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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. Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer. Here, the authors show MPM is heterogeneously composed of epithelioid and sarcomatoid components and their proportions associate with prognosis and could inform therapeutic strategies.

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. Our comprehensive genetic characterization of key‐altered genes including TERT promoter in malignant pleural mesothelioma led to the identification of new significant associations between the mutational status and the histological and molecular classifications. Our findings allow a better understanding of the genetic landscape in the context of tumor heterogeneity and highlight the high prognostic value of gene mutations in mesothelioma.

Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them. Resident memory T cells (Trm) are memory T cells that remain in tissue. Here, the authors show that induction of Trm cells is required for control of tumour growth following mucosal vaccination in mice bearing head and neck cancer and that Trm cells in human lung cancer correlates with a better survival.

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆I scF/I+V ) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. I sc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆I scF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆I scF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV 1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Ultrasound (US) measurements of diaphragmatic excursion (DE) are widely used to provide a non-invasive assessment of the diaphragmatic function at the bedside, especially in intensive care. However, this measurement has never been validated against a less operator-dependent technique such as MRI. Dynamic MRI is the only imaging modality that creates a four-dimensional reconstruction of the diaphragm. The primary objective of this study was to assess the agreement between DE obtained using dynamic MRI with those obtained using ultrasound. The secondary objectives were to define DE thresholds for the diagnosis of DD using MRI and to compare the performance of US and MRI to diagnose DD. Prospective single-center study in which consecutive outpatients referred for a dynamic thoracic MRI were included. This study was conducted at a university hospital in Paris, where there was daily access to ultrasound (US) and extensive expertise in diaphragmatic MRI The DE of each hemi-diaphragm was measured sequentially using ultrasound and MRI in random order, during spontaneous breathing (SB) and forced inspiration (FI) by independent observers blinded to each other. We analyzed the agreement between DE obtained using US and MRI for each hemi-diaphragm. We enrolled forty-five patients, aged 58 ± 36 years, of which twenty-eight (68%) had a confirmed DD. During SB, the mean bias for DE measurement was -3.8 mm, 95% CI [-7.1; -0.6] for the left hemi-diaphragm, and 1.0 mm, 95% CI [-3.5; 5.5] for the right hemi-diaphragm. Limits of agreement (millimeters) were [-25; 17] on the left side, and [-28; 30] on the right side. MRI threshold values for DE defining dysfunction were 11 mm for quiet SB, and 38 mm for FI. These thresholds had a sensitivity of 77.7% and a specificity of 77.4% during SB, with an AUC of 0.86. US and MRI provide different values for DE, probably because the measurements were not obtained exactly at the same localization. Nevertheless, diagnostic performances of MRI and US to recognize DD appeared comparable.

IntroductionLung graft allocation can be based on a score (Lung Allocation Score) as in the USA or sequential proposals combined with a discrete priority model as in France. We aimed to analyse the impact of allocation policy on the outcome of urgent lung transplantation (LT).MethodsUS United Network for Organ Sharing (UNOS) and French Cristal databases were retrospectively reviewed to analyse LT performed between 2007 and 2017. We analysed the mortality risk of urgent LT by fitting Cox models and adjusted Restricted Mean Survival Time. We then compared the outcome after urgent LT in the UNOS and Cristal groups using a propensity score matching.ResultsAfter exclusion of patients with chronic obstructive pulmonary disease/emphysema and redo LT, 3775 and 12 561 patients underwent urgent LT and non-urgent LT in the USA while 600 and 2071 patients underwent urgent LT and non-urgent LT in France. In univariate analysis, urgent LT was associated with an HR for death of 1.24 (95% CI 1.05 to 1.48) in the Cristal group and 1.12 (95% CI 1.05 to 1.19) in the UNOS group. In multivariate analysis, the effect of urgent LT was attenuated and no longer statistically significant in the Cristal database (HR 1.1 (95% CI 0.91 to 1.33)) while it remained constant and statistically significant in the UNOS database (HR 1.12 (95% CI 1.05 to 1.2)). Survival comparison of urgent LT patients between the two countries was significantly different in favour of the UNOS group (1-year survival rates 84.1% (80.9%–87.3%) vs 75.4% (71.8%–79.1%) and 3-year survival rates 66.3% (61.9%–71.1%) vs 62.7% (58.5%–67.1%), respectively).ConclusionUrgent LT is associated with adverse outcome in the USA and in France with a better prognosis in the US score-based system taking post-transplant survival into account. This difference between two healthcare systems is multifactorial.

Background Patients with non-small cell lung cancer (NSCLC) receiving curative surgery have a risk of relapse, and adjuvant treatments only translate into a 5% increase in 5-year survival. We assessed the clinical significance of epithelial–mesenchymal transition (EMT) and explored its association with the [SNAIL/miR-34]:[ZEB/miR-200] regulation hub to refine prognostic information. Methods We validated a 7-gene EMT score using a consecutive series of 176 resected NSCLC. We quantified EMT transcription factors, microRNAs (miRs) of the miR-200, miR-34 families and miR-200 promoter hypermethylation to identify outcome predictors. Results Most tumours presented with an EMT-hybrid state and the EMT score was not predictive of outcome. Individually, all miR-200 were inversely associated with the EMT score, but only chromosome-1 miRs, miR-200a, b, 429, were associated with disease-free survival ( p  = 0.08, 0.05 and 0.025) and overall survival ( p  = 0.013, 0.003 and 0.006). We validated these associations on The Cancer Genome Atlas data. Tumour unsupervised clustering based on miR expression identified two good prognostic groups, unrelated to the EMT score, suggesting that miR profiling may have an important clinical value. Conclusion miR-200 family members do not have similar predictive value. Core EMT-miR, regulators and not EMT itself, identify NSCLC patients with a low risk of relapse after surgery.

Background There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. Materials Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of < 500/μL and < 224/μL respectively. The prognostic value of T lymphopenia was analyzed in the whole population, in local/loco-regional (stage I-IIIB) and in advanced (stage IV) NSCLC disease, using the Kaplan-Meier method and Cox regression models for survival curves and multivariate analysis, respectively. Results Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/μL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1–2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9–3.8], p  = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065–3.817] p  = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/μL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. Conclusion We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. Trial registration EUDRACT: 2009-A00642–55. Highlights This study investigates the unknown prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC) with long-term follow-up CD4+ but not CD8 + T lymphopenia was associated with poor survival in patients with localized NSCLC The CD4+ T lymphopenia appears to be an independent prognostic factor for poor overall survival in local/loco-regional NSCLC. CD4+ T lymphocyte count ≤500/μL in peripheral blood is associated with a high risk of death in NSCLC

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS‐MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1‐mutated tumors could define a specific population with a distinct clinical and molecular profile. We performed NF1 sequencing using next generation sequencing (NGS) in 154 lung adenocarcinoma surgical specimens with known KRAS, EGFR, TP53, BRAF, HER2, and PIK3CA status, to evaluate the molecular and clinical specificities of NF1‐mutated lung cancers. Clinical data were retrospectively collected, and their associations with molecular profiles assessed. In this series, 24 tumors were NF1 mutated (17.5%) and 11 were NF1 deleted (8%). There was no mutation hotspot. NF1 mutations were rarely associated with other RAS‐MAPK pathway mutations. Most of patients with NF1 alterations were males (74.3%) and smokers (74.3%). Overall survival and disease‐free survival were statistically better in patients with NF1 alterations (N = 34) than in patients with KRAS mutations (N = 30) in univariate analysis. Our results confirm that NF1 is frequently mutated and represents a distinct molecular and clinical subtype of lung adenocarcinoma. Although NF1 gene is a regulator of RAS‐MAPK pathway, only few studies describe NF1 mutations in lung adenocarcinoma. In this study, we found that 17.5% were NF1 mutations and 8% were NF1 deletions: these NF1 alterations define a distinct clinical and molecular entity of lung adenocarcinoma.

Background Primary intestinal lymphangiectasia or Waldmann’s disease (ORPHA code: 90362) is a very rare disorder of unknown etiology, characterized by digestive lymphatic vessel dilations. Main body of the abstract The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Centers for Rare Vascular diseases and Rare Digestive diseases, is available from the French Health Authority website. The latter allow lymph leakage (chyle) into the intestinal lumen that is responsible for protein-losing gastroenteropathy, combining hypoalbuminemia, lymphopenia and hypogammaglobulinemia. Diagnosis is usually made before the age of 3, but primary intestinal lymphangiectasia may be discovered in adults. Edema of the lower limbs is the main clinical sign and serous effusions (pleura, peritoneum, pericardium) are sometimes abundant. Exudative gastroenteropathy is confirmed by increased α 1 -antitrypsin clearance. Esophagogastroduodenoscopy finds milky lesions corresponding to lymphangiectasias; duodenal biopsies confirm the diagnosis. Endoscopic videocapsule may be useful to evaluate the extent of the disease and/or if esophagogastroduodenoscopy is not contributory. In rare cases, the disease may be complicated by digestive or extra-digestive B-cell lymphoma in adults. Management is mainly based on a strict fat-free diet, combined with supplementation with medium-chain triglycerides, essential fatty acids and fat-soluble vitamins. Octreotide, a somatostatin analogue, has inconsistent efficacy, in combination with the fat-free diet and the sometimes-prescribed mammalian target of rapamycin-receptor inhibitor sirolimus, occasionally achieving positive effects. Diuretics and albumin infusions may be useful in addition to the fat-free diet. Intestinal resections are proposed for rare, localized, segmental forms of the disease. Short conclusion Primary intestinal lymphangiectasia is a chronic disease requiring a prolonged restrictive and constraining strict low-fat diet supplemented with medium-chain triglycerides and fat-soluble vitamins. Its evolution can be complicated by more-or-less severe serous effusions and rare lymphoma. Life-long clinical and biological monitoring is required.