Publications by authors named "Claire Danel"

94 Publications

Bronchodilation induced by PGE is impaired in Group III pulmonary hypertension.

Br J Pharmacol 2020 01 31;177(1):161-174. Epub 2019 Oct 31.

INSERM U1148, Hôpital Bichat, Paris, France.

Background And Purpose: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE and PGI induce potent relaxation of human bronchi from non-PH (control) patients via EP and IP receptors, respectively. However, the effects of PGE /PGI and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI -mimetics approved for treating PH Group I with several PGE -mimetics, in bronchial preparations derived from PH Group III and control patients.

Experimental Approach: Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE , PGI , and cAMP levels were determined by ELISA.

Key Results: Maximal relaxations induced by different EP receptor agonists (PGE , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI -mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI but not with PGE levels.

Conclusion And Implications: The PGI -mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP receptor agonists was decreased. Restoration of EP receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit.
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http://dx.doi.org/10.1111/bph.14854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976782PMC
January 2020

Clinicopathological and Molecular Study of Peritoneal Carcinomatosis Associated with Non-Small Cell Lung Carcinoma.

Pathol Oncol Res 2020 Oct 12;26(4):2795-2800. Epub 2019 Aug 12.

Assistance Publique - Hôpitaux de Paris, département de pathologie, Hôpital Bichat-Claude Bernard, Paris, France.

To retrospectively characterize the molecular features of Non-Small Cell Lung Carcinomas (NSCLC) with peritoneal carcinomatosis (PC), clinicopathological data of 12 patients diagnosed with NSCLC and PC between 2007 and 2016 were collected. Immunohistochemistry and Next Generation Sequencing (NGS) were performed on cases with available material. PC was the initial presentation of NSCLC in 17% of the cases. Overall, patients with PC displayed a poor median survival of 12 weeks. Histology was adenocarcinoma in 11 cases. 37.5% of cases showed PD-L1 immunostaining positivity (50% cut-off). ALK and ROS1 immunostainings were negative. Using NGS, we identified 17 molecular alterations in 9 genes (TP53, KRAS, STK11, BRAF, EGFR, DDR2, ERBB4, SMAD4, CTNNB1) in 88.9% of adenocarcinomas. To the best of our knowledge, 5 of these variants are not referenced in the literature. In conclusion, PC might be the initial presentation of NSCLC. Molecular profiling of our cases did not find any effective targetable alteration, except from high PD-L1 expression.
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http://dx.doi.org/10.1007/s12253-019-00713-1DOI Listing
October 2020

Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort.

Clin Lung Cancer 2019 09 13;20(5):e564-e575. Epub 2019 May 13.

Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Caen, France; Department of Pathology, CHU de Caen, Caen, France.

Background: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).

Patients And Methods: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.

Results: PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).

Conclusion: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.
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http://dx.doi.org/10.1016/j.cllc.2019.04.010DOI Listing
September 2019

NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas.

Cancer Med 2019 08 14;8(9):4330-4337. Epub 2019 Jun 14.

Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS-MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1-mutated tumors could define a specific population with a distinct clinical and molecular profile. We performed NF1 sequencing using next generation sequencing (NGS) in 154 lung adenocarcinoma surgical specimens with known KRAS, EGFR, TP53, BRAF, HER2, and PIK3CA status, to evaluate the molecular and clinical specificities of NF1-mutated lung cancers. Clinical data were retrospectively collected, and their associations with molecular profiles assessed. In this series, 24 tumors were NF1 mutated (17.5%) and 11 were NF1 deleted (8%). There was no mutation hotspot. NF1 mutations were rarely associated with other RAS-MAPK pathway mutations. Most of patients with NF1 alterations were males (74.3%) and smokers (74.3%). Overall survival and disease-free survival were statistically better in patients with NF1 alterations (N = 34) than in patients with KRAS mutations (N = 30) in univariate analysis. Our results confirm that NF1 is frequently mutated and represents a distinct molecular and clinical subtype of lung adenocarcinoma.
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http://dx.doi.org/10.1002/cam4.2175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675708PMC
August 2019

Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer.

Lung Cancer 2019 06 8;132:65-71. Epub 2019 Apr 8.

Thoracic Oncology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France; U830 INSERM "Genetics and biology of cancers", Research Centre, Institut Curie, 26 rue d'Ulm, 75005, Paris, France; Medicine Faculty, University Paris-Diderot, 46 rue Henri Huchard, 75018 Paris, France. Electronic address:

Introduction: Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit.

Methods: TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS).

Results: In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009).

Conclusions: TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2019.04.005DOI Listing
June 2019

Pulmonary Arterial Histologic Lesions in Patients With COPD With Severe Pulmonary Hypertension.

Chest 2019 07 11;156(1):33-44. Epub 2019 Mar 11.

Service de Pneumologie B et Transplantation Pulmonaire, Université Paris 7 Denis Diderot, Hôpital Bichat, Paris, France; INSERM U1152, Département Hospitalo-Universitaire FIRE, Laboratoire d'Excellence INFLAMEX, Université Paris 7 Denis Diderot, Paris, France. Electronic address:

Background: The development of pulmonary hypertension (PH) during the course of COPD is a well-known phenomenon, with the prevalence depending on the severity of airway obstruction. When mean pulmonary pressure (mPAP) level at rest is ≥ 35 mm Hg or ≥ 25 mm Hg with low cardiac index, the term severe PH is used. For these patients, little is known on the underlying histologic lesions. Our objective was to describe these lesions.

Methods: From the explants of patients undergoing lung transplantation, we compared retrospectively three groups of patients with COPD: severe PH-COPD (n = 10), moderate PH-COPD (mPAP between 25 and 34 mm Hg without low cardiac index) (n = 10), and no PH (mPAP < 25 mm Hg) (n = 10). Histologic analysis of the explanted lungs examined the wall of medium-size arteries, the remodeling of microvessels, and the pulmonary capillary density using morphometric measurements performed on three sections per patient.

Results: Compared with the moderate PH group, the remodeling score of the microvessels was significantly higher (P = .0045) and the capillary density was lower (P = .0049) in the severe PH-COPD group. The alterations of the medium-size arteries, important in group 1 PH, seemed less discriminating.

Conclusions: Patients with severe PH-COPD appear to have a specific histologic pattern, different from that observed in patients with COPD with moderate PH or without PH.
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http://dx.doi.org/10.1016/j.chest.2019.02.333DOI Listing
July 2019

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

Br J Cancer 2019 02 11;120(4):387-397. Epub 2019 Feb 11.

Department of Thoracic Oncology & CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France.

Background: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.

Methods: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.

Results: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.

Conclusions: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
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http://dx.doi.org/10.1038/s41416-019-0379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461894PMC
February 2019

C4d detection and histological patterns in the diagnosis of antibody-mediated rejection after lung transplantation: a single-centre study.

Histopathology 2019 Jun 1;74(7):988-996. Epub 2019 Apr 1.

Département de Pathologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.

Aims: Antibody-mediated rejection (AMR) is an emerging and challenging issue in transplantation. Endothelial deposition of C4d and microvascular inflammation (MI) are reliable markers of AMR in renal and cardiac transplantation, but remain controversial in the lung. Our aim was to assess C4d immunohistochemistry and histological patterns for the diagnosis of lung AMR.

Methods And Results: We reviewed 158 transbronchial biopsies (TBBs) (n = 85 clinically indicated, and n = 73 surveillance TBBs) from 48 recipients, blinded to clinical and serological data. C4d was scored as 0, 1+ (<10%), 2+ (10-50%) or 3+ (>50%). TBBs were reassessed for MI and acute lung injury (ALI). Donor-specific antibodies (DSAs), acute clinical graft dysfunction and chronic lung allograft graft dysfunction (CLAD) were recorded. C4d3+, C4d2+, C4d1+ and C4d0 occurred respectively in four (2.5%), six (3.8%), 28 (17.7%) and 120 (75.9%) TBBs. MI and ALI were rare but more frequent in C4d1-3+ TBBs than in the absence of C4d. C4d2+ was frequently observed with concomitant infection. Among the surveillance TBBs, only two (2.7%) showed MI. Neither ALI nor C4d3+ was diagnosed on surveillance TBBs. No significant association was found between histopathological findings and DSAs. All four patients with C4d3+ could retrospectively be diagnosed with AMR and developed CLAD.

Conclusion: Although rare, diffuse C4d deposition appears to be a strong indication of acute clinical AMR in lung transplant patients, whereas intermediate C4d2+ requires more investigations. In stable patients, histopathology and C4d may lack the sensitivity to diagnose subclinical AMR. This emphasises the need for a multidisciplinary evaluation of each suspected AMR case, and the need for complementary diagnostic tools.
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http://dx.doi.org/10.1111/his.13823DOI Listing
June 2019

Safe and effective use of nivolumab for treating lung adenocarcinoma associated with sporadic lymphangioleiomyomatosis: a rare case report.

BMC Pulm Med 2019 Jan 11;19(1):12. Epub 2019 Jan 11.

Service d'Oncologie Thoracique, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France.

Background: Sporadic lymphangioleiomyomatosis (LAM) is a rare form of diffuse parenchymal lung disease. PD-1 blocking antibodies constitute an essential treatment option for advanced non-small-cell lung cancer (NSCLC). The effect of immune checkpoint inhibitors in lymphangioleiomyomatosis patients with non-small cell lung cancer is unknown: concomitant symptomatic interstitial lung disease or the use of immunosuppressors was a key exclusion criterion in the original studies of immune checkpoint inhibitors, especially regarding the risk of interstitial lung disease exacerbation.

Case Presentation: A 48-year-old female, active smoker (36 pack-years), diagnosed with sporadic LAM since 2004 suffered from metastatic adenocarcinoma of the lung. Third-line therapy with nivolumab was started in 2015, with a major partial response. Due to pulmonary function alterations, sirolimus was also reinitiated in 2017 in conjunction with nivolumab, without any undesirable effects and a major partial response continuing up to May 2018.

Conclusions: This case highlights the safe and effective use of nivolumab for managing metastatic lung adenocarcinoma that occurred in a patient with sporadic LAM. In the current case, immunotherapy proved highly successful in managing the NSCLC tumor that occurred upon LAM follow-up, with both a significantly prolonged partial response and acceptable safety profile.
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http://dx.doi.org/10.1186/s12890-018-0775-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329093PMC
January 2019

[Autochthonous hydatid cyst of the lung].

Ann Pathol 2019 Feb 12;39(1):47-53. Epub 2018 Dec 12.

Département de pathologie, CHU Bichat-Claude-Bernard, AP-HP, 46, rue Henri-Huchard, 75018 Paris, France. Electronic address:

Cystic echinococcosis, or hydatidosis, also known as hydatid cyst, is a cosmopolitan parasitosis mainly present in breeding areas. This anthropozoonosis is related to the tissue development of an hydatid of an echinococcus tænia, Echinococcus granulosus, found in the digestive tract of canids, at the adult state. In France, this larval cestosis is essentially an import disease developed by patients from endemic areas such as East and North Africa, South America or Asia. However, autochtonous forms, although rare, still persist. Here we describe the case of a 39-year-old non-smoking patient from Paris, admitted in the emergency department for chest pain associated with sweating and chills. The clinical examination found the notion of a right lower lobar pulmonary nodule discovered 20 years ago, on a chest X-ray, but never explored. Thoracic computed tomography shows two large cystic opacities with endocystic flaky images, including one ruptured in the pleura with right pleural effusion. This radiological suspicion of fissured cystic echinococcosis was confirmed by positive hydatidosis serology. The multidisciplinary meeting retained the indication of right basal segmentectomy enlarged to a diaphragmatic patch, associated with treatment by albendazole. The diagnosis was confirmed by parasitological and pathological data. In this article, we will deal with the macroscopic and microscopic features of this rare parasitosis in metropolitan France and we will discuss the elements of management of a fresh resected specimen during macroscopic examination to prevent parasite swarming.
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http://dx.doi.org/10.1016/j.annpat.2018.10.003DOI Listing
February 2019

Lung histopathology of non-infectious pulmonary complications after allogeneic haematopoietic stem cell transplantation.

Histopathology 2018 Nov 19;73(5):832-842. Epub 2018 Aug 19.

Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France.

Aims: Non-infectious pulmonary complications (NIPCs) occur frequently following allogeneic haematopoietic stem cell transplantation (HSCT). As there is no consensus on the description of the related pulmonary pathological lesions, pathologist reports and clinical conclusions are largely inconsistent in routine practice. The aim of our study was to provide an accurate overview of post-allogeneic HSCT NIPCs from a large number of lung biopsies.

Methods And Results: We reviewed 61 lung biopsies in patients with an NIPC, including 51 surgical lung biopsies, four post-mortem biopsies and six lung explants. We found both bronchiolar (n = 59) and alveolar/interstitial pathologies (n = 27). We describe two types of bronchiolar lesions: bronchiolectasies (n = 37) and fibrous and cellular lesions with luminal narrowing (n = 43). We found a wide spectrum of airway/interstitial pathologies that were labelled using the terminology of the 2013 American Thoracic Society and European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs), including the following: organising pneumonia (OP, n = 8), non-specific interstitial pneumonia (NSIP, n = 9), diffuse alveolar damage (DAD, n = 6), lymphoid interstitial pneumonia (LIP, n = 1) and pleuroparenchymal fibroelastosis (PPFE, n = 2), as well as one instance of associated PPFE and NSIP.

Conclusions: Interstitial pathology was associated with bronchiolar lesions in 41% of the cases reviewed (n = 25). Lung airway and interstitial inflammation was still present in lung explants from patients who underwent lung transplantation for post-allogeneic HSCT end-stage respiratory insufficiency. Herein, we describe a wide spectrum of pathological lung lesions encountered in post-allogeneic HSCT NIPCs.
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http://dx.doi.org/10.1111/his.13697DOI Listing
November 2018

Clinical and molecular characteristics of unicentric mediastinal Castleman disease.

J Thorac Dis 2018 Apr;10(4):2079-2088

INSERM UMR-S1152, Bichat Hospital, Paris-Diderot University, Paris, France.

Background: Unicentric mediastinal Castleman disease (CD) is a rare condition, poorly characterized due to the small number of cases and the absence of genomic study. We analyzed clinical, radiological, histological and genomic patterns associated with mediastinal CD in a substantial case series. We retrospectively reviewed cases of unicentric mediastinal CD managed in 2 French thoracic surgery departments between 1988 and 2012. Clinical, radiological, surgical and pathological data were recorded. On available FFPE blocks we performed mutation screening by next-generation-sequencing, using AmpliSeq™ Cancer Hotspot v2 (Life Technologies) and immunohistochemistry (IHC) (AKT-mTOR pathway).

Results: Eleven patients were identified (mean age 41±15 years, sex-ratio 0.8, median follow-up 78 months). Surgical approach was thoracotomy (n=6), sternotomy (n=4), and VATS (n=1). Additional procedures included thymectomy in three cases, mediastinal lymphadenectomy in two cases, and bilobectomy in one case. One patient presented local relapse as a follicular dendritic cell sarcoma, leading to death 48 months after the first resection. Within 9 patients whose FFPE blocks were available, 2 mutations were found: VHL (p.F119L, 35%, n=1) and JAK3 (p.V718L, 53%, n=1). Phospho-AKT and phospho-mTOR stainings were negative in all cases, whereas phospho-S6RP staining was positive in eight cases, mainly in interfollicular cell cytoplasm.

Conclusions: From this series of patients with unicentric mediastinal CD, we observed 2 cases of potential driver mutations and 8 cases of phospho-S6RP activation not related to AKT-mTOR. Larger studies are required to decipher more precisely the molecular abnormalities and potential therapeutic targets underlying this uncommon condition.
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http://dx.doi.org/10.21037/jtd.2018.03.159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949489PMC
April 2018

[Hot lung nodules on PET-CT].

Ann Pathol 2017 Aug 25;37(4):327-331. Epub 2017 Jul 25.

Service d'anatomie et cytologie pathologiques, hôpital Bichat, 46, rue Henri-Huchard, 75877 Paris cedex 18, France.

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http://dx.doi.org/10.1016/j.annpat.2017.06.001DOI Listing
August 2017

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses.

Respir Res 2017 06 15;18(1):120. Epub 2017 Jun 15.

Département de Pathologie, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, 46 rue Henri Huchard, 75018, Paris, France.

Background: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS).

Methods: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry.

Results: Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%.

Conclusions: This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.
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http://dx.doi.org/10.1186/s12931-017-0605-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472872PMC
June 2017

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

Oncoimmunology 2017;6(4):e1286437. Epub 2017 Feb 21.

INSERM U970, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8 T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of -positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 ( = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in -positive ADC than in ADC or WT (non--mutated and non--mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8 T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8 T cells or PD-1CD8 T cells was also observed in -positive lung cancer patients compared with -mutated ( = 0.03) or WT patients ( = 0.012). These results strongly suggest that a subgroup of -positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.
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http://dx.doi.org/10.1080/2162402X.2017.1286437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414864PMC
February 2017

Inhibition of T Cell Alloreactivity by Bronchial Epithelium Is Impaired in Lung Transplant Recipients, Through Pathways Involving TGF-β, IL-10 and HLA-G.

Transplantation 2017 09;101(9):2192-2199

1 INSERM UMR1152, Paris Diderot University, Paris, France. 2 CEA, IMETI, Hemato-immunology research department, Saint-Louis Hospital, Paris, France. 3 Paris Diderot University, Sorbonne Paris Cité, IUH, Paris, France. 4 Pneumology B and Lung Transplantation Department, Bichat Hospital, Paris, France. 5 Laboratory of Excellence INFLAMEX, Université Sorbonne Paris-Cité, Paris, France. 6 Département Hospitalo-Universitaire FIRE, Paris, France. 7 Pathology Department, Bichat hospital, Paris, France. 8 Thoracic Surgery Department, Bichat hospital, Paris, France. 9 Anesthesia Intensive Care, Bichat Hospital, Paris, France.

Background: Bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx) results from bronchial epithelial cell (BECs) damages, thought to be orchestrated by T cells primed by antigen-presenting cell presenting alloantigens. In this cell cross-talk, BECs are also suspected to play a pivotal immunosuppressive role in T cell alloreactivity. We studied the immunomodulating role of BECs in a human ex vivo model of allogeneic T cell response, both in healthy subjects and LTx recipients.

Methods: BECs from 35 LTx recipients (n = 22 stable, n = 13 BOS) and healthy controls (n = 25) were cultured as primary cell cultures. Their inhibitory capacities through the involvement of tolerogenic molecules (HLA-G, TGF-β, and IL-10) were tested on a mixed lymphocyte reaction between antigen-presenting cells and recipient T cells.

Results: Control BECs inhibited T cell alloproliferation by a mean of 53 ± 7%. This inhibitory effect of BECs was significantly reduced in the stable LTx group (24 ± 8%, P = 0.009), but not in the BOS TxP group (53 ± 10%, P = 0.97). Neutralization of HLA-G, TGF-β, and IL-10 partially restored T cell alloproliferation, arguing for their involvement in the immunosuppressive effect of BECs. BECs culture supernatant from stable LTx patients with impaired BEC properties showed a skewed Th2-type secretion profile (high IL-4/IFN-γ ratio).

Conclusions: The inhibitory properties of BECs are dysregulated in stable LTx recipients, which could suggest their instrumental role in the initiation of BOS process and potential targeted therapies.
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http://dx.doi.org/10.1097/TP.0000000000001553DOI Listing
September 2017

Phenol-Soluble Modulins Contribute to Early Sepsis Dissemination Not Late Local USA300-Osteomyelitis Severity in Rabbits.

PLoS One 2016 8;11(6):e0157133. Epub 2016 Jun 8.

Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches, and EA 3647, Faculté de Médecine Paris-Île-de-France Ouest, Université Versailles-Saint-Quentin, Versailles, France.

Introduction: In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton-Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while α-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated.

Materials And Methods: We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14).

Results: Severe sepsis-related mortality tended to be lower for Δpsm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities.

Conclusion: Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898696PMC
July 2017

Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma.

PLoS One 2016 2;11(3):e0150042. Epub 2016 Mar 2.

Centre du Sommeil, Service de Physiologie-Explorations Fonctionnelles, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Obstructive sleep apnoea (OSA) is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA.

Materials And Methods: An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM) thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies.

Results: In total, 27/55 patients (49%) had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index (AHI; 14.2 ± 1.6 event/h [5-35]), the proportion of sputum neutrophils was higher and that of macrophages lower in OSA than non-OSA patients, with higher levels of interleukin 8 and matrix metalloproteinase 9. The RBM was significantly thinner in OSA than non-OSA patients (5.8 ± 0.4 vs. 7.8 ± 0.4 μm, p<0.05). RBM thickness and OSA severity assessed by the AHI were negatively correlated (rho = -0.65, p<0.05). OSA and non-OSA patients did not differ in age, sex, BMI, lung function, asthma control findings or treatment.

Conclusion: Mild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150042PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774979PMC
July 2016

Airway-Centered Fibroelastosis: A Distinct Entity.

Chest 2016 Mar 8;149(3):767-74. Epub 2016 Jan 8.

INSERM U1152, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Service de Pneumologie A, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Département hospitalo-universitaire FIRE, Competence Center for Rare Pulmonary Diseases, Paris, France.

Objective: To describe a new entity characterized by airway-centered fibroelastosis.

Methods: We identified cases with prominent airway-centered elastosis in lung samples, and little or no pleural involvement identified through a pathologic database at a single institution over an 8-year period.

Results: Airway-centered fibroelastosis was characterized by (1) extensive airway-centered fibroelastosis of the upper lobes on histopathology and (2) marked bronchial abnormalities with bronchial wall thickening, bronchial wall deformation, and bronchiectasis, along with progressive parenchymal retraction and predominantly subpleural upper-lobe consolidations on high-resolution CT. Pateints were five nonsmoking women aged between 38 and 56 years old. They experienced chronic dyspnea with acute attacks of wheezing and dyspnea. Moderate to severe physiological abnormalities were observed, with an obstructive pattern in three cases and a restriction in two. Despite inhaled and oral corticosteroids, the disease was progressive in all patients and evolved to chronic respiratory failure, requiring lung transplantation in two patients. Four patients had chronic asthma.

Conclusions: We consider airway-centered fibroelastosis to be a unique and distinct pathological entity in women that needs to be individualized, with a specific clinical, imaging, and pathological presentation. We hypothesize that airway-centered fibroelastosis may be idiopathic or asthma-associated.
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http://dx.doi.org/10.1016/j.chest.2015.10.065DOI Listing
March 2016

Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer.

Oncotarget 2017 Apr;8(14):23831-23840

INSERM UMR-S1147, Paris Sorbonne Cité Université, Paris, France.

STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15-57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.
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http://dx.doi.org/10.18632/oncotarget.6379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410347PMC
April 2017

Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case.

BMC Cancer 2015 Oct 19;15:732. Epub 2015 Oct 19.

AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France.

Background: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man.

Case Presentation: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation.

Conclusion: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.
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http://dx.doi.org/10.1186/s12885-015-1754-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612419PMC
October 2015

Ex vivo relaxations of pulmonary arteries induced by prostacyclin mimetics are highly dependent of the precontractile agents.

Prostaglandins Other Lipid Mediat 2015 Sep 8;121(Pt A):46-52. Epub 2015 Sep 8.

Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Beyazit, 34116 Istanbul, Turkey.

Prostacyclin (PGI2) mimetics (iloprost, treprostinil) are potent vasodilators (primarily via IP-receptor activation) and major therapeutic interventions for pulmonary hypertension (PH). Increased plasma levels of endothelin (ET-1), thromboxane (TxA2) and catecholamines have been demonstrated from patients with PH. In this study, we aimed to compare relaxant effects of iloprost and treprostinil on human (HPA) and rat pulmonary arteries precontracted with either ET-1, thromboxane (U46619) or an α-adrenergic receptor agonist (Norepinephrine, NE or phenylephrine, PE). Treprostinil and iloprost induced vasorelaxation of HPA precontracted with NE, ET-1 or U46619. We obtained greater relaxation response and sensitivity to treprostinil when ET-1 or U46619 were used to induce the precontraction in comparison to NE. In contrast, iloprost showed less relaxation response and sensitivity in HPA precontracted with U46619 versus NE. In the rat, treprostinil and iloprost induced vasorelaxation of pulmonary arteries precontracted with PE and U46619 but minimally with ET-1. However, in rat pulmonary arteries, PE-induced precontractions were comparatively low amplitude. Our study showed that the ex vivo relaxation or sensitivity of pulmonary arteries induced by PGI2 mimetics is highly dependent on both the pre-contraction agent and the species. To best extrapolate to effects on human tissue, our results suggest that U46619 is the appropriate contractile agent for assessing the relaxant effect of PGI2 mimetics in rat pulmonary arteries. Finally we suggest that in PH patients with high plasma concentration of TxA2, treprostinil (not iloprost) would be a preferential treatment. On the other hand, if the ET-1 plasmatic level is high, either treprostinil or iloprost will be effective.
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http://dx.doi.org/10.1016/j.prostaglandins.2015.09.002DOI Listing
September 2015

[Treatment of alveolar proteinosis by intrapulmonary transplantation of macrophages].

Med Sci (Paris) 2015 Mar 8;31(3):241-4. Epub 2015 Apr 8.

APHP, hôpital Bichat, DHU Fire, service de pneumologie A, centre de compétence des maladies pulmonaires rares, 46, rue Henri Huchard, 75018 Paris, France - Inserm unité 1152, Paris, France - Université Paris Diderot, Paris, France.

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http://dx.doi.org/10.1051/medsci/20153103005DOI Listing
March 2015

Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines.

Eur Respir Rev 2014 Jun;23(132):193-214

For a full list of the authors affiliations see the Acknowledgements section.

Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.
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http://dx.doi.org/10.1183/09059180.00001814DOI Listing
June 2014

Pneumothoraces in Birt-Hogg-Dubé syndrome compared to smoking related blebs.

Histopathology 2014 Aug 22;65(2):292-3. Epub 2014 May 22.

St Vincent's University Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1111/his.12425DOI Listing
August 2014

α-Hemolysin, not Panton-Valentine leukocidin, impacts rabbit mortality from severe sepsis with methicillin-resistant Staphylococcus aureus osteomyelitis.

J Infect Dis 2014 Jun 26;209(11):1773-80. Epub 2013 Dec 26.

Département de Médecine Aigüe Spécialisée, Hôpital Universitaire Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris, Garches.

Background: Severe sepsis, combining acute osteomyelitis and lung involvement, has been described increasingly in healthy children with the spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).

Methods: Outcomes (mortality, hematogenous spread, lung and bone involvements) of rabbit osteomyelitis caused by CA-MRSA LAC(WT) USA300 and its Panton-Valentine leukocidin (PVL)- and α-hemolysin (Hla)-negative isogenic derivatives (LACΔpvl and LACΔhla, respectively) were compared.

Results: Three days after inoculation (D3), all LAC(WT)- and LACΔpvl-, and 72% of LACΔhla-infected rabbits had no hematogenous spread and similar lung and bone bacterial densities. LACΔpvl and LACΔhla caused less severe histological lung lesions than LAC(WT) (P ≤ .01). Between D3 and D9, 10 (53%) LAC(WT)-, 11 (55%) LACΔpvl-, but no LACΔhla-infected rabbits (P < .005) died of severe sepsis with disseminated infection. Unlike deceased animals, most LAC(WT), LACΔpvl, and LACΔhla D14 survivors had no hematogenous spread (P < .001). LAC(WT) (88%) caused more bone abscesses than LACΔpvl (0, P = .001) or LACΔhla (30%, P = .01).

Conclusion: In this model, both PVL and Hla seemed to be required for early lung involvement via hematogenous spread. Hla, but not PVL, significantly impacted severe sepsis-related mortality. PVL was the predominant factor determining late-stage bone abscesses.
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http://dx.doi.org/10.1093/infdis/jit840DOI Listing
June 2014

Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dubé syndrome from those of tobacco-related spontaneous pneumothorax.

Histopathology 2014 Apr 26;64(5):741-9. Epub 2013 Dec 26.

Department of Histopathology, St Vincent's University Hospital, Dublin, Ireland.

Aims: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited genodermatosis that predisposes to cystic lung disease, leading to spontaneous pneumothoraces. This retrospective analysis of five BHD cases (two men, three women) compared lung histology and computed tomography (CT) imaging to a matched cohort of non-BHD patients with spontaneous pneumothoraces (SPN).

Methods And Results: Lung was sampled during pleurodesis to resect bullae. Recurrent pneumothoraces was seen in two patients. Fourteen sets of histological slides (seven in each group) and 10 CT scans (five in each group) were reviewed. CT scans in BHD showed multiple cysts with a basal predominance and intraparenchymal/peribronchial distribution. On histological examination, BHD lungs showed punch-out cysts with no inflammation, and lacked subpleural fibroelastotic scars and smoking changes. In contrast, all SPN cases showed respiratory bronchiolitis and subpleural fibroelastotic scars.

Conclusions: This study emphasizes the importance of smoking history and topography of the lesions in assessing cystic lung disease. Pathologists need to remain alert to the possibility of BHD in the setting of recurrent pneumothoraces in a non-smoker, in particular in a woman, at any age, and should take part in a multidisciplinary approach to the diagnosis of cystic lung disease to obtain clinical and CT scan details.
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http://dx.doi.org/10.1111/his.12318DOI Listing
April 2014

A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor.

Prostaglandins Other Lipid Mediat 2013 Dec 12;107:48-55. Epub 2013 Jul 12.

INSERM U698, CHU X. Bichat, 46 rue H. Huchard, Paris 75018, France; Paris Nord University, Sorbonne Paris Cité, UMR-S698, Paris F-75018, France.

Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.
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http://dx.doi.org/10.1016/j.prostaglandins.2013.07.001DOI Listing
December 2013