Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.

The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.

[News about targeted therapies in non-small-cell lung cancer in 2015 (except immuno-therapy)]. / Actualités sur les thérapies ciblées dans les cancers bronchiques non à petites cellules, hors immunothérapie.

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

[Pulmonary sarcomatoid carcinoma]. / Carcinomes sarcomatoïdes pulmonaires.

Pulmonary sarcomatoid carcinomas are a rare group of tumors accounting for about one percent of non-small cell lung carcinoma (NSCLC). In 2015, the World Health Organization classification united under this name all the carcinomas with sarcomatous-like component with spindle cell or giant cell appearance, or associated with a sarcomatous component sometimes heterologous. There are five subtypes: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. Clinical characteristics are not specific from the other subtypes of NSCLC. Epithelial to mesenchymal transition pathway may play a key role. Patients, usually tobacco smokers, are frequently symptomatic. Tumors are voluminous more often peripherical than central, with strong fixation on FDG TEP CT. Distant metastases are frequent with atypical visceral locations. These tumors have poorer prognosis than the other NSCLC subtypes because of great aggressivity, and frequent chemoresistance. Here we present pathological description and a review of literature with molecular features in order to better describe these tumors and perhaps introduce new therapeutics.

Nonsmall cell lung cancer from HIV-infected patients expressed programmed cell death-ligand 1 with marked inflammatory infiltrates.

OBJECTIVE: Immunotherapies targeting the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) checkpoint improved prognosis in lung cancer. PD-1/PD-L1 status, however, has not been investigated in human immunodeficiency virus (HIV)-positive patients. This study assessed PD-L1 status and tumor immune-cell infiltration in nonsmall cell lung cancer (NSCLC) in HIV patients. METHODS: Consecutive HIV patients treated between 1996 and 2014 were enrolled. PD-L1 tumor expression was assessed using immunohistochemistry with two antibodies (clones 5H1 and E1L3N), and tumor immune-cell infiltration with CD3, CD4, CD8, CD20, CD163, and MPO. PD-L1 expression and immune infiltration results were compared with those of 54 NSCLCs from unknown HIV status patients. RESULTS: Thirty-four HIV-positive patients were evaluated: predominantly men (88.2%) (median age: 51.1 years) presenting stage IV (38.2%) adenocarcinomas (76.5%). The median blood CD4 count was 480 cells/µL (86-1120) and 64% exhibited undetectable viral load. The PD-L1 score (percentage of positive cells × intensity) was higher in HIV-positive than HIV-undetermined patients with the E1L3N clone [median (range) 0 (0-150) versus 0 (0-26.7), P = 0.047], yet not with the 5H1 clone [0 (0-120) versus 0 (0-26.7) P = 0.07, respectively]. PD-L1 expression frequency did not differ between both cohorts (18.7 versus 9.3% using E1L3N and 10 versus 5.6% using 5H1 clone, respectively). There were significantly greater cytotoxic T-cell (P < 0.001), B-lymphocyte (P = 0.005), and activated macrophage (P < 0.001) infiltrations in the HIV-positive patients, but no differences for CD4 T cells. CONCLUSION: Tumors in HIV-positive patients seem to express higher PD-L1 levels with increased immune infiltration, supporting their inclusion in clinical trials assessing immune checkpoint inhibitors.

The value of molecular techniques to diagnose Ureaplasma urealyticum and Nocardia farcinica pleuropneumonia in a patient with diffuse large B-cell lymphoma.

An unusual case of pleural empyema related to Nocardia farcinica and Ureaplasma urealyticum, occurring after autologous haematopoietic stem cell transplantation in a 30-year-old patient with lymphoma, is reported. This case illustrates the role of repeated and comprehensive microbiological investigations and the contribution of molecular techniques in reaching the aetiological diagnosis.

Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages.

OBJECTIVES: Pulmonary sarcomatoid carcinomas (SC) are rare tumors, associated with worse prognosis and resistant to platinum-based regimens. Therapies targeting the PD-1/PD-L1 pathway are an emerging treatment for lung cancer. By characterizing intra-tumoral immune infiltration and evaluating PD-L1 expression, it could be possible to predict the efficacy of these new treatments. MATERIALS AND METHODS: From 1997 to 2013, data from all patients with SC who underwent lung resection was collected. Tumor-immune infiltration and PD-L1 expression were studied by immunochemistry tests, analyzing CD3 (clone SP7), CD4 (clone 1F6), CD8 (clone C8/144b), CD20 (clone L26), CD163 (clone 10D6), MPO (clone 59A5), and PD-L1 (clone 5H1). Results were compared to those of 54 NSCLC. RESULTS: In total, 75 SC were included. Forty (53%) SC expressed PD-L1 vs 11 NSCLC (20%) (p<0.0001). CD3+ tumor-infiltrating lymphocytes and CD163+ tumor-associated macrophages were more important in SC than in NSCLC (median 23% [17-30] of tumoral surface vs 17% [7-27], p=0.011 and 23% [17-30] vs 20% [13-23], p=0.002, respectively). In SC, the presence of Kirsten Ras (KRAS) mutations, blood vessel invasion, and TTF1+ positivity were associated with PDL1 expression. On multivariate analysis, only CD163+ macrophages and blood-vessel invasion were associated with tumoral PD-L1 expression. High levels of tumor-infiltrating lymphocytes (CD3+ or CD4+ and not CD8+) constituted a factor of good prognosis on survival. Interestingly, PD-L1 expression distinguishes subpopulations within tumor-infiltrating lymphocytes (CD3+ or CD4+) with different prognosis CONCLUSIONS: PD-L1 expression was higher in SC than in NSCLC as well as immune-cell infiltration by TCD3 cells and macrophages. This suggests that targeting the PD-1/PD-L1 pathway could represent a new potential therapy.

Causes of death in French cystic fibrosis patients: The need for improvement in transplantation referral strategies!

BACKGROUND: Little data exist on causes of death in cystic fibrosis (CF) patients in the era of lung transplantation. METHODS: Deaths in CF patients in France (2007-2010) were identified using the French CF Registry and causes of deaths were determined based on medical files by a mortality adjudication committee. RESULTS: Of 256 deaths, half occurred after lung transplantation and were related to early or late complications of transplantation, whereas half occurred in patients who did not receive lung transplantation and were primarily related to respiratory failure or massive hemoptysis. Among patients who did not receive lung transplantation, only 19% died while waiting on a lung transplantation list. Lack of listing for lung transplantation was primarily related to late, or to lack of transplantation referral, rather than to contraindication to transplantation. CONCLUSIONS: These data suggest that improvement in transplantation referral strategies may result in transplantation-related survival benefits.