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Proceedings of the National Academy of... Jul 2023The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the...
The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T) and P14 circulating memory CD8 T cells (T), with the former being more susceptible to radiation-induced numeric loss. While T cell numbers rapidly recovered, as previously described, the number of P14 T cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 T in irradiated hosts exhibited an inefficient transition to a central memory (CD62L) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with expressing the LCMV GP epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting T, rendering previously protected hosts susceptible to reinfection.
Topics: Mice; Animals; Whole-Body Irradiation; Neoplasm Recurrence, Local; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Immunologic Memory; Mice, Inbred C57BL
PubMed: 37364124
DOI: 10.1073/pnas.2302785120 -
Technology in Cancer Research &... 2023High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ...
High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ arcs to the inferior-most portion of the body that can be simulated in a head-first position and use 2D planning for the inferior body which can result in heterogeneous doses. Here, we describe our institution's unique protocol for delivering high-dose TBI entirely with VMAT and retrospectively compare dosimetric outcomes with helical tomotherapy (HT) plans. Additionally, we describe our method of oropharyngeal mucosal sparing that was implemented after fatal mucositis occurred in two patients. Thirty-one patients were simulated and treated in head-first (HFS) and feet-first (FFS) orientations. Patients were treated with VMAT (n = 26) or HT (n = 5). In VMAT plans, to synchronize doses between the orientations, images were deformably registered and the HFS dose was transferred to the FFS plan and used as a background dose when optimizing plans. Six to eight isocenters with two arcs per isocenter were generated. HT was delivered with an established technique. Patients were treated to 13.2 Gy over eight twice daily fractions. Dosimetric outcomes and toxicities were retrospectively compared. Prescription dose and organ at risk (OAR) constraints were met for all patients. Lower lung doses were achieved with VMAT relative to HT plans (7.4 vs 7.7 Gy, = .009). Statistically significant improvement in mucositis was not achieved after adopting a mucosal-sparing technique, however lower doses to the oropharyngeal mucosal were achieved (6.9 vs 14.1 Gy, = .009), and no further mucositis-related deaths occurred. This full-body VMAT method of TBI achieves dose goals, eliminates risk of heterogenous doses within the femur, and demonstrates that selective OAR sparing with the purpose of reducing TBI-related morbidity and mortality is possible at any institution with a VMAT-capable linear accelerator.
Topics: Humans; Radiotherapy, Intensity-Modulated; Whole-Body Irradiation; Radiotherapy Dosage; Feasibility Studies; Retrospective Studies; Radiotherapy Planning, Computer-Assisted; Organs at Risk
PubMed: 37287260
DOI: 10.1177/15330338231180779 -
Journal of Cancer Research and Clinical... Aug 2023Intensity-modulated helical tomotherapy (HT) is a promising technique in preparation for bone marrow transplantation. Nevertheless, radiation-sensitive organs can be...
Whole body irradiation with intensity-modulated helical tomotherapy prior to haematopoietic stem cell transplantation: analysis of organs at risk by dose and its effect on blood kinetics.
BACKGROUND
Intensity-modulated helical tomotherapy (HT) is a promising technique in preparation for bone marrow transplantation. Nevertheless, radiation-sensitive organs can be substantially compromised due to suboptimal delivery techniques of total body irradiation (TBI). To reduce the potential burden of radiation toxicity to organs at risk (OAR), high-quality coverage and homogeneity are essential. We investigated dosimetric data from kidney, lung and thorax, liver, and spleen in relation to peripheral blood kinetics. To further advance intensity-modulated total body irradiation (TBI), the potential for dose reduction to lung and kidney was considered in the analysis.
PATIENTS AND METHODS
46 patients undergoing TBI were included in this analysis, partially divided into dose groups (2, 4, 8, and 12 Gy). HT was performed using a rotating gantry to ensuring optimal reduction of radiation to the lungs and kidneys and to provide optimal coverage of other OAR. Common dosimetric parameters, such as D05, D95, and D50, were calculated and analysed. Leukocytes, neutrophils, platelets, creatinine, GFR, haemoglobin, overall survival, and graft-versus-host disease were related to the dosimetric evaluation using statistical tests.
RESULTS
The mean D95 of the lung is 48.23%, less than half the prescribed and unreduced dose. The D95 of the chest is almost twice as high at 84.95%. Overall liver coverage values ranged from 96.79% for D95 to 107% for D05. The average dose sparing of all patients analysed resulted in an average D95 of 68.64% in the right kidney and 69.31% in the left kidney. Average D95 in the spleen was 94.28% and D05 was 107.05%. Homogeneity indexes ranged from 1.12 for liver to 2.28 for lung. The additional significance analyses conducted on these blood kinetics showed a significant difference between the 2 Gray group and the other three groups for leukocyte counts. Further statistical comparisons of the dose groups showed no significant differences. However, there were significant changes in the dose of OAR prescribed with dose sparing (e.g., lung vs. rib and kidney).
CONCLUSION
Using intensity-modulated helical tomotherapy to deliver TBI is a feasible method in preparation for haematopoietic stem cell transplantation. Significant dose sparing in radiosensitive organs such as the lungs and kidneys is achievable with good overall quality of coverage. Peripheral blood kinetics support the positive impact of HT and its advantages strongly encourage its implementation within clinical routine.
Topics: Humans; Radiotherapy, Intensity-Modulated; Whole-Body Irradiation; Organs at Risk; Kinetics; Radiotherapy Dosage; Hematopoietic Stem Cell Transplantation; Radiotherapy Planning, Computer-Assisted
PubMed: 36856852
DOI: 10.1007/s00432-023-04657-7 -
European Journal of Nuclear Medicine... Jan 2024A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy...
PURPOSE
A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose.
METHODS
Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[F]fluoro-3'-deoxythymidine ([F]FLT) and 2-(5-[F]fluoropentyl)-2-methyl malonic acid ([F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results.
RESULTS
The hematopoietic bone marrow showed a significantly increased [F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data.
CONCLUSION
[F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.
Topics: Humans; Mice; Animals; Whole-Body Irradiation; Mice, Inbred C57BL; Positron-Emission Tomography; Disease Models, Animal; Cell Proliferation; Apoptosis; Dideoxynucleosides
PubMed: 37796306
DOI: 10.1007/s00259-023-06430-x -
Radiation Research Dec 2016Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment....
Understanding the dose-toxicity profile of radiation is critical when evaluating potential health risks associated with natural and man-made sources in our environment. The purpose of this study was to evaluate the effects of low-dose whole-body high-energy charged (HZE) iron (Fe) ions and low-energy gamma exposure on proliferation and differentiation of adult-born neurons within the dentate gyrus of the hippocampus, cells deemed to play a critical role in memory regulation. To determine the dose-response characteristics of the brain to whole-body Fe-ion vs. gamma-radiation exposure, C57BL/6J mice were irradiated with 1 GeV/n Fe ions or a static Cs source (0.662 MeV) at doses ranging from 0 to 300 cGy. The neurogenesis was analyzed at 48 h and one month postirradiation. These experiments revealed that whole-body exposure to either Fe ions or gamma radiation leads to: 1. An acute decrease in cell division within the dentate gyrus of the hippocampus, detected at doses as low as 30 and 100 cGy for Fe ions and gamma radiation, respectively; and 2. A reduction in newly differentiated neurons (DCX immunoreactivity) at one month postirradiation, with significant decreases detected at doses as low as 100 cGy for both Fe ions and gamma rays. The data presented here contribute to our understanding of brain responses to whole-body Fe ions and gamma rays and may help inform health-risk evaluations related to systemic exposure during a medical or radiologic/nuclear event or as a result of prolonged space travel.
Topics: Animals; Dose-Response Relationship, Radiation; Doublecortin Protein; Gamma Rays; Iron; Male; Mice; Mice, Inbred C57BL; Neurogenesis; Time Factors; Whole-Body Irradiation
PubMed: 27905869
DOI: 10.1667/RR14530.1 -
Cells Apr 2022The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian... (Review)
Review
The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.
Topics: Animals; Disease Models, Animal; Female; Mice; Ovarian Follicle; Ovarian Reserve; Primary Ovarian Insufficiency; Whole-Body Irradiation
PubMed: 35406783
DOI: 10.3390/cells11071219 -
International Journal of Molecular... Feb 2023For widespread cutaneous lymphoma, such as mycosis fungoides or leukemia cutis, in patients with acute myeloid leukemia (AML) and for chronic myeloproliferative... (Review)
Review
For widespread cutaneous lymphoma, such as mycosis fungoides or leukemia cutis, in patients with acute myeloid leukemia (AML) and for chronic myeloproliferative diseases, total skin irradiation is an efficient treatment modality for disease control. Total skin irradiation aims to homogeneously irradiate the skin of the entire body. However, the natural geometric shape and skin folding of the human body pose challenges to treatment. This article introduces treatment techniques and the evolution of total skin irradiation. Articles on total skin irradiation by helical tomotherapy and the advantages of total skin irradiation by helical tomotherapy are reviewed. Differences among each treatment technique and treatment advantages are compared. Adverse treatment effects and clinical care during irradiation and possible dose regimens are mentioned for future prospects of total skin irradiation.
Topics: Humans; Mycosis Fungoides; Skin Neoplasms; Radiotherapy, Intensity-Modulated; Leukemia; Lymphoma, T-Cell, Cutaneous; Radiotherapy Dosage; Whole-Body Irradiation
PubMed: 36901922
DOI: 10.3390/ijms24054492 -
Radiotherapy and Oncology : Journal of... Aug 2022Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children...
BACKGROUND AND PURPOSE
Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children.
MATERIAL AND METHODS
The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established.
RESULTS
Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies.
CONCLUSIONS
These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.
Topics: Bone Marrow; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 35661674
DOI: 10.1016/j.radonc.2022.05.027 -
Bone Jun 2021Irradiation therapy causes bone deterioration and increased risk for skeletal-related events. Irradiation interferes with trabecular architecture through increased...
Irradiation therapy causes bone deterioration and increased risk for skeletal-related events. Irradiation interferes with trabecular architecture through increased osteoclastic activity, decreased osteoblastic activity, and increased adipocyte expansion in the bone marrow (BM), which further compounds bone-related disease. Neutralizing antibodies to sclerostin (Scl-Ab) increase bone mass and strength by increasing bone formation and reducing bone resorption. We hypothesized that treatment with Scl-Ab would attenuate the adverse effects of irradiation by increasing bone volume and decreasing BM adipose tissue (BMAT), resulting in better quality bone. In this study, 12-week-old female C57BL/6J mice were exposed to 6 Gy whole-body irradiation or were non-irradiated, then administered Scl-Ab (25 mg/kg) or vehicle weekly for 5 weeks. Femoral μCT analysis confirmed that the overall effect of IR significantly decreased trabecular bone volume/total volume (Tb.BV/TV) (2-way ANOVA, p < 0.0001) with a -43.8% loss in Tb.BV/TV in the IR control group. Scl-Ab independently increased Tb.BV/TV by 3.07-fold in non-irradiated and 3.6-fold in irradiated mice (2-way ANOVA, p < 0.0001). Irradiation did not affect cortical parameters, although Scl-Ab increased cortical thickness and area significantly in both irradiated and non-irradiated mice (2-way ANOVA, p < 0.0001). Femoral mechanical testing confirmed Scl-Ab significantly increased bending rigidity and ultimate moment independently of irradiation (2-way ANOVA, p < 0.0001). Static and dynamic histomorphometry of the femoral metaphysis revealed osteoblast vigor, not number, was significantly increased in the irradiated mice treated with Scl-Ab. Systemic alterations were assessed through serum lipidomic analysis, which showed that Scl-Ab normalized lipid profiles in the irradiated group. This data supports the theory of sclerostin as a novel contributor to the regulation of osteoblast activity after irradiation. Overall, our data support the hypothesis that Scl-Ab ameliorates the deleterious effects of whole-body irradiation on bone and adipose tissue in a mouse model. Our findings suggest that future research into localized and systemic therapies after irradiation exposure is warranted.
Topics: Animals; Bone and Bones; Cancellous Bone; Female; Mice; Mice, Inbred C57BL; Osteoblasts; Osteogenesis; Whole-Body Irradiation
PubMed: 33737193
DOI: 10.1016/j.bone.2021.115918 -
International Journal of Radiation... Dec 2017Exposure to proton irradiation during missions in deep space can lead to bone marrow injury. The acute effects of proton irradiation on hematopoietic stem and progenitor...
PURPOSE
Exposure to proton irradiation during missions in deep space can lead to bone marrow injury. The acute effects of proton irradiation on hematopoietic stem and progenitor cells remain undefined and thus were investigated.
MATERIALS AND METHODS
We exposed male C57BL/6 mice to 0.5 and 1.0 Gy proton total body irradiation (proton-TBI, 150 MeV) and examined changes in peripheral blood cells and bone marrow (BM) progenitors and LSK cells 2 weeks after exposure.
RESULTS
1.0 Gy proton-TBI significantly reduced the numbers of peripheral blood cells compared to 0.5 Gy proton-TBI and unirradiated animals, while the numbers of peripheral blood cell counts were comparable between 0.5 Gy proton-TBI and unirradiated mice. The frequencies and numbers of LSK cells and CMPs in BM of 0.5 and 1.0 Gy irradiated mice were decreased in comparison to those of normal controls. LSK cells and CMPs and their progeny exhibited a radiation-induced impairment in clonogenic function. Exposure to 1.0 Gy increased cellular apoptosis but not the production of reactive oxygen species (ROS) in CMPs two weeks after irradiation. LSK cells from irradiated mice exhibited an increase in ROS production and apoptosis.
CONCLUSION
Exposure to proton-TBI can induce acute damage to BM progenitors and LSK cells.
Topics: Animals; Apoptosis; Blood Cell Count; Bone Marrow Cells; Dose-Response Relationship, Radiation; Hematopoietic Stem Cells; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Protons; Whole-Body Irradiation
PubMed: 28782442
DOI: 10.1080/09553002.2017.1356941