Publications by authors named "Marie-Christine Copin"

144 Publications

[Histological pulmonary features due to the Sars-CoV-2].

Rev Francoph Lab 2021 Jan 7;2021(528):30-35. Epub 2021 Jan 7.

Université d'Angers, Inserm, CRCINA, Angers, France.

The histological lesions associated with an infection with the Sars-CoV-2 are mainly observed at the respiratory tract level, but not exclusively. Analyses of these lesions strongly beneficied from autopsic studies allowing us to improve the knowledge of the pathophysiology mechanisms of this emerging infectious disease. Cytological analyses, notably those obtained from broncho-alveolar lavages, poorly contribute to the Covid-19 diagnosis, but can be usefull for eliminate a couple of differential diagnoses. Although non specific, the lesions observed in the pulmonary parenchyma can be directly associated with the presence of the Sars-CoV-2 thanks to ancillary tools allowing its detection. Indeed, the presence of the virus can be detected using immunohistochemistry, hybridization, molecular biology and/or electron microscopy approaches. Several uncertainties still exist concerning the direct role due to the Sars-CoV-2 in the observed lesions which can be due too to a cardiovascular failure and/or to the treatment(s) received in intensive care units. Thus, it is critical to keep going to increase our efforts for the tissue analyses, notably thanks to the autopsies of Covid-19 patients, in order to better understand the consequences of this infectious disease, and, particularly according the epidemiological factors and the different associated morbidities. An increased knowledge will participate to the further therapeutic strategies against the Covid-19. This review adresses the main histological lesions of the lung parenchyma currently described in patients infected by the Sars-CoV-2.
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http://dx.doi.org/10.1016/S1773-035X(20)30391-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834459PMC
January 2021

[Histopathological features due to the SARS-CoV-2].

Ann Pathol 2021 Feb 30;41(1):9-22. Epub 2020 Dec 30.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, Padova, Italie.

The infection due to the SARS-CoV-2 leads lesions mainly observed at the respiratory tract level, but not exclusively. The analyses of these lesions benefited from different autopsy studies. Thus, these lesions were observed in different organs, tissues and cells. These observations allowed us to rapidly improve the knowledge of the pathophysiological mechanisms associated with this emergent infectious disease. The virus can be detected in formalin fixed paraffin embedded tissues using immunohistochemistry, in situ hybridization, molecular biology and/or electron microscopy approaches. However, many uncertainties are still present concerning the direct role of the SARS-CoV-2 on the different lesions observed in different organs, outside the lung, such as the heart, the brain, the liver, the gastrointestinal tract, the kidney and the skin. In this context, it is pivotal to keep going to increase the different tissue and cellular studies in the COVID-19 positive patients aiming to better understanding the consequences of this new infectious disease, notably considering different epidemiological and co-morbidities associated factors. This could participate to the development of new therapeutic strategies too. The purpose of this review is to describe the main histological and cellular lesions associated with the infection due to the SARS-CoV-2.
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http://dx.doi.org/10.1016/j.annpat.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773006PMC
February 2021

[Renal granulomatous nephritis: Histopathological point of view].

Ann Pathol 2021 Apr 1;41(2):166-175. Epub 2020 Dec 1.

UMR9020 - UMR-S 1277, Inserm, CNRS, nephrology department, cancer heterogeneity, plasticity and resistance to therapies, Canther, CHU de Lille, université Lille, 59000 Lille, France.

Granulomatous interstitial nephritis (NIG) is a rare form of interstitial nephritis that can be related to acute or chronic clinical presentation. NIG is characterized by granulomas located to the renal interstitium and composed of either epithelioid histiocytes with giant cells and/or of foreign body reaction. The symptoms are unspecific and associate varying degrees of renal failure with abnormal urinanalysis. Extra-renal signs may point to systemic disease. Pathological examination from kidney percutaneous biopsy or surgical resection is required to assert NIG diagnosis and to guide the etiological research. The main causes of NIG are sarcoidosis, drug reactions, mycobacterial infections and crystalline nephropathies. Sarcoidosis is characterized by non-necrotic and well-formed giant cell epithelioid interstitial granulomas. Drug reactions have less well-defined granulomas with inconstant eosinophils. The presence of caseous necrosis within giant cell and epithelioid granulomas leads to infectious NIG diagnosis (tuberculosis and fungal infection). Identification of crystals within foreign body reaction can be improved by polarized light study. Xanthogranulomatous pyelonephritis and malakoplakia are rarer causes of NIG characterized by patches of histiocytes associated with inconstant giant cells. Differential diagnoses of NIG are represented by granulomatous reactions centered on glomeruli and vessels (vasculitis and emboli of cholesterol crystals). Less than 10% of NIG are idiopathic. The prognosis and the treatment vary according to the cause. The factors of poor renal prognosis are chronic irreversible tubulo-interstitial injury (tubular atrophy and interstitial fibrosis).
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http://dx.doi.org/10.1016/j.annpat.2020.11.001DOI Listing
April 2021

CXCL13 is expressed in various haematological disorders other than angioimmunoblastic T-cell lymphoma.

Pathol Res Pract 2020 08 21;216(8):153004. Epub 2020 May 21.

Univ. Lille, CHU Lille, Institut de Pathologie, Avenue Oscar Lambret, F-59000 Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.prp.2020.153004DOI Listing
August 2020

Complete and prolonged response to anti-PD1 therapy in an ALK rearranged lung adenocarcinoma.

Lung Cancer 2020 08 27;146:366-369. Epub 2020 May 27.

Univ Lille, Department of Thoracic Oncology, CHU Lille, F-59000, Lille, France. Electronic address:

Objective: Immune checkpoint inhibitors (ICI) have become a major treatment in advanced non small cell lung cancer (NSCLC). However, some patients do not benefit from ICI, especially those harboring an ALK rearrangement. Here, we report a case of prolonged complete tumor response to immunotherapy in an ALK-rearranged NSCLC patient.

Materials And Methods: We verify ALK expression and rearrangement on formalin-fixed paraffin-embedded tumor samples of the patient by Immunohistochemistry and Fluorescence In Situ Hybridization analysis. The patient provided written informed consent authorizing publication of clinical case.

Results: We report the case of 48 years old man with a ALK-rearranged NSCLC. This patient displayed a complete response for 16 months under nivolumab therapy in third line setting after ceritinib and platin based chemotherapy.

Conclusion: This is the first case of complete and prolonged response to ICI in ALK rearranged NSCLC. This case supports the idea that some ALK rearranged NSCLC could durably benefit from immunotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.008DOI Listing
August 2020

Paraffin Immunofluorescence Increases Light-Chain Detection in Extra-Renal Light Chain Amyloidosis and Other Light-Chain-Associated Diseases.

Arch Pathol Lab Med 2021 03;145(3):352-358

From the Université de Lille, CNRS, Inserm, CHU Lille, Pathology Department, Centre de Biologie Pathologie, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France (Gibier, Gnemmi).

Context.—: Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases.

Objectives.—: To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases.

Design.—: First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing.

Results.—: In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure.

Conclusions.—: We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases.
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http://dx.doi.org/10.5858/arpa.2020-0018-OADOI Listing
March 2021

[The "Conseil national professionnel d'anatomie et cytologie pathologiques" (CNPath): At the service of the profession].

Ann Pathol 2020 Sep 21;40(5):384-388. Epub 2020 May 21.

Service de pathologie, département de biologie et pathologie médicales, institut Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France.

The « conseils nationaux professionnels » (CNP) are professional boards existing since 2010. Their missions, organization and functioning have been defined by the decree 2019-17 of January 9, 2019. CNPs represent all the members of a medical specialty (or health profession). CNPs must include all the learned societies and all the representative structures and associations of the same medical specialty. Their bodies must strictly respect the parity between public and private health sectors. The main missions of CNPs include the contribution to the elaboration of the national priority directions for continuous medical education and the definition of the individual plan for continuous professional development (DPC) recommended for the specialty. CNPs also behave as a single window for ministries, State agencies, welfare system and colleges of physicians. They are likely to be strongly involved in the process of re-certification of physicians, established in July 2019. The Conseil national professionnel d'anatomie et cytologie pathologiques, termed CNPath, has been created in 2010 and officially recognized by the Ministry of Health in August 2019. The main current actions of CNPath are: the elaboration of the individual DPC scheme for the specialty and the definition of the minimal obligations requested for its validation, the long-expected recognition of the expertal consultation in pathology, the support to the nation-wide effort for the production of structured pathological reports and the launching of a plan for implementing digital pathology. An internet site is under construction, to diffuse all the relevant information and make available the documents useful to all pathologists.
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http://dx.doi.org/10.1016/j.annpat.2020.04.004DOI Listing
September 2020

Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection.

Intensive Care Med 2020 06 23;46(6):1124-1126. Epub 2020 Apr 23.

Pôle de reanimation, CHU Lille, Univ. Lille, Avenue Oscar Lambret, 59000, Lille, France.

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http://dx.doi.org/10.1007/s00134-020-06057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178098PMC
June 2020

2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations.

Nat Commun 2020 03 20;11(1):1509. Epub 2020 Mar 20.

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-UMR-S 1277, CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France.

Nonsense mutations cause about 10% of genetic disease cases, and no treatments are available. Nonsense mutations can be corrected by molecules with nonsense mutation readthrough activity. An extract of the mushroom Lepista inversa has recently shown high-efficiency correction of UGA and UAA nonsense mutations. One active constituent of this extract is 2,6-diaminopurine (DAP). In Calu-6 cancer cells, in which TP53 gene has a UGA nonsense mutation, DAP treatment increases p53 level. It also decreases the growth of tumors arising from Calu-6 cells injected into immunodeficient nude mice. DAP acts by interfering with the activity of a tRNA-specific 2'-O-methyltransferase (FTSJ1) responsible for cytosine 34 modification in tRNA. Low-toxicity and high-efficiency UGA nonsense mutation correction make DAP a good candidate for the development of treatments for genetic diseases caused by nonsense mutations.
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http://dx.doi.org/10.1038/s41467-020-15140-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083880PMC
March 2020

Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations.

J Thorac Oncol 2020 05 10;15(5):741-751. Epub 2020 Mar 10.

University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France; Thoracic Oncology Department, CHU Lille, University of Lille, Lille, France. Electronic address:

Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that in METex14 NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI-treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.
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http://dx.doi.org/10.1016/j.jtho.2020.01.027DOI Listing
May 2020

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

J Thorac Oncol 2020 06 9;15(6):1037-1053. Epub 2020 Mar 9.

MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Cochin-Hotel Dieu, Department of Pathology, Paris, France.

Introduction: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort.

Methods: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors.

Results: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification.

Conclusion: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.
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http://dx.doi.org/10.1016/j.jtho.2020.01.025DOI Listing
June 2020

An 80-Year-Old Woman With a Solitary Pulmonary Nodule.

Chest 2020 03;157(3):e85-e89

Pathology Department, Centre de Biologie Pathologie, University of Lille, CHU Lille, Lille, France.

Case Presentation: An 80-year-old-woman was referred for evaluation of chest pain that appeared after providing care at home for her sick husband, which included helping him to get up and move about. The pain was initially triggered by lifting heavy objects but then became constant, without exacerbating or relieving factors. The pain was located in the left hemithorax and was not associated with shortness of breath or cough. Because the patient did not feel any better after a month, her general practitioner ordered a radiograph, which revealed a suspicious pulmonary nodule in the left upper lobe. She was a lifelong nonsmoker and denied any drug abuse. She had not been professionally exposed to lung carcinogens. She had a medical history of type 2 diabetes, ischemic cardiomyopathy, and renal artery stenosis. Her father died of lung cancer. She resided in Lille, France, and did not report any recent travel.
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http://dx.doi.org/10.1016/j.chest.2019.10.056DOI Listing
March 2020

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival.

Mol Oncol 2020 06 10;14(6):1207-1223. Epub 2020 Mar 10.

Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors laboratory, France.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
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http://dx.doi.org/10.1002/1878-0261.12651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266286PMC
June 2020

Tubulointerstitial damage and interstitial immune cell phenotypes are useful predictors for renal survival and relapse in antineutrophil cytoplasmic antibody-associated vasculitis.

J Nephrol 2020 Aug 8;33(4):771-781. Epub 2020 Jan 8.

Pathology Department, Lille University Hospital (CHU), Pathology Institute, Inserm UMR-S1172 Lille, JPARC-Jean-Pierre Aubert Research Center, Team 'Mucins, Epithelial Differentiation and Carcinogenesis", Lille University, CHU Lille, Avenue Oscar Lambret, 59000, Lille, France.

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P < 0.0001) and IF/TA > 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.
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http://dx.doi.org/10.1007/s40620-019-00695-yDOI Listing
August 2020

"Idiopathic Eosinophilic Vasculitis": Another Side of Hypereosinophilic Syndrome? A Comprehensive Analysis of 117 Cases in Asthma-Free Patients.

J Allergy Clin Immunol Pract 2020 04 18;8(4):1329-1340.e3. Epub 2019 Dec 18.

Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Lille, France; Hôpital Ambroise Paré, Service de Médecine Interne, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France.

Background: The absence of asthma may rule out a diagnosis of eosinophilic granulomatosis with polyangiitis in patients with hypereosinophilic syndrome (HES) and features of vasculitis.

Objective: To describe eosinophilic vasculitis (EoV) as a possible manifestation of HES in asthma-free patients.

Methods: We screened our hospital database and the literature for patients with HES who met the following 4 criteria: (1) histopathological or clinical features of EoV (biopsy-proven vasculitis with predominant eosinophilic infiltration of the vessel wall and/or features of vasculitis with tissue and/or blood hypereosinophilia [absolute eosinophil count >1.5 G/L]); (2) no other obvious causes of reactive eosinophilia, organ damage, and vasculitis; (3) the absence of antineutrophil cytoplasmic antibodies; and (4) the absence of current asthma.

Results: Ten of our 83 (12%) asthma-free patients with HES and 107 additional cases in the literature met the criteria for EoV. After a critical analysis of the patients' clinical and laboratory characteristics and outcomes, we identified 41 cases of single-organ EoV (coronary arteritis, n = 29; temporal arteritis, n = 8; cerebral vasculitis, n = 4). Of the remaining 76 patients with EoV, the most frequent manifestations (>10%) were cutaneous vasculitis (56%), peripheral neuropathy (24%), thromboangiitis obliterans-like disease (16%), fever (13%), central nervous system involvement (13%), deep venous thrombosis (12%), and nonasthma lung manifestations (12%). Blood hypereosinophilia more than 1.5 G/L was observed in 79% of patients, and necrotizing vasculitis was observed in 44%.

Conclusions: Our results suggest that idiopathic EoV (HES-associated vasculitis) can be classified as an eosinophilic-rich, necrotizing, systemic form of vasculitis that affects vessels of various sizes in asthma-free patients.
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http://dx.doi.org/10.1016/j.jaip.2019.12.011DOI Listing
April 2020

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions.

EBioMedicine 2019 Oct 21;48:191-202. Epub 2019 Oct 21.

Toulouse University Hospital, Toulouse, France.

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.

Methods: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples.

Findings: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series.

Interpretation: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838392PMC
October 2019

High MET Overexpression Does Not Predict the presence of MET exon 14 Splice Mutations in NSCLC: Results From the IFCT PREDICT.amm study.

J Thorac Oncol 2020 01 9;15(1):120-124. Epub 2019 Oct 9.

Lille University Hospital, CHU Lille, Thoracic Oncology Department, Lille, France. Electronic address:

Introduction: MET proto-oncogene (MET) exon 14 splice site (METex14) mutations were recently described in NSCLC and has been reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations makes them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.

Methods: From The French Cooperative Thoracic Intergroup PREDICT.amm cohort of 843 consecutive patients with a treatment-naive advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next-generation sequencing. MET copy number analysis was also derived from the sequencing data.

Results: METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. An MET gene copy number increase was observed in seven additional patients (7.7%). Next-generation sequencing analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%), and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%), and IDH1 (1.1%).

Conclusions: The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET immunohistochemistry as a surrogate marker for METex14 mutations.
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http://dx.doi.org/10.1016/j.jtho.2019.09.196DOI Listing
January 2020

Assessment of T-cell polarization on the basis of surface marker expression: Diagnosis and potential therapeutic implications in lymphocytic variant hypereosinophilic syndrome.

J Allergy Clin Immunol Pract 2020 Mar 13;8(3):1110-1114.e2. Epub 2019 Sep 13.

Institut d'Immunologie, CHU de Lille, Lille, France; Univ. Lille, U995-LIRIC-Lille Inflammation Research International Center, Lille, France; Département de Médecine Interne, CHU de Lille, Lille, France; Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.08.049DOI Listing
March 2020

Renal Pathologic Findings in TAFRO Syndrome: Is There a Continuum Between Thrombotic Microangiopathy and Membranoproliferative Glomerulonephritis? A Case Report and Literature Review.

Front Immunol 2019 28;10:1489. Epub 2019 Jun 28.

Département de Médecine Interne et Immunologie Clinique, CHU Lille, Centre de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), LIRIC INSERM U995, Université de Lille, Lille, France.

TAFRO syndrome is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) that is characterized by thrombocytopenia, anasarca, fever and/or elevated serum C-reactive protein, renal dysfunction, and organomegaly. A 28-year-old woman with fever, weight gain of 13 kgs, lower extremity edema, hepatosplenomegaly, and multicentric peripheral lymphadenopathy was referred to our center. Laboratory investigations revealed anemia, thrombocytopenia, creatinine at 1.19 mg/dL and hypoalbuminemia at 33 g/L. Proteinuria was measured at 2 g/day including albuminuria at 1.5 g/day. Urinary sediment examination found leukocyturia at 44,000/mL and hematuria at 645,000/mL. Vascular endothelial growth factor (VEGF) level was elevated. A cervical lymph node biopsy found features consistent with the mixed histopathological subtype of iMCD. A renal biopsy revealed a membranoproliferative glomerulonephritis (MPGN) pattern. We initiated 3 days of methylprednisolone pulse-therapy at 1,000 mg per day, followed by prednisone 1 mg/kg/day and evolution was favorable. 19 iMCD patients with TAFRO syndrome had undergone a renal biopsy: 8 cases with author's diagnosis consistent with MPGN-like and 11 cases of thrombotic microangiopathy (TMA)-like glomerulopathy without fibrin thrombi in glomerular capillaries or arterioles and without typical biological signs. Clinical, biological, and outcome characteristics were similar between the cases described as having MPGN and TMA-like presentation. After a thorough review of histopathological descriptions for each case, MPGN lesions seems to be the consequences of chronic glomerular endothelial injury in persistent TMA. We suspect that VEGF and IL-6 play a key role in the physiopathology of the spectrum of renal involvement from TMA-like to MPGN observed in TAFRO syndrome. We present a Caucasian iMCD patient with TAFRO syndrome with renal insufficiency secondary to MPGN, which might be secondary to a chronic TMA-like disease. We suspect that there is a continuum between TMA and MPGN lesions in TAFRO syndrome favored by VEGF and IL-6.
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http://dx.doi.org/10.3389/fimmu.2019.01489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609882PMC
October 2020

Endocan regulates acute lung inflammation through control of leukocyte diapedesis.

J Appl Physiol (1985) 2019 09 11;127(3):668-678. Epub 2019 Jul 11.

University of Lille, U1019, UMR 8204, Center for Infection and Immunity of Lille, Lille, France.

Acute respiratory distress syndrome is a severe form of respiratory failure, occurring in up to 20% of patients admitted to the intensive care unit with sepsis. Dysregulated leukocyte diapedesis is a major contributor to acute respiratory distress syndrome. Endocan is a circulating proteoglycan that binds to the leukocyte integrin leukocyte functional antigen-1 and blocks its interaction with its endothelial ligand, ICAM-1. The objective of this study was to evaluate the role of endocan in the control of acute lung inflammation. In vitro, endocan inhibited human leukocyte transendothelial migration as well as ICAM-1-dependent migration but had a very mild effect on ICAM-1-dependent adhesion. Endocan also acted as an inhibitor of transendothelial migration of mouse leukocytes. The effect of systemic administration of recombinant human endocan was assessed in a model of acute lung inflammation in BALB/c mice. Treatment with endocan 1 h after intratracheal LPS challenge reduced the alveolar inflammatory response, diminished histological features of acute lung injury, and improved respiratory function. These results highlight the anti-inflammatory role of human endocan and its protective effect against acute lung injury. We show here that endocan inhibits ICAM-1-dependent human leukocyte transendothelial migration and ICAM-1-dependent adhesion. We also found that in BALB/c mice with tracheal LPS-induced acute lung injury treatment with recombinant human endocan reduces lung inflammation, notably through reduction of neutrophilic recruitment, and restores normal lung function. These results confirm the hypothesis that human endocan may have a protective effect against acute lung inflammation.
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http://dx.doi.org/10.1152/japplphysiol.00337.2019DOI Listing
September 2019

Relevance of Detection of Mechanisms of Resistance to ALK Inhibitors in ALK-Rearranged NSCLC in Routine Practice.

Clin Lung Cancer 2019 07 26;20(4):297-304.e1. Epub 2019 Feb 26.

Thoracic Oncology Department, Univ. Lille CHU Lille, Lille, France; UMR 8161 M3T Mechanisms of Tumorigenesis and Targeted Therapies, Univ. Lille CNRS Institut Pasteur de Lille, Lille, France. Electronic address:

Background: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice.

Materials And Methods: We performed a retrospective multicentric study with an aim to determine the frequency and clinical relevance of ALK alterations detected using targeted next-generation sequencing in patients with advanced ALK-rearranged NSCLC after progression during an ALK TKI treatment. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected.

Results: We identified 23 patients with advanced ALK-rearranged NSCLC who, between January 2012 and May 2017, had undergone at least 1 repeat biopsy at progression during an ALK TKI treatment. A resistance mechanism was identified in 9 of the 23 patients (39%). The anomalies involved included 9 ALK mutations in 8 patients and one ALK amplification. The ALK mutation rate was 15% after failure of a first ALK TKI and 33% after failure of 2 ALK TKI treatments. Five of 7 patients who received a different ALK TKI after detection of an ALK mutation achieved an objective response. All of the patients who received a TKI presumed to act on the detected ALK mutant achieved disease control.

Conclusion: Targeted next-generation sequencing is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It might help select the best treatment at the time of disease progression during treatment with an ALK TKI.
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http://dx.doi.org/10.1016/j.cllc.2019.02.013DOI Listing
July 2019

Childhood pulmonary Langerhans cell histiocytosis: a comprehensive clinical-histopathological and BRAF mutation study from the French national cohort.

Hum Pathol 2019 07 3;89:51-61. Epub 2019 May 3.

Pediatric Hemato-Oncology Department and French Referent Centre for Histiocytoses, APHP, CHU Armand-Trousseau, 75012 Paris, France.

Childhood pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease. Its pulmonary histopathology, according to comprehensive clinical-radiological findings and BRAF mutation status, has not yet been thoroughly documented. From the 167 childhood PLCH cases entered in the French National Histiocytosis Registry (1983-2016), we retrieved lung biopsies from a consecutive retrospective series of 17 patients, diagnosed when they were 2 weeks to 16 years old (median, 9.4 years), and report the clinical and histopathological findings herein. Histological analyses of biopsies (16 surgical and 1 postmortem) found the following features, alone or associated: Langerhans cell (LC) nodules with cavitation (9/17), cysts (14/17), fibrotic scars (2/17), peribronchiolar topographic distribution of the lesions (10/17), and accessory changes, like stretch emphysema (7/17). Those characteristics closely resemble those describing adult PLCH. However, unusual findings observed were 2 large nodules and a diffuse interstitial LC infiltrate. BRAF mutation was detected in 4 of 12 samples tested, notably in the 3 with unusual features. In conclusion, childhood PLCH mostly shares the common histology features already described in adult PLCH, regardless of age. Because smoking is considered the major trigger in PLCH pathogenesis, the findings based on this series suggest other inducers of bronchiolar LC recruitment, especially in very young patients.
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http://dx.doi.org/10.1016/j.humpath.2019.04.005DOI Listing
July 2019

Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer.

Mol Cancer Ther 2019 06 29;18(6):1137-1148. Epub 2019 Mar 29.

Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T, Lille, France.

Besides the detection of somatic receptor tyrosine kinases (RTK) mutations in tumor samples, the current challenge is to interpret their biological relevance to give patients effective targeted treatment. By high-throughput sequencing of the 58 RTK exons of healthy tissues, colorectal tumors, and hepatic metastases from 30 patients, 38 different somatic mutations in RTKs were identified. The mutations in the kinase domains and present in both tumors and metastases were reconstituted to perform an unbiased functional study. Among eight variants found in seven RTKs (EPHA4-Met726Ile, EPHB2-Val621Ile, ERBB4-Thr731Met, FGFR4-Ala585Thr, VEGFR3-Leu1014Phe, KIT-Pro875Leu, TRKB-Leu584Val, and NTRK2-Lys618Thr), none displayed significantly increased tyrosine kinase activity. Consistently, none of them induced transformation of NIH3T3 fibroblasts. On the contrary, two RTK variants (FGFR4-Ala585Thr and FLT4-Leu1014Phe) caused drastic inhibition of their kinase activity. These findings indicate that these RTK variants are not suitable targets and highlight the importance of functional studies to validate RTK mutations as potential therapeutic targets.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0582DOI Listing
June 2019

Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications.

Nat Commun 2019 03 22;10(1):1333. Epub 2019 Mar 22.

Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, 75006, Paris, France.

Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both on histology and molecular profiling. Histology addresses inter-tumor and intra-tumor heterogeneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, a combination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to a reconsideration of MPM molecular classifications. We show that each tumor can be decomposed as a combination of epithelioid-like and sarcomatoid-like components whose proportions are highly associated with the prognosis. Moreover, we show that this more subtle way of characterizing MPM heterogeneity provides a better understanding of the underlying oncogenic pathways and the related epigenetic regulation and immune and stromal contexts. We discuss the implications of these findings for guiding therapeutic strategies, particularly immunotherapies and targeted therapies.
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http://dx.doi.org/10.1038/s41467-019-09307-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430832PMC
March 2019

MET amplification increases the metastatic spread of EGFR-mutated NSCLC.

Lung Cancer 2018 11 11;125:57-67. Epub 2018 Sep 11.

Thoracic Oncology Department, CHU Lille, Siric OncoLille, F-59000, Lille, France; Univ Lille, Lille, France; Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000, Lille, France. Electronic address:

Background: Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown.

Methods: We investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression.

Results: MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification.

Conclusion: MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.008DOI Listing
November 2018

C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

J Allergy Clin Immunol Pract 2019 Apr 11;7(4):1347-1351.e3. Epub 2018 Oct 11.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), University of Lille, Lille, France; Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), France; CHU Lille, Institut d'Immunologie, University of Lille, Lille, France; Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, University of Lille, Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.10.002DOI Listing
April 2019

Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis.

Mol Cancer 2018 10 11;17(1):148. Epub 2018 Oct 11.

CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.
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http://dx.doi.org/10.1186/s12943-018-0891-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180566PMC
October 2018

Optimization of Routine Testing for MET Exon 14 Splice Site Mutations in NSCLC Patients.

J Thorac Oncol 2018 12 7;13(12):1873-1883. Epub 2018 Sep 7.

Lille University, CNRS, Institut Pasteur de Lille, Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France; Lille University, Thoracic Oncology Department, CHU Lille, Lille, France. Electronic address:

Introduction: Genomic alterations affecting splice sites of MNNG HOS transforming gene (MET) exon 14 were recently identified in NSCLC patients. Objective responses to MET tyrosine kinase inhibitors have been reported in these patients. Thus, detection of MET exon 14 splice site mutations represents a major challenge. So far, most of these alterations were found by full-exome sequencing or large capture-based next-generation sequencing (NGS) panels, which are not suitable for routine diagnosis.

Methods: Aiming to provide a molecular testing method applicable in routine practice, we first developed a fragment-length analysis for detecting deletions in introns flanking MET exon 14. Second, we designed an optimized targeted NGS panel called CLAPv1, covering the MET exon 14 and flanking regions in addition to the main molecular targets usually covered in genomic testing. In patients with MET exon 14 mutations, MET gene amplification, gene copy number and MET receptor expression were also determined.

Results: Among 1514 formalin-fixed paraffin-embedded NSCLC samples, nonoptimized NGS allowed detection of MET exon 14 mutations in only 0.3% of the patients, and fragment length analysis detected deletions in 1.1% of the patients. Combined, the optimized CLAPv1 panel and fragment-length analysis implemented for routine molecular testing revealed MET exon 14 alterations in 2.2% of 365 additional NSCLC patients. MET gene amplification or high gene copy number was observed in 6 of 30 patients (20%) harboring MET exon 14 mutations.

Conclusions: These results show that optimized targeted NGS and fragment-length analysis improve detection of MET alterations in routine practice.
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http://dx.doi.org/10.1016/j.jtho.2018.08.2023DOI Listing
December 2018

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.

Lancet Respir Med 2018 10 9;6(10):771-781. Epub 2018 Aug 9.

Medical Oncology Department, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain.

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.

Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.

Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.

Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.

Funding: "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
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http://dx.doi.org/10.1016/S2213-2600(18)30284-4DOI Listing
October 2018