Search

Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma.This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272.Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure).Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.French Cooperative Thoracic Intergroup.

e21623 Background: IMpower110 evaluated atezo mono in PD-L1–selected, chemo-naive patients (pts) with nonsquamous (nsq) or squamous (sq) NSCLC. At the interim analysis, IMpower110 met its primary OS endpoint, with a statistically significant and clinically meaningful improvement for atezo vs chemo in TC3 or IC3 wild-type ( EGFR/ALK-negative) pts. We report on the safety profile of atezo vs chemo in IMpower110. Methods: 572 pts with stage IV nsq or sq NSCLC, PD-L1 expression ≥ 1% on TC or IC and ECOG PS 0-1 were randomized 1:1 to receive atezo (1200 mg IV q3w) or chemo (4 or 6 21-day cycles). In the chemo arm, nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed (pem) 500 mg/m2 IV q3w; sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Safety was assessed in all treated pts (safety evaluable [SE] population [pop]), regardless of PD-L1 expression or EGFR/ALK status. AEs were summarized per MedDRA v22.0 and severity graded per NCI CTCAE v4.0. Immune-mediated AEs (imAEs) were defined per a sponsor-specified list of terms, regardless of whether the events led to systemic glucocorticoid, endocrine therapy, or other immunosuppressants use. Results: At data cutoff (Sep 10, 2018) within the ITT pop, treatment (tx) was ongoing in 90 (atezo: 31.6%) and 25 (chemo: 8.7%) pts, with 13.7 mo of follow-up. Within the SE pop (atezo: n = 286, chemo: n = 263), atezo pts had longer tx exposure (5.3 mo) vs chemo pts (pem, 3.5 mo; gem, 2.6 mo; carbo, 2.3 mo; cis, 2.1 mo). Atezo had a favorable safety profile vs chemo (table); safety data were consistent with data from a pooled atezo mono pop. imAEs occurred in 40.2% (atezo) and 16.7% (chemo) of pts and were Grade (Gr) 3-4 in 6.6% and 1.5%, respectively. Conclusions: Atezo was better tolerated than chemo and imAEs were generally low grade. Overall, the safety experience with atezo mono in IMpower110 was consistent with its known safety profile; no new safety signals were identified. Clinical trial information: NCT02409342. [Table: see text]

A 56-year-old HIV1/HBV co-infected Caucasian man with medical history of asthma and chronic obstructive pulmonary disease (COPD) presented with cough, increasing dyspnea, and general weakness. He h...

Introduction This phase II study evaluated the efficacy and safety of the pan-cyclin–dependent kinase inhibitor roniciclib with platinum-based chemotherapy in patients with extensive-disease SCLC. Methods In this randomized, double-blind study, unselected patients with previously untreated extensive-disease SCLC received roniciclib, 5 mg, or placebo twice daily according to a 3 days–on, 4 days–off schedule in 21-day cycles, with concomitant cisplatin or carboplatin on day 1 and etoposide on days 1 to 3. The primary end point was progression-free survival. Other end points included overall survival, objective response rate, and safety. Results A total of 140 patients received treatment: 70 with roniciclib plus chemotherapy and 70 with placebo plus chemotherapy. Median progression-free survival times was 4.9 months (95% confidence interval [CI]: 4.2–5.5) with roniciclib plus chemotherapy and 5.5 months (95% CI: 4.6–5.6) with placebo plus chemotherapy (hazard ratio [HR] = 1.242, 95% CI: 0.820–1.881, p = 0.8653). Median overall survival times was 9.7 months (95% CI: 7.9–11.1) with roniciclib plus chemotherapy and 10.3 months (95% CI: 8.7–11.9) with placebo plus chemotherapy (HR = 1.281, 95% CI: 0.776–1.912, p = 0.7858). The objective response rates were 60.6% with roniciclib plus chemotherapy and 74.6% with placebo plus chemotherapy. Common treatment-emergent adverse events in both groups included nausea, vomiting, and fatigue. Serious treatment-emergent adverse events were more common with roniciclib plus chemotherapy (57.1%) than with placebo plus chemotherapy (38.6%). Conclusions Roniciclib combined with chemotherapy demonstrated an unfavorable risk-benefit profile in patients with extensive-disease SCLC, and the study was prematurely terminated.

International audience; Calpain 1 is a proinflammatory calcium-activated cysteine protease, which can be partly externalized. Extracellular calpains limit inflammatory processes and promote tissue repair, through cell proliferation and migration. Toll like receptor (TLR) 2 has been identified as a target of extracellular calpains in lymphocytes. The aim was to investigate the externalization of calpain 1 and the release of soluble TLR2 during tumor progression of pulmonary lepidic predominant adenocarcinoma (LPA). Extracellular calpain 1, soluble fragment of TLR2 and cytokines were analyzed by ELISA in bronchoalveolar lavage fluid (BALF) supernatants from patients with LPA (n = 68). Source of calpain was analyzed by immunohistochemistry and soluble TLR2 by flow cytometry on polymorphonuclear neutrophils (PMN) and human lung cancer cell lines. Extracellular calpain 1, secreted by tumor cells, was associated to tumor progression, neutrophilic inflammation, with a poor prognostic factor on survival (P = 0.003). TLR2 was expressed on PMN and tumor cells and decreased after calpain exposure. Soluble fragment of TLR2 in BALF supernatants was correlated to the extracellular calpain 1 concentration (r = 0.624; P < 0.001), and its high level was associated with tumor progression and a pro-inflammatory environment. Extracellular calpain 1 secreted by tumor cells, could participate in inflammatory microenvironment and tumor progression through TLR2 in LPA.

Introduction L’osimertinib est un inhibiteur de tyrosine kinase (ITK) qui a montre sa superiorite par rapport aux autres ITK dans le cancer bronchique non a petites cellules (CBNPC) mute EGFR de stade avance. La comprehension des mecanismes de resistance a l’osimertinib est necessaire afin d’optimiser la prise en charge de ces patients lors de la progression. Methodes Nous avons recueilli les donnees histo-moleculaires de tous les patients traites par osimertinib de 9 hopitaux universitaires en Ile-de-France entre 2015 et 2018, a partir des prelevements plasmatiques et tumoraux realises lors de la progression. Tous les echantillons avaient ete analyses par Next Generation Sequencing. Le taux de reponse objective (TRO), la survie globale (SG), la survie sans progression (SSP) et la duree sous traitement jusqu’a arret (TTD) ont aussi ete recueillis. Resultats Deux cent vingt-six patients ont ete inclus (2e ligne et plus : 219 [97 %]). Il s’agissait dans la plupart des cas d’un adenocarcinome (n = 218, 95 %) avec une deletion de l’exon 19 du gene EGFR (n = 134, 59 %). Cent vingt et un patients (53 %) avaient une atteinte secondaire du systeme nerveux central (SNC) a l’introduction de l’osimertinib. La duree mediane de suivi etait de 11,6 mois (IQR : 4,6–18,2). Le TRO etait de 52 % et le TRO pour le SNC etait de 56 %. La SSP et la SG mediane etaient de 9,5 mois (IQR : 4,0–17,2) et de 24 mois (IQR [12,4–Non Atteinte (NA)]). Le TTD etait de 12,7 mois (IQR : 5,1–24). A la date de recueil, 150 patients (66 %) avaient progresse dont 73 prelevements contributifs (56 biopsies) ont ete analyses. Les alterations histo-moleculaires les plus frequentes etaient la mutation C797S (n = 9 [13 %]) et l’amplification de MET (n = 8 [11 %]). Une transformation histologique etait retrouvee chez 5 patients (9 % des biopsies). La perte de la T790 M etait retrouvee dans 68 % des cas. La SSP et la SG apres progression etaient de 6,0 mois (IQR : 2,0–10,4) et 15,1 mois (IQR : 6,7–NA) respectivement, et plus longues en cas de poursuite de l’osimertinib apres progression par rapport a l’introduction d’un nouveau traitement systemique : 10,4 mois (IQR : 8,7–20,6) et 22,6 mois (IQR : 9,9–NR) versus 3,2 mois (IQR : 1,3–5,4) et 10,2 mois (IQR : 3,8–18,1) (p Conclusion Ce travail « en vie reelle » confirme l’efficacite de l’osimertinib dans le CBNPC mute EGFR de stade avance. Les alterations les plus frequentes retrouvees a la progression etaient l’amplification de MET et la mutation C797S.

Introduction L’isolement de MNT dans les secretions respiratoires n’est pas toujours associe a une infection. Le diagnostic d’infection a MNT selon les criteres 2007 de l’American Thoracic Society (ATS) ne conduit pas necessairement a la mise en place d’un traitement dont l’impact pronostique est incertain. L’objectif de l’etude est de decrire et comparer les caracteristiques et la survie d’une cohorte de patients ayant au moins un prelevement respiratoire positif a MNT (MNT+). Methodes Cette etude retrospective a inclus tous les patients MNT+ identifies dans un Hopital Universitaire Parisien entre 01/2012 et 06/2016. Les patients ayant un antecedent de VIH et de mucoviscidose ont ete exclus. La mediane de suivi etait de 31 mois. Les patients ont ete classes en 3 categories : infectes (IF), indetermines (ID) ou colonises (CO) en tenant compte des criteres ATS. Resultats Cent soixante et onze patients MNT+ ont ete inclus et repartis en : 75 IF (44 %), 41 ID (24 %) et 55 CO (32 %). Il n’y avait pas de difference selon l’âge, le sex-ratio, le tabagisme, les comorbidites, la presence d’une coinfection bacterienne ou aspergillaire et la frequence des symptomes respiratoires et generaux entre les 3 groupes. L’IMC etait inferieur chez les IF (IF : 20, ID : 24, C0 : 23, p = 0,0002). La positivite de l’examen direct (IF : 51 %, ID : 7 %, CO : 0 %, p Conclusion Dans notre etude, 44 % des patients avec MNT+ sont classes comme des infections et 24 % restent avec une incertitude diagnostique du fait d’un TDM non compatible ou d’un autre diagnostic associe. Les infections se caracterisent par un IMC plus bas et avec plus souvent un aspect TDM cavitaire et des examens directs positifs. Ces caracteristiques semblent egalement associees a la mise en route d’un traitement, avec dans 1/3 des cas un arret pour toxicite.

Diagnostic and therapeutic strategy in lung cancer. Clinical signs that must lead a clinician to suspect lung cancer are non-specific, but are often linked to the appearance or modification of a respiratory or general symptom. When lung cancer is suspected, the following informations must be obtained through diagnostic assessment: histological proof of cancer, tumoral extension and comorbidities. Therapeutic strategy depends on the distinction between small-cell and non-smallcell lung cancer, and on tumoral extension. In the case of a localized carcinoma, the determinant item for therapeutic decision is operability. In advanced non-small-cell carcinoma, distinction between squamous and non-squamous lung cancer, and the presence of molecular anomalies guide the therapy. In spite of therapeutic advances (targeted therapies, immunotherapy), the treatment of the majority of patients relies on chemotherapy.Stratégie diagnostique et thérapeutique dans le cancer bronchique. Les signes cliniques devant conduire le clinicien à suspecter un cancer bronchique ne sont pas spécifiques, mais correspondent souvent à l’apparition ou à la modification d’un symptôme général ou respiratoire. En cas de suspicion de cancer bronchique, le bilan diagnostique comporte l’obtention d’une preuve histologique du cancer, un bilan d’extension et une évaluation des comorbidités. La stratégie thérapeutique dépend du type histologique, cancer bronchique à petites cellules ou cancer bronchique non à petites cellules, et de l’extension tumorale. Dans le cas d’un cancer localisé, l’élément déterminant pour la décision thérapeutique est l’opérabilité. Dans les cancers avancés non à petites cellules, la distinction entre épidermoïde et non épidermoïde ainsi que le résultat des recherches moléculaires conditionnent la prise en charge thérapeutique. Malgré les avancées thérapeutiques (thérapies ciblées, immunothérapie), le traitement de la majorité des patients repose sur la chimiothérapie.

Summary Background Despite recent progress, non-small cell lung cancer (NSCLC) first-line treatment remains a platinum-based doublet in most cases. No guidelines exist beyond third line. Chemotherapy rechallenge is an option, but little data is available in NSCLC. Our study aims to describe patients who underwent chemotherapy rechallenge while assessing its efficacy and safety. Methods Consecutive patients with advanced-stage NSCLC receiving first-line treatment in Tenon hospital in 2011 were included, with a 5-year follow-up. Patients were analyzed according to chemotherapy rechallenge or not. Chemotherapy rechallenge was defined as re-initiation of a previously administered chemotherapy agent at any point in the treatment sequence, with at least one treatment regimen between first use and rechallenge. Results Of 149 patients, 18 underwent chemotherapy rechallenge (12%). They were younger (56 vs. 61 years, P = 0.04), mostly women (61% vs. 30%, P = 0.02), with lepidic adenocarcinoma (23% vs. 3.5%, P = 0.03), a better general state of health (100% performance status 0–1 vs. 74%, P = 0.04), and fewer cardiovascular comorbidities (16% vs. 42%, P = 0.04). They were more likely to have received a receptor tyrosine kinase inhibitor treatment (89% vs. 43%, P = 0.0003). Progression-free survival was longer at first use than at rechallenge (median 9.2 vs. 2.7 months, P = 0.002). No increased toxicity was observed at rechallenge compared to first use. Finally, a subsequent line of treatment was given after rechallenge in 61% of the patients. Conclusion Patients eligible for chemotherapy rechallenge were those with good prognostic factors. Chemotherapy rechallenge may provide a well-tolerated additional line of treatment, with decreased efficacy compared to its first application.

International audience; Introduction: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity.Methods: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015.Results: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p

Since 1996, the life expectancy of people living with HIV (PLWHIV) has improved, while their risk of cancer is 2-3 times higher than in the general population. HIV-associated cancers remain a critical issue in this population and represent a particular care challenge due to the high risk of drug interactions and additive toxicity. The new standards of care with immunotherapy will also become a major issue for PLWHIV because of the potential impact on immunology and virology. Thus, the National Cancer Institute created the CANCERVIH national network in 2014 in France, enabling the establishment of a multidisciplinary national board of experts. This is an important first step that will help patients and health professionals provide optimal treatment to PLWHIV and prevent disparities. We hope that such a multidisciplinary council will make its voice heard in other countries and that this could be useful for patients with HIV-related cancers.

Background: Nivo is the gold standard for second line treatment of advanced NSCLC. Hyper-progression (HP) is a form of early progression observed during treatment by immune checkpoint inhibitors and usually fatal which has been poorly evaluated. Aim: To determine factors associated with HP in patients with advanced NSCLC treated with nivo. Methods: Our multi-center retrospective study included all patients with advanced NSCLC receiving nivo during the French authorisation for temporary use between January and December 2015. HP was defined as progression or death occurring before any tumour evaluation or before 3 injections of nivo. Results: 263 patients were included with 14.6-months median follow-up. Median overall survival (OS) at the date of cut-off was 10.1 months [95% CI (7.7 – 13.0)]. Baseline characteristics were as follows: 65 years, 68% male, 92% smokers, 62% with adenocarcinoma histology, 28% with squamous cell carcinoma and 10% with other, 66% with PS 0-1 at nivo initiation. Fifty-one patients (19%) had progressed before receiving 3 injections of nivo and a further 51 (19%) before receiving 5. Patients who presented with more rapid progression had worse PS at nivo initiation (p=0.042), worse PS at first nivo evaluation (p Conclusion: Nearly 20% of our patients experienced HP before 3 injections of nivo resulting in worsening OS. HP needs to be further studied in order to better select patients who will truly benefit from immune checkpoint inhibitors.

Though rare, severe hemoptysis (SH) is associated with a mortality rate exceeding 50% when not managed properly. Areas covered: This paper reviews the recent epidemiological data regarding SH, the role of multidetector computed tomography angiography (MDCTA), and fiberoptic bronchoscopy (FOB) in its management, as well as the value of current treatments. Expert commentary: MDCTA is becoming an essential modality, since it allows determining the location, etiology, and mechanism of the bleeding. FOB can be delayed, except when local control of bleeding is required. Emergency treatment relies on interventional radiology. Both bronchial and non-bronchial arteries should be explored during bronchial arteriography. Surgery must be considered in all operable patients if the cause of hemoptysis persists.

Objectives: In the LUX-Lung clinical trials of afatinib in EGFR mutation-positive NSCLC, tolerability-guided dose adjustment reduced the incidence and severity of adverse events while maintaining efficacy. The RealGiDo study evaluated the impact of afatinib dose adjustment in a real-world setting. Materials and methods: This non-interventional, observational study used medical records of EGFR mutation-positive NSCLC patients treated with first-line afatinib. Primary outcomes were adverse drug reaction (ADR) incidence and severity, time to treatment failure (TIT), and time to progression (TTP), relative to LUX-Lung 3 (LL3). Results: 228 patients were enrolled from 13 countries. Baseline characteristics were in line with LL3 but with more Del19 patients (78.1% vs. 49.0%) and fewer Asian patients (43.9% vs. 72.2%); 11.8% had ECOG performance status 2-3. A total of 71 (31.1%) received a modified starting dose of = grade 3 ADRs (28.4% vs. 48.9%) and serious adverse events (5.2% vs. 14.0%) than in LL3. Median TTF and TTP were 18.7 and 20.8 months, respectively, and were not impacted by reduced starting dose or dose modification. Conclusion. Real-world data show that afatinib dose adjustments reduced the frequency and intensity of ADRs without compromising effectiveness, highlighting the benefit of tailoring afatinib dose to optimise treatment outcomes and supporting clinical decision-making. The study is registered at clinicaltrials.gov (NCT02751879).

BackgroundRhabdomyosarcoma (RMS) is rare cancer affecting children and adults. Pleomorphic RMS histology is almost exclusive to adult patients and often resistant to chemotherapy.ObjectiveWe report the case of a 19-year-old patient who presented with a metastatic chemoresistant pleomorphic RMS.MethodsConsidering the poor prognosis and the few systemic therapeutic options, we decided to carry out a whole exome sequencing (WES) of the tumour and germline DNA.ResultsWES identified a germline variation (c.1863_1864insT) in the MLH1 gene corresponding to a pathogenic mutation: (p. Leu622Serfs*10), whereas the family history did not fit with classical criteria for Lynch syndrome. Loss-of-heterozygosity at MLH1 locus was found in the tumour. Immunohistochemistry showed loss of MLH1 and PMS2 nuclear expression in the tumour cells. In view of the mismatch repair defects and a high programmed cell death ligand 1 (PD-L1) expression (60% of tumour cells expressed PD-L1), we administrated an anti-PD-1 antibody to the patient. He achieved a rapid complete response of the lung metastases, which appears sustained after a 1-year follow-up.ConclusionThis observation of an RMS revealing an unexpected Lynch syndrome underlines the overlap between tumorous and germline molecular genetics and emphasises the major impact of cancer genomic medicine in clinical practice for guiding treatment decision.

Introduction This single-arm phase II trial aimed to evaluate a stop-and-go strategy with cisplatin-based chemotherapy and bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC). Methods Patients were initially treated with three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 1) followed by bevacizumab maintenance and after progression, re-introduction of three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 2) and pemetrexed plus bevacizumab maintenance. The primary endpoint was the proportion of patients with advanced non-squamous NSCLC receiving the complete sequence 2 without platinum dose reduction (hypothesis ≥75%). Results 120 patients with performance status ≤1 were included. Of 113 patients evaluable for efficacy, 65 (57.5%) entered in sequence 2 and 56 (86%) received the three planned cycles including 37 (56.9%, 95% CI 45.1 to 73.6) without platinum dose reduction. The median progression-free survival 1 (PFS1; inclusion to progression 1) was 5.6 months (95% CI 5.0 to 6.3) and median PFS2 (progression 1 to progression 2) was 6.8 months (95% CI 5.8 to 8.8). The median disease control duration (PFS1+PFS2; n=65) was 12.4 months (95% CI 11.2 to 14.9). The median overall survival was 17.7 months (95% CI 13.1 to 21.6) and 20.5 months (95% CI 16.9 to 26.9) for patients reaching the sequence 2 (n=65). Conclusion Although the stringent primary endpoint was not met, this stop-and-go strategy with platinum-based chemotherapy plus bevacizumab continuation beyond progression compares favourably with standard schedule, deserving to be further studied in advanced non-squamous NSCLC.

International audience; Background: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody.Methods: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed.Results: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naive to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. Conclusions: These data do not support rituximab as a second line therapy for patients with refractory aPAP.

Regulator of telomere length 1 (

Background Neuregulin-1 gene (NRG1) fusions function as oncogenic drivers across various solid tumors, most notably in invasive mucinous adenocarcinoma (IMA) of the lung, and represent a rational potential target for treatment. NRG1 is a growth factor, which binds to ErbB3 or ErbB4 inducing the formation of ErbB3 or 4-containing homo- or heterodimers and activating downstream ErbB-family signaling pathways. Therefore, the ErbB-family blocker afatinib may be a potential treatment option for patients with solid tumors harboring NRG1 fusions. Methods We report a case series of all known patients with NRG1 fusion-positive solid tumors who were treated with afatinib; afatinib therapy is ongoing for some patients. Results To date, 18 patients with NRG1 fusion-positive solid tumors have been treated with afatinib (Table). These include 12 cases of non-small cell lung cancer (NSCLC; 7 of which were reported as IMA), 5 cases of gastrointestinal (GI) cancer (primarily pancreatic ductal adenocarcinoma [PDAC]) and 1 case of ovarian cancer. Various NRG1 fusion partners were identified, most commonly CD74 in patients with NSCLC (n = 7; 58%) and ATP1B1 in patients with gastrointestinal cancer (n = 3; 60%). Best response with afatinib among patients with NSCLC was partial response (PR) lasting 24 months (10 months among those specifically with IMA of the lung). Patients with PDAC experienced PR of 3 and 5.5 months' duration, and one patient has an ongoing PR after 7 months. One patient with cholangiocarcinoma had a PR lasting 8 months; another patient with ovarian cancer had stable disease (SD) of unknown duration.Table63OTableTumor typeNRG1 fusion partnerBest response, physician assessedDuration of response, mosRefsNSCLCIMACD74PR101CD74PR6.52CD74PD*3CD74SD33SDC4PD3CD74PD3CD74PR-4ADCSLC3A2PR121SDC4PR125-PR246CD74PR14+4, 6SDC4SD46GIPDACATP1B1PR37ATP1B1PR5.58APPPR7+6, 8CholangiocarcinomaATP1B1PR85Colorectal (KRASm +ve)POMKSD49OvarianCLUSD-10*PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Conclusions Afatinib is a potential treatment option for some patients with solid tumors harboring NRG1 fusions. The efficacy and safety of afatinib will be evaluated in ongoing/planned prospective non-randomized clinical trials of targeted drugs in patients with advanced cancer with potentially actionable genomic variants (NCT02925234 and NCT02693535). Editorial acknowledgement Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo Smith Kline; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin. J. Cadranel: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AZ; Advisory / Consultancy, Non-remunerated activity/ies: BI; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Non-remunerated activity/ies: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis. B.A. Weinberg: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Caris Life Sciences; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AbbVie; Honoraria (self): Boerhinger ingelheim. S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Taiho (DSMB); Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Esanex; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Molecular Partners; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Rain Therapeutics; Research grant / Funding (institution): Threshold. K. Tolba: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Foundation One. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials : Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties, Licensing fees from patents or biological materials : Abbott Molecular; Licensing / Royalties, Licensing fees from patents or biological materials : GVKbio; Licensing / Royalties, Licensing fees from patents or biological materials: Chugai; Licensing / Royalties, Licensing fees from patents or biological materials : Genentech; Licensing / Royalties, Licensing fees from patents or biological materials: Foundation Medicine; Licensing / Royalties, Licensing fees from patents or biological materials: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): BI Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. P.K. Cheema: Honoraria (self), Advisory / Consultancy: Astrazeneca; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck. M.R. Jones: Full / Part-time employment: Qiagen. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. Solca: Full / Part-time employment: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Tahio; Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

Objective Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody–associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV. Methods We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV. Results A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1–156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%. Conclusion This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease.

Pulmonary sarcomatoid carcinomas are a rare group of tumors accounting for about one percent of non-small cell lung carcinoma (NSCLC). In 2015, the World Health Organization classification united under this name all the carcinomas with sarcomatous-like component with spindle cell or giant cell appearance, or associated with a sarcomatous component sometimes heterologous. There are five subtypes: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. Clinical characteristics are not specific from the other subtypes of NSCLC. Epithelial to mesenchymal transition pathway may play a key role. Patients, usually tobacco smokers, are frequently symptomatic. Tumors are voluminous more often peripherical than central, with strong fixation on FDG TEP CT. Distant metastases are frequent with atypical visceral locations. These tumors have poorer prognosis than the other NSCLC subtypes because of great aggressivity, and frequent chemoresistance. Here we present pathological description and a review of literature with molecular features in order to better describe these tumors and perhaps introduce new therapeutics.

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSe program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSe program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

Introduction Les consultations aux urgences pour des problemes respiratoires sont frequentes. Certains patients n’ont pas de criteres d’hospitalisation mais necessitent une reevaluation clinique a court terme par un pneumologue. Or, il existe une reelle difficulte d’acces aux soins specialises. Pour contourner cet obstacle, une consultation post-urgence (CPU) a ete mise en place dans le service de pneumologie de l’hopital Tenon. L’objectif de ce travail etait d’en evaluer l’activite et l’impact sur la prise en charge des patients.

Resume Les cellules inflammatoires et immunitaires, les fibroblastes et les cellules endotheliales forment le micro-environnement de la tumeur. L'immunite innee favorise l'inflammation et constitue la premiere ligne de defense non specifique contre les agents pathogenes ou les cellules ≪ transformees ≫. Elle se compose principalement des mastocytes, des macrophages, des neutrophiles et des cellules naturelles tueuses NK (Natural Killer). L'inflammation chronique est le lit du cancer. De nombreuses maladies inflammatoires chroniques sont associees a un surrisque de cancer. En ce qui concerne le cancer du poumon, l'inflammation chronique observee au cours de la BPCO, de l'emphyseme ou de la fibrose pulmonaire idiopathique est associee au developpement d'un cancer bronchique. Dans cet article, nous presentons les effets proet antitumoraux de l'inflammation liee au systeme immunitaire inne dans le cancer bronchique. La place du systeme immunitaire specifique est decrite dans un autre chapitre. Au cours de la progression tumorale, les cellules cancereuses vont pouvoir utiliser et/ou contourner les signaux issus des cellules inflammatoires afin de favoriser la proliferation tumorale, l'invasion tissulaire et la formation de metastases. Il n'y a pas d'agents therapeutiques disponibles qui ciblent specifiquement l'inflammation.

Resume Le bilan initial doit repondre a quatre imperatifs : apprecier l’etat clinique, obtenir une preuve diagnostique, definir le stade cTNM et, en cas de resecabilite, l'operabilite du patient. Les modalites du bilan locoregional basees sur les recommandations nationales et internationales sont resumees. L'examen clinique reste essentiel. Le scanner thoracique avec injection de produit de contraste iode est systematique, sauf contre-indication. La taille de la tumeur, son extension pleurale, parietale, endobronchique et mediastinale directe doivent etre precisees. Les performances du scanner pour predire l'envahissement ganglionnaire mediastinal sont mediocres (sensibilite [Se] = 61 % et specificite [Sp] = 79 %). La tomographie par emission de positons-tomodensitometrie (TEP-TDM) n'est pas indiquee en 1re intention, mais elle est indispensable chez un patient potentiellement eligible a un traitement curatif. Ses performances pour definir le statut mediastinal sont meilleures (Se = 80 % et Sp = 80-90 %). En l'absence d'un envahissement mediastinal massif, des explorations invasives sont indiquees en cas de ganglion ≥ 10 mm ou infracentimetrique fixant le fluorodesoxyglucose (FDG) ou devant la presence d'une adenopathie hilaire, d'une tumeur centrale ou > 3 cm. L’echoendoscopie bronchique et/ou œsophagienne est realisee en 1re intention, avant la mediastinoscopie. Les stades III doivent etre classes en potentiellement resecables, non resecables, potentiellement resecables avec risque de resection incomplete. Le respect des recommandations et une organisation adequate optimisent la prise en charge.

Resume Il n'y a pas de bonne definition de l'innovation therapeutique. Dans le domaine du cancer du poumon, il semble bien que ce soit la quantite de vie gagnee qui definisse le mieux l'innovation therapeutique pour le grand public comme pour les professionnels de sante. Les medicaments doivent subir un developpement long et multi-etape pour arriver jusqu’a leur autorisation de mise sur le marche (AMM). Ce developpement est tres couteux pour les industriels, et l'innovation therapeutique pese lourd economiquement pour la societe, du fait du remboursement des traitements. Le concept de therapeutique ciblee couplee a son biomarqueur predictif a permis de rationaliser et de raccourcir les delais d'obtention des AMM, mais le nivolumab, anticorps anti-PD1, a obtenu tres rapidement son AMM dans le traitement des carcinomes epidermoides, sans la necessite d'un biomarqueur predictif. Les agences de regulation ont egalement mis en place des procedures d’evaluation acceleree des molecules, comme les AMM conditionnelles. L'explosion des techniques de biologie moleculaire a aussi permis de decouvrir un grand nombre d'addictions oncogeniques rares, mais parfois partagees par differents cancers, menant a de nouvelles sortes d'essais therapeutiques de type basket, afin d'en evaluer l'efficacite. Finalement, la France propose des dispositifs reglementaires uniques a travers ses autorisations temporaires d'utilisation (ATU) et recommandations temporaires d'utilisation (RTU) pour offrir a tous – ou presque – un acces aux innovations therapeutiques.

Resume L'incidence et la mortalite par cancer chez les personnes vivant avec le VIH (PVVIH) ont evolue depuis les annees 1990 : le VIH ne represente plus qu'un quart des deces dans cette population. Cette evolution est liee a l’emergence de combinaisons antiretrovirales tres actives, ayant permis d'allonger l'esperance de vie des patients et de diminuer les complications liees au virus. Les cancers sont de ce fait devenus la premiere cause de mortalite. Du fait de l'immunodepression et du tabagisme important, le risque de cancer broncho-pulmonaire (CBP) est deux a trois fois plus eleve que celui de la population generale. Il est le plus frequent des cancers non classant sida et represente la premiere cause de deces par cancer. L’âge de survenue chez les PVVIH est plus jeune, et le pronostic plus mauvais. Le traitement du CBP chez les PVVIH est plus complexe que dans la population generale, en raison d'interactions medicamenteuses avec les antiretroviraux (ARV), de l'agressivite tumorale et de comorbidites particulieres. Une meilleure connaissance de la biologie moleculaire, l'immunotherapie et le depistage sont des axes de recherche majeurs pour ameliorer la survie des PVVIH atteintes de CBP. Pour toutes ces raisons, l'inclusion dans les essais therapeutiques dedies constitue une priorite.

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features

Resume L’hemorragie intra-alveolaire (HIA), maladie rare, est une urgence therapeutique car elle peut conduire rapidement vers une insuffisance respiratoire aigue asphyxiante avec deces. L’hemoptysie associee a une anemie et a des infiltrats pulmonaires suggere le diagnostic d’HIA mais elle peut manquer dans un tiers des cas, y compris chez des patients en detresse respiratoire. Le diagnostic d’HIA repose sur la realisation d’un lavage broncho-alveolaire. Les etiologies en sont tres nombreuses. Il importera de depister les HIA d’origine septique, puis de separer les HIA immunes (les vascularites liees aux anticorps anti-cytoplasme des polynucleaires neutrophiles [ANCA], les connectivites et le syndrome de Goodpasture) avec la recherche d’auto-anticorps et la realisation de biopsies au niveau des organes facilement accessibles, des HIA non immunes avec la realisation d’une echographie cardiaque. La biopsie pulmonaire doit rester exceptionnelle. En cas d’HIA immune inaugurale, un traitement par steroides et cyclophosphamide peut etre debute. Les indications du rituximab commencent a etre etablies (formes non graves et refractaires). Le benefice des echanges plasmatiques est indiscutable dans le syndrome de Goodpasture. Chez un patient suivi pour une maladie immune susceptible d’engendrer une HIA, on s’efforcera d’ecarter une infection dans un premier temps.

Introduction MNNG HOS transforming gene (MET) abnormalities such as amplification and exon 14 mutations may be responsive to targeted therapies. They are prevalent in lung sarcomatoid carcinomas (LSCs) and must be diagnosed as efficiently as possible. Hypothetically, c-MET overexpression by immunohistochemistry (IHC) may prove effective as a screening test for MET abnormalities. Methods Tissue samples were obtained from consecutive patients with a resected LSC in four oncologic centers. IHC was performed using the SP44 antibody (Ventana, Tucson, Arizona) and evaluated using the MetMab score and H-score. Fluorescence in situ hybridization was applied with the dual color probe set from Zytovision (Clinisciences, Nanterre, France). True MET amplification was diagnosed when MET gene copy number was 5 or greater and the ratio between MET gene copy number and chromosome 7 number was greater than 2. All MET exon 14 alterations including those affecting splice sites occurring within splice donor and acceptor sites were detected in the routine molecular testing on genetic platforms. Results A total of 81 LSCs were included. Fourteen (17%) exhibited positive IHC using the MetMab score and 15 (18.5%) using the H-score. MET amplification was detected in six tumors (8.5%) and MET exon 14 mutation in five (6%). A weak positive correlation between IHC and fluorescence in situ hybridization was found (r = 0.27, p = 0.0001). IHC sensitivity for MET amplification was 50%, with a specificity of 83%, positive predictive value of 21.4%, and negative predictive value of 94.7%. IHC sensitivity for MET exon 14 mutations was 20%, with a specificity of 83%, positive predictive value of 7%, and negative predictive value of 94%. Conclusion IHC is not a relevant screening tool for MET abnormalities in LSC.

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK) positive (ALK+) non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+) tumours. Patients received oral ceritinib (750 mg·day−1 as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4%) and those receiving prior crizotinib for >5 months (51.6% versus 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day−1) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC., Ceritinib (750 mg per day) showed similar efficacy as in clinical trials in crizotinib-pretreated ALK+ NSCLC patients http://ow.ly/8oXe30h27D0

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The aim of this systematic review is to evaluate the effectiveness and safety of EGFR‐TKIs versus single‐agent chemotherapy as second‐line treatments in patients with advanced NSCLC and wild‐type or unknown status for EGFR.

ObjectiveTo report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis).MethodsWe retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2).ResultsTen patients with metastatic cancer were included; median age was 73 (range 56–87) years. Median follow-up duration was 48 (range 16–88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5–87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059–16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement.ConclusionsirMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.

In this retrospective study, a beneficial effect of pirfenidone on lung function decline could not be demonstrated in patients carrying TERT/TERC mutation

Chronic pulmonary aspergillosis (CPA) complicates conditions including tuberculosis, chronic obstructive pulmonary disease and sarcoidosis, and is associated with high morbidity and mortality. Surgical cure should be considered where feasible; however, many patients are unsuitable for surgery due to extensive disease or poor respiratory function. Azoles are the only oral drug with anti-Aspergillus activity and itraconazole and voriconazole are considered as first-line drugs. A randomized controlled trial demonstrated improvement or stability in three-quarters of patients given 6 months of itraconazole, but a quarter relapsed on stopping therapy. Long-term treatment may therefore be required in some cases. Itraconazole, voriconazole and posaconazole require therapeutic drug monitoring. No published data are yet available for isavuconazole. Adverse drug effects of azoles are common, including peripheral neuropathy, heart failure, elevated liver enzymes, QTc prolongation and sun sensitivity. Many serious drug-drug interactions occur, including major interactions with rifamycins, simvastatin, warfarin, clopidogrel, immunosuppressant drugs like sirolimus. Furthermore, drug resistance occurs, including cross-resistance to all azoles, but the true prevalence is not yet determined. Intravenous therapy is possible with echinocandins or amphotericin B, but long-term use is challenging. Hemoptysis complicates CPA and can be fatal. Tranexamic acid should be given acutely to reduce bleeding. Bronchial artery embolization can stop acute bleeds. In some circumstances, emergency surgery may be necessary to resect the source of the bleed. Current CPA treatments can be beneficial but have many drawbacks. New oral anti-Aspergillus agents are needed, along with optimization of currently available treatments.

Contains fulltext : 193204.pdf (Publisher’s version ) (Closed access) The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

OBJECTIVE Immunotherapies targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) checkpoint improved prognosis in lung cancer. PD-1/PD-L1 status, however, has not been investigated in human immunodeficiency virus (HIV)-positive patients. This study assessed PD-L1 status and tumor immune-cell infiltration in nonsmall cell lung cancer (NSCLC) in HIV patients. METHODS Consecutive HIV patients treated between 1996 and 2014 were enrolled. PD-L1 tumor expression was assessed using immunohistochemistry with two antibodies (clones 5H1 and E1L3N), and tumor immune-cell infiltration with CD3, CD4, CD8, CD20, CD163, and MPO. PD-L1 expression and immune infiltration results were compared with those of 54 NSCLCs from unknown HIV status patients. RESULTS Thirty-four HIV-positive patients were evaluated: predominantly men (88.2%) (median age: 51.1 years) presenting stage IV (38.2%) adenocarcinomas (76.5%). The median blood CD4 count was 480 cells/μL (86-1120) and 64% exhibited undetectable viral load. The PD-L1 score (percentage of positive cells × intensity) was higher in HIV-positive than HIV-undetermined patients with the E1L3N clone [median (range) 0 (0-150) versus 0 (0-26.7), P = 0.047], yet not with the 5H1 clone [0 (0-120) versus 0 (0-26.7) P = 0.07, respectively]. PD-L1 expression frequency did not differ between both cohorts (18.7 versus 9.3% using E1L3N and 10 versus 5.6% using 5H1 clone, respectively). There were significantly greater cytotoxic T-cell (P

IntroductionLung cancer (LC) is the leading cause of death from cancer. Early diagnosis of LC is of paramount importance in terms of prognosis. The health authorities of most countries do not accept screening programmes based on low-dose chest CT (LDCT), especially in Europe, because they are flawed by a high rate of false-positive results, leading to a large number of invasive diagnostic procedures. These authorities advocated further research, including companion biological tests that could enhance the effectiveness of LC screening. The present project aims to validate early diagnosis of LC by detection and characterisation of circulating tumour cells (CTCs) in a peripheral blood sample taken from a prospective cohort of persons at high-risk of LC.Methods and analysisThe AIR Project is a prospective, multicentre, double-blinded, cohort study conducted by a consortium of 21 French university centres. The primary objective is to determine the operational values of CTCs for the early detection of LC in a cohort of asymptomatic participants at high risk for LC, that is, smokers and ex-smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 years, with chronic obstructive pulmonary disease (COPD). The study participants will undergo yearly screening rounds for 3 years plus a 1-year follow-up. Each round will include LDCT plus peripheral blood sampling for CTC detection. Assuming 5% prevalence of LC in the studied population and a 10% dropout rate, a total of at least 600 volunteers will be enrolled.Ethics and disseminationThe study sponsor is the University Hospital of Nice. The study was approved for France by the ethical committee CPP Sud-Méditerranée V and the ANSM (Ministry of Health) in July 2015. The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations.Trial registration numberNCT02500693.

Until 1996, AIDS was the leading cause of deaths from HIV infection. In 2010, because of introduction of powerful antiretroviral therapies, AIDS represented less than 25% of deaths. Cancer has become the leading cause of death in this population, and, because of smoking and immunosuppression, lung cancer risk is more important than in general population. Furthermore, treatment is more difficult, due to potential interactions between antiretroviral and anticancer therapies, to comorbidities and to tumor aggressiveness. Research will focus on molecular biology, immunotherapies and lung cancer screening in order to improve survival of HIV patients with lung cancer. For all these reasons, HIV patients must be included in clinical trials.

In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled “Immunotherapy, a new standard of care in thoracic malignancies?” was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events. The need for biological selection, currently based on immunohistochemistry testing to identify the tumour expression of programmed death ligand (PD-L)1, was stressed, as well as the need to harmonise PD-L1 testing and techniques. Finally, sessions were dedicated to the combination of ICIs and radiotherapy and the place of ICIs in nonsmall cell lung cancer with oncogenic addictions. Finally, an important presentation was dedicated to the future of antitumour vaccination and of all ongoing trials in thoracic oncology.

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials., Efficacy of nivolumab in nonsmall cell lung cancer http://ow.ly/k2uX30iGZbY

National audience; La fibrose pulmonaire idiopathique (FPI) est la forme la plus fréquente de pneumopathie interstitielle diffuse (PID) idiopathique chronique chez l’adulte. Il s’agit d’une maladie fibroproliférative, irréversible, de cause inconnue, dont l’évolution est habituellement progressive, survenant principalement à partir de 60 ans et limitée aux poumons. Qualifiée de maladie orpheline notamment en raison de l’absence de traitement ayant fait la preuve formelle de son efficacité jusqu’à une période très récente, la FPI est une maladie rare dont la prévalence a été évaluée aux États-Unis entre 14 et 28/100 000 personnes [1], ce qui correspondrait à un minimum de 9000 patients en France et une incidence entre 6,8 et 9/100 000 par an [1,2], soit un minimum de 4400 nouveaux patients par an en France.

Background: Nivo is authorised for 2nd line treatment of advanced NSCLC. Although 50% of pts progressed at 1st Nivo evaluation in phase III trials overall survival (OS) favoured Nivo suggesting better efficacy of treatments given post Nivo. Aim: To evaluate the efficacy of the next treatment received after Nivo progression in advanced NSCLC patients receiving Nivo. Methods: Our multi-center retrospective study included all pts receiving Nivo during the French authorisation for temporary use (ATU) between Jan and Dec 2015. Primary end point was progression free survival (PFS) on the next treatment given post Nivo. Results: Characteristics of the 297 pts included at Nivo initiation: 65 years, 69% males, 90% smokers; 61% adenocarcinoma, 29% squamous and 10% others; 68% PS 0-1. Nivo was given in 40%, 29% and 31% in 2nd, 3rd or ≥4th line treatment respectively. With a 22 months (mos) median follow-up, PFS on Nivo was 2,6 mos (95%CI [2.1-3.5]) and OS 10,9 mos [8,5 -NR]. 32% of pts died before further treatment, 4% were lost of follow-up, 24% were controlled, 5% were progressive but did not receive post Nivo treatment and 34% (n=101) received post Nivo treatment. Characteristics of these pts did not differ from that of the overall population. Most frequent drugs used were: 24% gemcitabine (G), 21% docetaxel (D) and 15% Erlotinib (E). The PFS after Nivo was 2.7 mos [2.1-3.4]; 2.7 mos for G, 2.7 mos for D and 1.8 mos for E. Treatment duration was >5 mos for G and >4 mos for D in 25% of pts. Conclusion: Nivo produced similar efficacy as in phase III trials. Although only 34% of pts received post Nivo treatment, 25% had longer treatment duration on G or D.