Missed irradiation of cellular blood components for vulnerable patients: Insights from 10 years of SHOT data.

BACKGROUND: Irradiation of cellular blood components is recommended for patients at risk of transfusion-associated graft-vs-host disease (TA-GvHD). Prestorage leucodepletion (LD) of blood components is standard in the UK since 1999. STUDY DESIGN AND METHODS: Analysis of 10 years' reports from UK national hemovigilance scheme, Serious Hazards of Transfusion (2010-2019), where patients failed to receive irradiated components when indicated according to British Society for Haematology guidelines (2011). RESULTS: There were 956 incidents of failure to receive irradiated components all due to errors. One hundred and seventy two incidents were excluded from analysis, 125 of 172 (72.7%) because of missing essential information. No cases of TA-GvHD were reported in this cohort. The 784 patients received 2809 components (number unknown for 67 incidents). Most failures occurred in patients treated with purine analogues (365) or alemtuzumab (69), or with a history of Hodgkin lymphoma (HL) (192). Together these make up 626 of 784 (79.9%). Poor communication is an important cause of errors. CONCLUSION: Leucodepletion appears to reduce the risk for TA-GvHD. None of 12 cases of TA-GvHD reported to SHOT prior to introduction of LD occurred in patients with conditions recommended for irradiated components by current guidelines. Irradiation indefinitely for all stages of HL is not based on good evidence and is a difficult guideline to follow. Further research on long-term immune function in HL is required. Variation between different national guidelines reflects the very limited evidence.

In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation.

Following cell stress such as ionising radiation (IR) exposure, multiple cellular pathways are activated. We recently demonstrated that ferredoxin reductase (FDXR) has a remarkable IR-induced transcriptional responsiveness in blood. Here, we provided a first comprehensive FDXR variant profile following DNA damage. First, specific quantitative real-time polymerase chain reaction (qPCR) primers were designed to establish dose-responses for eight curated FDXR variants, all up-regulated after IR in a dose-dependent manner. The potential role of gender on the expression of these variants was tested, and neither the variants response to IR nor the background level of expression was profoundly affected; moreover, in vitro induction of inflammation temporarily counteracted IR response early after exposure. Importantly, transcriptional up-regulation of these variants was further confirmed in vivo in blood of radiotherapy patients. Full-length nanopore sequencing was performed to identify other FDXR variants and revealed the high responsiveness of FDXR-201 and FDXR-208. Moreover, FDXR-218 and FDXR-219 showed no detectable endogenous expression, but a clear detection after IR. Overall, we characterised 14 FDXR transcript variants and identified for the first time their response to DNA damage in vivo. Future studies are required to unravel the function of these splicing variants, but they already represent a new class of radiation exposure biomarkers.

Proteomic changes by radio-mitigative thrombopoietin receptor agonist romiplostim in the blood of mice exposed to lethal total-body irradiation.

PURPOSE: The thrombopoietin receptor agonist romiplostim (RP) is a therapeutic agent for immune thrombocytopenia that can achieve complete survival in mice exposed to a lethal dose of ionizing radiation. The estimated mechanism of the radio-protective/mitigative effects of RP has been proposed; however, the detailed mechanism of action remains unclear. This study aimed to elucidate the mechanism of the radio-protective/mitigative effects of RP, the fluctuation of protein in the blood was analyzed by proteomics. MATERIALS AND METHODS: Eight-week-old female C57BL/6J mice were randomly divided into 5 groups; control at day 0, total-body irradiation (TBI) groups at day 10 and day 18, and TBI plus RP groups at day 10 and day18, consisting of 3 mice per group, and subjected to TBI with 7 Gy of 137Cs γ-rays at a dose rate of 0.74 Gy/min. RP was administered intraperitoneally to mice at a dose of 50 µg/kg once daily for 3 days starting 2 hours after TBI. On day 10 and day 18 after TBI, serum collected from each mouse was analyzed by liquid chromatography tandem mass spectrometry. RESULTS: Nine proteins were identified by proteomics methods from 269 analyzed proteins detected in mice exposed to a lethal dose of TBI: keratin, type II cytoskeletal 1 (KRT1), fructose-1, 6-bisphosphatase (FBP1), cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1), peptidyl-prolyl cis-trans isomerase A (PPIA), glycine N-methyltransferase (GNMT), glutathione S-transferase Mu 1 (GSTM1), regucalcin (RGN), fructose-bisphosphate aldolase B (ALDOB) and betain-homocysteine S-methyltransferase 1 (BHMT). On the 10th day after TBI, KRT1 was significantly increased (p < 0.05) by 4.26-fold compared to the control group in the TBI group and significantly inhibited in the TBI plus RP group (p < 0.05). Similarly, the expression levels of other 8 proteins detected at 18th day after TBI were significantly increased by 4.29 to 27.44-fold in the TBI group, but significantly decreased in the TBI plus RP group compared to the TBI group, respectively. CONCLUSION: Nine proteins were identified by proteomics methods from 269 analyzed proteins detected in mice exposed to a lethal dose of TBI. These proteins are also expected to be indicators of the damage induced by high-dose radiation.

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing.

In the event of a large-scale event leading to acute ionizing radiation exposure, high-throughput methods would be required to assess individual dose estimates for triage purposes. Blood-based gene expression is a broad source of biomarkers of radiation exposure which have great potential for providing rapid dose estimates for a large population. Time is a crucial component in radiological emergencies and the shipment of blood samples to relevant laboratories presents a concern. In this study, we performed nanopore sequencing analysis to determine if the technology can be used to detect radiation-inducible genes in human peripheral blood mononuclear cells (PBMCs). The technology offers not only long-read sequencing but also a portable device which can overcome issues involving sample shipment, and provide faster results. For this goal, blood from nine healthy volunteers was 2 Gy ex vivo X irradiated. After PBMC isolation, irradiated samples were incubated along with the controls for 24 h at 37°C. RNA was extracted, poly(A)+ enriched and reverse-transcribed before sequencing. The data generated was analyzed using a Snakemake pipeline modified to handle paired samples. The sequencing analysis identified a radiation signature consisting of 46 differentially expressed genes (DEGs) which included 41 protein-coding genes, a long non-coding RNA and four pseudogenes, five of which have been identified as radiation-responsive transcripts for the first time. The genes in which transcriptional expression is most significantly modified after radiation exposure were APOBEC3H and FDXR, presenting a 25- and 28-fold change on average, respectively. These levels of transcriptional response were comparable to results we obtained by quantitative polymerase chain reaction (qPCR) analysis. In vivo exposure analyses showed a transcriptional radioresponse at 24 h postirradiation for both genes together with a strong dose-dependent response in blood irradiated ex vivo. Finally, extrapolating from the data we obtained, the minimum sequencing time required to detect an irradiated sample using APOBEC3H transcripts would be less than 3 min for a total of 50,000 reads. Future improvements, in sample processing and bioinformatic pipeline for specific radiation-responsive transcript identification, will allow the provision of a portable, rapid, real-time biodosimetry platform based on this new sequencing technology. In summary, our data show that nanopore sequencing can identify radiation-responsive genes and can also be used for identification of new transcripts.

Developing Gender-Specific Gene Expression Biodosimetry Using a Panel of Radiation-Responsive Genes for Determining Radiation Dose in Human Peripheral Blood.

In a large-scale radiological incident, rapid and high-throughput biodosimetry would be needed. Gene expression-based biodosimetry is a promising approach to determine the dose received after radiation exposure. We previously identified 35 candidate genes as biodosimetry markers based on a systematic review. The goal of the current study was to establish and validate a specific gene expression-based radiological biodosimetry using a panel of highly radioresponsive genes in human peripheral blood for improving the accuracy of dose estimation. Human peripheral blood samples from 30 adult donors were irradiated to 0, 0.5, 1, 2, 3, 4, 6 and 8 Gy with 60Co γ rays at a dose rate of 1 Gy/min. We examined the expression patterns of candidate genes using real-time polymerase chain reaction (qRT-PCR) at 6, 12, 24 and 48 h postirradiation. Stepwise regression analysis was employed to develop the gene expression-based dosimetry models at each time point. Samples from another 10 healthy donors (blind samples) and four total-body irradiated (TBI) patients were used to validate the radiation dosimetry models. We observed significant linear dose-response relationships of CDKN1A, BAX, MDM2, XPC, PCNA, FDXR, GDF-15, DDB2, TNFRSF10B, PHPT1, ASTN2, RPS27L, BBC3, TNFSF4, POLH, CCNG1, PPM1D and GADD45A in human peripheral blood at the various time points. However, the expression levels of these genes were affected by inter-individual variations and gender. We found that the gender-dependent regression models could explain 0.85 of variance at 24 h postirradiation and could also accurately estimate the absorbed radiation doses with dose range of 0-5 Gy, in human peripheral blood samples irradiated ex vivo and from TBI patients, respectively. This study demonstrates that developing gender-specific biodosimetry based on a panel of highly radioresponsive genes may help advance the application of gene expression signature for dose estimation in the event of a radiological accident or in clinical treatment.

A computational model to investigate the influence of electrode lengths on the single probe bipolar radiofrequency ablation of the liver.

BACKGROUND AND OBJECTIVES: Recently, there have been calls for RFA to be implemented in the bipolar mode for cancer treatment due to the benefits it offers over the monopolar mode. These include the ability to prevent skin burns at the grounding pad and to avoid tumour track seeding. The usage of bipolar RFA in clinical practice remains uncommon however, as not many research studies have been carried out on bipolar RFA. As such, there is still uncertainty in understanding the effects of the different RF probe configurations on the treatment outcome of RFA. This paper demonstrates that the electrode lengths have a strong influence on the mechanics of bipolar RFA. The information obtained here may lead to further optimization of the system for subsequent uses in the hospitals. METHODS: A 2D model in the axisymmetric coordinates was developed to simulate the electro-thermophysiological responses of the tissue during a single probe bipolar RFA. Two different probe configurations were considered, namely the configuration where the active electrode is longer than the ground and the configuration where the ground electrode is longer than the active. The mathematical model was first verified with an existing experimental study found in the literature. RESULTS: Results from the simulations showed that heating is confined only to the region around the shorter electrode, regardless of whether the shorter electrode is the active or the ground. Consequently, thermal coagulation also occurs in the region surrounding the shorter electrode. This opened up the possibility for a better customized treatment through the development of RF probes with adjustable electrode lengths. CONCLUSIONS: The electrode length was found to play a significant role on the outcome of single probe bipolar RFA. In particular, the length of the shorter electrode becomes the limiting factor that influences the mechanics of single probe bipolar RFA. Results from this study can be used to further develop and optimize bipolar RFA as an effective and reliable cancer treatment technique.

Comparative In Vitro Study: Examining 635 nm Laser and 265 nm Ultraviolet Interaction with Blood.

Objective: This study represents a viable assessment of the effect of the low-level laser (LLL) of 635 nm and ultraviolet (UV) of 265 nm on biophysical properties of blood. Materials and methods: Blood samples were divided into two main groups: one for irradiation by LLL and the other for irradiation by UV. Each group was divided into three aliquots. First aliquot: whole blood was exposed to radiation. The second aliquot: erythrocytes were exposed to radiation and resuspended in autologous plasma. The third aliquot: plasma was exposed to radiation, and erythrocytes were resuspended in it. The following parameters were measured after irradiation by LLL and UV for all aliquots: whole blood viscosity, microscopic aggregation index, deformation index, and Zeta potential. Results: A decrease in whole blood viscosity due to irradiation by LLL was observed. To the contrary, an increase in whole blood viscosity due to irradiation by UV was detected. A significant reduction in erythrocytes' aggregation was observed as a result of LLL and UV radiation. Erythrocytes' deformability was strongly affected by UV radiation, while there was no significant effect from LLL. Another noticeable change observed was an increase in Zeta potential due to UV and a decrease in Zeta potential values, as a result of LLL irradiation. Conclusions: It can be concluded from this study that LLL and UV can be used to change some biological processes, as well as cellular properties.

Successful Migration from Radioactive Irradiators to X-ray Irradiators in One of the Largest Medical Centers in the US.

This paper summarizes about 9 years of effort by Mount Sinai to successfully migrate completely from radioactive irradiators to x-ray irradiators without compromising patient care or research studies. All the effort by Mount Sinai to permanently remove the risk of malicious use of radioactive materials as Radiological Dispersal Device or dirty bomb is reviewed. Due to the unique characteristics of the cesium chloride (CsCl) used in irradiators, it is especially susceptible to be used as a dirty bombs. Mount Sinai originally had four of such irradiators. To reduce and eventually remove the risk of malicious use of radioactive materials, Mount Sinai in New York City has taken several steps. One of such measures was to harden the radioactive irradiators to make the radioactive materials harder to be stolen for malicious purposes. By increasing the delay time, the local law enforcement agency (LLEA) will have more time to stop the intruder. Another measure taken was to implement enhanced security in facilities having radioactive materials. We collaborated with the National Nuclear Security Administration and used state-of-the-art security equipment such as Biometric Access Control and 24/7 video monitoring. In addition, a remote monitoring system with alarms was installed and connected to LLEA for constant monitoring and possible intervention, if necessary, in a timely manner. The other measure taken was to limit the number of people who have access to such radioactive materials. We adopted a single person operator method and reduced the number of people having access from 145 people to only a few people. The adoption of such measures has reduced the risk significantly; however, the best way to remove the permanent risk of these radioactive materials that may be used for a dirty bomb is to use alternative technology to replace these high-activity radioactive sources. In 2013, Mount Sinai purchased its first x-ray irradiator to investigate the feasibility of using x-ray irradiators instead of cesium irradiators for research purposes for cells and small mice. The results from comparison studies were promising, which led to the decision of permanent migration of all cesium irradiators to x-ray irradiators. As of January 2018, Mount Sinai successfully disposed all its Cs irradiators. At this time, Mount Sinai, as one of the largest health care institutions in NY with about 50,000 employees, has migrated completely to alternative technology and removed the risk of malicious use of radioactive materials permanently.

The effect of red-to-near-infrared (R/NIR) irradiation on inflammatory processes.

Introduction: Near-infrared (NIR) and red-to-near-infrared (R/NIR) radiation are increasingly applied for therapeutic use. R/NIR-employing therapies aim to stimulate healing, prevent tissue necrosis, increase mitochondrial function, and improve blood flow and tissue oxygenation. The wide range of applications of this radiation raises questions concerning the effects of R/NIR on the immune system. Methods: In this review, we discuss the potential effects of exposure to R/NIR light on immune cells in the context of physical parameters of light. Discussion: The effects that R/NIR may induce in immune cells typically involve the production of reactive oxygen species (ROS), nitrogen oxide (NO), or interleukins. Production of ROS after exposure to R/NIR can either be inhibited or to some extent increased, which suggests that detailed conditions of experiments, such as the spectrum of radiation, irradiance, exposure time, determine the outcome of the treatment. However, a wide range of immune cell studies have demonstrated that exposure to R/NIR most often has an anti-inflammatory effect. Finally, photobiomodulation molecular mechanism with particular attention to the role of interfacial water structure changes for cell physiology and regulation of the inflammatory process was described. Conclusions: Optimization of light parameters allows R/NIR to act as an anti-inflammatory agent in a wide range of medical applications.

Proteomic analysis of plasma proteins after low-level laser therapy in rats.

The laser radiation absorbed by cells induces production of reactive oxygen species (ROS), followed by the development of oxidative stress. Proteins are major targets for ROS due to their abundance in biological systems. The aim of the present pilot study was to examine the effects of transcutaneous laser blood irradiation (TLBI), i.e., low-level laser therapy (LLLT) at 830 nm on plasma proteome in Wistar rats. Rats were irradiated in the heart area (i.e. coronary arteries) daily (i.e., for 9-day period), by commercially available GaAsAl diode laser (Maestro/CCM, Medicom Prague, Czech Republic, lambda=830 nm, power density 450mW/cm(2), daily dose 60,3 J/ cm(2), irradiation time 134 sec). The comparison of blood plasma proteome from irradiated and non-irradiated rats was performed utilizing 2D electrophoresis followed by MALDI TOF/TOF mass spectrometry. LLLT led to a quantitative change in the acute phase proteins with antioxidant protection i.e., haptoglobin (log(2) fold change (FC)=3.5), hemopexin (log(2) FC=0.5), fibrinogen gamma (log2 FC=1.4), alpha-1-antitrypsin (log(2) FC=-2.2), fetuin A (log2 FC=-0.6) and fetuin B (log2 FC=-2.3). In comparison to conventional biochemical methods, the changes in protein levels in blood plasma induced by LLLT offer a deeper insight into the oxidative stress response.

Minimal uranium accumulation in lymphoid tissues following an oral 60-day uranyl acetate exposure in male and female C57BL/6J mice.

High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to uranyl acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (<0.01%) at both the 5 and the 50 ppm (mg/L) oral concentrations. In both male and female mice, there was limited U accumulation in immune organs. U only accumulated at low concentrations in the blood and bone marrow of male mice (0.6 and 16.8 ng/g, respectively). Consistent with previous reports, the predominant sites of U accumulation were the femur bones (350.1 and 399.0 ng/g, respectively) and kidneys (134.0 and 361.3 ng/g, respectively) of male and female mice. Findings from this study provide critical insights into the distribution and retention of U in lymphoid tissues following chronic drinking water exposure to U. This information will serve as a foundation for immunotoxicological assessments of U, alone and in combination with other metals.

Estimation of blood and bone marrow doses of thyroid carcinoma patients treated with 131I through gamma spectrometry.

131I therapy is the treatment for patients with differentiated thyroid carcinoma (DTC) to ablate remnant thyroid tissue after surgery. The aim of this study was to estimate the absorbed doses to the blood and bone marrow of patients with DTC using gamma spectrometry. The evaluation of the absorbed dose in blood and bone marrow is a good indicator of a patient's response and its radiological protection. The average of low activities administered (AAAL) to ten patients was 3.20 GBq and the average of high activities administered (AAAH) to eight patients was 4.95 GBq. The blood and bone marrow doses were determined according to Lassmann et al 2008, performing successive measurements of activity in blood samples and whole body. Blood samples of 2 ml were taken during the first 48 h; the first one was extracted 2 h after the administration of the capsule and the following ones were taken every 12 h. The whole-body measurements were made at regular intervals of time throughout the patient's isolation period using a mobile gamma spectrometry system located inside the isolation room of the Dr Hernán Henríquez Aravena Hospital. The average residence times in blood and whole-body were (6.9 ± 1.7) × 10-4 h ml-1 and (23.2 ± 4.5) h, respectively. The average doses in blood and bone marrow of patients with AAAL were (0.33 ± 0.09) Gy and (0.63 ± 0.18) Gy, respectively, and with AAAH were (0.48 ± 0.06) Gy and (0.87 ± 0.19) Gy, respectively. In all studied patients, the bone marrow doses were less than 2 Gy. The results were compared with the previously published values, finding some differences between the residence times and significant differences in the doses, which show the need to compare the different methodologies.

DosiKit, a New Immunoassay for Fast Radiation Biodosimetry of Hair and Blood Samples.

DosiKit is a field radiation biodosimetry immunoassay for fast triage of individuals exposed to external total-body or partial-body irradiation (TBI or PBI). Assay proof-of-concept based on γ-H2AX analysis of human blood samples has been previously described as a promising tool for rapid assessment of TBI. Here, we report on the performance of the assay for PBI based on an analysis of hair follicles irradiated with a 137Cs gamma-ray source, at doses ranging from 0 to 20 Gy and dose rates ranging from ∼0.8 to ∼3 Gy/min. First, we show that the DosiKit protocol allows extraction and analysis of hair follicle proteins. Next, we show that irradiated hair follicles trigger a DNA damage response by inducing dose-dependent γ-H2AX expression. Since γ-H2AX expression strongly decreases 2 to 4 h postirradiation, due to DNA repair, we hypothesized that an antibody targeting the S*/T*Q domains, phosphorylated by ATM for DNA repair activation (pSQTQ), would extend the postirradiation dosimetry time window. DosiKit analysis of pSQTQ in ex vivo irradiated cynomolgus monkey skin explants shows that these sequences are phosphorylated in a dose-dependent manner up to 8 h postirradiation, and that statistically different ranges of external radiation exposure can be distinguished (0-2 Gy, 5-10 Gy, 20 Gy). Since the DosiKit protocol is intended to be used on both blood and hair samples, we also show that SQTQ sequences are phosphorylated dose-dependently in human blood, allowing samples to be classified into three radiation dose ranges (0-0.1 Gy, 0.5-3 Gy and 5-8 Gy). In conclusion, radiation biodosimetry can be performed on both blood and hair samples up to 8 h after exposure using the DosiKit protocol, allowing the concomitant characterization of TBI and PBI for fast and efficient radiological crisis management.

Dosimetric and microdosimetric analyses for blood exposed to reactor-derived thermal neutrons.

Thermal neutrons are found in reactor, radiotherapy, aircraft, and space environments. The purpose of this study was to characterise the dosimetry and microdosimetry of thermal neutron exposures, using three simulation codes, as a precursor to quantitative radiobiological studies using blood samples. An irradiation line was designed employing a pyrolytic graphite crystal or-alternatively-a super mirror to expose blood samples to thermal neutrons from the National Research Universal reactor to determine radiobiological parameters. The crystal was used when assessing the relative biological effectiveness for dicentric chromosome aberrations, and other biomarkers, in lymphocytes over a low absorbed dose range of 1.2-14 mGy. Higher exposures using a super mirror will allow the additional quantification of mitochondrial responses. The physical size of the thermal neutron fields and their respective wavelength distribution was determined using the McStas Monte Carlo code. Spinning the blood samples produced a spatially uniform absorbed dose as determined from Monte Carlo N-Particle version 6 simulations. The major part (71%) of the total absorbed dose to blood was determined to be from the 14N(n,p)14C reaction and the remainder from the 1H(n,γ)2H reaction. Previous radiobiological experiments at Canadian Nuclear Laboratories involving thermal neutron irradiation of blood yielded a relative biological effectiveness of 26 ± 7. Using the Particle and Heavy Ion Transport Code System, a similar value of ∼19 for the quality factor of thermal neutrons initiating the 14N(n,p)14C reaction in soft tissue was determined by microdosimetric simulations. This calculated quality factor is of similar high value to the experimentally-derived relative biological effectiveness, and indicates the potential of thermal neutrons to induce deleterious health effects in superficial organs such as cataracts of the eye lens.

Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

PURPOSE: This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. PATIENTS AND METHODS: F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. RESULTS: MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. CONCLUSION: Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for patient selection and treatment optimization.

Deployment of the DosiKit System Under Operational Conditions: Experience From a French Defense National Nuclear Exercise.

Estimation of the dose received by accidentally irradiated victims is based on a tripod: clinical, biological, and physical dosimetry. The DosiKit system is an operational and mobile biodosimetry device allowing the measurement of external irradiation directly on the site of a radiological accident. This tool is based on capillary blood sample and hair follicle collection. The aim is to obtain a whole-body and local-surface dose assessment. This paper is about the technical evaluation of the DosiKit; the analytical process and scientific validation are briefly described. The Toulon exercise scenario was based on a major accident involving the reactor of a nuclear attack submarine. The design of the scenario made it impossible for several players (firefighters, medical team) to leave the area for a long time, and they were potentially exposed to high dose rates. The DosiKit system was fully integrated into a deployable radiological emergency laboratory, and the response to operational needs was very satisfactory.

Dose-dependent decrease in anti-oxidant capacity of whole blood after irradiation: A novel potential marker for biodosimetry.

Many reports have demonstrated that radiation stimulates reactive oxygen species (ROS) production by mitochondria for a few hours to a few days after irradiation. However, these studies were performed using cell lines, and there is a lack of information about redox homeostasis in irradiated animals and humans. Blood redox homeostasis reflects the body condition well and can be used as a diagnostic marker. However, most redox homeostasis studies have focused on plasma or serum, and the anti-oxidant capacity of whole blood has scarcely been investigated. Here, we report changes in the anti-oxidant capacity of whole blood after X-ray irradiation using C57BL/6 J mice. Whole-blood anti-oxidant capacity was measured by electron spin resonance (ESR) spin trapping using a novel spin-trapping agent, 2-diphenylphosphinoyl-2-methyl-3,4-dihydro-2H-pyrrole N-oxide (DPhPMPO). We found that whole-blood anti-oxidant capacity decreased in a dose-dependent manner (correlation factor, r > 0.9; P < 0.05) from 2 to 24 days after irradiation with 0.5-3 Gy. We further found that the red blood cell (RBC) glutathione level decreased and lipid peroxidation level increased in a dose-dependent manner from 2 to 6 days after irradiation. These findings suggest that blood redox state may be a useful biomarker for estimating exposure doses during nuclear and/or radiation accidents.

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223.

Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and ß-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of ß-irradiation was similar to baseline values, being in agreement with a negligible ß-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.

Ultraviolet Irradiation of Blood: "The Cure That Time Forgot"?

Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However with the development of antibiotics, UBI use declined and it has now been called "the cure that time forgot". Later studies were mostly performed by Russian workers and in other Eastern countries and the modern view in Western countries is that UBI remains highly controversial.This chapter discusses the potential of UBI as an alternative approach to current methods used to treat infections, as an immune-modulating therapy and as a method for normalizing blood parameters. No resistance of microorganisms to UV irradiation has been reported, and multi-antibiotic resistant strains are as susceptible as their wild-type counterparts. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. However the use of UBI to treat septicemia cannot be solely due to UV-mediated killing of bacteria in the blood-stream, as only 5-7% of blood volume needs to be treated with UV to produce the optimum benefit. UBI may enhance the phagocytic capacity of various phagocytic cells (neutrophils and dendritic cells), inhibit lymphocytes, and oxidize blood lipids. The oxidative nature of UBI may have mechanisms in common with ozone therapy and other oxygen therapies. There may be some similarities to extracorporeal photopheresis (ECP) using psoralens and UVA irradiation. However there are differences between UBI and ECP in that UBI tends to stimulate the immune system, while ECP tends to be immunosuppressive. With the recent emergence of bacteria that are resistant to all known antibiotics, UBI should be more investigated as an alternative approach to infections, and as an immune-modulating therapy.