Linear energy transfer dependence of transient yields in water irradiated by 150 keV – 500 MeV protons in the limit of low dose rates

2020 ◽  
Vol 98 (8) ◽  
pp. 427-433
Author(s):  
Ahmed Alanazi ◽  
Jintana Meesungnoen ◽  
Jean-Paul Jay-Gerin
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Low Dose ◽  
High Dose ◽  
Dose Rates ◽  
Normal Tissues ◽  
High Let ◽  
Proton Track ◽  
Electron And Photon ◽  
Anti Tumor Activity

FLASH radiotherapy is a new irradiation method in which large doses of ionizing radiation are delivered to tumors almost instantly (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. Although this technique is primarily studied in the context of electron and photon therapies, proton delivery at high dose rates can also reduce the adverse side effects on normal cells. So far, no definitive mechanism has been proposed to explain the differences in the responses to radiation between tumor and normal tissues. Given that living cells and tissues consist mainly of water, we set out to study the effects of high dose rates on the radiolysis of water by protons in the energy range of 150 keV – 500 MeV (i.e., for linear energy transfer (LET) values between ∼72.2 and 0.23 keV/μm, respectively) using Monte Carlo simulations. To validate our methodology, however, we, first, report here the results of our calculations of the yields (G values) of the radiolytically produced species, namely the hydrated electron ([Formula: see text]), •OH, H•, H2, and H2O2, for low dose rates. Overall, our simulations agree very well with the experiment. In the presence of oxygen, [Formula: see text] and H• atoms are rapidly converted into superoxide anion or hydroperoxyl radicals, with a well-defined maximum of [Formula: see text] at ∼1 μs. This maximum decreases substantially when going from low-LET 500 MeV to high-LET 150 keV irradiating protons. Differences in the geometry of the proton track structure with increasing LET readily explain this diminution in [Formula: see text] radicals.

Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3608-3608 ◽  
Author(s):  
Jeeyun Lee ◽  
Young Suk Park ◽  
James Burke ◽  
Ho Yeong Lim ◽  
Jihye Lee ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Dose Escalation ◽  
Low Dose ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Systemic Delivery ◽  
Dose Escalation Study ◽  
Gm Csf ◽  
Anti Tumor Activity ◽  
Dose Dependent

3608^ Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.

scholarly journals Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 116
Author(s):  
Ramon Ortiz ◽  
Ludovic De Marzi ◽  
Yolanda Prezado
Keyword(s):  
Radiation Therapy ◽  
Normal Tissue Complication Probability ◽  
Therapeutic Window ◽  
High Dose ◽  
Proof Of Concept ◽  
Normal Tissues ◽  
Arc Therapy ◽  
High Let ◽  
The Individual ◽  
First Time

(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.

scholarly journals Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

2021 ◽  
Vol 9 ◽  
Author(s):  
Pankaj Chaudhary ◽  
Giuliana Milluzzo ◽  
Hamad Ahmed ◽  
Boris Odlozilik ◽  
Aaron McMurray ◽  
...  
Keyword(s):  
Dose Rate ◽  
Biological Effects ◽  
Therapeutic Index ◽  
High Dose Rate ◽  
High Dose ◽  
Particle Accelerators ◽  
Dose Rates ◽  
Normal Tissues ◽  
Multiple Pulses ◽  
Tissue Sparing

The use of particle accelerators in radiotherapy has significantly changed the therapeutic outcomes for many types of solid tumours. In particular, protons are well known for sparing normal tissues and increasing the overall therapeutic index. Recent studies show that normal tissue sparing can be further enhanced through proton delivery at 100 Gy/s and above, in the so-called FLASH regime. This has generated very significant interest in assessing the biological effects of proton pulses delivered at very high dose rates. Laser-accelerated proton beams have unique temporal emission properties, which can be exploited to deliver Gy level doses in single or multiple pulses at dose rates exceeding by many orders of magnitude those currently used in FLASH approaches. An extensive investigation of the radiobiology of laser-driven protons is therefore not only necessary for future clinical application, but also offers the opportunity of accessing yet untested regimes of radiobiology. This paper provides an updated review of the recent progress achieved in ultra-high dose rate radiobiology experiments employing laser-driven protons, including a brief discussion of the relevant methodology and dosimetry approaches.

Induction of apoptosis by high linear energy transfer radiation: role of p53

2002 ◽  
Vol 80 (7) ◽  
pp. 644-649 ◽  
Author(s):  
D Coelho ◽  
B Fischer ◽  
V Holl ◽  
P Dufour ◽  
J M Denis ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Cell Line ◽  
Linear Energy Transfer ◽  
Lymphoblastoid Cell Line ◽  
Cellular Damage ◽  
Fast Neutrons ◽  
X Rays ◽  
Carbon Ions ◽  
High Let Radiation ◽  
High Let

The involvement of the tumor suppressor p53 gene in the sensitivity of many cell types towards low linear energy transfer (LET) radiation is now well established. However, little information is available on the relationship between p53 status of tumor cells and their ability to undergo apoptosis following exposure to high-LET radiation. Here we present the results of experiments carried out with the human lymphoblastoid cell line TK6 and its p53 knock-out counterpart NH32. Cells were irradiated at doses ranging from 0.25 to 8 Gy with fast neutrons (65 MeV), carbon ions (95 MeV/nucleon), and X rays (15 MV). For both cell lines, the occurrence of apoptosis, determined by the quantification of hypodiploid particles as well as the activation of several caspases, was compared with their sensitivity towards high-LET radiation. Results indicate that p53 is involved in the response of TK6 cells to fast neutrons and carbon ions, as measured by cell proliferation and occurrence of apoptosis. However, p53-deficient cells are still able to undergo apoptosis following irradiation. This suggests that heavy ions and fast neutrons induce cellular damage that is not under the control of p53. The involvement of executioner caspases in high-LET radiation induced apoptosis was also evaluated by use of specific inhibitors.Key words: fast neutrons, carbon ions, apoptosis, p53, lymphoblastoid cell line.

scholarly journals PV-0136: Linear energy transfer in normal tissues in spot scanning proton therapy of pro state cancer

2017 ◽  
Vol 123 ◽  
pp. S64-S65
Author(s):  
J. Pedersen ◽  
J. Bb Petersen ◽  
C.H. Stokkevåg ◽  
K.S. Ytre-Hauge ◽  
O. Casares-Magaz ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Proton Therapy ◽  
Linear Energy Transfer ◽  
Normal Tissues ◽  
Spot Scanning

scholarly journals Perturbed transcriptional profiles after chronic low dose rate radiation in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256667
Author(s):  
Hildegunn Dahl ◽  
Dag M. Eide ◽  
Torstein Tengs ◽  
Nur Duale ◽  
Jorke H. Kamstra ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Dose Rate ◽  
Low Dose ◽  
High Dose Rate ◽  
High Dose ◽  
Transcriptional Responses ◽  
Transcriptional Profiles ◽  
Dose Rates ◽  
Low Dose Rate ◽  
Genome Wide

Adverse health outcomes of ionizing radiation given chronically at low dose rates are highly debated, a controversy also relevant for other stressors. Increased knowledge is needed for a more comprehensive understanding of the damaging potential of ionizing radiation from all dose rates and doses. There is a lack of relevant low dose rate data that is partly ascribed to the rarity of exposure facilities allowing chronic low dose rate exposures. Using the FIGARO facility, we assessed early (one day post-radiation) and late (recovery time of 100–200 days) hepatic genome-wide transcriptional profiles in male mice of two strains (CBA/CaOlaHsd and C57BL/6NHsd) exposed chronically to a low dose rate (2.5 mGy/h; 1200h, LDR), a mid-dose rate (10 mGy/h; 300h, MDR) and acutely to a high dose rate (100 mGy/h; 30h, HDR) of gamma irradiation, given to an equivalent total dose of 3 Gy. Dose-rate and strain-specific transcriptional responses were identified. Differently modulated transcriptional responses across all dose rate exposure groups were evident by the representation of functional biological pathways. Evidence of changed epigenetic regulation (global DNA methylation) was not detected. A period of recovery markedly reduced the number of differentially expressed genes. Using enrichment analysis to identify the functional significance of the modulated genes, perturbed signaling pathways associated with both cancer and non-cancer effects were observed, such as lipid metabolism and inflammation. These pathways were seen after chronic low dose rate and were not restricted to the acute high dose rate exposure. The transcriptional response induced by chronic low dose rate ionizing radiation suggests contribution to conditions such as cardiovascular diseases. We contribute with novel genome wide transcriptional data highlighting dose-rate-specific radiation responses and emphasize the importance of considering both dose rate, duration of exposure, and variability in susceptibility when assessing risks from ionizing radiation.

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