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Resume Depuis plus de 10 ans, de nombreux essais therapeutiques ont ete menes pour evaluer la place des traitements adjuvants ou neoadjuvants dans les carcinomes bronchiques non a petites cellules (CBNPC). Certains concernent les cancers operables de tout stade, d’autres uniquement certains stades. Quatre essais ayant porte sur le benefice de la chimiotherapie adjuvante (IALT, UFT, JBR10 et ANITA) ont demontre l’interet de la chimiotherapie dans les stades II et IIIA. Le benefice dans les stades IB est egalement probable, au moins pour les tumeurs de plus de 4 cm. Les meta-analyses des essais de chimiotherapie neo-adjuvante ont egalement demontre son impact positif sur la survie globale.

Resume Les cancers bronchiques non a petites cellules (CBNPC) de stade III-N2 sont un groupe heterogene de cancers localement avances. Leur pronostic differe selon le nombre, la taille et la topographie des ganglions mediastinaux envahis. Deux situations cliniques peuvent etre distinguees : les CBNPC dont l’atteinte N2 est decouverte apres traitement chirurgical (minimal N2) et les CBNPC dont l’extension ganglionnaire est affirmee au bilan initial (clinical N2). Le traitement des CBNPC de stade III-N2 varie selon le contexte clinique. Dans les CBNPC minimal N2, la chimiotherapie postoperatoire a demontre son benefice, alors que l’interet de la radiotherapie reste incertain. Une nouvelle etude randomisee de phase III evaluant la place de la radiotherapie postoperatoire est actuellement en cours en France (Lung Art-IFCT0503). Dans les CBNPC avec extension ganglionnaire initiale (clinical N2), les possibilites d’une exerese chirurgicale doivent etre evaluees. Les cancers non resecables sont traites par radiochimiotherapie concomitante, permettant a la fois le controle local et le traitement des micrometastases. Les cancers resecables sont preferentiellement traites par chimiotherapie d’induction. La chirurgie est reservee aux patients repondeurs au traitement d’induction et candidats a une lobectomie. L’utilisation de cette strategie permet d’integrer dans la decision therapeutique la notion de « downstaging » mediastinal qui est un facteur pronostique important. La difficulte de cette approche est en partie liee a l’appreciation de la reponse au traitement neoadjuvant, sous-estimee par la tomodensitometrie. Une nouvelle evaluation histologique ganglionnaire par echo-endoscopie oesophagienne ou bronchique permet dans certains cas une meilleure selection des patients susceptibles de beneficier du traitement chirurgical.

Resume En Europe et aux Etats Unis, il est possible de prescrire un traitement par chimiotherapie ou par therapeutique ciblee en deuxieme ligne pour les patients atteints d’un carcinome bronchique non a petites cellules de stade metastatique. Le docetaxel a ete la premiere molecule a obtenir une autorisation de mise sur le marche (AMM), en ayant demontre un gain sur la survie compare a des soins de confort ou a une monotherapie dans deux etudes de phase III. Le pemetrexed a ete la seconde drogue a obtenir une AMM grâce a un essai de phase III dans lequel le bras de reference etait le docetaxel. L’efficacite etait comparable entre les deux drogues avec un profil de toxicite a la faveur du pemetrexed. Enfin, l’erlotinib, qui est un inhibiteur des recepteurs tyrosine kinase de l’EGF (Epidermal growh factor) , est la troisieme alternative validee en seconde ligne par une etude de phase III. Dans cette revue, nous presenterons ces etudes pivot et discuterons les strategies de choix therapeutiques. Nous aborderons aussi les donnees actuelles preliminaires concernant les essais de chimiotherapie de deuxieme ligne « dite precoce », c’est-a-dire initiee immediatement apres une premiere ligne mais comportant des molecules differentes.

Le bevacizumab en premiere ligne, associe a une chimiotherapie a base de platine, ameliore la survie des patients presentant un carcinome bronchique non a petites cellules non epidermoides metastatiques. L’AMM dans cette indication a ete obtenue en 2007. Ce traitement presente des effets secondaires specifiques en rapport avec son action anti angiogenique. A l’etat physiologique, le VEGF est un facteur important du processus de cicatrisation. Le bevacizumab retarde la cicatrisation et peut favoriser les saignements. L’objectif de cet article est d’analyser les risques specifiques lors des actes invasifs et d’emettre des recommandations pratiques. Malheureusement, les donnees de la litterature sont peu nombreuses. Nous nous appuierons donc essentiellement sur les etudes de chimiotherapie neoadjuvante dans le cancer colorectal metastatique avant metastasectomie hepatique et sur notre experience dans les metastasectomies pulmonaires de tumeurs solides sous bevacizumab. Nous recommandons un delais de 2 jours entre la pose d’un Dispositif Veineux Implantable et le bevacizumab, un delais d’au moins 5 semaines entre la derniere injection de bevacizumab et une chirurgie invasive et un delais de 4 semaines entre une chirurgie invasive et l’initiation du bevacizumab. Le recours a une equipe medicochirurgicale rompue a la prise en charge de ce type de patients est bien evidemment recommandee.

Endobronchial lipoma is a rare benign bronchial tumour. A search should be carried out on submillimetre MDCT scan slices in patients presenting segmental or lobar collapse or recurrent pulmonary infection in the same bronchial territories. The authors report MDCT and MR imaging in a patient with endobronchial lipoma discovered on an MDCT scan.

International audience; Platinum-based perioperative chemotherapy is actually the standard of care in stage II–IIIa non-small cell lung cancer (NSCLC). A benefit may also be seen in stage IB NSCLC with tumors of more than 4 cm of diameter. Perioperative chemotherapy improves 5-year survival of 4 to 15%. This benefit is mainly proved by postoperative chemotherapy trials. Nevertheless, preoperative chemotherapy has advantages: a better tolerance, an estimation of tumor chemosensibility, without an increased postoperative morbimortality. However, pTNM and pathological tumor analyses are modified. Indications of postoperative radiotherapy are limited. In early stage NSCLC (stage I-II), radiotherapy worsens survival. Radiotherapy is routinely achieved in NSCLC with parietal tumor invasion and incomplete tumor resection. Indications of immunotherapy and targeted therapies in case of oncogenic addiction remain to be established in resected NSCLC. Several biomarkers are studied to better describe the indications of perioperative chemotherapy: recognize groups of patients with a worse prognosis and distinguish chemosensibility of the tumor.; Une chimiothérapie à base de platine administrée en périopératoire a démontré un bénéfice sur la survie dans le traitement des cancers bronchiques non à petites cellules (CBNPC) de stades II, IIIA et peut être IB (tumeur de plus de 4 cm de diamètre). Ce gain de survie varie entre 4 et 15 % selon les études. Le niveau de preuve est plus élevé pour la chimiothérapie adjuvante que néo-adjuvante. La chimiothérapie néo-adjuvante présente cependant certains avantages : une meilleure adhésion au traitement et une évaluation de la chimiosensibilité de la tumeur. Néanmoins, l’analyse précise anatomopathologique et le pTNM sont modifiés. La place de la radiothérapie postopératoire est restreinte. Dans les stades précoces (stades I-II), elle est délétère sur la survie. Elle est réalisée en routine en cas d’atteinte pariétale avec résection incomplète. La place de l’immunothérapie ou des thérapies ciblées en situation d’addiction oncogéniques reste à déterminer dans les CBNPC réséqués. Plusieurs marqueurs biologiques sont étudiés pour mieux définir les indications à un traitement médical périopératoire afin de déterminer les groupes de patients ayant un pronostic péjoratif et identifier les patients ayant une tumeur chimiosensible.

In response to the paper by Popat et al. "Recurrent responses to non-small-cell lung cancer brain metastases with erlotinib", we wish to report a similar case and to provide comments. A 32-year-old Chinese never-smoker female presented a primary lung adenocarcinoma with brain metastasis and three subsequent responses to EGFR tyrosine kinase inhibitors (gefitinib and erlotinib). Direct sequencing of epidermal growth factor receptor (EGFR) gene exons 18 to 21 and K-ras gene was performed on tissue obtained from initial biopsies and post-chemotherapy surgical specimens. An EGFR exon 21 L858R point mutation was identified on pre- and post-chemotherapy samples. K-ras mutations and EGFR exon 20 T790M point mutations were not detected. Moreover, EGFR protein overexpression was observed by immunohistochemistry as well as EGFR gene high polysomy by fluorescent in situ hybridization. These case suggest that re-challenging patients with NSCLC several times with EGFR-TKI should be considered when progressive disease is observed under chemotherapy. However, we do not yet know whether this option should be considered in light of tumor molecular evaluation, or whether it should be proposed to patients who experienced a clinical response after a first administration.

Resume Le pronostic des cancers du poumon non a petites cellules reste mauvais. La chimiotherapie fait partie du traitement multimodal propose pour la plupart des stades de la maladie. Pouvoir adapter la prescription de chimiotherapie a certaines caracteristiques cliniques ou biologiques specifiques de chaque patient est une des priorites actuelles de la recherche translationnelle. Plusieurs marqueurs sont ainsi en cours de validation. Dans cette revue, nous discuterons la valeur predictive de ERCC1 (excision repair cross complementary group 1) pour apprecier la sensibilite au cisplatine, de la tubuline β de classe III pour les vinca-alcaloides et les taxanes, de RRM1 (ribonucleotide transferase subunit 1) pour la gemcitabine et enfin de certains parametres cliniques et biologiques pour la sensibilite a l’erlotinib. Les donnees seront presentees de facon separee pour les stades metastatiques et les stades localises.

Resume Depuis les annees 2000, sept essais randomises de phase III ont ete publies ou rapportes comparant dans le traitement des cancers bronchique non a petites cellules (CBNPC) la seule chirurgie a l’association chimiotherapie-chirurgie. Quatre d’entre eux (IALT, UFT, JBR10 et ANITA) sont positifs et demontrent l’interet de la chimiotherapie dans les stades II et IIIA. Le benefice dans les stades IB est egalement probable, au moins pour les tumeurs de plus de 4 cm. La predictivite de l’action de la chimiotherapie a partir de criteres biologiques constitue une importante voie de recherche.

Resume Le carcinome bronchiolo-alveolaire (CBA) est un adenocarcinome (ADC) pulmonaire primitif developpe aux depens des cellules de l’unite respiratoire terminale. Sa definition histologique restrictive, imposee par la classification anatomopathologique de l’OMS en 1999, necessite la realisation d’une exerese tumorale chirurgicale complete afin d’exclure tout signe d’invasion. Bien que les tumeurs de stades IIIB-IV soient exclues du cadre des CBA par la definition stricte de l’OMS, le premier « workshop » international consacre a cette tumeur en 2004 a souligne le continuum anatomoclinique existant entre le CBA de la classification OMS et les ADC mixtes avec composante CBA (ADC-CBA). En effet, le CBA et les ADC-CBA se distinguent des autres carcinomes non a petites cellules par une frequence accrue de survenue chez les femmes, les non fumeurs et les asiatiques. La progression tumorale essentiellement lepidique et aerogene de ces tumeurs explique la presentation volontiers pneumonique, multifocale ou diffuse et le deces plus souvent lie a la diffusion pulmonaire bilaterale qu’a la survenue de metastases extrathoraciques. L’evolution est plus lente et le pronostic meilleur que celui des autres ADC. Le traitement repose sur la chirurgie dans les formes localisees. La constatation frequente d’une surexpression du recepteur de l’« epidermal growth factor » (EGFR) et d’une amplification et/ou d’une mutation de son gene ainsi que l’observation de quelques cas de reponse majeure aux inhibiteurs de la tyrosine kinase de l’EGFR ont conduit a la realisation de plusieurs essais therapeutiques avec ces medicaments. Cependant, la place de la chimiotherapie a ete recemment reevaluee.

Purpose: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non–small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features. Experimental Design: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features. Results: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor α/tumor necrosis factor α receptor inhibitor, interleukin-1α /interleukin-1α receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis). Conclusions: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.

Resume Depuis 1996, la mortalite liee au SIDA a considerablement diminue grâce a l’introduction des tritherapies (HAART). Ceci s’est accompagne d’une augmentation de la proportion de deces par cancers non lies au SIDA, et en particulier, par cancer broncho-pulmonaire (CBP). Le risque de developper un CBP est plus eleve dans la population seropositive pour le virus de l’immunodeficience humaine (VIH+) que dans la population generale de meme âge, certainement parce que le tabagisme y est plus important, en particulier chez les toxicomanes, mais aussi pour d’autres raisons qui restent encore a determiner. L’âge moyen de decouverte du CBP est de 45 ans chez les patients VIH+, et la plupart sont symptomatiques. Le diagnostic est pose a un stade localement avance ou metastatique dans 75 a 90 % des cas, comme dans la population generale. L’adenocarcinome est le sous type histologique le plus frequent. Le pronostic est plus mauvais chez les patients VIH+ que chez les patients VIH indetermines. Les donnees concernant l’efficacite et la toxicite de la chimiotherapie sont insuffisantes. La chirurgie demeure le traitement de choix pour les maladies localisees si l’etat clinique et fonctionnel respiratoire le permet. Des etudes cliniques prospectives sont necessaires pour definir quelle serait la meilleure strategie de prise en charge du CBP chez le patient VIH+.

Resume Bien que la classification de l’Organisation Mondiale de la Sante (OMS) de 1999, revue en 2004, exclue par definition des carcinomes bronchiolo-alveolaires (CBA) les tumeurs de stades IIIB-IV (car inoperables), le premier « Workshop » international (novembre 2004, New York) consacre a cette tumeur a souligne l’existence d’un continuum entre le CBA de classification OMS et les adenocarcinomes avec composante de type CBA qui partagent les memes particularites epidemiologique, biologique, clinique, radiologique, pronostique et therapeutique. Ces constatations ont fait suggerer de ne pas inclure les ADC-CBA de stade IIIB-IV dans les etudes destinees aux autres cancers bronchiques non a petites cellules. L’objectif de cette revue est d’analyser les resultats des etudes prospectives actuellement disponibles concernant le traitement des ADC-CBA de stade IIIB-IV. Il n’y a pas d’etude avec des associations de chimiotherapie a base de platine. Une monotherapie par paclitaxel semble avoir une efficacite similaire a celle des inhibiteurs de la tyrosine kinase du recepteur de l’epidermal growth factor (gefitinib et erlotinib) (TKI-EGFR). Le profil de tolerance est en faveur des TKI-EGFR. Il semble que ce ne soit pas les memes malades qui repondent au paclitaxel et aux TKI-EGFR. Ces constatations invitent a poursuivre les etudes de strategies et la recherche de nouvelles molecules pour le traitement des ADC-CBA etendus.

The definition of broncho-pulmonary aspergillosis infections in non-immunocompromised patients remains vague and a wide range of clinical, radiological and pathological entities have been described with a variety of names, i.e. simple aspergilloma, complex aspergilloma, semi-invasive aspergillosis, chronic necrotizing pulmonary aspergillosis, chronic cavitary and fibrosing pulmonary and pleural aspergillosis, pseudomembranous tracheobronchitis caused by Aspergillus, and invasive aspergillosis. However, these disease entities share common characteristics suggesting that they belong to the same group of pulmonary aspergillosis infectious disorders: 1- a specific diathesis responsible for the deterioration in local or systemic defenses against infection (alcohol, tobacco abuse, or diabetes); 2- an underlying bronchopulmonary disease responsible or not for the presence of a residual pleural or bronchopulmonary cavity (active tuberculosis or tuberculosis sequelae, bronchial dilatation, sarcoidosis, COPD); 3- generally, the prolonged use of low-dose oral or inhaled corticosteroids and 4- little or no vascular invasion, a granulomatous reaction and a low tendency for metastasis. There are no established treatment guidelines for broncho-pulmonary aspergillosis infection in non-immunocompromised patients, except for invasive aspergillosis. Bronchial artery embolization may stop hemoptysis in certain cases. Surgery is generally impossible because of impaired respiratory function or the severity of the comorbidity and when it is possible morbidity and mortality are very high. Numerous clinical cases and short retrospective series have reported the effect over time of the various antifungal agents available. Oral triazoles, i.e. itraconazole, and in particular voriconazole, appear to provide suitable treatment for broncho-pulmonary aspergillosis infections in non-immunocompromised patients.

International audience; Introduction : Chemoresistance is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). As the Sonic Hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.Materials and Methods : From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n=36). Shh activation was evaluated through Gli1 and Gli2 expression by immunohistochemistry (IHC) (quantitative score). In vitro treatment studies with cisplatin, vismodegib (Shh-pathway inhibitor) or both were performed on NSCLC cell lines (H322 and A549) and on primary cultures from patients with sarcomatoid carcinoma (n=4).Results : Twelve patients were refractory to chemotherapy (r-patients, 33.3%) and 24 had controlled disease (c-patients). Gli1 expression did not differ between the r- and c-patients (p=0.35). Gli2 expression was more often positive in the r-patients (41.7% versus 8.3%, p=0.02). Progression-free survival (PFS) and overall survival (OS) in patients with Gli2-positive score were 2.1 and 8.0 months, respectively, versus 6.7 and 18.0 months in patients with Gli2-negative score (p=0.03; p=0.002). In multivariate analysis, Gli2 score was independently correlated with PFS (hazard ratio [HR]=2.64; 95% confidence interval [CI]: 1.05-6.63; p=0.04) and OS (HR=4.36; 95% CI: 1.67-11.36; p=0.003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than the H838 and A549 cell lines. The cisplatin - vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro.Conclusion : The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.

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.

International audience; Background - Chronic kidney disease (CKD) is frequent in individuals infected with human immunodeficiency virus (HIV). Progression to end-stage renal disease can be slowed by appropriate medical management. Methods - To assess whether active promotion of guidelines improves CKD management, we conducted a cluster randomized controlled trial within the French Hospital Database on HIV (FHDH-ANRS CO4). We randomized 46 centers participating in the FHDH to either simple information on guideline availability or active promotion with a multifaceted and repeated intervention comprising reminders and audit feedback and targeting of local opinion leaders carried out between April 2009 and April 2010. Outcome measure was CKD management adequacy assessed before and 2 years after the beginning of the intervention in HIV-infected patients with moderate to severe CKD. CKD management was considered adequate in case of referral to a nephrologist or if proteinuria, blood pressure, low-density lipoprotein cholesterol level, and glycemia had been measured during the previous year and medications had been prescribed when necessary. Results - Three hundred six patients were enrolled, of whom 238 (78%) completed the 2 years of follow-up. During the study period, the percentage of patients receiving adequate CKD management improved from 64.1% to 70.4% (+6.3%) in the active arm and from 68.3% to 75.6% (+7.3%) in the control arm (adjusted mean difference, -0.7 percentage points [95% confidence interval: -9.2 to 7.9]; P = .95). The biggest impact of active promotion was on the management of proteinuria and blood pressure. Conclusions - Adequate compliance with CKD management guidelines improved slightly between 2009 and 2011, with no difference between the simple information and active promotion arms. Clinical trials registration - CCTIRS 10.150 and CNIL DR-2010-379.

Resume Le carcinome bronchiolo-alveolaire (CBA) est un adenocarcinome (ADC) pulmonaire primitif developpe aux depens des cellules de l’unite respiratoire terminale. Sa definition histologique restrictive, imposee par la classification anatomopathologique de l’OMS en 1999, necessite la realisation d’une exerese tumorale chirurgicale complete afin d’exclure tout signe d’invasion. Bien que les tumeurs de stades IIIB-IV soient exclues du cadre des CBA par la definition stricte de l’OMS, le premier « workshop » international consacre a cette tumeur en 2004 a souligne le continuum anatomo-clinique existant entre le CBA de la classification OMS et les ADC mixtes avec composante CBA (ADC-CBA). En effet, le CBA et les ADC-CBA se distinguent des autres carcinomes non a petites cellules par une frequence accrue de survenue chez les femmes, les non-fumeurs et les Asiatiques. La progression tumorale essentiellement lepidique et aerogene de ces tumeurs explique la presentation volontiers pneumonique, multifocale ou diffuse et le deces plus souvent lie a la diffusion pulmonaire bilaterale qu’a la survenue de metastases extra-thoraciques. L’evolution est plus lente et le pronostic meilleur que celui des autres ADC. Le traitement repose sur la chirurgie dans les formes localisees. La constatation frequente d’une surexpression du recepteur de l’« epidermal growth factor » (EGFR) et d’une amplification et/ou d’une mutation de son gene ainsi que l’observation de quelques cas de reponse majeure aux inhibiteurs de la tyrosine-kinase de l’EGFR ont conduit a la realisation de plusieurs essais therapeutiques avec ces medicaments. Cependant, la place de la chimiotherapie a ete recemment re-evaluee.

In our hospital as in many others, primary lung cancer is the most frequent indication for FDG PET. Studies have assessed the clinical utility of this imaging modality in characterizing solitary pulmonary nodules or masses, initial staging, defining tumor volume in radiotherapy and searching for recurrence of or restaging non-small cell carcinoma; studies are currently underway to evaluate its use in early assessment of chemotherapy response. Small cell lung cancer has a high FDG uptake and PET/CT can be useful for rapid staging. False negative results may be due to pure bronchioloalveolar carcinomas and endocrine tumors. FDG-PET will certainly play a more important role in the diagnosis and follow-up of pleural cancers in the future. An unexpected positive FDG PET focus should be considered as a warning, but histological proof should precede any irrevocable decisions.

Resume Un certain nombre d’arguments conduisent a penser que le pronostic des cancers bronchiques non a petites cellules a pu s’ameliorer pendant ces vingt dernieres annees. La comparaison des etudes historiques menees pendant des periodes differentes met en evidence un gain de survie mais expose a de nombreux biais lies a la selection des malades et a l’effet Will Rogers. Les etudes prospectives randomisees demontrent un certain nombre de progres : la chimiotherapie peri-operatoire dans les stades operables, la radio-chimiotherapie concomitante dans les IIIB, les drogues recentes dans les stades IV ameliorent le pronostic. Pourtant, l’analyse des registres jusqu’a 1997 n’objective pas d’amelioration significative de la survie. Cette discordance pourrait s’expliquer par les differences entre la population generale (stade avance, PS eleve) et la population selectionnee par les essais therapeutiques. De plus, les conclusions de ces essais ne sont pas toujours appliquees. Enfin, les progres les plus importants sont posterieurs a 1997. En conclusion, le pronostic des cancers bronchiques non a petites cellules s’est ameliore dans une population selectionnee de malades. Pour esperer retrouver cette amelioration dans la population generale, il faut que celle-ci soit traitee selon les recommandations issues de ces essais.

The large majority of patients with acute respiratory failure present diffuse pulmonary opacities resulting from pulmonary embolism, intra-alveolar hemorrhage, or a classical cause of ARDS. In a small number of patients however, these opacities correspond to diffuse interstitial pneumonia. This should be suspected in light of the context, the time of formation, and the unusual respiratory and/or extrarespiratory signs. If there is a clinical doubt, thoracic scan and bronchoalveolar lavage should be performed together with infectious and immunology tests. Treatment depends on the cause and/or the type of lesion.

Resume Le cancer bronchique est une des pathologies tumorales les plus difficiles a irradier. A la difficulte balistique, due aux mouvements respiratoires, au nombre et a la faible tolerance des organes sains avoisinants, s’ajoute une difficulte dosimetrique due a la grande heterogeneite des tissus traverses. Aujourd’hui, l’irruption en radiotherapie thoracique de nouvelles techniques integrant dans la procedure de traitement les derniers developpements technologiques en matiere d’imagerie medicale, de contention, de dosimetrie, et d’appareils de traitement, suscitent des espoirs nouveaux pour le traitement des pathologies tumorales thoraciques. Deux techniques semblent particulierement prometteuses : la radiotherapie de conformation, et l’irradiation avec asservissement respiratoire. La radiotherapie de conformation, irradiation conformationnelle tridimensionnelle avec ou sans modulation d’intensite, a pour vocation d’aboutir a une irradiation de tres haute precision en integrant les derniers developpements technologiques de l’imagerie medicale. Ces outils sont utilises afin d’optimiser l’irradiation des volumes cibles pour eviter les recidives, tout en epargnant le plus possible les tissus sains. A terme, la protection accrue des tissus sains permet d’envisager une augmentation importante de la dose tumorale. Les techniques d’asservissement respiratoire representent un autre progres important pour le traitement des tumeurs mobiles avec la respiration. Ces techniques permettent de mieux adapter les champs d’irradiation a la tumeur et ainsi de proteger certains organes critiques (le poumon, le cœur…). Elles commencent a etre utilisees en routine, dans plusieurs centres, dans le monde. Les premiers resultats sont tres prometteurs. Cet article decrit ces techniques maintenant disponibles en radiotherapie thoracique.

International audience; OBJECTIVE: We aimed at assessing in persons living with HIV with a smoking history an association between lung cancer risk and protease inhibitors exposure, especially ritonavir. DESIGN: A nested case-control study was conducted within the ANRS CO4 FHDH, CO3 Aquitaine and Tenon's Hospital Cohorts. METHODS: Cases and controls were eligible if they were ex-smokers or current smokers at the index date, and had a CD4 cell count reported in the year preceding the index date. Cases were incident cases of lung cancer diagnosed between 1 January 2000 and 31 December 2011. All cancer cases were validated and histological types identified when available. Three controls were randomly selected by incidence density sampling using calendar time as the time axis, with individual matching on cohort, age (± 5 years), route of HIV acquisition, sex and hospital. Analyses were performed using conditional logistic regression adjusted for nadir CD4 cell count and smoking status. Ritonavir and protease inhibitors exposures were represented in separate models using categorical variables (never exposed, ever exposed). Several sensitivity analyses were performed. RESULTS: This study performed in 1447 persons living with HIV with a smoking history (383 lung cancer cases and 1064 control patients) did not evidence any association between lung cancer risk and protease inhibitors exposure including ritonavir. CONCLUSION: These results suggest that the risk of lung cancer is not influenced by pharmacologically induced P450 cytochrome protease inhibitors inhibition among smokers or ex-smokers

Central nervous system (CNS) metastases are common in patients with non-small cell lung cancer (NSCLC), particularly in adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. In single brain metastasis, surgery or stereotactic radiosurgery should be discussed. Whole-brain radiation therapy is necessary in case of multiple symptomatic metastases. Systemic treatment remains a challenge. Preclinical data and case series confirm the efficacy of EGFR tyrosine kinase inhibitor (TKI) on EGFR-mutated NSCLC CNS metastases. Detecting EGFR mutations in the brain is difficult, as a surgical specimen is needed. In leptomeningeal metastases, molecular analysis in the cerebrospinal fluid is a reliable method to detect EGFR mutations. In patients with mutated NSCLC, brain metastases present usually the same mutation as the primary tumor. In EGFR-mutated NSCLC, objective response rates of EGFR-TKIs were between 43% and 89%, with a progression-free survival of more than 6 months and an overall survival of more than 12 months. As CNS penetration of EGFR-TKIs is limited, dose escalation may be an option. The higher serum concentration of erlotinib compared to gefitinib may lead to higher cerebrospinal fluid concentration, and erlotinib may be more effective in CNS metastases as gefitinib. Data of EGFR-TKI efficacy in brain metastases of patients with EGFR wild-type NSCLC are scarce. Response rates seem disappointing. However, as TKIs are good radiosensitizers, several clinical trials are in progress to evaluate the efficacy of adding a TKI during whole-brain radiation therapy in NSCLC brain metastases.

The conformal radiotherapy approach, three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT), is based on modern imaging modalities, efficient 3D treatment planning systems, sophisticated immobilization devices and demanding quality assurance and treatment verification. The main goal of conformal radiotherapy is to ensure a high dose distribution tailored to the limits of the target volume while reducing exposure of healthy tissues. These techniques would then allow a further dose escalation increasing local control and survival. Non-small cell lung cancer (NSCLC) is one of the most difficult malignant tumors to be treated. It combines geometrical difficulties due to respiratory motion, and number of low tolerance neighboring organs, and dosimetric difficulties because of the presence of huge inhomogeneities. This localization is an attractive and ambitious example for the evaluation of new techniques. However, the published clinical reports in the last years described very heterogeneous techniques and, in the absence of prospective randomized trials, it is somewhat difficult at present to evaluate the real benefits drawn from those conformal radiotherapy techniques. After reviewing the rationale for 3DCRT for NSCLC, this paper will describe the main studies of 3DCRT, in order to evaluate its impact on lung cancer treatment. Then, the current state-of-the-art of IMRT and the last technical and therapeutic innovations in NSCLC will be discussed.

International audience; OBJECTIVE: To evaluate the impact of highly active antiretroviral therapy (HAART) on survival in HIV infected patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: All consecutive HIV infected patients with NSCLC diagnosed between 06/1996 and 03/2007 at two University hospitals in Paris (France) were prospectively followed until death. The association between survival and clinical and biological factors was analyzed by univariate and multivariate models. Survival analysis was performed by Kaplan-Meier estimates and the Cox proportional hazards regression model. RESULTS: During the study period, NSCLC was diagnosed in 49 consecutive HIV infected patients (median age 46 years); 84% had advanced disease. Median survival was 8.1 months (range 5-10 months). In multivariate analysis, baseline parameters with significant positive impact on survival included performance status (PS) < or =1 (HR=0.2, 95%CI [0.09, 0.46], p=0.0001), stage I-II disease (HR=0.15, 95%CI [0.04, 0.53], p=0.003), and use of HAART (HR=0.4, 95%CI [0.2, 0.9], p=0.027). CONCLUSION: HAART is a good prognostic factor for survival in HIV infected patients with NSCLC. Stage of disease and PS are two other valid survival prognostic factors.

Objectives Improved survival among HIV-infected individuals after the advent of combination antiretroviral therapy (cART) had drawn attention on non-AIDS-defining cancers. We evaluated the incidence and risk trends of lung cancer, Hodgkin's lymphoma, liver and anal cancers, focusing on patients with CD4 cell recovery and age at diagnosis, by comparison with the general population. Design Cohort study. Methods Standardized incidence rates were calculated in the HIV-infected individuals followed in the FHDH and the general population in France in 1997-2000, 2001-2004, and 2005-2009. We estimated standardized incidence ratios for each period and for patients with CD4 cell count at least 500 cells/μl for at least 2 years on cART. Results Among the 84,504 HIV-infected individuals, the risk of lung and anal cancers fell during the cART era, whereas that of Hodgkin's lymphoma and liver cancer remained stable. In 2005-2009, the standardized incidence ratios for lung cancer, Hodgkin's lymphoma, liver and anal cancers were, respectively, 2.8 [95% confidence interval (CI) 2.5-3.1], 26.5 (95% CI 23.2-30.1), 10.9 (95% CI 9.6-12.3) and 79.3 (95% CI 69.5-90.1). Among patients with CD4 cell recovery on cART, the risk was close to that of the general population for lung cancer, nine-fold higher for Hodgkin's lymphoma, and 2.4-fold higher for liver cancer. Age at diagnosis was significantly younger among HIV-infected individuals for lung cancer (-3.3 years), Hodgkin's lymphoma (-1 year) and liver cancer (-10.1 years). Conclusion HIV-infected patients were at a higher risk for the four cancers over 1997-2009. CD4 cell recovery appears to control the excess risk of lung cancer. For liver cancer and Hodgkin's lymphoma, our results suggest that CD4 should never drop below 500/μl 500 cells/μl to avoid the excess risk.

Objectives Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management. Materials and methods From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR , KRAS , HER2 , BRAF , PIK3CA , and MET genes mutations (PCR). Results Seventy-seven patients were included. Median age was 61 years (53–69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS , PIK3CA , EGFR , and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size p =0.011), no lymph-node metastasis (HR=3.25 [1.68–6.31], p p =0.002), no BVI (HR=1.22 [1.06–1.40], p =0.005), and no squamous component (HR=3.17 [1.48–6.79], p =0.01) were associated with longer OS. Biomarkers did not influence OS. Conclusion Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.

International audience; Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI) are a therapeutic option as second-line therapy in non-small-cell lung carcinoma (NSCLC), regardless of the EGFR gene status. Identifying patients with early progression during EGFR-TKI treatment will help clinicians to choose the best regimen, TKI or chemotherapy. From a prospective database, all patients treated with gefitinib or erlotinib between 2001 and 2010 were retrospectively reviewed. Patients were classified into two groups according to their tumor response by RECIST after 45 days of treatment, progressive disease (PD) or controlled disease (CD). Two hundred and sixty-eight patients were treated with EGFR-TKI, among whom 239 were classified as PD (n = 75) and CD (n = 164). Median overall survival was 77 days (95% CI 61–109) for PD and 385 days (95% CI 267–481) for CD. Patients with PD were of younger age (P = 0.004) and more frequently current smokers (P = 0.001) had more frequently a performance status ≥2 (P = 0.012), a weight loss ≥10% (P = 0.025), a shorter time since diagnosis (P < 0.0001), a pathological classification as non-otherwise-specified NSCLC (P = 0.01), and the presence of abdominal metasta-ses (P = 0.008). In multivariate analysis, abdominal metastases were the only factor associated with early progression (odds ratio (OR) 2.17, 95% CI [1.12– 4.19]; P = 0.021). Wild-type EGFR versus mutated EGFR was associated with early progression. The presence of abdominal metastasis was independently associated with early progression in metastatic NSCLC receiving EGFR-TKI.

Introduction Le pronostic du cancer bronchique non a petites cellules (CBNPC) est sombre chez les personnes vivant avec le VIH (PVVIH). Des avancees therapeutiques ont ete faites dans la population generale en termes d’immunotherapie ciblant notamment le checkpoint immunitaire PD-1/PD-L1. Nous avons etudie l’expression des biomarqueurs associes a ce checkpoint chez les PVVIH atteints d’un CBNPC. Methodes Les donnees etaient issues de patients PVVIH ayant un CBNPC, de tout stade, diagnostique consecutivement entre 1996 et 2014, ayant une biopsie disponible. L’expression tumorale de PD-L1 etait analysee en immunohistochimie par 2 anticorps (clone E1L3 N, Cell Signaling et clone 5H1, L Chen, Yale University) ainsi que celles de CD3 (clone SP7), CD4 (1F6), CD8 (C8/144b please provide the external repository name for the object ), CD20 (L26), CD163 (10D6) et MPO (59A5 [WM1]). Le score utilise etait le % de cellules positives/surface. Pour PD-L1, le marquage etait considere positif lorsque le % de cellules tumorales positives etait superieur a 5 %. Ces resultats ont ete compares a ceux d’une population de 54 patients atteints de CBNPC non-VIH. Resultats Trente-quatre biopsies etaient disponibles dont 44,1 % chirurgicales. Il y avait 88,2 % d’hommes, avec un âge median de 51,1 ans, et 76,5 % d’adenocarcinomes. Six pour cent etaient mutes EGFR , et 8,8 % mutes KRAS . Le taux median de CD4 etait de 480/μL (86–1120) et 64 % avaient une charge virale indetectable. Six tumeurs (17,6 %) presentaient une expression de PD-L1 avec l’anticorps de Cell Signaling, et 3 (8,8 %) avec celui de L. Chen. La comparaison des PVVIH et des non-VIH ne montrait aucune difference d’expression de PD-L1 entre ces 2 populations, pour les 2 anticorps ( p = 0,41 et p = 0,54) mais il existait une infiltration plus importante en CD8, CD20 et CD163 chez les PVVIH ( Tableau 1 ). Conclusion Les CBNPC des PVVIH avaient un infiltrat plus important en CD8, CD20 et CD163 que les non-VIH mais exprimaient PD-L1 de la meme facon. Ceci suggere la possibilite de realiser des essais evaluant les immunotherapies dans cette population.

Introduction Le parcours de soin des patients atteints de CBP est un processus complexe et le delai entre la suspicion diagnostique et l’annonce du projet therapeutique est une sequence faisant intervenir une grande variete de professionnels. Selon l’Institut national du cancer, les delais caracterisant ce parcours constituent de bons marqueurs de l’acces aux soins et pourraient etre integres dans les criteres d’agrement des etablissements. Methodes Les patients, pris en charge dans le service de pneumologie d’un hopital universitaire parisien pour un premier CBP primitif, et enregistres en reunion de concertation pluridisciplinaire, entre le 1/11/13 et le 31/10/14, ont ete inclus de maniere prospective. Chaque etape cle du parcours patient a ete mesuree ( Fig. 1 ) et nous avons determine les facteurs sociodemographiques, medicaux et organisationnels, influencant le delai global de prise en charge. Resultats Le delai global median (delai entre la premiere imagerie suspecte et le premier traitement) des 243 patients analyses, etait de 38 jours (33 jours pour la chimiotherapie et 87 jours pour la chirurgie). L’absence de signe clinique, le stade localise (I–II), le type histologique non a petites cellules, la necessite d’examens invasifs supplementaires et le mode d’entree programme a l’hopital, etaient des facteurs independants d’allongement du delai global. Conclusion Le delai global de prise en charge du CBP dans notre service etait conforme aux recommandations internationales. L’aspect organisationnel intra-hospitalier etait un facteur independant d’allongement de ce delai et est donc un enjeu majeur de notre systeme de soins.