter, was investigated in 60 MeV proton beams. We found that the amount of quenching varied with the chemical composition: peak-to-plateau ratios (1 cm into the plateau) ranged from 2.2 to 3.4, compared to 4.3 using an ionization chamber. The dose response, and thereby the quenching, was predominantly influenced by the curing agent concentration, which determined the dosimeter's deformation properties. The dose response was found to be linear at all depths. All chemical compositions of the dosimeter showed dose-rate dependency; however this was not dependent on the linear energy transfer. Track-structure theory was used to explain the observed quenching effects. In conclusion, this study shows that the silicone-based dosimeter has potential for use in measuring 3D-dose-distributions from proton beams.

  • 3. Krzempek, D.
    et al.
    Mianowska, G.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Stolarczyk, L.
    Kopeć, R.
    Sas-Korczyńska, B.
    Olko, P.
    CALIBRATION OF GAFCHROMIC EBT3 FILM FOR DOSIMETRY OF SCANNING PROTON PENCIL BEAM (PBS)2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 324-328Article in journal (Refereed)
    Abstract [en]

    Gafchromic EBT3 films are applied in proton radiotherapy for 2D dose mapping because they demonstrate spatial resolution well below 1mm. However, the film response must be corrected in order to reach the accuracy of dose measurements required for the clinical use. The in-house developed AnalyseGafchromic software allows to analyze and correct the measured response using triple channel dose calibration, statistical scan-to-scan fluctuations as well as experimentally determined dose and LET dependence. Finally, the optimized protocol for evaluation of response of Gafchromic EBT3 films was applied to determine 30 x 40 cm(2) dose profiles of the scanning therapy unit at the Cyclotron Centre Bronowice, CCB in Krakow, Poland.

  • 4. Nielsen, Steffen
    et al.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Grzanka, Leszek
    Swakon, Jan
    Olko, Pawel
    Andreassen, Christian Nicolaj
    Alsner, Jan
    Sørensen, Brita Singers
    Optimal reference genes for normalization of qPCR gene expression data from proton and photon irradiated dermal fibroblasts2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12688Article in journal (Refereed)
    Abstract [en]

    The transcriptional response of cells exposed to proton radiation is not equivalent to the response induced by traditional photon beams. Changes in cellular signalling is most commonly studied using the method Quantitative polymerase chain reaction (qPCR). Stable reference genes must be used to accurately quantify target transcript expression. The study aim was to identify suitable reference genes for normalisation of gene expression levels in normal dermal fibroblasts irradiated with either proton or photon beams. The online tool RefFinder was used to analyse and identify the most stably expressed genes from a panel of 22 gene candidates. To assess the reliability of the identified reference genes, a selection of the most and least stable reference genes was used to normalise target transcripts of interest. Fold change levels varied considerably depending on the used reference gene. The top ranked genes IPO8, PUM1, MRPL19 and PSMC4 produced highly similar target gene expression, while expression using the worst ranked genes, TFRC and HPRT1, was clearly modified due to reference gene instability.

  • 5. Nielsen, Steffen
    et al.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Grzanka, Leszek
    Swakon, Jan
    Olko, Pawel
    Andreassen, Christian Nicolaj
    Overgaard, Jens
    Alsner, Jan
    Singers Sørensen, Brita
    Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1406-1412Article in journal (Refereed)
    Abstract [en]

    Introduction: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients.

    Aim: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro.

    Methods: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions × 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis.

    Results: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type.

    Conclusions: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy.

  • 6. Singers Sørensen, Brita
    et al.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Nielsen, Steffen
    Horsman,, Michael R.
    Grzanka, Leszek
    Spejlborg, Harald
    Swakoń, Jan
    Olko, Paweł
    Overgaard, Jens
    Relative biological effectiveness (RBE) and distal edge effects of proton radiation on early damage in vivo2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1387-1391Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the present study was to examine the RBE for early damage in an in vivo mouse model, and the effect of the increased linear energy transfer (LET) towards the distal edge of the spread-out Bragg peak (SOBP).

    Method: The lower part of the right hind limb of CDF1 mice was irradiated with single fractions of either 6 MV photons, 240 kV photons or scanning beam protons and graded doses were applied. For the proton irradiation, the leg was either placed in the middle of a 30-mm SOBP, or to assess the effect in different positions, irradiated in 4 mm intervals from the middle of the SOBP to behind the distal dose fall-off. Irradiations were performed with the same dose plan at all positions, corresponding to a dose of 31.25 Gy in the middle of the SOBP. Endpoint of the study was early skin damage of the foot, assessed by a mouse foot skin scoring system.

    Results: The MDD50 values with 95% confidence intervals were 36.1 (34.2–38.1) Gy for protons in the middle of the SOBP for score 3.5. For 6 MV photons, it was 35.9 (34.5–37.5) Gy and 32.6 (30.7–34.7) Gy for 240 kV photons for score 3.5. The corresponding RBE was 1.00 (0.94–1.05), relative to 6 MV photons and 0.9 (0.85–0.97) relative to 240 kV photons. In the mice group positioned at the SOBP distal dose fall-off, 25% of the mice developed early skin damage compared with 0–8% in other groups. LETd,z = 1 was 8.4 keV/μm at the distal dose fall-off and the physical dose delivered was 7% lower than in the central SOBP position, where LETd,z =1 was 3.3 keV/μm.

    Conclusions: Although there is a need to expand the current study to be able to calculate an exact enhancement ratio, an enhanced biological effect in vivo for early skin damage in the distal edge was demonstrated.

  • 7.
    Thomas, Henry
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Ureba, Ana
    Stockholm University, Faculty of Science, Department of Physics.
    Tsubouchi, Toshiro
    Valdman, Alexander
    Siegbahn, Albert
    Stockholm University, Faculty of Science, Department of Physics.
    Development of an interlaced-crossfiring geometry for proton grid therapy2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1437-1443Article in journal (Refereed)
    Abstract [en]

    Background: Grid therapy has in the past normally been performed with single field photon-beamgrids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiringgrids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations.

    Material and methods: Dose profiles for single mm-wide proton beamlets (1, 2 and 3 mm FWHM) inwater were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets weredirected toward a cubic target volume, located at the center of a water tank. The aim was to deliver anearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue,i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of thetarget.

    Results: The relative increase of the beam width with depth was largest for the smallest beams(þ6.9mm for 1 mm wide and 150MeV proton beamlets). Satisfying dose coverage of the cubic targetvolume (r< ±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern ofthe dose distribution down to the target (valley-to-peak dose ratio<0.5 less than 1 cm before the tar-get). Center-to-center distances around 7–8 mm between the beams were found to give the best com-promise between target dose homogeneity and low peak doses outside of the target.

    Conclusions: A nearly homogeneous dose distribution can be obtained in a target volume by crossfir-ing grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution atlarge depths in the normal tissue, close to the target volume. We expect that the use of this methodwill increase the tumor control probability and improve the normal tissue sparing in grid therapy.

  • 8. Tsubouchi, Toshiro
    et al.
    Henry, Thomas
    Stockholm University, Faculty of Science, Department of Physics.
    Ureba, Ana
    Stockholm University, Faculty of Science, Department of Physics.
    Valdman, Alexander
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Albert
    Stockholm University, Faculty of Science, Department of Physics.
    Quantitative evaluation of potential irradiation geometries for carbon-ion beam grid therapy2018In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 45, no 3, p. 1210-1221Article in journal (Refereed)
    Abstract [en]

    Purpose: Radiotherapy using grids containing cm-wide beam elements has been carried out sporadically for more than a century. During the past two decades, preclinical research on radiotherapy with grids containing small beam elements, 25 m-0.7 mm wide, has been performed. Grid therapy with larger beam elements is technically easier to implement, but the normal tissue tolerance to the treatment is decreasing. In this work, a new approach in grid therapy, based on irradiations with grids containing narrow carbon-ion beam elements was evaluated dosimetrically. The aim formulated for the suggested treatment was to obtain a uniform target dose combined with well-defined grids in the irradiated normal tissue. The gain, obtained by crossfiring the carbon-ion beam grids over a simulated target volume, was quantitatively evaluated.

    Methods: The dose distributions produced by narrow rectangular carbon-ion beams in a water phantom were simulated with the PHITS Monte Carlo code. The beam-element height was set to 2.0 cm in the simulations, while the widths varied from 0.5 to 10.0 mm. A spread-out Bragg peak (SOBP) was then created for each beam element in the grid, to cover the target volume with dose in the depth direction. The dose distributions produced by the beam-grid irradiations were thereafter constructed by adding the dose profiles simulated for single beam elements. The variation of the valley-to-peak dose ratio (VPDR) with depth in water was thereafter evaluated. The separation of the beam elements inside the grids were determined for different irradiation geometries with a selection criterion.

    Results: The simulated carbon-ion beams remained narrow down to the depths of the Bragg peaks. With the formulated selection criterion, a beam-element separation which was close to the beam-element width was found optimal for grids containing 3.0-mm-wide beam elements, while a separation which was considerably larger than the beam-element width was found advantageous for grids containing 0.5-mm-wide beam elements. With the single-grid irradiation setup, the VPDRs were close to 1.0 already at a distance of several cm from the target. The valley doses given to the normal tissue at 0.5 cm distance from the target volume could be limited to less than 10% of the mean target dose if a crossfiring setup with four interlaced grids was used.

    Conclusions: The dose distributions produced by grids containing 0.5- and 3.0-mm wide beam elements had characteristics which could be useful for grid therapy. Grids containing mm-wide carbon-ion beam elements could be advantageous due to the technical ease with which these beams can be produced and delivered, despite the reduced threshold doses observed for early and late responding normal tissue for beams of millimeter width, compared to submillimetric beams. The treatment simulations showed that nearly homogeneous dose distributions could be created inside the target volumes, combined with low valley doses in the normal tissue located close to the target volume, if the carbon-ion beam grids were crossfired in an interlaced manner with optimally selected beam-element separations. The formulated selection criterion was found useful for the quantitative evaluation of the dose distributions produced by the different irradiation setups.

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