Original Article
Long Non-Coding RNA NANCI/NKX2-1 Duplex Impacts Prognosis in Stage I Non-Small-Cell Lung Cancer
La combinación de NANCI/NKX2-1 de ARN no codificante de cadena larga afecta al pronóstico del cáncer de pulmón de células no pequeñas en estadio i
Jorge Moisésa,f,1, Alfons Navarrob,1, Joan Josep Castellanob, Nuria Viñolasc, Laureano Molinsd, Jordi Canalsb, Bing Hanb, Jara Martínb, José Ramireze,f, Gerard Frigolae, Ramón María Marradesa,f,2, Mariano Monzób,2,
Corresponding author
a Department of Pneumology, Institut Clínic Respiratori (ICR), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain
b Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain
c Department of Medical Oncology, Institut Clínic de Malalties Hematològicas i Oncològiques (ICMHO), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain
d Department of Thoracic Surgery, Institut Clínic Respiratori (ICR), Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
e Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain
f CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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Barcelona, IDIBAPS, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Medical Oncology, Institut Clínic de Malalties Hematològicas i Oncològiques (ICMHO), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Thoracic Surgery, Institut Clínic Respiratori (ICR), Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La combinación de NANCI/NKX2-1 de ARN no codificante de cadena larga afecta al pronóstico del cáncer de pulmón de células no pequeñas en estadio <span class="elsevierStyleSmallCaps">i</span>" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0020" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 675 "Ancho" => 1333 "Tamanyo" => 72362 ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The cornerstone of treatment of early stage (I–II) non-small cell lung cancer (NSCLC) is surgery since the surgical removal of the tumor is considered potentially curative in these patients.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> The addition of adjuvant treatment after surgery (cisplatin-based chemotherapy) is clear for patients with N1 disease but more controversial in those with N0 disease.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> The identification of prognostic markers of high risk is critical to anticipate outcomes and to identify stage I patients likely to benefit from adjuvant treatment.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Long non-coding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides with no protein-coding capability.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> Their expression pattern is tissue- and cancer-type-specific,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> making them promising biomarkers. In NSCLC, several lncRNAs play a leading role in carcinogenesis where some of them act as biomarkers for treatment response and prognosis.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> Some lncRNAs can also be regulated by transcription factors, such as TP53,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> which is frequently mutated in NSCLC patients.</p><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">NKX2-1</span> gene (also known as <span class="elsevierStyleItalic">TTF-1</span>) plays an essential role in lung, thyroid and forebrain development during embryogenesis<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a> and complete loss of NKX2-1 results in the failed development of trachea or lung branching.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> Embryogenesis and cancer share a number of cellular and molecular features.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">9,10</span></a> However, as opposed to embryogenesis, cancer is characterized by dysregulated and uncontrolled cell proliferation. The expression of NKX2-1, a critical gene for lung development, has been widely studied in lung cancer where the absence of NKX2-1 expression defines a subgroup of NSCLC patients with dismal prognosis, particularly in early stage patients.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11,12</span></a> The LncRNA NANCI (NKX2-1 associated noncoding intergenic RNA) is a 2.5-kb lncRNA spatially located near the critical transcription factor <span class="elsevierStyleItalic">NKX2-1</span>.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> NANCI knockdown resulted in decreased expression of NKX2-1,<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> indicating that NANCI regulates NKX2-1 expression.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We hypothesized that NANCI and its regulated gene NKX2-1 are embryonic genes that become dysregulated during oncogenesis and could play a promising role as prognostic biomarkers in NSCLC. In order to test this hypothesis, we analyzed NANCI and NKX2-1 expression in human embryonic lung samples and in adult normal lung and stage I NSCLC tissue samples and correlated our findings with overall survival (OS) and disease-free survival (DFS).</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patient samples</span><p id="par0025" class="elsevierStylePara elsevierViewall">From June 2007 to July 2014, tumor and paired normal tissue samples were prospectively collected from 98 adult patients diagnosed with stage I NSCLC who underwent complete surgical resection at Hospital Clínic de Barcelona (Barcelona, Spain). None of the patients received neoadjuvant or adjuvant treatment. Tissue samples were immediately immersed in RNALater® (Ambion) and stored at −80<span class="elsevierStyleHsp" style=""></span>°C until processing. Clinical data were recorded on admission: age, gender, smoking history, preoperative pulmonary function tests (PFT), chronic obstructive pulmonary disease (COPD), Eastern Cooperative Oncology Group (ECOG) performance status (PS), clinical and postoperative staging according to the TNM 7th edition, which was used during diagnostic workout and treatment decision, type of surgical resection and pathological findings (histological subtype, and the presence of emphysema). The data referring to the TNM 8th edition are available in supplementary file 1. The mutational status of TP53 and K-RAS was assessed in 80% of patients, and EGFR mutational status was assessed in adenocarcinoma (ADK) patients, as previously described.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> Approval for the study was obtained from the Clinical Research Ethics Committee of the Hospital Clínic de Barcelona, and written informed consent was obtained from each participant in accordance with the Declaration of Helsinki.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Human embryonic samples</span><p id="par0030" class="elsevierStylePara elsevierViewall">Eighteen spontaneously aborted embryos and fetuses were donated with written informed consent to the Body Donation Service of the Human Anatomy and Embryology Unit of the School of Medicine of University of Barcelona for morphological and molecular studies. The samples included lungs from the 8th to the 13th week of development. Lung samples were obtained under control of an Olympus stereo microscope SZ61.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">RNA extraction and gene expression analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Total RNA was isolated from frozen tissue using TriZol® Reagent (Life Technologies) according to the manufacturer's protocol. RNA from samples was quantified using a NanoDrop ND-1000 Spectrophotometer (Fisher Scientific, Madrid, Spain). The High Capacity cDNA Reverse Transcription Kit® (Life Technologies) was used to obtain cDNA from 500<span class="elsevierStyleHsp" style=""></span>ng of total RNA as per manufacturer's protocol. NKX2-1 mRNA expression levels were quantified using a TaqMan Gene Expression assay (Hs00968940_m1) in a 7500 Real-Time PCR System (Life Technologies). NANCI expression levels were quantified using a custom Taqman Expression assay according to geneBank KF856952.1 accession number.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> The Taqman assay was designed to detect specifically NANCI expression since was designed in the 51nt in the 5′ region that not overlap with any transcript of SFTA3 gene. Relative expression levels were calculated by 2<span class="elsevierStyleSup">−Ct</span> method using 18S as endogenous control.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analyses</span><p id="par0040" class="elsevierStylePara elsevierViewall">The primary endpoints of the study were OS and DFS. OS was defined as the time from surgery to either death from any cause or last follow-up. DFS was defined as the time from surgery to either recurrence or death, or last follow-up. Optimal cut-offs of NANCI and NKX2-1 expression data for OS and DFS were assessed by means of maximally selected log-rank statistics using the Maxstat package (R statistical package, v. 2.8.1, Vienna, Austria) and Kaplan–Meier curves were drawn and compared by means of a log-rank test. All factors with <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.1 in the univariate analysis were included in the Cox multivariate regression analyses for DFS and OS. Student <span class="elsevierStyleItalic">t</span>-test or Mann–Whitney <span class="elsevierStyleItalic">U</span> test, as appropriate, were used for comparisons between two groups or ANOVA when more than 2 groups were compared. Pearson correlation was used to compare NANCI and NKX2-1 expression. All statistical analyses were performed using PASW Statistics 21 (SPSS Inc.) and R v2.8.1. The level of significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.05.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">NANCI and NKX2-1 expression in human lung embryogenesis and lung cancer</span><p id="par0045" class="elsevierStylePara elsevierViewall">The expression of NANCI and NKX2-1 was assessed in human embryonic lung tissue from embryos of 8–13 weeks of development and adult normal lung and lung cancer tissues (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). In embryonic samples, the expression of NANCI and NKX2-1 was highly correlated (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.8886, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C). When we compared the embryonic expression longitudinally from the 8th to the 13th week, significant changes in expression were observed. The expression of both NANCI and NKX2-1 increased as the lung became more differentiated, with the highest levels found in the normal adult tissue samples (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0002 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001, respectively). However, a significant reduction in overall levels was observed in lung tumor tissue compared to normal adult tissue (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001). A positive correlation between NANCI and NKX2-1 was also observed in tumor tissue (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.5521, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Patients</span><p id="par0050" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> displays the characteristics of the 98 stage I NSCLC patients included in the study. The majority were male (74.5%), with a mean age of 67.3 years (range, 38–84). Eighty-one patients (83%) had ECOG PS 1 and eighty-four patients (85%) were current or former smokers. Pulmonary function tests showed a mean FEV<span class="elsevierStyleInf">1</span>/FVC (%) ratio of 64.25<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.11, confirming COPD diagnosis in 68% of all patients, with a mean carbon monoxide diffusing capacity (DLCO%) of 73% (range, 35–101%).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The most frequent type of surgical resection was lobectomy in 79 patients (80.6%). Sixty-two patients (63.3%) had stage IA and 36 stage IB disease. Emphysema was found in 45.9% of patients. ADK was the most frequent histological subtype, accounting for 57 patients (58%), followed by squamous cell carcinoma (SCC) in 36 patients (36.7%). Twenty-nine patients died during follow-up, 17 of whom (58.6%) died after relapse.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">NANCI lncRNA expression and clinical–pathological characteristics</span><p id="par0060" class="elsevierStylePara elsevierViewall">NANCI lncRNA was differentially expressed according to histological subtype (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.013), with higher levels in ADK than in SCC (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004). NANCI lncRNA was downregulated in patients with DLCO <60% (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.044). Patients harboring TP53 mutations had a lower expression of NANCI (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.005). No significant differences in NANCI expression were found either in EGFR- or KRAS-mutated patients.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">NANCI lncRNA impacts prognosis in stage I NSCLC</span><p id="par0065" class="elsevierStylePara elsevierViewall">Using the cutoff identified by Maxstat package of R, patients were classified as having high (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>55) or low (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>43) NANCI lncRNA expression. With a mean follow-up of 40.4 months (±26.7 months), patients with low expression had shorter mean DFS (47.6 vs 69.3 months; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.032) and shorter mean OS (57.7 vs 77.6 months; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.021) than those with high expression (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The prognostic impact of NKX2-1 for the patients included in the present study was also evaluated and is shown in Supplementary Fig. 1A and B. Confirming our previous results in a smaller patient sample,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> low NKX2-1 levels were associated with shorter DFS and OS (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.037 and <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.005, respectively).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">NANCI/NKX2-1 duplex and clinical outcome</span><p id="par0075" class="elsevierStylePara elsevierViewall">In order to evaluate the combined impact of both NANCI and NKX2-1 expression, we classified patients in four groups: 49 (50%) with high NANCI/high NKX2-1; five (5.1%) with high NANCI/low NKX2-1; seven (7.1%) with low NANCI/high NKX2-1; and 36 (36.7%) with low NANCI/low NKX2-1.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Mean DFS was 71.2 months in patients with high NANCI/high NKX2-1, 19 months in those with high NANCI/low NKX2-1, 42.7 months in those with low NANCI/high NKX2-1, and 48 months in those with low NANCI/low NKX2-1 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.042; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C).</p><p id="par0085" class="elsevierStylePara elsevierViewall">Mean OS was 81.4 months in patients with high NANCI/high NKX2-1, 41 months in those with high NANCI/low NKX2-1, 67.2 months in those with low NANCI/high NKX2-1, and 56.7 months in those with low NANCI/low NKX2-1 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.024; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>D). Moreover, patients with high NANCI/high NKX2-1 duplex expression had longer DFS and OS than the other three groups (71.25 vs 46.3 months; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009; 81.3 vs 56.1 months; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004; <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The multivariate analysis for DFS, including gender, stage, emphysema and NANCI/NKX2-1 duplex, also identified high NANCI/high NKX2-1 duplex expression as a factor for longer DFS (HR: 0.346, 95% CI, 0.169–0.709; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004). In the multivariate analysis for OS, including gender, smoking status, emphysema and NANCI/NKX2-1 duplex, only high NANCI/high NKX2–1 duplex expression emerged as an independent factor for longer OS (HR: 0.309, 95% CI, 0.121–0.786; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.014; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). All the analyses using the 8th TNM edition are shown in supplementary document 1.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">Given the several shortfalls to the current approach for selecting surgical patients with a high risk of recurrence based on disease stage alone, the implementation of biomarkers for further stratification of risk has been studied in recent years. The prognostic role of single genes (<span class="elsevierStyleItalic">TP53</span>, <span class="elsevierStyleItalic">BRCA</span>, <span class="elsevierStyleItalic">ERCC1</span>, <span class="elsevierStyleItalic">RRM1</span>, <span class="elsevierStyleItalic">HER2</span>, <span class="elsevierStyleItalic">KRAS</span>), gene signatures, and immune biomarkers in NSCLC has been analyzed but the results require validation in prospective cohorts before their clinical application can be recommended.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Despite these challenges, the discovery of newer molecular markers or markers that could elucidate NSCLC oncogenic functionality are currently a promising area of research.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In the present study, we have examined the expression of the lncRNA NANCI in human lung embryos and lung cancer and evaluated its potential as a prognostic biomarker in stage I NSCLC. During organogenesis, lung specification begins around day 28 of gestation and is regulated by NKX2-1 expression on the ventral side of the anterior foregut endoderm. Ventral evagination results in the formation of trachea and bronchial branching, a process where Wnt2/2b and beta-catenin signaling are necessary.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> In addition, BMP signaling promotes NKX2-1 respiratory endoderm specification via SOX2 repression.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> NANCI is a lncRNA located downstream from NKX2-1 that acts in <span class="elsevierStyleItalic">cis</span> to regulate NKX2-1. In turn, NKX2-1 directly inhibits NANCI expression, generating a negative feedback loop, indicating that NANCI/NKX2-1 duplex is essential for buffering NKX2-1 expression.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> In fact, our results reinforce this idea, since NANCI and NKX2-1 showed a high correlation in embryonic samples and in tumor tissues. Moreover, in the present study, we have shown that NANCI and NKX2-1 expression was present in late embryogenesis (E8), with increased levels during the pseudoglandular phase of human lung development (E8-E13) and the highest levels in adult normal tissue. Interestingly, in the NSCLC samples, NKX2-1 and NANCI expression were downregulated compared to normal lung tissue samples, sharing similar expression patterns to the early embryonic lung samples at weeks 8–10. This finding led us to speculate that diminished NKX2-1 and NANCI expression could be explained by dedifferentiation, reinforcing previous research that revealed significant similarities between early embryonic lung and lung cancer.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">9,19</span></a> There is growing evidence that several lncRNAs play a key role in maintaining homeostasis in embryogenesis.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> LncRNAs can activate or repress gene expression, acting as scaffolds to guide chromatin-modifying complexes<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> and regulate neighboring protein-coding genes.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> The HOX family of genes,<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> the lncRNA MALALT1<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> and the lncRNA Fendrr<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> are also known to regulate both embryogenesis and carcinogenesis.</p><p id="par0105" class="elsevierStylePara elsevierViewall">When we correlated NANCI levels with the main clinic–pathological characteristics, we observed that NANCI was upregulated in ADK patients compared to SCC. This correlation was also observed in NKX2-1 levels, which was in line with previous studies in lung cancer cohorts.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">12,26</span></a> However, not all clinic–pathological correlations found for NKX2-1 were also valid for NANCI levels. For example, NKX2-1 downregulation was associated with smoking,<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> which had previously been studied functionally in thyroid gland development, where fetuses from smoke-exposed mothers had reduced NKX2-1 and GAT6 levels.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> Even though NANCI and NKX2-1 are strongly correlated, NANCI did not seem to be modified by smoke exposure. However, we found that patients with DLCO <60% had reduced expression of NANCI and NKX2-1. In emphysema, alveolar destruction is the pathophysiological cause of DLCO reduction.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> Abnormalities in DLCO can be found in smokers with early or mild emphysema.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Finally, we evaluated the potential role of NANCI expression as a prognostic biomarker. Low NANCI levels were associated with shorter DFS (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.032) shorter OS (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.021) in stage I NSCLC patients. Moreover, confirming our previous results,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> low NKX2-1 levels were also associated with worse outcome. As NANCI downregulation alone does not adversely affect embryonic lung development and concurrent heterozygous mutations in both NANCI and NKX2-1 lead to persistent NKX2-1 deficiency,<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> we analyzed the combinatory effect of both NKX2-1 and NANCI. Patients with high NANCI/high NKX2-1 expression showed the best prognosis, with longer DFS and longer OS, compared to patients with other combinations. In addition, high NANCI/high NKX2-1 expression emerged as the only independent prognostic factor for both DFS (HR: 0.346, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004) and OS (HR: 0.309, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.014) in our cohort of stage I NSCLC patients, confirming its potential as prognostic biomarker.</p><p id="par0115" class="elsevierStylePara elsevierViewall">To explore the prognostic impact of NANCI and NANCI/NKX2-1 according to the TNM 8th edition, we reclassified the cohort excluding 12 patients upstaged to IIA and confirmed the prognostic impact of NANCI in stage I NSCLC patients. In the multivariate analysis, the high/high NANCI/NKX2-1 combination remained an independent prognostic factor for OS (HR 0.29. <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012) (supplementary file 1).</p><p id="par0120" class="elsevierStylePara elsevierViewall">To the best of our knowledge, this is the first study to report a prognostic impact for the lncRNA NANCI and for the duplex NANCI-NKX2-1 in stage I NSCLC. Although the exact mechanism of NANCI–NKX2-1 regulation in NSCLC is not fully addressed in the present study, our results indicate that NANCI and NKX2-1 expression may be important factors in the differentiation that occurs during the development from fetal to adult lung and that the assessment of NANCI/NKX2-1 levels in lung cancer can help to identify high-risk patients with stage I NSCLC.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">NANCI/NKX2-1 duplex expression is correlated with prognosis in stage I NSCLC patients, defining subgroups of patients with differential outcomes who could benefit from a customized approach to treatment.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Data availability</span><p id="par0130" class="elsevierStylePara elsevierViewall">The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">This work was partially supported by grants from the <span class="elsevierStyleGrantSponsor" id="gs1">Ministry of Economy, Industry and Competition, Agencia Estatal de Investigación</span> co-financed with the <span class="elsevierStyleGrantSponsor" id="gs2">European Union FEDER</span> funds <span class="elsevierStyleGrantNumber" refid="gs2">SAF2017-88606-P</span> (AEI/FEDER, UE) and SDCSD from the <span class="elsevierStyleGrantSponsor" id="gs3">Universitat de Barcelona</span>. JJC and JC are APIF fellow of the Universitat de Barcelona. None of the funding bodies had any role in the design of the study and collection, analysis, and interpretation of data, or in writing the manuscript.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors’ contribution</span><p id="par0140" class="elsevierStylePara elsevierViewall">JM, AN, JC, JMa, JJC, BH performed the research; JM, AN, RM, MM designed and supervised the research; JM, AN analyzed the data, and wrote the manuscript; JM, NV, LM, JR, GF, RM selected cases and analyzed the clinical data; JR and GF provided samples and performed the histopathological review. All authors have seen and approved this final version of the manuscript and agree with the decision to submit.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres1393710" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1393709" "titulo" => "Abstract" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods and results" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1277449" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1393711" "titulo" => "Resumen" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Contexto global" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos y resultados" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1277450" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient samples" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Human embryonic samples" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "RNA extraction and gene expression analysis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analyses" ] ] ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "NANCI and NKX2-1 expression in human lung embryogenesis and lung cancer" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Patients" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "NANCI lncRNA expression and clinical–pathological characteristics" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "NANCI lncRNA impacts prognosis in stage I NSCLC" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "NANCI/NKX2-1 duplex and clinical outcome" ] ] ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Data availability" ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0085" "titulo" => "Authors’ contribution" ] 13 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 14 => array:2 [ "identificador" => "xack484591" "titulo" => "Acknowledgements" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-12-22" "fechaAceptado" => "2020-01-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1277449" "palabras" => array:8 [ 0 => "NANCI" 1 => "NKX2-1" 2 => "LncRNA" 3 => "NSCLC" 4 => "Early-stage" 5 => "Overall survival" 6 => "Disease-free survival" 7 => "Lung development" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1277450" "palabras" => array:8 [ 0 => "NANCI" 1 => "NKX2-1" 2 => "LncRNA" 3 => "CPCNP" 4 => "Estadios iniciales" 5 => "Supervivencia general" 6 => "Supervivencia libre de enfermedad" 7 => "Desarrollo pulmonar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">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).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods and results</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">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, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.032 and 57.7 vs 77.6 months, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.042) and OS (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009 and 81.3 vs 56.1 months, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004) and OS (HR 0.309, 95% CI, 0.121–0.786; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.014).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">NANCI and the NANCI-NKX2-1 duplex impacts prognosis in stage I NSCLC patients.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods and results" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Contexto global</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">NANCI, un ARN intergénico largo no codificante (lncRNA) es esencial para regular la expresión de NKX2-1 durante el desarrollo embrionario y en el tejido adulto. Analizamos la expresión de NANCI y NKX2-1 en muestras embrionarias de pulmón humano y tejidos pulmonares adultos, y evaluamos su potencial como marcadores pronósticos en el cáncer de pulmón de células no pequeñas (CPCNP) en estadio <span class="elsevierStyleSmallCaps">i</span>.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos y resultados</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La expresión de NANCI y NKX2-1 se evaluó mediante ensayos TaqMan® en 18 muestras embrionarias humanas de 8 a 13 semanas, 59 muestras de tejido pulmonar no tumoral (NT) y 98 muestras de tumor de CPCNP en estadio <span class="elsevierStyleSmallCaps">i</span>. La expresión de NANCI y NKX2-1 en muestras embrionarias y NSCLC se encontraba reducida en comparación con el tejido NT adulto. Los pacientes con baja expresión de NANCI tuvieron una supervivencia libre de enfermedad (SLE) y una supervivencia general (SG) más cortas que aquellos con niveles altos (47,6 frente a 69,3 meses; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,032 y 57,7 frente a 77,6 meses; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,021, respectivamente). Cuando se evaluaron los niveles de expresión de NANCI y NKX2-1 combinados se identificaron 4 grupos (NANCI alto/NKX2-1 alto, NANCI bajo/NKX2-1 alto, NANCI alto/NKX2-1 bajo y NANCI bajo/NKX2-1 bajo) con impacto variable en la SLE (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,042) y la SG (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,024). Curiosamente, la combinación de NANCI alto/NKX2-1 alto presentó unas SLE y SG más largas que los otros 3 grupos (71,25 frente a 46,3 meses; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,009 y 81,3 frente a 56,1 meses; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,004, respectivamente). En el análisis multivariante, la combinación de NANCI alto/NKX2-1 alto se identificó como un factor de pronóstico independiente para una SLE más larga (HR: 0,346; IC 95%: 0,169-0,709; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,004), al igual que la SG (HR: 0,309; IC 95%: 0,121-0,786; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,014).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusiones</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">NANCI y la combinación de NANCI-NKX2-1 afecta al pronóstico de los pacientes con CPCNP en estadio <span class="elsevierStyleSmallCaps">i</span>.</p></span>" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Contexto global" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos y resultados" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">JM and AN equally contributed to this paper.</p>" "identificador" => "fn0005" ] 1 => array:3 [ "etiqueta" => "2" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">RM and MM equally contributed as senior authors.</p>" "identificador" => "fn0010" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0160" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0100" ] ] ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1698 "Ancho" => 2181 "Tamanyo" => 185407 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">(A) NKX2-1 and (B) NANCI expression in embryonic (E) samples, non-tumoral tissue (NT) and tumoral tissue (TT). Pearson correlation graph of NKX2-1 and NANCI expression in embryonic samples (C) and NSCLC (D).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1964 "Ancho" => 2939 "Tamanyo" => 301506 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Kaplan–Meier analysis of disease-free survival (DFS) and overall survival (OS) according to NANCI expression levels (A and B) and NANCI/NKX2-1 duplex expression (C and D).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1982 "Ancho" => 1325 "Tamanyo" => 135905 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Kaplan–Meier analysis of disease-free survival (DFS) (A) and overall survival (OS) (B) according to high NANCI/high NKX2-1 duplex expression.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Bold values correspond to variables with p < 0.05.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>98(%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DFS<span class="elsevierStyleItalic">P</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OS<span class="elsevierStyleItalic">P</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NANCI expressionMean (SD) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">NANCI<span class="elsevierStyleItalic">P</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sex</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73 (74.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.028</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.052</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.24 (0.88) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.074 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 (25.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.86 (0.99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, years</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 (38–84) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (42.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.645 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.269 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.94 (0.92) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.059 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 (57.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.29 (0.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ECOG PS<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (17.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.246 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.059 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.484 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">81 (82.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stage</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 (63.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.208 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.390 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.06 (0.88) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.288 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 (36.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.27 (0.99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histology</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ADK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 (53.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.225 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.428 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.96 (0.73) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.013</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SCC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36 (36.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.27 (1.03) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Large cell carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (4.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.48 (0.39) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adenosquamous carcinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (1.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.8 (.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type of surgery</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lobectomy/bilobectomy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">79 (80.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.721 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.771 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.06 (0.95) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.264 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pneumonectomy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (3.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−2.44 (0.22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atypical resection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (8.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.27 (0.72) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anatomical resection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (8.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.52 (0.68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking history</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Current smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (28.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.231 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.198 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.04 (0.83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Former smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 (57.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.29 (0.99) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Never smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (14.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.14 (0.92) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relapse</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 (71.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.1 (0.97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.552 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (28.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.22 (0.78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Emphysema</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 (45.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.057 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.118 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.0 (0.79) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.105 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 (38.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.3 (0.88) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (15.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COPD<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 (60.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.613 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.518 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.95 (0.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.079 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (28.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.29 (0.85) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (11.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DLCO<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> (%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72.7 (35–101) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≥60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57/71 (80.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.320 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.146 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.04 (0.84) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.044</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><60% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14/71 (19.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.53 (0.66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Molecular Features</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TP53 mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23/75 (32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.296 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.990 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.6 (0.92) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.005</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TP53 WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52/75 (68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.01 (0.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KRAS mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11/78 (14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.776 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.798 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.99 (0.98) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.431 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">KRAS WT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67/78 (86) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−1.22 (0.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGFR mutation<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9/33 (27.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.192 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.075 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.69 (0.42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.547 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGFR WT<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24/33 (72.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−8.22 (0.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2391999.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Eastern Cooperative Oncology Group performance status.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">EGFR mutational status was assessed only in adenocarcinoma patients.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Chronic obstructive pulmonary disease.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Carbon monoxide diffusing capacity.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Main patient characteristics, univariate <span class="elsevierStyleItalic">P</span>-values (log-rank test) for disease-free survival (DFS) and overall survival (OS) and the mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard deviation (SD) of NANCI expression for each clinical characteristic compared by <span class="elsevierStyleItalic">t</span>-test or ANOVA test.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Bold values correspond to variables with p < 0.05.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hazard ratio (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Disease free survival</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1695 (0.610–4.639) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.305 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Stage IB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.929 (0.466–1.855) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.836 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Emphysema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.733 (0.843–3.464) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.137 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>High NANCI/high NKX2-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.346 (0.169–0.709)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.004</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Overall survival</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.499 (0.548–11.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.237 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Former/current smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.289 (0.209–25.08) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.498 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Emphysema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.279 (0.932–5.572) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.071 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>High NANCI/high NKX2-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.309 (0.121–0.786)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">0.014</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2391998.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Multivariate analysis for DFS and OS.</p>" ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 41344 ] ] 6 => array:7 [ "identificador" => "upi0010" "etiqueta" => "Supplementary Fig. S1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc2.pdf" "ficheroTamanyo" => 183980 ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Kaplan–Meier analysis of disease-free survival (DFS) (A) and overall survival (OS) (B) according to NKX2-1 expression levels.</p>" ] ] 7 => array:5 [ "identificador" => "fig0020" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 675 "Ancho" => 1333 "Tamanyo" => 72362 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adjuvant chemotherapy in non-small cell lung cancer: state-of-the-art" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Á. 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Zimmer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Cell Mol Biol (Noisy-le-grand)" "fecha" => "2005" "numero" => "Suppl. 51" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0190" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.M. Goss" 1 => "Y. Tian" 2 => "T. Tsukiyama" 3 => "E.D. Cohen" 4 => "D. Zhou" 5 => "M.M. Lu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.devcel.2009.06.005" "Revista" => array:6 [ "tituloSerie" => "Dev Cell" "fecha" => "2009" "volumen" => "17" "paginaInicial" => "290" "paginaFinal" => "298" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19686689" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0195" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MicroRNAs expressed during lung cancer development are expressed in human pseudoglandular lung embryogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Navarro" 1 => "R.M. Marrades" 2 => "N. Viñolas" 3 => "A. Quera" 4 => "C. Agusti" 5 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 1 | 8 |
| 2024 October | 30 | 22 | 52 |
| 2024 September | 32 | 21 | 53 |
| 2024 August | 46 | 40 | 86 |
| 2024 July | 30 | 20 | 50 |
| 2024 June | 31 | 30 | 61 |
| 2024 May | 100 | 22 | 122 |
| 2024 April | 23 | 26 | 49 |
| 2024 March | 20 | 21 | 41 |
| 2024 February | 25 | 18 | 43 |
| 2023 March | 4 | 4 | 8 |
| 2023 February | 31 | 10 | 41 |
| 2023 January | 16 | 20 | 36 |
| 2022 December | 41 | 21 | 62 |
| 2022 November | 35 | 18 | 53 |
| 2022 October | 49 | 33 | 82 |
| 2022 September | 19 | 16 | 35 |
| 2022 August | 26 | 34 | 60 |
| 2022 July | 21 | 31 | 52 |
| 2022 June | 21 | 25 | 46 |
| 2022 May | 22 | 28 | 50 |
| 2022 April | 19 | 18 | 37 |
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| 2020 November | 1 | 0 | 1 |
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