| 1. |
- Svendsen, Kristoffer, et al.
(författare)
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A focused very high energy electron beam for fractionated stereotactic radiotherapy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An electron beam of very high energy (50–250 MeV) can potentially produce a more favourable radiotherapy dose distribution compared to a state-of-the-art photon based radiotherapy technique. To produce an electron beam of sufficiently high energy to allow for a long penetration depth (several cm), very large accelerating structures are needed when using conventional radio-frequency technology, which may not be possible due to economical or spatial constraints. In this paper, we show transport and focusing of laser wakefield accelerated electron beams with a maximum energy of 160 MeV using electromagnetic quadrupole magnets in a point-to-point imaging configuration, yielding a spatial uncertainty of less than 0.1 mm, a total charge variation below 1 % and a focal spot of 2.3×2.6mm2. The electron beam was focused to control the depth dose distribution and to improve the dose conformality inside a phantom of cast acrylic slabs and radiochromic film. The phantom was irradiated from 36 different angles to obtain a dose distribution mimicking a stereotactic radiotherapy treatment, with a peak fractional dose of 2.72 Gy and a total maximum dose of 65 Gy. This was achieved with realistic constraints, including 23 cm of propagation through air before any dose deposition in the phantom.
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| 2. |
- Adrian, Gabriel, et al.
(författare)
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Cancer Cells Can Exhibit a Sparing FLASH Effect at Low Doses Under Normoxic In Vitro-Conditions
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irradiated with low doses in normoxia. Methods: Seven cancer cell lines (MDA-MB-231, MCF7, WiDr, LU-HNSCC4, HeLa [early passage and subclone]) and normal lung fibroblasts (MRC-5) were irradiated with doses ranging from 0 to 12 Gy using FLASH (≥800 Gy/s) or conventional dose rates (CONV, 14 Gy/min), with a 10 MeV electron beam from a clinical linear accelerator. Surviving fraction (SF) was determined with clonogenic assays. Three cell lines were further studied for radiation-induced DNA-damage foci using a 53BP1-marker and for cell cycle synchronization after irradiation. Results: A tendency of increased survival following FLASH compared with CONV was suggested for all cell lines, with significant differences for 4/7 cell lines. The magnitude of the FLASH-sparing expressed as a dose-modifying factor at SF=0.1 was around 1.1 for 6/7 cell lines and around 1.3 for the HeLasubclone. Similar cell cycle distributions and 53BP1-foci numbers were found comparing FLASH to CONV. Conclusion: We have found a FLASH effect appearing at low doses under normoxic conditions for several cell lines in vitro. The magnitude of the FLASH effect differed between the cell lines, suggesting inherited biological susceptibilities for FLASH irradiation.
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| 3. |
- Adrian, Gabriel, et al.
(författare)
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In vitro assays for investigating the FLASH effect
- 2022
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Ingår i: Expert Reviews in Molecular Medicine. - : Cambridge University Press (CUP). - 1462-3994. ; 24
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Forskningsöversikt (refereegranskat)abstract
- FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.
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| 4. |
- Adrian, Gabriel, et al.
(författare)
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The FLASH effect depends on oxygen concentration
- 2019
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 93:1106
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. METHODS: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. RESULTS: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5-10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. CONCLUSION: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. ADVANCES IN KNOWLEDGE: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.
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| 5. |
- Borg, David, et al.
(författare)
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Palliative short-course hypofractionated radiotherapy followed by chemotherapy in esophageal adenocarcinoma : the phase II PALAESTRA trial
- 2020
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Ingår i: Acta Oncologica. - 0284-186X. ; 59:2, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia. Methods: This phase II trial included treatment-naîve patients with dysphagia due to esophageal adenocarcinoma not eligible for curative treatment. External beam radiotherapy with 20 Gy in five fractions to the primary tumor was followed by four cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a five-grade scale. Results: From October 2014 to May 2018 a total of 29 patients were enrolled. The rate of dysphagia improvement was 79%, median duration of improvement 6.7 months (12.2 months for responders) and median overall survival 9.9 months. In the pre-specified per protocol analysis (23 patients) the rate of dysphagia improvement was 91%, median duration of improvement 12.2 months (14.0 months for responders) and median overall survival 16.0 months. The most common grade 3–4 adverse events were neutropenia (29%), infection (25%), anorexia (11%), esophagitis (11%) and fatigue (11%). Conclusion: Initial palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma.
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| 6. |
- Böhlen, Till Tobias, et al.
(författare)
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Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models : A Systematic Analysis
- 2023
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Ingår i: International Journal of Radiation Oncology Biology Physics. - 0360-3016. ; 117:4, s. 1007-1017
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed “FLASH effect”, also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. Methods and Materials: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. Results: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. Conclusions: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.
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| 7. |
- Børresen, Betina, et al.
(författare)
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Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: FLASH radiotherapy (RT) is a novel method for delivering ionizingradiation, which has been shown in preclinical studies to have a normal tissuesparing effect and to maintain anticancer efficacy as compared to conventionalRT. Treatment of head and neck tumors with conventional RT is commonlyassociated with severe toxicity, hence the normal tissue sparing effect of FLASHRT potentially makes it especially advantageous for treating oral tumors. In thiswork, the objective was to study the adverse effects of dogs with spontaneousoral tumors treated with FLASH RT.Methods: Privately-owned dogs with macroscopic malignant tumors of the oralcavity were treated with a single fraction of ≥30Gy electron FLASH RT andsubsequently followed for 12 months. A modified conventional linear acceleratorwas used to deliver the FLASH RT.Results: Eleven dogs were enrolled in this prospective study. High grade adverseeffects were common, especially if bone was included in the treatment field. Fourout of six dogs, who had bone in their treatment field and lived at least 5 monthsafter RT, developed osteoradionecrosis at 3-12 months post treatment. Thetreatment was overall effective with 8/11 complete clinical responses and 3/11partial responses.Conclusion: This study shows that single-fraction high dose FLASH RT wasgenerally effective in this mixed group of malignant oral tumors, but the risk ofosteoradionecrosis is a serious clinical concern. It is possible that the risk ofosteonecrosis can be mitigated through fractionation and improved doseconformity, which needs to be addressed before moving forward with clinicaltrials in human cancer patients.
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| 8. |
- Cooper, Christian R., et al.
(författare)
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Comet Assay Profiling of FLASH-Induced Damage : Mechanistic Insights into the Effects of FLASH Irradiation
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596. ; 24:8
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
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| 9. |
- Cooper, Christian R, et al.
(författare)
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FLASH irradiation induces lower levels of DNA damage ex vivo, an effect modulated by oxygen tension, dose, and dose rate
- 2022
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 95:1133
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen's role in the 'FLASH effect', we assessed DNA damage levels following irradiation at different oxygen tensions, doses and dose rates.METHODS: Samples of whole blood were irradiated (20 Gy) at various oxygen tensions (0.25-21%) with 6 MeV electrons at dose rates of either 2 kGy/s (FLASH) or 0.1 Gy/s (CONV), and subsequently with various doses (0-40 Gy) and intermediate dose rates (0.3-1000 Gy/s). DNA damage of peripheral blood lymphocytes (PBL) were assessed by the alkaline comet assay.RESULTS: Following 20 Gy irradiation, lower levels of DNA damage were induced for FLASH, the difference being significant at 0.25% (p < 0.05) and 0.5% O2 (p < 0.01). The differential in DNA damage at 0.5% O2 was found to increase with total dose and dose rate, becoming significant for doses ≥20 Gy and dose rates ≥30 Gy/s.CONCLUSION: This study shows, using the alkaline comet assay, that lower levels of DNA damage are induced following FLASH irradiation, an effect that is modulated by the oxygen tension, and increases with the total dose and dose rate of irradiation, indicating that an oxygen related mechanism, e.g. transient radiation-induced oxygen depletion, may contribute to the tissue sparing effect of FLASH irradiation.ADVANCES IN KNOWLEDGE: This paper is first to directly show that FLASH-induced DNA damage is modulated by oxygen tension, total dose and dose rate, with FLASH inducing significantly lower levels of DNA damage for doses ≥20 Gy and dose rates ≥30 Gy/s, at 0.5% O2.
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| 10. |
- Häggström, Henrik, et al.
(författare)
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Framtidens säkerhetstjänst i totalförsvaret
- 2024
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Mot bakgrund av en breddad och allt mer komplex hotbild mot Sverige och en ambition att stärka den svenska totalförsvarsförmågan har regeringen och Regeringskansliet på senare år skjutit till nya medel och försvarsanslag till det militära och civila försvaret, inklusive den militära Säkerhetstjänsten. De har även tagit fram ett antal nya lagar och regler som på olika sätt syftar till att vägleda säkerhetstjänstens verksamhet och stärka landets motståndskraft mot olika säkerhetshot inom ramen för totalförsvaret.Denna antologi har till uppgift att utifrån olika perspektiv analysera hur moderna hotbilder, ny teknik, lagstiftning, natomedlemskap och krav på samverkan med andra myndigheter och företag kommer påverka den militära säkerhetstjänstens och säkerhetsunderrättelsetjänstens verksamhet i framtiden. Antologin är skriven av några av Sveriges ledande experter på området i syfte att beskriva de utmaningar som den militära säkerhetstjänsten och säkerhetsunderrättelsetjänsten står inför samtidigt som totalförsvaret och krisberedskapen i Sverige återuppbyggs.Några av de frågor som ställs i antologin är hur och i vilken utsträckning det försämrade säkerhetsläget i vårt närområde, ny säkerhetsskyddslagstiftning, ambitionen att stärka det svenska totalförsvaret och Sveriges medlemskap i Nato kommer leda till att säkerhetstjänstens arbetsuppgifter förändras i framtiden? Slutsatserna från denna antologi är säkerhetstjänsten och säkerhetsunderrättelsetjänsterna i Sverige står inför ett paradigmskifte där det kommer vara nödvändigt att modernisera organisationen och implementera ny teknik för att anpassa sig till den digitala eran. Även vikten av intensifierad internationell samverkan kommer spela stor roll för säkerhetstjänstens möjligheter att bedriva ett effektivt arbete på nationell nivå i framtiden. Det multilaterala samarbetet är här för att stanna även om det är svårt och bygger på förtroenden mellan stater som inte alltid finns.
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| 11. |
- Kim, Michele M., et al.
(författare)
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Development of Ultra-High Dose Rate (FLASH) Particle Therapy
- 2022
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Ingår i: IEEE Transactions on Radiation and Plasma Medical Sciences. - 2469-7311. ; 6:3, s. 252-262
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Tidskriftsartikel (refereegranskat)abstract
- Research efforts in FLASH radiotherapy have increased at an accelerated pace recently. FLASH radiotherapy involves ultra-high dose rates and has shown to reduce toxicity to normal tissue while maintaining tumor response in pre-clinical studies when compared to conventional dose rate radiotherapy. The goal of this review is to summarize the studies performed to-date with proton, electron, and heavy ion FLASH radiotherapy, with particular emphasis on the physical aspects of each study and the advantages and disadvantages of each modality. Beam delivery parameters, experimental set-up, and the dosimetry tools used are described for each FLASH modality. In addition, modeling efforts and treatment planning for FLASH radiotherapy is discussed along with potential drawbacks when translated into the clinical setting. The final section concludes with further questions that have yet to be answered before safe clinical implementation of FLASH radiotherapy.
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| 12. |
- Konradsson, Elise, et al.
(författare)
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Beam control system and output fine-tuning for safe and precise delivery of FLASH radiotherapy at a clinical linear accelerator
- 2024
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHDR delivery. Materials and Methods: The beam control system is designed to interrupt the beam based on 1) a preset number of monitor units (MUs) measured by a monitor detector, 2) a preset number of pulses measured by a pulse-counting diode, or 3) a preset delivery time. For UHDR delivery, an optocoupler facilitates external control of the accelerator’s thyratron trigger pulses. A beam tuning process was established to maximize the output. We assessed the stability of the delivery, and the independent interruption capabilities of the three systems (monitor detector, pulse counter, and timer). Additionally, we explored a novel approach to enhance dosimetric precision in the delivery by synchronizing the trigger pulse with the charging cycle of the pulse forming network (PFN). Results: Improved beam tuning of gun current and magnetron frequency resulted in average dose rates at the dose maximum at isocenter distance of >160 Gy/s or >200 Gy/s, with or without an external monitor chamber in the beam path, respectively. The delivery showed a good repeatability (standard deviation (SD) in total film dose of 2.2%) and reproducibility (SD in film dose of 2.6%). The estimated variation in DPP resulted in an SD of 1.7%. The output in the initial pulse depended on the PFN delay time. Over the course of 50 measurements employing PFN synchronization, the absolute percentage error between the delivered number of MUs calculated by the monitor detector and the preset MUs was 0.8 ± 0.6% (mean ± SD). Conclusion: We present an upgraded beam control system and beam tuning process for safe and stable UHDR electron delivery of hundreds of Gy/s at isocenter distance at a clinical linac. The system can interrupt the beam based on monitor units and utilize PFN synchronization for improved dosimetric precision in the dose delivery, representing an important advancement toward reliable clinical FLASH trials.
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| 13. |
- Konradsson, Elise, et al.
(författare)
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Comparable Long-Term Tumor Control for Hypofractionated FLASH Versus Conventional Radiation Therapy in an Immunocompetent Rat Glioma Model
- 2022
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Ingår i: Advances in Radiation Oncology. - : Elsevier BV. - 2452-1094. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immunocompetent rat glioma model. Methods and Materials: Fisher 344 rats (N = 68) were inoculated subcutaneously with NS1 glioma cells and randomized into groups (n = 9-10 per group). CONV-RT (∼8 Gy/min) or FLASH-RT (70-90 Gy/s) was administered in 3 fractions of either 8 Gy, 12.5 Gy, or 15 Gy using a 10-MeV electron beam. The maximum tumor diameter was measured weekly, and overall survival was determined until day 100. Long-term tumor control was defined as no evident tumor on day 100. Animals were evaluated for acute dermal side effects at 2 to 5 weeks after completed RT and for late dermal side effects at 3 months after initiation of treatment. Results: Survival was significantly increased in all irradiated groups compared with control animals (P <.001). In general, irradiated tumors started to shrink at 1 week post–completed RT. In 40% (23 of 58) of the irradiated animals, long-term tumor control was achieved. Radiation-induced skin toxic effects were mild and consisted of hair loss, erythema, and dry desquamation. No severe toxic effect was observed. There was no significant difference between FLASH-RT and CONV-RT in overall survival, acute side effects, or late side effects for any of the dose levels. Conclusions: This study shows that hypofractionated FLASH-RT results in long-term tumor control rates similar to those of CONV-RT for the treatment of large subcutaneous glioblastomas in immunocompetent rats. Neither treatment technique induced severe skin toxic effects. Consequently, no significant difference in toxicity could be resolved, suggesting that higher doses may be required to detect a FLASH sparing of skin.
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| 14. |
- Konradsson, Elise, et al.
(författare)
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Correction for Ion Recombination in a Built-in Monitor Chamber of a Clinical Linear Accelerator at Ultra-High Dose Rates
- 2020
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Ingår i: Radiation Research. - 0033-7587. ; 194:6, s. 580-586
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Tidskriftsartikel (refereegranskat)abstract
- In the novel and promising radiotherapy technique known as FLASH, ultra-high dose-rate electron beams are used. As a step towards clinical trials, dosimetric advances will be required for accurate dose delivery of FLASH. The purpose of this study was to determine whether a built-in transmission chamber of a clinical linear accelerator can be used as a real-Time dosimeter to monitor the delivery of ultra-high-dose-rate electron beams. This was done by modeling the drop-in ion-collection efficiency of the chamber with increasing dose-per-pulse values, so that the ion recombination effect could be considered. The raw transmission chamber signal was extracted from the linear accelerator and its response was measured using radiochromic film at different dose rates/dose-per-pulse values, at a source-To-surface distance of 100 cm. An increase of the polarizing voltage, applied over the transmission chamber, by a factor of 2 and 3, improved the ion-collection efficiency, with corresponding increased efficiency at the highest dose-per-pulse values by a factor 1.4 and 2.2, respectively. The drop-in ion-collection efficiency with increasing dose-per-pulse was accurately modeled using a logistic function fitted to the transmission chamber data. The performance of the model was compared to that of the general theoretical Boag models of ion recombination in ionization chambers. The logistic model was subsequently used to correct for ion recombination at dose rates ranging from conventional to ultra-high, making the transmission chamber useful as a real-Time monitor for the dose delivery of FLASH electron beams in a clinical setup.
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| 15. |
- Konradsson, Elise, et al.
(författare)
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Establishment and Initial Experience of Clinical FLASH Radiotherapy in Canine Cancer Patients
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- FLASH radiotherapy has emerged as a treatment technique with great potential to increase the differential effect between normal tissue toxicity and tumor response compared to conventional radiotherapy. To evaluate the feasibility of FLASH radiotherapy in a relevant clinical setting, we have commenced a feasibility and safety study of FLASH radiotherapy in canine cancer patients with spontaneous superficial solid tumors or microscopic residual disease, using the electron beam of our modified clinical linear accelerator. The setup for FLASH radiotherapy was established using a short electron applicator with a nominal source-to-surface distance of 70 cm and custom-made Cerrobend blocks for collimation. The beam was characterized by measuring dose profiles and depth dose curves for various field sizes. Ten canine cancer patients were included in this initial study; seven patients with nine solid superficial tumors and three patients with microscopic disease. The administered dose ranged from 15 to 35 Gy. To ensure correct delivery of the prescribed dose, film measurements were performed prior to and during treatment, and a Farmer-type ion-chamber was used for monitoring. Treatments were found to be feasible, with partial response, complete response or stable disease recorded in 11/13 irradiated tumors. Adverse events observed at follow-up ranging from 3-6 months were mild and consisted of local alopecia, leukotricia, dry desquamation, mild erythema or swelling. One patient receiving a 35 Gy dose to the nasal planum, had a grade 3 skin adverse event. Dosimetric procedures, safety and an efficient clincal workflow for FLASH radiotherapy was established. The experience from this initial study will be used as a basis for a veterinary phase I/II clinical trial with more specific patient inclusion selection, and subsequently for human trials.
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| 16. |
- Konradsson, Elise, et al.
(författare)
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Evaluation of intensity-modulated electron FLASH radiotherapy in a clinical setting using veterinary cases
- 2023
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Ingår i: Medical Physics. - 0094-2405. ; 50:10, s. 6569-6579
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The increased normal tissue tolerance for FLASH radiotherapy (FLASH-RT), as compared to conventional radiotherapy, was first observed in ultra-high dose rate electron beams. Initial clinical trials in companion animals have revealed a high risk of developing osteoradionecrosis following high-dose single-fraction electron FLASH-RT, which may be related to inhomogeneities in the dose distribution. In the current study, we aim to evaluate the possibilities of intensity-modulated electron FLASH-RT in a clinical setting to ensure a homogeneous dose distribution in future veterinary and human clinical trials. Methods: Our beam model in the treatment planning system electronRT (.decimal, LLC, Sanford, FL, USA) was based on a 10-MeV electron beam from a clinical linear accelerator used to treat veterinary patients with FLASH-RT in a clinical setting. In electronRT, the beam can be intensity-modulated using tungsten island blocks in the electron block cutout, and range-modulated using a customized bolus with variable thickness. Modulations were first validated in a heterogeneous phantom by comparing measured and calculated dose distributions. To evaluate the impact of intensity modulation in superficial single-fraction FLASH-RT, a treatment planning study was conducted, including eight canine cancer patient cases with simulated tumors in the head-and-neck region. For each case, treatment plans with and without intensity modulation were created for a uniform bolus and a range-modulating bolus. Treatment plans were evaluated using a target dose homogeneity index (HI), a conformity index (CI), the near-maximum dose outside the target ((Figure presented.)), and the near-minimum dose to the target ((Figure presented.)). Results: By adding intensity modulation to plans with a uniform bolus, the HI could be improved (p = 0.017). The combination of a range-modulating bolus and intensity modulation provided a further significant improvement of the HI as compared to using intensity modulation in combination with a uniform bolus (p = 0.036). The range-modulating bolus also improved the CI compared to using a uniform bolus, both with an open beam (p = 0.046) and with intensity modulation (p = 0.018), as well as increased the (Figure presented.) (p = 0.036 with open beam and p = 0.05 with intensity modulation) and reduced the median (Figure presented.) (not significant). Conclusions: By using intensity-modulated electron FLASH-RT in combination with range-modulating bolus, the target dose homogeneity and conformity in canine patients with simulated tumors in complex areas in the head-and-neck region could be improved. By utilizing this technique, we hope to decrease the dose outside the target volume and avoid hot spots in future clinical electron FLASH-RT studies, thereby reducing the risk of radiation-induced toxicity.
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| 17. |
- Konradsson, Elise, et al.
(författare)
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Reconfiguring a Plane-Parallel Transmission Ionization Chamber to Extend the Operating Range into the Ultra-High Dose-per-pulse Regime
- 2024
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Ingår i: Radiation Research. - 0033-7587. ; 201:3, s. 252-260
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Tidskriftsartikel (refereegranskat)abstract
- This study aims to investigate the feasibility of enhancing the charge collection efficiency (CCE) of a transmission chamber by reconfiguring its design and operation. The goal was to extend the range of dose-per-pulse (DPP) values with no or minimal recombination effects up to the ultra-high dose rate (UHDR) regime. The response of two transmission chambers, with electrode distance of 1 mm and 0.6 mm, respectively, was investigated as a function of applied voltage. The chambers were mounted one-by-one in the electron applicator of a 10 MeV FLASH-modified clinical linear accelerator. The chamber signals were measured as a function of nominal DPP, which was determined at the depth of dose maximum using EBT-XD film in solid water and ranged from 0.6 mGy per pulse to 0.9 Gy per pulse, for both the standard voltage of 320 V and the highest possible safe voltage of 1,200 V. The CCE was calculated and fitted with an empirical logistic function that incorporated the electrode distance and the chamber voltage. The CCE decreased with increased DPP. The CCE at the highest achievable DPP was 24% (36%) at 320 V and 51% (82%) at 1,200 V, for chambers with 1 mm (0.6 mm) electrode distance. For the combination of 1,200 V- and 0.6-mm electrode distance, the CCE was»100% for average dose rate up to 70 Gy/s at the depth of dose maximum in the phantom at a source-to-surface distance of 100 cm. Our findings indicate that minor modifications to a plane-parallel transmission chamber can substantially enhance the CCE and extending the chamber's operating range to the UHDR regime. This supports the potential of using transmission chamber-based monitoring solutions for UHDR beams, which could facilitate the delivery of UHDR treatments using an approach similar to conventional clinical delivery.
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| 18. |
- Lempart, Michael, et al.
(författare)
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Modifying a clinical linear accelerator for delivery of ultra-high dose rate irradiation
- 2019
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140. ; 139, s. 40-45
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this study was to modify a clinical linear accelerator, making it capable of electron beam ultra-high dose rate (FLASH) irradiation. Modifications had to be quick, reversible, and without interfering with clinical treatments. Methods: Performed modifications: (1) reduced distance with three setup positions, (2) adjusted/optimized gun current, modulator charge rate and beam steering values for a high dose rate, (3) delivery was controlled with a microcontroller on an electron pulse level, and (4) moving the primary and/or secondary scattering foils from the beam path. Results: The variation in dose for a five-pulse delivery was measured to be 1% (using a diode, 4% using film) during 10 minutes after a warm-up procedure, later increasing to 7% (11% using film). A FLASH irradiation dose rate was reached at the cross-hair foil, MLC, and wedge position, with ≥30, ≥80, and ≥300 Gy/s, respectively. Moving the scattering foils resulted in an increased output of ≥120, ≥250, and ≥1000 Gy/s, at the three positions. The beam flatness was 5% at the cross-hair position for a 20 × 20 and a 10 × 10 cm2 area, with and without both scattering foils in the beam. The beam flatness was 10% at the wedge position for a 6 and 2.5 cm diametric area, with and without the scattering foils in the beam path. Conclusions: A clinical accelerator was modified to produce ultra-high dose rates, high enough for FLASH irradiation. Future work aims to fine-tune the dose delivery, using the on-board transmission chamber signal and adjusting the dose-per-pulse.
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| 19. |
- Liljedahl, Emma, et al.
(författare)
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Comparable survival in rats with intracranial glioblastoma irradiated with single-fraction conventional radiotherapy or FLASH radiotherapy
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Radiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to conventional radiotherapy (CONV-RT). Methods: Fully immunocompetent Fischer 344 rats with the GFP-positive NS1 intracranial glioblastoma model were irradiated with CONV-RT or FLASH-RT in one fraction of 20 Gy, 25 Gy or 30 Gy. Animals were monitored for survival and acute dermal side effects. The brains were harvested upon euthanasia and tumors were examined post mortem. Results: Survival was significantly increased in animals irradiated with CONV-RT and FLASH-RT at 20 Gy and 25 Gy compared to control animals. The longest survival was reached in animals irradiated with FLASH-RT and CONV-RT at 25 Gy. Irradiation at 30 Gy did not lead to increased survival, despite smaller tumors. Tumor size correlated inversely with irradiation dose, both in animals treated with CONV-RT and FLASH-RT. Acute dermal side effects were mild, but only a small proportion of the animals were alive for evaluation of those side effects. Conclusion: The dose response was similar for CONV-RT and FLASH-RT in the present model. Tumor size upon the time of euthanasia correlated inversely with the irradiation dose.
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| 20. |
- Lövgren, Nathalie, et al.
(författare)
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Feasibility and constraints of Bragg peak FLASH proton therapy treatment planning
- 2024
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: FLASH proton therapy (FLASH-PT) requires ultra-high dose rate (≥ 40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modulated proton therapy (IMPT). Materials and method: Bragg peak FLASH-PT and IMPT treatment plans were generated for bone (n=3), brain (n=3), and lung (n=4) targets using the MIROpt research treatment planning system and the Conformal FLASH library developed by Applications SA from the open-source version of UCLouvain. FLASH-PT beams were simulated using monoenergetic spot-scanned protons traversing through a conformal energy modulator, a range shifter, and an aperture. A dose rate constraint of ≥ 40 Gy/s was included in each FLASH-PT plan optimisation. Results: Space limitations in the FLASH-PT adapted beam nozzle imposed a maximum target width constraint, excluding 4 cases from the study. FLASH-PT plans did not satisfy the imposed target dose constraints (D95% ≥ 95% and D2%≤ 105%) but achieved clinically acceptable doses to organs at risk (OARs). IMPT plans adhered to all target and OAR dose constraints. FLASH-PT plans showed a reduction in both target homogeneity (p < 0.001) and dose conformity (non-significant) compared to IMPT. Conclusion: Without accounting for a sparing effect, IMPT plans were superior in target coverage, dose conformity, target homogeneity, and OAR sparing compared to FLASH-PT. Further research is warranted in treatment planning optimisation and beam delivery for clinical implementation of Bragg peak FLASH-PT.
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| 21. |
- Mannerberg, Annika, et al.
(författare)
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Faster and more accurate patient positioning with surface guided radiotherapy for ultra-hypofractionated prostate cancer patients
- 2021
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Ingår i: Technical Innovations and Patient Support in Radiation Oncology. - : Elsevier BV. - 2405-6324. ; 19, s. 41-45
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim of this study was to evaluate if surface guided radiotherapy (SGRT) can decrease patient positioning time for localized prostate cancer patients compared to the conventional 3-point localization setup method. The patient setup accuracy was also compared between the two setup methods. Materials and methods: A total of 40 localized prostate cancer patients were enrolled in this study, where 20 patients were positioned with surface imaging (SI) and 20 patients were positioned with 3-point localization. The setup time was obtained from the system log files of the linear accelerator and compared between the two methods. The patient setup was verified with daily orthogonal kV images which were matched based on the implanted gold fiducial markers. Resulting setup deviations between planned and online positions were compared between SI and 3-point localization. Results: Median setup time was 2:50 min and 3:28 min for SI and 3-point localization, respectively (p < 0.001). The median vector offset was 4.7 mm (range: 0–10.4 mm) for SI and 5.2 mm for 3-point localization (range: 0.41–17.3 mm) (p = 0.01). Median setup deviation in the individual translations for SI and 3-point localization respectively was: 1.1 mm and 1.9 mm in lateral direction (p = 0.02), 1.8 and 1.6 mm in the longitudinal direction (p = 0.41) and 2.2 mm and 2.6 mm in the vertical direction (p = 0.04). Conclusions: Using SGRT for positioning of prostate cancer patients provided a faster and more accurate patient positioning compared to the conventional 3-point localization setup.
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| 22. |
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| 23. |
- Mannerberg, Annika, et al.
(författare)
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Surface guided electron FLASH radiotherapy for canine cancer patients
- 2023
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Ingår i: Medical Physics. - 0094-2405. ; 50:7, s. 4047-4054
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundDuring recent years FLASH radiotherapy (FLASH-RT) has shown promising results in radiation oncology, with the potential to spare normal tissue while maintaining the antitumor effects. The high speed of the FLASH-RT delivery increases the need for fast and precise motion monitoring to avoid underdosing the target. Surface guided radiotherapy (SGRT) uses surface imaging (SI) to render a 3D surface of the patient. SI provides real-time motion monitoring and has a large scanning field of view, covering off-isocentric positions. However, SI has so far only been used for human patients with conventional setup and treatment.PurposeThe aim of this study was to investigate the performance of SI as a motion management tool during electron FLASH-RT of canine cancer patients.MethodsTo evaluate the SI system's ability to render surfaces of fur, three fur-like blankets in white, grey, and black were used to imitate the surface of canine patients and the camera settings were optimized for each blanket. Phantom measurements using the fur blankets were carried out, simulating respiratory motion and sudden shift. Respiratory motion was simulated using the QUASAR Respiratory Motion Phantom with the fur blankets placed on the phantom platform, which moved 10 mm vertically with a simulated respiratory period of 4 s. Sudden motion was simulated with an in-house developed phantom, consisting of a platform which was moved vertically in a stepwise motion at a chosen frequency. For sudden measurements, 1, 2, 3, 4, 5, 6, 7, and 10 Hz were measured. All measurements were both carried out at the conventional source-to-surface distance (SSD) of 100 cm, and in the locally used FLASH-RT setup at SSD = 70 cm. The capability of the SI system to reproduce the simulated motion and the sampling time were evaluated. As an initial step towards clinical implementation, the feasibility of SI for surface guided FLASH-RT was evaluated for 11 canine cancer patients.ResultsThe SI camera was capable of rendering surfaces for all blankets. The deviation between simulated and measured mean peak-to-peak breathing amplitude was within 0.6 mm for all blankets. The sampling time was generally higher for the black fur than for the white and grey fur, for the measurement of both respiratory and sudden motion. The SI system could measure sudden motion within 62.5 ms and detect motion with a frequency of 10 Hz. The feasibility study of the canine patients showed that the SI system could be an important tool to ensure patient safety. By using this system we could ensure and document that 10 out of 11 canine patients had a total vector offset from the reference setup position ConclusionsWe have shown that SI can be used for surface guided FLASH-RT of canine patients. The SI system is currently not fast enough to interrupt a FLASH-RT beam while irradiating but with the short sampling time sudden motion can be detected. The beam can therefore be held just prior to irradiation, preventing treatment errors such as underdosing the target.
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| 24. |
- Olivo, Gaia, et al.
(författare)
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Estimated gray matter volume rapidly changes after a short motor task
- 2022
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 32:19, s. 4356-4369
-
Tidskriftsartikel (refereegranskat)abstract
- Skill learning induces changes in estimates of gray matter volume (GMV) in the human brain, commonly detectable with magnetic resonance imaging (MRI). Rapid changes in GMV estimates while executing tasks may however confound between- and within-subject differences. Fluctuations in arterial blood flow are proposed to underlie this apparent task-related tissue plasticity. To test this hypothesis, we acquired multiple repetitions of structural T1-weighted and functional blood-oxygen level-dependent (BOLD) MRI measurements from 51 subjects performing a finger-tapping task (FTT; á 2 min) repeatedly for 30–60 min. Estimated GMV was decreased in motor regions during FTT compared with rest. Motor-related BOLD signal changes did not overlap nor correlate with GMV changes. Nearly simultaneous BOLD signals cannot fully explain task-induced changes in T1-weighted images. These sensitive and behavior-related GMV changes pose serious questions to reproducibility across studies, and morphological investigations during skill learning can also open new avenues on how to study rapid brain plasticity.
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| 25. |
- Pally, Dharma, et al.
(författare)
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Galectin-9 Signaling Drives Breast Cancer Invasion through Extracellular Matrix
- 2022
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8937 .- 1554-8929. ; 17:6, s. 1376-1386
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Tidskriftsartikel (refereegranskat)abstract
- Aberrations in glycan and lectin expression and function represent one of the earliest hallmarks of cancer. Among galectins, a conserved family of β-galactoside-binding lectins, the role of Galectin-9 in immune-tumor interactions is well-established, although its effect on cancer cell behavior remains unclear. In this study, we assayed for, and observed, an association between Galectin-9 expression and invasiveness of breast cancer cells in vitro and in vivo. Genetic perturbation and pharmacological inhibition using novel cognate inhibitors confirmed a positive correlation between Galectin-9 levels and the adhesion of invasive cancer cells to─and their invasion through─constituted organomimetic extracellular matrix microenvironments. Signaling experiments and unbiased quantitative proteomics revealed Galectin-9 induction of Focal Adhesion Kinase activity and S100A4 expression, respectively. FAK inhibition decreased S100A4 mRNA levels. Our results provide crucial insights into how elevated Galectin-9 expression potentiates the invasiveness of breast cancer cells during early steps of invasion.
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| 26. |
- Petersson, Kristoffer, et al.
(författare)
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A clinical distance measure for evaluating treatment plan quality difference with Pareto fronts in radiotherapy
- 2017
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Ingår i: Physics and imaging in radiation oncology. - : Elsevier BV. - 2405-6316. ; 3, s. 53-56
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Tidskriftsartikel (refereegranskat)abstract
- We present a clinical distance measure for Pareto front evaluation studies in radiotherapy, which we show strongly correlates (r = 0.74 and 0.90) with clinical plan quality evaluation. For five prostate cases, sub-optimal treatment plans located at a clinical distance value of >0.32 (0.28–0.35) from fronts of Pareto optimal plans, were assessed to be of lower plan quality by our (12) observers (p < .05). In conclusion, the clinical distance measure can be used to determine if the difference between a front and a given plan (or between different fronts) corresponds to a clinically significant plan quality difference.
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| 27. |
- Petersson, Kristoffer, et al.
(författare)
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A Quantitative Analysis of the Role of Oxygen Tension in FLASH Radiation Therapy
- 2020
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Ingår i: International Journal of Radiation Oncology Biology Physics. - : Elsevier BV. - 0360-3016. ; 107:3, s. 539-547
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Recent demonstrations of normal tissue sparing by high-dose, high-dose-rate FLASH radiation therapy have driven considerable interest in its application to improve clinical outcomes. However, significant uncertainty remains about the underlying mechanisms of FLASH sparing and how deliveries can be optimized to maximize benefit from this effect. Rapid oxygen depletion has been suggested as a potential mechanism by which these effects occur, but this has yet to be quantitatively tested against experimental data. Methods and Materials: Models of oxygen kinetics during irradiation were used to develop a time-dependent model of the oxygen enhancement ratio in mammalian cells that incorporates oxygen depletion. The characteristics of this model were then explored in terms of the dose and dose-rate dependence of the oxygen enhancement ratio. This model was also fit to experimental data from both in vitro and in vivo data sets. Results: In cases of FLASH radiation therapy, this model suggests that oxygen levels can be depleted by amounts that are sufficient to affect radiosensitivity only in conditions of intermediate oxygen tension, with no effect seen at high or very low initial oxygen levels. The model also effectively reproduced the dose, dose rate, and oxygen tension dependence of responses to FLASH radiation therapy in a range of systems, with model parameters compatible with published data. Conclusions: Oxygen depletion provides a credible quantitative model to understand the biological effects of FLASH radiation therapy and is compatible with a range of experimental observations of FLASH sparing. These results highlight the need for more detailed quantification of oxygen depletion under high-dose-rate radiation exposures in relevant systems and the importance of oxygen tension in target tissues for FLASH sparing to be observed.
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| 28. |
- Petersson, Kristoffer, et al.
(författare)
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Beam commissioning and measurements validating the beam model in a new TPS that converts helical tomotherapy plans to step-and-shoot IMRT plans.
- 2011
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Ingår i: Medical Physics. - : Wiley. - 0094-2405. ; 38:1, s. 40-46
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Tidskriftsartikel (refereegranskat)abstract
- A new type of treatment planning system called SHAREPLAN has been studied, which enables the transfer of treatment plans generated for helical tomotherapy delivery to plans that can be delivered on C-arm linacs. The purpose is to ensure continuous patient treatment during periods of unscheduled downtime for the TomoTherapy unit, particularly in clinics without a backup unit. The purpose of this work was to verify that the plans generated in this novel planning system are deliverable and accurate. The work consists primarily of beam commissioning, verification of the beam model, and measurements verifying that generated plans are deliverable with sufficient accuracy.
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| 29. |
- Petersson, Kristoffer, et al.
(författare)
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Conversion of helical tomotherapy plans to step-and-shoot IMRT plans-Pareto front evaluation of plans from a new treatment planning system
- 2011
-
Ingår i: Medical Physics. - : Wiley. - 0094-2405. ; 38:6, s. 3130-3138
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: The resulting plans from a new type of treatment planning system called SharePlan (TM) have been studied. This software allows for the conversion of treatment plans generated in a TomoTherapy system for helical delivery, into plans deliverable on C-arm linear accelerators (linacs), which is of particular interest for clinics with a single TomoTherapy unit. The purpose of this work was to evaluate and compare the plans generated in the SharePlan system with the original TomoTherapy plans and with plans produced in our clinical treatment planning system for intensity-modulated radiation therapy (IMRT) on C-arm linacs. In addition, we have analyzed how the agreement between SharePlan and TomoTherapy plans depends on the number of beams and the total number of segments used in the optimization. Methods: Optimized plans were generated for three prostate and three head-and-neck (H&N) cases in the TomoTherapy system, and in our clinical treatment planning systems (TPS) used for IMRT planning with step-and-shoot delivery. The TomoTherapy plans were converted into step-and-shoot IMRT plans in SharePlan. For each case, a large number of Pareto optimal plans were created to compare plans generated in SharePlan with plans generated in the Tomotherapy system and in the clinical TPS. In addition, plans were generated in SharePlan for the three head-and-neck cases to evaluate how the plan quality varied with the number of beams used. Plans were also generated with different number of beams and segments for other patient cases. This allowed for an evaluation of how to minimize the number of required segments in the converted IMRT plans without compromising the agreement between them and the original TomoTherapy plans. Results: The plans made in SharePlan were as good as or better than plans from our clinical system, but they were not as good as the original TomoTherapy plans. This was true for both the head-and-neck and the prostate cases, although the differences between the plans for the latter were small. The evaluation of the head-and-neck cases also showed that the plans generated in SharePlan were improved when more beams were used. The SharePlan Pareto front came close to the front for the TomoTherapy system when a sufficient number of beams were added. The results for plans generated with varied number of beams and segments demonstrated that the number of segments could be minimized with maintained agreement between SharePlan and TomoTherapy plans when 10-19 beams were used. Conclusions: This study showed (using Pareto front evaluation) that the plans generated in SharePlan are comparable to plans generated in other TPSs. The evaluation also showed that the plans generated in SharePlan could be improved with the use of more beams. To minimize the number of segments needed in a plan with maintained agreement between the converted IMRT plans and the original TomoTherapy plans, 10-19 beams should be used, depending on target complexity. SharePlan has proved to be useful and should thereby be a time-saving complement as a backup system for clinics with a single TomoTherapy system installed alongside conventional C-arm linacs. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3592934]
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Petersson, Kristoffer
(författare)
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Optimising the clinical use of tomotherapy
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radiotherapy is one of the major tools for treating cancer. Through research and technical development radiotherapy is becoming more advanced with new treatment techniques emerging. In the work presented in this thesis, well-known methods have been used, or modified for use, and new methods have been introduced in order to optimise the clinical use of an advanced radiotherapy treatment technique, specifically tomotherapy. In the presented work, tools used for fallback planning are evaluated. Methods are developed for the commissioning of them, evaluating the quality of the treatment plans (describes how patients are to be treated) they produce, and measurements are performed to ensure that the resulting treatments can be accurately delivered to the patients. These could assure an uninterrupted patient treatment with specialised treatment techniques. The results show that fallback planning is useful as it in many cases prevents a prolongation of the treatment which can have clinically significant impact. It should be an important time-saving complement, especially for clinics with a single specialised treatment unit such as tomotherapy, as they are more affected by its downtime. A method called clinical grading analysis (CGA) is presented as a way of comparing radiotherapy treatment plans. A CGA study takes advantage of the radiation oncologists’ clinical assessments to identify the clinical relevant differences between treatment plans. These subjective assessments are quantified in a CGA study, and used to decide which patients have a clinical benefit from treatment with one or the other of the advanced treatment techniques available to them. The results indicate that a CGA study provides a supporting framework for decision making regarding treatment techniques which helps to ensure a more optimal use of the clinic’s advanced treatment resources. Beam commissioning, plan quality assessment, and treatment deliverability measurements are important when introducing new techniques into the clinic. However, the work presented in this thesis shows that despite performing such investigations thoroughly, unexpected treatment side effects might occur. Hence, patient follow-up is of utmost importance when introducing new treatment techniques as it enables treatment adjustment to optimise the treatment outcome.
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| 34. |
- Petersson, Kristoffer, et al.
(författare)
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Treatment plan comparison using grading analysis based on clinical judgment.
- 2013
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Ingår i: Acta Oncologica. - 1651-226X. ; 52:3, s. 645-651
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. In this work we explore a method named clinical grading analysis (CGA) which is based on clinical assessments performed by radiation oncologists (ROs). The purpose is to investigate how useful the method is for treatment plan comparisons, and how the CGA results correlate with dosimetric evaluation parameters, traditionally used for treatment plan comparisons. Material and methods. Helical tomotherapy (HTT) and seven-beam step-and-shoot intensity modulated radiation therapy (SS-IMRT) plans were compared and assessed by 10 experienced ROs for 23 patient cases. A CGA was performed where the plans were graded based on how the ROs thought they compared to each other. The resulting grades from the CGA were analyzed and compared to dose-volume statistics and equivalent uniform dose (EUD) data. Results. For eight of the 23 cases the CGA revealed a significant difference between the HTT and the SS-IMRT plans, five cases were in favor of HTT, and three in favor of SS-IMRT. Comparing the dose-volume statistics and EUD-data with the result from the CGA showed that CGA results correlated well with dose-volume statistics for cases regarding difference in target coverage or doses to organs at risk. The CGA results also correlated well with EUD-data for cases with difference in clinical target volume (CTV) coverage but the correlation for cases with difference in planning target volume (PTV) coverage was not as clear. Conclusions. This study presents CGA as a useful method of comparing radiotherapy treatment plans. The proposed method offers a formalized way of introducing and evaluating the implementation of new radiotherapy techniques in a clinical setting. The CGA identify patients that have a clinical benefit of one or the other of the advanced treatment techniques available to them, i.e. in this study HTT and SS-IMRT, which facilitates a more optimal use of a clinics' advanced treatment resources.
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| 35. |
- Sesink, Anouk, et al.
(författare)
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The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest
- 2024
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Ingår i: NAR Cancer. - 2632-8674. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.
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| 36. |
- Stan, Tiberiu Loredan, et al.
(författare)
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Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis
- 2024
-
Ingår i: Neurotherapeutics. - : Elsevier. - 1878-7479 .- 1933-7213. ; 21:2, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.
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| 37. |
- Virta, Kristoffer, 1982-
(författare)
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Numerics of Elastic and Acoustic Wave Motion
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The elastic wave equation describes the propagation of elastic disturbances produced by seismic events in the Earth or vibrations in plates and beams. The acoustic wave equation governs the propagation of sound. The description of the wave fields resulting from an initial configuration or time dependent forces is a valuable tool when gaining insight into the effects of the layering of the Earth, the propagation of earthquakes or the behavior of underwater sound. In the most general case exact solutions to both the elastic wave equation and the acoustic wave equation are impossible to construct. Numerical methods that produce approximative solutions to the underlaying equations now become valuable tools. In this thesis we construct numerical solvers for the elastic and acoustic wave equations with focus on stability, high order of accuracy, boundary conditions and geometric flexibility. The numerical solvers are used to study wave boundary interactions and effects of curved geometries. We also compare the methods that we have constructed to other methods for the simulation of elastic and acoustic wave motion.
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| 38. |
- Vojnovic, Borivoj, et al.
(författare)
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Monitoring beam charge during FLASH irradiations
- 2023
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Ingår i: Frontiers in Physics. - 2296-424X. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- In recent years, FLASH irradiation has attracted significant interest in radiation research. Studies have shown that irradiation at ultra-high dose rates (FLASH) reduces the severity of toxicities in normal tissues compared to irradiation at conventional dose rates (CONV), as currently used in clinical practice. Most pre-clinical work is currently carried out using charged particle beams and the beam charge monitor described here is relevant to such beams. Any biological effect comparisons between FLASH and CONV irradiations rely on measurement of tissue dose. While well-established approaches can be used to monitor, in real time, the dose delivered during CONV irradiations, monitoring FLASH doses is not so straightforward. Recently the use of non-intercepting beam current transformers (BCTs) has been proposed for FLASH work. Such BCTs have been used for decades in numerous accelerator installations to monitor temporal and intensity beam profiles. In order to serve as monitoring dosimeters, the BCT output current must be integrated, using electronic circuitry or using software integration following signal digitisation. While sensitive enough for FLASH irradiation, where few intense pulses deliver the requisite dose, the inherent insensitivity of BCTs and the need for a wide detection bandwidth makes them less suitable for use during CONV “reference” irradiations. The purpose of this article is to remind the FLASH community of a different mode of BCT operation: direct monitoring of charge, rather than current, achieved by loading the BCT capacitively rather than resistively. The resulting resonant operation achieves very high sensitivities, enabling straightforward monitoring of output during both CONV and FLASH regimes. Historically, such inductive charge monitors have been used for single pulse work; however, a straightforward circuit modification allows selective resonance damping when repetitive pulsing is used, as during FLASH and CONV irradiations. Practical means of achieving this are presented, as are construction and signal processing details. Finally, results are presented showing the beneficial behaviour of the BCT versus an (Advanced Markus) ionisation chamber for measurements over a dose rate range, from <0.1 Gys−1 to >3 kGys−1.
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| 39. |
- Wilson, Joseph D., et al.
(författare)
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Ultra-High Dose Rate (FLASH) Radiotherapy : Silver Bullet or Fool's Gold?
- 2020
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 9
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Forskningsöversikt (refereegranskat)abstract
- Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.
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