[Radiation-induced lymphopenia: Lymphocytes as a new organ at risk]. / Lymphopénie radio-induite : les lymphocytes comme nouvel organe à risque.

Taking the immune system into account in the fight against tumors has upset the cancer treatment paradigm in the 21st century. Combination treatment strategies associating radiotherapy with immunotherapy are being increasingly implemented in clinical practice. In this context, lymphocytes, whether lymphocytes infiltrating the tumour, circulating blood lymphocytes or lymphocytes residing within the lymph nodes, are key players in cellular and humoral anti-tumor immunity. The significant radiosensitivity of lymphocytes was demonstrated in the early 1990s. Along with the cells of the digestive mucosa, lymphocytes are thus among the most radiosensitive cell types in the body. Compared to the old practices of external radiotherapy, current intensity modulated treatments have allowed a considerable improvement in acute and late toxicity, at the cost of a significant increase in the volume irradiated at low doses. This is not without consequence on the incidence of radiation-induced lymphopenia, with prognostic implications for many tumor types. Thus, in order not to hinder the action of antitumor immunity and the efficacy of immunotherapy, it is essential to consider lymphocytes as a new organ at risk in its own right. In this development, based on current data from the literature, we will begin by justifying the necessary prevention of radiation-induced lymphopenia, before providing the tools currently known to apprehend lymphocytes as a new multicompartments. Finally, we will broaden the perspective by outlining ways to develop research in this area.

[Radiation-induced pulmonary fibrosis: New potential targets]. / Fibrose pulmonaire radio-induite : nouvelles cibles pour demain.

Radiation-induced pulmonary fibrosis (RIPF) is one of the major and late complications of radiotherapy (RT) with an average incidence rate between 16 and 28% after RT. RIPF significantly affects the function of the affected tissues/organs as well as the quality of life and survival of patients. The process of radiation fibrogenesis is initiated by a very complex signaling network that involves several cellular and molecular factors and the development of effective treatments relies on a better understanding of the involved mechanisms. Despite a major advance in the field, to date there is no clinical treatment that has really shown efficacy in the prevention or treatment of RIPF. In the present review, we will discuss potential new therapeutic avenues that could effectively treat RIPF.

[Interactions between vascular endothelium and immune cells: A key control point of radiation-induced digestive lesions]. / Interactions endothélium vasculaire ­ cellules immunitaires : un point de contrôle clef des lésions digestives radio-induites.

Radiation-induced toxicity of the digestive tract is a major clinical concern as many cancer survivors have received radiotherapy for tumours of the abdominopelvic area. The coordination and orchestration of a tissue's response to stress depend not only on the phenotype of the cells that make up the tissue but also on cell-cell interactions. The digestive system, i.e., the intestine/colon/rectum, is made up of a range of different cell populations: epithelial cells, stromal cells, i.e. endothelial cells and mesenchymal lineages, immune cells and nerve cells. Moreover, each of these populations is heterogeneous and presents very significant plasticity and differentiation states. The pathogenesis of radiation-induced digestive lesions is an integrated process that involves multiple cellular compartments interacting in a complex sequence of events. Understanding all the cellular events and communication networks that contribute to the tissue's response to stress is therefore a major conceptual and methodological scientific challenge. The study of heterogeneous populations of cells in a tissue is now possible thanks to "single cell' RNA sequencing and spatial transcriptomics techniques, which enable a comprehensive study of the transcriptomic profiles of individual cells in an integrated system. In addition, the mathematical and bioinformatics tools that are now available for the large-scale analysis of data allow the inference of cell-cell communication networks. Such approaches have become possible through advances in bioinformatics algorithms for the analysis and deciphering of interaction networks. Interactions influence the tissue regeneration process through expression of various molecules, including metabolites, integrins, junction proteins, ligands, receptors and proteins secreted into the extracellular space. The vascular network is viewed as a key player in the progression of digestive lesions, which are characterised by infiltration of a range of immune cells. A better characterisation of endothelium/immune cell interactions in suitable preclinical models, as well as in humans, may help to identify some promising therapeutic targets for the prediction, prevention or treatment of digestive toxicity after radiotherapy.

Investigation of radiomics based intra-patient inter-tumor heterogeneity and the impact of tumor subsampling strategies.

While radiomics analysis has been applied for localized cancer disease, its application to the metastatic setting involves a non-exhaustive lesion subsampling strategy which may sidestep the intrapatient tumoral heterogeneity, hindering the reproducibility and the therapeutic response performance. Our aim was to evaluate if radiomics features can capture intertumoral intrapatient heterogeneity, and the impact of tumor subsampling on the computed heterogeneity. To this end, We delineated and extracted radiomics features of all visible tumors from single acquisition pre-treatment computed tomography of patients with metastatic lung cancer (cohort L) and confirmed our results on a larger cohort of patients with metastatic melanoma (cohort M). To quantify the captured heterogeneity, the absolute coefficient of variation (CV) of each radiomics index was calculated at the patient-level and a sensitivity analysis was performed using only a subset of all extracted features robust to the segmentation step. The extent of information loss by six commonly used tumor sampling strategies was then assessed. A total of 602 lesions were segmented from 43 patients (median age 57, 4.9% female). All robust radiomics indexes exhibited at least 20% of variation with significant heterogeneity both in heavily and oligo metastasized patients, and also at the organ level. None of the segmentation subsampling strategies were able to recover the true tumoral heterogeneity obtained by exhaustive tumor sampling. Image-based inter-tumor intra-patient heterogeneity can be successfully grasped by radiomics analyses. Failing to take into account this kind of heterogeneity will lead to inconsistent predictive algorithms. Guidelines to standardize the tumor sampling step and/or AI-driven tools to alleviate the segmentation effort are required.

[Immuno-radiotherapy: A review of the rationale, recent clinical developments and future prospects]. / Immuno-radiothérapie : une revue du rationnel, développements cliniques récents et perspectives futures.

Thanks to the success of checkpoint inhibitors, immunotherapy now plays a major role in the management of a large number of solid tumors, while the number of indications continues to grow and new combinations could, in the near future, further modify treatment standards. However, the response rates of immunotherapies as monotherapy are modest and their use is increasingly considered in combination with other cancer treatments (chemotherapy, surgery, radiotherapy or certain targeted therapies). Combinations with radiotherapy seem particularly attractive because there is a strong experimental rationale linking part of the efficacy of ionizing radiation to an induced stimulation of both of the innate and adaptive response. Many early phases and a number of large randomized combination trials have published efficacy and safety results, while important trials are still ongoing and will provide answers in the near future. This short review recalls the experimental biological rationale for immuno-radiotherapy and highlights some of the fundamental directions being explored, then presents the clinical efficacy and safety results available to date, those expected in the near future, and finally outlines the outlook in this rapidly evolving field.

Postgraduate oncology educational shifts during the COVID-19 pandemic: results of faculty and medical student surveys.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disrupted clinical practice, research and teaching. During peaks, virtual courses were implemented but these changes are poorly described, especially for oncology postgraduate students and faculty teachers. PATIENTS AND METHODS: We administered two surveys from June 2021 to October 2021 to students and faculty teachers (250 and 80 responses, respectively) who registered at Gustave Roussy School of Cancer Sciences (Université Paris-Saclay) during 3 consecutive university years (October 2018 to October 2021), where a major shift to e-learning was associated with COVID-19 pandemic. RESULTS: Most students were female (53%), attending physicians (50%), aged 30-39 years (54%) and 2020-2021 (66.4%) was the main year of training. Most faculty teachers were male (58%), aged 40-50 years (44%) and had participated in training for at least 3 years (83%). More than half of the students received 100% virtual training [55% versus 45% face-to-face/mixed teaching modalities; online (84%) versus remote teaching (16%)]. Only 34% of students declared >80% 'active listening' and only 16% of teachers considered e-learning to be more suitable (compared with face-to-face) for postgraduate education. Virtual teaching decreased student-teacher interactions as compared with mixed/face-to-face (lessons were sufficiently interactive for 54% students if virtual only teaching versus for 71% if other teaching modalities; P = 0.009). Teachers stated that virtual learning did not lead to any improvements in terms of attendance (68%), interaction (74%) and quality of teaching (68%). However, most faculty (76%) acknowledged that partial e-learning training should be maintained outside the pandemic, if it represents ≤50% of the whole teaching (teachers: 79% versus student: 66%; P = 0.04). CONCLUSIONS: COVID-19 accelerated the transition toward novel practices. Students and faculty teachers agreed on the need for future mixed (≤50% e-learning) teaching modalities. Adequate formation and the use of codified best newer virtual practices are required.

Tumour and normal tissue radiosensitivity.

The place of personalized treatments is highly increasing in medical and radiation oncology. During the last decades, a huge number of assays have been developed to predict responses of normal tissues and tumours. These tests have not yet been included into daily clinical practice but the recent developments of radiation oncology are paving the way of personalized strategies including the risk of tumour recurrence and normal tissue reactions. Concerning tumor radiosensitivity prediction, no test are currently used, even if the radiosensitivity index and the genome-based model for adjusting radiotherapy dose assays seem the most promising with level II of evidence. Commercial developments are under progress. Concerning normal tissue radiosensitivity prediction, single nucleotide polymorphims of prostate cancer patients and radiation-induced CD8 T-lymphocyte apoptosis breast and prostate assays are of level I of evidence. They can be proposed before the beginning of radiotherapy in order to propose personalized treatments according to both risks of tumour and normal tissue radiosensitivity. Commercial developments are also under way.

Specificities of clinical research in radiotherapy.

The aim of this review is to present the specificities of clinical research in radiation oncology. Objectives are similar to all research in oncology: to improve the efficacy and to decrease toxic effects. Phase III trials remain the main methodology to demonstrate an improvement in efficiency, but phase I-II and registers are also important tools to validate an improvement in the therapeutic index with new technologies. In this article we discuss the special features of end-points, selection of population, and design for radiation oncology clinical trials. Quality control of delivered treatments is an important component of these protocols. Financial issues are also discussed, in the particular context of France.

Increasing global accessibility to high-level treatments for cervical cancers.

Human papillomaviruses (HPV)-related gynecological cancers are a major health care issue, and a leading cause of cancer death in low- and middle-income countries (LMIC). In 2020, the World Health Organization launched a program aimed at cervical cancer elimination, by screening and vaccination strategies. Offering the best possible care to women diagnosed with invasive cancer is a complementary objective. Treatment of cervical cancer as per modern standards is complex and multimodal, mainly relying on surgery, external-beam radiotherapy (+/-chemotherapy) and brachytherapy. In parallel with the pivotal role of multidisciplinary discussion, international societies provide guidance to define the most effective and least toxic anti-cancer strategy, homogenize treatment protocols and provide benchmark quality indicators as a basis for accreditation processes. The challenge is to offer the appropriate diagnostic workup and treatment upfront and to avoid non- evidence-based treatment that consumes resources, impairs quality of life (QoL), and compromises oncological outcome. Various strategies may be applied for improving treatment quality: development of surgical mentorship, companion-training programs and international cooperation. The lack of radiotherapy/brachytherapy facilities is a major concern in LMIC. Reinforcing international support in terms of education, training, research and development and technical cooperation with national projects is required to increase access to minimum requirements but also introduce modern techniques, upgrade radiotherapy/brachytherapy services, and expand access to modern systemic treatments. In countries with robust economies, compliance to standards should also be increased. Integrative cancer care and multidisciplinary approaches are needed to tackle the dual challenge of increasing cure rates while minimizing QoL impairment. Appropriate dimensioning of the resources to avoid harmful treatment delays and access to expert referral centers is also a priority.

RadioTransNet: Preclinical research network coordinated at the SFRO and SFPM.

The RadioTransNet programme launched under the auspices of French societies for radiation oncology (SFRO) and medical physics (SFPM) was approved by the French national cancer institute (INCa) in December 2018 and is dedicated to proposing a relevant national and transversal structure for preclinical research including translational research in radiation oncology with well-defined priority areas of research. Its activities, coordinated by a scientific committee that includes radiation oncologists, medical physicists, academic biologists, are structured around several main areas, i.e.: target volume definition, interaction of radiation with normal tissues, combined treatments and modern dose calculation approaches. Four work packages have been created in these areas and are associated with other objectives pertaining to fundamental radiobiology, early implementation of new drugs in a preclinical setting, contribution of imaging in this task, research in medical physics including transversal components such as medical oncology, radiology, nuclear medicine and also cost/efficiency evaluation. All these tasks will be included in a national network that uses the complementary expertise provided by partners involved in the scheme. Calls for proposals will be selected by the scientific council to be submitted to INCa and the various academic associations to obtain funding for the human and technical resources required to conduct under optimal conditions projects in preclinical and translational research in radiation-oncology.

[Precision medicine and immuno-radiotherapy]. / Médecine de précision et immunoradiothérapie.

Numerous clinical studies aim to integrate immunotherapy in radiotherapy oncology, either for generating abscopal responses in metastatic patients in combination with radiotherapy, or in the treatment of a locally advanced tumor. The search for biomarkers of response to treatment is a major axis in the development of these therapeutic combinations, to allow the early identification of patients who will benefit from the treatment, in the context of an increasingly personalized approach. We review some of the strategies that can be applied for personalization to combined radiotherapy and immunotherapy treatments.

Clinical implementation of deep-learning based auto-contouring tools-Experience of three French radiotherapy centers.

Deep-learning (DL)-based auto-contouring solutions have recently been proposed as a convincing alternative to decrease workload of target volumes and organs-at-risk (OAR) delineation in radiotherapy planning and improve inter-observer consistency. However, there is minimal literature of clinical implementations of such algorithms in a clinical routine. In this paper we first present an update of the state-of-the-art of DL-based solutions. We then summarize recent recommendations proposed by the European society for radiotherapy and oncology (ESTRO) to be followed before any clinical implementation of artificial intelligence-based solutions in clinic. The last section describes the methodology carried out by three French radiation oncology departments to deploy CE-marked commercial solutions. Based on the information collected, a majority of OAR are retained by the centers among those proposed by the manufacturers, validating the usefulness of DL-based models to decrease clinicians' workload. Target volumes, with the exception of lymph node areas in breast, head and neck and pelvic regions, whole breast, breast wall, prostate and seminal vesicles, are not available in the three commercial solutions at this time. No implemented workflows are currently available to continuously improve the models, but these can be adapted/retrained in some solutions during the commissioning phase to best fit local practices. In reported experiences, automatic workflows were implemented to limit human interactions and make the workflow more fluid. Recommendations published by the ESTRO group will be of importance for guiding physicists in the clinical implementation of patient specific and regular quality assurances.

[Artificial intelligence, radiomics and pathomics to predict response and survival of patients treated with radiations]. / Intelligence artificielle en radiothérapie : radiomique, pathomique, et prédiction de la survie et de la réponse aux traitements.

Artificial intelligence approaches in medicine are more and more used and are extremely promising due to the growing number of data produced and the variety of data they allow to exploit. Thus, the computational analysis of medical images in particular, radiological (radiomics), or anatomopathological (pathomics), has shown many very interesting results for the prediction of the prognosis and the response of cancer patients. Radiotherapy is a discipline that particularly benefits from these new approaches based on computer science and imaging. This review will present the main principles of an artificial intelligence approach and in particular machine learning, the principles of a radiomic and pathomic approach and the potential of their use for the prediction of the prognosis of patients treated with radiotherapy.

[Application of a new methodology of a priori risk analysis in a radiotherapy department]. / Application d'une nouvelle méthodologie d'analyse de risques a priori dans un service de radiothérapie.

Since 2017, IRSN has been developing a new proactive risk analysis method. The Work Complexity Sharing and Exploration Spaces (EPECT in French) were tested for the first time in 2020 in the radiotherapy department of the Gustave Roussy Institute. The EPECT method makes it possible to anchor the analysis of risks incurred by patients in daily work situations and to involve the top management. The time required to involve the teams is comparable to or even less than that required for a conventional risk analysis. The cost/benefit ratio of the method seems to be advantageous because it provides access to numerous information on daily activities, which makes it possible to improve the safety of patient care in radiotherapy. The information gathered allows relevant actions to be envisaged at both the technical and organizational levels, and to be linked to departmental projects.

A wide-ranging Pseudomonas aeruginosa PeptideAtlas build: A useful proteomic resource for a versatile pathogen.

Pseudomonas aeruginosa is an important opportunistic human pathogen with high prevalence in nosocomial infections. This microorganism is a good model for understanding biological processes such as the quorum-sensing response, the metabolic integration of virulence, the mechanisms of global regulation of bacterial physiology, and the evolution of antibiotic resistance. Till now, P. aeruginosa proteomic data, although available in several on-line repositories, were dispersed and difficult to access. In the present work, proteomes of the PAO1 strain grown under different conditions and from diverse cellular compartments have been joined to build the Pseudomonas PeptideAtlas. This resource is a comprehensive mass spectrometry-derived peptide and inferred protein database with 71.3% coverage of the total predicted proteome of P. aeruginosa PAO1, the highest coverage among bacterial PeptideAtlas datasets. The proteins included cover 89% of metabolic proteins, 72% of proteins involved in genetic information processing, 83% of proteins responsible for environmental information processing, more than 88% of the ones related to quorum sensing and biofilm formation, and 89% of proteins responsible for antimicrobial resistance. It exemplifies a necessary tool for targeted proteomics studies, system-wide observations, and cross-species observational studies. The manuscript describes the building of the PeptideAtlas and the contribution of the different proteomic data used. SIGNIFICANCE: Pseudomonas aeruginosa is among the most versatile human bacterial pathogens. Studies of its proteome are very important as they can reveal virulence factors and mechanisms of antibiotic resistance. The construction of a proteomic resource such as the PeptideAtlas enables targeted proteomics studies, system-wide observations, and cross-species observational studies.

[Low-dose irradiation of non-malignant diseases: Did we throw the baby out with the bathwater?] / Irradiation à faible dose des affections non cancéreuses : avons-nous jeté le bébé avec l'eau du bain ?

The irradiation of non-malignant diseases, essentially for anti-inflammatory purpose, have been largely proposed and performed worldwide until the 1970-80s. At that time, the better assessment of the radio-induced malignancies, essentially in children and young patients, as well as the efficacy of the new anti-inflammatory drugs (steroids and non-steroids), led to the almost disappearance of those techniques, at least in France. In contrast, our German colleagues are still going on treating about 50,000 patients per year for non-malignant (more or less severe) diseases. After a short historical overview, the present article suggests that we were possibly going too far in the rejection of those low-dose irradiations for benign lesions. The recent emergence of new preclinical data, the better understanding of the risk of radio-induced secondary tumours (almost nil in the elderly), and the severity of some situations, such as the cytokine storm of the COVID-19, should probably lead us to reconsider those low - and sometimes very low (less than 1Gy) - irradiations for well-selected indications in the elderly.

[Retrospective study on the intensification of hypofractionated radiotherapy: The organizational change]. / Étude rétrospective sur l'intensification des pratiques de radiothérapie hypofractionnée : le virage organisationnel.

PURPOSE: External radiotherapy process is a chain of steps in which each of them is carried out only if the previous one has been completed. The development of hypofractionation practices in recent years tends to increase the workload of the stages of preparation for irradiation and to decrease the number of fractions per patient. The purpose of this retrospective study is to analyze the evolution of these practices in a single centre and to assess the organizational issues involved. MATERIAL AND METHODS: All radiation therapy records management data were extracted from the Radiation Therapy Information System. Radiotherapy sessions were identified by patient and by ICD (International Classification of Diseases) code. The filling rate of the treatment equipment was calculated using actual data from the radiotherapy department. RESULTS: From 2015 to 2019, there was an increase in the number of scans (+16%), the number of patients treated (+11.6%) and the volume of hours available for treatment (+12%). Also, there was a decrease in the total number of fractions (-5%), in the average number of fractions performed per treatment sequence (-19%), in the occupancy rate of the machines (-7%) and in the average number of fractions performed per patient treated for malignant tumours of the bronchi and lung (-38%), digestive organs (-37%), secondary (-19%) breast (-15%) and prostate (-15%). The number of fractions administered per treatment sequence between 2015 and 2019 decreased significantly for patients in age groups [20-69] (P<0.001) and [>70] (P<0.001). CONCLUSION: A paradox appears between the increase in the total number of patients treated and the decrease in the loading rate of linacs. This shift of workload has an impact on the quality and safety of care and on the organizational and investment strategies. It also has an economic impact where the model of reimbursement is based on per fraction pricing. A reorganization of radiotherapy services is inevitable.

[Treatment of primary disease for synchronous metastatic prostate cancer]. / Irradiation de la maladie primitive des cancers de la prostate avec métastases synchrones.

The management of early metastatic prostate cancer is based on systemic treatment by androgen deprivation therapy with or without chemotherapy or next-generation anti-androgen therapies. Local treatment of the prostate was initially used only to alleviate local symptoms. However, local radiotherapy of the prostate has been the subject of retrospective and prospective studies in patients with better prognostic factors, particularly in oligometastatic status. The results of these studies support that prostate radiotherapy can prolong the survival of patients with a low metastatic burden. This article states the biological bases, the main published and future published studies aimed to embed this strategy to optimize therapeutic management.