Multicentric development and evaluation of [18F]FDG PET/CT and CT radiomic models to predict regional and/or distant recurrence in early-stage non-small cell lung cancer treated by stereotactic body radiation therapy.

PURPOSE: To develop machine learning models to predict regional and/or distant recurrence in patients with early-stage non-small cell lung cancer (ES-NSCLC) after stereotactic body radiation therapy (SBRT) using [18F]FDG PET/CT and CT radiomics combined with clinical and dosimetric parameters. METHODS: We retrospectively collected 464 patients (60% for training and 40% for testing) from University Hospital of Liège and 63 patients from University Hospital of Brest (external testing set) with ES-NSCLC treated with SBRT between 2010 and 2020 and who had undergone pretreatment [18F]FDG PET/CT and planning CT. Radiomic features were extracted using the PyRadiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Clinical, radiomic, and combined models were trained and tested using a neural network approach to predict regional and/or distant recurrence. RESULTS: In the training (n = 273) and testing sets (n = 191 and n = 63), the clinical model achieved moderate performances to predict regional and/or distant recurrence with C-statistics from 0.53 to 0.59 (95% CI, 0.41, 0.67). The radiomic (original_firstorder_Entropy, original_gldm_LowGrayLevelEmphasis and original_glcm_DifferenceAverage) model achieved higher predictive ability in the training set and kept the same performance in the testing sets, with C-statistics from 0.70 to 0.78 (95% CI, 0.63, 0.88) while the combined model performs moderately well with C-statistics from 0.50 to 0.62 (95% CI, 0.37, 0.69). CONCLUSION: Radiomic features extracted from pre-SBRT analog and digital [18F]FDG PET/CT outperform clinical parameters in the prediction of regional and/or distant recurrence and to discuss an adjuvant systemic treatment in ES-NSCLC. Prospective validation of our models should now be carried out.

[Clinically amyopathic dermatomyositis : a rare entity associated with acute and severe interstitial lung disease]. / La dermatomyosite amyopathique : une entité rare associée à une pneumopathie interstitielle fulminante.

Dermatomyositis is a rare disease of unknown etiology characterized by a severe inflammatory myopathy associated with a cutaneous syndrome. Dermatomyositis is associated with multisystemic disorders mostly represented by cardiac, pulmonary and articular involvements, which are particularly associated with a bad prognosis. We report a case of a 50-year-old patient suffering from dermatomyositis associated with an interstitial lung disease with a particularly fast and pejorative clinical evolution. The anti-Melanoma Differentiation-Associated gene 5 (anti-MDA5) antibodies are frequently associated with a severe and rapidly progressive lung disease without myositis named «amyopathic dermatomyositis¼. High blood levels of anti-MDA5 were found in our patient. Despite maximal immunosuppressive treatment and supportive care, he died 3 months after the diagnosis. Patients may present different antibodies that correspond to distinct clinical phenotypes of dermatomyositis. The anti-MDA5 is known to be a marker of clinically amyopathic dermatomyositis (CADM) associated with a rapidly progressive interstitial lung disease. Moreover, blood level of anti-MDA5 antibody predicts the response to treatment and survival in CADM.

La dermatomyosite est une maladie rare, d'étiologie inconnue, caractérisée par une myopathie inflammatoire associée à un syndrome cutané typique. Outre l'atteinte musculaire et cutanée, la dermatomyosite peut se manifester par des atteintes organiques, notamment pulmonaires, cardiaques et articulaires qui contribuent à la sévérité de la maladie. Nous rapportons le cas d'un patient âgé de 50 ans atteint d'une dermatomyosite compliquée d'une pneumopathie interstitielle d'évolution clinique particulièrement rapide et péjorative. Le patient présentait des anticorps anti-MDA5 (anti-Melanoma Differentiation-Associated gene 5), anticorps associés assez fréquemment à une atteinte pulmonaire sévère et rapidement progressive, ainsi qu'à une présentation particulière de la maladie appelée «dermatomyosite amyopathique¼. Malgré un traitement immunosuppresseur intensif, l'état pulmonaire du patient s'est rapidement aggravé, entraînant son décès par insuffisance respiratoire trois mois après le diagnostic. Cette histoire clinique illustre le fait que les patients atteints de dermatomyosite peuvent présenter différents anticorps qui correspondent à des phénotypes cliniques distincts. L'association entre anticorps anti-MDA5 et la pathologie pulmonaire interstitielle justifie qu'un screening des anticorps anti-MDA5 soit réalisé chez les patients porteurs d'une dermatomyosite. De plus, le titrage sanguin des anti-MDA5 est un facteur pronostique de la réponse au traitement et de la survie.

Eosinophils and Lung Cancer: From Bench to Bedside.

Eosinophils are rare, multifunctional granulocytes. Their growth, survival, and tissue migration mainly depend on interleukin (IL)-5 in physiological conditions and on IL-5 and IL-33 in inflammatory conditions. Preclinical evidence supports an immunological role for eosinophils as innate immune cells and as agents of the adaptive immune response. In addition to these data, several reports show a link between the outcomes of patients treated with immune checkpoint inhibitors (ICI) for advanced cancers and blood eosinophilia. In this review, we present, in the context of non-small cell lung cancer (NSCLC), the biological properties of eosinophils and their roles in homeostatic and pathological conditions, with a focus on their pro- and anti-tumorigenic effects. We examine the possible explanations for blood eosinophilia during NSCLC treatment with ICI. In particular, we discuss the value of eosinophils as a potential prognostic and predictive biomarker, highlighting the need for stronger clinical data. Finally, we conclude with perspectives on clinical and translational research topics on this subject.

Probe-based confocal laser endomicroscopy for pleural malignancies diagnosis.

BACKGROUND AND OBJECTIVE: Probe based confocal laser endomicroscopy (pCLE) is an optical imaging technique allowing live tissue imaging at a cellular level. Currently, this tool remains experimental. Two studies regarding pleural disease have been published and suggest that pCLE could be valuable for pleural disease investigations. However, normal and malignant pleural pCLE features remain unknown. Therefore, we conducted a prospective trial of pCLE during medical thoracoscopy to study and describe the malignant and benign pleural pCLE features. METHODS: Every patient >18 years referred to our department for medical thoracoscopy was eligible. Medical thoracoscopy was performed under sedation, allowing spontaneous breathing. Five millilitres of fluorescein (10%) was intravenously administrated 5 min before image acquisition. The pCLE was introduced through the working channel of the thoracoscope and gently placed on the parietal pleura to record videos. Afterwards, biopsies were performed on the corresponding sites. Malignant and benign pleural pCLE features were precisely described and compared using 11 preselected criteria. RESULTS: A total of 62 patients were included in the analysis including 36 benign and 26 malignant pleura. Among our preselected criteria, 'abnormal tissue architecture' and 'dysplastic vessels' were strongly associated with malignancies (100% and 85% ss, 721% and 74% sp, respectively) whereas, the 'full chia seeds sign' and 'cell shape homogeneity' were associated with benignity (36% and 56% ss, 100% and 70% sp, respectively). No study-related adverse events occurred. CONCLUSION: Benign and malignant pleural involvement have clearly distinct pCLE features.

[Insights on immunotherapy in pulmonary oncology]. / Actualités concernant l'immunothérapie en oncologie pulmonaire.

Immunotherapy, based on the immune response to tumor cells, gives a new therapeutic hope for lung cancer whose prognosis remains dark. Four molecules are currently available in clinical practice. They were first studied for non-small cell cancers in the second and third line of treatment with a significant improvement in overall survival, then in maintenance treatment and more recently in the front line with a significant response. Their complications, mainly dysimmune adverse effects, are protean but immunotherapy remains better tolerated than chemotherapy. It opens many perspectives but further studies, including biomarkers, are still needed.

L'immunothérapie, basée sur la réponse immunitaire aux cellules tumorales, donne un nouvel espoir thérapeutique pour le cancer pulmonaire dont le pronostic reste sombre. Quatre molécules sont actuellement disponibles en pratique clinique. Elles ont tout d'abord été étudiées pour des cancers non à petites cellules en deuxième et troisième lignes de traitement, avec une amélioration significative de la survie globale, ensuite dans le traitement de maintenance et, plus récemment, en première ligne avec une réponse significative. Leurs complications, principalement dysimmunitaires, sont protéiformes, mais l'immunothérapie reste mieux tolérée que la chimiothérapie. Elle ouvre de nombreuses perspectives, mais des études complémentaires, entre autres sur les biomarqueurs, sont encore nécessaires.

FDG PET/CT texture analysis for predicting the outcome of lung cancer treated by stereotactic body radiation therapy.

INTRODUCTION: With (18)F-FDG PET/CT, tumor uptake intensity and heterogeneity have been associated with outcome in several cancers. This study aimed at investigating whether (18)F-FDG uptake intensity, volume or heterogeneity could predict the outcome in patients with non-small cell lung cancers (NSCLC) treated by stereotactic body radiation therapy (SBRT). METHODS: Sixty-three patients with NSCLC treated by SBRT underwent a (18)F-FDG PET/CT before treatment. Maximum and mean standard uptake value (SUVmax and SUVmean), metabolic tumoral volume (MTV), total lesion glycolysis (TLG), as well as 13 global, local and regional textural features were analysed. The predictive value of these parameters, along with clinical features, was assessed using univariate and multivariate analysis for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Cutoff values were obtained using logistic regression analysis, and survivals were compared using Kaplan-Meier analysis. RESULTS: The median follow-up period was 27.1 months for the entire cohort and 32.1 months for the surviving patients. At the end of the study, 25 patients had local and/or distant recurrence including 12 who died because of the cancer progression. None of the clinical variables was predictive of the outcome, except age, which was associated with DFS (HR 1.1, P = 0.002). None of the (18)F-FDG PET/CT or clinical parameters, except gender, were associated with OS. The univariate analysis showed that only dissimilarity (D) was associated with DSS (HR = 0.822, P = 0.037), and that several metabolic measurements were associated with DFS. In multivariate analysis, only dissimilarity was significantly associated with DSS (HR = 0.822, P = 0.037) and with DFS (HR = 0.834, P < 0.01). CONCLUSION: The textural feature dissimilarity measured on the baseline (18)F-FDG PET/CT appears to be a strong independent predictor of the outcome in patients with NSCLC treated by SBRT. This may help selecting patients who may benefit from closer monitoring and therapeutic optimization.

Increased of exhaled breath condensate neutrophil chemotaxis in acute exacerbation of COPD.

BACKGROUND: Neutrophils have been involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Underlying mechanisms of neutrophil accumulation in the airways of stable and exacerbated COPD patients are poorly understood. The aim of this study was to assess exhaled breath condensate (EBC) neutrophil chemotactic activity, the level of two chemoattractants for neutrophils (GRO-α and LTB4) during the course of an acute exacerbation of COPD (AECOPD). METHODS: 50 ex smoking COPD patients (33 with acute exacerbation and 17 in stable disease) and 20 matched ex smoking healthy controls were compared. EBC was collected by using a commercially available condenser (EcoScreen®). EBC neutrophil chemotactic activity (NCA) was assessed by using Boyden microchambers. Chemotactic index (CI) was used to evaluate cell migration. LTB4 and GROα levels were measured by a specific enzyme immunoassay in EBC. RESULTS: Stable COPD and outpatients with AECOPD, but not hospitalized with AECOPD, had raised EBC NCA compared to healthy subjects (p < 0.05 and p < 0.01 respectively). In outpatients with AECOPD EBC NCA significantly decreased 6 weeks after the exacerbation. Overall EBC NCA was weakly correlated with sputum neutrophil counts (r = 0.26, p < 0.05). CONCLUSIONS: EBC NCA rose during acute exacerbation of COPD in ambulatory patients and decreased at recovery. While LTB4 seems to play a role both in stable and in exacerbated phase of the disease, the role of GRO-α as a chemotactic factor during AECOPD is not clearly established and needs further investigation.

[Bronchial thermoplasty: a real advancement in the treatment of asthma]. / Thermoplastie bronchique: une réelle avancée dans le traitement de l'asthme.

New treatments are needed to improve the care of severe asthmatic patients. Bronchial thermoplasty aims to lessen the airway smooth muscles via the heating of bronchial walls by radiofrequency. The preliminary studies showed a good tolerance and some good efficacy. Randomized controlled trials have been undertaken on moderate to severe asthmatic patients, demonstrating an improvement in quality of life, rate of severe exacerbations and unscheduled medical visits. The main side-effects consist of asthma exacerbations, atelectasis and infections. Bronchial thermoplasty is an innovative treatment with good efficacy and acceptable tolerance for moderate to severe asthmatic patients. More studies are needed to better understand its mechanism of action and more clearly delineate the precise indications of this innovative technique.

Predictive clinical and dosimetric parameters for risk of relapse in early-stage non-small cell lung cancer treated by SBRT: A large single institution experience.

Purpose: To evaluate the impact of dosimetric parameters on efficacy of stereotactic body radiation therapy (SBRT) in early-stage non-small cell lung cancer (ES-NSCLC), using Hypofractionated Treatment Effects in the Clinic (HyTEC) reporting standards. Methods: From April 2010 to December 2020, 497 patients who received SBRT for ES-NSCLC at the University Hospital of Liège were retrospectively enrolled. A total dose of 40 to 60 Gy in 3-5 fractions (72-180 Gy biologically effective dose with an α/ß ratio of 10 (BED10)) was prescribed to the 80 % isodose line of the PTV. Potential clinical and dosimetric predictors of recurrence, overall survival (OS) and disease specific survival (DSS) were evaluated using univariate and multivariate analyses. Results: After a median follow-up of 32 months (range 3-143 months), the local control and disease-free survival (DFS) rates at 3 years were 91 % (95 % CI: 90 %-93 %) and 75 % (95 % CI: 73 %-77 %), respectively. The median OS was 41.6 months and the median DSS was not reached. On multivariate analysis, a higher gross tumor volume (GTV) Dmax (BED10) (cut-off 198 Gy) and a larger percent of the GTV receiving ≥110 % of the prescribed dose were predictive of a better local control, only GTV volume was correlated with DSS and no parameter was correlated with OS and regional or distant recurrences. Conclusion: Lung SBRT for ES-NSCLC in 3 to 5 fractions resulted in high local control rates. A higher percent of GTV receiving ≥110 % of the prescribed dose and a higher GTV Dmax (BED10) seem to allow a better local control.

Identification of CT radiomic features robust to acquisition and segmentation variations for improved prediction of radiotherapy-treated lung cancer patient recurrence.

The primary objective of the present study was to identify a subset of radiomic features extracted from primary tumor imaged by computed tomography of early-stage non-small cell lung cancer patients, which remain unaffected by variations in segmentation quality and in computed tomography image acquisition protocol. The robustness of these features to segmentation variations was assessed by analyzing the correlation of feature values extracted from lesion volumes delineated by two annotators. The robustness to variations in acquisition protocol was evaluated by examining the correlation of features extracted from high-dose and low-dose computed tomography scans, both of which were acquired for each patient as part of the stereotactic body radiotherapy planning process. Among 106 radiomic features considered, 21 were identified as robust. An analysis including univariate and multivariate assessments was subsequently conducted to estimate the predictive performance of these robust features on the outcome of early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy. The univariate predictive analysis revealed that robust features demonstrated superior predictive potential compared to non-robust features. The multivariate analysis indicated that linear regression models built with robust features displayed greater generalization capabilities by outperforming other models in predicting the outcomes of an external validation dataset.

Radiomics and Delta-Radiomics Signatures to Predict Response and Survival in Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

The aim of our study was to determine the potential role of CT-based radiomics in predicting treatment response and survival in patients with advanced NSCLC treated with immune checkpoint inhibitors. We retrospectively included 188 patients with NSCLC treated with PD-1/PD-L1 inhibitors from two independent centers. Radiomics analysis was performed on pre-treatment contrast-enhanced CT. A delta-radiomics analysis was also conducted on a subset of 160 patients who underwent a follow-up contrast-enhanced CT after 2 to 4 treatment cycles. Linear and random forest (RF) models were tested to predict response at 6 months and overall survival. Models based on clinical parameters only and combined clinical and radiomics models were also tested and compared to the radiomics and delta-radiomics models. The RF delta-radiomics model showed the best performance for response prediction with an AUC of 0.8 (95% CI: 0.65-0.95) on the external test dataset. The Cox regression delta-radiomics model was the most accurate at predicting survival with a concordance index of 0.68 (95% CI: 0.56-0.80) (p = 0.02). The baseline CT radiomics signatures did not show any significant results for treatment response prediction or survival. In conclusion, our results demonstrated the ability of a CT-based delta-radiomics signature to identify early on patients with NSCLC who were more likely to benefit from immunotherapy.

Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma.

Background: Only a fraction of patients with malignant pleural mesothelioma (MPM) will respond to chemo- or immunotherapy. For the majority, the condition will irremediably relapse after 13 to 18 months. In this study, we hypothesized that patients' outcome could be correlated to their immune cell profile. Focus was given to peripheral blood eosinophils that, paradoxically, can both promote or inhibit tumor growth depending on the cancer type. Methods: The characteristics of 242 patients with histologically proven MPM were retrospectively collected in three centers. Characteristics included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR). The mean absolute eosinophil counts (AEC) were determined by averaging AEC data sets of the last month preceding the administration of chemo- or immunotherapy. Results: An optimal cutoff of 220 eosinophils/µL of blood segregated the cohort into two groups with significantly different median OS after chemotherapy (14 and 29 months above and below the threshold, p = 0.0001). The corresponding two-year OS rates were 28% and 55% in the AEC ≥ 220/µL and AEC < 220/µL groups, respectively. Based on shorter median PFS (8 vs 17 months, p < 0.0001) and reduced DCR (55.9% vs 35.2% at 6 months), the response to standard chemotherapy was significantly affected in the AEC ≥ 220/µL subset. Similar conclusions were also drawn from data sets of patients receiving immune checkpoint-based immunotherapy. Conclusion: In conclusion, baseline AEC ≥ 220/µL preceding therapy is associated with worse outcome and quicker relapse in MPM.

Eosinophilic Pleural Effusion Induced by Paliperidone Palmitate: Case Report and Literature Review.

BACKGROUND: Eosinophilic pleural effusions are defined by an eosinophil count ≥ 10% in pleural fluid and represent approximately 10% of exudative pleural effusions. They are associated with a large spectrum of etiologies, both benign and malignant. Drug-induced eosinophilic pleural effusions remain rarely described. OBJECTIVE AND METHODS: After ruling out other causes with a careful diagnostic assessment, we retain paliperidone as the etiology, given the disappearance of the pleural effusion after drug discontinuation. RESULTS: We report the first case of eosinophilic pleural effusion induced by paliperidone palmitate treatment. CONCLUSION: After considering other etiologies, drug-induced eosinophilic pleural effusion should be sought.

HDAC Inhibition with Valproate Improves Direct Cytotoxicity of Monocytes against Mesothelioma Tumor Cells.

The composition of the tumor microenvironment (TME) mediates the outcome of chemo- and immunotherapies in malignant pleural mesothelioma (MPM). Tumor-associated macrophages (TAMs) and monocyte myeloid-derived immunosuppressive cells (M-MDSCs) constitute a major fraction of the TME. As central cells of the innate immune system, monocytes exert well-characterized functions of phagocytosis, cytokine production, and antibody-dependent cell-mediated cytotoxicity (ADCC). The objective of this study was to evaluate the ability of monocytes to exert a direct cytotoxicity by cell-to-cell contact with MPM cells. The experimental model is based on cocultures between human blood-derived monocytes sorted by negative selection and mesothelioma cell lines. Data show (i) that blood-derived human monocytes induce tumor cell death by direct cell-to-cell contact, (ii) that VPA is a pharmacological enhancer of this cytotoxic activity, (iii) that VPA increases monocyte migration and their aggregation with MPM cells, and (iv) that the molecular mechanisms behind VPA modulation of monocytes involve a downregulation of the membrane receptors associated with the M2 phenotype, i.e., CD163, CD206, and CD209. These conclusions, thus, broaden our understanding about the molecular mechanisms involved in immunosurveillance of the tumor microenvironment and open new prospects for further improvement of still unsatisfactory MPM therapies.

Oncological patients' reactions to COVID-19 pandemic: A single institution prospective study.

BACKGROUND: The spread of the COVID-19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients. AIM: An analysis of cancer patients fears, and awareness of COVID-19 has been done in this study. METHODS AND RESULTS: We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12-item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID-19 than cancer versus 26.4% in the post-acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post-acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID-19 than cancer and they complied with all preventive measures in more than 90% of the cases. CONCLUSIONS: Although cancer patients worried about COVID-19 and evaluated the risk of complication or death due to COVID-19 as extremely high, they were still asking for the best oncological treatment.

Asthma and COPD Are Not Risk Factors for ICU Stay and Death in Case of SARS-CoV2 Infection.

BACKGROUND: Asthmatics and patients with chronic obstructive pulmonary disease (COPD) have more severe outcomes with viral infections than people without obstructive disease. OBJECTIVE: To evaluate if obstructive diseases are risk factors for intensive care unit (ICU) stay and death due to coronavirus disease 2019 (COVID19). METHODS: We collected data from the electronic medical record from 596 adult patients hospitalized in University Hospital of Liege between March 18 and April 17, 2020, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We classified patients into 3 groups according to the underlying respiratory disease, present before the COVID19 pandemic. RESULTS: Among patients requiring hospitalization for COVID19, asthma and COPD accounted for 9.6% and 7.7%, respectively. The proportions of asthmatics, patients with COPD, and patients without obstructive airway disease hospitalized in the ICU were 17.5%, 19.6%, and 14%, respectively. One-third of patients with COPD died during hospitalization, whereas only 7.0% of asthmatics and 13.6% of patients without airway obstruction died due to SARS-CoV2. The multivariate analysis showed that asthma, COPD, inhaled corticosteroid treatment, and oral corticosteroid treatment were not independent risk factors for ICU admission or death. Male gender (odds ratio [OR]: 1.9; 95% confidence interval [CI]: 1.1-3.2) and obesity (OR: 8.5; 95% CI: 5.1-14.1) were predictors of ICU admission, whereas male gender (OR 1.9; 95% CI: 1.1-3.2), older age (OR: 1.9; 95% CI: 1.6-2.3), cardiopathy (OR: 1.8; 95% CI: 1.1-3.1), and immunosuppressive diseases (OR: 3.6; 95% CI: 1.5-8.4) were independent predictors of death. CONCLUSION: Asthma and COPD are not risk factors for ICU admission and death related to SARS-CoV2 infection.

Granulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer.

Objectives: To contribute to a precise and thorough knowledge of immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) and to emphasize the importance of this specific form of toxicity in terms of potential predictive value and long-term effects. Materials and Methods: We report the first case of granulomatosis with polyangiitis (GPA) in a patient treated with an anti-Programmed Death protein-1 (PD-1) antibody for advanced non-small-cell lung cancer (NSCLC). Results: After a single dose of this drug the patient showed severe myositis associated with a high anti-PR3 anti-neutrophil cytoplasmic antibody titer. Discontinuation of the anti-PD-1 and introduction of corticoids led to a remission of the irAE. Regarding tumor a partial response was noted. A year later a neutrophilic, sterile pleural exudate and cutaneous lesions appeared with the pathological findings of neutrophilic vasculitis. Retreatment with corticoids induced a new remission of symptoms. It remains unclear whether GPA was preexisting and clinically silent but revealed by the use of ICI or primarily induced by this treatment. Conclusions: irAE are rare when anti-PD-1 antibodies are used in monotherapy. They present with a distinct clinical picture and temporal course and require specific treatment. Patients with irAE usually have a favorable oncological outcome.

ADAM10 mediates malignant pleural mesothelioma invasiveness.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and mesothelioma development is very long, the local invasion of mesothelioma is very rapid leading to a mean survival of one year after diagnosis. ADAM10 (A Disintegrin And Metalloprotease) sheddase targets membrane-bound substrates and its overexpression is associated with progression in several cancers. However, nothing is known about ADAM10 implication in MPM. In this study, we demonstrated higher ADAM10 expression levels in human MPM as compared to control pleural samples and in human MPM cell line. This ADAM10 overexpression was also observed in murine MPM samples. Two mouse mesothelioma cell lines were used in this study including one primary cell line obtained by repeated asbestos fibre injections. We show, in vitro, that ADAM10 targeting through shRNA and pharmacological (GI254023X) approaches reduced drastically mesothelioma cell migration and invasion, as well as for human mesothelioma cells treated with siRNA targeting ADAM10. Moreover, ADAM10 downregulation in murine mesothelioma cells significantly impairs MPM progression in vivo after intrapleural cell injection. We also demonstrate that ADAM10 sheddase downregulation decreases the production of a soluble N-cadherin fragment through membrane N-cadherin, which stimulated mesothelioma cell migration. Taken together, we demonstrate that ADAM10 is overexpressed in MPM and takes part to MPM progression through the generation of N-cadherin fragment that stimulates mesothelioma cell migration. ADAM10 inhibition is worth considering as a therapeutic perspective in mesothelioma context.

Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism.

The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27-specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.

Endobronchial ultrasound and value of PET for prediction of pathological results of mediastinal hot spots in lung cancer patients.

SUMMARY: In the staging of lung cancer with positron emission tomography (PET) positive mediastinal lymph nodes, tissue sampling is required. The performance of transbronchial needle aspiration (TBNA) using linear endobronchial ultrasound (real-time EBUS-TBNA) under local anaesthesia and the value of PET for prediction of pathological results were assessed in that setting. The number of eluded surgical procedures was evaluated. All consecutive patients with suspected/proven lung cancers and FDG-PET positive mediastinal adenopathy were included. If no diagnosis was reached, further surgical sampling was required. Lymph node SUVmax (maximum standardized uptake value) was assessed in patients whose PET was performed in the leading centre. One hundred and six patients were included. The average number of TBNA samples per patient was 4.9+/-1.1. The prevalence of lymph node metastasis was 58%. Sensitivity, accuracy and negative predictive value of EBUS-TBNA in the staging of mediastinal hot spots were 95, 97 and 91%. Patients without malignant lymph node involvement showed lower SUVmax (respective median values of 3.7 and 10.0; p<0.0001). Surgical procedures were eluded in 56% of the patients. Real-time EBUS-TBNA should be preferred over mediastinoscopy as the first step procedure in the staging of PET mediastinal hot spots in lung cancer patients. In case of negative EBUS, surgical staging procedure should be undertaken. The addition of SUVmax cut-off may allow further refinement but needs validation.