Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism in SARS-CoV-2.

INTRODUCTION: Chronic thromboembolic pulmonary disease (CTEPD) consists of persistent pulmonary vascular obstruction on imaging and involves long-term functional limitations, with or without chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to evaluate the incidence and risk factors of both persistent pulmonary vascular defects and CTEPH after hospitalization in patients with COVID-19 and PE during a 2-year follow-up. METHODS: A prospective observational study was carried out in a tertiary hospital center. Patients were hospitalized between March 2020 and December 2021 with a diagnosis of PE during SARS-CoV-2 infection. Patients received anticoagulant treatment for at least 3 months and were followed up for 2 years. Between the third and fourth months after discharge, all patients were evaluated for the presence of residual thrombotic defects by CTPA and/or perfusion pulmonary scintigraphy. Clinical findings, lung function tests with DLCO, exercise capacity, and echocardiograms were also assessed. RESULTS: Of the 133 patients included, 18% had persistent thrombotic defects on lung imaging at follow-up. The incidence of CTEPD was 0.75% at 2 years of follow-up. Patients with persistent defects were significantly older, had a higher prevalence of systemic arterial hypertension, higher D-dimer and NT-proBNP levels, and more severe PE at diagnosis. Furthermore, there was a higher prevalence of right ventricular dysfunction on echocardiogram at diagnosis of PE (25.0% vs. 2.7%, p = 0.006). This was the only variable independently related to persistent defects in multivariate analyses (OR: 8.13 [95% CI: 1.82-36.32], p = 0.006). CONCLUSION: The persistence of thrombotic defects after PE is a common finding after SARS-CoV-2 infection, affecting 18% of the population. However, the incidence of CTEPH appears to be lower (0.75%) in COVID-19-related PE compared to that previously observed in PE unrelated to COVID-19.

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

Impact of high-flow oxygen therapy during exercise in idiopathic pulmonary fibrosis: a pilot crossover clinical trial.

BACKGROUND: Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT. METHODS: This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms. RESULTS: Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices. CONCLUSIONS: This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.

Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients.

Chronic obstructive pulmonary disease (COPD) is a chronic and often progressive disorder with a heterogeneous presentation and frequent systemic manifestations. Several aspects like persistence in smoking habit, continuous exacerbations, alpha-1-antitrypsin deficiency and inflammatory-immune response, are involved in the pathophysiology and progression of the disease. However, the role of natural killer (NK) cells remains controversial. Otherwise, human cytomegalovirus (HCMV) infection has been reported to induce an adaptive differentiation and expansion of an NK cell subset which carries the CD94/NKG2C receptor, which may contribute to an upset immune defense. For these reasons, our objective is to assess the distribution of NK cells and their subset in COPD patients and some of its phenotypes. METHODS: Peripheral blood samples were obtained from 66 COPD patients. HCMV serology and the proportions of total NK cells and the NKG2C+ and NKG2A+ subsets were evaluated by flow cytometry. The NKG2C genotype was also assessed. RESULTS: Eighty-eight per cent of COPD patients were HCMV(+), and the proportions of total NK cells were higher in patients with severe-very severe airway obstruction than in those with only mild-moderate involvement. There were no differences in the proportions of NKG2C+ cells between controls and COPD, either among COPD patients classified by severity of the disease. However, the percentage of NKG2C+ cells were higher in COPD patients with frequent exacerbations than in occasional exacerbators, and higher in cases with reduced lean mass (Fat free mass index) than in those with normal nutritional status. CONCLUSION: These results suggest a relationship between levels of NKG2C+ cells in COPD patients and clinical variables closely linked to a poor/worse prognosis.

How will lung cancer screening and lung nodule management change the diagnostic and surgical lung cancer landscape?

INTRODUCTION: Implementation of lung cancer screening, with its subsequent findings, is anticipated to change the current diagnostic and surgical lung cancer landscape. This review aimed to identify and present the most updated expert opinion and discuss relevant evidence regarding the impact of lung cancer screening and lung nodule management on the diagnostic and surgical landscape of lung cancer, as well as summarise points for clinical practice. METHODS: This article is based on relevant lectures and talks delivered during the European Society of Thoracic Surgeons-European Respiratory Society Collaborative Course on Thoracic Oncology (February 2023). Original lectures and talks and their relevant references were included. An additional literature search was conducted and peer-reviewed studies in English (December 2022 to June 2023) from the PubMed/Medline databases were evaluated with regards to immediate affinity of the published papers to the original talks presented at the course. An updated literature search was conducted (June 2023 to December 2023) to ensure that updated literature is included within this article. RESULTS: Lung cancer screening suspicious findings are expected to increase the number of diagnostic investigations required therefore impacting on current capacity and resources. Healthcare systems already face a shortage of imaging and diagnostic slots and they are also challenged by the shortage of interventional radiologists. Thoracic surgery will be impacted by the wider lung cancer screening implementation with increased volume and earlier stages of lung cancer. Nonsuspicious findings reported at lung cancer screening will need attention and subsequent referrals where required to ensure participants are appropriately diagnosed and managed and that they are not lost within healthcare systems. CONCLUSIONS: Implementation of lung cancer screening requires appropriate mapping of existing resources and infrastructure to ensure a tailored restructuring strategy to ensure that healthcare systems can meet the new needs.

Stage I and II nonsmall cell lung cancer treatment options.

Chest radiography, computed tomography (CT) and positron emission tomography (PET)-CT are required for staging nonsmall cell lung cancers. Stage I cancers may be up to 4 cm in maximal diameter, with stage IA tumours being up to 3 cm and stage IB up to 4 cm. A lung cancer becomes stage II if the tumour is between 4 and ≤5 cm (stage IIA), or it spreads to ipsilateral peribronchial or hilar lymph nodes (stage IIB). Stage IA tumours should be surgically resected, ideally using minimally invasive methods. Lobectomy is usually performed, although some studies have shown good outcomes for sublobar resections. If surgery is not possible, stereotactic body radiotherapy is a good alternative. This involves delivering a few high-dose radiation treatments at very high precision. For stage IB to IIB disease, combinations of surgery, chemotherapy or immunotherapy and radiotherapy are used. There is evidence that neoadjuvant treatment (immunotherapy with nivolumab and chemotherapy for stage IB and II) optimises outcomes. Adjuvant chemotherapy with a platinum-based doublet (typically cisplatin+vinorelbine) should be offered for resected stage IIB tumours and considered for resected IIA tumours. Adjuvant pembrolizumab is used for stage IB-IIIA following resection and adjuvant platinum-based chemotherapy. Osimertinib may be used for resected stage IB to IIIA cancers which have relevant mutations (epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution). There are no fixed guidelines for follow-up, but most centres recommend 6-monthly CT scanning for the first 2-3 years after definitive treatment, followed by annual scans.

Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

A lung adenocarcinoma patient with ROS1 fusion and NBN germline mutation achieves long progression-free survival from sintilimab combined with niraparib after failure of ROS1 inhibitors: a case report.

Background: Lung cancer is a malignant tumor with high morbidity and mortality worldwide. At present, the main treatment methods for patients with advanced non-small cell lung cancer (NSCLC) include molecular targeted therapy and immunotherapy. The efficacy rate of immune checkpoint inhibitor (ICI) monotherapy is relatively low. Studies have confirmed that some combination therapies have better anti-tumor efficacy and higher response rates, such as PD-1/PD-L1 inhibitors combined with chemotherapy or targeted therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors have become a new line of cancer therapy in ovarian and breast cancer, but it's not approved in lung cancer. Some reports show that homologous recombination repair (HRR) gene variants may be potential biomarkers for immunotherapy. However, whether lung cancer with HRR gene variants can be benefit from ICIs combined with PARP inhibitors is unknown. Case Description: We present a case of a 30-year-old man who was admitted to hospital with several months of cough and the chest computed tomography (CT) scan showed a mass about 2.6 cm × 2.1 cm in the left lung. Then he was diagnosed with lung adenocarcinoma (LUAD). Next generation sequencing (NGS) revealed that he harbors ROS1 fusion and NBN germline mutation. So, he received platinum-based chemotherapy and ROS1 inhibitors, but the disease continued to progress. Ultimately, the patient was switched to sintilimab combined with niraparib and the efficacy was evaluated as stable disease (SD), with a progression-free survival (PFS) of more than 12 months, and the overall survival (OS) is 23 months up to now. During the treatment, the major adverse events (AEs) observed were lymphopenia, nausea, vomiting, and edema. The AEs were tolerable. Conclusions: This case shows that the combination of small-molecule inhibitors and immunotherapy may improve survival in NSCLC patients with driver genes, and sintilimab combined with niraparib provides a successful clinical case for the treatment of refractory tumors HRR gene mutation, which can be used as a reference for personalized treatment. Of course, more clinical trials are needed to confirm this combination treatment strategy.

Association between histological diaphragm atrophy and ultrasound diaphragm expiratory thickness in ventilated patients.

BACKGROUND: Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients. METHODS: Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed. RESULTS: Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 µm2). CONCLUSIONS: Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous.

EGFR and KRAS Mutations in Lung Parenchyma of Subjects With EGFR/KRAS Wild-Type Lung Adenocarcinoma.

The acquisition of driver mutations in non-tumoral cells appears to be very important during the carcinogenesis of adenocarcinoma (ADC). Recent studies suggest that cancer-related mutations may not necessarily be present only in malignant cells, but also in histologically "healthy cells". Objective: to demonstrate the presence of EGFR or KRAS mutations in non-tumoral lung cells in subjects with ADC and negative mutational status. Results: mutations in EGFR or KRAS oncogenes were identified in the normal lung in 9.7% of the subjects. Exon 21 substitution L858R in EGFR was detected in two cases while the exon 19 deletion E746-A750 in the EGFR, the G12C and G12D substitutions in the KRAS were detected once. One patient presented three different mutations in the normal lung parenchyma (EGFR_L858R, KRAS_G12C and KRAS_G12D). The negative-mutation status of the tumor and the mutations detected in the "normal lung" were confirmed using highly sensitive and specific TaqMan PCR (CAST-PCR). No differences were found in terms of progression, progression-free survival or overall survival during the 18 months follow-up. Conclusions: These results confirm the presence of driver mutations in the histologically normal lung parenchyma cells in the absence of mutations coexisting with the primary tumor.

Incidence of pulmonary embolism in patients with non-invasive respiratory support during COVID-19 outbreak.

While the incidence of thrombotic complications in critically ill patients is very high, in patients under non-invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8-22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16-58)] compared to patients that continued with non-invasive support [11% (CI 5-18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2-16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis.

Case Report on a Patient with Steinert Disease Complicated by COVID-19.

SARS-CoV-2 infection is predominantly a respiratory disease with a diverse clinical spectrum. Pulmonary thromboembolic complications during COVID-19 pneumonia may be associated with a high mortality rate and post-mortem findings confirm the presence of platelet-fibrin thrombi in arterial vessels of patients together with lung tissue alterations. We present a patient transferred to the emergency department due to a syncope with no other associated symptoms, who was diagnosed with an acute pulmonary embolism (PE) concomitant with SARS-CoV-2 infection without lung infiltrates. Presenting with a PE as the only manifestation of this infection, reinforces our conception of COVID-19 as a heterogeneous disease of which we still know very little. We believe that while the virus is still circulating in our environment, we need to consider ruling out COVID-19 in all thrombotic events, even if the patients have no other risk factors.

EGFR and KRAS Mutations in the Non-Tumoral Lung. Prognosis in Patients with Adenocarcinoma.

Tumor recurrence is frequent and survival rates remain extremely low in lung adenocarcinoma (ADC). We hypothesize that carcinogenic factors will promote loco-regional modifications not only in the future tumor, but throughout the exposed lung. OBJECTIVE: To analyze whether the most prevalent mutations observed in ADC can also be observed in the non-neoplastic lung tissue, as well as the short-term prognosis implications of this finding. METHODS: Non-tumoral lung parenchyma specimens obtained during surgery from 47 patients with EGFR and/or KRAS abnormalities in their ADC tumors underwent similar genomic testing. Short-term outcomes were also recorded. RESULTS: The same mutations were present in the tumor and the histologically normal tissue in 21.3% of patients (SM group). Although local recurrences were similar in both groups, distant metastases were more frequent in the former (60 vs. 5.4%, p < 0.001). Moreover, SM patients showed lower time-to-progression (8.5 vs. 11.7 months, p < 0.001) and disease-free survival (8.5 vs. 11.2 months, p < 0.001). COX regression showed a higher risk of progression or death (DFS) in the SM group (HR 5.94, p < 0.01]. Similar results were observed when adjusting for potential confounding variables. CONCLUSIONS: These results confirm that genetic changes are present in the apparently normal lung in many ADC patients, and this finding has prognostic implications.

Nutritional status and muscle dysfunction in chronic respiratory diseases: stable phase versus acute exacerbations.

Nutritional abnormalities are frequent in different chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF), interstitial fibrosis and lung cancer, having important clinical consequences. However, nutritional abnormalities often remained underdiagnosed due to the relative lack of awareness of health professionals. Therefore, systematic anthropometry or even better, assessment of body composition, should be performed in all patients with chronic respiratory conditions, especially following exacerbation periods when malnutrition becomes more accentuated. Nutritional abnormalities very often include the loss of muscle mass, which is an important factor for the occurrence of muscle dysfunction. The latter can be easily detected with the specific assessment of muscle strength and endurance, and also negatively influences patients' quality of life and prognosis. Both nutritional abnormalities and muscle dysfunction result from the interaction of several factors, including tobacco smoking, low physical activity-sedentarism, systemic inflammation and the imbalance between energy supply and requirements, which essentially lead to a negative balance between protein breakdown and synthesis. Therapeutic approaches include improvements in lifestyle, nutritional supplementation and training. Anabolic drugs may be administered in some cases.

Bispectral index in hypercapnic encephalopathy associated with COPD exacerbation: a pilot study.

BACKGROUND: Hypercapnic encephalopathy is relatively frequent in severe exacerbations of COPD (ECOPDs), with its intensity usually being evaluated through clinical scales. Bispectral index (BIS) is a relatively new technique, based on the analysis of the electroencephalographic signal, which provides a good approximation to the level of consciousness, having already been validated in anesthesia. OBJECTIVE: The objective of the study was to evaluate the utility of BIS in the assessment of the intensity of hypercapnic encephalopathy in ECOPD patients. PATIENTS AND METHODS: A total of ten ECOPD patients were included, and the level of brain activity was assessed using BIS and different scales: Glasgow Coma Scale, Ramsay Sedation Scale (RSS), and Richmond Agitation-Sedation Scale. The evaluation was performed both in the acute phase and 3 months after discharge. RESULTS: BIS was recorded for a total of about 600 minutes. During ECOPD, BIS values ranged from 58.8 (95% CI: 48.6-69) for RSS score of 4 to 92.2 (95% CI: 90.1-94.3) for RSS score of 2. A significant correlation was observed between values obtained with BIS and those from the three scales, although the best fit was for RSS, followed by Glasgow and Richmond (r=-0.757, r=0.701, and r=0.615, respectively; P<0.001 for all). In the stable phase after discharge, BIS showed values considered as normal for a wake state (94.6; 95% CI: 91.7-97.9). CONCLUSION: BIS may be useful for the objective early detection and automatic monitoring of the intensity of hypercapnic encephalopathy in ECOPD, facilitating the early detection and follow-up of this condition, which may avoid management problems in these patients.

Molecular analysis of peripheral lung adenocarcinoma in brush cytology obtained by EBUS plus fluoroscopy-guided bronchoscopy.

BACKGROUND: More than 60% of patients with lung cancer are diagnosed at advanced stages. The introduction of targeted therapies requires molecular diagnosis to guide treatment. The aim of this study was to evaluate the feasibility of performing mutational analysis with brushing specimens obtained by radial-miniprobe endobronchial ultrasound (R-EBUS) plus fluoroscopy-guided bronchoscopy in patients with peripheral pulmonary adenocarcinoma. METHODS: Brushing specimens were deposited on cytological slides and were conserved in Roswell Park Memorial Institute (RPMI) culture medium. DNA was isolated to perform a mutational analysis with real-time quantitative polymerase chain reaction and Sanger sequencing for epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS). RESULTS: Thirty patients with adenocarcinoma were prospectively included. In 100% of the patients, the molecular study was viable with brushing specimens. In 16 (53.3%), KRAS or EGFR mutations were detected: 10 KRAS mutations (33.3%) and 6 EGFR mutations (20%). In a comparison with histological samples, a correlation of 86.6% was detected, and only 2 patients with wild-type results from brushing specimens presented with an EGFR mutation in histological samples. CONCLUSIONS: Brushing specimens conserved in RPMI medium and obtained by R-EBUS plus fluoroscopy-guided bronchoscopy are valid for molecular studies. They allow the detection of EGFR/KRAS mutations in patients with peripheral adenocarcinoma. In addition, invasive techniques are avoided, the risk of complications is reduced, and the obtained samples are optimized.

Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy.

Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor (EGFR) gene, Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), gene encoding neurofibromin (NF1), anaplastic lymphoma kinase (ALK) and ROS1 are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients.

[Role of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal tuberculosis]. / Utilidad de la punción aspirativa transbronquial guiada con ultrasonografía endobronquial en el diagnóstico de la tuberculosis mediastínica.

INTRODUCTION: Mediastinal tuberculosis (TB) is rare and a diagnostic challenge. Transbronchial needle aspiration guided by endoscopic ultrasonography (EBUS-TBNA) is an essential tool for staging and diagnosing patients with lung cancer but to date there are no studies in our environment evaluating its efficacy in mediastinal TB. METHODS: Patients with a final diagnosis of isolated intrathoracic tuberculous lymphadenitis over a 6-year period were included. We analyzed the cases on whom EBUS-TBNA was performed. RESULTS: Forty-six patients with mediastinal lymphadenopathy without pulmonary involvement were identified and 29 underwent EBUS-TBNA. In 28 of 29 patients (96.6%) EBUS-TBNA was diagnostic and cytological findings confirmed granulomas in 93% of cases. Microbiological investigation revealed positive TB culture in 14 (48.2%) and positive PCR for Mycobacterium tuberculosis in 30% of cases on whom it was carried out. Eighty-four per cent of the patients were immigrants and when compared with the native population we found statistical differences in immune status and culture yield. CONCLUSION: EBUS-TBNA is a safe and effective technique in the diagnosis of patients with suspected mediastinal TB.

Impact of hyponatremia on mortality and morbidity in patients with COPD exacerbations.

Hyponatremia is the most common electrolyte disorder in hospitalized patients, being associated with increased morbidity and mortality in different clinical conditions. However, the prevalence and impact of this electrolytic disorder in patients hospitalized for an exacerbation of COPD still remains unknown. The aim of the present study was to clarify these points. A total of 424 patients hospitalized due to a COPD exacerbation were consecutively included, showing a frequency of hyponatremia of 15.8% (hyposmolar in most cases). Even though patients with and without hyponatremia showed a similar age, comorbidities, lung function impairment, presence of previous exacerbations, hospitalizations, most of the comorbidities and the overall severity index (APACHE II), their clinical outcomes were worse. Indeed, their hospitalization length, mechanical ventilation requirements and deaths (both during admission and within the months following discharge) were higher than those of non-hyponatremic patients. A sodium threshold lower than 129.7 mEq/L exhibited the better discriminatory power for death prediction. We conclude that hyponatremia (especially if severe) is a predictive marker for a bad clinical course in COPD exacerbations and therefore, patients with this electrolyte abnormality should be carefully monitored.