In vivo assessment of TiO2 based wear nanoparticles in periprosthetic tissues.

A multimodal approach combining inductively coupled plasma mass spectrometry (ICP-MS), single-particle ICP-MS (spICP-MS), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDS) and Raman spectroscopy enabled a deeper insight into the balance between total titanium (Ti), the soluble titanium fraction and titanium dioxide based particle fraction levels in periprosthetic tissues collected from patients undergoing revision surgery. Hydrofluoric acid usage in the sample digestion allowed for complete digestion of TiO2 particles, thus enabling accurate estimation of total Ti levels. The TiO2 fraction represents 38-94% of the titanium load in the six samples where particles were detected, and the fraction is present mainly in samples from patients with aseptically loosened total hip arthroplasty. Further attention was given to this fraction determining the elemental composition, particle count, particle size and modification of TiO2. The spICP-MS analysis confirmed the presence of the TiO2-derived (nano)particles (NPs) with a 39- to 187-nm median size and particle count up to 2.3 × 1011 particles per gram of tissue. On top of that, the SEM-EDS confirmed the presence of the TiO2 nanoparticles with 230-nm median size and an anatase crystal phase was determined by Raman spectroscopy. This study presents a novel multimodal approach for TiO2 particle determination and characterization in tissue samples and is the first in vivo study of this character.

Cardiac doses with deep inspiration breath hold in breast cancer radiotherapy: direct comparison between WBI, PBI, and interstitial APBI.

Background: The optimal radiotherapy technique for cardiac sparing in left-sided early breast cancer (EBC) is not clear. In this context, the aim of our dosimetric study was to compare cardiac and lung doses according to the type of radiotherapy - whole breast irradiation (WBI), external partial breast irradiation (PBI), and multicatheter interstitial brachytherapy-accelerated partial breast irradiation (MIB-APBI). The dosimetric results with the WBI and PBI were calculated with and without DIBH. Materials and methods: Dosimetric study of 23 patients treated with WBI, PBI, with and without DIBH, or MIB-APBI. The prescribed dose was 40 Gy in 15 fractions for WBI and PBI and 34 Gy in 10 fractions (bid) for MIB-APBI. Doses to the organs-at-risk (OAR) - heart, left anterior descending coronary artery (LAD), left ventricle (LV), and left lung - were recalculated to the equivalent dose in 2-Gy fractions (EQD2). Results: The addition of DIBH significantly reduced EQD2 doses to all OARs (except for the left lung maximal dose) in WBI and PBI. MHD values were 0.72 Gy for DIBH-WBI, 1.01 Gy for MIB-APBI and 0.24 Gy for DIBH-PBI. There were no significant differences in cardiac doses between WBI with DIBH and PBI without DIBH. DIBH-PBI resulted in significantly lower mean doses to all OARs (except for maximum lung dose) compared to MIB-APBI. Conclusions: These results show that the use of DIBH significantly reduces cardiac doses in patients with left EBC. Partial irradiation techniques (PBI, MIB-APBI) significantly reduced cardiac doses due to the smaller clinical target volume. The best results were obtained with DIBH-PBI.

Total body irradiation for standard treatment rooms: a robust sweeping beam technique with respect to the body shape.

Background: The purpose of this work is to improve a sweeping beam technique for total body irradiation (TBI) on a low flat couch using a varying patient thickness model. We designed a flat couch for total body irradiation in supine and prone position. Three generic arcs with rectangular segments for a patient torso thickness of 16, 22 and 28 cm were generated with respect to varying patient thickness of four particular parts of the body: head, torso, thighs and calves. Materials and methods: Longitudinal and transversal dose profiles were measured using an ionization chamber and the EBT3 gafchromic film in a solid water slab phantom. The robustness of the method was examined in phantoms of different thicknesses. Results: Measured dose homogeneity stays within ±10% of prescribed dose for all of the three patient thickness models. The robustness of the method was evaluated as the increase in dose in the phantom center of 0.7% per 1 cm reduction in phantom thickness. Conclusion: The method is applicable for the broad range of patient sizes, comfortable for patients, robust and suitable for standard treatment rooms with a standard linear accelerator. It requires minimal investments into equipment.

Cardiac doses of accelerated partial breast irradiation with perioperative multicatheter interstitial brachytherapy.

PURPOSE: To quantify mean heart dose (MHD) and doses to the left anterior descending artery (LAD) and left ventricle (LV) in a retrospective series of patients who underwent perioperative accelerated partial breast irradiation with multicatheter interstitial brachytherapy (MIB-APBI). METHODS: Sixty-eight patients with low-risk left breast cancer were treated with MIB-APBI at our institution between 2012 and 2017. Interstitial tubes were inserted during the tumorectomy and sentinel node biopsy and APBI was started 6 days later. The prescribed dose was 34 Gy in 10 fractions (twice a day) to the clinical target volume (CTV). The heart, LAD, and LV were contoured and the distance between each structure and the CTV was measured. The MHD, mean and maximum LAD doses (LAD mean/max), and mean LV doses (LV mean) were calculated and corrected to biologically equivalent doses in 2­Gy fractionation (EQD2). We also evaluated the impact of the distance between the cardiac structures and the CTV and of the volume receiving the prescribed dose (V100) and high-dose volume (V150) on heart dosimetry. RESULTS: Mean EQD2 for MHD, LAD mean/max, and mean LV were 0.9 ± 0.4 Gy (range 0.3-2.2), 1.6 ± 1.1 Gy (range, 0.4-5.6), 2.6 ± 1.9 Gy (range, 0.7-9.2), and 1.3 ± 0.6 Gy (range, 0.5-3.4), respectively. MHD, LAD mean/max, and LV mean significantly correlated with the distance between the CTV and these structures, but all doses were below the recommended limits (German Society of Radiation Oncology; DEGRO). The MHD and LV mean were significantly dependent on V100. CONCLUSION: Perioperative MIB-APBI resulted in low cardiac doses in our study. This finding provides further support for the value of this technique in well-selected patients with early-stage left breast cancer.

Cardiotoxicity of radiation therapy in esophageal cancer.

With a development of radiotherapeutic techniques, availability of radiotherapy data on cardiotoxicity, and slowly improving esophageal cancer outcomes, an increasing emphasis is placed on the heart protection in radiation treated esophageal cancer patients. Radiation induced heart complications encompass mainly pericardial disease, cardiomyopathy, coronary artery atherosclerosis, valvular heart disease, and arrhythmias. The most frequent toxicity is pericardial effusion which is usually asymptomatic in the majority of patients. The use of modern radiotherapy techniques is expected to reduce the risk of cardiotoxicity, although this expectation has to be confirmed by clinical data.

Validation of dose distribution computation on sCT images generated from MRI scans by Philips MRCAT.

AIM: To evaluate calculation of treatment plans based on synthetic-CT (sCT) images generated from MRI. BACKGROUND: Because of better soft tissue contrast, MR images are used in addition to CT images for radiotherapy planning. However, registration of CT and MR images or repositioning between scanning sessions introduce systematic errors, hence suggestions for MRI-only therapy. The lack of information on electron density necessary for dose calculation leads to sCT (synthetic CT) generation. This work presents a comparison of dose distribution calculated on standard CT and sCT. MATERIALS AND METHODS: 10 prostate patients were included in this study. CT and MR images were collected for each patient and then water equivalent (WE) and MRCAT images were generated. The radiation plans were optimized on CT and then recalculated on MRCAT and WE data. 2D gamma analysis was also performed. RESULTS: The mean differences in the majority of investigated DVH points were in order of 1% up to 10%, including both MRCAT and WE dose distributions. Mean gamma pass for acceptance criteria 1%/1 mm were greater than 82.5%. Prescribed doses for target volumes and acceptable doses for organs at risk were met in almost all cases. CONCLUSIONS: The dose calculation accuracy on MRCAT was not significantly compromised in the majority of clinical relevant DVH points. The introduction of MRCAT into practise would eliminate systematic errors, increase patients' comfort and reduce treatment expenses. Institutions interested in MRCAT commissioning must, however, consider changes to established workflow.

Direct elemental analysis of plant oils by inductively coupled plasma mass spectrometry: Simple sample dilution combined with oxygen introduction into the plasma.

Assessment of trace metal concentrations in plant oils has been considered a crucial quality control marker for potential health risks, oil flavour, and oxidative stability. A straightforward inductively coupled plasma mass spectrometry (ICP-MS) methodology was developed and validated through introduction of argon:oxygen gas mixture into plasma, allowing for a direct elemental analysis of organic matrices. This approach offers the advantage of a simple one-step preparation of plant oil samples with negligible contamination risks. The complete solubilization of the oil matrix enables the determination of total metal content from a single test tube with low dilution factor of 5. The modified plasma conditions resulted in the development of a robust and accurate ICP-MS method providing limits of detection at sub ng·g-1 levels. The ICP-MS method allowed the determination of trace levels of Ba, Cd, Cu, Fe, Mn, Pb, Sn, V, and Zn in olive, sunflower and rapeseed oils.

Utilization of cone beam CT for reconstruction of dose distribution delivered in image-guided radiotherapy of prostate carcinoma - bony landmark setup compared to fiducial markers setup.

The purpose of this study was to compare two different styles of prostate IGRT: bony landmark (BL) setup vs. fiducial markers (FM) setup. Twenty-nine prostate patients were treated with daily BL setup and 30 patients with daily FM setup. Delivered dose distribution was reconstructed on cone-beam CT (CBCT) acquired once a week immediately after the alignment. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed 1 cm safety margin. Alternative plans assuming smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with initial ones. While the margin reduction in case of BL setup makes the prostate coverage significantly worse (p = 0.0003, McNemar's test), in case of FM setup with the reduced 7 mm margin, the prostate coverage is even better compared to BL setup with 10 mm margin (p = 0.049, Fisher's exact test). Moreover, partial volumes of organs at risk irradiated with a specific dose can be significantly lowered (p < 0.0001, unpaired t-test). Reducing of safety margin is not acceptable in case of BL setup, while the margin can be lowered from 10 mm to 7 mm in case of FM setup.

High-dose-rate brachytherapy at 3 Gy per fraction for lip carcinoma: Treatment outcomes and toxicity at 5-years.

PURPOSE: Low-dose-rate brachytherapy (LDR-BT) is a well-established treatment for lip cancer. High-dose-rate (HDR)-BT is a promising alternative to LDR-BT, but data are limited. In this context, we retrospectively evaluated treatment outcomes in a series of patients who underwent HDR-BT for lip carcinoma between 2003 and 2021. MATERIALS AND METHODS: A total of 32 patients were included in this study, with a median age of 73.5 years (range, 61 - 88). The indications for HDR-BT were as follows: primary treatment (n = 17), adjuvant treatment (n = 3), and recurrent disease after surgery (n = 12). The prescribed dose was 18 fractions of 3 Gy administered twice daily. RESULTS: At a median followup of 45 months (range, 12 -232), the 5-year local recurrence-free interval was 96.9% (95% CI: 90.9-100%), the disease-free interval was 85% (95% CI: 70.9-99.1), and 5-year overall survival was 64.7% (95% CI: 44.7-84.8). Eleven patients died, all on age related comorbidities. Acute toxicity manifested as G1 dry desquamation in 6 patients (18.8%), G2 erythema in 10 patients (31.2%) and G3 confluent moist desquamation in 16 patients (50%). Late complications included G1 fibrosis (100% of cases). G1 and G2 depigmentation was observed in 8 (25%) and 6 (18%) patients, G1 telangiectasia occurred in 5 patients (16%). CONCLUSIONS: These data support the use of HDR-BT for lip cancer. The dose and fractionation schedule used in this study (18 fractions x 3 Gy twice daily) seems to be effective and safe.

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment.

AIM: To assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction. BACKGROUND: Implementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution. MATERIALS AND METHODS: Seventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed. RESULTS: In 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively. CONCLUSION: Sufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.

Transcriptional Dynamics of DNA Damage Responsive Genes in Circulating Leukocytes during Radiotherapy.

External beam radiation therapy leads to cellular activation of the DNA damage response (DDR). DNA double-strand breaks (DSBs) activate the ATM/CHEK2/p53 pathway, inducing the transcription of stress genes. The dynamic nature of this transcriptional response has not been directly observed in vivo in humans. In this study we monitored the messenger RNA transcript abundances of nine DNA damage-responsive genes (CDKN1A, GADD45, CCNG1, FDXR, DDB2, MDM2, PHPT1, SESN1, and PUMA), eight of them regulated by p53 in circulating blood leukocytes at different time points (2, 6-8, 16-18, and 24 h) in cancer patients (lung, neck, brain, and pelvis) undergoing radiotherapy. We discovered that, although the calculated mean physical dose to the blood was very low (0.038-0.169 Gy), an upregulation of Ferredoxin reductase (FDXR) gene transcription was detectable 2 h after exposure and was dose dependent from the lowest irradiated percentage of the body (3.5% whole brain) to the highest, (up to 19.4%, pelvic zone) reaching a peak at 6-8 h. The radiation response of the other genes was not strong enough after such low doses to provide meaningful information. Following multiple fractions, the expression level increased further and was still significantly up-regulated by the end of the treatment. Moreover, we compared FDXR transcriptional responses to ionizing radiation (IR) in vivo with healthy donors' blood cells exposed ex vivo and found a good correlation in the kinetics of expression from the 8-hours time-point onward, suggesting that a molecular transcriptional regulation mechanism yet to be identified is involved. To conclude, we provided the first in vivo human report of IR-induced gene transcription temporal response of a panel of p53-dependant genes. FDXR was demonstrated to be the most responsive gene, able to reliably inform on the low doses following partial body irradiation of the patients, and providing an expression pattern corresponding to the % of body exposed. An extended study would provide individual biological dosimetry information and may reveal inter-individual variability to predict radiotherapy-associated adverse health outcomes.

High-Dose-Rate Brachytherapy as an Organ-Sparing Treatment for Early Penile Cancer.

BACKGROUND: Low-dose-rate brachytherapy is an effective organ-sparing treatment for patients with early-stage penile cancer. However, only limited data are available on the role of high-dose-rate brachytherapy (HDR-BT) in this clinical setting. METHODS: Between 2002 and 2020, 31 patients with early penile cancer were treated at our center with interstitial HDR BT at a dose of 18 × 3 Gy twice daily. A breast brachytherapy template was used for the fixation of stainless hollow needles. RESULTS: The median follow-up was 117.5 months (range, 5-210). Eight patients (25.8%) developed a recurrence; of these, seven were salvaged by partial amputation. Six patients died of internal comorbidities or a second cancer. The probability of local control at 5 and 10 years was 80.7% (95% CI: 63.7-97.7%) and 68.3% (95% CI: 44.0-92.6%), respectively. Cause-specific survival was 100%. Only one case of radiation-induced necrosis was observed. The probability of penile sparing at 5 and 10 years was 80.6% (95% CI: 63.45-97.7%) and 62.1% (95% CI: 34.8-89.4%), respectively. CONCLUSIONS: These results show that HDR-BT for penile cancer can achieve results comparable to LDR-BT with organ sparing. Despite the relatively large patient cohort-the second largest reported to date in this clinical setting-prospective data from larger samples are needed to confirm the role of HDR-BT in penile cancer.

The Changes in Pharyngeal Constrictor Muscles Related to Head and Neck Radiotherapy: A Systematic Review.

It is well known that radiation damage of the pharyngeal constrictor muscles, the glottic larynx, and the supraglottic larynx may lead to dysphagia, an unwanted effect of head and neck radiotherapy. The reduction of radiotherapy-induced dysphagia might be achieved by adaptive radiotherapy. Although the number of studies concerning adaptive radiotherapy of head and neck cancer is continuously increasing, there are only a few studies concerning changes in dysphagia-related structures during radiotherapy.The goal of this review is to summarize the current knowledge about volumetric, dosimetric, and other changes of the pharyngeal constrictor muscles associated with head and neck radiotherapy. A literature search was performed in the MEDLINE database according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The conclusions of 8 studies that passed the criteria indicate a significant increase in the volume and the thickness of the pharyngeal constrictor muscles during radiotherapy. Moreover, the changes in magnetic resonance imaging signal intensity of the pharyngeal constrictor muscles correlate with the absorbed dose (typically higher than 50 Gy) and also with the grade of dysphagia. This systematic review presents 2 variables, which are suitable for estimation of radiotherapy-related pharyngeal constrictor muscles changes-magnetic resonance imaging signal intensity and the thickness. In the case of the thickness, there is no consensus in the level of the measurement-C2 vertebra, C3 vertebra, and the middle of the craniocaudal axis are used. It seems that reference to a position associated with a vertebral body could be more reproducible and beneficial for future research. Although late pharyngeal toxicity remains a challenge in head and neck cancer treatment, better knowledge of radiotherapy-related changes in the pharyngeal constrictor muscles contributes to adaptive radiotherapy development and thus improves the treatment results.

Accelerated partial breast irradiation in elderly breast cancer patients.

Breast-conserving surgery with adjuvant whole-breast irradiation has become the standard treatment for early breast cancer (EBC) patients. Partial breast irradiation, which targets only the postoperative cavity, has been established as an alternative to whole-breast therapy in selected patients. The treatment of elderly breast cancer patients differs from the therapeutic approach in younger ones, as elderly patients are prone to geriatric frailty and comorbid conditions, the incidence and severity of which increase with age. A review of the evidence, process, techniques, and results of accelerated partial breast irradiation (APBI) in elderly EBC patients, seems to indicate that APBI is an advisable postoperative approach in properly selected elderly EBC patients, combining advantages of a radical approach that minimizes the risk of undertreatment with efficient reduction of redundant irradiated volume, treatment toxicity, overall treatment time, staff workload, radiation technique workflow, patient transportation, and the potential for non-compliance. There is no "one size fits all" technique of APBI, the best technique always depending on willing patients, individual anatomy, performance status, patient frailty and comorbid conditions, and tumour location.

The Time Between Chemoradiation and Surgery for Rectal Carcinoma Negatively Influences Mesorectal Excision Quality.

Total mesorectal excision quality (TMEq) is a prognostic factor associated with local recurrence in rectal adenocarcinoma. Neoadjuvant chemoradiotherapy (NCRT) reduces the risk of tumor recurrence, but may compromise TMEq. The time between NCRT and surgery (TTS) and how it influences TMEq and tumor control were evaluated. In prospective registry, 236 patients after NCRT and TME were analyzed. NCRT involved radiotherapy with 45 Gy to the pelvis, plus tumor boost dose 5.4 Gy with concurrent 5-fluorouracil infusion. NCRT was followed by TME after 9 weeks on average (median 9.4 ± SD 2.5). TMEq was parametrically analyzed by standard three-grade system. With median follow-up of 47.5 months, 3-year overall survival (OS) was 83.8%, disease-free survival (DFS) was 77.7%, and 6.4% was the rate of local recurrence (LR). TTS was not associated with OS, DFS, or LR. TMEq was found to be associated with LR in univariate analysis, but not in multivariate, where pathological tumor stage and resection margins remained dominant predictors. TMEq was negatively influenced by inferior location of the tumor, longer TTS, higher tumor and nodal stage, presence of tumor perforation, perineural invasion, and close/positive resection margins. Nonetheless, TTS remained a strong predictor of TMEq in multivariate analyses. TTS was proven to be an independent predictor of TMEq. With longer TTS, fewer complete TME with intact mesorectal plane were observed. However, TTS was not associated with survival deterioration or tumor recurrence. These were negatively influenced by other factors interfering with TMEq, especially by pathological tumor stage and resection margins.

Accelerated partial breast irradiation with perioperative multicatheter interstitial brachytherapy-A feasibility study.

PURPOSE: To assess the feasibility of high-dose-rate perioperative multicatheter interstitial brachytherapy to deliver accelerated partial breast irradiation (APBI) in selected patients with early breast cancer. METHODS AND MATERIALS: Perioperative multicatheter interstitial brachytherapy for APBI has been used at our department since 2012 for patients with low-risk breast cancer. Interstitial catheters were inserted perioperatively via hollow needles immediately following tumorectomy with sentinel node biopsy. APBI started on Day 6 after surgery. The prescribed dose was 34 Gy (10 fractions of 3.4 Gy bid). Hormonal therapy was prescribed in all cases. RESULTS: Between June 2012 and December 2017, 125 patients were scheduled for APBI. Of these, APBI was not performed in 12 patients (9.6%) due to adverse prognostic factors identified on the definitive biopsy. We observed wound dehiscence in 2/113 cases (1.8%), inflammatory complications requiring antibiotics in 7/113 cases (6.2%), transient Grade I radiodermatitis in 6/113 patients (4.4%), and seroma which resolved spontaneously in 3/113 patients (2.7%). With median followup of 39 months (range 3.3-75.3) no relapses were observed. No late complications in Radiation Therapy Oncology Group Grade 3 or higher were documented. Cosmetic outcome in patients with followup > 2 years was excellent or good in 92%. CONCLUSION: Our preliminary results show that the perioperative multicatheter interstitial high-dose-rate brachytherapy for APBI in selected patients with early breast cancer is feasible. This treatment schedule reduces treatment duration, spares the patients of repeated anesthesia, and enables precise application of the afterloading tubes under direct visual control.

The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood.

The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.

FDXR is a biomarker of radiation exposure in vivo.

Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. Here, FDXR transcriptional changes in blood were investigated in humans undergoing a range of external radiation exposure procedures covering several orders of magnitude (cardiac fluoroscopy, diagnostic computed tomography (CT)) and treatments (total body and local radiotherapy). Moreover, a method was developed to assess the dose to the blood using physical exposure parameters. FDXR expression was significantly up-regulated 24 hr after radiotherapy in most patients and continuously during the fractionated treatment. Significance was reached even after diagnostic CT 2 hours post-exposure. We further showed that no significant differences in expression were found between ex vivo and in vivo samples from the same patients. Moreover, potential confounding factors such as gender, infection status and anti-oxidants only affect moderately FDXR transcription. Finally, we provided a first in vivo dose-response showing dose-dependency even for very low doses or partial body exposure showing good correlation between physically and biologically assessed doses. In conclusion, we report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates.