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Pennock, Michael, Shouyi Wei, Chingyun Cheng, Haibo Lin, Shaakir Hasan, Arpit M. Chhabra, J. Isabelle Choi et al. "Proton Bragg Peak FLASH Enables Organ Sparing and Ultra-High Dose-Rate Delivery: Proof of Principle in Recurrent Head and Neck Cancer". Cancers 15, n.º 15 (28 de julho de 2023): 3828. http://dx.doi.org/10.3390/cancers15153828.
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Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90–100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.
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Zhu, Y. N., X. Zhang, Y. Lin, C. Lominska e H. Gao. "An Effective Dose Rate Optimization Algorithm for Efficient Conventional-Dose-Rate Proton Therapy and Ultra-High-Dose-Rate FLASH Proton Therapy". International Journal of Radiation Oncology*Biology*Physics 117, n.º 2 (outubro de 2023): S37—S38. http://dx.doi.org/10.1016/j.ijrobp.2023.06.306.
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Hughes, Jonathan R., e Jason L. Parsons. "FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy". International Journal of Molecular Sciences 21, n.º 18 (5 de setembro de 2020): 6492. http://dx.doi.org/10.3390/ijms21186492.
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FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy.
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Boudaghi Malidarreh, Roya, e Hesham M. H. Zakaly. "FLASH Radiation Therapy — Key physical irradiation parameters and beam characteristics". Journal of Instrumentation 19, n.º 02 (1 de fevereiro de 2024): P02035. http://dx.doi.org/10.1088/1748-0221/19/02/p02035.
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Abstract FLASH-RT represents a novel therapeutic radiation modality that holds remarkable potential for mitigating radiation therapy's adverse side effects. This cutting-edge technology allows for sparing healthy tissue while precisely targeting cancerous cells. This is possible by administering an ultra-high-dose-rate in less than a few hundred milliseconds. FLASH-RT has demonstrated impressive results in small-animal models, prompting scientists to adapt and advance existing technologies to make it a viable treatment option for humans. However, producing the ultra-high-dose-rate radiation required for the therapy remains a significant challenge. Several radiation sources, such as very high energy electrons (VHEEs), low energy electrons, x-rays, and protons, have been studied for their ability to deliver the necessary dose. Among them, FLASH-x-ray has gained the most attention owing to its capacity to penetrate deep-seated tumors. Despite the complexity of the process, the potential advantages of FLASH-RT made it an exciting area of research. To achieve the FLASH effect, high-frequency, pulsed irradiated accelerator technology can be employed. Sparing healthy tissue may allow for more aggressive and effective cancer treatments, leading to a better quality of life for patients. Ongoing research and development will be necessary to refine and optimize this approach to radiation therapy.
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Gazis, Nick, Andrea Bignami, Emmanouil Trachanas, Melina Moniaki, Evangelos Gazis, Dimitrios Bandekas e Nikolaos Vordos. "Simulation Dosimetry Studies for FLASH Radiation Therapy (RT) with Ultra-High Dose Rate (UHDR) Electron Beam". Quantum Beam Science 8, n.º 2 (24 de maio de 2024): 13. http://dx.doi.org/10.3390/qubs8020013.
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FLASH-radiotherapy (RT) presents great potential as an alternative to conventional radiotherapy methods in cancer treatment. In this paper, we focus on simulation studies for a linear particle accelerator injector design using the ASTRA code, which permits beam generation and particle tracking through electromagnetic fields. Space charge-dominated beams were selected with the aim of providing an optimized generated beam profile and accelerator lattice with minimized emittance. The main results of the electron beam and ultra-high dose rate (UHDR) simulation dosimetry studies are reported for the FLASH mode radiobiological treatment. Results for the percentage depth dose (PDD) at electron beam energies of 5, 7, 15, 25, 50, 100 MeV and 1.2 GeV for Poly-methyl-methacrylate (PMMA) and water phantom vs. the penetration depth are presented. Additionally, the PDD transverse profile was simulated for the above energies, delivering the beam to the phantom. The simulation dosimetry results provide an UHDR electron beam under the conditions of the FLASH-RT. The performance of the beam inside the phantom and the dose depth depends on the linear accelerator beam’s energy and stability.
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Ohsawa, Daisuke, Yota Hiroyama, Alisa Kobayashi, Tamon Kusumoto, Hisashi Kitamura, Satoru Hojo, Satoshi Kodaira e Teruaki Konishi. "DNA strand break induction of aqueous plasmid DNA exposed to 30 MeV protons at ultra-high dose rate". Journal of Radiation Research 63, n.º 2 (25 de dezembro de 2021): 255–60. http://dx.doi.org/10.1093/jrr/rrab114.
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Abstract Radiation cancer therapy with ultra-high dose rate exposure, so called FLASH radiotherapy, appears to reduce normal tissue damage without compromising tumor response. The aim of this study was to clarify whether FLASH exposure of proton beam would be effective in reducing the DNA strand break induction. We applied a simple model system, pBR322 plasmid DNA in aqueous 1 × TE solution, where DNA single strand breaks (SSBs) and double strand breaks (DSBs) can be precisely quantified by gel electrophoresis. Plasmid DNA were exposed to 27.5 MeV protons in the conventional dose rate of 0.05 Gy/s (CONV) and ultra-high dose rate of 40 Gy/s (FLASH). With both dose rate, the kinetics of the SSB and DSB induction were proportional to absorbed dose. The SSB induction of FLASH was significantly less than CONV, which were 8.79 ± 0.14 (10−3 SSB per Gy per molecule) and 10.8 ± 0.68 (10−3 SSB per Gy per molecule), respectively. The DSB induction of FLASH was also slightly less than CONV, but difference was not significant. Altogether, 27.5 MeV proton beam at 40 Gy/s reduced SSB and not DSB, thus its effect may not be significant in reducing lethal DNA damage that become apparent in acute radiation effect.
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Schulte, Reinhard, Carol Johnstone, Salime Boucher, Eric Esarey, Cameron G. R. Geddes, Maksim Kravchenko, Sergey Kutsaev et al. "Transformative Technology for FLASH Radiation Therapy". Applied Sciences 13, n.º 8 (17 de abril de 2023): 5021. http://dx.doi.org/10.3390/app13085021.
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The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.
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Lattery, Grant, Tyler Kaulfers, Chingyun Cheng, Xingyi Zhao, Balaji Selvaraj, Haibo Lin, Charles B. Simone, J. Isabelle Choi, Jenghwa Chang e Minglei Kang. "Pencil Beam Scanning Bragg Peak FLASH Technique for Ultra-High Dose Rate Intensity-Modulated Proton Therapy in Early-Stage Breast Cancer Treatment". Cancers 15, n.º 18 (14 de setembro de 2023): 4560. http://dx.doi.org/10.3390/cancers15184560.
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Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications.
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Okoro, Chidi M., Emil Schüler e Cullen M. Taniguchi. "The Therapeutic Potential of FLASH-RT for Pancreatic Cancer". Cancers 14, n.º 5 (24 de fevereiro de 2022): 1167. http://dx.doi.org/10.3390/cancers14051167.
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Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.
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Liu, G., L. Zhao, X. Li, S. Zhang, S. Dai, X. Lu e X. Ding. "A Novel Ultra-High Dose Rate Proton Therapy Technology: Spot-Scanning Proton Arc Therapy FLASH (SPLASH)". International Journal of Radiation Oncology*Biology*Physics 114, n.º 3 (novembro de 2022): S39—S40. http://dx.doi.org/10.1016/j.ijrobp.2022.07.402.
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van Marlen, Patricia, Max Dahele, Michael Folkerts, Eric Abel, Ben J. Slotman e Wilko Verbakel. "Ultra-High Dose Rate Transmission Beam Proton Therapy for Conventionally Fractionated Head and Neck Cancer: Treatment Planning and Dose Rate Distributions". Cancers 13, n.º 8 (13 de abril de 2021): 1859. http://dx.doi.org/10.3390/cancers13081859.
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Transmission beam (TB) proton therapy (PT) uses single, high energy beams with Bragg-peak behind the target, sharp penumbras and simplified planning/delivery. TB facilitates ultra-high dose-rates (UHDRs, e.g., ≥40 Gy/s), which is a requirement for the FLASH-effect. We investigated (1) plan quality for conventionally-fractionated head-and-neck cancer treatment using spot-scanning proton TBs, intensity-modulated PT (IMPT) and photon volumetric-modulated arc therapy (VMAT); (2) UHDR-metrics. VMAT, 3-field IMPT and 10-field TB-plans, delivering 70/54.25 Gy in 35 fractions to boost/elective volumes, were compared (n = 10 patients). To increase spot peak dose-rates (SPDRs), TB-plans were split into three subplans, with varying spot monitor units and different gantry currents. Average TB-plan organs-at-risk (OAR) sparing was comparable to IMPT: mean oral cavity/body dose were 4.1/2.5 Gy higher (9.3/2.0 Gy lower than VMAT); most other OAR mean doses differed by <2 Gy. Average percentage of dose delivered at UHDRs was 46%/12% for split/non-split TB-plans and mean dose-averaged dose-rate 46/21 Gy/s. Average total beam-on irradiation time was 1.9/3.8 s for split/non-split plans and overall time including scanning 8.9/7.6 s. Conventionally-fractionated proton TB-plans achieved comparable OAR-sparing to IMPT and better than VMAT, with total beam-on irradiation times <10s. If a FLASH-effect can be demonstrated at conventional dose/fraction, this would further improve plan quality and TB-protons would be a suitable delivery system.
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Wei, Shouyi, Haibo Lin, J. Isabelle Choi, Charles B. Simone e Minglei Kang. "A Novel Proton Pencil Beam Scanning FLASH RT Delivery Method Enables Optimal OAR Sparing and Ultra-High Dose Rate Delivery: A Comprehensive Dosimetry Study for Lung Tumors". Cancers 13, n.º 22 (18 de novembro de 2021): 5790. http://dx.doi.org/10.3390/cancers13225790.
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Purpose: While transmission proton beams have been demonstrated to achieve ultra-high dose rate FLASH therapy delivery, they are unable to spare normal tissues distal to the target. This study aims to compare FLASH treatment planning using single energy Bragg peak proton beams versus transmission proton beams in lung tumors and to evaluate Bragg peak plan optimization, characterize plan quality, and quantify organ-at-risk (OAR) sparing. Materials and Methods: Both Bragg peak and transmission plans were optimized using an in-house platform for 10 consecutive lung patients previously treated with proton stereotactic body radiation therapy (SBRT). To bring the dose rate up to the FLASH-RT threshold, Bragg peak plans with a minimum MU/spot of 1200 and transmission plans with a minimum MU/spot of 400 were developed. Two common prescriptions, 34 Gy in 1 fraction and 54 Gy in 3 fractions, were studied with the same beam arrangement for both Bragg peak and transmission plans (n = 40 plans). RTOG 0915 dosimetry metrics and dose rate metrics based on different dose rate calculations, including average dose rate (ADR), dose-averaged dose rate (DADR), and dose threshold dose rate (DTDR), were investigated. We then evaluated the effect of beam angular optimization on the Bragg peak plans to explore the potential for superior OAR sparing. Results: Bragg peak plans significantly reduced doses to several OAR dose parameters, including lung V7.4Gy and V7Gy by 32.0% (p < 0.01) and 30.4% (p < 0.01) for 34Gy/fx plans, respectively; and by 40.8% (p < 0.01) and 41.2% (p < 0.01) for 18Gy/fx plans, respectively, compared with transmission plans. Bragg peak plans have ~3% less in DADR and ~10% differences in mean OARs in DTDR and DADR relative to transmission plans due to the larger portion of lower dose regions of Bragg peak plans. With angular optimization, optimized Bragg peak plans can further reduce the lung V7Gy by 20.7% (p < 0.01) and V7.4Gy by 19.7% (p < 0.01) compared with Bragg peak plans without angular optimization while achieving a similar 3D dose rate distribution. Conclusion: The single-energy Bragg peak plans achieve superior dosimetry performances in OARs to transmission plans with comparable dose rate performances for lung cancer FLASH therapy. Beam angle optimization can further improve the OAR dosimetry parameters with similar 3D FLASH dose rate coverage.
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Vanreusel, Verdi, Alessia Gasparini, Federica Galante, Giulia Mariani, Matteo Pacitti, Madalina Cociorb, Andrea Giammanco et al. "Point scintillator dosimetry in ultra-high dose rate electron “FLASH” radiation therapy: A first characterization". Physica Medica 103 (novembro de 2022): 127–37. http://dx.doi.org/10.1016/j.ejmp.2022.10.005.
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Dirbas, Frederick, Stavros Melemenidis, Bill Loo, Kathleen Horst, Edward E. Graves, Suparna Dutt, Vignesh Viswanathan, Brianna Lau e Amy Yu. "Abstract P1-10-02: FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer". Cancer Research 83, n.º 5_Supplement (1 de março de 2023): P1–10–02—P1–10–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-10-02.
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Abstract Problem Statement: Radiation therapy (RT) for breast cancer (BC) can induce skin and soft tissue fibrosis, raises concerns over cardiac and pulmonary injury, is associated with higher rates of lymphedema and shoulder dysfunction with regional nodal irradiation, and significantly increases complication rates in women undergoing implant-based reconstruction due to radiation toxicity. Although these toxicities are not generally associated with higher mortality, in general, they can represent significant setbacks with respect to quality of life. These toxicities dissuade some patients from breast conservation leading to unnecessary mastectomy and can lead patients to omit reconstruction after mastectomy or choose more extensive autologous breast reconstruction. Women with implant-based reconstruction and radiotherapy have known higher rates of reconstruction failure. Purpose: Ultra-high dose rate radiation (FLASH) has been shown to induce less normal tissue toxicity, therefore if tumor control of FLASH-RT would be comparable to conventional radiotherapy (CONV) then it has the potential to lower morbidity associated with radiotherapy for breast cancer and allow overall improved outcomes. At first, we aimed to determine the effectiveness of FLASH-RT compared to CONV in eradicating small breast tumors in an orthotopic BC model using single-fraction 20 or 30Gy RT to compare effectiveness of FLASH-RT vs CONV. Methods: Radiation sensitive, syngeneic mammary tumor cell line Py117, that efficiently forms non-metastatic orthotopic tumors in C57BL/6 mice, were injected (106 cells) into the left 4th mammary fat pad. 30mm3 tumors or a range of greater volumes (200-800mm3) were irradiated with single-fraction 20 or 30Gy with a 2x2cm radiation field (~17MeV beams), exposing only 5mm of the surrounding tissue. FLASH RT was delivered with 2Gy per pulse at dose rate ~200Gy/s compared to CONV dose rate of 0.13Gy/s Results: Single-fraction 20Gy suppressed 30mm3 tumor growth until ~day 15 post-RT then regrew for both FLASH and CONV, while 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy. Larger tumors irradiated with 30Gy regressed until ~day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth suppression or tumor eradication between FLASH and CONV in any cohort. Conclusion: In this murine model of breast cancer, FLASH is as effective as CONV in controlling tumor growth. Future studies will extend the evaluation of the tumor control using clinically relevant fractionated dose schedules to be followed by comparisons of tumor control in xenograft models. Additional studies will assess normal tissue toxicity of FLASH vs CONV in murine models of implant-based breast reconstruction. We have established collaborations to understand differences in molecular pathways activated by FLASH vs CONV in tumor and normal tissue to explain the observed experimental differences in normal tissue, tumor, and cancer stem cells. Citation Format: Frederick Dirbas, Stavros Melemenidis, Bill Loo, Kathleen Horst, Edward E. Graves, Suparna Dutt, Vignesh Viswanathan, Brianna Lau, Amy Yu. FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-02.
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Yan, Ouying, Shang Wang, Qiaoli Wang e Xin Wang. "FLASH Radiotherapy: Mechanisms of Biological Effects and the Therapeutic Potential in Cancer". Biomolecules 14, n.º 7 (25 de junho de 2024): 754. http://dx.doi.org/10.3390/biom14070754.
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Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers.
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Kaulfers, Tyler, Grant Lattery, Chingyun Cheng, Xingyi Zhao, Balaji Selvaraj, Hui Wu, Arpit M. Chhabra et al. "Pencil Beam Scanning Proton Bragg Peak Conformal FLASH in Prostate Cancer Stereotactic Body Radiotherapy". Cancers 16, n.º 4 (15 de fevereiro de 2024): 798. http://dx.doi.org/10.3390/cancers16040798.
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Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.
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Ronga, Maria Grazia, Marco Cavallone, Annalisa Patriarca, Amelia Maia Leite, Pierre Loap, Vincent Favaudon, Gilles Créhange e Ludovic De Marzi. "Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy". Cancers 13, n.º 19 (30 de setembro de 2021): 4942. http://dx.doi.org/10.3390/cancers13194942.
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The development of innovative approaches that would reduce the sensitivity of healthy tissues to irradiation while maintaining the efficacy of the treatment on the tumor is of crucial importance for the progress of the efficacy of radiotherapy. Recent methodological developments and innovations, such as scanned beams, ultra-high dose rates, and very high-energy electrons, which may be simultaneously available on new accelerators, would allow for possible radiobiological advantages of very short pulses of ultra-high dose rate (FLASH) therapy for radiation therapy to be considered. In particular, very high-energy electron (VHEE) radiotherapy, in the energy range of 100 to 250 MeV, first proposed in the 2000s, would be particularly interesting both from a ballistic and biological point of view for the establishment of this new type of irradiation technique. In this review, we examine and summarize the current knowledge on VHEE radiotherapy and provide a synthesis of the studies that have been published on various experimental and simulation works. We will also consider the potential for VHEE therapy to be translated into clinical contexts.
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Agapov, A. V., E. A. Gritskova, S. A. Gustov, G. V. Mytsin, A. G. Molokanov, I. Khassenova, S. V. Shvidkij e K. N. Shipulin. "Delivery of High-Intensity Proton Beam for the Study of Flash-Effect in Radiotherapy". Meditsinskaya Fizika, n.º 4 (29 de dezembro de 2023): 29–39. http://dx.doi.org/10.52775/1810-200x-2023-100-4-29-39.
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Flash-therapy is a rapidly developing field of radiology that has the potential to revolutionize future cancer treatment techniques. The method involves delivery the therapeutic radiation dose to the tumor volume at an ultra-high dose rate in the beam, several orders of magnitude higher than that usually used in conventional radiotherapy. In this mode of irradiation, the degree of damage to normal tissues surrounding the tumor and falling under the influence of radiation decreases, at the same time, the effect on cancer cells remains at the same level, which preserves the prospect of local control of the tumor with a lower frequency of side effects.
The paper presents the results on the delivery of a high-intensity proton beam with an energy of 660 MeV from the Phasotron of the Joint Institute for Nuclear Research, Dubna, designed for radiobiological studies under flash therapy irradiation of cell cultures and small laboratory animals (mice, rats). In addition, the main design features and parameters of the created detectors for measuring the characteristics of this beam are presented.
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Yin, Lingshu, Umezawa Masumi, Kan Ota, Daniel M. Sforza, Devin Miles, Mohammad Rezaee, John W. Wong, Xun Jia e Heng Li. "Feasibility of Synchrotron-Based Ultra-High Dose Rate (UHDR) Proton Irradiation with Pencil Beam Scanning for FLASH Research". Cancers 16, n.º 1 (3 de janeiro de 2024): 221. http://dx.doi.org/10.3390/cancers16010221.
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Background: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. Methods: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. Results: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. Conclusions: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge.
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Vidalot, Jeoffray, Cosimo Campanella, Julien Dachicourt, Claude Marcandella, Olivier Duhamel, Adriana Morana, David Poujols et al. "Monitoring of Ultra-High Dose Rate Pulsed X-ray Facilities with Radioluminescent Nitrogen-Doped Optical Fiber". Sensors 22, n.º 9 (21 de abril de 2022): 3192. http://dx.doi.org/10.3390/s22093192.
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We exploited the potential of radiation-induced emissions (RIEs) in the visible domain of a nitrogen-doped, silica-based, multimode optical fiber to monitor the very high dose rates associated with experiments at different pulsed X-ray facilities. We also tested this sensor at lower dose rates associated with steady-state X-ray irradiation machines (up to 100 keV photon energy, mean energy of 40 keV). For transient exposures, dedicated experimental campaigns were performed at ELSA (Electron et Laser, Source X et Applications) and ASTERIX facilities from CEA (Commissariat à l’Energie Atomique—France) to characterize the RIE of this fiber when exposed to X-ray pulses with durations of a few µs or ns. These facilities provide very large dose rates: in the order of MGy(SiO2)/s for the ELSA facility (up to 19 MeV photon energy) and GGy(SiO2)/s for the ASTERIX facility (up to 1 MeV). In both cases, the RIE intensities, mostly explained by the fiber radioluminescence (RIL) around 550 nm, with a contribution from Cerenkov at higher fluxes, linearly depend on the dose rates normalized to the pulse duration delivered by the facilities. By comparing these high dose rate results and those acquired under low-dose rate steady-state X-rays (only RIL was present), we showed that the RIE of this multimode optical fiber linearly depends on the dose rate over an ultra-wide dose rate range from 10−2 Gy(SiO2)/s to a few 109 Gy(SiO2)/s and photons with energy in the range from 40 keV to 19 MeV. These results demonstrate the high potential of this class of radiation monitors for beam monitoring at very high dose rates in a very large variety of facilities as future FLASH therapy facilities.
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Kourkafas, G., J. Bundesmann, A. Denker, A. Dittwald, T. Fanselow, J. Heufelder, A. Weber e P. Mühldorfer. "Proton FLASH irradiation setup for preclinical studies at HZB". Journal of Physics: Conference Series 2687, n.º 9 (1 de janeiro de 2024): 092002. http://dx.doi.org/10.1088/1742-6596/2687/9/092002.
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Abstract The HZB cyclotron continues to provide protons for eye-tumor treatment in collaboration with the Charité – Universitätsmedizin Berlin after 24 years and more than 4400 patients so far. With the perspective of broadening its research capabilities in the field of radiation therapy, intensive effort has been dedicated towards proton FLASH irradiation, which requires ultra-high dose rates or beam intensities. By combining a fast and reliable switch-off mechanism, accurate dosimetry, and a double-scattering beam nozzle with a static 3D-printed range modulator, HZB is now able to deliver a dose rate above 150 Gy/s within a flat circular irradiation field of 18mm diameter and a 27mm spread-out Bragg peak with a distal fall-off of 1mm in water. The reproducibility of the delivered dose meets the clinical acceptance criteria for a total irradiation time as low as 2.5 ms. The first experiments with this setup were used on fibroblastic and sarcoma organoids. By adapting the design to a 35mm lateral field and using optimal accelerator tuning to increase beam transmission, similar or even higher dose rates are expected, satisfying thus the FLASH conditions for eye-tumor treatment with protons.
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Lyu, Feng, Shi-Yu Shang, Xian-Shu Gao, Ming-Wei Ma, Mu Xie, Xue-Ying Ren, Ming-Zhu Liu, Jia-Yan Chen, Shan-Shi Li e Lei Huang. "Uncovering the Secrets of Prostate Cancer’s Radiotherapy Resistance: Advances in Mechanism Research". Biomedicines 11, n.º 6 (3 de junho de 2023): 1628. http://dx.doi.org/10.3390/biomedicines11061628.
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Prostate cancer (PCa) is a critical global public health issue with its incidence on the rise. Radiation therapy holds a primary role in PCa treatment; however, radiation resistance has become increasingly challenging as we uncover more about PCa’s pathogenesis. Our review aims to investigate the multifaceted mechanisms underlying radiation therapy resistance in PCa. Specifically, we will examine how various factors, such as cell cycle regulation, DNA damage repair, hypoxic conditions, oxidative stress, testosterone levels, epithelial–mesenchymal transition, and tumor stem cells, contribute to radiation therapy resistance. By exploring these mechanisms, we hope to offer new insights and directions towards overcoming the challenges of radiation therapy resistance in PCa. This can also provide a theoretical basis for the clinical application of novel ultra-high-dose-rate (FLASH) radiotherapy in the era of PCa.
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Soderholm, Haille, Zara Kiger, Wonju Kim, Robbie Majzner e Bonnie Lau. "RBIO-06. COMBINING FLASH RADIOTHERAPY WITH GD2-CAR T CELL IMMUNOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA". Neuro-Oncology 25, Supplement_5 (1 de novembro de 2023): v257. http://dx.doi.org/10.1093/neuonc/noad179.0987.
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Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor related deaths in pediatric cancers. DIPG is completely lethal, and palliative radiation therapy (RT) to control symptoms is currently the standard-of-care treatment for DIPG, therefore effective treatment is urgently needed. In recent phase 1 clinical trials, the promising potential for using chimeric antigen receptor T cell immunotherapy against the disialoganglioside GD2 (GD2-CART) has been established, where 75% of patients exhibited clinical and radiographic improvement. There has also been emerging evidence advocating for the combined use of GD2-CART therapy with conventional radiation (CONV-RT) to enhance the immune response in other solid brain tumors. Ultra-high dose rate radiotherapy, abbreviated as FLASH-RT, is an emerging radiation technique shown to reduce normal brain tissue damage while preserving tumor control, as compared to CONV-RT. It is currently unknown how FLASH-RT will affect CART therapy. We hypothesize that effective treatment for DIPG can be achieved by combining FLASH-RT with GD2-CART immunotherapy. We have shown FLASH-RT to equivocally kill DIPG cells as well as the standard-of-care, CONV-RT; Given the neurological tissue sparing effects of FLASH-RT, this radiotherapy alone could be an improvement for DIPG treatment. Additionally, we have validated that GD2 is highly expressed in our DIPG cell line, suggesting high GD2-CART target specificity. Additionally, we have found that GD2 expression on DIPG tumor cells remains unchanged upon treatment with FLASH-RT. Therefore, we can utilize FLASH-RT to target GD2 CART while sparing normal tissue and minimizing neurotoxicity, allowing for a promising avenue of combination treatment for this devastating pediatric cancer.
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Minns, Hanna E., Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Matthew Gallitto, Luca Szalontay, Jovana Pavisic et al. "RADT-09. IMMUNE RESPONSE IN DIFFUSE MIDLINE GLIOMA (DMG) FOLLOWING FLASH OR CONVENTIONAL RADIATION". Neuro-Oncology 26, Supplement_4 (18 de junho de 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.769.
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Abstract BACKGROUND Diffuse Midline Glioma (DMG) is a fatal, unresectable, pediatric brain tumor with limited treatment options and a median survival of 9-15mths. As radiation therapy (RT) can only extend life by 3mths, novel RT techniques are needed, including ultra-high dose rate RT (FLASH). RT can stimulate immune responses in many cancers especially via type 1 interferon (IFN1) but the effect of RT on DMG is understudied as post treatment tissue is not readily available. METHODS We evaluated the effect of RT on immune response in an orthotopic syngeneic model of DMG, comparing FLASH, given at 90Gy/second, to conventional dose rate RT (CONV), given at 2Gy/min. We evaluated single-cell RNA sequencing (scRNA-seq) on CD45+ immune cells isolated from tumors 4 days post 15Gy FLASH or CONV RT and compared to unirradiated tumor (SHAM). We also performed flow cytometry on tumors at both day 4 and day 10 post-RT. RESULTS We find microglia (MG) are the most abundant immune cell type followed by non-resident myeloid cells including macrophages (MAC) and dendritic cells (DC). While there’s no significant difference in tumor growth or proportion of immune subtypes comparing FLASH, CONV and SHAM, we see similar IFN1 enrichment in MG comparing FLASH and CONV at day 4. Interestingly, at day 10 post-RT we observe higher IFN1 receptor (IFNAR1) by flow in MGs after CONV (p=0.016) and SHAM (p=0.040) compared to FLASH. At day 4 CONV shows higher IFN1 gene set enrichment in MACs and DCs compared to FLASH (both p<0.0001) as well as higher IFNAR1 in DCs comparing CONV to FLASH (p=0.0079), while day 10 post-RT shows equivalent IFNAR1 in MACs and DCs between dose rates. CONCLUSION Changes in DMG tumor immune microenvironment post-RT differ over time. Though both RT modalities increase IFN1, the timing of this response is dependent on both cell phenotype and dose.
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Gartrell, Robyn, Hanna Minns, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan et al. "IMMU-17. INDUCING IMMUNE RESPONSE WITH FLASH AND CONVENTIONAL DOSE-RATE RADIATION IN DIFFUSE MIDLINE GLIOMA (DMG)". Neuro-Oncology 25, Supplement_5 (1 de novembro de 2023): v145. http://dx.doi.org/10.1093/neuonc/noad179.0549.
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Abstract Diffuse Midline Glioma is a universally fatal inoperable pediatric brain tumor associated with H3K27M mutation and median survival of 9-15 months. Radiation therapy (RT) is the primary treatment, extending life by only three months. Conventional dose-rate RT (2Gy/min, CONV) can induce an immune response with type 1 interferon (IFN1) in multiple cancers including adult brain tumors. Ultra-fast dose-rate RT (90Gy/second, FLASH) has comparable tumor control to CONV with decreased toxicity, however, evaluation of immune response is limited. Using an orthotopic syngeneic model of brainstem DMG, we performed single-cell RNA sequencing (scRNA-seq) on CD45+ immune cells isolated from tumors four days post 15Gy FLASH or CONV RT, and compared to unirradiated tumor. We performed flow cytometry at day 4 and day 10 post-RT. ScRNA-seq reveals 33,308 immune cells in 17 unique clusters. Microglia (MG) make up 73.8% and non-resident myeloid cells make up 7.9% of cells and include macrophages (MAC), dendritic cells (DC) and Monocytes (MONO). Flow at day 4 and day 10 show no significant difference in proportion of immune cell subtypes comparing FLASH, CONV and tumor. With differential gene expression, FLASH and CONV provoke a similar inflammatory and IFN1 response in MG while in MACs and DCs IFN1 pathway expression is increased in CONV compared to FLASH (p< 0.001 for both), confirmed by flow at day 4 using IFNAR1 expression (MACs p< 0.05, DCs p< 0.01). Flow at day 10 post-RT shows increased IFNAR1 expression in MACs in both CONV and FLASH compared to tumor (p< 0.0001) while day 10 IFNAR1 in DCs is similar in all three groups. In summary, while immune proportions are similar comparing different dose rates of RT, IFN1 is differentially expressed in CONV compared to FLASH at day 4 in MACs and DCs, while this response at day 10 is similar comparing dose rates.
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Minns, Hanna, Oscar Padilla, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, Xu Zhang et al. "TMIC-68. EVALUATING FLASH AND CONVENTIONAL DOSE-RATE RADIATION AND IMMUNE RESPONSE WITH SINGLE-CELL SEQUENCING IN DIFFUSE MIDLINE GLIOMA (DMG)". Neuro-Oncology 24, Supplement_7 (1 de novembro de 2022): vii286. http://dx.doi.org/10.1093/neuonc/noac209.1111.
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Abstract Diffuse Midline Glioma – H3K27M mutant (DMG), is a fatal and inoperable pediatric brain tumor with limited treatment options as radiation provides only temporary reprieve, leaving the median survival between 9-15 months. Conventional dose-rate radiation (2Gray/minute, CONV) has been shown in other cancers to recruit an immune component, however, this has not been studied in DMG. Ultra-high dose-rate radiation given at 90 Gray/second (FLASH), is a novel technique associated with decreased toxicity and effective tumor control. Using a syngeneic model of brainstem DMG, we performed single-cell RNA sequencing on CD45+ immune cells isolated from tumors irradiated with 15Gray using FLASH or CONV, and compared to unirradiated tumor and normal brainstem. Isolation of 33,308 immune cells revealed 17 unique clusters, most abundant of which was microglia (73.8%), present in four distinct subtypes representing a spectrum from homeostatic to activated. In the most activated microglia, both FLASH and CONV showed an enrichment in type 1 interferon (IFN1) pathway scores compared to untreated tumors (p< 0.001 and p< 0.001, respectively). The most differential response was found in macrophages (MAC) and dendritic cells (DC) with a robust enrichment of IFN1 pathway scores for CONV compared to FLASH (p< 0.001, MAC and p< 0.001 DC). FLASH showed an increase in anti-inflammatory MAC markers such as Mrc1, Cd163, and Maf and an enrichment of myeloid-derived suppressor cell (MDSC) signature in monocytes, not seen in CONV (p< 0.001). Finally, we correlated our data with publicly available single-cell data taken from the cerebrospinal fluid of DMG patients treated with anti-GD2 CAR T Cell therapy and found similar inflammatory markers characteristic of our unirradiated murine tumors. In summary, our work is the first to study immune alterations comparing different dose-rates of radiation with single-cell resolution in DMG, highlighting the potential for combining radiation and immunotherapy in these tumors.
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Cunningham, Shannon, Shelby McCauley, Kanimozhi Vairamani, Joseph Speth, Swati Girdhani, Eric Abel, Ricky A. Sharma et al. "FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice". Cancers 13, n.º 5 (1 de março de 2021): 1012. http://dx.doi.org/10.3390/cancers13051012.
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Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.
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Kim, Michele M., Ioannis I. Verginadis, Denisa Goia, Allison Haertter, Khayrullo Shoniyozov, Wei Zou, Amit Maity et al. "Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model". Cancers 13, n.º 16 (23 de agosto de 2021): 4244. http://dx.doi.org/10.3390/cancers13164244.
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Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.
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Padilla, Oscar, Hanna Minns, Hong-Jian Wei, Andrea Webster-Carrion, Masih Tazhibi, Nicholas McQuillan, Xu Zhang et al. "91 Impact of ultra-fast ‘FLASH’ radiotherapy on single cell immunogenomics in diffuse intrinsic pontine glioma (DIPG)". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembro de 2021): A100. http://dx.doi.org/10.1136/jitc-2021-sitc2021.091.
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BackgroundDiffuse intrinsic pontine gliomas (DIPG’s) are immunologically inert tumors with a median survival of 9–15 months. Radiation therapy (RT) is the mainstay treatment for DIPG but is associated with immunodepletion of the tumor microenvironment (TME) at high dose ranges. FLASH, or ultra-fast dose rate RT, represents a novel ablative technique that may spare TME immune responses while decreasing tumor burden. Here, we present single-cell immune profiling of DIPG tumors treated with FLASH, conventional dose rate RT (CONV) or no RT (SHAM).MethodsMurine H3.3K27M mutant DIPG cells were stereotactically injected and tumor induction confirmed by magnetic resonance imaging (MRI) 15 days later. DIPG-bearing mice were randomly assigned to one of three treatment groups (n=4/group), FLASH, CONV or SHAM. A fourth group with no tumor (NML) was included as a negative biological control. A modified linear accelerator was used to deliver 15 Gy of electron RT to the brainstem at dose rates of 90 Gy/second and 2 Gy/minute, for the FLASH and CONV groups, respectively. Four days post-RT, mice brainstems were harvested, homogenized, stained for CD45 and tagged with a hashtag antibody specific to each group. CD45+ immune cells were isolated and sequenced using the 10X Genomics chromium single-cell 3’ platform. After processing and alignment of the reads using CellRanger with default parameters, the data was quality checked and filtered before hashtag demultiplexing, unsupervised clustering and downstream analysis was implemented following the Seurat R package. Differential expression evaluated based on the non-parametric Wilcoxon rank sum test. Key genes determine by an adjusted p value of < 0.05 based on bonferroni correction and |avg log2FC| > 0.8.ResultsPreliminary analysis identifies 15 clusters with distinct CD45 immune phenotypes (figure 1). Differential gene expression analysis by hashtag antibody (treatment group) reveals 14 clusters differentially expressing key genes, including 3 clusters upregulated in DIPG compared to NML, and 2 clusters upregulated in irradiated tumors compared to SHAM and NML (figure 2). Notably, analysis demonstrates an individual cluster upregulated in FLASH versus all other groups (p = 3.07E-171). Further deconvolution of specific immune phenotypes represented by each cluster is ongoing.Abstract 91 Figure 1tSNE plot based on clustering of RNA signatures, grouped by RNAAbstract 91 Figure 2tSNE plot based on clustering of RNA signatures, grouped by hashtag antibodyConclusionsOur preliminary analysis shows differential immune responses among DIPG tumors compared to NML. We also find several immune cell subsets that are unique to DIPG treated with CONV or FLASH compared to unirradiated samples. Most notably, we identify a single immune cell subset that is exclusive to FLASH alone, indicating that FLASH elicits a unique immune response in murine DIPG.
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Piruzan, Elham, Naser Vosoughi, Seied Rabi Mahdavi, Leila Khalafi e Hojjat Mahani. "Target motion management in breast cancer radiation therapy". Radiology and Oncology 55, n.º 4 (8 de outubro de 2021): 393–408. http://dx.doi.org/10.2478/raon-2021-0040.
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Abstract Background Over the last two decades, breast cancer remains the main cause of cancer deaths in women. To treat this type of cancer, radiation therapy (RT) has proved to be efficient. RT for breast cancer is, however, challenged by intrafractional motion caused by respiration. The problem is more severe for the left-sided breast cancer due to the proximity to the heart as an organ-at-risk. While particle therapy results in superior dose characteristics than conventional RT, due to the physics of particle interactions in the body, particle therapy is more sensitive to target motion. Conclusions This review highlights current and emerging strategies for the management of intrafractional target motion in breast cancer treatment with an emphasis on particle therapy, as a modern RT technique. There are major challenges associated with transferring real-time motion monitoring technologies from photon to particles beams. Surface imaging would be the dominant imaging modality for real-time intrafractional motion monitoring for breast cancer. The magnetic resonance imaging (MRI) guidance and ultra high dose rate (FLASH)-RT seem to be state-of-the-art approaches to deal with 4D RT for breast cancer.
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Vallicelli, E. A., A. Baschirotto e M. De Matteis. "Proton Sound Detector for beam range/dose measurement in FLASH hadron therapy". Journal of Instrumentation 17, n.º 07 (1 de julho de 2022): C07007. http://dx.doi.org/10.1088/1748-0221/17/07/c07007.
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Abstract Proton Sound Detectors (ProSDs) sense (at low latency, <1 ms) the thermoacoustic signal generated by the fast energy deposition at the Bragg peak of a proton beam penetrating an energy absorber. ProSDs are especially promising for experimental monitoring of high pulse rate (FLASH) hadron therapy treatments working in-sync with the beam. This paper presents a mixed signal detector, capable of sensing and processing high rate (1k beam shots/sec) ionacoustic signals with low latency (<1 ms). The system was validated by measuring the dose deposition of a 20 MeV proton beam in water, achieving 3.43% precision (±2.75 GyRMS) after 50 ms acquisition (77.56 Gy total dose deposition).
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Lu, Zhou, Xueting Zheng, Chenghe Ding, Zhiyan Zou, Yuanyuan Liang, Yan Zhou e Xiaoan Li. "Deciphering the Biological Effects of Radiotherapy in Cancer Cells". Biomolecules 12, n.º 9 (23 de agosto de 2022): 1167. http://dx.doi.org/10.3390/biom12091167.
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Radiotherapy remains an effective conventional method of treatment for patients with cancer. However, the clinical efficacy of radiotherapy is compromised by the development of radioresistance of the tumor cells during the treatment. Consequently, there is need for a comprehensive understanding of the regulatory mechanisms of tumor cells in response to radiation to improve radiotherapy efficacy. The current study aims to highlight new developments that illustrate various forms of cancer cell death after exposure to radiation. A summary of the cellular pathways and important target proteins that are responsible for tumor radioresistance and metastasis is also provided. Further, the study outlines several mechanistic descriptions of the interaction between ionizing radiation and the host immune system. Therefore, the current review provides a reference for future research studies on the biological effects of new radiotherapy technologies, such as ultra-high-dose-rate (FLASH) radiotherapy, proton therapy, and heavy-ion therapy.
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Krieger, Miriam, Steven Water, Michael M. Folkerts, Alejandro Mazal, Silvia Fabiano, Nicola Bizzocchi, Damien C. Weber, Sairos Safai e Antony J. Lomax. "A quantitative FLASH effectiveness model to reveal potentials and pitfalls of high dose rate proton therapy". Medical Physics 49, n.º 3 (27 de janeiro de 2022): 2026–38. http://dx.doi.org/10.1002/mp.15459.
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Telford, Tom, Jackson Roberts, Alicia Moggré, Juergen Meyer e Steven Marsh. "Noise Considerations for Tomographic Reconstruction of Single-Projection Digital Holographic Interferometry-Based Radiation Dosimetry". Photonics 10, n.º 2 (9 de fevereiro de 2023): 188. http://dx.doi.org/10.3390/photonics10020188.
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Optical Calorimetry (OC) is a 2D Digital Holographic Interferometry (DHI)-based measurement technique with potential applications for the 3D dosimetry of ultra-high dose rate (FLASH) radiation therapy beams through tomographic reconstruction. This application requires accurate measurements of DHI signals in environments with low signal-to-noise ratios (SNRs) in order to accurately measure absorbed energy to a medium per unit mass (Dose). However, tomographic reconstruction accuracy is sensitive to noise in the measurements. In this study, a virtual model of an OC dosimeter was used to characterize and model major sources of noise within a DHI setup, allowing for the modelled noise sources to be selectively reduced. The tomographic reconstruction of the 3D dose distribution was achieved using the inverse Abel transform. Reducing the noise contribution from atmospheric turbulence and mechanical vibration by one half improved the central axis reconstruction error from 6.5% to 1.3% and 1.1%, respectively, and the mean dose difference from 2.9% to 0.4% and 0.3%, respectively. This indicates the potential of the tomographic DHI-based 3D OC dosimeter to reconstruct accurate 3D dose distributions from a single projection if the specified sources of noise can be reduced to acceptable levels. The used methodology is applicable to any application of tomographic DHI where reconstruction quality is highly sensitive to noise.
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Mazal, Alejandro, Yolanda Prezado, Carme Ares, Ludovic de Marzi, Annalisa Patriarca, Raymond Miralbell e Vincent Favaudon. "FLASH and minibeams in radiation therapy: the effect of microstructures on time and space and their potential application to protontherapy". British Journal of Radiology 93, n.º 1107 (março de 2020): 20190807. http://dx.doi.org/10.1259/bjr.20190807.
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After years of lethargy, studies on two non-conventional microstructures in time and space of the beams used in radiation therapy are enjoying a huge revival. The first effect called “FLASH” is based on very high dose-rate irradiation (pulse amplitude ≥106 Gy/s), short beam-on times (≤100 ms) and large single doses (≥10 Gy) as experimental parameters established so far to give biological and potential clinical effects. The second effect relies on the use of arrays of minibeams (e.g., 0.5–1 mm, spaced 1–3.5 mm). Both approaches have been shown to protect healthy tissues as an endpoint that must be clearly specified and could be combined with each other (e.g., minibeams under FLASH conditions). FLASH depends on the presence of oxygen and could proceed from the chemistry of peroxyradicals and a reduced incidence on DNA and membrane damage. Minibeams action could be based on abscopal effects, cell signalling and/or migration of cells between “valleys and hills” present in the non-uniform irradiation field as well as faster repair of vascular damage. Both effects are expected to maintain intact the tumour control probability and might even preserve antitumoural immunological reactions. FLASH in vivo experiments involving Zebrafish, mice, pig and cats have been done with electron beams, while minibeams are an intermediate approach between X-GRID and synchrotron X-ray microbeams radiation. Both have an excellent rationale to converge and be applied with proton beams, combining focusing properties and high dose rates in the beam path of pencil beams, and the inherent advantage of a controlled limited range. A first treatment with electron FLASH (cutaneous lymphoma) has recently been achieved, but clinical trials have neither been presented for FLASH with protons, nor under the minibeam conditions. Better understanding of physical, chemical and biological mechanisms of both effects is essential to optimize the technical developments and devise clinical trials.
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Makowski, C., A. Schüller, M. Deutsch e C. Schmitzer. "FLASH Modalities Track (Oral Presentations) MULTI-LEAF FARADAY CUP FOR QUALITY ASSURANCE IN RADIATION THERAPY WITH ELECTRON AND ION BEAMS AT CONVETIONAL AND ULTRA-HIGH DOSE RATE". Physica Medica 94 (fevereiro de 2022): S61. http://dx.doi.org/10.1016/s1120-1797(22)01569-1.
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Stish, Brad J., Gina L. Mazza, Jones T. Nauseef, Michael Sandon Humeniuk, Thomas J. Smith, Cindy Tofthagen, Dayssy Alexandra Diaz Pardo et al. "Alliance A222001: A randomized, double-blind, placebo controlled phase II study of oxybutynin versus placebo for the treatment of hot flashes in men receiving androgen deprivation therapy." Journal of Clinical Oncology 42, n.º 17_suppl (10 de junho de 2024): LBA12004. http://dx.doi.org/10.1200/jco.2024.42.17_suppl.lba12004.
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LBA12004 Background: Hot flashes are among the most common adverse events impacting quality of life reported by patients receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer. Oxybutynin is an effective therapy for reducing frequency and severity of hot flashes in women. Pilot information supports that this drug may also benefit men with hot flashes related to ADT. Methods: Patients with prostate cancer receiving a stable regimen of ADT with at least 28 hot flashes per week were randomized to receive either oral oxybutynin 2.5 mg twice a day, oxybutynin 5 mg twice a day, or matching placebo doses for 6 weeks. The primary endpoint was the change in patient-reported hot flash scores (determined by multiplying the number of hot flashes by the mean hot flash severity [grade 0: none, 1: mild, 2: moderate, 3: severe, and 4: very severe]) from baseline to 6 weeks, as measured by a daily hot flash diary. A total of 87 patients provided 76% power to reject the null hypothesis of no between-arm mean difference in hot flash score reduction from baseline to 6 weeks, when comparing each oxybutynin arm to the combined placebo arms. This was based on a two-sided contrast estimated from a generalized linear mixed model, α= 0.10, intraclass correlation of 0.50, population standardized mean difference of 0.50, and 10% missing data rate. Results: 88 patients were accrued between 10/28/21 and 12/02/23. Six patients cancelled before starting treatment and one was ineligible, leaving 81 analyzed patients with a median age of 68. Baseline characteristics were balanced between arms with patients reporting an average of 10.15 (SD = 5.55) hot flashes per day and an average daily hot flash score of 18.23 (SD = 13.48) at enrollment. On average, patients on the placebo arm, low dose oxybutynin arm, and high dose oxybutynin arm had reductions of 2.15, 4.77, and 6.89 hot flashes/day, respectively. Compared to placebo arm patients, high dose oxybutynin arm patients had a greater reduction in hot flashes/day (p < 0.001), as did low dose oxybutynin arm patients (p = 0.02). Daily hot flash scores for the same three protocol arms reduced by an average of 4.85, 9.94, and 13.95 points, respectively. Compared to placebo arm patients, high dose oxybutynin arm patients had a greater reduction in daily hot flash scores (p = 0.002), as did low dose oxybutynin arm patients (p = 0.07). No treatment-related grade 3+ adverse events occurred. The most commonly reported oxybutynin-related grade 2 adverse event was dry mouth. Conclusions: Oxybutynin is superior to a placebo for the management of hot flashes in men associated with androgen deprivation therapy and appears to be well tolerated. Support: UG1CA189823; https://acknowledgments.alliancefound.org . Clinical trial information: NCT04600336 .
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Merzlikin, G. V., S. V. Akulinichev e I. A. Yakovlev. "Simulation of a proton beam facility in the TOPAS MC software package". Seriya 3: Fizika, Astronomiya, n.º 1_2023 (2 de junho de 2023): 2310201–1. http://dx.doi.org/10.55959/msu0579-9392.78.2310201.
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The aim of this work is to simulate the formation system of therapeutic proton beams at the accelerator of the Institute of Nuclear Research, Russian Academy of Sciences, using the TOPAS MC software package and to calculate, on this basis, the characteristics of irradiation of biological objects. As such characteristics, the dependence of the absorbed dose and linear energy transfer (LET) on the proton range in water and the effective dose of irradiation of HT-29 and HCT-116 cell lines used in real experiments are considered. Also, the uniformity of irradiation with a high dose rate of the studied biological objects was evaluated during the operation of the radiation unit in FLASH-therapy modes. The research is aimed at preparing and conducting radiobiological experiments with proton beams with a record dose rate.
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Tesse, R., C. Hernalsteens, E. Gnacadja, E. Ramoisiaux, N. Pauly e M. Vanwelde. "Achromatic gantry design using fixed-field spiral combined-function magnets". Journal of Physics: Conference Series 2420, n.º 1 (1 de janeiro de 2023): 012096. http://dx.doi.org/10.1088/1742-6596/2420/1/012096.
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Abstract Arc-therapy and flash therapy are promising proton therapy treatment modalities as they enable further sparing of the healthy tissues surrounding the tumor site. They impose strong constraints on the beam delivery system and rotating gantry structure, in particular in providing high dose rate and fast energy scanning. Fixed-field achromatic transport lattices potentially satisfy both constraints in allowing instant energy modulation and sufficient transmission efficiency while providing a compact footprint. The presented design study uses fixed-field magnets with spiral edges respecting the FFA scaling law. The cell structure and the layout are studied in simulation and integrated in a compact gantry. Results and further optimizations are discussed.
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Kirkby, Karen Joy, Norman Francis Kirkby, Neil Gunn Burnet, Hywel Owen, Ranald Iain Mackay, Adrian Crellin e Stuart Green. "Heavy charged particle beam therapy and related new radiotherapy technologies: The clinical potential, physics and technical developments required to deliver benefit for patients with cancer". British Journal of Radiology 93, n.º 1116 (1 de dezembro de 2020): 20200247. http://dx.doi.org/10.1259/bjr.20200247.
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In the UK, one in two people will develop cancer during their lifetimes and radiotherapy (RT) plays a key role in effective treatment. High energy proton beam therapy commenced in the UK National Health Service in 2018. Heavier charged particles have potential advantages over protons by delivering more dose in the Bragg peak, with a sharper penumbra, lower oxygen dependence and increased biological effectiveness. However, they also require more costly equipment including larger gantries to deliver the treatment. There are significant uncertainties in the modelling of relative biological effectiveness and the effects of the fragmentation tail which can deliver dose beyond the Bragg peak. These effects need to be carefully considered especially in relation to long-term outcomes. In 2019, a group of clinicians, clinical scientists, engineers, physical and life scientists from academia and industry, together with funding agency stakeholders, met to consider how the UK should address new technologies for RT, especially the use of heavier charged particles such as helium and carbon and new modes of delivery such as FLASH and spatially fractionated radiotherapy (SFRT). There was unanimous agreement that the UK should develop a facility for heavier charged particle therapy, perhaps constituting a new National Ion Research Centre to enable research using protons and heavier charged particles. Discussion followed on the scale and features, including which ions should be included, from protons through helium, boron, and lithium to carbon, and even oxygen. The consensus view was that any facility intended to treat patients must be located in a hospital setting while providing dedicated research space for physics, preclinical biology and clinical research with beam lines designed for both in vitro and in vivo research. The facility should to be able to investigate and deliver both ultra-high dose rate FLASH RT and SFRT (GRID, minibeams etc.). Discussion included a number of accelerator design options and whether gantries were required. Other potential collaborations might be exploited, including with space agencies, electronics and global communications industries and the nuclear industry. In preparation for clinical delivery, there may be opportunities to send patients overseas (for 12C or 4He ion therapy) using the model of the National Health Service (NHS) Proton Overseas Programme and to look at potential national clinical trials which include heavier ions, FLASH or SFRT. This could be accomplished under the auspices of NCRI CTRad (National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group). The initiative should be a community approach, involving all interested parties with a vision that combines discovery science, a translational research capability and a clinical treatment facility. Barriers to the project and ways to overcome them were discussed. Finally, a set of different scenarios of features with different costs and timelines was constructed, with consideration given to the funding environment (prer-Covid-19) and need for cross-funder collaboration.
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Taylor, R., A. F. Steinberg, J. Pasternak, R. B. Appleby, S. L. Sheehy e E. Benedetto. "Slow Extraction Techniques from Fixed Field Accelerators". Journal of Physics: Conference Series 2687, n.º 2 (1 de janeiro de 2024): 022022. http://dx.doi.org/10.1088/1742-6596/2687/2/022022.
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Abstract Fixed Field Accelerators are a candidate for future hadron cancer therapy facilities as their high repetition rate and large energy acceptance enables novel treatment modalities such as high dose rate FLASH. However, conventional dose delivery mechanisms are still necessary, requiring continuous beam delivery over 1–30s. This work is the first study of slow extraction from a scaling Fixed Field Accelerator, using the LhARA facility for baseline parameters. At a horizontal tune of 10/3, the intrinsic sextupole strength of the nonlinear FFA magnetic field is sufficient to excite the resonance, although extraction is better controlled using an additional excitation sextupole at a tune close to 8/3, with radiofrequency knock-out extraction. Including considerations of issues due to nonlinear fields and limitations required to keep the tune energy-independent, slow extraction from Fixed Field Accelerators is successfully demonstrated.
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Li, X. K., Z. Amirkhanyan, N. Aftab, P. Boonpornprasert, D. Dmytriiev, M. Frohme, G. Georgiev et al. "Overview of FLASHlab@PITZ: the new R&D platform for FLASH radiation therapy and radiation biology". Journal of Physics: Conference Series 2687, n.º 9 (1 de janeiro de 2024): 092006. http://dx.doi.org/10.1088/1742-6596/2687/9/092006.
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Abstract An R&D platform for electron FLASH radiation therapy and radiation biology is being prepared at the Photo Injector Test facility at DESY in Zeuthen (FLASHlab@PITZ). This platform is based on the unique beam parameters available at PITZ: ps scale electron bunches of up to 22 MeV with up to 5 nC bunch charge at MHz bunch repetition rate in bunch trains of up to 1 ms in length repeating at 1 to 10 Hz. It works together with the Technical University of Applied Sciences Wildau (TH Wildau) as partner in close vicinity for the biological resources. A startup beamline has been installed to allow dosimetry studies and irradiation experiments on chemical, biochemical and biological samples after a 60-degree dispersive arm. The measured dose and dose rates under different beam conditions and first experimental results will be reported in this paper. In addition, a dedicated beamline for FLASHlab@PITZhas been designed for better control of the high brightness electron beams. This includes a dogleg to translate the beam and a 2D kicker system to scan the tiny beam focused by quadrupoles across the samples within less than 1 ms. Simulation studies will be presented to demonstrate the extremely flexible dose parameters with various irradiation options for electron FLASH radiation therapy and radiation biology studies.
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Shibamoto, Yuta, e Seiya Takano. "Non-Surgical Definitive Treatment for Operable Breast Cancer: Current Status and Future Prospects". Cancers 15, n.º 6 (20 de março de 2023): 1864. http://dx.doi.org/10.3390/cancers15061864.
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This article reviews the results of various non-surgical curative treatments for operable breast cancer. Radiotherapy is considered the most important among such treatments, but conventional radiotherapy alone and concurrent chemoradiotherapy do not achieve high cure rates. As a radiosensitization strategy, intratumoral injection of hydrogen peroxide before radiation has been investigated, and high local control rates (75–97%) were reported. The authors treated 45 patients with whole-breast radiotherapy, followed by stereotactic or intensity-modulated radiotherapy boost, with or without a radiosensitization strategy employing either hydrogen peroxide injection or hyperthermia plus oral tegafur-gimeracil-oteracil potassium. Stages were 0–I in 23 patients, II in 19, and III in 3. Clinical and cosmetic outcomes were good, with 5-year overall, progression-free, and local recurrence-free survival rates of 97, 86, and 88%, respectively. Trials of carbon ion radiotherapy are ongoing, with promising interim results. Radiofrequency ablation, focused ultrasound, and other image-guided ablation treatments yielded complete ablation rates of 20–100% (mostly ≥70%), but long-term cure rates remain unclear. In these treatments, combination with radiotherapy seems necessary to treat the extensive intraductal components. Non-surgical treatment of breast cancer is evolving steadily, with radiotherapy playing a major role. In the future, proton therapy with the ultra-high-dose-rate FLASH mode is expected to further improve outcomes.
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Burnet, Neil G., Ranald I. Mackay, Ed Smith, Amy L. Chadwick, Gillian A. Whitfield, David J. Thomson, Matthew Lowe, Norman F. Kirkby, Adrian M. Crellin e Karen J. Kirkby. "Proton beam therapy: perspectives on the National Health Service England clinical service and research programme". British Journal of Radiology 93, n.º 1107 (março de 2020): 20190873. http://dx.doi.org/10.1259/bjr.20190873.
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The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit. The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.
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Chowdhury, Priyanka, Anastasia Velalopoulou, Ioannis Verginadis, George Morcos, Michele Kim, James Metz, Lei Dong, Alexander Lin e Constantinos Koumenis. "Abstract 6036: Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice". Cancer Research 84, n.º 6_Supplement (22 de março de 2024): 6036. http://dx.doi.org/10.1158/1538-7445.am2024-6036.
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Abstract Background- Recent studies have reported that ultra-high dose rate “FLASH” Proton radiation therapy (F-PRT) decreases normal tissue toxicity while maintaining tumor-controlling efficacy compared to Standard Proton RT (S-PRT), that are used for patient treatments. However, although highly efficacious in eliminating tumors, damage to the otherwise healthy salivary glands and oral mucosa is often unavoidable in patients with head and neck cancer, leaving patients with lifelong xerostomia and other comorbidities. Aim- In this study, we aimed to investigate the effect of F-PRT on radiation-induced oral mucositis and salivary gland dysfunction and in controlling orthotopic tumor growth. Methods- The head and neck area of C57Bl/6 mice was irradiated with a single dose of 16 Gy or a fractionated dose of 8 Gy x 3 of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s). Oral mucositis was analyzed by histopathological examination. Radiation-induced xerostomia was studied by measuring the saliva flow rate of mice. To examine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in mice and then irradiated with F-PRT/S-PRT. Results- Following irradiation with a single dose or a fractionated dose, saliva flow was reduced by both treatments. However, the F-PRT-treated mice showed a significant improvement in salivary flow at 14 days (p<0.05) and 28 days (p<0.005) post irradiation. Expression of AQP5 was found to be significantly down-regulated at 2, 5, 10, and 14 days post irradiation with S-PRT. However, mice irradiated with F-PRT showed a significant restoration of the AQP5 expression post-RT. Oral mucositis started to appear on day 14, which showed more severity on day 28 post-irradiation with S-PRT. Histopathological analysis showed the presence of lingual gland atrophy only in the tongue of mice treated with S-PRT 28 and 60 days post-irradiation. F-PRT ameliorates radiation-induced jawbone loss compared to S-PRT as observed in mice irradiated either with a single dose or in a fractionated regime. The surviving fraction of F-PRT-treated mice with orthotopic tongue tumors was significantly ameliorated compared to S-PRT-treated mice. Conclusion- This study demonstrates that F-PRT minimizes radiation-induced normal tissue toxicity after irradiation in mice’s head and neck region. Moreover, the ability of F-PRT to control orthotopic head and neck tumors further determines the efficacy of this modality for clinical applications. Citation Format: Priyanka Chowdhury, Anastasia Velalopoulou, Ioannis Verginadis, George Morcos, Michele Kim, James Metz, Lei Dong, Alexander Lin, Constantinos Koumenis. Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6036.
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Charuchinda, W., F. Horst, Y. Simeonov, C. Schuy, P. Penchev, P. Poulsen, M. Sitarz et al. "3D range-modulators for proton therapy: near field simulations with FLUKA and comparison with film measurements". Journal of Physics: Conference Series 2431, n.º 1 (1 de janeiro de 2023): 012081. http://dx.doi.org/10.1088/1742-6596/2431/1/012081.
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Abstract The 3D range-modulator is a device used in particle delivery systems that can create a highly conformal and homogeneous dose distribution in the target volume with mono-energetic beams, providing an option for high dose-rate FLASH therapy. In the normal case, the modulators are positioned at a typical distance of 30-50 cm in front of the target in order to avoid the fluence ripples resulting from the periodic structure of the modulators. FLUKA Monte Carlo simulation package was used to investigate the fluence distributions of protons penetrating through the 2D range-modulator, the simplified version of the 3D range-modulator, and to determine the minimum distance at which the fluence is homogeneous enough for the treatment. To implement the complex geometry of the modulator in FLUKA, a dedicated FLUKA user routine was developed for the simulation of the periodic pin structures. The highest fluence ripple occurred at a few centimetres behind the modulators and then faded away as the distance increased, which can be described by the edge-scattering effect and later by the blur-out of the overlapping contributions from the pins. Moreover, the dose distribution in water was investigated, particularly for small distances between the modulators and the water phantom. Furthermore, the Monte Carlo results were compared with radiochromic film measurements irradiated with a 3D-printed range modulator and showed a good qualitative agreement. Prospectively, for low modulator-to-target distances, the strong dose inhomogeneities which appear in the proximal part of the target, could introduce additionally a kind of ‘mini beam’ normal-tissue sparing by the 3D range-modulators.
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Song, Ge, Zhi Zheng, Yingming Zhu, Yaoting Wang e Song Xue. "A review and bibliometric analysis of global research on proton radiotherapy". Medicine 103, n.º 19 (10 de maio de 2024): e38089. http://dx.doi.org/10.1097/md.0000000000038089.
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Proton beam therapy (PBT) has great advantages as tumor radiotherapy and is progressively becoming a more prevalent choice for individuals undergoing radiation therapy. The objective of this review is to pinpoint collaborative efforts among countries and institutions, while also exploring the hot topics and future outlook in the field of PBT. Data from publications were downloaded from the Web of Science Core Collection. CiteSpace and Excel 2016 were used to conduct the bibliometric and knowledge map analysis. A total of 6516 publications were identified, with the total number of articles steadily increasing and the United States being the most productive country. Harvard University took the lead in contributing the highest number of publications. Paganetti Harald published the most articles and had the most cocitations. PHYS MED BIOL published the greatest number of PBT-related articles, while INT J RADIAT ONCOL received the most citations. Paganetti Harald, 2012, PHYS MED BIOL can be classified as classic literature due to its high citation rate. We believe that research on technology development, dose calculation and relative biological effectiveness were the knowledge bases in this field. Future research hotspots may include clinical trials, flash radiotherapy, and immunotherapy.
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Giordanengo, Simona, Leslie Fanola Guarachi, Saverio Braccini, Giuseppe A. P. Cirrone, Marco Donetti, Federico Fausti, Felix Mas Milian et al. "Fluence Beam Monitor for High-Intensity Particle Beams Based on a Multi-Gap Ionization Chamber and a Method for Ion Recombination Correction". Applied Sciences 12, n.º 23 (28 de novembro de 2022): 12160. http://dx.doi.org/10.3390/app122312160.
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This work presents the tests of a multi-gap detector (MGD), composed of three parallel-plate ionization chambers (ICs) with different gap widths, assembled to prove the capability of correcting for charge volume recombination which is expected to occur when high fluence rates are delivered. Such beam conditions occur with a compact accelerator for charged particle therapy developed to reduce the costs, to accomplish faster treatments and to exploit different beam delivery techniques and dose rates as needed, for example, for range modulation and FLASH irradiations, respectively. The MGD was tested with carbon ions at the Centro Nazionale di Adroterapia Oncologica (CNAO Pavia, Italy), and with protons in two different beam lines: at Bern University Hospital with continuous beams and at the Laboratori Nazionale del Sud (Catania, Italy) of the Italian National Center of Nuclear Physics (INFN) with pulsed beams. For each accelerator, we took measurements with different beam intensities (up to the maximum rate of ionization achievable) and changed the detector bias voltage (V) in order to study the charge collection efficiency. Charge recombination models were used to evaluate the expected collected charge and to measure the linearity of the rate of ionization with the beam fluence rate. A phenomenological approach was used to determine the collection efficiency (f1) of the chamber with thinnest gap from the relative efficiencies, f1/f2 and f1/f3, exploiting the condition that, for each measurement, the three chambers were exposed to the same rate of ionization. Results prove that two calibration curves can be determined and used to correct the online measurements for the charge losses in the ICs for recombination.
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Mihailidis, D. "DOSIMETRY IN FLASH (ULTRA-HIGH DOSE RATE) RADIOTHERAPY". Physica Medica 104 (dezembro de 2022): S5. http://dx.doi.org/10.1016/s1120-1797(22)03027-7.
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Bogaerts, Eva, Ellina Macaeva, Sofie Isebaert e Karin Haustermans. "Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect". International Journal of Molecular Sciences 23, n.º 20 (11 de outubro de 2022): 12109. http://dx.doi.org/10.3390/ijms232012109.
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FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.