Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer

<p>Abstract</p> <p>Background</p> <p>Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy.</p> <p>Case Presentation</p> <p>The medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed.</p> <p>Conclusion</p> <p>Physicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The association between selective EGFR-inhibitors and ILD should be further investigated.</p

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

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 −4–0·0282; 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

miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

APPORT DE LA TECHNIQUE D'HYBRIDATION IN SITU PAR FLUORESCENCE (F.I.S.H.) POUR LE DIAGNOSTIC DES LYMPHOMES A CELLULES DU MANTEAU

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude anatomo-pathologique de biopsies systématiques de reins transplantés à 1 an dans le cadre d'un protocole thérapeutique randomisé d'évaluation de l'équivalence immunosuppressive du mycophénolate mofétil par rapport à la ciclosporine

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

EXPRESSION DES APOMUCINES HUMAINES EN PATHOLOGIE TUMORALE BRONCHOPULMONAIRE ET PLEURALE (INTERET DANS LA COMPREHENSION DE L'HISTOGENESE NORMALE ET TUMORALE)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Le lymphome de la zone marginale ganglionnaire, un diagnostic d'exclusion (à propos de 24 cas)

Le lymphome de la zone marginale ganglionnaire est une pathologie rare, de présentation hétérogène, pour laquelle il n existe pas encore de marqueurs immunohistochimiques ou moléculaires spécifiques. Le diagnostic différentiel avec d autres lymphomes à petites cellules B peut s avérer parfois extrêmement difficile. La mise en place d une stratégie dans la réalisation des examens complémentaires est donc indispensable. Nous avons caractérisé sur le plan morphologique, immunohistochimique et moléculaire 24 cas de lymphome de la zone marginale ganglionnaire. L étude immunohistochimique a été réalisée avec les anticorps suivants : CD20, CD79a, CD3, CD5, CD21, CD23, CD43, CD10, Bcl6, Bcl2, cyclineD1, Sox11et Ki67. Une recherche de réarrangement de BCL1, BCL2, MALT1 pour l ensemble des cas, et de BCL6 pour 3 cas, a été effectuée. L exon 5 de MYD88 a été étudié pour la totalité des cas. Quatre types d architecture ont été observés : diffuse (37.5%), nodulaire (4.5%), nodulaire et diffuse (41.5%) et splénique (16.5%). Le polymorphisme cellulaire était prédominant (67%). La différenciation lymphoplasmocytaire était la plus fréquente (67%), tandis que le contingent monocytoïde pur était peu rencontré (4.5%). Une composante minoritaire était cependant souvent retrouvée (33%). L immunophénotype classique était observé dans 41.5% des cas. Les cellules tumorales de 5 cas étaient positives avec l anticorps anti-CD5. Cinq autre cas présentaient un marquage avec l anticorps anti-CD23 et un cas avec les anticorps anti-CD5 et anti-CD23. Les cellules tumorales de 3 cas étaient partiellement positives avec l anticorps anti-Bcl6. Trois cas ont été exclus au cours de l étude. Les cellules tumorales de l un d entre eux étaient positives avec les anticorps anti-cycline D1 et anti-Sox11. L étude FISH avait mis en évidence une t(11;14). Les deux autres cas présentaient un marquage partiel des cellules tumorales par l anticorps anti-Bcl6, ainsi qu une amplification du gène BCL6 en FISH. La mutation L265P de MYD88 a été retrouvée dans un cas dont la morphologie, le phénotype et l étude moléculaire étaient en faveur d un lymphome de la zone marginale ganglionnaire. Devant l importante variabilité de présentation morphologique et immunophénotypique des lymphomes de la zone marginale ganglionnaire, nous mettons en avant l intérêt d une étude immunohistochimique globale face à un lymphome à petites cellules B, notamment le bénéfice de l usage de différents marqueurs du centre germinatif et de la cycline D1. La FISH ainsi que la recherche de la mutation L265P de MYD88 présentent également un intérêt dans ce diagnostic.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF