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BackgroundIn the case of breast cancer (BC), radiotherapy (RT) helps reduce locoregional recurrence and BC-related deaths but can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular events. It is therefore of primary importance to early detect subclinical left ventricular (LV) dysfunction in BC patients after RT and to determine the dose–response relationships between cardiac doses and these events.MethodsWithin the frame of the MEDIRAD European project (2017–2022), the prospective multicenter EARLY‐HEART study (ClinicalTrials.gov Identifier: NCT03297346) included chemotherapy naïve BC women aged 40–75 years and treated with lumpectomy and adjuvant RT. Myocardial strain analysis was provided using speckle‐tracking echocardiography performed at baseline and 6 months following RT. A global longitudinal strain (GLS) reduction >15% between baseline and follow-up was defined as a GLS-based subclinical LV dysfunction. Individual patient dose distributions were obtained using multi-atlas-based auto-segmentation of the heart. Dose-volume parameters were studied for the whole heart (WH) and left ventricle (LV).ResultsThe sample included 186 BC women (57.5 ± 7.9 years, 64% left-sided BC). GLS-based subclinical LV dysfunction was observed in 22 patients (14.4%). These patients had significantly higher cardiac exposure regarding WH and LV doses compared to patients without LV dysfunction (for mean WH dose: 2.66 ± 1.75 Gy versus 1.64 ± 0.96 Gy, p = 0.01). A significantly increased risk of subclinical LV dysfunction was observed with the increase in the dose received to the WH [ORs from 1.13 (V5) to 1.74 (Dmean); p <0.01] and to the LV [ORs from 1.10 (V5) to 1.46 (Dmean); p <0.01]. Based on ROC analysis, the LV-V5 parameter may be the best predictor of the short-term onset of subclinical LV dysfunction.ConclusionThese results highlighted that all cardiac doses were strongly associated with the occurrence of subclinical LV dysfunction arising 6 months after BC RT. Whether measurements of GLS at baseline and 6 months after RT combined with cardiac doses can early predict efficiently subclinical events occurring 24 months after RT remains to be investigated.

International audience; Background: Breast cancer (BC) represents a major public health burden worldwide. Significant advances in treatments have been made in recent decades. Among them, radiotherapy (RT) allows reducing local recurrence and deaths resulting from BC. However, RT for BC can lead to cardiotoxicity, resulting in an increased risk of long-term major cardiovascular adverse events (MACE). Consequently, to detect early subclinical cardiac alterations is of primary importance.Objective: One of the aims of the MEDIRAD EARLY-HEART study is to determine the short-term impact of BC RT on subclinical cardiac function by means of echocardiography and to explore the dose-response relationship. Methods: Launched in 2017, the ongoing EARLY-HEART study is a prospective multicenter cohort study including women with BC aged 40 to 75 years and treated by RT in the Netherlands, Germany, France, Portugal and Spain. All women were chemotherapy naive. Echocardiographic exams after the RT+6-month follow-up (FU) will be available in September 2021 to determine if significant subclinical cardiac function alterations occurred. A RT+24-month FU is currently ongoing to determine if eventual previous alterations persist. Myocardial deformation analysis was provided by the 2D-speckle-tracking echocardiography. The global longitudinal strain (GLS), its worsening > 10% and the global longitudinal strain rate (GLSR) will be considered to evaluate subclinical cardiac dysfunction. Results: The EARLY-HEART cohort included 258 women with BC, with a mean age of 58.2±8.1 years, 63.5% with left-sided BC. Presence of pre-existing cardiovascular (CV) risk factors were recorded to allow adjustments in further analyses: obesity was present in 21.0% of the sample (mean body mass index of 26.3±4.6 kg/m²), hypertension in 48.2%, diabetes in 5.4% and 47.8% were current or former smoker. RT total dose varied from 40.05 Gray (Gy) to 50.40 Gy, and 46.1% received a boost (mean boost dose of 11.9±1.9 Gy). Among the 258 patients, 63.9% received concomitant hormonotherapy. Regarding subclinical cardiac investigations at baseline (before RT), 242 patients (93.8%) performed echocardiography exams, yielding a mean GLS of -19.3±3.3%. Full echocardiography analyses after the 6-month FU will be available soon to explore potential alterations of myocardial function between pre-RT time-point, 6-month and 24-month post-RT time-points using paired t tests. Future EARLY-HEART analyses will also provide accurate absorbed dose of cardiac structures (whole heart, right and left ventricles, right and left atrium) based on 3D-dosimetry to explore dose-response relationships using multivariate regressions. Subgroup and sensitivity analyses will be performed. Results of analyses of the relationship between radiation dose and subclinical cardiac function will be presented.Conclusion: Using strain analysis from echocardiography, the impact of RT on subclinical cardiac function in patients with BC are being explored within the MEDIRAD EARLY-HEART project. Epidemiological data regarding early alteration of GLS could contribute to adaptions in clinical practice about CV monitoring.

The Council Directive 2013/59/EURATOM of 5 December 2013 lays down basic safety standards for protection against the dangers arising from exposure to ionising radiation. It includes a new dose limit for the eye lens, with a reduction from 150 to 20 mSv peryear (average over five years, with no single year exceeding 50 mSv), that is to say 7.5 times lower than it was. The member states had four years (deadline February 2018) to implement the Directive into their legislation. The lowered dose limit raised a lot of issues, concerning the need for a dedicated eye lens dose monitoring, the choice of monitoring programme and the workers needing it, etc. Consequently, research studies and monitoring surveys were performed in the recent years, and in some member states new regulations and associated guidance were developed according to the new directive. The medical field is without a doubt the most affected, in particular interventional radiology and cardiology, thus input is needed from surgeons who now find themselves wearing another dosemeter. Dosimetryservices are also stakeholders, not only in terms of dosemeter supply but also for other organisational issues, including dose recording and record keeping, dose reporting, etc. The course will give an overview regarding the scientific background for the changes in legislation, the current status of regulations and guidance, what is currently available to support radiation protection of the lens and identify the questions that at yet remain to be fully answered. The following papers are based on the presentations given in the EURADOS Winter School 2020 held in Florence (Italy) on January 30th2020. Winter school scientific committee: Liz Ainsbury (PHE, UK), Isabelle Clairand (IRSN, France), Elena Fantuzzi (ENEA, Italy), Mercè Ginjaume (UPC, Spain), Francesco Rossi (AOU-Careggi, Italy).

International audience; 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 six 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.

International audience; Background: Breast cancer radiotherapy (BC RT) can be associated with long-term, silent and lately detected cardiotoxicity. Longitudinal strain (LS), based on 2D speckle-tracking echocardiography (2DSTE) can detect early subclinical left ventricular dysfunction. Little is known on the association between RT-induced cardiac doses and LS changes. Purpose: To analyze the relationship between cardiac doses and LS changes after RT in breast cancer patients.Methods: BACCARAT is a monocentric prospective cohort study that included BC patients treated with RT without chemotherapy. Global LS, in particular in the mid-layer of the myocardium (GLS-mid), was measured with 2DSTE before RT and 6 months after RT. We evaluated radiation doses to whole heart, left ventricle (LV), left anterior descending coronary artery (LAD). A subclinical event of cardiotoxicity "decreased GLS-mid≥10% " was defined as a relative decrease≥10%. Results: We included 94 patients (18 right-sided BC, 76 left-sided BC) aged 59±8 years. Mean doses to the heart, LV and LAD were respectively: 3.0±1.3 Gy, 6.6±3.2 Gy and 16.5±7.5 Gyfor the left-sided patients; 0.6±0.5 Gy, 0.2±0.2 Gy and 0.3±0.5 Gy for the right-sided patients. Left-sided BC patients had a significant decrease of GLS-mid (%relative change=9.0%, p=0.02); "decreased GLS-mid≥10%" was detected in 50% of left-sided BC patients and 38% in the right-sided group. We observed dose-response relationships with mean doses to the heart, the LV and the LAD in univariate analysis, that remained marginally significant in adjusted analysis for mean LV dose with an increase of the subclinical event by 11% for each increase of 1 Gy (OR=1.11, 95%CI [0.98 – 1.26]). Conclusion: This is the first study to establish dose-response relationships between BC RT-induced cardiac doses and decreased LS 6 months after RT. With longer follow-up, it remains to be determined whether these dose-related changes are confirmed and if detection of this subclinical LV dysfunction is related to clinical outcome.

Background Medical workers are the largest group of workers occupationally exposed to low doses of ionizing radiation (IR) worldwide. Aims This review presents all the cohorts of medical workers exposed in the world and summarizes cancer risks associated with radiation exposure in this population. Methods Epidemiological studies on health professionals exposed to IR published from 1975 to 2019 were reviewed. Strength of evidence was assessed according to the modified Royal College of General Practitioners three-star system. Results Among the 16 epidemiological studies focusing on cancers from 11 cohorts among medical staff exposed to radiation, higher risks of cancer were observed for pre-1950 exposure and for medical workers who performed fluoroscopically guided interventional procedures or radionuclides procedures compared to those who did not. However, strength of evidence supporting the associations remains moderate as several methodological limits including the lack of dosimetry data, lifestyle factors and recent updates may obscure the link between medical occupational exposure and cancer occurrence. Conclusions Excess risk of cancer is suspected for high and former exposures. The more highly exposed professions, i.e. interventional physicians and nuclear medicine workers, should be monitored carefully. Collaborative projects aiming to increase the quantity and quality of information of the studied populations would be a key point

International audience; Introduction: We plan to evaluate whether breast cancer (BC) treatment, including radiotherapy, is associated with an increased risk of cardiac arrhythmias and conduction disorders (ACD) characterized by implantation of pacemaker or defibrillator or hospitalization for rhythm disorders.Methods: Our study is based on the Echantillon Généraliste de Bénéficiaires (EGB), the 1/97 random sample of the French nationwide health database. We identify patients treated for BC between 2008 and 2012 and cases of ACD arising post BC until 2017. The ACD incidence rates according to BC treatment (Surgery±Chemotherapy±Radiotherapy) will be estimated and compared to the national incidence rates estimated from the EGB population.Results: Within an initial cohort of approximately 260 000 women in the EGB, nearly 3000 patients treated for BC. We should detect ~5000 incident cases of ACD in the EGB cohort. The observation of at least 85 incident cases of ACD in the BC subgroup instead of 60 (RR=1.4) will have a statistical power of 80%.Conclusion: The study is ongoing. It will allow quantifying the excess risk of ACD suspected for BC treatment, in particular mediastinal radiotherapy.

The rationale for the quest to close the left atrial appendage (LAA) for stroke prevention is composed of three elements: the concept that atrial fibrillation (AF) causes strokes, the concept that strokes are associated with thrombus formation in the LAA, and that these thrombi cause strokes by embolisation to the cerebral circulation. There are strong data supporting an association between AF and stroke. The Framingham study following 5,070 patients over 34 years demonstrated an approximately fivefold higher stroke risk in individuals with AF than in those without.1 Though this does not prove a causal relationship, it is important to mention that this risk remained even after adjustment for other risk factors such as hypertension, coronary artery disease, congestive heart failure, and age. Another element to support LAA closure is that there must be proof that thrombus formation occurs predominantly in the LAA. One would imagine that there are abundant data to support the concept that, in AF, thrombus formation occurs predominantly in the LAA; however, in almost all texts discussing the pathophysiology of stroke in AF there are few publications cited to support this concept. Blackshear et al included 1,288 patients with non-valvular AF who underwent either transoesophageal echocardiography (TOE) or autopsy. 2 Thrombus formation was reported in 222 patients, 91% of which was located in the LAA. It was further supported by a more comprehensive meta-analysis by Mahajan et al who demonstrated that 89% of thrombi in the left atrium (LA) were located in the LAA.3 This was corroborated by a study in the realm of degenerative aortic stenosis by Parashar et al.4 In this study, all left atrial thrombi resided in the LAA. It is worth mentioning that the LAA is the most common site of intracardiac thrombi not only in patients with AF but also in patients in sinus rhythm.5 More direct evidence is now available proving that a large proportion of strokes in AF are the result of thrombus in the LAA. The PROTECT AF and PREVAIL studies (described later in this document) provide evidence for the protective effect of LAA closure on thromboembolic events (Chapter 5), although some have debated the evidence (Chapter 6).6 In order to justify LAA closure it is important to show that, when thrombus occurs in the LAA, it can embolise in the cerebral circulation. o demonstrate this, a thrombus embolising to the brain would have to be caught in the act. Parekh et al describe real-time imaging capture of LAA thrombus embolisation during TOE with subsequent stroke after a delay of 4 hours of the witnessed embolisation, possibly due to initial retention at a non-occlusive location with subsequent fragmentation and delayed more distal embolisation.7 The fact that LAA closure prevents thromboembolic events as detailed above is also indirect proof for embolisation from LAA as a cause of embolic events.

International audience; Background: Breast radiotherapy (RT) is associated with long-term cardiac toxicity with clinical detection only relevant 10 to 15 years after RT. For early detection of left ventricular dysfunction, it has been shown that detecting a decreased LVEF after RT may be too late for treatment. Use of strain as a more sensitive parameters of LV dysfunction has been suggested, but little is known on the impact of RT-induced cardiac exposure on strain.Purpose: To analyze the relationship between cardiac exposure and myocardial strain changes after RT in breast cancer patients from the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study. Methods: BACCARAT is a monocentric prospective cohort study that included left or right unilateral breast cancer patients treated with RT without chemotherapy between 2015 and 2017. Each patient was included at baseline before RT and is followed for 2 years with repeated cardiac imaging examinations, including Siemens 2-dimensional speckle strain imaging for the detection of subclinical left ventricular abnormalities with measurement of global longitudinal strain (GLS). Individual dosimetric evaluation provided information on RT-induced absorbed doses for whole heart, left ventricle (LV), left main coronary artery (LM), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). For clinically meaningful purpose, the event “decreased GLS” was defined as ≥10% reduction, ie. % change, in GLS compared to baseline measurement.Results: This analysis was based on 94 patients (15 right-sided BC, 79 left-sided BC) aged 58±8 years with a follow-up of 6 months post RT. Mean doses to the heart, LV and LAD were respectively: 3.0 Gy, 6.7 Gy and 16.6 Gy for the left-sided patients; 0.6 Gy, 0.2 Gy and 0.3 Gy for the right-sided patients. Considering BC laterality as a raw index of exposure, an altered GLS was observed for left sided BC patients (-15.5±3.7% before RT vs. -14.1±4.0% at RT+6 months, p=0.02), but not for right sided BC patients (-15.0±4.2% vs. -15.0±4.2%, p=0.99). Half of the population (48%) had “decreased GLS” (38% among right-sided patients, 50% among left sided patients). Considering cardiac doses for the whole population, both mean dose to the heart and LV were significantly associated with “decreased GLS”: OR/1Gy=1.4 95%CI[1.1 – 1.9] (p=0.02) and OR/1Gy=1.2 95%CI[1.1 – 1.3] (p=0.01) even after adjustment on cardiac risk factors including age, hypertension, BMI and hypercholesterolemia. LV doses was the best predictor of “decreased GLS”, in particular the volume of LV receiving at least 10 Gy (OR/1%=1.07 [1.02 – 1.12] (p=0.007)). Patients with ≥15% of the LV receiving at least 10 Gy had 4 times more risk to have “decreased GLS” (OR=3.9 [1.6 – 9.9], p=0.0027).Conclusion: This study is the first to establish a dose-response relationship between RT-induced cardiac doses and decreased GLS 6 months after RT, illustrating the importance to reduce cardiac exposure in order to limit the risk of LV dysfunction. Longer follow-up until 2 years post RT will allow refining these results on the detection of sub-clinical LV dysfunction in patients treated for breast cancer.

International audience; Introduction : Dans la plupart des études épidémiologiques portant sur la cardiotoxicité radio-induite après une radiothérapie pour un cancer du sein, les doses sont généralement décrites comme celles reçues par le cœur dans sa globalité avec la mesure de la dose moyenne au cœur (DMC) [1]. Cette DMC est utilisée comme la dose de référence pour analyser la relation dose-réponse. Cependant, la distribution de la dose dans le cœur n'est pas homogène. Cette hétérogénéité intra-individuelle de l'exposition cardiaque lors d’une radiothérapie pour un cancer du sein est une particularité et une difficulté mal prise en compte dans les précédentes études de cardiotoxicité . La DMC pourrait être un indicateur médiocre pour évaluer la dose aux sous-structures cardiaques, en particulier l’artère coronaire interventriculaire antérieure qui est susceptible de recevoir des doses extrêmement élevées compte tenu de sa position anatomique sur le cœur [2]. La DMC pourrait donc être un critère de dose peu pertinent pour les études de cardiotoxicité induite par la radiothérapie et pour l’évaluation de la relation dose-réponse.Objectifs : Cette étude dosimétrique chez des patientes traitées par radiothérapie (RT) pour un cancer du sein avait pour objectifs : 1/ analyser la distribution des doses déterminée à l’échelle individuelle au niveau du cœur et de ses sous-structures, notamment les artères coronaires ; 2/ évaluer si la dose moyenne au cœur (DMC) est un bon indicateur de dose pour ces sous-structures.Méthodes : Les données proviennent de l’étude prospective BACCARAT [3] qui a inclus des patientes atteintes d'un cancer du sein unilatéral et traitées par RT (3D-CRT) entre 2015 et fin 2017 et suivies pendant 2 ans par des examens répétés d’imagerie cardiaque. En particulier un coroscanner a été réalisé avant la RT pour toutes les patientes. La fusion des images du scanner de planification de la RT et du coroscanner a permis de réaliser un contourage des artères coronaires. En utilisant la matrice de dose 3D générée par le système de planification de la RT et en y ajoutant les contours des artères coronaires, nous avons pu générer les doses moyennes et histogrammes doses-volumes des structures suivantes : Cœur entier, Ventricule Gauche, Artère coronaire interventriculaire antérieur (IVA), Artère coronaire circonflexe (Cx) et Artère coronaire droite (CD). Une analyse descriptive des doses physiques en Grays (Gy) a été réalisée, Dmoy était la dose moyenne à la structure d’intérêt. Résultats : L’évaluation dosimétrique rétrospective a été réalisée sur un total de 104 patientes de l’étude BACCARAT (89 seins gauches, 15 seins droits). La dose de rayonnement prescrite était de 50 Gy en 25 séances pour plus de trois quarts de la population ou de 47 Gy en 20 fractions de 2,35 Gy. Un boost de 9 à 15 Gy était appliqué sur le site de la tumeur si indiqué cliniquement. Une irradiation des aires ganglionnaires a été réalisée chez 31 patientes sein gauche et 1 patiente sein droit. Les distributions de doses ont été générées pour ces 89 patientes traitées du sein gauche (DMC = 2,9 ± 1,5 Gy, Dmoy_IVA= 15,7 ± 3,1 Gy) et ces 15 patients traitées du sein droit (DMC = 0,5 ± 0,1 Gy; Dmoy_CD = 1,2 ± 0,4 Gy). Pour les patientes sein gauche, le ratio Dmoy_IVA / DMC était d'environ 5. Les coefficients de corrélation entre DMC et Doy pour des sous-structures délimitées étaient tous statistiquement significatifs. Cependant, pour toutes les sous-structures, le coefficient de détermination R² indiquait que la proportion de la variance des Dmoy des sous-structures expliquée par la DMC était modérée à faible (en particulier R² = 0,45 pour l’IVA). Parmi les patientes sein gauche avec une DMC 0%). Conclusion : Notre étude montre que la DMC n’est pas suffisante pour estimer et prédire de façon satisfaisante la dose individuelle au ventricule gauche et aux artères coronaires, notamment à l’IVA. Pour étudier précisément la cardiotoxicité induite par la radiothérapie, il serait donc nécessaire de considérer les distributions de doses à ces sous structures cardiaques et ne plus se limiter à la DMC.

Jouer ne saurait être défini exclusivement par le faire, mais l’expérience englobe également l’être et l’attitude qui sous-tendent l’action : mission d’accompagnement délicate pour les équipes. De plus, au-delà des questions relatives à ses valeurs culturelles, éducatives et sociales, le jeu confronte également chacun à son parcours individuel et à sa propre relation avec le jeu. Ainsi, quel que soit le degré d’intégration du jeu, ou du jouet, dans les établissements, qu’il soit perçu comme u...