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Frontiers in Oncology 2019For patients with unfavorable or high-risk prostate cancer, dose escalated radiation therapy leads to improved progression free survival but attempts to deliver... (Review)
Review
For patients with unfavorable or high-risk prostate cancer, dose escalated radiation therapy leads to improved progression free survival but attempts to deliver increased dose by external beam radiation therapy (EBRT) alone can be limited by late toxicities to nearby genitourinary and gastrointestinal organs at risk. Brachytherapy is a method to deliver dose escalation in conjunction with EBRT with a potentially improved late toxicity profile and improved prostate cancer related outcomes. At least three randomized controlled trials have demonstrated improved biochemical control with the addition of either low-dose rate (LDR) or high-dose rate (HDR) brachytherapy to EBRT, although only ASCENDE-RT compared brachytherapy to dose-escalated EBRT but did report an over 50% improvement in biochemical failure with a LDR boost. Multiple single institution and comparative research series also support the use of a brachytherapy boost in the DE-EBRT era and demonstrate excellent prostate cancer specific outcomes. Despite improved oncologic outcomes with a brachytherapy boost in the high-risk setting, the utilization of both LDR, and HDR brachytherapy use is declining. The acute genitourinary toxicities when brachytherapy boost is combined with EBRT, particularly a LDR boost, are of concern in comparison to EBRT alone. HDR brachytherapy boost has many physical properties inherent to its rapid delivery of a large dose which may reduce acute toxicities and also appeal to the radiobiology of prostate cancer. We herein review the evidence for use of either LDR or HDR brachytherapy boost for high-risk prostate cancer and summarize comparisons between the two treatment modalities.
PubMed: 31921640
DOI: 10.3389/fonc.2019.01378 -
International Journal of Radiation... 2023Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the... (Review)
Review
PURPOSE
Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells.
METHODS
We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation.
RESULTS
Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition.
CONCLUSIONS
We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
Topics: Humans; Dose-Response Relationship, Radiation; Carcinogenesis; Stem Cells; Radiation Exposure; Mutation
PubMed: 36971595
DOI: 10.1080/09553002.2023.2194398 -
International Journal of Molecular... Oct 2022FLASH 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... (Review)
Review
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.
Topics: Humans; Radiotherapy Dosage; Reactive Oxygen Species; Neoplasms; Oxygen
PubMed: 36292961
DOI: 10.3390/ijms232012109 -
Applied Radiation and Isotopes :... Jul 2022In a radiation environment, such as the decommissioning site of a nuclear power station, visualization of the distribution of radioactive substances and estimation of...
In a radiation environment, such as the decommissioning site of a nuclear power station, visualization of the distribution of radioactive substances and estimation of the dose equivalent rate around the site can help reduce the exposure dose of workers and plan their work. The author has developed a method of visualizing the existence of a radiation source using a gamma-ray imager, estimating its radioactivity, and estimating the dose equivalent rate around the source. A Compton camera, which is a gamma-ray imager, is used to visualize the existence of aCs radiation source and estimate its radioactivity, and a three-dimensional (3D) model of the region around the source is generated using a simultaneous localization and mapping device based on 3D light detection and ranging. Next, the dose equivalent rate around the source is calculated by importing the 3D model data and radioactivity information into a particle and heavy ion transport code system. The validity of the calculated dose equivalent rates is also confirmed by comparing them with values measured using a survey meter. This method can be used not only to simply visualize a source and calculate the dose equivalent rate around it but also to evaluate how addition of shielding or removal of contaminated objects can contribute to reducing the dose equivalent rate.
Topics: Diagnostic Imaging; Gamma Rays; Heavy Ions; Humans; Monte Carlo Method; Radiation Dosage; Radioactivity
PubMed: 35500508
DOI: 10.1016/j.apradiso.2022.110254 -
Medical Physics May 2021Treatment planning in high dose-rate brachytherapy has traditionally been conducted with manual forward planning, but inverse planning is today increasingly used in... (Review)
Review
Treatment planning in high dose-rate brachytherapy has traditionally been conducted with manual forward planning, but inverse planning is today increasingly used in clinical practice. There is a large variety of proposed optimization models and algorithms to model and solve the treatment planning problem. Two major parts of inverse treatment planning for which mathematical optimization can be used are the decisions about catheter placement and dwell time distributions. Both these problems as well as integrated approaches are included in this review. The proposed models include linear penalty models, dose-volume models, mean-tail dose models, quadratic penalty models, radiobiological models, and multiobjective models. The aim of this survey is twofold: (i) to give a broad overview over mathematical optimization models used for treatment planning of brachytherapy and (ii) to provide mathematical analyses and comparisons between models. New technologies for brachytherapy treatments and methods for treatment planning are also discussed. Of particular interest for future research is a thorough comparison between optimization models and algorithms on the same dataset, and clinical validation of proposed optimization approaches with respect to patient outcome.
Topics: Algorithms; Brachytherapy; Humans; Male; Models, Theoretical; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted
PubMed: 33576027
DOI: 10.1002/mp.14762 -
Cells Nov 2021Anti-inflammatory low-dose therapy is well established, whereas the immunomodulatory impact of doses below 0.1 Gy is much less clear. In this study, we investigated...
Anti-inflammatory low-dose therapy is well established, whereas the immunomodulatory impact of doses below 0.1 Gy is much less clear. In this study, we investigated dose, dose rate and time-dependent effects in a dose range of 0.005 to 2 Gy on immune parameters after whole body irradiation (IR) using a pro-inflammatory (ApoE-/-) and a wild type mouse model. Long-term effects on spleen function (proliferation, monocyte expression) were analyzed 3 months, and short-term effects on immune plasma parameters (IL6, IL10, IL12p70, KC, MCP1, INFγ, TGFβ, fibrinogen, sICAM, sVCAM, sE-selectin/CD62) were analyzed 1, 7 and 28 days after Co60 γ-irradiation (IR) at low dose rate (LDR, 0.001 Gy/day) and at high dose rate (HDR). In vitro measurements of murine monocyte (WEHI-274.1) adhesion and cytokine release (KC, MCP1, IL6, TGFβ) after low-dose IR (150 kV X-ray unit) of murine endothelial cell (EC) lines (H5V, mlEND1, bEND3) supplement the data. RT-PCR revealed significant reduction of Ki67 and CD68 expression in the spleen of ApoE-/- mice after 0.025 to 2 Gy exposure at HDR, but only after 2 Gy at LDR. Plasma levels in wild type mice, showed non-linear time-dependent induction of proinflammatory cytokines and reduction of TGFβ at doses as low as 0.005 Gy at both dose rates, whereas sICAM and fibrinogen levels changed in a dose rate-specific manner. In ApoE-/- mice, levels of sICAM increased and fibrinogen decreased at both dose rates, whereas TGFβ increased mainly at HDR. Non-irradiated plasma samples revealed significant age-related enhancement of cytokines and adhesion molecules except for sICAM. In vitro data indicate that endothelial cells may contribute to systemic IR effects and confirm changes of adhesion properties suggested by altered sICAM plasma levels. The differential immunomodulatory effects shown here provide insights in inflammatory changes occurring at doses far below standard anti-inflammatory therapy and are of particular importance after diagnostic and chronic environmental exposures.
Topics: Aging; Animals; Apolipoproteins E; Cell Adhesion; Cell Line; Cytokines; Dose-Response Relationship, Radiation; Endothelial Cells; Female; Inflammation; Interleukin-6; Mice, Inbred C57BL; Monocytes; Radiation, Ionizing; Spleen; Time Factors; Mice
PubMed: 34831473
DOI: 10.3390/cells10113251 -
Radiation Research Mar 2022We report on effects of low-dose exposures of accelerated protons delivered at high-dose rate (HDR) or a simulated solar-particle event (SPE) like low-dose rate (LDR) on...
We report on effects of low-dose exposures of accelerated protons delivered at high-dose rate (HDR) or a simulated solar-particle event (SPE) like low-dose rate (LDR) on immediate DNA damage induction and processing, survival and in vitro transformation of low passage NFF28 apparently normal primary human fibroblasts. Cultures were exposed to 50, 100 and 1,000 MeV monoenergetic protons in the Bragg entrance/plateau region and cesium-137 γ rays at 20 Gy/h (HDR) or 1 Gy/h (LDR). DNA double-strand breaks (DSB) and clustered DNA damages (containing oxypurines and abasic sites) were measured using transverse alternating gel electrophoresis (TAFE) and immunocytochemical detection/scoring of colocalized γ-H2AX pS139/53BP1 foci, with their induction being linear energy transfer (LET) dependent and dose-rate sparing observed for the different damage classes. Relative biological effectiveness (RBE) values for cell survival after proton irradiation at both dose-rates ranged from 0.61-0.73. Transformation RBE values were dose-rate dependent, ranging from ∼1.8-3.1 and ∼0.6-1.0 at low doses (≤30 cGy) for HDR and LDR irradiations, respectively. However peak transformation frequencies were significantly higher (1.3-7.3-fold) for higher doses of 0.5-1 Gy delivered at SPE-like LDR. Cell survival and transformation frequencies measured after low-dose 500 MeV/n He-4, 290 MeV/n C-12 and 600 MeV/n Si-28 ion irradiations also showed an inverse dose-rate effect for transformation at SPE-like LDR. This work demonstrates the existence of inverse dose-rate effects for proton and light-ion-induced postirradiation cell survival and in vitro transformation for space mission-relevant doses and dose rates.
Topics: Cell Survival; DNA Damage; Dose-Response Relationship, Radiation; Fibroblasts; Humans; Ions; Protons; Relative Biological Effectiveness
PubMed: 34910217
DOI: 10.1667/RADE-21-00138.1 -
Mutation Research. Genetic Toxicology... 2021Previous studies showed that the yield of cobalt-60 γ-rays-induced nucleoplasmic bridges (NPB) in human peripheral blood lymphocytes is dose dependent. However, the... (Clinical Trial)
Clinical Trial
Previous studies showed that the yield of cobalt-60 γ-rays-induced nucleoplasmic bridges (NPB) in human peripheral blood lymphocytes is dose dependent. However, the influence of the radiation quality and dose rates on NPB frequencies has not been investigated. The present study aimed to investigate NPB frequencies in human peripheral blood lymphocytes induced by carbon ions and explore the dose rate effect on cobalt-60 γ-rays-induced NPB. To establish dose-response curves, human peripheral blood samples were irradiated with 0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 and 8.0 Gy of carbon ions at a dose rate of 3.0 Gy/min in vitro. To explore the dose rate effect, human peripheral blood samples were irradiated with 2.0 and 5.0 Gy of cobalt-60 γ-rays at dose rates of 0.2, 0.5, 1.0, 3.0, 5.0 and 10.0 Gy/min in vitro. NPB and micronuclei (MN) in binucleated cells were analyzed with the cytokinesis-block micronucleus cytome assay. Results showed that the dose-response curve of carbon ion-induced NPB frequencies follow a linear-quadratic model (R = 0.934). The relative biological effectiveness (RBE) values of carbon ions to cobalt-60 γ-rays decreased with increased NPB frequencies (ranging from 2.47 to 5.86). Compared with group 1.0 Gy/min, the NPB frequencies in groups 10.0 Gy/min (2.0 Gy), 5.0 and 10.0 Gy/min (5.0 Gy) were decreased significantly (P < 0.05). Carbon ion-induced NPB in human peripheral blood lymphocytes have a good dose-response relationship. Cobalt-60 γ-rays-induced NPB frequencies are affected by the specific dose rate.
Topics: Adult; Cobalt Radioisotopes; DNA Damage; Dose-Response Relationship, Radiation; Gamma Rays; Humans; Lymphocytes; Male; Micronucleus Tests
PubMed: 33678246
DOI: 10.1016/j.mrgentox.2021.503321 -
Reproductive Biology Dec 2023Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly...
Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.
Topics: Female; Mice; Animals; Ovarian Follicle; Ovary
PubMed: 37890397
DOI: 10.1016/j.repbio.2023.100817 -
Clinical NeuropharmacologyThe objective of our study was to evaluate the relationship between the loading dose and efficacy of lacosamide (LCM), when used in seizure clusters (SCs).
PURPOSE
The objective of our study was to evaluate the relationship between the loading dose and efficacy of lacosamide (LCM), when used in seizure clusters (SCs).
METHODS
A cohort of patients with SC treated with intravenous (IV)-LCM between September 2017 and September 2019 was retrospectively examined. Demographic data, type of seizure emergency, etiology, response rate, previous oral antiepileptic drugs used, total LCM loading dose, and side effects were reviewed.
RESULTS
Thirty-nine cases of epileptic emergencies treated with IV LCM were collected. The mean age was 59.25 years (18-88 years), and the median loading dose was 136.5 mg (100-300 mg) with a response rate in the whole population of 29.2%. Nine patients received a loading dose of 200 to 300 mg, and their response rate was 89%. Common side effects (drowsiness and dizziness) were mild. No electrocardiogram changes or other cardiovascular side effects, or unexpected side effects were seen.
CONCLUSIONS
In adults with SC, a loading dose of IV LCM of 200 mg or more achieved 89% response rate in this cohort. Loading doses of less than 300 mg caused mild side effects only.
Topics: Acetamides; Adult; Anticonvulsants; Humans; Lacosamide; Middle Aged; Retrospective Studies; Seizures; Treatment Outcome
PubMed: 33811195
DOI: 10.1097/WNF.0000000000000445