Joint EURADOS-EANM initiative for an advanced computational framework for the assessment of external dose rates from nuclear medicine patients.

BACKGROUND: In order to ensure adequate radiation protection of critical groups such as staff, caregivers and the general public coming into proximity of nuclear medicine (NM) patients, it is necessary to consider the impact of the radiation emitted by the patients during their stay at the hospital or after leaving the hospital. Current risk assessments are based on ambient dose rate measurements in a single position at a specified distance from the patient and carried out at several time points after administration of the radiopharmaceutical to estimate the whole-body retention. The limitations of such an approach are addressed in this study by developing and validating a more advanced computational dosimetry approach using Monte Carlo (MC) simulations in combination with flexible and realistic computational phantoms and time activity distribution curves from reference biokinetic models. RESULTS: Measurements of the ambient dose rate equivalent H*(10) at 1 m from the NM patient have been successfully compared against MC simulations with 5 different codes using the ICRP adult reference computational voxel phantoms, for typical clinical procedures with 99mTc-HDP/MDP, 18FDG and Na131I. All measurement data fall in the 95% confidence intervals, determined for the average simulated results. Moreover, the different MC codes (MCNP-X, PHITS, GATE, GEANT4, TRIPOLI-4®) have been compared for a more realistic scenario where the effective dose rate E of an exposed individual was determined in positions facing and aside the patient model at 30 cm, 50 cm and 100 cm. The variation between codes was lower than 8% for all the radiopharmaceuticals at 1 m, and varied from 5 to 16% for the face-to face and side-by-side configuration at 30 cm and 50 cm. A sensitivity study on the influence of patient model morphology demonstrated that the relative standard deviation of H*(10) at 1 m for the range of included patient models remained under 16% for time points up to 120 min post administration. CONCLUSIONS: The validated computational approach will be further used for the evaluation of effective dose rates per unit administered activity for a variety of close-contact configurations and a range of radiopharmaceuticals as part of risk assessment studies. Together with the choice of appropriate dose constraints this would facilitate the setting of release criteria and patient restrictions.

Influence of short-lived radioiodines other than 131I on screening direct thyroid measurements with TCS-172 NAI(TL) survey meters.

In a nuclear emergency, one of the actions taken for the sake of public is to monitor thyroid exposure to radioiodines. Japan's Nuclear Regulation Authority recently published a report on such monitoring and proposed direct thyroid measurements with conventional NaI(Tl) survey meters (e.g. Hitachi model TCS-172) as a primary screening method. A previous study proposed screening levels (SLs) used in these simplified measurements as the net reading values of the TCS-172 device. Age-specific SLs were derived from a thyroid equivalent dose of 100 mSv due to the inhalation intake of 131I. This study addressed the possible influence of short-lived iodine isotopes other than 131I on the simplified measurements. In preparation for such measurements, the responses of the device for 132I as an ingrowth component from 132Te, 133I, 134I and 135I in the thyroid were evaluated by numerical simulations using age-specific stylized phantoms in addition to those obtained for 131I in the previous study. The radioactivity ratios of the relevant isotopes were taken from the inventory data of the Fukushima Daiichi Nuclear Power Plant. The results were used to predict the net readings of the device when 132Te-132I and 133I as well as 131I were inhaled at 24 or 72 h after the shutdown of a nuclear power plant. In these cases, the signals from 132Te-132I and 133I become undetectable a couple of days after intake, which could lead to underestimations of the thyroid dose. To estimate the thyroid dose accurately from the simplified measurements, it is necessary to identify the exact time of intake after the shutdown and the actual physiochemical property of 132Te that affects the thyroid uptake of 132I.

Screening levels of TCS-172 NaI(Tl) survey meters used for direct thyroid measurements in nuclear disasters.

It is a challenging task to establish a feasible and robust method for the population monitoring of individuals' thyroid exposure following an accidental intake of radioiodines in a nuclear emergency, because of the time restriction. The authors previously proposed a method for such monitoring to obtain as many reliable human data as possible and one of the components is simplified measurements by conventional NaI(Tl) survey meters that are intended to be used for the initial triage to identify significantly exposed individuals and get an overall picture of the exposure levels in a target population in a timely manner. This study determined screening levels (SLs) for a conventional NaI(Tl) survey meter (model TCS-172, Hitachi, Japan) using the conversion factor (131I kBq in the thyroid per µSv h-1) that were obtained from experiments and simulations with age-specific phantoms. The results demonstrated that the derived SLs for 100 mSv thyroid equivalent dose were as follows: 0.2 µSv h-1 (SL1) for the age group ≤ 5-y-olds, 0.5 µSv h-1 (SL2) for the 10- and 15-y-old age groups and 1.0 µSv h-1 (SL3) for adults. These SLs would be reasonably available within 1 week after the intake of 131I on the safe side.

Early Development of Atherosclerotic Plaques in the Coronary Arteries after Radiotherapy for Breast Cancer (BACCARAT Study).

Background-Radiotherapy (RT) for breast cancer (BC) can lead to an increased risk of coronary artery disease several years after RT. The aim of this study was to evaluate the development of overall, non-calcified and calcified atherosclerotic plaques over 2 years after BC for RT and associations with cardiac exposure. Methods-The study included 101 left- or right-sided BC patients treated with RT without chemotherapy. A coronary CT angiography was performed before and 2 years after RT. Plaque development thorough the entire coronary network was defined as an increased number of plaques. Cardiac exposure was quantified with mean doses to the heart, left ventricle, and coronary arteries. Logistic regression models were used to assess association with doses. Results-At inclusion, 37% of patients had plaques, increasing to 42% two years after RT. Overall plaque development was observed in seven patients: five with calcified plaque development and four with non-calcified plaque development. The risk of overall plaque development was significantly associated with doses to the Left Main and Circumflex coronary arteries (OR at 1 Gy = 2.32, p = 0.03 and OR at 1 Gy = 2.27, p = 0.03, respectively). Specific analyses for calcified and non-calcified plaque development showed similar results. Conclusion-Our study suggests an association between coronary arteries exposure and the risk of developing both calcified and non-calcified atherosclerotic plaques over 2 years after BC RT. Trial registration number: NCT02605512.

Dysfunction of the Salivary and Lacrimal Glands After Radioiodine Therapy for Thyroid Cancer: Results of the START Study After 6-Months of Follow-Up.

Background: Understanding of changes in salivary and lacrimal gland functions after radioactive iodine therapy (131I-therapy) remains limited, and, to date, no studies have evaluated dose-response relationships between absorbed dose from 131I-therapy and dysfunctions of these glands. This study investigates salivary/lacrimal dysfunctions in differentiated thyroid cancer (DTC) patients six months after 131I-therapy, identifies 131I-therapy-related risk factors for salivary/lacrimal dysfunctions, and assesses the relationships between 131I-therapy radiation dose and these dysfunctions. Methods: A cohort study was conducted involving 136 DTC patients treated by 131I-therapy of whom 44 and 92 patients received 1.1 and 3.7 GBq, respectively. Absorbed dose to the salivary glands was estimated using a dosimetric reconstruction method based on thermoluminescent dosimeter measurements. Salivary and lacrimal functions were assessed at baseline (T0, i.e., immediately before 131I-therapy) and six months later (T6) using validated questionnaires and salivary samplings, with and without stimulation of the salivary glands. Statistical analyses included descriptive analyses and random-effects multivariate logistic and linear regressions. Results: There was no difference between T0 and T6 in the level of parotid gland pain, nor was there difference in the number of patients with hyposalivation, but there were significantly more patients with dry mouth sensation and dry eyes after therapy compared with baseline. Age, menopause, depression and anxiety symptoms, history of systemic disease, and not taking painkillers in the past three months were found to be significantly associated with salivary or lacrimal disorders. Significant associations were found between 131I-exposure and salivary disorders adjusted on the previous variables: for example, per 1-Gy increase in mean dose to the salivary glands, odds ratio = 1.43 [CI 1.02 to 2.04] for dry mouth sensation, ß = -0.08 [CI -0.12 to -0.02] mL/min for stimulated saliva flow, and ß = 1.07 [CI 0.42 to 1.71] mmol/L for salivary potassium concentration. Conclusions: This study brings new knowledge on the relationship between the absorbed dose to the salivary glands from 131I-therapy and salivary/lacrimal dysfunctions in DTC patients six months after 131I-therapy. Despite the findings of some dysfunctions, the results do not show any obvious clinical disorders after the 131I-therapy. Nevertheless, this study raises awareness of the risk factors for salivary disorders, and calls for longer follow-up. Clinical Trials Registration: Number NCT04876287 on the public website (ClinicalTrials.gov).

Early Coronary Artery Calcification Progression over Two Years in Breast Cancer Patients Treated with Radiation Therapy: Association with Cardiac Exposure (BACCARAT Study).

Background: Radiotherapy (RT) for breast cancer (BC) can induce coronary artery disease many years after RT. At an earlier stage, during the first two years after RT, we aimed to evaluate the occurrence of increased coronary artery calcium (CAC) and its association with cardiac exposure. Methods: This prospective study included 101 BC patients treated with RT without chemotherapy. Based on CAC CT scans performed before and two years after RT, the event 'CAC progression' was defined by an increase in overall CAC score (CAC RT+ two years­CAC before RT > 0). Dosimetry was evaluated for whole heart, left ventricle (LV), and coronary arteries. Multivariable logistic regression models were used to assess association with doses. Results: Two years after RT, 28 patients presented the event 'CAC progression', explained in 93% of cases by a higher CAC score in the left anterior descending coronary (LAD). A dose−response relationship was observed with LV exposure (for Dmean LV: OR = 1.15, p = 0.04). LAD exposure marginally explained increased CAC in the LAD (for D2 LV: OR =1.03, p = 0.07). Conclusion: The risk of early CAC progression may be associated with LV exposure. This progression might primarily be a consequence of CAC increase in the LAD and its exposure.

Association Between Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With Radiotherapy: A Case-Control Study.

Background: Previous studies suggested that radiation therapy (RT) for breast cancer (BC) can induce cardiac arrhythmias and conduction disorders. However, the association with mean heart dose and specific cardiac substructures doses was less studied. Materials and Methods: We conducted a nested case-control study based on French BC patients, enrolled in the European MEDIRAD-BRACE study (https://clinicaltrials.gov, Identifier: NCT03211442), who underwent three-dimensional conformal radiation therapy (3D-CRT) between 2009 and 2013 and were retrospectively followed until 2019. Cases were incident cases of cardiac arrhythmia. Controls without arrhythmia were selected with propensity-scored matching by age, duration of follow-up, chemotherapy, hypertension, and diabetes (ratio 1:4 or 5). Doses to the whole heart (WH), left and right atria (LA and RA), and left and right ventricles (LV and RV) were obtained after delineation with multi-atlas-based automatic segmentation. Results: The study included 116 patients (21 cases and 95 controls). Mean age at RT was 64 ± 10 years, mean follow-up was 7.0 ± 1.3 years, and mean interval from RT to arrhythmia was 4.3 ± 2.1 years. None of the results on association between arrhythmia and cardiac doses reached statistical significance. However, the proportion of right-sided BC was higher among patients with arrhythmia than among controls (57% vs. 51%, OR = 1.18, p = 0.73). Neither mean WH dose, nor LV, RV, and LA doses were associated with an increased risk of arrhythmia (OR = 1.00, p > 0.90). In contrast, the RA dose was slightly higher for cases compared to controls [interquartile range (0.61-1.46 Gy) vs. (0.49-1.31 Gy), p = 0.44], and a non-significant trend toward a potentially higher risk of arrhythmia with increasing RA dose was observed (OR = 1.19, p = 0.60). Subanalysis according to BC laterality showed that the association with RA dose was reinforced specifically for left-sided BC (OR = 1.76, p = 0.75), while for right-sided BC, the ratio of mean RA/WH doses may better predict arrhythmia (OR = 2.39, p = 0.35). Conclusion: Despite non-significant results, our exploratory investigation on BC patients treated with RT is the first study to suggest that right-sided BC patients and the right atrium irradiation may require special attention regarding the risk of cardiac arrhythmia and conduction disorders. Further studies are needed to expand on this topic.

Salivary Dysfunctions and Consequences After Radioiodine Treatment for Thyroid Cancer: Protocol for a Self-Controlled Study (START Study).

BACKGROUND: Following radioiodine (131I) therapy of differentiated thyroid cancer, the salivary glands may become inflamed, leading to dysfunctions and decreases in patients' nutritional status and quality of life. The incidence of these dysfunctions after 131I-therapy is poorly known, and no clinical or genetic factors have been identified to date to define at-risk patients, which would allow the delivered activity to be adapted to the expected risk of salivary dysfunctions. OBJECTIVE: The aims of this study are to estimate the incidence of salivary dysfunctions, and consequences on the quality of life and nutritional status for patients after 131I-therapy; to characterize at-risk patients of developing posttreatment dysfunctions using clinical, biomolecular, and biochemical factors; and to validate a dosimetric method to calculate the dose received at the salivary gland level for analyzing the dose-response relationship between absorbed doses to salivary glands and salivary dysfunctions. METHODS: This prospective study aims to include patients for whom 131I-therapy is indicated as part of the treatment for differentiated thyroid cancer in a Paris hospital (40 and 80 patients in the 1.1 GBq and 3.7 GBq groups, respectively). The follow-up is based on three scheduled visits: at inclusion (T0, immediately before 131I-therapy), and at 6 months (T6) and 18 months (T18) posttreatment. For each visit, questionnaires on salivary dysfunctions (validated French tool), quality of life (Hospital Anxiety and Depression scale, Medical Outcomes Study 36-Item Short Form Survey), and nutritional status (visual analog scale) are administered by a trained clinical research associate. At T0 and T6, saliva samples and individual measurements of the salivary flow, without and with salivary glands stimulation, are performed. External thermoluminescent dosimeters are positioned on the skin opposite the salivary glands and at the sternal fork immediately before 131I administration and removed after 5 days. From the doses recorded by the dosimeters, an estimation of the dose received at the salivary glands will be carried out using physical and computational phantoms. Genetic and epigenetic analyses will be performed to search for potential biomarkers of the predisposition to develop salivary dysfunctions after 131I-therapy. RESULTS: A total of 139 patients (99 women, 71.2%; mean age 47.4, SD 14.3 years) were enrolled in the study between September 2020 and April 2021 (45 and 94 patients in the 1.1 GBq and 3.7G Bq groups, respectively). T6 follow-up is complete and T18 follow-up is currently underway. Statistical analyses will assess the links between salivary dysfunctions and absorbed doses to the salivary glands, accounting for associated factors. Moreover, impacts on the patients' quality of life will be analyzed. CONCLUSIONS: To our knowledge, this study is the first to investigate the risk of salivary dysfunctions (using both objective and subjective indicators) in relation to organ (salivary glands) doses, based on individual dosimeter records and dose reconstructions. The results will allow the identification of patients at risk of salivary dysfunctions and will permit clinicians to propose a more adapted follow-up and/or countermeasures to adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT04876287; https://clinicaltrials.gov/ct2/show/NCT04876287. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35565.

The Nuclear Medicine Patient as a Line Source: The Source Length Is Certainly Not the Patient Height, But It Is a Reasonable Approximation.

ABSTRACT: Nuclear medicine patients are a source of exposure and should receive instructions to restrict contact time with different categories of people. The calculation of the restriction time requires that the dose rate at a given distance, known from an initial measurement and a whole-body retention function, can be extrapolated at other distances. As a basis for this extrapolation, it has been suggested to consider the patient as a line source. However, the validity of this suggestion is based on a few studies and limited measurement distances. We collected from the literature dose rates of nuclear medicine patients measured at different distances and investigated the robustness of the line source model. The cases of 18 F-FDG exams, 99m Tc bone scan exams, and 131 I for hyperthyroidism treatment and remnants ablation were considered. The data were pooled, different cases of measurement time after administration were considered, and the data were fitted according to the line source model in which the half patient thickness was introduced. It was found that the line source model fits well the data put with a source length that is radionuclide-specific and significantly different from the standard adult height. However, considering a standard source length of 176 cm and neglecting the patient thickness induced at maximum an overestimation by a factor of 2.5 when extrapolating from 1 m to 10 cm. Such an overestimation is not of considerable importance in the calculation of contact restriction times.

A mobile high-resolution gamma camera for therapeutic dose control during radionuclide therapy.

Objective.Molecular radiotherapy is the most used treatment modality against malign and benign diseases of thyroid. In that context, the large heterogeneity of therapeutic doses in patients and the range of effects observed show that individualized dosimetry is essential for optimizing treatments according to the targeted clinical outcome.Approach.We developed a high-resolution mobile gamma camera specifically designed to improve the quantitative assessment of the distribution and biokinetics of131I at patients's bedside after treatment of thyroid diseases. The first prototype has a field of view of 5 × 5 cm2and consists of a high-energy parallel-hole collimator made of 3D-printed tungsten, coupled to a 6 mm thick CeBr3scintillator readout by an array of silicon photomultiplier detectors. The intrinsic and overall imaging performance of the camera was evaluated with133Ba and131I sources. In order to test its quantification capability in realistic clinical conditions, two different 3D-printed thyroid phantoms homogeneously filled with131I were used. Both single view and conjugate view approaches have been applied, with and without scatter correction technique.Main Results.The camera exhibits high imaging performance with an overall energy resolution of 7.68 ± 0.01%, a submillimetric intrinsic spatial resolution of 0.74 ± 0.28 mm and a very low spatial distortion 0.15 ± 0.10 mm. The complete calibration of the camera shows an overall spatial resolution of 3.14 ± 0.03 mm at a distance of 5 cm and a corresponding sensitivity of 1.23 ± 0.01 cps/MBq, which decreases with distance and slightly changes with source size due to the influence of scattering. Activity recovery factors better than 97% were found with the thyroid phantoms.Significance.These preliminary results are very encouraging for the use of our camera as a tool for accurate quantification of absorbed doses and currently motivates the development of a fully operational clinical camera with a 10 × 10 cm2field of view and improved imaging capabilities.

Myocardial deformation after radiotherapy: a layer-specific and territorial longitudinal strain analysis in a cohort of left-sided breast cancer patients (BACCARAT study).

BACKGROUND: Radiotherapy for breast cancer (BC) and its resulting cardiac exposure are associated with subclinical left ventricular dysfunction characterized by early decrease of global longitudinal strain (LS) measurement based on 2D speckle-tracking echocardiography. Recent software allows multi-layer and segmental analysis of strain, which may be of interest to quantify and locate the impact of cardiac exposure on myocardial function and potentially increase the early detection of radiation-induced cardiotoxicity. The aim of the study was to evaluate whether decrease in LS 6 months after radiotherapy is layer-specific and if it varies according to the left ventricular regional level and the coronary arterial territories. METHODS: LS was measured at baseline before radiotherapy and 6 months post-radiotherapy. The LS was obtained for each myocardial layer (endocardial, mid-myocardial, epicardial), left ventricular regional level (basal, mid, apical) and coronary artery territory (left anterior descending artery (LAD), circumflex artery, right coronary artery). RESULTS: The study included 64 left-sided BC patients. Mean age was 58 years, mean doses to the heart, the left ventricle and the LAD were respectively 3.0, 6.7 and 16.4 Gy. The absolute decrease of LS was significant for the three layers (endocardial: - 20.0 ± 3.2% to - 18.8 ± 3.8%; mid-myocardial: - 16.0 ± 2.7% to - 15.0 ± 3.1%; epicardial: - 12.3 ± 2.5% to - 11.4 ± 2.8%, all p = 0.02), but only the relative decrease of LS in the endocardial layer was close to be significant (- 4.7%, p = 0.05). More precisely, the LS of the endocardial layer was significantly decreased for the most exposed parts of the left ventricle corresponding to the apical level (- 26.3 ± 6.0% vs. -24.2 ± 7.1%, p = 0.03) and LAD territory (- 22.8 ± 4.0% vs. -21.4 ± 4.8%, p = 0.03). CONCLUSION: Six months post-radiotherapy, LS decreased predominantly in the endocardial layer of the most exposed part of the left ventricle. For precise evaluation of radiotherapy-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

Co-exposure to internal and external radiation alters cesium biokinetics and retention in mice.

Exposures in post-accidental situations are complex and include both external exposure and internal contamination with several radionuclides. However, in vivo and in vitro studies generally use simplified exposures, while a recent study suggested that combined external irradiation and internal contamination may induce more severe biological effects compared to single exposures. In an attempt to test the hypothesis of potential non-additive effects of multiple radiological exposures, we used a mouse model of combined external x-ray irradiation at 1 and 5 Gy and internal contamination with injection of 20 KBq 137Cs. The results showed differential kinetics of 137Cs elimination in irradiated animals compared to sham-irradiated, 137Cs injected animals. Moreover, changes in plasma potassium and in relative testis weight were observed 38 days after irradiation and injection in co-exposed animals compared to 137Cs injection alone. These results demonstrate that an external exposure combined with an internal contamination may lead to unexpected changes in biokinetics of radionuclides and biological effects compared to single exposures.

Early detection of subclinical left ventricular dysfunction after breast cancer radiation therapy using speckle-tracking echocardiography: association between cardiac exposure and longitudinal strain reduction (BACCARAT study).

BACKGROUND: Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. METHODS: The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. RESULTS: A mean decrease of 6% in GLS was observed (- 15.1% ± 3.2% at 6 months vs. - 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01-1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01-1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01-1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01-15.70], p = 0.048). CONCLUSIONS: This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.

GPS-coupled contaminant monitors on free-ranging Chernobyl wolves challenge a fundamental assumption in exposure assessments.

Measurements of external contaminant exposures on individual wildlife are rare because of difficulties in using contaminant monitors on free-ranging animals. Most wildlife contaminant exposure data are therefore simulated with computer models. Rarely are empirical exposure data available to verify model simulations, or to test fundamental assumptions inherent in exposure assessments. We used GPS-coupled contaminant monitors to quantify external exposures to individual wolves (Canis lupus) living within the Belarus portion of Chernobyl's 30-km exclusion zone. The study provided data on animal location and contaminant exposure every 35 min for 6 months, resulting in ~6600 individual locations and 137Cs external exposure readings per wolf, representing the most robust external exposure data published to date on free ranging animals. The data provided information on variation in external exposure for each animal over time, as well as variation in external exposure among the eight wolves across the landscape of Chernobyl. The exposure data were then used to test a fundamental assumption in screening-level risk assessments, espoused in guidance documents of the U.S. Environmental Protection Agency and U.S. Department of Energy, - Mean contaminant concentrations conservatively estimate individual external exposures. We tested this assumption by comparing our empirical data to a series of simulations using the ERICA modeling tool. We found that modeled simulations of mean external exposure (10.5 mGy y-1), based on various measures of central tendency, under-predicted mean exposures measured on five of the eight wolves wearing GPS-contaminant monitors (i.e., 12.3, 26.3, 28.0, 28.8 and 35.7 mGy y-1). If under-prediction of exposure occurs for some animals, then arguably the use of averaged contaminant concentrations to predict external exposure is not as conservative as proposed by current risk assessment guidance. Thus, a risk assessor's interpretation of simulated exposures in a screening-level risk analysis might be misguided if contaminant concentrations are based on measures of central tendency. We offer three suggestions for risk assessors to consider in order to reduce the probability of underestimating exposure in a screening-level risk assessment.

Development of a dosimetric model for in vitro labelled cells with ß + emitters in PET tracking studies.

Positron emission tomography (PET) offers an effective method for tracking ß + emitters-labeled cells in vivo. However, in vitro high labelling activities used may cause cell damage or death. Our understanding of the impact of such procedure remains limited by the fact that the biological effects are usually linked to the activity per cell rather than the absorbed dose. To assess the dose delivered to the cells during the radiolabelling, a multi-cellular dosimetry computational tool was developed, allowing the study of two key parameters: the cell density and the labelling efficiency. Through a hybrid method based on Monte Carlo simulations (MCNP6 code) and an analytical approach implemented in Python, the mean absorbed dose received by a target cell was calculated for distributions with a very large number of cells-up to hundreds of millions. An advanced investigation of in vitro cell labelling with ß-emitting radionuclides was carried out via (i) a systematic study of the effects of the labelling parameters on the cell absorbed dose for 18F, 64Cu and 68Ga, and (ii) a quantitative comparison between cellular and conventional dosimetry. The results provided a thorough analysis of how the dose (self, cross and extracellular medium dose contributions) varies with the initial labelling parameters selected and highlighted the conditions where the cellular dosimetry is required over the conventional dosimetry. The dosimetric model was finally applied to real conditions of 18F-FDG labelling on the basis of eight reported studies. The results showed that similar activity per cell can lead to significantly different absorbed dose and pointed out differences between cellular and conventional dosimetry up to a factor of 5.

Is mean heart dose a relevant surrogate parameter of left ventricle and coronary arteries exposure during breast cancer radiotherapy: a dosimetric evaluation based on individually-determined radiation dose (BACCARAT study).

BACKGROUND: Intra-individual heterogeneity of cardiac exposure is an issue in breast cancer (BC) radiotherapy that was poorly considered in previous cardiotoxicity studies mainly based on mean heart dose (MHD). This dosimetric study analyzes the distribution of individually-determined radiation doses to the heart and its substructures including coronary arteries and evaluate whether MHD is a relevant surrogate parameter of dose for these substructures. METHODS: Data were collected from the BACCARAT prospective study that included left or right unilateral BC patients treated with 3D-Conformal Radiotherapy (RT) between 2015 and 2017 and followed-up for 2 years with repeated cardiac imaging examinations. A coronary computed tomography angiography (CCTA) was performed before RT for all patients. Registration of the planning CT and CCTA images allowed delineation of the coronary arteries on the planning CT images. Using the 3D dose matrix generated during treatment planning and the added coronary contours, dose distributions were generated for whole heart and the following substructures: left ventricle (LV), left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed, Dmean was the volume-weighted mean dose. RESULTS: Dose distributions were generated for 89 left-sided BC patients (MHD = 2.9 ± 1.5 Gy, Dmean_LAD = 15.7 ± 3.1 Gy) and 15 right-sided BC patients (MHD = 0.5 ± 0.1 Gy; Dmean_RCA = 1.2 ± 0.4 Gy). For left-sided BC patients, the ratio Dmean_LAD/MHD was around 5. Pearson correlation coefficients between MHD and Dmean for delineated substructures were all statistically significant. However, for all substructures, the coefficient of determination R2 indicated that the proportion of the variance in Dmean of the substructure predictable from MHD was moderate to low (in particular R2 = 0.45 for LAD). Among left-sided BC patients with MHD < 3Gy, 56% of patients could nevertheless receive LAD doses above 40Gy (V40 > 0). CONCLUSION: Our study illustrates that MHD is not enough to predict with confidence individual patient dose to the LV and coronary arteries, in particular the LAD. For precise radiotherapy-induced cardiotoxicity studies it would be necessary to consider the distribution of doses within these cardiac substructures rather than just the MHD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

A systematic experimental study of parameters influencing 131-iodine in vivo spectroscopic measurements using age-specific thyroid phantoms.

In case of nuclear accident, the internal exposure monitoring of the population will preferably focus on the detection of 131I in the thyroid by in vivo monitoring. In most cases, the calibration of in vivo monitoring is performed with an adult thyroid phantom, which raises doubts regarding the relevance of child exposure assessment. In this study, the influence on the calibration of the thyroid volume, the counting distance and the positioning variations are studied experimentally in a systematic way. A NaI and a germanium detector along with a realistic age-specific set of four thyroid phantoms were used to carry out this study. The thyroid phantom volumes correspond to the following ages: 5, 10, 15 and adult. It was found that the counting efficiency varies linearly with the thyroid volumes for both detectors and whatever the phantom-detector distance is. The variation in counting distance strongly influences the measurement. Whatever the thyroid volume, a 30% difference in efficiency was found between the measurement at the contact and 1 cm for the NaI detector. A mathematical model giving the variation of the counting efficiency as a function of phantom-detector distance is provided. The study of positioning uncertainty has shown that the lateral/vertical displacements induce negligible efficiency variations and that it is relatively independent of the thyroid volume. The counting distance is a major parameter, which must be considered to assess the uncertainty of the subjects' measurements. The data reported here might serve to extract useful orders of magnitude when similar detectors are used. For other detectors, a similar trend might be expected and the information provided here could reduce the amount of experimental work needed to obtain it.

Development and test of sets of 3D printed age-specific thyroid phantoms for 131I measurements.

In the case of a nuclear reactor accident the release contains a high proportion of iodine-131 that can be inhaled or ingested by members of the public. Iodine-131 is naturally retained in the thyroid and increases the thyroid cancer risk. Since the radiation induced thyroid cancer risk is greater for children than for adults, the thyroid dose to children should be assessed as accurately as possible. For that purpose direct measurements should be carried out with age-specific calibration factors but, currently, there is no age-specific thyroid phantoms allowing a robust measurement protocol. A set of age-specific thyroid phantoms for 5, 10, 15 year old children and for the adult has been designed and 3D printed. A realistic thyroid shape has been selected and material properties taken into account to simulate the attenuation of biological tissues. The thyroid volumes follow ICRP recommendations and the phantoms also include the trachea and a spine model. Several versions, with or without spine, with our without trachea, with or without age-specific neck have been manufactured, in order to study the influence of these elements on calibration factors. The calibration factor obtained with the adult phantom and a reference phantom are in reasonable agreement. In vivo calibration experiments with germanium detectors have shown that the difference in counting efficiency, the inverse of the calibration factor, between the 5 year and adult phantoms is 25% for measurement at contact. It is also experimentally evidenced that the inverse of the calibration factor varies linearly with the thyroid volume. The influence of scattering elements like the neck or spine is not evidenced by experimental measurements.

Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: the BACCARAT prospective cohort study.

BACKGROUND: Radiotherapy (RT) for breast cancer presents a benefit in terms of reducing local recurrence and deaths resulting from breast cancer but it can lead to secondary effects due to the presence of neighboring cardiac normal tissues within the irradiation field. Breast RT has been shown to be associated with long-term increased risk of heart failure, coronary artery disease, myocardial infarction and finally cardiovascular death more than 10 years after RT. However, there is still a lack of knowledge for early cardiotoxicity induced by breast RT that can appear long before the onset of clinically significant cardiac events. Based on a 2-year follow-up prospective cohort of patients treated with breast RT, the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study aims to enhance knowledge on detection and prediction of early subclinical cardiac dysfunction and lesions induced by breast RT and on biological mechanisms potentially involved, based on functional and anatomical cardiac imaging combined with simultaneous assessment of multiple circulating biomarkers and accurate heart dosimetry. METHODS/DESIGN: BACCARAT study consists in a monocentric prospective cohort study that will finally include 120 women treated with adjuvant 3D CRT for breast cancer, and followed for 2 years after RT. Women aged 50 to 70 years, treated for breast cancer and for whom adjuvant 3D CRT is indicated, without chemotherapy are eligible for the study. Baseline (before RT) and follow-up data include measurements of functional myocardial dysfunction including strain and strain rate based on 2D-speckle tracking echocardiography, anatomical coronary lesions including description of plaques in segments of coronary arteries based on Coronary computed tomography angiography, and a wide panel of circulating biomarkers. The absorbed dose is evaluated for the whole heart and its substructures, in particular the coronary arteries. Analysis on occurrence and evolution of subclinical cardiac lesions and biomarkers will be performed and completed with dose-response relationship. Multivariate model of normal tissue complication probability (NTCP) will also be proposed. DISCUSSION: Tools and results developed in the BACCARAT study should allow improving prediction and prevention of potential lesions to cardiac normal tissues surrounding tumors and ultimately enhance patients' care and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512.

Coronary stenosis risk analysis following Hodgkin lymphoma radiotherapy: A study based on patient specific artery segments dose calculation.

BACKGROUND AND PURPOSE: The dose effect-effect relationship for cardiac diseases following radiotherapy suffers from uncertainties. Three dimensional coronary artery (CA) dose calculation after mediastinal Hodgkin lymphoma radiotherapy was performed, using the patient's coronary CT angiography (CCTA), and the relationship between the coronary arteries' radiation doses and the risk of stenosis was estimated. MATERIALS AND METHODS: Radiotherapy simulation CT scans and CCTAs of patients treated for a mediastinal Hodgkin lymphoma were used to merge thoracic and detailed cardiovascular anatomies. Radiation treatment parameters were used to estimate CA radiation doses. Twenty-one patients without coronary stenosis (controls) were matched with twelve patients with stenosis (cases). CA segments were considered as sub-volumes of interest. Radiation doses to stenotic segments were compared with those received by normal segments (from cases and controls) using a logistic regression. RESULTS: In eleven cases out of twelve, the highest of the coronary dose distribution was on a damaged segment. Logistic regression with CA segments yielded an odds ratio associated with the risk of coronary stenosis of 1.049 per additional gray with the CA segment median dose (95% confidence interval, 1.004-1.095; p-value <0.05). CONCLUSION: The CA segment dose significantly increased the risk of stenosis on the segment. Such personalized CA dose calculations on larger cohorts are expected to improve the understanding of the cardiovascular radiation dose-effect relationship.