Quantitative analysis of airway obstruction in lymphangio-leio-myomatosis

Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease with progressive pulmonary function loss caused by progressively proliferating LAM cells. The degree of airway obstruction has not been well investigated within the pathogenesis of LAM. Using a combination of ex vivo computed tomography (CT), microCT and histology, the site and nature of airway obstruction in LAM explant lungs was compared with matched control lungs (n=5 each). The total number of airways per generation, total airway counts, terminal bronchioles number and surface density were compared in LAM versus control. Ex vivo CT analysis demonstrated a reduced number of airways from generation 7 on (p<0.0001) in LAM compared with control, whereas whole-lung microCT analysis confirmed the three- to four-fold reduction in the number of airways. Specimen microCT analysis further demonstrated a four-fold decrease in the number of terminal bronchioles (p=0.0079) and a decreased surface density (p=0.0079). Serial microCT and histology images directly showed the loss of functional airways by collapse of airways on the cysts and filling of the airway by exudate. LAM lungs show a three- to four-fold decrease in the number of (small) airways, caused by cystic destruction which is the likely culprit for the progressive loss of pulmonary function

The Role of a Panel of Pro-Fibrogenic miRs in Fibrotic Lung Disorders

Rationale: Pulmonary idiopathic fibrosis (IPF), Cryptogenetic organizing pneumonia (COP) and bronchiolitis obliterans syndrome (BOS) are rare pulmonary disorders, linked by the presence of fibrotic lesions. In our previous work (Di Carlo, 2016) on BOS we computationally identified a panel of candidate miRNAs and demonstrated by in situ hybridization analysis (ISH) and qRT-PCR, a dysregulation of two highly ranked miRNAs, miR-21 and miR-34a;ISH confirmed abnormal miR-21 and miR-34a expression in BOS lesions; other miRNAs where indicated as potential candidates in BOS by computational analysis. Aim We extended our previous work by analyzing the expression of miR-21, miR-34a and three other highly ranked miRNAs (miR-145, miR-146b-5p and miR-381) in BOS and other lung diseases associated with fibroblast activation/proliferation and collagen deposition. Identifying a specific profile of dysregulated miRNAs could provide useful diagnostic markers and potential therapeutic target. Methods :We evaluated miRNAs expression profile by ISH and RT-PCR quantification in a series of formalin-fixed and paraffin-embedded lung samples obtained from patients with IPF (n. 8), OP (n. 8), BOS (n. 12) and normal lung from organ donors. Results In BOS, COP and IPF/UIP miR-21 and miR-145 were expressed in fibroblasts of BO lesions, OP plugs and in fibroblast foci respectively, and in reactive alveolar epithelia; miR-146b expression correlated to the amount of inflammatory cell infiltrates and epithelial activation in all cases, while a weak expression was evident in OP and IPF/UIP lesions. miR-34a overexpression was associated with the activation of alveolar epithelia and to a lesser extent with fibroblast lesions in OP. miR-381 showed a weak expression in all diseases, and was localized especially in inflammatory cells. ISH data have been confirmed by qRTPCR analysis obtained on same samples. Conclusions: miR-21, miR-145 and miR-146b are over-expressed in fibroblasts in all the cases analyzed, but their expression is not disease-specific, although some differences are observed in different diseases. This finding underlies their role in non-specific fibrotic lung processes.ISH complements the results of qPCR, allows the precise cellular localization of miR expression, and improves correlations with cell-specific pathway

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. METHODS: We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). RESULTS: Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. CONCLUSIONS: ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Efficacy of two dosages of dexamethasone administered by submucosal injection on postoperative sequelae after third molar surgery: A retrospective study

ABSTRACT: Purpose: A retrospective clinical study was performed to compare the post-operative sequelae of the submucosal administration of two different low dosages of dexamethasone, after the surgical extraction of lower third molars. Methods: Data regarding edema, trismus, pain and analgesic consumption were collected from 150 subjects, selecting three equal groups (n= 50): a control group with no administered dexamethasone (G1); submucosal injection of dexamethasone 2 mg/0.5 ml (G2) and submucosal injection of dexamethasone 4 mg/1 ml (G3). Collected data were evaluated at three different time points: T0 before surgery, T1 on the third day after surgery and T2 on the 7th day after surgery. Patients’ gender and age were also considered for statistical purposes. Results: The effects on facial swelling reduction were statistically significant in G2 at T1 in the male subgroup. With trismus, the differences between the time points considered were statistically significant in G2 in the subgroup of subjects younger than 25 years old. Differences in analgesics taken were statistically significant when G1 and G2 were compared at T1. (Am J Dent 2022;35:233-237)

Effect of induction therapy on peripheral blood lymphocytes after lung transplantation: A multicenter international study

International audienceIntroduction: Lymphocytes, which are targeted by immunosuppressive therapies, may be influenced by induction and recipient characteristics. The objective of this study was to evaluate the influence of induction therapy on lymphocyte kinetics after lung transplantation (LTx) according to the recipient characteristics and allograft outcomes. Methods: We retrospectively collected total lymphocyte counts from peripheral blood, which was monitored before and after transplantation (days 7, 14, 30, 90, 180, 365 and 730) in patients from 3 different lung transplant centers in Europe who encountered different induction strategies (no induction, anti-thymocyte globulins and basiliximab). Results: A total of 164 recipients were included: 50 patients who did not receive induction therapy and 114 patients who received induction therapy (57 with anti-thymocyte globulins and 57 with basiliximab). The pre-transplant lymphocyte levels and induction therapy were associated with higher lymphocyte differences between pre-transplantation and day 7 (p < .001). The lymphocyte reconstitution was correlated with the pre-transplant weight (+10 cells/mu L/kg, 95%CI [+5; +15], p < 0.001), pre-transplant lymphocyte level (-248 cells/mu L, 95%CI [-368; -127] between low and high level recipients, p < 0.001), induction therapy with anti-thymocyte globulins (-636 cells/mu L, 95%CI [-797; -475], p < 0.001), and induction with basiliximab (-641 cells/mu L, 95%CI [-801; -481], p < 0.001) compared with no induction. Age was associated with a delayed reconstitution at day 30 (-9 cells/mu L/year, 95%CI [-17; -1], p = 0.04) and day 90 (-8 cells/mu L/year, 95%CI [-16; -1], p = 0.04). One-year mortality was associated with a lower lymphocyte count (-325 cells/mu L, 95%CI [-522; -128), p = 0.001) and a best predictive threshold of 1000 cells/mu L at day 90. Conclusion: The blood lymphocyte count after LTx is associated with the pre-transplant lymphocyte level, age, weight and induction therapy and predicts one-year mortality

Smart Sensors and Microtechnologies in the Precision Medicine Approach against Lung Cancer

Background and rationale. The therapeutic interventions against lung cancer are currently based on a fully personalized approach to the disease with considerable improvement of patients' outcome. Alongside continuous scientific progresses and research investments, massive technologic efforts, innovative challenges, and consolidated achievements together with research investments are at the bases of the engineering and manufacturing revolution that allows a significant gain in clinical setting. Aim and methods. The scope of this review is thus to focus, rather than on the biologic traits, on the analysis of the precision sensors and novel generation materials, as semiconductors, which are below the clinical development of personalized diagnosis and treatment. In this perspective, a careful revision and analysis of the state of the art of the literature and experimental knowledge is presented. Results. Novel materials are being used in the development of personalized diagnosis and treatment for lung cancer. Among them, semiconductors are used to analyze volatile cancer compounds and allow early disease diagnosis. Moreover, they can be used to generate MEMS which have found an application in advanced imaging techniques as well as in drug delivery devices. Conclusions. Overall, these issues represent critical issues only partially known and generally underestimated by the clinical community. These novel micro-technology-based biosensing devices, based on the use of molecules at atomic concentrations, are crucial for clinical innovation since they have allowed the recent significant advances in cancer biology deciphering as well as in disease detection and therapy. There is an urgent need to create a stronger dialogue between technologists, basic researchers, and clinicians to address all scientific and manufacturing efforts towards a real improvement in patients' outcome. Here, great attention is focused on their application against lung cancer, from their exploitations in translational research to their application in diagnosis and treatment development, to ensure early diagnosis and better clinical outcomes

Evaluating the stability of extended-pour alginate impression materials by using an optical scanning and digital method

Statement of problem: The dimensional stability of alginate dental impressions is a key factor for the reliability of delayed gypsum pouring and digital scanning. However, studies of the dimensional stability of alginates with conventional methods that consider the dimensional variations of large impressions are lacking. Purpose: The purpose of this in vitro study was to investigate and compare 2 digital methods for the analysis of dimensional stability of large impressions made with 5 different extended-pour alginates and to assess dimensional stability up to 5 days. Material and methods: Impressions of a simplified master maxillary model were made with Alginoplast, Blueprint, Hydrogum 5, Orthoprint, and Phase Plus and then analyzed at different time points. Digital scans of the alginate impression surfaces were obtained with a desktop scanner and analyzed by evaluating the linear measurements between reference points and by using a novel method that consists of the analysis of the entire scanned surface to evaluate the expansion and contraction of the impressions. Results: The first method revealed that the dimensional changes did not exceed 0.5%, with the exception of Phase Plus at day 3 (-0.6 \ub10.7%), and the average dimensional variation was always lower than or equal to 0.2 mm. Blueprint was the most stable material (-0.2 \ub10.6%). The second method revealed dimensional variations always lower than 0.03 mm and confirmed Blueprint as the best performing material (0.001 \ub10.006 mm) and Phase Plus the worst (-0.019 \ub10.006 mm). Conclusions: Both the methods used to evaluate alginate stability showed that the analyzed materials remain stable over time; the dimensional variations showed a similar trend, with differences in the absolute values depending on the applied method. Linear measurements are affected by the operator and choice of reference points; however, by evaluating the average variations of the entire structure surfaces, local variations should be minimized. The evaluation of the average variations with the second method offers the advantage of a rapid visual representation of these variations