Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

Differential effect of liver cirrhosis on the pregnane X receptor-mediated induction of CYP3A1 and 3A2 in the rat.

Conflicting results have been obtained by clinical studies investigating the effect of liver cirrhosis on enzyme induction. Because ethical concerns do not give consent for methodologically rigorous studies in humans, we addressed this question by examining the effect of the prototypical inducer dexamethasone (DEX) on the pregnane X receptor (PXR)-mediated induction of CYP3A1 and 3A2 in a validated animal model of liver cirrhosis obtained by exposure of rats to carbon tetrachloride. For this purpose, we assessed mRNA levels, protein expressions, and enzymatic activities of both CYP3A enzymes, as well as mRNA and protein expressions of PXR in rat populations rigorously stratified according to the severity of liver insufficiency. Constitutive mRNA and protein expressions of CYP3A1 and CYP3A2 and their basal enzyme activities were not affected by liver dysfunction. DEX treatment markedly increased steady-state mRNA level, protein content, and enzymatic activity of CYP3A1 in healthy and cirrhotic rats, irrespective of the degree of liver dysfunction. On the contrary, the inducing effect of DEX on gene and protein expressions and enzyme activity of CYP3A2 was preserved in moderate liver insufficiency, whereas it was greatly curtailed when liver insufficiency became severe. mRNA and protein expressions of PXR were neither reduced by liver dysfunction nor increased by DEX treatment. These results indicate that even the inducibility of cytochrome P450 isoforms under the transcriptional control of the same nuclear receptor may be differentially affected by cirrhosis and may partly explain why conflicting results were obtained by human studies

Class 1, 2 and 3 BRAF mutated metastatic colorectal cancer: a detailed clinical, pathological and molecular characterization

Purpose BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1 - V600E) or as dimers (class 2 - codons 597/601), and RAS-dependent with impaired kinase activity (class 3 - codons 594/596). While clinical, pathological and molecular features of V600E BRAF mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design Data from 117 BRAF (92 class 1, 12 class 2, and 13 class 3) mutated mCRC patients were collected. 540 BRAF wt mCRC were included as control. Immunohistochemical profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratins 7/20 profiles, tumor infiltrating lymphocytes (TILs) infiltration and BM1/BM2 categorization. OS and PFS were evaluated by Kaplan-Meier and log-rank test. Results Class 3 BRAF mutated mCRC were more frequently left sided (p=0.0028), pN0 (p=0.0159), and with no peritoneal metastases (p=0.0176) compared to class 1, whereas class 2 cases were similar to class 1. HR for OS, as compared to BRAF wt, was 2.38 (95%CI 1.61-3.54) for class 1, 1.90 (95% CI 0.85-4.26) for class 2 and 0.93 (95% CI 0.51-1.69) for class 3 (p<0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8 positive lymphocytes infiltration was observed in BRAF mutated class 2 (p= 0.033) compared to class 3 cases. Conclusions For the first time different clinical, pathological features and outcome data are reported according to the 3 BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the next future for such patients

Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial

Background: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). Methods: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. Findings: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57–0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7–135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). Interpretation: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. Funding: None