RESUMO
Uveal melanoma (UM) is a malignant intraocular tumor that spreads to the liver in half of the cases. Since hepatic cells could play a role in the therapeutic resistance of metastatic UM, the purpose of our study was to investigate the pro-invasive role of hepatic stellate cells (HSteCs) in metastatic UM at the micro- and macro-metastatic stages. We first performed an immunostaining with the alpha-smooth muscle actin (αSMA) to localize activated HSteCs in UM liver macro-metastases from four patients. Their accumulation of collagen was assessed with Masson's Trichrome stain. Next, we inoculated metastatic UM cells alone or with human HSteCs in triple-immunodeficient mice, in order to determine if HSteCs are recruited as early as the micro-metastatic stage. The growth of metastatic foci was imaged in the liver by ex vivo fluorescence imaging. Histological analyses were performed with Masson's Trichrome and Picrosirius Red stains, and antibodies against Melan-A and αSMA. The collagen content was measured in xenografts by quantitative polarization microscopy. In patient hepatectomy samples, activated HSteCs and their pathological matrix were localized surrounding the malignant lesions. In the mouse xenograft model, the number of hepatic metastases was increased when human HSteCs were co-inoculated. Histological analyses revealed a significant recruitment of HSteCs near the micro/macrolesions, and an increase in fibrillar collagen production. Our results show that HSteCs can provide a permissive microenvironment and might increase the therapeutic resistance of metastatic UM.
RESUMO
PURPOSE: The intensity of care provided to critically ill patients has been shown to be associated with mortality. In patients with traumatic brain injury (TBI), specialized neurocritical care is often required, but whether it affects clinically significant outcomes is unknown. We aimed to determine the association of the intensity of care on mortality and the incidence of withdrawal of life-sustaining therapies in critically ill patients with severe TBI. METHODS: We conducted a post hoc analysis of a multicentre retrospective cohort study of critically ill adult patients with severe TBI. We defined the intensity of care as a daily cumulative sum of interventions during the intensive care unit stay. Our outcome measures were all-cause hospital mortality and the incidence of withdrawal of life-sustaining therapies. RESULTS: Seven hundred sixteen severe TBI patients were included in our study. Most were male (77%) with a mean (standard deviation) age of 42 (20.5) yr and a median [interquartile range] Glasgow Coma Scale score of 3 [3-6]. Our results showed an association between the intensity of care and mortality (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.63 to 0.74) and the incidence of withdrawal of life-sustaining therapy (HR, 0.73; 95% CI, 0.67 to 0.79). CONCLUSION: In general, more intense care was associated with fewer deaths and a lower incidence of withdrawal of life-sustaining therapies in critically ill patients with severe TBI.