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We have undertaken an autopsy-based study to evaluate the etiologic importance of active and passive smoking, as well as socio-demographic variables, in the development of pathologic precursors of lung cancer. Lung specimens were taken at autopsy from 531 persons who had died within four hours from a cause other than respiratory or cancer in Athens (Greece) or the surrounding area. Specimens were examined blindly for basal cell hyperplasia, squamous cell metaplasia, cell atypia and mucous cell metaplasia, i.e., pathological entities considered as epithelial, possibly precancerous, lesions (EPPL). Interviews were conducted with next of kin of the deceased. Suitable autopsy specimens as well as completed interviews were eventually available for 275 subjects. EPPL score was regressed on the available independent variables. EPPL score was higher among active smokers than among nonsmokers, while ex-smokers occupied an intermediate position. Conditional on smoking habits, EPPL score was higher among women than among men and higher among manual than among non-manual workers, in agreement with the corresponding patterns with respect to lung cancer. Nonsmoking women married to ever smokers had significantly higher EPPL score than those married to never smokers. The overall findings of this study suggest that EPPL is a valuable indicator of lung cancer risk and that exposure to environmental tobacco smoke is associated with higher EPPL levels and therefore with higher lung cancer risk.

Objective.-The association between involuntary smoking and lung cancer has been supported by most epidemiologic studies, but a number of authors and interest groups claim that the possibility of bias has not been excluded. Few autopsy-based studies have explored the role of active smoking and other exposures in lung carcinogenesis, and none has been previously done to examine the role of passive smoking. We have undertaken such an autopsy-based study in Athens, Greece. Design.-Lung specimens were taken at autopsy from 400 persons 35 years of age or older, of both genders, who had died within 4 hours from a cause other than respiratory or cancer in Athens or the surrounding area. For each person at least seven tissue blocks were taken from the main and lobar bronchi and at least five blocks from the parenchyma, including an average of about 20 smaller cartilaginous bronchi and membranous bronchioles. The specimens were examined without knowledge of the exposures of the particular subject in Turin, Italy. For 283 (71%) of the subjects the preservation of the bronchial epithelium was satisfactory for pathological examination, and for 206 among them (73%) an interview could be arranged with their next of kin, focusing on smoking habits of the deceased and their spouses, as well as other variables. The interviewers were not aware of the results of the pathological examinations. Main Outcome Measure.-Specimens were examined for basal cell hyperplasia, squamous cell metaplasia, cell atypia, and (in membranous bronchioles and bronchiolo-alveolar airways) mucous cell metaplasia, ie, pathological entities that may be lung cancer risk indicators or epithelial, possibly precancerous, lesions (EPPL). The gland and wall thicknesses were also measured and their ratio calculated (Reid Index). Results.-In comparison with nonsmokers, EPPL values were significantly higher among current smokers and higher, but not significantly so, among former smokers. Furthermore, EPPL values were significantly higher among deceased nonsmoking women married to smokers rather than to nonsmokers. In this set of data neither occupation nor residence was associated with EPPL, but this could be due to the poor correlation of residential history with exposure to air pollution and the lack of adequate standardization of contemporary Greek occupations. The Reid Index was higher among smokers and former smokers in comparison with nonsmokers, among subjects with mainly urban residence in comparison with those with mainly rural residence, and among nonsmoking women married to smokers in comparison with those married to nonsmokers, but none of these differences was statistically significant. Conclusion.-These results provide support to the body of evidence linking passive smoking to lung-cancer, even though they are based on a study methodologically different from those that have previously examined this association.

In many instances, only post-mortem examination can provide probative data about (i) the presence of lung cancer and (ii) its relationship to exposure to asbestos. Moreover, the results of an autopsy may suggest that a thorough investigation of occupational history should be carried out, since such information is rarely recorded in clinical records. We considered pathological indicators for selecting subjects who had a high likelihood of previous occupational exposure to asbestos. The positive predictive value of pleural plaques ranged from 20 to 75%, depending on their size and on the concentrations of asbestos bodies and uncoated mineral fibres in the lung. The probability of no exposure was greater than 90% if neither asbestos bodies nor uncoated mineral fibres were found. Another purpose of our work on lung cancer and exposure to asbestos was to investigate the relationships between exposure and the occurrence of specific cell types of lung cancer in an autopsied population. Both work history and asbestos body count were considered. The matched analysis showed some tendency towards an association between the occurrence of adenocarcinoma and the presence of indicators of exposure to asbestos.

Objectives: Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. Design: Prospective, randomized, controlled experimental study. Setting: University research laboratory. Subjects: C57/BL6 mice weighing 28-30 g. Interventions: Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4°C), followed by 2 hours of warm (37°C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. Measurements and Main Results: Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. Conclusions: Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation. © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

BACKGROUND: Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury. METHODS: Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH₂O and 0 cmH₂O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH₂O and -3 cmH₂O PEEP (LOW STRESS). RESULTS: Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs. CONCLUSIONS: Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.

RATIONALE: Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase γ (PI3Kγ) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. OBJECTIVES: This study aimed to determine the specific role of the kinase activity of PI3Kγ in the pathogenesis of sepsis and multiorgan damage. METHODS: PI3Kγ wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation-induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3Kγ inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. MEASUREMENTS AND MAIN RESULTS: Both genetic and pharmaceutical PI3Kγ kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3Kγ pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. CONCLUSIONS: This study establishes PI3Kγ as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

OBJECTIVE: Limiting tidal volume (VT) may minimize ventilator-induced lung injury (VILI). However, atelectasis induced by low VT ventilation may cause ultrastructural evidence of cell disruption. Apoptosis seems to be involved as protective mechanisms from VILI through the involvement of mitogen-activated protein kinases (MAPKs). We examined the hypothesis that atelectasis may influence the response to protective ventilation through MAPKs. DESIGN: Prospective randomized study. SETTING: University animal laboratory. SUBJECTS: Adult male 129/Sv mice. INTERVENTIONS: Isolated, nonperfused lungs were randomized to VILI: VT of 20 mL/kg and positive end-expiratory pressure (PEEP) zero; low stretch/lung rest: VT of 6 mL/kg and 8-10 cm H2O of PEEP; low stretch/open lung: VT of 6 mL/kg, two recruitment maneuvers and 14-16 cm H2O of PEEP. Ventilator settings were adjusted using the stress index. MEASUREMENT AND MAIN RESULT: Both low stretch strategies equally blunted the VILI-induced derangement of respiratory mechanics (static volume-pressure curve), lung histology (hematoxylin and eosin), and inflammatory mediators (interleukin-6, macrophage inflammatory protein-2 [enzyme-linked immunosorbent assay], and inhibitor of nuclear factor-kB[Western blot]). VILI caused nuclear swelling and membrane disruption of pulmonary cells (electron microscopy). Few pulmonary cells with chromatin condensation and fragmentation were seen during both low stretch strategies. However, although cell thickness during low stretch/open lung was uniform, low stretch/lung rest demonstrated thickening of epithelial cells and plasma membrane bleb formation. Compared with the low stretch/open lung, low stretch/lung rest caused a significant decrease in apoptotic cells (terminal deoxynucleotidyl transferase mediated deoxyuridine-triphosphatase nick end-labeling) and tissue expression of caspase-3 (Western blot). Both low stretch strategies attenuated the activation of MAPKs. Such reduction was larger during low stretch/open lung than during low stretch/lung rest (p < 0.001). CONCLUSION: Low stretch strategies provide similar attenuation of VILI. However, low stretch/lung rest strategy is associated to less apoptosis and more ultrastructural evidence of cell damage possibly through MAPKs-mediated pathway. Comment in The role of positive end-expiratory pressure in modulating the apoptosis response during atelectasis-induced lung injury. [Crit Care Med. 2009]

Introduction: The aim of this feasibility study was to test the intraoperative use of this brand-new specimen PET/CT to guide robot-assisted radical prostatectomy and pelvic lymph node dissection., Materials and Methods: Three cases of robot-assisted radical prostatectomy and pelvic lymph node dissection were performed with intraoperative use of the specimen imager. Surgeries were performed with Da Vinci Xi robot. An intravenous injection of 68 Ga-PSMA-11 was performed in the OR and after complete excision, the specimens were analyzed with the imager., Results: The average nodal yield was 17.3 (5.8 SD) nodes per patient. Specimen PET/CT images showed a focal uptake in a metastatic node (TBR 13.6), and no uptake or diffuse, faint uptake in negative nodes (TBR range: 1-5.3). The specimen imager provided intraoperative PET/CT images that clearly showed negative surgical margins in two patients, whereas the results were uncertain in a locally advanced case., Conclusion: The intraoperative use of the specimen PET/CT imager is safe and feasible and could improve the evaluation of prostate surgical margins and lymph node status., (Copyright © 2023 Elsevier Inc. All rights reserved.)