heterogeneity of large cell carcinoma of the lung an immunophenotypic and mirna based analysis

Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]–specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation. Large cell carcinoma (LCC) of the lung is 1 of 4 major histopathologic tumor subtypes recognized by current classifications of lung tumors. However, although squamous cell carcinoma (SQCC), adenocarcinoma (ADC), and small cell carcinoma are well-defined entities with typical morphologic, immunophenotypic, and molecular features, LCCs, with the exception of the rare neuroendocrine, rhabdoid, basaloid, and lymphoepithelioma-like subtypes, are defined as poorly differentiated non–small cell tumors lacking features of ADC and SQCC. Therefore, the term LCC has frequently and improperly been used as a synonym of undifferentiated non–small cell lung carcinoma (NSCLC) and has been used as a "wastebasket" for tumors lacking a definite morphologic pattern. Studies show that, by using ancillary techniques, a relevant percentage of LCCs could be reclassified as SQCC or ADC. Gene profiling shows that most LCCs have profiles quite similar to ADC or SQCC. 1-3 Similarly, by using appropriate immunohistochemical stains, almost two thirds of LCCs can be reclassified as poorly differentiated ADC or SQCC. 4,5 These studies have profound clinical relevance because rendering a diagnosis of LCC may represent a challenge for oncologists who need accurate subtyping of lung cancers to provide patients with optimal targeted chemotherapeutic agents, showing different efficacy with specific NSCLC categories (usually effective for ADC and not for others). 6,

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

Oxidative stress and bronchopulmonary dysplasia: Evidences from microbiomics, metabolomics, and proteomics

Bronchopulmonary dysplasia is a major issue affecting morbidity and mortality of surviving premature babies. Preterm newborns are particularly susceptible to oxidative stress and infants with bronchopulmonary dysplasia have a typical oxidation pattern in the early stages of this disease, suggesting the important role of oxidative stress in its pathogenesis. Bronchopulmonary dysplasia is a complex disease where knowledge advances as new investigative tools become available. The explosion of the "omics" disciplines has recently affected BPD research. This review focuses on the new evidence coming from microbiomics, metabolomics and proteomics in relation to oxidative stress and pathogenesis of bronchopulmonary dysplasia. Since the pathogenesis is not yet completely understood, information gained in this regard would be important for planning an efficacious prevention and treatment strategy for the future

Impaired spatio-temporal coordination of subventricular neurogenesis is restored by physical exercise

A major aim of neural stem cells field is to harness endogenous neurogenesis to replace neurons damaged as a consequence of brain damage and neurodegeneration. Olfactory interneurons arise throughout life from neural stem cells residing in the subventricular zone (SVZ) of the lateral ventricle. Post mitotic neuroblast then migrate along the rostral migratory stream (RMS) to the olfactory bulb where undergone to fully maturation and functional integration in the olfactory circuitry. To ensure a continuous source of newly-generated adult interneurons, stem and progenitor cell proliferation, neuroblast migration, and terminal differentiation must be tightly coordinated. In this study we analyzed the effect of physical exercise in orchestrating the different steps of subventricular neurogenesis in a mouse lacking the antiproliferative gene Btg1 which displays an impaired subventricular neurogenesis. As previously demonstrated Btg1 loss-of-function mice exhibit a strong reduction of proliferation associated with a premature exit from the cell cycle and an anticipated migration toward the olfactory bulb where the neuroblast fail to fully differentiate and consequently to be specifically recruited in olfactory-dependent memory circuitry. In the study we demonstrate that running fully reverses the profound reduction of proliferation within the SVZ of the lateral ventricle in the Btg1-deficient mice, mainly through a recruitment and expansion of the quiescent neural stem cells (NSCs) . Moreover, cell cycle analysis reveals that 12 days of running induces a shortening of the S-phase and consequently of the whole cell cycle length in both neural stem (GFAP+, type C) and progenitor (DCX+, type A) cells of Btg1 knockout mice, allowing the restoring of a proper coordination between the cell cycle exit and the initial phase of post-mitotic neuroblasts migration. These events result in a increased rate of terminal maturation and integration in the olfactory- dependent memory circuits. Finally, as previously stated by others, we does not detect any beneficial effect of running in the subventricular zone wild type mice . All together these in vivo data suggest that a) the quiescent state of neural stem cells lacking the cell cycle inhibitory control can be reactivated by running; b) the cell cycle kinetics in the adult SVZ plays a pivotal role not only for proliferation but also for the tight coordination of cell cycle exit, migration and terminal differentiation. In vitro analysis demonstrates that running induces a great expansion of primary neurospheres isolated by Btg1 ko subvrenticular zone, supporting the in vivo observation about the increase of neural stem pool in this neurogenic niche. However the running-dependent hyperproliferation of the neural stem cells leads to a rapid depletion of the stem cell pool and /or to its ability to further expand in vitro. This fact suggest that the effect of running on the Btg1 knock out neural stem cell proliferation is not cell-autonomous but strictly dependent on niche environment. We can hypothesized that the presence of still unknown factors triggered by physical activity in the subventricular niche promotes and maintains in vivo the hyperproliferative state of neural stem cells in the Btg1 knockout mice

Antifungal prophylaxis: identification of preterm neonates at high risk for invasive fungal infection.

We read with great interest the article by Healy et al,1 who evaluated the impact of fluconazole prophylaxis (FP) for extremely low birth weight infants on invasive candidiasis (IC) incidence, IC-related mortality rates, and fluconazole susceptibility of Candida isolated. We wish to make some comments thereon. Healy et al1 demonstrated a decrease of IC in NICU infants, after the introduction of FP, from 0.6% to 0.3%, and a 3.6 fold decrease in ELBW infants. Recent studies have demonstrated that prophylactic use of fluconazole is effective in reducing the incidence of fungal colonization and fungal systemic infections in preterm neonates.2,3 However, because of the lack of larger multicenter randomized trials and data on long term neurodevelopment outcomes as well as concern about unwanted side effects and development of Candida resistance, FP in high risk infants remains controversial. For these reasons, selecting only those infants at highest risk for IC may delay or prevent the emergence of resistance. In recent studies, the criteria chosen to identify \u201cthe high-risk neonate\u201d were <1500 g birth weight (BW) and the presence of a central vascular catheter or endotracheal tube.4 These criteria seem to be too wide, because they could regard almost all the population sheltered in a NICU. In our NICU, FP as well as antibiotic prophylaxis did not exist, and Candida-related mortality was nearly 20% in extremely low birth weight infants. To prevent IC, we introduced a protocol of Candida surveillance cultures from stool and bronchoalveolar lavage fluid in intubated infants, and every infant who developed IC was identified and IC-related mortality was eliminated.5 All neonates with IC had a BW of 27 weeks

Effectiveness of treatment with surfactant in premature infants with respiratory failure and pulmonary infection

Surfactant inactivation is present in neonatal pneumonia

Unexpected effect of recruitment procedure on lung volume measured by respiratory inductive plethysmography (RIP) during high frequency oscillatory ventilation (HFOV) in preterm neonates with respiratory distress syndrome (RDS)

In clinical practice, one of the major problems in optimizing recruitment or lung volume during HFOV in preterm infants is the inability to accurately measure direct changes in lung volume at bedside

Proteomics and neonatal infection

Antimicrobial peptides plays an important role in the host innate defence network, even in humans. Recent studies demonstrated the capacity of human airways epithelial cells to synthesize antimicrobial peptides, and their multifunctional role in the primary immunity. The presence of ct-defensins in bronchoalveolar lavage fluid (BALF) was investigated in a cohort of preterm newborns with gestational age (GA) < or =30 weeks. BALF samples were analysed by High Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer. Our data show that preterm newborns, also at the lower GA, are able to produce defenses, underlining that their innate defence system is already active before the at-term delivery date

Efficacy of exogenous surfactant during conventional and high-frequency oscillatory ventilation in preterm infants with RDS

The immediate effects of exogenous surfactant on lung volume and hemodynamics in preterm infants have been poorly studied