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Frontiers in Public Health 2023Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and...
INTRODUCTION
Experimental studies complement epidemiological data on the biological effects of low doses and dose rates of ionizing radiation and help in determining the dose and dose rate effectiveness factor.
METHODS
Human VH10 skin fibroblasts exposed to 25, 50, and 100 mGy of Cs gamma radiation at 1.6, 8, 12 mGy/h, and at a high dose rate of 23.4 Gy/h, were analyzed for radiation-induced short- and long-term effects. Two sample cohorts, i.e., discovery ( = 30) and validation ( = 12), were subjected to RNA sequencing. The pool of the results from those six experiments with shared conditions (1.6 mGy/h; 24 h), together with an earlier time point (0 h), constituted a third cohort ( = 12).
RESULTS
The 100 mGy-exposed cells at all abovementioned dose rates, harvested at 0/24 h and 21 days after exposure, showed no strong gene expression changes. , involved in the regulation of the NOTCH signaling pathway, presented a consistent upregulation among both the discovery and validation cohorts, and was validated by qPCR. Gene set enrichment analysis revealed that the NOTCH pathway was upregulated in the pooled cohort ( = 0.76, normalized enrichment score (NES) = 0.86). Apart from upregulated apical junction and downregulated DNA repair, few pathways were consistently changed across exposed cohorts. Concurringly, cell viability assays, performed 1, 3, and 6 days post irradiation, and colony forming assay, seeded just after exposure, did not reveal any statistically significant early effects on cell growth or survival patterns. Tendencies of increased viability (day 6) and reduced colony size (day 21) were observed at 12 mGy/h and 23.4 Gy/min. Furthermore, no long-term changes were observed in cell growth curves generated up to 70 days after exposure.
DISCUSSION
In conclusion, low doses of gamma radiation given at low dose rates had no strong cytotoxic effects on radioresistant VH10 cells.
Topics: Humans; Dose-Response Relationship, Radiation; Radiation, Ionizing; Gamma Rays; Fibroblasts; Radiation Exposure
PubMed: 38162630
DOI: 10.3389/fpubh.2023.1297942 -
Radiation and Environmental Biophysics Aug 2021Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific...
Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific bodies. It has long been assumed that radiation-induced cancer risks at low doses or low-dose rates are lower (per unit dose) than those at higher doses and dose rates. Based on a mixture of experimental and epidemiologic evidence the International Commission on Radiological Protection recommended the use of a dose and dose-rate effectiveness factor for purposes of radiological protection to reduce solid cancer risks obtained from moderate-to-high acute dose studies (e.g. those derived from the Japanese atomic bomb survivors) when applied to low dose or low-dose rate exposures. In the last few years there have been a number of attempts at assessing the effect of extrapolation of dose rate via direct comparison of observed risks in low-dose rate occupational studies and appropriately age/sex-adjusted analyses of the Japanese atomic bomb survivors. The usual approach is to consider the ratio of the excess relative risks in the two studies, a measure of the inverse of the dose rate effectiveness factor. This can be estimated using standard meta-analysis with inverse weighting of ratios of relative risks using variances derived via the delta method. In this paper certain potential statistical problems in the ratio of estimated excess relative risks for low-dose rate studies to the excess relative risk in the Japanese atomic bomb survivors are discussed, specifically the absence of a well-defined mean and the theoretically unbounded variance of this ratio. A slightly different method of meta-analysis for estimating uncertainties of these ratios is proposed, motivated by Fieller's theorem, which leads to slightly different central estimates and confidence intervals for the dose rate effectiveness factor. However, given the uncertainties in the data, the differences in mean values and uncertainties from the dose rate effectiveness factor estimated using delta-method-based meta-analysis are not substantial, generally less than 70%.
Topics: Humans; Meta-Analysis as Topic; Neoplasms, Radiation-Induced; Radiation Dosage; Risk; Uncertainty
PubMed: 34218328
DOI: 10.1007/s00411-021-00921-x -
Journal of Radiation Research Jan 2022The dose rate of atomic bomb (A-bomb) radiation to the survivors has still remained unclear, although the dose-response data of A-bomb cancers has been taken as a...
The dose rate of atomic bomb (A-bomb) radiation to the survivors has still remained unclear, although the dose-response data of A-bomb cancers has been taken as a standard in estimating the cancer risk of radiation and the dose and dose-rate effectiveness factor (DDREF). Since the applicability of the currently used DDREF of 2 derived from A-bomb data is limited in a narrow dose-rate range, 0.25-75 Gy/min as estimated from analysis of DS86 dosimetry data in the present study, a non-tumor dose (Dnt) was applied in an attempt to gain a more universal dose-rate effectiveness factor (DREF), where Dnt is an empirical parameter defined as the highest dose at which no statistically significant tumor increase is observed above the control level and its magnitude depends on the dose rate. The new DREF values were expressed as a function of the dose rate at four exposure categories, i.e. partial body low LET, whole body low linear energy transfer (LET), partial body high LET and whole body high LET and provided a value of 14 for environmental level radiation at a dose rate of 10-9 Gy/min for whole body low LET.
Topics: Linear Energy Transfer; Neoplasms; Nuclear Warfare; Nuclear Weapons; Radiometry; Risk
PubMed: 34927198
DOI: 10.1093/jrr/rrab109 -
Journal of Applied Clinical Medical... May 2016Volumetric-modulated arc therapy (VMAT) plans may require more control points (or segments) than some of fixed-beam IMRT plans that are created with a limited number of...
Volumetric-modulated arc therapy (VMAT) plans may require more control points (or segments) than some of fixed-beam IMRT plans that are created with a limited number of segments. Increasing number of control points in a VMAT plan for a given prescription dose could create a large portion of the total number of segments with small number monitor units (MUs) per segment. The purpose of this study is to investigate the impact of the small number MU/segment on the delivery accuracy of VMAT delivered with various dose rates. Ten patient datasets were planned for hippocampus sparing for whole brain irradiation. For each dataset, two VMAT plans were created with maximum dose rates of 600 MU/min (the maximum field size of 21 × 40 cm2) and 1000 MU/min (the maximum field size of 15 × 15 cm2) for a daily dose of 3 Gy. Without reoptimization, the daily dose of these plans was purposely reduced to 1.5 Gy and 1.0 Gy while keeping the same total dose. Using the two dose rates and three different daily doses, six VMAT plans for each dataset were delivered to a physical phantom to investigate how the changes of dose rate and daily doses impact on delivery accuracy. Using the gamma index, we directly compared the delivered planar dose profiles with the reduced daily doses (1.5 Gy and 1.0 Gy) to the delivered planar dose at 3 Gy daily dose, delivered at dose rate of 600 MU/min and 1000 MU/min, respectively. The average numbers of segments with MU/segment ≤ 1 were 35 ± 8, 87 ± 6 for VMAT-600 1.5 Gy, VMAT-600 1 Gy plans, and 30 ± 7 and 42 ± 6 for VMAT-1000 1.5 Gy and VMAT-1000 1 Gy plans, respectively. When delivered at 600 MU/min dose rate, the average gamma index passing rates (1%/1 mm criteria) of comparing delivered 1.5 Gy VMAT planar dose profiles to 3.0 Gy VMAT delivered planar dose profiles was 98.28% ± 1.66%, and the average gamma index passing rate of comparing delivered 1.0 Gy VMAT planar dose to 3.0 Gy VMAT delivered planar dose was 83.75% ± 4.86%. If using 2%/2mm and 3%/3 mm criteria, the gamma index passing rates were greater than 97% for both 1.5 Gy VMAT and 1.0 Gy VMAT delivered planar doses. At 1000MU/min dose rate, the average gamma index passing rates were 96.59% ± 2.70% for 1.5 Gy VMAT planar dose profiles and 79.37% ± 9.96% for 1.0 Gy VMAT planar dose profiles when compared to the 3.0 Gy VMAT planar delivered dose profile. When using 2%/2 mm and 3%/3 mm criteria, the gamma index passing rates were greater than 93% for both 1.5 Gy VMAT and 1.0 Gy VMAT planar delivered dose. Under a stricter gamma index criterion (1%/1 mm), significant differences in delivered planar dose profiles at different daily doses were detected, indicating that the known communication delay between the MU console and MLC console may affect VMAT delivery accuracy.
Topics: Humans; Organs at Risk; Particle Accelerators; Phantoms, Imaging; Radiometry; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated
PubMed: 27167278
DOI: 10.1120/jacmp.v17i3.6046 -
Advances in Radiation Oncology 2022Research suggests that in addition to the dose-rate, a dose threshold is also important for the reduction in normal tissue toxicity with similar tumor control after...
Single-fraction 34 Gy Lung Stereotactic Body Radiation Therapy Using Proton Transmission Beams: FLASH-dose Calculations and the Influence of Different Dose-rate Methods and Dose/Dose-rate Thresholds.
PURPOSE
Research suggests that in addition to the dose-rate, a dose threshold is also important for the reduction in normal tissue toxicity with similar tumor control after ultrahigh dose-rate radiation therapy (UHDR-RT). In this analysis we aimed to identify factors that might limit the ability to achieve this "FLASH"-effect in a scenario attractive for UHDR-RT (high fractional beam dose, small target, few organs-at-risk): single-fraction 34 Gy lung stereotactic body radiation therapy.
METHODS AND MATERIALS
Clinical volumetric-modulated arc therapy (VMAT) plans, intensity modulated proton therapy (IMPT) plans and transmission beam (TB) plans were compared for 6 small and 1 large lung lesion. The TB-plan dose-rate was calculated using 4 methods and the FLASH-percentage (percentage of dose delivered at dose-rates ≥40/100 Gy/s and ≥4/8 Gy) was determined for various variables: a minimum spot time (minST) of 0.5/2 ms, maximum nozzle current (maxN) of 200/40 0nA, and 2 gantry current (GC) techniques (energy-layer based, spot-based [SB]).
RESULTS
Based on absolute doses 5-beam TB and VMAT-plans are similar, but TB-plans have higher rib, skin, and ipsilateral lung dose than IMPT. Dose-rate calculation methods not considering scanning achieve FLASH-percentages between ∼30% to 80%, while methods considering scanning often achieve <30%. FLASH-percentages increase for lower minST/higher maxN and when using SB GC instead of energy-layer based GC, often approaching the percentage of dose exceeding the dose-threshold. For the small lesions average beam irradiation times (including scanning) varied between 0.06 to 0.31 seconds and total irradiation times between 0.28 to 1.57 seconds, for the large lesion beam times were between 0.16 to 1.47 seconds with total irradiation times of 1.09 to 5.89 seconds.
CONCLUSIONS
In a theoretically advantageous scenario for FLASH we found that TB-plan dosimetry was similar to that of VMAT, but inferior to that of IMPT, and that decreasing minST or using SB GC increase the estimated amount of FLASH. For the appropriate machine/delivery parameters high enough dose-rates can be achieved regardless of calculation method, meaning that a possible FLASH dose-threshold will likely be the primary limiting factor.
PubMed: 35634574
DOI: 10.1016/j.adro.2022.100954 -
Cancers Apr 2023Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is...
Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.
PubMed: 37174045
DOI: 10.3390/cancers15092579 -
The British Journal of Radiology May 2022FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen's role in the 'FLASH effect', we assessed DNA...
OBJECTIVE
FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen's role in the 'FLASH effect', we assessed DNA damage levels following irradiation at different oxygen tensions, doses and dose rates.
METHODS
Samples of whole blood were irradiated (20 Gy) at various oxygen tensions (0.25-21%) with 6 MeV electrons at dose rates of either 2 kGy/s (FLASH) or 0.1 Gy/s (CONV), and subsequently with various doses (0-40 Gy) and intermediate dose rates (0.3-1000 Gy/s). DNA damage of peripheral blood lymphocytes (PBL) were assessed by the alkaline comet assay.
RESULTS
Following 20 Gy irradiation, lower levels of DNA damage were induced for FLASH, the difference being significant at 0.25% ( < 0.05) and 0.5% O ( < 0.01). The differential in DNA damage at 0.5% O was found to increase with total dose and dose rate, becoming significant for doses ≥20 Gy and dose rates ≥30 Gy/s.
CONCLUSION
This study shows, using the alkaline comet assay, that lower levels of DNA damage are induced following FLASH irradiation, an effect that is modulated by the oxygen tension, and increases with the total dose and dose rate of irradiation, indicating that an oxygen related mechanism, transient radiation-induced oxygen depletion, may contribute to the tissue sparing effect of FLASH irradiation.
ADVANCES IN KNOWLEDGE
This paper is first to directly show that FLASH-induced DNA damage is modulated by oxygen tension, total dose and dose rate, with FLASH inducing significantly lower levels of DNA damage for doses ≥20 Gy and dose rates ≥30 Gy/s, at 0.5% O.
Topics: DNA Damage; Electrons; Humans; Oxygen; Radiation Dosage
PubMed: 35171701
DOI: 10.1259/bjr.20211150 -
International Journal of Radiation... May 2024Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use...
PURPOSE
Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery.
METHODS AND MATERIALS
The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation.
RESULTS
The dose rate, which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity.
CONCLUSIONS
The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session.
PubMed: 38750904
DOI: 10.1016/j.ijrobp.2024.04.071 -
Pain Feb 2017Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of...
Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chi-Square Distribution; Chronic Pain; Cohort Studies; Depression; Dose-Response Relationship, Drug; Electronic Health Records; Female; Humans; Male; Middle Aged; Probability; Time Factors; United States; United States Department of Veterans Affairs; Young Adult
PubMed: 28092649
DOI: 10.1097/j.pain.0000000000000763 -
Journal of Medical Physics Apr 2011Intracavitary brachytherapy is an integral part of radiotherapy for locally advanced gynecologic malignancies. A dosimetric intercomparison of high dose rate...
Intracavitary brachytherapy is an integral part of radiotherapy for locally advanced gynecologic malignancies. A dosimetric intercomparison of high dose rate intracavitary brachytherapy (HDR_BT) and intensity-modulated radiotherapy in cervical carcinoma has been made in the present study. CT scan images of 10 patients treated with HDR_BT were used for this study. A sliding-window IMRT (IMRT_SW) and step-and-shoot IMRT plans were generated using 6-MV X-rays. The cumulative dose volume histograms of target, bladder, rectum and normal tissue were analyzed for both techniques and dose distributions were compared. It was seen that the pear-shaped dose distribution characteristic of intracavitary brachytherapy with sharp dose fall-off outside the target could be achieved with IMRT. The integral dose to planning target volume was significantly higher with HDR_BT in comparison with IMRT. Significant differences between the two techniques were seen for doses to 1 cc and 2 cc of rectum, while the differences in 1 cc and 2 cc doses to bladder were not significant. The integral doses to the nontarget critical and normal structures were smaller with HDR_BT and with IMRT. It is concluded that IMRT can be the choice of treatment in case of non-availability of HDR brachytherapy facilities or when noninvasive treatments are preferred.
PubMed: 21731228
DOI: 10.4103/0971-6203.79687