[Ethical stakes of information in radiation oncology: Thinking the risk and building the therapeutic alliance]. / Enjeux éthiques de l'information en oncologie radiothérapie : penser le risque et construire l'alliance thérapeutique.

Informing patients before receiving radiation therapy is a fundamental ethical imperative. As a condition of the possibility of autonomy, information allows people to make health decisions concerning themselves, which is required by French law. This information includes in particular the potential risks due to radiation therapy. It is therefore necessary to think about what risk is, and how to define and assess it, in order to finally communicate it. The practice of informing people involves many ethical issues relating to the very content of the information, the form in which it is transmitted or even the intention that leads the health professional to say (or not to say) the risk. The transmission of information also questions the way to build a relationship of trust with the patients and how to integrate their own representations about these treatments. Between the risks of paternalism or even defensive medicine, this practice is at the heart of our professional practice.

[Crisis situations: Ethical reflection on prioritization of care access in radiation oncology]. / Situations de crise : réflexion éthique sur la priorisation de l'accès aux soins en oncologie radiothérapie.

Understood as a disruption of the conditions of care practice according to established protocols or procedures, crisis situations in radiation oncology departments can have multiple causes. Their seriousness can sometimes impose changes in the decision-making, organizational or technical paradigms. A possible consequence may be the need to make prioritization decisions in access to care, when there is a mismatch between the care needs of a population and the available health resources (whether technical or human). The specificities of care pathways and the wide variety of clinical situations in radiation oncology make these ethical decisions particularly difficult. Anticipation, collegial and multi-professional decision-making procedures or the integration of patient representatives in these prioritization processes are essential tools. Particular attention must be paid to the information to be provided to patients in a concern of transparency and respect. Prioritization situations are real tests for our departments. They go beyond the purely technical aspect of radiation oncology. They can lead to real ethical suffering for health professionals when their values come up against the limits imposed by crisis situations.

The inverse square law: A basic principle in brachytherapy.

The purpose of this article is to remind the importance of the inverse square law in radiotherapy and especially in brachytherapy. Indeed, beyond the impact in radiation therapy with high energy beam, there is the use of radionuclides and low energy photons with short FSD where it is still more important. Comparisons between Iridium Brachytherapy and low energy X-rays brachytherapy show equivalent dose distributions in the first few centimeters. If the inverse square law is not the only element influencing the dose distributions calculations, it must not be forgotten. And it is playing a major role in brachytherapy with short FSD (<6cm).

Radiotherapy and pregnancy.

We present the updated recommendations of the French society for radiation oncology on radiotherapy and pregnancy. The occurrence of cancer during pregnancy is a rare event (approximately 1 in 1000 pregnancies). The risks for the embryo or the foetus depend on the gestational age at the time of irradiation. The main risks are malformations with microcephaly and mental retardation. There is also a risk of radiation-induced cancer in the unborn child. In the case of only supradiaphragmatic irradiation, radiotherapy can be performed most often in pregnant women without risk to the foetus. On the other hand, in the case of an indication for subdiaphragmatic irradiation, therapeutic termination of the pregnancy should be proposed. In all cases, when radiotherapy is chosen, a phantom estimation of the dose delivered to the foetus, confirmed by in vivo measurement, is recommended. Conformational radiotherapy is the preferred technique because of the lower dose delivered to the foetus (except in tumour locations where other techniques such as IMRT are recommended).

Radiotherapy for penile cancers.

Penile cancers are uncommon and should be treated in expert center. Radiotherapy indications are mainly limited to exclusive brachytherapy for early stage penile glans cancer. Brachytherapy yields to excellent outcome for disease control and organ and function preservation. Only scarce data are available for external beam radiation therapy. It could be considered as palliative setting for irradiation of the primary tumor. For lymph node irradiation, external beam radiation therapy (with or without chemotherapy) could be discussed either as neoadjuvant approach prior to surgery for massive inguinal lymph node invasion or as adjuvant approach in case of high-risk of relapse. However, these cases should be discussed on an individual basis, as the level of evidence is poor. We present the recommendations of the French Society of Oncological Radiotherapy on the indications and techniques for external beam radiotherapy and brachytherapy for penile glans cancer.

A priori quality assurance using a benchmark case of the randomized phase 2 GORTEC 2014-14 in oligometastatic head and neck cancer patients.

PURPOSE: A Benchmark Case (BC) was performed as part of the quality assurance process of the randomized phase 2 GORTEC 2014-14 OMET study, testing the possibility of multisite stereotactic radiation therapy (SBRT) alone in oligometastatic head and neck squamous cell carcinoma (HNSCC) as an alternative to systemic treatment and SBRT. MATERIAL AND METHODS: Compliance of the investigating centers with the prescription, delineation, planning and evaluation recommendations available in the research protocol was assessed. In addition, classical dosimetric analysis was supplemented by quantitative geometric analysis using conformation indices. RESULTS: Twenty centers participated in the BC analysis. Among them, four major deviations (MaD) were reported in two centers. Two (10%) centers in MaD had omitted the satellite tumor nodule and secondarily validated after revision. Their respective DICE indexes were 0.37 and 0 and use of extracranial SBRT devices suboptimal There were significant residual heterogeneities between participating centers, including those with a similar SBRT equipment, with impact of plan quality using standard indicators and geometric indices. CONCLUSION: A priori QA using a BC conditioning the participation of the clinical investigation centers showed deviations from good SBRT practice and led to the exclusion of one out of the twenty participating centers. The majority of centers have demonstrated rigorous compliance with the research protocol. The use of quality indexes adds a complementary approach to improve assessment of plan quality.

[Ethical stakes in palliative care in radiation oncology]. / Enjeux éthiques de la pratique des soins à visée palliative en oncologie radiothérapique.

In 2021, the Ethics Commission of the SFRO has chosen the issue of the practice of palliative care in radiotherapy oncology. Radiation oncology plays a central role in the care of patients with cancer in palliative phase. But behind the broad name of palliative radiotherapy, we actually find a large variety of situations involving diverse ethical issues. Radiation oncologists have the delicate task to take into account multiple factors throughout a complex decision-making process. While the question of the therapeutic indication and the technical choice allowing it to be implemented remains central, reflection cannot be limited to these decision-making and technical aspects alone. It is also a question of being able to create the conditions for a singularity focused care and to build an authentic care relationship, beyond technicity. It is through this daily ethical work, in close collaboration with patients, and under essential conditions of multidisciplinarity and multiprofessionalism, that our fundamental role as caregiver can be deployed.

Contact X-ray brachytherapy for rectal cancer: Past, present, and future.

The Papillon experience and the Lyon R96-02 trial have shown that contact X-ray brachytherapy of 50kV is efficient and safe to achieve long term local control and organ preservation for cT1 and early cT2-3 rectal cancers. The OPERA trial, using the Papillon 50™ machine, brings further support to this preservation strategy for selected T2T3ab lesions. Future trials using a contact X-ray boost will try to consolidate and enlarge its place in organ preservation for rectal cancers.

[Health democracy: Patient partnership]. / Démocratie sanitaire : le patient partenaire de sa prise en charge.

In 2019, the scientific committee of the French society of radiation oncology (SFRO) created an ethics committee. Its mission is to provide our professional community with food for thought on ethical issues, and to identify its specificities within the radiation oncology departments. For the 2020 annual conference, the commission looked into the evolution of the patient-carer relationship, and more particularly to the strong idea of patient partnership. Indeed, the writing of the White Book of Cancer gave voice to sick people and stressed the need for new devices, such as the Caregiving Time. Patients can no longer be considered as objects of care but as people whose dignity and autonomy must be imperatively respected. The acquisition of knowledge allows a bilateral exchange, prerequisite of a dynamic collaboration. Patients can be partners in their own care, partners in training and research (expert patient), but also partners in health institutions and policies. It is this notion of partnership and involvement of the person in their path of care in radiation oncology that we will analyse here. It will be about defining it, by developing the concept of autonomy, and bringing out its complexity and ambivalence through two examples from our clinical practice: the shared decision-making process for patients with localized prostate cancer and the patient's involvement in the success of his radiotherapy.

A brief history of contact X-ray brachytherapy 50 kVp.

Contact X ray brachytherapy 50 kVp was initiated in the 1930s with the Siemens unit and popularized with the Philips unit in the 1950s. A renaissance was seen in the early 2000s with the Intrabeam™ unit for breast IORT. Presently the Papillon™ systems thanks to its high dose rate (>10Gy/mn) can be used to treat breast (IORT), skin, eyelid and rectal cancers. Future developments are expected to consolidate the place of contact radiotherapy as a safe and efficient treatment for accessible early tumors.

Mitochondrial lineage A2ah found in a pre-Hispanic individual from the Andean region.

OBJECTIVES: The aim of this study was to contribute to the knowledge of pre-Hispanic Andean mitochondrial diversity by analyzing an individual from the archaeological site Pukara de La Cueva (North-western Argentina). The date of the discovery context (540 ± 60 BP) corresponds to the Regional Developments II period. METHODS: Two separate DNA extractions were performed from dentin powder of one tooth. HVR I was amplified by PCR from each extract in three overlapping fragments and the haplotype was determined by consensus among all obtained sequences. The procedures were carried out under strict protocols developed for working with ancient DNA. RESULTS: The individual belonged to the A2ah lineage due to the presence of the 16097C and 16098G transitions, which constitute its distinctive motif. This lineage is very rare in Native American populations and was described in four individuals from current groups inhabiting the Bolivian Llanos, two from South-eastern Brazil, and one from the Gran Chaco region. In addition, two other mutations (16260T and 16286T) were shared with one of the individuals from the Bolivian Llanos region. CONCLUSIONS: Considering that the origin of this lineage was postulated for the South American lowlands, the present pre-Hispanic discovery in the Andean area could be taken as a new evidence of gene flow between these regions. Also, it allows the questioning of the geographical origin of this mitochondrial lineage.

[Autism spectrum disorders and bisphenol A: Is serotonin the lacking link in the chain?] / Les relations entre le bisphénol A et les troubles du spectre autistique se précisent : la sérotonine est-elle le lien manquant ?

The etiology of autism spectrum disorders (ASD) is believed to be multifactorial and to involve genetic and environmental components. Environmental chemical exposures are increasingly understood to be important in causing neurotoxicity in fetuses and newborns. Recent data from the Centers for Disease Control and Prevention in the United States suggest a substantial increase in ASD prevalence, only partly explicable by factors such as diagnostic substitution. Bisphenol A (BPA) is an ubiquitous xenoestrogen widely employed in a variety of consumer products including plastic and metal food and beverage containers, dental sealants and fillings, medical equipment and thermal receipts. Therefore, most people are exposed almost continuously to BPA in industrialized countries. Sources of BPA exposure are predominantly diet, but also through inhalation or dermal absorption. BPA can be measured in many human fluids and tissues including saliva, serum, urine, amniotic fluid, follicular fluid, placental tissue and breast milk. There is concern that BPA exposure may influence human brain development and may contribute to the increasing prevalence of neurodevelopmental and behavioural problems. Epigenetic mechanisms are suggested by a mouse study that demonstrated that BPA exposure during gestation had long lasting, transgenerational effects on social recognition. Previous epidemiological studies suggested a relationship between maternal BPA exposure and ASD. A recent study of 46 children with ASD and 52 controls found for the first time a direct association between children with ASD and BPA exposure and demonstrated that BPA is not metabolized well in children with ASD. The metabolomic analyses showed a correlation between ASD and essential amino acid metabolism pathways. Essential amino acids are precursors of neurotransmitters, for example tryptophan for serotonin. Fetal and prenatal BPA exposure was suggested to perturb the serotonergic system in rat and mice models. On the other hand, hyperserotonemia was reported in approximately one-third of autistic patients and also in relatives. Moreover, neuroimaging studies revealed two fundamentally different types of serotonin synthesis abnormality in children with autism compared to age-matched nonautistic children, a difference in whole-brain capacity and focal abnormalities. Finally, decreased serotonin transporter and serotonin receptor binding have been reported in both children and adults with autism. So, the link between BPA and autism could be a defect of the normal in utero or perinatal serotonergic system development. In France, BPA was banned in baby bottles in 2010 and in any food or beverage packaging since January 2015. Therefore, there is an urgent need to find safe alternatives in the use of BPA in the manufacture of industrial products.

Deterministic model for the transport of energetic particles: Application in the electron radiotherapy.

A new deterministic method for calculating the dose distribution in the electron radiotherapy field is presented. The aim of this work was to validate our model by comparing it with the Monte Carlo simulation toolkit, GEANT4. A comparison of the longitudinal and transverse dose deposition profiles and electron distributions in homogeneous water phantoms showed a good accuracy of our model for electron transport, while reducing the calculation time by a factor of 50. Although the Bremsstrahlung effect is not yet implemented in our model, we propose here a method that solves the Boltzmann kinetic equation and provides a viable and efficient alternative to the expensive Monte Carlo modeling.

[Gap junctions: A new therapeutic target in major depressive disorder?]. / Les jonctions gap: une nouvelle cible thérapeutique pour le traitement des troubles dépressifs majeurs?

Major depressive disorder is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and is associated with excess mortality, especially from cardiovascular diseases and through suicide. The treatments of this disease with tricyclic antidepressants and monoamine oxidase inhibitors are poorly tolerated and those that selectively target serotonin and norepinephrine re-uptake are not effective in all patients, showing the need to find new therapeutic targets. Post-mortem studies of brains from patients with major depressive disorders described a reduced expression of the gap junction-forming membrane proteins connexin 30 and connexin 43 in the prefrontal cortex and the locus coeruleus. The use of chronic unpredictable stress, a rodent model of depression, suggests that astrocytic gap junction dysfunction contributes to the pathophysiology of major depressive disorder. Chronic treatments of rats with fluoxetine and of rat cultured cortical astrocytes with amitriptyline support the hypothesis that the upregulation of gap junctional intercellular communication between brain astrocytes could be a novel mechanism for the therapeutic effect of antidepressants. In conclusion, astrocytic gap junctions are emerging as a new potential therapeutic target for the treatment of patients with major depressive disorder.

[Management of locally advanced anal canal carcinoma with modulated arctherapy and concurrent chemotherapy]. / Place de l'arcthérapie modulée et de la chimiothérapie concomitante dans la prise en charge des cancers du canal anal localement évolués.

The standard treatment of locally advanced (stage II and III) squamous cell carcinoma of the anal canal consists of concurrent chemoradiotherapy (two cycles of 5-fluoro-uracil, mitomycin C, on a 28-day cycle), with a dose of 45 Gy in 1.8 Gy per fraction in the prophylactic planning target volume and additional 14 to 20 Gy in the boost planning target volume (5 days per week) with a possibility of 15 days gap period between the two sequences. While conformal irradiation may only yield suboptimal tumor coverage using complex photon/electron field junctions (especially on nodal areas), intensity modulated radiation therapy techniques (segmented static, dynamic, volumetric modulated arc therapy and helical tomotherapy) allow better tumour coverage while sparing organs at risk from intermediate/high doses (small intestine, perineum/genitalia, bladder, pelvic bone, etc.). Such dosimetric advantages result in fewer severe acute toxicities and better potential to avoid a prolonged treatment break that increases risk of local failure. These techniques also allow a reduction in late gastrointestinal and skin toxicities of grade 3 or above, as well as better functional conservation of anorectal sphincter. The technical achievements (simulation, contouring, prescription dose, treatment planning, control quality) of volumetric modulated arctherapy are discussed.

[Bilateral adrenal hemorrhage revealing hyperhomocysteinemia]. / Hémorragie surrénalienne bilatérale révélant une hyperhomocystéinémie.

INTRODUCTION: Bilateral adrenal hemorrhage remains a rare disease. It has several etiologies, and clinical presentation is not specific. CASE REPORT: We report a 45-year old man without known prothrombotic factor who presented with acute left sided abdominal pain left revealing a bilateral adrenal hemorrhage. The diagnostic work-up identified a significant hyperhomocysteinemia associated with a previously undiagnosed homozygous mutation of the 5,10 methylene-tetrahydrofolate reductase gene. The outcome was associated with the occurrence of an adrenal insufficiency.

Opiate dependence induces network state shifts in the limbic system.

Among current theories of addiction, hedonic homeostasis dysregulation predicts that the brain reward systems, particularly the mesolimbic dopamine system, switch from a physiological state to a new "set point." In opiate addiction, evidence show that the dopamine system principal targets, prefrontal cortex (PFC), nucleus accumbens (NAC) and basolateral amygdala complex (BLA) also adapt to repeated drug stimulation. Here we investigated the impact of chronic morphine on the dynamics of the network of these three interconnected structures. For that purpose we performed simultaneous electrophysiological recordings in freely-moving rats subcutaneously implanted with continuous-release morphine pellets. Chronic morphine produced a shift in the network state underpinned by changes in Delta and Gamma oscillations in the LFP of PFC, NAC and BLA, in correlation to behavioral changes. However despite continuous stimulation by the drug, an apparent normalization of the network activity and state occurred after 2 days indicating large scale adaptations. Blockade of µ opioid receptors was nonetheless sufficient to disrupt this acquired new stability in morphine-dependent animals. In line with the homeostatic dysregulation theory of addiction, our study provides original direct evidence that the PFC-NAC-BLA network of the dependent brain is characterized by a de novo balance for which the drug of abuse becomes the main contributor.

[Brachytherapy dose calculation]. / Calcul de la distribution de dose en curiethérapie.

Brachytherapy dose distribution calculation has evolved from the simple use of charts to the TG-43 formalism. It depends on the physical and geometrical characteristics of each source, the position of the source relatively to the calculation point and on the medium composition. Its principles and limitations are presented as well as the different dosimetric systems associated with implementing rules and the definition of the prescribed dose. The new generation of algorithms and their contributions are discussed.

[Radionuclides, technologies and quality control in brachytherapy]. / Radioéléments, appareillages et contrôle de qualité en curiethérapie.

Brachytherapy consists in placing radioactive sources directly in contact with the tumoral bed. The type of source, its characteristics and its use will be adapted regarding the kind of treatment foreseen. Modern brachytherapy techniques employ remote afterloading technologies allowing better quality and security in the delivery of treatment. This development of technology goes with an increase need of quality control of equipments, including radionuclides, and procedures.

[Mechanisms of action of glucocorticoids]. / Mécanismes d'action des glucocorticoïdes.

Glucocorticoids exert their actions at nuclear levels through genomic mechanisms including both transcriptional activation (transactivation) and gene expression repression (transrepression). Transactivation mechanisms are mediated by transcription factors, the main one being the activated glucocorticoid receptor (GR). These mechanisms contribute to both powerful therapeutic effects of glucocorticoids on inflammatory and immune diseases, and adverse effects than can be harmful on vital functions. Non-genomic mechanisms, which act faster than genomic ones, have also been explored. They also involve the GR in different membranous and cytosolic sites. The phenomenon of glucocorticoid resistance is also complex and several different mechanisms may mediate this phenomenon. Among them are alterations in number, binding affinity or phosphorylation status of the GR, changes in capacity of cellular apoptosis, polymorphic changes or expression of proteins involved in the genomic actions of glucocorticoids. Finally, some proteins, which mediate glucocorticoid activity could be therapeutic targets for reducing glucocorticoid-induced adverse effects.