Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the mutated (mostly comutated with) and the wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for and genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non-small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). mutation and protein loss were detected in 47% ( = 37) and 72% ( = 78) of the cases, respectively. Patients with wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7-11.6 months] than those treated with SCLC-PE [5.8 (5.5-6.1); = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors ( = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an mutation or lost RB1 protein. Patients with LCNEC tumors that carry a wild-type gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for mutated or with lost protein expression. .

Lipopolysaccharide (LPS), a major proinflammatory glycolipid component of the gram-negative bacterial cell wall, is one of the agents ubiquitously present as contaminant on airborne particles, including air pollution, organic dusts, and cigarette smoke. Chronic exposure to significant levels of LPS is reported to be associated with the development and/or progression of many types of lung diseases, including asthma, chronic bronchitis, and progressive irreversible airflow obstruction, that are all characterized by chronic inflammatory processes in the lung. In the present study, pathologic effects of long-term LPS exposure to the lung were investigated in detail. To this end, a murine model in which mice were exposed to repeated intratracheal instillation of Escherichia coli LPS was developed. We show that long-term LPS instillation in mice results in persistent chronic pulmonary inflammation, characterized by peribronchial and perivascular lymphocytic aggregates (CD4(+), CD8(+), and CD19(+)), parenchymal accumulation of macrophages and CD8(+) T cells, and altered cytokine expression. Furthermore, airway and alveolar alterations such as mucus cell metaplasia, airway wall thickening, and irreversible alveolar enlargement accompanied the chronic inflammatory response. Interestingly, the observed inflammatory and pathologic changes mimic changes observed in human subjects with chronic inflammatory lung diseases, especially chronic obstructive pulmonary disease (COPD), suggesting that this murine model could be applicable to dissect the role of inflammation in the pathogenesis of these disease conditions.

No abstract

S100A4/Mts1 confers a metastatic phenotype in tumor cells and may also be related to resistance to apoptosis and angiogenesis. Approximately 5% of transgenic mice overexpressing S100A4/Mts1 develop pulmonary arterial changes resembling human plexogenic arteriopathy with intimal hyperplasia leading to occlusion of the arterial lumen. To assess the pathophysiological significance of this observation, immunohistochemistry was applied to quantitatively analyze S100A4/Mts1 expression in pulmonary arteries in surgical lung biopsies from children with pulmonary hypertension secondary to congenital heart disease. S100A4/Mts1 was not detected in pulmonary arteries with low-grade hypertensive lesions but was expressed in smooth muscle cells of lesions showing neointimal formation and with increased intensity in vessels with an occlusive neointima and plexiform lesions. Putative downstream targets of S100A4/Mts1 include Bax, which is pro-apoptotic, and the pro-angiogenic vascular endothelial growth factor (VEGF). The increase in S100A4/Mts1 expression precedes heightened expression of Bax in progressively severe neointimal lesions but in non-S100A4/Mts1-expressing cells. VEGF immunoreactivity did not correlate with severity of disease. The relationship of increased S100A4/Mts1 to pathologically similar lesions in the transgenic mice and patients occurs despite differences in localization (endothelial versus smooth muscle cells).