Is Hepatic Resection for Large or Multinodular Hepatocellular Carcinoma Justified? Results From a Multi-Institutional Database

Background The role of surgical resection in patients with large or multinodular hepatocellular carcinoma (HCC) remains unclear. This study evaluated the long-term outcome of patients with hepatic resection for large (>5 cm in diameter) or multinodular (more than three nodules) HCC by using a multi-institutional database.Methods The perioperative and long-term outcomes of 404 patients with small HCC (<5 cm in diameter; group 1) were compared with those of 380 patients with large or multinodular HCC (group 2). The prognostic factors in the latter group were analyzed.Results The postoperative complication rate (27% vs. 23%; P = .16) and hospital mortality rate (2.4% vs. 2.7%; P = .82) were similar between groups. The overall survival rates were significantly higher in group 1 than group 2 (1 year, 88% vs. 74%; 3 years, 76% vs. 50%; 5 years, 58% vs. 39%; P < .001). Among patients in group 2, five independent prognostic factors were identified to be associated with a worse overall survival: namely, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, and positive histological margin.Conclusions Hepatic resection can be safely performed in patients with large or multinodular HCC, with an overall 5-year survival rate of 39%. Symptomatic disease, the presence of cirrhosis, a multinodular tumor, microvascular invasion, and a positive histological margin are independently associated with a less favorable survival outcome.     

Relevance of Toll-like receptor-4 polymorphisms in renal transplantation

BACKGROUND: Polymorphisms in Toll-like receptor-4 (TLR4) have been reported to be associated with a blunted immune response to microbial pathogens, as well as a decreased risk of atherosclerosis in the general population. We assessed the impact of the two TLR4 variants on the risk of severe infection, the incidence of acute rejection, and the occurrence of atherosclerotic complications in renal transplant recipients (RTR). METHODS: TLR-4 polymorphisms were assessed in a cohort of 238 RTR. Post-transplant atherosclerotic events, acute rejection, severe bacterial infection, cytomegalovirus (CMV) disease, and opportunistic infections were evaluated as outcomes. RESULTS: The patients were followed for a mean duration of 95 +/- 29 months after transplant. TLR4 polymorphism was observed in 27 (11.3%) RTR. Subjects with TLR4 polymorphisms were less likely to experience post-transplant atherosclerotic events (RR 0.44; 95% CI 0.21 to 0.93; P= 0.02) and acute rejection (RR 0.41; 95% CI 0.30 to 0.83; P= 0.01), but presented severe bacterial infections (RR 1.33; 95% CI 1.12 to 1.67; P= 0.01) and opportunistic infections (RR 3.03; 95% CI 1.72 to 8.29; P= 0.008) more frequently. TLR4 polymorphism was marginally associated with CMV disease (RR 1.47; 95% CI 0.95 to 2.64; P= 0.08). CONCLUSION: RTR with TLR4 polymorphism present a lower risk of post-transplant atherosclerotic events and acute allograft rejection, but experience severe infectious episodes more frequently. This subset of RTR may benefit from a less potent immunosuppression regimen, along with increased preventive measures against infectious agents.     

Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis

Liver X receptor-alpha and -beta are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterolstimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-alpha and/or liver X receptor-beta; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-alpha-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-beta-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-alpha-/- mice whereas in liver X receptor-beta-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-alpha and liver X receptor-beta are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-beta was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-beta and that oxysterols, acting via liver X receptor-beta, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyperproliferation and/or altered differentiation.     

POLLAR: Impact of air POLLution on Asthma and Rhinitis; a European Institute of Innovation and Technology Health (EIT Health) project

Allergic rhinitis (AR) is impacted by allergens and air pollution but interactions between air pollution, sleep and allergic diseases are insufficiently understood. POLLAR (Impact of air POLLution on sleep, Asthma and Rhinitis) is a project of the European Institute of Innovation and Technology (EIT Health). It will use a freely-existing application for AR monitoring that has been tested in 23 countries (the Allergy Diary, iOS and Android, 17,000 users, TLR8). The Allergy Diary will be combined with a new tool allowing queries on allergen, pollen (TLR2), sleep quality and disorders (TRL2) as well as existing longitudinal and geolocalized pollution data. Machine learning will be used to assess the relationship between air pollution, sleep and AR comparing polluted and non-polluted areas in 6 EU countries. Data generated in 2018 will be confirmed in 2019 and extended by the individual prospective assessment of pollution (portable sensor, TLR7) in AR. Sleep apnea patients will be used as a demonstrator of sleep disorder that can be modulated in terms of symptoms and severity by air pollution and AR. The geographic information system GIS will map the results. Consequences on quality of life (EQ-5D), asthma, school, work and sleep will be monitored and disseminated towards the population. The impacts of POLLAR will be (1) to propose novel care pathways integrating pollution, sleep and patients’ literacy, (2) to study sleep consequences of pollution and its impact on frequent chronic diseases, (3) to improve work productivity, (4) to propose the basis for a sentinel network at the EU level for pollution and allergy, (5) to assess the societal implications of the interaction. MASK paper N°32.     

Lung real time three-dimensional imaging in critically ill ventilated patients: a global diagnosis concordance study

Lung ultrasound (LUS) increases clinical diagnosis performance in intensive care unit (ICU). Real-time three-dimensional (3-D) imaging was compared with two-dimensional (2-D) LUS by assessing the global diagnosis concordance. In this single center, prospective, observational, pilot study, one trained operator performed a 3-D LUS immediately after a 2-D LUS in eight areas of interest on the same areas in 16 ventilated critically ill patients. All cine loops were recorded on a computer without visible link between 2-D and 3-D exams. Two experts blindly reviewed cine loops. Four main diagnoses were proposed: normal lung, consolidation, pleural effusion and interstitial syndrome. Fleiss κ and Cohen’s κ values were calculated. In 252 LUS cine loops, the concordance between 2-D and 3-D exams was 83.3% (105/126), 77.6% (99/126) and 80.2% (101/126) for the trained operator and the experts respectively. The Cohen’s κ coefficient value was 0.69 [95% Confidence Interval (CI) 0.58–0.80] for expert 1 meaning a substantial agreement. The inter-rater reliability was very good (Fleiss’ κ value?=?0.94 [95% CI 0.87–1.0]) for 3-D exams. The Cohen’s κ was excellent for pleural effusion (κ=?0.93 [95% CI 0.76–1.0]), substantial for normal lung diagnosis (κ?=?0.68 [95% CI 0.51–0.86]) and interstitial syndrome (κ?=?0.62 [95% CI 0.45–0.80]) and fair for consolidation diagnoses (κ?=?0.47 [95% CI 0.30–0.64]). In ICU ventilated patients, there was a substantial concordance between 2-D and 3-D LUS with a good inter-rater reliability. However, the diagnosis concordance for lung consolidation is poor.     

Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo

Vascular endothelial cells are thought to be the main source of plasma tissue-type plasminogen activator (t-PA) and von Willebrand factor (VWF). Previous studies have suggested that both t-PA and VWF are acutely released in response to the same stimuli, both in cultured endothelial cells and in vivo. However, the subcellular storage compartment in endothelial cells has not been definitively established. We tested the hypothesis that t-PA is localized in Weibel-Palade (WP) bodies, the specialized endothelial storage granules for VWF. In cultured human umbilical vein endothelial cells (HUVECs), t-PA was expressed in a minority of cells and found in WP bodies by immunofluorescence. After up-regulation of t-PA synthesis either by vascular endothelial growth factor (VEGF) and retinoic acid or by sodium butyrate, there was a large increase in t-PA-positive cells. t-PA was exclusively located to WP bodies, an observation confirmed by immunoelectron microscopy. Incubation with histamine, forskolin, and epinephrine induced the rapid, coordinate release of both t-PA and VWF, consistent with a single storage compartment. In native human skeletal muscle, t-PA was expressed in endothelial cells from arterioles and venules, along with VWF. The 2 proteins were found to be colocalized in WP bodies by immunoelectron microscopy. These data indicate that t-PA and VWF are colocalized in WP bodies, both in HUVECs and in vivo. Release of both t-PA and VWF from the same storage pool likely accounts for the coordinate increase in the plasma level of the 2 proteins in response to numerous stimuli, such as physical activity, beta-adrenergic agents, and 1-deamino-8d-arginine vasopressin (DDAVP) among others.