305 research outputs found
Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients
Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours
Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?
A substantial proportion of patients with nononcogene-addicted non-small-cell lung cancer (NSCLC) has 'aggressive disease', as reflected in short time to progression or lack of disease control with initial platinum-based chemotherapy. Recently, clinical correlates of aggressive disease behavior during first-line therapy have been shown to predict greater benefit from addition of nintedanib to second-line docetaxel in adenocarcinoma NSCLC. Positive predictive effects of aggressive disease have since been reported with other anti-angiogenic agents (ramucirumab and bevacizumab), while such features may negatively impact on outcomes with nivolumab in nonsquamous NSCLC with low PD-L1 expression. Based on a review of the clinical data, we recommend aggressive nonsquamous NSCLC should be defined by progression within <6-9Â months of first-line treatment initiation
Senicapoc treatment in COVID-19 Patients with Severe Respiratory Insufficiency - A Randomized, Open-Label, Phase II Trial
BACKGROUND: The aim of the current study was to determine if treatment with senicapoc, improves the PaO(2)/FiO(2) ratio in patients with COVIDâ19 and severe respiratory insufficiency. METHODS: Investigatorâinitiated, randomized, openâlabel, phase II trial in four intensive care units (ICU) in Denmark. We included patients aged âĽ18âyears and admitted to an ICU with severe respiratory insufficiency due to COVIDâ19. The intervention consisted of 50âmg enteral senicapoc administered as soon as possible after randomization and again after 24âh. Patients in the control group received standard care only. The primary outcome was the PaO(2)/FiO(2) ratio at 72âh. RESULTS: Twenty patients were randomized to senicapoc and 26 patients to standard care. Important differences existed in patient characteristics at baseline, including more patients being on nonâinvasive/invasive ventilation in the control group (54% vs. 35%). The median senicapoc concentration at 72âh was 62.1âng/ml (IQR 46.7â71.2). The primary outcome, PaO(2)/FiO(2) ratio at 72âh, was significantly lower in the senicapoc group (mean 19.5 kPa, SD 6.6) than in the control group (mean 24.4 kPa, SD 9.2) (mean difference â5.1 kPa [95% CI â10.2, â0.04] p =â.05). The 28âday mortality in the senicapoc group was 2/20 (10%) compared with 6/26 (23%) in the control group (OR 0.36 95% CI 0.06â2.07, p =â.26). CONCLUSIONS: Treatment with senicapoc resulted in a significantly lower PaO(2)/FiO(2) ratio at 72âh with no differences for other outcomes
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