Gene Expression and Cellular Markers of Occupational Radiation Exposure in Chernobyl Shelter Construction Workers.

Low-dose radiation effects were studied in Ukrainian personnel of the Chernobyl exclusion zone. The aim of this study was to determine the influence of borderline exposure to annual professional limits and age on expression of molecular markers. Study groups included 300 radiation workers performing construction work on the New Safe Confinement (Arch) upon the Chernobyl "Shelter" [external dose, 26.1 ± 18.1 mSv; age, 43.1 ± 10.3 y overall and 48.7 ± 5.9 y for 69 control persons]. Methods included gene expression using RT-PCR, flow cytometry of lymphocyte antigens, gamma-H2AX, Cyclin D1 expression, and relative telomere length using flow-FISH. A statistically significant upregulation of VEGFA BAX, DDB2, NFKB1 was shown at doses below 35 mSv. In workers aged under 40 y with doses higher than 35 mSv, an upregulation of 16 genes was revealed-VEGFA, TERF2, TERF1, BIRC5, BAX, TP53, DDB2, CDKN1B, CDKN2A, NFKB2, MAPK14, TGFBR1, MKNK2, CDKN1A, NFKB1, TP53I3; and four genes were downregulated-MADD, FASL, CSF2, and TERT. In workers older than 40 y, 8 genes were upregulated and 12 were downregulated. All groups showed an increased and dose-dependent gamma-H2AX expression. Downregulation of CCND1 genes in older groups was accompanied by lower numbers of Cyclin D1 protein expression and lower CD3 and CD4 cell counts. Upregulation of CSF2 in those over 40 y old positively correlated with B-cell and NK-cell counts. A non-linear type of gene expression response was demonstrated: in doses over 35 mSv for those over 40 y, the increased expression of gamma-H2AX is associated with upregulation of cell survival positive regulators-BIRC5, BRCA1, DDB2, CCND1, TERT genes, and longer telomeres; the younger age group was characterized by TERF1 and TERF2 upregulation and telomere shortening.

Misuse of a Medical Radioisotope: 125I Labeled Playing Cards in Germany, a Case Study.

The security of medical radioactive sources, both open and sealed, is an important consideration for reducing the risk of an intentional or inadvertent additional radiation dose to the public, according to the principle of keeping any additional radiation dose as low as reasonably achievable. The detection and following radiological investigation of the misuse of iodine-125 (I), a medically used radionuclide, in Germany is described in detail with the aim of sharing experience and raising awareness. The misuse of I shows that the security of I is not guaranteed completely at the present time.

Detection of Embedded Low-level Radioactive Shrapnel after the Explosion of a Radiological Dispersal Device in Radiological Emergency Imaging.

Concern about the threat of a terrorist attack with a Radiological Dispersal Device has increased considerably over the last few years, and this comes along with an immense challenge, especially regarding medical treatment of combined injuries with incorporated radioactive fragments. In such scenarios, the identification and surgical exploration of radioactive fragments is a major issue to prevent further radiation-induced effects like wound healing disorders, onset of acute radiation syndrome, and as a late-effect cancer. However, in a usual emergency setting, it is unclear how this task can be achieved. Within this study, we evaluated the feasibility of different radiological methods to identify and locate an incorporated radioactive fragment. We placed two different Cs sources and several non-radioactive fragments representing sham control samples within a human spine phantom. Standard emergency imaging procedures were performed, including plane radiography and different CT scans (64 row, 384 row dual energy, 320 row without iterative metal artifact reduction), respectively. Eight radiologists were blinded toward the results and asked to identify the radioactive fragments within the provided images. For both sources, correct identification was rather low (15.63%). Furthermore, none of the questioned radiologists (N = 0) stated that they were able to identify the radioactive shrapnel distinctly. Positive predictive value was accordingly low (15.63%). Most participants recommended a scintigraphy-based technique for identification (26.67%) rather than radiographic procedures (6.67%). Identification and location of incorporated small radioactive fragments with low energies by standard radiological procedures prior to surgical exploration is not promising. Nevertheless, procedures that can achieve this aim are needed direly in the case of a terrorist attack with a radiological dispersal device and should be available in an emergency department.

Salivary gland function in thyroid cancer patients with radioiodine administration history.

AIM: Radioiodine (RAI) improves survival in patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC). Although there has been an ongoing debate on RAI-induced salivary gland damage, published data have been inconsistent. Therefore, the purpose of our study was to compare salivary gland function in intermediate and high risk DTC patients after single or repeated RAI treatment with their age- and sex-matched RAI-naive counterparts. METHODS: Uptake and excretion of parotid and submandibular glands were quantitatively evaluated using 99mTc-pertechnetate salivary gland scintigraphy in 23 patients previously treated with RAI. Patients (median 9.25 GBq 131I-NaI; Q1-Q3: 5.55-16.65; range: 5.55-27.5) were divided into subgroups according to previously administered 131I-NaI activity using cut-off values 5.55 GBq and 9.25 GBq. Their salivary gland scintigraphy results were compared with RAI-naive patients using Mann-Whitney test. RESULTS: Compared to RAI-naive patients, parotid glands pertechnetate uptake was significantly lower in those treated with > 9.25 GBq (P=0.034) and parotid glands excretion fraction was already decreased with RAI activities > 5.55 GBq (P=0.031). In submandibular glands, no statistically significant difference in either function was observed even with RAI activity > 9.25 GBq. CONCLUSION: Our data suggest that RAI therapy using activities ≤ 5.55 GBq does not substantially decrease saliva production. Activities > 5.55 GBq may lead to significant decrease in parotid excretion, and activities > 9.25 GBq also diminish parotid uptake. Surprisingly, submandibular glands, providing majority of seromucinous saliva under basal condition, seem to be unaffected even by RAI activities above 9.25 GBq.

A 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo.

Searching for actinide decorporation agents with advantages of high decorporation efficiency, minimal biological toxicity, and high oral efficiency is crucial for nuclear safety and the sustainable development of nuclear energy. Removing actinides deposited in bones after intake is one of the most significant challenges remaining in this field because of the instantaneous formation of highly stable actinide phosphate complexes upon contact with hydroxyapatite. Here we report a hydroxypyridinone-based ligand (5LIO-1-Cm-3,2-HOPO) exhibiting stronger affinity for U(VI) compared with the reported tetradentate hydroxypyridinone ligands. This is further revealed by the first principles calculation analysis on bonding between the ligand and uranium. Both in vitro uranium removal assay and in vivo decorporation experiments with mice show that 5LIO-1-Cm-3,2-HOPO can remove uranium from kidneys and bones with high efficiencies, while the decorporation efficiency is nearly independent of the treatment time. Moreover, this ligand shows a high oral decorporation efficiency, making it attractive for practical applications.

The relationship of lymphocyte recovery and prognosis of esophageal cancer patients with severe radiation-induced lymphopenia after chemoradiation therapy.

INTRODUCTION: Radiation-induced lymphopenia (RIL) during therapy is associated with poor prognosis but is often temporary and resolves after treatment completion in esophageal cancer. How lymphocyte recovery contributes to prognosis is unknown. METHODS: We reviewed 755 patients with stage I-III esophageal carcinoma who received concurrent chemoradiation therapy (CRT) with or without surgery in 2004-2015. Complete blood counts were obtained before, during, and at first follow-up after CRT. Lymphopenia was graded per the Common Terminology Criteria for Adverse Events v4.03 during CRT (G) and as recovery after CRT (Gr). Clinical factors and lymphopenia grade were tested for association with survival in univariable and multivariable Cox proportional hazard regression analyses. RESULTS: During CRT, 294 patients (38.9%) had G4 lymphopenia; by the first follow-up, 406 patients (53.8%) had recovered (Gr0-1). Relative to patients with G0-3 lymphopenia during CRT, G4 lymphopenia independently predicted worse OS in multivariable analyses. However, lymphocyte recovery was not associated with a better prognosis. Patients with G4 lymphopenia during CRT and recovery (Gr0-1) afterward still had poorer 5-year OS rate than patients with G0-3 during CRT without recovery (Gr2-4) afterward (36.6% vs. 51.9%, HR = 1.40, 95% CI 1.04-1.89, P = 0.027). Moreover, the lymphocyte recovery ability (post-CRT ALC divided by pre-CRT ALC) was not affected by lymphopenia grade during CRT (0.66 in G0-3 vs. 0.65 in G4, p = 0.473). Among patients with G4 lymphopenia during treatment, lymphocyte recovery was only associated with pre-CRT lymphocyte counts. CONCLUSION: Lymphocyte count recovery after CRT does not alter the poor long-term outcomes brought about by high-grade lymphopenia during CRT.

Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment.

With 5-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidaemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to paediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g. echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in paediatric cancer patients and childhood cancer survivors.

Cytokines and radiation-induced pulmonary injuries.

Radiation therapy is one of the most common treatment strategies for thorax malignancies. One of the considerable limitations of this therapy is its toxicity to normal tissue. The lung is the major dose-limiting organ for radiotherapy. That is because ionizing radiation produces reactive oxygen species that induce lesions, and not only is tumor tissue damaged, but overwhelming inflammatory lung damage can occur in the alveolar epithelium and capillary endothelium. This damage may result in radiation-induced pneumonitis and/or fibrosis. While describing the lung response to irradiation generally, the main focus of this review is on cytokines and their roles and functions within the individual stages. We discuss the relationship between radiation and cytokines and their direct and indirect effects on the formation and development of radiation injuries. Although this topic has been intensively studied and discussed for years, we still do not completely understand the roles of cytokines. Experimental data on cytokine involvement are fragmented across a large number of experimental studies; hence, the need for this review of the current knowledge. Cytokines are considered not only as molecular factors involved in the signaling network in pathological processes, but also for their diagnostic potential. A concentrated effort has been made to identify the significant immune system proteins showing positive correlation between serum levels and tissue damages. Elucidating the correlations between the extent and nature of radiation-induced pulmonary injuries and the levels of one or more key cytokines that initiate and control those damages may improve the efficacy of radiotherapy in cancer treatment and ultimately the well-being of patients.

Bowel morbidity following radiochemotherapy and image-guided adaptive brachytherapy for cervical cancer: Physician- and patient reported outcome from the EMBRACE study.

BACKGROUND/PURPOSE: This study describes late bowel morbidity prospectively assessed in the multi-institutional EMBRACE study on MRI-guided adaptive brachytherapy in locally advanced cervical cancer (LACC). MATERIALS/METHODS: A total of 1176 patients were analyzed. Physician reported morbidity (CTCAE v.3.0) and patient reported outcome (PRO) (EORTC QLQ C30/CX24) were assessed at baseline and at regular follow-up. RESULTS: At 3/5 years the actuarial incidence of bowel morbidity grade 3-4 was 5.0%/5.9%, including incidence of stenosis/stricture/fistula of 2.0%/2.6%. Grade 1-2 morbidity was pronounced with prevalence rates of 28-33% during follow-up. Diarrhea and flatulence were most frequently reported, significantly increased after 3 months and remained elevated during follow-up. Incontinence gradually worsened with time. PRO revealed high prevalence rates. Diarrhea ≥"a little" increased from 26% to 37% at baseline to 3 months and remained elevated, difficulty in controlling bowel increased from 11% to 26% at baseline to 3 months gradually worsening with time. Constipation and abdominal cramps improved after treatment. CONCLUSION: Bowel morbidity reported in this large cohort of LACC patients was limited regarding severe/life-threatening events. Mild-moderate diarrhea, flatulence and incontinence were prevalent after treatment with PROs indicating a considerable and clinically relevant burden. Critical knowledge based on the extent and manifestation pattern of treatment-related morbidity will serve future patient management.

Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

While thyroid cancer risks from exposure to ionizing radiation early in life are well characterized quantitatively, the association of radiation with nonmalignant, functional thyroid disorders has been less studied. Here, we report on a risk analysis study of hypothyroidism with radiation dose to the thyroid gland and the hypothalamic-pituitary axis among survivors of childhood cancer. Utilizing data from the Childhood Cancer Survivor Study, a cohort of 14,364 five-year survivors of childhood cancer diagnosed at 26 hospitals in the U.S. and Canada between 1970 and 1986 and followed through 2009, the occurrence of hypothyroidism was ascertained among 12,015 survivors through serial questionnaires. Radiation doses to the thyroid gland and pituitary gland were estimated from radiotherapy records. Binary outcome regression was used to estimate prevalence odds ratios for hypothyroidism at five years from diagnosis of childhood cancer and Poisson regression to model incidence rate ratios (RR) after the first five years. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred five or more years after cancer diagnosis. The cumulative proportion affected with hypothyroidism (prevalence at five years after cancer diagnosis plus incidence through 30 years after cancer diagnosis) was highest among five-year survivors of Hodgkin lymphoma (32.3%; 95% CI: 29.5-34.9) and cancers of the central nervous system (17.7%; 95% CI: 15.2-20.4). The incidence rate was significantly associated with radiation dose to the thyroid and pituitary. The joint association of hypothyroidism with thyroid and pituitary dose was sub-additive for pituitary doses greater than 16 Gy. In particular, a very strong thyroid radiation dose dependence at low-to-moderate pituitary/hypothalamic doses was diminished at high pituitary doses. Radiation-related risks were higher in males than females and inversely associated with age at exposure and time since exposure but remained elevated more than 25 years after exposure. Our findings indicated that hypothyroidism was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI: 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (CCNU) (RR = 3.0; 95% CI: 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI: 1.0-1.8), with a significant dose response for CCNU ( P < 0.01). The risk of hypothyroidism among childhood cancer survivors treated with radiation depends both on direct, dose-dependent radiation-induced damage to the thyroid gland and on dose-dependent indirect effects secondary to irradiation of the hypothalamic-pituitary axis. The dose-response relationship for each site depends on dose to the other. Radiation-related risk persists for more than 25 years after treatment. Treatment with certain chemotherapy agents may increase the risk of hypothyroidism.

Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: The EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO). MATERIAL AND METHODS: A total of 1176 patients were analysed. Median follow up (FU) was 27 (1-83) months. Morbidity (CTCAE v.3) and PRO (EORTC QLQ-C30&CX24) was prospectively assessed at baseline (BL), and during FU. RESULTS: The most frequent symptoms were frequency/urgency, incontinence, and cystitis with grade 2-4 prevalence rates of 4.3%, 5.0% and 1.7% and grade 1-4 prevalence rates of 24.5%, 16.1% and 5.8% at 3-years. The most frequent PRO endpoints were "urinary frequency" and "leaking of urine". Prevalence of "Quite a bit" or "very much" bother fluctuated from 14.0% to 21.5% for "frequency", while "leaking of urine" increased from 4.6% at BL to 9.3% at 3-years. Actuarial 3-year incidence of grade 3-4 urinary morbidity was 5.3% with most events being urinary frequency, incontinence and ureteral strictures. Grade 3-4 fistula, bleeding, spasm and cystitis were all <1.0% at 3/5-years. No grade 5 toxicity occurred. CONCLUSION: Urinary grade 3-4 morbidity with IGABT was limited. Urinary morbidity grade 2-4 comprises mainly frequency/urgency, incontinence and cystitis and has considerable prevalence in PRO. Various urinary morbidity endpoints have different patterns of manifestation and time course.

Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study.

OBJECTIVE: To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study. METHODS: Morbidity was prospectively assessed according to CTCAE v.3 and patient-reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed. RESULTS: A total of 1176 patients were analyzed with a median follow-up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3-year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G ≥ 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes. CONCLUSION: Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies.

Protective effect of mitochondrial-targeted antioxidant MitoQ against iron ion 56Fe radiation induced brain injury in mice.

Exposure to iron ion 56Fe radiation (IR) during space missions poses a significant risk to the central nervous system and radiation exposure is intimately linked to the production of reactive oxygen species (ROS). MitoQ is a mitochondria-targeted antioxidant that has been shown to decrease oxidative damage and lower mitochondrial ROS in a number of animal models. Therefore, the present study aimed to investigate role of the mitochondrial targeted antioxidant MitoQ against 56Fe particle irradiation-induced oxidative damage and mitochondria dysfunction in the mouse brains. Increased ROS levels were observed in mouse brains after IR compared with the control group. Enhanced ROS production leads to disruption of cellular antioxidant defense systems, mitochondrial respiration dysfunction, altered mitochondria dynamics and increased release of cytochrome c (cyto c) from mitochondria into cytosol resulting in apoptotic cell death. MitoQ reduced IR-induced oxidative stress (decreased ROS production and increased SOD, CAT activities) with decreased lipid peroxidation as well as reduced protein and DNA oxidation. MitoQ also protected mitochondrial respiration after IR. In addition, MitoQ increased the expression of mitofusin2 (Mfn2) and optic atrophy gene1 (OPA1), and decreased the expression of dynamic-like protein (Drp1). MitoQ also suppressed mitochondrial DNA damage, cyto c release, and caspase-3 activity in IR-treated mice compared to the control group. These results demonstrate that MitoQ may protect against IR-induced brain injury.

Enhanced radiation damage caused by iodinated contrast agents during CT examination.

OBJECTIVE: To access the effect of iodinate contrast agent (ICA) on DNA double-stand breaks (DSBs) in human peripheral blood lymphocytes during computed tomography (CT) examinations. MATERIALS AND METHODS: This present study was approved by the institutional ethics committee; written informed patient consent was obtained from 70 patients. A total of 48 patients underwent computed tomography urography (CTU), in which only one time CT scanning was examined after injecting ICA, and 22 patients received unenhanced whole abdominal CT, among them 10 patients were selected to get ICA injection immediately after irradiation. Blood samples were taken from all patients prior to and immediately after CT scan, as well as 8min after the injection of ICA. The lymphocytes in these blood samples were separated by using density-gradient centrifugation, fixed and immunostained with γH2AX antibody. The average number of phosphorylated histone H2AX (γH2AX) foci per lymphocyte was counted under a fluorescence microscopy. Differences in the number of γH2AX-foci were statistically analyzed using independent sample t test and one way ANOVA. RESULT: The three patient groups had no significant differences in the baseline foci numbers(P>0.05). The γH2AX-focus levels increased in both groups after CT scan. Patients who underwent CTU examinations had a greater DSBs level (mean±standard error of mean, 0.945±0.184 foci per cell) than those who received unenhanced whole abdominal CT scan (mean±standard error of mean, 0.700±0.112 foci per cell), increasing by about 37.9%; The ICA injected before CT scan itself had an effect on the DSBs, which increased DSBs level by approximately 90.3% (0.059±0.018vs 0.031±0.025, P<0.05), but no significant difference was found if added after irradiation, increasing DSBs level only by 3.2% approximately (0.711±0.091vs 0.689±0.108, P=0.499). CONCLUSION: The iodinated contrast agent itself can lead to an increase in the level of DSBs as assessed with γH2AX foci formation, and the application of ICA can amplify DNA damage induced by diagnostic x-ray procedures such as whole abdominal CT.

Efficacy of repeated low-dose bevacizumab treatment with long-dosing interval for radiation-induced brain necrosis: A case report.

A 40-year-old Chinese female patient, with radiation-induced brain necrosis after radiosurgery, was treated 6 times with a single dose of 200 mg (3.27 mg/kg) bevacizumab each time, and with an interval of 12-16 weeks between each treatment. Neurological symptoms such as dizziness, fatigue, and headache disappeared after each administration of bevacizumab. The results suggest that repeated bevacizumab treatment using a low-dose and long-dosing interval may significantly alleviate radiation necrosis and its symptoms.