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Background High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor., Highlights • This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer. • Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype. • Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.

International audience

BackgroundTriple negative breast cancer (TNBC) accounts for 10-20% of breast cancers but has no specific therapy. While TNBC may be more sensitive to chemotherapy than other types of breast cancer, it has a poor prognosis. Most TNBC relapses occur during the five years following treatment, however predictive biomarkers of metastatic relapse are still lacking. High tumour-infiltrating lymphocytes (TILs) levels before and after neo-adjuvant chemotherapy (NAC) are associated with lower relapse risk and longer survival but TILs assessment is highly error-prone and still not introduced into the clinic. Therefore, having reliable biomarker of relapse, but easier to assess, remains essential for TNBC management. Searching for such biomarkers among serum/plasma proteins, circulating tumoral DNA (ctDNA) and blood cells appear relevant.MethodsThis single-centre and prospective study aims to discover predictive biomarkers of TNBC relapse and particularly focuses on plasma proteins. Blood samples will be taken at diagnosis, on the day of first-line or post-NAC surgery, on the day of radiotherapy start, then 6 months and one year after radiotherapy. A blood sample will be taken at the time of metastatic relapse diagnosis. Blood samples will be used for circulating protein quantification, blood cell counts and circulating tumour DNA quantification. A tumour RNA signature, based on the analysis of the RNA expression of 6 genes, will also be tested from the initial biopsy taken routinely. In NAC patients, TILs quantity will be assessed on TNBC pre-treatment biopsy and surgical specimen.Ethics and DisseminationINSTIGO belongs to category 2 interventional research on humans. This study has been approved by the SUD-EST IV ethics committee and is conducted in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study findings will be published in peer-reviewed medical journals.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04438681.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.

Triple-negative breast cancers (TNBC), representing 10% to 20% of breast cancer diagnoses, are characterized by the lack of estrogen, progesterone, and human epidermal growth factor 2 receptor expression. Due to the absence of specific targeted therapy, chemotherapy remains their standard treatment. Despite a good initial response, nearly half of patients do not obtain a complete pathological response and develop drug resistance followed by rapid tumor relapse, often within 3 years. Multiple studies have sought to identify effective therapeutic strategies over the past few years, but none have been shown to be effective for all these patients. It turns out that TNBC itself is a particularly heterogeneous subgroup. Stratifying TNBC patients is therefore an essential step in improving the care pathway. Biomarkers prediction of metastatic recurrence is therefore crucial. Thus, the general objective of this thesis is to characterize the gene expression profile of metastatic TNBC, in order to understand the involved mechanisms and to create tools to identify them. 26 TNBC samples were selected at the Jean Perrin Center for their completed clinical follow-up over 5 years. Their gene expression profile was analyzed by RNA-Seq. Among the 1309 genes differentially expressed between tumors that progressed to metastasize and those that responded to chemotherapy, the role of SHISA3 was studied in vitro and in vivo. Our results define SHISA3 as a tumor suppressor gene, a candidate to serve as a therapeutic target. By combining JPC data with 39 additional expression profiles from the TCGA dataset, we have developed a molecular prognostic signature, predictive of metastatic risk with high clinical value. This signature allows the classification of TNBC patients into low- and high-risk groups of metastatic relapse. Overall, our work paves the way for the development of personalized treatments for TNBC in order to improve patient care., Les cancers du sein triple négatifs (CSTN) représentent 10 à 20% des diagnostics de cancer du sein. Ils sont caractérisés par l'absence d'expression des récepteurs aux œstrogènes, à la progestérone et au facteur de croissance épidermique humain 2. Compte tenu de l'absence de thérapie ciblée spécifique, la chimiothérapie reste leur seul traitement. Malgré une bonne réponse initiale, près de la moitié des patientes n'obtiennent pas de réponse pathologique complète et développent une chimiorésistance puis une rechute tumorale rapide, souvent dans les 3 ans. De multiples études ont cherché à identifier des stratégies thérapeutiques efficaces au cours des dernières années, mais aucune ne s'est avérée efficace sur l'ensemble de ces patientes. Il s'avère en effet que le CSTN est lui-même un sous-groupe particulièrement hétérogène. La stratification des patientes CSTNs est donc une étape essentielle pour améliorer le parcours de soins. Des biomarqueurs prédictifs de la récidive métastatique sont donc cruciaux. Ainsi, l'objectif général de cette thèse était de caractériser l'expression génique des carcinomes mammaires triple négatifs capables de métastaser, afin de contribuer à comprendre les mécanismes mis en jeu et créer des outils pour les identifier. 26 échantillons de CSTN ont été sélectionnés au Centre Jean Perrin pour la complétude de leur suivi clinique sur 5 ans. Leur profil d'expression génique a été analysé par RNA-Seq. Parmi les 1309 gènes différentiellement exprimés entre les tumeurs qui ont évolué en métastases et celles qui ont répondu à la chimiothérapie, le rôle de SHISA3 a été étudié in vitro et in vivo. Nos résultats font de lui un gène suppresseur de tumeur, candidat pour servir de cible thérapeutique. En combinant ces données à 39 profils d'expression supplémentaires issus du programme TCGA, nous avons développé une signature moléculaire pronostique, prédictive du risque métastatique avec une valeur clinique, qui permet de classer les patientes atteintes de CSTN en faible et haut risque de rechute métastatique. Dans son ensemble, notre travail ouvre la voie au développement de traitements personnalisés du CSTN afin d'améliorer la prise en charge des patientes.

International audience; Background and purpose: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients.Materials and methods: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150–200 mg/m2 on days 1–5 every 28 days).Results: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (−54%) was observed in peripheral blood mononuclear cells.Conclusion:This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Cancer drug resistance is a complex biological process representing a major challenge in Oncology for the optimization of cancer treatments. It is the main cause of treatment failure and is frequently associated with a significant risk of tumor relapse or recurrence. In this context, the "Résistance" group, part of the IMoST team (UMR INSERM / UCA 1240) has focused its research works on the study of cancer resistance through the development of in vitro preclinical tools. For this, this group uses Triple Negative Breast Cancer (CSTN) as study model, a breast cancer subtype particularly aggressive and often prone to the development of resistant profiles. One of the main mechanisms involved in cancer resistance is the basal or induced overexpression of transmembrane proteins called MultiDrug Resistance (MDR). These ubiquitous members of the ABC transporters superfamily are involved in the cellular cross-resistance to many cancer treatments, in particular by extracellular efflux of a large panel of xenobiotics. In this context, the “Résistance” group is developing LightSpot® fluorescent probes to detect and quantify the presence of MDR proteins. The first part of this works allowed to validate the use of this type of probes for the detection of cancer resistance established by the Permeability-glycoprotein (P-gp), a major MDR protein. In particular, the LightSpot®-FL-1 probe enables the sensitive and complete detection and quantification of P-gp, on fresh or fixed 2D and 3D cell models. On the other hand, the "Resistance" group is developing models of spheroids, faithfully mimicking the resistance of avascular tumor micro-regions. These 3D cell culture models have a great potential for high-throughput drug screening. Thus, the second part of this works allowed the development of an innovative concept for the preservation of CSTN MDA-MB-231 spheroids, as an alternative to conventional cryopreservation techniques. This concept involves maintaining spheroids for up to 7 days in OptiPASS® medium, in anoxia and at 4 °C. The results have demonstrated that these storage conditions preserved the integrity of various parameters of the spheroids, in particular their growth, their viability and their response to various anticancer drugs. This protocol for the preservation of spheroids will in particular allow to optimize their use, transport, and integration into large drug screening platforms. All of this doctoral research work focused on the development (1) of fluorescent tracers for the detection of MDR proteins and (2) of a spheroid storage protocol, are enhanced by a direct industrial transfer, within the BIORCELL3D consortium. The latter created by the strong public / private collaboration between the "Resistance" group and the BIOPASS and BIOMARQUEURS companies has enabled the development of an important value chain., La résistance des cellules tumorales aux traitements est un processus biologique complexe représentant un défi majeur en Oncologie pour l’optimisation des traitements du cancer. Elle constitue la principale cause d’échec thérapeutique et est souvent associée à un risque important de rechute ou de récidives tumorales. Dans ce contexte, le groupe « Résistance » faisant partie de l’équipe IMoST (UMR INSERM/UCA 1240) a focalisé ses axes de recherche sur l’étude de la résistance tumorale par le développement d’outils précliniques in vitro. Pour ce faire, il utilise le modèle d’étude du Cancer du Sein Triple Négatif (CSTN), un sous-type de cancer du sein particulièrement agressif et souvent sujet au développement de profils résistants. L’un des principaux mécanismes impliqués dans la résistance tumorale est la surexpression basale ou induite de protéines transmembranaires appelées « MultiDrug Resistance » (MDR). Ces membres extrêmement ubiquitaires de la superfamille des transporteurs ABC sont impliqués dans la résistance croisée des cellules aux traitements anticancéreux, notamment par efflux extracellulaire d’un large panel de xénobiotiques. Dans ce cadre, le groupe « Résistance » développe des traceurs fluorescents LightSpot® permettant de détecter et quantifier la présence de protéines MDR. La première partie de ces travaux de thèse ont permis de valider l’utilisation de ce type de traceurs pour la détection de la résistance tumorale instaurée par la Permeability-glycoprotein (P-gp), une protéine MDR majeure. Notamment, le traceur LightSpot®-FL-1 permet de détecter et quantifier de manière sensible et complète la P-gp, sur des modèles cellulaires 2D et 3D, à l’état frais ou fixé. D’autre part le groupe « Résistance » développe des modèles de sphéroïdes, mimant fidèlement la résistance de microrégions tumorales avasculaires. Ces modèles de cultures cellulaires 3D présentent un fort potentiel pour le screening de médicaments à grande échelle. La seconde partie de ces travaux de thèse a permis de développer un concept innovant de préservation de sphéroïdes de CSTN MDA-MB-231, comme alternatif aux techniques conventionnelles de cryopréservation. Ce concept implique de maintenir les sphéroïdes jusqu’à 7 jours dans le milieu OptiPASS®, en anoxie et à 4°C. Les résultats obtenus ont démontré que ces conditions de conservations maintiennent intègres différents paramètres des sphéroïdes, notamment leur croissance, leur viabilité et leur réponse vis-à-vis de différents traitements anticancéreux. Ce protocole de préservation de sphéroïdes pourra notamment permettre d’optimiser leur utilisation, leur transport et leur intégration dans des grandes plateformes de screening médicamenteux. L’ensemble de ces travaux de recherche doctorale focalisés sur le développement (1) de traceurs fluorescents de détection des protéines MDR et (2) d’un protocole de conservation de sphéroïdes, sont valorisés par un transfert industriel direct, au sein du consortium BIORCELL3D. Ce dernier créé par la forte collaboration public/privé entre le groupe de « Résistance » et les sociétés BIOPASS et BIOMARQUEURS a permis l’élaboration d’une importante chaine de valorisation.

International audience; Background: Stereotactic radiotherapy (SRT) should be applied with a biologically effective dose with an α/β of 12 (BED12) ≥ 40 Gy to reach a 1-year local control (LC) ≥ 70%. The aims of this retrospective study were to report a series of 81 unresected large brain metastases treated with Linac-based multifraction SRT according to the ICRU 91 and to identify predictive factors associated with LC.Methods: Included in this study were the first 81 brain metastases (BM) consecutively treated with Linac-based volumetric modulated arc therapy (VMAT) multifraction SRT from 2017 to 2019. The prescribed dose was 33 Gy for the GTV and 23.1 Gy (70% isodose line) for the PTV in 3 fractions (3f). Mean BM largest diameter and GTV were 25.1 mm and 7.2 cc respectively. Mean follow-up was 10.2 months.Results: LC was 79.7% and 69.7% at 1 and 2 years respectively. Significant predictive factors of LC were GTV D98% (HR = 0.84, CI 95% = 0.75-0.95, p = 0.004) and adenocarcinoma as the histological type (HR = 0.29, CI 95% = 0.09-0.96, p = 0.042) in univariate and multivariate analysis. A threshold of 29 Gy for GTV D98% was significantly correlated to LC (1-year LC = 91.9% for GTV D98% ≥ 29 Gy vs 69.6% for GTV D98% < 29 Gy (p = 0.030)), corresponding to a BED12 = 52.4 Gy. No tumor progression was observed for a BED12 ≥ 53.4 Gy, corresponding to a GTV D98% ≥ 20 Gy /1f and GTV D98% ≥ 29.4 Gy 3f. Median OS was 15 months. Symptomatic radionecrosis occurred in 4.9% of cases.Conclusion: The GTV D98% is a strong reproducible significant predictive factor of LC for brain SRT. Dose prescription should lead to a GTV BED12 98% ≥ 52.4-53.4 Gy to significantly improve LC, corresponding to respectively a GTV D98% ≥ 19.7-20 Gy/1f and 29-29.4 Gy/3f.

In Europe, inappropriate reimbursement and funding rules and regulations act as disincentives to best breast cancer care or, at worst, hinder best care. This problem was the focus of the 12th European Breast Cancer Conference (EBCC) manifesto, discussed during the virtual conference. As patient involvement is indispensable in driving changes to clinical practice, Europa Donna the European patient advocacy group was closely involved in the 12th manifesto. Reimbursement policies have rarely evolved with advances in breast cancer care such as outpatient (ambulatory) care rather than inpatient admission, use of oral or subcutaneous anti-cancer drugs rather than day-hospital intravenous administration, oncoplastic surgery techniques to minimize mastectomy rates, breast reconstructive surgery, risk-reducing surgery for BRCA mutation carriers, or use of hypo-fractionated breast radiation therapy. Although each European country, region and centre will have to understand how their reimbursement policies may hinder best care and find their own solutions, the problems are similar throughout Europe and some solutions can be broadly applied. This manifesto is not calling for more funding or demanding changes that will result in more expensive care. Reimbursement, if better aligned with guidelines and optimal clinical practice, will deliver more cost-effective healthcare. This will release resources, support more equitable use of finite funding and resources, so allowing more European breast cancer patients to benefit from evidence-based treatment recommended by national and international guidelines., Highlights • Reimbursement rules for breast cancer care are not in line with evidence-based medicine and clinical practice guidelines. • Reimbursement rules hamper access to best practice treatments such as:outpatient (ambulatory) care rather than inpatient or day-hospital admission,oncoplastic breast surgery to limit need for mastectomy risk-reducing surgery for BRCA mutation carriers,or moderately hypofractionated post-operative radiation therapy. • Reimbursements aligned with optimal clinical practice guidelines can drive more cost-effective care. • This will lead to more equitable use of finite healthcare resources and improve cancer outcomes for more European patients. • Direct involvement of patients through education will allow them to understand and demand optimal guideline-driven care. • Patient understanding, support and engagement is vital to improve reimbursement rules and optimise care.

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices. ispartof: EUROPEAN JOURNAL OF CANCER vol:146 pages:30-47 ispartof: location:England status: published

International audience; Purpose: To evaluate the relevance of CEST frequency selectivity in simultaneous in vivo imaging of both of chondrosarcoma’s phenotypic features, that are, its high proteoglycan concentration and its hypoxic core.Methods: Swarm rat chondrosarcomas were implanted subcutaneously in NMRI nude mice. When tumors were measurable (12‐16 days postoperative), mice were submitted to GAG, guanidyl, and APT CEST imaging. Proteoglycans and hypoxia were assessed in parallel by nuclear imaging exploiting 99mTc‐NTP 15‐5 and 18F‐FMISO, respectively. Data were completed by ex vivo analysis of proteoglycans (histology and biochemical assay) and hypoxia (immunofluorescence).Results: Quantitative analysis of GAG CEST evidenced a significantly higher signal for tumor tissues than for muscles. These results were in agreement with nuclear imaging and ex vivo data. For imaging tumoral pH in vivo, the CEST ratio of APT/guanidyl was studied. This highlighted an important heterogeneity inside the tumor. The hypoxic status was confirmed by 18F‐FMISO PET imaging and ex vivo immunofluorescence.Conclusion: CEST MRI simultaneously imaged both chondrosarcoma properties during a single experimental run and without the injection of any contrast agent. Both MR and nuclear imaging as well as ex vivo data were in agreement and showed that this chondrosarcoma animal model was rich in proteoglycans. However, even if tumors were lightly hypoxic at the stage studied, acidic areas were highlighted and mapped inside the tumor.

International audience; Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers

International audience; Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

Rheumatoid arthritis (RA) is associated with a decrease in lean mass and stability or even an increase in fat and ectopic adipose tissue. A few data are available on body composition changes under treatment, and data are still controversial. Body composition was assessed before initiation of biologic disease-modifying antirheumatic drug (bDMARD) and after 6 and 12 months of stable treatment. Eighty-three RA patients were included (75% of women, mean age 58.5 &plusmn, 10.8 years) of whom 47 patients treated with TNF inhibitor (TNFi), 18 with non-TNF-targeted biologic (Non-TNFi), and 18 with conventional DMARD (cDMARD) alone. In the TNFi group, total lean mass, fat-free mass index, and skeletal muscle mass index significantly increased at 1 year. An increase in subcutaneous adipose tissue (SAT) without change for the visceral or body fat composition was associated. These changes were associated with an improvement in strength and walking test. In non-TNFi or cDMARD groups, no significant changes for body composition or muscle function were observed at 1 year. However, no significant differences for treatment x time interaction were noted between group treatments. In active RA patients starting first bDMARD, treatment with TNFi over 1 year was associated with favorable changes of the body composition and muscle function.

International audience; Pathogenic variants (PVs) in BRCA genes have been mainly associated with an increasing risk of triple negative breast cancer (TNBC). The contribution of PVs in non-BRCA genes to TNBC seems likely since the processing of homologous recombination repair of double-strand DNA breaks involves several genes. Here, we investigate the susceptibility of genetic variation of the BRCA and non-BRCA genes in 30 early-onset Moroccan women with TNBC. Methods: Targeted capture-based next generation sequencing (NGS) method was performed with a multigene panel testing (MGPT) for variant screening. Panel sequencing was performed with genes involved in hereditary predisposition to cancer and candidate genes whose involvement remains unclear using Illumina MiSeq platform. Interpretation was conducted by following the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria. Results: PVs were identified in 20% (6/30) of patients with TNBC. Of these, 16.7% (5/30) carried a BRCA PV [10% (3/30) in BRCA1, 6.7% (2/30) in BRCA2] and 6.6% (2/30) carried a non-BRCA PV. The identified PVs in BRCA genes (BRCA1 c.798_799delTT, BRCA1 c.3279delC, BRCA2 c.1310_1313del, and BRCA2 c.1658T>G) have been reported before and were classified as pathogenic. The identified founder PVs BRCA1 c.798_799del and BRCA2 c.1310_1313delAAGA represented 10% (3/30). Our MGPT allowed identification of several sequence variations in most investigated genes, among which we found novel truncating variations in PALB2 and BARD1 genes. The PALB2 c.3290dup and BARD1 c.1333G>T variants are classified as pathogenic. We also identified 42 variants of unknown/uncertain significance (VUS) in 70% (21/30) of patients with TNBC, including 50% (21/42) missense variants. The highest VUS rate was observed in ATM (13%, 4/30). Additionally, 35.7% (15/42) variants initially well-known as benign, likely benign or conflicting interpretations of pathogenicity have been reclassified as VUS according to ACMG-AMP. Conclusions: PALB2 and BARD1 along with BRCA genetic screening could be helpful for a larger proportion of early-onset TNBC in Morocco.

International audience

International audience; Plasticizers added to polyvinylchloride (PVC) used in medical devices can be released into patients’ biological fluids. Di-(2-ethylhexyl)phthalate (DEHP), a well-known reprotoxic and endocrine disruptor, must be replaced by alternative compounds. Di-(2-ethylhexyl) terephthalate (DEHT) is an interesting candidate due to its lower migration from PVC and its lack of reprotoxicity. However, there is still a lack of data to support the safety of its human metabolites with regard to their hormonal properties in the thyroid system. The effects of DEHT metabolites on thyroid/hormone receptors (TRs) were compared in vitro and in silico to those of DEHP. The oxidized metabolites of DEHT had no effect on T3 receptors whereas 5-hydroxy-mono-(ethylhexyl)phthalate (5-OH-MEHP) appeared to be primarily an agonist for TRs above 0.2 µg/mL with a synergistic effect on T3. Monoesters (MEHP and mono-(2-ethylhexyl)terephthalate, MEHT) were also active on T3 receptors. In vitro, MEHP was a partial agonist between 10 and 20 µg/mL. MEHT was an antagonist at non-cytotoxic concentrations (2–5 µg/mL) in a concentration-dependent manner. The results obtained with docking were consistent with those of the T-screen and provide additional information on the preferential affinity of monoesters and 5-OH-MEHP for TRs. This study highlights a lack of interactions between oxidized metabolites and TRs, confirming the interest of DEHT.

Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.

International audience

International audience

Annexine A1 (ANXA1) belongs to the annexin superfamily, which includes proteins capable of binding membrane phospholipids in a calcium dependent manner. This is a multifunctional protein initially described for its anti-inflammatory properties. ANXA1 can be nuclear, cytosolic, membrane and it can also be secreted and cleaved in surrounding environment. It presents a real interest in oncology due to its deregulation in many cancers. Depending on cancer types, ANXA1 is up- or down-regulated compared to normal tissues. It is overexpressed in triple negative breast cancer relative to other subtypes of breast tumors and in melanoma compared to melanocytes. In both pathologies, ANXA1 is associated with proliferation, migration and invasion processes, but the exact mechanism of its roles in tumors still unknown, especially those mediated by extracellular fraction. Studies carried out with Anxa1 null mice have shown the ANXA1 from stromal cells implication in tumor development and progression.The first objective of this work was to test the opportunity to block extracellular ANXA1 with a monoclonal patented antibody, VJ4B6, to decrease migration (in vitro) and dissemination (in vivo). Our results showed that VJ4B6 was unable to limit cellular migration of triple negative breast cancer (MDA-MB-231-luc) and melanoma (SK-MEL-28 and A375-MA2) cell lines presenting extracellular ANXA1. This antibody was also unable to decrease tumor development and dissemination of B16Bl6 melanoma in vivo. The second objective was to study the role of ANXA1 from tumoral and stromal cells in melanoma development and dissemination. Our results highlighted involvement of tumoral ANXA1 in proliferation of A375-MA2 and SK-MEL-28 melanoma cells in vitro. The use of Anxa1 null mice allowed to reveal that stromal ANXA1 promotes tumor development and metastases formation of murine B16Bl6 cells in vivo. Interestingly, studies of tumors showed that stromal ANXA1 absence limits both proliferation of tumor cells and angiogenesis. This could explain the decreased progression of tumors in Anxa1 null mice. Furthermore, tumors developed in these mice presented overexpression of lymphocyte markers (CD3, CD4, FoxP3, CD8a, NKp46) compared to those developed in wild-type mice. This lymphocyte influx concerned both pro- and anti-tumoral lymphocytes. Our hypothesis is that lymphocyte influx is a result of increased tumor vessels permeability in tumors from Anxa1 null mice.; L’annexine A1 (ANXA1) appartient à la vaste superfamille des annexines qui englobe des protéines capables de se lier aux phospholipides membranaires de façon calcium dépendante. C’est une protéine multifonctionnelle initialement décrite pour ses propriétés anti-inflammatoires. Elle est présente dans le noyau, le cytosol et les membranes cellulaires et peut également être sécrétée et clivée dans le milieu environnant. L’ANXA1 présente un important intérêt en oncologie du fait de sa dérégulation dans de nombreux cancers. En fonction des types de cancers, l’ANXA1 est surexprimée ou sous-exprimée par rapport au tissu sain. Elle est surexprimée dans le cancer du sein triple négatif par rapport aux autres sous-types de tumeurs mammaires et dans les mélanomes par rapport aux mélanocytes. Dans ces deux pathologies, bien que l’ANXA1 soit associée aux processus de prolifération, migration et invasion, les mécanismes précis de son rôle au sein d’une tumeur restent mal connus, notamment ceux impliquant la fraction extracellulaire. Les études menées sur des souris n’exprimant pas l’Anxa1 ont également montré que l’ANXA1 stromale est impliquée dans le développement et la progression tumorale.Le premier objectif a donc été de tester la possibilité de bloquer la protéine extracellulaire via un anticorps monoclonal breveté, le VJ4B6, pour diminuer la migration (in vitro) et la dissémination (in vivo). Nos données montrent que le VJ4B6 ne permet pas de limiter la migration cellulaire des lignées de cancer du sein triple négatif (MDA-MB-231-luc) et de mélanome (SK-MEL-28 et A375-MA2) présentant de l’ANXA1 extracellulaire. Cet anticorps ne permet pas non plus de limiter le développement et la dissémination tumorale du mélanome B16Bl6 in vivo. Le second objectif a été d’étudier le rôle de l’ANXA1 tumorale et stromale dans le développement et la dissémination du mélanome. Nos résultats ont montré que l’ANXA1 tumorale est impliquée dans la prolifération des cellules A375-MA2 et SK-MEL-28 in vitro. L’utilisation de souris invalidées pour l’Anxa1 a également permis de mettre en évidence que l’ANXA1 stromale favorise le développement tumoral et la formation de métastases des cellules murines B16Bl6 in vivo. De façon intéressante, les études réalisées sur les tumeurs ont montré que l’absence d’ANXA1 stromale limite la prolifération des cellules tumorales ainsi que l’angiogenèse. Ceci peut donc expliquer la progression limitée des tumeurs chez les souris invalidées. De plus, les tumeurs développées chez ces dernières présentent une surexpression des marqueurs lymphocytaires (CD3, CD4, FoxP3, CD8a, NKp46) par rapport à celles développées chez les souris sauvages. Cet afflux lymphocytaire concerne à la fois les lymphocytes pro- et anti-tumoraux. Nous avons donc émis l’hypothèse que ce dernier soit une conséquence d’une perméabilité accrue des vaisseaux tumoraux au niveau des tumeurs des souris invalidées pour l’Anxa1.

Nowadays, epigenetic mechanisms have been clearly identified as being involved in breastcarcinogenesis. Advances in research in the field have highlighted the possible use of proteins regulatingepigenetic mechanisms as a therapeutic target in the fight against breast cancer. The variation in thebalance of these epigenetic proteins is a significant factor in the initiation and progression of breastcancer. The histone acetyl-transferase TIP60 and the histone deacetylase SIRT1 are epigeneticantagonist proteins which equilibrium is greatly impacted in breast cancer. Understanding themechanisms leading to this imbalance in carcinogenesis, the role of the histone acetyl transferase TIP60in breast cancer has been investigated in this thesis. To determine the role of TIP60 in breast cancer, theeffects of TIP60 inhibition in breast cancer in vivo and in vitro were investigated. Indeed, this inhibitionof TIP60 induced by two specific inhibitors of TIP60 (TH1834 and NU9056), demonstrated the impactsof these inhibitors on the acetylation of TIP60 targets such as the H3K4ac mark involved in genetranscription, but also in the expression of specific hormone receptors such as AR and NR3C2 in vitro.In addition, this inhibition leads to a decrease in breast tumor growth in vivo. In parallel, the role ofTIP60 in chromatin integrity and plasticity in breast cancer has also been investigated. For this, we havefollowed the variation of the actors in the complex that constitutes TIP60/P400/H4K12ac in theprogression of breast cancer ex vivo and in vitro. This revealed that there is the installation of aTIP60/P400/H4K12ac constituent skeleton to maintain the integrity and plasticity of the chromatin,following the loss of its principal skeleton SUV39H1/H3K9me3/HP1. Indeed, our work has highlightedthe fundamental role of TIP60 in breast cancer, but also its possible use as a therapeutic target in thefight against breast cancer.; De nos jours, les mécanismes épigénétiques ont clairement été identifiés comme étant impliqués dans la carcinogenèse du sein. L’avancée des recherches dans le domaine a mis en lumière une possible utilisation des protéines régulant les mécanismes épigénétiques comme cible thérapeutique dans la lutte contre le cancer du sein. La variation de l’équilibre de ces protéines épigénétiques est un facteur marquant dans l’initiation et la progression tumorale du cancer du sein. L’histone acétyl-transféraseTIP60 et histone déacétylase SIRT1 sont des protéines épigénétiques antagonistes qui voient leurs équilibres grandement impacté dans le cancer du sein, la compréhension des mécanismes aboutissant à ce déséquilibre permettra de mieux comprendre la carcinogenèse du sein. C’est dans cette optique qu’on s’est intéressé au rôle de l’histone acétyl-transférase TIP60 dans le cancer du sein. Pour déterminer le rôle de TIP60 dans le cancer du sein, on a suivi l’effet de l’inhibition de l’activité de TIP60 dans le cancer du sein in vivo et in vitro. En effet, cette inhibition de TIP60 induite par les deux inhibiteurs spécifiques de TIP60 (TH1834 et NU9056), nous a permis de voir que l’utilisation de ces inhibiteurs impactait l’acétylation des cibles de TIP60 telles que la marque H3K4ac impliquée dans la transcription des gènes, mais aussi dans l’expression de certains récepteurs hormonaux tels que AR et NR3C2 in vitro. De plus, cette inhibition entraîne une diminution de la croissance tumorale du sein in vivo. En parallèle, on s’est intéressés aussi au rôle de TIP60 dans l’intégrité et la plasticité chromatinienne dans le cancer sein. Pour cela, nous avons suivi la variation des acteurs du complexe que constitueTIP60/P400/H4K12ac dans la progression du cancer du sein ex vivo et in vitro. Cela nous a permis devoir qu’il y a l’installation d’un squelette constitue de TIP60/P400/H4K12ac pour maintenir l’intégrité et la plasticité de la chromatine suite à la perte de son squelette principale SUV39H1/H3K9me3/HP1.En effet, nos travaux ont mis en évidence le rôle fondamental de TIP60 dans le cancer du sein, mais aussi sa possible utilisation comme cible thérapeutique dans la lutte contre le cancer du sein.

Background Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype. Case presentation An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l). Conclusions ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative “overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.

RET (rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but RET aberrations are involved in many pathologies. While RET loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, RET gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. RET-altered (RET+) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti-RET activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective RET inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of RET and its role in different kinds of tumors, clinical features of RET+ tumors, clinically actionable genetic RET alterations and their diagnosis, and the available data and results of nonselective and selective targeting of RET.

International audience; Purpose: The purpose of this study was to create an algorithm to detect and classify pulmonary nodules in two categories based on their volume greater than 100 mm3 or not, using machine learning and deep learning techniques.Materials and method: The dataset used to train the model was provided by the organization team of the SFR (French Radiological Society) Data Challenge 2019. An asynchronous and parallel 3-stages pipeline was developed to process all the data (a data "pre-processing" stage; a "nodule detection" stage; a "classifier" stage). Lung segmentation was achieved using 3D U-NET algorithm; nodule detection was done using 3D Retina-UNET and classifier stage with a support vector machine algorithm on selected features. Performances were assessed using area under receiver operating characteristics curve (AUROC).Results: The pipeline showed good performance for pathological nodule detection and patient diagnosis. With the preparation dataset, an AUROC of 0.9058 (95% confidence interval [CI]: 0.8746-0.9362) was obtained, 87% yielding accuracy (95% CI: 84.83%-91.03%) for the "nodule detection" stage, corresponding to 86% specificity (95% CI: 82%-92%) and 89% sensitivity (95% CI: 84.83%-91.03%).Conclusion: A fully functional pipeline using 3D U-NET, 3D Retina-UNET and classifier stage with a support vector machine algorithm was developed, resulting in high capabilities for pulmonary nodule classification.

Highlights • This ESO-ESMO ABC 5 Clinical Practice Guideline provides key recommendations for managing advanced breast cancer patients • It provides updates on the management of patients with all breast cancer subtypes, LABC, follow-up, palliative and supportive care • Updated diagnostic and treatment algorithms are also provided • All recommendations were compiled by a multidisciplinary group of international experts • Recommendations are based on available clinical evidence and the collective expert opinion of the authors

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07–0.70, p = 0.01 and HR 0.38; 95% CI 0.15–0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Au fil des annees, la famille des antidepresseurs s’est enrichie de plusieurs classes pharmacologiques. Neanmoins, pres de 30 % des depressions restent resistantes aux traitements medicamenteux. L’apport de techniques telles les psychotherapies, l’electro-convulsivotherapie ou la stimulation magnetique transcrânienne permet aujourd’hui une meilleure prise en charge des patients. La mise au point de neuroprotecteurs fait naitre de nouveaux espoirs.

PURPOSE This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. MATERIALS AND METHODS Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. RESULTS The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq. CONCLUSIONS The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.

International audience

Objectives Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation. Methods Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n = 102; 18–37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit. Results A gradual decrease in patients’ serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P > 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = –0.27, P = 0.003; CRP: r = –0.16, P = 0.06). Conclusion This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled. ClinicalTrials.gov Identifier NCT03666091.

© 2020 The Author(s)., Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions., GDD was supported in part by the Ludwig Center at Harvard; the Dr Miriam and Sheldon G. Adelson Medical Research Foundation; and the Pan Mass Challenge (no grant numbers). IMS is supported by the National Institutes of Health/National Cancer Institute (grant number K08 CA241085). JYB was supported by NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS), EURACAN (EC 739521), LYRICAN (INCA-DGOS-INSERM 12563), LabEx DEvweCAN (ANR-10-LABX-0061), Institut Convergence PLASCAN (17-CONV-0002), RHU4 DEPGYN (ANR-18-RHUS-0009).

Objectives/hypothesis PENTOCLO treatment, associating pentoxifylline, tocopherol, and clodronate, resolves radiation-induced fibrosis. The main aim of the present study was to prospectively assess efficacy in mandibular osteoradionecrosis (ORN). Study design Prospective cohort study. Methods Twenty-seven patients with mandibular ORN were included in the Pentoclauvergne Study between January 2014 and February 2016. After an initial 28-day phase of antibiotic, antifungal, and corticosteroid therapy, they received the PENTOCLO association daily until cure or a maximum of 24 months. The main assessment criterion was exposed bone area (EBA); secondary criteria comprised the Subjective, objective, management, and analytic (SOMA) score. Results Under PENTOCLO, EBA decreased by 28% at 2 months, 55% at 6 months, and 92% at 24 months; the SOMA score decreased by 23%, 38%, and 50%, respectively. A complete treatment course cured 76.5% of patients at a mean 9.6 months. Conclusions PENTOCLO is a simple, well-tolerated, and effective treatment for mandibular ORN. Level of evidence 4 Laryngoscope, 130:E559-E566, 2020.

Background A surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence. Aims To assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up. Methods A multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT. Results A total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038). Conclusions PET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up.

Objectifs La chimiotherapie neoadjuvante est fortement recommandee pour les patients presentant un carcinome vesical infiltrant le muscle de stade localise avant cystectomie, neanmoins le schema optimal de cette chimiotherapie reste a ce jour discute. Methodes Entre fevrier 2013 et mars 2018, 494 patients (pts) ont ete randomises dans 28 centres francais, ils recevaient soit 6 cycles de MVAC dose-dense (dd) toutes les 2 semaines (bras experimental), soit 4 cycles de GC toutes les 3 semaines (bras standard) avant chirurgie (groupe neoadjuvant) ou apres chirurgie (groupe adjuvant). L’objectif principal non rapporte dans cette analyse etait la survie sans progression a 3 ans. Les objectifs secondaires analyses etaient la toxicite de la chimiotherapie et la reponse anatomopathologique. Resultats Dans le groupe neoadjuvant group (218 pts dd-MVAC et 219 pts GC), 60 % ont recu 6 cycles dans le bras dd-MVAC, 84 % ont recu 4 cycles dans le bras GC, avec une cystectomie pour 199 pts (91 %) et 198 pts (90 %), respectivement. Une reponse histologique complete (ypT0pN0) etait observee respectivement chez 84 pts (42 %) et 71 pts (36 %). De plus, un meilleur controle local etait rapporte pour le bras dd-MVAC (p = 0,02). Une maladie confinee a l’organe ( Fig. 1 ). Conclusion L’analyse des objectifs secondaires de VESPER demontre que la toxicite du schema dd-MVAC est acceptable, mais avec plus d’asthenie et de troubles GI en neoadjuvant que le GC. Par contre, il existait un meilleur controle tumoral local dans le bras dd-MVAC.

International audience

High-throughput sequencing analysis represented both a medical diagnosis and technological revolution. Gene panel analysis is now routinely performed in the exploration of hereditary predisposition to cancer, which is becoming increasingly heterogeneous, both clinically and molecularly. We present 1,530 patients with suspicion of hereditary predisposition to cancer, for which 2 types of analyses were performed: a) oriented according to the clinical presentation (n = 417), or b) extended to genes involved in hereditary predisposition to adult cancer (n = 1,113). Extended panel analysis had a higher detection rate compared to oriented analysis in hereditary predisposition to breast / ovarian cancer (p < 0.001) and in digestive cancers (p < 0.094) (respectively 15 % versus 5 % and 19.3 %, versus 12.5 %). This higher detection is explained by the inclusion of moderate penetrance genes, as well as the identification of incident mutations and double mutations. Our study underscores the utility of proposing extended gene panel analysis to patients with suspicion of hereditary predisposition to adult cancer. This article is protected by copyright. All rights reserved.

Resume Le cancer de l’endometre est frequent chez la femme âgee et souvent associe a des comorbidites. Sa prise en charge en cas de situation metastatique et/ou de rechute necessite une approche multidisciplinaire. Les progres recents dans la comprehension de l’oncogenese et la classification moleculaire permettent d’envisager de nouvelles perspectives therapeutiques. Ces premieres recommandations etablies, selon la methodologie des recommandations pour la pratique clinique (RPC) Nice-Saint-Paul, visent a integrer les avancees moleculaires dans la prise en charge diagnostique et therapeutique. En 2020, le diagnostic histologique du cancer de l’endometre est base sur la morphologie et l’immunohistochimie incluant au minimum p53, les recepteurs aux œstrogenes et a la progesterone. La recherche d’une deficience du systeme de reparation des mesappariements de l’ADN (MMR) doit etre realisee de facon systematique pour toutes les tumeurs endometriales avancees a visee oncogenetique et theranostique. Elle peut etre recherchee dans un premier temps par une analyse en immunohistochimie avec les 4 marqueurs (MLH1, MSH2, MSH6, PMS2). Le traitement medical tient compte du type histologique, de la presence de recepteurs hormonaux et du profil de la patiente pour orienter vers une chimiotherapie (carboplatine–paclitaxel) ou une hormonotherapie (par exemple de type progestatifs) ; en cas d’une deficience MMR, la meilleure option est de proposer un essai d’immunotherapie. Dans le cadre de la prise en charge globale du cancer avance de l’endometre, la place de la radiotherapie (et a un moindre niveau, de la chirurgie) doit etre discutee, notamment en cas d’evolution exclusivement locoregionale ou de maladie oligometastatique.

International audience; Concurrent chemoradiotherapy improves the outcome of locally advanced head and neck cancers and the current reference chemotherapy is cisplatin. These results are obtained at the cost of increased toxicities. To limit the risk of toxicity, organ at riskdose constraints have been established starting with 2D radiotherapy, then 3D radiotherapy and intensity-modulated radiotherapy. Regarding grade ≥3 acute toxicities, the scientific literature attests that concurrent chemoradiotherapy significantly increases risks of mucositis and dysphagia. Constraints applied to the oral mucosa volume excluding the planning target volume, the pharyngeal constrictor muscles and the larynx limit this adverse impact. Regarding late toxicity, concurrent chemoradiotherapy increases significantly the risk of postoperative neck fibrosis and hearing loss. However, for some organs at risk, concurrent chemotherapy appears to increase late radiation induced effect, even though the results are less marked (brachial plexus, mandible, pharyngeal constrictor muscles, parotid gland). This additional adverse impact of concomitant chemotherapy may be notable only when organs at risk receive less than their usual dose thresholds and this would be vanished when those thresholds are exceeded as seems to be the situation for the parotid glands. Until the availability of more robust data, it seems appropriate to apply the principle of delivering dose to organs at risk as low as reasonably achievable.

Background Palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are rare variants of psoriasis. Knowledge of the efficacy of biologics is scarce. Objectives To evaluate the real-life efficacy of tumour necrosis factor blockers and ustekinumab in PPP and in ACH. Methods A multicentre retrospective descriptive study was conducted in 19 dermatology departments, including all patients with PPP or ACH seen from 2014 to 2016 who received one of the studied biologics. The data were collected by a standardized document. Factors associated with complete clearance (CC) were analysed by multivariate analysis, estimating odds ratios (ORs) and 95% confidence intervals (CIs). Results Among 92 patients included, 50 received adalimumab, 44 ustekinumab, 36 etanercept and 31 infliximab. Improvement and CC were observed in 83.9% and 20.0% patients receiving infliximab, 75.0% and 38.6% ustekinumab, 57.1% and 20.0% etanercept and 60.4% and 29.2% adalimumab. We found no significant difference in CC rates or duration of treatment among the biological treatments (P = 0.18 and P = 0.10, respectively). On multivariate analysis, CC with etanercept was associated with the ACH form and not smoking [OR = 9.5 (95% CI 1.1-82.7), P = 0.04 and 0.1 (0.01-0.9), P = 0.04]; with ustekinumab, male sex and absence of obesity [6.0 (1.3-28.6), P = 0.02 and 4.7 (1.0-22.7), P = 0.05]; with adalimumab, the ACH form [11.9 (2.7-52.3), P = 0.001]; and with infliximab, obesity [5.6 (1.1-29.4), P = 0.04]. Conclusions We found no difference in efficacy between TNF blockers and ustekinumab and among the three different TNF blockers in real life for PPP or ACH, which reveals the heterogeneity of clinical response to biologics in pustular psoriasis as compared with plaque psoriasis.

Resume Objectif de l’etude Cet article a pour objectif de decrire et de recenser les essais cliniques qui ont change nos pratiques dans les cancers du sein, les cancers urologiques, les cancers gynecologiques, les cancers des voies aerodigestives superieures et les cancers digestifs ces dix dernieres annees. Materiel et methodes Nous avons repertorie et selectionne les etudes publiees entre 2010 et 2020. Les articles ont ete identifies dans la base de donnees Medline a l’aide du moteur de recherche PubMed et des connaissances des auteurs. Resultats Cinq a six essais ont ete selectionnes dans le cancer du sein, les cancers urologiques, les cancers gynecologiques, les cancers des voies aerodigestives superieures et les cancers digestifs posant les differentes questions fondamentales en radiotherapie. Conclusion En fonction des maladies, les questions soulevees ces dix dernieres annees restent des questions fondamentales comme la place du traitement neoadjuvant, la place de l’hypofractionnement ou encore le type de chimiotherapie concomitante a la radiotherapie.

Summary Background Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC. Methods This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II–III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing. Findings Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7–24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1–24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50–65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34–49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6–27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57–79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38–61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4–35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3–4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group). Interpretation In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile. Funding F Hoffmann-La Roche/Genentech.

Chemotherapy-induced peripheral neuropathy (CIPN) is challenging for oncologists. Many publications mention the high incidence of CIPN and the lack of effective preventive/management strategies and robust diagnostic tools. This cross-sectional study was aimed at assessing the practice of French oncologists for CIPN prevention, diagnosis and management. This web-based survey was sent to French oncologists by the regional cancer networks. Incidence and impact of CIPN were assessed using visual analogue scales (VAS) and diagnostic strategies were recorded. Also recorded were the drugs used to prevent or manage CIPN and their perceived efficacy and safety (VAS). Among the 210 oncologists included, the perceived incidence of CIPN was about 36.2 ± 22.1% of patients. About 99.5% of oncologists declared that they assess CIPN during medical follow-up. The use of drugs to prevent CIPN was reported by 9.6% of oncologists (group B vitamins (35.0%) and calcium and magnesium infusion (25.0%)). In the case of CIPN, the therapeutic adjustment of neurotoxic anticancer drugs is performed by 99.0% of oncologists (chemotherapy change (49.8%), dose reduction (30.9%) or interruption (19.3%)). The pharmacological management of CIPN was declared by 72.9% of oncologists. The main drugs used are pregabalin (75.8%), amitriptyline (32.7%) and gabapentin (25.5%). Duloxetine (ASCO recommendation) is used by only 11.8% of oncologists. Oncologists were clearly aware of CIPN risks, but its incidence tended to be underestimated and the ASCO recommendations for the management of CIPN were not followed. The prevention, diagnosis and management of CIPN remain problematic in clinical practice in France. ClinicalTrials.gov : NCT03854864

Objective Principal objective of this work was to analyse the cost effectiveness of different sequences of cytogenetic techniques from the hospital's point of view, after prenatal ultrasound has identified fetal malformations. Methods Cytogenetic tests were performed for each case in 3 strategies, and their results are reported and compared to one reference strategy. Two new simulated strategies were considered: chromosomal microarrays alone and a direct test + CMA. Main outcomes measures cost-effectiveness ratio. Results A single test result was positive in 234 of the 835 pregnancies studied (28%). CMA alone would have identified 239 abnormalities. In the simulated direct test + CMA sequence, the direct test alone would have been positive for 66.1% of the abnormalities identified. When testing was indicated for NT, reference strategy (Direct + karyotyping) costs 1 084.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively 992.7 and 550.0 euros by positive test results. For OUM indications, reference strategy costs 2 937.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively, 2 118.4 and 1 304.7 euros by positive test results. Conclusions CMA appears to be the most effective test for prenatal cytogenetic diagnosis of fetal abnormalities identified by ultrasound.

Para-aortic lymph node status at initial assessment is the most important prognostic factor and a key point for the therapeutic strategy in patients with locally advanced cervical cancer. Undiagnosed lymph node metastasis is a major clinical problem as the finding of positive para-aortic lymph nodes leads to treatment modification, with a possible impact on disease free survival. When aortic lymph node disease is discovered, radiotherapy is extended to the para-aortic area, and other treatment modalities may be considered. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is the most accurate imaging examination to assess para-aortic extension in patients with locally advanced cervical cancer. The gold standard to identify para-aortic extension remains histologic evaluation of the lymph nodes. Indeed, PET/CT fails to detect approximately 10–15% of patients with negative PET/CT aortic nodes who have lymph node metastasis on pathologic staging. Patients with positive pelvic lymph nodes have para-aortic extension in 25–30% of cases, and surgical staging will lead to treatment modification and probably to improved para-aortic and distant control. Surgical staging also avoids unnecessary toxicity associated with extended field radiation in approximately 75% of patients with pelvic lymph node metastasis. The best modality to identify para-aortic extension is histological evaluation of the lymph nodes, but the survival benefit of surgical staging remains controversial. On the other hand, current studies include a majority of patients without pelvic lymph node spread, who are likely to be those who will benefit the least from surgical staging.

Patients with metastatic breast cancer (MBC) often require inpatient palliative care (IPC). However, mounting evidence suggests age-related disparities in palliative care delivery. This study aimed to assess the cumulative incidence function (CIF) of IPC delivery, as well as the influence of age.The national ESME (Epidemio-Strategy-Medical-Economical)-MBC cohort includes consecutive MBC patients treated in 18 French Comprehensive Cancer Centres. ICD-10 palliative care coding was used for IPC identification.Our analysis included 12,375 patients, 5093 (41.2%) of whom were aged 65 or over. The median follow-up was 41.5 months (95% confidence interval [CI], 40.5-42.5). The CIF of IPC was 10.3% (95% CI, 10.2-10.4) and 24.8% (95% CI, 24.7-24.8) at 2 and 8 years, respectively. At 2 years, among triple-negative patients, young patients (65 yo) had a higher CIF of IPC than older patients after adjusting for cancer characteristics, centre and period (65+/65: β = -0.05; 95% CI, -0.08 to -0.01). Among other tumour sub-types, older patients received short-term IPC more frequently than young patients (65+/65: β = 0.02; 95% CI, 0.01 to 0.03). At 8 years, outside large centres, IPC was delivered less frequently to older patients adjusted to cancer characteristics and period (65+/65: β = -0.03; 95% CI, -0.06 to -0.01).We found a relatively low CIF of IPC and that age influenced IPC delivery. Young triple-negative and older non-triple-negative patients needed more short-term IPCs. Older patients diagnosed outside large centres received less long-term IPC. These findings highlight the need for a wider implementation of IPC facilities and for more age-specific interventions.

International audience

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 μmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.

Background Perioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting. Objective We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting. Design, setting and participants A total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk. Outcome measurements and statistical analysis The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses. Results and limitations In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p = 0.2). An organ-confined status ( Conclusions The toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p = 0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021. Patient summary The authors have designed a randomized phase III controlled study comparing the efficacy of gemcitabine and cisplatin, and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) in patients for whom chemotherapy has been decided, before or after radical cystectomy. Higher toxicity regarding asthenia and gastrointestinal side effects along with a better bladder control rate were observed in the dd-MVAC arm. However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.

Throughout March and April 2020, dermatologists have observed an outbreak of chilblains despite climatic conditions not conducive to their apparition. These lesions have occurred simultaneously to the COVID‐19 epidemic, suggesting a relationship between their onset and SARS‐CoV‐2 infection. Here we describe a series of 10 patients presenting chilblain‐like lesions in whom we have searched for evidence of SARS‐CoV‐2 infection.