• Cardio-oncology
• Cardiotoxicity
• Radiation
• Radiotherapy

• Humans
• Radiation Injuries/etiology
• Heart Diseases/etiology
• Radiotherapy/adverse effects
• Cardiotoxicity/etiology
• Neoplasms/radiotherapy
• Global Health

• Humans
• Cosmic Radiation/adverse effects
• Space Flight
• Cardiovascular System/radiation effects
• Cardiovascular Diseases

• Humans
• History, 20th Century
• History, 21st Century
• Acute Radiation Syndrome/drug therapy
• Medical Countermeasures
• Radiation-Protective Agents/therapeutic use
• Radiation-Protective Agents/pharmacology
• Animals
• Radiation Injuries/prevention & control
• Radiation Injuries/etiology
• United States

• R33 AI080553 NIAID NIH HHS
• U19 AI067773 NIAID NIH HHS
• 5U19AI067773-18, AND AFRRI AFR-B2-12812. NIAID
• R33-AI080553, JPC-6/7 NIAID

• Atherosclerosis
• Carotid stenosis
• Radiotherapy
• Statin

• Humans
• Male
• Female
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
• Carotid Stenosis/drug therapy
• Middle Aged
• Retrospective Studies
• Head and Neck Neoplasms/radiotherapy
• Head and Neck Neoplasms/drug therapy
• Aged
• Disease Progression
• Radiation Injuries/etiology
• Radiation Injuries/drug therapy
• Radiation Injuries/diagnostic imaging
• Cancer Survivors
• Adult
• Cohort Studies
• Follow-Up Studies
• Radiotherapy/adverse effects

• 81925031 National Natural Science Foundation of China
• 81820108026 National Natural Science Foundation of China
• 81872549 National Natural Science Foundation of China
• 82003389 National Natural Science Foundation of China
• 81801229 National Natural Science Foundation of China
• 202007030001 Science and Technology Program of Guangzhou
• 2018B030340001 Key-Area Research and Development Program of Guangdong Province

• Cancer
• Cardiovascular disease
• Ischemic stroke
• Myocardial infarction
• Statin
• Venous thromboembolism

• Humans
• Case-Control Studies
• Venous Thromboembolism/drug therapy
• Venous Thromboembolism/etiology
• Venous Thromboembolism/epidemiology
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Neoplasms/complications
• Neoplasms/drug therapy
• Risk Factors

• cerebrovascular disease
• radiation-induced vascular disease
• stroke

• epithelial regeneration
• inflammation
• metformin
• minipigs
• pravastatin
• radiation-induced intestinal injury

• Mice
• Animals
• Swine
• Swine, Miniature
• Pravastatin/pharmacology
• Pravastatin/therapeutic use
• Metformin/pharmacology
• Metformin/therapeutic use
• Diabetes Mellitus, Type 2
• Intestines
• Radiation Injuries
• Intestinal Diseases

• ASCVD score
• Framingham score
• USPSTF
• head and neck cancer
• radiation therapy
• statins

• accelerated atherosclerosis
• cancer
• chemotherapy
• coronary spasm
• coronary thrombosis
• endothelial dysfunction
• prevention
• radiotherapy

• cancer
• cardio-oncology
• coronary artery disease
• peripheral arterial disease
• radiation therapy

• in-vitro model
• ionizing radiation
• microenvironment
• microvasculature
• organ-on-chip
• radiobiological models
• radiotherapy

• Carotid arteries
• Head and neck cancer
• Radiotherapy
• Stroke
• Transient ischemic attack

• Damage
• Gastritis
• Gastrointestinal
• Gastrointestinal bleeding
• Oesophagitis
• Radiation
• Ulcers

Radiotherapy-induced cardiovascular disease is an emerging problem in a growing population of cancer survivors where traditional treatments, such as anti-platelet and lipid-lowering drugs, have limited benefits. The aim of the study was to investigate vascular inflammatory patterns in human cancer survivors, replicate the findings in an animal model, and evaluate whether interleukin-1 (IL-1) inhibition could be a potential treatment.

Irradiated human arterial biopsies were collected during microvascular autologous free tissue transfer for cancer reconstruction and compared with non-irradiated arteries from the same patient. A mouse model was used to study the effects of the IL-1 receptor antagonist, anakinra, on localized radiation-induced vascular inflammation. We observed significant induction of genes associated with inflammasome biology in whole transcriptome analysis of irradiated arteries, a finding supported by elevated protein levels in irradiated arteries of both, pro-caspase and caspase-1. mRNA levels of inflammasome associated chemokines CCL2, CCL5 together with the adhesion molecule VCAM1, were elevated in human irradiated arteries as was the number of infiltrating macrophages. A similar pattern was reproduced in Apoe−/− mouse 10 weeks after localized chest irradiation with 14 Gy. Treatment with anakinra in irradiated mice significantly reduced Ccl2 and Ccl5 mRNA levels and expression of I-A^b.

Anakinra, administered directly after radiation exposure for 2 weeks, ameliorated radiation induced sustained expression of inflammatory mediators in mice. Further studies are needed to evaluate IL-1 blockade as a treatment of radiotherapy-induced vascular disease in a clinical setting.

• Anakinra
• CCL2
• Interleukin-1
• MCP-1
• Radiation
• Vascular disease

• antioxidants
• free radicals
• ionizing radiations
• radiomitigators
• radioprotectors

• OTR2017-17899INVES UV
• SAF2017-83458-R Ministerio de Economía y Competitividad (MINECO)
• no Elysium Health Inc., NY, USA.

Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.

• pravastatin
• proctitis
• radiation
• thrombomodulin

• Animals
• Disease Models, Animal
• Endothelial Cells/cytology
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Endothelial Cells/radiation effects
• Female
• Gene Expression Regulation/drug effects
• Human Umbilical Vein Endothelial Cells
• Humans
• Leukocytes/drug effects
• Leukocytes/metabolism
• Mice
• Pravastatin/administration & dosage
• Pravastatin/pharmacology
• Proctitis/drug therapy
• Proctitis/etiology
• THP-1 Cells
• Thrombomodulin/metabolism

• biological indicators
• radiation damage
• whole body irradiation
• mice

• Acute Radiation Syndrome/blood
• Acute Radiation Syndrome/etiology
• Acute Radiation Syndrome/metabolism
• Animals
• Biomarkers/blood
• Chromatography, Liquid
• Cytokines/blood
• Female
• Hematopoiesis/radiation effects
• High-Throughput Screening Assays
• Male
• Mice
• Mice, Inbred C57BL
• Radiation Injuries, Experimental/blood
• Radiation Injuries, Experimental/etiology
• Radiation Injuries, Experimental/metabolism
• Sex Factors
• Tandem Mass Spectrometry
• Time Factors
• Whole-Body Irradiation

• HHSN272201000046C NIAID NIH HHS
• U01 AI107340 NIAID NIH HHS

• Radiation biodosimetry
• blood biomarkers
• human radiotherapy patient studies
• immunoassays
• point of care test

• intestinal epithelial cells
• irradiation
• oxidative stress
• pravastatin
• radiation-induced enteropathy

Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins.

Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5–650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF).

PAI-1 gene expression was increased in both arteries (p = 0.012) and veins (p < 0.001) in irradiated compared to unirradiated control vessels. IHC and IF indicated that cells expressing PAI-1 were located in the adventitia of both arteries and veins and colocalized with cells positive for CD68, CD45, and α-SMA in arteries and with CD45 and α-SMA in veins.

The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.

Lack of animal model of radiation induced muscle fibrosis, this study aimed to establish such a model by using 90 Gy single dose irradiation to mimic clinical relevance and also to explore the potential post-irradiation regenerative mechanism.

SD rats were randomly divided into dose investigation groups and time gradient groups. Group1–6 were irradiated with a single dose of 65Gy, 70Gy, 75Gy, 80Gy, 85Gy and 90Gy respectively, and the degree of rectus femoris fibrosis in the irradiated area was detected at 4 weeks after irradiation. Group 7–9 were irradiated with a single dose of 90Gy, and the results were detected 1, 2, 4, and 8 weeks after irradiation. Then the general condition of rats was recorded. Masson staining was used to detect muscle fibrosis. The ultrastructure of muscles was observed by electron microscope, and the expression changes of satellite cell proliferation and differentiation related genes were detected by quantitative real-time-PCR.

A single dose of 90Gy irradiation could cause muscle fibrosis in rats. As time goes on, the severity of muscle fibrosis and the expression of TGF- β1 increased. Significant swelling of mitochondria, myofilament disarrangement and dissolution, obvious endothelial cell swelling, increased vascular permeability, decrease of blood cell, deposition of fibrosis tissue around the vessel could be found compared with the control group. At around the 4th week, the expressions of Pax7, Myf5, MyoD, MyoG, Mrf4 increased.

Irradiation of 90Gy can successfully establish the rat model of radiation-induced muscle fibrosis. This model demonstrated that regenerative process was initiated by the irradiation only at an early stage, which can serve a suitable model for investigating regenerative therapy for post-radiation muscle fibrosis.

• Muscle fibrosis
• Radiation damage
• Radiotherapy
• Rat model
• Satellite cell

• hypopituitarism
• nasopharyngeal carcinoma
• radiotherapy
• thalamic infarction

• Brain Infarction/diagnostic imaging
• Brain Infarction/etiology
• Carcinoma/radiotherapy
• Disease Management
• Female
• Humans
• Mesencephalon/diagnostic imaging
• Mesencephalon/pathology
• Middle Aged
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms/radiotherapy
• Radiation Injuries/diagnostic imaging
• Thalamus/diagnostic imaging
• Thalamus/pathology

• Fibrotic tissue
• Radiosensitivity
• Senescence
• Senescence-associated secretion phenotype

• Apoptosis/radiation effects
• Cellular Senescence/radiation effects
• Fibrosis/etiology
• Humans
• Neoplasms/radiotherapy
• Radiation Injuries/etiology
• Radiation, Ionizing

• Radiation
• clinical implications
• immune system
• inflammation
• normal tissue

• Bystander Effect
• DNA Damage
• DNA Repair
• Fibrosis
• Gastrointestinal Tract/radiation effects
• Genes, Tumor Suppressor
• Hematopoiesis/radiation effects
• Humans
• Inflammation/etiology
• Inflammation Mediators/physiology
• Lung/radiation effects
• Radiation, Ionizing
• Radiodermatitis/etiology
• Toll-Like Receptors/physiology

Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA.

From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors.

The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01).

Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.

• Cerebrovascular events
• Hydroxymethylglutaryl-CoA reductase inhibitors
• Ischemic attack, transient
• Radiation
• Radiotherapy
• Stroke

• atherosclerosis
• carotid artery
• hypercholesterolemia
• radiotherapy

Thoracic radiotherapy causes damage of normal lung tissue, which limits the cumulative radiation dose and, hence, confines the anticancer efficacy of radiotherapy and impacts the quality of life of tumor patients. Ras-homologous (Rho) small GTPases regulate multiple stress responses and cell death. Therefore, we investigated whether pharmacological targeting of Rho signaling by the HMG-CoA-reductase inhibitor lovastatin influences ionizing radiation (IR)-induced toxicity in primary human lung fibroblasts, lung epithelial and lung microvascular endothelial cells in vitro and subchronic mouse lung tissue damage following hypo-fractionated irradiation (4x4 Gy). The statin improved the repair of radiation-induced DNA double-strand breaks (DSBs) in all cell types and, moreover, protected lung endothelial cells from IR-induced caspase-dependent apoptosis, likely involving p53-regulated mechanisms. Under the in vivo situation, treatment with lovastatin or the Rac1-specific small molecule inhibitor EHT1864 attenuated the IR-induced increase in breathing frequency and reduced the percentage of γH2AX and 53BP1-positive cells. This indicates that inhibition of Rac1 signaling lowers IR-induced residual DNA damage by promoting DNA repair. Moreover, lovastatin and EHT1864 protected lung tissue from IR-triggered apoptosis and mitigated the IR-stimulated increase in regenerative proliferation. Our data document beneficial anti-apoptotic and genoprotective effects of pharmacological targeting of Rho signaling following hypo-fractionated irradiation of lung cells in vitro and in vivo. Rac1-targeting drugs might be particular useful for supportive care in radiation oncology and, moreover, applicable to improve the anticancer efficacy of radiotherapy by widening the therapeutic window of thoracic radiation exposure.

Dose escalation is now the standard of care for the treatment of prostate cancer with radiation therapy. However, the rectum tends to be the dose-limiting structure when treating prostate cancer, given its close proximity. Early and late toxicities can occur when the rectum receives large doses of radiation therapy. New technologies allow for prevention of these toxicities. In this review, we examine the evidence that supports various dose constraints employed to prevent these rectal injuries from occurring. We also examine the use of intensity-modulated radiation therapy and how this compares to older radiation therapy techniques that allow for further sparing of the rectum during a radiation therapy course. We then review the literature on endorectal balloons and the effects of their daily use throughout a radiation therapy course. Tissue spacers are now being investigated in greater detail; these devices are injected into the rectoprostatic fascia to physically increase the distance between the prostate and the anterior rectal wall. Last, we review the use of systemic drugs, specifically statin medications and antihypertensives, as well as their impact on rectal toxicity.

• prevention
• prostate
• radiation therapy
• rectal toxicity

• Acetylcysteine/therapeutic use
• Adrenergic beta-Antagonists/therapeutic use
• Aerospace Medicine
• Angiotensin Receptor Antagonists/therapeutic use
• Angiotensin-Converting Enzyme Inhibitors/therapeutic use
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Astronauts
• Calcium Channel Blockers/therapeutic use
• Fingolimod Hydrochloride/therapeutic use
• Free Radical Scavengers/therapeutic use
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Hypoglycemic Agents/therapeutic use
• Immunosuppressive Agents/therapeutic use
• Metformin/therapeutic use
• Pentoxifylline/therapeutic use
• Radiation Injuries/prevention & control
• Radiation-Protective Agents/therapeutic use
• Space Flight

• U54 GM104942 NIGMS NIH HHS

• ANOVA, analysis of variance
• BNF, British National Formulary
• Big data
• CHHiP
• CHHiP, Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer
• Data linkage
• EPIC, Expanded Prostate Cancer Index Composite
• FACT-P, Functional Assessment of Cancer Therapy-Prostate
• GEE, Generalized Estimating Equations
• GP, General Practitioner
• ICD10, International Classification of Disease version 10
• ICR, Institute of Cancer Research
• IMRT, Intensity Modulated Radiotherapy
• LENT/SOMA, Late Effects Normal Tissue Toxicity; subjective, objective, management, and analytic
• Late-effects
• PCa, Prostate cancer
• PROs, Patient Reported Outcomes
• QOL, Quality of life
• RCGP RSC
• RCGP, Royal College of General Practitioners
• RCT, Randomised Control Trial
• REC, Research Ethics Committee
• RSC, Research & Surveillance Centre
• RTOG, Radiation Therapy Oncology Group
• Radiotherapy-related side-effects
• SHA2-512, Secure Hash Algorithm 2 with 512 bit hash values
• UCLA-PCI, University of California, Los Angeles Prostate Cancer Index
• UK, United Kingdom

Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

• cytokines
• cytotoxic T-cells
• natural killer cells
• radiation-induced bystander effects
• radiotherapy

• breast cancer
• radiation dermatitis
• radiotherapy
• skin toxicity

• 3-hyrdoxyl-3-methyl-glutaryl-conenzyme A reductase
• DNA damage response
• DNA double-strand breaks
• mesothelioma
• pravastatin
• radioprotectant
• radiotherapy
• statin

• enhanced permeability and retention
• ionizing radiation
• nanoparticle delivery
• tumor microenvironment

Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents.

• inflammation
• oxidative stress
• radiotherapy
• toxicity

• Pelvic radiotherapy
• Radiation
• Toxicity

Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients’ quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and a change in functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues.

• Carotid stenosis
• Follow-up
• Pathogenesis
• Prevention
• Radiotherapy
• Risk factors
• Treatment