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Systemic nocardiosis is an infectious disease that is rarely associated with mediastinal lymph nodes.We report the case of a 72-year-old male patient treated with a high dose of oral corticosteroids for rheumatoid polyarthritis. This patient presented with rapid overall deterioration associated with mediastinal lymph nodes. Endobronchial ultrasound enabled us to establish a diagnosis of systemic nocardiosis. The patient recovered after having received suitable antibiotic treatment for four months.This work reports on a rare clinical presentation of systemic nocardiosis associated with mediastinal lymphadenopathies and highlights the key role of endobronchial ultrasound in diagnosing mediastinal lymph nodes, especially in differential diagnosis for lung cancer.

Background: Few data are available on programmed cell-death-protein-1–ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes. Methods: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016. Results: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7–16) months for all patients, 7 (5–10), 21 (10–not reached) and not reached months for metastatic, stage III and localized forms ( p = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC–/IC+ profile. Comparing IC+ versus IC– metastatic LCNEC, the former had significantly longer progression-free survival [9 (4–13) versus 4 (1–8) months; p = 0.03], with a trend towards better median OS [12 (7–18) versus 9.5 (4–14) months; p = 0.21]. Compared to patients with TC– tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1–6.2) versus 11 (8–18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC– metastatic LCNECs than those with TC–IC+ lesions (2 versus 8 months, respectively; p = 0.04). Conclusion: TC–/IC+ was the most frequent PD-L1–expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.

Resume Les tumeurs neuro-endocrines pulmonaires primitives regroupent plusieurs entites cliniques et evolutives distinctes, correspondant a quatre principaux sous-types : les tumeurs carcinoides typiques, de bas grade de malignite ; les carcinoides atypiques, de grade intermediaire ; les carcinomes neuro-endocrines a petites et a grandes cellules, de haut grade de malignite, et plus frequents. Le bilan pre-therapeutique des tumeurs carcinoides fait l’objet de recommandations precises. Sur le plan biologique, la suspicion clinique d’un syndrome fonctionnel doit etre confirmee par les dosages adequats. En cas de tumeur carcinoide metastatique, la prise en charge comporte le controle d’un eventuel syndrome secretoire par les analogues de la somatostatine, en plus du traitement oncologique, reposant sur l’evaluation de l’evolutivite tumorale, avec la possibilite d’une surveillance, d’un traitement local des metastases, d’un traitement par analogues de la somatostatine, par everolimus, ou chimiotherapie en cas de criteres d’agressivite tumorale. En cas de carcinome neuro-endocrine a grandes cellules, l’analyse moleculaire d’un panel d’alterations oncogenique pourrait guider la strategie de chimiotherapie ; l’association platine et etoposide est classiquement utilisee. En seconde ligne, en l’absence de standard therapeutique, l’essai IFCT-FFCD-GERCOR NIPINEC ouvre en France en 2018 se propose d’evaluer le nivolumab associe ou non a l’ipilimumab.

Introduction Les fusions de RET sont d’authentiques drivers oncogeniques retrouves dans 1 a 2% des cancers pulmonaires non a petites cellules (CBNPC). Le Selpercatinib (LOXO-292) est un inhibiteur selectif et puissant des tyrosines kinases de RET. Selon les resultats de l’etude de phase I/II LIBRETTO 001, cette molecule demontre une activite antitumorale importante et durable, avec un profil de tolerance acceptable, chez les patients atteints d’un CBNPC presentant une fusion de RET [1] . Sur 105 patients tous prealablement traites, le taux de reponse objective etait de 64% avec une mediane de survie sans progression (PFS) de 17,5 mois. Methodes Nous rapportons l’histoire clinique de deux patients atteints d’adenocarcinome bronchique de stade IV porteurs d’une fusion KIF5B-RET, pris en charge en 2019, traites par Selpercatinib apres une premiere ligne de chimiotherapie a base de sels de platine. L’objectif de ces observations est de decrire leur evolution et la tolerance de ce traitement. Resultats Le premier patient porteur d’un adenocarcinome avec metastases osseuses, hepatiques et pleurales est traite par Selpercatinib a partir de juillet 2019. la tolerance est bonne. La PFS est de 8 mois jusqu’a progression de lesions cerebrales, pour lesquelles il beneficie d’une radiotherapie panencephalique. La molecule est changee pour du Pralsetinib pendant 3 mois jusqu’a une nouvelle progression conduisant a reprendre une chimiotherapie. Le patient decede d’une evolution thoracique. La deuxieme patiente a un CBNPC avec des lesions cerebrales ; le Selpercatinib est debute en fevrier 2020. La PFS est actuellement de plus de 7 mois. Elle presente une reponse complete au niveau cerebral avec disparition de la metastase frontale et une reponse partielle a l’etage thoracique. Un mois apres le debut du traitement, elle developpe une hepatite de grade II avec cytolyse asymptomatique, conduisant a une diminution de 25% de la dose. La tolerance clinique est bonne. Dans la phase I/II de l’essai LIBRETTO, seul 2% des patients a du interrompre le Selpercatinib en raison d’evenement indesirable relie au traitement. Conclusion Tout comme les resultats de l’essai de phase I/II LIBRETTO OO1, ces deux cas cliniques illustrent l’efficacite et la bonne tolerance du Selpercatinib chez les patients porteurs d’un transcrit de fusion RET. Il existe une reponse non negligeable des metastases cerebrales.

Resume Les neoplasies neuro-endocrines pulmonaires primitives regroupent plusieurs entites cliniques et evolutives distinctes, correspondant a quatre principaux sous-types : les tumeurs endocrines bien differenciees dont les carcinoides typiques, de bas grade de malignite et les carcinoides atypiques, de grade intermediaire ; les carcinomes neuroendocrines a petites et a grandes cellules, de haut grade de malignite, et plus frequents. Le bilan pre-therapeutique des tumeurs carcinoides fait l’objet de recommandations precises. Sur le plan biologique, la suspicion clinique d’un syndrome fonctionnel doit etre confirmee par les dosages adequats. En cas de tumeur carcinoide metastatique, la prise en charge comporte le controle d’un eventuel syndrome secretoire carcinoide par les analogues de la somatostatine, en plus du traitement oncologique, reposant sur l’evaluation de l’evolutivite tumorale, avec la possibilite d’une surveillance, d’un traitement local des metastases, d’un traitement par analogues de la somatostatine, par everolimus, ou chimiotherapie en cas de criteres d’agressivite tumorale. La radiotherapie interne vectorisee par 177Lu-Dotatate des tumeurs exprimant des recepteurs a la somatostatine est une option interessante qui n’a pas encore ete validee en routine. En cas de carcinome neuro-endocrine a grandes cellules, l’association platine et etoposide est classiquement utilisee en premiere ligne. En seconde ligne, il n’existe pas de standard therapeutique. Les resultats de l’essai IFCT-FFCD-GERCOR « NIPINEC » evaluant le nivolumab associe ou non a l’ipilimumab en seconde et troisieme ligne sont en attente. L’analyse moleculaire d’un panel d’alterations oncogenique pourrait guider la decision therapeutique. © 2021 SPLF. Publie par Elsevier Masson SAS. Tous droits reserves.

Introduction Les tumeurs carcinoides (TC) bronchiques sont des tumeurs neuroendocrines malignes de bas grade ou de grade intermediaire. Du fait de leur rarete, le niveau de connaissance sur leur prise en charge est faible. L’objectif principal de l’enquete ENCART est de dresser l’etat des lieux de la prise en charge de ces tumeurs en France. Methodes Notre enquete aborde les donnees descriptives des repondants, l’organisation de la prise en charge des TC bronchiques, le traitement des tumeurs localisees/localement avancees et des formes metastatiques. Ce questionnaire informatise a ete diffuse avec le soutien de l’IFCT, CPHG, GTE et SFCTCV. Nous presentons ici les resultats obtenus sur 3 criteres predefinis : specialite, lieu d’exercice et appartenance a un groupe/intergroupe ou societe savante. Resultats Nous avons obtenu 199 reponses. Les TC localisees ou localement avancees sont prises en charge surtout par les pneumologues (84 %) et les chirurgiens (98 %) sans difference selon les lieux d’exercice. Les TC metastatiques sont plutot prises en charge par les oncologues. Les participants connaissent au moins un referentiel dedie aux TC dans 81 % des cas, mais le referentiel utilise differe selon la specialite et la societe savante. Les participants connaissent la RCP RENATEN de leur ville dans 78 % des cas. Les pneumologues, chirurgiens et praticiens des CHG et du prive connaissent moins cette RCP que les oncologues, endocrinologues et praticiens des CHU et CLCC. L’octreoscan est largement accessible quelle que soit la specialite et le lieu d’exercice. Il existe une nette difference entre les CHU et les CLCC, d’une part, et les CHG et le prive, d’autre part, pour l’acces a la TEP Gallium, ainsi que l’acces a des traitements specifiques (radiofrequence, chimioembolisation). La radiotherapie metabolique est accessible aux oncologues (83 %) et aux endocrinologues (83 %), moins aux pneumologues (41 %). Le reseau TENPath n’est connu que de 27 % des repondants. Conclusion Cette enquete confirme l’implication des pneumologues, chirurgiens thoraciques et oncologues dans la prise en charge des TC bronchiques. Nos resultats soulignent la place preferentielle des CHU, CHG, CLCC et centres prives dans la prise en charge des TC de stades localises/localement avances et celle des CLCC pour les stades metastatiques. ENCART pointe des differences, en fonction de la specialite, du lieu d’exercice et de l’appartenance ou non a des instances professionnelles, dans le recours a certaines options diagnostiques et therapeutiques.

Introduction Les tumeurs carcinoides (TC) bronchiques representent moins de 2 % de l’ensemble des cancers du poumon. Du fait de leur rarete, peu de donnees sont disponibles sur leur prise en charge. L’objectif de l’enquete ENCART est de recenser les pratiques therapeutiques declarees. Methodes L’enquete (63 questions) porte sur la prise en charge des formes localisees/localement avancees et des tumeurs metastatiques. Elle a ete diffusee en ligne avec le soutien de l’IFCT, CPHG, GTE et SFCTCV, Nous rapportons ici les reponses selon la specialite, le lieu d’exercice et l’appartenance a un groupe ou une societe savante en les confrontant au referentiel AURA 2019 cite par 67 % des repondants comme reference. Resultats En cas d’atteinte bronchique proximale, la desobstruction en bronchoscopie rigide n’est jamais realisee a titre therapeutique exclusif, sauf contre-indication chirurgicale, en accord avec le referentiel AURA. Un curage mediastinal est realise au cours du geste chirurgical dans 95 % des cas. En cas de carcinoides typiques (CT) le curage ganglionnaire doit etre systematique pour tous les chirurgiens thoraciques et oncologues. En considerant que le curage peut etre facultatif dans les CT, 8 % des pneumologues et 25 % des endocrinologues ne suivent pas les recommandations. Dans les stades pN2 un traitement complementaire est rarement propose, en conformite avec le referentiel. En cas de traitement adjuvant, il s’agit de maniere equivalente d’une chimiotherapie (15 %) ou d’une radiotherapie (16 %) pour les pneumologues ; les oncologues optent plutot pour la radiotherapie, les endocrinologues pour la chimiotherapie. La surveillance se prolonge majoritairement (71 %) pendant plus de 10 ans conformement au referentiel. En 1re ligne metastatique les analogues de la somatostatine sont les plus utilises (43 %) mais 25 % des oncologues et 17 % des pneumologues prescrivent une chimiotherapie a base de platine/etoposide en contradiction avec le referentiel. Le recours a cette association varie en fonction du lieu d’exercice et de l’appartenance a un groupe. Conclusion Notre enquete de pratique demontre des differences dans la prise en charge des TC bronchiques selon la specialite du praticien, son lieu d’exercice et son appartenance a un groupe professionnel. ENCART pointe egalement certaines pratiques non conformes au referentiel AURA.

Introduction Le nivolumab en monotherapie 240 mg/15 j est reconnu comme le traitement de reference de 2e ligne du CPNPC de stade 4, quel que soit le statut PD-L1. Il n’existe pas de recommandation claire sur la poursuite du Nivolumab chez les long-repondeurs au-dela de 2 ans de traitement. L’etude CheckMate384 a montre une efficacite et une tolerance similaire avec l’espacement des doses a 480 mg/1 mois. L’objectif de cette nouvelle etude est de decrire la survie globale, la survie sans recidive et le profil de tolerance de patients pour lesquels les injections de nivolumab 240 mg ont ete espacees tous les mois, apres 2 ans de reponse partielle ou complete sous nivolumab 240 mg/15 j. Methodes Cette etude est observationnelle monocentrique. Depuis juin 2017, 5 patients ont ete inclus dans l’etude. Ils devaient etre porteurs d’un CPNPC de stade 4 et presenter une reponse partielle ou complete au TEP-scanner apres au moins 2 ans de traitement par nivolumab 240 mg/15 j, prescrit dans les conditions de l’AMM et en l’absence de toxicite de grade > 1. Apres validation en RCP, les cures etaient espacees tous les mois. Un scanner d’evaluation etait realise toutes les 4 cures. Au debut de la maintenance par nivolumab 240 mg/1 mois, les patients avaient un âge moyen de 62 ans, un sex-ratio a 3/2, ils etaient tous fumeurs et en bon etat general (PS ≤2 : 80 %). Le statut PDL1 n’etait pas renseigne dans 4 cas en raison de l’anciennete du diagnostic histologique. Resultats Sur les 5 patients inclus, 4 patients presentent toujours une reponse complete en aout 2019, 1 patient est decede du fait d’une insuffisance respiratoire chronique. La survie globale est de 52,2 mois (30 mois ; 69 mois). Depuis le debut de la maintenance par nivolumab mensuel, la survie sans recidive moyenne est de 12,2 mois (1 mois ; 26 mois). Aucune toxicite de grade ≥ 2 n’a ete observee. Conclusion Bien que ces resultats soient tout a fait preliminaires, il semble que la posologie de nivolumab 240 mg/1 mois parvienne a maintenir une reponse oncologique comparable au nivolumab 240 mg/15 jours apres 2 ans de traitement, sans majoration ou apparition de nouvelles toxicites. Des resultats complementaires seront presentes grâce a l’inclusion de nouveaux patients a partir de septembre 2019. Ces constatations necessiteraient au mieux la confirmation par une etude de phase III couplee a une analyse cout/efficacite, ou au moins la mise en place d’un registre national pour recenser des pratiques similaires dans les autres centres de cancerologie thoracique.

Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p 0.01). Univariate analysis showed a higher risk of death among patients with PS1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001),1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients.NCT02293733.

Resume Un patient, aux antecedents de carcinome epidermoide pulmonaire du lobe superieur droit traite par radiotherapie et chimiotherapie concomitante 14 ans auparavant, est pris en charge pour dyspnee. L’endoscopie bronchique revele l’existence d’une obstruction complete de la bronche souche droite dont l’aspect macroscopique est fortement evocateur d’une re-evolution neoplasique. Neanmoins les prelevements realises ne retrouvent qu’un tissu necrotique et inflammatoire sans criteres de malignite. Malgre la realisation d’une desobstruction bronchique en bronchoscopie rigide, on assiste a une recidive rapide et complete conduisant a la mise en place d’une prothese en Y. De nouveau les examens histologiques, bacteriologiques et mycologiques reviennent negatifs. Le patient est rapidement re-hospitalise pour tableau d’infection pulmonaire qui retrouve une recidive peri- et intraprothetique de l’obstruction. La mise en culture des prelevements biopsiques permet cette fois la mise en evidence d’un Actinomyces meyeri. Une antibiotherapie adaptee permet alors la regression complete de l’obstruction. Le patient decedera quelques mois plus tard d’une hemoptysie massive apres le retrait de la prothese, l’autopsie retrouvant un orifice fistuleux entre la bronche souche droite et l’artere pulmonaire, sans argument pour une recidive neoplasique ou la persistance de lesions liees a l’actinomycose.

Background : The rearrangement of the anaplastic lymphoma kinase (ALK) is the oncogenic driver of 5% of advanced NSCLC and is identified on tumor by immunohistochemistry and FISH. Molecular pathologists are often hindered by the poor quality and quantity of available material to determine ALK -status and liquid biopsies represent an interesting alternative. Point mutations and indels are routinely detected in circulating-free DNA; however, data are scarce on detection of fusion transcripts in blood. Material and Methods : Sensitivity and specificity of specific- ALK rearrangements primer and probes using ddPCR were tested in tumors, cell lines, blood samples from healthy donors and patients with ALK -rearranged tumors. Results : On tissue, all FISH-positive and –negative samples were respectively positive and negative using ddPCR, indicating 100% specificity in tumors. Sensibility was 0.1% in cell lines. Interestingly, questionable cases by FISH were all positive by ddPCR. Blood samples of healthy donors were negative for ALK -rearrangement indicating a 100% specificity. Two non-smoking women with positive EML4 - ALK -positive stage IV adenocarcinoma confirmed by IHC and FISH in the tumor were found positive in the plasma with 3.45 and 13.36 copies/mL of plasma respectively. Conclusion : ddPCR is promising for the determination ALK -status in blood. It can be easily implemented in clinical practice. Detection of circulating free RNA may be extended to other fusion genes involved in lung carcinogenesis ( i.e. ROS1 -rearrangements) and to other tumor types ( i.e. sarcomas).

Objectives The aim of this retrospective study was to analyse the efficacy of gemcitabine-oxaliplatin (gemox) or 5-fluorouracil-oxaliplatin (folfox) in the treatment of metastatic pulmonary carcinoid tumors. Patients and methods 45 patients were included in two tertiary referral centers between January 1999 and January 2013. Typical, atypical carcinoids or not otherwise specified carcinoids were diagnosed according to WHO criteria in 19%, 57%, and 24% of cases by two expert pathologists. Patients had synchronous (38%) or metachronous (62%) metastastic disease (median of 2 (1–5) metastatic sites). Seventy-nine percent had progressive disease before start of chemotherapy. Treatment consisted of: gemcitabine 1000mg/m 2 and oxaliplatin 100mg/m 2 every 2 weeks (gemox regimen, n=24) or 5-fluorouracil (5-FU) (400mg/m 2 in bolus injection and 5-FU 2400mg/m 2 in 46h-infusion) and oxaliplatin 85mg/m 2 (folfox regimen, n=21) every 2 weeks. Tumor response was assessed according to RECIST criteria every 8–12 weeks. Progression free survival and overall survival were assessed using Kaplan Meier curves. Results Patients received oxaliplatin-based chemotherapy in first-line (20%), second-line (33%), or post-second-line (47%) systemic treatment. The median number of cycles was 8 (1–12). Nine (20%) stopped oxaliplatin before 8 cycles because of toxicity. Nine patients (20%) had a partial response and 29 (64%) had stable disease. Median progression free survival (PFS) was 15 (6–25) months. Median overall survival (OS) was 34 (21–49) months. No significant difference was observed in response and PFS between either regimens. Conclusions Our results suggest that either gemcitabine-oxaliplatin or 5-fluorouracil-oxaliplatin combinations are attractive chemotherapy regimen in metastatic pulmonary carcinoid tumors.

Le traitement de reference actuel des patients presentant un cancer bronchique non a petites cellules localement avance au thorax (CBNPC) comporte une association concomitante d’une radiotherapie et d’une chimiotherapie a base de sels de platine. L’integration a ces traitements des therapeutiques moleculaires ciblees (TC) represente une voie de recherche prometteuse et un espoir d’amelioration therapeutique. Il existe en effet un rationnel preclinique bien etabli pour soutenir l’hypothese d’une synergie d’action entre TC et radiation ionisantes et de nombreuses donnees experimentales temoignent de l’existence d’un effet radio sensibilisant des therapeutiques ciblees inhibant l’activation d’EGFR (anti-EGFR). Les donnees cliniques actuellement disponibles sont plus preliminaires et seule la faisabilite de l’association concomitante anti-EGFR et radiotherapie a ete demontree. Toutefois des etudes prometteuses de phase II associant le cetuximab, un anticorps monoclonal humanise ciblant EGFR, et une radiotherapie concomitante ont conduit au developpement de cette molecule en phase III dans cette situation. L’objectif de ce travail est de revenir brievement sur les donnees experimentales et le rationnel preclinique des associations radiotherapie-TC et de faire une synthese des principales etudes cliniques actuellement disponibles.

Resume Introduction La ponction biopsie transparietale est un geste de radiologie interventionnelle couramment effectue dans l’exploration d’un nodule pulmonaire. Ce geste est en general bien tolere. La survenue d’une embolie gazeuse apres une ponction biopsie pulmonaire transparietale est extremement rare. Observation Nous rapportons le cas d’une femme de 62 ans ayant presente dans les suites d’une ponction transparietale a l’aiguille d’un infiltrat pulmonaire des signes neurologiques a type d’agitation, de syndrome meninge et d’hemiplegie evocateurs d’embolie gazeuse. L’evolution a ete favorable grâce au traitement par oxygenotherapie hyperbare. Conclusion L’embolie gazeuse est une complication rare des biopsies pulmonaires transparietales survenant le plus souvent dans les minutes qui suivent le geste. Le caractere retarde de l’embolie gazeuse par rapport a la biopsie rapporte ici est exceptionnel. Le risque est plus important dans les biopsies d’infiltrats que de nodules. La survenue d’un pneumothorax potentiellement responsable d’une surpression ou d’une hemorragie alveolaire au decours d’une biopsie pulmonaire transparietale doit inciter a une surveillance accrue.

Key points Standard treatment of advanced non-small cell lung cancer is based on several lines of therapy separated by treatment-free intervals in which each new line is started when tumour progression is detected. The maintenance strategy consists of pursuing an appropriate, well-tolerated treatment after the end of first-line chemotherapy in order to maintain the initial therapeutic benefit and to avoid rapid clinical deterioration that would rule out further treatment. Two kinds of maintenance therapy have been investigated : continuation maintenance which consists in continuing a targeted agent or a chemotherapy agent that was part of initial induction therapy and switch maintenance defined by initiating a new agent immediately after the end of induction chemotherapy. Clinical trials show that maintenance strategy provides a significant benefit in terms of disease control and improves overall survival for switch maintenance with pemetrexed or erlotinib. Survival benefit appears to be due mainly to the progression-free survival gain and to the increase in the proportion of patients who can receive several lines of treatment . Maintenance therapy is an important option for patients receiving first-line treatment , particularly for those with rapid disease progression. The choice of continuation or switch maintenance will depend on drug used in combination to platinum for induction treatment, response to first-line, histology and patient's preference.

Resume La strategie therapeutique des cancers bronchiques non a petites cellules avances repose sur l’administration de plusieurs lignes de traitement, determinees par la constatation d’une progression de la maladie, et separees par des intervalles libres de tout traitement. La strategie de maintenance consiste en la poursuite d’un traitement adapte, peu toxique, des la fin de la chimiotherapie de premiere ligne dans le but de maintenir le benefice therapeutique obtenu et d’eviter une progression rapide de la maladie pouvant etre incompatible avec l’administration d’un traitement ulterieur. Les essais conduits montrent que la strategie de maintenance prolonge la duree du controle de la maladie et ameliore la survie de maniere cliniquement significative avec le pemetrexed et l’erlotinib. Le gain de survie pourrait etre lie a la majoration de la survie sans progression et a l’augmentation de la proportion des patients exposes a plusieurs lignes de traitement actif. La maintenance constitue une option therapeutique importante en premiere ligne, particulierement en cas de maladie d’evolution rapide, avec ulterieurement la necessite de preciser les criteres permettant la selection des patients beneficiant le plus de cette strategie.

Introduction La fibroelastose pleuro-parenchymateuse est une recente entite clinicopathologique inclue dans la classification multidisciplinaire internationale des pneumopathies interstitielles idiopathiques de 2012. En 2017, seulement une centaine de cas sont decrits dans la litterature. Methodes Nous rapportons le cas d’un patient de 73 ans presentant une dyspnee stade III NYHA associee a une toux seche. Il a une ACFA paroxystique traitee depuis 1 an par rivaroxaban, amiodarone (entre 2016–2017) bisoprolol, un tabagisme sevre estime a 50 paquets–annees et une exposition professionnelle au sulfate dimethylique, au benzene et au diclorethane. Resultats A l’examen physique, il ne presente pas de platythorax mais un hippocratisme digital et on retrouve des crepitants bibasaux velcros ( Fig. 1 ). La radiographie thoracique retrouve une ascension des hiles et une retraction des sommets. Le scanner thoracique montre des condensations bilaterales a predominance apicales associees a une fibrose sous-pleurale. La fibroscopie bronchique est macroscopiquement normale. Les prelevements microbiologiques sont negatifs (bacteriologie standard, BK et mycologie). Il n’y a pas de cellule neoplasique ni macrophages spumeux. Au LBA, on retrouve une alveolite a 230 mega/L a predominance de PNN. Il a une hypereosinophilie sanguine a 1 G/L et des IgE totales augmentees a 288 Ui/mL. Les serologies VIH, VHB, VHC le bilan d’auto-immunite et la recherche de parsitose domestique sont negatives. Le PET scanner retrouve des fixations moderees des apex (SUV max 3). Au niveau fonctionnel respiratoire, il a trouble ventilatoire restrictif associe a un trouble de diffusion et une hypoxemie de repos, associee a une desaturation au TM6 a 86 % sous 6L/min d’oxygene pour une distance parcourue de 150 metres. La biopsie pulmonaire diagnostique n’est pas conseillee en raison du haut risque de morbi-mortalite et notamment de pneumothorax chronique. Conclusion Ce patient presente une fibroelastose pleuro-parenchymateuse certaine apres avis au centre de competences en maladies rares pulmonaires de Lyon. Son origine professionnelle est fortement suspectee. A l’heure actuelle, aucun traitement n’a demontre d’efficacite en termes de survie ou de ralentissement du declin de la fonction respiratoire. Un traitement par nintedanib est instaure depuis aout 2017.

Resume Le traitement de premiere ligne des cancers bronchiques non a petites cellules a recemment evolue avec le developpement de plusieurs options therapeutiques construites autour de la chimiotherapie associant un sel de platine et un cytotoxique de troisieme generation. Ces nouvelles approches consistent en l’introduction du pemetrexed dans les schemas therapeutiques de premiere ligne, l’adjonction d’un anticorps monoclonal anti-angiogenique (bevacizumab) ou anti-EGFR (cetuximab) a la chimiotherapie, l’utilisation d’une maintenance therapeutique pour les maladies controlees a la fin de la chimiotherapie a base de platine, et l’utilisation des inhibiteurs de tyrosine kinase de l’EGFR des la premiere ligne pour les patients dont la tumeur exprime une mutation de l’EGFR. Ces schemas therapeutiques ont permis de franchir le plateau therapeutique obtenu avec la seule chimiotherapie ; les progres futurs viendront probablement d’une approche therapeutique plus rationnelle et personnalisee grâce a une meilleure connaissance des facteurs predictifs d’efficacite de ces traitements.

L’hyperplasie neuroendocrine pulmonaire diffuse idiopathique ( Diffuse idiopathic pulmonary neuroendocrine cells hyperplasia ; DIPNECH) est un etat pre-neoplasique pulmonaire diffus rare et meconnu, frequemment associe a de veritables tumeurs carcinoides typiques. Nous rapportons ci-dessous deux cas cliniques concernant des patientes presentant une symptomatologie respiratoire aspecifique pour lesquelles une tomodensitometrie est realisee, revelant pour la premiere patiente, une image nodulaire unique et pour la deuxieme, l’existence de micronodules pulmonaires multiples. L’anatomopathologie de la biopsie pulmonaire montre chez ces deux patientes d’une part une proliferation de cellules neuroendocrines disseminee dans la paroi bronchique, au contact de la membrane basale de l’epithelium bronchique, d’autre part des tumorlets. De plus, une tumeur carcinoide typique est mise en evidence chez la premiere patiente. La faible prevalence de cette pathologie ne permet son etude que par le biais de petites series ou de cas isoles rendant la prise en charge therapeutique difficile. L’evolution lente permet une surveillance clinique tomodensitometrique et endoscopique prolongee. En cas de tumeur carcinoide averee, l’exerese chirurgicale est le traitement de reference.

Introduction Nous presentons l’observation d’une pericardite constrictive initialement revelee par un epanchement pleural gauche de grande abondance chez une patiente dyspneique sans autres signes cliniques associes. Cas clinique Seul le catheterisme cardiaque a pose le diagnostic de certitude par l’aspect caracteristique en dip-plateau du ventricule droit. Apres bilan, aucune etiologie n’a ete retrouvee a cette pericardite constrictive. Conclusion Suite a la mise en place d’un traitement par corticoides, l’evolution est a ce jour favorable.

Resume Le recepteur de l’epidermal growth factor (EGFR) exercant un role important dans la croissance tumorale des cancers bronchiques non a petites cellules peut etre bloque par de petites molecules inhibant specifiquement la phosphorylation des residus tyrosine de son domaine intracellulaire. Deux molecules, l’erlotinib et le gefitinib ont ete ainsi developpees en monotherapie chez des patients atteints de CBNPC avances en rechute apres une ou plusieurs lignes de chimiotherapie ; l’erlotinib a demontre par rapport a un placebo un benefice de survie significatif en deuxieme ou troisieme ligne therapeutique chez des patients non selectionnes. Le benefice therapeutique s’observe dans la majorite des sous-groupes de patients, meme si la probabilite de reponse est accrue chez les femmes, les Asiatiques, les non-fumeurs et en cas d’adenocarcinome. Les mutations heterozygotes acquises de l’EGFR constituent un determinant majeur de la reponse au traitement ainsi qu’une avancee considerable dans la comprehension de la carcinogenese des adenocarcinomes; l’augmentation du nombre de copies du gene de l’EGFR semble correlee au benefice de survie constate en seconde ou troisieme ligne. L’optimisation de l’utilisation de ces molecules, en particulier en premiere ligne de traitement, reposera sur une selection plus adequate des patients, notamment sur le plan biologique ou moleculaire.

Purpose The objective of this randomised phase II study was to evaluate the impact in terms of response and toxicities of induction or consolidation chemotherapy respectively before or after concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer. Patients and methods In the induction arm, patients received induction chemotherapy with cisplatin (80 mg/m 2 ) and paclitaxel (200 mg/m 2 ) on days 1 and 29 followed by a concurrent chemoradiotherapy (66 Gy in 33 fractions, cisplatin 80 mg/m 2 days 1, 29 and 57, vinorelbine 15 mg/m 2 days 1, 8, 29, 36, 57 and 64). In consolidation arm, the same concurrent chemoradiotherapy began on day 1 followed by two cycles of cisplatin and paclitaxel. Results One hundred twenty seven patients were randomised. The intent to treat response rates in induction and consolidation arms were 58% and 56% respectively. Median survival was 19.6 months in induction arm and 16.3 months in consolidation arm and 4-year survival rates were 21% and 30% respectively. Haematologic and non-haematologic toxicities were similar in both arms, except grade 3/4 oesophagitis, more frequent in consolidation arm than in induction arm (17% versus 10%). Conclusion Cisplatin-based chemotherapy as induction or consolidation with concurrent chemoradiotherapy can be administrated safely. Response rates were similar in both arms with a trend in favour for consolidation arm for long-term survival.

A patient with a history of squamous cell carcinoma of the right upper lung lobe treated 14 years before by concomitant chemo-radiotherapy was referred on account of dyspnea. Bronchial endoscopy revealed complete obstruction of the right main bronchus highly suggestive of a tumor recurrence. However, biopsy samples only showed inflammatory and necrotic tissue with no evidence of malignancy. Despite complete tissue resection by rigid bronchoscopy, a rapid and complete recurrence occurred requiring the placement of a Y-shaped bronchial prosthesis. Repeat histological, bacteriological and mycological analyses were negative. The patient was soon readmitted to hospital for a lung infection due to recurrence of obstruction inside and around the prosthesis. Bacterial examination of biopsy samples identified Actinomyces meyeri. Appropriate antibiotic therapy led to a complete regression of the bronchial obstruction. Unfortunately, the patient died a few months later due to massive hemoptysis after the removal of the prosthesis. Autopsy examination showed a fistula between the right main bronchus and pulmonary artery, with no evidence of neoplastic recurrence nor the persistence of lesions associated with actinomycosis.

Introduction Vandetanib inhibits vascular endothelial growth factor receptor (VEGFR) 2 tyrosine kinase activity in endothelial cells and, to a lesser degree, endothelial growth factor receptor (EGFR) tyrosine kinase activity in tumor cells. Vandetanib has been developed for the treatment of non–small-cell lung cancer (NSCLC), either alone or in combination with second-line chemotherapy. We describe a case of interstitial lung disease (ILD) in a patient who received vandetanib in a randomized, controlled, double-blind trial by comparing a pemetrexed combination with either vandetanib or placebo.

Percutaneous transthoracic needle biopsy is a useful and common procedure in the investigation of a lung nodule. The occurrence of air embolism after percutaneous transthoracic needle biopsy is extremely rare.We report a 62-year-old woman who presented with neurological signs including restlessness, meningeal signs and focal neurologic deficits 4 hours after percutaneous transthoracic lung biopsy, related to air embolism. The outcome was favorable with hyperbaric oxygen therapy.Percutaneous transthoracic needle biopsy complicated by air embolism has been rarely reported. It usually occurs within minutes after the biopsy. The late onset of this adverse event in our patient is exceptional. Air embolism occurs more frequently after biopsy of lung infiltrates compared to nodules. Occurrence of a pneumothorax or an intraalveolar haemorrhage following a percutaneous transthoracic needle biopsy may be warning manifestations and justify a close monitoring.

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (ADC-WBF) belong to the same anatomo-clinical entity and show very similar epidemiologic, clinical and biological characteristics. However there is a lack of consensus for the treatment of unresectable forms. Although epidermal growth factor receptor tyrosine kinase inhibitors and paclitaxel do have some efficacy, the aim of this review is to assess the role that pemetrexed, a new generation antifolate, could play in this context. Pemetrexed has proved to be particularly effective in advanced lung adenocarcinomas and unresectable mesotheliomas, and cases of major and sustained responses of ADC-WBF to pemetrexed have been reported. The preclinical rationale explaining this efficacy is that it inhibits the growth of BAC cell lines in vitro. BAC tumors overexpress FR-alpha, a protein involved in pemetrexed intracellular transport, at rates higher than those observed in lung adenocarcinomas and mesotheliomas and it would seem that pemetrexed efficacy is correlated to FR-alpha expression. The role played by thymidylate synthase expression level in sensitivity to pemetrexed also needs to be specifically explored in ADC-WBF. The results of two phase II trials, SWOG 0526 and IFCT 05-04, will hopefully provide decisive information on the relevance of pemetrexed in ADC-WBF management and the molecular predictors of response.

Inhibition of specific processes essential for tumour vascular development is one of the key strategies for the treatment of non- small cell lung cancer (NSCLC). Many agents target the Vascular Endothelial Growth Factor (VEGF) pathway, either by preventing VEGF receptor binding or inhibiting VEGF receptor signalling in endothelial cells. Bevacizumab is a monoclonal antibody specific for VEGF-A. Combination of bevacizumab with standard first-line chemotherapy in NSCLC leads to an improvement in response rates and progression-free survival compared to chemotherapy alone and a significant survival advantage with carboplatin- paclitaxel chemotherapy. Toxicity issues are of concern with the possible occurrence of hypertension and an increased risk of arterial thrombo-embolism. The occurrence of fatal pulmonary haemorrhage after necrosis of the primary tumour is a specific toxicity in NSCLC which requires appropriate selection of patients before treatment; excluding squamous cell carcinoma, haemorrhagic tumours and tumour invasion of major blood vessels. The use of bevacizumab combined with chemotherapy represent a first step in the development of antiangiogenic treatments in NSCLC, with the future possibility of using it in earlier stages of disease.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an uncommon preneoplastic condition, often associated with typical carcinoid tumours. The observations reported below concern two women, both suffering from chronic pulmonary symptoms. These patients underwent computed tomography that showed a solitary nodule in the first patient and multiple sub centimetre nodules in the second. In both cases histological studies of the pulmonary biopsies revealed: a proliferation of neuroendocrine cells dispersed in the bronchial and bronchiolar epithelium, more specifically superficial to the basement membrane; some tumourlets; a typical carcinoid tumour was also found in the first patient's biopsy. The choice of treatment remains difficult, mainly because the existing studies are restricted to small numbers of patients or isolated cases, a consequence of the low prevalence of this disease. Considering its slow evolution, management by long-term clinical, endoscopic and radiologic surveillance may be considered. If a carcinoid tumour is present or appears during the surveillance, the standard treatment is still surgical resection.

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma mixed subtype with bronchioloalveolar features (ADC-WBF) represent a unique anatomo-clinical entity accounting for some 20% of non-small cell lung cancers (NSCLC). These tumors seem less sensitive to chemotherapy than other NSCLC. We report two cases of advanced ADC-WBF treated with second-line and fourth-line pemetrexed. Major and durable radiological response associated with clinical and functional improvement was achieved in both patients, without important drug toxicity. After treatment arrest, the two patients experienced progressive disease but responded to retreatment with pemetrexed. Recent data suggest that paclitaxel-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors could be an acceptable therapeutic strategy in unresectable CBA and ADC-WBF. The cases reported here and preclinical findings suggest a therapeutic efficacy of pemetrexed in these tumors. Prospective studies are required to evaluate this hypothesis.

Thoracic irradiation is a major weapon in the treatment of nonmetastatic primary lung cancer, in particular in patients presenting a locally advanced disease of the mediastinium. Acute radiation pneumonitis (ARP) is one of the main limiting toxicities. The purpose of this work is to sum up the current state of knowledge of the factors of risk of developing ARP. The incidence after conventional irradiation, in patients with non small cell lung cancer (NSCLC) is about 7 to 10% in the moderate although symptomatic forms of ARP and about 1 to 3% in the severe forms. The factors related to the patient, the tumour or treatments prior to the irradiation do not determine any specific risk of ARP besides an age of over 65 years that remains debatable. The validated predictive factors of ARP are mainly related to the irradiation factors (healthy lung volumes irradiated, average dose of irradiation, etc.). Nevertheless, in spite of the adjustment of these parameters, the individual susceptibility to the toxicity of thoracic radiotherapy remains significant, directing current research to the biological markers intrinsic to the patient. In particular, the involvement of early variations of certain cytokines (IL-6, IL-10, TGF-ss) in the occurrence of ARP during irradiation has been suggested and studies are under way to confirm their involvement and determine their role.

We report a case of constrictive péricarditis initially revealed by a massive left sided pleural effusion.The patient was dyspnoeic without any associated clinical signs. Only cardiac catheterization gave the diagnosis with a characteristic dip-plateau of the right ventricle. After full assessment, no aetiology was found.After a treatment with corticosteroids, the progress has been favourable to date.

The epidermal growth factor receptor (EGFR) plays an important role in non-small cell lung cancer growth. Small molecules can specifically target the tyrosine kinase activity of the EGFR's intracellular domain and thus inhibit downstream pathways influencing cell proliferation and survival. Gefitinib and erlotinib have been developed as single-agents for the treatment of patients who have relapsed following one or more courses of chemotherapy. Erlotinib has exhibited significant overall survival benefit in a second- or third-line setting compared to placebo for unselected patients. A beneficial effect on survival has been observed in almost all subgroups of patients and the response rate was higher in women, non-smokers, Asian patients and patients with adenocarcinoma. Somatic mutations in the tyrosine kinase domain of EGFR have been shown to be strong predictive markers for drug response to gefitinib or erlotinib and led to a new insight into adenocarcinoma carcinogenesis. High EGFR gene copy number seems to be predictive of EGFR tyrosine kinase inhibitors-related effect on survival observed in second- or third-line treatment. Future use of EFGR tyrosine kinase inhibitors should be based on improved clinical and molecular selection of patients who are likely to derive the greatest benefit from these drugs, especially in first-line setting.

PurposeTo investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non–small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis.Patients and MethodsNinety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses.ResultsForty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFα, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011).ConclusionEarly variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

A 68-year-old man with a history of large cell lung carcinoma presented 1 year after surgical management of the initial lesion, with a complete unilateral IX-XII cranial nerve palsy with Horner's sign. This rare multiple cranial nerve palsy is called Villaret's syndrome. It suggests an extracranial lesion located in the retroparotid space. Complete basal skull radiology work up including computed tomography and magnetic resonance imaging confirmed the location of the causal lesion in the retroparotid space.

International audience; Background and purpose: Clinical and dosimetric prognostic factors for radiation pneumonitis (RP) have been reported after three-dimensional conformal radiotherapy (3D-CRT) in patients with non-small cell lung cancer (NSCLC). Patients and methods: Ninety-six patients who received 3D-CRT for stage IA to IIIB NSCLC were evaluated prospectively. Surgery was performed before radiation in 51 % of the patients (n = 49). RP was diagnosed six-eight weeks after 3D-CRT using the Lent-Solna classification. Factors evaluated included treatment factors such as total mean lung dose (MLD), and dose-volume histogram (DVH) thresholds for several radiation dose steps. These thresholds were originally determined from the median of the irradiated lung volume at each step. Results: Six patients could not be evaluated for RP six weeks after 3D-CRT. Of the 90 remaining patients, 40 (44%) had RP (i.e. grade greater than or equal to 1) at 6 weeks, including 7 patients (7.8%) with severe RP (grade greater than or equal to 2). Regarding the whole toxicity (grade greater than or equal to 1), age ( greater than or equal to 60 years), MLD, V20 and V30 were significantly related to RP. DVH thresholds determined for radiation doses from 20 to 40 Gy were also predictive of RP. Considering only severe RP (grade greater than or equal to 2), only MLD, V20 and V30 remained associated with increased acute pulmonary toxicity. Conclusions: In this study, dosimetric factors (MLD, V20, V30) and age ( greater than or equal to60 years) were predictive of RP regarding the whole pulmonary toxicity (grade greater than or equal to 1). In addition, thresholds from 20 to 40 Gy, based on a stratification according to the median of the percentage of irradiated lung volume, were also predictive factors. They may, therefore, help discriminate patients at high and low risk for RP. However, only MLD, V20 and V30 remained associated with severe RP (grade : 2), probably due to the small number of severe events in our series.

We report a case of catheter-related bacteremia in a 63-year-old patient caused by Staphylococcus intermedius. Clinical resolution of the infection was obtained after removal of the intravenous device and antibiotic treatment. This observation emphasizes the risk of confusion between S. intermedius and Staphylococcus aureus if only a coagulase test is done.

Aim: Background: EGFR-TKI are a standard treatment for patients (pts) with NSCLC harboring activating EGFR mutations. All pts develop acquired resistance. At progression, the standard treatment is chemotherapy. Retrospective studies suggest that continuous use of EGFR-TKI beyond progressive disease (PD) may benefit some pts. Objective: The purpose of our retrospective multicentric study is to determine the frequency of continuation of EGFR-TKIs beyond RECIST-PD, and investigate the association of pts and disease characteristics with continuation of EGFR-TKIs at progression. Methods: Main inclusion criteria were: pts with NSCLC and activating EGFR mutations, EGFR-TKIs as their initial systemic therapy received between January 2010 and July 2012, Measurable lesion according to RECIST 1.1, acquired resistance to EGFR-TKI according to Jackman's criteria. Following data were collected: demographic and clinical data, Progression free survival (PFS), Overall Survival (OS), mutational status, mode of progression, therapeutic approach at PD. A comparison of clinical data and outcome of pts receiving EGFR-TKI beyond PD (group 1) versus discontinuing EGFR-TKI at PD (group 2) was made. Results: 133 pts were recruited in 29 centers: age 69 ± 12.7 years, female 67.6%, EGFR mutation exon 19/21/others: 65.4 %/ 30.8%/ 3.8%, adenocarcinoma 98%, never smokers 68.5%, PS 0/1: 80,5%. First line treatment: gefitinib 77.4%, erlotinib 21.8%. 40.6% pts continued EGFR-TKI beyond RECIST-PD (25,6% EGFR-TKI alone, 15% EGFR-TKI combined with local treatment). 59.3% pts changed treatment (39.8% chemotherapy, 7.5% combination chemotherapy +EGFR-TKI, 12% BSC). Median PFS was 9,4 (CI95% :8-10,9) months and median OS was 21,6 (CI95%18,7-25,8) months in the entire population. In group 1 and 2, m PFS was 10,1 (CI95% :7,7-12,3) and 8,7 (CI 95% :7,5-10,9) (p = 0,34) months and m OS was 23 and 20,4 months respectively (p = 0,08). All comparative data between groups 1 and 2, univariate and mutivariate analysis will be presented. Conclusions: This large retrospective study confirms that, in some circumstances, continuous use of EGFR-TKI beyond PD does not hamper OS and should be considered.Prospective studies will help to determine which patients benefit more this strategy. Clinical trial information: Supported by an academic grant from boehringer ingelheim, Hoffman Roche. Disclosure: J.B. Auliac: In the last five years, JB Auliac has received honoraria for attending scientific meetings, speaking, organizing research or consulting, from Boehringer Ingelheim, Hoffman-Roche, Lilly and Pfizer; C. Decroisette Phan van Ho: consultancy Hoffman roche; S. Bota Ouchlif: travel/accomodation meeting: Lilly; R. Corre: board membership: roche, lilly consultancy: roche, lilly travel/accommodations meeting: lilly, roche; P. Fournel: consultancy: roche, lilly, boehringer ingelheim; A. Vergnenegre: consultancy: roche grants/grants pending:roche, lilly, boehringer; L. Greillier: consultancy: roche, lilly grants/grants pending: roche travel/accommodation meeting: lilly, roche; R. Gervais: consultancy: Roche, Astra Zeneca et Boehringer ingelheim. All other authors have declared no conflicts of interest.