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In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITWe performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITWe showed that up-regulated genes in FHITThese data suggest that ICI might not be a relevant option for NSCLC patients with FHIT

Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2-targeted therapy has given rise to disappointing results in non-small cell lung cancer (NSCLC). With the aim of refining the target population for anti-HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti-HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT-silenced tumour cell lines. Finally, we showed that the FHITlow /pHER2high phenotype predicts sensitivity to an anti-HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT-inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti-HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

International audience; The gene cluster region, CHRNA3/CHRNA5/CHRNB4, encoding for nicotinic acetylcholine receptor (nAChR) subunits, contains several genetic variants linked to nicotine addiction and brain disorders. The CHRNA5 single-nucleotide polymorphism (SNP) rs16969968 is strongly associated with nicotine dependence and lung diseases. Using immunostaining studies on tissue sections and air-liquid interface airway epithelial cell cultures, in situ hybridisation, transcriptomic and cytokines detection, we analysed rs16969968 contribution to respiratory airway epithelial remodelling and modulation of inflammation. We provide cellular and molecular analyses which support the genetic association of this polymorphism with impaired ciliogenesis and the altered production of inflammatory mediators. This suggests its role in lung disease development.

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for the rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AEC) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lung of smokers and non-smokers using transcriptomic data for whole lung tissues, isolated large AEC, and isolated small AEC. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified a nAChR transcriptomic print at a single cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChRs to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.

Rationale Thoracic endometriosis is a rare disorder that can involve airways, pleura and lung parenchyma. It is the most frequent form of extra-abdominopelvic endometriosis. Multiple lung cavitations are a rare feature of thoracic endometriosis. Patient concerns A 46-year-old woman was referred to our hospital after incidental finding of multiple pulmonary cavitations with surrounding areas of ground glass opacity on a thoraco-abdominal computed tomography-scan performed for abdominal pain. Retrospectively, the patient also reported mild hemoptysis occurring 4 months ago. Diagnoses Positron emission tomography-computed tomography scan revealed moderate and homogeneous [18F] fluoro-2-deoxy-D-glucose (18F-FDG) uptake in pulmonary cavitations (maximum standardized uptake value 5.7). The diagnosis of thoracic endometriosis was confirmed by histological examination of surgical resection of a left lower lobe cavitation. Interventions and outcome Gonadotropin-releasing hormone analogues associated with add-back therapy was started. Four months after initiating pharmacological treatment, the chest computed tomography-scan showed a dramatic decrease in lung cavitations size. Lessons Thoracic endometriosis is a rare disorder requiring a multidisciplinary management including gynaecologist, pulmonologist, radiologist, nuclear physician, pathologist and thoracic surgeon for early diagnosis and treatment. Our case report highlights that an increased 18F-FDG uptake can be found in thoracic endometriosis syndrome presenting as multiple lung cavitations.

Despite its efficacy in solid tumours, in particular HER2

Background: An alteration of primary cilia is observed in remodelled airways in the context of COPD. Since this organelle is required to activate Hedgehog (HH) signalling pathway orchestrating cell fate during lung development, we explored HH activation during human airway epithelial cell differentiation and in adult lungs from COPD and non-COPD patients. Methods: Human airway epithelial cells were cultured from nasal polyps and bronchial brushing in air-liquid interface conditions to reconstitute an epithelium representative of the adult airways. ELISA and immunostaining analysis of the principal ligand Sonic Hedgehog (SHH) were performed at different steps of differentiation on airway epithelial cell cultures, bronchial aspirations and formalin-fixed paraffin embedded lung tissues of non-COPD and COPD patients. Results: Non-differentiated airway epithelial cells produced SHH in vitro during the course of differentiation (from 6pg/ml at ALI-0 to 238pg/ml at ALI-35). Depriving culture medium of SHH with a specific antibody induced epithelial remodelling particularly impacting ciliogenesis (2 fold decrease of ciliated cells). SHH was observed on bronchial tissue sections and detected by ELISA with a 2 fold decrease expression for COPD patients. Conclusion: These findings suggest a crucial involvement of HH pathway in airway basal cells to guide differentiation and indicate an alteration of its activation in COPD patients. Measuring HH elements in biological samples may help categorize COPD patients and propose novel diagnostic and therapeutic strategies.

In non-metastatic non-small-cell lung cancer (NSCLC), outcomes remain poor. Adjuvant chemotherapies provide a limited improvement in disease-free survival. Recent exploratory studies on early-stage NSCLC show that immunotherapy given according to Programmed Death&ndash, Ligand 1 expression generates variable results, emphasizing a need to improve tumor characterization. We aimed to conjointly assess NSCLC, the expression of PD&ndash, L1, and epithelial&ndash, mesenchymal transition, frequently involved in tumor aggressiveness. 188 resected NSCLCs were analyzed. Among 188 patients with curatively resected NSCLC, 127 adenocarcinomas and 61 squamous cell carcinomas were stained for PD&ndash, L1 and vimentin expression. Overall survival has been compared regarding PD&ndash, L1 and vimentin statuses both separately and conjointly in Tumor Cancer Genome Atlas databases. PD&ndash, L1 and vimentin higher expressions were strongly associated (OR = 4.682, p &lt, 0.0001). This co-expression occurred preferentially in tumors with lymph node invasion (p = 0.033). PD&ndash, L1 was significantly associated with high EMT features. NSCLC harboring both PD&ndash, L1high/vimentinhigh expressions were significantly associated with poor overall survival (p = 0.019). A higher co-expression of vimentin and PD&ndash, L1 was able to identify patients with worse outcomes. Similar to an important prognostic marker in NSCLC, this tandem marker needs to be further presented to anti-PD&ndash, L1 immunotherapies to improve outcome.

Background: Airway remodelling is a hallmark of COPD but its physiopathology remains unclear. Since Hedgehog (HH) pathway has been shown to regulate repair and regeneration in the mouse lung, we investigated its role in human airway epithelial cell differentiation in the context of COPD. Methods: Sections from formalin-fixed paraffin embedded lung tissues of non-COPD and COPD patients were stained to characterize the localization and activation of HH pathway elements. Human airway primary cells obtained from nasal polyps were differentiated in vitro at the air-liquid interface. RT-qPCRs, western-blots and immunofluorescent studies were performed during the kinetic of epithelial cell differentiation with or without HH inhibitors. Results: A comparison of immunostaining analysis on tissue sections pointed towards an alteration of HH pathway in COPD patients including a decrease of Gli2 expression. Hedgehog pathway was activated in the course of airway epithelial cells differentiation in vitro as shown by the increase of the transcription factors Gli1 and Gli2 (protein and RNA expression). Hedgehog inhibitors induced epithelial remodelling characterized by a 2 fold decrease of ciliated cells and a 2 fold increase of secretory cells. Conclusion: These findings indicate that HH pathway contributes to airway epithelial cell plasticity and suggest its involvement in airway remodelling in COPD. Restoring HH signalling may help correct the remodelling observed in COPD patients.

Non-differentiated airway epithelial cells display primary cilia and their number is associated with COPD featureshttp://ow.ly/wiGH30jDbeG

Epithelial-to-mesenchymal transition (EMT) is believed to contribute to tumour invasion. Vimentin expression by carcinoma cells is a largely recognized marker of EMT. This study aimed at examining vimentin expression in non small cell lung carcinomas (NSCLC) by immunohistochemistry to evaluate potential correlations between vimentin expression and the differentiation status, the TNM stage and the outcome of the patients. 295 NSCLC including 164 squamous cell carcinomas (SCC), 108 adenocarcinomas (AC) and 23 other NSCLC carcinomas have been examined by immunohistochemistry. Vimentin was indeed detected in 145 cases (49.2%). It was principally present in isolated tumour cells and invasive clusters, particularly in cells at the tumour/stroma interface. Vimentin expression was significantly more expressed in large cell neuroendocrine, adeno-squamous and sarcomatoid carcinomas than in SCC and AC and was significantly associated with the differentiation status of carcinomas. The follow-up of 193 patients further demonstrated that an extensive expression of vimentin (>50% of tumour cells) was associated with the occurrence of metastases. In conclusion, our data demonstrate that vimentin expression is a frequent event in NSCLC and that its expression can be associated with a lack of differentiation and the occurrence of metastases.

Introduction La sarcoidose est une granulomatose systemique d’etiologie inconnue. Les formes associees a une hemorragie intra-alveolaire sont exceptionnelles. Observation Les auteurs rapportent un cas de sarcoidose aigue chez un homme jeune, caucasien, ayant une exposition a la fumee de tabac et de cannabis. Le scanner thoracique revele des adenopathies mediastinales associees a des masses alveolaires predominant dans les regions superieures des deux champs pulmonaires. L’aspect macroscopique du lavage bronchiolo-alveolaire et la formule cytologique sont compatibles avec une hemorragie intra- alveolaire. En raison de la survenue d’une insuffisance respiratoire aigue, un traitement par corticoides par voie intraveineuse a ete debute entrainant une rapide amelioration clinique et gazometrique. La mediastinoscopie a permis d’etablir le diagnostic de sarcoidose sur la presence de nombreux granulomes epitheloides et gigantocellulaires. Conclusion Cette observation est l’occasion d’une revue de la litterature sur les formes de sarcoidose associees a la survenue d’une hemorragie intra-alveolaire.

Resume Introduction La pneumonectomie laisse en place un moignon d’artere pulmonaire plus long a droite qu’a gauche. Le cul-de-sac vasculaire ainsi forme peut etre le siege de la constitution, souvent tardive, d’un thrombus. La prevalence, les facteurs de risque et les consequences de ces thrombus sur moignon demeurent meconnus. Observations Nous rapportons trois cas de thrombose arterielle pulmonaire survenue apres pneumonectomie droite pour cancer bronchique. Le diagnostic a ete etabli par une tomodensitometrie thoracique realisee dans le cadre de la surveillance evolutive de la maladie neoplasique. Aucune complication embolique n’a ete observee malgre l’absence de traitement anticoagulant. Discussion La prevalence de cette complication est estimee a 12 %. La decouverte est souvent fortuite a l’occasion d’un scanner thoracique realise a titre systematique. Le thrombus prend l’aspect d’une lacune hypodense, a bord proximal net, convexe ou concave, moule par le produit de contraste et comblant le moignon. Une seule migration embolique est rapportee dans la litterature recente. L’evolution habituellement benigne n’incite pas a proposer d’anticoagulation systematique.

Introduction Les tumeurs pulmonaires ressemblant au poumon fœtal sont rares (0,5 % des tumeurs pulmonaires) et constituent un groupe heterogene qui va de l’adenocarcinome fœtal decrit par Kradin en 1982 au pneumoblastome decrit en 1952 par Barnard. Objectifs Nous rapportons 3 observations d’adenocarcinome fœtal dont une forme bien differenciee ou de bas grade (AFBG), une forme peu differenciee ou de haut grade (AFHG) et un pneumoblastome afin d’en preciser les caracteristiques anatomocliniques, immunohistochimiques et moleculaires. Cas anatomocliniques 1) Homme de 57 ans, fumeur, asymptomatique ; decouverte fortuite d’une tumeur peripherique de 4 cm du lobe superieur droit (LSD) opere et chimiotherape. AFBG pur avec morules, necrose punctiforme et bourgeon endobronchique, infiltrant la plevre viscerale (pT2a N0 M0). TTF1 et s-catenine nucleocytoplasmique positifs ; Chromogranine A et Synaptophysine negatives. Remaniements EML4-ALK+. Absence de recidive a 2 ans. 2) Homme de 49 ans, fumeur actif, asymptomatique ; decouverte radiologique d’une tumeur peripherique de 2,5 cm du LSD traitee par lobectomie et curage ganglionnaire. AFBG sans morule TTF1+, CDX2+ avec bourgeon endobronchique, associe a un contingent peu differencie solide riche en atypies de haut grade necrose, NCAM (CD56)+, alpha-foetoproteine+, Glypican3 + s-catenine membranaire (stade pT1a N0 M0). Recul de 1 an sans recidive. 3) Femme de 43 ans, fumeuse ; decouverte fortuite d’une tumeur de 11 cm du LSD traitee par pneumonectomie et curage ganglionnaire. Pneumoblastome biphasique avec contingent fœtal et stroma blastemateux sans contingent heterologue, necrose avec bourgeon endobronchique (pT3 N0 M1b). TTF1-, CDX2-, alpha-foetoproteine-, s-catenine+, NCAM+, p53+, Vimentine+. Decedee a 3 mois post-operatoire de metastases surrenaliennes. Absence de mutation KRAS et EGFR. Discussion l’adenocarcinome fœtal bien differencie synonyme de bas grade est considere dans l’OMS comme une variante de bon pronostic, asymptomatique dans 2/3 des cas. Typiquement decrit chez la femme, il existe chez l’homme et est associe a une expression nucleaire et cytoplasmique de la s-catenine. Le caractere heterogene de l’adenocarcinome fœtal de haut grade decrit par Nakatani puis Morita et al., 2013 est confirme dans notre cas par un contingent peu differencie exprimant NCAM, alpha-foetoproteine, Glypican 3 avec s-catenine membranaire. Le pneumoblastome biphasique doit etre distingue morphologiquement de l’adenocarcinome fœtal de haut grade notamment grâce a l’expression de β-catenine, sa survie etant de 16 % a 5 ans et de 8 % a 10 ans. Conclusion Il s’agit de tumeurs pulmonaires de type fœtal chez 3 adultes fumeurs de decouverte fortuite, peripheriques avec composante endobronchique histologique atteignant preferentiellement le LSD, bien individualisees morphologiquement en ce qui concerne l’AFBG et le pneumoblastome et de diagnostic plus difficile pour l’AFHG.

Background Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD. Methods Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze. Results 13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [−0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 105 AU in COPD GOLD D vs 12.8 ± 0.13 105 AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]). Conclusion Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD. Electronic supplementary material The online version of this article (doi:10.1186/s12931-014-0151-9) contains supplementary material, which is available to authorized users.

Broncholithiasis is characterized by calcified perihilar and mediastinal lymph nodes eroding into the tracheobronchial tree. We report herein 4 cases of symptomatic broncholithiasis managed by surgical resection in 2 cases and bronchoscopic removal in 2 cases. From our experience and from the literature review, bronchoscopic removal should be considered in cases of uncomplicated and loose broncholithiasis, whereas surgical management should be chosen first in complicated cases such as obstructive pneumonitis, bronchiectasis, massive hemoptysis, and bronchoesophageal fistulas.