Publications by authors named "Jorge Moisés"

18 Publications

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Lung Function sequelae in COVID-19 Patients 3 Months After Hospital Discharge.

Arch Bronconeumol 2021 Feb 24. Epub 2021 Feb 24.

Respiratory Institute, Hospital Clinic, University of Barcelona, C/Villaroel 170, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBER), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Roselló 149, 08036 Barcelona, Spain.

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http://dx.doi.org/10.1016/j.arbres.2021.01.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903150PMC
February 2021

Beta-2-Glycoprotein-I Deficiency Could Precipitate an Antiphospholipid Syndrome-like Prothrombotic Situation in Patients With Coronavirus Disease 2019.

ACR Open Rheumatol 2021 Mar 19. Epub 2021 Mar 19.

Hospital 12 de Octubre, Healthcare Research Institute and Biomedical Research Centre Network for Epidemiology and Public Health, Madrid, Spain.

Objective: Patients with coronavirus disease 2019 (COVID-19) present coagulation abnormalities and thromboembolic events that resemble antiphospholipid syndrome (APS). This work has aimed to study the prevalence of APS-related antigens, antibodies, and immune complexes in patients with COVID-19 and their association with clinical events.

Methods: A prospective study was conducted on 474 adults with severe acute respiratory syndrome coronavirus 2 infection hospitalized in two Spanish university hospitals. Patients were evaluated for classic and extra-criteria antiphospholipid antibodies (aPLs), immunoglobulin G (IgG)/immunoglobulin M (IgM) anticardiolipin, IgG/IgM/immunoglobulin A (IgA) anti-β2-glicoprotein-I (aβ2GPI), IgG/IgM antiphosphatidylserine/prothrombin (aPS/PT), the immune complex of IgA aβ2GPI (IgA-aβ2GPI), bounded to β2-glicoprotein-1 (β2GPI) and β2GPI levels soon after COVID-19 diagnosis and were followed-up until medical discharge or death.

Results: Prevalence of aPLs in patients with COVID-19 was as follows: classic aPLs, 5.8%; aPS/PT, 4.6%; IgA-aβ2GPI, 15%; and any aPL, 21%. When patients were compared with individuals of a control group of a similar age, the only significant difference found was the higher prevalence of IgA-aβ2GPI (odds ratio: 2.31; 95% confidence interval: 1.16-4.09). No significant differences were observed in survival, thrombosis, or ventilatory failure in aPL-positive versus aPL-negative patients. β2GPI median levels were much lower in patients with COVID-19 (15.9 mg/l) than in blood donors (168.8 mg/l; P < 0.001). Only 3.5% of patients with COVID-19 had normal levels of β2GPI (>85 mg/l). Low levels of β2GPI were significantly associated with ventilatory failure (P = 0.026).

Conclusion: β2GPI levels were much lower in patients with COVID-19 than in healthy people. Low β2GPI-levels were associated with ventilatory failure. No differences were observed in the COVID-19 evolution between aPL-positive and aPL-negative patients. Functional β2GPI deficiency could trigger a clinical process similar to that seen in APS but in the absence of aPLs.
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http://dx.doi.org/10.1002/acr2.11245DOI Listing
March 2021

Multimodal prehabilitation as strategy for reduction of postoperative complications after cardiac surgery: a randomised controlled trial protocol.

BMJ Open 2020 12 22;10(12):e039885. Epub 2020 Dec 22.

Anaesthesiology and Intensive Care, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain

Introduction: Prehabilitation programmes that combine exercise training, nutritional support and emotional reinforcement (multimodal prehabilitation) have demonstrated efficacy reducing postoperative complications in the context of abdominal surgery. However, such programmes have seldom been studied in cardiac surgery, one of the surgeries associated with higher postoperative morbidity and mortality. This trial will assess the feasibility and efficacy in terms of reduction of postoperative complications and cost-effectiveness of a multimodal prehabilitation programme comparing to the standard of care in cardiac surgical patients.

Methods And Analysis: This is a single-centre, randomised, open-label, controlled trial with a 1:1 ratio. Consecutive 160 elective valve replacement and/or coronary revascularisation surgical patients will be randomised to either standard of care or 4-6 weeks of multimodal prehabilitation that will consist in (1) two times/week supervised endurance and strength exercise training sessions, (2) promotion of physical activity and healthy lifestyle, (3) respiratory physiotherapy, (4) nutrition counselling and supplementation if needed, and (5) weekly mindfulness sessions. Baseline, preoperative and 3-month postoperative data will be collected by an independent blinded evaluator. The primary outcome of this study will be the incidence of postoperative complications.

Ethics And Dissemination: This study has been approved by the Ethics Committee of Clinical investigation of Hospital Clinic de Barcelona (HCB/2017/0708). The results will be disseminated in a peer-reviewed journal.

Trial Registration Number: NCT03466606.
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http://dx.doi.org/10.1136/bmjopen-2020-039885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757458PMC
December 2020

Phenotypic characterisation of early COPD: a prospective case-control study.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

CIBER de Enfermedades Respiratorias, Madrid, Spain.

The phenotypic characteristics of chronic obstructive pulmonary disease (COPD) in individuals younger than 50 years of age (early COPD) are not well defined. This prospective, multicentre, case-control study sought to describe these characteristics and compare them with those of smokers (≥10 pack-years) of similar age with normal spirometry (controls). We studied 92 cases (post-bronchodilator forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) <0.7) and 197 controls. Results were contrasted with participants with similar inclusion criteria recruited into the ECLIPSE and COPDGene cohorts. Cases had moderate airflow limitation (FEV 71.3±20.8%) but were often symptomatic, used healthcare resources frequently, had air trapping (residual volume 150.6±55.5% ref.), had reduced diffusing capacity (84.2±20.7% ref.) and had frequent evidence of computed tomography (CT) emphysema (61%). Of note, less than half of cases (46%) had been previously diagnosed with COPD. Interestingly, they also often reported a family history of respiratory diseases and had been hospitalised because of respiratory problems before the age of 5 years more frequently than controls (12% 3%, p=0.009). By and large, these observations were reproduced when available in the ECLIPSE and COPDGene cohorts. These results show that early COPD is associated with substantial health impact and significant structural and functional abnormalities, albeit it is often not diagnosed (hence, treated). The fact that a sizeable proportion of patients with early COPD report a family history of respiratory diseases and/or early-life events (including hospitalisations before the age of 5 years) renders further support to the possibility of early-life origin of COPD.
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http://dx.doi.org/10.1183/23120541.00047-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533304PMC
October 2020

Different Types of Statins and All-Cause Mortality during Anticoagulation for Venous Thromboembolism: Validation Study from RIETE Registry.

TH Open 2020 Jul 17;4(3):e236-e244. Epub 2020 Sep 17.

Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Spain.

 We previously reported that during the course of anticoagulation for venous thromboembolism (VTE) patients using statins were at a lower risk to die than nonusers.  We used the R egistro I nformatizado E nfermedad T rombo E mbólica (RIETE) registry to validate our previous findings in a subsequent cohort of patients and to compare the risk of death according to the use of different types of statins.  From January 2018 to December 2019, 19,557 patients with VTE were recruited in RIETE. Of them, 4,065 (21%) were using statins (simvastatin, 1,406; atorvastatin, 1,328; rosuvastatin, 246; and others, 1,085). During anticoagulation (192 vs.182 days, for statin and no statin users respectively), 500 patients developed a VTE recurrence, 519 suffered major bleeding, and 1,632 died (fatal pulmonary embolism [PE], 88 and fatal bleeding, 78). On multivariable analysis, statin users were at a lower risk to die (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.59-0.79) than nonusers. When separately analyzing the drugs, on multivariable analysis, patients using simvastatin (HR = 0.64; 95% CI: 0.52-0.80), atorvastatin (HR 0.72; 95% CI: 0.58-0.89), or other statins (HR = 0.67; 95% CI: 0.52-0.87) were at a lower risk to die than nonusers. For those using rosuvastatin, difference was not statistically significant (HR = 0.77; 95% CI: 0.50-1.19), maybe due to the sample size.  Our data validate previous findings and confirm that VTE patients using statins at baseline are at a lower risk to die than nonusers. No statistically differences were found according to type of statins.
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http://dx.doi.org/10.1055/s-0040-1716734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498305PMC
July 2020

Association Between Systemic and Pulmonary Vascular Dysfunction in COPD.

Int J Chron Obstruct Pulmon Dis 2020 26;15:2037-2047. Epub 2020 Aug 26.

Department of Pulmonary Medicine, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Introduction: In chronic obstructive pulmonary disease (COPD), endothelial dysfunction and stiffness of systemic arteries may contribute to increased cardiovascular risk. Pulmonary vascular disease (PVD) is frequent in COPD. The association between PVD and systemic vascular dysfunction has not been thoroughly evaluated in COPD.

Methods: A total of 108 subjects were allocated into four groups (non-smoking controls, smoking controls, COPD without PVD and COPD with PVD). In systemic arteries, endothelial dysfunction was assessed by flow-mediated dilation (FMD) and arterial stiffness by pulse wave analysis (PWA) and pulse wave velocity (PWV). PVD was defined by a mean pulmonary artery pressure (PAP) ≥25 mmHg at right heart catheterization or by a tricuspid regurgitation velocity >2.8 m/s at doppler echocardiography. Biomarkers of inflammation and endothelial damage were assessed in peripheral blood.

Results: FMD was lower in COPD patients, with or without PVD, compared to non-smoking controls; and in patients with COPD and PVD compared to smoking controls. PWV was higher in COPD with PVD patients compared to both non-smoking and smoking controls in a model adjusted by age and the Framingham score; PWV was also higher in patients with COPD and PVD compared to COPD without PVD patients in the non-adjusted analysis. FMD and PWV correlated significantly with forced expiratory volume in the first second (FEV), diffusing capacity for carbon monoxide (DL) and systolic PAP. FMD and PWV were correlated in all subjects.

Discussion: We conclude that endothelial dysfunction of systemic arteries is common in COPD, irrespective if they have PVD or not. COPD patients with PVD show increased stiffness and greater impairment of endothelial function in systemic arteries. These findings suggest the association of vascular impairment in both pulmonary and systemic territories in a subset of COPD patients.
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http://dx.doi.org/10.2147/COPD.S257679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457710PMC
August 2020

Extracellular Vesicle lincRNA-p21 Expression in Tumor-Draining Pulmonary Vein Defines Prognosis in NSCLC and Modulates Endothelial Cell Behavior.

Cancers (Basel) 2020 Mar 20;12(3). Epub 2020 Mar 20.

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain.

Hypoxia-induced upregulation of lincRNA-p21 in tumor tissue was previously shown by our group to be related to poor prognosis in resected non-small cell lung cancer (NSCLC) patients. In the present study, we have evaluated the presence of lincRNA-p21 in extracellular vesicles (EVs) from NSCLC patients and assessed its potential as a prognostic biomarker. High EV lincRNA-p21 levels in blood from the tumor-draining vein were associated with shorter time to relapse and shorter overall survival. Moreover, the multivariate analysis identified high lincRNA-p21 levels as an independent prognostic marker. In addition, lincRNA-p21 was overexpressed in H23 and HCC44 NSCLC cell lines and their derived EVs under hypoxic conditions. Functional assays using human umbilical vein endothelial cells (HUVECs) showed that tumor-derived EVs enriched in lincRNA-p21 affected endothelial cells by promoting tube formation and enhancing tumor cell adhesion to endothelial cells. Additionally, the analysis of selected EV microRNAs related to angiogenesis and metastasis showed that the microRNAs correlated with EV lincRNA-p21 levels in both patients and cell lines. Finally, EV co-culture with HUVEC cells increased the expression of microRNAs and genes related to endothelial cell activation. In conclusion, EV lincRNA-p21 acts as a novel prognosis marker in resected NSCLC patients, promoting angiogenesis and metastasis.
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http://dx.doi.org/10.3390/cancers12030734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140053PMC
March 2020

Long Non-Coding RNA NANCI/NKX2-1 Duplex Impacts Prognosis in Stage I Non-Small-Cell Lung Cancer.

Arch Bronconeumol 2020 10 14;56(10):630-636. Epub 2020 Mar 14.

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain. Electronic address:

Background: NANCI, an intergenic long non-coding RNA (lncRNA) is essential for buffering NKX2-1 expression during embryonic development and in adult tissue. We analyzed NANCI and NKX2-1 in human lung embryonic samples and adult lung tissues and evaluated their potential as prognostic markers in stage I non-small cell lung cancer (NSCLC).

Methods And Results: NANCI and NKX2-1 expression was assessed by TaqMan assays in 18 human embryonic samples from 8 to 13 weeks, 59 non-tumoral (NT) lung tissue samples, and 98 stage I NSCLC tumor samples. NANCI and NKX2-1 expression in embryonic and NSCLC samples were downregulated in comparison to adult NT tissue. Patients with low expression of NANCI had shorter disease-free survival (DFS) and overall survival (OS) than those with high levels (47.6 vs 69.3 months, P=0.032 and 57.7 vs 77.6 months, P=0.021, respectively). When the expression levels of NANCI and NKX2-1 were evaluated in combination, four groups were identified (high NANCI/high NKX2-1, low NANCI/high NKX2-1, high NANCI/low NKX2-1 and low NANCI/low NKX2-1) with differential impact on DFS (P=0.042) and OS (P=0.024). Interestingly, the high NANCI/high NKX2-1 duplex group had longer DFS and OS than the other three groups (71.25 vs 46.3 months, P=0.009 and 81.3 vs 56.1 months, P=0.004, respectively). In the multivariate analysis, the high NANCI/high NKX2-1 duplex was identified as an independent prognostic factor for longer DFS (HR 0.346, 95% CI, 0.169-0.709; P=0.004) and OS (HR 0.309, 95% CI, 0.121-0.786; P=0.014).

Conclusions: NANCI and the NANCI-NKX2-1 duplex impacts prognosis in stage I NSCLC patients.
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http://dx.doi.org/10.1016/j.arbres.2020.01.011DOI Listing
October 2020

Effects of Pulmonary Hypertension on Exercise Capacity in Patients With Chronic Obstructive Pulmonary Disease.

Arch Bronconeumol 2020 08 23;56(8):499-505. Epub 2019 Nov 23.

Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Spain.

Introduction: The impact of pulmonary hypertension (PH) on exercise tolerance in chronic obstructive pulmonary disease (COPD) has not been fully elucidated. It is necessary to characterize pulmonary hemodynamics in patients with moderate to severe COPD in order to improve their management. The aim of the study was to determine whether in COPD the presence of PH is associated with reduced exercise tolerance in a cohort of stable COPD patients.

Methods: Cross-sectional analysis of 174 COPD patients clinically stable: 109 without PH and 65 with PH (COPD-PH). We assessed socio-demographic data, lung function, quality of life, dyspnea, cardiopulmonary exercise testing (CPET), constant workload endurance time (CWET), and six-minute walk test (6MWT). We elaborated a logistic regression model to explore the impact of PH on exercise capacity in COPD patients.

Results: COPD-PH patients showed lower exercise capacity both at maximal (CPET) (43(20) versus 68(27) Watts and 50(19)% versus 71(18)% predicted peak oxygen consumption (VOpeak), COPD-PH and COPD, respectively), and at submaximal tests (6MWT) (382(94) versus 486(95) m). In addition, the COPD-PH group had lower endurance time than the non-PH COPD group (265(113) s and 295(164) s, respectively).

Conclusions: The presence of PH is an independent factor that impairs exercise capacity in COPD.
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http://dx.doi.org/10.1016/j.arbres.2019.10.015DOI Listing
August 2020

Acute exacerbations of idiopathic pulmonary fibrosis: Does clinical stratification or steroid treatment matter?

Chron Respir Dis 2019 Jan-Dec;16:1479973119869334

1 Servei de Pneumologia, Respiratory Institute, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is defined as a sudden acceleration of the disease with the appearance of pulmonary infiltrates superimposed on the characteristic pattern of IPF that leads to a significant decline in lung function. It has high in-hospital mortality rates, despite medical treatment with systematic steroids. We sought to investigate whether there were in-hospital mortality differences according to clinical stratification (AE, suspected AE, or AE of known cause) and/or treatment with systemic steroids. We reviewed the clinical characteristics and outcomes of patients with IPF admitted to our hospital during the years 2003-2014 due to a worsening of their clinical status. We identified 50 IPF patients, 9 with AE (18%), 12 with suspected exacerbation (24%), and 29 with AE of known cause (58%), mostly respiratory infections. In-hospital mortality was similar in the three groups (33% vs. 17% vs. 34%, respectively). Likewise, we did not find differences between them with respect to the use of systemic steroids (length of treatment duration or total dose). Nevertheless, there was an independent association between in-hospital mortality and high average daily steroid dose. We did not observe significant differences in prognosis or use of systemic steroids according to current diagnostic stratification groups in patients hospitalized because of an exacerbation of IPF.
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http://dx.doi.org/10.1177/1479973119869334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704413PMC
April 2020

Clinical significance of long non-coding RNA HOTTIP in early-stage non-small-cell lung cancer.

BMC Pulm Med 2019 Feb 28;19(1):55. Epub 2019 Feb 28.

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Casanova 143, 08036, Barcelona, Spain.

Background: HOTTIP, a long non-coding RNA located in the HOXA cluster, plays a role in the patterning of tissues with mesodermal components, including the lung. Overexpression of HOXA genes, including HOTTIP, has been associated with a more aggressive phenotype in several cancers. However, the prognostic impact of HOTTIP has not yet been explored in non-small-cell lung cancer (NSCLC). We have correlated HOTTIP expression with time to relapse (TTR) and overall survival (OS) in early-stage NSCLC patients.

Methods: Ninety-nine early-stage NSCLC patients who underwent surgical resection in our center from June 2007 to November 2013 were included in the study. Mean age was 66; 77.8% were males; 73.7% had stage I disease; and 55.5% had adenocarcinoma. A validation data set comprised stage I-II patients from The Cancer Genome Atlas (TCGA) Research Network.

Results: HOTTIP was expressed in all tumor samples and was overexpressed in squamous cell carcinoma (p = 0.007) and in smokers (p = 0.018). Patients with high levels of HOTTIP had shorter TTR (78.3 vs 58 months; p = 0.048) and shorter OS (81.2 vs 61 months; p = 0.023) than those with low levels. In the multivariate analysis, HOTTIP emerged as an independent prognostic marker for TTR (OR: 2.05, 95%CI: 1-4.2; p = 0.05), and for OS (OR: 2.31, 95%CI: 1.04-5.1; p = 0.04). HOTTIP was validated as a prognostic marker for OS in the TCGA adenocarcinoma cohort (p = 0.025). Moreover, we identified a 1203-mRNA and a 61-miRNA signature that correlated with HOTTIP expression.

Conclusions: The lncRNA HOTTIP can be considered a prognostic biomarker in early-stage NSCLC.
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http://dx.doi.org/10.1186/s12890-019-0816-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393998PMC
February 2019

Exosome Analysis in Tumor-Draining Pulmonary Vein Identifies NSCLC Patients with Higher Risk of Relapse after Curative Surgery.

Cancers (Basel) 2019 Feb 21;11(2). Epub 2019 Feb 21.

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, 08036 Barcelona, Spain.

Since tumor-draining pulmonary vein blood (PV) is enriched in tumor-secreted products, we hypothesized that it would also be enriched in tumor-derived exosomes, which would be important in the metastasis process. We characterized exosomes from PV of 61 resected non-small cell lung cancer (NSCLC) patients to evaluate its potential as relapse biomarkers. Exosomes were characterized using transmission electron microscopy, western blot and nanoparticle tracking analysis and we examined time to relapse (TTR) and overall survival (OS). Differences between PV and peripheral vein were found. PV was enriched in smaller exosomes than the paired peripheral vein ( = 0.01). Moreover, PV exosome size mode was able to identify relapsed patients (Area under the curve [AUC] = 0.781; 95%CI: 0.6641⁻0.8978), in whom exosome size was smaller (<112 nm; < 0.001). The combination of PV exosome size and N (lymph node involvement) showed an AUC of 0.89 (95%CI: 0.80⁻0.97). Moreover, smaller PV exosome size was associated with shorter TTR (28.3 months vs. not reached, < 0.001) and OS (43.9 months vs. not reached, = 0.009). Multivariate analyses identified PV exosome size and stage as independent prognostic markers for TTR and OS. PV exosome size is a promising relapse biomarker after surgery that can add valuable information to clinical variables.
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http://dx.doi.org/10.3390/cancers11020249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407158PMC
February 2019

Prehabilitation in thoracic surgery.

J Thorac Dis 2018 Aug;10(Suppl 22):S2593-S2600

General Thoracic Surgery Department, Clinical Respiratory Institute, Hospital Clínic of Barcelona, Barcelona, Spain.

Surgical resection remains the best treatment option for patients with early stage of non-small cell lung cancer (NSCLC). However, it may be responsible of postoperative complication and mortality, especially in patients with impaired pulmonary function. Enhanced recovery after surgery (ERAS) programs have been focused mainly in minimal invasive surgery approach during lung resection and respiratory rehabilitation after surgery. Preoperative exercise-based intervention (prehabilitation) has demonstrated reduction of morbi-mortality in other surgeries but in thoracic surgery continues to be under discussion. Cardio-pulmonary exercise test (CPET) is the gold standard technique to predict postoperative morbi-mortality. The implementation of a preoperative respiratory rehabilitation could optimize patient's physical capacity before surgery and improve outcomes and enhance recovery. The aim of this systematic review of the literature is to identify the effectiveness and safety of prehabilitation programs in thoracic surgery, the type of exercise and its duration, and the group of patients with best benefit. Prehabilitation is a safe intervention without side effects in patients. High-intensity interval training (HIT) with duration of 2 to 6 weeks seems to be the best exercise programme in a prehabilitation intervention but it exists heterogeneity in terms of intensity and duration. Prehabilitation increase exercise capacity and significantly enhances pulmonary function. But the reduction of postoperative complication and mortality has not been clearly demonstrated. Different criteria selection, type of intervention and small sample size, in addition to no randomization, could justify disparate results. It seems that not all patients can benefit from prehabilitation and it could be indicated only in patients with impaired lung function. Further randomized clinical trials with enough patients, correct duration of HIT (2 to 6 weeks) and focused in COPD patients are needed to clarify the suitability of prehabilitation. Meanwhile, safety of prehabilitation and good results of some studies support this intervention in high-risk patients.
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http://dx.doi.org/10.21037/jtd.2018.08.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178292PMC
August 2018

Immunotherapy: a new standard of care in thoracic malignancies? A summary of the European Respiratory Society research seminar of the Thoracic Oncology Assembly.

Eur Respir J 2018 02 14;51(2). Epub 2018 Feb 14.

Dept of Respiratory Medicine, Hôpital Tenon AP-HP, Université Paris 6 Pierre et Marie Curie, Paris, France

In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled "Immunotherapy, a new standard of care in thoracic malignancies?" was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events. The need for biological selection, currently based on immunohistochemistry testing to identify the tumour expression of programmed death ligand (PD-L)1, was stressed, as well as the need to harmonise PD-L1 testing and techniques. Finally, sessions were dedicated to the combination of ICIs and radiotherapy and the place of ICIs in nonsmall cell lung cancer with oncogenic addictions. Finally, an important presentation was dedicated to the future of antitumour vaccination and of all ongoing trials in thoracic oncology.
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http://dx.doi.org/10.1183/13993003.02072-2017DOI Listing
February 2018

NKX2-1 expression as a prognostic marker in early-stage non-small-cell lung cancer.

BMC Pulm Med 2017 Dec 13;17(1):197. Epub 2017 Dec 13.

Department of Pneumology, Institut Clínic Respiratori (ICR), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

Background: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR.

Methods: mRNA and miRNA expression was determined using TaqMan assays in 110 early-stage NSCLC patients. TP53, KRAS, and EGFR mutations were assessed by Sanger sequencing.

Results: NKX2-1 expression was upregulated in never-smokers (P = 0.017), ADK (P < 0.0001) and patients with wild-type TP53 (P = 0.001). A negative correlation between NKX2-1 and miR-365 expression was found (ρ = -0.287; P = 0.003) but there was no correlation between NKX2-1 and miR-33a expression. Overall survival (OS) was longer in patients with high expression of NKX2-1 than in those with low expression (80.8 vs 61.2 months (P = 0.035), while a trend towards longer OS was observed in patients with low miR-365 levels (P = 0.07). The impact of NKX2-1 on OS and DFS was higher in patients with neither TP53 nor KRAS mutations. Higher expression of NKX2-1 was related to higher OS (77.6 vs 54 months; P = 0.017) and DFS (74.6 vs 57.7 months; P = 0.006) compared to low expression. The association between NKX2-1 and OS and DFS was strengthened when the analysis was limited to patients with stage I disease (P = 0.005 and P=0.003 respectively).

Conclusions: NKX2-1 expression impacts prognosis in early-stage NSCLC patients, particularly in those with neither TP53 nor KRAS mutations.
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http://dx.doi.org/10.1186/s12890-017-0542-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727907PMC
December 2017

Cavitating Pulmonary Nodules in a Patient Receiving Anti-TNF.

Arch Bronconeumol 2018 08 3;54(8):431-432. Epub 2017 Nov 3.

Servei de Pneumologia i Al·lèrgia, Institut Clínic Respiratori, Hospital Clínic de Barcelona, Barcelona, España. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2017.08.017DOI Listing
August 2018

LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation.

J Thorac Oncol 2016 12 2;11(12):2173-2182. Epub 2016 Aug 2.

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.

Introduction: Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53-dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC.

Methods: LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry.

Results: LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p < 0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density.

Conclusions: Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis.
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http://dx.doi.org/10.1016/j.jtho.2016.07.015DOI Listing
December 2016

The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer.

Oncotarget 2015 Oct;6(31):31544-56

Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.

The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression.
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http://dx.doi.org/10.18632/oncotarget.3003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741623PMC
October 2015